JP3012317B2 - External parts - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to an external member. For details, a patch test for medical or medical assistance, which is directly applied on the skin for the purpose of patch test, hemostasis, disinfection, protection of diseased parts of the body, and administration of drugs to the local or circulatory system. And external members such as plasters and poultices for the purpose of analgesic and anti-inflammatory.

[Prior art] Conventionally, an external member is known in which a polymer material layer having pressure-sensitive adhesive properties at room temperature is laminated on a support such as paper, nonwoven fabric, thermoplastic resin, etc. It is well known that dermatitis on an applied skin surface, that is, a so-called bandage, is blurred due to the relationship between adhesive strength and irritation because it is applied over time.

In order to improve this bandage rash, research on resin or raw rubber as an adhesive component, research on a permeable support that does not inhibit skin physiological action, and study on a method of applying the support to the support have been attempted.

For example, it has been found that the addition of a specific silicone compound, i.e., a polyoxyalkylene-modified organopolysiloxane, to a polymer layer having pressure-sensitive adhesive properties at room temperature reduces skin irritation and reduces bandage rash. (JP-A-63-46463). Further research has been advanced, and it has been found that the combined use of the polyoxyalkylene-modified organopolysiloxane and the carboxyvinyl polymer which is a water-soluble polymer can increase the adhesiveness and reduce the skin irritation ( JP-A-1-9956
3).

By the way, many proteases are known to exist in the skin for maintaining homeostasis of the structure and function of the skin, and their important roles have been receiving attention in recent years.

Protease or proteolytic enzyme is a generic name for enzymes that catalyze the hydrolysis of peptide bonds. This protease is classified into peptidases and proteinases. The former is an enzyme that cleaves peptide bonds from outside the amino or carboxyl terminal of a protein or peptide chain, and the latter is an enzyme that cleaves a specific bond inside a peptide chain. Also,
This proteinase is customarily a "protease"
These are generally classified into four types: 1) serine, 2) thiol (cysteine), 3) carboxyl, and 4) metalloproteinases, depending on the nature of the active site. Specific inhibitors exist.

[Problems to be Solved by the Invention] However, despite the aforementioned attempts, bandage rash is still one of the well-known contact dermatitis dermatitis.

In view of such circumstances, the present inventors have conducted intensive studies. The external material containing the protease inhibitor has remarkably low skin irritation and can reduce bandage rash.Furthermore, by combining a polyoxyalkylene-modified organopolysiloxane and a carboxyvinyl polymer in the polymer layer, The present inventors have found a novel fact that a higher effect can be obtained, and have completed the present invention based on this finding.

[Means for Solving the Problems] That is, the present invention relates to an external member comprising a sheet or a tape-like support and a polymer material layer having pressure-sensitive adhesive property laminated thereon, wherein the polymer material layer has a protease inhibitory action. One or more compounds selected from compounds having the following formula:

 Hereinafter, the configuration of the present invention will be described in detail.

Examples of the support used in the present invention include papers such as Japanese paper and kraft paper, cloths such as cotton cloth, cloth and non-woven cloth, vinyl chloride, polypropylene, polyethylene, polyester, polycarbonate, and copolymers thereof, cellophane and the like. Plastic films, metal foils, and laminates of these various supports.

The compound having a protease inhibitory action used in the present invention means any chemical substance capable of reversibly or irreversibly inhibiting the hydrolysis action of the protease or proteolytic enzyme. Specific examples include the following substances.

(1) Animal or plant-derived compounds Preferably, they are bovine pancreatic basic trypsin inhibitor, aprotinin, soybean trypsin inhibitor, lima bean protease inhibitor, corn protease inhibitor and the like.

(2) Microorganism-derived compound Preferably, antipine, plasminostreptin,
Further, compounds such as leupeptin represented by the following general formula are included.

R ₁ = CH ₃ CO, CH ₃ CH ₂ CO R ₂ = L-Leu, L-Ile, L-Val R ₃ = L-Leu, L-Ile, L-Val (Leu: leucine, Ile: isoleucine, Val : Valine) (3) benzamidine and derivatives thereof preferably benzamidine, p-aminobenzamidine,
m-aminobenzamidine, phenylguanosine, (2R, 4
R) -4-Methyl-1- [N2- (3-methyl-1,2,3,4-
Tetrahydro-8-quinolinsulfonyl) -L-arginyl] -2-piperidinecarboxylic acid monohydrate, dansylarginine-N- (3-ethyl-
1,5-pentanyl) amide and the like.

(4) Acetamide and derivatives thereof Acetamide, 2-phenylacetamide, cyclohexylguanidine and the like are preferable.

(5) Guanidine and derivatives thereof Preferably, phenylguanidine, cyclohexylguanidine and the like are used.

(6) ω-amino acids preferably tranexamic acid, p-aminomethylbenzoic acid, 4-aminomethylbicyclo (2.2.2.) Octane-1
-Carboxylic acid, 5- [trans-4- (aminomethyl)
Cyclohexyl] tetrazole, 3- [trans-4-
(Aminomethyl) cyclohexyl] -2-oxopropionate, trans-4- (aminomethyl) cyclohexylglyoxal monohydrate, trans-4- (aminomethyl) cyclohexanehydroxamic acid, or n = 1 to 1 in the following general formula A substance having a carbon number of 8;

NH ₂ (CH ₂ ) n COOH The present invention is not limited to these, but among these ω-amino acids, particularly, ε-aminocaproic acid, tranexamic acid and p-aminomethylbenzoic acid when n = 5 Excellent effects are observed.

(7) Fluorophosphoric acid and derivatives thereof Preferably, diisopropylfluorophosphoric acid and the like are used.

(8) fluorosulfonic acid and its derivatives, preferably phenylmethanesulfonyl fluoride,
(P-amidinophenyl) -methanesulfonyl fluoride.

(9) Guanidinobenzoic acid and its derivatives preferably p-nitrophenyl-p'-guanidinobenzoic acid, 3 ', 6'-bis (4-guanidinobenzoyloxy) -5- (N'-4-carboxyphenyl) Thioureido spiro [isobenzofuran-1 (3H), 9 '-(9H)
Xanzen] -3-one and the like.

(10) Lysine and derivatives thereof Preferred are compounds represented by the following general formula.

(Phe: phenylalanine, Ala: alanine) The present invention is not limited to these, but among these lysines and derivatives thereof, R ₂ CHCH ₂ Cl has a particularly excellent effect.

(11) Arginine and derivatives thereof Preferably, they are compounds represented by the following general formula.

(Phe: phenylalanine, Pro: broline, Glu: glutamic acid, Gly: glycine, Ile: isoleucine, Ala: alanine) The present invention is not limited to these, but among these arginines and derivatives thereof, R ₂ CHCH ₂ Cl has a particularly excellent effect.

The above substances are known not only to have a protease inhibitory action but also to have a skin irritation lowering action and a skin roughening prevention / improvement action.

In the present invention, one or more of the above compounds having a protease inhibitory action can be used in combination.

In the present invention, the compounding amount of the compound having the protease inhibitory action in the polymer substance layer is preferably 0.0001 to 20% by weight, more preferably 0.001 to 5.0% by weight. 0.
If it is less than 0001% by weight, the effect of the present invention is not sufficient, and if it exceeds 20% by weight, it is not preferable in terms of formulation and disadvantageous in cost.

Examples of the polymer substance having pressure-sensitive adhesive properties at room temperature used in the present invention include acrylic polymer substances such as (meth) acrylic acid-n-butyl ester, (meth) acrylic acid-n-hexyl ester, and ( (Meth) acrylic acid-2-ethylbutyl ester, (meth) acrylic acid isooctyl ester, (meth) acrylic acid-2-ethylhexyl ester, (meth) acrylic acid-n-decyl ester, (meth) acrylic acid-n- Dodecyl ester,
(Meth) such as (meth) acrylic acid tridecyl ester
(Meth) acrylic acid, itaconic acid, maleic acid, maleic anhydride, (meth) acrylic acid-2-hydroxyethyl ester, (meth) acrylic acid-2 copolymerizable with alkyl acrylate and / or the above esters -Hydroxypropyl ester, (meth) acrylamide,
N, N-dimethyl (meth) acrylamide, dimethylamino (meth) acrylate, diethylaminoethyl (meth) acrylate, (meth) acrylic acid-2
Rubber-based polymer substances, such as polyisoprene rubber, such as monomers having a functional group such as methoxyethyl ester and / or copolymers with vinyl-based monomers such as acronitrile, vinyl acetate and vinyl propionate; , Polyisobutylene rubber, polybutene rubber, butyl rubber, styrene-butadiene rubber, styrene-butadiene-styrene copolymer rubber, styrene-isoprene-styrene copolymer rubber, silicone rubber, natural rubber, etc .; alcohol,
Examples include polyvinyl ether and polyvinyl acetate. In the present invention, these high-molecular substances are used alone or in combination in consideration of adhesion, compatibility and the like.

The polyoxyalkylene-modified organopolysiloxane used in the present invention is a compound represented by the following general formulas [A] to [D].

The polyoxyalkylene-modified organopolysiloxane used in the present invention preferably has an average molecular weight of 3,000 or more, more preferably 5,000 or more. Further, those containing 2 to 80% by weight of a polyoxyalkylene group in the polyoxyalkylene-modified organopolysiloxane molecule are preferable, and 11 to 50 are more preferable in view of the effect.
% By weight.

The compounding amount of the polyoxyalkylene-modified organopolysiloxane is 0.1 to 90% by weight, preferably 0.1 to 50% by weight in the polymer material layer. A large amount is undesirable because it tends to impair the adhesiveness of the external member on the skin.

The carboxyvinyl polymer used in the present invention is a water-soluble vinyl polymer having a carboxyl group in the molecule, and is a polymer mainly containing acrylic acid having an average molecular weight of about 1,000,000 to 3,000,000. Commercial products include Carboball (Goodrich Chemical Co., Ltd.), Hibiswako (Wako Pure Chemical Industries, Ltd.) and the like. These substances are widely used as thickeners for liquids because they become thickened gels by neutralization, but in the external member of the present invention, they are added and dispersed in the polymer material layer without neutralization. Used. In order to improve the dispersibility in the polymer layer, it is preferable to dissolve it in an appropriate amount of water or alcohol before use. The amount of water or alcohol used may be the minimum required to uniformly disperse the carboxyvinyl polymer.

The compounding amount of the carboxyvinyl polymer is preferably 0.5 to 5.0% by weight based on the total amount of the polymer phase. When the content is less than 0.5% by weight, no improvement in adhesion is observed, and when the content exceeds 5.0% by weight, no further improvement is seen.

In the present invention, in addition to the above essential components, various additives such as a drug, a dissolution / diffusion improver, a water retention agent, a keratin softener, a percutaneous absorption enhancer, and the like can be blended in the polymer substance layer. .

Specific examples of these agents include: a. Analgesic and anti-inflammatory agents: for example, salicylic acid, methyl salicylate,
Glycol salicylate, 1-menthol, camphor,
Nonylate varnishylamide, tocopherol, peppermint oil,
Thymol, Capsicum extract, Capsicum powder, Tocopherol acetate, dl-Camphor, Acetaminophen, Mefenamic acid, Flufenamic acid, Indomethacin, Diclofenac, Alcloenac, Oxyfenbutazone,
Phenylbutazone, ibuprofen, flurbuprofen, etc. b. Antibacterial substances: for example, nitrofurazone, nystatin,
Acetosulfamine, clotrimazole, pentamycin, amphotericin B, pyrrolnitrin, etc. c. Antibiotics: for example β-lactan antibiotics (penicillins, cephalosporins), oxytetracycline, fradiomycin sulfate, erythromycin, clos D. Vitamins: for example, vitamin A, ergocalciferol, cholecalciferol, octothiamine, riboflavin butyrate, tocopherol, ascorbic acid, etc. e. Coronary vasodilators: for example, nitroglycerin, nifemipine, dipyridamole, isorsorby Dozi night rate,
Erythritol tetranitrate, pentaerythrose tetranitrate, etc. f. Antihistamines: eg diphenhydramine hydrochloride, chlorpheniramine, diphenylimidazole, etc. g. Corticosteroids: eg hydrocortisone,
Presonisolone, paramethasone, beclomethasone propionate, flumethasone, betamethasone, beclomethasone supionate, dexamethasone, triamcinolone, triamcinolone acetonide, fluocinolone, fluocinolone acetonide, fluocinolone acetonide acetate, clobezole propionate, etc. Barbitals such as, for example, phenobarbital, amobarbital, cyclobarbital i. Tranquilizers: for example fluphenazine, thioridazine,
Benzodiazepines (eg diazepam, lorazeban,
Flunitrazeban), chlorpromazine, etc. j. Antihypertensives: for example, clonidine, kallikrein, etc. k. Antihypertensive diuretics: for example, hydrothiazide, bendroflumesiazide, etc. l. Anesthetics: for example, lidocaine, benzocaine, ethyl aminobenzoate, etc. m. Antiepileptic Agent: For example, nitrazepam, meprobamate and the like can be mentioned.

Transdermal absorption enhancers include dimethylsulfoxide, dodecylsulfoxide, methyloctylsulfoxide, dimethyldecylphosphoxide, mono- or diethylacetamide, N-hydroxyethyl lactamide, dimethylacetamide, N, N- Dimethyl dodecamide, dimethyl formamide, diethyl toluate, tetrahydrofurfuryl alcohol, tetrahydrofuran, sorbitol, dodecylpyrrolidone, methylpyrrolidone, urea, diethyl adipate, squalene, squalane, acetylated lanolin, cetyl lactate, dioctyl sebacate, ethoxylated stearyl Alcohol, lanolin lanolin alcohol, higher fatty acid alcohol, salicylic acid, stilisooctanoate, liquid paraffin, squalane, petrolatum, amino , Proteolytic enzymes, ethyl nicotinate, 1-menthol, sulpur, higher fatty acid triglyceride, polyoxyalkylene glycol, fatty acid mono (or di) ethanolamide, ethylene glycol monoethyl ether, polyoxypropylene alkyl ether, polyglycerin alkyl ester, And higher alkyl sulfones.

In addition, lanolin, olive oil,
Glycerin, benzyl alcohol, butyl benzoate, isopropyl siristate, octanol, 1,3-
Butylene glycol, (poly) ethylene glycol and the like.

Other optional components include a filler, an adhesion aid, and a softener for maintaining the shape retention of the polymer material layer.

Fillers include silica, titanium oxide, calcium carbonate, kaolin, mica, zinc white, aluminum hydroxide, barium sulfate, starch, talc, clay, and the like.Adhesion aids include ethyl acetate, butyl acetate, triethyl citrate, and butyl. Examples of softeners such as alcohols include various plasticizers, polybutene, and polyisobutylene low-polymer.

To manufacture the external member according to the present invention, any known method used for manufacturing a pressure-sensitive adhesive sheet or tape can be used. For example, a polymer substance solution dissolved in a solvent, or an emulsion in which the polymer substance is dispersed in an aqueous medium, a compound having a protease inhibitory action,
In some cases, a polyoxyalkylene-modified organopolysiloxane and a carboxyvinyl polymer are added and dispersed, and then the solution or emulsion is applied on a sheet or tape-like support, and dried to form an external member. A polymer substance layer (pressure-sensitive adhesive layer) is formed on a sheet or tape-like support without adding a compound having a protease inhibitory action and a polyoxyalkylene-modified organopolysiloxane in the same manner as described above. And a method of applying the compound having the protease inhibitory action, and depending on the case *, a polyoxyalkylene-modified organopolysiloxane and a carboxyvinyl polymer by a method such as coating or spraying.

In order to form a polymer material layer (pressure-sensitive adhesive layer) on a sheet or tape-like support, the polymer material solution or emulsion is spray-coated, roll-coated,
Known coating means such as a gravure coating method, a reverse coating method, a dip coating method, a screen printing method, and a flexographic printing method can be used.

The drying of the coating film may be performed under such conditions that the liquid component of the aqueous medium, the solvent in the polymer solution and the like are scattered. Examples include hot air drying, drying by infrared irradiation, drying by far infrared irradiation, etc.
It may be heated for about 10 minutes.

The thickness of the polymer material layer having pressure-sensitive adhesiveness varies depending on the type of the external member. Generally, the thickness after drying is preferably 0.5 mm or less for plasters and 0.5 mm or more for plasters and cataplasms.

The external member of the present invention can be variously modified within a range that does not impair the effect.

[Examples] Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto. In Examples, “parts” means “parts by weight”. The evaluation method and the experimental method used in the present invention will be described prior to the examples.

Skin irritation A test piece 4 cm wide and 7 cm long was made from each external application material, and this was applied to the forearm of a subject who was relatively easily rashed to a bandage for 48 hours and then peeled off, and 2 hours and 5 hours after peeling off the test piece The 24-hour skin irritation value was evaluated. The evaluation of irritation was performed according to the following criteria.

No reaction such as erythema is observed ....-slight erythema is recognized .... ± erythema is recognized. … Strong erythema and edema are observed ………… Retention Force A test piece 4 cm wide and 7 cm long is made from each external application material, and this is attached to the forearm of the subject for 48 hours, and the test piece comes off the skin. It was determined whether or not.

Glue residue For each external member, it was determined whether or not the adhesive remained on the release sheet when the release sheet was peeled from the pressure-sensitive adhesive layer during use. Also, affix an external component to the human forearm
When peeling off after 48 hours, it was determined whether or not adhesive residue was left on the applied skin surface.

Examples 1 and 2 and Comparative Example 1 Adhesive using a commercially available set of an acrylic adhesive containing acrylic acid ester as a main component and a curing agent containing ethyl acetate as a main solvent (Sibinol AT-301, manufactured by Seiden Chemical Co., Ltd.) 80
1 part of tranexamic acid and 20 parts by weight of a curing agent having 20% by weight of a polyoxyethylene group
After adding and mixing 4 parts of a polyoxyethylene-modified organopolysiloxane having an average molecular weight of 6000 and 10 parts of a 30% aqueous solution of carboxyvinyl polymer, apply the mixture uniformly on a polyolefin-based nonwoven fabric and dry at room temperature. In this way, a member for external use was obtained. Further, in the same manner to obtain a polyoxyethylene-modified organopolysiloxane and an external member without carboxyvinyl polymer,
This was designated as Example 2. Further, an external member containing no tranexamic acid, polyoxyethylene-modified organopolysiloxane and carboxyvinyl polymer was obtained in the same manner as in Example 1, and this was designated as Comparative Example 1.

Table 1 shows the results of skin irritation evaluation conducted on 20 subjects in Examples 1, 2 and Comparative Example 1.
Shown in

As is clear from Table 1, the skin irritation was found to be strong in Comparative Example 1 whereas the skin irritation was reduced in Example 2 containing tranexamic acid. In Example 1 in which a polyoxyethylene-modified organopolysiloxane and a carboxyvinyl polymer were blended, skin irritation was further reduced. In addition, it can be seen that even the test subject who showed a slight irritation value lost irritation by 24 hours.

Regarding the adhesive residue and the holding power, in Comparative Example 1, the phenomenon of adhesive residue on the release sheet and on the surface of the applied skin was observed, whereas in Examples 1 and 2, this phenomenon was not observed. Also, the holding power to the skin was good.

Example 3 1 part of tranexamic acid in Example 1 was replaced with leupeptin 0.5
Parts of polyoxyethylene-modified organopolysiloxane 45 parts having the structure of the general formula (B), containing 75% by weight of polyoxyethylene groups, and having an average molecular weight of 30,000. Department, 30
The same formulation as in Example 1, except that 10 parts of a 30% aqueous solution of carboxyvinyl polymer was changed to 20 parts of a 30% aqueous solution of carboball,
An external member was obtained in the same manner.

The external member of the present invention had little skin irritation, no adhesive residue was observed, and good holding power to the skin.

Example 4 One part of tranexamic acid in Example 1 was replaced with tosylarginine
3.5 parts by weight of 4 parts of polyoxyethylene-modified organopolysiloxane, polyoxyethylene-modified organopolysiloxane having a structure of the general formula (C), containing 7% by weight of polyoxyethylene groups and having an average molecular weight of 3000 Add 0.5% of the 30% carboxyvinyl polymer aqueous solution to 5 parts
An external member was obtained by the same method and the same method as in Example 2 except that the parts were changed.

The external preparation of the present invention had little skin irritation, no adhesive residue was observed, and good holding power on the skin.

Example 5 1 part of tranexamic acid in Example 1 was added to 0.05 part of tosyl ridyl chloromethyl ketone, 4 parts of polyoxyethylene-modified organopolysiloxane, and 50 parts by weight of a polyoxyethylene group having a structure of the general formula (A). %, The average molecular weight is
20 parts of polyoxyethylene-modified organopolysiloxane of 20000 are added to 30% carboxyvinyl polymer aqueous solution
An external member was obtained in the same manner as in Example 1, except that the part was changed to 20 parts of a 30% carboball aqueous solution.

The external member of the present invention had little skin irritation, no adhesive residue was observed, and good holding power to the skin.

Example 6 7 parts of p-aminobenzamidine was mixed with 100 parts of a commercially available vinyl adhesive mainly containing polyvinyl alcohol,
Thereafter, the mixture was uniformly applied on a polyethylene film and dried to obtain an external member.

The external member of the present invention had little skin irritation, no adhesive residue was observed, and good holding power to the skin.

Example 7 80 parts of the same adhesive and curing agent 20 as used in Example 1
Then, 0.01 part of cyclohexylguanidine was added to and mixed with the mixture, and the mixture was uniformly applied to a polyolefin-based nonwoven fabric and dried to obtain a member for external use.

The external use member of the present invention had little skin irritation, no adhesive residue was observed, and good holding power to the skin.

Example 8 10 parts of gelatin, 10 parts of kaolin, 5 parts of polyvinyl alcohol, 5 parts of glycerin, 15 parts of propylene glycol, polyacrylic diacid, 30 parts of purified water, 5 parts of menthol,
Methyl salicylate 4 parts, dl-camphor 1 part, thymol 0.
5 parts, soybean trypsin inhibitor 0.01 part, ascorbic acid 1 part, arginine 3 parts, fructose 3 parts, having a structure of the general formula (B), and having a polyoxyethylene group
After adding and mixing 10 parts of a polyoxyethylene-modified organopolysiloxane containing 75% by weight and having an average molecular weight of 30,000 and a 30% aqueous solution of a carboxyvinyl polymer,
The composition was uniformly applied to a polyolefin-based nonwoven fabric to obtain a member for external use.

The external member of the present invention had little skin irritation, no adhesive residue was observed, and good holding power to the skin.

Example 9 To 100 parts of a commercially available polyvinyl adhesive containing polyvinyl alcohol as a main component, 11.7 parts of -menthol, 12.4 parts of methyl salicylate, 0.5 parts of peppermint oil, 2.0 parts of dl-camphor, 0.5 parts of thymol, 0.3 parts of tocopherol acetate, It has a structure of 3.4 parts of glycol salicylate, 0.05 parts of aprotinin, 5 parts of lysine, and the general formula (B).
75 parts by weight of a polyoxyethylene-modified organopolysiloxane having an average molecular weight of 30,000 and 3 parts by weight of a polyoxyethylene group having the structure of the general formula (A)
3 parts of a polyoxyethylene-modified organopolysiloxane having an average molecular weight of 6000 and 10 parts of a 30% aqueous solution of carboxyvinyl polymer are added and mixed, and then uniformly applied to a polyolefin-based nonwoven fabric, dried and dried. I got

The external member of the present invention had little skin irritation, no adhesive residue was observed, and good holding power to the skin.

[Effects of the Invention] The external use member of the present invention has little skin irritation, extremely high human body safety, and excellent adhesiveness and adhesive residue.

Claims (4)

(57) [Claims] An external member comprising a sheet or a tape-shaped support and a polymer material layer having a pressure-sensitive adhesive property laminated thereon, wherein the polymer material layer has one or more compounds selected from compounds having a protease inhibitory action. An external member characterized by mixing two or more types. 2. The external member according to claim 1, wherein the polymer layer further contains a polyoxyalkylene-modified organopolysiloxane and / or a carboxyvinyl polymer. 3. The external use member according to claim 2, wherein the polyoxyalkylene-modified organopolysiloxane is selected from compounds represented by the following general formulas [A] to [D]. 4. The external member according to claim 2, wherein the polyoxyalkylene-modified organopolysiloxane has an average molecular weight of 3,000 or more.