CA2228118A1 - Multiblock biodegradable hydrogels for use as controlled release agents for drugs delivery and tissue treatments agents - Google Patents
Multiblock biodegradable hydrogels for use as controlled release agents for drugs delivery and tissue treatments agents Download PDFInfo
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- CA2228118A1 CA2228118A1 CA002228118A CA2228118A CA2228118A1 CA 2228118 A1 CA2228118 A1 CA 2228118A1 CA 002228118 A CA002228118 A CA 002228118A CA 2228118 A CA2228118 A CA 2228118A CA 2228118 A1 CA2228118 A1 CA 2228118A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1274—Non-vesicle bilayer structures, e.g. liquid crystals, tubules, cubic phases, cochleates; Sponge phases
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7015—Drug-containing film-forming compositions, e.g. spray-on
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS 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
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/42—Use of materials characterised by their function or physical properties
- A61L15/58—Adhesives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS 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
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/42—Use of materials characterised by their function or physical properties
- A61L15/60—Liquid-swellable gel-forming materials, e.g. super-absorbents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS 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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0031—Hydrogels or hydrocolloids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS 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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0042—Materials resorbable by the body
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS 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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L71/00—Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
- C08L71/02—Polyalkylene oxides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S424/00—Drug, bio-affecting and body treating compositions
- Y10S424/13—Burn treatment
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S524/00—Synthetic resins or natural rubbers -- part of the class 520 series
- Y10S524/916—Hydrogel compositions
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S525/00—Synthetic resins or natural rubbers -- part of the class 520 series
- Y10S525/941—Polymer mixture containing block copolymer is mixed or reacted with chemical treating agent
Abstract
Gel-forming macromers including at least four polymeric blocks, at least two of which are hydrophobic and at least one of which is hydrophilic, and including a cross-linkable group are provided. The macromers can be covalently cross-linked to form a gel on a tissue surface in vivo. The gels formed from the macromers have a combination of properties including thermosensitivity and lipophilicity, and are useful in a variety of medical applications including drug delivery and tissue coating.
Description
WO 97/05185 PCT~US96/12285 ULl~RI~X~ RIQ~ RADABLEHnnDR ~ ELSFOR USE ASCONTRO~ .~ RELEAsEAGEN
FOR DRUGS DELIVERY ~ND TISSUE TREATMENT AGENTS
Background of the Invention The present invention is generally in the area of biodegradable polymers for use in drug delivery and bi~mP-1ir~l applir~ti~ n~.
Biodegradable polymers have been developed for use in a variety of surgical and drug delivery appli~tion~. The synthesis and biodegradability of poly(lactic acid) was reported by Knlk~rni et al., Arch. Surg., 93:839 (1966). Biodegradable polyallhydlides and polyorthoesters having labile backbone linkages have been developed.
Domb et al., Macromolecules, 22:3200 (1989); and Heller et al., '~iodegradable Polymers as Drug Delivery Systems," Chasin, M. and Langer, R., Eds., Dekker, New York, 121-161 (1990), the r~ clQsllres of which are incorporated herein. Polymers which degrade into naturally occnrring materials, such as poly~min~-ids, also have been developed.
Polyesters of ~x-hydroxy acids, such as lactic acid or glycolic acid, are widely used as biodegradable materials for applications ranging from closure devices, including sutures and staples, to drug delivery ~y~L~llls.
Holland et al., Controlled Release, 4:155-180, (1986); U.S. Patent No.
4,741,337 to Smith et al.; and Spili;~ew~hi et al., J. Control. Rel., _:197-203 (1985), the disclosures of which are incorporated herein.
Degradable polymers cont~ining water-soluble polymer elPnnPn have been described. Degradable polymers have been formed by copolymerization of lactide, glycolide, and ~-caprolactone with the polyether, polyethylene glycol ("PEG"), to increase the hydrophilicity and degradation rate. Sawhney et al., J. Biomed. Mater. Res. 24:1397-1411 (1990). U.S. Patent No. 4,716,203 to Casey et al. describes the synthesis of a block copolymer of PGA (poly(glycolic acid)) and PEG. U.S. Patent W O 97/05185 PCT~US96/12285 No. 4,716,203 to Casey et al. describes the ~y~ e~is of PGA-PEG
diblock copolymers.
Polymers formed from croc~link~hle mollull~ or prepolymers have been developed in the prior art. Croc~lin'~l hyaluronic acid has been used as a degradable swelling polymer for biom~ r~l applications.
U.S. Patent No. 4,987,744 and 4,957,744 to Della Valle et al.; and Della Valle et al., Polym. Mater. Sci. Eng., 62:731-735 (1991).
U.S. Patent No. 5,410,016 to Hubbell et al., the disclosure of which in incorporated herein, discloses the in situ crosslinking of biodegradable, water-soluble macro-monomers, (",llaclull~l~") to form barrier coatings and matrices for delivery of biologically active agents.
Other polymers for drug delivery or other biomf~lir~l applir~ti~-n~ are escrihecl in U.S. Patent No. 4,938,763 to Dunn, U.S. Patent Nos.
5,160,745 and 4,818,542 to DeLuca, U.S. Patent No. 5,219,564 to Zalipsky, U.S. Patent No. 4,826,945 to Cohn, and U.S. Patent Nos.
5,078,994 and 5,429,826 to Nair, the disclosures of which are incorporated herein by ,~fel~llce. Methods for delivery of the polymers m~teri~l~ include syringes (U.S. Patent No. 4,938,763 to Dunn et al.) spray applicators (WO 94/21324 by Rowe et al.) and caLllet~l delivery systems (U.S. Patent Nos. 5,328,471; and 5,213,580 to Slepian). The synthesis of lllaclulllers including a central chain of polyethylene glycol, with an oligomeric hydroxyacid at each end and acrylic esters at the ends of the hydroxy acid oligomer also has been reported. Sawhney A. S. et al., Macromolecules, 26: 581 (1993); and PCT WO 93/17669 by Hubbell J. A. et al., the disclosures of which are incorporated herein by reference.
Thermal volume changes in polymeric gels, such as esters and amides of polyacrylic acid, have been described. For example, poly(N-isopropyl acrylamide) based hydrogels, which are thPrmos~iLivt;
in aqueous systems, have been used for controlled drug delivery and other applications. U.S. Patent No. 5,403,893 to Tanaka et al.; and Hoffman WO 97/05185 PCT~US96/12285 A.S. etal., J. ControlledRelease, 6:297 (1987), thedisclosures of which are incorporated herein. Poly(N-isopropyl acrylamide), however, is non-degradable and is not suitable for applications where biodegradable polymers are required. Non-biodegradable polymeric systems for drug 5 delivery are disadvantageous since they require removal after the drug-polymer device is implanted.
It is an object of the invention to provide i~ ov~d polymer systems for use in drug delivery and other biom~ ir~l applir~ti- ~ such as surgical applications. It is an ~ltliti~n~l object of the invention to provide 10 polymer systems for use in controlled drug delivery which are capable of releasing a biologically active agent in a predictable and controlled rate.
It is a further object of the invention to provide polymers for use in controlled drug delivery which release the active agent locally at a particular targeted site where it is needed. It is another object of the 15 invention to provide polymer systems for use in drug delivery which have ~elLies including volume and drug release which are variable with Lc;~ ldlule or other parameters such as pH or ion coll~ Lion.
Sl.~..--.~. J/ of the Invention Macromers are provided which are capable of gelling in an aqueous solution. In one embo-lim.ont the macLclllc;l~ include at least four polymeric blocks, at least one of which is hydlophilic and at least two of which are hydrophobic, and include a crt .~link~hle group. The 25 polymer blocks may be select~l to provide macromers with dirre~
selected piope,Lies. The macromers can be covalently cro~link~-l to form a gel on a tissue surface in vivo. The gels formed from the macromers have a combination of properties including thermose~ ivily and lipophilicity, and are useful in a variety of m.-rlir~l applications inr.lll-ling 30 drug delivery and tissue coating.
W O 97/05185 PCT~US96/12285 Brief Des~ Lion of the Figures Figure 1 is a scheme showing the dirr~ L gel states and ~l~clLies of one embodiment of a thermulei,~ol~iv~ biodegradable 5 macromer formed from a poly~..~ylene oxide-polyethylene oxide block copolymer.
Figure 2 is a graph of ~ eldLul~-dependent ch~ges in gel volume of gels formed by photopolymerization of an acrylated poly~ro~ylene oxide-polyethylene oxide block copolymer co..li.i,.;..~ a biodegradable region.
Figure 3 is a graph showing the effects of lelllpel~Lulc; on ~i~xtr~n release from a gel formed by photopolymerization of an acrylated poly~lo~ylene oxide-polyethylene oxide block copolymer.
Figure 4 is a graph illu~LldLhlg the variation in the speed of photocros~linl-in~ of acrylated poly~lv~ylene oxide-polyethylene oxide block copolymers having incorporated therein dirr~lc~ bio~legr~ hle regions.
Figure 5 is a graph showing the in vitro profiles of degr~ ti~ n rate of gels formed by photocro~linking of acrylated poly~ro~ylene oxide-polyethylene oxide block copolymers having incol~uldL~d therein dirrer~llL biodegradable regions.
Figure 6 is a graph illustrating the bioc~ p~l;l,ility of gels formed by photocro~linl~ing acrylated polyl,lopylene oxide-polyethylene oxide block copolymers having incorporated therein dirr~l~llL biodegradable regions.
Figure 7 shows graphs illu~LIdlillg release of fluolc:scellL dextran from gels formed by photocro~linkin~ acrylated poly~lo~ylene oxide-polyethylene oxide block copolymers having incorporated therein biodegradable linkers.
Figure 8 shows graphs of transition l~ dLulc:s of gels formed from maclulllel~ col~ g biodegradable linkers.
Figure 9 illustrates tbe chrmir~l structures of bio~legr~ ble cros~ hle llla~lumcl~, con~i~ting of acrylated poly(propylene oxide)-poly(ethylene oxide) block copolymers having incorporated therein a ~ biodegradable linker.
S Figure 10 is a graph of absorbance of a hydrophobic dye vs. log (weight %) of solutions of biodegradable ma~;,u"lc;,.. having a hydrophobic region incorporated therein.
Figure 11 is a sçhrm~tir- illustration of a cell membrane inrhl~lin~
hydrophobic bilayer with a macromer including a hydrophobic tail 10 diffused into the bilayer.
Figure 12 is a sch~ tir illustration of nanospheres or microspheres which can be formed by agy,lc;~,~lion and subsequent polylll~ lion of hydrophilic macrulll......
Figure 13 is a graph which shows the rate of release of a small 15 drug from gels formed from hydrophobic maclu"~el~,.
Figures 14 and 15 are graphs showing dirrusiviLy of a ,,~ ly water soluble drug through a hydrophobic hydrogel.
Figure 16 is a graph showing the release of tetracycline from a hydrogel formed from mollolll~l~ including a biodegradable region.
Detailed Des~ lion of the Invention Macromers are provided which are cro~link~hle to form hydrogels which are useful as matrices for controlled drug delhery. In a plGr~ d 25 embodiment, biodegradable macromers are provided in a ph~ re~ltir~lly acceptable carrier, and are capable of cr{!~linkins~, covalently or non-covalently, to form hydrogels which are thermoresponsive. A
biologically active agent may be incorporated within the macromer ~ solution or in the reslllting hydrogel after cro~linking. The hydrogels 30 have properties, such as volume and drug release rate, which are dependent upon tel~l~e~dLu~. The hydrogels may be formed in sit~, for example, at a tissue site, and may be used for for controlled delivery of bioactive substances and as tissue coatings. The l,la.;l.,llle,., used to form the hydrogels may be fabricated with domains having specific ~lop~ies including select~l hydrophobicity, hydrophilicity, thermos~l~,ilivi~y or 5 biodegradability, and combinations thereof.
M~v~
The macro-monomers ("ma~ lllel,") which are ionically or covalently cro~link~hle to form hydrogels preferably consist of a block copolymer. The macromers can be quickly polymerized from aqueous 10 solutions. The macromers are advantageously capable of thermolc~ ible gelation behavior, and preferably may be polymerized in a solution state or in a gel state. The macromers are defined as including a hydrophilic block capable of absorbing water, and at least one block, distinct from the hydrophilic block, which is s~lmriently hydrophobic to 15 ~lc~ i~Le from, or otherwise change phase while within, an aqueous solution, con~ tin~ of water, preferably cnnt~ining salts, buffers, drugs or polymerizing reagents, at tempt;ldLulcs within or near the physiologically compatible range, for example 0 to 65~C. The hydrophilic block optionally may be an amphiphilic block. The macromer may include 20 more than one of the same or dirr~.c~lL hydrophilic or hydrophobic region.
Preferably, the macro.ll~l, include at least three blocks, or more preferably four blocks.
The block copolymers may be linear (AB, ABA, ABABA or ABCBA type), star (AnB or BAnC, where B is at least n-valent, and n is 25 3 to 6) or branched (multiple A's depending from one B). In these formulae, either A or B may be the hydrophilic block, and the other the ~mphir~thic or hydrophilic block, and the additional block C may be either.
In another embodiment, the macromer includes at least four 30 covalently-linked polymeric blocks, wherein: at least one, or in another embodiment, at least two blocks are hydrophilic, and the hydrophilic W O 97/05185 PCT~US96/12285 blocks individually have a water solubility of at least 1 gram/liter; at least two blocks are sufficiently hydrophobic to ag ,l~aLe to form mir~ellp~s in an aqueous continuous phase; and the macromer further includes at least ~ one cro~clin'~hle group. The cros~link~hle groups optionally may be S s~dldL~d by at least one degradable linkage capable of degrading under physiological conditions. In one embo~limPnt at least one hydrophobic block may be sepd~L~d from any reactive group by at least one hydrophilic block.
The lllacrolller further may include five total blocks having the same or dirr~ ,.iies such as thermal ,~l~,iLi~/ily, hydl~hilicity or hydrophobicity. Each block also may have a combination of ~ .Lies.
For example, a block may be hydrophilic and also thermosel~,iliv~.
itiorl~lly, the multiblock macromer may include chPrni- ~lly distinct blocks or may incorporate more than one of the same irlPnti~l block.
The macromer is fabricated with a structure and with ~ro~e,lies suitable for diLr~lcllt applications. For example the macromer may include a central block of dimer fatty acid which includes central llydloca~bon chain of about 30 carbon atoms and two terminal carboxy groups which are esterified with a thermose~ iv~ poloxamer, such as Pluronic L1050.
This central molecule further is polyl~rt~tPd at each hydroxy l~ lC, and end capped with acryloyl chloride. An another embodiment is a poloxamer including polyhydroxy groups polym~ri7Pcl on each end, and wherein the molecule is end capped at each end with a reactive group such as an acrylate or a secondary isocyanate.
The configuration of the ma~ , may be presel~ctPA dt:~JCll lhlg on the use of the macromer. The macromers may include at least two hydrophobic blocks, s~a-~led by a hydrophilic block. The mac,c...e,., also may be fabricated with a cro~link~hle group which is s~dldlt;:d by a degradable group from any other cro~slink~hle group. One ~-~rt;~L~,d 30 embodiment is wherein the dry macromer absorbs at least about 10% in weight of water. The molecular weight of the macromer preferably is at least 1000 Daltons, or optionally is at least 2000 Daltons, or in an iv~ embodiment, at least 4000 Daltons.
In a ~l~Çellc,d embo~im~ t, the macromer includes at least one th~rm~lly scl~ iv~ region, and an aqueous solution of the lllaclulllcl is 5 capable of gelling either ionically and/or by covalent crosslinking to produce a hydrogel with a L~ aLure dependent volume. This permits the rate of release of a drug incorporated in the hydrogel to change depending upon the volume of the hydrogel. Useful lllaclul~ . are those which are, for example, capable of thermolcv~,..ible gelation of an aqueous solution of the macromer at a concentration of at least 2% by weight, and wherein the gelation L~ ldLule is b~Lwcell about 0~C and about 65~C. The macromer also may have a phase transition L~ alulc in the range of 0 to 100~C, and wherein the transition L~ c~dLul~ is affected by the ionic culll~osiLion of an aqueous solution of the lllaclu or trne concentration of macromer in the aqueous solution.
The macromers may be formed by modification of m~t~ and methods described in the prior art. Macromers including a central chain of polyethylene glycol, with oligomeric hydroxy acid at each end and acrylic esters at the ends of the hydroxy acid oligomer are described in Sawhney A. S. et al., Macromolecules, 26: 581 (1993); and PCT WO
93/17669 by Hubbell J. A. et al., the disclosures of which are incorporated herein by reference. U.S. Patent No. 5,410,016 to Hubbell et al., the disclosure of which is incorporated herein by lcfe~ ce, discloses that biodegradable, water-soluble maclulll~l~. can be croS~r in situ to form barrier coatings and depots or matrices for delivery of biologically active agents such as thel~t;uLic drugs. In addition to the m~t~,ri~l~ and methods described in U.S. Patent No. 5,410,016, m~t~ri~l~
and methods described by Dunn (U.S. Patent No. 4,938,763), DeLuca (U.S. Patent Nos. 5,160,745; and 4,818,542), Zalipsky (U.S. Patent No.
5,219,564), Cohn (U.S. Patent No. 4,826,945), Nair (U.S. Patent Nos.
S,078,994; and 5,429,826), the disclosures of which are incul~ola~d herein by l~Ç~lGllce, are useful to form the macromers described herein.
For example, the macromer may include a poloxamer backbone extPn-lPd with hydrophobic materials, such as oligolactate moieties, which S serve as the biodegradable segment of the molecule, wh~cill the PEO-PPO-PEO-lactate copolymer is l~ ed by acrylate moieties. The m~tPri~lc can be combined with, then delivered and photopolyllle.i~d in situ, onto target organs to conform to a specific shape.
The macromers and hydrogels formed thelc;rl~lll preferably are 10 bioco~ a~il)le, preferably not causing or enhancing a biological reaction when implanted or otherwise ~lminictered within a ..-~,..,..~1. The macromers, and any breakdown products of the hydrogels or lllaclulll~
preferably are not signifif~ntly toxic to living cells, or to Ol~"i~."c. The hydrogels also may have liquid crystalline properties for example at high 15 concentration, which are useful in controlling the rate of drug delivery.
Ionic ~lopelLies can be provided in the backbone of the macrolll~
col~llillg the further plopCl~y of control of delivery and/or physical state by control of the ionic envhol~llelll, including pH, of the macrom~r or gel. In one emborlimPnt the critical ion culllpo~iLion is the hydrogen ion 20 concentration. For example, when a polo~minP, such as a Tetronic surfactant, is used as the core of the macromer, then the resl~lting macromer has the ionic groups (amines) in the core, and the macromers' ability to gel upon changes in temperature is affected by the pH of the solution.
Tl~.. ose.. i;live Regions The macromers may be provided with one or more regions which have plopelLies which are thermoresponsive. As used herein, thermoresponsiveness is defined as including ~rup~l~ies of a hydrogel, such as volume, transition from a liquid to a gel, and permeability to 30 biologically active agents, which are dependent upon the ~elll~t;laLul~ of the hydrogel. In one embodiment, the macromers are capable of -,v~.~ible gelation which is controlled by le~ aluic. The reversible gel further optionally may be cros~link~l in situ into an irreversibly and covalently crosclink~cl gel. This permits the macromer to be applied reliably in surgical applications on a specific area of tissue wilhuu~
5 running off or being washed off by body fluids prior to gelation or cro~linking.
In one p~cr~.lcd embo~lim~ont7 the macromers are capable of gelling thermoreversibly, for example, due to the content of poloxamer regions. Since gelling is thermol~v~l~ible, the gel will .l;x~ on 10 cooling. The macromers may further include cro~link~ble groups which permit the gel to be further covalently crosslinked for example by photopolymPri7~tion. After cro~linking, the gels are ill~ve.~il,ly c~v~ krrl However, they retain other ~ignifi~nt thermoresponsive p,~,pel~ies, such as cl~ g~s in volume and in permeability.
By appl~,~,id~ choice of macromer composition, hydrogels can be created in situ which have thermosensitive properties, including volume changes and drug release which are dependent upon ~ e~ e, which can be used to control drug delivery from the hydrogel. Control of drug delivery can be further controlled by adjnstrnPnt of properties such as hydrophobicity of amphiphilic or other regions in the gel. Change in volume of the hydrogel may readily be measured by ex~ntin~ti-)n of macroscopic ullle~LldilRd samples during l~ eld~ulc excursions.
Changes in excess of 100% in volume may be obtained with hydrogels formed from the ma~ , such as an acrylate-capped polyglycolide-dc:livdli~ed poloxamer of about 30% PPO (poly~u~3ylene oxide) content, the exp~n~ion occ~rrin~ gradually on change of the ~ellll)ela~UlC from about 0~C to body le~l~pe,dlulc (37~C). Changes of more than 5% in any linear tiimen~ion may be effective in altering the release rate of a macromolecular drug.
The macronlel~ preferably include thermogelling macromers, such as "poloxamers", i.e., poly(ethylene oxide)-poly(propylene -WO 97/05185 PCT~US96/12285 oxide)-poly(ethylene oxide) ("PEO-PPO-PEO"), block copolymers.
Aqueous polymeric solutions of poloxamers undergo lllicrophase transitions at an upper critical solution tc~ Jcldlul~7 causing a characteristic gel form~tinn This transition is dependent on concc,lLlaLion S and composition of the block copolymer. Alexandridis et al., Macromolecules, 27:2414 (1994). The segment~l polyether portion of the molecule gives water solubility and thermosel~iLiviLy. The m~tori51 also advantageously have been demo"~ t.od to be biocomp~tihle.
For example, the macromer may include a poloxamer backbone 10 extended with hydrophobic materials, such as oligolactate moieties~ which serve as the biodegradable segment of the molecule, wherein the PEO-PPO-PEO-lactate copolymer is tf rmin~t~-l by acrylate moieties. The materials can be combined with a bioactive agent, then delivered and photopolymerized in situ. In addition to poloxamer cores, me~o~ols, 15 such as "lc~ ed Pluronics" (PPO-PEO-PPO copolymers) and polo~ , such as TetronicTM surfactants, may be used.
Other polymer blocks which may be provided in the monorner which are capable of temperature dependent volume changes include water soluble blocks such as polyvinyl alcohol, polyvinyl-pyrrolidone, 20 polyacrylic acids, esters and amides, soluble celluloses, peptides and ploLeills, dextrans and other polysaccharides. ~ lition~lly, polymer blocks with an upper critical point may be used, such as other polyalkylene oxides, such as mixed polyalkylene oxides and esters, dclivaLi;Gcd celluloses, such as hydro~y~ruL,yllllethyl cellulose, and natural 25 gums such as konjac gluco...~
In another embodiment, the macromer is defined as having an optically anisotropic phase at a col~ ion at or below the m~xim~l solubility of the macromer in an aqueous solution, at a lclll~cl~Lu between about 0 and 65~C.
CrQ~link~hle Groups.
The macromers preferably include croeelink~hle groups which are capable of forming covalent bonds with other compounds while in aqueous solution, which perrnit crr,ee1inking of the ,l~ac,~.",t,~, to form a 5 gel, either after, or independently from thermally dependent gellation of the macromer. Ch~mic~lly or ionically croeelink~ble groups known in the art may be provided in the macromers. The croe.clint-~hle groups in one pl~re.,ed embodiment are polymerizable by photoinitiation by free radical generation, most preferably in the visible or long wavelength ultraviolet 10 radiation. The pl~re~ d croeelink~hle groups are ~ .-.,.Ir~l groups including vinyl groups, allyl groups, Cillll,.lll~tPS, acrylates, diacrylates, oligoacrylates, methacrylates, tlimrth~rrylates, olig~ mPtho~crylates, or other biologically acceptable photopolymerizable groups.
Other polym~-ri7~tion rh~mietrirs which may be used include, for 15 example, reaction of amines or alcohols with isocyanate or isothio,;y~lt;, or of amines or thiols with aldehydes, epoxides, oxiranes, or cyclic imines; where either the amine or thiol, or the other l~a.;La~L, or both, may be covalently ~tt~rh~Cl to a macromer. Mixtures of covalent polymerization systems are also contemplated. Sulfonic acid or 20 carboxylic acid groups may be used.
Preferably, at least a portion of the macromers will have more than one croeelink~hle reactive group, to permit formation of a coherent hydrogel after cro~elinkinp of the macromers. Up to 100% of the macromers may have more than one reactive group. Typically, in a 25 sy"ll,esis, the pe~-;e~ ge will be on the order of 50 to 90%, for example, 75 to 80%. The percentage may be reduced by addition of small co-monomers cont~ining only one active group. A lower limit for crosslinker concentration will depend on the p~ Lies of the particular macromer and the total macromer collce"Ll~Lion, but will be at least about 30 3% of the total molar conce~L~dLion of reactive groups. More preferably, the cro~eelink~r co~c~l~L~aLion will be at least 10%, with higher W O 97/05185 PCT~US96/1228~.
conr~ntr,.tions, such as 50% to 90%, being optimal for m;-xi",...--.,~dalion of many drugs. Optionally, at least part of the cro~lin~in~
function may be provided by a low-molecular weight crosslinker. When the drug to be delivered is a macromolecule, higher ranges of polyvalent 5 macromers (i.e., having more than one reactive group) are ~lercl.~,d. If the gel is to be biodegradable, as is plcrc..cd in most applications, then the cros~linking reactive groups should be sepal~lcd from each other by biodegradable links. Any linkage known to be biodegradable under in vivo conditions may be suitablel such as a degradable polymer block.
10 The use of ethylenically ul~ Luldt~d groups, cro~link~-d by free radical polymerization with chlomi~ ~l and/or photoactive initiators, is ~.~cÇ~ ,d as the cro~ nk~hle group.
The macromer may also include an ionically charged moiety covalently ~tt,.-~hto-' to the macromer, which optionally permits gell~ti(~n or 15 cros~linking of the macromer.
Hy~l~c~hobic R~gjf~r..c;
The macromers further may include hydrophobic c.om~in.~. The hydrophobicity of the gel may be modified to alter drug delivery or three ~lim~n~ion,.l configuration of the gel. Amphiphilic regions may be provided in the maclu.llel~. which in aqueous solution tend to aggregate to form micellar domain, with the hydrophobic regions oriented in the interior of these domains (the "core"), while the hydrophilic c'.~.m,.in~
orient on the exterior ( "the corona"). These microscopic "cores" can entrap hydrophobic drugs, thus providing micrul~;s~;.vu.,~ for sn~t~in~od drug release. K~t~nk~ K., et al., J. Controlled Release, 24:119 (1993).
The fim~l~m~nt~l parameter of this supramolecular assemblage of amphiphilic polymers in aqueous solution is the Critical Micellar Conre-ntr~tinn (CMC), which can be defined as the lowest co~ c~ lion at which the dissolved macromolecules begin to self-assemble. By selection of the hydrophilic and other ~lom~in~, drug delivery can be controlled and enh~nred.
In one embodimlont, the macro,llel~ are provided with at least one hydrophobic zone, and can form micelles in~ ing a region in which hydrophobic materials will tend to bind and thus tend to reduce escape of the drug from the formed gel. The hydlu~hobic zone may be el-h~ ed S by addition of materials, including polymers, which do not collLlil,uL~ to the formation of a gel ll~Lwol~ but which segregate into such zones to e~nh~n~e their ~lo~cllies, such as a fatty acid, hydrocarbon, lipid, or a sterol.
The ability of the macromonomers in one embodiment to form 10 mirell~r hydrophobic centers not only allows the controlled dissolution of hydrophobic bioactive compounds but also permits the hydrogel to selectively "expand" and "contract" around a transition L~ a~ul~,. This provides an "on-off" thermocontrol switch which permits the th~rm~lly sensitive delivery of drugs.
The cell membrane is composed of a bilayer with the inner region being hydrophobic. This bilayer is believed to have a fluid and dynamic structure, i.e., hydrophobic molecules can move around in this ~Llu~;Lul~.
A hydrophobic tail incorporated in a macromer can diffuse into this lipid bilayer and result in the rest of the macromonomer (thus, the hydrogel) to 20 better adhere to the tissue surface (see Figure 11). The choice of molecular group to be used as hydrophobic tail is guided by the fatty acid composition of the bilayèr to assure .. i.~i.. ~lLulbalion of the bilayer structure. Examples of suitable groups are fatty acids, diacylglycerols, molecules from membranes such as phosphatidylserine, and polycyclic 25 hydrocall,olls and de~ aLivl:s, such as cholesterol, cholic acid, steroids and the like. Preferred hydrophobic groups for this purpose are normal co.~ of the human body. These molecules will be used at a low c~lllcelllldlion relative to native molecules in the membrane.
Use of macromers carrying one or more hydrophobic groups can 30 hll~rov~ the adherence of a hydrogel to a biological material by anchoring a se~;lllenL of the hydrogel in the lipid bilayer. This anchoring will cause WO 97/05185 PCTAJS96/122~5 ",il.i".~l p~Lulbalion to the underlying tissue because the insertion of the fatty acid tertnin~l of the macromer into the lipid membrane involves purely physical i~lr~ n. The macromer may be applied by using a ~ prewash of the surface with these molecules, in effect '~le~a~ g' the 5 surface for coupling and/or an in situ photopoly~ l~c lion of a llli~lule of these lipid-pe~.~lf~ g molecules with the cro.~linl-~hle mac~
The hydrophobic region may include oligomers of hydroxy acids such as lactic acid or glycolic acid, or oligomers of caprolactone, amino acids, anhydrides, orthoesters, phosph~7Pn~oc, phosphates, polyhydlo~y 10 acids or copolymers of these ~.u~u"ils. Additionally the hydrophobic region may be formed of poly(propylene oxide), poly(butylene oxide), or a hydrophobic non-block mixed poly(alkylene oxide) or copolymers thereof. Biodegradable hyd~ obic polyanhydrides are disclosed in, for example, U.S. Patent Nos. 4,757,128, 4,857,311, 4,888,176, and 4,789,724, the disclosure of which is incorporated by l.re,~ .lce herein.
Poly L-lactide, or poly D,L-lactide for example may be used. In another embodiment the hydrophobic region may be a polyester which is a copolymer of poly(lactic-co-glycolic) acid (PLGA).
The macromer also may be provided as a llli~lUle including a 20 hydrophobic material non-covalently associated with the macromer, wherein the hydlu~hobic material is, for example, a hydrocarbon, a lipid, a fatty acid, or a sterol.
Hydrophilic E~ n~.
Water soluble hydrophilic oligomers available in the art may be 25 incorporated into the biodegradable macl~lllel~.. The hydrophilic region can be for example, polymer blocks of poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(vhlyl~y"olidone), poly(ethyloxazoline), or polysaccharides or carbohydrates such as hyaluronic acid, dextran, heparan sulfate, cho,ldroiLi,l sulfate, hepcmn, or 30 ~lgin~tt~, or ~loL~ s such as gelatin, collagen, albDin, ovalbuminL, or polyamino acids.
CA 02228118 1998-01-2i, Biodegradable R~gion~
Biodegradable molecules or polymers thereof available in the art may be incorporated into the macromers. The biodegradable region is preferably hydrolyzable under in vivo conditions. In some embo-limfnt~, S the dirrt;~ L ~l~,pc;,lies, such as biodegradability and hydrophobicity or hydrophilicity, may be present within the same region of the ll,acr~lllel.
Useful hydrolyzable groups include polymers and oligomers of glycolide, lactide, epsilon-caprolactone, other hydroxy acids, and other biologically degradable polymers that yield m~t~ri~l~ that are non-toxic or 10 present as normal metabolites in the body. Preferred poly(alpha-hydroxy acids) are poly(glycolic acid), poly(DL-lactic acid) and poly(L-lactic acid). Other useful materials include poly(amino acids), polycarbonates, poly(anhydrides), poly(or~oesters), poly(phnsph~in~s) and poly(phosphoesters). Polylactones such as poly(epsilon-caprolactone), 15 poly(delta-caprolactone), poly(delta-valerolactone) and poly(gamma-butyrolactone), for example, are also useful. The biodegradable regions may have a degree of polym.ori7~tinn ranging from one up to values that would yield a product that was not ~ lly water soluble. Thus, monomeric, dimeric, trim~rir, oligu~ ic, and 20 polymeric regions may be used.
Biodegradable regions can be constructed from polymers or monomers using linkages susceptible to biodegradation, such as ester, peptide, anhydride, orthoester, phosph~7in~ and phosphnest~r bonds. The time required for a polymer to degrade can be tailored by selecting 25 ~Lo~Lial~ monomers. Dirr~ ces in crystallinity also alter ~l~ogr~ tinn rates. For relatively hydrophobic polymers, actual mass loss only begins when the oligomeric fragments are small enough to be water soluble.
Thus, initial polymer molecular weight inflll~nres the degradation rate.
W O 97/05185 PCTrUS96/12285 Tl~ Appli~ti~n~
Biodegradable, telllp.,.dLule responsive hydrogels can be fonned in situ and may be use in a variety of Ll~ uLic applir~tion~ including - surgical applications. In one embodiment the gels can be applied topically 5 to the skin to treat a variety of conditions such as abrasion, k~ r~loses, infl~mm~tory del...~oses, injury reslllting from a surgical procedure, and disturbed k.".l;--;,~lion. The hydrogels may include Lhcla~culic agents such as antibiotics, or antifungals for the localized tre~tmtont of dirr~,lc;llLskin conditions.
Macromers which are liquid at room temperature and gel at body Lelll~c;laLulc, such as lllacl~,lllers including a PluronicTM poloxamer, may be used in tre~tmpnt of burns and other external injuries. The hydrogels are useful in burn applications, since the hydrogel layer formed on the skin provides local or tr~n~dPrm~l delivery of drug to the burn site;
15 m~int~in~ high moisture levels on severely burned sites, thus rl;~
dehydration; adheres strongly to the damaged tissue, and is elastic, thus mi..i...i~ g dcl~ tion and "peeling" of the hydrogel dressing; and absorbs exudate from the wound. Hydrogels may be sel~octed whic,h dissolve into components which are absorbable and non-toxic, which 20 promote healing, and gel spontaneously and quickly on the burn site, prior to optional further cro.sslinkinp.
The macromers also may be applied to biological tissue, or on the surface of a mtorlit~l device, to form hydrogels in a variety of surgical applications for the Ll~ of tissue or organs. The gel also may be 25 applied b~lw~ell two surfaces, such as tissue sllrf~res, to adhere th~
surfaces. The hydrogels may be applied to tissue such as vascular tissue, for example for the treatment of restenosis of the arteries or in angioplasty procedures. A biologically active material may be provided in the gel optionally in the form of particles, microparticles, pro-drug 30 conjugates, or liposomes. The macl~lllc;l~. may be de~ign~d such ~hat the cro.c.~link~1 gel changes in permeability in response to a change in laLule~ ionic concentration or a change in pH, thereby ~ltering the rate of drug release from the hydrogel.
Drug Deli~
The macr~l.c.~, may be cros~linkr~l lev~ ,ibly or hle~,.,.~,ibly to 5 form gels for controlled drug delivery applir-~tion~ The composition and plul.e,lies of the macromers can be selected and fabricated to produce hydrogels with desired drug delivery ~ llies. The drug may be provided in the macromer solution prior to or after ~-lmini~tration, and either before or after gel formation, depending on the macromer 10 composition.
For example, the gels can be ~le~ nt?d to have a selected rate of drug release, such as first order or zero order drug release kin~tirs For specific drugs, such as peptides, the composition of the gel may be ~e~ignrcl to result in pulsatile or mixed wave release chara~;lt;li.,lics in 15 order to obtain m~ximllm drug efficacy and to minimi7~ side effects and tolerance development. Bae et al., Pharnmcel~ticn~ Research, 8: 531 (1991).
The drug release profiles can be sPlecte~l by the use of ma~
and gels formed ll-t;lc;r.~ that respond to specific extrrn~l stimuli such 20 as ultrasound, temperature, pH or electric current. For example, the extent of swelling and size of these hydrogels can be mo~ tr~l Changes in~l~lrecl in the swelling directly correlate to the rate of release of the incorporated drugs. Through this, a particular release profile may be obtained. The hydrogels are preferably biodegradable so that removal is 25 not required after ~lmini~tration or implantation.
The gels permit controlled drug delivery and release of a biologically active agent in a predictable and conkolled manner locally at the targeted site where it is needed, when the tissue to be keated is localized. In other embo-lim~nt~, the gels also can be used for systemic 30 delivery.
W O 97/05185 PCTAUS96/lZ285 A variety of th~d~ uLiC agents can be delivered using the hydrogels. Examples include synthetic inorganic and organic compounds, plo~ills and peptides, polysaccharides and other sugars, lipids, gangliosides, and nucleic acid sequences having Iht;ld~JeUIiC, prophylactic 5 or diagnostic activities. Nucleic acid seqll~nrçs include genes, ~nti~en~e molecules which bind to complem~nt~ry DNA to inhibit lldnsc,i~lion, and ribozymes. The agents to be incorporated can have a variety of biological activities, such as vasoactive agents, neuroactive agents, hollll~es, ~ntiro~gulants, immlmomo~ tinp agents, cytotoxic agents, antibiotics, 10 antivirals, ~nti~n~e, antigens, and antibodies. Proteins including antibodies or antigens can also be delivered. Proteins are defined as con~i~ting of 100 amino acid residues or more; peptides are less than 100 amino acid residues. Unless otherwise stated, the term protein refers to both ploleins and peptides. Examples include insulin and other 15 hormones.
Specific m~f~ri~lc include antibiotics, antivirals, ~ntiinfl~mm~tories, both steroidal and non-steroidal, alllhle-,~lastics, anti-spasmodics including channel blockers, modulators of cell-extracellular matrix interactions inrll7tling cell growth inhibitors and anti-adhesion 20 molecules, enzymes and enzyme inhibitors, ~nti~o~gulants and/or alllillllolllbotic agents, growth factors, DNA, RNA, il~ ul~ of DNA, RNA or protein synthesis, compounds mocll-l~ting cell migr~tiQn, proliferation and/or growth, vasodilating agents, and other drugs c~ mm~ nly used for the keatment of injury to tissue. Specific examples of 25 these compounds include angiotensin collv~llhlg enzyme i-.hil~ilol~, prostacyclin, heparin, salicylates, nitrates, calcium channel blocking drugs, streptokinase, urokinase, tissue pl~min--gen activator (TPA) and anisoylated plasminogen activator (TPA) and anisoylated plasminogen-streptokinase activator complex (APSAC), colchicine and alkylating 30 agents, and aptomers. Specific examples of modulators of cell hllt;la~;lions include interleukins, platelet derived growth factor, acidic and W O 97/05185 PCT~US96/12285 basic ~lbroblast growth factor (FGF), LldnsrolllldLion growth factor B
(TGF 1~), epidermal growth factor (EGF), insulin-like growth factor, and antibodies thereto. Specific examples of nucleic acids include genes and cDNAs encoding yroteills~ expression vectors, ~ n~e and other 5 oligonucleotides such as ribozymes which can be used to regulate or ~JlCVt~llL gene e~yl~ssion. Specific examples of other bioactive agents include modified extracellular matrix components or their .-,ce~Lul~, and lipid and cholesterol seq~lestrants.
Examples of L,ro~ s further include cytok-ines such as i..~.f~,lolls 10 and interleukins, poetins, and colony-sfim~ ting factors. Carbohyd dLes include Sialyl Lewis~ which has been shown to bind to l~;ct:~Lol~ for selçctin~ to inhibit infl~mm~tion. A "Deliverable growth factor equivalent" (abbreviated DGFE), a growth factor for a cell or tissue, may be used, which is broadly construed as including growth factors, 15 cytokines, illl~.r~ olls, int-orlellkin~, ylvl~ills, colony-stimnl~tin~ factors, gibberellins, auxins, and viL~-ills; further including peptide fr~gm~ont~ or other active fragments of the above; and further inrll~-lin~ vectors, i.e., nucleic acid constructs capable of synthtosi7ing such factors in the target cells, whether by Lldl~Ço-l-lalion or Lldnsie.l~ ression; and further 20 inrln~lin~ effectors which stimnl~tr or depress the synthesis of such factors in the tissue, including natural signal molecules, ~ ç~e and triplex nucleic acids, and the like. Exemplary DGFE's are vascular endothelial growth factor (VEGF), endothelial cell growth factor (ECGF), basic fibroblast growth factor (bFGF), bone morphogenetic protein 25 (BMP), and platelet derived growth factor (PDGF), and DNA's encoding for them. Exemplary clot dissolving agents are tissue pl~mint)gen activator, streptokinase, urokinase and heparin.
Drugs having antioxidant activity (i.e., de~Lloyi..g or pl~v~llL~g formation of active oxygen) may be provided in the hydrogel, which are 30 useful, for example, in the yl~v~llLion of adhesions. Examples include superoxide ~ mnt~e, or other protein drugs include CZ~t~ ÇS, WO 97/05185 PCT~US96/12285 peroxidases and general oxi~ es or oxidative enzymes such as cytochrome P450, glutathione peroxidase, and other native or de~ uled hem~lul~ills.
M~mm~ n stress response proteins or heat shock ploltills, such as heat shock protein 70 (hsp 70) and hsp 90, or those stimuli which act to inhibit or reduce stress response ~roleills or heat shock protein c~ion, for example, flavonoids, may be provided in the hydrogel.
The lllac~ may be provided in pll~. ",~ ir~l acceptable carriers known to those skilled in the art, such as saline or phosphate buffered saline. For example, suitable carriers for pal~ dl l.,.i..~-alion may be used.
A~ lion of Mae~
Modern surgical procedures which provide access to a variety of organs using minim~lly invasive surgical devices may be used to apply the macromers. Using techniques such as laparoscopy/endoscopy, it is possible to deposit a macromonomer solution at a localized site and subsequently polymerize it inside the body. This method of "on-site"
polymerization offers unique advantages such as co- ro~ ily to specific organs and adherence to underlying tissue. Hill-West J. L. et al., Obstetncs & aynecology, 83:59 (1994). (~thPter delivery systems available in the art also may be used as described, for example, in U.S.
Patent Nos. 5,328,471 and 5,213,580 to Slepian. The macromer also may applied during surgery con~ cte~l through the c~nm-l~ of a trocar.
Fo....~tioll of Microspheres In one embo-liment the biodegrabable lllaclulllers are crosslinked, either reversibly or nonreversibly to form microspheres. As used herein, the term "microspheres" includes includes particles having a Ul~iÇullll sphl-rir~1 shape or an irregular shape, and microcapsules (having a core and an outer layer of polymer) which generally have â ~ mPt~pr from the n~nomPter range up to about S mm. In a ~,~r~l,.,d embodiment, tlhe microspheres are dispersed in biocompatible, bio~legr~ hle hydrogel W O 97/05185 PCT~US96/12285 m~trires. The llliclu~heres are useful for controlled release and L~t;L~d delivery of dlugs within the body.
The microspheres are formed in one embodiment by aggl~ ion and subsequent polymerization of portions of the macromers which are S similar in charge properties such as hydrophilicity. This results in a matrix which consists of spollL~.leuusly-assembled "nodes", which may be cros~iinkecl covalently, and may be further covalently linked to hydrophilic bridges of the macromers to form a hydrogel.
When the macromer is amphiphilic and includes hydlophobic and 10 hydlulJhilic domains, in an aqueous ellvhulllllent, at or above a certain concentration, the molecules to arrange themseIves into olg~l~i~d structures called micelles, at the critical micellar concellL.~lion (CMC).
These micelles can be of different shapes and sizes, though are gen.or:~lly spherical or elliptical shape. When the solution is water, the hydl~hobic 15 portions are at the center of the micelle while the hydrophilic tails orient themselves toward water. The interior core of a typical sllrf~rt~nt has a size from 10-30 Angstroms. PluronicTU poloxamer based biodegTadable macromers, as described in Examplel, undergo micellization in an aqueous e..vholl...ent with CMC values ranging between 0 and 5% (w/v).
20 After photopolymerization and gelation, this micellar structure is p.~i,e.v~;d in the crosslinked gel. On a microscopic level, the gel co.lL~.. s micelles which are interconnrcted by covalent bonds to form the gel.
These micellar domains or microspheres can be used for the controlled or ~.,xl;.;..~(l release of drugs. A scl~ tic .~l~,sellL~Lion of such a material 25 is shown in Figure 12. Controlled, pseudo-zero order release of small compounds such as chlorohexidine is possible from such hydrogels.
The hydrogel thus is formed in one embodiment by providing a solution of macromer in aqueous solution (with or without drug);
"freezing" the micellar structure of the macromer by a ch~mir~l 30 cro~linking via a chemical reaction; adding the drug to the ~;lu~ d macromer if it has not been already added; and using the reslllt~nt di~ ed composite, co..~;~i,.iu~ microspheres con~icfin~ of drug~ tin~
micellar cores, for drug delivery.
In addition to photopolymerization, crosslinking can be implem~nt~l by, for example, isocyanate-amine ~ y, or hy~ y- or 5 aldehyde-amine ch~mi~try, to freeze micellar structure. For example, isocyanate If ~ poloxamer lactate diol can react in water to form crosslinked polyulelllalle based n~wolh~. This is an advantageous method of forming a drug delivery device for local or systemic delivery, because the formation of the delivery-controlling micropheres and the 10 ,lliclu~here-confining gel is accomplished ~imll1t~nl~ously, and may be accomplished at the site of delivery in a few seconds by photopolymerization .
In one embodiment the macromer inrlucles PEO segments, and hydrophobic "ends" cont~ining reactive groups, and the mi-~ell~r domains 15 are hydrophobic and are interlinked by the PEG segments to form a hydrogel. Reversible gelling microsphere -follllill~ macl~ also may be made from PluronicsTM (PEG-PPO-PEG), lactylated and acrylate-capped, which are gelled and reacted in a non-aqueous phase. A
hydrophilic drug then may be added (while in the hydl~J~hobic solvent) 20 which partitions to the hydrophilic core. Because the micelles have been cross-linked in the hydrophobic el,vil:ol-lllent, they will not be able to revert to the Collroll~latiOn which they would normally assume in a hydrophilic ellvi~o~----~.-l The trapped hydrophilic drug molecules then need to diffuse through a relatively hydrophobic region to escape iFrom the 25 nanoparticle. This permits flexibility in the formation of llli~ ~heres.
They may be hydrophilic or hydrophobic d~elldillg on the solven~ in which they are polymerized, and on the composition of the macromers.
In other embo~limentc, physical or ch~mir~l cro~linking to form hydrogels (or organogels) can occur in zones other than those le~ol~il)le 30 for the plilll~ly sll~t~in~l release characteristics of the matrix. For example, "single-ended" materials could have ~lt~rn~tive reaction sites on W O 97/05185 PCT~US96/12285 the non-micellar ends, which could subseqllçntly reacted to form a gel.
Since matrix-controlled drug delivery is a function of both diffusion from the micelles and of matrix degradation, manipulation of the macromolecular backbone can also control matrix degr~ tion. This can S occur through stabilization of hydrolytic groups by their rhPmi~l and physical ellvil~ ent (for example, macl~ based on reverse PluronicTM gels are more stable than normal PluronicTM gels, in aqueous solution). It is possible that the increased hydrophobicity of the environment of the lactide ester bonds, due to the adjacent block being~0 PPO rather than PEO, inhibits hydrolysis of the bond.
i vely~ and particularly in gel-forming compositions, the cross-linking reactive groups or biodegradable groups may be in the hydrophilic portions of the macromers, so that the hydrophobic ~iom~in~
would not be locally cro~link~-~l in the hydrophobic regions, while the 15 micelles would still be stabilized by the cros~linking of the material, and particular hydrophobic sections of macromers would be steri~lly r~ ed to one or only a few dirrel~ micelles. In either of these cases, the hydrophobic zones are not rigidly cros~lin~ l but are co""~ to crosslinks via the hydrophilic blocks, which may be very flexible. The 20 hydrophobic blocks thus can associate above or below a critical Lt;llll)tldlUl'e, and dissociate on change in l~ll.pcldlul~. This allows, for example, both th~nnosçn~itive gelation and thermosellsiliv~ variation in drug diffusion rate.
The hydrogels may be ~lç~i~nf~l to be biodegradable by 25 incorporation of a group such as a lactide, glycolide or other self-degrading linkage. ~lle~ liv~1y, this is not .-~cç~.y when non-gelled nanospheres are formed, since these are small enough to be removed by phagocytosis. Control of the rates of delivery of both small and large molecules can be obtained by control of the hydrophobicity of 30 the associating hydrophobic domains of amphip~thic hydrogels.
The cro~ nk~l microspheres con~ g a biologically active agent, in either gel or dispersion form, can be made in a single step. In addition to drug delivery applications, the method is suitable for ~ non-m~ r~l uses inrhl-lin~ delivery of ~grir~ lral materials such as 5 herbicides and pr~tir~ s and in water tre~tmrnt The present invention will be further understood by l~Ç~ e to the following non-limiting examples.
Example 1: S~ and Thermal R~p~ ,", of F127~ rt:~e)6-Acrylate.
a) Synthesis.
F127-(lactate)O-acrylate (lml~rt~cl control) (=F127A2?) was synth~,si7~o~1 by acrylatinglOO g of PluronicTM F127 (poly~r~ylene oxide-polyethylene oxide block copolymer, BASF, mol. wt. 12000) ("F127") in ~ hydl~us toluene using kiethylamine and acryloyl chloride, in an argon 15 atmosphere at 60~C for 10 mimltes. The hot, turbid reaction ~ Lule was filtered and the filtrate was added to a large excess of hexane. The monomer was collected by vacuum filtration and dried in VaCUULU to a constant weight.
F127-(lactate)6-acrylate was synthrsi7pA as follows. F127 ~was 20 melt dried in vacuo at 100~C for 4 hours. D,L-lactide (Boel.~ ,el Ingelheim) was added to the melt under a nitrogen flush, followed by nll~us octoate as a ring opening catalyst. After a reaction time of 4 hours, the melt was dissolved in toluene and pl~ ildled in a large excess of hexane. Acrylation of F127-(lactate)6 was carried out as described 25 above for the acrylation of F127-(lactate)O-acrylate. All macr~ mo were characterized by NMR and HPLC.
The relationship between the macromer, the thermally-reversible (physical) gel, and the ill~vel,ible (cro~linkt~l) gel is shown in Figure 1.
b) Measurement of the sol-~el transition as a function of 30 concelllldlion and len,~.dlule.
W O 97/05185 PCT~US96/12285 Thermo~ ible gel formation of the aqueous solutions of the macromonomers at a certain transition It;~ dLul~; was df m~ ed This transition temperature was recorded as a function of fe-..pe~ e and collcelll.~lion. The results ~l~mo..~.aLtd that sol-gel transition can be 5 controlled through the incorporation of hydrophobic lactyl units.
Transition ~lllpeldlulc: as a function of concentration was f ....;..~od by ~r~dlillg 20% w/v aqueous solutions of F127-(lactate)0-acrylate and F127-(lactate)6-acrylate as stock solutions. 15 % (w/v), 12.5% (w/v), 10% (w/v) and 5% (w/v) macr~ mon-mfr 10 aqueous? solutions in screw cap vials were ~ al~d by dilutions of the stock solutions. The solutions were allowed to equilibrate at 25~C. The vials were inverted and observed for fluid flow. The concentration at which no fluid flow was observed was recorded (see Table 1).
The transition ~ ldlule as a fucntion of tel~ldlul~ was 15 ~lele....i.~ by ~r~alillg 10% (w/v) aqueous solutions of F127-(lactate)6-acrylate and F127-(lactate)0-acrylate and equilil)laLi l~, them at room L~ peldLul~. (The concentration of the solutions are wt/vol% in aqueous solution unless otherwise stated.) The sample vials were immersed in a te~ )eldlule controlled bath and the fluid flow was 20 observed at dir~l~llL tempelaLules. The l~ll~e.dlulc at which no fluid flow was observed was recorded (see Table 1).
Sol-Gel Sol-Gel ~ Macromonomers Transition (% Tr~n~hio~, w/v)** ( o C)***
F127-(Lactate)0- 30 40 Acrylate F127-(Lactate)6- 10 25 Acrylate ** Sol-Gel Transition as a function of cOllc~llLlaLio (temperature 25~C).
***Sol-Gel Transition of 10% w/v solutions as a r.....
of temperature.
c) Poly~ alion and Mea~ul~ of hydro~el ~lim~n~ions.
A 10% solution of F127-(lactate)6-acrylate in PBS (ph- sph~
buffered saline) was polymerized using long wave UV light. The polymerizations were performed in a cylindrical plastic mold. Darocur~
2959 (Ciba Geigy) was used as the photoinitiator. The hydrogel was allowed to reach equilibrium swelling by immersing in PBS for 24 hours 20 at ambient L~lllyeldLul'e. The change in ~1im~n~ion of the hydrogel at temp~ Lules ranging from 0-50~C was measured using vernier calipers, and is shown in Figure 2. At low l~lllycl~Lul~ s, the hydrophobic PPO
(polypropylene oxide) segments of the hydrogel may dissolve and swell, and increase the dimensions of the gel. At high Lt;llly~atUlCS, the PPO
25 segmrnt~ may become hydrophobic and collapse into lllicr~,lllicellar hydrophobic (1om~in~, which exclude water resllltin~ in reduced swelling and smaller dimensions.
d) De~radation ~yelilllents~
~ Hydrogels were pl~ar~d using 10% macromonomer solution as30 mentioned before and the degradation of hydrogel was m~,niL~l. d ~ lav;~l~f L~ ;r~lly at various intervals of time. The e~y~lilll~llL~ were pelrolllled at 37~C in PBS. The lactate based photopolymerized hydrogel completely degraded in 22 days (at 37~C, in PBS).
WO 97/05185 PCTrUS96/12285 Thus, the macru~ can be photopolymerized to form thermoresponsive hydrogels which degrade under physiological conditions.
The mac~ and related prior art m~t~ri~l~ are referred to 5 herein in the form XXXLLAA, where XXX is either part of the trade name of a precursor polymer (e.g., L81 for Pluronic~ L81 poloxamer) or refers to another property of the base polymer (e.g., 8K for 8,000 nnmin~l Dalton PEO). LL denotes the If~l.l.i..~l block, typically of a degradable hydro~y acid (e.g., L5 denotes an average of 5 lactate residues 10 per arm of the polymer), where L, G, C and TMC or T l~l~sellL, respectively, lactate, glycolate, epsilon-capl~,at~:, and trimethylenecarbonate. AA represents a Ir~ l group; for example, A
is for acrylate, so A2 would l~l~ s~llL 2 acrylate l~ linns on the ma~ lller as a whole.
Example 2: Dextran Release by F127A2.
The non-degradable material, F127A2, was made as described above in Example 1, with no addition of hydroxy acid to the Pluronic~
polymer backbone. Dextran (labeled with fluorescein) of molecular weight 71,000 daltons was mixed at 1% final concentration with F127A2 lllacl-,lller (final concentration 10% wt/vol, in water) and polylllel~d as described in Example 1. Release of dextran was (1etf-. Illillf~Cl by visible absoll,allce. Release kinetics were ~i~nifir~nt1y altered by tel~ lalu.c;, as shown in Figure 3.
h',Y~ e 3. Synthesis of M~ with Biode~. ~!f T,inkin~ Groups.
Four monomer types were made by the general procedures described in Example 1, each cont~ining about 4 units of each of four different biodegradable linkers, clecign~tPcl by L (lactate), C
(caprolactone), G (glycolide), and TMC (trimethylene calbO~).
Parameters for the synthesis of the therrnosen~itive macromo~ are listed in Table 2. Properties of the monomers characterized are listed in W O 97/05185 PCT~US96/12285 Table 3, in~ ing biodegradable segment and end group incorporation by HPLC and NMR, and Mn tl~t-ortnin~cl by GPC and NMR.
- M.W. PPO PEOFeed Ratio Temp Compound(g/mole) M.W. M.W.Monomer/ ~C/ Yield diol time(g) (h) F127L4A2 12600 3780 8820 4 180-80.46 F127C4A2 12600 3780 8820 4 180-81.38 F127G4A2 12600 3780 8820 4 180-71.89 F127TMC4A212600 3780 8820 4 180-79.29 W O 97/0518~ PCT~US96/12285 Macro- Biodeg. Biode~ End End Mn Mn Mn mono- Seg. Seg. Group Group GPC NMR Expected mer Incorp. Incorp. Incorp. Incorp. g/mol g/mol g/mol (HPLC) (MNR) (HPLC) (NMR) F127- 5.68~t 5.58 2.09~ 2.00 1080 11316 12998 L4A2 0.01 0.01 0 F127- 5.39i 5.04 2.05i 2.31 1080 10804 12942 G4A2 0.02 0.02 o F127- 5.49i 5.45 2.09~t 2.11 1000 13062 13166 C4A2 0.02 0.03 0 F127- -- 3.26 2.08i 2.09 1210 NA
TMC- 0.03 0 The mollo~ differed in their rate of polym~ri~tion and rate of S degr~ tio~ The long UV photopolyl~ Lion profiles are shown in Figure 4. The in vitro degradation profiles of the cro~linke~l hydrogels are shown in Figure S.
The macrulll.,l~ had similar bioc~ ihility proffles, as shown in Figure 6, as l~easul~d by the HFF cell a&esion test. In Figure 7, release 10 rates of fluolescellL ~lextr~n at 37~C and 0~C is shown for a prior art m~teri~l (F127A2) and for "~acl~.ll,ers with degradable hydrophobic blocks formed of lactide (F127L4A2), glycolide (F127G4A2) and caprolactone (F127C4A2). A longer period of quasi-zero order delivery, after the initial burst, and a distinct dirr~l~nce in the rates of efflux 15 b~Lweell the lower and higher ~ )ela~ull,s, is obtained with the lllacl~ûlllel~ including the degradable blocks, in c~ ,ison to the prior art material. In Figure 8, the transition L~ laLul~,s (for vûlume change and change of ~1extr~n release rate) are shown as a filntrtion of llla~;lOln"~
concenration in the gel for the above materials and also a trimethylene SUBSTITUTE SHEET (RULE 26) WO 97/05185 PCT~U~96/12285 carbonate based m~tt~ri~l (F127TMC4A2), a "reverse" Iclo~ ol mzlt~riz-with lactide (25R8L4A2), and a "normal" m~tPri~l (F68IAA2) of equivalent hydrophobicity.
The HFF test was con~ ctecl as follows:
S a.) P1G~ aL;On of Gel.
0.5 gram of test material was dissolved in 4.5 ml ~L~ldald recu,..~ n solution (Irgacure 1200 ppm, 3% Pluronic F127). The solution was filter sterilized using 0.2 micron filter. In a sterile hood, a glass coverslip (18 mm sq) was sterilizPd using 70% ethanol and was placed in a 6 well, 35 mm tissue culture dish. 200 ,.4L of the sterile macromonomer solution was spread on a sterile coverslip. The solution was then exposed to long wavelength W light (Black Ray, 20 mW/cm2, 1 minute) to forrn a gel.
c) Plc~)alaLion of Cell Suspension.
Human r~c~in fibroblasts (HFF) cells were ~?ulcllased from ATCC. Cells were used at a passage 22-23. HFF cells were cultured in a standard tissue culture ware in a hllmitlifiPA ~tmosphPre co"l;l;";..g 5%
CO2. Cells were rlpt~rhpcl from the culture flask using a 3 ml trypsin/EDTA solution (0.05% /0.53 mm) and centrifuged (2500 rpm, 3 20 Illill~ s). The cell pilot was resuspended in cell culture mP~ lm (DMEM
+ 10% FCS) at a concellLlaLion of 250000 cells/ml.
d) Cell ~tt~rllment assay.
The gels were washed with 3 ml DMEM (Dulbecco's Modified Eagles' Medium) solution and then seeded with 25000 cells/cm2 cell 25 density. After 18 h, the gel surface and tissue culture poly~ly~ e surface were observed under microscope and photographed. The gels were ale-l from coverslip and Lldn~r~ d into a new petri dish. The cells adhered to the gels were ~let~hP~l using 3 ml trypsin/EDTA (0.05% /
0.53 mm) solution. A Coulter counter was used to d~ lllille the cell 30 density.
W O 97/05185 PCT~US96/12285 Example 4: Effects of T,inkin~ Group Hy~ kicity on Small Mol~c-llP Delivery.
Micelle-forming biodegradable maclulll~ were ~y~ and characterized which included a a non-thermosel~iliv~ core. The macromers illustrated the effects of hydrophobicity on delivery capacity for small hydrophobic molecules. The macromers were formed by ~yll~ g copolymers of PEG (molecular weight 8000) with dirr~
combin~tion~ of polycaprolactone and polyglycolate which were then end capped with acrylate moieties. The structures are shown in Figure 9, where p is the number of glycolic acid groups and q is the number of caprolactone groups. Hydrophobicity of the mixed hydroxy acid blocks hlcleases from A to D. The ability of these monomers to solubilize model hydrophobic drugs was demonstrated by a study of the CMC
through the gradual dissolution of a molecular probe, 1,6 diphenyl 1,3,5-hf~x~ nf~ (DPH).
effect of hydrophobicity on drug incorporation into gels a) Synthesis of monomers.
The molecular structures of the monomers are shown in Figure 9.
Polyethylene glycol 8000 (Union Carbide) was melt-dried at 100-110~C in vacuum (10-15 mm Hg) for 4-6 hours. Caprolactone (predi~tillP~1 Aldrich), and glycolide, were charged at a~lopliate ratios into a Srhl~onk-type reaction vessel and stannous 2-et_yl hPx~no~t~ (Sigma) was added as a ring opening catalyst. The reaction was carried out for 4 hours in an inert atmosphere at 180~C. The reaction llli~lUlc; was then cooled to 80~C, dissolved in toluene, ~l~ci~ led in hexane and the product was collected by vacuum filtration. The product was redissolved in toluene and dried by azeotropic ~ till~tinn.
Acrylation was carried out by the dropwise addition of a 2 molar excess of acryloyl chloride and triethylamine under a llillogell flush at 65~C for 1 hour. By-product salts were removed by vacuum filtration.
Ihe product was isolated by precipitation in a large excess of hexane -W O 97/05185 PCT~US96/12285 followed by vacuum filtration. The mol~oml.. were c]~ d by NMR on a Varian 300 MHz nuclear m~gn~tic ~e~;L~ eter.
b) Dete....i"~lion of Critical Micellar ConcellLlaliol s.
~ The hydrophobic dye 1,6, diphenyl 1,3,5-h~x;~ n~ (Aldrich), (DPH), which demul~Llates enh~n~ed absoll,allce (356 nm) at the ~CMC
due to associative hllel~cLions, was used in this study. ~k x~ et al., Macromolecules, 27:2414 (1994). A stock solution of DPH was ~,le~ ,d in methanol (0.4 mM). Aqueous mon-)m~r solutions were al~d by dissolution in PBS and dilution to the desired C~n~ ion~.
10 ,~1 of the dye solution were added to each vial with equilibration for at least 1 hour. The absorption spectra of the polymer/dye/water solutions were recorded in the 250-500 nm range using a Hitachi W-VIS
Spe~;L~ ullleLer .
c) Photopolymerization.
Photopolyllle~ lion of the polymer solutions were carried out in both visible and ultraviolet light systems as described in: Sawhney A. S.
et al., Macromolecules, 26: 581 (1993); and PCT WO 93/17669 by Hubbell J. A. et al.
d) In vitro de~radation.
200 ~1 of 10% monomer solution were W polymerized to form a gel. The degradation of the hydrogels was monitored at 37~C in PBS.
e) Results In the synthesis, hydrophobic se~,...e~ ; of the mollolll~,ls were changed by using various combinations of cal~ro~-L~ and glycolate link~ges 25 in the molecule. The critical mirelli7~til)n point was obtained from the first inflection of the absorption vs. concentration curve. The curves are shown in Figure 10. It is evident from the curves that the solubility of the dye is ~;:"h~ e-l with increasing concentration of the monomer. The CMC values during aggregation and photopolymerization for various 30 monomers are listed in Table 4.
W O 97/05185 PCT~US96/12285 Critical Gel* Time Gel** Time Total Monomer Micellar Tniti~t~d Tniti~t~-l Using Degr~ ti~n Concentration Using UV Visible Light time (days) (%) Light (secs) (secs) A 0.92 5.5~tO.4 8.9 i O.l 10 B 0.55 5.8~t0.1 8.2~t0.5 14 C 0.32 5.2~t0.2 9.8~t0.4 16 D 0.28 4.6 + 0.1 10.4 + 0.3 44 * 2,2-Dimethoxy-2-pheny~ .Innf~! as UV initiator, Long UV light, 20 -, conc.
** Eosin, tri~ n( l--ninP il~itiating system; g~een light source, 20% .. 1--,.. - -conc.
T~BL E 4 The CMC value is lowered with increase in cd~l~al~ content of the monomer. This may be due to the tighter aggregation of the hyd~hobic ca~loaLe moieties. The fast gelling ability of these monomers under W
and visible light is il1llctr~te~ in Table 4. The gel times range bc;lweell 4-12 seconds. The photopolymerized hydrogels degrade under aqueous conditions. The degradation times, i.e., times to subst~nti~lly complete dissolution, varied from 10-44 days, increasing with cap/gly ratio. The fast gelation times of these monomers, their ability to dissolve hydrophobic solutes and their controlled degradation rates render them excellent c~n~ tt-s for localized drug delivery.
FY~mple 5: Synthesis of Ma~lvllltl~7 Fo Liquid Crystal Phases.
a) Synthesis of Macromers.
PlOSL4A2, P84LS A2 and T904LS A2 macromers were synth~si7e~
by ~ dar~ procedures, generally as described in Example 1, from commercial base polymers (P105 Pluronic~ poloxamer; T904 Tetronic four-armed ionic-group cont~ining polaxamer; P84 Pluronic~ reverse poloxamer, or meroxapol).
b) Charaeleli~dlion of optical effects and dru~ release l r~,.lies.
Aqueous solutions were prepared, and observed for anomalous 5 optical effects ("Schlieren") without cro~linking. Rates of release of a drug were observed, wherein the drug had a molecular weight about 500 D, and ~ub~LdllLial water solubility, as well as a hydl~hobic region.
Aqueous solutions of all three ll,ac,~""ers formed "Schlieren" type liquid crystalline phases at concelllldLions of 55% and higher, at room 10 lelll~eldlul~,s. A temperature study of the LC phases showed that the LC
phases for P84L4A2 and T904L4A2 are not stable at tempcldluies higher than 30-35~C. The LC phase for these two polymers "phase se~ s"
into two phases at T>35~C, one being an isotropic polymeric phase that is not ~ .ell~ to light and another phase that seemed to consist of water. In contrast, a cc,ncellL,aL~d solution of P105L4A2 (75%w/v) displays a highly anisotropic LC phase that m~int~in~ its stability to L,ldLUl~;S Up to 110 C.
Aqueous solutions of P105L4A2 (in high concellL,dLions) formed a highly anisotropic liquid crystalline phase (LC phase) that results in good 20 drug enL,~lllent to slow down release. It was also observed that P84LSA2 and T904L5A2 had ~ nific~nt dirf~ ,llces in the self-assembling characteristics (LC). It is possible that the drug is entrapped in the stable, highly oriented LC Phase of a plO5L4A2/water system. P84L4A2 and T904L4A2 form LC phases with water, but these phases are not stable 25 above 30-35~C. At higher LelllpelaLul~s, the drug as well as some of the water are excluded from the polymeric cl-)m~in~.
EXAMPLE 6. Trr~ of Burns.
The pluronic poloxamer based macromonomers, such as F127-TMC acrylate, have a "paste-like" con~i~t~nry at L~ "dLures 30 above 37~C, and have flow characteristics at low le~ e~dlules. A "cool"
formnl~te~l solution, optionally cn..~ .g an a~,~,ial~ drug (such as an antibiotic) is poured on a burn site, providing instant relief. At body L~ c/dlulcs, the formulation gels to a paste like col-c;x~ y. The gel is then crosslinlr~d, preferably by the action of light on an inrhlded photoinitiator. The charac~ Lion of photopoly...~ d hydrogels as 5 carriers for thela~c~uLic materials to influence wound healing is described in Sawhney et al., "The 21st Annual Meeting of the Society for BiulllaL~lials," March 18-22, 1995, San I~lancisco, CA, Abstract, the disclosure of which is incorporated herein by lc~felc:llce.
The hydrogel layer on the skin provides tr~n.cderm~l delivery of 10 drug to the burn site; m~int~in~ high moisture levels on severely burned sites, thus ~l~v~llLillg dehydration; adheres strongly to the 11~m~d tissue, and is elastic, thus preventing del~min~tion and "peeling" of the hydrogel dressing; and absorbs exudate from the wound. After a suitable time, controlled by the nature of the lining group (trimethylene calbullale in this 15 example, giving a residence time of over a week), the gel will dissolve into components which are absorbable or innocuous. It has been demol~Llat~d in other experiments that related gel forrmll~ti~ns, based on a polyethyleneglycol backbone such as the material 8KLSA2 (i.e,. PEO of m- lecnl~r weight 8,000, with 5 lactate groups on each end 1. . Illill ~lr~l 20 with acrylate groups), do not retard the healing of full thicknPss biopsy wounds in rat skin. The pentablock polymer F127-TMC acrylate of Example 3 is improved in cu~ alison to the prior-art 8KL5A2 polyethylene glycol-based triblock formula in that it gels spontaneously on the burn site, and thus does not tend to run off the site before it can be 25 photocros~lin1~~d.
EXAMPLE 7: Use of Hydrophobic Ma~ u~ to Il,clease Tissue Adherence.
Use of macromers carrying one or more hydlu~?hobic groups can improve the adherence of a hydrogel to a biological material. A
30 macromer having having this property was synth~si~e~l The base polymer was a Tetronics" 4-armed polymer based on e~ylene ~ l,;"~, where each arm is a PEG-PPO-PEG triblock copolymer. The base polymer was ext~n~led with lactide as previously described in Example 1, and then capped with about two moles of palmitoyl chloride per mole of - polymer, in order to cap about half of the arms. The ~ r of the hydroxyls were capped with acroyl chloride, as described in Example 1.
The res lltin~ macromer was di~l~ed in water and was polymerized in contact with tissue, to which it adhered tenaciously.
Example 8: Formation of Microspheres PluronicTM based biodegradable macromers made as described above above, such as the materials of Example 3, in an aqueous solution formed micelles with a CMC value ranging from about 1 % to 5 % w/v.
After photopolym~qri7~tion, the structure of the micelle is sub~ lly ~1~S~1V~d.
Example 9: Synthesis of F127-Dimer Is~u.ale-F127 T ~t~te Acrylate Two molecules of a macromer diol (Pluronic F127) are coupled with one molecule of a diisocyanate (dimer isocyanate) to produce higher di- and tri- functional alcohols, to provide l.laclulll~l~ with high elasticity,high ~ t~n~ihility and high tissue adherence.
The following reagents are used: Pluronic F127 (BASF lot # WPM
N 581B, Mn=12200); dimer isocyanate (DDI-1410, Henkel Lot# HL
20037, % NCO= 14.1 %); and dibutyltin dilaurate.
Synthesis of F127-DDI-F127: 366 g of Pluronic F127 was heated to 100~C under vacuum for four hours to produce a melt. DDI-1410 (8.94g) and dibutyltin dilaurate (O.llSg) was added to the melt (melt Lt;LL1~)e;1a~U1e 70~C) and stirred vigorously for 4 hours. The llli~lu~Le readily cryst~lli7Pd when cooled. Product was a white waxy crystalline m~t~ri~l. Theoretical molecular weight=24,996 Daltons.
Synthesis of F127-DDI-F127 T ~rt~t~s diol: lOOg of F127-DDI-F127 was dried for 4 hours under vacuum at 100~C. 4.67 g of (D,L) Lactide was charged to the reaction pot under an argon flush. SL~L~US
CA 02228ll8 l998-0l-28 W O 97/05185 PCTrUS96/12285 2-e~yl h~n~t~ (0.5 mole percent) was added to the reaction. The melt was vigorously stirred at 150~C under argon for 4 hours. The product was isolated by ~ iL~lion in hexane, followed by filtration. The product was a white, crystalline, flaky material.
Synthesis of F127-DDI-F127 T.~et~t-o,5 acrylate: 100g of F127-DDI-F127 T ~rt~tPs diol was charged into a 1000 ml three-necked reaction vessel. 800 ml of toluene (Aldrich, 0.005% water content) was added to the flask. 50-75 ml of toluene was azeotroped off to ensure moisture free re~ct~nt~. 2.427 ml of predistilled triethylamine, followed by 2.165 mls of acryloyl chloride was added to the reaction IlliXIulG at 65~C. After one hour of reaction time, the turbid reaction mi~lure was f~tered, and isolated into a white powder by precipitation into a large excess of hexane. The product was collected by vacuum filtration and dried to a constant weight.
Molecular structure de~ aLion was carried out by NMR, IR.
The product was found to be soluble in water and crosslinkable by visible and W light. Percent water uptake of fully cured 10%w/w hydrogels=22.1%. Hydrogels formed by photopolylll~ alion at 10%
concentration while on dead bovine tissue were AeLe~ to be gen~or~lly well adherent.
P105-DDI-P105 lactate acrylate and L81-DDI-L81 lactate acrylate was ,yll~ ci~ from the respective Pluronic poloxamer starting materials (P105,L81) by the procedure described above. These macromers were insoluble in water. They were used to enc~ulate bioactive molecules in hydrophobic matrices to achieve s -ct~in~d drug release.
Example 10: Sy~ e~,;s of F127-DDI-F127 Iso~ .~ c Iso~ le The synthesis and polymeri7~tion of a macromer which crosslinks without involving free radical polymerization is demonstrated. 50 g of F127-DDI-F127 diol, prepared as in Example 9, was dissolved in 100 ml of toluene in a three necked reaction flask. 90 ml of toluene was ~ till~l WO 97/05185 PCT~US96/12285 off azeotr~,~ically at 110~C under argon. The flask was ~ .o.1 at 100~C for 12 hours under vacuum (12 mm Hg). The reaction flask was then cooled to room temp, and 200 ml of dry methylene chloride was - added to the reaction flask. 0.445 g of isophorone isocyanate (Aldrich) 5 was added (in a bolus) to the reaction flask at approximately 30~C. 0.15g of dil~ulylLill laurate was added to the reaction ~ lu~e. The reaction ~i~Lulc: was stirred under argon at 30~C for 12 hours, and ~ iLal~;d in 1000 ml of hexane (EM Sciences). White flakes were collected by vacuum filtration, and rinsed with 150 ml of hexane. The product was 10 dried in a vacuum oven to a constant weight. Chara~;Le~lion by ~MR, IR showed synthesis of the expected material.
The polyll~~ bility of F127-DDI-F127 isophorone isocyalldL~
was ev~ln~t~l Partially dried product (0.16g) was added to 1.44 g of deionized water. The product initially formed bubbles in contact with water, then dissolved over approximately 3 days to form a viscous solution. To test polylllel~bility, 200 mg of F127-DDI-F127 isophorone isocyanate solution of polyethyleneimine in methylene chloride. The solution was stirred vigorously for a few seconds. A gelatineous product was observed. Gel time: 5.9 seconds. Polyethyleneilllille is believed to have hemostatic properties; this formulation thus is potentially suitable for a topical wound dressing. In addition, structures formed of these materials can be used as drug depots.
Example 11: Effect of Hydrophobicity on Drug R~l~qce Kin~ti~e for Bulk Devices.
Macromers were synth~si7~o~1 having a wide range of hydrophobicities ranging from 0-90% PPO content. All maclolllGl~ were tested at 15% macromer collct;llL~Lion except those whose PPO content was greater than 60% which were used neat. Figure 13 shows the rate of release of a small drug from gels of these ma~ ll~l~. At 10 and 15%
macromer loading (8KL10, prior art; 25R8LAA2, based on a "reverse"
Pluronic polymer) and PPO content of less than 60% hydrophobic W O 97/05185 PCT~US96/12285 partitioning did not show a ~ignifir~nt effect on prolonging 500 Da sparingly soluble drug release. Devices ~ al,d with neat ma~
(PPO content > 60%; P84LSA2 and L81LSA2, ~y~ d by general procedures as described above) showed a signifi~nt ability of these highly S hydrophobic, dense macromers to retard water permeation and drug dissolution. In the extreme case (L81LSA2; PPO content = 90%), the release kin.otirs showed first order release with half of the drug being released from the device over 17 days with the r~m~in~ r being eluted from the device over a total of 66 days.
Example 12: Effect of Polymer Hydrophobicity on Drug D;rru~ivily Membranes of constant thickn~ss were p,~a,~d from neat macromers of Example 11, and used as the diffusion barrier in a two-c~ alL~ent dialysis cell. Figures 14 and lS show the h~ ase in the conce"L,~Iion of SOO Da drug in the receptor side of the cell over time.
The diffusion coefficient c~lr~ tion was based on the following relationship:
D =JI(A*(ACIAX) where D is the diffusion coefficient, J is the measured flux, A is the exposed area of the film, AC is the concentration ~r~(1ient across the film and ~x is the average film thickn~ss. The diffusion coefficients for macromers having 50% (PlOSLSA2) or 90% (L81LSA2) relative hydrophobic domain and were calculated to 1.6xlO~9cm2/sec and 5.63x10-I0cm2/sec, respectively. Thus, diffusion was faster in the more hydrophobic material, as expected for a drug of low water solubility.
F,Y~ 'e 13~ e of Tt:LI~y~ e and Taxol.
A 30% w/w solution of F127 trimethylene carbonate acrylate (as described in Example 3) in phosphate buffered saline, pH7.4 was prepared. 3000 ppm Darocur~ (Ciba Geigy) was incorporated in the solutions as phuL~uuLiator. Tetracycline (free base, crystalline, F.~V.
.44) was incorporated in the macromer solution by equilibration for 12 hours at 37 degrees C. Then, 200 microliters of the solution was cro~slink~l by W light (10 W/cm2, full cure). In vitro release of 5 tetracycline from the 200 microliter cured gel, after a brief rinse, was carried out in 5 mls PBS, pH 7.4, 37~C. The PBS was ex~h~ èdl daily to ensure "sink" conditions. The release profile is seen Figure 16. After an initial burst, tetracycline was released steadily for nearly a week.
Taxol was incorporated into gels by similar procedures, except that 10 TweenTM ~", r~ was used to solubilize the Taxol conrçntrate. ~, similar release pattern to that seen with tetracycline was observed.
F~Y5~ 1e 14: Urethane-c~ ..;..g ll~.lUl~
PEO of molecular weight 1450 was reacted with approxim~ly 1 mole of lactide per end, using procedures described above, to give 1.4KL2. The 1.4KL2 was weighed into a 100 ml flask (8.65 g) and 270 ml of dried toluene was added. About 50 ml of toluene was ~ tillP,1 off to remove residual water as the azeotrope, and the solution was cooled.
Then 0.858 g (825 microliter) of commercial 1,6 hexane-diisocy~aLt; was added, and also 1 drop of dibuLyll;~ lrate (ca. 0.02g). The solution was at 60 degrees at addition, and warmed to 70 degrees over about 10 ...;..~l~s. Heat was applied to m~int~in the solution at about 75 degrees for about 3.5 hours. NMR and IR spectra confirm~r1 colkiun~ion of the diisocyanate, and the r~-slllting solution was therefore exl~ecl~cl to contain l;.,g PEO and hexane blocks, linked by u~Lll~le linkages, and 25 ~. ~ llrC~ by hydroxyls. This material can be capped with l~,ac~ive end groups, optionally after further extension with hydroxy acids, to form a reactive macromer. The urethane links and hexane blocks are present to promote tissue adherence.
W O 97/05185 PCT~US96/12285 Modifications and vOli~Lions of the present invention will be obvious to those skilled in the art from the fo~oi~ ~let~ilPcl description.
Such mo~lifi~tions and variations are intended to come within the scope of the following claims.
FOR DRUGS DELIVERY ~ND TISSUE TREATMENT AGENTS
Background of the Invention The present invention is generally in the area of biodegradable polymers for use in drug delivery and bi~mP-1ir~l applir~ti~ n~.
Biodegradable polymers have been developed for use in a variety of surgical and drug delivery appli~tion~. The synthesis and biodegradability of poly(lactic acid) was reported by Knlk~rni et al., Arch. Surg., 93:839 (1966). Biodegradable polyallhydlides and polyorthoesters having labile backbone linkages have been developed.
Domb et al., Macromolecules, 22:3200 (1989); and Heller et al., '~iodegradable Polymers as Drug Delivery Systems," Chasin, M. and Langer, R., Eds., Dekker, New York, 121-161 (1990), the r~ clQsllres of which are incorporated herein. Polymers which degrade into naturally occnrring materials, such as poly~min~-ids, also have been developed.
Polyesters of ~x-hydroxy acids, such as lactic acid or glycolic acid, are widely used as biodegradable materials for applications ranging from closure devices, including sutures and staples, to drug delivery ~y~L~llls.
Holland et al., Controlled Release, 4:155-180, (1986); U.S. Patent No.
4,741,337 to Smith et al.; and Spili;~ew~hi et al., J. Control. Rel., _:197-203 (1985), the disclosures of which are incorporated herein.
Degradable polymers cont~ining water-soluble polymer elPnnPn have been described. Degradable polymers have been formed by copolymerization of lactide, glycolide, and ~-caprolactone with the polyether, polyethylene glycol ("PEG"), to increase the hydrophilicity and degradation rate. Sawhney et al., J. Biomed. Mater. Res. 24:1397-1411 (1990). U.S. Patent No. 4,716,203 to Casey et al. describes the synthesis of a block copolymer of PGA (poly(glycolic acid)) and PEG. U.S. Patent W O 97/05185 PCT~US96/12285 No. 4,716,203 to Casey et al. describes the ~y~ e~is of PGA-PEG
diblock copolymers.
Polymers formed from croc~link~hle mollull~ or prepolymers have been developed in the prior art. Croc~lin'~l hyaluronic acid has been used as a degradable swelling polymer for biom~ r~l applications.
U.S. Patent No. 4,987,744 and 4,957,744 to Della Valle et al.; and Della Valle et al., Polym. Mater. Sci. Eng., 62:731-735 (1991).
U.S. Patent No. 5,410,016 to Hubbell et al., the disclosure of which in incorporated herein, discloses the in situ crosslinking of biodegradable, water-soluble macro-monomers, (",llaclull~l~") to form barrier coatings and matrices for delivery of biologically active agents.
Other polymers for drug delivery or other biomf~lir~l applir~ti~-n~ are escrihecl in U.S. Patent No. 4,938,763 to Dunn, U.S. Patent Nos.
5,160,745 and 4,818,542 to DeLuca, U.S. Patent No. 5,219,564 to Zalipsky, U.S. Patent No. 4,826,945 to Cohn, and U.S. Patent Nos.
5,078,994 and 5,429,826 to Nair, the disclosures of which are incorporated herein by ,~fel~llce. Methods for delivery of the polymers m~teri~l~ include syringes (U.S. Patent No. 4,938,763 to Dunn et al.) spray applicators (WO 94/21324 by Rowe et al.) and caLllet~l delivery systems (U.S. Patent Nos. 5,328,471; and 5,213,580 to Slepian). The synthesis of lllaclulllers including a central chain of polyethylene glycol, with an oligomeric hydroxyacid at each end and acrylic esters at the ends of the hydroxy acid oligomer also has been reported. Sawhney A. S. et al., Macromolecules, 26: 581 (1993); and PCT WO 93/17669 by Hubbell J. A. et al., the disclosures of which are incorporated herein by reference.
Thermal volume changes in polymeric gels, such as esters and amides of polyacrylic acid, have been described. For example, poly(N-isopropyl acrylamide) based hydrogels, which are thPrmos~iLivt;
in aqueous systems, have been used for controlled drug delivery and other applications. U.S. Patent No. 5,403,893 to Tanaka et al.; and Hoffman WO 97/05185 PCT~US96/12285 A.S. etal., J. ControlledRelease, 6:297 (1987), thedisclosures of which are incorporated herein. Poly(N-isopropyl acrylamide), however, is non-degradable and is not suitable for applications where biodegradable polymers are required. Non-biodegradable polymeric systems for drug 5 delivery are disadvantageous since they require removal after the drug-polymer device is implanted.
It is an object of the invention to provide i~ ov~d polymer systems for use in drug delivery and other biom~ ir~l applir~ti- ~ such as surgical applications. It is an ~ltliti~n~l object of the invention to provide 10 polymer systems for use in controlled drug delivery which are capable of releasing a biologically active agent in a predictable and controlled rate.
It is a further object of the invention to provide polymers for use in controlled drug delivery which release the active agent locally at a particular targeted site where it is needed. It is another object of the 15 invention to provide polymer systems for use in drug delivery which have ~elLies including volume and drug release which are variable with Lc;~ ldlule or other parameters such as pH or ion coll~ Lion.
Sl.~..--.~. J/ of the Invention Macromers are provided which are capable of gelling in an aqueous solution. In one embo-lim.ont the macLclllc;l~ include at least four polymeric blocks, at least one of which is hydlophilic and at least two of which are hydrophobic, and include a crt .~link~hle group. The 25 polymer blocks may be select~l to provide macromers with dirre~
selected piope,Lies. The macromers can be covalently cro~link~-l to form a gel on a tissue surface in vivo. The gels formed from the macromers have a combination of properties including thermose~ ivily and lipophilicity, and are useful in a variety of m.-rlir~l applications inr.lll-ling 30 drug delivery and tissue coating.
W O 97/05185 PCT~US96/12285 Brief Des~ Lion of the Figures Figure 1 is a scheme showing the dirr~ L gel states and ~l~clLies of one embodiment of a thermulei,~ol~iv~ biodegradable 5 macromer formed from a poly~..~ylene oxide-polyethylene oxide block copolymer.
Figure 2 is a graph of ~ eldLul~-dependent ch~ges in gel volume of gels formed by photopolymerization of an acrylated poly~ro~ylene oxide-polyethylene oxide block copolymer co..li.i,.;..~ a biodegradable region.
Figure 3 is a graph showing the effects of lelllpel~Lulc; on ~i~xtr~n release from a gel formed by photopolymerization of an acrylated poly~lo~ylene oxide-polyethylene oxide block copolymer.
Figure 4 is a graph illu~LldLhlg the variation in the speed of photocros~linl-in~ of acrylated poly~lv~ylene oxide-polyethylene oxide block copolymers having incorporated therein dirr~lc~ bio~legr~ hle regions.
Figure 5 is a graph showing the in vitro profiles of degr~ ti~ n rate of gels formed by photocro~linking of acrylated poly~ro~ylene oxide-polyethylene oxide block copolymers having incol~uldL~d therein dirrer~llL biodegradable regions.
Figure 6 is a graph illustrating the bioc~ p~l;l,ility of gels formed by photocro~linl~ing acrylated polyl,lopylene oxide-polyethylene oxide block copolymers having incorporated therein dirr~l~llL biodegradable regions.
Figure 7 shows graphs illu~LIdlillg release of fluolc:scellL dextran from gels formed by photocro~linkin~ acrylated poly~lo~ylene oxide-polyethylene oxide block copolymers having incorporated therein biodegradable linkers.
Figure 8 shows graphs of transition l~ dLulc:s of gels formed from maclulllel~ col~ g biodegradable linkers.
Figure 9 illustrates tbe chrmir~l structures of bio~legr~ ble cros~ hle llla~lumcl~, con~i~ting of acrylated poly(propylene oxide)-poly(ethylene oxide) block copolymers having incorporated therein a ~ biodegradable linker.
S Figure 10 is a graph of absorbance of a hydrophobic dye vs. log (weight %) of solutions of biodegradable ma~;,u"lc;,.. having a hydrophobic region incorporated therein.
Figure 11 is a sçhrm~tir- illustration of a cell membrane inrhl~lin~
hydrophobic bilayer with a macromer including a hydrophobic tail 10 diffused into the bilayer.
Figure 12 is a sch~ tir illustration of nanospheres or microspheres which can be formed by agy,lc;~,~lion and subsequent polylll~ lion of hydrophilic macrulll......
Figure 13 is a graph which shows the rate of release of a small 15 drug from gels formed from hydrophobic maclu"~el~,.
Figures 14 and 15 are graphs showing dirrusiviLy of a ,,~ ly water soluble drug through a hydrophobic hydrogel.
Figure 16 is a graph showing the release of tetracycline from a hydrogel formed from mollolll~l~ including a biodegradable region.
Detailed Des~ lion of the Invention Macromers are provided which are cro~link~hle to form hydrogels which are useful as matrices for controlled drug delhery. In a plGr~ d 25 embodiment, biodegradable macromers are provided in a ph~ re~ltir~lly acceptable carrier, and are capable of cr{!~linkins~, covalently or non-covalently, to form hydrogels which are thermoresponsive. A
biologically active agent may be incorporated within the macromer ~ solution or in the reslllting hydrogel after cro~linking. The hydrogels 30 have properties, such as volume and drug release rate, which are dependent upon tel~l~e~dLu~. The hydrogels may be formed in sit~, for example, at a tissue site, and may be used for for controlled delivery of bioactive substances and as tissue coatings. The l,la.;l.,llle,., used to form the hydrogels may be fabricated with domains having specific ~lop~ies including select~l hydrophobicity, hydrophilicity, thermos~l~,ilivi~y or 5 biodegradability, and combinations thereof.
M~v~
The macro-monomers ("ma~ lllel,") which are ionically or covalently cro~link~hle to form hydrogels preferably consist of a block copolymer. The macromers can be quickly polymerized from aqueous 10 solutions. The macromers are advantageously capable of thermolc~ ible gelation behavior, and preferably may be polymerized in a solution state or in a gel state. The macromers are defined as including a hydrophilic block capable of absorbing water, and at least one block, distinct from the hydrophilic block, which is s~lmriently hydrophobic to 15 ~lc~ i~Le from, or otherwise change phase while within, an aqueous solution, con~ tin~ of water, preferably cnnt~ining salts, buffers, drugs or polymerizing reagents, at tempt;ldLulcs within or near the physiologically compatible range, for example 0 to 65~C. The hydrophilic block optionally may be an amphiphilic block. The macromer may include 20 more than one of the same or dirr~.c~lL hydrophilic or hydrophobic region.
Preferably, the macro.ll~l, include at least three blocks, or more preferably four blocks.
The block copolymers may be linear (AB, ABA, ABABA or ABCBA type), star (AnB or BAnC, where B is at least n-valent, and n is 25 3 to 6) or branched (multiple A's depending from one B). In these formulae, either A or B may be the hydrophilic block, and the other the ~mphir~thic or hydrophilic block, and the additional block C may be either.
In another embodiment, the macromer includes at least four 30 covalently-linked polymeric blocks, wherein: at least one, or in another embodiment, at least two blocks are hydrophilic, and the hydrophilic W O 97/05185 PCT~US96/12285 blocks individually have a water solubility of at least 1 gram/liter; at least two blocks are sufficiently hydrophobic to ag ,l~aLe to form mir~ellp~s in an aqueous continuous phase; and the macromer further includes at least ~ one cro~clin'~hle group. The cros~link~hle groups optionally may be S s~dldL~d by at least one degradable linkage capable of degrading under physiological conditions. In one embo~limPnt at least one hydrophobic block may be sepd~L~d from any reactive group by at least one hydrophilic block.
The lllacrolller further may include five total blocks having the same or dirr~ ,.iies such as thermal ,~l~,iLi~/ily, hydl~hilicity or hydrophobicity. Each block also may have a combination of ~ .Lies.
For example, a block may be hydrophilic and also thermosel~,iliv~.
itiorl~lly, the multiblock macromer may include chPrni- ~lly distinct blocks or may incorporate more than one of the same irlPnti~l block.
The macromer is fabricated with a structure and with ~ro~e,lies suitable for diLr~lcllt applications. For example the macromer may include a central block of dimer fatty acid which includes central llydloca~bon chain of about 30 carbon atoms and two terminal carboxy groups which are esterified with a thermose~ iv~ poloxamer, such as Pluronic L1050.
This central molecule further is polyl~rt~tPd at each hydroxy l~ lC, and end capped with acryloyl chloride. An another embodiment is a poloxamer including polyhydroxy groups polym~ri7Pcl on each end, and wherein the molecule is end capped at each end with a reactive group such as an acrylate or a secondary isocyanate.
The configuration of the ma~ , may be presel~ctPA dt:~JCll lhlg on the use of the macromer. The macromers may include at least two hydrophobic blocks, s~a-~led by a hydrophilic block. The mac,c...e,., also may be fabricated with a cro~link~hle group which is s~dldlt;:d by a degradable group from any other cro~slink~hle group. One ~-~rt;~L~,d 30 embodiment is wherein the dry macromer absorbs at least about 10% in weight of water. The molecular weight of the macromer preferably is at least 1000 Daltons, or optionally is at least 2000 Daltons, or in an iv~ embodiment, at least 4000 Daltons.
In a ~l~Çellc,d embo~im~ t, the macromer includes at least one th~rm~lly scl~ iv~ region, and an aqueous solution of the lllaclulllcl is 5 capable of gelling either ionically and/or by covalent crosslinking to produce a hydrogel with a L~ aLure dependent volume. This permits the rate of release of a drug incorporated in the hydrogel to change depending upon the volume of the hydrogel. Useful lllaclul~ . are those which are, for example, capable of thermolcv~,..ible gelation of an aqueous solution of the macromer at a concentration of at least 2% by weight, and wherein the gelation L~ ldLule is b~Lwcell about 0~C and about 65~C. The macromer also may have a phase transition L~ alulc in the range of 0 to 100~C, and wherein the transition L~ c~dLul~ is affected by the ionic culll~osiLion of an aqueous solution of the lllaclu or trne concentration of macromer in the aqueous solution.
The macromers may be formed by modification of m~t~ and methods described in the prior art. Macromers including a central chain of polyethylene glycol, with oligomeric hydroxy acid at each end and acrylic esters at the ends of the hydroxy acid oligomer are described in Sawhney A. S. et al., Macromolecules, 26: 581 (1993); and PCT WO
93/17669 by Hubbell J. A. et al., the disclosures of which are incorporated herein by reference. U.S. Patent No. 5,410,016 to Hubbell et al., the disclosure of which is incorporated herein by lcfe~ ce, discloses that biodegradable, water-soluble maclulll~l~. can be croS~r in situ to form barrier coatings and depots or matrices for delivery of biologically active agents such as thel~t;uLic drugs. In addition to the m~t~,ri~l~ and methods described in U.S. Patent No. 5,410,016, m~t~ri~l~
and methods described by Dunn (U.S. Patent No. 4,938,763), DeLuca (U.S. Patent Nos. 5,160,745; and 4,818,542), Zalipsky (U.S. Patent No.
5,219,564), Cohn (U.S. Patent No. 4,826,945), Nair (U.S. Patent Nos.
S,078,994; and 5,429,826), the disclosures of which are incul~ola~d herein by l~Ç~lGllce, are useful to form the macromers described herein.
For example, the macromer may include a poloxamer backbone extPn-lPd with hydrophobic materials, such as oligolactate moieties, which S serve as the biodegradable segment of the molecule, wh~cill the PEO-PPO-PEO-lactate copolymer is l~ ed by acrylate moieties. The m~tPri~lc can be combined with, then delivered and photopolyllle.i~d in situ, onto target organs to conform to a specific shape.
The macromers and hydrogels formed thelc;rl~lll preferably are 10 bioco~ a~il)le, preferably not causing or enhancing a biological reaction when implanted or otherwise ~lminictered within a ..-~,..,..~1. The macromers, and any breakdown products of the hydrogels or lllaclulll~
preferably are not signifif~ntly toxic to living cells, or to Ol~"i~."c. The hydrogels also may have liquid crystalline properties for example at high 15 concentration, which are useful in controlling the rate of drug delivery.
Ionic ~lopelLies can be provided in the backbone of the macrolll~
col~llillg the further plopCl~y of control of delivery and/or physical state by control of the ionic envhol~llelll, including pH, of the macrom~r or gel. In one emborlimPnt the critical ion culllpo~iLion is the hydrogen ion 20 concentration. For example, when a polo~minP, such as a Tetronic surfactant, is used as the core of the macromer, then the resl~lting macromer has the ionic groups (amines) in the core, and the macromers' ability to gel upon changes in temperature is affected by the pH of the solution.
Tl~.. ose.. i;live Regions The macromers may be provided with one or more regions which have plopelLies which are thermoresponsive. As used herein, thermoresponsiveness is defined as including ~rup~l~ies of a hydrogel, such as volume, transition from a liquid to a gel, and permeability to 30 biologically active agents, which are dependent upon the ~elll~t;laLul~ of the hydrogel. In one embodiment, the macromers are capable of -,v~.~ible gelation which is controlled by le~ aluic. The reversible gel further optionally may be cros~link~l in situ into an irreversibly and covalently crosclink~cl gel. This permits the macromer to be applied reliably in surgical applications on a specific area of tissue wilhuu~
5 running off or being washed off by body fluids prior to gelation or cro~linking.
In one p~cr~.lcd embo~lim~ont7 the macromers are capable of gelling thermoreversibly, for example, due to the content of poloxamer regions. Since gelling is thermol~v~l~ible, the gel will .l;x~ on 10 cooling. The macromers may further include cro~link~ble groups which permit the gel to be further covalently crosslinked for example by photopolymPri7~tion. After cro~linking, the gels are ill~ve.~il,ly c~v~ krrl However, they retain other ~ignifi~nt thermoresponsive p,~,pel~ies, such as cl~ g~s in volume and in permeability.
By appl~,~,id~ choice of macromer composition, hydrogels can be created in situ which have thermosensitive properties, including volume changes and drug release which are dependent upon ~ e~ e, which can be used to control drug delivery from the hydrogel. Control of drug delivery can be further controlled by adjnstrnPnt of properties such as hydrophobicity of amphiphilic or other regions in the gel. Change in volume of the hydrogel may readily be measured by ex~ntin~ti-)n of macroscopic ullle~LldilRd samples during l~ eld~ulc excursions.
Changes in excess of 100% in volume may be obtained with hydrogels formed from the ma~ , such as an acrylate-capped polyglycolide-dc:livdli~ed poloxamer of about 30% PPO (poly~u~3ylene oxide) content, the exp~n~ion occ~rrin~ gradually on change of the ~ellll)ela~UlC from about 0~C to body le~l~pe,dlulc (37~C). Changes of more than 5% in any linear tiimen~ion may be effective in altering the release rate of a macromolecular drug.
The macronlel~ preferably include thermogelling macromers, such as "poloxamers", i.e., poly(ethylene oxide)-poly(propylene -WO 97/05185 PCT~US96/12285 oxide)-poly(ethylene oxide) ("PEO-PPO-PEO"), block copolymers.
Aqueous polymeric solutions of poloxamers undergo lllicrophase transitions at an upper critical solution tc~ Jcldlul~7 causing a characteristic gel form~tinn This transition is dependent on concc,lLlaLion S and composition of the block copolymer. Alexandridis et al., Macromolecules, 27:2414 (1994). The segment~l polyether portion of the molecule gives water solubility and thermosel~iLiviLy. The m~tori51 also advantageously have been demo"~ t.od to be biocomp~tihle.
For example, the macromer may include a poloxamer backbone 10 extended with hydrophobic materials, such as oligolactate moieties~ which serve as the biodegradable segment of the molecule, wherein the PEO-PPO-PEO-lactate copolymer is tf rmin~t~-l by acrylate moieties. The materials can be combined with a bioactive agent, then delivered and photopolymerized in situ. In addition to poloxamer cores, me~o~ols, 15 such as "lc~ ed Pluronics" (PPO-PEO-PPO copolymers) and polo~ , such as TetronicTM surfactants, may be used.
Other polymer blocks which may be provided in the monorner which are capable of temperature dependent volume changes include water soluble blocks such as polyvinyl alcohol, polyvinyl-pyrrolidone, 20 polyacrylic acids, esters and amides, soluble celluloses, peptides and ploLeills, dextrans and other polysaccharides. ~ lition~lly, polymer blocks with an upper critical point may be used, such as other polyalkylene oxides, such as mixed polyalkylene oxides and esters, dclivaLi;Gcd celluloses, such as hydro~y~ruL,yllllethyl cellulose, and natural 25 gums such as konjac gluco...~
In another embodiment, the macromer is defined as having an optically anisotropic phase at a col~ ion at or below the m~xim~l solubility of the macromer in an aqueous solution, at a lclll~cl~Lu between about 0 and 65~C.
CrQ~link~hle Groups.
The macromers preferably include croeelink~hle groups which are capable of forming covalent bonds with other compounds while in aqueous solution, which perrnit crr,ee1inking of the ,l~ac,~.",t,~, to form a 5 gel, either after, or independently from thermally dependent gellation of the macromer. Ch~mic~lly or ionically croeelink~ble groups known in the art may be provided in the macromers. The croe.clint-~hle groups in one pl~re.,ed embodiment are polymerizable by photoinitiation by free radical generation, most preferably in the visible or long wavelength ultraviolet 10 radiation. The pl~re~ d croeelink~hle groups are ~ .-.,.Ir~l groups including vinyl groups, allyl groups, Cillll,.lll~tPS, acrylates, diacrylates, oligoacrylates, methacrylates, tlimrth~rrylates, olig~ mPtho~crylates, or other biologically acceptable photopolymerizable groups.
Other polym~-ri7~tion rh~mietrirs which may be used include, for 15 example, reaction of amines or alcohols with isocyanate or isothio,;y~lt;, or of amines or thiols with aldehydes, epoxides, oxiranes, or cyclic imines; where either the amine or thiol, or the other l~a.;La~L, or both, may be covalently ~tt~rh~Cl to a macromer. Mixtures of covalent polymerization systems are also contemplated. Sulfonic acid or 20 carboxylic acid groups may be used.
Preferably, at least a portion of the macromers will have more than one croeelink~hle reactive group, to permit formation of a coherent hydrogel after cro~elinkinp of the macromers. Up to 100% of the macromers may have more than one reactive group. Typically, in a 25 sy"ll,esis, the pe~-;e~ ge will be on the order of 50 to 90%, for example, 75 to 80%. The percentage may be reduced by addition of small co-monomers cont~ining only one active group. A lower limit for crosslinker concentration will depend on the p~ Lies of the particular macromer and the total macromer collce"Ll~Lion, but will be at least about 30 3% of the total molar conce~L~dLion of reactive groups. More preferably, the cro~eelink~r co~c~l~L~aLion will be at least 10%, with higher W O 97/05185 PCT~US96/1228~.
conr~ntr,.tions, such as 50% to 90%, being optimal for m;-xi",...--.,~dalion of many drugs. Optionally, at least part of the cro~lin~in~
function may be provided by a low-molecular weight crosslinker. When the drug to be delivered is a macromolecule, higher ranges of polyvalent 5 macromers (i.e., having more than one reactive group) are ~lercl.~,d. If the gel is to be biodegradable, as is plcrc..cd in most applications, then the cros~linking reactive groups should be sepal~lcd from each other by biodegradable links. Any linkage known to be biodegradable under in vivo conditions may be suitablel such as a degradable polymer block.
10 The use of ethylenically ul~ Luldt~d groups, cro~link~-d by free radical polymerization with chlomi~ ~l and/or photoactive initiators, is ~.~cÇ~ ,d as the cro~ nk~hle group.
The macromer may also include an ionically charged moiety covalently ~tt,.-~hto-' to the macromer, which optionally permits gell~ti(~n or 15 cros~linking of the macromer.
Hy~l~c~hobic R~gjf~r..c;
The macromers further may include hydrophobic c.om~in.~. The hydrophobicity of the gel may be modified to alter drug delivery or three ~lim~n~ion,.l configuration of the gel. Amphiphilic regions may be provided in the maclu.llel~. which in aqueous solution tend to aggregate to form micellar domain, with the hydrophobic regions oriented in the interior of these domains (the "core"), while the hydrophilic c'.~.m,.in~
orient on the exterior ( "the corona"). These microscopic "cores" can entrap hydrophobic drugs, thus providing micrul~;s~;.vu.,~ for sn~t~in~od drug release. K~t~nk~ K., et al., J. Controlled Release, 24:119 (1993).
The fim~l~m~nt~l parameter of this supramolecular assemblage of amphiphilic polymers in aqueous solution is the Critical Micellar Conre-ntr~tinn (CMC), which can be defined as the lowest co~ c~ lion at which the dissolved macromolecules begin to self-assemble. By selection of the hydrophilic and other ~lom~in~, drug delivery can be controlled and enh~nred.
In one embodimlont, the macro,llel~ are provided with at least one hydrophobic zone, and can form micelles in~ ing a region in which hydrophobic materials will tend to bind and thus tend to reduce escape of the drug from the formed gel. The hydlu~hobic zone may be el-h~ ed S by addition of materials, including polymers, which do not collLlil,uL~ to the formation of a gel ll~Lwol~ but which segregate into such zones to e~nh~n~e their ~lo~cllies, such as a fatty acid, hydrocarbon, lipid, or a sterol.
The ability of the macromonomers in one embodiment to form 10 mirell~r hydrophobic centers not only allows the controlled dissolution of hydrophobic bioactive compounds but also permits the hydrogel to selectively "expand" and "contract" around a transition L~ a~ul~,. This provides an "on-off" thermocontrol switch which permits the th~rm~lly sensitive delivery of drugs.
The cell membrane is composed of a bilayer with the inner region being hydrophobic. This bilayer is believed to have a fluid and dynamic structure, i.e., hydrophobic molecules can move around in this ~Llu~;Lul~.
A hydrophobic tail incorporated in a macromer can diffuse into this lipid bilayer and result in the rest of the macromonomer (thus, the hydrogel) to 20 better adhere to the tissue surface (see Figure 11). The choice of molecular group to be used as hydrophobic tail is guided by the fatty acid composition of the bilayèr to assure .. i.~i.. ~lLulbalion of the bilayer structure. Examples of suitable groups are fatty acids, diacylglycerols, molecules from membranes such as phosphatidylserine, and polycyclic 25 hydrocall,olls and de~ aLivl:s, such as cholesterol, cholic acid, steroids and the like. Preferred hydrophobic groups for this purpose are normal co.~ of the human body. These molecules will be used at a low c~lllcelllldlion relative to native molecules in the membrane.
Use of macromers carrying one or more hydrophobic groups can 30 hll~rov~ the adherence of a hydrogel to a biological material by anchoring a se~;lllenL of the hydrogel in the lipid bilayer. This anchoring will cause WO 97/05185 PCTAJS96/122~5 ",il.i".~l p~Lulbalion to the underlying tissue because the insertion of the fatty acid tertnin~l of the macromer into the lipid membrane involves purely physical i~lr~ n. The macromer may be applied by using a ~ prewash of the surface with these molecules, in effect '~le~a~ g' the 5 surface for coupling and/or an in situ photopoly~ l~c lion of a llli~lule of these lipid-pe~.~lf~ g molecules with the cro.~linl-~hle mac~
The hydrophobic region may include oligomers of hydroxy acids such as lactic acid or glycolic acid, or oligomers of caprolactone, amino acids, anhydrides, orthoesters, phosph~7Pn~oc, phosphates, polyhydlo~y 10 acids or copolymers of these ~.u~u"ils. Additionally the hydrophobic region may be formed of poly(propylene oxide), poly(butylene oxide), or a hydrophobic non-block mixed poly(alkylene oxide) or copolymers thereof. Biodegradable hyd~ obic polyanhydrides are disclosed in, for example, U.S. Patent Nos. 4,757,128, 4,857,311, 4,888,176, and 4,789,724, the disclosure of which is incorporated by l.re,~ .lce herein.
Poly L-lactide, or poly D,L-lactide for example may be used. In another embodiment the hydrophobic region may be a polyester which is a copolymer of poly(lactic-co-glycolic) acid (PLGA).
The macromer also may be provided as a llli~lUle including a 20 hydrophobic material non-covalently associated with the macromer, wherein the hydlu~hobic material is, for example, a hydrocarbon, a lipid, a fatty acid, or a sterol.
Hydrophilic E~ n~.
Water soluble hydrophilic oligomers available in the art may be 25 incorporated into the biodegradable macl~lllel~.. The hydrophilic region can be for example, polymer blocks of poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(vhlyl~y"olidone), poly(ethyloxazoline), or polysaccharides or carbohydrates such as hyaluronic acid, dextran, heparan sulfate, cho,ldroiLi,l sulfate, hepcmn, or 30 ~lgin~tt~, or ~loL~ s such as gelatin, collagen, albDin, ovalbuminL, or polyamino acids.
CA 02228118 1998-01-2i, Biodegradable R~gion~
Biodegradable molecules or polymers thereof available in the art may be incorporated into the macromers. The biodegradable region is preferably hydrolyzable under in vivo conditions. In some embo-limfnt~, S the dirrt;~ L ~l~,pc;,lies, such as biodegradability and hydrophobicity or hydrophilicity, may be present within the same region of the ll,acr~lllel.
Useful hydrolyzable groups include polymers and oligomers of glycolide, lactide, epsilon-caprolactone, other hydroxy acids, and other biologically degradable polymers that yield m~t~ri~l~ that are non-toxic or 10 present as normal metabolites in the body. Preferred poly(alpha-hydroxy acids) are poly(glycolic acid), poly(DL-lactic acid) and poly(L-lactic acid). Other useful materials include poly(amino acids), polycarbonates, poly(anhydrides), poly(or~oesters), poly(phnsph~in~s) and poly(phosphoesters). Polylactones such as poly(epsilon-caprolactone), 15 poly(delta-caprolactone), poly(delta-valerolactone) and poly(gamma-butyrolactone), for example, are also useful. The biodegradable regions may have a degree of polym.ori7~tinn ranging from one up to values that would yield a product that was not ~ lly water soluble. Thus, monomeric, dimeric, trim~rir, oligu~ ic, and 20 polymeric regions may be used.
Biodegradable regions can be constructed from polymers or monomers using linkages susceptible to biodegradation, such as ester, peptide, anhydride, orthoester, phosph~7in~ and phosphnest~r bonds. The time required for a polymer to degrade can be tailored by selecting 25 ~Lo~Lial~ monomers. Dirr~ ces in crystallinity also alter ~l~ogr~ tinn rates. For relatively hydrophobic polymers, actual mass loss only begins when the oligomeric fragments are small enough to be water soluble.
Thus, initial polymer molecular weight inflll~nres the degradation rate.
W O 97/05185 PCTrUS96/12285 Tl~ Appli~ti~n~
Biodegradable, telllp.,.dLule responsive hydrogels can be fonned in situ and may be use in a variety of Ll~ uLic applir~tion~ including - surgical applications. In one embodiment the gels can be applied topically 5 to the skin to treat a variety of conditions such as abrasion, k~ r~loses, infl~mm~tory del...~oses, injury reslllting from a surgical procedure, and disturbed k.".l;--;,~lion. The hydrogels may include Lhcla~culic agents such as antibiotics, or antifungals for the localized tre~tmtont of dirr~,lc;llLskin conditions.
Macromers which are liquid at room temperature and gel at body Lelll~c;laLulc, such as lllacl~,lllers including a PluronicTM poloxamer, may be used in tre~tmpnt of burns and other external injuries. The hydrogels are useful in burn applications, since the hydrogel layer formed on the skin provides local or tr~n~dPrm~l delivery of drug to the burn site;
15 m~int~in~ high moisture levels on severely burned sites, thus rl;~
dehydration; adheres strongly to the damaged tissue, and is elastic, thus mi..i...i~ g dcl~ tion and "peeling" of the hydrogel dressing; and absorbs exudate from the wound. Hydrogels may be sel~octed whic,h dissolve into components which are absorbable and non-toxic, which 20 promote healing, and gel spontaneously and quickly on the burn site, prior to optional further cro.sslinkinp.
The macromers also may be applied to biological tissue, or on the surface of a mtorlit~l device, to form hydrogels in a variety of surgical applications for the Ll~ of tissue or organs. The gel also may be 25 applied b~lw~ell two surfaces, such as tissue sllrf~res, to adhere th~
surfaces. The hydrogels may be applied to tissue such as vascular tissue, for example for the treatment of restenosis of the arteries or in angioplasty procedures. A biologically active material may be provided in the gel optionally in the form of particles, microparticles, pro-drug 30 conjugates, or liposomes. The macl~lllc;l~. may be de~ign~d such ~hat the cro.c.~link~1 gel changes in permeability in response to a change in laLule~ ionic concentration or a change in pH, thereby ~ltering the rate of drug release from the hydrogel.
Drug Deli~
The macr~l.c.~, may be cros~linkr~l lev~ ,ibly or hle~,.,.~,ibly to 5 form gels for controlled drug delivery applir-~tion~ The composition and plul.e,lies of the macromers can be selected and fabricated to produce hydrogels with desired drug delivery ~ llies. The drug may be provided in the macromer solution prior to or after ~-lmini~tration, and either before or after gel formation, depending on the macromer 10 composition.
For example, the gels can be ~le~ nt?d to have a selected rate of drug release, such as first order or zero order drug release kin~tirs For specific drugs, such as peptides, the composition of the gel may be ~e~ignrcl to result in pulsatile or mixed wave release chara~;lt;li.,lics in 15 order to obtain m~ximllm drug efficacy and to minimi7~ side effects and tolerance development. Bae et al., Pharnmcel~ticn~ Research, 8: 531 (1991).
The drug release profiles can be sPlecte~l by the use of ma~
and gels formed ll-t;lc;r.~ that respond to specific extrrn~l stimuli such 20 as ultrasound, temperature, pH or electric current. For example, the extent of swelling and size of these hydrogels can be mo~ tr~l Changes in~l~lrecl in the swelling directly correlate to the rate of release of the incorporated drugs. Through this, a particular release profile may be obtained. The hydrogels are preferably biodegradable so that removal is 25 not required after ~lmini~tration or implantation.
The gels permit controlled drug delivery and release of a biologically active agent in a predictable and conkolled manner locally at the targeted site where it is needed, when the tissue to be keated is localized. In other embo-lim~nt~, the gels also can be used for systemic 30 delivery.
W O 97/05185 PCTAUS96/lZ285 A variety of th~d~ uLiC agents can be delivered using the hydrogels. Examples include synthetic inorganic and organic compounds, plo~ills and peptides, polysaccharides and other sugars, lipids, gangliosides, and nucleic acid sequences having Iht;ld~JeUIiC, prophylactic 5 or diagnostic activities. Nucleic acid seqll~nrçs include genes, ~nti~en~e molecules which bind to complem~nt~ry DNA to inhibit lldnsc,i~lion, and ribozymes. The agents to be incorporated can have a variety of biological activities, such as vasoactive agents, neuroactive agents, hollll~es, ~ntiro~gulants, immlmomo~ tinp agents, cytotoxic agents, antibiotics, 10 antivirals, ~nti~n~e, antigens, and antibodies. Proteins including antibodies or antigens can also be delivered. Proteins are defined as con~i~ting of 100 amino acid residues or more; peptides are less than 100 amino acid residues. Unless otherwise stated, the term protein refers to both ploleins and peptides. Examples include insulin and other 15 hormones.
Specific m~f~ri~lc include antibiotics, antivirals, ~ntiinfl~mm~tories, both steroidal and non-steroidal, alllhle-,~lastics, anti-spasmodics including channel blockers, modulators of cell-extracellular matrix interactions inrll7tling cell growth inhibitors and anti-adhesion 20 molecules, enzymes and enzyme inhibitors, ~nti~o~gulants and/or alllillllolllbotic agents, growth factors, DNA, RNA, il~ ul~ of DNA, RNA or protein synthesis, compounds mocll-l~ting cell migr~tiQn, proliferation and/or growth, vasodilating agents, and other drugs c~ mm~ nly used for the keatment of injury to tissue. Specific examples of 25 these compounds include angiotensin collv~llhlg enzyme i-.hil~ilol~, prostacyclin, heparin, salicylates, nitrates, calcium channel blocking drugs, streptokinase, urokinase, tissue pl~min--gen activator (TPA) and anisoylated plasminogen activator (TPA) and anisoylated plasminogen-streptokinase activator complex (APSAC), colchicine and alkylating 30 agents, and aptomers. Specific examples of modulators of cell hllt;la~;lions include interleukins, platelet derived growth factor, acidic and W O 97/05185 PCT~US96/12285 basic ~lbroblast growth factor (FGF), LldnsrolllldLion growth factor B
(TGF 1~), epidermal growth factor (EGF), insulin-like growth factor, and antibodies thereto. Specific examples of nucleic acids include genes and cDNAs encoding yroteills~ expression vectors, ~ n~e and other 5 oligonucleotides such as ribozymes which can be used to regulate or ~JlCVt~llL gene e~yl~ssion. Specific examples of other bioactive agents include modified extracellular matrix components or their .-,ce~Lul~, and lipid and cholesterol seq~lestrants.
Examples of L,ro~ s further include cytok-ines such as i..~.f~,lolls 10 and interleukins, poetins, and colony-sfim~ ting factors. Carbohyd dLes include Sialyl Lewis~ which has been shown to bind to l~;ct:~Lol~ for selçctin~ to inhibit infl~mm~tion. A "Deliverable growth factor equivalent" (abbreviated DGFE), a growth factor for a cell or tissue, may be used, which is broadly construed as including growth factors, 15 cytokines, illl~.r~ olls, int-orlellkin~, ylvl~ills, colony-stimnl~tin~ factors, gibberellins, auxins, and viL~-ills; further including peptide fr~gm~ont~ or other active fragments of the above; and further inrll~-lin~ vectors, i.e., nucleic acid constructs capable of synthtosi7ing such factors in the target cells, whether by Lldl~Ço-l-lalion or Lldnsie.l~ ression; and further 20 inrln~lin~ effectors which stimnl~tr or depress the synthesis of such factors in the tissue, including natural signal molecules, ~ ç~e and triplex nucleic acids, and the like. Exemplary DGFE's are vascular endothelial growth factor (VEGF), endothelial cell growth factor (ECGF), basic fibroblast growth factor (bFGF), bone morphogenetic protein 25 (BMP), and platelet derived growth factor (PDGF), and DNA's encoding for them. Exemplary clot dissolving agents are tissue pl~mint)gen activator, streptokinase, urokinase and heparin.
Drugs having antioxidant activity (i.e., de~Lloyi..g or pl~v~llL~g formation of active oxygen) may be provided in the hydrogel, which are 30 useful, for example, in the yl~v~llLion of adhesions. Examples include superoxide ~ mnt~e, or other protein drugs include CZ~t~ ÇS, WO 97/05185 PCT~US96/12285 peroxidases and general oxi~ es or oxidative enzymes such as cytochrome P450, glutathione peroxidase, and other native or de~ uled hem~lul~ills.
M~mm~ n stress response proteins or heat shock ploltills, such as heat shock protein 70 (hsp 70) and hsp 90, or those stimuli which act to inhibit or reduce stress response ~roleills or heat shock protein c~ion, for example, flavonoids, may be provided in the hydrogel.
The lllac~ may be provided in pll~. ",~ ir~l acceptable carriers known to those skilled in the art, such as saline or phosphate buffered saline. For example, suitable carriers for pal~ dl l.,.i..~-alion may be used.
A~ lion of Mae~
Modern surgical procedures which provide access to a variety of organs using minim~lly invasive surgical devices may be used to apply the macromers. Using techniques such as laparoscopy/endoscopy, it is possible to deposit a macromonomer solution at a localized site and subsequently polymerize it inside the body. This method of "on-site"
polymerization offers unique advantages such as co- ro~ ily to specific organs and adherence to underlying tissue. Hill-West J. L. et al., Obstetncs & aynecology, 83:59 (1994). (~thPter delivery systems available in the art also may be used as described, for example, in U.S.
Patent Nos. 5,328,471 and 5,213,580 to Slepian. The macromer also may applied during surgery con~ cte~l through the c~nm-l~ of a trocar.
Fo....~tioll of Microspheres In one embo-liment the biodegrabable lllaclulllers are crosslinked, either reversibly or nonreversibly to form microspheres. As used herein, the term "microspheres" includes includes particles having a Ul~iÇullll sphl-rir~1 shape or an irregular shape, and microcapsules (having a core and an outer layer of polymer) which generally have â ~ mPt~pr from the n~nomPter range up to about S mm. In a ~,~r~l,.,d embodiment, tlhe microspheres are dispersed in biocompatible, bio~legr~ hle hydrogel W O 97/05185 PCT~US96/12285 m~trires. The llliclu~heres are useful for controlled release and L~t;L~d delivery of dlugs within the body.
The microspheres are formed in one embodiment by aggl~ ion and subsequent polymerization of portions of the macromers which are S similar in charge properties such as hydrophilicity. This results in a matrix which consists of spollL~.leuusly-assembled "nodes", which may be cros~iinkecl covalently, and may be further covalently linked to hydrophilic bridges of the macromers to form a hydrogel.
When the macromer is amphiphilic and includes hydlophobic and 10 hydlulJhilic domains, in an aqueous ellvhulllllent, at or above a certain concentration, the molecules to arrange themseIves into olg~l~i~d structures called micelles, at the critical micellar concellL.~lion (CMC).
These micelles can be of different shapes and sizes, though are gen.or:~lly spherical or elliptical shape. When the solution is water, the hydl~hobic 15 portions are at the center of the micelle while the hydrophilic tails orient themselves toward water. The interior core of a typical sllrf~rt~nt has a size from 10-30 Angstroms. PluronicTU poloxamer based biodegTadable macromers, as described in Examplel, undergo micellization in an aqueous e..vholl...ent with CMC values ranging between 0 and 5% (w/v).
20 After photopolymerization and gelation, this micellar structure is p.~i,e.v~;d in the crosslinked gel. On a microscopic level, the gel co.lL~.. s micelles which are interconnrcted by covalent bonds to form the gel.
These micellar domains or microspheres can be used for the controlled or ~.,xl;.;..~(l release of drugs. A scl~ tic .~l~,sellL~Lion of such a material 25 is shown in Figure 12. Controlled, pseudo-zero order release of small compounds such as chlorohexidine is possible from such hydrogels.
The hydrogel thus is formed in one embodiment by providing a solution of macromer in aqueous solution (with or without drug);
"freezing" the micellar structure of the macromer by a ch~mir~l 30 cro~linking via a chemical reaction; adding the drug to the ~;lu~ d macromer if it has not been already added; and using the reslllt~nt di~ ed composite, co..~;~i,.iu~ microspheres con~icfin~ of drug~ tin~
micellar cores, for drug delivery.
In addition to photopolymerization, crosslinking can be implem~nt~l by, for example, isocyanate-amine ~ y, or hy~ y- or 5 aldehyde-amine ch~mi~try, to freeze micellar structure. For example, isocyanate If ~ poloxamer lactate diol can react in water to form crosslinked polyulelllalle based n~wolh~. This is an advantageous method of forming a drug delivery device for local or systemic delivery, because the formation of the delivery-controlling micropheres and the 10 ,lliclu~here-confining gel is accomplished ~imll1t~nl~ously, and may be accomplished at the site of delivery in a few seconds by photopolymerization .
In one embodiment the macromer inrlucles PEO segments, and hydrophobic "ends" cont~ining reactive groups, and the mi-~ell~r domains 15 are hydrophobic and are interlinked by the PEG segments to form a hydrogel. Reversible gelling microsphere -follllill~ macl~ also may be made from PluronicsTM (PEG-PPO-PEG), lactylated and acrylate-capped, which are gelled and reacted in a non-aqueous phase. A
hydrophilic drug then may be added (while in the hydl~J~hobic solvent) 20 which partitions to the hydrophilic core. Because the micelles have been cross-linked in the hydrophobic el,vil:ol-lllent, they will not be able to revert to the Collroll~latiOn which they would normally assume in a hydrophilic ellvi~o~----~.-l The trapped hydrophilic drug molecules then need to diffuse through a relatively hydrophobic region to escape iFrom the 25 nanoparticle. This permits flexibility in the formation of llli~ ~heres.
They may be hydrophilic or hydrophobic d~elldillg on the solven~ in which they are polymerized, and on the composition of the macromers.
In other embo~limentc, physical or ch~mir~l cro~linking to form hydrogels (or organogels) can occur in zones other than those le~ol~il)le 30 for the plilll~ly sll~t~in~l release characteristics of the matrix. For example, "single-ended" materials could have ~lt~rn~tive reaction sites on W O 97/05185 PCT~US96/12285 the non-micellar ends, which could subseqllçntly reacted to form a gel.
Since matrix-controlled drug delivery is a function of both diffusion from the micelles and of matrix degradation, manipulation of the macromolecular backbone can also control matrix degr~ tion. This can S occur through stabilization of hydrolytic groups by their rhPmi~l and physical ellvil~ ent (for example, macl~ based on reverse PluronicTM gels are more stable than normal PluronicTM gels, in aqueous solution). It is possible that the increased hydrophobicity of the environment of the lactide ester bonds, due to the adjacent block being~0 PPO rather than PEO, inhibits hydrolysis of the bond.
i vely~ and particularly in gel-forming compositions, the cross-linking reactive groups or biodegradable groups may be in the hydrophilic portions of the macromers, so that the hydrophobic ~iom~in~
would not be locally cro~link~-~l in the hydrophobic regions, while the 15 micelles would still be stabilized by the cros~linking of the material, and particular hydrophobic sections of macromers would be steri~lly r~ ed to one or only a few dirrel~ micelles. In either of these cases, the hydrophobic zones are not rigidly cros~lin~ l but are co""~ to crosslinks via the hydrophilic blocks, which may be very flexible. The 20 hydrophobic blocks thus can associate above or below a critical Lt;llll)tldlUl'e, and dissociate on change in l~ll.pcldlul~. This allows, for example, both th~nnosçn~itive gelation and thermosellsiliv~ variation in drug diffusion rate.
The hydrogels may be ~lç~i~nf~l to be biodegradable by 25 incorporation of a group such as a lactide, glycolide or other self-degrading linkage. ~lle~ liv~1y, this is not .-~cç~.y when non-gelled nanospheres are formed, since these are small enough to be removed by phagocytosis. Control of the rates of delivery of both small and large molecules can be obtained by control of the hydrophobicity of 30 the associating hydrophobic domains of amphip~thic hydrogels.
The cro~ nk~l microspheres con~ g a biologically active agent, in either gel or dispersion form, can be made in a single step. In addition to drug delivery applications, the method is suitable for ~ non-m~ r~l uses inrhl-lin~ delivery of ~grir~ lral materials such as 5 herbicides and pr~tir~ s and in water tre~tmrnt The present invention will be further understood by l~Ç~ e to the following non-limiting examples.
Example 1: S~ and Thermal R~p~ ,", of F127~ rt:~e)6-Acrylate.
a) Synthesis.
F127-(lactate)O-acrylate (lml~rt~cl control) (=F127A2?) was synth~,si7~o~1 by acrylatinglOO g of PluronicTM F127 (poly~r~ylene oxide-polyethylene oxide block copolymer, BASF, mol. wt. 12000) ("F127") in ~ hydl~us toluene using kiethylamine and acryloyl chloride, in an argon 15 atmosphere at 60~C for 10 mimltes. The hot, turbid reaction ~ Lule was filtered and the filtrate was added to a large excess of hexane. The monomer was collected by vacuum filtration and dried in VaCUULU to a constant weight.
F127-(lactate)6-acrylate was synthrsi7pA as follows. F127 ~was 20 melt dried in vacuo at 100~C for 4 hours. D,L-lactide (Boel.~ ,el Ingelheim) was added to the melt under a nitrogen flush, followed by nll~us octoate as a ring opening catalyst. After a reaction time of 4 hours, the melt was dissolved in toluene and pl~ ildled in a large excess of hexane. Acrylation of F127-(lactate)6 was carried out as described 25 above for the acrylation of F127-(lactate)O-acrylate. All macr~ mo were characterized by NMR and HPLC.
The relationship between the macromer, the thermally-reversible (physical) gel, and the ill~vel,ible (cro~linkt~l) gel is shown in Figure 1.
b) Measurement of the sol-~el transition as a function of 30 concelllldlion and len,~.dlule.
W O 97/05185 PCT~US96/12285 Thermo~ ible gel formation of the aqueous solutions of the macromonomers at a certain transition It;~ dLul~; was df m~ ed This transition temperature was recorded as a function of fe-..pe~ e and collcelll.~lion. The results ~l~mo..~.aLtd that sol-gel transition can be 5 controlled through the incorporation of hydrophobic lactyl units.
Transition ~lllpeldlulc: as a function of concentration was f ....;..~od by ~r~dlillg 20% w/v aqueous solutions of F127-(lactate)0-acrylate and F127-(lactate)6-acrylate as stock solutions. 15 % (w/v), 12.5% (w/v), 10% (w/v) and 5% (w/v) macr~ mon-mfr 10 aqueous? solutions in screw cap vials were ~ al~d by dilutions of the stock solutions. The solutions were allowed to equilibrate at 25~C. The vials were inverted and observed for fluid flow. The concentration at which no fluid flow was observed was recorded (see Table 1).
The transition ~ ldlule as a fucntion of tel~ldlul~ was 15 ~lele....i.~ by ~r~alillg 10% (w/v) aqueous solutions of F127-(lactate)6-acrylate and F127-(lactate)0-acrylate and equilil)laLi l~, them at room L~ peldLul~. (The concentration of the solutions are wt/vol% in aqueous solution unless otherwise stated.) The sample vials were immersed in a te~ )eldlule controlled bath and the fluid flow was 20 observed at dir~l~llL tempelaLules. The l~ll~e.dlulc at which no fluid flow was observed was recorded (see Table 1).
Sol-Gel Sol-Gel ~ Macromonomers Transition (% Tr~n~hio~, w/v)** ( o C)***
F127-(Lactate)0- 30 40 Acrylate F127-(Lactate)6- 10 25 Acrylate ** Sol-Gel Transition as a function of cOllc~llLlaLio (temperature 25~C).
***Sol-Gel Transition of 10% w/v solutions as a r.....
of temperature.
c) Poly~ alion and Mea~ul~ of hydro~el ~lim~n~ions.
A 10% solution of F127-(lactate)6-acrylate in PBS (ph- sph~
buffered saline) was polymerized using long wave UV light. The polymerizations were performed in a cylindrical plastic mold. Darocur~
2959 (Ciba Geigy) was used as the photoinitiator. The hydrogel was allowed to reach equilibrium swelling by immersing in PBS for 24 hours 20 at ambient L~lllyeldLul'e. The change in ~1im~n~ion of the hydrogel at temp~ Lules ranging from 0-50~C was measured using vernier calipers, and is shown in Figure 2. At low l~lllycl~Lul~ s, the hydrophobic PPO
(polypropylene oxide) segments of the hydrogel may dissolve and swell, and increase the dimensions of the gel. At high Lt;llly~atUlCS, the PPO
25 segmrnt~ may become hydrophobic and collapse into lllicr~,lllicellar hydrophobic (1om~in~, which exclude water resllltin~ in reduced swelling and smaller dimensions.
d) De~radation ~yelilllents~
~ Hydrogels were pl~ar~d using 10% macromonomer solution as30 mentioned before and the degradation of hydrogel was m~,niL~l. d ~ lav;~l~f L~ ;r~lly at various intervals of time. The e~y~lilll~llL~ were pelrolllled at 37~C in PBS. The lactate based photopolymerized hydrogel completely degraded in 22 days (at 37~C, in PBS).
WO 97/05185 PCTrUS96/12285 Thus, the macru~ can be photopolymerized to form thermoresponsive hydrogels which degrade under physiological conditions.
The mac~ and related prior art m~t~ri~l~ are referred to 5 herein in the form XXXLLAA, where XXX is either part of the trade name of a precursor polymer (e.g., L81 for Pluronic~ L81 poloxamer) or refers to another property of the base polymer (e.g., 8K for 8,000 nnmin~l Dalton PEO). LL denotes the If~l.l.i..~l block, typically of a degradable hydro~y acid (e.g., L5 denotes an average of 5 lactate residues 10 per arm of the polymer), where L, G, C and TMC or T l~l~sellL, respectively, lactate, glycolate, epsilon-capl~,at~:, and trimethylenecarbonate. AA represents a Ir~ l group; for example, A
is for acrylate, so A2 would l~l~ s~llL 2 acrylate l~ linns on the ma~ lller as a whole.
Example 2: Dextran Release by F127A2.
The non-degradable material, F127A2, was made as described above in Example 1, with no addition of hydroxy acid to the Pluronic~
polymer backbone. Dextran (labeled with fluorescein) of molecular weight 71,000 daltons was mixed at 1% final concentration with F127A2 lllacl-,lller (final concentration 10% wt/vol, in water) and polylllel~d as described in Example 1. Release of dextran was (1etf-. Illillf~Cl by visible absoll,allce. Release kinetics were ~i~nifir~nt1y altered by tel~ lalu.c;, as shown in Figure 3.
h',Y~ e 3. Synthesis of M~ with Biode~. ~!f T,inkin~ Groups.
Four monomer types were made by the general procedures described in Example 1, each cont~ining about 4 units of each of four different biodegradable linkers, clecign~tPcl by L (lactate), C
(caprolactone), G (glycolide), and TMC (trimethylene calbO~).
Parameters for the synthesis of the therrnosen~itive macromo~ are listed in Table 2. Properties of the monomers characterized are listed in W O 97/05185 PCT~US96/12285 Table 3, in~ ing biodegradable segment and end group incorporation by HPLC and NMR, and Mn tl~t-ortnin~cl by GPC and NMR.
- M.W. PPO PEOFeed Ratio Temp Compound(g/mole) M.W. M.W.Monomer/ ~C/ Yield diol time(g) (h) F127L4A2 12600 3780 8820 4 180-80.46 F127C4A2 12600 3780 8820 4 180-81.38 F127G4A2 12600 3780 8820 4 180-71.89 F127TMC4A212600 3780 8820 4 180-79.29 W O 97/0518~ PCT~US96/12285 Macro- Biodeg. Biode~ End End Mn Mn Mn mono- Seg. Seg. Group Group GPC NMR Expected mer Incorp. Incorp. Incorp. Incorp. g/mol g/mol g/mol (HPLC) (MNR) (HPLC) (NMR) F127- 5.68~t 5.58 2.09~ 2.00 1080 11316 12998 L4A2 0.01 0.01 0 F127- 5.39i 5.04 2.05i 2.31 1080 10804 12942 G4A2 0.02 0.02 o F127- 5.49i 5.45 2.09~t 2.11 1000 13062 13166 C4A2 0.02 0.03 0 F127- -- 3.26 2.08i 2.09 1210 NA
TMC- 0.03 0 The mollo~ differed in their rate of polym~ri~tion and rate of S degr~ tio~ The long UV photopolyl~ Lion profiles are shown in Figure 4. The in vitro degradation profiles of the cro~linke~l hydrogels are shown in Figure S.
The macrulll.,l~ had similar bioc~ ihility proffles, as shown in Figure 6, as l~easul~d by the HFF cell a&esion test. In Figure 7, release 10 rates of fluolescellL ~lextr~n at 37~C and 0~C is shown for a prior art m~teri~l (F127A2) and for "~acl~.ll,ers with degradable hydrophobic blocks formed of lactide (F127L4A2), glycolide (F127G4A2) and caprolactone (F127C4A2). A longer period of quasi-zero order delivery, after the initial burst, and a distinct dirr~l~nce in the rates of efflux 15 b~Lweell the lower and higher ~ )ela~ull,s, is obtained with the lllacl~ûlllel~ including the degradable blocks, in c~ ,ison to the prior art material. In Figure 8, the transition L~ laLul~,s (for vûlume change and change of ~1extr~n release rate) are shown as a filntrtion of llla~;lOln"~
concenration in the gel for the above materials and also a trimethylene SUBSTITUTE SHEET (RULE 26) WO 97/05185 PCT~U~96/12285 carbonate based m~tt~ri~l (F127TMC4A2), a "reverse" Iclo~ ol mzlt~riz-with lactide (25R8L4A2), and a "normal" m~tPri~l (F68IAA2) of equivalent hydrophobicity.
The HFF test was con~ ctecl as follows:
S a.) P1G~ aL;On of Gel.
0.5 gram of test material was dissolved in 4.5 ml ~L~ldald recu,..~ n solution (Irgacure 1200 ppm, 3% Pluronic F127). The solution was filter sterilized using 0.2 micron filter. In a sterile hood, a glass coverslip (18 mm sq) was sterilizPd using 70% ethanol and was placed in a 6 well, 35 mm tissue culture dish. 200 ,.4L of the sterile macromonomer solution was spread on a sterile coverslip. The solution was then exposed to long wavelength W light (Black Ray, 20 mW/cm2, 1 minute) to forrn a gel.
c) Plc~)alaLion of Cell Suspension.
Human r~c~in fibroblasts (HFF) cells were ~?ulcllased from ATCC. Cells were used at a passage 22-23. HFF cells were cultured in a standard tissue culture ware in a hllmitlifiPA ~tmosphPre co"l;l;";..g 5%
CO2. Cells were rlpt~rhpcl from the culture flask using a 3 ml trypsin/EDTA solution (0.05% /0.53 mm) and centrifuged (2500 rpm, 3 20 Illill~ s). The cell pilot was resuspended in cell culture mP~ lm (DMEM
+ 10% FCS) at a concellLlaLion of 250000 cells/ml.
d) Cell ~tt~rllment assay.
The gels were washed with 3 ml DMEM (Dulbecco's Modified Eagles' Medium) solution and then seeded with 25000 cells/cm2 cell 25 density. After 18 h, the gel surface and tissue culture poly~ly~ e surface were observed under microscope and photographed. The gels were ale-l from coverslip and Lldn~r~ d into a new petri dish. The cells adhered to the gels were ~let~hP~l using 3 ml trypsin/EDTA (0.05% /
0.53 mm) solution. A Coulter counter was used to d~ lllille the cell 30 density.
W O 97/05185 PCT~US96/12285 Example 4: Effects of T,inkin~ Group Hy~ kicity on Small Mol~c-llP Delivery.
Micelle-forming biodegradable maclulll~ were ~y~ and characterized which included a a non-thermosel~iliv~ core. The macromers illustrated the effects of hydrophobicity on delivery capacity for small hydrophobic molecules. The macromers were formed by ~yll~ g copolymers of PEG (molecular weight 8000) with dirr~
combin~tion~ of polycaprolactone and polyglycolate which were then end capped with acrylate moieties. The structures are shown in Figure 9, where p is the number of glycolic acid groups and q is the number of caprolactone groups. Hydrophobicity of the mixed hydroxy acid blocks hlcleases from A to D. The ability of these monomers to solubilize model hydrophobic drugs was demonstrated by a study of the CMC
through the gradual dissolution of a molecular probe, 1,6 diphenyl 1,3,5-hf~x~ nf~ (DPH).
effect of hydrophobicity on drug incorporation into gels a) Synthesis of monomers.
The molecular structures of the monomers are shown in Figure 9.
Polyethylene glycol 8000 (Union Carbide) was melt-dried at 100-110~C in vacuum (10-15 mm Hg) for 4-6 hours. Caprolactone (predi~tillP~1 Aldrich), and glycolide, were charged at a~lopliate ratios into a Srhl~onk-type reaction vessel and stannous 2-et_yl hPx~no~t~ (Sigma) was added as a ring opening catalyst. The reaction was carried out for 4 hours in an inert atmosphere at 180~C. The reaction llli~lUlc; was then cooled to 80~C, dissolved in toluene, ~l~ci~ led in hexane and the product was collected by vacuum filtration. The product was redissolved in toluene and dried by azeotropic ~ till~tinn.
Acrylation was carried out by the dropwise addition of a 2 molar excess of acryloyl chloride and triethylamine under a llillogell flush at 65~C for 1 hour. By-product salts were removed by vacuum filtration.
Ihe product was isolated by precipitation in a large excess of hexane -W O 97/05185 PCT~US96/12285 followed by vacuum filtration. The mol~oml.. were c]~ d by NMR on a Varian 300 MHz nuclear m~gn~tic ~e~;L~ eter.
b) Dete....i"~lion of Critical Micellar ConcellLlaliol s.
~ The hydrophobic dye 1,6, diphenyl 1,3,5-h~x;~ n~ (Aldrich), (DPH), which demul~Llates enh~n~ed absoll,allce (356 nm) at the ~CMC
due to associative hllel~cLions, was used in this study. ~k x~ et al., Macromolecules, 27:2414 (1994). A stock solution of DPH was ~,le~ ,d in methanol (0.4 mM). Aqueous mon-)m~r solutions were al~d by dissolution in PBS and dilution to the desired C~n~ ion~.
10 ,~1 of the dye solution were added to each vial with equilibration for at least 1 hour. The absorption spectra of the polymer/dye/water solutions were recorded in the 250-500 nm range using a Hitachi W-VIS
Spe~;L~ ullleLer .
c) Photopolymerization.
Photopolyllle~ lion of the polymer solutions were carried out in both visible and ultraviolet light systems as described in: Sawhney A. S.
et al., Macromolecules, 26: 581 (1993); and PCT WO 93/17669 by Hubbell J. A. et al.
d) In vitro de~radation.
200 ~1 of 10% monomer solution were W polymerized to form a gel. The degradation of the hydrogels was monitored at 37~C in PBS.
e) Results In the synthesis, hydrophobic se~,...e~ ; of the mollolll~,ls were changed by using various combinations of cal~ro~-L~ and glycolate link~ges 25 in the molecule. The critical mirelli7~til)n point was obtained from the first inflection of the absorption vs. concentration curve. The curves are shown in Figure 10. It is evident from the curves that the solubility of the dye is ~;:"h~ e-l with increasing concentration of the monomer. The CMC values during aggregation and photopolymerization for various 30 monomers are listed in Table 4.
W O 97/05185 PCT~US96/12285 Critical Gel* Time Gel** Time Total Monomer Micellar Tniti~t~d Tniti~t~-l Using Degr~ ti~n Concentration Using UV Visible Light time (days) (%) Light (secs) (secs) A 0.92 5.5~tO.4 8.9 i O.l 10 B 0.55 5.8~t0.1 8.2~t0.5 14 C 0.32 5.2~t0.2 9.8~t0.4 16 D 0.28 4.6 + 0.1 10.4 + 0.3 44 * 2,2-Dimethoxy-2-pheny~ .Innf~! as UV initiator, Long UV light, 20 -, conc.
** Eosin, tri~ n( l--ninP il~itiating system; g~een light source, 20% .. 1--,.. - -conc.
T~BL E 4 The CMC value is lowered with increase in cd~l~al~ content of the monomer. This may be due to the tighter aggregation of the hyd~hobic ca~loaLe moieties. The fast gelling ability of these monomers under W
and visible light is il1llctr~te~ in Table 4. The gel times range bc;lweell 4-12 seconds. The photopolymerized hydrogels degrade under aqueous conditions. The degradation times, i.e., times to subst~nti~lly complete dissolution, varied from 10-44 days, increasing with cap/gly ratio. The fast gelation times of these monomers, their ability to dissolve hydrophobic solutes and their controlled degradation rates render them excellent c~n~ tt-s for localized drug delivery.
FY~mple 5: Synthesis of Ma~lvllltl~7 Fo Liquid Crystal Phases.
a) Synthesis of Macromers.
PlOSL4A2, P84LS A2 and T904LS A2 macromers were synth~si7e~
by ~ dar~ procedures, generally as described in Example 1, from commercial base polymers (P105 Pluronic~ poloxamer; T904 Tetronic four-armed ionic-group cont~ining polaxamer; P84 Pluronic~ reverse poloxamer, or meroxapol).
b) Charaeleli~dlion of optical effects and dru~ release l r~,.lies.
Aqueous solutions were prepared, and observed for anomalous 5 optical effects ("Schlieren") without cro~linking. Rates of release of a drug were observed, wherein the drug had a molecular weight about 500 D, and ~ub~LdllLial water solubility, as well as a hydl~hobic region.
Aqueous solutions of all three ll,ac,~""ers formed "Schlieren" type liquid crystalline phases at concelllldLions of 55% and higher, at room 10 lelll~eldlul~,s. A temperature study of the LC phases showed that the LC
phases for P84L4A2 and T904L4A2 are not stable at tempcldluies higher than 30-35~C. The LC phase for these two polymers "phase se~ s"
into two phases at T>35~C, one being an isotropic polymeric phase that is not ~ .ell~ to light and another phase that seemed to consist of water. In contrast, a cc,ncellL,aL~d solution of P105L4A2 (75%w/v) displays a highly anisotropic LC phase that m~int~in~ its stability to L,ldLUl~;S Up to 110 C.
Aqueous solutions of P105L4A2 (in high concellL,dLions) formed a highly anisotropic liquid crystalline phase (LC phase) that results in good 20 drug enL,~lllent to slow down release. It was also observed that P84LSA2 and T904L5A2 had ~ nific~nt dirf~ ,llces in the self-assembling characteristics (LC). It is possible that the drug is entrapped in the stable, highly oriented LC Phase of a plO5L4A2/water system. P84L4A2 and T904L4A2 form LC phases with water, but these phases are not stable 25 above 30-35~C. At higher LelllpelaLul~s, the drug as well as some of the water are excluded from the polymeric cl-)m~in~.
EXAMPLE 6. Trr~ of Burns.
The pluronic poloxamer based macromonomers, such as F127-TMC acrylate, have a "paste-like" con~i~t~nry at L~ "dLures 30 above 37~C, and have flow characteristics at low le~ e~dlules. A "cool"
formnl~te~l solution, optionally cn..~ .g an a~,~,ial~ drug (such as an antibiotic) is poured on a burn site, providing instant relief. At body L~ c/dlulcs, the formulation gels to a paste like col-c;x~ y. The gel is then crosslinlr~d, preferably by the action of light on an inrhlded photoinitiator. The charac~ Lion of photopoly...~ d hydrogels as 5 carriers for thela~c~uLic materials to influence wound healing is described in Sawhney et al., "The 21st Annual Meeting of the Society for BiulllaL~lials," March 18-22, 1995, San I~lancisco, CA, Abstract, the disclosure of which is incorporated herein by lc~felc:llce.
The hydrogel layer on the skin provides tr~n.cderm~l delivery of 10 drug to the burn site; m~int~in~ high moisture levels on severely burned sites, thus ~l~v~llLillg dehydration; adheres strongly to the 11~m~d tissue, and is elastic, thus preventing del~min~tion and "peeling" of the hydrogel dressing; and absorbs exudate from the wound. After a suitable time, controlled by the nature of the lining group (trimethylene calbullale in this 15 example, giving a residence time of over a week), the gel will dissolve into components which are absorbable or innocuous. It has been demol~Llat~d in other experiments that related gel forrmll~ti~ns, based on a polyethyleneglycol backbone such as the material 8KLSA2 (i.e,. PEO of m- lecnl~r weight 8,000, with 5 lactate groups on each end 1. . Illill ~lr~l 20 with acrylate groups), do not retard the healing of full thicknPss biopsy wounds in rat skin. The pentablock polymer F127-TMC acrylate of Example 3 is improved in cu~ alison to the prior-art 8KL5A2 polyethylene glycol-based triblock formula in that it gels spontaneously on the burn site, and thus does not tend to run off the site before it can be 25 photocros~lin1~~d.
EXAMPLE 7: Use of Hydrophobic Ma~ u~ to Il,clease Tissue Adherence.
Use of macromers carrying one or more hydlu~?hobic groups can improve the adherence of a hydrogel to a biological material. A
30 macromer having having this property was synth~si~e~l The base polymer was a Tetronics" 4-armed polymer based on e~ylene ~ l,;"~, where each arm is a PEG-PPO-PEG triblock copolymer. The base polymer was ext~n~led with lactide as previously described in Example 1, and then capped with about two moles of palmitoyl chloride per mole of - polymer, in order to cap about half of the arms. The ~ r of the hydroxyls were capped with acroyl chloride, as described in Example 1.
The res lltin~ macromer was di~l~ed in water and was polymerized in contact with tissue, to which it adhered tenaciously.
Example 8: Formation of Microspheres PluronicTM based biodegradable macromers made as described above above, such as the materials of Example 3, in an aqueous solution formed micelles with a CMC value ranging from about 1 % to 5 % w/v.
After photopolym~qri7~tion, the structure of the micelle is sub~ lly ~1~S~1V~d.
Example 9: Synthesis of F127-Dimer Is~u.ale-F127 T ~t~te Acrylate Two molecules of a macromer diol (Pluronic F127) are coupled with one molecule of a diisocyanate (dimer isocyanate) to produce higher di- and tri- functional alcohols, to provide l.laclulll~l~ with high elasticity,high ~ t~n~ihility and high tissue adherence.
The following reagents are used: Pluronic F127 (BASF lot # WPM
N 581B, Mn=12200); dimer isocyanate (DDI-1410, Henkel Lot# HL
20037, % NCO= 14.1 %); and dibutyltin dilaurate.
Synthesis of F127-DDI-F127: 366 g of Pluronic F127 was heated to 100~C under vacuum for four hours to produce a melt. DDI-1410 (8.94g) and dibutyltin dilaurate (O.llSg) was added to the melt (melt Lt;LL1~)e;1a~U1e 70~C) and stirred vigorously for 4 hours. The llli~lu~Le readily cryst~lli7Pd when cooled. Product was a white waxy crystalline m~t~ri~l. Theoretical molecular weight=24,996 Daltons.
Synthesis of F127-DDI-F127 T ~rt~t~s diol: lOOg of F127-DDI-F127 was dried for 4 hours under vacuum at 100~C. 4.67 g of (D,L) Lactide was charged to the reaction pot under an argon flush. SL~L~US
CA 02228ll8 l998-0l-28 W O 97/05185 PCTrUS96/12285 2-e~yl h~n~t~ (0.5 mole percent) was added to the reaction. The melt was vigorously stirred at 150~C under argon for 4 hours. The product was isolated by ~ iL~lion in hexane, followed by filtration. The product was a white, crystalline, flaky material.
Synthesis of F127-DDI-F127 T.~et~t-o,5 acrylate: 100g of F127-DDI-F127 T ~rt~tPs diol was charged into a 1000 ml three-necked reaction vessel. 800 ml of toluene (Aldrich, 0.005% water content) was added to the flask. 50-75 ml of toluene was azeotroped off to ensure moisture free re~ct~nt~. 2.427 ml of predistilled triethylamine, followed by 2.165 mls of acryloyl chloride was added to the reaction IlliXIulG at 65~C. After one hour of reaction time, the turbid reaction mi~lure was f~tered, and isolated into a white powder by precipitation into a large excess of hexane. The product was collected by vacuum filtration and dried to a constant weight.
Molecular structure de~ aLion was carried out by NMR, IR.
The product was found to be soluble in water and crosslinkable by visible and W light. Percent water uptake of fully cured 10%w/w hydrogels=22.1%. Hydrogels formed by photopolylll~ alion at 10%
concentration while on dead bovine tissue were AeLe~ to be gen~or~lly well adherent.
P105-DDI-P105 lactate acrylate and L81-DDI-L81 lactate acrylate was ,yll~ ci~ from the respective Pluronic poloxamer starting materials (P105,L81) by the procedure described above. These macromers were insoluble in water. They were used to enc~ulate bioactive molecules in hydrophobic matrices to achieve s -ct~in~d drug release.
Example 10: Sy~ e~,;s of F127-DDI-F127 Iso~ .~ c Iso~ le The synthesis and polymeri7~tion of a macromer which crosslinks without involving free radical polymerization is demonstrated. 50 g of F127-DDI-F127 diol, prepared as in Example 9, was dissolved in 100 ml of toluene in a three necked reaction flask. 90 ml of toluene was ~ till~l WO 97/05185 PCT~US96/12285 off azeotr~,~ically at 110~C under argon. The flask was ~ .o.1 at 100~C for 12 hours under vacuum (12 mm Hg). The reaction flask was then cooled to room temp, and 200 ml of dry methylene chloride was - added to the reaction flask. 0.445 g of isophorone isocyanate (Aldrich) 5 was added (in a bolus) to the reaction flask at approximately 30~C. 0.15g of dil~ulylLill laurate was added to the reaction ~ lu~e. The reaction ~i~Lulc: was stirred under argon at 30~C for 12 hours, and ~ iLal~;d in 1000 ml of hexane (EM Sciences). White flakes were collected by vacuum filtration, and rinsed with 150 ml of hexane. The product was 10 dried in a vacuum oven to a constant weight. Chara~;Le~lion by ~MR, IR showed synthesis of the expected material.
The polyll~~ bility of F127-DDI-F127 isophorone isocyalldL~
was ev~ln~t~l Partially dried product (0.16g) was added to 1.44 g of deionized water. The product initially formed bubbles in contact with water, then dissolved over approximately 3 days to form a viscous solution. To test polylllel~bility, 200 mg of F127-DDI-F127 isophorone isocyanate solution of polyethyleneimine in methylene chloride. The solution was stirred vigorously for a few seconds. A gelatineous product was observed. Gel time: 5.9 seconds. Polyethyleneilllille is believed to have hemostatic properties; this formulation thus is potentially suitable for a topical wound dressing. In addition, structures formed of these materials can be used as drug depots.
Example 11: Effect of Hydrophobicity on Drug R~l~qce Kin~ti~e for Bulk Devices.
Macromers were synth~si7~o~1 having a wide range of hydrophobicities ranging from 0-90% PPO content. All maclolllGl~ were tested at 15% macromer collct;llL~Lion except those whose PPO content was greater than 60% which were used neat. Figure 13 shows the rate of release of a small drug from gels of these ma~ ll~l~. At 10 and 15%
macromer loading (8KL10, prior art; 25R8LAA2, based on a "reverse"
Pluronic polymer) and PPO content of less than 60% hydrophobic W O 97/05185 PCT~US96/12285 partitioning did not show a ~ignifir~nt effect on prolonging 500 Da sparingly soluble drug release. Devices ~ al,d with neat ma~
(PPO content > 60%; P84LSA2 and L81LSA2, ~y~ d by general procedures as described above) showed a signifi~nt ability of these highly S hydrophobic, dense macromers to retard water permeation and drug dissolution. In the extreme case (L81LSA2; PPO content = 90%), the release kin.otirs showed first order release with half of the drug being released from the device over 17 days with the r~m~in~ r being eluted from the device over a total of 66 days.
Example 12: Effect of Polymer Hydrophobicity on Drug D;rru~ivily Membranes of constant thickn~ss were p,~a,~d from neat macromers of Example 11, and used as the diffusion barrier in a two-c~ alL~ent dialysis cell. Figures 14 and lS show the h~ ase in the conce"L,~Iion of SOO Da drug in the receptor side of the cell over time.
The diffusion coefficient c~lr~ tion was based on the following relationship:
D =JI(A*(ACIAX) where D is the diffusion coefficient, J is the measured flux, A is the exposed area of the film, AC is the concentration ~r~(1ient across the film and ~x is the average film thickn~ss. The diffusion coefficients for macromers having 50% (PlOSLSA2) or 90% (L81LSA2) relative hydrophobic domain and were calculated to 1.6xlO~9cm2/sec and 5.63x10-I0cm2/sec, respectively. Thus, diffusion was faster in the more hydrophobic material, as expected for a drug of low water solubility.
F,Y~ 'e 13~ e of Tt:LI~y~ e and Taxol.
A 30% w/w solution of F127 trimethylene carbonate acrylate (as described in Example 3) in phosphate buffered saline, pH7.4 was prepared. 3000 ppm Darocur~ (Ciba Geigy) was incorporated in the solutions as phuL~uuLiator. Tetracycline (free base, crystalline, F.~V.
.44) was incorporated in the macromer solution by equilibration for 12 hours at 37 degrees C. Then, 200 microliters of the solution was cro~slink~l by W light (10 W/cm2, full cure). In vitro release of 5 tetracycline from the 200 microliter cured gel, after a brief rinse, was carried out in 5 mls PBS, pH 7.4, 37~C. The PBS was ex~h~ èdl daily to ensure "sink" conditions. The release profile is seen Figure 16. After an initial burst, tetracycline was released steadily for nearly a week.
Taxol was incorporated into gels by similar procedures, except that 10 TweenTM ~", r~ was used to solubilize the Taxol conrçntrate. ~, similar release pattern to that seen with tetracycline was observed.
F~Y5~ 1e 14: Urethane-c~ ..;..g ll~.lUl~
PEO of molecular weight 1450 was reacted with approxim~ly 1 mole of lactide per end, using procedures described above, to give 1.4KL2. The 1.4KL2 was weighed into a 100 ml flask (8.65 g) and 270 ml of dried toluene was added. About 50 ml of toluene was ~ tillP,1 off to remove residual water as the azeotrope, and the solution was cooled.
Then 0.858 g (825 microliter) of commercial 1,6 hexane-diisocy~aLt; was added, and also 1 drop of dibuLyll;~ lrate (ca. 0.02g). The solution was at 60 degrees at addition, and warmed to 70 degrees over about 10 ...;..~l~s. Heat was applied to m~int~in the solution at about 75 degrees for about 3.5 hours. NMR and IR spectra confirm~r1 colkiun~ion of the diisocyanate, and the r~-slllting solution was therefore exl~ecl~cl to contain l;.,g PEO and hexane blocks, linked by u~Lll~le linkages, and 25 ~. ~ llrC~ by hydroxyls. This material can be capped with l~,ac~ive end groups, optionally after further extension with hydroxy acids, to form a reactive macromer. The urethane links and hexane blocks are present to promote tissue adherence.
W O 97/05185 PCT~US96/12285 Modifications and vOli~Lions of the present invention will be obvious to those skilled in the art from the fo~oi~ ~let~ilPcl description.
Such mo~lifi~tions and variations are intended to come within the scope of the following claims.
Claims (34)
1. A macromer comprising at least four covalently linked polymeric blocks and at least two crosslinkable groups, wherein a) at least one block is hydrophilic, wherein each hydrophilic block individually has a water solubility of at least 1 gram/liter; and b) at least two blocks are hydrophobic, wherein the macromer is capable of being gelled when the crosslinkable groups are crosslinked, and wherein one of the blocks is a thermoresponsive block, the crosslinkable groups are independently selected from the group consisting of epoxides, isocyanates, isothiocyanates, aldehydes, amines, sulfonic acids, carboxylic acids and ethylenically unsaturated groups, and the crosslinkable groups are separated by at least one degradable linkage that is capable of degrading under physiological conditions.
2. The macromer of claim 1 wherein the hydrophilic blocks are the same or different and are selected from the group consisting of poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(vinylpyrrolidone), poly(ethyloxazoline), polysaccharides and amino acid polymers.
3. The macromer of claim 1 wherein the hydrophobic blocks are the same or different and are selected from the group consisting of polypropylene oxide, polybutylene oxide, hydrophobic mixed poly(alkylene oxides), polyhydroxy acids, polylactones, polyamino acids, polyanhydrides, polyorthoesters, polyphosphazenes, and polyphosphates.
4. The macromer of claim 1 wherein the crosslinkable group is selected from the group consisting of epoxides, isocyanates, isothiocyanates, aldehydes, amines, sulfonic acids and carboxylic acids.
5. The macromer of claim 1 wherein the crosslinkable groups comprise ethylenically unsaturated groups.
6. The macromer of claim 1, further comprising at least one ionically charged moiety covalently attached to the macromer.
7. The macromer of claim 1 comprising at least two chemically distinct hydrophobic blocks.
8. The macromer of claim 1 wherein at least one hydrophobic block is separated from any crosslinkable group by at least one hydrophilic block.
9. The macromer of claim 1 wherein each hydrophobic block is separated from any other hydrophobic block by a hydrophilic block.
10. The macromer of claim 1 wherein the macromer is capable of thermoreversible gelation in an aqueous solution of the macromer at a concentration of at least 2% by weight, and wherein the gelation temperature is between about 0°C and about 65°C.
11. A composition comprising a macromer as described in claim 1 and a therapeutic agent.
12. A composition comprising a macromer as described in claim 1 and a hydrophobic material non-covalenty associated with the macromer.
13. The composition of claim 12, wherein the hydrophobic material is selected from the group consisting of hydrocarbons, lipids, fatty acids, and sterols.
14. A composition including a macromer as described in claim 1 and a pharmaceutically acceptable carrier.
15. The composition of claim 14 wherein the carrier is suitable for parenteral administration.
16. The composition of claim 14, wherein the macromer is gelled.
17. The composition of claim 14, wherein the crosslinkable groups on the macromer are covalently crosslinked.
18. The composition of claim 17 further comprising a therapeutic agent.
19. The composition of claim 18, wherein the therapeutic agent is provided in a form selected from the group consisting of particles, pro-drug conjugates, and liposomes.
20. The composition of claim 17 wherein the gel is in a form suitable for application to a surface of a biological tissue.
21. The composition of claim 17, macromer comprising a medical device, wherein the gel is formed on a surface of the medical device.
22. The composition of claim 17 wherein the gel is formed between opposed surfaces, and adheres the surfaces together.
23. Use of a macromer as described in claim 1 in a method for treating a medical condition comprising applying an aqueous solution of the macromer to tissue in vivo.
24. The use of claim 23 wherein the aqueous solution further comprises a dissolved or suspended therapeutic agent.
25. The use of claim 23 wherein the medical condition is a burn or abrasion of the skin.
26. The use of claim 23 wherein the medical condition is an injury resulting from a surgical intervention.
27. The use of claim 26 wherein the surgery is angioplasty.
28. The use of claim 26 wherein the surgery is conducted through the cannula of a trocar.
29. A method for controlling the rate of delivery of a biologically active material, comprising:
a) mixing an active material with a solution of a macromer comprising at least four covalently linked polymeric blocks and at least two crosslinkable groups, wherein i) at least one block is hydrophilic, wherein each hydrophilic block individually has a water solubility of at least 1 gram/liter; and ii) at least two blocks are hydrophobic, wherein the macromer is capable of being gelled when the crosslinkable groups are crosslinked, and wherein one of the blocks is a thermoresponsive block, the crosslinkable groups are independently selected from the group consisting of epoxides, isocyanates, isothiocyanates, aldehydes, amines, sulfonic acids, carboxylic acids and ethylenically unsaturated groups, and the crosslinkable groups are separated by at least one degradable linkage that is capable of degrading under physiological conditions.
b) crosslinking the macromer to form a gel; and c) changing the permeability of the gel to effect controlled delivery of the material.
a) mixing an active material with a solution of a macromer comprising at least four covalently linked polymeric blocks and at least two crosslinkable groups, wherein i) at least one block is hydrophilic, wherein each hydrophilic block individually has a water solubility of at least 1 gram/liter; and ii) at least two blocks are hydrophobic, wherein the macromer is capable of being gelled when the crosslinkable groups are crosslinked, and wherein one of the blocks is a thermoresponsive block, the crosslinkable groups are independently selected from the group consisting of epoxides, isocyanates, isothiocyanates, aldehydes, amines, sulfonic acids, carboxylic acids and ethylenically unsaturated groups, and the crosslinkable groups are separated by at least one degradable linkage that is capable of degrading under physiological conditions.
b) crosslinking the macromer to form a gel; and c) changing the permeability of the gel to effect controlled delivery of the material.
30. The method of claim 29 wherein the crosslinked gel changes in permeability in response to changes in ionic concentration or changes in pH.
31. The method of claim 29 wherein at least one hydrophobic block aggregates in aqueous solution to form a hydrophobic domain.
32. The method of claim 31 wherein the hydrophobicity of the domain is controlled by selecting the hydrophobicity of the block.
33. The method of claim 31 wherein the hydrophobicity of the domain is controlled by adding hydrophobic materials to the gel-forming macromer solution.
34. The method of claim 29 wherein the active material is in the form selected from the group consisting of particles, pro-drug conjugates and liposomes.
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1996
- 1996-07-26 EP EP96926138A patent/EP0842209B1/en not_active Expired - Lifetime
- 1996-07-26 AT AT96926138T patent/ATE342295T1/en not_active IP Right Cessation
- 1996-07-26 US US08/692,914 patent/US6201065B1/en not_active Expired - Lifetime
- 1996-07-26 WO PCT/US1996/012285 patent/WO1997005185A2/en active IP Right Grant
- 1996-07-26 JP JP9507762A patent/JPH11510837A/en not_active Withdrawn
- 1996-07-26 CA CA002228118A patent/CA2228118A1/en not_active Abandoned
- 1996-07-26 DE DE69636626T patent/DE69636626T2/en not_active Expired - Lifetime
-
2000
- 2000-11-09 US US09/710,416 patent/US6410645B1/en not_active Expired - Lifetime
-
2002
- 2002-04-02 US US10/114,722 patent/US6639014B2/en not_active Expired - Lifetime
-
2003
- 2003-08-27 US US10/650,163 patent/US6923986B2/en not_active Expired - Fee Related
-
2005
- 2005-06-22 US US11/158,565 patent/US7250177B2/en not_active Expired - Fee Related
- 2005-10-05 JP JP2005293028A patent/JP2006097031A/en not_active Withdrawn
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US20020151650A1 (en) | 2002-10-17 |
DE69636626D1 (en) | 2006-11-23 |
US7250177B2 (en) | 2007-07-31 |
JPH11510837A (en) | 1999-09-21 |
WO1997005185A3 (en) | 1997-03-13 |
US6923986B2 (en) | 2005-08-02 |
US20050238722A1 (en) | 2005-10-27 |
ATE342295T1 (en) | 2006-11-15 |
US6201065B1 (en) | 2001-03-13 |
WO1997005185A2 (en) | 1997-02-13 |
US6639014B2 (en) | 2003-10-28 |
US20040072961A1 (en) | 2004-04-15 |
EP0842209B1 (en) | 2006-10-11 |
US6410645B1 (en) | 2002-06-25 |
MX9801706A (en) | 1998-05-31 |
EP0842209A2 (en) | 1998-05-20 |
JP2006097031A (en) | 2006-04-13 |
DE69636626T2 (en) | 2007-08-30 |
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