USRE44145E1 - Preparation of hydrophilic pressure sensitive adhesives having optimized adhesive properties - Google Patents

Preparation of hydrophilic pressure sensitive adhesives having optimized adhesive properties Download PDF

Info

Publication number
USRE44145E1
USRE44145E1 US11/150,811 US15081105A USRE44145E US RE44145 E1 USRE44145 E1 US RE44145E1 US 15081105 A US15081105 A US 15081105A US RE44145 E USRE44145 E US RE44145E
Authority
US
United States
Prior art keywords
composition
hydrophilic polymer
poly
plasticizer
adhesive
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US11/150,811
Inventor
Mikhail M. Feldstein
Nicolai A. Platè
Anatoly E. Chalykh
Gary W. Cleary
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AV Topchiev Institute of Petrochemical Synthesis
Corium LLC
Original Assignee
AV Topchiev Institute of Petrochemical Synthesis
Corium International Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US09/900,697 external-priority patent/US6576712B2/en
Application filed by AV Topchiev Institute of Petrochemical Synthesis, Corium International Inc filed Critical AV Topchiev Institute of Petrochemical Synthesis
Priority to US11/150,811 priority Critical patent/USRE44145E1/en
Assigned to CAPITAL ROYALTY PARTNERS II L.P., CAPITAL ROYALTY PARTNERS II - PARALLEL FUND "A" L.P., PARALLEL INVESTMENT OPPORTUNITIES PARTNERS II L.P. reassignment CAPITAL ROYALTY PARTNERS II L.P. SECURITY AGREEMENT Assignors: CORIUM INTERNATIONAL, INC.
Assigned to SILICON VALLEY BANK reassignment SILICON VALLEY BANK SECURITY AGREEMENT Assignors: CORIUM INTERNATIONAL, INC.
Priority to US13/761,118 priority patent/USRE45666E1/en
Application granted granted Critical
Publication of USRE44145E1 publication Critical patent/USRE44145E1/en
Assigned to CAPITAL ROYALTY PARTNERS II ? PARALLEL FUND ?B? (CAYMAN) L.P., CAPITAL ROYALTY PARTNERS II (CAYMAN) L.P., CAPITAL ROYALTY PARTNERS II L.P., CAPITAL ROYALTY PARTNERS II ? PARALLEL FUND ?A? L.P. reassignment CAPITAL ROYALTY PARTNERS II ? PARALLEL FUND ?B? (CAYMAN) L.P. SECURITY INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CORIUM INTERNATIONAL, INC.
Assigned to CORIUM INTERNATIONAL, INC. reassignment CORIUM INTERNATIONAL, INC. RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: SILICON VALLEY BANK
Assigned to CORIUM INTERNATIONAL, INC. reassignment CORIUM INTERNATIONAL, INC. RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: CAPITAL ROYALTY PARTNERS II - PARALLEL FUND "A" L.P., CAPITAL ROYALTY PARTNERS II - PARALLEL FUND "B" (CAYMAN) L.P., CAPITAL ROYALTY PARTNERS II (CAYMAN) L.P., CAPITAL ROYALTY PARTNERS II L.P., PARALLEL INVESTMENT OPPORTUNITIES PARTNERS II L.P.
Assigned to CORIUM INTERNATIONAL, INC. reassignment CORIUM INTERNATIONAL, INC. RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: CAPITAL ROYALTY PARTNERS II - PARALLEL FUND "A" L.P., CAPITAL ROYALTY PARTNERS II - PARALLEL FUND "B" (CAYMAN) L.P., CAPITAL ROYALTY PARTNERS II (CAYMAN) L.P., CAPITAL ROYALTY PARTNERS II L.P., PARALLEL INVESTMENT OPPORTUNITIES PARTNERS II L.P.
Assigned to CORIUM, INC. reassignment CORIUM, INC. CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: CORIUM INTERNATIONAL, INC.
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42Use of materials characterised by their function or physical properties
    • A61L15/58Adhesives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42Use of materials characterised by their function or physical properties
    • A61L15/44Medicaments
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0014Skin, i.e. galenical aspects of topical compositions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/70Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/70Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7069Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42Use of materials characterised by their function or physical properties
    • A61L15/58Adhesives
    • A61L15/585Mixtures of macromolecular compounds

Definitions

  • This invention relates to preparation of adhesive compositions. More particularly, the invention relates to preparation of hydrophilic pressure sensitive adhesive (PSA) compositions having optimized adhesive properties and that are useful, for example, in transdermal drug delivery systems and other medical, pharmaceutical and cosmetic products that adhere to the skin or other body surface.
  • PSA pressure sensitive adhesive
  • the invention has utility in a number of fields, including transdermal drug delivery, iontophoretic systems, biomedical electrode fabrication, wound healing, and skin care and cosmetic products.
  • Pressure-sensitive adhesives are well known and have been used for many years in a variety of industrial, consumer and medical applications. Pressure-sensitive adhesives are characterized as being normally tacky and exhibiting instant tack when applied to a substrate. Many polymers have been used to manufacture pressure sensitive adhesives as, for example, acrylic and methacrylic ester homo- or copolymers, butyl rubber-based systems, silicones, urethanes, vinyl esters and amides, olefin copolymer materials, natural or synthetic rubbers, and the like. All the PSAs are elastomers, i.e. they exhibit viscoelastic properties typical of rubbers.
  • Examples of pressure sensitive adhesives that have been proposed for use in transdermal drug delivery systems include polysiloxanes (e.g., polydimethyl siloxanes, polydiphenyl siloxanes, and siloxane blends), polyisobutylenes, polyacrylates, acrylic acid-acrylate copolymers (e.g., copolymers of acrylic acid copolymers with 2-ethylhexyl acrylate or isooctyl acrylate), and tacky rubbers such as polyisobutene, polybutadiene, polystyrene-isoprene copolymers, polystyrene-butadiene copolymers, and neoprene (polychloroprene). All of these PSAs are hydrophobic polymers and their common disadvantage is a loss in adhesion toward hydrated substrates.
  • PSAs are hydrophobic polymers and their common disadvantage is a loss in adhesion toward hydrated substrates.
  • Bioadhesion is defined as a pressure sensitive adhesion with respect to highly hydrated biological tissues such as mucosal tissue.
  • PSAs rubber, polysiloxanes and acrylates
  • BAs bioadhesives
  • water should provide a plasticizing effect on a polymer, i.e., the polymer should he hydrophilic.
  • the range of typical BAs includes slightly cross-linked polyacrylic and polymethacrylic acids (EP 0371 421) as well as blends of hydrophilic cellulose derivatives to (40-95%) with polyethylene glycol (PEG) (U.S. Pat. No. 4,713,243).
  • PSA and BA polymeric materials of different hydrophilicity and thus different solubilities in water or in the liquids secreted by the skin and mucosa (sweat, mucus, saliva etc.).
  • Attempts to combine the properties of PSAs and BAs have been described by Biegajski et al. in U.S. Pat. No. 5,700,478, where a water-soluble pressure-sensitive mucoadhesive was obtained by blending of 95-40% polyvinylpyrrolidone (PVP) with 0-50% hydroxypropyl cellulose (HPC) and 11-60% glycerol.
  • PVP polyvinylpyrrolidone
  • HPC hydroxypropyl cellulose
  • hydrophilic polymer blends coupling the properties of PSAs and BAs involve polyacrylic acid-polyvinyl alcohol (PAA-PVA) interpolymeric complexes formed by hydrogen bonding between the monomer units of the complementary polymers chains and plasticized with PEG-200, glycerol or polypropylene glycol (PPG), molecular weight 425 g/mol (German Patent Application DE 42 19 368).
  • PAA-PVA polyacrylic acid-polyvinyl alcohol
  • PPG polypropylene glycol
  • the adhesive should maintain its bond for as long a period of time as necessary and be resistant to inadvertent removal, yet be easily removed without removing any skin or leaving a residue (a suitable strength of an adhesive joint with the skin ranges from about 200 to 400 N/m under the 180 degree peel test).
  • High tack i.e., greater than about 50 g/cm 2
  • the adhesive should not be weakened or destroyed by exposure to moisture or high humidity.
  • the adhesive should resist skin movement and be able to transfer a mechanical load from the adhesive backing to the skin.
  • the solubility of the active agent in the reservoir of a transdermal drug delivery device is of decisive importance. With higher solubility, it is possible to increase the rate of transdermal delivery (i.e., the rate at which the active agent migrates from the device and into the skin or mucosal tissue). Because many therapeutic agents are ionogenic organic substances having a higher solubility in hydrophilic media than in lipophilic media, adhesive reservoirs based on hydrophilic polymers would be more versatile than adhesive reservoirs based on hydrophobic polymers. Furthermore, as noted above, pressure sensitive adhesives for application to mucosal tissue should adhere well to hydrated substrates, and hydrophilic adhesives would therefore be ideal.
  • hydrophobic PSAs have been “hydrophilized” by incorporation of non-tacky hydrophilic polymers and fillers into a hydrophobic adhesive.
  • polyisobutylene (PIB) PSA has been hydrophilized by incorporation of cellulose and cellulose derivatives (U.S. Pat. No. 4,231,369), polyvinyl alcohol (PVA), pectin and gelatin (U.S. Pat. Nos. 4,367,732 and 4,867,748), and SiO 2 (U.S. Pat. No. 5,643,187).
  • Rubber adhesives have also been modified by filling with amphiphilic surfactants, or by treating the PSA polymer with a plasma-oxygen discharge.
  • Acrylic PSAs can be hydrophilized by incorporation of PVP (U.S. Pat. No. 5,645,855). Hydrophilization of hydrophobic adhesives, while somewhat effective, tends to result in a partial loss of adhesion.
  • hydrophilic adhesive composition suitable for use in a wide variety of contexts, e.g., in a topically applied drug delivery system, which composition meets all of the above criteria and provides for an effective delivery rate of any active agent, whether hydrophilic, ionogenic, or lipophilic in nature.
  • the adhesive compositions combine the properties of pressure-sensitive adhesives and bioadhesives and can be used in a number of contexts, including not only transdermal, transmucosal and topical drug delivery systems but also in wound healing products, biomedical electrodes, iontophoretic systems, bioadhesive cushions, and the like.
  • the adhesive compositions can be used with a number of active agents, regardless of hydrophilicity, hydrophobicity, and molecular structure.
  • the adhesive composition may be readily tailored during manufacture with respect to hygroscopicity, the desired degree of hydrophilicity, adhesive and cohesive strength, and drug delivery kinetics.
  • a method for preparing an adhesive composition having an optimized degree of adhesion comprising:
  • T g ⁇ ⁇ predicted w pol T g pol + w pl T g pl ( 1 ) and plotting T g predicted versus w pl , for each composition;
  • a method for preparing an adhesive composition having a predetermined degree of adhesion comprising:
  • T g ⁇ ⁇ predicted w pol T g pol + w pl T g pl ( 1 ) and plotting T g predicted versus w pl for each composition;
  • a hydrophilic pressure sensitive adhesive composition comprises (1) a hydrophilic polymer having a glass transition temperature T g pol , and (2) a complementary hydroxyl-terminated or carboxyl-terminated short-chain plasticizing agent having a glass transition temperature T g pl and capable of hydrogen bonding or electrostatic bonding to the hydrophilic polymer, wherein the weight ratio of hydrophilic polymer to complementary short-chain plasticizing agent is selected so to provide a predetermined deviation in (a) the actual glass transition temperature T g actual of the composition from (b) the predicted glass transition temperature T g predicted calculated for the composition using the Fox equation.
  • the predetermined deviation is the maximum negative deviation of T g actual from T g predicted .
  • the difference between T g pol and T g pl is at least about 50° C., such that T g actual for each composition is determined solely by T g pl .
  • a drug delivery system for the topical or transdermal administration of a pharmacologically active agent.
  • the drug delivery system includes:
  • the adhesive compositions herein are also useful in a host of additional applications, e.g., in bandages, wound and burn dressings, ostomy devices, prosthesis securing means, face masks, sound, vibration or impact absorbing materials, and the like.
  • the compositions may be rendered electrically conductive by incorporation of water and/or another electrically conductive material, and may thus be used for attaching an electroconductive article, such as an electrode (e.g., a transcutaneous electric nerve stimulation, or “TENS” electrode, an electrosurgical return electrode or an EKG monitoring electrode), to an individual's body surface.
  • an electrode e.g., a transcutaneous electric nerve stimulation, or “TENS” electrode, an electrosurgical return electrode or an EKG monitoring electrode
  • FIG. 1 represents a schematic view of the molecular design of a hydrogen-bonded or electrostatic-bonded network complex formed by a long-chain hydrophilic polymer and a short-chain plasticizer.
  • FIG. 2 is a graph illustrating the adhesion characteristics of a PVP-PEG (m.w. 400 g/mole) blend, evaluated in terms of the 180° peel force needed to rupture an adhesive bond with a polyethylene (PE) substrate at a debonding rate of 10 mm/min, with respect to the compositional behavior of the glass transition temperature, T g , in the blend.
  • the points denote experimental data, whereas the line connecting the T g s of PVP and PEG-400 was obtained using the Fox equation.
  • FIG. 3 is a plot of ⁇ C p T g against the composition of PVP blends with PEG-400.
  • FIG. 6 illustrates the squeezing kinetics of PVP-PEG adhesive hydrogel under a fixed compressive load and squeeze recoil upon its removal.
  • the h value is the distance (mm) between the upper and lower plates of the squeeze-recoil tester, which is equal to the thickness of specimen.
  • FIG. 8 outlines the creep-recoil functions for the PVP-PEG adhesive hydrogel compared to polybutadiene (PB) and polyisoprene (PI) rubbers.
  • FIG. 9 exhibits the water vapor absorption isotherms for PVP and its blends with PEG-400 at ambient temperature.
  • FIG. 10 displays the isotherms of water vapor sorption by polyvinyl caprolactam (PVCap) and PVP at ambient temperature.
  • FIG. 11 outlines the effect of relative humidity (RH) on the adhesion of PVP-PEG and PVCap-PEG hydrogels.
  • active agent drug
  • therapeutic agent a chemical material or compound suitable for transdermal or transmucosal administration and which induces a desired effect.
  • agents that are therapeutically effective, prophylactically effective, or cosmetically effective are also included.
  • derivatives and analogs of those compounds or classes of compounds specifically mentioned which also induce the desired effect.
  • transdermal drug delivery is meant administration of a drug to the skin surface of an individual so that the drug passes through the skin tissue and into the individual's blood stream.
  • transdermal is intended to include “transmucosal” drug administration, i.e., administration of a drug to the mucosal (e.g., sublingual, buccal, vaginal, rectal) surface of an individual so that the drug passes through the mucosal tissue and into the individual's blood stream.
  • Topical administration is used in its conventional sense to mean delivery of an active agent to the skin or mucosa, as in, for example, topical drug administration in the prevention or treatment of various skin disorders, the application of cosmetics and cosmeceuticals (including moisturizers, masks, sunscreens, etc.), and the like.
  • Topical administration in contrast to transdermal administration, provides a local rather than a systemic effect.
  • body surface is used to refer to skin or mucosal tissue, including the interior surface of body cavities that have a mucosal lining.
  • skin should be interpreted as including “mucosal tissue” and vice versa.
  • transdermal when used herein, as in “transdermal drug administration” and “transdermal drug delivery systems,” it is to be understood that unless explicitly indicated to the contrary, both “transmucosal” and “topical” administration and systems are intended as well.
  • crosslinked refers to a composition containing intramolecular and/or intermolecular crosslinks, whether arising through covalent or noncovalent bonding.
  • Noncovalent bonding includes hydrogen bonding, electrostatic (ionic) bonding, and absorption.
  • the invention provides a method for obtaining hydrophilic PSAs by mixing a specific amount of a selected hydrophilic polymer with a specific amount of a selected complementary short-chain plasticizer capable of hydrogen bonding to the hydrophilic polymer.
  • Suitable hydrophilic polymers include repeating units derived from an N-vinyl lactam monomer, a carboxy vinyl monomer, a vinyl ester monomer, an ester of a carboxy vinyl monomer, a vinyl amide monomer, and/or a hydroxy vinyl monomer.
  • Such polymers include, by way of example, poly(N-vinyl lactams), poly(N-vinyl acrylamides), poly(N-alkylacrylamides), substituted and unsubstituted acrylic and methacrylic acid polymers, polyvinyl alcohol (PVA), polyvinylamine, copolymers thereof and copolymers with other types of hydrophilic monomers (e.g. vinyl acetate).
  • Nonlimiting examples of non-N-vinyl lactam comonomers useful with N-vinyl lactam monomeric units include N,N-dimethylacrylamide, acrylic acid, methacrylic acid, hydroxyethylmethacrylate, acrylamide, 2-acrylamido-2-methyl-1-propane sulfonic acid or its salt, and vinyl acetate.
  • Poly (N-alkylacrylamides) include, by way of example, poly(methacrylamide) and poly(N-isopropyl acrylamide) (PNIPAM).
  • Polymers of carboxy vinyl monomers are typically formed from acrylic acid, methacrylic acid, crotonic acid, isocrotonic acid, itaconic acid and anhydride, a 1,2-dicarboxylic acid such as maleic acid or fumaric acid, maleic anhydride, or mixtures thereof, with preferred hydrophilic polymers within this class including polyacrylic acid and polymethacrylic acid, with polyacrylic acid most preferred.
  • Preferred hydrophilic polymers herein are the following: poly(N-vinyl lactams), particularly polyvinyl pyrrolidone (PVP) and poly(N-vinyl caprolactam) (PVC); poly(N-vinyl acetamides), particularly polyacetamide per se; polymers of carboxy vinyl monomers, particularly polyacrylic acid and polymethacrylic acid; and copolymers and blends thereof. PVP and PVC are particularly preferred.
  • the molecular weight of the hydrophilic polymer is not critical; however, the weight average molecular weight of the hydrophilic polymer is generally in the range of approximately 100,000 to 2,000,000, more typically in the range of approximately 500,000 to 1,500,000.
  • the hydrophilic polymer may or may not be adhesive in nature, as a nonadhesive hydrophilic polymer will become adhesive upon admixture with a predetermined quantity of the plasticizing agent.
  • the complementary short-chain plasticizing agent is terminated with hydroxyl groups, amino or carboxyl groups, and is typically a monomeric or oligomeric material that has a glass transition temperature T g in the range of about ⁇ 100° C. to about ⁇ 30° C. and a melting temperature T m lower than about 20° C.
  • the plasticizing agent may be also amorphous.
  • the difference between the T g values of polymer and plasticizer has a decisive significance for the adhesive behavior of the polymer-plasticizer blend. Preferably, the difference is greater than about 50° C., preferably greater than about 100° C., and most preferably in the range of about 150° C. to about 300° C.
  • the hydrophilic polymer and complementary short-chain plasticizer should be compatible, i.e.
  • the plasticizing agent will have a molecular weight in the range from about 45 to about 800, preferably in the range of about 45 to about 600.
  • suitable plasticizing agents include, but are not limited to, low molecular weight polyalcohols (e.g.
  • glycerol monomeric or oligoalkylene glycols such as ethylene glycol and propylene glycol, ether alcohols (e.g., glycol ethers), alkane diols from butane diol to octane diol includingly, carboxyl-terminated and amino-terminated derivatives of polyalkylene glycols such as polyethylene glycol, and carbonic diacids.
  • ether alcohols e.g., glycol ethers
  • alkane diols from butane diol to octane diol includingly, carboxyl-terminated and amino-terminated derivatives of polyalkylene glycols such as polyethylene glycol, and carbonic diacids.
  • Polyalkylene glycols, optionally carboxyl-terminated, are preferred herein, and polyethylene glycol having a molecular weight in the range of about 300 to 600 is an optimal plasticizing agent.
  • the hydrophilic polymer and plasticizer should be miscible with respect to each other and have disparate chain lengths (as may be deduced from the above).
  • the ratio of the weight average molecular weight of the hydrophilic polymer to that of the short-chain plasticizer should be within about 200 and 200,000, preferably within about 1,250 and 20,000.
  • the polymer and the plasticizer should contain complementary functional groups capable of hydrogen bonding or electrostatic bonding to each other.
  • the complementary functional groups of the polymer are located throughout the polymeric structure, while the functional groups of the plasticizer are preferably located at the two termini of a linear molecule, and are not present along the backbone, if the plasticizer is a polymer or an oligomer.
  • the plasticizer has been found to decrease the glass transition temperature of the hydrophilic polymer/plasticizer composition to a greater degree than predicted by the Fox equation, which is given by equation (1)
  • T g ⁇ ⁇ predicted w pol T g pol + w pl T g pl ( 1 )
  • T g predicted is the predicted glass transition temperature of the hydrophilic polymer/plasticizer composition
  • w pol is the weight fraction of the hydrophilic polymer in the composition
  • w pl is the weight fraction of the plasticizer in the composition
  • T g pol is the glass transition temperature of the hydrophilic polymer
  • T g pl is the glass transition temperature of the plasticizer.
  • the weight ratio of hydrophilic polymer to plasticizer should be of a specified value in order for adhesion to appear in a blend of a non-tacky hydrophilic polymer and a short-chain complementary plasticizer.
  • FIG. 2 illustrates, in PVP blends with PEG-400 adhesion is inherent only in those compositions that demonstrate negative deviations from the T g value predicted by the Fox equation (1). The larger the negative deviation, the higher the adhesion. This finding is generally applicable and is not limited to PVP-PEG-400 blends.
  • the negative deviation is within the range about 30° C. to about 150° C., preferentially from about 50° C. to about 120° C.
  • the extent of the negative T g deviation depends on the difference between the T g s of blend components, i.e., between T g pol and T g pl . In general, the negative T g deviation should be approximately 20-40% of the difference between the T g values of unblended polymer and plasticizer.
  • ⁇ C p T g product Another general predictor of pressure-sensitive adhesive behavior in polymers is the ⁇ C p T g product, where ⁇ C p is the change in heat capacity at the polymer transition point from the glassy to the viscoelastic state.
  • This product features a measure of the amount of heat that has to be expended in order to provide the polymer transition from the glassy to the viscoelastic state and to impart translational mobility to polymeric segments.
  • the ⁇ C p T g product decreases, passing through a minimum that corresponds to the maximum in blend adhesion ( FIG. 3 ). It is the product ⁇ C p T g which sets the PSAs apart from non-adhesive polymers (Table 1).
  • ⁇ C p T g values which are associated with the adhesive PVP-PEG blends and hydrophobic PSA's (PDMS, PIB and natural rubber), are notably grouped within a narrow area ranging from 45.0 to 92.0 J/g, predominantly near 65-80 J/g.
  • Non-adhesive polymers exhibit higher ⁇ C p T g values.
  • the ⁇ C p T g value outlines a subtle balance between free volume and cohesive interactions energy in polymers (Feldstein et al. (1999), Polym Mater. Sci. Eng. 81:467-468).
  • the enhanced free volume has to be counterbalanced by a high attractive interaction energy in order for adhesion to appear.
  • Enhanced free volume results in high molecular mobility and liquid-like fluidity of a PSA polymer, whereas substantial cohesive interaction energy provides cohesive toughness and rubber-like resistance to flow.
  • T g actual for the present adhesive compositions will generally be substantially lower than that predicted by the Fox equation, particularly since the composition of preferred adhesives herein is selected to correspond to the maximum negative deviation of T g actual from T g predicted , the heat required to transform a glassy polymer blend to a viscoelastic composition is minimal.
  • Equation (2) establishes a general relation of adhesive strength to the measures of molecular mobility (D) and cohesive toughness ( ⁇ f ) of PSA polymer.
  • equation (2) explains why adhesion goes through a maximum upon mixing a hydrophilic polymer with a short-chain plasticizer bearing complementary reactive functional groups at the chain ends.
  • Forming hydrogen or electrostatic bonds through both terminal groups of the plasticizer provides noncovalent crosslinking of the hydrophilic polymer chains into a supramolecular network structure of a polymer blend. Due to the considerable length and flexibility of plasticizer chains, the network structure provides enhanced free volume and molecular mobility coupled with high cohesive strength, i.e. the properties governing the adhesive behavior of polymer blends. With the increase in plasticizer concentration the molecular mobility (D) increases, whereas the cohesive strength ( ⁇ f ) follows the opposite pattern.
  • the Kovacs equation (3) holds if the difference in T g between the glass transition temperature of a PEG plasticizer component and the glass transition temperature of a PVP polymer (and between any miscible hydrophilic polymer and complementary plasticizer) is larger than about 50° C.:
  • hydrophilic polymer and the plasticizing agent are blended in a ratio designed to optimize adhesive and cohesive strength as well as hydrophilicity and thus, in drug delivery systems, the kinetics of drug delivery.
  • the ratio is as discussed above, i.e., a preferred weight ratio of hydrophilic polymer to plasticizer should be in the range defined by the maximum values of the negative T g deviations from the weight-average magnitudes calculated using the Fox equation (1) or outlined by the minimum values of the ⁇ C p T g criterion ( FIGS. 2 and 3 ).
  • the free volume and cohesive energy of polymer compositions have to be in a specified ratio in order for a composition to exhibit pressure-sensitive adhesion.
  • Feldstein et al. (1999) “Quantitative relationship between molecular structure and adhesion of PVP-PEG hydrogels,” Polym. Mater. Sci. Eng. 81:465-466; Feldstein et al. (1999), “Contribution of molecular mobility to debonding of pressure sensitive adhesive hydrogels,” Polym. Mater. Sci. Eng. 81:465-466; Feldstein et al. (1999), “A structure—property relationship and quantitative approach to the development of universal transdermal drug delivery system,” in: T. Sohn and V. A.
  • the composition may or may not be hydrated, depending on the desired use.
  • transdermal and transmucosal drug delivery systems will generally contain zero to about 7 wt. % water
  • products such as facial masks, electroconductive adhesive products, cosmeceutical products, topical pharmaceutical formulations, and other products in which a gel type adhesive (i.e., a hydrogel adhesive) is desired, will generally contain about 7 wt. % to about 40 wt. % water.
  • the optimum degree of hydration depends on the nature and hygroscopic of the hydrophilic polymer and the short-chain plasticizer. For example, an optimum PVP-PEG-400 system for most uses will contain from 2 to 20 wt.
  • % of residual water preferably from 2 to 12 wt. % water, most preferably between 6 and 10 wt. % water.
  • the rise in plasticizer hygrosopicity with the decrease in PEG chain length leads to an increase in the degree of optimum hydration, whereas the replacement of highly hygrosopic PVP with less hygrosopic PVCap results in the decrease of hydration providing best adhesion.
  • some hydration will occur upon application of the adhesive composition to skin or other body surface.
  • a hydrogel may be advantageous in a number of contexts.
  • compositions are self-adhesive and normally do not require the addition of tackifiers.
  • other additives may be incorporated into the present adhesive compositions, so long as they are not detrimental to the composition in any way.
  • the following optional components are often present in adhesive formulations and are presented here for illustrative purposes only and are not meant to limit the adhesive compositions in any way.
  • These optional components include including fillers, chain transfer agents for controlling molecular weight (e.g., carbon tetrabromide, mercaptans, or alcohols), pigments, dyes, refractive particles, preservatives, stabilizers, toughening agents, anti-microbial agents (e.g., mercurochrome, silver sulfadiazine, povidine iodine, iodine), cosmetic agents (e.g., glycerine, urea, allantoin, sulfur, anthraquinone, hydroquinones), moisturizers, humectants, anesthetics (e.g., benzocaine), healing agents (e.g., collagen), and the like.
  • chain transfer agents for controlling molecular weight e.g., carbon tetrabromide, mercaptans, or alcohols
  • pigments e.g., carbon tetrabromide, mercaptans, or alcohols
  • dyes
  • the adhesive compositions may be rendered electrically conductive for use in biomedical electrodes and other electrotherapy contexts, i.e., to attach an electrode or other electrically conductive member to the body surface.
  • the adhesive compositions may be used to attach a transcutaneous nerve stimulation electrode, an electrosurgical return electrode, or an EKG electrode to a patient's skin or mucosal tissue.
  • these applications involve modification of the adhesive composition so as to contain a conductive species, thereby rendering the adhesive composition as a whole conductive.
  • Suitable conductive species include the ionically conductive electrolytes that are commonly used for application to the skin or other body surface, and include ionizable inorganic salts, organic compounds, or combinations of both.
  • the adhesive composition should be covalently crosslinked.
  • the hydrophilic polymer may be covalently crosslinked, either intramolecularly or intermolecularly, and/or the hydrophilic polymer and the plasticizer may be covalently crosslinked. In the former case, there are no covalent bonds linking the hydrophilic polymer to the plasticizer, while in the latter case, there are covalent crosslinks binding the hydrophilic polymer to the plasticizer.
  • the hydrophilic polymer, or the hydrophilic polymer and the plasticizer may be covalently crosslinked using heat, radiation, or a chemical curing (crosslinking) agent.
  • a free radical polymerization initiator should be added into the polymer blend, i.e., the admixture of the hydrophilic polymer and the plasticizer.
  • the free radical polymerization initiator can be any of the known free radical-generating initiators conventionally used in vinyl polymerization and is preferably an organic peroxide or azo compound.
  • the initiators can be used in conventional amounts, generally from 0.01 to 15%, preferably 0.05 to 10%, more preferably from about 0.1% to about 5% and especially from a out 0.5% to about 4% by weight of the polymerisable material.
  • Suitable organic peroxides include dialkyl peroxides such as t-butyl peroxide and 2,2 bis(t-butylperoxy)propane, diacyl peroxides such as benzoyl peroxide and acetyl peroxide, peresters such as t-butyl perbenzoate and t-butyl per-2-ethylhexanoate, perdicarbonates such as dicetyl peroxy dicarbonate and dicyclohexyl peroxy dicarbonate, ketone peroxides such as cyclohexanone peroxide and methylethylketone peroxide, and hydroperoxides such as cumene hydroperoxide and tert.butyl hydroperoxide.
  • dialkyl peroxides such as t-butyl peroxide and 2,2 bis(t-butylperoxy)propane
  • diacyl peroxides such as benzoyl peroxide and acetyl
  • Suitable chemical curing agents also referred to as chemical cross-linking “promoters,” include, without limitation, polymercaptans such as 2,2-dimercapto diethylether, dipentaerythritol hexa(3-mercaptopropionate), ethylene bis(3-mercaptoacetate), pentaerythritol tetra(3-mercaptopropionate), pentaerythritol tetrathioglycolate, polyethylene glycol dimercaptoacetate, polyethylene glycol di(3-mercaptopropionate), trimethylolethane tri(3-mercaptopropionate), trimethylolethane trithioglycolate, trimethylolpropane tri(3-mercaptopropionate), trimethylolpropane trithioglycolate, dithioethane, di- or trithiopropane and 1,6-hexane dithiol.
  • the crosslinking promoter is added to
  • Examples of monomeric precursors and corresponding polymeric products are as follows: N-vinyl amide precursors for a poly(N-vinyl amide) product; N-alkylacrylamides for a poly(N-alkylacrylamide) product; acrylic acid for a polyacrylic acid product; methacrylic acid for a polymethacrylic acid product; acrylonitrile for a poly(acrylonitrile) product; and N-vinyl pyrrolidone (NVP) for a polyviny lpyrrolidone product.
  • Polymerization may be carried out in bulk, in suspension, in solution, or in an emulsion.
  • Solution polymerization is preferred, and polar organic solvents such as ethyl acetate and lower alkanols (e.g., ethanol, isopropyl alcohol, etc.) are particularly preferred.
  • polar organic solvents such as ethyl acetate and lower alkanols (e.g., ethanol, isopropyl alcohol, etc.) are particularly preferred.
  • synthesis will typically take place via a free radical polymerization process in the presence of a free radical initiator as described above.
  • the multifunctional comonomer include, for example, bisacrylamide, acrylic or methacrylic esters of diols such as butanediol and hexanediol (1,6-hexane diol diacrylate is preferred), other acrylates such as pentaerythritol tetraacrylate, and 1,2-ethylene glycol diacrylate, and 1,12-dodecanediol diacrylate.
  • the amount used will preferably be such that the weight ratio of crosslinking agent to hydrophilic polymer is in the range of about 1:100 to 1:5.
  • chemical crosslinking is combined with radiation curing.
  • the adhesive compositions of the invention are extrudable, and thus may be prepared using a simple blending and extruding process.
  • the components of the composition are weighed out and then admixed, for example using a Baker Perkins Blender, generally although not necessarily at an elevated temperature, e.g., about 35° C. to about 90° C.
  • Solvents may, if desired, be added.
  • Preferred solvents are aqueous solvents or alcohols (e.g., ethanol, methanol, isopropanol, etc.). Any crosslinking is carried out subsequently.
  • the resulting composition can be extruded using a single or twin extruder, or pelletized.
  • the adhesive composition may be prepared or extruded onto the backing layer or release liner of such a system.
  • drug delivery systems generally comprise: (A) a drug reservoir containing a therapeutically effective amount of the active agent; (B) an adhesive means for maintaining the system in active agent transmitting relationship to a body surface; and (C) a backing layer that serves as the outer surface of the device during use, wherein (D) a release liner generally covers the exposed adhesive during storage and prior to use.
  • Suitable active agents include the broad classes of compounds normally delivered through body surfaces and membranes; these active agents, in general, include: analeptic agents; analgesic agents; anesthetic agents; antiarthritic agents; respiratory drugs, including antiasthmatic agents; anticancer agents, including antineoplastic drugs; anticholinergics; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antihelminthics; antihistamines; antihyperlipidemic agents; antihypertensive agents; anti-infective agents such as antibiotics and antiviral agents; antiinflammatory agents; anti-migraine preparations; antinauseants; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics; antispasmodics; antitubercular agents; antiulcer agents; antiviral agents; anxiolytics; appetite suppressants; attention deficit disorder (“ADD”) and attention deficit hyperactivity disorder
  • Suitable enhancers include, for example, the following: sulfoxides such as dimethylsulfoxide (DMSO) and decylmethylsulfoxide (C 10 MSO); ethers such as diethylene glycol monoethyl ether (available commercially as Transcutol®) and diethylene glycol monomethyl ether; surfactants such as sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer (231, 182, 184), Tween (20, 40, 60, 80) and lecithin (U.S.
  • sulfoxides such as dimethylsulfoxide (DMSO) and decylmethylsulfoxide (C 10 MSO)
  • ethers such as diethylene glycol monoethyl ether (available commercially as Transcutol®) and diethylene glycol monomethyl ether
  • surfactants such as sodium laurate, sodium lauryl sulfate, cetyl
  • alcohols such as ethanol, propanol, octanol, decanol, benzyl alcohol, and the like
  • fatty acids such as lauric acid, oleic acid and valeric acid
  • fatty acid esters such as isopropyl myristate, isopropyl palmitate, methylpropionate, and ethyl oleate
  • polyols and esters thereof such as propylene glycol, ethylene glycol, glycerol, butanediol, polyethylene glycol, and polyethylene glycol monolaurate (“PEGML”; see, e.g., U.S. Pat.
  • amides and other nitrogenous compounds such as urea, dimethylacetamide (DMA), dimethylformamide (DMF), 2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanolamine, diethanolamine and triethanolamine; terpenes; alkanones; and organic acids, particularly salicylic acid and salicylates, citric acid and succinic acid.
  • DMA dimethylacetamide
  • DMF dimethylformamide
  • 2-pyrrolidone 2-pyrrolidone
  • 1-methyl-2-pyrrolidone 1-methyl-2-pyrrolidone
  • ethanolamine diethanolamine and triethanolamine
  • terpenes alkanones
  • organic acids particularly salicylic acid and salicylates, citric acid and succinic acid.
  • a preferred enhancer is ethanol, which not only serves as a permeation enhancer, but also solubilizes many active agents of interest and in addition improves adhesion.
  • An ethanol-water mixture may also be used.
  • a range of above mentioned skin permeability enhancers serves concomitantly in the adhesive composition as appropriate plasticizing agents, e.g. polyols such as propylene glycol, ethylene glycol, glycerol, butanediol, hexanediol and polyethylene glycol.
  • plasticizing agents e.g. polyols such as propylene glycol, ethylene glycol, glycerol, butanediol, hexanediol and polyethylene glycol.
  • the backing layer of the transdermal drug delivery device functions as the primary structural element of the transdermal system and provides the device with flexibility, drape and, optionally, occlusivity.
  • the material used for the backing layer should be inert and incapable of absorbing drug, enhancer or other components of the pharmaceutical composition contained within the device.
  • the material used for the backing layer should permit the device to follow the contours of the skin and be worn comfortably on areas of skin such as at joints or other points of flexure, that are normally subjected to mechanical strain with little or no likelihood of the device disengaging from the skin due to differences in the flexibility or resiliency of the skin and the device.
  • Examples of materials useful for the backing layer are polyesters, polyethylene, polypropylene, polyurethanes and polyether amides.
  • the laminated structure includes a release liner. Immediately prior to use, this layer is removed from the device so that the system may be affixed to the skin.
  • the release liner should be made from a drug/vehicle impermeable material, and is a disposable element which serves only to protect the device prior to application.
  • the release liner is formed from a material impermeable to the components of the device and the pharmaceutical composition contained therein.
  • Additional layers may also be present in any of these drug delivery systems.
  • Fabric layers may be used to facilitate fabrication of the device, while a rate-controlling membrane may be used to control the rate at which a component permeates out of the device.
  • the component may be a drug, a permeation enhancer, or some other component contained in the drug delivery system.
  • a rate-controlling membrane in the system on the skin side of the drug reservoir.
  • the materials used to form such a membrane are selected to limit the flux of one or more components contained in the drug formulation, and the membrane may be either microporous or dense.
  • Representative materials useful for forming rate-controlling membranes include polyolefins such as polyethylene and polypropylene, polyamides, polyesters, ethylene-ethacrylate copolymer, ethylene-vinyl acetate copolymer, ethylene-vinyl methylacetate copolymer, ethylene-vinyl ethylacetate copolymer, ethylene-vinyl propylacetate copolymer, polyisoprene, polyacrylonitrile, ethylene-propylene copolymer, polysiloxane-polycarbonate block copolymer and the like.
  • polyolefins such as polyethylene and polypropylene, polyamides, polyesters, ethylene-ethacrylate copolymer, ethylene-vinyl acetate copolymer, ethylene-vinyl methylacetate copolymer, ethylene-vinyl ethylacetate copolymer, ethylene-vinyl propylacetate copolymer, polyiso
  • the adhesive compositions of the invention are useful in any number of additional contexts wherein adhesion of a product to a body surface is called for or desirable.
  • These applications include, for example, pressure-relieving cushions for application to a foot, wherein the cushions may or may not contain medication for transdermal or topical delivery, e.g., salicylic acid or the like.
  • Such cushions will generally be comprised of a flexible, resilient outer layer, fabricated from a foam pad, fabric, or the like, with a layer of an adhesive composition of the invention laminated thereto for application to the skin surface.
  • cohesive strength is important for the product to function as a pressure-relieving cushion, and the hydrophilic polymer should therefore be covalently crosslinked to a degree sufficient to impart the necessary cohesive strength.
  • the adhesive compositions are also useful in conjunction with medical devices to be affixed to a body surface, diagnostic systems or devices to be affixed to a body surface, and any other application wherein adhesion to a body surface is necessary or desired.
  • the present invention represents an important advance in the field of pressure sensitive adhesives, particularly bioadhesives.
  • the novel adhesive compositions adhere well to hydrated surfaces such as mucosal tissue, are suitable for long-term skin contact and are nonirritating, noncomedogenic and nonsensitizing, are permeable to and physically and chemically compatible with a variety of drugs and drug types, and can enhance the rate at which an active agent migrates into a body surface.
  • the present adhesive composition can be used in a variety of contexts, and can be readily tailored during manufacture with respect to hygroscopicity and the desired degree of hydrophilicity, adhesive and cohesive strength.
  • Adhesive joint strength of the adhesive hydrogels to standard polyethylene (PE) film of 100 m in thickness was evaluated by a 180° peel test with an Instron 1221 Tensile Strength Tester at the peeling rate of 10 mm/min.
  • a low-density PE film, crystallinity 45%, contact angle 105°, surface energy 28.5 mJ/m 2 was employed as a standard substrate.
  • the adhesives were saturated with water by equilibrating in dessicators with a controlled pressure of water vapor of 50% at ambient temperature for 6-7 days. The time to attain a maximum strength of adhesive contact with the substrate was 15-20 min.
  • the character of adhesive joint failure was observed with a TV camera interfaced to an IBM computer and photographed with a microscope. The locus of failure was ascertained by contact angle measurement of the detached substrate surface.
  • Phase behavior of the hydrophilic polymers blends with PEG-400 over an entire compositional range was investigated by Differential Scanning Calorimetry (DSC) using a Mettler TA 4000/DSC-30 differential scanning calorimeter calibrated with indium and gallium.
  • DSC Differential Scanning Calorimetry
  • the samples were first quench cooled with liquid nitrogen from ambient temperature to ⁇ 100° C. over 2-3 minutes and then heated at a rate of 20° C. min ⁇ 1 to 220° C. Upon heating, a heat capacity jump followed by a single exotherm coupled with a symmetric endotherm, and a high temperature endotherm, were normally observed for the blends.
  • Viscoelastic properties and the durability of adhesive joints of adhesive hydrogels were studied using a squeeze-recoil technique on a DTDM thermomechanical analyzer (microdilatometer) as described by Kotomin et al. (1999), “Squeeze-recoil analysis of adhesive hydrogels and elastomers” Polym Mater. Sci. Eng. 81:425-426 and Kotomin et al. (2000), “Durability and fracture of some viscoelastic adhesives” Proceed. 23 rd Adhesion Soc. Annual Meeting, Myrtle Beach, S.C., pp. 413-415.
  • the polymer sample was placed between two flat silica surfaces formed by loading rod and supporting plate and subjected to the action of a fixed compressive load, followed by removing the compressive load to allow the sample relaxation.
  • Table 2 reports the properties of PVP adhesive blends with PEG-400.
  • Examples 1-4 and FIGS. 2 and 3 demonstrate the effect of PVP-PEG blend composition on adhesive properties.
  • the relationship of adhesion to the phase behavior of PVP-PEG blends is also shown, described in terms of the negative T g deviation from the weight-average magnitudes ( ⁇ T g ), found with the Fox equation (1), and the ⁇ C p T g value.
  • the adhesion appears in a narrow range of concentration.
  • the maximum adhesion corresponds to the maximum ⁇ T g values and to the minimum ⁇ C p T g value.
  • Examples 1, 5-9 and FIG. 4 reveal the impact of relative humidity (RH) of the surrounding atmosphere on the adhesive behavior of PVP-PEG blends.
  • PVP is a hygroscopic polymer that absorbs more than 25% water upon exposure to a high RH ( FIG. 9 ).
  • RH relative humidity
  • PVP-overloaded blends having higher glass transition temperatures, where debonding proceeds through an adhesive mechanism, the blend hydration increased the force required to rupture adhesive bond.
  • the effect of additional plasticizer reduces the adhesion.
  • an adhesive remainder occurs at the substrate interface upon adhesive joint failure (Table 1).
  • Examples 1, 10 and 11 exhibit the effects of the chain length of the hydrophilic polymer (PVP) on adhesive joint strength.
  • peel strength of an adhesive joint tended to decrease with the reduction of molecular weight.
  • Examples 12-16 demonstrate the impact of adhesive layer thickness upon adhesive joint strength. In accordance with Equation 2, the peel force required to rupture an adhesive joints was found to increase with the increase in thickness of the adhesive layer.
  • the tacky blends can be obtained by mixing PVP with hydroxyl-terminated (Examples 17-41) or carboxyl terminated (Examples 42-47) short-chain plasticizers.
  • Short-chain plasticizers include: ethylene glycol (Examples 17-19) and its polymers (PEG), ranging in molecular weight from 200 to 600 g/mol (Examples 20-23); low molecular weight 1,3- and 1,2-propylene glycol (PG) (Examples 24, 25); and alkane diols from propane diol up to pentane diols (PD) and hexane diol (HD) inclusive (Examples 27-39).
  • Polypropylene glycol (PPG) has been found to be a good plasticizer for PVP, but does not develop any adhesion or tack (Example 26).
  • the glass transition temperatures of plasticizers examined were within the range of ⁇ 59° C.
  • the plasticizer has to be either amorphous or crystalline, but the melting temperature of appropriate plasticizers, T m , is normally lower than 50° C., the value found for 1,6-hexane diol (HD) (Examples 33-37).
  • T m melting temperature of appropriate plasticizers
  • the adhesive strength correlates with maximum ⁇ T g and minimum ⁇ C p T g values.
  • the highest peel strength was found for PVP blends with glycerol (Example 41), which possesses a high density of hydroxyl groups per molecule. Strictly speaking, the carbonic diacids of Table 3 and Examples 44-47 are not acting as plasticizers but rather as noncovalent crosslinking agents and cohesive interaction enhancers.
  • carbonic diacids can be employed in combination with plasticizers so as to reduce T g to the values inherent in PSAs.
  • plasticizers For proper adhesion, carbonic diacids can be employed in combination with plasticizers so as to reduce T g to the values inherent in PSAs.
  • Such approach has been used in a Plastoid adhesive blend (U.S. Pat. Nos. 5,730,999 and 5,993,849, EP 848960 A3), where EUDRAGIT E-100 was crosslinked by succinic acid and plasticized with tributylcitrate.
  • Dry blends of PVP with 50% of carbonic diacids have been found to exhibit high T g values (28,-34,-43, and 24° C. for SA, MA, GA, and AA, respectively) and, therefore, develop no adhesion.
  • the PEG-600 terminated by carboxyl groups (Examples 42, 43), serves as both a crosslinking agent and a plasticizer, imparting adhesion to PVP blends.
  • PSA Compositions Prepared by Mixing Different Hydrophilic Polymers with Complementary Short-chain Plasticizers
  • the left branches of the curves in FIG. 11 correspond to adhesive debonding, while the right branches correspond to miscellaneous and cohesive types of adhesive bond failure.
  • increase in polymer molecular weight results in an increase in cohesive toughness and adhesion.
  • the sorption and adhesive properties of PVCap-PEG hydrogels are thus ideal for pharmaceutical applications.
  • PVCap exhibits a Lower Critical Solution Temperature (LCST) about 35° C. (see Kirsh Y. E., Water soluble poly(N-vinylamides), Wiley, N.Y., 1998). Below this temperature the PVCap is easily soluble in water and behaves like moderately hydrophilic polymer, while above LCST the PVCap becomes insoluble in water hydrophobic polymer. This property is highly useful for the development of thermoresponsive or so-called “smart” adhesive hydrogels.
  • LCST Critical Solution Temperature
  • PNIPAM/PEG400 250,000 157 64 36 50 66 89.0 230 misc. 55.
  • Luviscol73/PEG400 100,000 57.5 30 70 50 37.1 65.9 High** cohesive 62. 36 64 34.0 79.4 High** cohesive 63. Luviscol37/PEG400 100,000 29 17 83 50 9.3 138.7 High** cohesive 64.
  • the adhesive hydrogels of the invention display a number of useful viscoelastic properties, similar to the properties of cured rubbers ( FIGS. 6-8 ).
  • adhesive hydrogels are hydrophilic and water-soluble rubbers, featuring rubber-like elasticity as one of their major performance properties. Both the rubber-like elastic and viscous contributions to the rheology of the present adhesive hydrogels are illustrated by the data in FIG. 6 .
  • the yield stress in the PVP-PEG adhesive hydrogel is associated with a critical magnitude of shear stress in the flow curve shown in FIG. 7 , at which the apparent shear viscosity climbs to infinity and the deformation rate drops tending to zero.
  • the yield stress is an integral measure of cohesive strength, which has been shown to relate to the ⁇ f value in equation (2) and which determines the adhesive properties of an adhesive polymer (Feldstein et al. (2000), “Molecular insight into theological and diffusion determinants of pressure-sensitive adhesion,” Proceed. 23 rd Annual Meeting Adhesion Soc., pp. 54-56).
  • the relaxation of polymer deformation occurs, termed the “retardation,” when deformation changes its sign and the polymer returns, more or less, to its initial shape.
  • the adhesive hydrogel demonstrated ( FIG. 6 ) the instantaneous (Hooke's) retardation, followed by a creep recoil.
  • the obtained Se magnitude corresponds to an average molecular weight of polymer chain between entanglements Mc ⁇ 130,000 g/mol, which is typical of slightly cross-linked rubbers, whereas the n value is a characteristic of highly dense network.
  • the obtained S e and ⁇ values refer most likely to the contribution of network formed by the entanglements of PVP chains, while the n exponent relates to the contribution of the much more dense and faster relaxing H-bonded network.
  • the superposition of the recoil compliance profiles for PVP-PEG hydrogel and PB rubber ( FIG. 8 ) provides evidence that the hydrogel retardation properties are typical of elastomers. Accordingly, the adhesive hydrogels described represent, in essence, water-soluble rubbers.
  • Therapeutic agents were first dissolved in a mixture of PEG-400 (plasticizer) and ethyl alcohol (solvent). Upon complete drug dissolution, the PVP or another hydrophilic polymer was dissolved in the earlier prepared mixture, forming casting solution that was cast onto polyethylene terephthalate backing film of 0.02 mm in thickness and dried at temperatures of 20-60° C.
  • In vitro drug delivery rate determination from water-soluble PSA matrices was performed using human cadaver skin or a skin-imitating Carbosil membrane to protect the matrices from dissolving in the receptor solution.
  • the patch was adhered to the center of a Carbosil membrane sheet of twice its area.
  • the membrane margins were then wrapped around the sample.
  • the back side of the packet was closely attached to a steel plate-holder to prevent direct contact of the matrix with the receptor solution.
  • cadaver skin epidermis can be used instead of a Carbosil membrane.
  • the holder with the wrapped sample was then submerged into an aqueous sink and in vitro drug delivery rate was determined using a USP rotating cylinder method paddle-over-disc.
  • the rate of drug appearance rate in a receptor solution (0.15 M NaCl) at 35.0 ⁇ 0.5° C. was determined spectrophotometrically.
  • Drug permeability coefficients through skin epidermis (P s ) and a Carbosil membrane (P m ) were measured as the fluxes of drug delivered from the hydrophilic PSA matrix normalized by the drug concentration in the donor vehicle, taking the matrix density (1.10 ⁇ 0.12 g/cm 3 ) into account.
  • compositions and properties of prepared therapeutic systems are presented in the Table 5.
  • the hydrophilic PSA matrices based on both the PVP and PVCap blends with PEG-400 provide high delivery rates through both the skin-imitating Carbosil membrane and human skin epidermis.
  • the hydrophilic PSA matrices allow us to enhance appreciably the rates of drug delivery compared to known hydrophobic PSAs such as PIB, PDMS and styrene-butadiene rubbers.
  • the rates of drug delivery from the PVCap-PEG matrices are enhanced compared to the PVP-PEG matrix (compare examples 66 and 67, 71 and 72, 80 and 81).
  • TDP topical dermal patch
  • Example 82 refers to an antifungal topical dermal patch based on the PVP-PEG PSA matrix.
  • the patch is composed of a nonocclusive cotton textile backing on one side of the drug-loaded PVP-PEG adhesive matrix and a protective layer on the other side, which is removed before patch application to the skin.
  • the patch is designed for topical targeted treatment of mycosis and contains 3% of chinosol (8-hydroxyquinoline sulfate) as an antifungal agent.
  • the salt form of the drug serves to reduce its percutaneous absorption into systemic circulation.
  • in vivo chinosol release rate from the Chinosive TDP in human volunteers averages only 0.42 ⁇ g/cm 2 h as has been evaluated from the drug remainder in the patch removed from the skin.
  • the topical antifungal monotherapy with the chinosol-containing patch results in essential acceleration of the treatment compared to the control group treated by the clotrimazol.
  • hydrophilic PSA matrices outlined by this invention provide the performance properties useful in application dosage forms designed for transdermal and dermal drug delivery.

Abstract

A method for preparing hydrophilic pressure sensitive adhesive (PSA) compositions is provided, wherein the method enables preparation of adhesives having a particular, optimized degree of adhesion. That is, the hydrophilic PSA is comprised of a hydrophilic polymer and a complementary short-chain plasticizing agent, wherein the hydrophilic polymer and plasticizing agent are capable of hydrogen bonding or electrostatic bonding to each other and are present in a ratio that optimizes key characteristics of the adhesive composition, such as adhesive strength, cohesive strength and hydrophilicity. The adhesive is useful in a wide variety of contexts, e.g., as a biomedical adhesive for application to the skin or other body surface, and as such finds utility in the areas of drug delivery systems (e.g., topical, transdermal, transmucosal, iontophoretic), medical skin coverings and wound healing products and biomedical electrodes.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS
More than one reissue application has been filed for the reissue of U.S. Pat. No. 6,576,712. The reissue applications are the present application and U.S. patent application Ser. No. 13/761,118, filed Feb. 6, 2013. This application is a reissue application of U.S. patent application No. 09/900,697, filed Jul. 6, 2001, now U.S. Pat. No. 6,576,712 which is a continuation-in-part of U.S. patent application Ser. No. 09/847,532, filed May 1, 2001 now abandoned, which claimedclaims priority under 35 U.S.C. §119(e)(1) to U.S. Provisional Patent Application No. 60/216,386, filed Jul. 7, 2000.
TECHNICAL FIELD
This invention relates to preparation of adhesive compositions. More particularly, the invention relates to preparation of hydrophilic pressure sensitive adhesive (PSA) compositions having optimized adhesive properties and that are useful, for example, in transdermal drug delivery systems and other medical, pharmaceutical and cosmetic products that adhere to the skin or other body surface. The invention has utility in a number of fields, including transdermal drug delivery, iontophoretic systems, biomedical electrode fabrication, wound healing, and skin care and cosmetic products.
BACKGROUND
Pressure-sensitive adhesives are well known and have been used for many years in a variety of industrial, consumer and medical applications. Pressure-sensitive adhesives are characterized as being normally tacky and exhibiting instant tack when applied to a substrate. Many polymers have been used to manufacture pressure sensitive adhesives as, for example, acrylic and methacrylic ester homo- or copolymers, butyl rubber-based systems, silicones, urethanes, vinyl esters and amides, olefin copolymer materials, natural or synthetic rubbers, and the like. All the PSAs are elastomers, i.e. they exhibit viscoelastic properties typical of rubbers.
Pressure sensitive adhesives are used extensively in transdermal drug delivery devices, or “patches,” that adhere to the skin or mucosal tissue during use. Adhesive, transport, reservoir and biological properties of polymeric composites constitute a basis for their application in transdermal drug delivery systems, as follows:
    • Adhesive: High tack coupled with an optimum slip-stick transition point.
    • Transport: Drug release kinetics controlled in terms of transdermal delivery rate and the functional lifetime of device.
    • Reservoir: Drug compatibility and ability to be stored in a stable form tailored to the incorporated drug of interest.
    • Biological: No toxicity, skin irritation and sensitization.
      Such diverse requirements are difficult to combine in a single system.
Examples of pressure sensitive adhesives that have been proposed for use in transdermal drug delivery systems include polysiloxanes (e.g., polydimethyl siloxanes, polydiphenyl siloxanes, and siloxane blends), polyisobutylenes, polyacrylates, acrylic acid-acrylate copolymers (e.g., copolymers of acrylic acid copolymers with 2-ethylhexyl acrylate or isooctyl acrylate), and tacky rubbers such as polyisobutene, polybutadiene, polystyrene-isoprene copolymers, polystyrene-butadiene copolymers, and neoprene (polychloroprene). All of these PSAs are hydrophobic polymers and their common disadvantage is a loss in adhesion toward hydrated substrates.
“Bioadhesion” is defined as a pressure sensitive adhesion with respect to highly hydrated biological tissues such as mucosal tissue. In contrast to conventional PSAs (rubber, polysiloxanes and acrylates) that adhere mainly to dry substrates, bioadhesives (BAs) exhibit good tack when adhered to hydrated biological substrates. To be bioadhesive, water should provide a plasticizing effect on a polymer, i.e., the polymer should he hydrophilic. For example, the range of typical BAs includes slightly cross-linked polyacrylic and polymethacrylic acids (EP 0371 421) as well as blends of hydrophilic cellulose derivatives to (40-95%) with polyethylene glycol (PEG) (U.S. Pat. No. 4,713,243).
Bioadhesives become tacky as the crosslinked polymer swells in significant quantities of water. The cohesive strength of highly swollen hydrophilic polymers is generally low and the BAs thus differ from the PSAs in this regard.
For a number of practical purposes, it can be highly useful to have a range of PSA and BA polymeric materials of different hydrophilicity and thus different solubilities in water or in the liquids secreted by the skin and mucosa (sweat, mucus, saliva etc.). Attempts to combine the properties of PSAs and BAs have been described by Biegajski et al. in U.S. Pat. No. 5,700,478, where a water-soluble pressure-sensitive mucoadhesive was obtained by blending of 95-40% polyvinylpyrrolidone (PVP) with 0-50% hydroxypropyl cellulose (HPC) and 11-60% glycerol. Other examples of hydrophilic polymer blends coupling the properties of PSAs and BAs involve polyacrylic acid-polyvinyl alcohol (PAA-PVA) interpolymeric complexes formed by hydrogen bonding between the monomer units of the complementary polymers chains and plasticized with PEG-200, glycerol or polypropylene glycol (PPG), molecular weight 425 g/mol (German Patent Application DE 42 19 368).
The ideal performance characteristics of an adhesive intended for use on human skin and/or mucosal tissue present difficult and conflicting technical requirements. Initially, of course, the pressure sensitive adhesive should be suitable for long-term skin contact, and permeable to and physically and chemically compatible with the active agent and any permeation enhancers or other vehicles or additives that are present. The ideal adhesive should also be nonirritating, noncomedogenic and nonsensitizing, yet bond quickly to skin or mucosal tissue at the intended site of use with only very slight pressure. The adhesive should maintain its bond for as long a period of time as necessary and be resistant to inadvertent removal, yet be easily removed without removing any skin or leaving a residue (a suitable strength of an adhesive joint with the skin ranges from about 200 to 400 N/m under the 180 degree peel test). High tack (i.e., greater than about 50 g/cm2) should be coupled with an optimum transition point from adhesive to cohesive failure. Furthermore, the adhesive should not be weakened or destroyed by exposure to moisture or high humidity. Finally, in order to protect a wound or maintain the integrity of placement of an electrode or other device, the adhesive should resist skin movement and be able to transfer a mechanical load from the adhesive backing to the skin.
For many pharmaceuticals, the solubility of the active agent in the reservoir of a transdermal drug delivery device is of decisive importance. With higher solubility, it is possible to increase the rate of transdermal delivery (i.e., the rate at which the active agent migrates from the device and into the skin or mucosal tissue). Because many therapeutic agents are ionogenic organic substances having a higher solubility in hydrophilic media than in lipophilic media, adhesive reservoirs based on hydrophilic polymers would be more versatile than adhesive reservoirs based on hydrophobic polymers. Furthermore, as noted above, pressure sensitive adhesives for application to mucosal tissue should adhere well to hydrated substrates, and hydrophilic adhesives would therefore be ideal.
General advantages of hydrophilic adhesives are as follows:
    • 1. Hydrophilic adhesives can provide greater adhesion compared with hydrophobic adhesives, because the surface energy of hydrophilic adhesives is typically higher and closer to that of biological substrates such as skin and mucosal membranes.
    • 2. Hydrophilic adhesives are compatible with a wide variety of drugs, excipients and additives.
    • 3. The plasticizing effect of water sorbed by hydrophilic adhesives from hydrated skin or mucosal tissues enhances adhesion, in contrast to hydrophobic adhesives.
    • 4. The enhanced solubility of drugs in hydrophilic adhesives facilitates control over drug release kinetics.
    • 5. With hydrophilic adhesives, based on hydrophilic polymers, there is an expanded capability to control and manipulate the adhesive-cohesive balance.
    • 6. The adhesive properties of hydrophilic polymers are considerably less sensitive to their molecular weight than those of hydrophobic polymers, as a result of specific intramolecular and intermolecular interaction within hydrophilic adhesives.
In order to increase the hydrophilicity of an adhesive composition, hydrophobic PSAs have been “hydrophilized” by incorporation of non-tacky hydrophilic polymers and fillers into a hydrophobic adhesive. Thus, polyisobutylene (PIB) PSA has been hydrophilized by incorporation of cellulose and cellulose derivatives (U.S. Pat. No. 4,231,369), polyvinyl alcohol (PVA), pectin and gelatin (U.S. Pat. Nos. 4,367,732 and 4,867,748), and SiO2 (U.S. Pat. No. 5,643,187). Rubber adhesives have also been modified by filling with amphiphilic surfactants, or by treating the PSA polymer with a plasma-oxygen discharge. Acrylic PSAs can be hydrophilized by incorporation of PVP (U.S. Pat. No. 5,645,855). Hydrophilization of hydrophobic adhesives, while somewhat effective, tends to result in a partial loss of adhesion.
Accordingly, there is a need in the art for a novel hydrophilic adhesive composition suitable for use in a wide variety of contexts, e.g., in a topically applied drug delivery system, which composition meets all of the above criteria and provides for an effective delivery rate of any active agent, whether hydrophilic, ionogenic, or lipophilic in nature.
The present invention is addressed to the aforementioned need in the art, and enables the development of a wide range of hydrophilic pressure-sensitive adhesives that not only meet all of the aforementioned criteria but provide other advantages as well. For example, the adhesive compositions combine the properties of pressure-sensitive adhesives and bioadhesives and can be used in a number of contexts, including not only transdermal, transmucosal and topical drug delivery systems but also in wound healing products, biomedical electrodes, iontophoretic systems, bioadhesive cushions, and the like. Also, the adhesive compositions can be used with a number of active agents, regardless of hydrophilicity, hydrophobicity, and molecular structure. Manufacture of adhesive products using the present compositions is readily accomplished by a simple extrusion process, obviating the need for organic solvents and the conventional, time-consuming blending and casting method. Finally, the adhesive composition may be readily tailored during manufacture with respect to hygroscopicity, the desired degree of hydrophilicity, adhesive and cohesive strength, and drug delivery kinetics.
SUMMARY OF THE INVENTION
It is thus a primary object to address the above-described need in the art by providing a method for making hydrophilic pressure sensitive adhesive compositions useful in transdermal drug delivery systems, iontophoretic systems, wound healing products, biomedical electrodes, and other devices and systems requiring a bioadhesive.
It is another object of the invention to provide a hydrophilic pressure sensitive adhesive that is optimized with respect to adhesive strength, cohesive strength and hydrophilicity.
It is another object of the invention to provide a therapeutic system for the topical or transdermal administration of a pharmacologically active agent, wherein the system is provided with an adhesive means comprised of a hydrophilic pressure sensitive adhesive composition as provided herein.
Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.
In one aspect of the invention, then, a method is provided for preparing an adhesive composition having an optimized degree of adhesion, comprising:
    • (a) preparing a plurality of compositions each comprised of a hydrophilic polymer having a glass transition temperature Tg pol admixed with a plasticizer having a glass transition temperature Tg pl and capable of covalently or noncovalently crosslinking the hydrophilic polymer, wherein the weight fraction of the hydrophilic polymer in each composition is wpol, and the weight fraction of the plasticizer in each composition is wpl;
    • (b) calculating predicted glass temperatures Tg predicted for each composition using the Fox equation (1)
1 T g predicted = w pol T g pol + w pl T g pl ( 1 )
and plotting Tg predicted versus wpl, for each composition;
    • (c) determining the glass transition temperature Tg actual for each composition, and plotting Tg actual versus wpl, for each composition;
    • (d) identifying the region of the plots of (b) and (c) wherein Tg actual is less than Tg predicted; such that there is a negative deviation from Tg predicted;
    • (e) within the region identified in (d), identifying the optimum weight of plasticizer wpl optimum at which the negative deviation from Tg predicted is at a maximum; and
    • (f) admixing a monomeric precursor to the hydrophilic polymer and the plasticizer under polymerizing conditions to provide an adhesive composition having an optimized degree of adhesion, wherein the weight fraction of plasticizer in the composition is wpl optimums and the weight fraction of the hydrophilic polymer in the composition is l-wpl optimum.
In some cases, e.g., when a lower degree of adhesion is desired, the selected weight percent of the plasticizer will not correspond to the maximum negative deviation of Tg actual Tg predicted, but will correspond to some other predetermined deviation of Tg actual from Tg predicted. Accordingly, in another aspect of the invention, a method is provided for preparing an adhesive composition having a predetermined degree of adhesion, comprising:
    • (a) preparing a plurality of compositions each comprised of a hydrophilic polymer having a glass transition temperature Tg pol admixed with a plasticizer having a glass transition temperature Tg pl and capable of covalently or noncovalently crosslinking the hydrophilic polymer, wherein the weight fraction of the hydrophilic polymer in each composition is wpol, and the weight fraction of the plasticizer in each composition is wpl, such that wpol is equal to l-wpl;
    • (b) calculating predicted glass temperatures Tg predicted for each composition using the Fox equation (1)
1 T g predicted = w pol T g pol + w pl T g pl ( 1 )
and plotting Tg predicted versus wpl for each composition;
    • (c) determining the glass transition temperature Tg actual for each composition, and plotting Tg actual versus wpl for each composition;
    • (d) identifying the region of the plots of (b) and (c) wherein Tg actual has a predetermined deviation from Tg predicted; and
    • (e) admixing a monomeric precursor to the hydrophilic polymer and the plasticizer under polymerizing conditions to provide an adhesive composition having a predetermined degree of adhesion, wherein the weight percent of plasticizer in the composition corresponds to a value within the region identified in section (d).
In another aspect of the invention, a hydrophilic pressure sensitive adhesive composition is provided that comprises (1) a hydrophilic polymer having a glass transition temperature Tg pol, and (2) a complementary hydroxyl-terminated or carboxyl-terminated short-chain plasticizing agent having a glass transition temperature Tg pl and capable of hydrogen bonding or electrostatic bonding to the hydrophilic polymer, wherein the weight ratio of hydrophilic polymer to complementary short-chain plasticizing agent is selected so to provide a predetermined deviation in (a) the actual glass transition temperature Tg actual of the composition from (b) the predicted glass transition temperature Tg predicted calculated for the composition using the Fox equation. For maximum adhesion, the predetermined deviation is the maximum negative deviation of Tg actual from Tg predicted. Preferably, the difference between Tg pol and Tg pl is at least about 50° C., such that Tg actual for each composition is determined solely by Tg pl.
In related aspects of the invention, a hydrophilic pressure sensitive adhesive composition is provided that comprises (a) a hydrophilic polymer, and (b) a complementary hydroxyl-terminated or carboxyl-terminated short-chain plasticizing agent capable of hydrogen bonding or electrostatic bonding to the hydrophilic polymer, wherein the ratio of hydrogen bonding to covalent crosslinks and/or the ratio of the hydrophilic polymer to the plasticizing agent are selected to optimize the hydrophilicity, adhesive strength and cohesive strength of the composition.
In a further aspect of the invention, a drug delivery system is provided for the topical or transdermal administration of a pharmacologically active agent. The drug delivery system includes:
    • (A) a drug reservoir comprising (1) a substantially non-aqueous pressure sensitive adhesive matrix of a hydrophilic polymer having a glass transition temperature Tg pol, and a complementary hydroxyl-terminated or carboxyl-terminated short-chain plasticizing agent having a glass transition temperature Tg pl and capable of hydrogen bonding or electrostatic bonding to the hydrophilic polymer, wherein the weight ratio of hydrophilic polymer to complementary short-chain plasticizing agent is selected so to provide a predetermined deviation in (a) the actual glass transition temperature Tg actual of the composition from (b) the predicted glass transition temperature Tg predicted for the composition calculated using the Fox equation, and (2) a therapeutically effective amount of the active agent; and
    • (B) a backing layer laminated to the drug reservoir that serves as the outer surface of the device during use.
The adhesive compositions herein are also useful in a host of additional applications, e.g., in bandages, wound and burn dressings, ostomy devices, prosthesis securing means, face masks, sound, vibration or impact absorbing materials, and the like. The compositions may be rendered electrically conductive by incorporation of water and/or another electrically conductive material, and may thus be used for attaching an electroconductive article, such as an electrode (e.g., a transcutaneous electric nerve stimulation, or “TENS” electrode, an electrosurgical return electrode or an EKG monitoring electrode), to an individual's body surface.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 represents a schematic view of the molecular design of a hydrogen-bonded or electrostatic-bonded network complex formed by a long-chain hydrophilic polymer and a short-chain plasticizer.
FIG. 2 is a graph illustrating the adhesion characteristics of a PVP-PEG (m.w. 400 g/mole) blend, evaluated in terms of the 180° peel force needed to rupture an adhesive bond with a polyethylene (PE) substrate at a debonding rate of 10 mm/min, with respect to the compositional behavior of the glass transition temperature, Tg, in the blend. The points denote experimental data, whereas the line connecting the Tgs of PVP and PEG-400 was obtained using the Fox equation.
FIG. 3 is a plot of ΔCpTg against the composition of PVP blends with PEG-400.
FIG. 4 shows the effects of the plasticizer-hydrophilic polymer ratio and the relative humidity of the surrounding atmosphere on the adhesion of PVP plasticized with PEG-400, evaluated in terms of 180° peel force.
FIG. 5 represents the Kovacs plot for miscible PVP-PEG blends.
FIG. 6 illustrates the squeezing kinetics of PVP-PEG adhesive hydrogel under a fixed compressive load and squeeze recoil upon its removal. The h value is the distance (mm) between the upper and lower plates of the squeeze-recoil tester, which is equal to the thickness of specimen.
FIG. 7 is the PVP-PEG adhesive hydrogel flow curve under a compressive load of 1 N at 20° C.
FIG. 8 outlines the creep-recoil functions for the PVP-PEG adhesive hydrogel compared to polybutadiene (PB) and polyisoprene (PI) rubbers.
FIG. 9 exhibits the water vapor absorption isotherms for PVP and its blends with PEG-400 at ambient temperature.
FIG. 10 displays the isotherms of water vapor sorption by polyvinyl caprolactam (PVCap) and PVP at ambient temperature.
FIG. 11 outlines the effect of relative humidity (RH) on the adhesion of PVP-PEG and PVCap-PEG hydrogels.
DETAILED DESCRIPTION OF THE INVENTION
Before describing the present invention in detail, it is to be understood that unless otherwise indicated this invention is not limited to specific therapeutic agents, polymeric materials, drug delivery devices, or the like, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.
It must be noted that, as used in this specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a hydrophilic polymer” includes a mixture of two or more such polymers, reference to “a cross-linking agent” includes mixtures of two or more cross-linking agents, and the like.
In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set out below.
The terms “active agent,” “drug,” and “therapeutic agent” are used interchangeably herein to refer to a chemical material or compound suitable for transdermal or transmucosal administration and which induces a desired effect. The terms include agents that are therapeutically effective, prophylactically effective, or cosmetically effective. Also included are derivatives and analogs of those compounds or classes of compounds specifically mentioned which also induce the desired effect.
By “transdermal” drug delivery is meant administration of a drug to the skin surface of an individual so that the drug passes through the skin tissue and into the individual's blood stream. The term “transdermal” is intended to include “transmucosal” drug administration, i.e., administration of a drug to the mucosal (e.g., sublingual, buccal, vaginal, rectal) surface of an individual so that the drug passes through the mucosal tissue and into the individual's blood stream.
The term “topical administration” is used in its conventional sense to mean delivery of an active agent to the skin or mucosa, as in, for example, topical drug administration in the prevention or treatment of various skin disorders, the application of cosmetics and cosmeceuticals (including moisturizers, masks, sunscreens, etc.), and the like. Topical administration, in contrast to transdermal administration, provides a local rather than a systemic effect.
The term “body surface” is used to refer to skin or mucosal tissue, including the interior surface of body cavities that have a mucosal lining. The term “skin” should be interpreted as including “mucosal tissue” and vice versa.
Similarly, when the term “transdermal” is used herein, as in “transdermal drug administration” and “transdermal drug delivery systems,” it is to be understood that unless explicitly indicated to the contrary, both “transmucosal” and “topical” administration and systems are intended as well.
“Hydrophobic” polymers and “hydrophilic” polymers are defined herein as suggested by Zaikov et al. (1987), “Diffusion of electrolytes in polymers,” VSP (Utrecht—Tokyo). It is based on the amount of water vapor absorbed by polymers at 100% relative humidity. According to this classification, the hydrophobic polymers absorb only up to 1 wt. % water at 100% relative humidity (“rh”), while the moderately hydrophilic polymer absorbs 1-10% wt. % of water at 100% rh. Hydrophilic polymers are capable of sorbing more than 10 wt. % of water, while hygroscopic polymers sorb more than 20 wt. % of water.
The term “crosslinked” herein refers to a composition containing intramolecular and/or intermolecular crosslinks, whether arising through covalent or noncovalent bonding. “Noncovalent” bonding includes hydrogen bonding, electrostatic (ionic) bonding, and absorption.
The terms “tack” and “tacky” are qualitative. However, the terms “substantially nontacky” “slightly tacky” and “tacky,” as used herein, may be quantified using the values obtained in a PKI or TRBT tack determination method, as follows. By “substantially nontacky” is meant a composition that has a tack value that is less than about 25 g-cm/sec, by “slightly tacky” is meant a composition that has a tack value in the range of about 25 g-cm/sec to about 100 g-cm/sec, and by “tack” is meant a hydrogel that has a tack value of at least 100 g-cm/sec.
Unless otherwise indicated, all molecular weight values given herein are weight average molecular weights.
In a first embodiment, the invention provides a method for obtaining hydrophilic PSAs by mixing a specific amount of a selected hydrophilic polymer with a specific amount of a selected complementary short-chain plasticizer capable of hydrogen bonding to the hydrophilic polymer. Suitable hydrophilic polymers include repeating units derived from an N-vinyl lactam monomer, a carboxy vinyl monomer, a vinyl ester monomer, an ester of a carboxy vinyl monomer, a vinyl amide monomer, and/or a hydroxy vinyl monomer. Such polymers include, by way of example, poly(N-vinyl lactams), poly(N-vinyl acrylamides), poly(N-alkylacrylamides), substituted and unsubstituted acrylic and methacrylic acid polymers, polyvinyl alcohol (PVA), polyvinylamine, copolymers thereof and copolymers with other types of hydrophilic monomers (e.g. vinyl acetate).
Poly(N-vinyl lactams) useful herein are preferably non-crosslinked homopolymers or copolymers of N-vinyl lactam monomer units, with N-vinyl lactam monomer units representing the majority of the total monomeric units of a poly(N-vinyl lactams) copolymer. Preferred poly(N-vinyl lactams) for use in conjunction with the invention are prepared by polymerization of one or more of the following N-vinyl lactam monomers: N-vinyl-2-pyrrolidone; N-vinyl-2-valerolactam; and N-vinyl-2-caprolactam. Nonlimiting examples of non-N-vinyl lactam comonomers useful with N-vinyl lactam monomeric units include N,N-dimethylacrylamide, acrylic acid, methacrylic acid, hydroxyethylmethacrylate, acrylamide, 2-acrylamido-2-methyl-1-propane sulfonic acid or its salt, and vinyl acetate.
Poly (N-alkylacrylamides) include, by way of example, poly(methacrylamide) and poly(N-isopropyl acrylamide) (PNIPAM).
Polymers of carboxy vinyl monomers are typically formed from acrylic acid, methacrylic acid, crotonic acid, isocrotonic acid, itaconic acid and anhydride, a 1,2-dicarboxylic acid such as maleic acid or fumaric acid, maleic anhydride, or mixtures thereof, with preferred hydrophilic polymers within this class including polyacrylic acid and polymethacrylic acid, with polyacrylic acid most preferred.
Preferred hydrophilic polymers herein are the following: poly(N-vinyl lactams), particularly polyvinyl pyrrolidone (PVP) and poly(N-vinyl caprolactam) (PVC); poly(N-vinyl acetamides), particularly polyacetamide per se; polymers of carboxy vinyl monomers, particularly polyacrylic acid and polymethacrylic acid; and copolymers and blends thereof. PVP and PVC are particularly preferred.
The molecular weight of the hydrophilic polymer is not critical; however, the weight average molecular weight of the hydrophilic polymer is generally in the range of approximately 100,000 to 2,000,000, more typically in the range of approximately 500,000 to 1,500,000. The hydrophilic polymer may or may not be adhesive in nature, as a nonadhesive hydrophilic polymer will become adhesive upon admixture with a predetermined quantity of the plasticizing agent.
The complementary short-chain plasticizing agent is terminated with hydroxyl groups, amino or carboxyl groups, and is typically a monomeric or oligomeric material that has a glass transition temperature Tg in the range of about −100° C. to about −30° C. and a melting temperature Tm lower than about 20° C. The plasticizing agent may be also amorphous. The difference between the Tg values of polymer and plasticizer has a decisive significance for the adhesive behavior of the polymer-plasticizer blend. Preferably, the difference is greater than about 50° C., preferably greater than about 100° C., and most preferably in the range of about 150° C. to about 300° C. The hydrophilic polymer and complementary short-chain plasticizer should be compatible, i.e. capable of forming a homogeneous blend that exhibits a single Tg, intermediate between those of the unblended components. Generally, the plasticizing agent will have a molecular weight in the range from about 45 to about 800, preferably in the range of about 45 to about 600. Examples of suitable plasticizing agents include, but are not limited to, low molecular weight polyalcohols (e.g. glycerol), monomeric or oligoalkylene glycols such as ethylene glycol and propylene glycol, ether alcohols (e.g., glycol ethers), alkane diols from butane diol to octane diol includingly, carboxyl-terminated and amino-terminated derivatives of polyalkylene glycols such as polyethylene glycol, and carbonic diacids. Polyalkylene glycols, optionally carboxyl-terminated, are preferred herein, and polyethylene glycol having a molecular weight in the range of about 300 to 600 is an optimal plasticizing agent.
The hydrophilic polymer and plasticizer should be miscible with respect to each other and have disparate chain lengths (as may be deduced from the above). The ratio of the weight average molecular weight of the hydrophilic polymer to that of the short-chain plasticizer should be within about 200 and 200,000, preferably within about 1,250 and 20,000. Also, the polymer and the plasticizer should contain complementary functional groups capable of hydrogen bonding or electrostatic bonding to each other. Ideally, the complementary functional groups of the polymer are located throughout the polymeric structure, while the functional groups of the plasticizer are preferably located at the two termini of a linear molecule, and are not present along the backbone, if the plasticizer is a polymer or an oligomer. Forming hydrogen bonds or ionic bonds between the two terminal functional groups of the plasticizer and the corresponding functional groups contained along the backbone of the hydrophilic polymer results in a noncovalently linked supramolecular network structure outlined in simplified view in FIG. 1. Strong interaction between the complementary groups of the plasticizer and hydrophilic polymer imparts cohesive strength to the network. At the same time, due to the length and flexibility of the plasticizer molecules, they behave as spacers, creating a free volume between cohesively interacting macromolecules of the hydrophilic polymer. In this way, the apparently conflicting performance properties of pressure-sensitive adhesives are both achieved: a liquid-like fluidity needed for adhesive bonding, coupled with a rubber-like resistance to shear deformation necessary to dissipate the detaching energy under adhesive joint failure.
In addition, the plasticizer has been found to decrease the glass transition temperature of the hydrophilic polymer/plasticizer composition to a greater degree than predicted by the Fox equation, which is given by equation (1)
1 T g predicted = w pol T g pol + w pl T g pl ( 1 )
where Tg predicted is the predicted glass transition temperature of the hydrophilic polymer/plasticizer composition, wpol is the weight fraction of the hydrophilic polymer in the composition, wpl is the weight fraction of the plasticizer in the composition, Tg pol is the glass transition temperature of the hydrophilic polymer, and Tg pl is the glass transition temperature of the plasticizer. The inventors herein have now discovered that an adhesive composition having an optimized (e.g., maximized) degree of adhesion can be prepared from a hydrophilic polymer and a complementary plasticizer by selecting the components and their relative amounts to give a predetermined deviation from Tg predicted, even if each component individually is non-tacky. Generally, the predetermined deviation from Tg predicted will be the maximum negative deviation, such that this is the point where adhesive strength is maximized.
That is, the weight ratio of hydrophilic polymer to plasticizer should be of a specified value in order for adhesion to appear in a blend of a non-tacky hydrophilic polymer and a short-chain complementary plasticizer. As FIG. 2 illustrates, in PVP blends with PEG-400 adhesion is inherent only in those compositions that demonstrate negative deviations from the Tg value predicted by the Fox equation (1). The larger the negative deviation, the higher the adhesion. This finding is generally applicable and is not limited to PVP-PEG-400 blends. Preferably, the negative deviation is within the range about 30° C. to about 150° C., preferentially from about 50° C. to about 120° C. The extent of the negative Tg deviation depends on the difference between the Tgs of blend components, i.e., between Tg pol and Tg pl. In general, the negative Tg deviation should be approximately 20-40% of the difference between the Tg values of unblended polymer and plasticizer.
Another general predictor of pressure-sensitive adhesive behavior in polymers is the ΔCpTg product, where ΔCp is the change in heat capacity at the polymer transition point from the glassy to the viscoelastic state. This product features a measure of the amount of heat that has to be expended in order to provide the polymer transition from the glassy to the viscoelastic state and to impart translational mobility to polymeric segments. As PVP mixing with PEG-400 occurs, the ΔCpTg product decreases, passing through a minimum that corresponds to the maximum in blend adhesion (FIG. 3). It is the product ΔCpTg which sets the PSAs apart from non-adhesive polymers (Table 1). The ΔCpTg values, which are associated with the adhesive PVP-PEG blends and hydrophobic PSA's (PDMS, PIB and natural rubber), are notably grouped within a narrow area ranging from 45.0 to 92.0 J/g, predominantly near 65-80 J/g. Non-adhesive polymers exhibit higher ΔCpTg values.
TABLE 1
Glass transition characteristics of representative polymers.
ΔCpTg
Polymer Tg, K ΔCp, J/gK J/g
Polydimethylsiloxane
150 0.30 45.0
Polyisobuthylene 200 0.40 79.6
Natural rubber 200 0.46 92.0
Polyethylene 237 0.39 92.5
PEG-400 200 0.51 101.4
Bisphenol polycarbonate 415 0.25 103.9
Polymethyl methacrylate 385 0.29 112.8
Poly(N-vinyl pyrrolidone) 449 0.27 121.2
Polypropylene 253 0.55 139.2
Polystyrene 375 0.38 141.0
Polyvinyl acetate 305 0.50 153.4
Polyethylene terephthalate 340 0.49 165.7
Polyvinyl chloride 355 0.63 229.9
The ΔCpTg value outlines a subtle balance between free volume and cohesive interactions energy in polymers (Feldstein et al. (1999), Polym Mater. Sci. Eng. 81:467-468). In general, the enhanced free volume has to be counterbalanced by a high attractive interaction energy in order for adhesion to appear. Enhanced free volume results in high molecular mobility and liquid-like fluidity of a PSA polymer, whereas substantial cohesive interaction energy provides cohesive toughness and rubber-like resistance to flow. As the actual glass transition temperature Tg actual for the present adhesive compositions will generally be substantially lower than that predicted by the Fox equation, particularly since the composition of preferred adhesives herein is selected to correspond to the maximum negative deviation of Tg actual from Tg predicted, the heat required to transform a glassy polymer blend to a viscoelastic composition is minimal.
When reduced to the most basic molecular level, all performance properties of polymeric materials are interrelated through the structure and interaction of the involved macromolecules. This is also the case for the interrelationship between the diffusivity and tack of pressure-sensitive adhesives. As has been recently shown (Feldstein et al. (2000), Proceed. 23rd Annual Meeting Adhesion Soc., pp. 54-56), with a cohesive type of adhesive debonding (which is typical of various PSA polymers and polymeric blends) the peel force P necessary to rupture the adhesive bond, P, relates to a self-diffusion coefficient of a PSA polymer segment, D, by equation (2):
P = b · l a · N · τ · D 12 RT σ f 2 ( 2 )
where b is the width and l the thickness of the adhesive layer, a is a size of diffusing polymer segment, N is Avogadro's number, τ is a segmental relaxation time and σf is a critical stress at adhesive polymer fracture under detaching tensile force. Equation (2) establishes a general relation of adhesive strength to the measures of molecular mobility (D) and cohesive toughness (σf) of PSA polymer.
While not wishing to be bound by theory, the inventors herein believe that equation (2) explains why adhesion goes through a maximum upon mixing a hydrophilic polymer with a short-chain plasticizer bearing complementary reactive functional groups at the chain ends. Forming hydrogen or electrostatic bonds through both terminal groups of the plasticizer provides noncovalent crosslinking of the hydrophilic polymer chains into a supramolecular network structure of a polymer blend. Due to the considerable length and flexibility of plasticizer chains, the network structure provides enhanced free volume and molecular mobility coupled with high cohesive strength, i.e. the properties governing the adhesive behavior of polymer blends. With the increase in plasticizer concentration the molecular mobility (D) increases, whereas the cohesive strength (σf) follows the opposite pattern. For this reason, lower ratios (i.e., a lower relative amount of hydrophilic polymer) results in a liquid or semi-liquid composition, while higher ratios (i.e., a higher relative amount of hydrophilic polymer) gives a rise to a high cohesive strength material. High cohesive strength can in turn cause a deterioration in mechanical properties and, with drug delivery systems, can also lower the rate of drug release.
As is evident from the data in FIG. 4, water absorption causes opposite effects on the adhesion of blends of hydrophilic polymers underloaded with a short-chain telechelic plasticizer (27.3%) and overloaded with such plasticizer (45.8 and 52.9%). Water vapour absorption is associated with a significant plasticizing action of water as reflected by a significant reduction in glass transition temperature of hydrophilic polymer. The left-hand (ascending) branch of the curves in FIG. 3 correspond to compositions in the immediate vicinity of the glass transition, and water behaves there as a plasticizer by promoting the transition of the PSA into a viscoelastic state and enhancing adhesion. By contrast, for rubbery blends in the right-hand (descending) branches of the plot, water serves as a cosolvent and contributes to the reduction of adhesive toughness by decreasing the cohesive strength of hydrogels (equation (2)). In this way, by varying the ratio of the plasticizer to the hydrophilic polymer, a composition may be transformed from bioadhesive to pressure-sensitive adhesive.
The PVP-PEG system is considered here as a model, but it is to be understood that the invention is not limited in this regard, and a number of hydrophilic polymers and plasticizers may be substituted for PVP and PEG, respectively. The broad applicability of the invention results primarily from the properties of the plasticizers rather than those of the hydrophilic polymers. This fundamental conclusion has also a theoretical confirmation. As is evident from Examples 1-67, a specific type of compositional behavior of the blend Tg, outlined by both the negative deviations from the weight-average magnitudes obtained with the Fox equation (1), −ATg, and the ΔCpTg quantity, is a factor controlling adhesion. Over the years, numerous equations have been proposed to express the Tg-composition dependence of miscible polymer blends and plasticized systems (see Aubin (1988), Prud'homme R. E. “Analysis of the glass transition temperature of miscible polymer blends,” Macromolecules 21:2945-2949). In general, it is observed, that Tg varies monotonically as a function of composition demonstrating a rapid initial reduction followed by a gradual leveling off the response as a plasticizer is added. The difference between measured Tg values and those predicted with relevant equations is usually considered a measure of the strength of interactions between molecules of the involved components. The Kovacs equation (3) holds if the difference in Tg between the glass transition temperature of a PEG plasticizer component and the glass transition temperature of a PVP polymer (and between any miscible hydrophilic polymer and complementary plasticizer) is larger than about 50° C.:
T g = T gPEC + f gPVP Δ α PEG · ϕ PVP ϕ PEG ( 3 )
where ƒg is the fractional free volume of PVP at Tg, Δα is the thermal expansion coefficient for PEG and φ is polymer volume fraction in the blend. The ƒg factor has been found to be of the same universal magnitude, about 0.025, for all polymers (see Ferry (1970). Viscoelastic Properties of Polymers, 2nd Ed., Wiley: N.Y., Chapter 11). The Kovacs equation (3) manifests theoretically that the specific behavior of a PVP-PEG system is due to the PEG properties. Actually, no other factors relating to PVP, except for the universal ƒg value (which, again, is of a common magnitude for different polymers), control the blend Tg. Thus, the validity of the Kovacs equation for the PVP-PEG system implies that the difference between the Tgs of a hydrophilic polymer and a short-chain complementary plasticizer should be larger than 50° C. in order for pressure-sensitive adhesion to appear upon blending the polymer and plasticizer.
Equation (3) indicates also that for every given short-chain telechelic plasticizer, the blend composition that corresponds to the maximum negative deviation in Tg actual from Tg predicted and, consequently, to the maximum adhesion, is practically unaffected by the structure of the higher-Tg hydrophilic complementary polymer. In other words, if the highest degree of adhesive strength appears in PVP-PEG blends at a PEG concentration of 36 wt. %, PEG blends with other complementary hydrophilic polymers will also exhibit the maximum degree of adhesion in vicinity of 36 wt. % plasticizer, providing that the Tg of the hydrophilic polymer is more than 50° C. higher than the Tg of the plasticizer.
The hydrophilic polymer and the plasticizing agent are blended in a ratio designed to optimize adhesive and cohesive strength as well as hydrophilicity and thus, in drug delivery systems, the kinetics of drug delivery. The ratio is as discussed above, i.e., a preferred weight ratio of hydrophilic polymer to plasticizer should be in the range defined by the maximum values of the negative Tg deviations from the weight-average magnitudes calculated using the Fox equation (1) or outlined by the minimum values of the ΔCpTg criterion (FIGS. 2 and 3).
The free volume and cohesive energy of polymer compositions have to be in a specified ratio in order for a composition to exhibit pressure-sensitive adhesion. See Feldstein et al. (1999), “Quantitative relationship between molecular structure and adhesion of PVP-PEG hydrogels,” Polym. Mater. Sci. Eng. 81:465-466; Feldstein et al. (1999), “Contribution of molecular mobility to debonding of pressure sensitive adhesive hydrogels,” Polym. Mater. Sci. Eng. 81:465-466; Feldstein et al. (1999), “A structure—property relationship and quantitative approach to the development of universal transdermal drug delivery system,” in: T. Sohn and V. A. Voicu (eds.), NBC (Nuclear, Biological, and Chemical) Risks—Current Capabilities and Future Perspectives for Protection, Kluwer Academic Publishers, NATO Science Series: 1. Disarmament Technologies, vol. 25, Dordrecht-Boston-London, (1999), pp. 441-458; and Feldstein et al. (2000), “Molecular insight into Theological and diffusion determinants of pressure sensitive adhesion,” Proceed. 23rd Annual Meeting Adhesion Soc. 2000, pp. 54-56.
Generally, for high adhesion, substantial cohesive interactions have to be counterbalanced by a large free volume. The energy of cohesive interactions in adhesive gels is controlled by both the hydrophilic polymer/short-chain plasticizer ratio and the crosslinker/hydrophilic polymer ratio. As a measure of adhesion, the durability of adhesive joints under fixed detaching force, t* (sec), may be employed, using a squeeze-recoil test described by Kotomin et al. (2000), “Durability and fracture of some viscoelastic adhesives,” Proceed. 23rd Annual Meeting Adhesion Soc., pp. 413-415. A longer period of durability indicates a higher degree of adhesion in terms of a conventional peel test.
The composition may or may not be hydrated, depending on the desired use. For example, transdermal and transmucosal drug delivery systems will generally contain zero to about 7 wt. % water, while products such as facial masks, electroconductive adhesive products, cosmeceutical products, topical pharmaceutical formulations, and other products in which a gel type adhesive (i.e., a hydrogel adhesive) is desired, will generally contain about 7 wt. % to about 40 wt. % water. The optimum degree of hydration depends on the nature and hygroscopic of the hydrophilic polymer and the short-chain plasticizer. For example, an optimum PVP-PEG-400 system for most uses will contain from 2 to 20 wt. % of residual water, preferably from 2 to 12 wt. % water, most preferably between 6 and 10 wt. % water. It will be appreciated that the rise in plasticizer hygrosopicity with the decrease in PEG chain length leads to an increase in the degree of optimum hydration, whereas the replacement of highly hygrosopic PVP with less hygrosopic PVCap results in the decrease of hydration providing best adhesion. However, some hydration will occur upon application of the adhesive composition to skin or other body surface. In some cases, it may be desirable to add water or an organic solvent such as ethanol to the adhesive composition prior to use, so as to generate a hydrogel. A hydrogel may be advantageous in a number of contexts.
The compositions are self-adhesive and normally do not require the addition of tackifiers. However, other additives may be incorporated into the present adhesive compositions, so long as they are not detrimental to the composition in any way. For example, the following optional components are often present in adhesive formulations and are presented here for illustrative purposes only and are not meant to limit the adhesive compositions in any way. These optional components include including fillers, chain transfer agents for controlling molecular weight (e.g., carbon tetrabromide, mercaptans, or alcohols), pigments, dyes, refractive particles, preservatives, stabilizers, toughening agents, anti-microbial agents (e.g., mercurochrome, silver sulfadiazine, povidine iodine, iodine), cosmetic agents (e.g., glycerine, urea, allantoin, sulfur, anthraquinone, hydroquinones), moisturizers, humectants, anesthetics (e.g., benzocaine), healing agents (e.g., collagen), and the like. Insoluble fibrous fillers may be advantageously incorporated to control the degree of hydration when the adhesive is on the skin or other body surface. Such fillers can include cellulosic materials as described in International Patent Publication No. WO 89/03859, e.g., woven and non-woven paper and cotton materials. Other suitable fillers are inert, i.e., substantially non-adsorbent, and include, for example, polyethylenes, polypropylenes, polyurethane polyether amid copolymers, polyesters and polyester copolymers, nylon and rayon. These additives, and amounts thereof, are selected in such a way that they do not significantly interfere with polymerization, crosslinking or the desired chemical and physical properties of the final adhesive.
The adhesive compositions may be rendered electrically conductive for use in biomedical electrodes and other electrotherapy contexts, i.e., to attach an electrode or other electrically conductive member to the body surface. For example, the adhesive compositions may be used to attach a transcutaneous nerve stimulation electrode, an electrosurgical return electrode, or an EKG electrode to a patient's skin or mucosal tissue. Generally, these applications involve modification of the adhesive composition so as to contain a conductive species, thereby rendering the adhesive composition as a whole conductive. Suitable conductive species include the ionically conductive electrolytes that are commonly used for application to the skin or other body surface, and include ionizable inorganic salts, organic compounds, or combinations of both. Examples of ionically conductive electrolytes include, but are not limited to, ammonium sulfate, ammonium acetate, monoethanolamine acetate, diethanolamine acetate, sodium lactate, sodium citrate, magnesium acetate, magnesium sulfate, sodium acetate, calcium chloride, magnesium chloride, calcium sulfate, lithium chloride, lithium perchlorate, sodium citrate and potassium chloride, and redox couples such as a mixture of ferric and ferrous salts such as sulfates and gluconates. Preferred salts are potassium chloride, sodium chloride, magnesium sulfate, and magnesium acetate, and potassium chloride is most preferred for EKG applications. Although virtually any amount of electrolyte may be present in the adhesive compositions of the invention, it is preferable that any water-soluble electrolyte be present at a concentration in the range of about 0.1 to about 15 wt % of the mixture. The procedure described in U.S. Pat. No. 5,846,558 to Nielsen et al. for fabricating biomedical electrodes may be adapted for use with the adhesive compositions of the invention, and the disclosure of that patent is incorporated by reference with respect to manufacturing details. Other suitable fabrication procedures may be used as well, as will be appreciated by those skilled in the art.
For certain applications, particularly when high cohesive strength is desired, the adhesive composition should be covalently crosslinked. The hydrophilic polymer may be covalently crosslinked, either intramolecularly or intermolecularly, and/or the hydrophilic polymer and the plasticizer may be covalently crosslinked. In the former case, there are no covalent bonds linking the hydrophilic polymer to the plasticizer, while in the latter case, there are covalent crosslinks binding the hydrophilic polymer to the plasticizer. The hydrophilic polymer, or the hydrophilic polymer and the plasticizer, may be covalently crosslinked using heat, radiation, or a chemical curing (crosslinking) agent.
For thermal crosslinking of the adhesive composition, a free radical polymerization initiator should be added into the polymer blend, i.e., the admixture of the hydrophilic polymer and the plasticizer. The free radical polymerization initiator can be any of the known free radical-generating initiators conventionally used in vinyl polymerization and is preferably an organic peroxide or azo compound. The initiators can be used in conventional amounts, generally from 0.01 to 15%, preferably 0.05 to 10%, more preferably from about 0.1% to about 5% and especially from a out 0.5% to about 4% by weight of the polymerisable material. Suitable organic peroxides include dialkyl peroxides such as t-butyl peroxide and 2,2 bis(t-butylperoxy)propane, diacyl peroxides such as benzoyl peroxide and acetyl peroxide, peresters such as t-butyl perbenzoate and t-butyl per-2-ethylhexanoate, perdicarbonates such as dicetyl peroxy dicarbonate and dicyclohexyl peroxy dicarbonate, ketone peroxides such as cyclohexanone peroxide and methylethylketone peroxide, and hydroperoxides such as cumene hydroperoxide and tert.butyl hydroperoxide. Suitable azo compounds include azo bis (isobutyronitrile) and azo bis (2,4-dimethylvaleronitrile). The temperature and thermally crosslink the adhesive composition will depend on the actual components and may be readily deduced by one of ordinary skill in the art, but typically ranges from about 80° C. to about 200° C.
The hydrophilic polymer, or the hydrophilic polymer and the plasticizer, may also be crosslinked with radiation, typically in the presence of a photoinitator. The radiation may be ultraviolet, alpha, beta, gamma, electron beam, and x-ray radiation, although ultraviolet radiation is preferred. Useful photosensitizers are triplet sensitizers of the “hydrogen abstraction” type, and include benzophenone and substituted benzophenone and acetophenones such as benzyl dimethyl ketal, 4-acryloxybenzophenone (ABP), 1-hydroxy-cyclohexyl phenyl ketone, 2,2-diethoxyacetophenone and 2,2-dimethoxy-2-phenylacetophenone, substituted alpha-ketols such as 2-methyl-2-hydroxypropiophenone, benzoin ethers such as benzoin methyl ether and benzoin isopropyl ether, substituted benzoin ethers such as anisoin methyl ether, aromatic sulfonyl chlorides such as 2-naphthalene sulfonyl chloride, photoactive oximes such as 1-phenyl-1,2-propanedione-2-(O-ethoxy-carbonyl)-oxime, thioxanthones including alkyl- and halogen-substituted thioxanthonse such as 2-isopropylthioxanthone, 2-chlorothioxanthone, 2,4 dimethyl thioxanone, 2,4 dichlorothioxanone, and 2,4-diethyl thioxanone, and acyl phosphine oxides. Radiation having a wavelength of 200 to 800 nm, preferably, 200 to 500 nm, is preferred for use herein, and low intensity ultraviolet light is sufficient to induce crosslinking in most cases. However, with photosensitizers of the hydrogen abstraction type, higher intensity UV exposure may be necessary to achieve sufficient crosslinking. Such exposure can be provided by a mercury lamp processor such as those available from PPG, Fusion, Xenon, and others. Crosslinking may also be induced by irradiating with gamma radiation or an electron beam. Appropriate irradiation parameters, i.e., the type and dose of radiation used to effect crosslinking, will be apparent to those skilled in the art.
Suitable chemical curing agents, also referred to as chemical cross-linking “promoters,” include, without limitation, polymercaptans such as 2,2-dimercapto diethylether, dipentaerythritol hexa(3-mercaptopropionate), ethylene bis(3-mercaptoacetate), pentaerythritol tetra(3-mercaptopropionate), pentaerythritol tetrathioglycolate, polyethylene glycol dimercaptoacetate, polyethylene glycol di(3-mercaptopropionate), trimethylolethane tri(3-mercaptopropionate), trimethylolethane trithioglycolate, trimethylolpropane tri(3-mercaptopropionate), trimethylolpropane trithioglycolate, dithioethane, di- or trithiopropane and 1,6-hexane dithiol. The crosslinking promoter is added to the uncrosslinked hydrophilic polymer to promote covalent crosslinking thereof, or to a blend of the uncrosslinked hydrophilic polymer and the plasticizer, to provide crosslinking between the two components.
The hydrophilic polymer may also be crosslinked prior to admixture with the plasticizer. In such a case, it may be preferred to synthesize the polymer in crosslinked form, by admixing a monomeric precursor to the polymer with multifunctional comonomer and copolymerizing. Examples of monomeric precursors and corresponding polymeric products are as follows: N-vinyl amide precursors for a poly(N-vinyl amide) product; N-alkylacrylamides for a poly(N-alkylacrylamide) product; acrylic acid for a polyacrylic acid product; methacrylic acid for a polymethacrylic acid product; acrylonitrile for a poly(acrylonitrile) product; and N-vinyl pyrrolidone (NVP) for a polyviny lpyrrolidone product. Polymerization may be carried out in bulk, in suspension, in solution, or in an emulsion. Solution polymerization is preferred, and polar organic solvents such as ethyl acetate and lower alkanols (e.g., ethanol, isopropyl alcohol, etc.) are particularly preferred. For preparation of hydrophilic vinyl polymers, synthesis will typically take place via a free radical polymerization process in the presence of a free radical initiator as described above. The multifunctional comonomer include, for example, bisacrylamide, acrylic or methacrylic esters of diols such as butanediol and hexanediol (1,6-hexane diol diacrylate is preferred), other acrylates such as pentaerythritol tetraacrylate, and 1,2-ethylene glycol diacrylate, and 1,12-dodecanediol diacrylate. Other useful multifunctional crosslinking monomers include oligomeric and polymeric multifunctional (meth)acrylates, e.g., poly(ethylene oxide) diacrylate or poly(ethylene oxide) dimethacrylate; polyvinylic crosslinking agents such as substituted and unsubstituted divinylbenzene; and difunctional urethane acrylates such as EBECRYL® 270 and EBECRYL® 230 (1500 weight average molecular weight and 5000 weight average molecular weight acrylated urethanes, respectively—both available from UCB of Smyrna, Ga.), and combinations thereof. If a chemical crosslinking agent is employed, the amount used will preferably be such that the weight ratio of crosslinking agent to hydrophilic polymer is in the range of about 1:100 to 1:5. To achieve a higher crosslink density, if desired, chemical crosslinking is combined with radiation curing.
The adhesive compositions of the invention are extrudable, and thus may be prepared using a simple blending and extruding process. The components of the composition are weighed out and then admixed, for example using a Baker Perkins Blender, generally although not necessarily at an elevated temperature, e.g., about 35° C. to about 90° C. Solvents may, if desired, be added. Preferred solvents are aqueous solvents or alcohols (e.g., ethanol, methanol, isopropanol, etc.). Any crosslinking is carried out subsequently. The resulting composition can be extruded using a single or twin extruder, or pelletized.
In the manufacture of transdermal (or transmucosal) drug delivery system, the adhesive composition may be prepared or extruded onto the backing layer or release liner of such a system. That is, such drug delivery systems generally comprise: (A) a drug reservoir containing a therapeutically effective amount of the active agent; (B) an adhesive means for maintaining the system in active agent transmitting relationship to a body surface; and (C) a backing layer that serves as the outer surface of the device during use, wherein (D) a release liner generally covers the exposed adhesive during storage and prior to use.
Any number of active agents can be administered using the drug delivery systems of the invention. Suitable active agents include the broad classes of compounds normally delivered through body surfaces and membranes; these active agents, in general, include: analeptic agents; analgesic agents; anesthetic agents; antiarthritic agents; respiratory drugs, including antiasthmatic agents; anticancer agents, including antineoplastic drugs; anticholinergics; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antihelminthics; antihistamines; antihyperlipidemic agents; antihypertensive agents; anti-infective agents such as antibiotics and antiviral agents; antiinflammatory agents; anti-migraine preparations; antinauseants; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics; antispasmodics; antitubercular agents; antiulcer agents; antiviral agents; anxiolytics; appetite suppressants; attention deficit disorder (“ADD”) and attention deficit hyperactivity disorder (“ADHD”) drugs; cardiovascular preparations including calcium channel blockers, antianginal agents, central nervous system (“CNS”) agents, beta-blockers and antiarrhythmic agents; central nervous system stimulants; cough and cold preparations, including decongestants; diuretics; genetic materials; herbal remedies; hormonolytics; hypnotics; hypoglycemic agents; immunosuppressive agents; leukotriene inhibitors; mitotic inhibitors; muscle relaxants; narcotic antagonists; nicotine; nutritional agents, such as vitamins, essential amino acids and fatty acids; ophthalmic drugs such as antiglaucoma agents; parasympatholytics; peptide drugs; psychostimulants; sedatives; steroids, including progestogens, estrogens, corticosteroids, androgens and anabolic agents; smoking cessation agents; sympathomimetics; tranquilizers; and vasodilators including general coronary, peripheral and cerebral. Specific active agents with which the present adhesive compositions are useful include, without limitation, anabasine, capsaicin, isosorbide dinitrate, aminostigmine, glyceryl trinitrate, verapamil, propranolol, silabolin, foridone, clonidine, cytisine, phenazepam, nifedipine, fluacizin, and salbutamol.
With some active agents, it may be necessary to administer the drug along with a permeation enhancer in order to achieve a therapeutically effective flux through the skin. Suitable enhancers include, for example, the following: sulfoxides such as dimethylsulfoxide (DMSO) and decylmethylsulfoxide (C10MSO); ethers such as diethylene glycol monoethyl ether (available commercially as Transcutol®) and diethylene glycol monomethyl ether; surfactants such as sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer (231, 182, 184), Tween (20, 40, 60, 80) and lecithin (U.S. Pat. No. 4,783,450); the 1-substituted azacycloheptan-2-ones, particularly 1-n-dodecylcyclazacycloheptan-2-one (available under the trademark Azone® from Nelson Research & Development Co., Irvine, Calif.; see U.S. Pat. Nos. 3,989,816, 4,316,893, 4,405,616 and 4,557,934); alcohols such as ethanol, propanol, octanol, decanol, benzyl alcohol, and the like; fatty acids such as lauric acid, oleic acid and valeric acid; fatty acid esters such as isopropyl myristate, isopropyl palmitate, methylpropionate, and ethyl oleate; polyols and esters thereof such as propylene glycol, ethylene glycol, glycerol, butanediol, polyethylene glycol, and polyethylene glycol monolaurate (“PEGML”; see, e.g., U.S. Pat. No. 4,568,343); amides and other nitrogenous compounds such as urea, dimethylacetamide (DMA), dimethylformamide (DMF), 2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanolamine, diethanolamine and triethanolamine; terpenes; alkanones; and organic acids, particularly salicylic acid and salicylates, citric acid and succinic acid. Mixtures of two or more enhancers may also be used. A preferred enhancer is ethanol, which not only serves as a permeation enhancer, but also solubilizes many active agents of interest and in addition improves adhesion. An ethanol-water mixture may also be used. It is pertinent to note, that a range of above mentioned skin permeability enhancers serves concomitantly in the adhesive composition as appropriate plasticizing agents, e.g. polyols such as propylene glycol, ethylene glycol, glycerol, butanediol, hexanediol and polyethylene glycol.
The backing layer of the transdermal drug delivery device functions as the primary structural element of the transdermal system and provides the device with flexibility, drape and, optionally, occlusivity. The material used for the backing layer should be inert and incapable of absorbing drug, enhancer or other components of the pharmaceutical composition contained within the device. The material used for the backing layer should permit the device to follow the contours of the skin and be worn comfortably on areas of skin such as at joints or other points of flexure, that are normally subjected to mechanical strain with little or no likelihood of the device disengaging from the skin due to differences in the flexibility or resiliency of the skin and the device. Examples of materials useful for the backing layer are polyesters, polyethylene, polypropylene, polyurethanes and polyether amides. The layer is preferably in the range of about 15 microns to about 250 microns in thickness, and may, if desired, be pigmented, metallized, or provided with a matte finish suitable for writing. The layer is preferably nonocclusive (or “breathable”), i.e., is preferably permeable to moisture.
During storage and prior to use, the laminated structure includes a release liner. Immediately prior to use, this layer is removed from the device so that the system may be affixed to the skin. The release liner should be made from a drug/vehicle impermeable material, and is a disposable element which serves only to protect the device prior to application. Typically, the release liner is formed from a material impermeable to the components of the device and the pharmaceutical composition contained therein.
Additional layers, e.g., intermediate fabric layers and/or rate-controlling membranes, may also be present in any of these drug delivery systems. Fabric layers may be used to facilitate fabrication of the device, while a rate-controlling membrane may be used to control the rate at which a component permeates out of the device. The component may be a drug, a permeation enhancer, or some other component contained in the drug delivery system.
In any of these transdermal systems, it may be desirable to include a rate-controlling membrane in the system on the skin side of the drug reservoir. The materials used to form such a membrane are selected to limit the flux of one or more components contained in the drug formulation, and the membrane may be either microporous or dense. Representative materials useful for forming rate-controlling membranes include polyolefins such as polyethylene and polypropylene, polyamides, polyesters, ethylene-ethacrylate copolymer, ethylene-vinyl acetate copolymer, ethylene-vinyl methylacetate copolymer, ethylene-vinyl ethylacetate copolymer, ethylene-vinyl propylacetate copolymer, polyisoprene, polyacrylonitrile, ethylene-propylene copolymer, polysiloxane-polycarbonate block copolymer and the like.
The adhesive compositions of the invention are useful in any number of additional contexts wherein adhesion of a product to a body surface is called for or desirable. These applications include, for example, pressure-relieving cushions for application to a foot, wherein the cushions may or may not contain medication for transdermal or topical delivery, e.g., salicylic acid or the like. Such cushions will generally be comprised of a flexible, resilient outer layer, fabricated from a foam pad, fabric, or the like, with a layer of an adhesive composition of the invention laminated thereto for application to the skin surface. In this embodiment, cohesive strength is important for the product to function as a pressure-relieving cushion, and the hydrophilic polymer should therefore be covalently crosslinked to a degree sufficient to impart the necessary cohesive strength.
Another application of the present adhesives is in wound dressing products and other medical skin coverings such as adhesive tapes or the like. Such adhesive compositions may or may not be medicated; if medicated, they will generally contain anti-infective agents and/or other types of pharmacologically active agents. Medical skin coverings such as adhesive tapes and wound dressings may be readily fabricated using conventional manufacturing techniques, including the procedure described in U.S. Pat. No. 5,985,990, the disclosure of which is incorporated by reference herein.
The adhesive compositions are also useful in conjunction with medical devices to be affixed to a body surface, diagnostic systems or devices to be affixed to a body surface, and any other application wherein adhesion to a body surface is necessary or desired.
Accordingly, the present invention represents an important advance in the field of pressure sensitive adhesives, particularly bioadhesives. The novel adhesive compositions adhere well to hydrated surfaces such as mucosal tissue, are suitable for long-term skin contact and are nonirritating, noncomedogenic and nonsensitizing, are permeable to and physically and chemically compatible with a variety of drugs and drug types, and can enhance the rate at which an active agent migrates into a body surface. Furthermore, the present adhesive composition can be used in a variety of contexts, and can be readily tailored during manufacture with respect to hygroscopicity and the desired degree of hydrophilicity, adhesive and cohesive strength.
The practice of the present invention will employ, unless otherwise indicated, conventional techniques of drug delivery and associated manufacturing techniques, which are within the skill of the art. Such techniques are fully explained in the literature. See Remington: The Science and Practice of Pharmacy, cited supra, as well as Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th Ed. (New York: McGraw-Hill, 1996).
It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, the foregoing description, as well as the examples which follow, are intended to illustrate and not limit the scope of the invention. Other aspects, advantages and modifications will be apparent to those skilled in the art to which the invention pertains. All patents, patent applications, journal articles and other references cited herein are incorporated by reference in their entireties.
The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the compounds of the invention, and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.) but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in ° C. and pressure is at or near atmospheric.
EXAMPLES 1-16 Preparation of PSA Matrices by Blending PVP and PEG400: Effects of Composition, Hydration and the Thickness of Adhesive Layer
Adhesive films of 250-300 μm in thickness were prepared by dissolving hydrophilic polymers and PEG (Mw=400) in a common solvent (ethyl alcohol) followed by casting the solution on a backing film and drying. Unsupported PVP-PEG hydrogels were obtained by casting the relevant solutions onto release liner followed by drying at ambient temperature.
Adhesive joint strength of the adhesive hydrogels to standard polyethylene (PE) film of 100 m in thickness was evaluated by a 180° peel test with an Instron 1221 Tensile Strength Tester at the peeling rate of 10 mm/min. A low-density PE film, crystallinity 45%, contact angle 105°, surface energy 28.5 mJ/m2, was employed as a standard substrate. The adhesives were saturated with water by equilibrating in dessicators with a controlled pressure of water vapor of 50% at ambient temperature for 6-7 days. The time to attain a maximum strength of adhesive contact with the substrate was 15-20 min. The character of adhesive joint failure was observed with a TV camera interfaced to an IBM computer and photographed with a microscope. The locus of failure was ascertained by contact angle measurement of the detached substrate surface.
Phase behavior of the hydrophilic polymers blends with PEG-400 over an entire compositional range was investigated by Differential Scanning Calorimetry (DSC) using a Mettler TA 4000/DSC-30 differential scanning calorimeter calibrated with indium and gallium. In the DSC apparatus, the samples were first quench cooled with liquid nitrogen from ambient temperature to −100° C. over 2-3 minutes and then heated at a rate of 20° C. min−1 to 220° C. Upon heating, a heat capacity jump followed by a single exotherm coupled with a symmetric endotherm, and a high temperature endotherm, were normally observed for the blends. These four transitions were respectively attributed to glass transition, PEG cold crystallization, melting, and water thermodesorption (see Feldstein et al. (2000), “Coherence of thermal transitions in poly(N-vinyl pyrrolidone)-poly (ethylene glycol) compatible blends,” Polymer 41(14):5327-5359). The glass transition temperatures, Tg, were recorded at half-height of the relevant heat capacity jumps in DSC heating thermograms. All reported values are the average of replicate experiments varying less than 1-2%. Samples of 5-15 mg in weight were sealed in standard aluminum pans supplied with pierced lids so that absorbed moisture could evaporate upon heating. An argon purge (50 mL min−1) was used to avoid moisture condensation at the sensor. The content of absorbed water in the blends was determined by weighing the samples before and after DSC scans using a Mettler Analytical Balance, AE 240, with an accuracy of ±0.01 mg. Weight loss of the sample after scanning was compared to the amount of desorbed water evaluated from the enthalpy change associated with water evaporation from the sample by DSC.
Water vapor sorption: Adhesive films were equilibrated at room temperature in desiccators over aqueous H2SO4 solutions of controlled density which maintained the required relative humidity ranged from 10 to 90%. Equilibrium water sorption was measured gravimetrically and confirmed with a vacuum assembly containing a quartz-spring microbalance.
Viscoelastic properties and the durability of adhesive joints of adhesive hydrogels were studied using a squeeze-recoil technique on a DTDM thermomechanical analyzer (microdilatometer) as described by Kotomin et al. (1999), “Squeeze-recoil analysis of adhesive hydrogels and elastomers” Polym Mater. Sci. Eng. 81:425-426 and Kotomin et al. (2000), “Durability and fracture of some viscoelastic adhesives” Proceed. 23rd Adhesion Soc. Annual Meeting, Myrtle Beach, S.C., pp. 413-415. The polymer sample was placed between two flat silica surfaces formed by loading rod and supporting plate and subjected to the action of a fixed compressive load, followed by removing the compressive load to allow the sample relaxation.
Table 2 reports the properties of PVP adhesive blends with PEG-400. Examples 1-4 and FIGS. 2 and 3 demonstrate the effect of PVP-PEG blend composition on adhesive properties. The relationship of adhesion to the phase behavior of PVP-PEG blends is also shown, described in terms of the negative Tg deviation from the weight-average magnitudes (−ΔTg), found with the Fox equation (1), and the ΔCpTg value. In the PVP-PEG blends, the adhesion appears in a narrow range of concentration. The maximum adhesion corresponds to the maximum −ΔTg values and to the minimum ΔCpTg value. While not wishing to be bound by theory, the implication of the former finding would appear to be that the adhesion is provided by the formation of a stoichiometric hydrogen-bonded network PVP-PEG complex. This conclusion can be established by a comparison of the compositional profile of adhesion with the data on PVP-PEG hydrogen bonding presented in Feldstein et al. (2001), “Relation of glass transition temperature to the hydrogen bonding degree and energy in poly(N-vinyl pyrrolidone) blends with hydroxyl-containing plasticizers: 2. Effects of poly (ethylene-glycol) chain length,” Polymer 42:981-990. The latter observation implies that the adhesion is controlled by a specific counterbalance of enhanced free volume against the strong favorable interaction between blended components: high molecular weight PVP and short-chain PEG macromolecules, bearing reactive groups at both chain ends (Feldstein et al. (1999), “Contribution of molecular mobility to debonding of pressure-sensitive adhesive hydrogels,” Polym Mater. Sci. Eng. 81:467-468).
Examples 1, 5-9 and FIG. 4 reveal the impact of relative humidity (RH) of the surrounding atmosphere on the adhesive behavior of PVP-PEG blends. PVP is a hygroscopic polymer that absorbs more than 25% water upon exposure to a high RH (FIG. 9). With PVP-overloaded blends, having higher glass transition temperatures, where debonding proceeds through an adhesive mechanism, the blend hydration increased the force required to rupture adhesive bond. In contrast, with PEG-overloaded, plasticized blends, the effect of additional plasticizer reduces the adhesion. As a result of enhanced fluidity and decreased cohesive strength of the hydrophilic composite, an adhesive remainder occurs at the substrate interface upon adhesive joint failure (Table 1).
Examples 1, 10 and 11 exhibit the effects of the chain length of the hydrophilic polymer (PVP) on adhesive joint strength. In general, peel strength of an adhesive joint tended to decrease with the reduction of molecular weight. Examples 12-16 demonstrate the impact of adhesive layer thickness upon adhesive joint strength. In accordance with Equation 2, the peel force required to rupture an adhesive joints was found to increase with the increase in thickness of the adhesive layer.
TABLE 2
Adhesive properties and phase behavior of PVP blends with PEG-400/
PVP Composition, wt % RH, Thickness −ΔTg, ΔCpTg, Peel Debonding
No. MW PVP PEG-400 % (μm) K J/g Force, N/m mode
1. 1,000,000 64 36 50 130 71 46.2 370 misc.
2. 73 27 39 119.0 83 adhesive
3. 54 46 65.2 92.6 95 cohesive
a. 47 53 37.2 77.2 64 cohesive
5. 64 36 20 130 69 30 adhesive
6. 40 73 90 adhesive
7. 65 70.5 59.1 330 cohesive
8. 80 66.2 42 cohesive
9. 90 77 96.0 cohesive
10. 150,000 64 36 50 130 82.0 15 cohesive
11. 8,000 87.5 0 cohesive
12. 1,000,000 64 36 50 250 390 misc.
13. 175 390 misc.
14. 119 330 adhesive
15. 70 210 adhesive
16. 50 185 adhesive
EXAMPLES 17-47 Preparation of PSA Matrices by Blending PVP with Different Short-chain Plasticizers. Effects of Composition, and the Relation of Adhesion to Phase State
Using the preparation procedure and evaluation tests described in Example 1, the samples of PVP K-90 blends with various plasticizers were obtained and tested at 50% RH and ambient temperature. The results are set forth in the Table 3. The tacky blends can be obtained by mixing PVP with hydroxyl-terminated (Examples 17-41) or carboxyl terminated (Examples 42-47) short-chain plasticizers. Short-chain plasticizers include: ethylene glycol (Examples 17-19) and its polymers (PEG), ranging in molecular weight from 200 to 600 g/mol (Examples 20-23); low molecular weight 1,3- and 1,2-propylene glycol (PG) (Examples 24, 25); and alkane diols from propane diol up to pentane diols (PD) and hexane diol (HD) inclusive (Examples 27-39). Polypropylene glycol (PPG) has been found to be a good plasticizer for PVP, but does not develop any adhesion or tack (Example 26). The glass transition temperatures of plasticizers examined were within the range of −59° C. to −116° C. To induce adhesion, the plasticizer has to be either amorphous or crystalline, but the melting temperature of appropriate plasticizers, Tm, is normally lower than 50° C., the value found for 1,6-hexane diol (HD) (Examples 33-37). The adhesive strength correlates with maximum −ΔTg and minimum ΔCpTg values. The highest peel strength was found for PVP blends with glycerol (Example 41), which possesses a high density of hydroxyl groups per molecule. Strictly speaking, the carbonic diacids of Table 3 and Examples 44-47 are not acting as plasticizers but rather as noncovalent crosslinking agents and cohesive interaction enhancers. For proper adhesion, carbonic diacids can be employed in combination with plasticizers so as to reduce Tg to the values inherent in PSAs. Such approach has been used in a Plastoid adhesive blend (U.S. Pat. Nos. 5,730,999 and 5,993,849, EP 848960 A3), where EUDRAGIT E-100 was crosslinked by succinic acid and plasticized with tributylcitrate. Dry blends of PVP with 50% of carbonic diacids have been found to exhibit high Tg values (28,-34,-43, and 24° C. for SA, MA, GA, and AA, respectively) and, therefore, develop no adhesion. However, once the blends are hydrated, their glass transition temperatures decrease to about −55° C. to −65° C., and adhesion appears (see Examples 44-47). The PEG-600, terminated by carboxyl groups (Examples 42, 43), serves as both a crosslinking agent and a plasticizer, imparting adhesion to PVP blends.
EXAMPLES 48-64 PSA Compositions Prepared by Mixing Different Hydrophilic Polymers with Complementary Short-chain Plasticizers
These examples demonstrate that not only PVP but a range of different hydrophilic polymers become tacky upon mixture with short-chain plasticizers bearing complementary reactive groups at the chain ends. Suitable hydrophilic polymers include poly(N-vinyl amides) such as PVP (Examples 1-47), poly(N-vinyl caprolactam) (PVCap) (Examples 48-52) and poly(N-vinyl acetamide) (PVAA, Example 53), poly(N-alkyl acrylamides), exemplified by poly(N-isopropyl acrylamide) (PNIPAM, Example 54), polymethacrylic and polyacrylic acid (PMA, PAA, Examples 55-60), and the copolymers thereof exemplified in the Table 4 (Luviscols VAP®, commercially available from BASF; Examples 61-64). Luviscol VAP 37 is a copolymer of vinylpyrrolidone (VP, 30%) with 70% vinylacetate (VA). Luviscol VAP 73 contains 70% of VP and 30% of VA.
Among the polymers in Table 4, the best performance properties were found for PEG-400 blends with PVCap. The data presented in FIGS. 9-11 compare the hygroscopicity and adhesion of PVPCap-PEG-400 and PVP-PEG-400 blends. As follows from the data in FIG. 10, the PVPCap takes up nearly four times less water than PVP under comparable conditions. According to the Zaikov-Iordanskii-Markin classification of polymer hydrophilicity, PVP is hygroscopic, whereas PVCap is a moderately hydrophilic polymer. Compared to a PVP blend with 36 wt. % of PEG-400, the PVCap plasticized with the same amount of PEG-400 exhibited much higher adhesion. The left branches of the curves in FIG. 11 correspond to adhesive debonding, while the right branches correspond to miscellaneous and cohesive types of adhesive bond failure. As follows from Examples 1, 10, and 11, increase in polymer molecular weight results in an increase in cohesive toughness and adhesion. The sorption and adhesive properties of PVCap-PEG hydrogels are thus ideal for pharmaceutical applications. It should also be noted that PVCap exhibits a Lower Critical Solution Temperature (LCST) about 35° C. (see Kirsh Y. E., Water soluble poly(N-vinylamides), Wiley, N.Y., 1998). Below this temperature the PVCap is easily soluble in water and behaves like moderately hydrophilic polymer, while above LCST the PVCap becomes insoluble in water hydrophobic polymer. This property is highly useful for the development of thermoresponsive or so-called “smart” adhesive hydrogels.
TABLE 3
Adhesive and phase properties of PVP blends with short-chain plasticizers
Tg, Tm, Composition, wt. % −ΔTg, ΔCpTg, Peel Force, Debonding
No. Plasticizer ° C. ° C. Plasticizer PVP K J/g N/m mode
17. Ethylene glycol −112 25 75 n/d n/d 123 adhesive
18. 36 64 60 62.0 142 adhesive
19. 45 55 a/d n/d 127 ± 15 adhesive
20. PEG-200 −70 n/a 36 64 82 195 cohesive
21. PEG-300 −70 n/a 75 110 adhesive
22. PEG-600 −70 16 68 75.3 15 adhesive
23. PEG-1000 −70 39 60 22.71 0
24. 1,3-Propylene −116 n/a 35 65 55 47.9 116 ± 10 adhesive
Glycol
25. 1,2-Propylene −95 n/a 35 65 42 56.5 180 ± 20 adhesive
Glycol
26. PPG-425 −68 n/a 34 66 75 68.3 0
27. 1,5-PD −104 −12.5 43 57  0 47.1 0
28. 50 50 55 72.6 30 cohesive
29. 66.5 33.5   32.5 105.0 10 cohesive
30. 2,4-PD −59 n/a 32 68 02 59.7 0 adhesive
31. 49 51   65.4 89.0 190 adhesive
32. 65.5 34.5   39.5 140.1 0 cohesive
33. 1,6-HD −99 49.1 33 67   27.4 29.32 0
34. 37.6 62.4   83.1 59.6 11 cohesive
35 45 55 64.6 cohesive
36. 50 50   55.6 58.6 19 cohesive
37. 66.6 33.4   38.5 101.0 0 cohesive
38. 2,5-HD −62 n/a 49 51   65.32 76.4 26 adhesive
39. 66 34   40.1 122.2 10 cohesive
40. Glycerol −74 n/a 23.4 76.6  138.1 45.92 adhesive
41. 38 62   70.5 85.7 850 misc.
42. Carboxyl-terminated −49 12 36 64 752 55.9 8.5 adhesive
43. PEG-600 50 50 55 112 346.5 ± 15   cohesive
44. Succinic acid (SA) n/d 188 50 50 n/d 26.1/75.03 0/62 adhesive
45. Malonic acid (MA) n/d 135 50 50 n/d 52.5/80.13 7.6/71   adhesive
46. Glutaric acid (GA) n/d 96 50 50 n/d 129/853 0/94 adhesive
47. Adipic acid (AA) n/d 152 TBD TBD n/d 58.1/893   TBD adhesive
1The ΔCp value has been found to be decreased due to a high degree of blend crystallinity.
2The blend is inhomogeneous. Two glass transitions are observed. The data relate to the lower glass transition temperature.
3The data refer to dry blends and those containing 25% of water, respectively.
TABLE 4
Adhesive properties of PEG-400 miscible blends with various hydrophilic polymers.
Polymer/ Polymer Composition, wt. % RH, −ΔTg, ΔCpTg, Peel Force Debond.
No. Plasticizer MW Tg, ° C. Polymer Plasticizer % K J/g N/m mode
48. PVCap/PEG-400 100,000 165 64 36 40 71 88.3 533 misc.
49. 50 363 cohesive
50. 60 300 cohesive
51. 80 23 cohesive
52. PVCap/PEG400 1,000,000 197 64 36 50 81 98.0 150 adhesive
53. PVAA/PEG400 1,000,000 64 36 50 397 adhesive
54. PNIPAM/PEG400 250,000 157 64 36 50 66 89.0 230 misc.
55. PMAA*/PEG400 150,000 36 64 50 0
56. 47 53 27.5 ± 5 adhesive
57. 63 37 72 cohesive
58. PAA/PEG400 150,000 47 53 50 51 adhesive
59. PMAA*/1,5 PD 150,000 36 64 50 0
60. 50 50 22.3 adhesive
61. Luviscol73/PEG400 100,000 57.5 30 70 50 37.1 65.9 High** cohesive
62. 36 64 34.0 79.4 High** cohesive
63. Luviscol37/PEG400 100,000 29 17 83 50 9.3 138.7 High** cohesive
64. 36 64 24.4 180.1 High** cohesive
*PMAA exhibits no glass transition; therefore, the negative deviation from weight-average magnitudes cannot be evaluated.
**Adhesion is very strong, but cannot be measured because the blend provides an inseparable adhesive joint with siliconized release liner.
In addition to pressure-sensitive adhesion, the adhesive hydrogels of the invention display a number of useful viscoelastic properties, similar to the properties of cured rubbers (FIGS. 6-8). In fact, adhesive hydrogels are hydrophilic and water-soluble rubbers, featuring rubber-like elasticity as one of their major performance properties. Both the rubber-like elastic and viscous contributions to the rheology of the present adhesive hydrogels are illustrated by the data in FIG. 6.
Under a fixed compressive force, hydrogel squeezing occurs, and the instantaneous compressibility (Hooke's elasticity) of the PVP-PEG adhesive hydrogel is proportional to the applied compressive load (FIG. 6). Hooke's compression is followed by a squeezing flow (creep), which reflects the viscous flow contribution to hydrogel rheology. As compression is developing, the stress within the adhesive polymer decreases gradually, achieving a critical value of yield stress at which the hydrogel ceases to flow and the squeezing flow is stopped. Occurrence of yield stress is a characteristic feature of crosslinked or highly ordered supramolecular structures, typical of polymer networks or liquid-crystalline polymers. Commodity polymers exhibit no yield stress. The yield stress in the PVP-PEG adhesive hydrogel is associated with a critical magnitude of shear stress in the flow curve shown in FIG. 7, at which the apparent shear viscosity climbs to infinity and the deformation rate drops tending to zero. The yield stress is an integral measure of cohesive strength, which has been shown to relate to the σf value in equation (2) and which determines the adhesive properties of an adhesive polymer (Feldstein et al. (2000), “Molecular insight into theological and diffusion determinants of pressure-sensitive adhesion,” Proceed. 23rd Annual Meeting Adhesion Soc., pp. 54-56).
Upon removal of compressive load, the relaxation of polymer deformation occurs, termed the “retardation,” when deformation changes its sign and the polymer returns, more or less, to its initial shape. Again, the adhesive hydrogel demonstrated (FIG. 6) the instantaneous (Hooke's) retardation, followed by a creep recoil. The Hooke's elastic retardation value is proportional to compressive force (FIG. 6), and the slope of this linear relationship outlines the elastic relaxation shear modulus of adhesive hydrogel G=2·105 Pa. This value found for the PVP-PEG adhesive hydrogel is well known to be also inherent in various PSA polymers and slightly crosslinked rubbers.
Upon the removal of compressive bonding force, the adhesive hydrogel is allowed to relax and creep recovery occurs, accompanied by a gradual growth in creep compliance, FIG. 8. Kinetics of PVP-PEG hydrogel creep recovery, described by creep-recoil function S(t), follow the phenomenological Dickie-Ferry equation (4), based on the model developed to describe the relaxation of slightly crosslinked rubbers:
S ( t ) = S e [ 1 + ( t τ ) - n ] - 1 ( 4 )
where S(t) is recoil compliance and Se is the equilibrium tensile compliance, t=time, τ is a characteristic (retardation) time, n denotes a Chasset-Thirion exponent. Computer simulation of the recoil function kinetic profiles in FIG. 8 provide the evaluation of PVP-PEG hydrogel equilibrium creep recoil compliance Se=1.56·10−5 Pa−1, retardation time τ=1.8·103 s and the Chasset-Thirion exponent n=0.99. The obtained Se magnitude corresponds to an average molecular weight of polymer chain between entanglements Mc≈130,000 g/mol, which is typical of slightly cross-linked rubbers, whereas the n value is a characteristic of highly dense network. Thus, the obtained Se and τ values refer most likely to the contribution of network formed by the entanglements of PVP chains, while the n exponent relates to the contribution of the much more dense and faster relaxing H-bonded network. The superposition of the recoil compliance profiles for PVP-PEG hydrogel and PB rubber (FIG. 8) provides evidence that the hydrogel retardation properties are typical of elastomers. Accordingly, the adhesive hydrogels described represent, in essence, water-soluble rubbers.
EXAMPLES 65-82 Therapeutic Systems Based on Hydrophilic PSA Matrices
Preparation:
Therapeutic agents (drugs) were first dissolved in a mixture of PEG-400 (plasticizer) and ethyl alcohol (solvent). Upon complete drug dissolution, the PVP or another hydrophilic polymer was dissolved in the earlier prepared mixture, forming casting solution that was cast onto polyethylene terephthalate backing film of 0.02 mm in thickness and dried at temperatures of 20-60° C.
In vitro drug delivery rate determination from water-soluble PSA matrices was performed using human cadaver skin or a skin-imitating Carbosil membrane to protect the matrices from dissolving in the receptor solution. The patch was adhered to the center of a Carbosil membrane sheet of twice its area. The membrane margins were then wrapped around the sample. The back side of the packet was closely attached to a steel plate-holder to prevent direct contact of the matrix with the receptor solution. In a similar fashion, cadaver skin epidermis can be used instead of a Carbosil membrane. The holder with the wrapped sample was then submerged into an aqueous sink and in vitro drug delivery rate was determined using a USP rotating cylinder method paddle-over-disc. The rate of drug appearance rate in a receptor solution (0.15 M NaCl) at 35.0±0.5° C. was determined spectrophotometrically.
Drug permeability coefficients through skin epidermis (Ps) and a Carbosil membrane (Pm)were measured as the fluxes of drug delivered from the hydrophilic PSA matrix normalized by the drug concentration in the donor vehicle, taking the matrix density (1.10±0.12 g/cm3) into account.
Results
The compositions and properties of prepared therapeutic systems are presented in the Table 5.
TABLE 5
Properties of drug-loaded hydrophilic matrices.
Drug content Delivery rate in vitro
Matrix in the matrix μg/cm2h across: Pm (104) Ps (104)
Drug composition (%) Carbosil Human skin cm/h cm/h
65. Anabasine PVP-PEG 1.6 150 ± 20 106.3 ± 12.0
66. Isosorbide PVP-PEG 9.6 384 ± 48 13.0 ± 4.3 44 ± 5 1.5 ± 0.5
dinitrate
67. Isosorbide PVCap-PEG 9.6 411 ± 49 47.1 ± 5  
dinitrate
68. Aminostigmine PVP-PEG 14.3 625 ± 20  33.7 ± 12.0
7.6 263 ± 10
4.0 65 ± 5
69. Glyceryl PVP-PEG 7.3 160 ± 40 12.4 ± 4.0 25.6 ± 1.4 1.9 ± 0.5
trinitrate 1.9  45 ± 12
70. Verapamil PVP-PEG 39.1 110 ± 20 21.4 ± 1.5 0.4 ± 0.1
24.3 110 ± 16
13.8  95 ± 19  6 ± 2
3.9 78 ± 6
71. Propranolol PVP-PEG 13.8 118 ± 25  26.0 ± 15.0 10.6 ± 1.1 2.1 ± 0.2
7.4 79 ± 6
72. Propranolol PVCap-PEG 13.8 145 ± 30 13.0 ± 1.9
73. Silabolin PVP-PEG 13.9 131 ± 30 10.3 ± 0.5
10.8 107 ± 21
7.2  65 ± 14
74. Foridone PVP-PEG 13.8 37.3 ± 4.5  4.2 ± 1.5
10.8 34.1 ± 4.0
7.4 24.8 ± 3.0
3.1 20.6 ± 1.9
75. Clonidine PVP-PEG 7.7 26.8 ± 0.8  0.75 ± 0.04  4.0 ± 1.1 0.6 ± 0.2
1.4  5 ± 2 0.78 ± 0.1
76. Cytisine PVP-PEG 7.4 21 ± 3  9.0 ± 4.0  3.0 ± 0.5 1.3 ± 0.5
77. Phenazepam PVP-PEG 7.4 11 ± 2  1.4 ± 0.3
6.8  7 ± 2
78. Nifedipin PVP-PEG 15.4 19 ± 3  1.3 ± 0.2
79. Fluacizin PVP-PEG 13.8  5 ± 1  6 ± 2  0.4 ± 0.1 0.4 ± 0.1
80. Salbutamol PVP-PEG 13.8  0.10 ± 0.04 0.003
81. Salbutamol PVCap-PEG 13.8 4.9 ± 1   0.4 ± 0.1
82. Chinosol PVP-PEG 3.0 n/a n/a n/a n/a

As follows from the data in Table 5, the hydrophilic PSA matrices based on both the PVP and PVCap blends with PEG-400 (36 wt. % of the plasticizer in the blends) provide high delivery rates through both the skin-imitating Carbosil membrane and human skin epidermis. As comparative data in the Table 6 indicate, the hydrophilic PSA matrices allow us to enhance appreciably the rates of drug delivery compared to known hydrophobic PSAs such as PIB, PDMS and styrene-butadiene rubbers. In turn, the rates of drug delivery from the PVCap-PEG matrices are enhanced compared to the PVP-PEG matrix (compare examples 66 and 67, 71 and 72, 80 and 81).
TABLE 6
Comparative study of in vitro drug delivery rates (μg/cm2h) from the
hydrophilic PVP-PEG matrix and conventional hydrophobic matrices
Delivery rate Release rate
from hydrophilic from Composition
matrix via hydrophobic of hydrophobic
Drug Carbosil matrices matrix
Aminostigmine 625 ± 20 8 ± 1 Styrene butadiene
rubber
Nitroglycerin
160 ± 40 80 ± 10 PDMS,
(Nitroderm ® TTS)
Silabolin 131 ± 30 16 ± 7  Styrene butadiene
rubber
Propranolol 118 ± 25 56 ± 4  Styrene butadiene
rubber
Clonidine
 5 ± 2 1.6 ± 0.2 PIB (Catapress ®
TTS)
Drug targeting is necessary not only in systemic transdermal delivery, but also in topical delivery. Thus, the stratum corneum and epidermis are the targets for antifungal drugs and germicides. Ointments have often proven inconvenient to use and require multiple repeated daily application. Patches have now been developed that are more convenient to use and administered twice weekly, thereby improving patient acceptability. The application of a topical dermal patch (TDP) to human skin allows localization of drug concentration in damaged skin and does not involve the entire body. Furthermore, the continuous drug contact with the damaged tissue permits one to accelerate the recovery of diseased or wounded skin. For this purpose, a patch should be a non-occlusive. Hydrophilic PSA matrix, covered by a moisture permeable textile material as a backing, meets best this requirement.
Example 82 refers to an antifungal topical dermal patch based on the PVP-PEG PSA matrix. The patch is composed of a nonocclusive cotton textile backing on one side of the drug-loaded PVP-PEG adhesive matrix and a protective layer on the other side, which is removed before patch application to the skin. The patch is designed for topical targeted treatment of mycosis and contains 3% of chinosol (8-hydroxyquinoline sulfate) as an antifungal agent. The salt form of the drug serves to reduce its percutaneous absorption into systemic circulation. As the result, in vivo chinosol release rate from the Chinosive TDP in human volunteers averages only 0.42 μg/cm2 h as has been evaluated from the drug remainder in the patch removed from the skin. As clinical studies with volunteers have shown, the topical antifungal monotherapy with the chinosol-containing patch results in essential acceleration of the treatment compared to the control group treated by the clotrimazol.
Thus, the hydrophilic PSA matrices outlined by this invention provide the performance properties useful in application dosage forms designed for transdermal and dermal drug delivery.

Claims (98)

What is claimed is:
1. A method of preparing an adhesive composition having an optimized degree of adhesion, comprising:
(a) preparing a plurality of compositions each comprised of a hydrophilic polymer having a glass transition temperature Tg pol admixed with a plasticizer miscible therewith and having a glass transition temperature Tg pl and capable of covalently or noncovalently crosslinking the hydrophilic polymer, wherein the weight fraction of the hydrophilic polymer in each composition is wpol, and the weight fraction of the plasticizer in each composition is wpl;
(b) calculating predicted glass temperatures Tg predicted for each composition using the Fox equation (1)
1 T g predicted = w pol T g pol + w pl T g pl ( 1 )
and plotting Tg predicted versus wpl for each composition;
(c) determining the glass transition temperature Tg actual for each composition, and plotting Tg actual versus wpl for each composition;
(d) identifying the region of the plots of (b) and (c) wherein Tg actual is less than Tg predicted; such that there is a negative deviation from Tg predicted;
(e) within the region identified in (d), identifying the optimum weight fraction of plasticizer wpl optimum at which the negative deviation from Tg predicted is at a maximum; and
(f) admixing a monomeric precursor to the hydrophilic polymer and the plasticizer under polymerizing conditions to provide an adhesive composition having an optimized degree of adhesion, wherein the weight fraction of plasticizer in the composition is wpl optimum, and the weight fraction of the hydrophilic polymer in the composition is 1-wpl optimum.
2. The method of claim 1, wherein the plasticizer is capable of covalently crosslinking the hydrophilic polymer.
3. The method of claim 1, wherein the plasticizer is capable of noncovalently crosslinking the hydrophilic polymer.
4. The method of claim 1, wherein the plasticizer is capable of crosslinking the hydrophilic polymer by hydrogen bonding thereto.
5. A method of preparing an adhesive composition having an optimized degree of adhesion, comprising:
(a) preparing a plurality of compositions each comprised of a hydrophilic polymer having a glass transition temperature Tg pol admixed with a plasticizer miscible therewith and having a glass transition temperature Tg pl and capable of covalently or noncovalently crosslinking the hydrophilic polymer, wherein the weight fraction of the hydrophilic polymer in each composition is wpol, and the weight fraction of the plasticizer in each composition is wpl, such that wpol is equal to 1-wpl;
(b) calculating predicted glass temperatures Tg predicted for each composition using the Fox equation (1)
1 T g predicted = w pol T g pol + w pl T g pl ( 1 )
and plotting Tg predicted versus wpl for each composition;
(c) determining the glass transition temperature Tg actual for each composition, and plotting Tg actual versus wpl for each composition;
(d) identifying the region of the plots of (b) and (c) wherein Tg actual has a predetermined deviation from Tg predicted; and
(e) admixing a monomeric precursor to the hydrophilic polymer and the plasticizer under polymerizing conditions to provide an adhesive composition having a desired degree of adhesion, wherein the weight percent of plasticizer in the composition corresponds to a value within the region identified in section (d).
6. The method of claim 5, wherein the plasticizer is capable of covalently crosslinking the hydrophilic polymer.
7. The method of claim 5, wherein the plasticizer is capable of noncovalently crosslinking the hydrophilic polymer.
8. The method of claim 5, wherein the plasticizer is capable of crosslinking the hydrophilic polymer by hydrogen bonding thereto.
9. The method of claim 1, wherein the difference between Tg pol and Tg pl is at least about 50° C., such that Tg actual for each composition is determined solely by Tg pl.
10. The method of claim 2, wherein the difference between Tg pol and Tg pl is at least about 50° C., such that Tg actual for each composition is determined solely by Tg pl.
11. The method of claim 1, wherein the hydrophilic polymer is selected from the group consisting of poly(N-vinyl lactams), poly(N-vinyl amides), poly(N-alkylacrylamides), polyacrylic acid, polymethacrylic acid, polyvinyl alcohol, polyvinylamine, and copolymers and blends thereof.
12. The method of claim 11, wherein the hydrophilic polymer is selected from the group consisting of poly(N-vinyl lactams), poly(N-vinyl amides), poly(N-alkylacrylamides), and copolymers and blends thereof.
13. The method of claim 12, wherein the hydrophilic polymer is a poly(N-vinyl lactam).
14. The method of claim 13, wherein the hydrophilic polymer is a poly(N-vinyl lactam) homopolymer.
15. The method of claim 14, wherein the poly(N-vinyl lactam) is selected from the group consisting of polyvinyl pyrrolidone, polyvinyl caprolactam, and blends thereof.
16. The method of claim 15, wherein the poly(N-vinyl lactam) is polyvinyl pyrrolidone.
17. The method of claim 15, wherein the poly(N-vinyl lactam) is polyvinyl caprolactam.
18. The method of claim 12, wherein the hydrophilic polymer is a poly(N-vinyl amide).
19. The method of claim 18, wherein the poly(N-vinyl amide) is polyacetamide.
20. The method of claim 12, wherein the hydrophilic polymer is a poly(N-alkylacrylamide).
21. The method of claim 20, wherein the poly(N-alkylacrylamide) is polymethacrylamide or poly(N-isopropyl acrylamide).
22. The method of claim 1, wherein the hydrophilic polymer has a weight average molecular weight in the range of approximately 100,000 to 2,000,000.
23. The method of claim 22, wherein the hydrophilic polymer has a weight average molecular weight in the range of approximately 500,000 to 1,500,000.
24. The method of claim 1, wherein Tg pl is in the range of approximately −100° to −30° C.
25. The method of claim 24, wherein the melting temperature of the plasticizer is lower than about 50° C.
26. The method of claim 1, wherein the plasticizing agent has a molecular weight in the range of about 45 to 800.
27. The method of claim 26, wherein the plasticizing agent has a molecular weight in the range of about 45 to 600.
28. The method of claim 24, wherein the plasticizing agent has a molecular weight in the range of about 300 to 600.
29. The method of claim 26, wherein the plasticizing agent is selected from the group consisting of of polyalcohols, monomeric and oligomeric alkylene glycols, polyalkylene glycols, carboxyl-teminated polyalkylene glycols, amino-terminated polyalkylene glycols, ether alcohols, alkane diols and carbonic diacids.
30. The method of claim 29, wherein the plasticizing agent is selected from the group consisting of polyalkylene glycols and carboxyl-terminated polyalkylene glycols.
31. The method of claim 30, wherein the plasticizing agent is selected from the group consisting of polyethylene glycol and carboxyl-terminated polyethylene glycol.
32. The method of claim 31, wherein the plasticizing agent is polyethylene glycol.
33. The method of claim 1, wherein the adhesive composition further includes a photoinitator, and, following step (e), the adhesive composition is crosslinked using radiation.
34. The method of claim 1, wherein step (e) further includes admixing the hydrophilic polymer and the plasticizing agent with at least one chemical crosslinking agent that covalently crosslinks the adhesive composition.
35. The method of claim 34, wherein the at least one chemical crosslinking agent is selected from the group consisting of dipentaerythritol pentaacrylate, ethylene glycol dimethacrylate, and triethylene glycol dimethacrylate.
36. The method of claim 35, wherein the weight ratio of the chemical crosslinking agent to the hydrophilic polymer is below 5%.
37. The method of claim 1, wherein, following step (e), the adhesive composition is crosslinked using heat.
38. The method of any one of claim 33, 34 or 36, wherein the crosslinking density of the crosslinked adhesive composition provides a swell ratio in the range of approximately 20 to approximately 60.
39. A hydrophilic pressure sensitive adhesive composition comprising (1) a hydrophilic polymer having a glass transition temperature Tg pol, and (2) a complementary hydroxyl-terminated or carboxyl-terminated short-chain plasticizing agent having a glass transition temperature Tg pl and capable of hydrogen bonding or electrostatic bonding to the hydrophilic polymer, wherein the weight ratio of hydrophilic polymer to complementary short-chain plasticizing agent is selected so to provide a predetermined deviation in (a) the actual glass transition temperature Tg actual of the composition from (b) the predicted glass transition temperature Tg predicted calculated for the composition using Fox equation (1)
1 T g predicted = w pol T g pol + w pl T g pl . ( 1 )
40. The composition of claim 39, wherein the predetermined deviation is the maximum negative deviation.
41. A hydrophilic, substantially nonaqueous pressure sensitive adhesive composition comprising (a) a hydrophilic polymer, and (b) a complementary hydroxyl-terminated or carboxyl-terminated short-chain plasticizing agent capable of hydrogen bonding or electrostatic bonding to the hydrophilic polymer,
wherein the ratio of hydrogen bonding to covalent crosslinks is selected to optimize adhesive strength, cohesive strength, and hydrophilicity;
wherein the plasticizing agent decreases the glass transition temperature Tg of the hydrophilic composition according to Fox equation (1)
1 T g predicted = w pol T g pol + w pl T g pl ( 1 )
wherein Tg predicted is the predicted glass transition temperature of the hydrophilic polymer/plasticizer composition, wpol is the weight fraction of the hydrophilic polymer in the composition, wpl is the weight fraction of the plasticizer in the composition, Tg pol is the glass transition temperature of the hydrophilic polymer, and Tg pl is the glass transition temperature of the plasticizer; and
wherein maximum adhesiveness is achieved at a point of maximum negative deviation from Tg predicted.
42. A hydrophilic pressure sensitive adhesive composition comprising (a) a hydrophilic polymer and (b) a complementary hydroxyl-terminated or carboxyl-terminated short-chain plasticizing agent capable of hydrogen bonding or electrostatic bonding to the hydrophilic polymer,
wherein the hydrophilic polymer and the plasticizing agent are crosslinked to a predetermined extent, and the extent of crosslinking and the ratio of the hydrophilic polymer to the plasticizing agent are selected to optimize the hydrophilicity, adhesive strength and cohesive strength of the composition;
wherein the plasticizing agent decreases the glass transition temperature Tg of the hydrophilic composition according to Fox equation (1)
1 T g predicted = w pol T g pol + w pl T g pl ( 1 )
wherein Tg predicted is the predicted glass transition temperature of the hydrophilic polymer/plasticizer composition, wpol is the weight fraction of the hydrophilic polymer in the composition, wpl is the weight fraction of the plasticizer in the composition, Tg pol is the glass transition temperature of the hydrophilic polymer, and Tg pl is the glass transition temperature of the plasticizer; and
wherein maximum adhesiveness is achieved at a point of maximum negative deviation from Tg predicted.
43. The composition of any one of claim 39, 41 or 42, wherein the adhesive composition is substantially nonaqueous.
44. The composition of claim 39, wherein the difference between Tg pol and Tg pl is at least about 50° C., such that Tg actual for each composition is determined solely by Tg pl.
45. The composition of claim 39, wherein the hydrophilic polymer is selected from the group consisting of poly(N-vinyl lactams), poly(N-vinyl amides), poly(N-alkylacrylamides), polyacrylic acid, polymethacrylic acid, polyvinyl alcohol, polyvinylamine, and copolymers and blends thereof.
46. The composition of claim 45, wherein the hydrophilic polymer is selected from the group consisting of poly(N-vinyl lactams), poly(N-vinyl amides), poly(N-alkylacrylamides), and copolymers and blends thereof.
47. The composition of claim 46, wherein the hydrophilic polymer is a poly(N-vinyl lactam).
48. The composition of claim 47, wherein the hydrophilic polymer is a poly(N-vinyl lactam) homopolymer.
49. The composition of claim 48, wherein the poly(N-vinyl lactam) is selected from the group consisting of polyvinyl pyrrolidone, polyvinyl caprolactam, and blends thereof.
50. The composition of claim 49, wherein the poly(N-vinyl lactam) is polyvinyl pyrrolidone.
51. The composition of claim 49, wherein the poly(N-vinyl lactam) is polyvinyl caprolactone.
52. The composition of claim 39, wherein the hydrophilic polymer is a poly(N-vinyl amide).
53. The composition of claim 52, wherein the poly(N-vinyl amide) is polyacetamide.
54. The composition of claim 39, wherein the hydrophilic polymer is a poly(N-alkylacrylamide).
55. The composition of claim 54, wherein the poly(N-alkylacrylamide) is polymethacrylamide or poly(N-isopropyl acrylamide).
56. The composition of claim 39, wherein the hydrophilic polymer has a weight average molecular weight in the range of approximately 100,000 to 2,000,000.
57. The composition of claim 56, wherein the hydrophilic polymer has a weight average molecular weight in the range of approximately 500,000 to 1,500,000.
58. The composition of claim 39, wherein Tg pl is in the range of approximately −100° to −30° C.
59. The composition of claim 58, wherein the melting temperature of the plasticizer is lower than about 50° C.
60. The composition of claim 39, wherein the plasticizing agent has a molecular weight in the range of about 45 to 800.
61. The composition of claim 60, wherein the plasticizing agent has a molecular weight in the range of about 45 to 600.
62. The composition of claim 61, wherein the plasticizing agent has a molecular weight in the range of about 300 to 600.
63. The composition of claim 60, wherein the plasticizing agent is selected from the group consisting of of polyalcohols, monomeric and oligomeric alkylene glycols, polyalkylene glycols, carboxyl-teminated polyalkylene glycols, amino-terminated polyalkylene glycols, ether alcohols, alkane diols and carbonic diacids.
64. The composition of claim 63, wherein the plasticizing agent is selected from the group consisting of polyalkylene glycols and carboxyl-terminated polyalkylene glycols.
65. The composition of claim 64, wherein the plasticizing agent is selected from the group consisting of polyethylene glycol and carboxyl-terminated polyethylene glycol.
66. The composition of claim 65, wherein the plasticizing agent is polyethylene glycol.
67. The composition of claim 39, wherein the composition is covalently crosslinked.
68. The composition of claim 67, wherein the crosslinking density of the crosslinked adhesive composition provides a swell ratio in the range of approximately 20 to approximately 60.
69. A therapeutic system for the topical or transdermal administration of a pharmacologically active agent, comprising:
(A) a drug reservoir comprising (1) a substantially non-aqueous pressure sensitive adhesive matrix of a hydrophilic polymer having a glass transition temperature Tg pol, and a complementary hydroxyl-terminated or carboxyl-terminated short-chain plasticizing agent having a glass transition temperature Tg pl and capable of hydrogen bonding or electrostatic bonding to the hydrophilic polymer, wherein the weight ratio of hydrophilic polymer to complementary short-chain plasticizing agent is selected so to provide a predetermined deviation in (a) the actual glass transition temperature Tg actual of the composition from (b) the predicted glass transition temperature Tg predicted for the composition calculated using Fox equation (1)
1 T g predicted = w pol T g pol + w pl T g pl , ( 1 )
 and (2) a therapeutically effective amount of the active agent; and
(B) a backing layer laminated to the drug reservoir that serves as the outer surface of the device during use.
70. The system of claim 69, wherein the predetermined deviation is the maximum negative deviation.
71. The system of claim 69, wherein the hydrophilic polymer is comprised of repeating units resulting from polymerization of an N-vinyl lactam monomer, a carboxy vinyl monomer, a vinyl ester monomer, an ester of a carboxy vinyl monomer, a vinyl amide monomer, a hydroxy vinyl monomer, or a combination thereof.
72. The system of claim 71, wherein the hydrophilic polymer is selected from the group consisting of poly(N-vinyl lactams), poly(N-vinyl amides), poly(N-alkylacrylamides), polyacrylic acid, polymethacrylic acid, polyvinyl alcohol, polyvinylamine, and copolymers and blends thereof.
73. The system of claim 72, wherein the hydrophilic polymer is selected from the group consisting of poly(N-vinyl lactams), poly(N-vinyl amides), poly(N-alkylacrylamides), and copolymers and blends thereof.
74. The system of claim 73, wherein the hydrophilic polymer is a poly(N-vinyl lactam).
75. The system of claim 74, wherein the hydrophilic polymer is a poly(N-vinyl lactam) homopolymer.
76. The system of claim 75, wherein the poly(N-vinyl lactam) is selected from the group consisting of polyvinyl pyrrolidone, polyvinyl caprolactam, and blends thereof.
77. The system of claim 76, wherein the poly(N-vinyl lactam) is polyvinyl pyrrolidone.
78. The system of claim 76, wherein the poly(N-vinyl lactam) is polyvinyl caprolactone.
79. The system of claim 73, wherein the hydrophilic polymer is a poly(N-vinyl amide).
80. The system of claim 79, wherein the poly(N-vinyl amide) is polyacetamide.
81. The system of claim 73, wherein the hydrophilic polymer is a poly(N-alkylacrylamide).
82. The system of claim 81, wherein the poly(N-alkylacrylamide) is polymethacrylamide or poly(N-isopropyl acrylamide).
83. The system of claim 69, wherein the hydrophilic polymer has a weight average molecular weight in the range of approximately 100,000 to 2,000,000.
84. The system of claim 83, wherein the hydrophilic polymer has a weight average molecular weight in the range of approximately 500,000 to 1,500,000.
85. The system of claim 69, wherein Tg pl is at least 50° C. below Tg pol.
86. The system of claim 85, wherein Tg pl is in the range of approximately −100° to −30° C.
87. The system of claim 69, wherein the melting temperature of the plasticizer is lower than about 50° C.
88. The system of claim 87, wherein the plasticizing agent has a molecular weight in the range of about 45 to 800.
89. The system of claim 88, wherein the plasticizing agent has a molecular weight in the range of about 45 to 600.
90. The system of claim 89, wherein the plasticizing agent has a molecular weight in the range of about 300 to 600.
91. The system of claim 88, wherein the plasticizing agent is selected from the group consisting of of polyalcohols, monomeric and oligomeric alkylene glycols, polyalkylene glycols, carboxyl-teminated polyalkylene glycols, amino-terminated polyalkylene glycols, ether alcohols, alkane diols and carbonic diacids.
92. The system of claim 91, wherein the plasticizing agent is selected from the group consisting of polyalkylene glycols and carboxyl-terminated polyalkylene glycols.
93. The system of claim 92, wherein the plasticizing agent is selected from the group consisting of polyethylene glycol and carboxyl-terminated polyethylene glycol.
94. The system of claim 93, wherein the plasticizing agent is polyethylene glycol.
95. The system of claim 69, wherein the composition is covalently crosslinked.
96. The system of claim 95, wherein the crosslinking density of the crosslinked adhesive composition provides a swell ratio in the range of approximately 20 to approximately 60.
97. The system of claim 69, wherein the backing layer is non-occlusive.
98. The system of claim 69, wherein the backing layer is occlusive.
US11/150,811 2000-07-07 2005-06-10 Preparation of hydrophilic pressure sensitive adhesives having optimized adhesive properties Expired - Lifetime USRE44145E1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US11/150,811 USRE44145E1 (en) 2000-07-07 2005-06-10 Preparation of hydrophilic pressure sensitive adhesives having optimized adhesive properties
US13/761,118 USRE45666E1 (en) 2000-07-07 2013-02-06 Preparation of hydrophilic pressure sensitive adhesives having optimized adhesive properties

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US21638600P 2000-07-07 2000-07-07
US84753201A 2001-05-01 2001-05-01
US09/900,697 US6576712B2 (en) 2000-07-07 2001-07-06 Preparation of hydrophilic pressure sensitive adhesives having optimized adhesive properties
US11/150,811 USRE44145E1 (en) 2000-07-07 2005-06-10 Preparation of hydrophilic pressure sensitive adhesives having optimized adhesive properties

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US09/900,697 Reissue US6576712B2 (en) 2000-07-07 2001-07-06 Preparation of hydrophilic pressure sensitive adhesives having optimized adhesive properties

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US09/900,697 Continuation US6576712B2 (en) 2000-07-07 2001-07-06 Preparation of hydrophilic pressure sensitive adhesives having optimized adhesive properties

Publications (1)

Publication Number Publication Date
USRE44145E1 true USRE44145E1 (en) 2013-04-09

Family

ID=47999402

Family Applications (2)

Application Number Title Priority Date Filing Date
US11/150,811 Expired - Lifetime USRE44145E1 (en) 2000-07-07 2005-06-10 Preparation of hydrophilic pressure sensitive adhesives having optimized adhesive properties
US13/761,118 Expired - Lifetime USRE45666E1 (en) 2000-07-07 2013-02-06 Preparation of hydrophilic pressure sensitive adhesives having optimized adhesive properties

Family Applications After (1)

Application Number Title Priority Date Filing Date
US13/761,118 Expired - Lifetime USRE45666E1 (en) 2000-07-07 2013-02-06 Preparation of hydrophilic pressure sensitive adhesives having optimized adhesive properties

Country Status (1)

Country Link
US (2) USRE44145E1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015042165A1 (en) 2013-09-17 2015-03-26 Corium International, Inc. Topical adhesive composition, and device, for improving aesthetic appearance of skin

Citations (277)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2561071A (en) 1949-09-21 1951-07-17 Prisk Howard Conley Holder for subcutaneous administration of medicaments
US2579403A (en) 1950-06-01 1951-12-18 Slomowitz Julius Medical bandage
US3150977A (en) 1959-12-23 1964-09-29 Gevaert Photo Prod Nv Light-sensitive photographic materials
GB1108837A (en) 1965-11-30 1968-04-03 Astra Pharma Prod Improvements in material for causing local anaesthesia
US3689439A (en) 1968-06-12 1972-09-05 Gaf Corp Process for preparing a crosslinked porous polyvinyl pyrrolidone granule
US3721657A (en) 1969-07-28 1973-03-20 M Seiderman Hydrophilic gel polymers of vinylpyrrolidine and hydroxyalkyl methacrylate
US3749755A (en) 1969-12-22 1973-07-31 Basf Ag Thermoplastic molding compositions of high impact resistance
US3852228A (en) 1971-01-07 1974-12-03 D Brothers Thixotropic coating composition
US3957605A (en) 1973-09-10 1976-05-18 Union Carbide Corporation Process for radiation cocrosslinking water soluble polymers and products thereof
US3993551A (en) 1973-09-10 1976-11-23 Union Carbide Corporation Process for cocrosslinking water soluble polymers and products thereof
US3996934A (en) 1971-08-09 1976-12-14 Alza Corporation Medical bandage
US4091090A (en) 1974-07-08 1978-05-23 Johnson & Johnson Potentiated anesthetics
US4093673A (en) 1974-11-14 1978-06-06 Ppg Industries, Inc. Coating compositions composed of hydroxyfunctional polymers or copolymers and alkoxysilanes
US4160020A (en) 1975-11-24 1979-07-03 Alza Corporation Therapeutic device for osmotically dosing at controlled rate
US4231369A (en) 1977-05-24 1980-11-04 Coloplast International A/S Sealing material for ostomy devices
US4277580A (en) 1978-05-22 1981-07-07 Texaco Inc. Terpolymer of N-vinyl pyrrolidone in alkoxylated form
US4325851A (en) 1980-10-24 1982-04-20 Herman Colon Water-activatable hot-melt adhesives
US4346709A (en) 1980-11-10 1982-08-31 Alza Corporation Drug delivery devices comprising erodible polymer and erosion rate modifier
US4367732A (en) 1980-12-05 1983-01-11 Coloplast A/S Skin barrier
JPS58162681U (en) 1982-04-22 1983-10-29 ソニー株式会社 Electrical equipment operating device
JPS59196817A (en) 1983-04-21 1984-11-08 Sekisui Chem Co Ltd Application drug
US4492685A (en) 1979-08-14 1985-01-08 Key Pharmaceuticals, Inc. Protective skin matrix
DE8509793U1 (en) 1985-04-02 1985-05-15 Allpack Industrielle Lohnverpackung GmbH & Co KG, 7050 Waiblingen Pharmaco adhesive plaster
US4529601A (en) 1977-12-01 1985-07-16 Astra Lakemedel Aktiebolag Local anesthetic mixture for topical application and method for obtaining local anesthesia
US4552751A (en) 1980-10-17 1985-11-12 Ono Pharmaceutical Co., Ltd. Long-lasting multi-layered film preparation
US4557934A (en) 1983-06-21 1985-12-10 The Procter & Gamble Company Penetrating topical pharmaceutical compositions containing 1-dodecyl-azacycloheptan-2-one
US4568343A (en) 1984-10-09 1986-02-04 Alza Corporation Skin permeation enhancer compositions
US4587289A (en) 1982-09-27 1986-05-06 Ahmet Comert Adhesive thermoplastic compositions
US4593053A (en) 1984-12-07 1986-06-03 Medtronic, Inc. Hydrophilic pressure sensitive biomedical adhesive composition
US4624665A (en) 1984-10-01 1986-11-25 Biotek, Inc. Method of transdermal drug delivery
US4699146A (en) 1982-02-25 1987-10-13 Valleylab, Inc. Hydrophilic, elastomeric, pressure-sensitive adhesive
US4713243A (en) 1986-06-16 1987-12-15 Johnson & Johnson Products, Inc. Bioadhesive extruded film for intra-oral drug delivery and process
US4743249A (en) 1986-02-14 1988-05-10 Ciba-Geigy Corp. Dermal and transdermal patches having a discontinuous pattern adhesive layer
US4750482A (en) * 1982-02-25 1988-06-14 Pfizer Inc. Hydrophilic, elastomeric, pressure-sensitive adhesive
US4771105A (en) 1986-02-05 1988-09-13 Sekisui Kaseihin Kogyo Kabushiki Kaisha Water-absorbent resin and process for producing the same
EP0303445A1 (en) 1987-08-13 1989-02-15 Walton S.A. Clebopride transdermal patch
WO1989003859A1 (en) 1987-10-23 1989-05-05 Vsesojuzny Nauchno-Issledovatelsky Institut Biotek Composition of polymer diffusion matrix for transdermally introducing pharmaceutical substances
US4849224A (en) 1987-11-12 1989-07-18 Theratech Inc. Device for administering an active agent to the skin or mucosa
US4863738A (en) 1987-11-23 1989-09-05 Alza Corporation Skin permeation enhancer compositions using glycerol monooleate
US4863970A (en) 1986-11-14 1989-09-05 Theratech, Inc. Penetration enhancement with binary system of oleic acid, oleins, and oleyl alcohol with lower alcohols
US4867748A (en) 1986-10-17 1989-09-19 Coloplast A/S Dressing with hydrocolloid
US4871536A (en) 1982-06-17 1989-10-03 L'oreal Composition based on cationic polymers, anionic polymers and waxes for use in cosmetics
US4873299A (en) 1986-03-21 1989-10-10 Basf Aktiengesellschaft Batchwise preparation of crosslinked, finely divided polymers
US4877628A (en) 1987-09-03 1989-10-31 International Flavors & Fragrances Inc. Process for preparing a coated food product
US4904247A (en) 1984-08-31 1990-02-27 Kendall Company Pressure-sensitive hydrophilic laminate structures for use in wound dressing, transdermal and topical drug delivery
US4906169A (en) 1986-12-29 1990-03-06 Rutgers, The State University Of New Jersey Transdermal estrogen/progestin dosage unit, system and process
US4927408A (en) 1988-10-03 1990-05-22 Alza Corporation Electrotransport transdermal system
US4945084A (en) 1987-07-08 1990-07-31 Norman Oksman Method and composition for topically treating anorectal or other dermal wounds
US4973468A (en) 1989-03-22 1990-11-27 Cygnus Research Corporation Skin permeation enhancer compositions
US4983395A (en) 1987-11-12 1991-01-08 Theratech Inc. Device for administering an active agent to the skin or mucosa
US5023084A (en) 1986-12-29 1991-06-11 Rutgers, The State University Of New Jersey Transdermal estrogen/progestin dosage unit, system and process
US5053227A (en) 1989-03-22 1991-10-01 Cygnus Therapeutic Systems Skin permeation enhancer compositions, and methods and transdermal systems associated therewith
US5057500A (en) 1990-02-12 1991-10-15 Dermatologic Research Corporation Treatment of pruritis with esters and amides
JPH0366612B2 (en) 1982-06-29 1991-10-18 Shimadzu Corp
JPH03247334A (en) 1990-02-26 1991-11-05 Sumitomo Rubber Ind Ltd Cold insulant
JPH03275619A (en) 1990-03-23 1991-12-06 Nitsusui Seiyaku Kk External agent composition
US5073381A (en) 1988-08-15 1991-12-17 University Of Akron Amphiphilic networks
US5102662A (en) 1989-12-08 1992-04-07 Dow Corning Corporation Insect repellent plastic
US5125894A (en) 1990-03-30 1992-06-30 Alza Corporation Method and apparatus for controlled environment electrotransport
US5133970A (en) 1989-07-24 1992-07-28 Rohm Gmbh Chemische Fabrik Water-soluble pressure-sensitive skin-adhesive and use thereof
US5141750A (en) 1986-06-13 1992-08-25 Alza Corporation Delayed onset transdermal delivery device
JPH04266818A (en) 1991-02-21 1992-09-22 Sekisui Chem Co Ltd Tacky agent for medical application
EP0516026A1 (en) 1991-05-28 1992-12-02 Takeda Chemical Industries, Ltd. Hydrogel and method of producing same
US5173302A (en) 1990-09-28 1992-12-22 Medtronic, Inc. Hydrophilic pressure sensitive adhesive for topical administration of hydrophobic drugs
WO1993002717A1 (en) 1991-08-09 1993-02-18 Smith & Nephew Plc Adhesive products
US5196405A (en) 1987-07-08 1993-03-23 Norman H. Oskman Compositions and methods of treating hemorrhoids and wounds
US5200190A (en) 1988-10-11 1993-04-06 Sekisui Kagaku Kogyo Kabushiki Kaisha Percutaneous pharmaceutical preparation
US5224928A (en) 1983-08-18 1993-07-06 Drug Delivery Systems Inc. Mounting system for transdermal drug applicator
US5232702A (en) 1991-07-22 1993-08-03 Dow Corning Corporation Silicone pressure sensitive adhesive compositons for transdermal drug delivery devices and related medical devices
US5234690A (en) 1991-08-23 1993-08-10 Cygnus Therapeutic Systems Transdermal drug delivery device using an unfilled microporous membrane to achieve delayed onset
US5234957A (en) 1991-02-27 1993-08-10 Noven Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
US5240995A (en) 1989-02-09 1993-08-31 Alza Corporation Electrotransport adhesive
US5254346A (en) 1988-02-23 1993-10-19 Tucker Mark J Occlusive body for administering a physiologically active substance
US5270358A (en) 1989-12-28 1993-12-14 Minnesota Mining And Manufacturing Company Composite of a disperesed gel in an adhesive matrix
US5276079A (en) * 1991-11-15 1994-01-04 Minnesota Mining And Manufacturing Company Pressure-sensitive poly(n-vinyl lactam) adhesive composition and method for producing and using same
WO1994005340A1 (en) 1992-08-27 1994-03-17 Coloplast A/S A dressing for dosing one or more medicaments
US5296512A (en) 1989-04-26 1994-03-22 Rohm Gmbh Chemische Fabrik Water-soluble pressure-sensitive skin adhesive, its use, and agents provided with it
US5300291A (en) 1988-03-04 1994-04-05 Noven Pharmaceuticals, Inc. Method and device for the release of drugs to the skin
US5310563A (en) 1991-10-25 1994-05-10 Colgate-Palmolive Company Dental material and method for applying preventative and therapeutic agents
US5322689A (en) 1992-03-10 1994-06-21 The Procter & Gamble Company Topical aromatic releasing compositions
US5326685A (en) 1991-02-13 1994-07-05 Gaglio Thomas J Viscous fluid dispensing apparatus
US5332576A (en) 1991-02-27 1994-07-26 Noven Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
DE4219368C2 (en) 1992-06-12 1994-07-28 Lohmann Gmbh & Co Kg Electrically conductive transparent pressure sensitive adhesive films, process for their production and use for the production of biomedical electrodes
US5338490A (en) 1991-11-15 1994-08-16 Minnesota Mining And Manufacturing Company Two-phase composites of ionically-conductive pressure-sensitive adhesive, biomedical electrodes using the composites, and methods of preparing the composite and the biomedical electrodes
US5342623A (en) 1986-09-12 1994-08-30 Alza Corporation Subsaturated transdermal therapeutic system having improved release characteristics
US5354823A (en) 1993-08-09 1994-10-11 Isp Investments Inc. Films and extrusions of cured crosslinked vinyl lactam polymer and method of preparation
US5362420A (en) 1991-11-15 1994-11-08 Minnesota Mining And Manufacturing Company Low impedance pressure sensitive adhesive composition and biomedical electrodes using same
JPH06100467B2 (en) 1989-02-06 1994-12-12 株式会社シ−エックスア−ル Proximity sensor
EP0371421B1 (en) 1988-11-28 1994-12-21 The B.F. Goodrich Company Crosslinked polyacrylic acid
US5376377A (en) 1990-10-29 1994-12-27 Alza Corporation Transdermal contraceptive formulations, methods and devices
US5422119A (en) 1987-09-24 1995-06-06 Jencap Research Ltd. Transdermal hormone replacement therapy
US5438076A (en) 1988-05-03 1995-08-01 Perio Products, Ltd. Liquid polymer composition, and method of use
US5446070A (en) 1991-02-27 1995-08-29 Nover Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
US5456745A (en) 1988-08-13 1995-10-10 Lts Lohmann Therapie-Systeme Gmbh & Co. Kg Flexible, hydrophilic gel film, the process for its production and the use of it
US5462743A (en) 1992-10-30 1995-10-31 Medipro Sciences Limited Substance transfer system for topical application
US5462745A (en) 1986-09-12 1995-10-31 Alza Corporation Subsaturated transdermal therapeutic system having improved release characteristics
SU1459215A1 (en) 1986-12-30 1995-11-20 Всесоюзный Научно-Исследовательский Институт Биотехнологии Composition of polymeric diffusion matrix for transdermal administration of drugs
EP0581581A3 (en) 1992-07-29 1996-01-17 Johnson & Johnson Consumer Bioadhesive treatment compositions and methods of use
US5492943A (en) 1994-06-20 1996-02-20 Hollister Incorporated Adhesive skin barrier composition for ostomy appliance
US5508367A (en) 1993-11-29 1996-04-16 Adhesives Research, Inc. Water-soluble pressure sensitive adhesive
US5508024A (en) 1992-05-22 1996-04-16 International Research And Development Corp. Topical antiperspirant composition consisting essentially of non-toxic water-insoluble occlusive film-forming antiperspirant polymer
EP0545594B1 (en) 1991-11-22 1996-05-01 Colgate-Palmolive Company Oral composition having improved tooth whitening effect
US5527271A (en) 1994-03-30 1996-06-18 Bristol-Myers Squibb Co. Thermoplastic hydrogel impregnated composite material
WO1996019205A1 (en) 1994-12-21 1996-06-27 Theratech, Inc. Transdermal delivery system with adhesive overlay and peel seal disc
US5543148A (en) 1994-07-12 1996-08-06 Combe, Incorporated Stick delivery system for topical application of a treatment agent
US5563153A (en) 1995-02-22 1996-10-08 University Of Kansas Medical Center Sterile topical anesthetic gel
EP0737477A1 (en) 1993-12-27 1996-10-16 Akzo Nobel N.V. Percutaneously absorbable preparation
US5575654A (en) 1992-11-24 1996-11-19 Fontenot; Mark G. Apparatus and method for lightening teeth
US5593686A (en) 1984-03-01 1997-01-14 Sandoz Ltd. Pharmaceutical compositions
US5594068A (en) 1993-05-28 1997-01-14 Eastman Chemical Company Cellulose ester blends
US5614178A (en) 1992-07-28 1997-03-25 The Procter & Gamble Company Compositions for topical delivery of drugs comprising a mixture of high and low HLB surfactants and alkoxylated ether
WO1997011676A1 (en) 1995-09-25 1997-04-03 Robert Eric Montgomery Tooth bleaching compositions
US5631267A (en) 1993-02-02 1997-05-20 Mayo Foundation For Medical Education & Research Method for the treatment of eosinophil-associated diseases by administration of topical anesthetics
US5633010A (en) 1992-10-05 1997-05-27 Minnesota Mining And Manufacturing Company Adhesive compositions, wound dressings and methods
US5641507A (en) 1993-12-06 1997-06-24 Devillez; Richard L. Delivery system for dermatological and cosmetic ingredients
US5641504A (en) 1988-06-09 1997-06-24 Alza Corporation Skin permeation enhancer compositions using glycerol monolinoleate
US5643187A (en) 1992-01-17 1997-07-01 Coloplast A/S Dressing
US5645062A (en) 1993-02-15 1997-07-08 Anderson; John Mccune Biomedical electrode device
US5645855A (en) 1996-03-13 1997-07-08 Ridge Scientific Enterprises, Inc. Adhesive compositions including polyvinylpyrrolidone acrylic acid polymers, and polyamines
US5656286A (en) 1988-03-04 1997-08-12 Noven Pharmaceuticals, Inc. Solubility parameter based drug delivery system and method for altering drug saturation concentration
US5660178A (en) 1992-12-01 1997-08-26 Minnesota Mining And Manufacturing Company Hydrophilic pressure sensitive adhesives
US5663010A (en) 1993-11-30 1997-09-02 Olimpio Stocchiero Device to exhaust the fumes produced inside accumulator batteries
US5674561A (en) 1994-01-28 1997-10-07 Minnesota Mining And Manufacturing Company Polymerized microemulsion pressure sensitive adhesive compositions and methods of preparing and using same
US5700478A (en) 1993-08-19 1997-12-23 Cygnus, Inc. Water-soluble pressure-sensitive mucoadhesive and devices provided therewith for emplacement in a mucosa-lined body cavity
JPH1017448A (en) 1996-06-28 1998-01-20 Lion Corp Plaster for oral cavity
US5719197A (en) 1988-03-04 1998-02-17 Noven Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
US5718187A (en) 1992-12-15 1998-02-17 The Gsi Group, Inc. Poultry feeder
US5718886A (en) 1996-03-11 1998-02-17 Laclede Professional Products, Inc. Stabilized anhydrous tooth whitening gel
US5723145A (en) * 1993-09-30 1998-03-03 Takiron Co., Ltd. Transdermal absorption preparation
US5725876A (en) 1996-05-17 1998-03-10 Noven Pharmaceuticals Inc., Compositions and methods for using low-swell clays in nicotine containing dermal compositions
US5726250A (en) 1994-07-11 1998-03-10 Adhesives Research, Inc. Covalently crosslinked water-absorbent graft copolymer
US5730999A (en) 1993-03-27 1998-03-24 Roehm Gmbh Chemische Fabrik Dermal therapeutic system made of a meltable poly (meth) acrylate
US5744155A (en) 1993-08-13 1998-04-28 Friedman; Doron Bioadhesive emulsion preparations for enhanced drug delivery
US5762956A (en) 1996-04-24 1998-06-09 Rutgers, The State University Of New Jersey Transdermal contraceptive delivery system and process
US5770220A (en) 1993-12-04 1998-06-23 Lts Lohmann Therapie Systeme Gmbh Active substance-containing patch
US5773490A (en) 1993-06-24 1998-06-30 Takiron Co., Ltd. Pressure sensitive adhesive for transdermal absorption formulations
US5780050A (en) 1995-07-20 1998-07-14 Theratech, Inc. Drug delivery compositions for improved stability of steroids
US5785527A (en) 1997-01-10 1998-07-28 Ultradent Products, Inc. Stable light or heat activated dental bleaching compositions
US5785976A (en) 1993-03-05 1998-07-28 Pharmacia & Upjohn Ab Solid lipid particles, particles of bioactive agents and methods for the manufacture and use thereof
US5788983A (en) 1989-04-03 1998-08-04 Rutgers, The State University Of New Jersey Transdermal controlled delivery of pharmaceuticals at variable dosage rates and processes
US5800832A (en) 1996-10-18 1998-09-01 Virotex Corporation Bioerodable film for delivery of pharmaceutical compounds to mucosal surfaces
WO1998037870A1 (en) 1997-02-28 1998-09-03 Cygnus, Inc. Transdermal delivery of basic drugs using nonpolar adhesive systems and acidic solubilizing agents
US5804611A (en) 1995-09-22 1998-09-08 Kansai Paint Co., Ltd. Composition used for hydrophilization and method for hydrophilization using said composition
US5827525A (en) 1995-09-12 1998-10-27 Bristol-Myers Squibb Company Buccal delivery system for therapeutic agents
US5830932A (en) 1991-08-20 1998-11-03 Bioderm, Inc. External incontinence device and vapor-absorptive adhesive compositions
US5837713A (en) 1997-02-26 1998-11-17 Mayo Foundation For Medical Education And Research Treatment of eosinophil-associated pathologies by administration of topical anesthetics and glucocorticoids
US5846558A (en) 1996-03-19 1998-12-08 Minnesota Mining And Manufacturing Company Ionically conductive adhesives prepared from zwitterionic materials and medical devices using such adhesives
WO1998055044A1 (en) 1997-06-06 1998-12-10 The Procter & Gamble Company A delivery system for a tooth whitener using a strip of material having low flexural stiffness
US5851549A (en) 1994-05-25 1998-12-22 Becton Dickinson And Company Patch, with system and apparatus for manufacture
EP0511782B1 (en) 1991-04-23 1998-12-23 Perio Products Limited Polymer composition for tooth bleaching and other dental uses thereof
US5853755A (en) 1993-07-28 1998-12-29 Pharmaderm Laboratories Ltd. Biphasic multilamellar lipid vesicles
US5858332A (en) 1997-01-10 1999-01-12 Ultradent Products, Inc. Dental bleaching compositions with high concentrations of hydrogen peroxide
US5858410A (en) 1994-11-11 1999-01-12 Medac Gesellschaft Fur Klinische Spezialpraparate Pharmaceutical nanosuspensions for medicament administration as systems with increased saturation solubility and rate of solution
US5863662A (en) 1996-05-14 1999-01-26 Isp Investments Inc. Terpolymer for ink jet recording
US5876746A (en) 1995-06-07 1999-03-02 Cygnus, Inc. Transdermal patch and method for administering 17-deacetyl norgestimate alone or in combination with an estrogen
US5879691A (en) 1997-06-06 1999-03-09 The Procter & Gamble Company Delivery system for a tooth whitener using a strip of material having low flexural stiffness
EP0838225A3 (en) 1996-10-25 1999-03-24 Hiji, Yasutake Aqueous local anesthetic solution
WO1999017738A1 (en) 1997-10-03 1999-04-15 Lavipharm Laboratories, Inc. A prolamine-plant polar lipid composition, its method of preparation and applications thereof
US5900249A (en) 1998-02-09 1999-05-04 Smith; David J. Multicomponent pain relief topical medication
US5902598A (en) 1997-08-28 1999-05-11 Control Delivery Systems, Inc. Sustained release drug delivery devices
US5911980A (en) 1996-06-27 1999-06-15 Macrochem Corporation Lipophilic and amphiphilic or hydrophilic film-forming polymer compositions, and use thereof in topical agent delivery system and method of delivering agents to the skin
US5912271A (en) 1994-07-12 1999-06-15 Astra Ab Pharmaceutical preparation for pain management
US5916587A (en) 1992-12-31 1999-06-29 Sunkyong Industries Co., Ltd. Transdermal delivery matrix for piroxicam
US5942543A (en) 1994-07-15 1999-08-24 Ernst; Amy A. Topical anesthetic comprising lidocaine, adrenaline, and tetracaine, and its method of use
US5945457A (en) * 1997-10-01 1999-08-31 A.V. Topchiev Institute Of Petrochemical Synthesis, Russian Academy Of Science Process for preparing biologically compatible polymers and their use in medical devices
US5948433A (en) 1997-08-21 1999-09-07 Bertek, Inc. Transdermal patch
US5948416A (en) 1995-06-29 1999-09-07 The Procter & Gamble Company Stable topical compositions
US5948430A (en) 1996-11-11 1999-09-07 Lts Lohmann Therapie-Systeme Gmbh Water soluble film for oral administration with instant wettability
WO1999044678A1 (en) 1998-03-06 1999-09-10 Spectrx, Inc. Apparatus for electroporation through microporated tissue
WO1999047128A1 (en) 1998-03-19 1999-09-23 Bristol-Myers Squibb Company Biphasic controlled release delivery system for high solubility pharmaceuticals and method
US5958379A (en) 1994-09-30 1999-09-28 Mika Pharma Gesellschaft Fuer Die Entwicklung Und Vermarktung Pharmazeutischer Producte Mbh Pharmaceutical composition
US5958446A (en) 1988-03-04 1999-09-28 Noven Pharmaceuticals, Inc. Solubility parameter based drug delivery system and method for altering drug saturation concentration
US5962011A (en) 1993-12-06 1999-10-05 Schering-Plough Healthcare Products, Inc. Device for delivery of dermatological ingredients
WO1999054422A1 (en) 1998-04-21 1999-10-28 Coloplast A/S A pressure sensitive adhesive composition
US5976565A (en) 1996-06-20 1999-11-02 Lavipharm Laboratories, Inc. Device for topical treatment of acne and its method of manufacture
US5985311A (en) 1995-07-22 1999-11-16 Labtec Gesellschaft Fuer Techologische Forschung Und Entwicklung Mbh Transdermal hormone patch
US5985990A (en) 1995-12-29 1999-11-16 3M Innovative Properties Company Use of pendant free-radically polymerizable moieties with polar polymers to prepare hydrophilic pressure sensitive adhesive compositions
US5985860A (en) 1992-06-03 1999-11-16 Toppo; Frank System for transdermal delivery of pain relieving substances
US5990179A (en) 1995-04-28 1999-11-23 Alza Corporation Composition and method of enhancing electrotransport agent delivery
US5989569A (en) 1997-06-06 1999-11-23 The Procter & Gamble Company Delivery system for a tooth whitener using a permanently deformable strip of material
US5993836A (en) 1998-04-28 1999-11-30 Castillo; James G. Topical anesthetic formulation
US5993849A (en) 1996-12-20 1999-11-30 Roehm Gmbh Chemische Fabrik Hydrophilic adhesive and binder for medications
US5997886A (en) 1997-11-05 1999-12-07 The Procter & Gamble Company Personal care compositions
US6004566A (en) 1992-03-26 1999-12-21 Pharmos Corp. Topical and transdermal delivery system utilizing submicron oil spheres
US6004578A (en) 1996-10-24 1999-12-21 Alza Corporation Permeation enhances for transdermal drug delivery compositions, devices and methods
US6007837A (en) 1996-07-03 1999-12-28 Alza Corporation Drug delivery devices and process of manufacture
US6045811A (en) 1997-06-06 2000-04-04 The Procter & Gamble Company Delivery system for an oral care substance using a permanently deformable strip of material
US6051609A (en) 1997-09-09 2000-04-18 Tristrata Technology, Inc. Additives enhancing the effect of therapeutic agents
US6063399A (en) 1996-12-20 2000-05-16 Roehm Gmbh Chemische Fabrik Adhesive binders for dermal or transdermal therapy systems
US6068650A (en) 1997-08-01 2000-05-30 Gentronics Inc. Method of Selectively applying needle array configurations
US6075626A (en) 1997-06-25 2000-06-13 Denso Corporation Hologram
US6083421A (en) 1996-01-19 2000-07-04 Huang; Lizi Film coating composition for whitening teeth
US6093328A (en) 1994-12-08 2000-07-25 Santina; Peter F. Method for removing toxic substances in water
US6096328A (en) 1997-06-06 2000-08-01 The Procter & Gamble Company Delivery system for an oral care substance using a strip of material having low flexural stiffness
US6135126A (en) 1997-08-07 2000-10-24 Microlin, L.C. Brush that delivers beneficial agents
US6142939A (en) 1993-11-15 2000-11-07 Spectrx, Inc. Microporation of human skin for drug delivery and monitoring applications
US6162456A (en) 1992-09-24 2000-12-19 Ortho-Mcneil Pharmaceutical, Inc. Adhesive transdermal drug delivery matrix of a physical blend of hydrophilic and hydrophobic polymers
US6165499A (en) 1996-03-25 2000-12-26 Lts Lohmann Therapie-Systeme Gmbh Transdermal therapeutic system with small application-area thickness and great flexibility, and production process
US6193993B1 (en) 1998-03-03 2001-02-27 Eisai Co., Ltd. Suppository containing an antidementia medicament
US6197331B1 (en) 1997-07-24 2001-03-06 Perio Products Ltd. Pharmaceutical oral patch for controlled release of pharmaceutical agents in the oral cavity
US6201164B1 (en) 1996-07-11 2001-03-13 Coloplast A/S Hydrocolloid wound gel
WO2000069421A3 (en) 1999-05-18 2001-03-22 Sanol Arznei Schwarz Gmbh Transdermal therapeutic system (tts) containing tolterodine
US6212671B1 (en) 1997-10-20 2001-04-03 Mitsubishi Electric System Lsi Design Corporation Mask pattern data producing apparatus, mask pattern data producing method and semiconductor integrated circuit device
US6221341B1 (en) 1997-11-19 2001-04-24 Oraceutical Llc Tooth whitening compositions
US6231885B1 (en) 1997-09-17 2001-05-15 Permatec Technologie Ag Composition for controlled and sustained transdermal administration
US6248363B1 (en) 1999-11-23 2001-06-19 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
US20010006677A1 (en) 1996-10-29 2001-07-05 Mcginity James W. Effervescence polymeric film drug delivery system
US6264981B1 (en) 1999-10-27 2001-07-24 Anesta Corporation Oral transmucosal drug dosage using solid solution
US6270792B1 (en) 1998-09-18 2001-08-07 Laboratories D'hygiene Et De Dietique Sterile nonstick compress
US6275728B1 (en) 1998-12-22 2001-08-14 Alza Corporation Thin polymer film drug reservoirs
WO2001068045A1 (en) 2000-03-17 2001-09-20 Lg Household & Health Care Ltd Patches for teeth whitening
US6306370B1 (en) 1997-05-30 2001-10-23 Ultradent Products, Inc. Compositions and methods for whitening and desensitizing teeth
US6312666B1 (en) 1998-11-12 2001-11-06 3M Innovative Properties Company Methods of whitening teeth
US6316022B1 (en) 1995-06-07 2001-11-13 Noven Pharmaceuticals, Inc. Transdermal compositions containing low molecular weight drugs which are liquid at room temperatures
WO2001087276A1 (en) 2000-05-16 2001-11-22 Samyang Corporation Hydrogel composition for transdermal drug delivery
US6322774B1 (en) 1999-12-20 2001-11-27 Ultradent Products, Inc. Dental bleaching compositions containing sucralose
US20010046471A1 (en) 2000-05-09 2001-11-29 Marek Przemyslaw A. Infrared thermograpy and methods of use
US6329472B1 (en) 1998-11-18 2001-12-11 Basf Aktiengesellschaft Water-soluble or water-dispersible graft copolymers based on a polyvinyllactam, their preparation and use
WO2001026637A3 (en) 1999-10-13 2001-12-13 Lohmann Therapie Syst Lts Transdermal therapeutic system for administering acetylsalicylic acid and/or salicylic acid
US20020004190A1 (en) 2000-05-26 2002-01-10 Adam Diasti Method for whitening teeth
US20020009420A1 (en) 2000-04-11 2002-01-24 Mclaughlin Gerald Composition and method for whitening teeth
JP2002029949A (en) 2000-07-19 2002-01-29 Lion Corp Composition for oral cavity
US6368576B1 (en) 1998-11-12 2002-04-09 Ultradent Products, Inc. Methods for bleaching, opacifying and desensitizing teeth
WO2002004570A3 (en) 2000-07-07 2002-04-18 Av Topchiev Inst Petrochemical Preparation of hydrophilic pressure sensitive adhesives having optimized adhesive properties
US20020048602A1 (en) 2000-06-22 2002-04-25 Alliance Pharmaceutical Corp. Methods and compositions for the delivery of pharmaceutical agents and/or the prevention of adhesions
KR20020045224A (en) 2000-12-08 2002-06-19 성재갑 Peroxide Stabilized Patches for Teeth Whitening
US20020076487A1 (en) 2000-03-06 2002-06-20 Bohdan Zajac Method for protecting paint on an article, a composition useful therefor, and a method for making the composition
US6419906B1 (en) 2001-03-12 2002-07-16 Colgate Palmolive Company Strip for whitening tooth surfaces
US6419905B1 (en) 1998-03-20 2002-07-16 Biocosmetics, S.L. Tooth whitening composition
US20020106335A1 (en) 2000-09-20 2002-08-08 Orlowski Jan A. Two-part composition for high efficacy teeth whitening comprising a mixture of peroxides and/or percarbonates of metals
US6451240B1 (en) 1999-06-09 2002-09-17 The Procter & Gamble Company Method of manufacturing an intracutaneous microneedle array
US6451777B1 (en) 1998-07-17 2002-09-17 The University Of Texas Southwestern Medical Center Method for regulating hair growth
US20020131990A1 (en) 2000-11-30 2002-09-19 Barkalow David G. Pullulan free edible film compositions and methods of making the same
US6461636B1 (en) 1998-05-15 2002-10-08 Schwarz Pharma Ag Transdermal therapeutic system containing pergolide
WO2002087645A1 (en) 2001-05-01 2002-11-07 A.V. Topchiev Institute Of Petrochemical Synthesis Hydrogel compositions
US20020197284A1 (en) 1999-12-16 2002-12-26 Luo Eric C. Transdermal and topical administration of local anesthetic agents using basic enhancers
WO2003000216A1 (en) 2001-06-23 2003-01-03 Lg Household & Health Care Ltd. Multiple-layered patches for teeth whitening
KR20030000299A (en) 2001-06-23 2003-01-06 주식회사 엘지생활건강 Semi-transparent patches for teeth whitening
KR20030000528A (en) 2001-06-26 2003-01-06 주식회사 엘지생활건강 Patches for teeth whitening
WO2002087642A3 (en) 2001-05-01 2003-01-09 Av Topchiev Inst Petrochemical Two-phase, water-absorbent bioadhesive composition
KR20030003969A (en) 2001-07-04 2003-01-14 주식회사 엘지생활건강 Manufacturing process of patches for teeth whitening
KR20030003973A (en) 2001-07-04 2003-01-14 주식회사 엘지생활건강 Flexible patches for teeth whitening
US20030055190A1 (en) 1998-09-22 2003-03-20 Hsing-Yeh Parker Acrylic polymer compositions with crystalline side chains and processes for their preparation
WO2002089849B1 (en) 2001-05-07 2003-04-03 Corium Int Compositions and delivery systems for administration of a local anesthetic agent
US6562363B1 (en) 1997-09-26 2003-05-13 Noven Pharmaceuticals, Inc. Bioadhesive compositions and methods for topical administration of active agents
US20030100654A1 (en) 2001-06-29 2003-05-29 Theary Chheang Devices, compositions, and methods incorporating adhesives whose performance is enhanced by organophilic clay constituents
US20030103427A1 (en) 1998-05-09 2003-06-05 Lg Electronics Inc. Method for forming an information recording medium having information on spare area, and method and apparatus for recording/ reproducing data to/ from the medium
US6585997B2 (en) 2001-08-16 2003-07-01 Access Pharmaceuticals, Inc. Mucoadhesive erodible drug delivery device for controlled administration of pharmaceuticals and other active compounds
US6591124B2 (en) 2001-05-11 2003-07-08 The Procter & Gamble Company Portable interstitial fluid monitoring system
US6596298B2 (en) 1998-09-25 2003-07-22 Warner-Lambert Company Fast dissolving orally comsumable films
US20030152615A1 (en) 2001-06-18 2003-08-14 Noven Pharmaceuticals, Inc. Enhanced drug delivery in transdermal systems
US20030152528A1 (en) 2001-05-01 2003-08-14 Parminder Singh Hydrogel compositions for tooth whitening
US6611706B2 (en) 1998-11-09 2003-08-26 Transpharma Ltd. Monopolar and bipolar current application for transdermal drug delivery and analyte extraction
US20030180229A1 (en) 2002-03-21 2003-09-25 Kosti Carl M. Bleach stable toothpaste
US6638528B1 (en) 2000-01-20 2003-10-28 Noven Pharmaceuticals, Inc. Compositions and methods to effect the release profile in the transdermal administration of active agents
WO2003089046A1 (en) 2002-04-16 2003-10-30 Cyto Pulse Sciences, Inc. Method of treating biological materials with translating electrical fields and electrode polarity reversal
US20030225356A1 (en) 2002-05-24 2003-12-04 Kulichikhin Valery G. Composition for cushions, wound dressings and other skin-contacting products
US6667410B2 (en) 2000-09-18 2003-12-23 Board Of Regents, The University Of Texas System Conversion of α,β-unsaturated ketones and α,β-unsaturated esters into α-hydroxy ketones and α-hydroxy esters using Mn(III) catalyst, phenylsilane and dioxygen
US20030235549A1 (en) 2001-05-01 2003-12-25 Parminder Singh Hydrogel compositions demonstrating phase separation on contact with aqueous media
US20040005277A1 (en) 2002-07-02 2004-01-08 Willison Michael P. Device and method for delivering an oral care agent
US6689344B2 (en) 2000-03-17 2004-02-10 Lg Household & Healthcare Ltd. Patches for teeth whitening
US6696459B1 (en) 1994-12-22 2004-02-24 Ligand Pharmaceuticals Inc. Steroid receptor modulator compounds and methods
US6708060B1 (en) 1998-11-09 2004-03-16 Transpharma Ltd. Handheld apparatus and method for transdermal drug delivery and analyte extraction
US20040053901A1 (en) 1999-11-24 2004-03-18 Te-Yen Chien Transdermal hormone delivery system: compositions and methods
US6711435B2 (en) 1998-11-09 2004-03-23 Transpharma Ltd. Transdermal drug delivery and analyte extraction
US20040105834A1 (en) 2001-05-01 2004-06-03 Corium International Hydrogel compositions with an erodible backing member
WO2004045569A1 (en) 2002-11-21 2004-06-03 Lg Household & Health Care Ltd. Dry type patches safe for gum
US6750291B2 (en) 2002-04-12 2004-06-15 Pacific Corporation Film-forming agent for drug delivery and preparation for percutaneous administration containing the same
US20040136927A1 (en) 2000-03-17 2004-07-15 Ji-Young Kim Apparatus and method for whitening teeth
WO2004054638A3 (en) 2002-12-13 2004-08-12 Corium Int Inc Dermal, transdermal, mucosal or transmucosal ingredient delivery devices
US6805874B1 (en) 2002-12-03 2004-10-19 Permamed Ag Method and skin cleansing compositions for dermatological basic treatment
US20040219111A1 (en) 2000-03-17 2004-11-04 Ji-Young Kim Method and device for teeth whitening using a dry type adhesive
US20040258723A1 (en) 2001-05-01 2004-12-23 Parminder Singh Hydrogel compositions demonstrating phase separation on contact with aqueous media
US20050113510A1 (en) 2001-05-01 2005-05-26 Feldstein Mikhail M. Method of preparing polymeric adhesive compositions utilizing the mechanism of interaction between the polymer components
WO2005074894A1 (en) 2004-01-30 2005-08-18 Corium International Rapidly dissolving film for delivery of an active agent
WO2004093786A3 (en) 2003-04-16 2006-03-23 Corium Int Covalent and non-covalent crosslinking of hydrophilic polymers and adhesive compositions prepared therewith
CA2520986C (en) 1998-09-25 2007-11-13 Warner-Lambert Company Physiological compatible film

Family Cites Families (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5599373A (en) 1988-09-30 1997-02-04 F.P.S.- Finances Products Services, S.R.L. Sulfur-based chemical soil-corrective in the form of pellets for agricultural use
JPH01151524A (en) 1988-11-10 1989-06-14 Yamanouchi Pharmaceut Co Ltd 'satotsu-ko' poultice and preparation thereof
US4953053A (en) 1989-01-31 1990-08-28 Harnischfeger Corporation Method and apparatus for detecting mechanical overload of a hoist
DE3910543A1 (en) 1989-04-01 1990-10-11 Lohmann Therapie Syst Lts TRANSDERMAL THERAPEUTIC SYSTEM WITH INCREASED ACTIVE FLUID AND METHOD FOR THE PRODUCTION THEREOF
US5206385A (en) 1992-01-24 1993-04-27 Isp Investments Inc. Urea-hydrogen peroxide-polyvinylpyrrolidone process
US5183901A (en) 1992-01-24 1993-02-02 Isp Investments Inc. Urea-hydrogen peroxide-polyvinylpyrrolidone
US5827213A (en) 1995-10-19 1998-10-27 Ole R. Jensen Heel and elbow dressing
JP3628809B2 (en) 1996-06-10 2005-03-16 アルケア株式会社 Drug sustained-release medical preparation and method for producing the same
DE19640365A1 (en) 1996-09-30 1998-04-02 Basf Ag Polymer-hydrogen peroxide complexes
US5958984A (en) 1996-10-10 1999-09-28 Devillez; Richard L. Method and composition for skin treatment
DE19652268C2 (en) 1996-12-16 2000-06-29 Lohmann Therapie Syst Lts Medicinal preparation for the release of apomorphine in the oral cavity
US5843472A (en) 1997-02-28 1998-12-01 Cygnus, Inc. Transdermal drug delivery sytem for the administration of tamsulosin, and related compositions and methods of use
US5894017A (en) 1997-06-06 1999-04-13 The Procter & Gamble Company Delivery system for an oral care substance using a strip of material having low flexural stiffness
US20020018754A1 (en) 1999-03-15 2002-02-14 Paul Albert Sagel Shapes for tooth whitening strips
EP1002158B1 (en) 1997-08-05 2001-05-30 B-MAC, besloten vennootschap met beperkte aansprakelijkheid Vibrating device for processing a floor layer
AU735912B2 (en) 1997-08-29 2001-07-19 Avery Dennison Corporation Biological fluid absorbing pressure sensitive adhesives
US6072100A (en) 1998-01-28 2000-06-06 Johnson & Johnson Consumer Products, Inc. Extrudable compositions for topical or transdermal drug delivery
AU746339B2 (en) 1998-04-29 2002-04-18 Arius Two, Inc. Pharmaceutical carrier device suitable for delivery of pharmaceutical compounds to mucosal surfaces
CA2369012A1 (en) 1999-04-13 2000-10-19 Hisamitsu Pharmaceutical Co., Inc. Preparations for percutaneous absorption
US6962691B1 (en) 1999-05-20 2005-11-08 U & I Pharmaceuticals Ltd. Topical spray compositions
KR20020032521A (en) 1999-07-02 2002-05-03 데이비드 엠 모이어 Delivery system for oral care compositions comprising organosiloxane resins using a removable backing strip
AU779027B2 (en) 1999-07-27 2005-01-06 Hisamitsu Pharmaceutical Co., Inc. Patches for external use
US20030104041A1 (en) 1999-12-16 2003-06-05 Tsung-Min Hsu Transdermal and topical administration of drugs using basic permeation enhancers
US6602912B2 (en) 2000-06-30 2003-08-05 Dermatrends, Inc. Transdermal administration of phenylpropanolamine
JP2001213768A (en) 2000-02-01 2001-08-07 Okayama Taiho Pharmaceutical Co Ltd Poultice
PL360092A1 (en) 2000-06-28 2004-09-06 The Procter & Gamble Company Structures and compositions increasing the stability of peroxide actives
JP2002145746A (en) 2000-11-02 2002-05-22 Haruyuki Kawahara Tooth bleaching agent
BR0115523A (en) 2000-12-22 2003-09-16 Aspen Aerogels Inc Composite
NZ530439A (en) 2001-04-20 2004-11-26 Lavipharm Lab Inc Intraoral delivery of nicotine for smoking cessation
US20050215727A1 (en) 2001-05-01 2005-09-29 Corium Water-absorbent adhesive compositions and associated methods of manufacture and use
US6656493B2 (en) 2001-07-30 2003-12-02 Wm. Wrigley Jr. Company Edible film formulations containing maltodextrin
WO2003011259A1 (en) 2001-07-30 2003-02-13 Wm. Wrigley Jr. Company Improved edible film formulations containing maltodextrin
US6732383B2 (en) 2001-12-03 2004-05-11 The Burton Corporation Goggle with side arm for wearing with a helmet
AU2003240824B9 (en) 2002-05-31 2008-09-25 University Of Mississippi Transmucosal delivery of cannabinoids
DE10236349A1 (en) 2002-08-08 2004-02-19 Basf Coatings Ag Coil coating composition, useful in automobile manufacture, comprises a binding agent comprising at least one polyester and a cross-linking agent comprising at least two amine group-containing resins of different reactivity
FR2846663B1 (en) 2002-11-05 2006-08-11 Rhodia Elect & Catalysis LIGHT-EMITTING MATERIAL, PARTICULARLY FOR GREENHOUSE WALLS, COMPRISING AS A BARIUM AND MAGNESIUM SILICATE ADDITIVE
US7112713B2 (en) 2003-03-12 2006-09-26 Gelsus Research And Consulting, Inc. Dressing based on the Teorell-Meyer gradient
WO2004103328A1 (en) 2003-04-30 2004-12-02 Icure Pharmaceutical Corporation Patch for tooth whitening
US7649029B2 (en) 2004-05-17 2010-01-19 3M Innovative Properties Company Dental compositions containing nanozirconia fillers
RU2393877C2 (en) 2004-08-05 2010-07-10 Кориум Интернэшнл, Инк. Adhesive composition
ATE413166T1 (en) 2004-11-22 2008-11-15 Hisamitsu Pharmaceutical Co TRANSDERMAL PLASTER CONTAINING A MELTING POINT-LOWERING EXCIPIENT
CA2822643A1 (en) 2004-12-21 2006-06-29 Corium International, Inc. Sustained release tooth whitening formulations and systems
US20060182788A1 (en) 2005-01-27 2006-08-17 Parminder Singh Hydrophilic biocompatible adhesive formulations and uses
US20060264805A1 (en) 2005-05-11 2006-11-23 Corium International, Inc. Permeabilization of biological membranes
KR20090009235A (en) 2006-04-11 2009-01-22 니찌방 가부시기가이샤 Tamsulosin-containing percutaneous absorption type preparation
CA2751884C (en) 2009-01-14 2018-09-25 Corium International, Inc. Transdermal administration of tamsulosin

Patent Citations (320)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2561071A (en) 1949-09-21 1951-07-17 Prisk Howard Conley Holder for subcutaneous administration of medicaments
US2579403A (en) 1950-06-01 1951-12-18 Slomowitz Julius Medical bandage
US3150977A (en) 1959-12-23 1964-09-29 Gevaert Photo Prod Nv Light-sensitive photographic materials
GB1108837A (en) 1965-11-30 1968-04-03 Astra Pharma Prod Improvements in material for causing local anaesthesia
US3689439A (en) 1968-06-12 1972-09-05 Gaf Corp Process for preparing a crosslinked porous polyvinyl pyrrolidone granule
US3721657A (en) 1969-07-28 1973-03-20 M Seiderman Hydrophilic gel polymers of vinylpyrrolidine and hydroxyalkyl methacrylate
US3749755A (en) 1969-12-22 1973-07-31 Basf Ag Thermoplastic molding compositions of high impact resistance
US3852228A (en) 1971-01-07 1974-12-03 D Brothers Thixotropic coating composition
US3996934A (en) 1971-08-09 1976-12-14 Alza Corporation Medical bandage
US3957605A (en) 1973-09-10 1976-05-18 Union Carbide Corporation Process for radiation cocrosslinking water soluble polymers and products thereof
US3993551A (en) 1973-09-10 1976-11-23 Union Carbide Corporation Process for cocrosslinking water soluble polymers and products thereof
US4091090A (en) 1974-07-08 1978-05-23 Johnson & Johnson Potentiated anesthetics
US4093673A (en) 1974-11-14 1978-06-06 Ppg Industries, Inc. Coating compositions composed of hydroxyfunctional polymers or copolymers and alkoxysilanes
US4160020A (en) 1975-11-24 1979-07-03 Alza Corporation Therapeutic device for osmotically dosing at controlled rate
US4231369A (en) 1977-05-24 1980-11-04 Coloplast International A/S Sealing material for ostomy devices
US4562060A (en) 1977-12-01 1985-12-31 Astra Lakemedel Aktiebolag Local anesthetic mixture for topical application, process for its preparation, as well as method for obtaining local anesthesia
US4529601A (en) 1977-12-01 1985-07-16 Astra Lakemedel Aktiebolag Local anesthetic mixture for topical application and method for obtaining local anesthesia
US4277580A (en) 1978-05-22 1981-07-07 Texaco Inc. Terpolymer of N-vinyl pyrrolidone in alkoxylated form
US4492685A (en) 1979-08-14 1985-01-08 Key Pharmaceuticals, Inc. Protective skin matrix
US4552751A (en) 1980-10-17 1985-11-12 Ono Pharmaceutical Co., Ltd. Long-lasting multi-layered film preparation
US4325851A (en) 1980-10-24 1982-04-20 Herman Colon Water-activatable hot-melt adhesives
US4346709A (en) 1980-11-10 1982-08-31 Alza Corporation Drug delivery devices comprising erodible polymer and erosion rate modifier
US4367732A (en) 1980-12-05 1983-01-11 Coloplast A/S Skin barrier
US4750482A (en) * 1982-02-25 1988-06-14 Pfizer Inc. Hydrophilic, elastomeric, pressure-sensitive adhesive
US4699146A (en) 1982-02-25 1987-10-13 Valleylab, Inc. Hydrophilic, elastomeric, pressure-sensitive adhesive
JPS58162681U (en) 1982-04-22 1983-10-29 ソニー株式会社 Electrical equipment operating device
US4871536A (en) 1982-06-17 1989-10-03 L'oreal Composition based on cationic polymers, anionic polymers and waxes for use in cosmetics
JPH0366612B2 (en) 1982-06-29 1991-10-18 Shimadzu Corp
US4587289A (en) 1982-09-27 1986-05-06 Ahmet Comert Adhesive thermoplastic compositions
JPS59196817A (en) 1983-04-21 1984-11-08 Sekisui Chem Co Ltd Application drug
US4557934A (en) 1983-06-21 1985-12-10 The Procter & Gamble Company Penetrating topical pharmaceutical compositions containing 1-dodecyl-azacycloheptan-2-one
US5224928A (en) 1983-08-18 1993-07-06 Drug Delivery Systems Inc. Mounting system for transdermal drug applicator
US5593686A (en) 1984-03-01 1997-01-14 Sandoz Ltd. Pharmaceutical compositions
US4904247A (en) 1984-08-31 1990-02-27 Kendall Company Pressure-sensitive hydrophilic laminate structures for use in wound dressing, transdermal and topical drug delivery
US4624665A (en) 1984-10-01 1986-11-25 Biotek, Inc. Method of transdermal drug delivery
US4568343A (en) 1984-10-09 1986-02-04 Alza Corporation Skin permeation enhancer compositions
US4593053A (en) 1984-12-07 1986-06-03 Medtronic, Inc. Hydrophilic pressure sensitive biomedical adhesive composition
EP0184470B1 (en) 1984-12-07 1991-04-17 Medtronic, Inc. Hydrophilic, pressure sensitive biomedical adhesive composition
DE8509793U1 (en) 1985-04-02 1985-05-15 Allpack Industrielle Lohnverpackung GmbH & Co KG, 7050 Waiblingen Pharmaco adhesive plaster
US4771105A (en) 1986-02-05 1988-09-13 Sekisui Kaseihin Kogyo Kabushiki Kaisha Water-absorbent resin and process for producing the same
US4743249A (en) 1986-02-14 1988-05-10 Ciba-Geigy Corp. Dermal and transdermal patches having a discontinuous pattern adhesive layer
US4873299A (en) 1986-03-21 1989-10-10 Basf Aktiengesellschaft Batchwise preparation of crosslinked, finely divided polymers
US5141750A (en) 1986-06-13 1992-08-25 Alza Corporation Delayed onset transdermal delivery device
US4713243A (en) 1986-06-16 1987-12-15 Johnson & Johnson Products, Inc. Bioadhesive extruded film for intra-oral drug delivery and process
US5342623A (en) 1986-09-12 1994-08-30 Alza Corporation Subsaturated transdermal therapeutic system having improved release characteristics
US5462745A (en) 1986-09-12 1995-10-31 Alza Corporation Subsaturated transdermal therapeutic system having improved release characteristics
US4867748A (en) 1986-10-17 1989-09-19 Coloplast A/S Dressing with hydrocolloid
US4863970A (en) 1986-11-14 1989-09-05 Theratech, Inc. Penetration enhancement with binary system of oleic acid, oleins, and oleyl alcohol with lower alcohols
US4906169A (en) 1986-12-29 1990-03-06 Rutgers, The State University Of New Jersey Transdermal estrogen/progestin dosage unit, system and process
US5023084A (en) 1986-12-29 1991-06-11 Rutgers, The State University Of New Jersey Transdermal estrogen/progestin dosage unit, system and process
SU1459215A1 (en) 1986-12-30 1995-11-20 Всесоюзный Научно-Исследовательский Институт Биотехнологии Composition of polymeric diffusion matrix for transdermal administration of drugs
US4945084A (en) 1987-07-08 1990-07-31 Norman Oksman Method and composition for topically treating anorectal or other dermal wounds
US5196405A (en) 1987-07-08 1993-03-23 Norman H. Oskman Compositions and methods of treating hemorrhoids and wounds
EP0303445A1 (en) 1987-08-13 1989-02-15 Walton S.A. Clebopride transdermal patch
US4877628A (en) 1987-09-03 1989-10-31 International Flavors & Fragrances Inc. Process for preparing a coated food product
US5422119A (en) 1987-09-24 1995-06-06 Jencap Research Ltd. Transdermal hormone replacement therapy
WO1989003859A1 (en) 1987-10-23 1989-05-05 Vsesojuzny Nauchno-Issledovatelsky Institut Biotek Composition of polymer diffusion matrix for transdermally introducing pharmaceutical substances
US4983395A (en) 1987-11-12 1991-01-08 Theratech Inc. Device for administering an active agent to the skin or mucosa
US4849224A (en) 1987-11-12 1989-07-18 Theratech Inc. Device for administering an active agent to the skin or mucosa
US4863738A (en) 1987-11-23 1989-09-05 Alza Corporation Skin permeation enhancer compositions using glycerol monooleate
US5254346A (en) 1988-02-23 1993-10-19 Tucker Mark J Occlusive body for administering a physiologically active substance
US5958446A (en) 1988-03-04 1999-09-28 Noven Pharmaceuticals, Inc. Solubility parameter based drug delivery system and method for altering drug saturation concentration
US6024976A (en) 1988-03-04 2000-02-15 Noven Pharmaceuticals, Inc. Solubility parameter based drug delivery system and method for altering drug saturation concentration
US5656286A (en) 1988-03-04 1997-08-12 Noven Pharmaceuticals, Inc. Solubility parameter based drug delivery system and method for altering drug saturation concentration
US5719197A (en) 1988-03-04 1998-02-17 Noven Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
US5300291A (en) 1988-03-04 1994-04-05 Noven Pharmaceuticals, Inc. Method and device for the release of drugs to the skin
US5438076A (en) 1988-05-03 1995-08-01 Perio Products, Ltd. Liquid polymer composition, and method of use
US5641504A (en) 1988-06-09 1997-06-24 Alza Corporation Skin permeation enhancer compositions using glycerol monolinoleate
US5456745A (en) 1988-08-13 1995-10-10 Lts Lohmann Therapie-Systeme Gmbh & Co. Kg Flexible, hydrophilic gel film, the process for its production and the use of it
US5073381A (en) 1988-08-15 1991-12-17 University Of Akron Amphiphilic networks
US4927408A (en) 1988-10-03 1990-05-22 Alza Corporation Electrotransport transdermal system
EP0364211B1 (en) 1988-10-11 1994-12-21 Shire Holdings Ltd. A percutaneous pharmaceutical preparation
US5200190A (en) 1988-10-11 1993-04-06 Sekisui Kagaku Kogyo Kabushiki Kaisha Percutaneous pharmaceutical preparation
EP0371421B1 (en) 1988-11-28 1994-12-21 The B.F. Goodrich Company Crosslinked polyacrylic acid
JPH06100467B2 (en) 1989-02-06 1994-12-12 株式会社シ−エックスア−ル Proximity sensor
US5240995A (en) 1989-02-09 1993-08-31 Alza Corporation Electrotransport adhesive
US5344394A (en) 1989-02-09 1994-09-06 Alza Corporation Iontophoretic device incorporating an electrotransport adhesive
US5053227A (en) 1989-03-22 1991-10-01 Cygnus Therapeutic Systems Skin permeation enhancer compositions, and methods and transdermal systems associated therewith
US4973468A (en) 1989-03-22 1990-11-27 Cygnus Research Corporation Skin permeation enhancer compositions
US5788983A (en) 1989-04-03 1998-08-04 Rutgers, The State University Of New Jersey Transdermal controlled delivery of pharmaceuticals at variable dosage rates and processes
US5296512A (en) 1989-04-26 1994-03-22 Rohm Gmbh Chemische Fabrik Water-soluble pressure-sensitive skin adhesive, its use, and agents provided with it
US5133970A (en) 1989-07-24 1992-07-28 Rohm Gmbh Chemische Fabrik Water-soluble pressure-sensitive skin-adhesive and use thereof
US5102662A (en) 1989-12-08 1992-04-07 Dow Corning Corporation Insect repellent plastic
US5270358A (en) 1989-12-28 1993-12-14 Minnesota Mining And Manufacturing Company Composite of a disperesed gel in an adhesive matrix
US5057500A (en) 1990-02-12 1991-10-15 Dermatologic Research Corporation Treatment of pruritis with esters and amides
JPH03247334A (en) 1990-02-26 1991-11-05 Sumitomo Rubber Ind Ltd Cold insulant
JPH03275619A (en) 1990-03-23 1991-12-06 Nitsusui Seiyaku Kk External agent composition
US5125894A (en) 1990-03-30 1992-06-30 Alza Corporation Method and apparatus for controlled environment electrotransport
US5173302A (en) 1990-09-28 1992-12-22 Medtronic, Inc. Hydrophilic pressure sensitive adhesive for topical administration of hydrophobic drugs
US5376377A (en) 1990-10-29 1994-12-27 Alza Corporation Transdermal contraceptive formulations, methods and devices
US5326685A (en) 1991-02-13 1994-07-05 Gaglio Thomas J Viscous fluid dispensing apparatus
JPH04266818A (en) 1991-02-21 1992-09-22 Sekisui Chem Co Ltd Tacky agent for medical application
US5234957A (en) 1991-02-27 1993-08-10 Noven Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
US5446070A (en) 1991-02-27 1995-08-29 Nover Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
US5332576A (en) 1991-02-27 1994-07-26 Noven Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
EP0511782B1 (en) 1991-04-23 1998-12-23 Perio Products Limited Polymer composition for tooth bleaching and other dental uses thereof
EP0516026A1 (en) 1991-05-28 1992-12-02 Takeda Chemical Industries, Ltd. Hydrogel and method of producing same
US5232702A (en) 1991-07-22 1993-08-03 Dow Corning Corporation Silicone pressure sensitive adhesive compositons for transdermal drug delivery devices and related medical devices
WO1993002717A1 (en) 1991-08-09 1993-02-18 Smith & Nephew Plc Adhesive products
US5830932A (en) 1991-08-20 1998-11-03 Bioderm, Inc. External incontinence device and vapor-absorptive adhesive compositions
US5234690A (en) 1991-08-23 1993-08-10 Cygnus Therapeutic Systems Transdermal drug delivery device using an unfilled microporous membrane to achieve delayed onset
US5310563A (en) 1991-10-25 1994-05-10 Colgate-Palmolive Company Dental material and method for applying preventative and therapeutic agents
US5362420A (en) 1991-11-15 1994-11-08 Minnesota Mining And Manufacturing Company Low impedance pressure sensitive adhesive composition and biomedical electrodes using same
US5276079A (en) * 1991-11-15 1994-01-04 Minnesota Mining And Manufacturing Company Pressure-sensitive poly(n-vinyl lactam) adhesive composition and method for producing and using same
US5338490A (en) 1991-11-15 1994-08-16 Minnesota Mining And Manufacturing Company Two-phase composites of ionically-conductive pressure-sensitive adhesive, biomedical electrodes using the composites, and methods of preparing the composite and the biomedical electrodes
EP0545594B1 (en) 1991-11-22 1996-05-01 Colgate-Palmolive Company Oral composition having improved tooth whitening effect
US5643187A (en) 1992-01-17 1997-07-01 Coloplast A/S Dressing
US5322689A (en) 1992-03-10 1994-06-21 The Procter & Gamble Company Topical aromatic releasing compositions
US6004566A (en) 1992-03-26 1999-12-21 Pharmos Corp. Topical and transdermal delivery system utilizing submicron oil spheres
US5508024A (en) 1992-05-22 1996-04-16 International Research And Development Corp. Topical antiperspirant composition consisting essentially of non-toxic water-insoluble occlusive film-forming antiperspirant polymer
US5985860A (en) 1992-06-03 1999-11-16 Toppo; Frank System for transdermal delivery of pain relieving substances
DE4219368C2 (en) 1992-06-12 1994-07-28 Lohmann Gmbh & Co Kg Electrically conductive transparent pressure sensitive adhesive films, process for their production and use for the production of biomedical electrodes
US5614178A (en) 1992-07-28 1997-03-25 The Procter & Gamble Company Compositions for topical delivery of drugs comprising a mixture of high and low HLB surfactants and alkoxylated ether
EP0581581A3 (en) 1992-07-29 1996-01-17 Johnson & Johnson Consumer Bioadhesive treatment compositions and methods of use
US6153215A (en) 1992-08-27 2000-11-28 Colorplast A/S Dressing for dosing one or more medicaments
WO1994005340A1 (en) 1992-08-27 1994-03-17 Coloplast A/S A dressing for dosing one or more medicaments
US6162456A (en) 1992-09-24 2000-12-19 Ortho-Mcneil Pharmaceutical, Inc. Adhesive transdermal drug delivery matrix of a physical blend of hydrophilic and hydrophobic polymers
US5633010A (en) 1992-10-05 1997-05-27 Minnesota Mining And Manufacturing Company Adhesive compositions, wound dressings and methods
US5462743A (en) 1992-10-30 1995-10-31 Medipro Sciences Limited Substance transfer system for topical application
US5575654A (en) 1992-11-24 1996-11-19 Fontenot; Mark G. Apparatus and method for lightening teeth
US5660178A (en) 1992-12-01 1997-08-26 Minnesota Mining And Manufacturing Company Hydrophilic pressure sensitive adhesives
EP0672094B1 (en) 1992-12-01 1997-09-24 Minnesota Mining And Manufacturing Company Hydrophilic polyoxyethylene pressure sensitive adhesives
US5718187A (en) 1992-12-15 1998-02-17 The Gsi Group, Inc. Poultry feeder
US5916587A (en) 1992-12-31 1999-06-29 Sunkyong Industries Co., Ltd. Transdermal delivery matrix for piroxicam
US5631267A (en) 1993-02-02 1997-05-20 Mayo Foundation For Medical Education & Research Method for the treatment of eosinophil-associated diseases by administration of topical anesthetics
US5645062A (en) 1993-02-15 1997-07-08 Anderson; John Mccune Biomedical electrode device
US5785976A (en) 1993-03-05 1998-07-28 Pharmacia & Upjohn Ab Solid lipid particles, particles of bioactive agents and methods for the manufacture and use thereof
US5730999A (en) 1993-03-27 1998-03-24 Roehm Gmbh Chemische Fabrik Dermal therapeutic system made of a meltable poly (meth) acrylate
US5594068A (en) 1993-05-28 1997-01-14 Eastman Chemical Company Cellulose ester blends
US5773490A (en) 1993-06-24 1998-06-30 Takiron Co., Ltd. Pressure sensitive adhesive for transdermal absorption formulations
US5853755A (en) 1993-07-28 1998-12-29 Pharmaderm Laboratories Ltd. Biphasic multilamellar lipid vesicles
US5354823A (en) 1993-08-09 1994-10-11 Isp Investments Inc. Films and extrusions of cured crosslinked vinyl lactam polymer and method of preparation
US5744155A (en) 1993-08-13 1998-04-28 Friedman; Doron Bioadhesive emulsion preparations for enhanced drug delivery
US5700478A (en) 1993-08-19 1997-12-23 Cygnus, Inc. Water-soluble pressure-sensitive mucoadhesive and devices provided therewith for emplacement in a mucosa-lined body cavity
US5723145A (en) * 1993-09-30 1998-03-03 Takiron Co., Ltd. Transdermal absorption preparation
US6142939A (en) 1993-11-15 2000-11-07 Spectrx, Inc. Microporation of human skin for drug delivery and monitoring applications
US5508367A (en) 1993-11-29 1996-04-16 Adhesives Research, Inc. Water-soluble pressure sensitive adhesive
US5663010A (en) 1993-11-30 1997-09-02 Olimpio Stocchiero Device to exhaust the fumes produced inside accumulator batteries
US5770220A (en) 1993-12-04 1998-06-23 Lts Lohmann Therapie Systeme Gmbh Active substance-containing patch
US5962011A (en) 1993-12-06 1999-10-05 Schering-Plough Healthcare Products, Inc. Device for delivery of dermatological ingredients
US5641507A (en) 1993-12-06 1997-06-24 Devillez; Richard L. Delivery system for dermatological and cosmetic ingredients
EP0737477A1 (en) 1993-12-27 1996-10-16 Akzo Nobel N.V. Percutaneously absorbable preparation
US6221383B1 (en) 1994-01-07 2001-04-24 Noven Pharmaceuticals, Inc. Solubility parameter based drug delivery system and method for altering drug saturation concentration
US5674561A (en) 1994-01-28 1997-10-07 Minnesota Mining And Manufacturing Company Polymerized microemulsion pressure sensitive adhesive compositions and methods of preparing and using same
US5527271A (en) 1994-03-30 1996-06-18 Bristol-Myers Squibb Co. Thermoplastic hydrogel impregnated composite material
US5851549A (en) 1994-05-25 1998-12-22 Becton Dickinson And Company Patch, with system and apparatus for manufacture
US5492943A (en) 1994-06-20 1996-02-20 Hollister Incorporated Adhesive skin barrier composition for ostomy appliance
US5726250A (en) 1994-07-11 1998-03-10 Adhesives Research, Inc. Covalently crosslinked water-absorbent graft copolymer
US5543148A (en) 1994-07-12 1996-08-06 Combe, Incorporated Stick delivery system for topical application of a treatment agent
US5912271A (en) 1994-07-12 1999-06-15 Astra Ab Pharmaceutical preparation for pain management
US5942543A (en) 1994-07-15 1999-08-24 Ernst; Amy A. Topical anesthetic comprising lidocaine, adrenaline, and tetracaine, and its method of use
US5958379A (en) 1994-09-30 1999-09-28 Mika Pharma Gesellschaft Fuer Die Entwicklung Und Vermarktung Pharmazeutischer Producte Mbh Pharmaceutical composition
US5858410A (en) 1994-11-11 1999-01-12 Medac Gesellschaft Fur Klinische Spezialpraparate Pharmaceutical nanosuspensions for medicament administration as systems with increased saturation solubility and rate of solution
US6093328A (en) 1994-12-08 2000-07-25 Santina; Peter F. Method for removing toxic substances in water
US5662925A (en) 1994-12-21 1997-09-02 Theratech, Inc. Transdermal delivery system with adhesive overlay and peel seal disc
WO1996019205A1 (en) 1994-12-21 1996-06-27 Theratech, Inc. Transdermal delivery system with adhesive overlay and peel seal disc
US6696459B1 (en) 1994-12-22 2004-02-24 Ligand Pharmaceuticals Inc. Steroid receptor modulator compounds and methods
US5563153A (en) 1995-02-22 1996-10-08 University Of Kansas Medical Center Sterile topical anesthetic gel
US5990179A (en) 1995-04-28 1999-11-23 Alza Corporation Composition and method of enhancing electrotransport agent delivery
US6316022B1 (en) 1995-06-07 2001-11-13 Noven Pharmaceuticals, Inc. Transdermal compositions containing low molecular weight drugs which are liquid at room temperatures
US5876746A (en) 1995-06-07 1999-03-02 Cygnus, Inc. Transdermal patch and method for administering 17-deacetyl norgestimate alone or in combination with an estrogen
US5972377A (en) 1995-06-07 1999-10-26 Cygnus, Inc. Transdermal patch and method for administering 17-deacetyl norgestimate alone or in combination with an estrogen
US5948416A (en) 1995-06-29 1999-09-07 The Procter & Gamble Company Stable topical compositions
US5780050A (en) 1995-07-20 1998-07-14 Theratech, Inc. Drug delivery compositions for improved stability of steroids
US5985311A (en) 1995-07-22 1999-11-16 Labtec Gesellschaft Fuer Techologische Forschung Und Entwicklung Mbh Transdermal hormone patch
US5827525A (en) 1995-09-12 1998-10-27 Bristol-Myers Squibb Company Buccal delivery system for therapeutic agents
US5804611A (en) 1995-09-22 1998-09-08 Kansai Paint Co., Ltd. Composition used for hydrophilization and method for hydrophilization using said composition
US6312670B1 (en) 1995-09-25 2001-11-06 R. Eric Montgomery Tooth bleaching compositions
WO1997011676A1 (en) 1995-09-25 1997-04-03 Robert Eric Montgomery Tooth bleaching compositions
US5985990A (en) 1995-12-29 1999-11-16 3M Innovative Properties Company Use of pendant free-radically polymerizable moieties with polar polymers to prepare hydrophilic pressure sensitive adhesive compositions
US6083421A (en) 1996-01-19 2000-07-04 Huang; Lizi Film coating composition for whitening teeth
US5718886A (en) 1996-03-11 1998-02-17 Laclede Professional Products, Inc. Stabilized anhydrous tooth whitening gel
US5645855A (en) 1996-03-13 1997-07-08 Ridge Scientific Enterprises, Inc. Adhesive compositions including polyvinylpyrrolidone acrylic acid polymers, and polyamines
US5846558A (en) 1996-03-19 1998-12-08 Minnesota Mining And Manufacturing Company Ionically conductive adhesives prepared from zwitterionic materials and medical devices using such adhesives
US6165499A (en) 1996-03-25 2000-12-26 Lts Lohmann Therapie-Systeme Gmbh Transdermal therapeutic system with small application-area thickness and great flexibility, and production process
US5762956A (en) 1996-04-24 1998-06-09 Rutgers, The State University Of New Jersey Transdermal contraceptive delivery system and process
US5863662A (en) 1996-05-14 1999-01-26 Isp Investments Inc. Terpolymer for ink jet recording
US5725876A (en) 1996-05-17 1998-03-10 Noven Pharmaceuticals Inc., Compositions and methods for using low-swell clays in nicotine containing dermal compositions
US5976565A (en) 1996-06-20 1999-11-02 Lavipharm Laboratories, Inc. Device for topical treatment of acne and its method of manufacture
US5911980A (en) 1996-06-27 1999-06-15 Macrochem Corporation Lipophilic and amphiphilic or hydrophilic film-forming polymer compositions, and use thereof in topical agent delivery system and method of delivering agents to the skin
JPH1017448A (en) 1996-06-28 1998-01-20 Lion Corp Plaster for oral cavity
US6007837A (en) 1996-07-03 1999-12-28 Alza Corporation Drug delivery devices and process of manufacture
US6201164B1 (en) 1996-07-11 2001-03-13 Coloplast A/S Hydrocolloid wound gel
US5800832A (en) 1996-10-18 1998-09-01 Virotex Corporation Bioerodable film for delivery of pharmaceutical compounds to mucosal surfaces
US6004578A (en) 1996-10-24 1999-12-21 Alza Corporation Permeation enhances for transdermal drug delivery compositions, devices and methods
EP0838225A3 (en) 1996-10-25 1999-03-24 Hiji, Yasutake Aqueous local anesthetic solution
US20010006677A1 (en) 1996-10-29 2001-07-05 Mcginity James W. Effervescence polymeric film drug delivery system
US6177096B1 (en) 1996-11-11 2001-01-23 Lts Lohmann Therapie-Systeme Gmbh Water soluble film for oral administration with instant wettability
US6709671B2 (en) 1996-11-11 2004-03-23 Lts Lohmann Therapie-Systeme Ag Water soluble film for oral administration with instant wettability
US5948430A (en) 1996-11-11 1999-09-07 Lts Lohmann Therapie-Systeme Gmbh Water soluble film for oral administration with instant wettability
US5993849A (en) 1996-12-20 1999-11-30 Roehm Gmbh Chemische Fabrik Hydrophilic adhesive and binder for medications
EP0848960B1 (en) 1996-12-20 2002-04-24 Röhm GmbH & Co. KG Adhesive for dermal or transdermal therapy systems
US6063399A (en) 1996-12-20 2000-05-16 Roehm Gmbh Chemische Fabrik Adhesive binders for dermal or transdermal therapy systems
US5785527A (en) 1997-01-10 1998-07-28 Ultradent Products, Inc. Stable light or heat activated dental bleaching compositions
US5858332A (en) 1997-01-10 1999-01-12 Ultradent Products, Inc. Dental bleaching compositions with high concentrations of hydrogen peroxide
US5837713A (en) 1997-02-26 1998-11-17 Mayo Foundation For Medical Education And Research Treatment of eosinophil-associated pathologies by administration of topical anesthetics and glucocorticoids
WO1998037870A1 (en) 1997-02-28 1998-09-03 Cygnus, Inc. Transdermal delivery of basic drugs using nonpolar adhesive systems and acidic solubilizing agents
US6306370B1 (en) 1997-05-30 2001-10-23 Ultradent Products, Inc. Compositions and methods for whitening and desensitizing teeth
US6096328A (en) 1997-06-06 2000-08-01 The Procter & Gamble Company Delivery system for an oral care substance using a strip of material having low flexural stiffness
US5989569A (en) 1997-06-06 1999-11-23 The Procter & Gamble Company Delivery system for a tooth whitener using a permanently deformable strip of material
US5879691A (en) 1997-06-06 1999-03-09 The Procter & Gamble Company Delivery system for a tooth whitener using a strip of material having low flexural stiffness
US6045811A (en) 1997-06-06 2000-04-04 The Procter & Gamble Company Delivery system for an oral care substance using a permanently deformable strip of material
WO1998055044A1 (en) 1997-06-06 1998-12-10 The Procter & Gamble Company A delivery system for a tooth whitener using a strip of material having low flexural stiffness
US5891453A (en) 1997-06-06 1999-04-06 The Procter & Gamble Company Delivery system for a tooth whitener using a strip of material having low flexural stiffness
US6075626A (en) 1997-06-25 2000-06-13 Denso Corporation Hologram
US6197331B1 (en) 1997-07-24 2001-03-06 Perio Products Ltd. Pharmaceutical oral patch for controlled release of pharmaceutical agents in the oral cavity
US6068650A (en) 1997-08-01 2000-05-30 Gentronics Inc. Method of Selectively applying needle array configurations
US6135126A (en) 1997-08-07 2000-10-24 Microlin, L.C. Brush that delivers beneficial agents
US5948433A (en) 1997-08-21 1999-09-07 Bertek, Inc. Transdermal patch
US5902598A (en) 1997-08-28 1999-05-11 Control Delivery Systems, Inc. Sustained release drug delivery devices
US6051609A (en) 1997-09-09 2000-04-18 Tristrata Technology, Inc. Additives enhancing the effect of therapeutic agents
US6231885B1 (en) 1997-09-17 2001-05-15 Permatec Technologie Ag Composition for controlled and sustained transdermal administration
US6562363B1 (en) 1997-09-26 2003-05-13 Noven Pharmaceuticals, Inc. Bioadhesive compositions and methods for topical administration of active agents
US5945457A (en) * 1997-10-01 1999-08-31 A.V. Topchiev Institute Of Petrochemical Synthesis, Russian Academy Of Science Process for preparing biologically compatible polymers and their use in medical devices
WO1999017738A1 (en) 1997-10-03 1999-04-15 Lavipharm Laboratories, Inc. A prolamine-plant polar lipid composition, its method of preparation and applications thereof
US6212671B1 (en) 1997-10-20 2001-04-03 Mitsubishi Electric System Lsi Design Corporation Mask pattern data producing apparatus, mask pattern data producing method and semiconductor integrated circuit device
US5997886A (en) 1997-11-05 1999-12-07 The Procter & Gamble Company Personal care compositions
US6221341B1 (en) 1997-11-19 2001-04-24 Oraceutical Llc Tooth whitening compositions
US20010021374A1 (en) 1997-11-19 2001-09-13 Oraceutical Llc Tooth whitening compositions
US5900249A (en) 1998-02-09 1999-05-04 Smith; David J. Multicomponent pain relief topical medication
US6193993B1 (en) 1998-03-03 2001-02-27 Eisai Co., Ltd. Suppository containing an antidementia medicament
WO1999044678A1 (en) 1998-03-06 1999-09-10 Spectrx, Inc. Apparatus for electroporation through microporated tissue
WO1999047128A1 (en) 1998-03-19 1999-09-23 Bristol-Myers Squibb Company Biphasic controlled release delivery system for high solubility pharmaceuticals and method
EP1066823B1 (en) 1998-03-20 2003-02-05 Biocosmetics, S.L. Tooth whitening composition
US6419905B1 (en) 1998-03-20 2002-07-16 Biocosmetics, S.L. Tooth whitening composition
WO1999054422A1 (en) 1998-04-21 1999-10-28 Coloplast A/S A pressure sensitive adhesive composition
US5993836A (en) 1998-04-28 1999-11-30 Castillo; James G. Topical anesthetic formulation
US20030103427A1 (en) 1998-05-09 2003-06-05 Lg Electronics Inc. Method for forming an information recording medium having information on spare area, and method and apparatus for recording/ reproducing data to/ from the medium
US6714497B2 (en) 1998-05-09 2004-03-30 Lg Electronics Inc. Method for forming an information recording medium having information on spare area, and method and apparatus for recording/reproducing data to/from the medium
US6461636B1 (en) 1998-05-15 2002-10-08 Schwarz Pharma Ag Transdermal therapeutic system containing pergolide
US6451777B1 (en) 1998-07-17 2002-09-17 The University Of Texas Southwestern Medical Center Method for regulating hair growth
WO2000016725A3 (en) 1998-09-18 2002-10-03 Lhd Lab Hygiene Dietetique Sterile non-adhesive compress
US6270792B1 (en) 1998-09-18 2001-08-07 Laboratories D'hygiene Et De Dietique Sterile nonstick compress
US20030055190A1 (en) 1998-09-22 2003-03-20 Hsing-Yeh Parker Acrylic polymer compositions with crystalline side chains and processes for their preparation
US6552147B2 (en) 1998-09-22 2003-04-22 Rohm And Haas Company Acrylic polymer compositions with crystalline side chains and processes for their preparation
US6596298B2 (en) 1998-09-25 2003-07-22 Warner-Lambert Company Fast dissolving orally comsumable films
CA2520986C (en) 1998-09-25 2007-11-13 Warner-Lambert Company Physiological compatible film
US6611706B2 (en) 1998-11-09 2003-08-26 Transpharma Ltd. Monopolar and bipolar current application for transdermal drug delivery and analyte extraction
US6708060B1 (en) 1998-11-09 2004-03-16 Transpharma Ltd. Handheld apparatus and method for transdermal drug delivery and analyte extraction
US6711435B2 (en) 1998-11-09 2004-03-23 Transpharma Ltd. Transdermal drug delivery and analyte extraction
US6368576B1 (en) 1998-11-12 2002-04-09 Ultradent Products, Inc. Methods for bleaching, opacifying and desensitizing teeth
US6312666B1 (en) 1998-11-12 2001-11-06 3M Innovative Properties Company Methods of whitening teeth
US6329472B1 (en) 1998-11-18 2001-12-11 Basf Aktiengesellschaft Water-soluble or water-dispersible graft copolymers based on a polyvinyllactam, their preparation and use
US6275728B1 (en) 1998-12-22 2001-08-14 Alza Corporation Thin polymer film drug reservoirs
WO2000069421A3 (en) 1999-05-18 2001-03-22 Sanol Arznei Schwarz Gmbh Transdermal therapeutic system (tts) containing tolterodine
US6783769B1 (en) 1999-05-18 2004-08-31 Schwarz Pharma Ag Transdermal therapeutic system TTS containing tolterodine
US6451240B1 (en) 1999-06-09 2002-09-17 The Procter & Gamble Company Method of manufacturing an intracutaneous microneedle array
WO2001026637A3 (en) 1999-10-13 2001-12-13 Lohmann Therapie Syst Lts Transdermal therapeutic system for administering acetylsalicylic acid and/or salicylic acid
US6264981B1 (en) 1999-10-27 2001-07-24 Anesta Corporation Oral transmucosal drug dosage using solid solution
US6248363B1 (en) 1999-11-23 2001-06-19 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
US20040053901A1 (en) 1999-11-24 2004-03-18 Te-Yen Chien Transdermal hormone delivery system: compositions and methods
US6673363B2 (en) 1999-12-16 2004-01-06 Dermatrends, Inc. Transdermal and topical administration of local anesthetic agents using basic enhancers
US20020197284A1 (en) 1999-12-16 2002-12-26 Luo Eric C. Transdermal and topical administration of local anesthetic agents using basic enhancers
US6322774B1 (en) 1999-12-20 2001-11-27 Ultradent Products, Inc. Dental bleaching compositions containing sucralose
US6638528B1 (en) 2000-01-20 2003-10-28 Noven Pharmaceuticals, Inc. Compositions and methods to effect the release profile in the transdermal administration of active agents
US6806308B2 (en) 2000-03-06 2004-10-19 Chemico Systems, Inc. Method for protecting paint on an article, a composition useful therefor, and a method for making the composition
US20020076487A1 (en) 2000-03-06 2002-06-20 Bohdan Zajac Method for protecting paint on an article, a composition useful therefor, and a method for making the composition
US20040136927A1 (en) 2000-03-17 2004-07-15 Ji-Young Kim Apparatus and method for whitening teeth
US6780401B2 (en) 2000-03-17 2004-08-24 Lg Household & Healthcare Ltd. Patches for teeth whitening
WO2001068045A1 (en) 2000-03-17 2001-09-20 Lg Household & Health Care Ltd Patches for teeth whitening
US20050031554A1 (en) 2000-03-17 2005-02-10 Ji-Young Kim Patches for teeth whitening
CA2402021C (en) 2000-03-17 2005-04-12 Lg Household & Health Care Ltd. Patches for teeth whitening
US6682721B2 (en) 2000-03-17 2004-01-27 Lg Household & Healthcare Ltd. Patches for teeth whitening
US6689344B2 (en) 2000-03-17 2004-02-10 Lg Household & Healthcare Ltd. Patches for teeth whitening
US20040219111A1 (en) 2000-03-17 2004-11-04 Ji-Young Kim Method and device for teeth whitening using a dry type adhesive
US6558654B2 (en) 2000-04-11 2003-05-06 Mclaughlin Gerald Composition and method for whitening teeth
US20020009420A1 (en) 2000-04-11 2002-01-24 Mclaughlin Gerald Composition and method for whitening teeth
US20010046471A1 (en) 2000-05-09 2001-11-29 Marek Przemyslaw A. Infrared thermograpy and methods of use
US6762202B2 (en) 2000-05-09 2004-07-13 Nitromed, Inc. Infrared thermography and methods of use
WO2001087276A1 (en) 2000-05-16 2001-11-22 Samyang Corporation Hydrogel composition for transdermal drug delivery
US6517350B2 (en) 2000-05-26 2003-02-11 Dentovations Inc. Method for whitening teeth
US20020004190A1 (en) 2000-05-26 2002-01-10 Adam Diasti Method for whitening teeth
US20020048602A1 (en) 2000-06-22 2002-04-25 Alliance Pharmaceutical Corp. Methods and compositions for the delivery of pharmaceutical agents and/or the prevention of adhesions
WO2002004570A3 (en) 2000-07-07 2002-04-18 Av Topchiev Inst Petrochemical Preparation of hydrophilic pressure sensitive adhesives having optimized adhesive properties
US6576712B2 (en) 2000-07-07 2003-06-10 A. V. Topchiev Institute Of Petrochemical Synthesis Preparation of hydrophilic pressure sensitive adhesives having optimized adhesive properties
JP2002029949A (en) 2000-07-19 2002-01-29 Lion Corp Composition for oral cavity
US6667410B2 (en) 2000-09-18 2003-12-23 Board Of Regents, The University Of Texas System Conversion of α,β-unsaturated ketones and α,β-unsaturated esters into α-hydroxy ketones and α-hydroxy esters using Mn(III) catalyst, phenylsilane and dioxygen
US20020106335A1 (en) 2000-09-20 2002-08-08 Orlowski Jan A. Two-part composition for high efficacy teeth whitening comprising a mixture of peroxides and/or percarbonates of metals
US6488913B2 (en) 2000-09-20 2002-12-03 Scientific Pharmaceuticals, Inc Two-part composition for high efficacy teeth whitening comprising a mixture of peroxides and/or percarbonates of metals
US20020131990A1 (en) 2000-11-30 2002-09-19 Barkalow David G. Pullulan free edible film compositions and methods of making the same
KR20020045224A (en) 2000-12-08 2002-06-19 성재갑 Peroxide Stabilized Patches for Teeth Whitening
US6419906B1 (en) 2001-03-12 2002-07-16 Colgate Palmolive Company Strip for whitening tooth surfaces
US20030170308A1 (en) 2001-05-01 2003-09-11 Cleary Gary W. Hydrogel compositions
US20040105834A1 (en) 2001-05-01 2004-06-03 Corium International Hydrogel compositions with an erodible backing member
US20030235549A1 (en) 2001-05-01 2003-12-25 Parminder Singh Hydrogel compositions demonstrating phase separation on contact with aqueous media
US20050113510A1 (en) 2001-05-01 2005-05-26 Feldstein Mikhail M. Method of preparing polymeric adhesive compositions utilizing the mechanism of interaction between the polymer components
WO2002087645A1 (en) 2001-05-01 2002-11-07 A.V. Topchiev Institute Of Petrochemical Synthesis Hydrogel compositions
US6803420B2 (en) 2001-05-01 2004-10-12 Corium International Two-phase, water-absorbent bioadhesive composition
US20030152528A1 (en) 2001-05-01 2003-08-14 Parminder Singh Hydrogel compositions for tooth whitening
US20040258723A1 (en) 2001-05-01 2004-12-23 Parminder Singh Hydrogel compositions demonstrating phase separation on contact with aqueous media
WO2002087642A3 (en) 2001-05-01 2003-01-09 Av Topchiev Inst Petrochemical Two-phase, water-absorbent bioadhesive composition
WO2002089849B1 (en) 2001-05-07 2003-04-03 Corium Int Compositions and delivery systems for administration of a local anesthetic agent
US6591124B2 (en) 2001-05-11 2003-07-08 The Procter & Gamble Company Portable interstitial fluid monitoring system
US20030152615A1 (en) 2001-06-18 2003-08-14 Noven Pharmaceuticals, Inc. Enhanced drug delivery in transdermal systems
KR20030000299A (en) 2001-06-23 2003-01-06 주식회사 엘지생활건강 Semi-transparent patches for teeth whitening
CA2451431C (en) 2001-06-23 2012-03-13 Lg Household & Health Care Ltd. Multiple-layered patches for teeth whitening
WO2003000216A1 (en) 2001-06-23 2003-01-03 Lg Household & Health Care Ltd. Multiple-layered patches for teeth whitening
KR20030000528A (en) 2001-06-26 2003-01-06 주식회사 엘지생활건강 Patches for teeth whitening
US20030100654A1 (en) 2001-06-29 2003-05-29 Theary Chheang Devices, compositions, and methods incorporating adhesives whose performance is enhanced by organophilic clay constituents
US6884833B2 (en) 2001-06-29 2005-04-26 3M Innovative Properties Company Devices, compositions, and methods incorporating adhesives whose performance is enhanced by organophilic clay constituents
KR20030003969A (en) 2001-07-04 2003-01-14 주식회사 엘지생활건강 Manufacturing process of patches for teeth whitening
KR20030003973A (en) 2001-07-04 2003-01-14 주식회사 엘지생활건강 Flexible patches for teeth whitening
US6585997B2 (en) 2001-08-16 2003-07-01 Access Pharmaceuticals, Inc. Mucoadhesive erodible drug delivery device for controlled administration of pharmaceuticals and other active compounds
US6759030B2 (en) 2002-03-21 2004-07-06 Carl M. Kosti Bleach stable toothpaste
US20030180229A1 (en) 2002-03-21 2003-09-25 Kosti Carl M. Bleach stable toothpaste
US6750291B2 (en) 2002-04-12 2004-06-15 Pacific Corporation Film-forming agent for drug delivery and preparation for percutaneous administration containing the same
WO2003089046A1 (en) 2002-04-16 2003-10-30 Cyto Pulse Sciences, Inc. Method of treating biological materials with translating electrical fields and electrode polarity reversal
WO2003099344B1 (en) 2002-05-24 2004-04-08 Corium Int Skin adhesive for cushions and wound dressings
US20030225356A1 (en) 2002-05-24 2003-12-04 Kulichikhin Valery G. Composition for cushions, wound dressings and other skin-contacting products
US20040005277A1 (en) 2002-07-02 2004-01-08 Willison Michael P. Device and method for delivering an oral care agent
CA2506073C (en) 2002-11-21 2009-05-26 Lg Household & Health Care Ltd. Dry type patches safe for gum
WO2004045569A1 (en) 2002-11-21 2004-06-03 Lg Household & Health Care Ltd. Dry type patches safe for gum
US6805874B1 (en) 2002-12-03 2004-10-19 Permamed Ag Method and skin cleansing compositions for dermatological basic treatment
US20040166147A1 (en) 2002-12-13 2004-08-26 Schering-Plough Healthcare Products, Inc. Dermal, transdermal, mucosal or transmucosal ingredient delivery devices
WO2004054638A3 (en) 2002-12-13 2004-08-12 Corium Int Inc Dermal, transdermal, mucosal or transmucosal ingredient delivery devices
WO2004071323A3 (en) 2003-02-05 2004-10-14 Corium Int Hydrogel compositions for tooth whitening
WO2004093786A3 (en) 2003-04-16 2006-03-23 Corium Int Covalent and non-covalent crosslinking of hydrophilic polymers and adhesive compositions prepared therewith
WO2004103201A3 (en) 2003-05-19 2005-02-24 Corium Int Hydrogel composition demonstrating phase separation
WO2005027768A3 (en) 2003-09-12 2005-07-07 Corium Int Hydrogel compositions with an erodible backing member
WO2005074894A1 (en) 2004-01-30 2005-08-18 Corium International Rapidly dissolving film for delivery of an active agent

Non-Patent Citations (75)

* Cited by examiner, † Cited by third party
Title
Aubin (1988), "Analysis of the Glass Transition Temperature of Miscible Polymer Blends," Macromolecules 21:2945-1949.
Aubin, et al., "Analysis of the glass transistion temperature of miscible polymer blends", Macromolecules, vol. 21, pp. 2945-2949, (1988).
Bairamov et al. (2000), "Kinetic Parameters of Poly(N-Vinyl Pyrrolidone) Spontaneous Mixing with Shoft-Chain Poly(Ethylene Glycol)," Polym. Mater. Sci. Eng. 82:7-8.
Bairamov, et al., "Kinetic parameters of poly(N-vinyl pyrrolidone) spontaneous mixing with short-chain poly(ethylene glycol)", Polym. Mater. Sci. Eng., vol. 82, pp. 7-8, (2000).
Borodulina et al. (2001), "Viscoelasticity of Pressure-Sensitive Adhesive and Bioadhesive Hydrogels Under Compressive Load," Proceed. 24th Annual Meeting Adhesion Soc., pp. 147-149.
Borodulina, et al. "Viscoelasticity of Pressure-sensitive adhesive and bioadhesive hydrogels under compressive load", Proceed. 24th Annual Meeting Adhesion Soc., pp. 147-149, (2001).
Chalykh et al. (1999), "Effects of Composition and Hydration on Adhesive Properties of Poly(N-Vinyl Pyrrolidone)-Poly(Ethylene Glycol) Hydrogels," Polym. Mater. Sci. Eng. 81:456-457.
Chalykh et al. (1999), "Fracture Mechanics of Poly(N-Vinyl Pyrrolidone)-Poly(Ethylene Glycol) Hydrogel Adhesive Joints," Polym. Mater. Sci. Eng. 81:427-428.
Chalykh, et al., "Effects of composition and hydration on adhesive properties of poly(N-vinyl pyrrolidone)-poly(ethylene glycol) hydrogels", Polym. Mater. Sci. Eng., vol. 81, pp. 456-457, (1999).
Chalykh, et al., "Fracture mechanics of poly(N-vinyl pyrrolidone)-poly(ethylene glycol) hydrogel adhesive joints," Polym. Mater. Sci. Eng., vol. 81, pp. 427-428, (1999).
Chalykh, et al., "Pressure-sensitive adhesion in the blends of poly(N-vinyl pyrrolidone) and poly(ethylene glycol) of disparate chain lengths," J. Adhesion, vol. 78, pp. 667-694, (2002).
Cleary, et. al., A new polymer blend adhesive with combined properties to adhere to either skin or mucosa for drug delivery, podium abstract, 30th Annual Meeting and Exposition of the Controlled Release Society, Glasgow, Scotland, Jul. 19-23, 2003, Abstract #123.
Database WPI Section Ch, Week 198451, Derwent Publicztions Ltd., London, GB; AN 1984-315114 & JP 59196817 A (Sekisuki Chem Ind Co Ltd) Nov. 8, 1984 (Nov. 8, 2984) abstract.
Database WPI Section Ch, Week 199118, Derwent Publications Ltd., London, GB; AN 1991-128478 & JP 03066612 A (Sato Pharm Co Ltd) Mar. 22, 1991 (Mar. 22, 1991) abstract.
Database WPI Section Ch, Week 199150, Derwent Publications Ltd., London, GB; AN 1991-366353 & JP 03247334 A (Sumitomo Rubber Ind Ltd) Nov. 5, 1991 (Nov. 5, 1991) abstract.
Database WPI Section Ch, Week 199627, Derwent Publications Ltd., London, GB; AN 1996-266746 & SS 1459215 A ( A Med Cardiology Res Centre) Nov. 20, 1995 (Nov. 20, 1995) abstract.
Emla Cream, (lidocaine 2.5% and prilocaine 2.5%), EMLA Anesthetic Disc, (lidocaine 2.5% and prilocaine 2.5% cream), Topical adhesive system, Detailed description.
Feldstein (2001), "Peculiarities of Glass Transition Temperature Relation to the Composition of Poly(N-Vinyl Pyrrolidone) Blends with Short Chain Poly(Ethylene Glycol)," Polymer 42(18):7719-7726.
Feldstein et al. (1996), "Effect of Hydrophilic Matrix Hydration on Transdermal Drug Delivery Kinetics: II. In Vitro Cytisine Delivery from Cypercuten TTS," Prediction of Percutaneous Penetration 4b:65-67, Brain et al. (Eds.).
Feldstein et al. (1996), "Effect of Hydrophilic Matrix Hydration on Transdermal Drug Delivery Kinetics: III. In Vitro Clonidine Delivery from Clopercuten TTS," Prediction of Percutaneous Penetration 4b:68-70, Brain et al. (Eds.).
Feldstein et al. (1996), "Effect of Hydrophilic Matrix Hydration on Transdermal Drug Delivery Kinetics: IV. In Vitro-In Vivo Correlation," Prediction of Percutaneous Penetration 4b:71-73, Braine et al. (Eds.).
Feldstein et al. (1999), "A Structure-Property Relationship and Quantitative Approach to the Development of Universal Transdermal Drug Delivery System," NBC (Nuclear, Biological, and Chemical) Risks-Current Capabilities and Future Perspectives for Protection 25:441-458, Kluwer Academic Publishers, Netherlands, NATO Science Series: 1. Disarmament Technologies.
Feldstein et al. (1999), "Contribution of Molecular Mobility to Debonding of Pressure-Sensitive Adhesive Hydrogels," Polym. Mater. Sci. Eng. 81:467-468.
Feldstein et al. (1999), "Quantitative Relationship between Molecular Structure and Adhesion of PVP-PEG Hydrogels," Polym. Mater. Sci. Eng. 81:465-466.
Feldstein et al. (2000), "Coherence of Thermal Transitions in Poly(N-Vinyl Pyrrolidone)-Poly(Ethylene Glycol) Compatible Blends-1. Interrelations Among the Temperatures of Melting, Maximum Cold Crystallization Rate and Glass Transition," Polymer 41:5327-5338.
Feldstein et al. (2000), "Coherence of Thermal Transitions in Poly(N-Vinyl Pyrrolidone)-Poly(Ethylene Glycol) Compatible Blends-2. The Temperature of Maximum Cold Crystallization Rate Versus Glass Transition," Polymer 41:5339-5348.
Feldstein et al. (2000), "Coherence of Thermal Transitions in Poly(N-Vinyl Pyrrolidone)-Poly(Ethylene Glycol) Compatible Blends-3. Impact of Sorbed Water Upon Phase Behaviour," Polymer 41:5349-5359.
Feldstein et al. (2000), "Effects of Chains Orientation, Free Volume and Interaction on Glass Transition in Poly(N-Vinyl Pyrrolidone)-Poly(Ethylene Glycol) Blends Involving a Stoichiometric Hydrogen-Bonded Network Complex," Polym. Mater. Sci. Eng. 82:365-366.
Feldstein et al. (2000), "Molecular Insight into Rheological and Diffusion Determinants of Pressure Sensitive Adhesion," Proceed. 23rd Annual Meeting Adhesion Soc., pp. 54-56.
Feldstein et al. (2001), "Correlations Between Activation Energy for Debonding and that for Self-Diffusionin Pressure-Sensitive Hydrogels," Proceed. 24th Annual Meeting Adhesion Soc., pp. 137-140.
Feldstein, et al., "A structure-property relationship and quantitative approach to the development of universal transdermal drug delivery system," NBC Risks, vol. 25, pp. 441-458, (1999).
Feldstein, et al., "Coherence of thermal transitions in poly(N-vinyl pyrrolidone)-poly(ethylene glycol) compatible blends: 1. Interrelations among the temperatures of melting, maximum cold crystalization rate and glass transition", Polymer, vol. 41, pp. 5327-5338, (2000).
Feldstein, et al., "Coherence of thermal transitions in poly(N-vinyl pyrrolidone)-poly(ethylene glycol) compatible blends: 2. The temperature of maximum cold crystalization rate versus glass transition", Polymer, vol. 41, pp. 5339-5348, (2000).
Feldstein, et al., "Coherence of thermal transitions in poly(N-vinyl pyrrolidone)-poly(ethylene glycol) compatible blends: 3. Impact of sorbed water upon phase behavior", Polymer, vol. 41, pp. 5439-5359, (2000).
Feldstein, et al., "Contribution of molecular mobility to debonding of pressure-sensitive adhesive hydrogels", Polym. Mater. Sci. Eng., vol. 81, pp. 467-468, (1999).
Feldstein, et al., "Correlations between activation energy for debonding and that for self-diffusion in pressure-sensitive hydrogels", Proceed. 24th Annual Meeting Adhession Soc., pp. 137-140, (2001).
Feldstein, et al., "Effect of hydrophilic matrix hydration on transdermal drug delivery kinetics: I. The matrix hydration In Vivo and In Vitro", Prediction of Percutaneous Penetration, vol. 4b, pp. 61-64, Brian, et al., (Eds.) (1996).
Feldstein, et al., "Effect of hydrophilic matrix hydration on transdermal drug delivery kinetics: II. In Vitro cytasine Delivery From Cypercuten TTS", Prediction of Percutaneous Penetration, vol. 4b, pp. 65-67, Brian, et al., (Eds.) (1996).
Feldstein, et al., "Effect of hydrophilic matrix hydration on transdermal drug delivery kinetics: III. In Vitro clonide delivery from clopercuten TTS", Prediction of Percutaneous Penetration, vol. 4b, pp. 68-70, Brian, et al., (Eds.) (1996).
Feldstein, et al., "Effect of hydrophilic matrix hydration on transdermal drug delivery kinetics: IV. In Vitro-In Vivo correlation," Prediction of Percutaneous Penetration, vol. 4b, pp. 71-73, Brian, et al., (eds.) (1996).
Feldstein, et al., "Effects of chains orientation, free volume and interaction on glass transition in poly(N-vinyl pyrrolidone)-poly(ethylene glycol) blends involving a stoichiometric hydrogen-Bbonded network complex", Polym. Mater. Sci. Eng., vol. 82, pp. 365-366, (2000).
Feldstein, et al., "General approach to the molecular design of hydrophilic pressure-sensitive adhesives," Proc. 25th Ann. Mtg. and 2nd World Congress on Adhesion and Related Phenomena, Orlando, FL, vol. 1, pp. 292-294 (2002).
Feldstein, et al., "Molecular insight into rheologival and diffusion determinants of pressure sensitive adhesion", Proceed. 23rd Annual Meeting Adhesion Soc., pp. 54-56, (2000).
Feldstein, et al., "Peculiarities of glass transition temperature relation to the composition of poly(N-vinyl pyrolidone) blends with short chain poly(ethylene glycol)", Polymer, vol. 42, pp. 7719-7726, (2001).
Feldstein, et al., "Quantitative relationship between molecular structure and adhesion of PVP-PEG hydrogels", Polym. Mater. Sci Eng., vol. 81, pp. 465-466, (1999).
Feldstein, et al., "Relation of glass transition temperature to the hydrogen bonding degree and energy in poly(N-vinyl pyrrolidone) blends with hydroxyl-containing plasticizers: 2. Effects of poly(ethylene glycol) chain length", Polymer, vol. 42, pp. 981-990, (2001).
Feldstein, et al., "Universal hydrophilic drug-containing adhesive matrix for systemic and topical transdermal drug delivery", Proc. 1st World Meeting APGI/APV, Budapest, 9/11, 2 pages, (1995).
Felstein et al. (1995), "Universal Hydrophilic Drug-Containing Adhesive Matrix for Systemic and Topical Transdermal Drug Delivery," Proc. 1st World Meeting APGI/APV, Budapest, 9/11.
Felstein et al. (1996), "Effect of Hydrophilic Matrix Hydration on Transdermal Drug Delivery Kinetics: I. The Matrix Hydration In Vivo and In Vitro," Prediction of Percutaneous Penetration 4b:61-64, Brain et al. (Eds.).
Handbook of Pharmaceutical Excipients, Arther H. Kibbe, ed., 3rd ed., pp. 401-406, (2000).
Hawley's Condensed Chemical Dictionary, 14th Edition, Citation, "Oligomer, A polymer molecule of only a few monomer units (dimer, trimer, tetramer)", John Wiley and Sons, Inc., (2002).
International Search Report for PCT/US2000/18557 mailed Oct. 17, 2000.
International Search Report for PCT/US2001/21417 mailed Feb. 25, 2002.
International Search Report for PCT/US2002/13680 mailed Sep. 18, 2002.
International Search Report for PCT/US2002/14260 Mailed Sep. 17, 2002.
International Search Report for PCT/US2002/14725 mailed Sep. 27, 2002.
International Search Report for PCT/US2003/039717 Mailed Jun. 28, 2004.
International Search Report for PCT/US2003/16408 Mailed Dec. 8, 2003.
International Search Report for PCT/US2004/003443 Mailed Aug. 20, 2004.
International Search Report for PCT/US2004/011567 Mailed Jan. 10, 2006.
International Search Report for PCT/US2004/015448 Mailed Dec. 28, 2004.
International Search Report for PCT/US2004/029620 Mailed Jun. 1, 2005.
International Search Report for PCT/US2005/0002873 Mailed Apr. 27, 2005.
Kotomin, et al., "Durability and fracture of some visceolastic adhesives," Proceed. Of The 23rd Annual Meeting Of The Adhesion Soc., pp. 413-415, (2000).
Kotomin, et al., "Squeeze-recoil analysis of adhesive hydrogels and elastomers", Polym. Mater. Sci. Eng., vol. 81, pp. 425-426, (1999).
MSDS (Material Safety Data Sheet), Lactic Acid, No. L0522, (2008).
Patent Abstracts of Japan, vol. 017, No. 055 (C-1023) Feb. 3, 1993 (Feb. 3, 2003) & JP 04 266818 A (Sekisui Chem Co Ltd), Sep. 22, 1992 (Sep. 22, 1992) abstract.
Roos et al. (2001), "Probe Tack Investigations of Poly(Vinyl Pyrrolidone)-Poly(Ethylene Glycol) Blends," Proceed. 24th Annual Meeting Adhesion Soc., pp. 277-279.
Roos, et al., "Probe tack investigation of poly(vinyl pyrrolidone)-poly(ethylene glycol) blends", Proceed. 24th Annual Meeting Adhesion Soc., pp. 277-279, (2001).
Sintov, et al., "Radiofrequency-driven skin microchanneling as a new way for electically assisted transdermal delivery of hydrophilic drugs", J. Contr.Release, vol. 89, pp. 311-320, (2003).
Supplementary European Search Report for EP04783729.9 Mailed Jun. 5, 2009.
Vartapetian et al. (2001), "Molecular Dynamics in Poly(N--Vinyl Pyrrolidone)-Poly(Ethylene Glycol) Blends by Pulsed Field Gradient NMR Method: Effects of Aging, Hydration and PEG Chain Length," Macromol. Chem. Phys. 202(12):2648-1652.
Vartapetian et al. (2001), "Self-Diffusion in Poly(N-Vinyl Pyrrolidone)-Poly(Ethylene Glycol) Systems," Colloid Polym. Sci. 279(6):532-538.
Vartapian, et al., "Molecular dynamics in poly(N-vinyl pyrrolidone)-poly(ethylene glycol) blends by pulsed-field gradient NMR method: effects of aging, hydration and PEG chain length", Macromol. Chem. Phys., vol. 202, pp. 2648-2652, (2001).
Vartapian, et al., "Self-diffusion in poly(N-vinyl pyrrolidone)-poly(ethylene glycol) systems", Colloid Polym. Sci., vol. 279, pp. 532-538, (2001).

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015042165A1 (en) 2013-09-17 2015-03-26 Corium International, Inc. Topical adhesive composition, and device, for improving aesthetic appearance of skin

Also Published As

Publication number Publication date
USRE45666E1 (en) 2015-09-08

Similar Documents

Publication Publication Date Title
US6576712B2 (en) Preparation of hydrophilic pressure sensitive adhesives having optimized adhesive properties
ES2587187T3 (en) Biphasic water absorbent bioadhesive composition
RU2326893C2 (en) Covalent and non-covalent linking of hydrophilic polymers and adhesive compositions with them
RU2411045C2 (en) Hydrophilic biologically compatible adhesive compositions and application thereof
EP1951211B2 (en) Transdermal preparations containing hydrophobic non-steroidal anti-inflammatory drugs
EP2968652B1 (en) Improving adhesive properties
US4954343A (en) Dermal pharmaceutical preparations
RU2585787C2 (en) Hydrophilic thermally switched pressure-sensitive adhesive composition reversibly coming off in water at elevated temperatures
RU2276177C2 (en) Preparation of hydrophilic pressure-sensitive adhesives with optimized adhesive properties
USRE45666E1 (en) Preparation of hydrophilic pressure sensitive adhesives having optimized adhesive properties
JP3144895B2 (en) Medical adhesive tape or sheet
AU2001273230A1 (en) Preparation of hydrophilic pressure sensitive adhesives having optimized adhesive properties
JP2971998B2 (en) Acrylic pressure-sensitive adhesive sheet and pressure-sensitive adhesive preparation using the same
JPH0339485B2 (en)
JPS61221120A (en) Medical material for external use
KR20090110255A (en) Transdermal drug administration device
JP2647222B2 (en) Transdermal formulation
KR102371530B1 (en) Enhanced drug delivery from adhesives
JPH09176000A (en) Plaster for medical use
JPH0587489B2 (en)
JPH0772131B2 (en) External patch
JPH01297068A (en) Tacky adhesive agent for treatment and tacky tacky adhesive agent formulation for treatment
JPH064533B2 (en) External pharmaceutical material
JPH0698184B2 (en) Resin used for medical adhesive and medical adhesive sheet or tape using the same
JPS6368523A (en) Plaster preparation for external use

Legal Events

Date Code Title Description
AS Assignment

Owner name: CAPITAL ROYALTY PARTNERS II L.P., TEXAS

Free format text: SECURITY AGREEMENT;ASSIGNOR:CORIUM INTERNATIONAL, INC.;REEL/FRAME:028895/0961

Effective date: 20120713

Owner name: PARALLEL INVESTMENT OPPORTUNITIES PARTNERS II L.P.

Free format text: SECURITY AGREEMENT;ASSIGNOR:CORIUM INTERNATIONAL, INC.;REEL/FRAME:028895/0961

Effective date: 20120713

Owner name: CAPITAL ROYALTY PARTNERS II - PARALLEL FUND "A" L.

Free format text: SECURITY AGREEMENT;ASSIGNOR:CORIUM INTERNATIONAL, INC.;REEL/FRAME:028895/0961

Effective date: 20120713

AS Assignment

Owner name: SILICON VALLEY BANK, CALIFORNIA

Free format text: SECURITY AGREEMENT;ASSIGNOR:CORIUM INTERNATIONAL, INC.;REEL/FRAME:028927/0365

Effective date: 20120906

AS Assignment

Owner name: CAPITAL ROYALTY PARTNERS II ? PARALLEL FUND ?A? L.P., TEXAS

Free format text: SECURITY INTEREST;ASSIGNOR:CORIUM INTERNATIONAL, INC.;REEL/FRAME:034535/0238

Effective date: 20141202

Owner name: CAPITAL ROYALTY PARTNERS II ? PARALLEL FUND ?B? (CAYMAN) L.P., TEXAS

Free format text: SECURITY INTEREST;ASSIGNOR:CORIUM INTERNATIONAL, INC.;REEL/FRAME:034535/0238

Effective date: 20141202

Owner name: CAPITAL ROYALTY PARTNERS II (CAYMAN) L.P., TEXAS

Free format text: SECURITY INTEREST;ASSIGNOR:CORIUM INTERNATIONAL, INC.;REEL/FRAME:034535/0238

Effective date: 20141202

Owner name: CAPITAL ROYALTY PARTNERS II ? PARALLEL FUND ?B? (C

Free format text: SECURITY INTEREST;ASSIGNOR:CORIUM INTERNATIONAL, INC.;REEL/FRAME:034535/0238

Effective date: 20141202

Owner name: CAPITAL ROYALTY PARTNERS II ? PARALLEL FUND ?A? L.

Free format text: SECURITY INTEREST;ASSIGNOR:CORIUM INTERNATIONAL, INC.;REEL/FRAME:034535/0238

Effective date: 20141202

Owner name: CAPITAL ROYALTY PARTNERS II L.P., TEXAS

Free format text: SECURITY INTEREST;ASSIGNOR:CORIUM INTERNATIONAL, INC.;REEL/FRAME:034535/0238

Effective date: 20141202

FPAY Fee payment

Year of fee payment: 12

AS Assignment

Owner name: CORIUM INTERNATIONAL, INC., CALIFORNIA

Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:SILICON VALLEY BANK;REEL/FRAME:044229/0054

Effective date: 20171120

AS Assignment

Owner name: CORIUM INTERNATIONAL, INC., CALIFORNIA

Free format text: RELEASE BY SECURED PARTY;ASSIGNORS:CAPITAL ROYALTY PARTNERS II L.P.;CAPITAL ROYALTY PARTNERS II - PARALLEL FUND "A" L.P.;CAPITAL ROYALTY PARTNERS II - PARALLEL FUND "B" (CAYMAN) L.P.;AND OTHERS;REEL/FRAME:045513/0686

Effective date: 20180305

Owner name: CORIUM INTERNATIONAL, INC., CALIFORNIA

Free format text: RELEASE BY SECURED PARTY;ASSIGNORS:CAPITAL ROYALTY PARTNERS II L.P.;CAPITAL ROYALTY PARTNERS II - PARALLEL FUND "A" L.P.;CAPITAL ROYALTY PARTNERS II - PARALLEL FUND "B" (CAYMAN) L.P.;AND OTHERS;REEL/FRAME:046909/0855

Effective date: 20180305

AS Assignment

Owner name: CORIUM, INC., CALIFORNIA

Free format text: CHANGE OF NAME;ASSIGNOR:CORIUM INTERNATIONAL, INC.;REEL/FRAME:048841/0324

Effective date: 20190314