JPH034523B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to drug stabilization in a drug-containing paste using an acrylic copolymer as a drug-retaining matrix. Conventionally, rubbers such as natural rubber and synthetic rubber, or natural resins have been used as the drug-retaining matrix for drug-containing pastes, but stabilizers, anti-aging agents, and preservatives are added to stabilize this matrix. There are problems with drugs being degraded or irritating the skin due to compounding agents such as drugs. On the other hand, drug-containing pastes that combine acrylic acid-acrylic acid ester copolymers and drugs have recently been proposed, but the above copolymers do not require the use of polymerization initiators that generate hydroperoxides or peroxides. Because they are copolymerized, even if they are stable under normal conditions, they are unstable in high temperatures and humidity, so antioxidants and pH adjusters must be selected depending on the combination with each individual drug. The complexity was overwhelming. The present inventors have conducted extensive research on the fact that acrylic copolymers are suitable substances as a matrix for holding drugs, and have found that they can be used as polymerization initiators for copolymerizing polymerizable monomers with each other. The inventors discovered that a stable drug-containing paste can be produced by using an azo polymerization initiator, leading to the present invention. That is, the present invention provides a copolymer obtained by copolymerizing a (meth)acrylic acid ester with a vinyl ester copolymerizable therewith and/or a vinyl monomer having a functional group using an azo polymerization initiator. The present invention provides a stabilized drug-containing paste that serves as a drug-retaining body. The stabilized drug-containing paste of the present invention is usually spread on a flexible support such as plastic film, nonwoven fabric, cloth, or aluminum foil to a thickness of about 0.01 to 0.5 mm, and It is used to continuously deliver active drugs systemically or locally through the integument or mucous membrane. (a) Azo polymerization initiator, (b) (meth)acrylic acid ester, (c) used in carrying out the present invention
Vinyl esters copolymerizable with (meth)acrylic esters and (d) vinyl monomers having functional groups copolymerizable with (meth)acrylic esters include the following. (a) Azobisisobutyronitrile, diazomethane, diphenyldiazomethane, q-anthryldiazomethane, methylphenyldiazomethane,
Methyl-α,α′-azobisisobutyrate, tetramethyltetrazene, etc. (b) Methyl (meth)acrylate, methyl (meth)acrylate, butyl (meth)acrylate, (meth)acrylic acid 2- Ethylhexyl, (meth)
Isooctyl acrylate, ethoxyethyl (meth)acrylate, etc., (c) Vinyl acetate, styrene, methylstyrene, vinyl propionate, etc., (d) (meth)acrylic acid, (meth)acrylamide, (meth)acrylic acid 2- hydroxyethyl,
Azo polymerization initiators such as dimethylaminoethyl (meth)acrylate, acrylonitrile, vinylpyrrolidone, etc.
It is added in an amount of 0.005 to 1 part by weight per 100 parts by weight in total. The (meth)acrylic acid ester is used in an amount ranging from 30 to 99.5% (by weight) of the total amount of the copolymer. It is desirable to sufficiently replace the dissolved oxygen in each of the polymerizable monomers with an inert gas in advance, and all steps of polymerization reaction, aging, and drug compounding are performed under an inert gas atmosphere. is desirable. There are no substantial restrictions on the drugs used in carrying out the present invention, and any drug that exhibits pharmacological activity can be used. Examples include fludroxycortide, fluocinolone acetonide, prednisolone, beclomethasone propionate, hydrocortisone, fludrocortisone acetate, dexamethasone acetate, dexamethasone, fluoromesolone,
Examples include anti-inflammatory corticosteroids such as betamethasone, analgesic and anti-inflammatory agents such as indomethacin, methyl salicylate, and diclofenac, tranquilizers, antibiotics, insecticides, repellents, and attractants. In order to further improve the stability of the stabilized drug-containing paste of the present invention, an appropriate amount of auxiliary stabilizing ingredients may be added. In the stabilized drug-containing paste of the present invention constructed in this manner, the drug in the copolymer is decomposed by oxidation, hydrolysis, rearrangement reaction, etc. from the time of its manufacture until the end of its shelf life. It has the characteristic that it rarely decreases. Such characteristics will be demonstrated more specifically from the examples of the present invention shown below. Part of the text refers to parts by weight. Example 1 42.9 parts of ethyl acetate, 94 parts of 2-ethylhexyl acrylate, 6 parts of acrylic acid, and 0.1 part of azobisisobutyronitrile were placed in a three-necked round-bottomed flask.
Displace the dissolved oxygen in the formulation with an inert gas. Next, the flask was heated to 60°C to start the polymerization reaction, and the reaction temperature was controlled at 60 to 61°C.
107.1 parts of ethyl acetate was added dropwise to react for about 12 hours, and the temperature was further raised to 75-77°C and aged for about 3 hours to form a copolymer solution (polymerization rate 98.9%, viscosity 590 poise).
get. Next, 0.2 parts of fluocinolone acetonide is added and dissolved to 100 parts of the solid content of the copolymer solution to obtain a stabilized drug-containing paste (solution) of the present invention. In order to evaluate the properties of the paste (solution), this was applied to a polyethylene film to a thickness of 50 μm after drying, and dried at 90°C for 7 minutes to form a drug-containing paste. get the agent. Example 2 Three types of patches were obtained in the same manner as in Example 1, except that 0.2 part of the stabilizing component below was added together with fluocinolone acetonide. A Ethylenediaminetetraacetic acid B Malic acid C Tocopherol Example 3 Isoamyl acrylate 80 parts Vinyl acetate 18 parts 2-hydroxyethyl acrylate 2 parts Methyl-α,α'-azobisisobutyrate
0.1 part Copolymer solution (polymerization rate 97.5%, viscosity, 730 poise) in the same manner as in Example 1 using the above formulation
get. Next, 0.75 parts of prednisolone is added and dissolved in 100 parts of the solid content of the copolymer solution to obtain a stabilized drug-containing paste (solution) of the present invention. Thereafter, the same procedure as in Example 1 is carried out to obtain a patch. Example 4 In Example 3, 0.2 parts of stabilizing components A, B, and C used in Example 2 are added together with prednisolone to obtain three types of patches. Comparative Example 1 A patch using benzoyl peroxide instead of azobisisobutyronitrile in Example 1 and a patch adding the same stabilizing components A, B, and C as in Example 2 are obtained. Comparative Example 2 A patch using benzoyl peroxide instead of methyl-α,α'-azobisisobutyrate in Example 3, and a patch adding stabilizing components A, B, and C in the same manner as in Example 4. get the agent. Table 1 shows the peroxide value (POV) and stability of the drug-containing plasters of the patches prepared in Examples 1 to 4 and Comparative Examples 1 to 2, measured by the drug content in the plaster. . To determine the peroxide value, add 1 g of paste to a mixture of glacial acetic acid and chloroform (1:1) (25 ml), dissolve it, add 1 ml of saturated potassium iodide solution, leave it in a cool, dark room for 10 minutes, and then distill it. Add 30 ml of water and /% starch solution and titrate with 1/100N sodium thiosulfate solution. The drug content was determined by extracting the drug from a fixed area of the patch layer with methanol (3 times at 40°C), concentrating the extract at low temperature, and adding a mixture of ethanol:hexane (3:1). The eluate is quantified using high-performance liquid chromatography, and the ratio to the set amount of drug is measured.

[Table] As is clear from the above examples, the drug-containing paste of the present invention using an azo polymerization initiator as a polymerization initiator for an acrylic copolymer has excellent stability; The fact that an azo polymerization initiator contributes to drug stabilization in this system is remarkable.
As in Examples 2 and 4, the combined use of stabilizing components can provide even greater stabilizing effects.

Claims (1)

[Claims] 1 A copolymer obtained by copolymerizing a (meth)acrylic acid ester with a vinyl ester copolymerizable therewith and/or a vinyl monomer having a functional group using an azo polymerization initiator is used as a drug holding body. A stabilized drug-containing paste characterized by: