JPH04503519A - Transdermal nitroglycerin patch with penetration enhancer - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Weight of transdermal nitroglycerin batch Komei containing penetration enhancer The present invention relates to the transdermal release of nitrogcerin, particularly by using penetration enhancers. Regarding transdermal release.

Many drugs are destroyed during the first pass through the liver when taken orally. Destroyed. The rapid metabolism of the above-mentioned drugs limits the pharmacological activity of these drugs. In consideration of these difficulties, a large number of various treatments have been used. Release systems have been developed. In recent years, drug The field of drug release has attracted increasing attention from researchers.

However, efficacy issues arise when using transdermal delivery systems.

The device must deliver a sufficient amount of the pharmaceutically active ingredient to the patient; and sufficient amounts of the drug to produce the desired pharmacological effect over a period of time. In order to achieve the desired efficacy over a given period of time, it must penetrate the patient's skin. Various means can be used to obtain .

One means of attempting to increase the amount of drug released is to simply increase the concentration of drug. can increase the amount of drug penetrating the patient's skin by increasing By including higher concentrations of the pharmaceutically active agent in the delivery system in the hope that It was thought that However, this concept can be administered through the skin. ie, the skin acts as a rate limiting means.

Another means of increasing the amount of drug administered and thereby the desired effect Obtaining includes increasing the surface area of the delivery system that contacts the skin.

An increase in surface area increases the amount of drug released to the patient; There are practical limits to increasing this surface area. extremely large The cost of producing a release system is high, and it is difficult to manufacture a release system that covers a large portion of the skin. It is inconceivable that a patient would wear a delivery system that does this.

A completely different concept for increasing the transdermal release of pharmaceutically active agents is the drug release system. This is done by incorporating one or more skin penetration enhancers into the system. but However, the use of such enhancers is subject to certain limitations, e.g. The pharmaceutical agent is a dermatological agent with respect to the pharmaceutically active agent and the release system in which it is formulated. must be physically acceptable and compatible.

Numerous patents and publications indicate that penetration enhancers are generally used to administer nitroglycerin transdermally. Therefore, it was disclosed that it is useful for releasing. However, the present invention The penetration enhancer is surprisingly #J superior to previously known penetration enhancers.

U.S. Pat. No. 4,291,015 to Kieth et al. The general state of the art is presented and, in particular, for the specific release of pharmaceutically active agents. The use of a polymeric diffusion matrix is disclosed. Matri yku the drug is applied to the skin where it is covered by the support layer and diffusion of the drug occurs; The drug is then delivered transdermally to the patient.

U.S. Pat. A related transdermal delivery system has been disclosed (U.S. Pat. No. 4,390,520). According to this system, the drug does not adhere to the skin during use. dispersed in a pressure-sensitive adhesive. The drug easily diffuses from the adhesive and penetrates the skin. absorbed through.

U.S. Pat. No. 4,751.087 describes butyl stearate, ethyl oleate, Glyceryl and equivalent fatty acid esters with 14 to 20 carbon atoms Penetration enhancer in transdermal release of nitroglycerin in combination with monolaurate It is disclosed that it can be used as

In European Patent Application No. 123.948, published on November 7, 1984, Logglutamyloxy-2,3-dihydroxypropane is administered transdermally to nitroglycerin. It is disclosed for use as a penetration enhancer for sexual release.

U.S. Pat. No. 3,711,602 discloses that dimethyl sulfoxide (DMSO) is used as a penetration enhancer for a number of drugs, one of which is nitroglycerin. This is disclosed.

European Patent Application No. 179,277, published April 30, 1986, states that nitro Dialkyl phosphates as penetration enhancers for coronary vasodilators such as glycerin It is disclosed whether it is used.

European Patent No. 196,769, published October 8, 1986, discloses certain advantages. Adhesive layer containing a desirable silicone polymer matrix and skin penetration enhancer. A transdermal batch is disclosed. Some special penetration enhancers may slightly Disclosed as having permeation-enhancing activity, but inferior to many disclosed esters The infiltration obtained by using 9 selected penetration enhancers has been shown to There is no mention of in-vivo blood concentrations.

British Patent Application No. 2,081,582A published February 24, 1982, Combining a silicone bomber support layer with a hydrophobic solvent system (e.g. mineral oil) It has been disclosed that nitroglycerin can be used in combination to promote the penetration of nitroglycerin.

PCT Application No. 86102052 published on April 9, 1987 (Publication No. WO 37101935) for transdermal penetration enhancers. The use of hydro-IH-azepine and related compounds is disclosed.

More recently, there has been evidence regarding the use of oleic acid as a penetration enhancer.

[Cooper, Eugene, R.I. Increased skin permeability of lipophilic molecules (Increased SkinPerme ability for Lipophilic Molecules), Jo Urnal of Pharma-ceutical 5 Sciences, 73 Volume, No. 8, August 1984. discloses the use of various concentrations of oleic acid in the presence of pyrene glycol. . Oleic acid is thought to facilitate the penetration of the active ingredient salicylic acid. Change Cooper described the use of oleic acid in combination with 1°2-butanediol. is disclosed. Specifically, the paper states, ``Other diols also exhibit this cooperative effect with lipids. However, the effect becomes less pronounced as the chain length increases. It has been shown that Cooper treats the skin with surfactants can have a substantial effect on increasing the penetration of polar molecules. This shows that However, such surfactants are usually non- does not increase transdermal penetration of polar molecules; therefore, Cooper The use of phosphoric acids alone or in combination with short chain length diols is only indicated. and large amounts of oleic acid alone or with long chain length diols. It does not include anything about using them in combination, and in fact, This is shown in contrast to the use of long chain diols.

US Pat. No. 4,305,936 discloses a method consisting of a corticosteroid in a carrier. A topical or topical application solution is disclosed. The carrier contains 6 to 22 carbon atoms. Solubilization of glycerol esters of fatty acids with JP11-4jij! −%, Al Canol co-solvent 10-50% by weight and water 20-5Of! Consists of amount%. Furthermore , the patent states that the carrier may contain other "non-essential ingredients", e.g., in amounts up to 10% by weight. It is stated that suitable auxiliary adjuvants can be included. oleic Acids are mentioned as suitable auxiliary adjuvants. The patent states that oleic acid Contains all information regarding the effect that the drug may have on promoting penetration. It is unlikely that large amounts of oleic acid, alone or in combination with long-chain diols, It cannot be assumed that all matters related to the use of these materials are included.

Oleic acid is used as a vehicle with salicylic acid and carbinoxamine. used. “Percutaneous absorption of drugs from oily vehicles” Absorption of Drugs From 0ily Vehicle es), Washitake et al., Journal of Pha rmaceutical 5 sciences.

64, No. 3, pp. 397-401, Washitake et al. It has been demonstrated that the effects of the drug vary depending on the active ingredient. Therefore, pharmaceutical activity The skin penetration of sexual compounds may be enhanced by the use of oleic acid. It is impossible to predict exactly what will happen.

U.S. Pat. No. 4,455,146 describes heat dissolved in oil or higher fatty acids. A plaster consisting of a plastic elastomer, a tackifying resin and an active ingredient Disclosed. "Higher fatty acid" is 2 parts per 100 parts by weight of thermoplastic elastomer. The active ingredient, which may be present in a range of 5 to 370 parts by weight, is a thermoplastic elastomer. may be present in an amount ranging from 0.09 to 110 parts by weight per part by weight of , lines 3 to 35), oleic acid is one of the "preferred" higher fatty acids. ” (see column 3, lines 16-17).

In European Patent No. 43,738 published on January 13, 1982, 03-C4 di ols, diol esters or diol ethers (including butanediol) and and cell envelope-disrupting compounds, such as compound R3-X [wherein R3 is 7 non-terminal alkenyl having ~22 carbons and X can be OH (e.g., oleic acid, linoleic acid) Enhanced dermal penetration of lipophilic compounds using a method is disclosed.

PCT Publication No. 87103490 published on June 18, 1987 states that 2-ethyl-1,3-hexanediol and/or oleic acid as promoters Transdermal release of a drug using a preferred oleic acid concentration of 5% is disclosed. ing.

U.S. Pat. No. 4,537,776 discloses (a) N-methylpyrrolidone, pyrrolidone, Lydone or N-(2-hydroxyethyl)pyrrolidone, preferably N-(2- (hydroxyethyl) pyrrolidone; and (b) iMB cell efenvero-1 damage. Transdermal delivery of drugs with a ratio of 1=5 to 500:1 is disclosed.

U.S. Pat. No. 4,557,934 describes 1-dodecyl-azacyclohebutylene Ru.

In European Patent Application No. 267,617 published on May 18, 1988, ethano Lower alkanols such as alcohols and cell envelope damaging compounds, e.g. A penetration-enhancing vehicle containing a combination of InPi or oleyl alcohol is It is shown.

U.S. Pat. No. 4,322,433 describes a biphasic solution suitable for nitroglycerin. The sustained release of the ream carrier has been disclosed. As a component, 08-C18 aliphatic Alcohol and hydrophilic components, such as water or propylene glycol, are Included in a ratio that provides a hydrophilic/lipophilic equilibrium value.

Although many transdermal penetration enhancers are known, transdermal administration of pharmacologically active drugs to patients is There remains a need for enhancers that significantly increase the rate of sexual release.

Other types of transdermal release systems are known, each with varying pharmaceutical activity. It has numerous advantages and disadvantages for transdermal drug delivery. With conventional formulations , none give the release seen with the present invention, and the in vitro results of the present invention showed approximately a 2-fold increase in penetration over commercially available transdermal nitroglycerin formulations, In vivo results show an increase of approximately 4@.

Ordinary Q! illusion The present invention comprises a vasodilatory effective amount of nitroglycerin in combination with a carrier; The above carriers, N-methyl-2-pyrrolidone alone, oleic acid, lysate, etc. Nolic acid, isopropyl linoleate [e.g. Pan Dyke Division O Van Mallinckrodt Incorporated (Van DykDivision) of Mallinckrodt. Inc. ), Berby, New Chassis le alcohol, 1-dodecyl-azacyclohebutan-2-one and butanedi combination with at least one skin penetration enhancer selected from the group consisting of all Apply to a transdermal nitroglycerin patch. N-methyl-2-pyrroli When combining Don with another skin penetration enhancer, N-methyl-2-pyrrolidone and A combination of oleic acid is preferred.

Another embodiment of the invention provides for combining a vasodilatory effective amount of nitroglycerin with a carrier. the carrier is oleyl alcohol, linoleic acid, linoleic acid Isopropyl, butanediol, 1-dodecyl-azacyclohebutan-2-one and at least one skin penetration enhancer selected from the group consisting of oleic acid. with the exception of 1-dodecyl-azacyclohebutan-2-one or oleic acid with the proviso that if present, a second penetration enhancer must be present. , including transdermal nitroglycerin patches. Olay as a standalone penetration enhancer A carrier comprising alcohol is preferred.

Yet another aspect of the invention provides that two or more regions, e.g., one region is vasodilatory. an effective amount of nitroglycerin, a pressure sensitive adhesive, and N-methyl-2-pyrrolidone; selected from the group consisting of leic acid and 1-dodecyl-azacyclohebutan-2-one; at least one penetration enhancer selected, the other region being , a vasodilatory effective amount of nitroglycerin, and N-methyl-2-pyrrolidone and and one type of penetration enhancer selected from oleyl alcohol. A novel transdermal nitroglycerin patch containing

Furthermore, the invention provides that the regions are separated from each other by portions of impermeable support material. including the novel transdermal nitroglycerin patch described above. The preferred patch is , contains two regions: a central region and an outer region.

In yet another aspect, the invention provides for administering a vasodilatory effective amount of nitroglycerin. administering a vasodilatory effective amount of nitroglycerin to a human in need of such treatment. applying a transdermal patch as described above to the skin of said human. The present invention relates to the treatment of mammals, such as humans, including the application of nitrates.

Explanation of Emperor Shinae As used herein, the term "transdermal" has its conventional meaning. through the skin of patients requiring this type of treatment, which is used to elicit systemic effects. Refers to the introduction and release of pharmacological or pharmaceutical compounds. Therefore, medicine Transdermal release of drugs goes beyond mere topical application of drugs to treat diseases, symptoms or disorders. It is effective for treatment. The transdermal system described herein It is useful in eliciting a vasodilatory effect through the release of serine.

The amount of nitroglycerin that can be released transdermally is determined by using penetration enhancers. It can be increased by A compound may be useful as a transdermal penetration enhancer. To be of use, a compound must meet a number of different requirements. First, the compound may produce unacceptable adverse reactions when used topically. , dermatological, for example, does not cause local irritation or swelling. Second, the penetration enhancer must be scientifically acceptable, such as nitroglycerin or and other components of the transdermal delivery system (e.g., polymeric adhesives or matrices) Penetration enhancer and nitroglycerin must be compatible If the nitroglycerine is Or it may be made non-absorbable. Third, the penetration enhancer is suitable for human medicinal use. Preferably, it is approved for use.

Transdermal batches not described herein may include, for example, adhesive matrices, polymer Conventional optional method by batch matrix or reservoir generally includes one or more support layers, an adhesive, nitroglycerin, 1 More than one kind of penetration enhancer, any rate controlling membrane and remove before application to expose the adhesive Consists of a release liner. The polymeric matrix batch further comprises a polymeric matrix. -contains a matrix molding material.

As used herein, the support layer is composed of nitroglycerin or other ingredients of the batch. Examples of conventional transdermal support materials that do not adversely react include: Foam, metal foil, polyester, low density polyethylene, vinyl chloride and polyvinyl chloride Liden copolymers and their laminates. Water resistant polyethylene or similar Vinyl is preferred.

The adhesive used in the batches described herein can be any pharmaceutically acceptable Pressure-sensitive polymer adhesives, such as acrylic adhesives, vinyl acetate adhesives, silicone For example, Monken 1 -・RA2484, RA233 from Mon5anto Co,) 3. Acrylic adhesives such as RA2397, R363 and R362 are suitable. Ru. Other acrylic adhesives, such as Molton Thiokol Incoholate Durotak manufactured by Morton Th1okol, Inc. (Durotak) ■ and Polyvinyl Gemmicals Limited <Polyv Neocryl by inyJ Chemicals, Ltd. ) TMXA5210 may be used.

A number of silicone-based adhesives, such as Dow-Corni Q72929, Q27406, X72920 respectively manufactured by and 355 may be used.

As a vinyl acetate adhesive, Air 10 Ducts (Air Products) Flexcryl 1614.1617.1618 and There are 1625. Natural and synthetic rubber adhesives include polyisobutylene, There are oprene, polybutadiene and polyisoprene.

Adhesives may be used alone or combined in batches.

The adhesive material may be further modified, if necessary, by the use of diluents or thickeners. Preferred diluents are organic or inorganic solvents, such as ethanol or It's water. Preferred thickeners include acrylic polymer thickeners, such as Uno Union Am5co R by Unocal There is ES6038. A thickener is used to increase the viscosity of the adhesive mixture from about 6,000 to 10 ．． Adjust to 0OOcps and coat onto the support material. Crosslinking agents, e.g. Aero Typhoid resin (Aerotex Re5in) 3730 [American cyanamide (American Cyanamide) may be added to accelerate curing.

Examples of polymeric matrix materials are polyvinyl alcohol, polyvinylpyrroli Don, gelatin and partially hydrolyzed polyvinyl alcohol. @of Drugs may be incorporated into the matrix material, for example gelling agents, e.g. Klucel™, povidone or gelatin; or hygroscopic agents such as gelatin; Lyserine, sorbitol or glycol. With such drugs, The matrix material is easier to handle and more easily releases nitroglycerin. Affects output speed.

Suitable materials for rate control membranes include ethylene-vinyl acetate (EVA) copolymers. membrane (e.g. vinyl acetate 1-20%), polyvinyl alcohol (PVA) gel or and silicone coating.

Protection used to prevent dirt from sticking to batches during transport and storage Release liners for polyethylene and polyethylene-coated paper, polystyrene and manufactured from materials such as polycarbonate and preferably not easily removable. coated with silicone.

The skin penetration enhancers used herein are as follows: N-methyl-2- Pyrrolidone, 1-dodecyl-azacyclohebutan-2-one, oleic acid, oleic acid alcohol, linoleic acid, in70 linoleic acid and butanediol. one or more, each used alone or in combination to increase release; Contains at selected concentrations when used.

As used herein, the term "temperature %j" refers to the total batch weight. Concerning the weight ratio of specific components to each other. Total batch weight refers to adhesive matrix , refers to the weight of the polymeric matrix or reservoir contents, but not the supporting material. , does not include a release liner or rate controlling membrane.

When N-methyl-2-pyrrolidone is used as a penetration enhancer, it is used at a concentration of about 5 to It can be present in an amount of about 30%. N when used as a sole penetration enhancer The preferred concentration of -methyl-2-pyrrolidone is 10-20%. Promotion of @ penetration Preferred concentrations of N-methyl-2-pyrrolidone when used in combination with promoters is 10%.

When oleic acid is used herein as a penetration enhancer, it is 2-pyrrolidone, 1-dodecyl-azacyclo 7\butan-2-one, linoleic acid or used in combination with isopropyl linoleate at a temperature of 2.5-10% .

The preferred concentration of oleic acid used herein is 10%.

1-dodecyl-azacyclohebutan-2-one is used as a penetration enhancer in the present invention. When used in In this specification, used in combination with don, oleic alcohol or oleyl alcohol. The preferred concentration of 1-dodecyl-azacyclohebutan-2-one when used in It is 10%.

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

Similarly, linole numbers, if present, are used at concentrations of 5-15%, with 10% being preferred. and if butanediol is present, it is used at a concentration of 2 to 10%, 5% is preferred, preferably when linoleic acid and butanediol are present are used in combination at concentrations of 10% and 5%, respectively.

Impropyl linoleate, if present, is used at a temperature of about 5-30% and about 1 0% is preferred.

Preferred skin penetration enhancers include oleyl alcohol alone at a concentration of 10% as well as Combination of N-methyl-2- and lolidone at 10% and oleic acid at a concentration of 10% It's a combination.

Adhesive matrix transdermal devices are preferred and methods for making them include There are no methods known in the art for manufacturing the adhesive matrix transdermal device of the present invention. The preferred method for A thin layer of permeation enhancer and adhesive diluent or thickener) can be used as a release liner. The polymer blend is then cured to form a polymer adhesive. (including shaping and drying in an oven), and then laminating the support material to form the result. The next step, which includes applying an adhesive layer to the suitably sized batch, is automatically The batch is preferably sealed in a protective pouch.

The layer of polymer blend cast on the release liner according to the preferred method is preferably Typically, the thickness is about 5 mils to about 10 mils. The cast layer is preferably about 8 Dry for about 20 minutes at a temperature of 0°C. Specific examples of formulations are shown below.

Polymeric matrix transdermal batches are also manufactured by known methods. Poly If a polymeric matrix is present, coat the support layer with an adhesive and The mercuric matrix can be adhered to its support layer, fixing the batch to the skin At the same time, a polymeric matrix is used to transfer the drug directly from the matrix to the skin. You can leave a rim of adhesive around the trix. Alternatively, a polymeric matrix The matrix can be adhered to the support and the adhesive can be applied around the perimeter of the matrix. It may also be coated onto a support.

Reservoir-type patches can also be manufactured by known methods, e.g. adhesive A layer of adhesive can be applied to the release liner and a rate controlling membrane is laminated to the adhesive side. part of the solution containing nitroglycerin and one or more penetration enhancers. minutes (e.g. polymer blend) onto the membrane! and then support The material can be heat sealed to the rate controlling membrane around the edge of the patch.

Alternative formulations yielding surprisingly superior release in nitroglycerin transdermal patches A representative example is provided in the Examples below.

Inusei 1 (adhesive matrix) Ingredients: Kageyu-tachi Z-tachiage Acrylic adhesive 37.4 Acrylic polymer thickener 2.6 N-methyl-2-pyrrolidone 10 Oleic acid 10 Crying method: Mix and smooth adhesive, penetration enhancer, thickener and nitroglycerin Mix until . Blend the adhesive by checking the viscosity and adding thickener if necessary. Increase the viscosity of the resin at the required level.

A 5-10 mil layer of the polymer blend is cast onto the release liner. That layer is 8 Dry for 20 minutes at 0°C. Dry the supporting material into a thin polymer film using conventional equipment layered on.

Punch out patches of desired dimensions using an automatic punching machine; punch out patches using a pouch machine; is enclosed in a pouch and sealed by heat sealing.

Hanjeong District λ (Adhesive matrix) Ingredients Acrylic adhesive 47.4 Acrylic polymer thickener 2,6 Oleyl alcohol 10.0 The method described in Example 1 is used.

Kanjeong-ku Dan (adhesive matrix) Company Xniji◇Lee Acrylic adhesive 42.4 Acrylic polymer thickener 2.6 Linoleic acid 10.0 Butanediol 5.0 The method described in Example 1 is used.

A copy of the sample (adhesive matrix) Aruko X Koji Z standing Acrylic adhesive 34.8 Silicone adhesive 3.9 Acrylic polymer thickener 1.3 m-pyrrole 10.0 Olein'fIi10.0 The method described in Example 1 is used.

cold weather (polymer matrix) Polyvinyl alcohol 25.3 Polyvinylpyrrolidone 3.1 Nitroglycerin 22.0 Oleyl alcohol/oleic acid 10.0 method Mix Gesselin and water and heat to 90°C; then incubate at least 70°C. After gradually adding polyvinyl alcohol and polyvinylpyrrolidone, Stir at 90°C until dissolution is complete. oleyl alcohol and oleic acid Add, stir, add nitroglycerin, and stir until thoroughly mixed.

The mixture is molded into a glass or stainless steel mold with a thickness of about 3 to 4 mm. Manufacture the matrix. After drying the matrix for 10-60 minutes, the desired Cut to size and glue to support material.

In vitro release studies demonstrating the unexpected superiority of the formulations described herein. The results are shown in Table 1 below (m-pyrrole is another name for N-methyl-2-pyrrolidone. ) 0 Release rate of nitroglycerin from various transdermal patches (μg/cm 2/hr) using a single compartment of cells spreading through heat-isolated human cadaveric epidermis. was measured.

rainbow emission <rrcq/cm2/hour) Penetration enhancer orthoacrylic 11.3±0.5 7.6±2.07 8.9±2. 40% nitro in 6 series adhesive glycerin 2) Warm punishment 10%m-Pyrrole 21.1±3.1 12.4±0.36 None 15%m- Pyrrole None 13.2±2.7 None 20% m-pyrrole 17.5±1. 96 None None 10% Oleyl Alcohol None None 17.0±0.31 0% linoleic acid None None 16.7±3.3+5% Butanediol 10% m-pyrrole None None 16.2±1.5+2.5% Oleic acid 10% m-pyrrole None None 11.1 ± 3.1 + 5% oleic acid 10% m-pyrrole None 29.7±5.56 None From the results in Table 1 above, The formulations described herein are intended to exceed the standard (i.e., penetration enhancer failure). It can be seen that it also provides excellent release promotion.

Treating a patient in need of coronary vasodilation using the batch described herein For this reason, the clinician should go to the hospital! severity of symptoms and patient age, weight, and overall Next, the clinician must consider the clinical symptoms of the patient's skin. to select a specific batch that contains and releases the desired amount of nitroglycerin. For example, a typical nitroglycerin batch described herein is It may contain about 5 to about 120 mg, preferably about 40 mg, of glycerin; The area can be about 5 to about 20 cm, preferably about 100 m2. , one batch is applied to the patient's skin, removed and replaced after 24 hours, and the main Of course, patients who undergo qualitatively continuous coronary vasodilation are selectively and even fewer. or as determined by the clinician with instructions to use a larger number of batches. the duration of the batch or other proprietary clinical variations to the regimen described above; Adjust.

Another aspect of the invention is that the nitroglycerin demonstrated from the present transdermal batch This is due to its unique absorption profile. Currently available nitroglycerides This batch has been proven to absorb sero-orders of drugs, but this batch Constant variation resulting in a curvilinear profile as opposed to a period plateau effect. Provides an absorbing profile that changes the absorption profile. This curve profile shows that the blood concentration is 12~ near M, which shows an increase for 14 hours, a steady state for a certain period of time, and then a decrease; that dosing from currently commercially available batches can lead to drug resistance; The provision of medication must proceed in the direction of intermittent dosing, e.g. The batch must be removed for a period of time (preferably overnight) in an open cycle and It was suggested that the drug should not be administered. Basically, this batch is Such I! without the need to remove batches for a fixed time! IT provides continuous medication and This also reduces the burden on patients.

In another embodiment of the invention, the transdermal batch formulations described above are may be combined in a single batch form to give separately functional formulations, e.g. , a concentric ring batch with a central part and an outer part is the end of this kind of batch. be. The use of this type of batch and the enhanced release produced by this dual formulation batch The surprising delinquency of Susumu is illustrated in Table 2 below. The surface areas were equal and the surface areas of the center and outer ring parts were kept constant. Note.

Clothes Release (mg/am2/hour) Experiment 1 Experiment 2 Total pig Penetration enhancer-incompatible acrylic adhesive 4.8±0.6 5.1±0.640% Troglycerin A record of intoxication] l Yiso Loyalty Tate scolding leg 10% oleic acid 10% oleyl 16.3±0.8 23.1±3.8+1 0% m-virol alcohol 10% oleic acid None 8.7±0.5 None + 10% m-virol From the above data, transdermal nitroglycerides using the penetration enhancers described herein Phosphorbatch has been shown to provide surprisingly superior release enhancement over conventional formulations. It is clear that

Procedural amendment February 17, 1992

Claims (13)

[Claims] 1. a vasodilatory effective amount of nitroglycerin and a carrier, the carrier being an N-methyl -2-pyrrolidone alone or with oleic acid, oleyl alcohol, and linoleic acid. from the group consisting of oleic acid, isopropyl linoleate, azone and butanediol adhesive in combination with at least one selected skin penetration enhancer. Dermal Nitroglycerin Patch, Polymeric Matrix Transdermal Nitroglycerin Patch or Reservoir Transdermal Nitroglycerin Patch. 2. N-methyl-2-pyrrolidone alone in an amount of about 5 to about 30% of the total patch weight or oleic acid in an amount of about 2.5 to about 10% of the total patch weight, total patch weight. oleyl alcohol in an amount of about 5 to about 20% of the total patch weight, about 5 to about 15% of the total patch weight. linoleic acid in an amount of about 5% to about 30% of the total patch weight, isopropyl linoleate , 1-dodecyl-azacycloheptane-2 in an amount of about 5 to about 20% of the total patch weight. - and butanediol in an amount of about 2% to about 10% of the total patch weight. Claims comprising: in combination with at least one skin penetration enhancer selected from 1. The transdermal nitroglycerin patch according to 1. 3. Acrylic adhesive 37.4%, N-methyl-2-pyrrolidone 10%, Olay Transdermal adhesive according to claim 2, comprising 10% phosphoric acid and 40% nitroglycerin. patch. 4. Human skin in need of treatment to administer a vasodilatory effective amount of nitroglycerin comprising applying a transdermal patch according to claim 1, 2 or 3 to the skin. A vasodilatory effective dose of nitroglycerin for humans in need of such treatment. How to administer. 5. a vasodilatory effective amount of nitroglycerin and a carrier, wherein the carrier alcohol, linoleic acid, isopropyl linoleate, butanediol, 1-d selected from the group consisting of decyl-azacycloheptan-2-one and oleic acid; at least one skin penetration enhancer containing 1-dodecyl-azacic If loheptan-2-one or oleic acid is present, a second penetration enhancer Adhesive transdermal nitroglycerin patch, polymeric, provided that - matrix transdermal nitroglycerin patch or reservoir transdermal nitrog lyserine patch. 6. oleyl alcohol in an amount of about 5% to about 20% of the total patch weight; linoleic acid in an amount of about 5 to about 15%; linoleic acid in an amount of about 5 to about 30% of the total patch weight; isopropyl sulfate and butanediol in an amount of about 2% to about 10% of the total patch weight. alone or at least one skin penetration enhancer selected from the group consisting of; 1-dodecyl-azacycloheptane-2- in an amount of about 5 to about 20% of the total patch weight. from the group consisting of oleic acid in an amount of from about 2.5% to about 10% of the total patch weight. according to claim 5, comprising in combination with one or more selected skin penetration enhancers. Transdermal nitroglycerin patch. 7. Acrylic adhesive 47.4%, oleyl alcohol 10% and nitroglycerate Adhesive transdermal patch according to claim 5 or 6, comprising 40% serine. 8. Human skin in need of treatment to administer a vasodilatory effective amount of nitroglycerin applying a transdermal patch according to claim 5, 6 or 7 to the skin. a vasodilatory effective amount of nitroglycerin for humans in need of such treatment; How to administer. 9. comprising a vasodilatory effective amount of nitroglycerin distributed between the two regions; one region of comprises nitroglycerin and a first carrier, the first carrier comprising: N-methyl-2-pyrrolidone in an amount of about 5 to about 30% of the total patch weight, total patch weight oleic acid in an amount of about 2.5% to about 10% by weight and about 5% to about 20% by weight of the total patch. selected from the group consisting of 1-dodecyl-azacycloheptan-2-one in an amount of at least one skin penetration enhancer, and the other region contains nitroglyceride. phosphorus and a second carrier, the second carrier being about 5% to about 30% of the total patch weight. in an amount of N-methyl-2-pyrrolidone or in an amount of about 5% to about 20% of the total patch weight. Transdermal nitroglycerin patch containing oleyl alcohol. 10. In humans in need of treatment that administers a vasodilatory effective amount of nitroglycerin. Such method comprises applying a transdermal patch according to claim 9 to the skin. Administering a vasodilatory effective amount of nitroglycerin to a human in need of treatment Method. 11. A vasodilatory effective amount of nitroglycerin and a carrier are mixed and the resulting mixture is applying the compound to a support material, wherein the carrier is N-methyl-2-pyromethane. Lydon alone or with oleic acid, oleyl alcohol, linoleic acid, linoleic acid, isopropyl acid, 1-dodecyl-azacycloheptan-2-one and buta combination with at least one skin penetration enhancer selected from the group consisting of A method of manufacturing a transdermal nitroglycerin patch comprising: 12. A vasodilatory effective amount of nitroglycerin and a carrier are mixed and the resulting mixture is applying the compound to a support material, wherein said carrier is oleyl alcohol, Nolic acid, isopropyl linoleate, butanediol, 1-dodecylazacic At least one selected from the group consisting of loheptan-2-one and oleic acid skin penetration enhancers of the following types, with the exception of 1-dodecyl-azacycloheptane-2- or oleic acid is present, the provision that a second penetration enhancer is present. A method of manufacturing a transdermal nitroglycerin patch. 13. A vasodilatory effective amount of Nitroglycide distributed between two regions of a transdermal patch. 1. A method of making a transdermal patch comprising serine, comprising: (a) a vasodilatory effective amount of serine; Mix a portion of loglycerin and a first carrier and use the resulting mixture as a support material. the first carrier in an amount of about 5 to about 30% of the total patch weight. N-methyl-2-pyrrolidone, Olay in an amount of about 2.5 to about 10% of the total patch weight acid and 1-dodecyl-azacyclohep in an amount of about 5% to about 20% of the total patch weight. at least one skin penetration enhancer selected from the group consisting of tan-2-ones; and (b) a vasodilatory effective amount of the remainder of the nitroglycerin and the third. mixing the two carriers and applying the resulting mixture to a second area of the support material; The carrier is N-methyl-2-pyrrolidone or N-methyl-2-pyrrolidone in an amount of about 5% to about 30% of the total patch weight. or oleyl alcohol in an amount of about 5% to about 20% of the total patch weight; The manufacturing method described below.