JPS6125686B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a paste for pharmaceutical preparations that is supported on the surface of a backing member made of a composite film and is useful for use as a stick-on type. Prednisolone, which has an OH group at the 17th carbon position of the steroid skeleton, is an active drug that is susceptible to deterioration, and there is a problem that the prednisolone is degraded over time in the polymer matrix in which it is maintained in a dissolved state. This is thought to be due to the fact that prednisolone, which has an OH group at the 17th carbon position of the steroid skeleton, undergoes an oxidation reaction and becomes a ketone at the 17th position.
Furthermore, hydroperoxides and peroxides are generally used as polymerization initiators when making acrylic copolymers, and it is thought that their residual substances have the effect of accelerating the oxidation reaction of prednisolone. The inventors of the present invention have conducted various studies on methods for suppressing the oxidation reaction of prednisolone without causing other undesirable effects, and without having any adverse effects on the human body to which prednisolone is applied. It has been discovered that good results can be obtained by spreading a specific acrylic copolymer in combination with thioglycerol in the backing member,
This led to the present invention. That is, the present invention involves copolymerizing (meth)acrylic acid alkyl ester and vinyl acetate and/or (meth)acrylic acid spread on the surface of a backing member made of a composite film using an azo polymerization initiator. The present invention provides a paste for pharmaceutical preparations, which is characterized in that prednisolone as an active drug and thioglycerol as a stabilizer for the drug are blended into a copolymer. The copolymer used in carrying out the present invention is
A (meth)acrylic acid alkyl ester having an average C number of alkyl groups of 4 to 12 and vinyl acetate and/or (meth)acrylic acid, the former: the latter = 1:1
It is blended at a ratio of ~0.01 (weight ratio) and copolymerized using an azo polymerization initiator. Examples of azo polymerization initiators include azobisisobutyronitrile, diazomethane, diphenyldiazomethane, methylphenyldiazomethane, and methyl-
α. Examples include α'-azobisisobutyrate. The paste of the present invention is applied to the surface of a backing member made of a composite film laminated with ethylene-vinyl acetate copolymer, polyolefin resin film, other plastic films, paper, cloth, nonwoven fabric, foamed film, etc., with a thickness of about 10 to 500 μm. , and is applied directly to the application site on the body.
Used to deliver active drugs. These backing members are laminated with highly flexible ethylene-vinyl acetate copolymer, so they are more flexible than when a single layer of polyolefin resin film is used, and can be applied to the skin without causing any discomfort. It can be attached to. Furthermore, since the copolymer has excellent anchoring properties with the plaster of the present invention, the backing member does not fall off during application, and no adhesive remains when peeled off from the skin. The content of prednisolone in the plaster is 2 to 100 μg per square cm ² , preferably 4 to 100 μg, when the thickness when supported on the surface of the backing member is 40 μm.
It is preferable to mix the amount to 50 μg from the viewpoint of pharmacological activity, prevention of side effects, and economy. The content of thioglycerol is determined based on prednisolone, and is blended in an amount of 0.5 to 200% by weight, and practically 10 to 100% by weight of the drug contained. If it is less than 0.5% by weight, the effect of addition cannot be obtained, and if it is more than 200% by weight, the solubility in the copolymer is poor and problems such as blooming and decreased adhesive strength occur, which is not preferable. In this way, a paste for pharmaceutical preparations that uses an azo type as a polymerization initiator for an acrylic copolymer and thioglycerol as a stabilizer eliminates one of the factors that cause the oxidation reaction of prednisolone, and further stabilizes it. Since it is used in combination with other agents, it has the characteristic that decomposition and modification hardly occur. In addition, by using the composite film for the backing member, flexibility can be imparted, and by appropriately changing the film laminated with the ethylene-vinyl acetate copolymer, it is important to prevent irritation on the skin surface to which it is applied. The moisture permeability can also be changed arbitrarily. These features will be demonstrated more specifically from the examples of the present invention shown below. Note that "middle of the text" indicates parts by weight. Example 1 37.5 parts of 2-ethylhexyl acrylate, 12.5 parts of vinyl acetate, 0.5 parts of methacrylic acid, 0.1 part of azobisisobutyronitrile and 50 parts of ethyl acetate were mixed into an inert mixture using a reactor equipped with a reflux condenser and a stirrer. Polymerization is carried out under a gas atmosphere for 8 hours (60°C) to obtain a copolymer. 0.75 parts of prednisolone and thioglycerol were added and mixed as shown in Table 1 to 100 parts of the solid content of the copolymer, and this was mixed into a composite film of ethylene-vinyl acetate copolymer and polyethylene with a thickness of 50 μm. The thickness after drying is 40μ on the copolymer side with a ratio of 1:4).
After coating and drying, a release paper having better self-supporting properties than the film is attached to the surface of the plaster to obtain the easy-to-handle pharmaceutical preparation having the plaster of the present invention. In order to observe the stability of prednisolone in this formulation, a stability test was conducted using the following test method. The sample is sealed in a well-sealed aluminum laminate bag and stored at 70°C for 10 days, after which the drug residual rate in the plaster is measured. The results are shown in Table 1. Weight percentages are percentages of drug.

[Table] Table 2 shows the results of a pallor test based on vasoconstriction by pasting a sample (10 mmφ) on the flexor side of the forearm of 10 panelists. The strength at that time was judged according to the following criteria. 0...No reaction, 1...Slight paleness, 2...Very clear paleness, 3...Clear paleness.

[Table] Example 2 A copolymer was obtained in the same manner as in Example 1 using 65 parts of 2-ethylhexyl acrylate, 35 parts of vinyl acetate, 0.1 part of azobisisobutyronitrile, and 50 parts of ethyl acetate. 0.75 parts of prednisolone and 0.25 parts of thioglycerol are added to 100 parts of the solid content of the copolymer, and a pharmaceutical preparation is obtained in the same manner as in Example 1. Comparative Example 1 0.75 parts of prednisolone alone was added and mixed to 100 parts of the solid content of the copolymer used in Example 1, and the following procedure was carried out in the same manner as in Example 1 to obtain a pharmaceutical preparation. Comparative Example 2 0.75 parts of prednisolone and 0.5 parts of each of the following four components (antioxidants) were separately blended to 100 parts of the solid content of the copolymer used in Example 1.
Obtain pharmaceutical formulations (2A to 2D) in the same manner as above. A: Butylated hydroxytoluene B: - Ascorbic acid C: Butylated hydroxyanisole D: Ethylenediaminetetraacetic acid disodium salt Table 3 shows the stability test of prednisolone (70℃
The results are shown after storage for 10 days).

[Table] Table 4 shows the results of stability tests of prednisolone under other storage conditions (40°C x 90% RH).

[Table] Parts added were used.
As is clear from the above examples, by adding prednisolone in combination with thioglycerol to a specific acrylic copolymer using an azo polymerization initiator, a pharmaceutical preparation that is stable and has excellent pharmacological effects can be obtained. The fact that a plaster of 100% can be obtained is remarkable.

Claims (1)

[Claims] 1. A (meth)acrylic acid alkyl ester and vinyl acetate and/or (meth)acrylic acid spread on the surface of a backing member made of a composite film laminated with an ethylene-vinyl acetate copolymer are mixed with an azo polymerization initiator. 1. A paste for pharmaceutical preparations, characterized in that prednisolone as an active drug and thioglycerol as a stabilizer for the drug are blended into a copolymer obtained by copolymerizing the drug.