JPS60166611A - Remedying material - Google Patents

Abstract

PURPOSE:To provide a remedying material obtained by applying a drug-containing adhesive layer containing a dihydropyridine-type Ca<2+>-antagonist useful for the remedy of stenocardia, etc. and a specific copolymer to a substrate capable of shielding the light having specific wavelength, thereby improving the compatibility and the light-stability of said drug. CONSTITUTION:The remedying material for applying to the skin and effecting the transcutaneous administration of a dihydropyridine-type Ca<2+>-antagonist such as nifedipin, etc., is composed of a drug-containing adhesive layer composed essentially of the physiologically effective amount of said drug and a copolymer composed mainly of (A) an alkyl (meth)acrylate and (B) a vinyl monomer containing saturated or unsaturated heterocyclic group having one or more N atoms, preferably composed of 60-95wt% component A and 5-40wt% component B, and a substrate capable of shielding the light of visible - ultraviolet range at a shielding rate of >=80% at 420+ or -50nm wavelength and supporting said drug-containing adhesive layer. The compatibility of the drug can be improved and the decomposition with light can be suppressed thereby.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a therapeutic member for transdermally administering a specific drug into the body by pasting it on the skin. The present invention provides a disease treatment member in which a specific copolymer layer contains a dihydropyridine type Ca antagonist stably against photodecomposition reactions.

Ca'' antagonists reduce myocardial contractility by suppressing the influx of Ca''+ into myocardial and vascular smooth muscle cells,
It also improves the balance of oxygen demand and supply in the myocardium by increasing coronary blood flow through its coronary vasodilatory action, and these vasodilatory effects are used to treat and prevent angina pectoris, heart failure, and hypertension.

Conventionally, drugs for treating the above-mentioned symptoms, particularly angina pectoris, and 1. Drugs such as nitroglycerin, isosorbitol nitrate, and nianizibine are available in tablets, fine granules, and soft capsules. There was a problem with the sustainability of prevention of attacks, which are difficult to predict.

Among the Ca antagonists mentioned above, dihydropyridine-based ones are highly effective against angina pectoris, but on the other hand, they are extremely unstable to light because they have a functional group with high photosensitivity. ,
It was necessary to devise ways of packaging and manufacturing process. In addition, these drugs are poorly soluble substances and cannot be mixed with water, organic solvents, lanolin, or commonly known sticky substances such as natural rubber sticky substances, synthetic rubber sticky substances, and acrylic acid alkyl esters. / Acrylic acid copolymers etc. also crystallize and are hardly compatible, so there has been a need for a means to improve compatibility in preparing preparations for transdermal administration.

Therefore, the present inventors aimed to improve the compatibility with the drug and to suppress the photodegradation reaction of the drug, with the aim of providing long-lasting effects for seizure prevention and rapid efficacy for treatment when seizures occur. As a result of studying methods to achieve this, we found that a copolymer θ\, which is made by copolymerizing a (meth)acrylic acid alkyl ester with a specific vinyl monomer, is extremely compatible with dihydropyridine-based Ca''+ antagonists. It was discovered that the photodecomposition of the drug can be suppressed by blocking light of a specific wavelength, and that the photodecomposition of the drug can be suppressed, leading to the present invention.

That is, the present invention comprises a pharmacologically effective amount of a dihydropyridine-based Ca2+ antagonist, (a) a (meth)acrylic acid alkyl ester, and (b) a vinyl-based compound containing a saturated or unsaturated heterocyclic group having at least one nitrogen atom. Mainly monomer and 1
- a drug-containing adhesive layer containing a copolymer as an essential component,
The present invention provides an entire member for treating diseases characterized by being provided on a carrier capable of blocking light in the visible region and ultraviolet region.

The drug-containing adhesive layer constituting the disease treatment member of the present invention contains a dihydropyridine-based Ca antagonist that is highly effective in treating diseases such as angina pectoris, heart failure, and hypertension, or in preventing attacks. By applying the adhesive layer of the member to the skin surface of the body, a pharmacologically effective amount of the Ca''+ antagonist contained therein diffuses through the adhesive layer and is released onto the skin surface. It is absorbed percutaneously and continuously.

Dihydropyridine-based Ca"+ to achieve the above purpose
The antagonist is a reduced type Ca antagonist having a dihydropyridine ring in its skeleton structure, for example, nipazibine (N1
vadlpIne), nifedipine (N1fe old pi
ne), nitrendipine (N1trendipine)
) Nicardipine (N15oldipine), Nimodlpine (Nimodipine) %Nildipine (N
i1udipine), nicardipine (N1card
ipine), etc., and at least one type is selected from these groups as appropriate depending on the purpose and use.1. and use it. The drug is incorporated into the drug-containing adhesive layer at a concentration of 5 to 30% to form a disease treatment member.
If the S content is less than 1% by weight, it may not be particularly effective in treating diseases or preventing attacks;
If the content exceeds the above, the effect commensurate with the increased amount will not be seen much, and various problems such as insufficient adhesion to the skin may occur, so it is preferable.

The essential components constituting the adhesive layer and the copolymer in 17 include (a) (meth)acrylic acid alkyl ester and (b)
) is mainly composed of a vinyl monomer containing a saturated or unsaturated heterocyclic group having at least one nitrogen atom, (
Component a) and I- are preferably linear or branched alkyl groups having 2 to 14 carbon atoms, such as (meth)acrylic acid ethyl ester, (meth)acrylic acid butyl ester, (meth)acrylic acid Examples include pentyl ester, (meth)acrylic acid toxyl ester, (meth)acrylic acid octyl ester, (meth)acrylic acid nonyl ester, (meth)acrylic acid dodecyl ester, etc., and one or more of the above monomers are used. It may be used in combination.

The monomer of component (b) is a component to improve the compatibility and quick-acting properties of the dihydropyridine-based Ca''+ antagonist in the adhesive layer, and has the same degree of polarity as the drug. is preferable, and a vinyl monomer containing a group containing a pyridine skeleton or a pyridine-like skeleton, that is, a saturated or unsaturated heterocyclic group having at least one nitrogen atom, is used. , such as vinylpyridine, vinylpiperidine, vinylpyrimidine, vinylpyrazine, vinylpiperazine, vinylpyrrolidone, vinylpiperidone, vinylpyrrolidine, vinylvirol, vinylimidazole,
Examples include vinyl pyrazole, vinyl imidacilline, vinyl caprolactam, vinyl thiazole, vinyl oxazole, acryloylmorpholine, etc. Furthermore, one or more alkyl-substituted derivatives and various isomers of these monomers may be used in combination.

A copolymer mainly composed of the above components (a) and (b) has a weight of 60 to 95, respectively, and a copolymer with a weight of 5 to 40 has a weight of 12 and is used for skin adhesion of disease treatment members and dihydropyridine-based Ca2+ antagonists. It has a good balance of compatibility with

Furthermore, in addition to the above components (a) and fb), a monomer having a copolymerizable functional group can be copolymerized as a third component in order to modify the copolymer. Examples include carboxyl group-containing monomers such as (meth)acrylic acid, itaconic acid, maleic acid, maleic anhydride, and crotonic acid, (meth)acrylic acid 2-hydroxyethyl ester, (meth)acrylic acid 2-hydroxy Hydroxyl group- or alkoxyl group-containing monomers such as propyl ester, (meth)acrylic acid 2-methoxyethyl ester, (meth)acrylic acid 2-ethoxyethyl ester, vinyl ester monomers such as vinyl acetate and vinyl propionate. Examples include. When the copolymerization ratio of the monomer is 20 wt. Effective.

The purpose of the adhesive layer containing the above-mentioned essential ingredients is to adhere to the skin surface, dissolve and retain the drug, and spread and move the drug.In order to more reliably achieve these purposes, for example, Various glycols such as propylene glycol, triethylene glycol, polyethylene glycol, ethyl alcohol, salicylic acid, dimethyl sulfoxide, dimethyl acetamide, urea, diethyl sebacate, propylene ester, N-methylpyrrolidone, crotamiton, lanolin,
One or more auxiliary substances such as mineral oil can be added as required. However, when considering the cohesive force of the adhesive layer and the balance of skin adhesion, it is necessary to consider [
, it is preferable to mix in a range of 0.5 to 20 parts by weight.

The carrier constituting the disease treatment member of the present invention not only supports the adhesive layer, but also has a light-shielding ability to suppress the photodecomposition reaction of the dihydropyridine-based Ca antagonist with high photoliS responsiveness. There is no particular restriction as long as it is a film or sheet that can be used and has a light-shielding ability, and can be appropriately selected from various plastic films, papers, nonwoven fabrics, woven fabrics, foils, and the like.

Light shielding means and 17, metal thin film lamination method, light shielding powder non-blending method,
A coloring method etc. can be used, and in any method, it is necessary to be able to block light in the visible region and ultraviolet region, but dihydropyridine-based C
a” + highest wavelength of photosensitivity of antagonist 420 ± 50
It is preferable to use a carrier designed to have a light shielding rate of 80 inches or more.

The metal N film used in the metal thin film lamination method is AJA,
A film made of AI%Au or a metal such as Cu is used, but an inexpensive and chemically stable M thin film is preferably used. In addition to bonding the gold-X thin film, the thin film lamination method uses a sputtering method, an ion blasting method, a vacuum evaporation method, and other known metal deposition methods in a vacuum. It is installed and used. The thickness of these thin film layers is dihydropyridine-based Ca2
+ 80A or more is required to suppress the photolysis reaction of the antagonist, and the desired L (is 100A or more).

In addition, in the case of a method that does not contain light-shielding powder, a light-shielding powder such as fine carbon powder or fine metal powder is mixed into a plastic resin, and a carrier is formed by extrusion molding or the like, or a carrier material such as nonwoven fabric is mixed with the light-shielding powder. It is impregnated with powder to form a carrier.

Furthermore, in the coloring method, a colored plastic carrier containing a red, orange, green, brown, etc. pigment or printed with a pigment using ink is preferably used, and preferably a red film is used.

As described above, the disease treatment member of the present invention is composed of a saturated or unsaturated heterocyclic group-containing vinyl monomer having at least one cylindrical atom as the component (b) for forming a drug-containing adhesive layer. By using dihydropyridine Ca
The compatibility of the antagonist with the adhesive layer is improved [7], and the polarity can be improved, resulting in sustained release, which is a necessary characteristic for the treatment of diseases such as angina pectoris, heart failure, and hypertension, and for the prevention of seizures. Because it has both high efficacy and rapid release properties, it is highly effective in treating the above-mentioned diseases. In addition, by adding a light-shielding carrier to the carrier, the photodegradation reaction associated with the high photosensitivity of the dihydropyridine thread Ca2+ antagonist can be suppressed. [--It is possible to prevent a rapid drop in the drug content during use and to supply parts of uniform quality, which is effective.

Hereinafter, the failure of the main beat (11) will be shown in 1-1 and more specifically the removal of LI11, but the misfire l-111 will not be limited to these examples, but will be based on Shikawa's technical ideas. Various applications are possible within a range that does not deviate from the following.In addition, parts in the text indicate parts by weight.

Example 1 In a nitrogen gas atmosphere, 75 parts of acrylic acid 2-ethyl I+/hexyl ester, 20 parts of l-vinyl-2-pyrrolidone, 5 parts of methacrylic acid, and 100 parts of ethyl acetate were charged into a fourth flask, and polymerization was started. Hitoshi] and 1. Then, 0.2 parts of azobisisobutyronitrile (AIBN) was added 11, and the content temperature was maintained at 60 to 63°C 1.The reaction was controlled by stirring and portionwise addition of 133.3 parts of ethyl acetate. A time-varying polymerization reaction was carried out, and the content temperature was further raised to 70-75°C for 1° and aged for 2 hours to obtain a copolymer solution. Polymerization rate and viscosity of a solution with a solid content of 30% by weight at 30°C is 99.6%
and 35 () Boys.

Nianidipine was added to the obtained copolymer solution so that the content in the member was 400μI/2-2, and mixed with polyethylene/AA vapor deposited film (deposition thickness 15 (IA light shielding rate 94%/421) m). Apply to the side so that the thickness after drying is 50 μm, and dry at 90°C for 8 minutes.1. A disease treatment member containing Nianidipine was obtained.

Example 2 In a nitrogen gas atmosphere, 80 parts of acrylic acid isononyl ester, 15 parts of 1-vinylimidazole, 5 parts of acrylic acid 2-methoxyethyl ester, and 25 parts of ethyl acid were charged into a four-bottle flask, and polymerization was carried out. Add an initiator and 11.1 parts of AIBN, and add 2 parts of ethyl acetate (
18. Add 3 parts in divided drops 1. Then, the same operation as in Example 1 was carried out to obtain a copolymer solution.

The polymerization rate and the bath liquid volume at 30° C. with a solid content of 3% by weight and 1% by weight were 99.8 inches and 290 voices.

Add nipadipine to the obtained copolymer solution until the metal part in the member is 2
00μIIA:d, polyester/Ai vapor deposited film (deposition thickness 200A, light shielding rate 97%/
The thickness after drying is 4 on the polyester side of 42 (lflf).
Apply to 0μF71 and dry at 80℃ for 9 minutes1.
A disease treatment member containing niadipine was obtained.

Example 3 In a nitrogen gas atmosphere, 70 parts of acrylic acid 2-ethylhexyl ester, 30 parts of acryloylmorpholine, and 100 parts of ethyl acetate were charged into a fourth flask, and a polymerization initiator and 1 to 2 parts of AIBN were added to I7. Then, the same operation as in Example 1 was carried out while 133.3 parts of ethyl acetate was added dropwise in portions to obtain a copolymer solution.The polymerization rate and the viscosity of the solution with a solid content of 30% by weight at 30°C were 99.5. % and 33C
) was Boyes.

Nifedipine was added and mixed to the obtained copolymer solution so that the content in the member was 400 μI/cd, and the mixture was placed on a silicone-treated release material to a thickness of 50 μm after drying.
After drying at 80℃ for 8 minutes, polyethylene red film (shading rate 89%/420 nm
) to 5#1. A disease treatment member containing nifedipine was obtained.

Comparative Examples 1 to 3 Comparative Examples 1 to 3 correspond to Examples 1 to 3, and 1-vinyl-2-pyrrolidone, l-
Except for vinylimidazole and acryloylmorpholine,
A copolymer solution was obtained by replacing Example 1 with the same amount of vinyl probionic acid and the others with the same amount of ethyl acetate, and then performing the same operations as in each Example to treat the target disease containing a dihydropyridine-based Ca21 antagonist. A therapeutic member was obtained.

The measurement results of each characteristic of the disease treatment member obtained in each Example and Comparative Example are shown in Table 1.1. Ta.

Table 1 The eyelid test method in Table 1 was measured under the following measurement conditions. ■) Each sample (5 x 5 cm) was pasted on the inside of the upper arm for 24 hours. There was no peeling of the terminal and almost no body hair was pulled out. The adhesiveness of /f was rated as ○ and 12, the adhesiveness that caused the terminal peeling or pulling out body hair was rated as △ and 17, and the one that caused the phenomenon of falling off during application was rated as ×.

2) Each sample (5×1 occm) was left in a thermostat at 25° C. for 17 days, and drug crystallization on the surface of the adhesive layer of the sample was examined using a magnifying glass on the 3rd and 10th day after leaving.

○ means that no crystals form, △ means that crystals form on a part of the surface, and X means that crystals form on the entire surface.

3) Each sample (3 (1 mφ) was pasted on the abdomen of a rat whose hair had been removed 1° in advance. Blood was collected 1 hour and 8 hours later, and the blood concentration of each drug was measured using a gas chromatograph 4-WK. Measurement 1.

4) After irradiating each sample (5 x 10 cyx) with room scattered light for 12 hours from the carrier side or adhesive layer side, the drug residual rate in each sample was measured. Ta.

As is clear from Table 1, the disease treatment member of the present invention has good skin adhesion and dihydropyridine-based Ca2+
It also has good compatibility with the anti-monostatic drug, so it has both short-time release, that is, immediate action, and sustained release.Also, by using a light-shielding carrier, the drug contained in the drug can be easily released. Almost no photodecomposition reaction occurred.

Patent Applicant Nitto Electric Industry Co., Ltd. Representative (Upper Third Part Procedure Amendment) 1. Indication of the case 1982 Patent Application No. 23673 2. Name of the invention Member for disease treatment 3. Person making the amendment Related: Patent applicant postal code: 567 Address: 1-1-2-4 Shimohozumi, Ibaraki City, Osaka Prefecture Date of amendment order: May 29, 1980

Claims (4)

[Claims] (1) Pharmacologically effective amount of dihydropyridine Ca
Essential components are an antagonist, (a) (meth)acrylic acid alkyl ester, and (b) a 1-copolymer mainly composed of a vinyl monomer containing a saturated or unsaturated heterocyclic group having at least one nitrogen atom. A disease treatment member comprising a drug-containing adhesive layer provided on a carrier capable of blocking light in the visible and ultraviolet regions. (2) The member for disease treatment according to claim 1, wherein the dihiF loviridine Ca21 antagonist is at least one selected from the group of nipadipine, nianidipine, nitrendipine, nicardipine, nimodipine, nildipine, and nicardipine. (3) The copolymer has (a) W content of 60 to 95 weight-It%
and (b) If. The member for treating a disease according to claim 1, which comprises 5 to 40 minutes of severe disease. (4) The member for disease treatment according to claim 1, wherein the carrier has a light shielding rate of 80% or more for light having a wavelength of 420±50.