KR950003696B1 - Transdermal Nitroglycerin Patches with Penetration Enhancers - Google Patents

Abstract

No content.

Description

[Name of invention]

Transdermal Nitroglycerin Patches with Penetration Enhancers

Detailed description of the invention

[Background of invention]

The present invention relates to transdermal transport of nitroglycerin, in particular through transdermal transport.

Many drugs are destroyed in the first route through the oral administration time. Because of the rapid metabolism of these drugs, the pharmacological activity and therapeutic effects of these drugs are not constant. Because of these difficulties, many different drug delivery systems have been developed. In recent years, researchers in the field of pharmacological drug transport have increased interest in the use of transdermal transport systems.

However, the use of transdermal transport systems raises efficacy issues. The device must supply the patient with a sufficient amount of pharmacologically active ingredient and the sufficient amount of drug must penetrate the patient's skin over time to achieve the desired pharmacological effect.

One approach to increasing the amount of drug being transported is to increase the concentration of pharmacologically active drug in the transport system with the expectation that simply increasing the concentration of the drug can increase the amount of drug that penetrates the patient's skin. May be included. However, this concept is limited by the amount of drug that can be administered through the skin, ie the skin acts as a rate-limiting means.

Other methods for obtaining the desired effect by increasing the drug dosage include increasing the contact surface area of the skin with the transport system. Although increasing the surface area may increase the amount of drug transported to the patient, there are, of course, practical limitations in that the surface area must be increased. The cost of manufacturing a very large transportation system is limited and patients do not prefer to use a transportation system that covers much of the skin.

A completely different concept for increasing transdermal transport of pharmacologically active agents follows the introduction of one or more dermal penetration enhancers in the drug delivery system. However, the use of such enhancers is subject to the limitation that, for example, penetration enhancers are dermatologically acceptable and the transport systems into which they are incorporated, as well as pharmacologically active agents, must be compatible.

A number of patents and publications describe penetration enhancers generally useful for the transdermal delivery of nitroglycerin. However, the penetration enhancers of the present invention are significantly superior to those previously known.

US Pat. No. 4,291,015 to Keith, et al describes the general situation in the field of transdermal transport, in particular the use of polymeric diffusion matrices for sustained release of pharmacologically active agents. This matrix is applied by the backing layer and applied to the skin to which the drug diffuses so that the drug is transdermally transported to the patient.

U.S. Patent 4,409,206 describes a related transdermal transport system in which the drug is dispersed in an adhesive (Ref. U.S. Patent 4,390,520). According to this system, the drug in use is dispersed in a pressure sensitive adhesive that adheres to the skin. The drug is simply dispersed from the adhesive and absorbed through the skin.

US Pat. No. 4,751,087 describes the use of butyl stearate, ethyl oleate and equivalent fatty acid esters having 14 to 20 carbon atoms with glyceryl monolaurate as penetration enhancer in the transdermal transport of nitroglycerin.

European Patent Application No. 123,948, published November 7, 1984, describes the use of 1-pyro glutamyloxy-2,3-dihydroxypropane as a penetration enhancer for transdermal transport of nitroglycerin.

US Patent No. 3,711,602 describes the use of dimethyl sulfoxide (DMSO) as a penetration enhancer for many drugs, one of which is nitroglycerin.

European Patent Application No. 179,277, published April 30, 1986, describes the use of dialkyl phosphates as penetration enhancers for coronary vasodilators such as nitroglycerin.

European Patent Application No. 196,769, published October 8, 1986, describes a transdermal patch consisting of an adhesive layer comprising certain preferred silicone polymer matrices and skin tackifiers. Although certain special penetration enhancers have been described as having some penetration enhancer activity, they have been shown to be inferior to many of the esters described. There is no mention of in vivo blood levels achieved through the use of selected penetration enhancers.

British Patent Application No. 2,081,582A, published February 24, 1982, describes the use of a silicone polymer backing layer in combination with a hydrophobic solvent system (such as an optical oil) to increase nitroglycerin penetration.

PCT Application No. 86/02052 (Publication No. WO87 / 01935), published April 9, 1987, describes the use of 1-dodecanoyl hexahydro-1H-azepine as well as related compounds for transdermal penetration increase. It is.

More recently, the use of oleic acid as a penetration enhancer has been taught (Cooper, Eugene, R., "Increased Skin Permeability for Lipophilic Molecules" Journal of Pharmaceutiocal Sciences, Vol. 73, No. 8, August 1984). Cooper describes the use of different concentrations of oleic acid in the presence of propylene glycol as a solid. Oleic acid appears to enhance the penetration of the active ingredient salicylic acid. Cooper also describes the use of oleic acid in combination with 1,2-butanediol. This document specifically describes that "other diols also exhibit synergistic effects with lipids, but this effect is known to decrease with increasing chain length." Cooper teaches that skin treatment with surfactants can have a practical effect in increasing the penetration of polar molecules. However, such surfactants generally do not increase the transdermal penetration of non-polar molecules. Therefore, Cooper teaches the use of oleic acid in combination with a small amount of oleic acid alone or with short chain length diols and practically opposes the use of such long chain diols by not teaching the use of large amounts of oleic acid alone or in combination with long chain diols. Doing.

US Pat. No. 4,305,936 describes topical or topical solutions consisting of corticosteroids in a carrier. The carrier consists of 1 to 4% by weight solubilizer of glycerol esters of fatty acids having 6 to 22 carbon atoms, 10 to 50% by weight alkanol co-solvent and 20 to 50% by weight water. The patent also suggests that the carrier may comprise other "non-essential ingredients" such as suitable auxiliary excipients in amounts of up to 10% by weight. Oleic acid is mentioned as a suitable auxiliary excipient. This patent does not teach any teaching about whether oleic acid may have an effect on penetration enhancement, nor does it teach any use of oleic acid alone or in combination with long-chain diols.

Oleic acid has been used as a vehicle incorporating salicylic acid and carbineoxamine (see "Percutaneous Absorption of Drugs From Oily Vehicles" Washitake, et al., Journal of Pharmaceutical Sciences, Vol. 64 No. 3, pages 397-401). . Wasashitake et al. Have demonstrated that the oleic acid effect varies depending on the active ingredient. Therefore, it is impossible to accurately predict whether skin penetration of pharmacologically active compounds is increased by the use of oleic acid.

U.S. Patent No. 4,455,146 describes a plaster composed of thermoplastic elastomer, adhesive-providing resin and active ingredient dissolved in oil or higher fatty acids. “Higher fatty acids” may be present in the range of 25 to 370 parts by weight per 100 parts by weight of thermoplastic elastomer. The active ingredient may be present in an amount ranging from 0.09 to 110 parts by weight per 100 parts by weight of the thermoplastic elastomer (see paragraph 4, lines 3 to 35). Oleic acid is referred to as "one of the preferred" higher fatty acids (see paragraph 3, lines 16-17).

European Patent Application 43,738, published January 13, 1982, discloses C ₃ -C ₄ diols, diol esters or diol ethers (including butanediol) and cell-membrane disrupting mixtures, ie compounds R ³ -X wherein R ³ is carbon number Non-terminal alkenyl having 7 to 22 and X is OH), for example, a lipophilic compound having increased skin penetration using a bicomponent vehicle containing oleic acid, linoleic acid or linolenic acid.

PCT Publication No. 87/03490, published June 18, 1987, describes a drug in which 2-ethyl-1,3-hexanediol and / or oleic acid, where the preferred oleic acid concentration is 5%, is used as a penetration enhancer. Transdermal transport is described.

U.S. Patent 4,537,776 discloses a) N-methyl-pyrrolidone, pyrididone or N- (2-hydroxyethyl) pyrrolidone, preferably N- (2-hydroxyethyl) pyrrolidone and b Transdermal transport of drugs using a combination of cell-enveloped egg compounds 1: 5 to 500: 1, such as oleic acid or oleyl alcohol, is described.

US Pat. No. 4,557,934 discloses 1-dodecyl-azacycloheptan-2-one in combination with N-substituted azacycloalkyl-2-ones such as C ₃ -C ₄ diols or N-methyl-2-pyrrolidone. (Ie Azone , Penetration-enhancing vehicle, which is available from Nlson Research and Development, Co., Irvine, CA.

European Patent Application No. 267,617, published May 18, 1988, describes a penetration-enhancing vehicle comprising a combination of lower alkanols such as ethanol and cell-external membrane scattering compounds such as oleic acid or oleyl alcohol.

U.S. Patent No. 4,322,433 describes a sustained release biphasic cream carrier suitable for nitroglycerin. This component includes C ₈ -C ₁₈ aliphatic alcohols and hydrophilic components such as water or propylene glycol in a ratio that provides a particular hydrophilic / lipophilic balance.

Although some transdermal penetration enhancers are known, there is a need for enhancers that significantly increase the rate of transdermal transport of pharmacologically active agents to patients.

Other forms of transdermal transport systems are known and each has various advantages and disadvantages with respect to transdermal transport of different forms of pharmacologically active drug. There is no conventional formulation that provides a flux of the present invention which results in an about 2 fold increase in in vitro and a 4 fold increase in vivo over commercially available transdermal nitroglycerin formulations.

Summary of the Invention

The invention relates to N-methyl-2-pyrrolidone alone or to oleic acid, linoleic acid, isopropyl, linoleate (e.g. Ceraphyl ^TM IPL, manufactured by Van Dyk Divison of Mallinckrodt, Inc., Belleville, NJ), oleyl alcohol It relates to a transdermal nitroglycerin patch comprising a carrier comprising at least one skin permeation enhancer selected from the group consisting of 1-dodecyl-azacycloheptan-2-one and butanediol and an vasodilating effective amount of nitroglycerin. When N-methyl-2-pyrrolidone is combined with other skin penetration enhancers, a combination of N-methyl-2-pyrrolidone and oleic acid is preferred.

Another aspect of the invention is oleyl alcohol, linoleic acid, isopropyl linoleate, butanediol, 1-dodecyl-azacycloheptan-2-one and oleic acid, provided that 1-dodecyl-azacycloheptan-2-one or oleic acid When present, a second penetrant enhancer) is directed to a transdermal nitroglycerin patch comprising a vasodilating effective amount of nitroglycerin together with a carrier comprising at least one skin penetrant enhancer selected from the group consisting of: As the sole penetration enhancer, a carrier containing oleyl alcohol is preferable.

Another aspect of the invention is directed to two or more regions, such as vasodilator effective amounts of nitroglycerin, pressure sensitive adhesives and N-methyl-2-pyrrolidone, oleic acid and 1-dodecyl-azacycloheptan-2-one. Two regions, one region consisting of one or more combinations of penetration enhancers selected from the group consisting of and another region consisting of vasodilator-effective amount of nitroglycerin and a penetration enhancer selected from N-methyl-2-pyrrolidone and oleyl alcohol A novel transdermal nitroglycerin patch.

Further areas of the invention include novel transdermal nitroglycerin patches as described above, separated from one another by impermeable backing material regions.

Another aspect of the invention is the application of the aforementioned transdermal patch to the skin of a person in need of vasodilation treatment, comprising administering an effective vasodilation amount of nitroglycerin to a mammal such as a human. To a method of treatment.

[details]

As used herein, the term "transdermal" is used in the conventional sense and means to introduce systemic effects by introducing and transporting pharmacological or medical compounds through the patient's skin in need of treatment.

The amount of nitroglycerin that can be received transdermally can be increased through the use of penetration enhancers. In order for a compound to be used as a transdermal penetration enhancer, the compound must meet a number of different requirements. First, the compound should be dermatologically acceptable so that no side effects, such as local irritation or local swelling, are unacceptable upon topical use. Second, penetration enhancers should be chemical with the nitroglycerin and other components of the transdermal delivery system (eg polymeric adhesives or matrices). If the penetration enhancer and nitroglycerin are incompatible, separation or chemical reactions of the components occur, resulting in inactivation or non-absorption of the nitroglycerin. Third, it is preferable that the penetration enhancer is recognized for human medicine.

The transdermal patches described herein may be in any conventional patch form such as, for example, adhesive matrices, polymeric matrices or storage patches, and generally have one or more backing layers, adhesives, nitroglycerin, one or more penetrants, and any rate control. It consists of a release liner that is removed to expose the membrane and the adhesive before application. Polymer matrix patches also include polymer-matrix forming materials.

As used herein, the backing layer can be any conventional transdermal backing material that does not react back with nitroglycerin or other ingredients in the patch. Examples thereof include foams, metal foils, polyesters, low density polyethylene, copolymers of vinyl chloride and polyvinylidene chloride and stacks thereof. Water resistant polyethylene or vinyl is preferred.

The adhesive used in the patches described herein can be a pharmaceutically acceptable pressure sensitive polymer adhesive, such as acrylic, vinyl acetate, silicone or synthetic or natural rubber adhesives. For example, acrylic adhesives such as RA 2484, RA 2333, RA 2397, R363 and R362 from Monsanto Co. are suitable. Durotak, manufactured by Morton Thiokol, Inc. And other acrylic adhesives such as Neoocryl ^™ XA 5210 manufactured by Polyvinyl Chemicals, Ltd. may be used.

Multiple silicone base adhesives, such as Q72929, Q27406, X72920 and 355, each manufactured by Dow Corning, can be used.

Vinyl acetate adhesives include Flexcryl 1614, 1617, 1618 and 1625 from Air Products. Natural and synthetic rubber adhesives include polyisobutylene, neoprene, polybutadiene and polyisoprene.

The adhesive may be used alone or in combination during the patch.

The adhesive material may also be modified, if desired, through the use of diluents or thickeners. Preferred diluents are organic or inorganic solvents such as ethanol or water. Preferred thickeners include acrylic polymer midpoints such as Union Amsco RES 6038, manufactured by Unocal. A thickener is used to adjust the viscosity of the adhesive mixture to about 6,000 to 10,000 cps for coating on the backing material. Crosslinking agents such as Aerotex Resin 3730 (manufactured by American Cyanamid) may be added to facilitate curing.

Examples of polymeric matrix materials are polyvinyl alcohol, polyvinyl pyrrolidone, gelatin and partially hydrolyzed polyvinyl alcohol. Other agents, such as gelling agents (eg Klucel ^™ , povidone or gelatin), or hygroscopic agents (eg glycerin, sorbitol or glycerol) can be incorporated into the matrix material. Such formulations facilitate handling of the matrix material and affect the nitroglycerin transport rate.

Suitable materials for rate-controlling membranes include ethylene-vinylacetate (EVA) copolymer membranes (eg, 1-20% vinylacetate), polyvinyl alcohol (PVA) gels, and silicone films.

Protective release liners used to prevent dirt from adhering to the patch during shipping and storage are made from materials such as polyethylene and polyethylene coated paper, polystyrene and polycarbonate, and are preferably silicon-coated to facilitate removal. .

As used herein, dermal penetration enhancers include one or more of the following: N-methyl-2-pyrrolidone, 1-dodecyl-aza, respectively, at selected concentrations when used alone or in combination to increase flow. Cycloheptan-2-one, oleic acid, oleyl alcohol, linoleic acid, isopropyl linoleate and butanediol.

As used herein, the term "% concentration" is the weight ratio of a particular component to the total weight of the patch. The total patch weight represents the weight of the adhesive matrix, polymer matrix or storage component but does not include the weight of the backing material, release liner or rate-controlling membrane.

When N-methyl-2-pyrrolidone is used as a penetration enhancer, it may be present in amounts ranging from about 5 to 30% concentration. When used alone as a penetration enhancer, the preferred concentration of N-methyl-2-pyrrolidone is 10-20%. When used in combination with other penetration enhancers, the preferred concentration of N-methyl-2-pyrrolidone is 10%.

When oleic acid is used herein as a penetration enhancer, it is used at a concentration of 2.5 to 10% with N-methyl-2-pyrrolidone, 1-dodecyl-azacycloheptan-2-one, linoleic acid or isopropyl linoleate. . As used herein, the preferred concentration of oleic acid is 10%.

When 1-dodecyl-azacycloheptan-2-one in the present invention is used as a penetration enhancer, it is generally in the range of 5 to 20% concentration and used with N-methyl-2-pyrrolidone, oleic acid or oleyl alcohol. do. As used herein, the preferred concentration of 1-dodecyl-azacycloheptan-2-one is 10%.

When oleyl alcohol is used herein as a penetration enhancer, it is used alone or in combination with other penetration enhancers at a concentration of 5 to 20%, preferably about 10%.

Similarly, linoleic acid, if present, is used at a concentration of 5 to 15% and a 10% concentration is preferred, butanediol is used at a concentration of 2 to 10% and a 5% concentration is preferred if present. If present, linoleic acid and butanediol are used in admixture at 10% concentration and 5% concentration, respectively.

If present, isopropyl linoleate is used at a concentration of about 5-30%, with a concentration of about 10% being preferred.

Skin penetration enhancers are 10% concentration in oleyl alcohol alone, preferably about 10% N-methyl-2-pyrrolidone and 10% oleic acid in combination.

Adhesive matrix transdermal devices are preferred and methods for their preparation are known in the art. Preferred methods for making the adhesive matrix transdermal device of the present invention include casting a thin layer of a polymer blend (i.e. a mixture of adhesive, active ingredient, skin penetration enhancer and adhesive diluent or sensitizer) onto the material used as the removal liner. Curing the polymer blend (including drying in an oven) to form a polymer adhesive and laminating the backing material to the resulting adhesive layer. A suitably standardized patch can then be punched out automatically, preferably the patch is sealed in a protective pouch.

According to a preferred method, the polymer blend layer thickness cast on the removal liner is from about 5 mils to about 10 mils. The cast layer is preferably dried at about 80 ° C. for about 20 minutes. Specific examples of formulations are shown below.

Polymer matrix transdermal patches are also prepared by known methods. If a polymer matrix is present, the adhesive is used to coat the backing layer, adhere the polymer matrix to the backing layer, and the adhesive edge around the polymeric matrix to allow the patch to adhere to the skin while allowing the drug to move directly from the matrix to the skin. Leaves. Alternatively, the polymeric matrix can be attached to the back and the adhesive can be coated on the back around the matrix.

Storage-patches may also be prepared by known methods. For example, an adhesive layer can be applied to the removal liner, the rate-controlling membrane can be laminated to the adhesive side, and a portion of the solution comprising nitroglycerin and one or more penetration enhancers (eg polymer blends) can be placed on the membrane. The back material may then be heat-sealed to the rate-controlling membrane around the patch edge.

Representative examples of formulations where unexpectedly good flow occurs in nitroglycerin transdermal patches are described in the Examples below.

Example 1

(Adhesive matrix)

Component% (w / w)

Acrylic Adhesive 37.4

Acrylic Polymer Thickener 2.6

N-methyl-2-pyrrolidone 10

Oleic acid 10

Nitroglycerin 40

100

Method of manufacture:

Combine the adhesive, penetration enhancer, thickener and nitroglycerin and mix until soft. Record the viscosity and, if desired, add a thickener to increase the viscosity of the adhesive blend to the required level.

The polymer blend is cast into 5-10 mil layers on the removal liner. The layer is dried at 80 ° C. for 20 minutes. The backing material is laminated to a dry polymer film using conventional apparatus.

Using an automatic punch machine, punch into a patch of the desired size. Using a pouch machine, the patch is wrapped in a pouch and heat-sealed and sealed.

Example 2

(Adhesive matrix)

Component% (w / w)

Acrylic Adhesive 47.4

Acrylic Polymer Thickener 2.6

Oleyl alcohol 10.0

Nitroglycerin 40.0

100.0

The method described in Example 1 is used.

Example 3

(Adhesive matrix)

Component% (w / w)

Acrylic adhesive 42.4

Acrylic Polymer Thickener 2.6

Linoleic acid 10.0

Butanediol 5.0

Nitroglycerin 40.0

100.0

The method described in Example 1 is used.

Example 4

(Adhesive Matrix)

Component% (w / w)

Acrylic adhesive 34.8

Silicone adhesive 3.9

Acrylic Polymer Thickener 1.3

m-pyrrole 10.0

Oleic Acid 10.0

Nitroglycerin 40.0

100.0

The method described in Example 1 is used.

Example 5

(Polymer matrix)

Component% (w / w)

Glycerin 11.5

Polyvinyl Alcohol 25.3

Polyvinyl Pyrrolidone 3.1

Nitroglycerin 22.0

Oleyl Alcohol / Oleic Acid 10.0

Water 28.1

100.0

Method of manufacture:

The combined glycerin and water are heated to 90 ° C. and after reaching 70 ° C. or higher, polyvinyl alcohol and polyvinyl pyrrolidone are added slowly and stirred at 90 ° C. until decomposition is complete. Oleyl alcohol and oleic acid are added, stirred, nitroglycerin is added and stirred until thoroughly mixed.

The mixture is poured into glass or stainless butyl to prepare a matrix about 3-4 mm thick. The matrix is dried for 10-16 minutes and then cut to the desired size to adhere to the backing material.

In vitro flow test results demonstrate the superiority of the formulations described herein that were not expected and are shown in Table 1 below (m-pyrrole is another name for N-methyl-2-pyrrolidone). The flow rate of nitroglycerin (μg / cm 2 / hour) from different transdermal patches is measured through the heat-separated human carcass epidermis using single compartment diffuse cells.

TABLE 1

From the above results in Table 1, it can be seen that the formulations described herein have a significantly better flow increase than the baseline (ie, formulations without penetration enhancers).

In order to treat patients requiring coronary vasodilation using the patches described herein, the clinician should check the severity of the treatment, the age, weight and overall condition of the patient. The clinician then selects a particular patch to contain and transport the desired amount of nitroglycerin for application to the skin of the patient. For example, conventional nitroglycerin patches described herein contain about 5 to about 120 mg of nitroglycerin and preferably contain about 40 mg and have an area of about 5 to about 20 cm 2, preferably about 10 cm 2. One patch is applied to the patient's skin and removed and replaced after 24 hours to allow for continuous coronary vasodilation to occur. Of course, the patient may use a few or multiple patches, the elapsed time of application of the patch, or other unique clinical modifications of the therapies described above, as determined by the clinician.

Another aspect of the invention is the unique absorption profile of nitroglycerin as evidenced from direct transdermal patches. While commercially available nitroglycerin patches have proven to be progressively extinguished by drug absorption, these patches provide a constantly changing absorption profile that results in a curved profile contrary to the prolonged plateau effect. This curved profile indicates that the blood concentration increases over 12 to 14 hours, maintained for a period of time, and then decreased. Recently, it has been suggested that the administration of commercially available patches can lead to drug resistance, which can be prevented by intermittent administration, ie by removing the patch and not administering the drug for a certain period of time (preferably overnight) within each 24 hour period. come. In fact, the patch of the present invention can be intermittently administered without having to be removed for a certain time, thereby improving patient satisfaction.

In another aspect of the invention, the preceding transdermal patch formulations can be combined in a single patch arrangement in which the formulations act independently of each other. For example, concentric ring patches with central and outer regions are one such patch. The use of such patches, and the exceptionally good flow increase produced by the dual-formulation patches, are illustrated in Table 2 below. As can be seen from Table 2, the surface areas of the patches tested are the same, and the surface areas of the central and outer ring regions remain constant.

TABLE 2

From the data, it can be seen that transdermal nitroglycerin patches using penetration enhancers, as herein provided, provide a much better flow increase than prior formulations.

Claims (6)

The vasodilator effective amount of nitroglycerin and N-methyl-2-pyrrolidone is alone or in an amount of from about 5 to about 30% of the total patch weight or from about 2.5 to about 10% of the patch weight Oleyl alcohol in an amount from about 5 to about 20% by weight, oleic acid in an amount from about 5 to about 15% by weight of the patch, isopropyl linoleate in an amount from about 5 to about 30% by weight of the patch, by weight of the patch A carrier comprising at least one skin penetration enhancer selected from the group consisting of 1-dodecyl-azacycloheptan-2-one in an amount of 5 to about 20% and butanediol in an amount of about 2 to about 10% by weight of the total patch. Adhesive, polymeric matrix or hypotonic nitroglycerin patches. Vasodilator effective amount of nitroglycerin, about 5 to about 20 weight percent of oleic alcohol, patch weight of about 5 to about 15% linoleic acid, patch weight of about 5 to about 30% isopropyl Linoleate, and at least one skin penetration enhancer selected from the group consisting of about 2% to about 10% butanediol by weight of the patch charge or about 5% to about 20% of 1-dodecyl-azacycloheptan-2 by the total weight of the patch. -An adhesive, polymeric matrix or hypotonic transdermal nitroglycerin patch comprising a carrier comprising at least one skin permeation enhancer selected from the group consisting of about 2 to about 10% of oleic acid in the total weight of the patch. A vasodilating effective amount of nitroglycerin distributed between the two regions, wherein one region comprises nitroglycerin and from about 5 to about 30% of the total patch weight of N-methyl-2-pyrrolidone, the total patch weight A first carrier comprising at least one skin penetration enhancer selected from the group consisting of about 2.5 to about 10% oleic acid and about 5 to about 20% 1-dodecyl-azacycloheptan-2-one of the total weight of the patch And a second region comprising nitroglycerin and from about 5% to about 30% by weight of the total weight of the patch or N-methyl-2-pyrrolidone or from about 5% to about 20% of the oleyl alcohol by weight of the total patch. A transdermal nitroglycerin patch comprising a carrier. Vasodilatation effective amount of nitroglycerin, N-methyl-2-pyrrolidone alone or consisting of oleic acid, oleyl alcohol, linoleic acid, isopropyl linoleate, 1-dodecyl-azacycloheptan-2-one and butanediol A method for preparing a transdermal nitroglycerin patch characterized by mixing with a carrier comprising at least one skin penetration enhancer selected from the group and applying the resulting mixture to the backing material. A vasodilating effective amount of nitroglycerin comprises at least one skin penetration enhancer selected from the group consisting of oleyl alcohol, linoleic acid, isopropyl linoleate, butanediol, 1-dodecyl-azacycloheptan-2-one and oleic acid, 1 When dodecyl-azacycloheptan-2-one or oleic acid is present, a second penetrant enhancer is mixed with a carrier present and the resulting mixture is applied to the backing material to produce a transdermal nitroglycerin patch. Way. (a) a portion of the vasodilator effective amount of nitroglycerin is selected from about 5 to about 30% of the total patch weight of N-methyl-2-pyrrolidone, about 2.5 to about 10% of the total patch weight of oleic acid and the total patch weight. Mixing the resulting mixture with a first carrier comprising at least one skin penetration enhancer selected from the group consisting of about 5 to about 20% 1-dodecyl-azacycloheptan-2-one and applying the resulting mixture to the first region of the backing material To; (b) a portion of the vasodilator effective amount of nitroglycerin comprising about 5 to about 30% N-methyl-2-pyrrolidone of the total weight of the patch or about 5 to about 20% oleyl alcohol of the total weight of the patch. A method for producing a dermal patch comprising a vasodilating effective amount of nitroglycerin distributed between two regions, characterized by applying a mixture obtained by mixing with a second carrier to a second region of the backing material.