JPH03261722A - 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 stabilizer thereto. CONSTITUTION:One to 20wt.% of 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 0.5-20wt.% (preferably 1-10wt.%) of a stabilizer consisting of an organic acid metal salt composed of univalent and/or bivalent metals and an organic acid and, preferably, 1-20wt.% of an absorbefacient. Nicorandil of isolated state can be extremely highly stabilized to enable the selection range of the absorbefacient to be used in combination. 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. 58-17468 and elsewhere.

In general, when administering drugs orally, it is difficult to obtain constant absorption of the drug depending on conditions such as the presence or absence of pH 1 contents in the stomach or intestines, and it is also difficult to administer a fixed amount to the body for 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
．． 62-36316.62-36317.63-513
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
No. 315.63-152316.63-2927 and Japanese Patent Application No. 62-80276). 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. 62-103018
．． 62-161727), and at that time, JP-A Nos. 63-152315 and 63-152316
In the formulation of this issue, 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, the percutaneous absorption of nicorandil in its salt state is significantly reduced, and therefore, 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 improves the percutaneous absorption of nicorandil in a free state compared to conventional formulations, and optionally uses a stabilizer that can stabilize nicorandil in a free state extremely well. Provided is a transdermal absorption preparation containing an absorption enhancer that further improves the absorption of the skin.

In addition, in the case of patches, it is difficult to ensure the stability of nicorandil and increase transdermal absorption with conventional formulations using acrylic bases compared to formulations containing rubber bases. 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 1 to 20% by weight of nicorandil and 0.0% by weight of a stabilizer for stabilizing nicorandil in the base for the transdermal absorption preparation. 5 to 20% by weight, most of the nicorandil is uniformly dispersed in the substrate in the form of fine crystals with an average particle size of 2 μm or more, and the stabilizer is monovalent and/or
Alternatively, it is characterized by being an organic acid metal salt consisting of a divalent metal and an organic acid. The formulation of the present invention is typically provided as an ointment or patch.

In the formulation of the present invention, nicorandil is preferably a free compound, and is mixed into the base in an amount capable of exhibiting a predetermined medicinal effect, usually in a proportion of 1 to 20% by weight. Since nicorandil cannot ensure 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 (this particle size is referred to herein as the Feret diameter measured using a microscope). (Powder and granular material engineering by Shigeo Nimiwa: 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. Among polymers, acrylic acid alkyl ester-acrylic acid copolymers, polyisoprene rubber, 5IS (styrene-isoprene-styrene block copolymer rubber), styrene-butadiene rubber, polyisobutylene rubber, butyl rubber, natural rubber, silicone rubber, etc. 1 or 2 of
A composition consisting only of a mixture of at least one species, or a composition containing a tackifier, a softener, an anti-aging agent, etc. as required, is used. Acrylic bases are preferred because they are less likely to 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, an organic metal salt consisting of a monovalent and/or divalent metal and an organic acid is used as a stabilizer for nicorandil. According to the present invention, when the above-mentioned metal salt is added to a transdermal absorption preparation of nicorandil, the nicorandil can be made into a crystalline state with an average particle size of 2 μm or more without converting it into a salt state, which is much more effective than conventional preparations. It has been found that nicorandil can be stably retained. Preferred such metals are sodium, potassium, magnesium, calcium, barium, copper and zinc due to their ease of availability. Metals other than monovalent and divalent metals cannot provide the sufficient stabilizing effect aimed at in the present invention. All of the stabilizers of the present invention are readily available or can be produced by those skilled in the art.

There is no particular limit to the number of carbon atoms in the organic acid moiety of the stabilizer, ranging from those with a small number of carbon atoms such as acetic acid and propionic acid, to those with a small number of carbon atoms such as capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, and oleic acid. Can be used up to large items. Acids with a large number of carbon atoms are particularly preferred because they are highly hydrophobic. The organic acid moiety of the stabilizer is not limited to -basic carboxylic acids, but also includes polybasic carboxylic acids, organic phosphoric acids, organic sulfonic acids, and the like.

Stabilizers are salts consisting of a combination of the above metals and organic acids, including sodium laurate, potassium myristate,
Examples include magnesium stearate, calcium oleate, sodium adipate, sodium fumarate, zinc stearate, and the like. Furthermore, some stabilizers have a stabilizing effect and an effect of promoting transdermal absorption of nicorandil, and can be useful additives for the formulation of the present invention. Examples include sodium lauroyl sarcosinate,
Examples include sodium oleyl phosphate and sodium lauryl phosphate.

These stabilizers are preferably mixed into the formulation in an amount that ensures the stability of nicorandil and does not impair the adhesion of the formulation to the skin, and is usually 0.5 to 20% by weight, preferably 1 to 10% by weight. Mix in %.

The present invention further includes 1 to 20% by weight of an absorption enhancer in the base of the formulation to aid in transdermal absorption of nicorandil.
Such formulations are an important aspect of the present invention. That is, although the stability of nicorandil is generally likely to be impaired when an absorption enhancer is added, the stability of this formulation can be ensured by the presence of the stabilizer. Therefore, according to the present invention, the range of selection of absorption enhancers can be expanded.

Therefore, the absorption enhancers used in the formulation of the present invention include:
Absorption enhancers conventionally known to be able to be used to promote the absorption of nicorandil, such as lauroyl sarcosine salt, A
In addition to ZONE, isopropyl myristate, and isopropyl palmitate, the present inventors have newly discovered an absorption enhancer in which the number of moles of ethylene oxide added is 1 to 6 and the number of carbon atoms in the aliphatic group is 8 to 20. Examples include polyoxyethylene aliphatic ethers or polyoxyethylene aliphatic esters. Specific examples thereof include polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, polyoxyethylene monooleate, and the like.

Other examples of absorption enhancers are oleic acid and oleyl alcohol, which are also absorption enhancers discovered by the inventors. 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.

When the preparation of the present invention is used as a patch, additives may be added to the base to further enhance the stabilizing effect of the organic metal salt. Such additives are liquids or semi-solids that hardly dissolve nicorandil;
Examples of liquid components include organic acid esters such as isopropyl myristate and diethyl sebacate, or oils such as olive oil, and examples of semi-solid components include oils such as cocoa butter and petrolatum.

The following method is adopted as a method for manufacturing the nicorandil preparation.

1) Mix crystalline nicorandil and stabilizer into the base, as well as components to be added as necessary, in the crystalline state. 2) After uniformly dissolving or dissolving the base, nicorandil, and stabilizer in a solvent, the solvent is removed. 3) Nicorandil and a stabilizer are mixed or dissolved in advance, then recrystallized and uniformly dispersed in the base.

In the case of patches, a support is provided to impart self-supporting properties to the transdermal absorption preparation and to prevent drug volatilization and migration 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 made of rubber and/or synthetic resins; films or sheets made of fibers such as nonwoven fabrics, woven fabrics, and paper; Metal stone: 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 5 to 150 μm.

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

Implementation Ml (Ointment) Plastibase 74.999% by weight Oleyl alcohol 5% by weight Butylated hydroxytoluene 0.001% by weight Nicorandil (average particle size 3
oμm) 15% by weight sodium laurate
5% by weight nicorandil crystals with an average particle size of 30 μm, powdered sodium laurate and oleyl alcohol were placed in a vacuum grinder with butylated hydroxytoluene (antioxidant), and plastibase was gradually added and kneaded. I won the gold medal and got 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 2 weeks 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 79.85% by weight butylated hydroxytoluene 0.15% by weight nicorandil (average particle size 30 μm) 15% by weight magnesium stearate 5% 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 mixed until the mixture was evenly mixed to obtain a rubber adhesive.

Add nicorandil, butylated hydroxytoluene and powdered magnesium stearate to this adhesive solution,
The mixture was stirred with a day silver 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.

The stability test was conducted by putting this adhesive patch into an aluminum bag, adding a desiccant, sealing it, storing it at 50°C for 2 weeks, and then examining the remaining amount.

In the skin permeation test, a patch with an area of 3.14 an2 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, nicorandil permeated through the skin. This was done by measuring the amount.

Example 3 Patch acrylic adhesive 80% by weight nicorandil (average particle size 30 μm) 15% by weight sodium fumarate 50 parts by weight of 2-ethylhexyl acrylate, 50 parts by weight of 2-ethylhexyl methacrylate and cyclo 40 parts by weight of Hegyu San 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 obtain an acrylic adhesive. I got it.

A patch was obtained in the same manner as in Example 2, except that an acrylic adhesive was used instead of a rubber adhesive and sodium fumarate was used as a stabilizer for nicorandil, and a stability test and a skin permeability test were conducted. Ta.

Example 4 Patch acrylic adhesive 67.994% by weight Oleic acid 12% by weight Butylated hydroxytoluene 0.006% by weight Nicorandil (average particle size 3
0μm) 15% by weight potassium acetate
The same procedure as in Example 3 was carried out, except that 5% by weight butylated hydroxytoluene and oleic acid were added as an absorption enhancer, and sodium fumarate was replaced with potassium acetate as a stabilizer of nicorandil.

Example 5 Patch acrylic adhesive 70% by weight polyoxyethylene lauryl ether (2 moles of ethylene oxide added) 5% by weight isopropyl myristate 5% by weight nicorandil (average particle size 30 μm) 15% by weight calcium stearate
5% by weight Same as Example 4, except that oleic acid was replaced with polyoxyethylene lauryl ether and isopropyl myristate as the absorption enhancer, potassium acetate was replaced with calcium stearate as the stabilizer, and butylated hydroxytoluene was not added. It was carried out in

Example 6 Patch acrylic adhesive 74.999% by weight Polyoxyethylene monooleate (number of moles of ethylene oxide added: 4.2) 5% by weight Butylated hydroxytoluene 0.001% by weight Nicorandil (average particle size 30 μm) 15% by weight % Sodium Stearate 5% by weight It was carried out in the same manner as Jitsutetsu 4 except that polyoxyethylene monooleate was used instead of oleic acid and sodium stearate was used instead of potassium acetate.

Example 7 Patch rubber adhesive 81.85% by weight Butylated hydroxytoluene 0.15% by weight Nicorandil (average particle size 30 μm) 15% by weight Sodium lauroyl sarcosinate 3% by weight Using sodium lauroyl sarcosine without using magnesium stearate The same procedure as in Example 2 was carried out except for the following.

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 2 was carried out except that magnesium stearate was not used.

Comparative Example 2 Acrylic adhesive 80% by weight nicorandil (average particle size 2 μm) 15% by weight fumaric acid 5% by weight Nicorandil and fumaric acid were once mixed in tetrahydrofuran (T
The procedure was carried out in the same manner as in Example 3, except that the mixture was dissolved in HF) and then mixed into the adhesive solution. Incidentally, the average particle size of nicorandil was 2 μm.

Comparative Example 3 Acrylic adhesive 67.994% by weight Oleic acid 12% by weight Butylhydroxytoluene 0.006% by weight Nicorandil (average particle size 3
0m) 15% by weight potassium chloride
The same procedure as in Example 4 was carried out except that potassium chloride was used in place of 5% by weight potassium acetate.

Comparative Example 4 Acrylic adhesive 79.999% by weight Polyoxyethylene monooleate (number of moles of ethylene oxide added 4.2) 5% by weight Butylated hydroxytoluene O,001 weight 11% Nicorandil (average particle size 30 μm) 15% by weight The same procedure as in Example 6 was carried out except that sodium stearate was not used.

The results of the stability test and skin permeability test for the above examples and comparative examples were as follows.

Stability test 50°C 2 week survival rate Skin permeability test (mg/3.14cm2・24h) (%) 8 0 2 7 3 8 7 (Effects of the invention) The present invention provides nicorandil with extremely good storage stability. A transdermal absorption preparation was provided. According to one aspect of the present invention, a transdermal absorption preparation of nicorandil is provided which has extremely good transdermal absorption properties and is capable of transdermally absorbing a sufficient amount of nicorandil to exert a therapeutic effect. The transdermal absorption preparation of the present invention can prevent angina attacks for 24 hours or more simply by applying it to the human chest. Furthermore, in this preparation, the drug does not decompose and lose its efficacy during storage, and there is no risk of irritation to the skin when applied.

Claims (1)

[Claims] 1. 1 to 20% by weight of N-(2-hydroxyethyl)nicotinamide nitrate (hereinafter referred to as nicorandil) and 0 stabilizers for keeping nicorandil stable in the formulation.
．． A transdermal absorption preparation containing 5 to 20% by weight in a base for a transdermal absorption preparation, in which the majority of nicorandil is uniformly dispersed in the base in the form of fine crystals with an average particle size of 2 μm or more. 1. A transdermal absorption preparation, characterized in that the stabilizer is an organic acid metal salt consisting of a monovalent and/or divalent metal and an organic acid. 2. The transdermal absorption preparation according to claim 1, wherein the base further contains 1 to 20% by weight of an absorption enhancer that helps absorption of nicorandil through the skin.