JPH03261721A - Drug preparation for transcutaneous absorption - Google Patents

Abstract

PURPOSE:To obtain a drug preparation for transcutaneous absorption having the stability as well as good transcutaneous absorbability of nicorandil by uniformly dispersing nicorandil in a base agent in the form of fine crystal particles having specific particle diameter and compounding a specific absorbefacient thereto. CONSTITUTION:N-(2-hydroxyethyl)nicotinamide nitrate (nicorandil) having antistenocardiac action is uniformly dispersed in a base agent in the form of fine crystal particles mostly having an average particle diameter of >=2mum, preferably >=4mum and the dispersion is compounded with 1-20wt.% (preferably 2-15wt.%) of an absorbefacient consisting of oleic acid and/or oleyl alcohol. A preferable transcutaneous absorbability can be imparted without lowering the stability of free nicorandil and an acrylic base agent can be used in the preparation.

Description

Detailed Description of the Invention (Field of Industrial Application) The present invention provides excellent stability and absorbability of N-(2-hydroxyethyl)nicotinamide nitrate (hereinafter referred to as nicorandil), which has antianginal action. The present invention relates to transdermal absorption preparations.

(Prior art) Nicorandil has a coronary vasodilatory effect and a coronary artery spasm suppressing effect, and is an effective drug as a therapeutic agent for various types of angina pectoris with little effect on cardiac hemodynamics and cardiac function. It is described in Japanese Patent Publication No. 58-17463 and elsewhere.

In general, when administering drugs orally, it is difficult to obtain consistent absorption of the drug depending on conditions such as the presence or absence of pH 1 contents in the stomach or intestine, and it is also difficult to gradually administer a fixed amount over a long period of time. Oral administration of nicorandil may sometimes cause side effects such as orthostatic anemia and headache due to a sudden increase in blood concentration.

Therefore, many transdermal absorption preparations of nicorandil have been developed because they maintain a constant blood concentration for a long time, reduce the side effects mentioned above, and are expected to improve convenience and functionality. .

For example, JP 59-10513.61-78720
．． 62-36316.62-3631? , 63-513
There are 26 items listed.

When developing such transdermal absorption preparations, an important issue is how to efficiently absorb nicorandil through the skin, but in addition, it is necessary to solve the serious problem of nicorandil's low stability. There is. In other words, since nicorandil has low skin permeability, absorption enhancers are often added to make transdermal preparations, but there is a problem in that absorption enhancers drastically reduce the stability of nicorandil. . The reason why nicorandil is unstable is that
It is known that this is because the nitric acid ester group is unstable in aqueous solution and causes a series of decomposition reactions starting with hydrolysis (Pharmaceutical Research, Vol. 14, No. 6, 96
8-979, 1983). It is also known that nicorandil causes a polymerization reaction depending on temperature. Therefore, when formulating nicorandil, it is necessary to fully consider stability and transdermal absorption.

However, the nicorandil transdermal absorption preparation of the above application does not take into consideration the stability of nicorandil, and therefore has the drawback that long-term stability is hardly ensured.

On the other hand, studies have also been conducted on transdermal absorption preparations to improve the stability of nicorandil (for example, JP-A-63-152
315.63-152316.63-2927 and Japanese Patent Application No. 80276/1982). All of these formulations are based on techniques that attempt to improve the stability by using salts of nicorandil with inorganic or organic acids, or by forming salts of nicorandil in the coexistence of inorganic or organic acids (e.g. Japanese Patent Publication No. 62-10301
8.62-161727);
In the formulation No. 6, the stability of nicorandil is further improved by using nicorandil in the form of fine crystals with a particle size of 2 μm or more. However, although the stability of nicorandil has been considerably improved in these conventional formulations, there is a problem in that nicorandil has a markedly reduced transdermal absorbability in its salt form, and a solution to this problem has been strongly desired.

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

Specifically, the present invention contains nicorandil in a free state to improve its transdermal absorption compared to conventional formulations, and moreover, achieves preferable transdermal absorption without impairing the stability of nicorandil in its free state. The present invention provides a transdermal absorption preparation containing an absorption enhancer that can be administered.

In addition, in the case of patches, conventional formulations using an acrylic base have difficulty securing nicorandil stability but increasing transdermal absorption compared to formulations containing a rubber base. However, the present invention provides a transdermal absorption preparation of nicorandil which is good not only when the base is a rubber base but also when the base is an acrylic base.

Furthermore, the present invention provides a transdermal absorption preparation of nicorandil that has excellent adhesion to the skin and is less irritating.

(Means for Solving the Problems) The transdermal absorption preparation of the present invention contains nicorandil and an absorption enhancer in a base for the transdermal absorption preparation, and most of the nicorandil is fine with an average particle size of 2 μm or more. It is characterized in that it is crystalline and uniformly dispersed in the base, and that the absorption enhancer is at least one compound selected from the group consisting of oleic acid and oleyl alcohol. The formulation of the present invention is typically provided as an ointment or patch.

In the formulation of the present invention, nicorandil may be in the form of a pharmaceutically acceptable salt, but preferably free nicorandil is used, and the amount in the base that can exert the prescribed medicinal effect is usually 1 to 20% by weight. %. Since nicorandil cannot ensure stability in a solution state or a fine particle state, it is necessary to set the particle size of nicorandil to 2 μm or more, preferably 4 μm or more (this particle size is determined by microscopic measurement in this specification). diameter (according to Shigeo Fumiwa, Powder and Granule Engineering: Asakura Shoten).

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

In the case of ointments, such bases include one of Plastibase, white petrolatum, liquid paraffin, isopropyl myristate, medium chain fatty acid triglyceride, etc.
It may be composed only of seeds or a mixture of two or more kinds, or it may contain stabilizers, preservatives, dispersants, etc., if necessary.

In the case of a patch, the base has a saturated solubility of nicorandil of 5.
% or less and has pressure-sensitive adhesive properties at room temperature. Examples include, but are not limited to, polyvinyl alkyl ether, poly(meth)acrylate, polyurethane, polyamide, ethylene-vinyl acetate, etc. Polymer, acrylic acid alkyl ester-acrylic acid copolymer, polyisoprene rubber, SIS (styrene-
isoprene-styrene block copolymer rubber), styrene-butadiene rubber, polyisobutylene rubber, butyl rubber, natural rubber, silicone rubber, etc., or a mixture of two or more thereof, or adhesive as required. Those containing imparting agents, softeners, anti-aging agents, etc. are used. Acrylic bases are preferred because they do not easily cause skin irritation, have excellent stability of the base itself, have good compatibility with compounding agents, and are free from the risk of phase separation during storage.

In the present invention, oleic acid and/or
Or use oleyl alcohol.

For aliphatic acids or alcohols with a higher number of carbon atoms,
Because it solidifies at low temperatures, it reduces adhesiveness, reduces the effective area for application to the skin, and adversely affects the expression of drug efficacy. In addition, those with a shorter carbon number have higher hydrophilicity and dissolve nicorandil, impairing stability. These substances significantly improve the transdermal absorption of nicorandil contained in transdermal preparations without accelerating its decomposition even when it is in a free state. It has been found that because the solubility of the adsorbent is high, bleeding of the absorption enhancer does not occur, and adhesion to the skin is not inhibited, resulting in a large percutaneous absorption promoting effect.

The amount of the absorption enhancer to be used is preferably within a range that does not impair the stability of nicorandil or minimize the decrease in stability, and does not impair the adhesion of the formulation to the skin, and is usually 1 to 20% by weight. , preferably 2 to 25% by weight.

In order to prevent oxidation of the absorption enhancer used in the present invention,
As an antioxidant, one or a mixture of two or more of propyl gallate, butylated hydroxyanisole, butylated hydroxytoluene, and citric acid or ascorbic acid is added, preferably from 0.1 to 5, based on the amount of absorption enhancer. is 0. It can also be added in an amount of 4 to 3% by weight.

In addition to the absorption enhancer, one or more substances that do not impair the stability of nicorandil or minimize the decrease in stability and improve the transdermal absorption of nicorandil without impairing the adhesion of the formulation to the skin are added. Furthermore, for example 0.5~
It can be added in an amount of 20% by weight, preferably 1 to 10% by weight. Examples of such substances are, for example, lauroyl sarcosine salt, AZONE, myristate, soprovir,
In addition to isopropyl palmitate, a new absorption enhancer discovered by the present inventors is polyoxyethylene aliphatic ether having an ethylene oxide addition mole number of 1 to 6 and an aliphatic group having 8 to 20 carbon atoms. or polyoxyethylene aliphatic esters. Specific examples thereof include polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, polyoxyethylene monooleate, and the like.

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

1) Mix the base and absorption enhancer uniformly, and knead nicorandil in a crystalline state. 2) After uniformly dissolving the base, absorption enhancer, and nicorandil in a solvent, the solvent is removed and nicorandil is recrystallized. 3) After uniformly dissolving the base and 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 is provided to provide self-supporting properties to the transdermal absorption preparation and to prevent volatilization and migration of the drug in the adhesive layer, such as polyethylene, polypropylene, polyacrylate, polyurethane, polyester. ,
Films made of polyvinyl alcohol, polyvinyl chloride, polyvinylidene chloride, polyamide or ethylenic copolymers, porous films or sheets of rubber and/or synthetic resin type; films or sheets made of fibers such as non-woven fabrics, woven fabrics, paper, etc.: Metal seedlings: A film or sheet of metal foil with metal vapor deposition on the surface can be used. Among these materials, materials that have conformability to the skin surface are preferably used. The thickness of the support is generally 500 μm or less,
Preferably it is 5 to 150 μm.

EXAMPLES The present invention will be explained in more detail with reference to Examples below.

Example 1 (Ointment) Plastibase 79.996% by weight Oleic acid 8% by weight Butylated hydroxytoluene 0.004% by weight Nicorandil (average particle size 3
0 μm) 15 weight 1% Nicorandil crystals having an average particle size of 30 μm, oleic acid and butylated hydroxytoluene were placed in a vacuum crusher and kneaded while gradually adding Plastibase to obtain an ointment.

For the stability test, place the ointment in a plastic airtight container and
This was carried out by storing the sample at 0°C for one week and then examining the remaining amount.

In the skin permeation test, 0.2 g of the ointment was placed on a Franz diffusion cell set with the excised skin of a nude mouse, and the area was approximately 3 cm.
The test was carried out by applying the product uniformly so that the amount of nicorandil permeated through the skin was measured after 24 hours.

Example 2 Patch rubber adhesive 74.85% by weight Oleic acid 10% by weight Butylated hydroxytoluene 0.15% by weight Nicorandil (average particle size 2
, 7μm) 15% by weight 1.4-cis polybutadiene 70
Parts by weight, 30 parts by weight of natural rubber, and 40 parts by weight of terpene resin were added to cyclohexane so that the solid content was about 20% by weight, and the mixture was mixed until the mixture was evenly mixed to obtain a rubber adhesive.

Nicorandil and oleic acid were added to this adhesive solution together with butylated hydroxytoluene, and the mixture was stirred with a Daysilver to obtain a dispersion in which the mixture was uniformly dispersed.

This was coated on a polyethylene terephthalate release paper liner so that the thickness after drying was 100 μm, and dried.
An adhesive layer was formed. A support laminated with polyethylene terephthalate and ethylene-vinyl acetate copolymer was brought into close contact with this adhesive layer to obtain a patch.

In the stability test, this patch was placed in an aluminum bag and sealed, and
The sample was stored at 0°C for one week, and the remaining amount was then determined.

For the skin permeability test, a patch with an area of 3.14 an" was punched out, and the release paper liner was peeled off and applied onto a Franz diffusion cell set with the excised skin of a nude mouse. After 24 hours, the patch was permeated through the skin. This was done by measuring the amount of nicorandil.

Example 3 Patch acrylic adhesive 72.994% by weight Oleic acid 12% by weight Butylated hydroxytoluene 0.006% by weight Nicorandil (average particle size 4
．． 3 μm) 15% by weight 50 parts by weight of 2-ethylhexyl acrylate, 5 parts by weight of 2-ethylhexyl methacrylate
0 parts by weight, 40 parts by weight of cyclohexane, and 0.012 parts by weight of hexamethylene glycol dimethacrylate were mixed uniformly, 0.2 parts by weight of lauroyl peroxide was added, and a polymerization reaction was carried out at 70°C by a conventional method to form an acrylic adhesive. obtained the drug.

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 conducted.

Example 4 Patch acrylic adhesive 72.994% by weight oleyl alcohol 12% by weight butylated hydroxytoluene 0.006% by weight nicorandil (average particle size 5
Example 3 was repeated except that oleic acid was replaced with oleyl alcohol as the 15% by weight absorption enhancer.

Comparative Example 1 Rubber adhesive 84.85% by weight Butylated hydroxytoluene 0.15% by weight Nicorandil (average particle size 30 μm) 15% by weight The same procedure as in Example 3 was carried out except that the amount of acrylic adhesive was increased.

Comparative Example 3 Acrylic adhesive 82% by weight lauric acid jetanolamide 3% by weight nicorandil (average particle size 50 μm) 15% by weight oleic acid and 3% by weight lauric acid jetanolamide was used instead of butylated hydroxytoluene. , carried out in the same manner as in Example 3.

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

Except for not using oleic acid and increasing the amount of rubber adhesive.
It was carried out in the same manner as in Example 2.

Comparative Example 2 Acrylic adhesive 85% by weight nicorandil (average particle size 15 μm) Added 15% by weight oleic acid and butylated hydroxytoluene Stability test 50°C 1 week survival rate (%) Skin permeability test (mg/3.14co+・24h) 4 1 8 8 9 1 6 2 Just by pasting it on a human Komabe, it can prevent angina pectoris attacks for more than 24 hours.In addition, this preparation can prevent the drug from degrading during storage. The medicinal efficacy is not lost,
There is no risk of skin irritation due to application.

Comparative example 1 98 0.302 9
3 0.26 3 7 1.87

Claims (1)

[Claims] 1. A transdermal absorption preparation containing N-(2-hydroxyethyl)nicotinamide nitrate (hereinafter referred to as nicorandil) and an absorption enhancer that helps absorption of nicorandil through the skin in a base for a transdermal absorption preparation. A preparation, wherein most of the nicorandil is uniformly dispersed in the base in the form of fine crystals with an average particle size of 2 μm or more, and the absorption enhancer is at least one selected from the group consisting of oleic acid and oleyl alcohol. A transdermal absorption preparation characterized by being a compound of seeds.