JPS60252412A - Therapeutic poultice preparation - Google Patents

Abstract

PURPOSE:To therapeutic poultice preparation containing a specific tackifier to increase the moisture permeability of the whole preparation and to decrease the skin irritation, and containing a carboxylic acid-based nonsteroidal anti-inflammatory agent and a transcutaneous absorption promoting agent to suppress the lowering of the anti-inflammatory activity and of the transcutaneous absorption property. CONSTITUTION:A therapeutic poultice preparation having a moisture permeability of 2,000-5,000g/m<2>/24hr, especially a tape containing a non-steroidal anti-inflammatory agent having excellent transcutaneous absorption property and anti- inflammatory effect, is composed of layers of (A) an acrylic tackifier obtained by polymerizing a monomer mixture consistin of (i) 40-99wt% alkyl acrylate and/or methacrylate having 4-12C alkyl group, (ii) 1-40wt% one or more vinyl monomers selected from alkyl acrylate and methacrylate having 1-3C alkyl group, vinyl acetate and styrene, and (iii) 0-10wt% alpha,beta-unsaturated carboxylic acid, (B) a carboxylic acid-based non-steroidal anti-inflammatory agent, and (C) an agent to promote the transcutaneous absorption.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to patch therapeutic preparations, particularly tape preparations of non-steroidal anti-inflammatory drugs that cause less skin damage.

Conventional technology Traditionally, non-steroidal anti-inflammatory drugs include salicylic acid type (aspirin, etc.), anthranilic acid type (mefenamic acid, flufenamic acid%), phenylacetic acid type (diclofenac, etc.), and inviracetic acid type (indomethacin, etc.). ,
Propionic acid type (ibuprofen, flurpiprofe/
, ketoflofen, etc.), pyrazolones (phenylbutacin, etc.), penzozyazines (piroxicam, etc.), and basic ones (mevirizole).
However, when administered orally, side effects such as gastrointestinal disorders, liver disorders, and skin disorders may occur. On the other hand, if it is administered transdermally, what about the gastrointestinal tract? It is said that gastrointestinal disorders are rare compared to other systems in which indomethacin is used, but skin disorders are said to occur quite frequently, and are considered to be a particular problem with topical indomethacin.

In addition, nonsteroidal external preparations include ointments, creams, sprays, lotions, tapes, and drops, but ointments, creams, sprays, and lotions require accurate dosage. Moreover, it has the disadvantage that it can be rubbed off by clothes.To prevent this disadvantage, covering it with a plastic film and fixing it with tape or a bandage has been done, but it is cumbersome. Since it contains gold and has weak adhesive properties, it must be fixed with tape or bandages, making it difficult to apply to moving parts of joints.

On the other hand, although tapes solve all of the above-mentioned drawbacks, their major drawbacks are that they cause strong irritation to the skin, such as blockage of the shed due to sealing, swelling of the skin, and physical irritation due to high adhesiveness.

Purpose of the Invention In view of the above-mentioned circumstances, the inventors conducted intensive research in an attempt to develop a non-steroidal anti-inflammatory drug tape that is less irritating to the skin. By foaming the entire adhesive layer and increasing the moisture permeability of this layer, we succeeded in reducing skin irritation by increasing the moisture permeability of the entire patch treatment preparation compared to conventional products. .

Mayu, as a result of increasing moisture permeability, the sealing effect decreases and the amount of transdermal absorption decreases, which is compensated for by incorporating all transdermal absorption enhancers, and furthermore, as a non-steroidal anti-inflammatory agent. All of the relatively potent cardinic acid compounds were selected to prevent the anti-inflammatory efficacy of the patch treatment from decreasing.

Structure of the Invention The patch therapeutic preparation of the present invention has a moisture permeability of 4000 P/rr?
(A) (1) Alkyl acrylate whose alkyl group has 4 to 12 carbon atoms/or methacrylate 40 to 99% by weight (2 ) At least one vinyl monomer selected from the group consisting of alkyl acrylates and methacrylates whose alkyl group has 1 to 3 carbon atoms, vinyl acetate and styrene (3) α, β-unsaturated Acrylic adhesive obtained by t-polymerization of a monomer mixture consisting of 0 to 10% by weight of carboxylic acid (e.g. acrylic acid, methacrylic acid or itaconic acid) (B) Carzenic acid non-steroidal anti-inflammatory 2000-5000
f/n? This is a therapeutic patch preparation that has moisture permeability for 24 hours.

Next, the constituent elements will be explained in detail.

In the present invention, the C base material is 2000 to 5000? /n? /2
In order to form a patch therapeutic preparation with a high moisture permeability of 4 hours, the base material itself is required to have a high moisture permeability.

That is, the base material used in the present invention has at least 4000
f/rr? It is necessary to have moisture permeability for 24 hours, and cloth, nonwoven fabric, Japanese paper, etc. are suitable. Moisture permeability is 4000 r/rr? /If the base material is used for less than 24 hours, if an adhesive containing a drug or the like is applied thereon, the 200%
0~5000ri/rr? It is difficult to obtain patch therapeutic formulations with moisture permeability in the range of /24 hours.

(Adhesive) In the present invention (C), the adhesive that is blended with a drug and applied onto a substrate is (1) an alkyl acrylate and/or methacrylate whose alkyl group has 4 to 12 carbon atoms; 99% by weight, (2) the number of carbon atoms in the alkyl group is 1
1 to 40% by weight of at least one vinyl monomer selected from the group consisting of alkyl acrylates and methacrylates, vinyl acetate and styrene;
) An acrylic pressure-sensitive adhesive obtained by total polymerization of a monomer mixture consisting of 0 to 10 parts of α,β-unsaturated carzenic acid.

In the above pressure-sensitive adhesive, component (1) (l-1i) is a component that provides adhesiveness and is particularly preferably present in an amount of 50% by weight or more.

In addition, component (2) is a component that balances adhesiveness and cohesiveness, and if this component is present at 4 (N181 or more), the release properties of the drug will decrease.In particular, it is preferably 30% by weight or less.Furthermore, component (3) is a component that provides cohesive properties, and since too much of this component will result in a hard adhesive, a weight ratio of 2 to 8 is particularly appropriate.As component (3), acrylic acid, methacrylic acid, itaconic acid, etc. are preferred. The glass transition temperature T2 of the above-mentioned pressure-sensitive adhesive used in the present invention is -70' to -20°C, which corresponds to the glass transition temperature of common pressure-sensitive adhesives.

Solvent C) Examples of solvents for the adhesive include ethyl acetate, acetone, n-hexane, n-hebutane, cyclohexane, toluene, etc., and a mixture of these in an amount of 3 to 20 times the amount of the adhesive, preferably 4 to 10 times the amount of the adhesive. Use.

(Drug) In the present invention, the drug blended into the adhesive and applied onto the base material is a so-called carzenic acid-based non-steroidal anti-inflammatory agent, which is highly effective and has a short biological half-life. Salicylic acids (aspirin, etc.), anthranilic acids (mefenamic acid, flufenamic acid, etc.), phenylacetic acids (dichloromethacin, etc.), indoleacetic acids (indomethacin, etc.),
Typical examples include propionic acids (e.g., e-j-f'lofen, flurbiprofen, ketoprofen, etc.). Particularly preferred are phenylacetic acid, inviracetic acid, and propionic acid-based anti-inflammatory agents, which exhibit their medicinal effects when administered orally in relatively small doses.

Similarly, although they are nonsteroidal anti-inflammatory agents, pyrazoformes have particularly strong side effects and have a long biological half-life, so they are not suitable for transdermal administration.

(Transdermal Absorption Enhancer) Although the therapeutic patch preparation of the present invention exhibits high moisture permeability, there is a high possibility that its sealing effect will be reduced. Therefore, in the present invention, a transdermal absorption enhancer is added to %% to speed up the penetration of the drug into the skin. Transdermal absorption enhancers suitable for use in the present invention include benzoic acid, cinnamic acid, and the like. These M's make the pH of the adhesive acidic to 4-6 and also help alleviate skin irritation.

In the wallet treatment formulation of the present invention, the transdermal absorption enhancer is 0.
It is preferable to mix 1 to 10% by weight, and most preferably about several inches.

(Manufacturing method) The patch therapeutic preparation with high moisture permeability of the present invention can be obtained by mixing an adhesive, a drug, and a transdermal absorption enhancer, and applying the mixture onto a highly moisture permeable base material and drying it. . In particular, dry 8
When heating is carried out at a temperature of about 0 to 140°C, the F-adhesive layer foams as the solvent evaporates, increasing the moisture permeability of the layer.
1. It increases the moisture permeability of the entire formulation. It is more preferable.

Functions and Effects of the Present Invention The therapeutic patch preparation of the present invention exhibits high moisture permeability in the base material and the entire preparation, so irritation to the skin caused by the adhesive is alleviated, making it a therapeutic patch preparation with low moisture permeability. There are fewer skin disorders. Furthermore, the entire patch treatment preparation has high moisture permeability, which reduces the sealing performance and allows the drug to pass through.
7/7N Zuichi East! Mountain Dragon 11ty It, +
Since the drug is supplemented with 1j) 1Δ and the drug itself is a highly effective calzenic acid type, the wallet treatment preparation of the present invention is also excellent in terms of anti-inflammatory effect.

The wallet treatment preparation of the present invention is extremely useful in that it does not cause the problems of conventional oral administration, such as side effects on the gastrointestinal tract or forgetting to take a dose, and exhibits its efficacy in a sustained manner.

EXAMPLES Next, the present invention will be explained in more detail with reference to Examples.
The present invention is not limited to this example.

Example 1 2-ethylhexyl acrylate 90 f, methyl acrylate 52, acrylic acid 5 and benzoyl peroxide k
In a reactor equipped with a reflux condenser, a stirrer, a nitrogen inlet tube, and a thermometer, 200 y of ethyl acetate was added as a solvent.
Polymerization was carried out at 60° C. for 2 hours. 29' (i7) benzoic acid was added to 80v of the purified copolymer, and ethyl acetate was added so that the solid content concentration was 22.
Add to ethanol (8:2, weight ratio - same below) mixed system, and add to 4.32 f of diclofenac sodium methanol-ethanol (6:4) solution,
The solids concentration was increased by 20 weight.

On this nf silicone-treated release liner, J5 with a coating amount of 40 f/rrl after solvent volatilization was applied and dried under intense heat (100°C hot air to volatilize the phosphorus agent. The adhesive layer was foamed by heating.Next, a rayon nonwoven fabric with a basis weight of 4o2/- was pressure-transferred onto the adhesive surface of the release liner, cut into pieces of s 10 x 10 tyn, sealed in aluminum foil, and stored. This tape preparation contained 0.2 da -27' of IVC sodium hydroxide (20 µm in one tape).

Example 2 Copolymerization was carried out in the same manner as in Example 1 using a monomer mixture consisting of 80% by weight of 2-ethylhexyl acrylate, 9% by weight of vinyl acetate, 6% by weight of methyl acrylate, and 5% by weight of acrylic acid. . This copolymerized purified product 80y and cinnamic acid 2f
was dissolved in ethyl acetate, and a solution of 4.32 P of ibuzolo-7ene was added to give a solid content of 20% by weight.
And so. Similar to 1, the solid content was coated on the mold release liner at a solid content of 50 ml/- and dried, and then a stretchable elastic cloth (warp thread No. 16 urethane blended cotton thread 30 pieces/ l n s weft yarn No. 14 cotton yarn 42 pieces/1n)
It was transferred to VC, cut into 1010x10 pieces, glued to aluminium, and stored. Ibuprofen 0.25~ per dld of this tape preparation? Contains 7 tons (25 grams per sheet).

Example 3 Same as Example 1 using a monomer mixture consisting of 50 fji% of 2-ethylhexyl acrylate, 26% by weight of butyl acrylate, 10% by weight of ethyl acrylate, 9 parts by weight of vinyl acetate, and 5 parts by weight of itaconic acid. Purified copolymer 809 obtained by copolymerizing and purifying benzoic acid 22 was dissolved in an ethyl acetate-acetone (8:2) mixed system. To this, the entire methanol solution of 3.34 f of indomethacin was added to make a bath solution with a solid content of 20 weight liters, and as in Example 1, transfer coating was applied to a rayon nonwoven fabric so that the solid content was 40 r/ffIt. A tape preparation was obtained. This tape agent total 1
It was cut into 0x10 crniC and stored after being cut into aluminum.

This tape contained 0.16 to 0.16 grams of indomethacin in d (16 grams per tape).

Comparative Example 1 A formulation similar to Example 1 but containing no benzoic acid was prepared.

Comparative Example 1' The same formulation as in Example 1 was used, except that a non-moisture permeable polyethylene film with a thickness of 80 μm was used as the tape base material.

Comparative Example 2 A similar formulation as in Example 2 was used as the tape base material, using a non-moisture-permeable polyethylene film J-wo with a thickness of 80 μm.

Comparative Example 3 A polyethylene film having a thickness of 80 μm and having no moisture permeability was used as the tape base material with the same ↓ agent as in Example 3.

Evaluation of Teso agent JIS Z 0208 (cup method) was conducted under the leadership of K.

After 24 hours in a constant temperature and humidity chamber at 40 weight 1°C, 90 weight 2% R, H, and wind speed 1 m 71 seconds, the moisture absorbent (salt f-hycalcium)
Calculated based on the weight increase.

Z Elution A sample piece of a predetermined size was placed in 100°C of distilled water at 37°C, sampled with a microsyringe while gently stirring, and analyzed by high performance liquid chromatography to determine the amount of elution.

Skin irritation: Prick the backs of 6 male New Zealand P white herons, and apply 4 samples (2 x 2 cm) on each side (total of 8 samples on both sides) to the back line for 24 hours, and then peel them off. The condition of the skin was observed 1 hour and 24 hours after peeling.

4. Remaining amount of patch The drug content of the 7t 24 hour patch sample used in the skin irritation test was analyzed using high performance liquid chromatography.

Claims (1)

[Claims] Moisture permeability is 4. GOO9/rr? /A moisture permeable base material for 24 hours or more, and (A) Alkyl acrylate L whose alkyl group has 4 to 12 carbon atoms /Mataha methacrylate 40~
99% by weight, selected from the group consisting of aracyl acrylates and methacrylates in which the alkyl group has 1 to 3 carbon atoms, vinyl acetate and styrene, containing 1 to 40% by weight of at least one vinyl monomer. An acrylic pressure-sensitive adhesive obtained by polymerizing a monomer mixture consisting of 0 to 10% by weight of α,β-unsaturated carboxylic acid. (B) Carboxylic acid non-steroidal inflammatory agent and -(
0) A layer of a mixture consisting of a transdermal absorption enhancer, and a layer of 2,000 to 5,000 f/lr? /2
A therapeutic patch that has a moisture permeability of 4 hours.