JP3002491B2 - Transdermal formulation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention is excellent in the stability and absorbability of N- (2-hydroxyethyl) nicotinamide nitrate (hereinafter referred to as nicorandil) having an antianginal effect. Percutaneous absorption preparations.

(Prior art) Nicorandil has a coronary vasodilatory action and a coronary artery spasm inhibitory action, and is an effective drug as a therapeutic agent for angina pectoris of various disease types with little effect on cardiac hemodynamics and cardiac function,
It is described in JP-B-58-17463 and others.

In general, in oral administration of a drug, it is difficult to obtain a constant absorption of the drug depending on conditions such as pH in the stomach or intestine, presence or absence of contents, and it is difficult to gradually administer a constant amount of the drug for a long time. Oral administration of nicorandil may sometimes cause side effects such as orthostatic anemia and headache due to a rapid increase in blood concentration. Therefore, a constant blood concentration is maintained for a long time, the above-mentioned side effects are reduced, and simplicity,
Numerous developments of percutaneous absorption preparations of nicorandil have been made for reasons such as improvement in functionality. For example, JP-A-59-10513, 61-78720, 62-36316, 62-3
6317 and 63-51326.

In developing such transdermal preparations, how to efficiently absorb nicorandil from the skin is an important issue.In addition, it is necessary to solve the serious problem of low stability of nicorandil. There is. That is,
Because nicorandil has low skin permeability, an absorption enhancer is often added in order to obtain a transdermal absorption preparation, but the absorption enhancer has a problem in that the stability of nicorandil is extremely lost. It is known that nicorandil is unstable because its nitrate group is unstable in aqueous solution and causes a series of decomposition reactions starting with hydrolysis (Pharmaceutical Research, Vol. 14, No. No. 6, 96
8-979, 1983). It is also known that nicorandil causes a polymerization reaction depending on the temperature. Therefore, in formulating nicorandil, it is necessary to sufficiently consider stability and transdermal absorbability.

However, the nicorandil transdermal preparation of the above application has a drawback that long-term stability can hardly be secured because the stability of nicorandil is not considered.

On the other hand, transdermal preparations for improving the stability of nicorandil have been studied (for example, see JP-A-63-15231).
5, 63-152316, 63-2927 and Japanese Patent Application No. 62-8027
6). Any of these preparations is intended to improve the stability by using a salt of nicorandil with an inorganic acid or an organic acid, or by forming a salt of nicorandil in the presence of an inorganic or organic acid (for example, JP-A-62-103018, 62-161727) are applied. In the preparations described in JP-A-63-152315 and JP-A-63-152316, nicorandil is further used as fine crystals having a particle size of 2 μm or more. Further, the stability of nicorandil is further improved. However, although the stability of nicorandil is considerably improved in these conventional preparations, nicorandil has a problem that transdermal absorbability is remarkably reduced in a salt state, and a solution has been strongly desired.

(Problems to be Solved by the Invention) The present invention provides a transdermal absorption preparation which achieves both stability of nicorandil and good transdermal absorption.

In detail, the present invention contains nicorandil in a free state to improve its percutaneous absorption as compared with conventional preparations, and furthermore, to provide a favorable percutaneous absorption without impairing the stability of free nicorandil. Provided is a percutaneous absorption preparation containing a given absorption enhancer.

In the case of patches, conventional preparations using acryl-based bases are more difficult to secure nicorandil stability and increase percutaneous absorption than preparations containing rubber bases, compared to preparations containing rubber bases. However, the present invention provides a good nicorandil transdermal preparation not only when the base is an acrylic base but also a rubber base.

Further, the present invention provides a transdermal absorption preparation of nicorandil, which is excellent in sticking property to the skin and less irritating.

(Means for Solving the Problems) The percutaneous absorption preparation of the present invention is a percutaneous absorption preparation containing nicorandil and an absorption enhancer that assists absorption of nicorandil from the skin in a base for the percutaneous absorption preparation. Most of the nicorandil is in the form of fine crystals having an average particle size of 2 μm or more and is uniformly dispersed in the base, and the absorption promoter has an ethylene oxide addition mole number of 1 to 6 and an aliphatic group. Is a compound having at least one compound selected from the group consisting of polyoxyethylene aliphatic ethers and polyoxyethylene aliphatic esters having 8 to 20 carbon atoms. The formulations of the present invention are typically provided as an ointment or patch.

In the preparation of the present invention, nicorandil may be in the form of a pharmaceutically acceptable salt, but preferably free nicorandil is used, and an amount capable of exhibiting a predetermined medicinal effect in the base, usually 1 to 20% by weight %. Since nicorandil cannot secure stability in a solution state or a fine particle state, the particle size of nicorandil needs to be 2 μm or more, preferably 4 μm or more. (Granular process: by Shigeo Miwa: Asakura Shoten).

Therefore, in the present invention, it is first necessary to uniformly disperse solid or crystalline nicorandil in the base. Therefore, usable bases are limited to those having low solubility of nicorandil. For example, those having a solubility of nicorandil in the base of 5% or less are preferably used.

As such a base, in the case of an ointment, plastibase, white petrolatum, liquid paraffin, isopropyl myristate, medium chain fatty acid triglyceride, or the like, is composed of only one kind or a mixture of two or more kinds, or If necessary, a mixture containing a stabilizer, a preservative, a dispersant, and the like is used.

The base in the case of a patch is a general adhesive having a saturated solubility of nicorandil of 5% or less and having pressure-sensitive adhesive properties at room temperature, and is not limited thereto. For example, polyvinyl alkyl ether, Poly (meth) acrylate, polyurethane, polyamide, ethylene-vinyl acetate copolymer, alkyl acrylate-acrylic acid copolymer, polyisoprene rubber, SIS (styrene-isoprene-styrene block copolymer rubber), styrene-butadiene Rubber, polyisobutylene rubber, butyl rubber, natural rubber, silicone rubber, etc., composed of only one or a mixture of two or more of them, or compounded with tackifiers, softeners, antioxidants, etc. as necessary What was done is used. Acrylic bases are preferred from the viewpoints that they do not easily cause skin irritation, that the bases themselves are excellent in stability, that they have good compatibility with the compounding agent, and that there is no risk of phase separation during storage.

In the present invention, the following formula: R—O— (CH ₂ CH ₂ O) n—H or (Wherein, R represents a C ₈ -C ₂₀ saturated or unsaturated aliphatic group, and n represents a number of 1 to 6) or a specific polyoxyethylene aliphatic ether or polyoxyethylene Aliphatic esters are used as absorption enhancers. These substances significantly enhance the transdermal absorbability of nicorandil contained in transdermal preparations without promoting the decomposition even when nicorandil contained in the free form is used. It has been found that because of its high solubility, bleeding of the absorption enhancer does not easily occur and does not inhibit adhesion to the skin, so that the effect of promoting percutaneous absorption is large.
The number of moles of ethylene oxide added to the polyoxyethylene aliphatic ethers or polyoxyethylene aliphatic esters is 1 to 6, preferably 2 to 4.2. If the number of moles of ethylene oxide added is large, the stability of nicorandil is impaired because it has high hydrophilicity and easily absorbs moisture or increases the solubility of nicorandil in a base. Conversely,
Without ethylene oxide, a sufficient absorption promoting effect cannot be obtained in most cases.

As the aliphatic group in polyoxyethylene aliphatic ethers or polyoxyethylene aliphatic esters, a short-chain hydrocarbon having low hydrophobicity reduces the stability of nicorandil, and therefore has 8 to 20 carbon atoms. is necessary. For example, a long-chain saturated hydrocarbon or a long-chain unsaturated hydrocarbon such as an octyl group, a cetyl group, a lauryl group, a palmitine group, a stearyl group, and an oleyl group having higher hydrophobicity is preferable. If the number of carbon atoms exceeds 20, they become solid at room temperature. Therefore, if they are added in an amount that satisfies the promotion of drug absorption, the adhesiveness is reduced and the sticking property to the skin is impaired. In addition,
All of these absorption enhancers are easily manufactured or available to those skilled in the art.

The amount of the absorption enhancer used is preferably in a range that does not impair the stability of nicorandil, or minimizes the decrease in stability, and does not impair the sticking property of the preparation to the skin. %, Preferably 2 to 15% by weight.

When polyoxyethylene aliphatic ether or polyoxyethylene aliphatic ester having an unsaturated hydrocarbon group is used as an absorption promoter, propyl gallate, butylhydroxyanisole, butylhydroxytoluene and citric acid are used as antioxidants. Alternatively, one or a mixture of two or more of ascorbic acid may be used in an amount of, for example, 0.1 to 5, preferably 0.4 to 5, based on the amount of polyoxyethylene aliphatic ether or polyoxyethylene aliphatic ester.
3% by weight can be added.

In addition to nicorandil other than polyoxyethylene aliphatic ether or polyoxyethylene aliphatic ester, nicorandil transdermally without impairing the stability of the nicorandil or minimizing the decrease in stability and without impairing the adhesiveness of the preparation to the skin One or more substances for improving the absorbability can be further added, for example, 0.5 to 20% by weight, preferably 1 to 10% by weight. Examples of such substances include lauroyl sarcosine salt, AZONE, isopropyl myristate,
Mention may be made of isopropyl palmitate, as well as oleic acid and oleyl alcohol as described in the specification of the present application filed on even date.

The following method can be adopted as a method for producing the preparation of the present invention.

1) A base and an absorption promoter are uniformly mixed, and nicorandil is kneaded into the mixture in a crystalline state. 2) After uniformly dissolving the base, the absorption promoter and nicorandil in a solvent, the solvent is removed and nicorandil is recrystallized. 3) After uniformly dissolving the base and the absorption enhancer in a poor solvent of nicorandil, nicorandil is added in a crystalline state and uniformly dispersed, and then the solvent is removed.

In the case of a patch, a support for imparting self-supporting properties to the transdermal absorption preparation and preventing volatilization and migration of the drug in the adhesive layer is provided, for example, polyethylene, polypropylene, polyacrylate, polyurethane, polyester. Polyvinyl alcohol, polyvinyl chloride, polyvinylidene chloride, polyamide or ethylenic copolymer film, rubber and / or synthetic resin porous film or sheet; non-woven fabric, woven fabric, paper or other fiber film or sheet A metal foil; a metal foil film or sheet having a surface subjected to metal vapor deposition can be used. Among these materials, materials having the ability to follow the skin surface are preferably used. The thickness of the support is generally 500 μm or less, preferably 5 to 150 μm.

 The invention is further described by the following examples.

Example 1 Ointment Plastibase 80% by weight Polyoxyethylene lauryl ether (number of moles of ethylene oxide added 2) 5% by weight Nicorandil (average particle size 50 μm) 15% by weight A crystal of nicorandil having an average particle size of 50 μm and polyoxyethylene lauryl ether The mixture was put into a vacuum grinder and kneaded while gradually adding plastibase to obtain an ointment with uniform quality.

Stability test puts ointment in plastic airtight container,
The test was performed by storing at 50 ° C. for one week and examining the remaining amount thereafter.

How Skin permeation test that measures the nicorandil amount of the 0.2g of ointment through the skin uniformly applied 24 hours after as the area on the diffusion cell of a Franz set with nude mice skin removed is about 3 cm ² I went in.

Example 2 Patch Rubber-based adhesive 79.85% by weight Polyoxyethylene lauryl ether (2 moles of ethylene oxide added) 5% by weight Butylhydroxytoluene 0.15% by weight Nicorandil (average particle size 2.7 μm) 15% by weight 1,4-cis polybutadiene 70 parts by weight, 30 parts by weight of natural rubber, and 40 parts by weight of a terpene resin were added to cyclohexane so that the solid content was about 20% by weight, and mixed until uniform in quality to obtain a rubber-based pressure-sensitive adhesive.

Add nicorandil, polyoxyethylene lauryl ether and butylhydroxytoluene to this adhesive solution,
The mixture was stirred with a dissolver to obtain a dispersion in which the mixture was uniformly dispersed.

This is coated on a polyethylene terephthalate release paper liner so that the thickness after drying becomes 100 μm, and dried,
An adhesive layer was formed. A support prepared by laminating polyethylene terephthalate and an ethylene-vinyl acetate copolymer was adhered to the adhesive layer to obtain a patch.

In the stability test, this patch was sealed in an aluminum bag,
It was stored at 50 ° C. for one week, and the remaining amount was checked thereafter.

Skin permeability test punching such that the area of the patch is 3.14 cm ^2, peel the release paper liner attached to the top of the Franz diffusion cell was set nude mice skin removed,
Twenty-four hours later, the measurement was performed by measuring the amount of nicorandil permeated through the skin.

Example 3 Patch Acrylic adhesive 80% by weight Polyoxyethylene lauryl ether (2 moles of ethylene oxide added) 5% by weight Nicorandil (average particle diameter 4.3 μm) 15% by weight 2-ethylhexyl acrylate 50 parts by weight of 2-ethylhexyl methacrylate 50 parts by weight of acrylate, 40 parts by weight of cyclohexane and 0.012 parts by weight of hexamethylene glycol dimethacrylate are uniformly mixed, and 0.2 parts by weight of lauroyl peroxide is added. Was.

A patch was obtained in the same manner as in Example 2 except that an acrylic adhesive was used instead of the rubber adhesive, and a stability test and a skin permeability test were performed.

Example 4 Patch Adhesive Acrylic adhesive 79.999% by weight Polyoxyethylene oleyl ether (2 moles of ethylene oxide added) 5% by weight Butyl hydroxytoluene 0.001% by weight Nicorandil (average particle size 50 μm) 15% by weight Polyoxyethylene as an absorption promoter Example 3 was carried out in the same manner as in Example 3, except that lauryl ether was replaced with polyoxyethylene oleyl ether.

Example 5 Patch Adhesive Acrylic adhesive 79.999% by weight Polyoxyethylene oleyl ether (4.2 moles of ethylene oxide added) 5% by weight Butyl hydroxytoluene 0.001% by weight Nicorandil (average particle diameter 120 μm) 15% by weight Polyethylene having 2 moles of ethylene oxide added Example 4 was carried out in the same manner as in Example 4 except that polyoxyethylene oleyl ether having an ethylene oxide addition mole number of 4.2 was used instead of oxyethylene oleyl ether.

Example 6 Patch Adhesive Acrylic adhesive 79.999% by weight Polyoxyethylene monooleate (2 moles of ethylene oxide added) 5% by weight Butyl hydroxytoluene 0.001% by weight Nicorandil (average particle diameter 50 μm) 15% by weight Poly as an absorption promoter Example 3 was carried out in the same manner as in Example 3, except that oxyethylene lauryl ether was replaced with polyoxyethylene monooleate.

Example 7 Patch Adhesive Acrylic adhesive 79.999% by weight Polyoxyethylene monooleate (moles of ethylene oxide added: 6) 5% by weight Butyl hydroxytoluene 0.001% by weight Nicorandil (average particle size: 50 μm) 15% by weight Number of moles of ethylene oxide added: 2 Example 6 was carried out in the same manner as in Example 6 except that polyoxyethylene monooleate having 6 ethylene oxide addition moles was used instead of the polyoxyethylene monooleate.

Comparative Example 1 Plastibase 85% by weight Nicorandil (average particle size: 12 μm) 15% by weight The same operation as in Example 1 was carried out except that polyoxyethylene lauryl ether was not used and the amount of plastibase was 85% by weight.

Comparative Example 2 Rubber-based adhesive 84.85% by weight Butylhydroxytoluene 0.15% by weight Nicorandil (average particle size 30 μm) 15% by weight Same as Example 2 except that polyoxyethylene lauryl ether was not used and the amount of rubber-based adhesive was increased. Carried out.

Comparative Example 3 Acrylic pressure-sensitive adhesive 85% by weight Nicorandil (average particle size 50 μm) 15% by weight The same operation as in Example 3 was carried out except that the amount of the acrylic pressure-sensitive adhesive was increased without adding polyoxyethylene lauryl ether.

Comparative Example 4 Acrylic adhesive 75% by weight Polyoxyethylene lauryl ether (number of moles of ethylene oxide added: 9) 10% by weight Nicorandil (average particle size: 30 μm) 15% by weight Ethylene oxide instead of polyoxyethylene lauryl ether having 2 number of moles of ethylene oxide added Example 3 was carried out in the same manner as in Example 3 except that polyoxyethylene lauryl ether having 9 additional moles was used.

The results of the stability test and skin permeability test for the above Examples and Comparative Examples were as follows.

(Effect of the Invention) According to the present invention, there is provided a nicorandil transdermal absorption preparation capable of securing the storage stability of nicorandil and percutaneously absorbing a necessary and sufficient amount of nicorandil for exhibiting a therapeutic effect. The transdermal absorption preparation of the present invention can prevent the attack of angina for more than 24 hours simply by applying it to the human chest. In addition, this preparation does not degrade the drug during the storage period and loses its medicinal effect, and there is no fear of skin irritation due to application.

Continued on the front page (72) Inventor Satoshi Uenoyama 2-1-13-1 Wakayamadai, Shimamoto-cho, Mishima-gun, Osaka Prefecture (72) Inventor Taneno Izumoto Oyamazaki-cho, Oyamazaki-cho, Okukun-gun, Kyoto Prefecture 32 (58) Survey Field (Int.Cl. ⁷ , DB name) A61K 31/455 A61K 47/32 A61K 9/06 A61K 9/70 CA (STN)

Claims (1)

(57) [Claims] 1. A base for percutaneous absorption preparations containing N- (2-hydroxyethyl) nicotinamide nitrate (hereinafter referred to as nicorandil) and an absorption enhancer which assists absorption of nicorandil from the skin. A percutaneous absorption preparation, wherein nicorandil is uniformly dispersed in the base in the form of fine crystals having an average particle size of 2 μm or more and 120 μm or less, and the absorption enhancer has an ethylene oxide addition mole number of 1 to 6. A transdermal absorption preparation characterized in that it is at least one compound selected from the group consisting of polyoxyethylene aliphatic ethers and polyoxyethylene aliphatic esters having 8 to 20 carbon atoms in the aliphatic group.