JPH09136834A - Transdermal patch - Google Patents

Abstract

(57) [Abstract] [PROBLEMS] To provide a transdermal absorption patch that releases ibudilast in a stable manner for a long time with less skin irritation. A percutaneous absorption patch comprising a pressure-sensitive adhesive layer laminated on one surface of a support, wherein the pressure-sensitive adhesive layer comprises a (meth) acrylic acid alkyl ester having an alkyl group having 6 or more carbon atoms. To 60% by weight and 2-ethylhexyl methacrylate 40 to 90% by weight, based on the entire adhesive layer, 1 to 20% by weight of ibudilast, 10 to 40% by weight of isopropyl myristate, and diethanolamide lauric acid. A transdermal patch containing 0.1 to 5% by weight and 5 to 20% by weight of silicic acid anhydride as an irritation reducing agent.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a stable agent for improving bronchial asthma and cerebrovascular disease, ibudilast (generic name, 3-isobutyryl-2-isopropylpyrazolo [1,5-a] pyridine), for a long time. Percutaneous absorption patch to be released into

[0002]

2. Description of the Related Art When ibudilast is administered to humans with a non-sustained release formulation, its concentration in blood is rapidly increased due to rapid absorption from the digestive tract, and side effects such as nausea and vomiting are observed. . Japanese Unexamined Patent Publication No. 60-193913 proposes capsules, tablets, etc. that are sustained-released in oral preparations for the purpose of improving this side effect. But,
Since bronchial asthma is a common disease in children and cerebrovascular disease is a common disease in elderly people, it is strongly desired to develop a dosage form of ibudilast that is easier to administer.

JP-A-7-149645 proposes a tape preparation containing an absorption promoter. In such tape preparations, the absorption of the drug is increased by the addition of the absorption enhancer, and it is possible to prepare a low-area preparation that is easier to use, but on the other hand, the addition of the absorption enhancer is seen to increase the skin irritation. Therefore, these well-balanced preparations have been desired.

[0004]

SUMMARY OF THE INVENTION In view of the above, it is an object of the present invention to provide a transdermal absorption patch that releases ibudilast in a stable manner for a long time with less skin irritation.

[0005]

The transdermal patch of the present invention is a transdermal patch formed by laminating an adhesive layer on one surface of a support, wherein the adhesive layer is an alkyl group. (Meth) acrylic acid alkyl ester having 6 or more carbon atoms of 10 to
60 wt% and 2-ethylhexyl methacrylate 40
To 90% by weight, based on the entire adhesive layer, 1-20% by weight of ibudilast, 10-40% by weight of isopropyl myristate, 0.1-5% by weight of lauric acid diethanolamide, and irritation. It contains 5 to 20% by weight of silicic acid anhydride as a reducing agent. Hereinafter, the present invention will be described in detail.

The support used in the present invention is not particularly limited as long as it has flexibility and is impermeable to the drug. Usually, the support used for transdermal absorption patches is used. be able to. Examples of the material of the support include cellulose acetate, ethyl cellulose, polyethylene terephthalate, plasticized vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyethylene, polyurethane, poly Examples thereof include vinylidene chloride and aluminum, and these are used as, for example, a single-layer sheet (film) or a laminate of two or more sheets (laminate).

The pressure-sensitive adhesive layer used in the present invention comprises a pressure-sensitive adhesive and other components. The pressure-sensitive adhesive comprises 10 to 60% by weight of a (meth) acrylic acid alkyl ester having an alkyl group having 6 or more carbon atoms and 40 to 90% by weight of 2-ethylhexyl methacrylate. The above-mentioned pressure-sensitive adhesive is obtained by copolymerizing these components and has a property of being pressure sensitive at room temperature.

The (meth) acrylic acid alkyl ester having an alkyl group having 6 or more carbon atoms is not particularly limited, but is preferably obtained from an aliphatic alcohol having 6 to 18 carbon atoms and (meth) acrylic acid ( Examples thereof include (meth) acrylic acid alkyl ester.

Examples of the (meth) acrylic acid ester include hexyl acrylate, octyl acrylate, 2-ethylhexyl acrylate, isooctyl acrylate, decyl acrylate, isodecyl acrylate, lauryl acrylate, stearyl acrylate, and methacryl. 2-ethylhexyl acid, isooctyl methacrylate, decyl methacrylate, isodecyl methacrylate, lauryl methacrylate, stearyl methacrylate and the like can be mentioned.

The above (meth) acrylic acid esters 10 to 6
The pressure-sensitive adhesive of the present invention is obtained by copolymerizing 0% by weight with 40 to 90% by weight of the 2-ethylhexyl methacrylate. If the compounding ratio of the above-mentioned 2-ethylhexyl methacrylate is too low, the cohesive force will decrease, and if it is too high, the adhesive force will decrease.

A functional monomer or a polyfunctional monomer may be further copolymerized in the pressure-sensitive adhesive for the purpose of imparting cohesive force. The functional monomer is not particularly limited, and examples thereof include a monomer having a hydroxyl group and a monomer having a carboxyl group. The monomer having a hydroxyl group is not particularly limited, and examples thereof include hydroxyalkyl (meth) acrylate such as 2-hydroxyethyl (meth) acrylate and hydroxypropyl (meth) acrylate.

The above-mentioned monomer having a carboxyl group is not particularly limited, and examples thereof include α, β unsaturated carboxylic acids such as acrylic acid and methacrylic acid; maleic acid monoalkyl esters such as butyl maleate; maleic acid; fumaric acid; Examples thereof include crotonic acid. Furthermore, maleic anhydride also gives the same (co) polymer component as maleic acid.

The polyfunctional monomer is not particularly limited, and examples thereof include di (meth) acrylic acid ester obtained by combining poly (methylene) acrylic acid such as hexamethylene glycol and octamethylene glycol with (meth) acrylic acid. Examples thereof include di (meth) acrylic acid esters obtained by binding (meth) acrylic acid with polyalkylene glycols such as polyethylene glycol and polypropylene glycol.

As copolymerizable monomers other than the above, vinyl acetate, styrene, α-methylstyrene, vinyl chloride, acrylonitrile, ethylene, propylene, butadiene, vinylpyrrolidone and the like may be copolymerized.

In the present invention, the ibradist is contained in an amount of 1 to 20% by weight based on the whole pressure-sensitive adhesive layer. If the content of ibudilast is too small, the application area will be large to secure the required dose, and the adhesiveness will be poor and it will be difficult to apply for a long time. Since the adhesiveness is lowered and the sticking property is poor and sticking for a long time is difficult, the range is limited.

In the present invention, isopropyl myristate is contained in an amount of 10 to 40% by weight based on the whole pressure-sensitive adhesive layer. If the content of isopropyl myristate is too small, the application area will be large to secure the required dose, and the adhesiveness will be poor and it will be difficult to apply for a long time, making it inconvenient to use. Since the cohesive force of the agent decreases and sticking becomes difficult, it is limited to the above range.

In the present invention, lauric acid diethanolamide is contained in an amount of 0.1 to 5% by weight based on the whole pressure-sensitive adhesive layer. If the content of lauric acid diethanolamide is too small, the application area will be large in order to secure the required dose, and the adhesiveness will be poor and it will be difficult to apply for a long time. Since it has poor compatibility with adhesives and lacks adhesive strength, it cannot be used.
It is limited to the above range.

In the present invention, silicic acid anhydride is contained as an irritation reducing agent in an amount of 5 to 20% by weight based on the whole pressure-sensitive adhesive layer. If the content of silicic acid anhydride is too small, there is no effect of reducing skin irritation, and if it is too large, the adhesive force is reduced due to the effect of increasing the cohesive force of silicic acid anhydride, and the sticking property deteriorates. Limited.

The above-mentioned silicic acid anhydride is made of silicon oxide and is preferably a fine powder having a particle size of about 0.01 to several tens of μm. Normal,
The silicic acid anhydride is generally a hydrophilic one having a hydroxyl group on the surface, but there is also a hydrophobic silicic acid anhydride whose surface is covered with a dimethylsilanol group. Such hydrophobic silicic acid anhydride is obtained by treating the surface of silicic acid anhydride particles having a hydroxyl group on the surface with dimethyldichlorosilane. In the present invention, as the above-mentioned silicic acid anhydride, hydrophilic silicic acid anhydride and hydrophobic silicic acid anhydride may be used alone, or both may be mixed and used.

[0020]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 2-Ethylhexyl acrylate (hereinafter referred to as EHA)
10 mol% (36.4 g), dodecyl methacrylate 1
0 mol% (50.2 g), 2-ethylhexyl methacrylate 80 mol% (313.3 g), and 1,6-hexamethylene glycol dimethacrylate 0.02 wt%
(52.0 mg) was charged into a separable flask, and 400.0 g of ethyl acetate was further added to adjust the monomer concentration to 50.
% By weight. This solution was heated to a temperature of 60 ° C. under a nitrogen atmosphere, and 2 g of lauroyl peroxide was added to cyclohexane 10
Polymerization initiator solution dissolved in 0 g and ethyl acetate 24
0 g was added little by little, and the polymerization reaction was carried out for 12 hours. Thus, an ethyl acetate solution of an acrylic pressure-sensitive adhesive (hereinafter referred to as acrylic A) having a solid content of 35% by weight was obtained.

50.5% by weight of acrylic A as a solid content, 8.8% by weight of ibudilast, 11.5% by weight of silicic acid anhydride (Aerosil 200: Nippon Aerosil, hereinafter the same), 26.5% by weight of isopropyl myristate, Lauric acid diethanolamide (2.7% by weight) and ethyl acetate were further added so that the solid content concentration became 25% by weight, and the whole was homogenized to obtain a coating liquid. This coating solution was applied onto a silicone-treated release paper having a thickness of 48 μm so that the thickness after drying would be 80 μm, and then 60
The mixture was dried in a gear oven at 30 ° C. for 30 minutes, and a support having a thickness of 38 μm (a laminate of polyethylene terephthalate and ethylene-vinyl acetate copolymer; hereinafter referred to as PET-EVA) was attached to give a preparation.

Examples 2, 3 and Comparative Examples 1 to 4 The formulations of Examples 2, 3 and Comparative Examples 1 to 4 had the compositions shown in Table 1 (numerical values represent% by weight) and were the same as in Example 1. Prepared. In Table 1, IPM represents isopropyl myristate and LD represents lauric acid diethanolamide.

With respect to the preparations obtained in Examples 1 to 3 and Comparative Examples 1 to 4, the skin transferability and skin irritation of the drug were evaluated by the following experiments. Skin transfer amount Guinea pigs (6 weeks old, male) were shaved on the abdomen, and the above-mentioned preparation (punched into a circle of 3.14 cm ² ) was applied thereto. After 24 hours, the preparation was peeled off and immersed in tetrahydrofuran overnight to extract the drug remaining in the preparation. The residual amount of the drug was measured by high performance liquid chromatography, and the amount transferred into the body was calculated from the difference from the initial drug amount.
The average transfer amount per 3.14 cm ² is shown. The unit of numerical values in Table 1 is μg. The value shows the average value of n = 3.

Skin irritation The abdomen of a guinea pig (6 weeks old, male) was shaved, and the above-mentioned preparation (punched out to 3.14 cm ² ) was applied.
The preparation was peeled off after 24 hours, and the skin irritation was measured 24 hours after peeling according to the following criteria. The value shows the average value of n = 6.

Criteria 0: No skin irritation 1: Slight erythema is observed 2: Clear erythema is observed 3: Strong erythema is observed

[0027]

[Table 1]

[0028]

As described above, the percutaneous absorption patch of the present invention was prepared by applying ibudilast, isopropyl myristate, lauric acid diethanolamide, and silicic acid anhydride in the pressure-sensitive adhesive layer, and the preparation was applied to the skin. At this time, it is considered that isopropyl myristate and lauric acid diethanolamide act on the skin as an absorption enhancer to enhance the skin permeability of ibudilast. As a result, an effective amount of permeation can be obtained with a small-area preparation. Furthermore, it is possible to suppress the skin irritation, which is increased only by adding the absorption enhancer, by adding silicic acid anhydride. Further, since it is a percutaneous absorption enhancer, its blood concentration gradually increases, side effects such as nausea and vomiting are suppressed, and pain to patients is reduced. Further, it facilitates medication for children with bronchial asthma and elderly people with cerebrovascular disorders.

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Claims (1)

[Claims] 1. A transdermal patch, comprising a pressure-sensitive adhesive layer laminated on one surface of a support, wherein the pressure-sensitive adhesive layer has an alkyl group having 6 or more carbon atoms (meth) acrylic acid alkyl ester. An adhesive consisting of 10 to 60% by weight and 40 to 90% by weight of 2-ethylhexyl methacrylate, ibudilast 1 to 20% by weight, isopropyl myristate 10 to 40% by weight, and diethanolaminium laurate with respect to the entire adhesive layer. A percutaneous absorption patch containing 0.1 to 5% by weight of D and 5 to 20% by weight of silicic acid anhydride as an irritation reducing agent.