JPH0376285B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a therapeutic device for transdermally administering a specific drug into the body by applying it to the skin surface, and more specifically, the present invention relates to a therapeutic device for transdermally administering a ^specific drug into the body by applying it to the skin surface. The present invention provides a disease-treating member containing a specific copolymer layer that is stable against reactions. Ca ²⁺ antagonists reduce myocardial contractility by suppressing the influx of Ca ²⁺ into myocardial and vascular smooth muscle cells, and increase coronary blood flow by dilating coronary vessels. As a result, it improves the oxygen supply and demand balance in the myocardium, and these effects are used to treat and prevent angina, heart failure, and hypertension. Conventionally, drugs such as nitroglycerin, isosorbitate nitrate, and nifedipine have been known as therapeutic drugs for the above-mentioned symptoms, especially angina pectoris, in the form of tablets, fine granules, soft capsules, etc. Although these types of drugs satisfy the requirement of rapid action, they have problems in providing long-lasting effects to prevent attacks that are difficult to predict in advance. Among the above Ca ²⁺ antagonists, dihydropyridine-based drugs are highly effective against angina pectoris, but on the other hand, they are extremely unstable to light because they have a highly photosensitized functional group. , 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 generally known sticky substances such as natural rubber sticky substances, synthetic rubber sticky substances, acrylic acid alkyl esters/acrylic acid. Since copolymers and the like also undergo crystallization and are hardly compatible, 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 investigating ways to achieve this, we found that a copolymer made by copolymerizing a (meth)acrylic acid alkyl ester with a specific vinyl monomer has extremely good compatibility with dihydropyridine-based Ca ²⁺ antagonists. They discovered that photodecomposition of the drug can be suppressed by not causing crystallization and by blocking light of a specific wavelength, leading to the present invention. That is, the present invention comprises a pharmacologically effective amount of a dihydropyridine Ca ²⁺ antagonist, (a) an alkyl (meth)acrylate ester, and (b) a saturated or unsaturated heterocyclic group containing at least one nitrogen atom. A disease characterized in that a drug-containing adhesive layer containing a copolymer mainly composed of vinyl monomers as an essential component is provided on a carrier capable of blocking light in the visible and ultraviolet regions. The present invention provides a therapeutic member. The drug-containing adhesive layer constituting the disease treatment member of the present invention contains a dihydropyridine-based Ca ²⁺ antagonist that is 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 ²⁺ antagonist contained therein diffuses through the adhesive layer and is released onto the skin surface. It is released transdermally and is absorbed continuously. Dihydropyridine system for achieving the above purpose
Ca ²⁺ antagonists are reduced Ca ²⁺ antagonists that have a dihydropyridine ring in their backbone structure, such as the generic names Nivadipine, Nifedipine, and Nitrendipine.
Examples include Nisoldipine, Nimodipine, Niludipine, Nicardipine, etc., and at least one member from these groups is appropriately selected and used depending on the purpose and use. The drug is contained in the drug-containing adhesive layer in a range of 0.5 to 30% by weight to produce a disease treatment member, but if the content is less than 0.5% by weight, it is not significantly effective in treating the disease or preventing attacks. In addition, if the content is 30% by weight or more, the effect commensurate with the increased amount may not be seen, and various problems such as insufficient adhesion to the skin may occur, which is not desirable. . The copolymer as an essential component constituting the adhesive layer includes (a) (meth)acrylic acid alkyl ester and (b) a vinyl monomer containing a saturated or unsaturated heterocyclic group having at least one nitrogen atom. Component (a) is preferably a linear or branched alkyl group having 2 to 14 carbon atoms, such as (meth)acrylic acid ethyl ester,
(meth)acrylic acid butyl ester, (meth)acrylic acid pentyl ester, (meth)acrylic acid hexyl ester, (meth)acrylic acid octyl ester, (meth)acrylic acid nonyl ester, (meth)acrylic acid dodecyl ester, etc. The above monomers may be used alone or in combination. The monomer of component (b) is a component that improves the compatibility and quick-acting properties of the dihydropyridine Ca ²⁺ antagonist in the adhesive layer, and has a polarity comparable to that of the drug. is preferred, and a vinyl monomer containing a group having a pyridine skeleton or a pyridine-like skeleton, ie, a saturated or unsaturated heterocyclic group having at least one nitrogen atom, is used. Examples of these monomers include vinylpyridine, vinylpiperidine,
Vinylpyrimidine, vinylpyrazine, vinylpiperazine, vinylpyrrolidone, vinylpiperidine,
Vinylpyrrolidine, vinylpyrrole, vinylimidazole, vinylpyrazole, vinylimidazoline, vinylcaprolactam, vinylthiazole,
Examples include vinyloxazole and acryloylmorpholine, and 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) with a content of 60 to 95% by weight and 5 to 40% by weight, respectively, is effective for skin adhesion of disease treatment members and as a dihydropyridine Ca ²⁺ antagonist. It has a good balance of compatibility with Furthermore, in addition to the above components (a) and (b), a monomer having a copolymerizable functional group can be copolymerized as a third component in order to modify the copolymer. For example, (meth)acrylic acid, itaconic acid, maleic acid, maleic anhydride,
carboxyl group-containing monomers such as crotonic acid,
Hydroxyl group or alkoxyl group such as (meth)acrylic acid 2-hydroxyethyl ester, (meth)acrylic acid 2-hydroxypropyl ester, (meth)acrylic acid 2-methoxyethyl ester, (meth)acrylic acid 2-ethoxyethyl ester Examples include vinyl ester monomers such as vinyl acetate and vinyl propionate. When the copolymerization ratio of the monomer is 20% by weight or less, the adhesive layer has good cohesive force and skin adhesion, and is more effective against the transfer of dihydropyridine-based Ca ²⁺ antagonists onto the skin surface. It is true. The purpose of the adhesive layer consisting of the above-mentioned essential components is to adhere to the skin surface, dissolve and retain the drug, and facilitate the diffusion and mobility of the drug. , triethylene glycol, various glycols such as polyethylene glycol, ethyl alcohol, salicylic acid, dimethyl sulfoxide, dimethyl acetamide, urea, diethyl sepacate, propylene carbonate, N-methylpyrrolidone, crotamine, lanolin mineral oil and other auxiliary substances as necessary. One or more types can be added. However, in consideration of the cohesive force of the adhesive layer and the balance of skin adhesion, it is preferable to mix it in an amount of 0.5 to 20 parts by weight based on 100 parts by weight of the copolymer. The carrier constituting the disease treatment member of the present invention is
A material that not only supports the adhesive layer but also has a light-shielding ability to suppress the photodecomposition reaction of the dihydropyridine-based Ca ²⁺ antagonist, which is highly photosensitive, is used.
There is no particular limitation as long as it is a film or sheet that has light-blocking ability, and can be appropriately selected from various plastic films, papers, nonwoven fabrics, woven fabrics, foils, and the like. As a light shielding method, a metal thin film lamination method, a light shielding powder compounding method, a coloring method, etc. can be used, and in any of the methods, it is necessary to be able to shield light in the visible region and ultraviolet region. Preferably, the dihydropyridine Ca ²⁺ antagonist has a blocking rate of 80% for light at a wavelength of 420±50 nm, which has the highest photosensitivity.
It is preferable to use a carrier designed to meet the above requirements. The metal thin film used in the metal thin film deposition method is
A material made of metal such as Al, Ag, An, or Cu is used, but an inexpensive and chemically stable Al thin film is preferably used. In addition to bonding metal thin films, the thin film lamination method uses sputtering, ion plating, vacuum evaporation, and other known vacuum metal deposition methods to coat one or both surfaces of the support, or the inside of the support. Set it up and use it. The thickness of these thin film layers is based on dihydropyridine Ca ²⁺
In order to suppress the photolysis reaction of the antagonist, the thickness is required to be 80 Å or more, and preferably 100 Å or more. In addition, in the case of a light-shielding powder compounding method, 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 the powder is attached to a carrier material such as nonwoven fabric. impregnated with the material to form a carrier. Furthermore, in the coloring method, red, orange, green,
A colored plastic carrier containing a dye such as brown or printed with a dye using ink is preferred, and preferably a red film is used. As described above, the disease treatment member of the present invention contains a vinyl monomer containing a saturated or unsaturated heterocyclic group having at least one nitrogen atom as the component (b) for forming the drug-containing adhesive layer. By using
The dihydropyridine-based Ca ²⁺ antagonist has improved compatibility with the adhesive layer and can improve polarity, a property necessary for the treatment of diseases such as angina pectoris, heart failure, and hypertension, and for the prevention of attacks. Since it has both a certain sustained release property and an immediate release property, it is highly effective in treating the above-mentioned diseases. In addition, by using a light-shielding carrier as a carrier, the photodegradation reaction associated with the high photosensitivity of dihydropyridine-based Ca ²⁺ antagonists can be suppressed, and the drug content during storage of disease treatment components can be reduced. It is possible to prevent the drug content from decreasing or rapidly decreasing during use of the adhesive, and it is possible to supply components of uniform quality. Examples of the present invention will be shown below and explained in more detail, but the present invention is not limited to these examples and can be applied in various ways without departing from the technical idea of the present invention. be. Note that parts in the text indicate parts by weight. Example 1 In a nitrogen gas atmosphere, 75 parts of acrylic acid 2-ethylhexyl ester was placed in a four-necked flask.
-20 parts of vinyl-2-pyrrolidone, 5 parts of methacrylic acid
100 parts of ethyl acetate, 0.2 parts of azobisisobutyronitrile (AIBN) was added as a polymerization initiator, and while maintaining the internal bath temperature at 60 to 63°C,
The reaction was controlled by stirring and partial dropwise addition of 133.3 parts of ethyl acetate, and the polymerization reaction was allowed to proceed for 8 hours.The inner bath temperature was further raised to 70-75°C, and the mixture was aged for 2 hours 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 99.6% and 350 poise. Nifedipine was added and mixed to the obtained copolymer solution so that the content in the member was 400 μg/cm ² ,
It was applied to the polyethylene side of a polyethylene/Al vapor-deposited film (deposition thickness: 150 Å light shielding rate: 94%/420 nm) to a dry thickness of 50 μm, and dried at 90°C for 8 minutes to obtain a disease treatment member containing nifedipine. . Example 2 In a nitrogen gas atmosphere, 80 parts of isononyl acrylate, 15 parts of 1-vinylimidazole, 5 parts of 2-methoxyethyl acrylate, and 25 parts of ethyl acetate were charged into a four-neck flask, and a polymerization initiator was added. 0.1 part of AIBN was added thereto, and the same operation as in Example 1 was carried out while 208.3 parts of ethyl acetate was added dropwise in portions to obtain a copolymer solution. The polymerization rate and the solution viscosity at 30° C. with a solid content of 30% by weight were 99.8% and 290 poise. Nivadipine was added to the obtained copolymer solution and mixed so that the content in the member was 200 μg/cm ² , and after drying it was applied to the polyester side of a polyester/Al vapor deposited film (deposition thickness 200 Å light shielding rate 97%/420 nm). It was coated to a thickness of 40 μm and dried at 80° C. for 9 minutes to obtain a disease treatment member containing nivadipine. Example 3 In a nitrogen gas atmosphere, 70 parts of acrylic acid 2-ethylhexyl ester was placed in a four-necked flask.
30 parts of acryloylmorpholine and 100 parts of ethyl acetate were charged, 0.2 parts of AIBN was added as a polymerization initiator, and 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 a solution with a solid content of 30% by weight at 30℃ are
It was 99.5% and 330 poise. Nifedipine was added and mixed to the obtained copolymer solution so that the content in the member was 400 μg/cm ² ,
It was coated on a silicone-treated release material to a dry thickness of 50 μm, dried at 80°C for 8 minutes, and then coated with a polyethylene red film (shading rate 89).
%/420 nm) to obtain a disease treatment member containing nifedipine. Comparative Examples 1 to 3 Comparative Examples 1 to 3 correspond to Examples 1 to 3, and 1-vinyl-2-pyrrolidone, 1-vinylimidazole, and acryloyl mormoline were removed from each example, and Example 1 A copolymer solution was obtained by replacing only one part with the same amount of vinyl propionate and the other with the same amount of ethyl acetate, and then using the same procedure as in each example to prepare the desired dihydropyridine-based Ca ²⁺ antagonist-containing copolymer solution. A member for disease treatment was obtained. Table 1 shows the measurement results of each characteristic of the disease treatment member obtained in each Example and Comparative Example.

【table】

[Table] The test method in the table was measured under the following measurement conditions. (1) Each sample (5 x 5 cm) is pasted on the inside of the upper arm for 24 hours, and the adhesion is marked as ○ if the terminal does not peel off and almost no body hair is pulled out. Adhesiveness was rated as △, and those in which the phenomenon of falling off occurred during pasting were rated as ×. (2) Each sample (5 x 10 cm) was left in a thermostat at 25°C, and the 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. A sample in which no crystals were formed was rated as ○, a sample in which crystals were formed on a part of the surface was rated as △, and a sample in which crystals were formed on the entire surface was rated as x. (3) Each sample (3 cmφ) was pasted on the abdomen of a rat whose hair had been removed in advance, and blood was collected 1 hour and 8 hours later, and the blood concentration of each drug was measured using a gas chromatography device. (4) After irradiating each sample (5 x 10 cm) with room scattered light for 12 hours from the carrier side or the adhesive layer side, the drug residual rate in each sample was measured. As is clear from Table 1, the disease-treating member of the present invention has good skin adhesion and good compatibility with dihydropyridine-based Ca ²⁺ antagonists, so it can be released in a short time, that is, it is fast-acting. The drug had both high performance and sustained release properties, and due to the use of a light-shielding carrier, almost no photodecomposition reaction of the drug contained therein occurred.

Claims (1)

[Claims] 1. Pharmacologically effective amount of dihydropyridine
Essentially a copolymer consisting mainly of a Ca ²⁺ antagonist, (a) (meth)acrylic acid alkyl ester, and (b) 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 as a component 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 dihydropyridine Ca ²⁺ antagonist is at least one selected from the group of nivadipine, nifedipine, nitrendipine, nisoldipine, nimodipine, nildipine, and nicardipine. 3 The copolymer contains 60 to 95% by weight of component (a) and component 5 (b).
40% by weight of the member for treating diseases according to claim 1. 4. The member for disease treatment according to claim 1, wherein the carrier has a light shielding rate of 80% or more for light with a wavelength of 420±50 nm.