CA2126214A1 - Vegetable oil-based skin permeation enhancer compositions, and associated methods and systems - Google Patents
Vegetable oil-based skin permeation enhancer compositions, and associated methods and systemsInfo
- Publication number
- CA2126214A1 CA2126214A1 CA002126214A CA2126214A CA2126214A1 CA 2126214 A1 CA2126214 A1 CA 2126214A1 CA 002126214 A CA002126214 A CA 002126214A CA 2126214 A CA2126214 A CA 2126214A CA 2126214 A1 CA2126214 A1 CA 2126214A1
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- Prior art keywords
- oil
- drug
- mixture
- weight
- amount
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- 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
Abstract
Methods and compositions are provided which increase the permeability of skin to transdermally administered pharmacologically active agents. The compositions are formulated with one or more vegetable oils as skin permeation enhancers; a preferred composition contains both coconut oil and soybean oil. Drug delivery systems for administering drugs transdermally in combination with the vegetable oil-based enhancer compositions are provided as well.
Description
~'~93/127~ PCT/US92/10673 -1- 21~fi~
ENHANC R COMPOSITIONS ~D ASSOCIATED METHODS AND
SYSTEMS
,Descri~tion Technical ~ield ~- This invention relates generally to methods and compositions for enhancing the permeability vf the skin to pharmacologically active agents, and more particularly to novel skin permeation enhancer compositions containing vegetable oil mixtures.
Backaround The delivery of drugs through the skin provides many advantages; primarily, such a means cf delivery is a comfortable, convenient and noninvasive way of administering drugs. The variable rates of absorption and metabolism encountered in oral treatment are avoided, and other inherent 2S inconveniences -- e.g., gastrointestinal irritation and the like -- are eliminated as well. l`ransdermal drug delivery also makes possible a high degree of control over blood concentrations of any particular drug.
Skin is a structurally complex, relatively thick membrane. Molecules moving from the environment into and through intact skin must first penetrate the stratum corneum and any material on its surface. They must then penetrate the viable epidermis, the papillary dermis, and the capillary walls into the blood stream or lymph channels. To be so absorbed, ``
molecules must overcome a different resistance to SUBSTITUTE SHEET
WO93/12744 212 6 21~ -2- PCT/US92/1067 penetration in each type of tissue. Transport across the skin membrane is thus a complex phenomenon.
However, it is the cells of the stratum corneum which present the primary barrier to absorption of topical compositions or transdermally administered drugs. The stratum corneum is a thin layer of dense, highly keratinized cells approximately 10-15 microns thick over most of the body. It is believed to be the high degree of keratinization within these cells as well as their dense packing which creates in most cases a substantially impermeable barrier to drug penetration.
-In order to increase skin permeability, andin particular to increase the permeability of the stratum corneum (i.e., so as to achieve enhanced penetration, through the skin, of the drug to be administered transdermally), the skin may be pretreated with a penetration enhancing agent (or "permeation enhancer", as sometimes referred to herein) prior to application of a drug.
Alternatively, and preferably, a drug and a permeation enhancer are concurrently delivered.
The present invention is directed to a novel method and composition for enhancing the penetration of a drug through skin. The invention is premised on the discovery that certain vegetable oils used individually or in combination are effective in r enhancing the penetration of pharmacologically active agents through the skin.
While there are a number of patents and ~ ;
publications which relate to the usP of a variety of ~ `
different skin permeation enhancars, applicants are unaware of any art which relates to the use of vegetable oils as disclosed herein as skin permeation enhancers.
The following references relate generally to the use of permeation enhancers in transdermal `':
SUBSTITUTE SHEEr :~ : ``
~'~93/l27~ 2 1~ ~ 2 1l PCT/US9~/10$73 formulations. U.S. Patent Nos. 4,006,218, 3,551,554 and 3,472,931, for example, respectively describe the use of dimethylsulfoxide (DMSO), dimethyl formamide (DMF) and N,N-dimethylacetamide (DMA) to enhance the absorption of pharmacologically active agents through the stratum corneum. Other compounds which have been used to enhance skin permeability include:
decylmethylsulfoxide (C~SO); Transcutol, cited in the preceding section; polyethylene glycol monolaurate (PEGML); (see, e.g., U.S. Pat~nt No. 4,56~,343);
glycerol monolaurate (U.S. Patent No. 4,746,515);
~propylene glycol monolaurate (see European Patent Application No. 87402945.7, Published as EP
Publication No. 272 987, which derives from U.S.
Patent Application Serial No. 945,356, filed 22 December 1986, of common assignment herewith); ethanol (e.g., as in U.S. Patent No. 4,379,454); eucalyptol (~.S. Patent No. ~,440,777); lecithin (U.S. Patent No.
4,783,450); the 1-substituted azacycloheptan-2-ones, particularly 1-n-dodecylcyclazacycloheptan-2-one (available under the trademark Azone~ from Nelson Research & Development Co., Irvine, CA; see U.S.
Patent Nos. 3,989,816, 4,316,893, 4,405,616 and 4,557,934); propylene glycol in combination with a fatty acid such as linoleic acid (European Pate~t Publication No. 261429]; "cell envelope disordering compounds" such as methyl laurate or oleic acid in combin3tion with N-(hydroxyethyl) pyrrolidone ~U.S.
Patent No. 4,537,776) or C3 - C4 diols (U.S. Patent No.
4,55~,872, European Patent Application Publication No.
043738). U.S. Patent No. 4,764,379 discloses a binary enhancer composition of ethanol and glycerol monolaurate.
SUBSTITUTE ~;HEET
.. . .... .. .. . . ...... . ..... . . .
Wo93/127~ ~ 12~21 1 4 PCT/US92/10~73 Disclosure of the Invention Accordingly, it is an object of the present invention to provide a method for enhancing the flux of the drug through the skin comprising transdermally administering the drug in combination with a permeation-enhancing amount of a vegetable oil as will be described herein.
It is another object of the present invention to provide such a method in which the vegetable oil composition is a mixture of vegetable oils.
~ It is still another object of the invention to provide a composition of matter for delivering a drug through the skin which comprises: (a) a therapeutically effective amount of at least one drug;
and (b) a permeation-enhancing amount of a vegetable oil composition as will be described in detail herein.
It is a further object of the invention to provide transdermal delivery systems for using the aforementioned compositions and carrying out the administration method.
Additional objects, advantaqas and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.
In one aspect of the invention, a method is provided for enhancing the flux of the drug through the skin, comprising transdermally administering the drug in combination with a permeation-enhancing amount of a vegetable oil composition containing at least one vegetable oil selected from the group consisting of almond oil, babassu oil, castor oil, Clark A oil, coconut oil, corn oil, cotton seed oil, jojoba oil, linseed oil, mustard oil, olive oil, palm oil, peanut oil, safflower oil, sesame oil, soybean oil, SUBSTITUTE SHEET
~93/127~ 2 1 2 S ~ 1 4 PCT/US92/10673 sunflower-seed oil and wheat germ oil. Preferred vegetable oils are those which do not contain large amounts of saturated fatty acids or large amounts of fatty acids containing less than about eight or more than about fourteen carbon atoms. Accordingly, preferred vegetable oils within the aforementioned group include coconut oil, corn oil, cotton seed oil, linseed oil, mustard oil, olive oil, palm oil, peanut oil, safflower oil and soybean oil. With most drugs, mixtures of vegetable oils appear to be preferred rather than individual vegetable oils, and a particularly preferred vegetabie oil composition for , use herein is a mixture of coconut oil and soybean oil.
A In another aspect of the invention, a composition of matter is provided that is useful for - the delivery of a drug through the skin, which comprises a therapeutically effective amount of the drug to be administered and a permeation-enhancing `~
amount of a vegetable oil composition which contains at least one vegetable oil selected from the aforementioned group.
In still another aspect of the invention, a transdermal system is provided which is useful for the administration of a drug through the skin, wherein the system includes a source of the drug to be administered, a source of a permeation enhancer composition effective to increase the flux of the drug through the skin, wherein the permeation enhancer composition contains at least one vegetable oil, and wherein the system further in ludes a means for maintaining the system in drug and enhancer composition transmitting relationship to the skin, e.g., a contact adhesive layer which serves as the basal surface of the system and adheres to the skin during use.
SUBSTITUTE SHEEr WO~3/127~ PCT/US9211067 2 ~f~2~ 6-.~ .
Modes for Carrvina Out the Invention Before describing the present invention in detail, it is to be understood that this invention is not limited to particular drugs or transdermal systems described herein as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.
It must be noted that, as used in this specification and the appended claims, the singular ~forms "a", "an" and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "a vegetable oil^' includes a mixture of two or more vegetable oils, reference to "a drug" includes reference to one or more drugs, and the like.
In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set out below.
"Penetration enhancement" or "permeation enhancement" as used herein relates to an increase in the permeability of skin to a pharmacologically active agent, i.e., so as to increase the rate at which the Z5 drug permeates through the skin and enters the bloodstream. The enhanced permeation effected t~.rough the use of such enhancers, and, in particular, through the use of the enhancer composition of the present invention, can be observed by measuring the rate of diffusion of drug through animal or human skin using a diffusion cell apparatus as described in the Examples herein.
By "transdermal" delivery, applicants intend to include both transdermal ~or "percutaneous") and transmucosal administration, i.e., delivery by passage of a drug through the skin or mucosal tissue and into the bloodstream.
SUBSTITUTE SHEET
~ ^93/127~ 2 ~62 ~4 PCT/US92/10673 "Carriers" or "vehicles" as used herein refer to carrier materials suitable for transdermal drug administration, and include any such materials known in the art-, e.g., any liquid, gel, solvent, -5 liquid diluent, solubilizer, or the like, which is nontoxic and which does not interact with other components of the composition in a deleterious manner.
Examples of suitable carriers for use herein include water, silicone, liquid sugars, waxes, petroleum lO jelly, and a variety of other materials.
By the term "pharmacologically active agent~
or "drug" as used herein is meant any chemical material or compound sùitable for transdermal or trans mucosal administration which induces a desired ~ `
15 systemic effect. Such substances include the broad classes of compounds normally delivered through body surfaces and membranes, including skin. In general, this includes: anti- infectives such as antibiotics ~ ' and antiviral agents; analgesics and analgesic 20 combinations; anorexics; antihelminthics; `~
antiarthritics; antiasthmatic agents; anticonvulsants; -~
antidepressants; antidiabetic agents; antidiarrheals;
antihistamines; antiinflammatory agents; antimigraine r preparations; antinauseants; antineoplastics;
25 antiparkinsonism drugs; antipruritics; antipsychotics;
antipyretics; antispasmodics; anticholinergics;
sympathomimetics; xanthine derivatives; cardiovascular preparation includinq calcium channel blockers and beta-blockers such as pindolol and antiarrhythmic;
30 antihypertensives; diuretics; vasodilators including general coronary, peripheral and cerebral; central nervous system stimulants; cough and cold preparations, including decongestants; hormones such as estradiol and other steroids, including 35 corticosteroids; hypnotics; immunosuppressives; muscle -`
relaxants; parasympatholytics; psychostimulants;
sedatives; and tranquilizers.
8UBSTITUTE SHEEl' WO93/127~ PCT/US92/10~3 ~12~14 -8-Preferred drugs for use in conjunction with the enhancer composition of the present invention include narcotic analgesics such as buprenorphine or salts thereof (e.g., buprenorphine hydrochloride), antianxiety drugs such as alprazolam, hyponetic/sedative drugs such as triazolam, calcium channel blockers or anti-anginal drugs such as nifedipine, and antineoplastics such as tamoxifen.
By "therapeutically effective" amount of a pharmacologically active agent is meant a nontoxic but suf~icient amount of a compound to provide the de~ired therapeutic effect. An "effective" amount of a permeation enhancer as used herein means an amount that will provide the desired increase in skin lS permeability and, correspondingly, the desired depth of penetration, rate of administration, and amount of -drug delivered. ;~
In a preferred embodiment, as noted above, -~
the enhancer composition of the invention is a ~--vegetable oil composition which contains at least one vegetable oil as described above. In a particularly ~ -~
preferred embodiment, the vegetable oil composition is a mixture of coconut oil and soybean oil; such compositions will include on the order of lO wt.%
percent to 90 wt.% coconut oil, and, correspondingly, 9o wt.% to lO wt.% soybean oil. An exemplary coconut oil/soybean oil mixture is that manufactured and sold under the trademark Drewmulse~ D-4661, available from Stepan, Marywood, NJ. T~e combination of coconut and soybean oil has been found by the inventors herein to be far superior to most other permeation enhancers which are currently commercially available and is, furthermore, superior to the use of particular vegetable oils used individually, at least with some drugs.
The composition may in addition include one or more selected carriers or excipients, and various SUBSTIT~JTE SHEElr' `'~93/12744 2 ~ 2 6 2 1 ~ PCT~US92/tO673 agents and ingredients commonly employed in dermatological ointments and lotions. For examples, fragrances, opacifiers, preservatives, anti-oxidants, gelling agents, perfumes, thickening agents, stabilizers, surfactants, emollients, coloring agents, and the like may be present. The composition may also include additional permeation enhancers, e.g., dimethylsulfoxide (DMSO), dimethyl formamide (DMF), N,N-dimethylacetamide (DMA), decylmethylsulfoxide ~ -(CI~So), polyethylene glycol monolaurate (PEGML), glycerol monolaurate, lecithin, the l-substituted azacycloheptan-2-ones, particularly 1-n-dodecylcyclazacycloheptan-2-one (available under the trademark Azone~ from Nelson Research & Development Co., Irvine, CA), alcohols, and the like.
Partlcularly preferred additional enhancers for use in - ;
conjunction with the present invention are those described in commonly assigned U.S. Patent No. `~
S,059,426 to Chiang et al., i.e., containing an ether component selected from the group consisting of ~iethylene glycol monoethylether, diethylene glycol monomethylether, and mixtures thereof, and an ester component given by the formula [CH3(CH2)mCOO]~ in which m is an integer in the range of 8 to 16, n is 1 or 2, and R is a lower alkyl (Cl-C3) residue that is either unsubstituted or substitutPd with one or two hydroxyl groups. The disclosure of the aforementloned patent is hereby incorporated by reference in its entirety.
The relative amounts of the components in these compositions can vary a great deal. For example, the amount vf drug or drugs present in the composition will depend on a variety of factors, including the disease to be treated, the nature and activity of the drug, the desired effect, possible adverse reactions, the ability and speed of tha drug to reach its intended target, and other factors within the particular knowledge of the patient and physician.
W093/12744 2 1 2 ~ 2 ~ o- PCT/US92/~067~
The amount of enhancer present in the composition will similarly depend on a number of factors, e.g., on the depth of cutaneous penetration desired, the strength of the particular enhancer, the specific drug or drugs selected, and the like. Preferred compositions will typically contain on the order of about l wt.% to lO
wt.% drug, and about 5 wt.S to 25 wt.% enhancer, with the remainder of the composition being either a liquid ~ ~
or polymeric carrier (including optional additives as ~ ;
lO outlined above). The enhancer portion of the `
composition may contain only vegetable oil or it may contain vegetable oil in combination with additional ~ -skin permeation enhancers as described above. It is --preferred, however, that the compositions of the present invention contain on the order of from about 5 : -:
wt.% to lO wt.% vegetable oil.
The method of delivery of the present compositions may also vary, but necessarily involves application of the selected composition to a defined ` ~-~
surface of the skin or other tissue for a period of -time sufficient to provide the desired blood level of drug for the desired period of time. The method may involve direct application of the composition as an ointment, gel, cream, or the like, or may involve use of a drug delivery device as taught, for example, in U.S. Patent Nos. 3,742,951, 3,797,494 and 4,568,343.
The method may also involve pre-treatment of the skin with a vegetable oil enhanrer to increase the `
permeability of the skin to the applied drug.
A transdermal delivery system can be constructed with the enhancer composition described hereinabove to deliver drugs for sustained drug delivery. The targeted skin flux for delivery of a particular drug can be achieved by adjusting vehicle composition and vehicle loading, as well as by adjusting the surface area through which the compositions are administered to skin.
SUBSTITUTE SHEEr ~'~93/127~ 2 1 2 6 2 1~ PCT/US92/10673 Preferred transdermal drug delivery systems for use herein contain one or more drug/permeation enhancer reservoirs, a backing layer, and optionally one or more additional layers as those skilled in the art of transdermal drug delivery will readily appreciate.
The drug/permeation enhancer reservoir(s) will typically be in the form of a matrix comprising rubber or other polymeric material, e.g., natural and synthetic rubbers such as polybutylene, polyisobutylene, polybutadiene, polyethylene, styrene-butadiene copolymers, polyisoprene, polyurethane, copolyesters, ethylene/acrylic copolymers, polyether amides, silicones and their copolymers, and butadiene/acrylonitrile copolymers, ethylene vinyl acetate, gelled or thickened mineral oil, petroleum jelly and various aqueous gels and hydrophilic polymers that may serve as thickening agents. The matrix is applied to skin using a suitable adhesive as described, for example, in U.S. Patent No. 4,s68,343, supra. In some cases, the matrix may itself be comprised of an adhesive material.
The drug reservoir layer is formulated so as to contain the selected pharmacologically active 2S agent(s) as well as the above enhancer composition.
In a preferred embodiment, the layer will contain about 1 wt.% to lO wt.% drug, 5 wt.% to 25 wt.% total enhancer and 65 wt.% to 94 wt.% polymeric adhesive and optionally tackifiers, surfactants or other additives.
The pressure-sensitive adhesive which serves as the reservoir for this mixture is typically a polyisobutylene, silicone or acrylate adhesive. The layer may be formulated so that the selected drug is contained therein below saturation, at saturation, or in excess.
The backing membrane, which may be either occlusive or nonocclusive, is preferably comprised of SUBSTITUTE ~ EEl-W093/127~ 2 1 2 6 2 1 ~ -12- PCT/US92/1~67~
a flexible, stretchable, polymer film, e.g., of polyether urethane, polyester urethane, polyamide, or other related copolymers. The material and thickness selected for the backing membrane is preferably such that a transdermal system can be provided having good wearability for at least a seven-day application.
The vegetable oil skin permeation enhancer ;
compositions of the present invention give rise to a number of advantages which are unsuggested by the prior art of which applicants are aware. First, the particularly preferred mixture of soybean oil and coconut oil provides for a very high skin flux relative to other types of enhancers (as may be deduced in the examples below). In addition, it has been found that vegetable oils in general produce virtually no skin irritation or sensitization problems. Indeed, the inclusion of vegetable oils in transdermal formulations appears to reduce the skin irritation and sensitization which is problematic with some drugs. Finally, the vegetable oil compositions that are the focus of the present invention have been found to be completely compatible with a wide variety of drugs in transdermal formulations.
_ _ It is to be understood that while the invention has been descrihed in conjunction with the preferred specific embodiments thereof, that the fore~oing description as well as the examples which follow are intended to illustrate and not limit the scope of the invention. Other aspects, advantages and modifications within the scope of the invention will be apparent to those skilled in the art to which the invention pertains.
' ~93/127~ 2 1 2 6 2 1 1 PCT/US92/10673 ExPerimental In vitro Franz flow-through cells were used to compare the penetration of various drug-enhancer formulations through skin. A piece of human cadaver skin was mounted between the two half-cells and fastened with a clamp.
Drug-enhancer solutions (prepared with different drugs and enhancers as will be described individually for each example herein) were applied to the donor compartment to start the experiment. The receiver compartment was filled with distilled, deionized water and the temperature was maintained at 32C. Samples were taken at preset time intervals and assayed by HPLC. The flux was calculated from the slope of the cumulative amounts of drug in the receiver compartment versus time.
ExamPle 1 The above procedure was used to evaluate the penetration of buprenorphine hydrochloride through skin using a variety of vehicles. In Table l, results obtained with mixtures of coconut oil, soybean oil, almond oil, and olive oil with mineral oil are set forth. All oils were obtained from Stepan, Marywood, NJ, except for babassu oil (Croda, NY) and Clark A oil (obtained from the J S & A Group, Northbrook, IL). In Table 2, penetration of buprenorphine hydrochloride through skin is evaluated in coconut oil, soybean oil, almond oil, olive oil, and mixed vegetable oil ~Drewmul~e~ D-4661; see above) versus buprenorphine in mineral oil as a control. Tables 3 and 4 represent still further flux studies with buprenorphine hydrochloride. In those tables, "PG" represents propylene glycol. As may be deduced from the tables, the mixed vegetable oil seemed to be the most effective in enhancing total buprenorphine skin flux.
w093/127~ 2 1 2 6 2 1 ~ -14- PCT/US92/1067~
The abbreviations used in the tables are as follows: "Bu HCl" represents buprenorphine ~- .
hydrochloride, "Q" represents total cumulative amount of drug permeated, "TEWL" represents transepidermal 5 water loss, "F" and ~M~ represent female and male, ~
"PG" represents propylene glycol, "PEG" represents ~.
polyethylene glycol, and "mixed vegetable oil" ~:
represents the Drewmulse D-4661 mixture of coconut oil and soybean oil. ~;
`- :
`'` . .
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SUBSTITUTE SHEET : ` `
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ENHANC R COMPOSITIONS ~D ASSOCIATED METHODS AND
SYSTEMS
,Descri~tion Technical ~ield ~- This invention relates generally to methods and compositions for enhancing the permeability vf the skin to pharmacologically active agents, and more particularly to novel skin permeation enhancer compositions containing vegetable oil mixtures.
Backaround The delivery of drugs through the skin provides many advantages; primarily, such a means cf delivery is a comfortable, convenient and noninvasive way of administering drugs. The variable rates of absorption and metabolism encountered in oral treatment are avoided, and other inherent 2S inconveniences -- e.g., gastrointestinal irritation and the like -- are eliminated as well. l`ransdermal drug delivery also makes possible a high degree of control over blood concentrations of any particular drug.
Skin is a structurally complex, relatively thick membrane. Molecules moving from the environment into and through intact skin must first penetrate the stratum corneum and any material on its surface. They must then penetrate the viable epidermis, the papillary dermis, and the capillary walls into the blood stream or lymph channels. To be so absorbed, ``
molecules must overcome a different resistance to SUBSTITUTE SHEET
WO93/12744 212 6 21~ -2- PCT/US92/1067 penetration in each type of tissue. Transport across the skin membrane is thus a complex phenomenon.
However, it is the cells of the stratum corneum which present the primary barrier to absorption of topical compositions or transdermally administered drugs. The stratum corneum is a thin layer of dense, highly keratinized cells approximately 10-15 microns thick over most of the body. It is believed to be the high degree of keratinization within these cells as well as their dense packing which creates in most cases a substantially impermeable barrier to drug penetration.
-In order to increase skin permeability, andin particular to increase the permeability of the stratum corneum (i.e., so as to achieve enhanced penetration, through the skin, of the drug to be administered transdermally), the skin may be pretreated with a penetration enhancing agent (or "permeation enhancer", as sometimes referred to herein) prior to application of a drug.
Alternatively, and preferably, a drug and a permeation enhancer are concurrently delivered.
The present invention is directed to a novel method and composition for enhancing the penetration of a drug through skin. The invention is premised on the discovery that certain vegetable oils used individually or in combination are effective in r enhancing the penetration of pharmacologically active agents through the skin.
While there are a number of patents and ~ ;
publications which relate to the usP of a variety of ~ `
different skin permeation enhancars, applicants are unaware of any art which relates to the use of vegetable oils as disclosed herein as skin permeation enhancers.
The following references relate generally to the use of permeation enhancers in transdermal `':
SUBSTITUTE SHEEr :~ : ``
~'~93/l27~ 2 1~ ~ 2 1l PCT/US9~/10$73 formulations. U.S. Patent Nos. 4,006,218, 3,551,554 and 3,472,931, for example, respectively describe the use of dimethylsulfoxide (DMSO), dimethyl formamide (DMF) and N,N-dimethylacetamide (DMA) to enhance the absorption of pharmacologically active agents through the stratum corneum. Other compounds which have been used to enhance skin permeability include:
decylmethylsulfoxide (C~SO); Transcutol, cited in the preceding section; polyethylene glycol monolaurate (PEGML); (see, e.g., U.S. Pat~nt No. 4,56~,343);
glycerol monolaurate (U.S. Patent No. 4,746,515);
~propylene glycol monolaurate (see European Patent Application No. 87402945.7, Published as EP
Publication No. 272 987, which derives from U.S.
Patent Application Serial No. 945,356, filed 22 December 1986, of common assignment herewith); ethanol (e.g., as in U.S. Patent No. 4,379,454); eucalyptol (~.S. Patent No. ~,440,777); lecithin (U.S. Patent No.
4,783,450); the 1-substituted azacycloheptan-2-ones, particularly 1-n-dodecylcyclazacycloheptan-2-one (available under the trademark Azone~ from Nelson Research & Development Co., Irvine, CA; see U.S.
Patent Nos. 3,989,816, 4,316,893, 4,405,616 and 4,557,934); propylene glycol in combination with a fatty acid such as linoleic acid (European Pate~t Publication No. 261429]; "cell envelope disordering compounds" such as methyl laurate or oleic acid in combin3tion with N-(hydroxyethyl) pyrrolidone ~U.S.
Patent No. 4,537,776) or C3 - C4 diols (U.S. Patent No.
4,55~,872, European Patent Application Publication No.
043738). U.S. Patent No. 4,764,379 discloses a binary enhancer composition of ethanol and glycerol monolaurate.
SUBSTITUTE ~;HEET
.. . .... .. .. . . ...... . ..... . . .
Wo93/127~ ~ 12~21 1 4 PCT/US92/10~73 Disclosure of the Invention Accordingly, it is an object of the present invention to provide a method for enhancing the flux of the drug through the skin comprising transdermally administering the drug in combination with a permeation-enhancing amount of a vegetable oil as will be described herein.
It is another object of the present invention to provide such a method in which the vegetable oil composition is a mixture of vegetable oils.
~ It is still another object of the invention to provide a composition of matter for delivering a drug through the skin which comprises: (a) a therapeutically effective amount of at least one drug;
and (b) a permeation-enhancing amount of a vegetable oil composition as will be described in detail herein.
It is a further object of the invention to provide transdermal delivery systems for using the aforementioned compositions and carrying out the administration method.
Additional objects, advantaqas and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.
In one aspect of the invention, a method is provided for enhancing the flux of the drug through the skin, comprising transdermally administering the drug in combination with a permeation-enhancing amount of a vegetable oil composition containing at least one vegetable oil selected from the group consisting of almond oil, babassu oil, castor oil, Clark A oil, coconut oil, corn oil, cotton seed oil, jojoba oil, linseed oil, mustard oil, olive oil, palm oil, peanut oil, safflower oil, sesame oil, soybean oil, SUBSTITUTE SHEET
~93/127~ 2 1 2 S ~ 1 4 PCT/US92/10673 sunflower-seed oil and wheat germ oil. Preferred vegetable oils are those which do not contain large amounts of saturated fatty acids or large amounts of fatty acids containing less than about eight or more than about fourteen carbon atoms. Accordingly, preferred vegetable oils within the aforementioned group include coconut oil, corn oil, cotton seed oil, linseed oil, mustard oil, olive oil, palm oil, peanut oil, safflower oil and soybean oil. With most drugs, mixtures of vegetable oils appear to be preferred rather than individual vegetable oils, and a particularly preferred vegetabie oil composition for , use herein is a mixture of coconut oil and soybean oil.
A In another aspect of the invention, a composition of matter is provided that is useful for - the delivery of a drug through the skin, which comprises a therapeutically effective amount of the drug to be administered and a permeation-enhancing `~
amount of a vegetable oil composition which contains at least one vegetable oil selected from the aforementioned group.
In still another aspect of the invention, a transdermal system is provided which is useful for the administration of a drug through the skin, wherein the system includes a source of the drug to be administered, a source of a permeation enhancer composition effective to increase the flux of the drug through the skin, wherein the permeation enhancer composition contains at least one vegetable oil, and wherein the system further in ludes a means for maintaining the system in drug and enhancer composition transmitting relationship to the skin, e.g., a contact adhesive layer which serves as the basal surface of the system and adheres to the skin during use.
SUBSTITUTE SHEEr WO~3/127~ PCT/US9211067 2 ~f~2~ 6-.~ .
Modes for Carrvina Out the Invention Before describing the present invention in detail, it is to be understood that this invention is not limited to particular drugs or transdermal systems described herein as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.
It must be noted that, as used in this specification and the appended claims, the singular ~forms "a", "an" and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "a vegetable oil^' includes a mixture of two or more vegetable oils, reference to "a drug" includes reference to one or more drugs, and the like.
In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set out below.
"Penetration enhancement" or "permeation enhancement" as used herein relates to an increase in the permeability of skin to a pharmacologically active agent, i.e., so as to increase the rate at which the Z5 drug permeates through the skin and enters the bloodstream. The enhanced permeation effected t~.rough the use of such enhancers, and, in particular, through the use of the enhancer composition of the present invention, can be observed by measuring the rate of diffusion of drug through animal or human skin using a diffusion cell apparatus as described in the Examples herein.
By "transdermal" delivery, applicants intend to include both transdermal ~or "percutaneous") and transmucosal administration, i.e., delivery by passage of a drug through the skin or mucosal tissue and into the bloodstream.
SUBSTITUTE SHEET
~ ^93/127~ 2 ~62 ~4 PCT/US92/10673 "Carriers" or "vehicles" as used herein refer to carrier materials suitable for transdermal drug administration, and include any such materials known in the art-, e.g., any liquid, gel, solvent, -5 liquid diluent, solubilizer, or the like, which is nontoxic and which does not interact with other components of the composition in a deleterious manner.
Examples of suitable carriers for use herein include water, silicone, liquid sugars, waxes, petroleum lO jelly, and a variety of other materials.
By the term "pharmacologically active agent~
or "drug" as used herein is meant any chemical material or compound sùitable for transdermal or trans mucosal administration which induces a desired ~ `
15 systemic effect. Such substances include the broad classes of compounds normally delivered through body surfaces and membranes, including skin. In general, this includes: anti- infectives such as antibiotics ~ ' and antiviral agents; analgesics and analgesic 20 combinations; anorexics; antihelminthics; `~
antiarthritics; antiasthmatic agents; anticonvulsants; -~
antidepressants; antidiabetic agents; antidiarrheals;
antihistamines; antiinflammatory agents; antimigraine r preparations; antinauseants; antineoplastics;
25 antiparkinsonism drugs; antipruritics; antipsychotics;
antipyretics; antispasmodics; anticholinergics;
sympathomimetics; xanthine derivatives; cardiovascular preparation includinq calcium channel blockers and beta-blockers such as pindolol and antiarrhythmic;
30 antihypertensives; diuretics; vasodilators including general coronary, peripheral and cerebral; central nervous system stimulants; cough and cold preparations, including decongestants; hormones such as estradiol and other steroids, including 35 corticosteroids; hypnotics; immunosuppressives; muscle -`
relaxants; parasympatholytics; psychostimulants;
sedatives; and tranquilizers.
8UBSTITUTE SHEEl' WO93/127~ PCT/US92/10~3 ~12~14 -8-Preferred drugs for use in conjunction with the enhancer composition of the present invention include narcotic analgesics such as buprenorphine or salts thereof (e.g., buprenorphine hydrochloride), antianxiety drugs such as alprazolam, hyponetic/sedative drugs such as triazolam, calcium channel blockers or anti-anginal drugs such as nifedipine, and antineoplastics such as tamoxifen.
By "therapeutically effective" amount of a pharmacologically active agent is meant a nontoxic but suf~icient amount of a compound to provide the de~ired therapeutic effect. An "effective" amount of a permeation enhancer as used herein means an amount that will provide the desired increase in skin lS permeability and, correspondingly, the desired depth of penetration, rate of administration, and amount of -drug delivered. ;~
In a preferred embodiment, as noted above, -~
the enhancer composition of the invention is a ~--vegetable oil composition which contains at least one vegetable oil as described above. In a particularly ~ -~
preferred embodiment, the vegetable oil composition is a mixture of coconut oil and soybean oil; such compositions will include on the order of lO wt.%
percent to 90 wt.% coconut oil, and, correspondingly, 9o wt.% to lO wt.% soybean oil. An exemplary coconut oil/soybean oil mixture is that manufactured and sold under the trademark Drewmulse~ D-4661, available from Stepan, Marywood, NJ. T~e combination of coconut and soybean oil has been found by the inventors herein to be far superior to most other permeation enhancers which are currently commercially available and is, furthermore, superior to the use of particular vegetable oils used individually, at least with some drugs.
The composition may in addition include one or more selected carriers or excipients, and various SUBSTIT~JTE SHEElr' `'~93/12744 2 ~ 2 6 2 1 ~ PCT~US92/tO673 agents and ingredients commonly employed in dermatological ointments and lotions. For examples, fragrances, opacifiers, preservatives, anti-oxidants, gelling agents, perfumes, thickening agents, stabilizers, surfactants, emollients, coloring agents, and the like may be present. The composition may also include additional permeation enhancers, e.g., dimethylsulfoxide (DMSO), dimethyl formamide (DMF), N,N-dimethylacetamide (DMA), decylmethylsulfoxide ~ -(CI~So), polyethylene glycol monolaurate (PEGML), glycerol monolaurate, lecithin, the l-substituted azacycloheptan-2-ones, particularly 1-n-dodecylcyclazacycloheptan-2-one (available under the trademark Azone~ from Nelson Research & Development Co., Irvine, CA), alcohols, and the like.
Partlcularly preferred additional enhancers for use in - ;
conjunction with the present invention are those described in commonly assigned U.S. Patent No. `~
S,059,426 to Chiang et al., i.e., containing an ether component selected from the group consisting of ~iethylene glycol monoethylether, diethylene glycol monomethylether, and mixtures thereof, and an ester component given by the formula [CH3(CH2)mCOO]~ in which m is an integer in the range of 8 to 16, n is 1 or 2, and R is a lower alkyl (Cl-C3) residue that is either unsubstituted or substitutPd with one or two hydroxyl groups. The disclosure of the aforementloned patent is hereby incorporated by reference in its entirety.
The relative amounts of the components in these compositions can vary a great deal. For example, the amount vf drug or drugs present in the composition will depend on a variety of factors, including the disease to be treated, the nature and activity of the drug, the desired effect, possible adverse reactions, the ability and speed of tha drug to reach its intended target, and other factors within the particular knowledge of the patient and physician.
W093/12744 2 1 2 ~ 2 ~ o- PCT/US92/~067~
The amount of enhancer present in the composition will similarly depend on a number of factors, e.g., on the depth of cutaneous penetration desired, the strength of the particular enhancer, the specific drug or drugs selected, and the like. Preferred compositions will typically contain on the order of about l wt.% to lO
wt.% drug, and about 5 wt.S to 25 wt.% enhancer, with the remainder of the composition being either a liquid ~ ~
or polymeric carrier (including optional additives as ~ ;
lO outlined above). The enhancer portion of the `
composition may contain only vegetable oil or it may contain vegetable oil in combination with additional ~ -skin permeation enhancers as described above. It is --preferred, however, that the compositions of the present invention contain on the order of from about 5 : -:
wt.% to lO wt.% vegetable oil.
The method of delivery of the present compositions may also vary, but necessarily involves application of the selected composition to a defined ` ~-~
surface of the skin or other tissue for a period of -time sufficient to provide the desired blood level of drug for the desired period of time. The method may involve direct application of the composition as an ointment, gel, cream, or the like, or may involve use of a drug delivery device as taught, for example, in U.S. Patent Nos. 3,742,951, 3,797,494 and 4,568,343.
The method may also involve pre-treatment of the skin with a vegetable oil enhanrer to increase the `
permeability of the skin to the applied drug.
A transdermal delivery system can be constructed with the enhancer composition described hereinabove to deliver drugs for sustained drug delivery. The targeted skin flux for delivery of a particular drug can be achieved by adjusting vehicle composition and vehicle loading, as well as by adjusting the surface area through which the compositions are administered to skin.
SUBSTITUTE SHEEr ~'~93/127~ 2 1 2 6 2 1~ PCT/US92/10673 Preferred transdermal drug delivery systems for use herein contain one or more drug/permeation enhancer reservoirs, a backing layer, and optionally one or more additional layers as those skilled in the art of transdermal drug delivery will readily appreciate.
The drug/permeation enhancer reservoir(s) will typically be in the form of a matrix comprising rubber or other polymeric material, e.g., natural and synthetic rubbers such as polybutylene, polyisobutylene, polybutadiene, polyethylene, styrene-butadiene copolymers, polyisoprene, polyurethane, copolyesters, ethylene/acrylic copolymers, polyether amides, silicones and their copolymers, and butadiene/acrylonitrile copolymers, ethylene vinyl acetate, gelled or thickened mineral oil, petroleum jelly and various aqueous gels and hydrophilic polymers that may serve as thickening agents. The matrix is applied to skin using a suitable adhesive as described, for example, in U.S. Patent No. 4,s68,343, supra. In some cases, the matrix may itself be comprised of an adhesive material.
The drug reservoir layer is formulated so as to contain the selected pharmacologically active 2S agent(s) as well as the above enhancer composition.
In a preferred embodiment, the layer will contain about 1 wt.% to lO wt.% drug, 5 wt.% to 25 wt.% total enhancer and 65 wt.% to 94 wt.% polymeric adhesive and optionally tackifiers, surfactants or other additives.
The pressure-sensitive adhesive which serves as the reservoir for this mixture is typically a polyisobutylene, silicone or acrylate adhesive. The layer may be formulated so that the selected drug is contained therein below saturation, at saturation, or in excess.
The backing membrane, which may be either occlusive or nonocclusive, is preferably comprised of SUBSTITUTE ~ EEl-W093/127~ 2 1 2 6 2 1 ~ -12- PCT/US92/1~67~
a flexible, stretchable, polymer film, e.g., of polyether urethane, polyester urethane, polyamide, or other related copolymers. The material and thickness selected for the backing membrane is preferably such that a transdermal system can be provided having good wearability for at least a seven-day application.
The vegetable oil skin permeation enhancer ;
compositions of the present invention give rise to a number of advantages which are unsuggested by the prior art of which applicants are aware. First, the particularly preferred mixture of soybean oil and coconut oil provides for a very high skin flux relative to other types of enhancers (as may be deduced in the examples below). In addition, it has been found that vegetable oils in general produce virtually no skin irritation or sensitization problems. Indeed, the inclusion of vegetable oils in transdermal formulations appears to reduce the skin irritation and sensitization which is problematic with some drugs. Finally, the vegetable oil compositions that are the focus of the present invention have been found to be completely compatible with a wide variety of drugs in transdermal formulations.
_ _ It is to be understood that while the invention has been descrihed in conjunction with the preferred specific embodiments thereof, that the fore~oing description as well as the examples which follow are intended to illustrate and not limit the scope of the invention. Other aspects, advantages and modifications within the scope of the invention will be apparent to those skilled in the art to which the invention pertains.
' ~93/127~ 2 1 2 6 2 1 1 PCT/US92/10673 ExPerimental In vitro Franz flow-through cells were used to compare the penetration of various drug-enhancer formulations through skin. A piece of human cadaver skin was mounted between the two half-cells and fastened with a clamp.
Drug-enhancer solutions (prepared with different drugs and enhancers as will be described individually for each example herein) were applied to the donor compartment to start the experiment. The receiver compartment was filled with distilled, deionized water and the temperature was maintained at 32C. Samples were taken at preset time intervals and assayed by HPLC. The flux was calculated from the slope of the cumulative amounts of drug in the receiver compartment versus time.
ExamPle 1 The above procedure was used to evaluate the penetration of buprenorphine hydrochloride through skin using a variety of vehicles. In Table l, results obtained with mixtures of coconut oil, soybean oil, almond oil, and olive oil with mineral oil are set forth. All oils were obtained from Stepan, Marywood, NJ, except for babassu oil (Croda, NY) and Clark A oil (obtained from the J S & A Group, Northbrook, IL). In Table 2, penetration of buprenorphine hydrochloride through skin is evaluated in coconut oil, soybean oil, almond oil, olive oil, and mixed vegetable oil ~Drewmul~e~ D-4661; see above) versus buprenorphine in mineral oil as a control. Tables 3 and 4 represent still further flux studies with buprenorphine hydrochloride. In those tables, "PG" represents propylene glycol. As may be deduced from the tables, the mixed vegetable oil seemed to be the most effective in enhancing total buprenorphine skin flux.
w093/127~ 2 1 2 6 2 1 ~ -14- PCT/US92/1067~
The abbreviations used in the tables are as follows: "Bu HCl" represents buprenorphine ~- .
hydrochloride, "Q" represents total cumulative amount of drug permeated, "TEWL" represents transepidermal 5 water loss, "F" and ~M~ represent female and male, ~
"PG" represents propylene glycol, "PEG" represents ~.
polyethylene glycol, and "mixed vegetable oil" ~:
represents the Drewmulse D-4661 mixture of coconut oil and soybean oil. ~;
`- :
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~ 93/12744 2 1 2 6 ~ ~ ~ PCT/US92/10673 Exam~e 2 The same procedure was used to evaluate the penetration of alprazolam through skin, again using a variety of skin permeation enhancer formulations.
Results are summarized in Tables 5 and 6 (abbreviations used are as in Example 1).
.
: - .
SUBSTITUTE ~;HEEl' W093/127~ PCT/US92/10673 -20~
2 ~ ~ `
Table 5 Al~razolam Skin Flux Cumulative amount of Alprazolam after ~B hr # Formulation Flux ~g/cm2~hr) (~g/cm~) __ _ 1) Alprazolam 0.12 4.61 ~aturated in PG O.lg 7.42 0.16 6.34 Av.- 0.15 ~ 0.03 Av.- 6.12 + 1.4 2) Alprazolam O.65 13.72 -(~aturated) I 10~ 0.54 5.91 Oli~e Oil in PG 0.64 - 16.39 Av.. 0.61 ~ 0.05 Av.- 12.01 + 5.45 3) Alprazolam 0,33 28.81 (~aeuxated) + 0.35~ 22.39 10% Coconut Oil 0.15 25.46 ~n PG A~... 0.2~ + 0.11 Av.- 25.5~ ~ 3.20 4) Alprazolam 0.18 6.99 (~aturated) + lO~ 0.18 7.93 Almond 0~1 in PG 0.36 ~4.27 `
Av.- 0.24 + 0.10 A~.- 9.73 , 3.96 5) Alprazolam (~at- 15.11 602.4 urated) ~ 10% Mixed 49.99 1652.9 Veg~table Oil-PG 17.64 718.1 Av.~27.55 + l9.~9Av.- 991.1 + 576 SUBSTITUTE 9HEEl-~'-' 93/12744 2 1 2 ~ 2 1 4 PCIIUS92/10673 +~ oO
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SUBSTITUTE ~EEr WO~3~127~ PCT/US92/1067~ .
2~2621~ -22-Again, the use of the mixed vegetabl~ oil was found to provide significant enhancement relative to other enhancer formulations.
Example 3 The above method was then used to compare the penetration of triazolam through the skin using a number of different skin permea~ion enhancer formulations. Tables 7 and 8 summarize the results (abbreviations used are as in Example 1).
..
SUBSTITUTE StlEET
~'~93/12744 21262 1~ PCI/US92/10673 Table 7 Triazolam Skin Flux Cumulative Amount of Triazolam After # Formulatio~ Flux (~g/om2/hr) 4~ hr (~g/cm2) .
1) Triazolam O.062 4.01 ~aturated in PG 0.041 1.65 0.042 1.64 lo Av., 0.0051 + 0.01 Av.- 2.43 2) Triazolam O.064 2.55 (Baturated) ~10~ 0.052 3.11 Olive Oil in PG 0.044 2.~1 Av... 0.053 + 0.01 Av.- 2.72 + 0.33 3) Triazolam 0.213 9.41 7 15 (saturated) O.Og9 3.89 + 10% Coconut 0.174 6.92 Oil in PG Av.- 0.161 + 0.06 Av.- 6.76 + 2.73 4) Triazolam 0.065 9.01 (~aturated) +lOS 0.088 11.62 :.;
Almond Oil in PG 0.514 21.48 A~.- 0.222 Av.- 14.04 .
5) Triazolam 6.359 252.19 (saturated) ~10~ 4.879 195.54 ~ixed Vegetable 3.462 137.41 .
Oil-PG Av.- 4.91 + 1.45 Av.- 195.04 + 57.39 SUBSTITUTE SHEEr WO93/127~ PCT/US9~/10673 ~126~1~
Table 8 Triazolam_Skin Flux Cumulati~e amount of Tria~olam Af~er # Formulation Flux (~g/cm2/hr) 48 Hr (~g/cm2/hr) 1) Triazolam 0.127 6.263 saturaeed in PG 0.077 3.215 0.069 2.765 Av.~ 0.091 ~ 0.031 A~.- 4.081 + 1.90 2) ~riazolam 16.11 658.B
(saturated) ~10% ~.744 377.4 PGWL in PG 1.074 44.99 Av.- 8.642 , 7.52 A~.~360.4 1 307.3 3) Tr$azolam 1~23~ Sl.95 (saturated) ~10~ 1.76 74.14 :
Glyceryl 0.51 20.44 .-Monooleate in PG Av.- 1.166 ~ 0.63 A~.- 48.~4 + 26.9 4) Tr~azolam 1.77 75.46 .-(~aturated) ~10~ 6.12 265.1 Mixed Vegetable 12.24 524.7 Oil in PG A~.~ 6.71 ~ 5.25 ~v.. 28~.42~225.5 SUBSTITUTE 5HEEr 3/127~ -25- PCT/US92/10673 Again, as with the preceding examples, the use of mixed vegetable oils as a s~in permeation enhancer composition provided a very significant increase in skin flux relative to the other enhancer 5 formulations tested.
Exam~le 4 The above method was used to compare the penetration of ni~edipine through the skin using a variety of permeation enhancer formulations. Results are summarized in Table 9. In the table, "NFD"
represents nifedipine... 8abassu oil is a mixture of ~
lauric/myristic/palmitic/stearic/oleic/linoleic fatty .`
acids. Clark A oil consists of oxygenated peanut oil, peach kernel oil, grape seed oil, botanical complex i.
XX1, essential oils (45% borneol, rosemary, terenbenthine, eucalyptus, arnica, juniper (trace ..
element complex), 100% pure plant extract).
~UBSTITUTE SHEET
PCT/US92/10673.
W093 2 ~ 26-Table g Nifedi~_ne Averaae Cumulative Release and Skin Flux Values for Various Oils Used in_Feasibility Study Q +sd Flux +sd Formulation (~g/cm) (mcgtcm2/hr) 1. NFD saturated in 0.77 + 0.07 33.32 + 2.74 10 mixed vegetable oil 2. NFD saturated 0.13 + 0.01 6.03 + 0.33 in olive oil 3. NFD saturated 0.11 ~ 0.01 5.08 + 0.41 in almond oil :~
4. NFD saturated 0.18 + 0.05 8.01 + 2.20 15 in coconut oil 5. NFD saturated 0.17 + 0.05 8.24 + 2.05 in soybean oil 6. NFD saturated 0.13 + 0.05 - 6.07 + 2.08 in jojoba oil -7. NFD saturated 0.14 + 0.02 6.25 + 0.96 20 in babassu oil 8. NFD saturated 0.14 ~ 0.01 6.17 + 0.48 in cottonseed oil 9. NFD saturated 0.53 + 0.12 23.59 + 5.62 in Clark A oil 10. NFD saturated 0.01 + 0.00 5.04 + 0.78 25 in mineral oil SUBSTITUTE 5HEEl-`-'~93/12744 -27~ ~ ~ 2 1 ~ PCT/US92/10673 As may be seen in the table, the mixed vegetable oil formulation provided significant enhancement relative to the other compositions.
. 5 Exam~le 5 ~-The above method was then used to compare :
the penetration of tamoxifen through the skin using a :~
number of different permeation enhancer formulations.
Results are set forth in Table 10.
: ' wos3/l27~ PCT/US92/1067 Table lo Tamoxlfen Skin Flux Stud~
# Name of Formulation Av Flux (~g/cm2/hr) 1) ~amoxifen (saturated) in 0.187 + 0.036 mineral oil 2) Tamoxifen (~aturated) + 10~ 0.060 ~ O.OOB
10mixed vegeeable oil in mineral oil :
3) Tamox$fen ~saturated) + 10~ 0.181 + 0.055 oli~e oil in mlneral oil 4) Tamoxifen (saturated) + ~0% 0.133 + 0.050 almo~d oil in mineral oil 5) Tamoxifen (~aturated) ~ 10~ 0.337 + 0.054 15soybean oil in mineral oil 6) Tamoxifen ~saturated) ~ 10% 0.153 , 0.047 coconut o~l in mineral oil 7) Tamoxlfen (saturated) + lOt 0.242 + O.02 cotton ~eed oil in m$naral oil 8) Tamoxifen (~aturated) I 10~ 0.766 ~ O.08 20~o~oba oil i~ mi~eral oil 9) T~moxifen (saturated) + 10~ 0.484 + 0.40 baba~su oil in mlneral oi~
Note: All formulation~ contain tamoxi~en ~aturated in PG solution.
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SUBSTlTUTE SHEEl~
~ 93/12744 2 1 2 6 ~ ~ ~ PCT/US92/10673 Exam~e 2 The same procedure was used to evaluate the penetration of alprazolam through skin, again using a variety of skin permeation enhancer formulations.
Results are summarized in Tables 5 and 6 (abbreviations used are as in Example 1).
.
: - .
SUBSTITUTE ~;HEEl' W093/127~ PCT/US92/10673 -20~
2 ~ ~ `
Table 5 Al~razolam Skin Flux Cumulative amount of Alprazolam after ~B hr # Formulation Flux ~g/cm2~hr) (~g/cm~) __ _ 1) Alprazolam 0.12 4.61 ~aturated in PG O.lg 7.42 0.16 6.34 Av.- 0.15 ~ 0.03 Av.- 6.12 + 1.4 2) Alprazolam O.65 13.72 -(~aturated) I 10~ 0.54 5.91 Oli~e Oil in PG 0.64 - 16.39 Av.. 0.61 ~ 0.05 Av.- 12.01 + 5.45 3) Alprazolam 0,33 28.81 (~aeuxated) + 0.35~ 22.39 10% Coconut Oil 0.15 25.46 ~n PG A~... 0.2~ + 0.11 Av.- 25.5~ ~ 3.20 4) Alprazolam 0.18 6.99 (~aturated) + lO~ 0.18 7.93 Almond 0~1 in PG 0.36 ~4.27 `
Av.- 0.24 + 0.10 A~.- 9.73 , 3.96 5) Alprazolam (~at- 15.11 602.4 urated) ~ 10% Mixed 49.99 1652.9 Veg~table Oil-PG 17.64 718.1 Av.~27.55 + l9.~9Av.- 991.1 + 576 SUBSTITUTE 9HEEl-~'-' 93/12744 2 1 2 ~ 2 1 4 PCIIUS92/10673 +~ oO
S ~ O N
. ~ O -~ +l O ~ - +1 ~D
~D ~ ~ a~
rl N ~ _ _ ~ ::
2 5 ~ ~
o ~
3 0 U ,_1 N N 5~ N C) ¦ e ~ "C o~ ~ ~"
--~ ~ + ~ + ~
SUBSTITUTE ~EEr WO~3~127~ PCT/US92/1067~ .
2~2621~ -22-Again, the use of the mixed vegetabl~ oil was found to provide significant enhancement relative to other enhancer formulations.
Example 3 The above method was then used to compare the penetration of triazolam through the skin using a number of different skin permea~ion enhancer formulations. Tables 7 and 8 summarize the results (abbreviations used are as in Example 1).
..
SUBSTITUTE StlEET
~'~93/12744 21262 1~ PCI/US92/10673 Table 7 Triazolam Skin Flux Cumulative Amount of Triazolam After # Formulatio~ Flux (~g/om2/hr) 4~ hr (~g/cm2) .
1) Triazolam O.062 4.01 ~aturated in PG 0.041 1.65 0.042 1.64 lo Av., 0.0051 + 0.01 Av.- 2.43 2) Triazolam O.064 2.55 (Baturated) ~10~ 0.052 3.11 Olive Oil in PG 0.044 2.~1 Av... 0.053 + 0.01 Av.- 2.72 + 0.33 3) Triazolam 0.213 9.41 7 15 (saturated) O.Og9 3.89 + 10% Coconut 0.174 6.92 Oil in PG Av.- 0.161 + 0.06 Av.- 6.76 + 2.73 4) Triazolam 0.065 9.01 (~aturated) +lOS 0.088 11.62 :.;
Almond Oil in PG 0.514 21.48 A~.- 0.222 Av.- 14.04 .
5) Triazolam 6.359 252.19 (saturated) ~10~ 4.879 195.54 ~ixed Vegetable 3.462 137.41 .
Oil-PG Av.- 4.91 + 1.45 Av.- 195.04 + 57.39 SUBSTITUTE SHEEr WO93/127~ PCT/US9~/10673 ~126~1~
Table 8 Triazolam_Skin Flux Cumulati~e amount of Tria~olam Af~er # Formulation Flux (~g/cm2/hr) 48 Hr (~g/cm2/hr) 1) Triazolam 0.127 6.263 saturaeed in PG 0.077 3.215 0.069 2.765 Av.~ 0.091 ~ 0.031 A~.- 4.081 + 1.90 2) ~riazolam 16.11 658.B
(saturated) ~10% ~.744 377.4 PGWL in PG 1.074 44.99 Av.- 8.642 , 7.52 A~.~360.4 1 307.3 3) Tr$azolam 1~23~ Sl.95 (saturated) ~10~ 1.76 74.14 :
Glyceryl 0.51 20.44 .-Monooleate in PG Av.- 1.166 ~ 0.63 A~.- 48.~4 + 26.9 4) Tr~azolam 1.77 75.46 .-(~aturated) ~10~ 6.12 265.1 Mixed Vegetable 12.24 524.7 Oil in PG A~.~ 6.71 ~ 5.25 ~v.. 28~.42~225.5 SUBSTITUTE 5HEEr 3/127~ -25- PCT/US92/10673 Again, as with the preceding examples, the use of mixed vegetable oils as a s~in permeation enhancer composition provided a very significant increase in skin flux relative to the other enhancer 5 formulations tested.
Exam~le 4 The above method was used to compare the penetration of ni~edipine through the skin using a variety of permeation enhancer formulations. Results are summarized in Table 9. In the table, "NFD"
represents nifedipine... 8abassu oil is a mixture of ~
lauric/myristic/palmitic/stearic/oleic/linoleic fatty .`
acids. Clark A oil consists of oxygenated peanut oil, peach kernel oil, grape seed oil, botanical complex i.
XX1, essential oils (45% borneol, rosemary, terenbenthine, eucalyptus, arnica, juniper (trace ..
element complex), 100% pure plant extract).
~UBSTITUTE SHEET
PCT/US92/10673.
W093 2 ~ 26-Table g Nifedi~_ne Averaae Cumulative Release and Skin Flux Values for Various Oils Used in_Feasibility Study Q +sd Flux +sd Formulation (~g/cm) (mcgtcm2/hr) 1. NFD saturated in 0.77 + 0.07 33.32 + 2.74 10 mixed vegetable oil 2. NFD saturated 0.13 + 0.01 6.03 + 0.33 in olive oil 3. NFD saturated 0.11 ~ 0.01 5.08 + 0.41 in almond oil :~
4. NFD saturated 0.18 + 0.05 8.01 + 2.20 15 in coconut oil 5. NFD saturated 0.17 + 0.05 8.24 + 2.05 in soybean oil 6. NFD saturated 0.13 + 0.05 - 6.07 + 2.08 in jojoba oil -7. NFD saturated 0.14 + 0.02 6.25 + 0.96 20 in babassu oil 8. NFD saturated 0.14 ~ 0.01 6.17 + 0.48 in cottonseed oil 9. NFD saturated 0.53 + 0.12 23.59 + 5.62 in Clark A oil 10. NFD saturated 0.01 + 0.00 5.04 + 0.78 25 in mineral oil SUBSTITUTE 5HEEl-`-'~93/12744 -27~ ~ ~ 2 1 ~ PCT/US92/10673 As may be seen in the table, the mixed vegetable oil formulation provided significant enhancement relative to the other compositions.
. 5 Exam~le 5 ~-The above method was then used to compare :
the penetration of tamoxifen through the skin using a :~
number of different permeation enhancer formulations.
Results are set forth in Table 10.
: ' wos3/l27~ PCT/US92/1067 Table lo Tamoxlfen Skin Flux Stud~
# Name of Formulation Av Flux (~g/cm2/hr) 1) ~amoxifen (saturated) in 0.187 + 0.036 mineral oil 2) Tamoxifen (~aturated) + 10~ 0.060 ~ O.OOB
10mixed vegeeable oil in mineral oil :
3) Tamox$fen ~saturated) + 10~ 0.181 + 0.055 oli~e oil in mlneral oil 4) Tamoxifen (saturated) + ~0% 0.133 + 0.050 almo~d oil in mineral oil 5) Tamoxifen (~aturated) ~ 10~ 0.337 + 0.054 15soybean oil in mineral oil 6) Tamoxifen ~saturated) ~ 10% 0.153 , 0.047 coconut o~l in mineral oil 7) Tamoxlfen (saturated) + lOt 0.242 + O.02 cotton ~eed oil in m$naral oil 8) Tamoxifen (~aturated) I 10~ 0.766 ~ O.08 20~o~oba oil i~ mi~eral oil 9) T~moxifen (saturated) + 10~ 0.484 + 0.40 baba~su oil in mlneral oi~
Note: All formulation~ contain tamoxi~en ~aturated in PG solution.
SU~3STITUTE 5HEET
Claims (14)
1. A method for enhancing the flux of a drug through the skin, comprising:
applying to the skin of a human patient a composition comprising a pharmaceutically active drug in combination with a permeation enhancing amount of a mixture of vegetable oils selected from the group consisting of almond oil, babassu oil, caster oil, Clark A oil, coconut oil, corn oil, cotton seed oil, jojoba oil, linseed oil, mustard oil, olive oil, palm oil, peanut oil, safflower oil, sesame oil, soybean oil, sunflower-seed oil and wheat germ oil, wherein the drug is present in the composition in an amount in the range of from about 1% to about 10% by weight and the-mixture of vegetable oils is present in the composition in an amount in the range of from about 5%
to about 25% by weight.
applying to the skin of a human patient a composition comprising a pharmaceutically active drug in combination with a permeation enhancing amount of a mixture of vegetable oils selected from the group consisting of almond oil, babassu oil, caster oil, Clark A oil, coconut oil, corn oil, cotton seed oil, jojoba oil, linseed oil, mustard oil, olive oil, palm oil, peanut oil, safflower oil, sesame oil, soybean oil, sunflower-seed oil and wheat germ oil, wherein the drug is present in the composition in an amount in the range of from about 1% to about 10% by weight and the-mixture of vegetable oils is present in the composition in an amount in the range of from about 5%
to about 25% by weight.
2. The method of claim 1, wherein the mixture of vegetable oils is comprised of a mixture of coconut oil and soybean oil.
3. The method of any of claims 1 or 2, wherein the mixture of vegetable oils is present in an amount in the range of from about 5% to about 10% by weight.
4. The method of any of claims 1 or 2 t wherein the mixture of vegetable oils comprises 10% to 90% by weight coconut oil and 90% to 10% by weight of soybean oil.
5. The method of any of claims 1, 2, 3, or 4, wherein the drug is administered in combination with an additional permeation enhancer selected from the group consisting of dimethylsulfoxide, dimethylformamide, N,N-dimethylacetamide, declymethylsulfoxide, polyethylene glycol monolaurate, glycerol monolaurate, lecithin, 1-n-dodecylcyclazacycloheptan-2-one, an alcohol, diethylene glycol monoethylether, and diethylene glycol monomethylether.
6. A composition comprising:
(a) a therapeutically effective amount of a pharmaceutically active drug; and (b) a permeation enhancing amount of a mixture of vegetable oil, selected from the group consisting of almond oil, babassu oil, castor oil, Clark A oil, coconut oil, corn oil, cotton seed oil, jojoba oil, linseed oil, mustard oil, olive oil, palm oil, peanut oil, safflower oil, sesame oil, soybean oil, sunflower-seed oil and wheat germ oil, wherein the drug is present in the composition in any amount in the range of from about 1% to about 10% by weight and the mixture of vegetable oils is present in an amount of about 5% to about 25% by weight.
(a) a therapeutically effective amount of a pharmaceutically active drug; and (b) a permeation enhancing amount of a mixture of vegetable oil, selected from the group consisting of almond oil, babassu oil, castor oil, Clark A oil, coconut oil, corn oil, cotton seed oil, jojoba oil, linseed oil, mustard oil, olive oil, palm oil, peanut oil, safflower oil, sesame oil, soybean oil, sunflower-seed oil and wheat germ oil, wherein the drug is present in the composition in any amount in the range of from about 1% to about 10% by weight and the mixture of vegetable oils is present in an amount of about 5% to about 25% by weight.
7. The composition of claim 6, wherein the mixture of vegetable oils is present in an amount in the range of from about 5% to about 10% by weight, and wherein the mixture of vegetable oils comprises 10% to 90% by weight coconut oil and 90% to 10% by weight of soybean oil.
8. The composition of any of claims 6 or 7, further including an additional permeation enhancer selected from the group consisting of dimethylsulfoxide, dimethylformamide, N,N-dimethylacetamide, declymethylsulfoxide, polyethylene glycol monolaurate, glycerol monolaurate, lecithin, 1-n-dodecylcyclazacycloheptan-2-one, an alcohol, diethylene glycol monoethylether, and diethylene glycol monomethylether.
9. A system for the transdermal administration of a drug, comprising:
(a) a matrix reservoir comprised of a polymeric material having dispersed therein a pharmaceutically active drug in a therapeutically effective amount and a permeation enhancing amount of a mixture of vegetable oils selected from the group consisting of almond oil, babassu oil, castor oil, Clark A oil, coconut oil, corn oil, cotton seed oil, jojoba oil, linseed oil, mustard oil, olive oil, palm oil, peanut oil, safflower oil, sesame oil, soybean oil, sunflower-seed oil and wheat germ oil, wherein the drug is present in the matrix in an amount in the range of about 1% to about 10% by weight and the mixture of vegetable oils is present in the composition in an amount in the range of from about 5%
to about 25% by weight;
(b) a backing layer positioned on a surface of the matrix; and (c) a pressure sensitive adhesive layer positioned on a surface of the matrix opposite the surface having the backing layer thereon.
(a) a matrix reservoir comprised of a polymeric material having dispersed therein a pharmaceutically active drug in a therapeutically effective amount and a permeation enhancing amount of a mixture of vegetable oils selected from the group consisting of almond oil, babassu oil, castor oil, Clark A oil, coconut oil, corn oil, cotton seed oil, jojoba oil, linseed oil, mustard oil, olive oil, palm oil, peanut oil, safflower oil, sesame oil, soybean oil, sunflower-seed oil and wheat germ oil, wherein the drug is present in the matrix in an amount in the range of about 1% to about 10% by weight and the mixture of vegetable oils is present in the composition in an amount in the range of from about 5%
to about 25% by weight;
(b) a backing layer positioned on a surface of the matrix; and (c) a pressure sensitive adhesive layer positioned on a surface of the matrix opposite the surface having the backing layer thereon.
10. The system of claim 9, wherein the mixture of vegetables oils is present in an amount in the range of from about 5% to about 10% by weight, and wherein the mixture of vegetable oils comprises 10% to 90% by weight coconut oil and 90% to 10% by weight of soybean oil.
11. The system of any of claims 9 or 10, further comprising:
an additional permeation enhancer selected from the group consisting of dimethylsulfoxide, dimethylformamide, N,N-dimethylacetamide, declymethylsulfoxide, polyethylene glycol monolaurate, glycerol monolaurate, lecithin, 1-n-dodecylcyclazacycloheptan-2-one, an alcohol, diethylene glycol monoethylether, and diethylene glycol monomethylether.
an additional permeation enhancer selected from the group consisting of dimethylsulfoxide, dimethylformamide, N,N-dimethylacetamide, declymethylsulfoxide, polyethylene glycol monolaurate, glycerol monolaurate, lecithin, 1-n-dodecylcyclazacycloheptan-2-one, an alcohol, diethylene glycol monoethylether, and diethylene glycol monomethylether.
12. The method of claim 1, wherein the drug is a drug selected from the group consisting of a narcotic analgesic, buprenorphine and salts thereof, including buprenorphine hydrochloride, a calcium channel blocker, an anti-anginal drug, including nifedipine, a sedative, including triazolam, an anti-anxiety drug including alprazolam and an anti-neoplastic agent, including tamoxifen.
13. The composition of claim 6, wherein the drug is a drug selected from the group consisting of a narcotic analgesic, buprenorphine and salts thereof, including buprenorphine hydrochloride, a calcium channel blocker, an anti-anginal drug, including nifedipine, a sedative, including triazolam, an anti-anxiety drug including alprazolam and an anti-neoplastic agent, including tamoxifen.
14. The system of claim 9, wherein the drug is a drug selected from the group consisting of a narcotic analgesic, buprenorphine and salts thereof, including buprenorphine hydrochloride, a calcium channel blocker, an anti-anginal drug, including nifedipine, a sedative, including triazolam, an anti-anxiety drug including alprazolam and an anti-neoplastic agent, including tamoxifen.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US07/810,963 | 1991-12-20 | ||
US07/810,963 US5229130A (en) | 1991-12-20 | 1991-12-20 | Vegetable oil-based skin permeation enhancer compositions, and associated methods and systems |
Publications (1)
Publication Number | Publication Date |
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CA2126214A1 true CA2126214A1 (en) | 1993-07-08 |
Family
ID=25205155
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002126214A Abandoned CA2126214A1 (en) | 1991-12-20 | 1992-12-10 | Vegetable oil-based skin permeation enhancer compositions, and associated methods and systems |
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Country | Link |
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US (1) | US5229130A (en) |
EP (1) | EP0617600A4 (en) |
JP (1) | JP3026602B2 (en) |
AU (1) | AU3247293A (en) |
CA (1) | CA2126214A1 (en) |
TW (1) | TW262385B (en) |
WO (1) | WO1993012744A1 (en) |
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GB2537647A (en) * | 2015-04-22 | 2016-10-26 | Cosmetic Warriors Ltd | Composition |
JP7325792B2 (en) * | 2017-06-30 | 2023-08-15 | 三省製薬株式会社 | Skin Permeation Enhancers and Skin Topics |
RU2697411C2 (en) * | 2017-10-11 | 2019-08-14 | федеральное государственное автономное образовательное учреждение высшего образования Первый Московский государственный медицинский университет имени И.М. Сеченова Министерства здравоохранения Российской Федерации (Сеченовский университет) | Composition for treating parkinson's disease |
CN112040948A (en) * | 2018-03-29 | 2020-12-04 | 顺天医药生技股份有限公司 | Compositions and methods for treating pruritus |
US20200368360A1 (en) * | 2019-05-23 | 2020-11-26 | Professional Compounding Centers Of America, Inc. | Skin permeation enhancing composition |
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US3551554A (en) * | 1968-08-16 | 1970-12-29 | Crown Zellerbach Corp | Enhancing tissue penetration of physiologically active agents with dmso |
US3472931A (en) * | 1969-01-17 | 1969-10-14 | Foster Milburn Co | Percutaneous absorption with lower alkyl amides |
DE2446162A1 (en) * | 1974-09-27 | 1976-04-15 | Schlafhorst & Co W | METHOD AND DEVICE FOR FEEDING EMPTY CONICAL SPOOL CASES TO THE INDIVIDUAL SPINDLE UNITS OF A TEXTILE MACHINE |
US3989816A (en) * | 1975-06-19 | 1976-11-02 | Nelson Research & Development Company | Vehicle composition containing 1-substituted azacycloheptan-2-ones |
US4405616A (en) * | 1975-06-19 | 1983-09-20 | Nelson Research & Development Company | Penetration enhancers for transdermal drug delivery of systemic agents |
US4316893A (en) * | 1975-06-19 | 1982-02-23 | Nelson Research & Development Co. | Vehicle composition containing 1-substituted azacycloalkan-2-ones |
CA1165240A (en) * | 1980-07-09 | 1984-04-10 | The Procter & Gamble Company | Penetrating topical pharmaceutical compositions |
US4379454A (en) * | 1981-02-17 | 1983-04-12 | Alza Corporation | Dosage for coadministering drug and percutaneous absorption enhancer |
US4440777A (en) * | 1981-07-07 | 1984-04-03 | Merck & Co., Inc. | Use of eucalyptol for enhancing skin permeation of bio-affecting agents |
US4552872A (en) * | 1983-06-21 | 1985-11-12 | The Procter & Gamble Company | Penetrating topical pharmaceutical compositions containing corticosteroids |
US4557934A (en) * | 1983-06-21 | 1985-12-10 | The Procter & Gamble Company | Penetrating topical pharmaceutical compositions containing 1-dodecyl-azacycloheptan-2-one |
US4537776A (en) * | 1983-06-21 | 1985-08-27 | The Procter & Gamble Company | Penetrating topical pharmaceutical compositions containing N-(2-hydroxyethyl) pyrrolidone |
JPS60174716A (en) * | 1984-02-21 | 1985-09-09 | Yamanouchi Pharmaceut Co Ltd | Medicinal patch |
US4626539A (en) * | 1984-08-10 | 1986-12-02 | E. I. Dupont De Nemours And Company | Trandermal delivery of opioids |
US4568343A (en) * | 1984-10-09 | 1986-02-04 | Alza Corporation | Skin permeation enhancer compositions |
US4908389A (en) * | 1986-08-27 | 1990-03-13 | Warner-Lambert Company | Penetration enhancement system |
ATE68704T1 (en) * | 1986-12-18 | 1991-11-15 | Bauer Kurt Heinz | NIFEDIPIN CONCENTRATE STABILIZED AGAINST LIGHT EFFECTS AND PROCESS FOR ITS PRODUCTION. |
AU601528B2 (en) * | 1986-12-22 | 1990-09-13 | Ortho-Mcneil Pharmaceutical, Inc. | Resilient transdermal drug-delivery device and compositions and devices employing fatty acid esters/ethers of alkanediols and percutaneous absorption enhancers |
US4900555A (en) * | 1987-02-26 | 1990-02-13 | Alza Corporation | Skin permeation enhancer compositions using sucrose esters |
US4746515A (en) * | 1987-02-26 | 1988-05-24 | Alza Corporation | Skin permeation enhancer compositions using glycerol monolaurate |
CH674618A5 (en) * | 1987-04-02 | 1990-06-29 | Ciba Geigy Ag | |
US4783450A (en) * | 1987-04-13 | 1988-11-08 | Warner-Lambert Company | Use of commercial lecithin as skin penetration enhancer |
US4764379A (en) * | 1987-08-24 | 1988-08-16 | Alza Corporation | Transdermal drug delivery device with dual permeation enhancers |
US5019395A (en) * | 1988-03-08 | 1991-05-28 | Warner-Lambert Company | Compositions with enhanced penetration |
US4973468A (en) * | 1989-03-22 | 1990-11-27 | Cygnus Research Corporation | Skin permeation enhancer compositions |
US5225198A (en) * | 1991-08-27 | 1993-07-06 | Cygnus Therapeutic Systems | Transdermal administration of short or intermediate half-life benzodiazepines |
BR9200386A (en) * | 1992-01-30 | 1992-07-07 | Giuseppe Betti | BASIC VEHICLE EMULSION |
-
1991
- 1991-12-20 US US07/810,963 patent/US5229130A/en not_active Expired - Lifetime
-
1992
- 1992-12-10 CA CA002126214A patent/CA2126214A1/en not_active Abandoned
- 1992-12-10 JP JP5511695A patent/JP3026602B2/en not_active Expired - Lifetime
- 1992-12-10 EP EP93901004A patent/EP0617600A4/en not_active Withdrawn
- 1992-12-10 WO PCT/US1992/010673 patent/WO1993012744A1/en not_active Application Discontinuation
- 1992-12-10 AU AU32472/93A patent/AU3247293A/en not_active Abandoned
-
1993
- 1993-01-18 TW TW082100284A patent/TW262385B/zh active
Also Published As
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TW262385B (en) | 1995-11-11 |
JP3026602B2 (en) | 2000-03-27 |
US5229130A (en) | 1993-07-20 |
EP0617600A1 (en) | 1994-10-05 |
WO1993012744A1 (en) | 1993-07-08 |
JPH07506562A (en) | 1995-07-20 |
AU3247293A (en) | 1993-07-28 |
EP0617600A4 (en) | 1995-06-14 |
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Legal Events
Date | Code | Title | Description |
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EEER | Examination request | ||
FZDE | Discontinued |