NOVEL TRANSDERMAL ANTI-ANGINAL PHARMACEUTICAL DOSAGE UNIT AND PROCESS FOR ITS ADMINISTRATION

Abstract: Novel transdermal nitroglycerin or other anti-anginal pharmaceutical polymer matrix dosage units have been developed which comprise a backing layer, an adjoining layer of a solid polymer matrix in which the pharmaceutical is microdispersed, and a biologically acceptable adhesive polymer layer which has dispersed one or more skin permeation enhancers. Novel process of administration of the anti-anginal pharmaceutical using the novel polymer matrix dosage units is also provided.

Description: DESCRIPTION NOVEL TRANSDERMAL ANTI-ANGINAL PHARMACEUTICAL DOSAGE UNIT AND PROCESS FOR ITS ADMINISTRATION CROSS REFERENCE TO RELATED APPLICATION This application is a continuation-in-part of U.S. application Ser. No. 06/770,968, filed August 30, 1985, which is a continuation-in-part of U.S. application Ser. No. 06/705/194, filed February 25, 1985, by Yie W. Chien and Chia-Shun Lee. Technical Field This invention relates to a novel transdermal nitro- glycerin or other anti-anginal pharmaceutical absorption dosage unit comprising a backing layer; an intermediate adjoining layer of solid polymer matrix in which the anti- " anginal pharmaceutical is dispersed; and a final biologi¬ cally acceptable adhesive layer which is in communication with the solid polymer matrix layer and is adapted to adhere to the skin of a subject being administered nitroglycerin or other anti-anginal pharmaceutical, the adhesive layer having dispersed therein an effective amount of one or more skin permeation enhancing compounds for the nitroglycerin or other anti-anginal pharmaceutical dispersed in the polymer matrix layer. Background Art It has been found that nitroglycerin and other anti- anginal pharmaceuticals are absorbed to a degree through the skin. This is referred to as transdermal absorption. Anti- anginal pharmaceuticals as used herein mean the nitrate and nitrite ester s of mono- and poly-hydric alcohols which are pharmaceutically acceptable, have anti-anginal effective- ness, and are susceptibl e to transdermal absorption. One means of effecting -transdermal absorption of an anti-anginal has been to distribute nitroglycerin within a polymeric disc or a container of a gel, which is brought into contact with an area of the skin of the subj ect to be treated wi th the nitroglycerin. Also, ointments or lotions containing nitro¬ glycerin have been applied to an area of the skin of the subj ect to be treated. Problems encountered in such treat- ment include inadequate control over the rate and duration of transdermal absorption or the rate can be too slow in the case of certain dosage forms, especially from nitroglycerin- containing discs or nitroglycerin-containing gel container dosage units or pads. Nitroglycerin has been administered using tablet f ormulations by which the ni troglycerin is absorbed through the sublingual mucosa. Such sublingual mucosa absorpti on is rapid and ef f ective to treat acute angina attacks, but does not provide sustai ned, constant bl ood lev el s of nitroglycer in together w ith long-term absor pti on. It has been f ound that th e tr ansderm al absorption rates of certain pharmaceuticals can be increased by use of absorption promoting compounds (also referred to as skin permeation enhancers) with the pharmaceutical to be absorbed when compounding in the polymeric disc or the pharmaceutical-containing gel. It is desired to improve the dosage unit forms or devices by which nitroglycerin or other anti-anginal pharma¬ ceuticals are transdermally absorbed, especially in view of the importance of their administration by this means. Desired transdermal absorption would provide an avoidance of the large, unwanted destruction of anti-anginal pharmaceu¬ tical such as nitroglycerin by metabolism in the gastro¬ intestinal tract and "first-pass-- hepatic elimination, which is usually about 90 percent or more of orally administered nitroglycerin. The transdermal absorption minimizes inter- and intra-patient variations regarding incompatibilities and metabolisms. By transdermal absorption, it is deemed pos¬ sible to provide more constant concentration of the anti- anginal pharmaceuticals in the body and to realize a greater pharmaceutical efficiency. It is also possible, by proper transdermal absorption, to reduce the frequency of effective dosing. Transdermal administration provides most of the advantages of intravenous and sublingual dosing without most of the disadvantages of such dosing. It is desired that improved transdermal nitroglycerin absorption dosage unit forms and processes of transdermal administration be developed. A number of advantages would result. Summary o Invent on This invention relates to an improved transdermal anti- anginal pharmaceutical containing dosage unit comprising- a) a backing layer which is substantially impervious to the anti-anginal pharmaceutical to be delivered trans- dermally; b) a polymer matrix disc layer which is in contact with said backing layer and which has dispersed therein an amount of nitroglycerin or other anti-anginal pharma¬ ceutical which will provide a dosage amount of the anti-anginal pharmaceutical to be delivered transder- mally; and c) an adhesive layer which is adhered to said anti-anginal pharmaceutical-containing polymer matrix disc layer and which has distributed therein an effective amount of one or more skin absorption enhancers which provide substantial skin absorption enhancement for said anti- anginal pharmaceitucal. The backing layer is made from materials that are substantially impermeable with regard to the nitroglycerin or other anti-anginal pharmaceutical of the transdermal dosage unit. It can be made of polymers such as polyethy- lene, polypropylene, polyvinylchloride, polyesters such as pol (ethylene phthalate), and laminates of polymer films with metallic foils such as aluminum foil. The polymer matrix disc layer is fabricated from bio¬ logically acceptable polymers. The polymer matrix disc layer which has the nitroglycerin or other anti-anginal pharmaceutical distributed therein can suitably * be made of a medical-grade silicone polymer such as a polydimethyl- siloxane polymer, or a siloxane polymer having methylvinyl siloxane groups. The nitroglycerin or other anti-anginal pharmaceutical is suitably dispersed in the silicone poly- mer, to which mixture a curing agent is suitably added. The polymer-anti-anginal pharmaceutical mixture is then formed into a layer of an appropriate thickness and is cured. The matrix layer is adhered to the backing layer. Other suit¬ able polymers can be used in the formation of the polymer matrix disc layer are elastomers or thermoplastics. Care must be taken that the polymer selected is compatible with the nitroglycerin or other anti-anginal pharmaceutical, permits its release for transdermal absorption and is free or sufficiently free from any biologically unacceptable components. Finally, the adhesive layer is applied to the polymer matrix disc layer. The skin permeation enhancer compound is mixed thoroughly with the adhesive polymer which is suitable for adhesion to the skin locus to which the transdermal matrix dosage unit will be applied. The adhesive polymer- skin permeation enhancer layer can be applied to the polymer matrix disc layer by coating or by solvent casting. Alter- natively, part of the adhesive skin permeation enhancer layer can be applied to the inner surface of the release liner and the remainder can be applied to the matrix layer surface; the two adhesive-skin permeation enhancer surfaces then are pressed together to form a single layer. The adhesive polymer-skin permeation enhancer layer is desirably thin in the micron-range thickness, suitably 10-300 microns in thickness, desirably about 20 to 250 microns, and prefer¬ ably about 50 to 200 microns in thickness. The transdermal nitroglycerin or other anti-anginal pharmaceutical absorption dosage units of this invention have an Enhancing Factor of at least 1.2, preferably at least 1.3, and more preferably at least about 2.0. Enhancing Factor is defined as the ratio of normalized permeation rate [in mcg/cm 2 /hr] of a dosage unit of this invention with skin permeation enhancer/ the normalized per- meation rate of a corresponding dosage unit without enhancer in the adhesive layer. The invention also is a process for administering a nitroglycerin or other anti-anginal pharmaceutical transder- mally by forming the anti-anginal pharmaceutical-containing polymer matrix disc dosage unit having a polymer matrix disc layer which has the pharmaceutical dosage dispersed therein, to which matrix disc is adhered a skin permeation enhancer- containing adhesive layer and, by applying said dosage unit by way of said adhesive layer to the skin of the subject to be treated, whereby said pharmaceutical is transdermally administered to said subject to achieve desired systemic effects. Detailed Description of the Invention and the Preferred Embodiments This invention relates to a transdermal anti-anginal pharmaceutical-containing matrix dosage unit comprising: a) a backing layer which is substantially impervious to the anti-anginal pharmaceutical to be delivered trans- dermally; b) a polymer matrix disc layer which is in contact with said backing layer and which has dispersed therein an amount of the nitroglycerin or other anti-anginal phar- maceutical which will provide a dosage amount of the pharmaceutical to be delivered transdermally; and c) an adhesive layer which is adhered to said pharmaceuti- cal-containing polymer matrix disc layer and which has distributed therein an effective amount of one or more skin absorption enhancers which provide substantial skin absorption enhancement for said pharmaceutical; said dosage unit having an enhancing factor of at least 1.2. The backing layer . is made from materials that are substantially impermeable with regard to the nitroglycerin or other anti-anginal pharmaceutical of the transdermal dosage unit. It can be made of polymers such as polyethy- lene, polypropylene, polyvinylchloride; polyesters such as poly(ethylene phthalate), and laminates of polymer films with metallic foils such as aluminum foil. The polymer matrix disc layer is fabricated from bio¬ logically acceptable polymers. The polymer matrix disc layer which has the nitroglycerin, for example, distributed therein can suitably be made of a medical-grade silicone polymer, such as polydimethylsiloxane polymer or other sili¬ cone polymer containing methylvinyl siloxane groups. The nitroglycerin e.g., is suitably dispersed in the silicone polymer t which mixture a curing agent is suitably added. The polymer-nitroglycerin mixture is then formed into an appropriate thickness and cured. The matrix layer is adhered to the backing layer, which can be done directly. Other suitable elastomer or thermoplastic polymers can also be used in the formulation of the polymer matrix disc layer. Care must be taken that the polymer selected is compatible with the nitroglycerin, permits its release for transdermal absorption and is free or sufficiently free from an bio- logically unacceptable components. Finally, the adhesive layer is applied to the polymer matrix disc layer. The skin permeation enhancer compound is mixed thoroughly with the adhesive polymer which is suitable for adhesion to the skin locus to which the transdermal matrix delivery dosage unit will be applied. The adhesive polymer-skin permeation enhancer layer can be applied to the polymer matrix disc layer by coating or by solvent casting. Part of the adhesive polymer-skin permeation enhancer layer can be applied to a release liner and combined with the part pplied to the matrix disc layer by application of pressure. The layer is desirably thin, in the micron-range thickness, suitably about 10-300 microns in thickness, desirably about 20 to 500 microns, and preferably about 50 to 200 microns in thickness. The invention also is a process for administering a nitroglycerin or other anti-anginal pharmaceutical transder- mally by forming polymer matrix disc delivery dosage unit having a polymer matrix disc which has the anti-anginal pharmaceutical dosage dispersed therein, to which matrix disc is adhered a skin permeation enhancer-containing adhe- sive layer and, by applying said dosage unit by way of said adhesive layer to the skin of the subject to be treated, whereby said anti-anginal pharmaceutical, such as nitro- glycerin, is transdermally administered to said subject to achieve systemic effects. The backing layer can be made of any suitable material which is impermeable to the nitroglycerin of the polymer matrix layer. The backing layer serves as a protective cover for the matrix layer and provides also a support function. Examples of materials that are suitable are films of high and low density polyethylene, polypropylene, poly- vinylchloride, polyesters such as poly (ethylene phthalate) and the like. Preferably, the materials for the backing layer are laminates of such polymer films with a metal foil such as aluminum foil. In such laminates, a polymer film of the laminate will usually be in contact with the polymer matrix layer. The backing layer can overlay the matrix and adhesive layer as desired for protection and to provide the desired pharmaceutical elegance of the final matrix dosage unit form. The protective layer can be any appropriate thickness which will provide the desired protective and support functions. A suitable thickness will be from about 10 to about 200 microns. Desirably, the thickness will be from about 20 to about 150 microns, and preferably be from about 30 to 100 microns. The polymer matrix layer can be made from silicone elastomers of the general polydimethyl siloxane structure, such as silicone polymers of the fol lowing formula: CH; Si — CH, wherein R is alkyl or alkoxy containing 1-7 carbon atoms vinyl or phenyl and wherein n is about 100-5000. The silicone polymers selected preferably are cross linkable at moderate temperatures such as at room tempera ture, using cross-linking catalysts which are biologicall acceptable in the final polymer matrix and which are com patible with nitroglycerin or other anti-anginal pharmaceu tical to be used in making the polymer matrix dosage form Some suitable siloxane polymers are crosslinkable copolymer having dimethyl and methylvinyl sil xane « * 'b *; rh can b cross-linked as by using a suitable p-roxme catalyst o. suitable tin or platinum catalyst system. her cross linking sites can be present in the polysiioxa.ie elastomer used. Suitable siloxane medical-grade polymers are sol under the designations Silastic 382, Q7-4650, Q7-4665, Q7- 4735, Q7-4750, Q7-4765 and MDX-4-4210. Generally, polymers used to form the biologically acceptable polymer matrix are those capable of forming a thin layer of coatings or a disc of drug-dispersing matrix through which nitroglycerin or other anti-anginal pharmaceu¬ tical can pass at a controlled rate. Suitable polymers are biologically-acceptable and compatible with the pharmaceuti¬ cal, non-allergenic and insoluble in and non-irritating to body fluids or tissues with which the device is contacted. The use of soluble polymers is to be avoided since dissolu¬ tion or erosion of the matrix would affect the release rate of the nitroglycerin or other anti-anginal pharmaceutical as well as the capability of the dosage unit to remain in place for convenience of removal. Exemplary materials for fabricating the biologically acceptable polymer matrix include polyethylene, polypropy- lene, ethylene/propylene copolymers, ethylene/ethylacrylate copolymers, ethylene/vinyl acetate copolymers, silicone elastomers, especially the medical-grade poly-dimethyl- siloxanes, neoprene rubber, chlorinated polyethylene, poly- vinyl chloride; vinyl chloride-vinyl acetate copolymer, polymethacrylate polymer (hydrogel) , polyvinylidene chlo¬ ride, poly (ethylene terephthalate), butyl rubber, epichloro- hydrin rubbers, ethylene-vinyl alcohol copolymer, ethylene- vinyloxy ethanol copolymer; silicone copolymers, for example, silicone-polycarbonate copolymers; cellulose poly- mers, for example methyl or ethyl cellulose hydroxypropyl methyl cellulose, and cellulose esters; polycarbonates; . , the biologically acceptable polymer matrix should be selected from polymers with glass transition temperatures below room temperature. The polymer may, but need not necessarily, have a degree of crystallinity at room tempera¬ 0 ture. Cross-linkable onomeric units or sites can be incor¬ porated into such polymers. For example, cross-linking 5 monomers can be incorporated into polyacrylate polymers, which provide sites for cross-linking the matrix after microdispersing the nitroglycerin or other anti-anginal 0 pharmaceuticals into the polymer. Known cross-linkable monomers for polyacrylate polymers include polymethacrylic 5 esters of polyols such as butylene diacrylate and dimethacrylate, trimethylol propane trimethacrylate and the like other monomers ' which provide such sites include allyl 0 acrylate, allyl methacrylate, diallyl aleate and the like. The adhesive layer is suitably made using a silicone 5 adhesive, such as a polydimethylsiloxane adhesive of the following formula: wherein x shows the unit is repeated to the extent to pro¬ vide desired properties. 50 For example, adhesive products sold by Dow Corning under the designation DC-355 are suitable for ._ in making -> the adhesive layer. The adhesive polymer must be biol * >gi- •caliy acceptύt-ie and coir.-pr. * tibie with the nitroglycerin and sk n permeat on enhancer used. Certain poly-acrylate adhe¬ sive polymers (in the form of an alkyl ester, amide, free acid, or the like) can also be used with anti-anginal phar¬ maceuticals. Other suitable hypoallergenic pressure-sensi¬ tive contact adhesive compositions are also known. A pre- ferred adhesive layer is pressure-sensitive. The adhesive layer then is finally covered with a releaseable protective layer liner which is made from mate¬ rials which are substantially impermeable to nitroglycerin or other anti-anginal pharmaceuticals used, the skin permea- tion enhancer used and any other components of the polymer matrix dosage unit. The polymer materials and metal foil laminates used for the backing layer can be used to make the protective layer, provided the layer is made strippable or releasable such as by applying conventional siliconizing. In making the nitroglycerin or other anti-anginal phar¬ maceutical containing polymer matrix disc layer, silicone elastomers such as polydimethylsiloxane of the formula described above can be suitably used. In making nitro- glycerin-dispersed polymer matrix disc dosage units, it has been found suitable to use lactose as a dispersing agent to stabilize the nitroglycerin. Other suitable dispersing agents can also be used to replace lactose as long as they can produce a stable dispersion. A dispersing agent might be unnecessary if the anti-anginal pharmaceutical is a solid. Depending upon the drug loading desired, a suitable amount of a dispersing agent has been found to be 1-9 equi- valents (by weight) based on the weight of nitroglycerin. The blend of nitroglycerin with dispersing agent then is added to the polymer used to make the matrix disc layer. The amount of nitroglycerin added depends upon the amount of nitroglycerin dosage desired in each dosage unit and the amount which can be incorporated into the polymer matrix disc to retain suitable structural, diffusion and other properties in the final matrix disc. It has been found, for example, that up to 30 parts of nitroglycerin dispersion can be satisfactorily added to 70 parts of the polyer used in making the matrix disc, such as silicone elastomers. The mixture of the polymer and nitroglycerin/dispersing agent is then thoroughly mixed using a high-torque mixer to form a homogeneous microdispersion of nitroglycerin in the polymer. With continued agitation, an amount of cross-linking cata¬ lyst is desirably added together with relatively low molecu¬ lar weight polymer having a compatible chemical structure. For example, when pol dimethylsiloxane is used as the poly¬ mer, a relatively low molecular weight polydimethylsiloxane and a cross-linking catalyst is added (such as 10 parts by weight of the low molecular weight polydimethylsiloxane and 30 drops of stannous octanoate per lOOg. amount of the final polydimethylsiloxane-nitroglycerin mixture) to the above illustrative composition of 20 parts of nitroglycerin dis- persion and 70 parts of polydimethylsiloxane polymer. Again, the mixture is agitated with a high-torgue mixer to form a uniform admixture. After each ' mixing step, the composition is subjected to vacuum to remove any entrapped air. It is also desirable to add an amount of dextran to the polymeric mixture used in making the matrix, if it is compatible with the polymer used. It has been found useful to incorporate about one to about ten parts by weight based on the polymer of dextran, preferably about three to about eight parts by weight, and usually about six parts by weight being a preferable amount depending upon the polymer and anti-anginal pharmaceutical used. The deaerated mixture is then placed in a device maker and heated to suitable elevated temperature to promote cross-linking. A suitable temperature for cross-linking when the polymer used is polydimethylsiloxane of the above formula and the cross-linking catalyst is stannous octanoate, is from about 10°C to about 200°C, desirably about 20°C to about 100°C. The temperature used should not cause significant degradation of nitroglycerin. The polymer matrix sheet desirably is about 0.05 to 5 mm, preferably about 0.1 to about 3 mm in thickness. The resulting cross- linked polymer matrix sheet is removed from the device maker and can be cut to form discs with desired shapes and sizes. The discs are then attached to a backing sheet, as described above, using an area, suitably about 5 to 100 sq. cm., preferably, about 8 to about 80 sq. cm., generally about 10 to 60 sq. cm. being more preferable. The shape of the discs can vary; they can be circular, square, rectangular, or other desired shapes. The nitroglycerin-containing polymer matrix disc layer, generally speaking, should contain some excess amount of the dispersed nitroglycerin over the dosage amount desired to be transdermally absorbed by the subject to be treated. Ordi¬ narily, this excess is small, such as less than 2-fold excess. Generally speaking, an amount of the nitroglycerin used, which is sufficient, is less than 2 to about 10 times the desired dosage to less than 2 to about 5 times, the desired dosage to be transdermally absorbed being adequate, depending upon the physiochemical properties of nitrogly- cerin, as well as the nature of the polymer of the matrix disc layer and other factors. The amount of nitroglycerin loading in the matrix can be varied, depending upon the polymer used in making the matrix layers, the dosage desired, the skin permeation enhancer system or systems used and the like. Ordinarily, however, in using silicone poly¬ mers for making the matrix layer, use of up to about 10 percent loading of nitroglycerin is adequate. It has been observed that a greater loading does not assure a greater transdermal absorption of nitroglycerin and at least at times results in no significant increase. The adhesive polymer layer containing the skin permea- tion enhancer is made as by dissolving the enhancer compound in a solvent for the enhancer which is compatible with the adhesive polymer solution used to make the adhesive layer containing the skin permeation enhancer. Any suitable amount of solvent can be used as necessary to dissolve the quantity of enhancer to ber admised with the adhesive poly¬ mer solution used. For example, 3 to 10 parts os solvent can be used to dissolve one part of skin permeation en- hancer, depending upon the solubility of the enhancer. When using polydimethylsiloxane adhesive solution, it has been found suitable to use 2 to 30 parts of skin permeation enhancer in 20 to 50 parts of solvent (such as acetone, methyl ethyl ketone, ethyl acetate or other suitable sol¬ vent) and add the solution to 100 parts of the adhesive solution. The enhancer-adhesive combination is thoroughly mixed and a coating thereof is applied using a film coating machine to the matrix disk layer or to a strippable release liner, as described above. Preferably, in order to assure adequate adhesion of the adhesive polymer layer to the skin of the subject treated, an enhancer-adhesive polymer solu¬ tion having a relatively low concentration of enhancer, e.g., 1-2 percent based on the weight of the adhesive poly- mer is used to apply a coating to the release liner. The thickness of this coating ordinarily is a minor percentage of the thickness of the final adhesive layer, such as 20-40 percent of the total adhesive polymer layer. The remainder of the adhesive polymer layer having a suitable higher concentration of the enhancer is used to coat the matrix disc layer. Suitable higher concentrations of enhancer are usually 10 to about 30 percent based on the adhesive polymer weight, depending on solubility, desired final amount of skin enhancer agent and other factors. The solvent of the respective coatings is removed by evaporation. The respec¬ tive coatings are combined to make the final adhesive poly- mer-enhancer agent layer by appl ication of constant pres¬ sure. A sui tabl e r el ease l ine r be i ng a poly (e thyl ene phthalate) laminated with aluminum foil. The poly (ethylene phthalate) side to which the adhesive-enhancer coating is applied, is made strippable to conventional siliconizing or by other suitable means, such as fluorocarbon-coating. The thickness of the adhesive-enhancer layer normally applied is about 10 to about 200 microns, preferably about 30 to about 150 microns. The amount of enhancer in the adhesive layer depends in part on the rapidity at which it is desired that nitroglycerin be absorbed. Generally speaking, about 1 to about 30 percent of skin permeation enhancer based on the weight of the adhesive is suitable depending upon the enhan- cer, matrix polymer, adhesive and other factors. Desirably, about 2 to 20 percent of skin permeation enhancers are used depending upon the above recited factors. The adhesive layer containing the skin permeation enhancer is applied to the polymer matrix disc surfaces by application of a con- stant pressure. The four-layer transdermal nitroglycerin polymer matrix dosage units are excised. The backing layer as desired can be shaped around the sides of the dosage unit including the polymer matrix layer if such protection is desired. The resulting nitroglycerin polymer matrix dosage unit forms are then placed in appropriate storage until they are to be applied in transdermal treatment. The pharmaceutical nitroglycerin is dispersed in the polymer matrix disc layer. Another type of pharmaceutical may also be dispersed in the polymer matrix disc layer, which includes any pharmaceutical which is capable of being transdermally or topically administered to a subject to be treated and which does not materially interfere with the desired nitrogen absorption and treatment. Such additional pharmaceutical used should have a daily effective dose of less than about 100 mg. With the controlled release of nitroglycerin and any additional pharmaceutical at a rela¬ tively steady-state rate over a prolonged period, typically 24 hours or longer, the patient is provided with the benefit of a steady infusion of the pharmaceutical component over a prolonged period. It will be appreciated that the nitroglycerin may be added to the above mixture not only in the form of the pure chemical compound, but also in admixture with other pharma¬ ceuticals which may be transdermally applied or with other ingredients which are not incompatible with the desired objective of transdermally administering nitroglycerin to a patient. Thus, it will be suggested to those in the art of nitroglycerin treatment to consider substitution in part or in total other anti-anginal nitrate or nitrite compounds or other pharmaceuticals which have anti-anginal treatment properties. Anti-anginal pharmaceuticals used in this invention are nitrate or nitrite esters of mono-or poly- hydric alcohols which are pharmaceutically acceptable, which have anti-anginal effectiveness and which are susceptible to transdermal absorption and can be selected from but are not limited to nitroglycerin, isosorbide dinitrate, penta- erythrityl tetranitrate, erythrityl tetranitrate, amyl nitrite and the like. The skin permeation enhancers which can be used in carrying out this invention can vary. Ones that give pre- ferred results with the polymer matrix dosage unit form having nitroglycerin can vary. In some instances, the use of permeation enhancer in making a polymer matrix dosage form will result in good or even excellent absorption of nitroglycerin, might result in relatively low enhancement when another dosage unit form of the invention is used. Use of combinations of two or more of the skin permeation enhancer compounds frequently result in superior results, such as greater transdermal absorption. Some amount of skin permeation enhancer can also be incorporated into the poly¬ mer matrix layer, if desired, the amount used in the matrix layer can be varied so long as it is effective, such as an amount equivalent to the amount used in making the adhesive layer or an amount which is 20-80% of the concentration used in the adhesive layer. The skin permeation enhancers can be varied if desired in the respective layers. Specific skin permeation enhancers which can be used in making the polymer matrix dosage forms of this invention include saturated and unsaturated fatty acids and their esters, alcohols, monoglycerides, acetates, diethanolamides and N,N-dimethylamides, such as oleic acid, capric or decanoic acid, propyl decanoate, prόpyl or isopropyl oleate, oleyl acetate, propyl or isopropyl myristate, myristyl alco¬ hol, myristyl N,N-dimethyl amide, stearic acid and stearyl alcohol, propyl stearate monostearin, and combinations of them with, for example, l-dodecylazacycloheptan-2-one sold under the trademark Azone by Nelson Research and Develop¬ ment; decyl methyl sulfoxide, dimethyl sulfoxide, salicylic acid and derivatives, N, -diethylm-toluamide, crotamiton, 1- substituted azacycloalkan-2-ones such as disclosed in U. S. Patent 4,316,893 (the 1-substituent having 0-17 carbon atoms, preferably, 1-11 carbon atoms), squalane and various other compounds which are biologically compatible and have transdermal permeation activity. It has been found useful to incorporate menthol with one or more skin permeation enhancers, even though it is not currently certain whether menthol alone has skin permeation enhancer activity. Ethyl alcohol and other short chain alkanols (with 1-4 carbon atoms) which have substantially the same properties and activity as ethyl alcohol do not come within the definition of skin permeation enhancer as used herein. The following examples are in illustration of the invention and are not intended to be limiting. EXAMPLE 1 A dispersion of 10 parts by weight each of pure nitro¬ glycerin oil and lactose is made by using a high-torque mixer (sold by Cole-Parmer Company). The ni troglycerin- lactose dispersion is homogeneously dispersed in 70 parts of silicone elastomer using the high-torque mixer and at about 1,000 rpm. The silicone elastomer is a polydmethylsiloxane polymer sold by Dow Corning Company under the designation Silastic Medical Grade 382 Elastomer. The elastomer is believed to have the following structural formula: wherein n indicates the number of repeating units. With continued agitation, 10 parts of DC-360 (silicone medical fluid) and 30 drops (for every 100 g of the mixture) of a cross-linking agent designated as catalyst M is added, which is stannous octanoate. After each addition of the material, the mixture is thoroughly mixed and is placed under vacuum to remove entrapped air. The nitroglycerin-polydimethylsiloxane dispersion is placed into a device maker and is cross-linked at room temperature or at an elevated temperature (60° - 100°C) to form a cross linked, medicated polymer sheet, which has a thickness of 0.2-2 mm. The medicated polymer sheet is removed from the device maker and is cut into circular discs of about 3-20 sq. cm. The discs are attached to a backing layer of heat sealable polyester film which is laminated to aluminum foil. This laminate is sold by 3M Company as Scotchpak 1006. The medicated discs are attached to the backing layer using an adhesive polymer solution, a silicone adhesive polymer sold by Dow Corning as DC-355 or medical-grade adhesive A being suitable. Alternately, the discs can be formed directly on the backing layer and in practice are. The skin permeation enhancer-adhesive layer is made by dissolving the necessary weight of a skin permeation enhan¬ cer in 30 parts of acetone. The acetone solution then is added to 100 parts of a silicone adhesive solution sold by Dow-Corning under the designation DC-355. The mixture is thoroughly mixed to form a homogeneous mixture of skin permeation enhancer and adhesive polymer. The adhesive polymer layer is formed by making multiple coatings. Desirably, a coating of adhesive polymer solution containing 1-2 percent enhancing agent is applied to the release liner (a fluorocarbon-coated polyester film). This lower concentration of enhancing agent aids assurance that the surface of the final adhesive layer when applied to skin of the subject treated will satisfactorily adhere. The remaining portion of the adhesive coating necessary to make up the final adhesive layer thickness has a higher enhancing agent content (10-30 percent) and is applied to the matrix layer. The solvent of the respective coatings is removed by evaporation. The release liner so-coated is then applied to the adhesive coated matrix layer under a constant pressure to provide a firmly adhered strip of a four-layered struc¬ ture as follows: 1. Backing layer 2. Nitroglycerin-containing polymer matrix layer 3. Skin permeation enhancer-adhesive layer (50-200 micron thickness) 4. Release film layer which can be readily removed to permit application to the skin of the subject to re¬ ceive transdermally the nitroglycerin. By use of an appropriate cutter, the strip is cut into a suitable shape such as circular to provide the transdermal nitroglycerin polymer matrix dosage units which have an area of about 20 sq. cm. The above poly mer matr ix di sc dosage units ar e made using the f oll ow ing skin pe rmeati on enhancers as shown in the TABLES. Use of £___!_£.- butyl alcohol did not function as a skin permeation enhancer but rather the dosage units using tert- butyl alcohol resulted in less nitroglycerin absorption than the absorption from a controlled unit in which no enhancer compound was added to the adhesive layer. The transdermal absorption of nitroglycerin from the nitroglycerin polymer matrix dosage units of this invention is evaluated by use of skin from a "hairless * - mouse or human cadaver by following the procedure described by P. R. Keshary and Y. W. Chien, in Drug Develop. & Ind. Pharm., _Lϋ (6) 883-913(1984). The following TABLES show the transdermal absorption of nitroglycerin from the nitroglycerin-containing polymer matrix disc dosage units made by the above procedure: TABLE I SKIN PERMEATION ENHANCEMENT OF NITROGLYCERIN BY VARIOUS ENHANCERS Dosage Enhancing (2) Agents (1) Permeation Rate Factors (1.6 mg/cra 2 ) (mcg/cm 2 /hr± S.D.) 1. None 25.72 ± 5.41 1.00 2. Stearic Acid 27.26 ± 2.53 1.06 3. Stearyl Alcohol 25.38 ± 0.05 0.99 4. Stearyl Propyl Ester 42.91 + 4.81 1.67 5. Mono-Stearin 36.82 + 0.01 1.43 6. Oleic Acid 70.55 + 11.06 2.74 7. Oleyl Alcohol 61.74 + 5.83 2.40 8. Oley Propyl Ester 62.40 + 11.12 2.43 9. Mono-Olein 51.14 + 10.52 1.99 10. Myristic Acid 28.04 + 1.33 1.09 11. Myristyl Alcohol 45.72 + 2.33 1.78 12, Myristyl Propyl Ester 49.46 ± 5.62 1.92 13. Mono-Myristein 22.54 ± 2.90 0.88 14. ϋ-Decyl Alcohol 65.59 + 11.39 2.55 15, Decyl Acetate 40.01 + 5.28 1.56 16. 1-Dodecylazacyclo- heptan-2-One 35.83 ± 3.90 1.39 17. Decyl- Methyl Sulfoxide 56.68 + 1.82 2.20 18. T-Butanol 22.73 ± 2.02 0.88 19. 1-Propanol 27.56 + 3.41 1.07 20, 2-Propanol 27.06 + 4.69 1.05 21. Triethanolamine 28.62 + 4.79 1.11 22. Malonic Acid Diethyl Ester 40.12 + 2.20 1.56 23, Maleic Acid Diethyl Ester 30.01 ± 3.83 1.17 24, Mandelic Acid Ethyl Ester 27.09 + 0.20 1.05 25, Glycylglycine 36.94 ± 4.36 1.44 1) Contained in the adhesive layer at a surface concentratio 1.6 mg/cm 2 . 2) Enhancing Factor = (Normalized Permeation Rate) Enhancer TABLE II EFFECT OF LOCATION AND CONCENTRATION OF PROPYL OLEATE, AS SKIN PERMEATION ENHANCER, ON TRANSDERMAL ABSORPTION OF NITROGLYCERIN Normalized Concentration of Enhancer in Permeation Rate Enhancin Polymer Matrix Adhesive Layer (mcg/cm 2 /hr ± S .D . ) Factor* 0.0% 0.0% 40.33 ± 6.04 1.00 2.5% 46.09 ± 5.07 1. 14 2.5% 59.68 ± 17.34 1.48 2.5% 2.5% 71.00 ± 14.48 1.76 5.0% 65 .86 + 22.6 L 1.63 5.0% 87 .72 ± 16.31 2.18 5 .0% 5 .0% 109.58 ± 10.03 2.72 10.0% 125.86 ± 12.21 3. 12 Enhancement Factor = (Normalized Permeation Rate) Enhancer 40.33 TABLE III EFFECT OF SKIN PERMEATION ENHANCER CONCENTRATION IN ADHESIVE LAYER ON THE ENHANCEMENT OF TRANSDERMAL ABSORPTION OF NITROGLYCERIN Enhancing Cone. Enhancing Factor (rng/cm 2 ) A* B C D E F G H 0 1.00 1.00 1.00- 1.00 1.00 1.00 1.00 1. 0.08 1.16 — — — — — — 0.20 1.41 — — — — — — 0.37 1.68 — — — — — — 0.66 2.41 — — — — — — 0.80 — 2.59 1.67 1.22 1.69 1.56 1.61 1. 0.96 1.99 — — — — ' — 1.27 1.41 — — — — — — 1.59 1.44 4.11 1.92 2.43 2.82 2.58 1.87 2. 2.40 — — — — — — 2.02 3.18 1.51 4.41 3.07 3.08 2.65 1.50 — 1. 4.78 — — 3.41 3.78 — 1.74 — 1. 5.00 — — — — — — 1.36 10.00 — — — — — — 1.22 *Enhancer A = l-Dodecylazacycloheptan-2-one B = Decanoic acid C = Propyl myristate D = Propyl oleate • E = Oleyl alcohol F = 1-monolauroyl-rac-glycerol G = Decylmethyl sulfoxide H = Myristic acid, N,N-dimethylamide TABLE IV EFFECT OF ENHANCER CONCENTRATION ON SKIN PERMEATION ENHANCEMENT OF NITROGLYCERIN BY COMBINATION OF .ENHANCERS Enhancin Concentration of Enhancers in Adhesive Layer* (mg/cm 2 ) Factor A B C D 1.27 1.41 1.27 1.27 2.15 1.27 — 1.27 1.63 .27 1.27 1.28 1.27 .27 1.27 2.37 0.34 3.2 — — 2.34 0.34 — 3.2 — 2.81 0.34 — — 2.3 1.87 0.17 1.6 — 1.84 0.17 — 1.6 — 1.85 0.17 — — 1.09 1.35 0.17 0.83 0.83 — 1.87 0.17 0.83 — 0.79 2.83 0.17 — 0.83 0.79 1.78 0.085 0.83 0.83 0.55 2.34 *Enhancer A l-Dodecylazacyloheptan-2-one B Propyl oleate C Propyl myristate D Decylmethyl sulfoxide TABLE V SKIN PERMEATION ENHANCEMENT OF NITROGLYCERIN BY COMBINATION OF ENHANCERS Enhancing Enhancers Cone. Permeation Rate Factor (I τιg/3.14cm 2 ) (mcg/cmVhr + S.D.) A 1 B None 30.84 ± 1.32 1.00 1.0 1-Dodecylazacycloheptan- 2-one 1.0 42.68 + 3.07 1.38 1.0 +Propyl Myristate 5.0 63.83 + 2.23 2.07 1.5 10.0 88.54 + 1.31 2.87 2.0 +Propyl Oleate 5.0 69.00 + 2.76 2.24 1.6 10.0 83.50 + 3.87 2.71 1.9 +Myristyl Acetate 5.0 116.01 + 25.71 -3.76 2.7 10.0 103.89 + 18.41 3.37 2.4 +01eyl Acetate 5.0 89.71 + 0.64 2.91 2.1 10.0 107.03 + 2.14 3.47 2.5 +Glycylglycine 5.0 47.30 + 0.90 1.53 1.1 +Decylmethyl Sulfoxide 5.0 81.17 + 7.11 2.63 1.9 1-Dodecylazacycloheptan- 2-one 2.0 46.71 + 3.39 1.51 1.0 +Propyl Myristate 5.0 71.58 + 14.57 2.32 1.5 10.0 82.15 + 0.05 2.66 1.7 +Propyl Oleate 5.0 50.20 + 2.62 1.63 1.0 10.0 79.90 + 18.95 2.59 1.7 +Salicylic Acid 5.0 52.11 + 0.40 1.69 1.1 10.0 41.15 + 6.80 1.33 0.8 1-Enhancing Factor A = normalized permeation rate with defined skin permeation enhancer content/normalized permeation rate of a corresponding dosage unit with no enhancer. 2-Enhancing Factor B = normalized permeation rate with defined combination of skin permeation enhancer content /normalized permeation rate of a corresponding dosage unit with only the defined amount of the enhancer of the combination, l-dodecylazacycloheptan-2-one. TABLE VI SKIN PERMEATION ENHANCEMENT OF NITROGLYCERIN BY COMBINATION OF l-DODECYLAZACYCLOHEPTAN-2-ONE WITH OTHER SKIN PERMEATION ENHANCERS Enhancin Concentration of Enhancers in Adhesive Layer* (mg/cm 2 ) Factor A B C D E F G 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1.00 0.34 — — 1.18 0.34 0.8 — 2.61 0.34 1.6 — 4.43 0.34 — 1.6 3.82 0.34 0.8 0.8 4 . 38 0.34 0.8 1.6 3 .61 0.34 — 0.8 0.8 3.05 0.34 — — 1.6 2.47 0.34 0.8 — 0.8 4 .33 0.34 0.8 — 1.6 4 .31 0. 34 — 0.8 0.8 2.69 0.34 0.8 — 0.8 2.22 Εnhancer A = l-Dodecylazac-ycloheptarr-2-one B = Decanoic acid; C = Decanol D = Oleic acid E = Oleyl alcohol F = Laurie acid G = Decyl methyl sulfoxide TABLE VII SKIN PERMEATION ENHANCEMENT BY VARIOUS GLYCERIDES Glycerides Skin Permeation Rate (mcg/cm 2 /hr) Enhancing (1.6 mg/cm 2 ) With Without Factor 1-Monolauroyl- 88.02 ± 19.71 34.1 ± 1.62 2.58 RAC-Glycerol 1-Monomyristoly- 29.88 ± 3.84 34.1 ± 1.62 0.88 RAC-Glycerol 1-Monopalmitoyl- 29.39 ± 1.76 34.1 ± 1.62 0.86 RAC-Glycerol 1,2-Dimyristoyl- 40.64 ± 4.27 39.4 ±.4.32 1.03 RAC-Glycerol 1 , 3-Dimyristoyl- 32.13 ± 6.94 34.1 ± 1.62 0.94 RAC-Glycerol 1,2,3-Trimyristoyl- 32.36 ± 4.61 39.4 ± 4.32 0.82 RAC-Glycerol TABLE VIII SKIN PERMEATION ENHANCEMENT OF NITROGLYCERIN BY UNSATURATED FATTY ACID ESTERS H H / C = C O / CH 3 CH 2 6 CH 2 CH 2 (CH 2 ) 6 C-OR Normalized Enhancing Enhancers R Permeation Rate* Factor (1.6 mg/cm 2 ) (mcg/cm 2 /hr±S.D.) Methyl Oleate CH, 77.56 ± 3.54 2.62 Ethyl Oleate CH 3 CH 2 68.48 ± 9.77 2.31 Propyl Oleate CH 3 CH 2 CH 2 71.96 ± 12.82 2.43 Butyl Oleate CH 3 CH-,CH 2 CH 2 61.00 ± 3.22 2.06 Oleyl Acetate CH 3 C 69.05 ± 8.88 2.33 *Normalized Permeation Rate Without Enhancer = 29.66 ± 0.83 for Nitroglyce TABLE IX SKIN PERMEATION ENHANCEMENT OF NITROGLYCERIN BY UNSATURATED FATTY ACID PROPYL ESTERS Enhancing Agents Skin Permeation Rate (meg/cm 3 /hr+ S.D.) Enhancing With Without Factor Monoenoic Acid Oleic Acid 72.81 ± 12.97 30.01 ± 4.29 2.43 Propyl Ester Dienoic Acid Linoleic Acid 73.89 ± 16.03 30.01 ± 4 .29 2.46 Propyl Ester Tetraenoic Acid Arachidonic Acid 70.71 ± 31.76 30.01 + 4 . 29 2.30 Pro^,. Ester TABLE X SKIN PERMEATION ENHANCEMENT OF NITROGLYCERIN BY SATURATED FATTY ACID AMIDE Normalized Enhancing Enhancers n Permeation Rate* Factor (1.6 mg/cm 2 ) (mcg/cm 2 /hr±S .D . ) N-Caproic Acid 33.49 ± 4. 12 1.21 N , N-Dimethylamide Laurie Acid 10 47.33 ± 1.76 1.71 N , N-Dimethylamide Myristic Acid 12 55.83 ± 7. 39 2.02 N , N-Dimethylamide *Normalized Permeation Rate Without Enhancer = 27.65 ± 2.47 for Nitroglycerin. TABLE XI SKIN PERMEATION ENHANCEMENT OF NITROGLYCERIN BY VARIOUS MYRISTYL DERIVATIVES Myristyl Derivative Skin Permeation Rat e (mcg/cmVhr± S.D. ) Enhancin With Without Factor Myristic Acid 31.24 ± 1.48 28.66 ± 2.72 1.09 Myristate Sodium 36.28 ± 4.06 39.38 ± 4.32 0.92 Myristyl Esters : Methyl 63.36 ± 8.66 32.52 ± 3.52 1.95 Ethyl 52.40 ± 1.47 28.66 ± 2.72 1.83 Propyl 67.77 + 7.70 35 .24 ± 1.75 1.92 Isopropyl 61.29 ± 4 .49 35. 24 ± 1.75 1.74 Myristyl 40.30 ± 0.03 28. 86 ± 0.91 1 . 40 Myristyl Alcohol 51.30 ± 2.62 28.86 ± 0.91 1 .78 Myristyl Acetate 58.54 ± 3.88 28.86 ± 0.91 2 .03 Myristyl 57.87 ± 7.66 28.86 ± 2.72 2.02 N , N-Dimethylamide TABLE XII ENHANCEMENT IN TRANSDERMAL ABSORPTION OF NITROGLYCERIN BY SATURATED FATTY ACIDS \\ CH 3 (CH 2 ) n C-OH Normalized Enhancin Enhancers n Permeation Rate Factor (1.6 mg/cm 2 ) (mcg/cm 2 /hr±S .D . ) Butanoic acid 34.98 ± 0.48 0.89 Hexanoic acid 36.00 ± 1.93 0.92 Octanoic acid 101.80 ± 25.9 2.60 Decanoic acid 159. 12 ± 75.5 4.07 Dodecanoic acid 10 114.67 ± 13.7 2.93 Tetradecanoic acid 12 42.64 ± 2.02 1.09 Octadecanoic acid 16 41.44 ± 3.85 1.06 TABLE XIII SKIN PERMEATION ENHANCEMENT OF NITROGLYCERIN BY SATU A TED FATTY ACID PROPYL ESTERS O CH 3 (CH 2 ) n C- / OCH 2 CH 2 CH 3 Normalized Enhan Enhancers n Permeation Rate* Fact (1.6 mg/cm 2 ) (rncg/cm 2 /hr±S.D.) Hexanoic acid propyl ester 4 43.67 ± 3.90 1.43 Octanoic acid propyl ester 49.69 ± 3.12 1.62 Decanoic acid propyl ester 69.02 ± 12.54 2.26 Dodecanoic acid propyl ester 10 58.59 ± 2.95 1.92 Tetradecanoic acid propyl ester 12 57.58 ± 6.54 1.88 Hexadecanoic acid propyl ester 14 48.11 ± 5.97 1.57 Octadecanoic acid propyl ester 16 51.02 ± 5.72 1.67 *Normalized Permeation Rate Without Enhancer = 30.58 ± 1.71 for Nitroglycerin E AMPLE Following generally the procedure of Example 1, 15 percent W/W of nitroglycerin is incorporated into a poly¬ dimethylsiloxane sold under the designation Silastic Medical Grade 382 Elastomer to provide nitroglycerin containing matrix layer units. Also, following generally the procedure of Example 1, 15 percent W/W of nitroglycerin i s incor- porated into a polymethylvinyl siloxane sold under the desig¬ nation Silastic Medical Grade MDX4-4210 to f orm ni tro¬ glycer in containing matr ix layer units using a two-stage platinum catalyst for crosslinking. Skin permeation enhan¬ cers are incorporated into the adhesive compositions used to form the adhesive layer in the manner described in Example 1. The concentration of skin permeation enhancer used are shown in the follow ing TABLES. As described in Exampl e 1 , the adhesive layer is f ormed by making mul tiple coatings. At times, the adhesive coating solution (10-20%) is further diluted with regard to the skin permeation enhancer content by adding f ur ther adhesive polymer, which composition is appl ied to the rel ease liner. The rel ease l iner surf ace with the adhesive coating then is applied to the adhesive layer which has been applied to the matrix surface to result in a unitary adhesiv e layer. When the rel ease liner is removed when the final dosage unit is being prepared f or appl ication to the subj ect being treated, the thin coating of the adhesive having low content of skin permeation enhan¬ cer (usually no more than 1-2 percent enhancer) adheres satisf actorily to the sk in of the subj ect being treated. The thickness of this layer is typically about 100 microns. The skin permeation enhancer concentrations of the adhesive compositions making up the adhesive layers are shown in the following TABLES: TABLE XIV SYNERGISTIC EFFECT IN SKIN PERMEABILITY ENHANCEMENT OF NITROGLYCERIN 1 Enhancers comoosition Cmσ/c 2 ) Enhancement Factor (+) menthol capric ac id 3rd enhancer MDX4-421Q DC-382 1.6 — — 0.93 — 0.8 0.8 — 3.40 — — 0.8 — 2.26 2.80 0.8 0.8 Decanol 0.8 6.74 0.8 0.8 Decanol 1.6 7.49 7.76 0.8 0.8 Oleyl alcohol 0.8 6.13 5.29 0.8 0.8 Oleyl alcohol 1.6 6.34 4.61 0.8 0.8 Salicylic acid 0.8 4.01 3.47 Methyl 0.8 0.8 Salicylate 0.8 2.50 3.36 1) 15% W/W in either MDX4-4210 or DC- 382 type si 1 icone matrix. TABLE XV SYNERGISTIC EFFECT IN SKIN PERMEABILITY ENHANCEMENT OF NITROGLYCERIN 1 * Enhancers combination 3 * (mg/cm 2 ) Enhancement Factor ___- E_ <__ _L_ E_ E_ ____________1_T 7 DC-382 1.0 1.0 — — — — 1.72 1.0 — 1.0 — — — 3.32 2.96 1.0 — — 1.0 — — 3.10 3.45 • 1.0 1.0 — — 1.6 — 2.40 3.37 1.0 — 1.0 — 1.6 — 16.68 7.24 1.0 — — 1.0 1.6 — 12.39 1.0 — — -- 1.6 -- — 2.09 — 1.0 — — 1.6 1.0 4.04 0.8 — 1.6 0.8 -- 5.80 1 *Drug loading = 15% W/W 2 *Contains 6% dextran 3 *A = Decylmethyl sulfoxide . B = Octanol C = Decanol D = Oleyl alcohol E = Squalane F = Capric acid AB E X EFFECT OF ENHANCER LOCATION ON SKIN PERMEABILITY AND ENHANCEMENT OF NITROGLYCERIN BY PROPYL OLEATE Enhancer Concentration Permeation Rate Enhancement Factor ifø£j____ Adhesive (mcg/cmVhr) 0% 0% 40.33 ± 6.04 1.00 2.5% — 46.09 + 5.07 1.14 — 2.5% 59.68 + 17.34 1.48 2.5% 2.5% 71.00 + 14.48 1.76 5.0% — 65.86 ± 22.61 1.63 — 5.0% 87.72 ± 16.31 2.18 5.0% 5.0% 109.58 + 10.03 2.72 __. 10.0% 125.86 ± 12.21 3.12 TABLE XVII SYNERGISTIC EFFECT IN SKIN PERMEABILITY ENHANCEMENT OF NITROGLYCERIN 3 * Enhancement Factor **5 -* (-) menthol 1.6 — 0.90 0.8 0.8 2.29 (+) menthol 1.6 — 0.93 0.8 0.8 3.40 (±) menthol 1.6 — . 1.01 0.8 0.8 3.01 0.8 2.26 a *10% W/W in MDX4-4210-tyρe silicone matrix. - -----**SSkkiinn ppeerrmmeeaation rate for control device = 30.33 ± 0.2 mcg/cm 2 /hr. c * M Meenntthhooll hhaass been reportedly used to relieve local irritation or for counterirritant purposes. B E XVIII SILICONE ELASTOMER COMPOSITION ON SKIN PERMEATION RATE OF NITROCLYCERIN Drug Loading Skin Permeation Rate (mcg/cm 2 /hr) (% W/W) DC-382 a * MDX-4-4210 b * 10 37.79 ± 8.12 33.28 ± 4.77 ~ 15 33.05 ± 0.99 37.60 ± 11.87 20 30.14 ± 1.19 33.40 ± 4.44 a *Tin-catalyzed 2-part system t* *Platinum-catalyzed 2-part system EXAMPLE 3 Dosage units are made using poly ethylvinylsiloxane sold by Dow Corning under the designation MDX 4-4210 by following the general procedure described in Example 1. The polymer matrix layers have a nitroglycerin content of 12 percent and 6 percent of dextran based on the weight of the silicone polymer. The adhesive layer (thickness of about 300 microns) applied to the matrix layer has 3 percent squalane, 2.2 percent decylmethyl sulfoxide and 2.2 percent oleyl alcohol, based on the adhesive polymer weight. It is made by first applying to a release liner and then applying the coating to the matrix surface. The outer adhesive layer is applied to the release liner of the final dosage unit has 2 percent squalane, 1 percent decylmethyl sulfoxide and 1 percent oleyl alcohol; it has a thickness of about 100 microns. A laminating machine is employed to apply the respective adhesive layers to make the final matrix dosage unit. The dosage units show retention of nitroglycerin skin permeation rate after storage for one week at 25°, 37°, and 45°, respectively. EXAMPLE 4 Examples 1-3 are essentially repeated using effective dosage amounts of isosorbate dinitrate, pentaerythrityl tritrani trate, erythrityl tetranitrate, and amyl nitrite respectively, instead of nitroglycerin.

Claims: WHAT IS CLAIMED IS: 1. A transdermal nitroglycerin or other anti-anginal phar- maceutical polymer matrix dosage unit comprising: a) a backing layer which is substantially impervious to the pharmaceutical to be delivered transder- mall ; b) a polymeric matrix disc layer which is adhered to said backing layer and which has microdispersed therein an amount of the pharmaceutical which will provide a dosage amount of the pharmaceutical to be delivered transdermally; and c) an adhesive layer which is adhered to said pharma- ceutical containing polymeric matrix disc layer and which has distributed therein an effective amount of one or more skin permeation enhancers which provide substantial skin absorption enhance¬ ment for said pharmaceutical; said dosage unit having an enhancing factor of at least 1.2. 2. A transdermal nitroglycerin or other anti- anginal phar¬ maceutical polymer matrix dosage unit of claim 1 wherein the polymer matrix disc layer is a cross-linked polysiloxane polymer of the following formula: wherein R is alkyl or alkoxy having 1-7 carbon atoms, vinyl, phenyl or combination thereof; and wherein n is about 100 to about 5,000. 3. A transdermal polymer matrix dosage unit of claim 1 wherein the polymer matrix disc layer has microdisper- sion compartments and has a cross sectional dimensio of from about 10 to about 200 microns. 4. A transdermal polymer matrix dosage unit of claim 2 wherein the polymer matrix disc layer has microdisper sion compartments and has a cross sectional dimensio of from about 10 to about 200 microns. 5. A transdermal polymer matrix dosage unit of claim wherein R in the polysiloxane formula is selected fro alkoxy, alkyl, vinyl, phenyl and combinations thereof. wherein the adhesive layer is made using a silicone polymer adhesive. 7. A transdermal polymer matrix dosage unit of claim 4 wherein the adhesive layer is made from a pressure- sensitive adhesive and the dosage unit has a releasable protective layer. 8. A transdermal polymer matrix dosage unit of claim 4 wherein the adhesive layer is made using a silicone polymer adhesive and the dosage unit has a releasable protective layer. 9. A transdermal polymer matrix dosage unit of claim 4 wherein the enhancing factor is at least 1.3. 10. A transdermal polymer matrix dosage unit of claim 4 wherein the enhancing factor is at least about 2. 11. A transdermal nitroglycerine or other anti-anginal pharmaceutical polymer matrix dosage unit comprising: a) a backing layer which is substantially impervious to the pharmaceutical to be delivered transder¬ mally; b) a polymeric matrix disc layer which has a thick¬ ness of from about 0.1 to about 5mm, has microdis- persed therein an amount of the pharmaceutical which can be delivered transdermally in a dosage amount, is composed of a cross-linked pol siloxane polymer with the pharmaceutical in microdispersion compartments, and has a cross sectional dimension of f om about 10 to about 200 microns; c) a polysiloxane adhesive layer which is adhered to said nitroglycerin or other anti-anginal pharma¬ ceutical containing polymer matrix disc layer and has distributed therein from about 1 to about 30 percent of one or more skin absorption enhancers based on the weight of the polysiloxane adhesive, which are effective in the enhancement of the transdermal absorption of the pharmaceutical in the polymer matrix disc layer; said dosage unit having an enhancing factor of at least 1.2. 12. A transdermal polymer matrix dosage unit of claim 11 wherein the skin permeation enhancement compound i selected from decyl methyl sulfoxide, 1-dodecylaza cycloheptan-2-one, a compound of the formula: O wherein R is H or a lower alkyl group, m is 5-7 and is 0-17;saturated and unsaturated fatty acids in thei alkyl esters, alcohols, monoglyce ides, diethanol amides, triethanolamine complex, N, N-dimethylamid derivatives, and acetate esters of said alcohol deriva tives; propyl or isopropyl myristate; myristyl alcohol propyl or isopropyl oleate; oleic acid; oleyl alcohol; oleyl acetate; monoolein; myristyl N, N-dimethyl amide; stearic acid; stearyl alcohol; propyl stearate; mono- stearin; mono-myristein; salicylic acid and deriva¬ tives; glycylglycine; N, N-diethyl-M-toluamide; squa- lane; capric acid; crotamiton; and combinations thereof. 13. A transdermal polymer matrix dosage unit of claim 11 wherein the skin permeation enhancer is selected from the group represented by the following formula: CH 3 (CH 2 ) n -C00H wherein n is an integer from 6 to 10. 14. A transdermal polymer matrix dosage unit of claim 11 wherein the skin permeation enhancer is decanoic acid. 15. A transdermal polymer matrix dosage unit of claim 11 wherein the skin permeation enhancer is a combination of decanoic acid or decanol and 1-dodecylazacyclo- heptan-2-one. 16. A transdermal polymer matrix dosage unit of claim 11 wherein both the matrix layer and the adhesive layer have eff ective amount of one or more skin permeation enhancers. 17. A transdermal polymer matrix dosage unit of claim 11 wherein the skin permeation enhancer is a combination of l-dodecylazacylcloheptan-2-one, decanoic acid and decanol or oleyl alcohol. 18. A transdermal polymer matrix dosage unit of claim 11 wherein the skin permeation enhancer is a combination of squalane, decylmethyl sulfoxide and oleyl alcohol. 19. A transdermal polymer matrix dosage unit of claim 18 in which the polymer of matrix layer is a polydimethyl¬ siloxane or polysiloxane having methylvinyl units, has about 1 to about 10 percent based on the polymer weight of dextran and at least about 10 percent by weight of nitroglycerin as the anti-anginal pharmaceutical. 20. A method of administering nitroglycerin transdermally by forming a nitroglycerin-containing polymer matrix disc dosage unit having a polymer matrix disc which has the nitroglycerin dosage microdispersed therein, which matrix disc is adhered to a skin permeation enhancer- containing adhesive polymer layer, and by applying said dosage unit by way of said adhesive layer to the skin of the subject to be treated, whereby said nitrogly¬ cerin is. transdermally administered in dosage amount systematically effective to said subject.

Inventors: CHIEN YIE W, LEE CHIA-SHUN, CHIEN, YIE, W., LEE, CHIA-SHUN
Applicants: UNIV NEW JERSEY
Application year: 1986
Main classification: A61L15
IPC codes: A61K9