JPS63270060A - Antibacterial adhesive member - Google Patents

Abstract

PURPOSE:To obtain an antibacterial adhesive member having an excellent antibacterial property, having no skin irritability and not coloring an adapting area, by laminating a copolymer of specific vinylsalicylic acid or methyl ester thereof and (meth)acrylic ester to a flexible carrier. CONSTITUTION:Since an antibacterial copolymer consisting of 5-50wt.% of a monomer composed of vinylsalicylic acid or ester thereof and 95-50wt.% of (meth)acrylic ester has desired coagulability, said copolymer can be used as the adhesive of an adhesive type drug member for external application. In order to further enhance coagulability, a monomer or polar monomer copolymerizable with said monomer is pref. compounded in a range of 10% or less by wt. of all of the monomers to be copolymerized with said monomers. The solution of this antibacterial copolymer is applied to a flexible carrier and dried to form the antibacterial copolymer layer on said carrier. The antibacterial adhesive member thus obtained is used as an emergency adhesive plaster or a roller bandage as it is. As the vinylsalicylic acid monomer, 3-vinylsalicylic acid, 4-vinylsalicylic acid and 5-vinylsalicylic acid are used.

Description

[Detailed description of the invention] (a) Industrial application fields The present invention relates to an antibacterial adhesive member having antibacterial properties.

(b) Prior art In recent years, patch-type external medical devices have been developed in which a drug is contained in a pressure-sensitive adhesive layer to form a drug-containing adhesive layer, and this layer is attached to the skin to absorb the drug transdermally. Many have been developed.

Transdermal administration of drugs is less cumbersome when administered than oral administration, injections, suppositories, etc., and the drug is not metabolized by the liver, does not cause gastrointestinal disorders, and has a limited drug release rate. It has advantages such as being able to reduce the number of times of administration and being painless during administration, and it is thought that various patch-type external medical devices will be developed in the future.

By the way, if this type of external medicinal material is applied to the same site for a long period of time, microorganisms such as bacteria will grow at the interface between the adhesive layer containing Drug 1 and the skin, causing skin irritation and seriously interfering with the therapeutic effect. There may be cases where

For this reason, there is a strong demand for patch-type external medical members having antibacterial properties, and in response to these demands, the following have been proposed as antibacterial external medical members.

The first medicinal material for external use is a soft blue sheet containing an antibiotic such as fradiomycin sulfate.

Also, as a second external medicinal component. This is the last volume of a wound treatment product containing Mercurochrome in a rubber adhesive.

Furthermore, the third external medicinal component is a pressure-sensitive adhesive containing a polyvinylpyrrolidone-I2 complex. (c) Problems to be solved by the invention However, the first external medicinal component is However, since it has no adhesive function, its uses are limited, and the antibiotic is unstable and easily decomposes, so the above problems have not been sufficiently solved.

In addition, the above-mentioned second external medicinal component not only colors the skin, but also
A sufficient effect could not be obtained.

Furthermore, in the above-mentioned third external pharmaceutical component, I2 is volatile, has a large oral change, and has the problem of skin irritation, so it was not completely satisfactory.

It is also possible to obtain antibacterial properties by mixing polymeric ammonium salts into pressure-sensitive adhesives, but in general,
Highly hydrophilic polymeric ammonium salts have poor compatibility with pressure-sensitive adhesives, so they cannot be mixed uniformly, resulting in problems such as reduced adhesive functionality.

(d) Means for Solving the Problems The present inventors have made extensive studies to solve the above problems, and have found that both the vinyl salicylic acid monomer and its polymer exhibit excellent antibacterial effects; In addition, copolymers using this monomer can exhibit selectivity in their activity by changing the type and composition of the monomer (＠References DIJTSSON, ^, C0et, al,, J, Ma
cromol, Sci+Cbe1. +^21 (1) Near 7.1984) and completed the present invention.

That is, the present invention provides 3-vinylsalicylic acid and its methyl ester represented by the supplementary formula, or 4-vinylsalicylic acid represented by 5-50% by weight of 5-vinylsalicylic acid represented by CH2I;
It is characterized by laminating layers containing an antibacterial copolymer containing 95 to 50% by weight of (meth)acrylic acid ester as an essential component.

The present invention will be explained in detail below.

The carrier used in the present invention may be any carrier that is flexible and does not cause a significant discomfort when applied to the skin, but specific examples include polyolefin, polyester,
Various plastic films or sheets such as polyurethane, polyvinyl alcohol, polyvinylidene chloride, etc.
Furthermore, foamable sheets or films made of rubber and synthetic resin,
Examples include nonwoven fabric, metal foil, and laminated films/sheets thereof.

The feature of the present invention is that 3-vinylsalicylic acid and its methyl ester represented by the structural formula, or 4-vinylsalicylic acid represented by C)(=CH2) or 5-vinylsalicylic acid represented by
Vinyl salicylic acid is present in an amount of 5 to 50 ffl%, preferably 5 to 20% by weight, and a (meth)acrylic acid ester is present in an amount of 95 to 50% by weight.
It consists of laminated layers containing an antibacterial copolymer of 1% by weight as an essential component.

The monomers of 3-vinylsalicylic acid and its methyl ester, 4-vinylsalicylic acid or 5-vinylsalicylic acid used in the present invention can be prepared by a known method from 3-ethyl 7-ethyl, 4-ethylphenol or 5-ethylphenol. In other words, literature (M I-^S8 to T, ct, af,,
J Polym, Sic:Polym, CI+em,
Ed, Vo weight 8.2755 (1980) and Dav
id Tirrell, et, al,, Makromo
Chem, 181.2097 (1980)).

If the mixing ratio of the vinyl salicylic acid (and its ester) monomer and (meth)acrylic acid ester is outside the above range, it is not preferable because the desired antibacterial properties, adhesive properties, and cohesive properties may not be obtained. It is.

The (meth)acrylic ester used in the present invention is not particularly limited as long as it imparts tackiness and adhesion to the antibacterial copolymer layer, but examples include n-butyl acrylate, Weight - Butyl methacrylate, hexyl acrylate, 2-ethylbutyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tetrahydrofurfuryl acrylate, methoxypolyethylene glyph acrylate, butoxydiethylene glycol acrylate, methoxyethyl acrylate, 3-ethoxypropyl acrylate, ethoxyethyl acrylate, butquinethyl acrylate, and the like.

These copolymers have a lath transition point of -10 to -70°C, and not only provide adhesiveness and adhesion to the antibacterial copolymer layer, but also have sufficient free volume at the operating temperature. Therefore, the diffusion of the contained drug in the copolymer is large,
More of the contained drug can be released in a limited time.

In the present invention, the antibacterial copolymer of 5 to 50% by weight of vinyl salicylic acid (and its ester) monomer and 95 to 50% of (meth)acrylic acid ester has the desired cohesive property; In order to improve the performance, it is preferable to mix and copolymerize monomers or polar monomers copolymerizable with these monomers in an amount of 10% by weight or less of the total monomers.

Examples of such copolymerizable monomers or polar monomers include (meth)acrylic acid, itafonic acid, maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, acrylonitrile, vinyl acetate, and vinyl propionate. Examples include polar monomers and styrene monomers.

A solution of the antibacterial copolymer is applied onto the flexible carrier and dried to form a layer of the antibacterial copolymer on the carrier.

The antibacterial adhesive member thus obtained can be used as it is as an emergency bandage, 8-glue.

In a preferred embodiment of the present invention, as described above, an antibacterial copolymer formed by polymerizing vinyl salicylic acid (or its ester) contains a transdermally absorbable drug. Particularly important and desirable are those that can be administered cutaneously into a living body to treat or prevent diseases.

The transdermal absorbable drug used in the present invention is not particularly limited as long as it is absorbed transdermally into the body when applied to the skin surface. Examples of such drugs include the following.

b) Corticosteroid M: For example, hydrofutisone, prednisolone, beclomethasone probionate, flumethacin, triamcinolone, triamcinolone acetonide, fluocimerone, fluocinolone acetonide V1
Fluocinolone acetonide acetate, clobetasol propionate, etc.) Analgesic anti-inflammatory agents: e.g. 7cetamino7ene, mefenamic acid, flu7enamic acid, indomethacin, cyclo7enac, cyclo7enac sodium, alcro7enac, oxy7entazone , phenylftasone, iffuro-7ene, flurbipro-7ene, salicylic acid, methyl salicylate, l-menthol, can-77-, slingtsuk, tolmetin sodium, naproxen, 7-en, etc. c) Hypnotic sedatives: e.g. phenoparbital , amoparbital, cyfrobarbicur, triazolam, nitrazepam, lorazepam, haloperidol, etc.; 2) tranquilizers: e.g., flu7enanone, teolitanone, noazepam, flunoazepam, flunitrazepam, haloperidol, chlorpromanone, etc.; e) antihypertensive agents: e.g. Clonidine, clonidine hydrochloride,
Pindolol, propranolol, propranolol hydrochloride, b7ranol, indenolol, nivanopine, nimodipine, roanidixine, nidorenzubin, nipranolol, bucumolol, nianizibine, etc.) Antihypertensive diuretics: e.g. hydrothiazide, pendroarnathiazide, cyclobenziazide, etc.) ) Antibiotics: e.g. penicillin, tetracycline,
Oxytetracycline, 7-radiomycin sulfate, erythromycin, chloramphenicol, etc.; 1) Anesthetics: e.g., ridocaine, nobcaine hydrochloride, benzicaine, ethyl ami-7 benzoate, etc.; 4) Antibacterial substances: e.g., penzalfnium hydrochloride, nitro-7. razon, nyscutin, acetosulfamine, clotrimazole, etc.; n) Antifungal substances: e.g., pentamycin, amphotericin B1 pyrrolnidoline, clotrimazole, etc.; l) vitamins: e.g., vitamin A1, ergocalin, cholecalciferol, octothiazine. , riboflavin butyrate, etc.) Anti-epileptic agents: e.g. nitrazepam, mepropamate, clonazepam, etc. W> Tl vasodilatory agents: e.g. nitroglycerin, nitroglycol, insorbido nonitrate, erythritol tetranitrate, pentaerythritol tetranitrate antihistamines: e.g. noaenhydramine hydrochloride,
Chlorpheniramine, diphenylimixol, etc. ii) Antitussive M: For example, dextromethorphan hydrobromide, telbutasone sulfate, ephedrine, ephedrine hydrochloride, slubutamol acid, isoprotyl hydrochloride, isoprotyl sulfate, etc. d) Sex hormones: e.g. propsterone, estranool, etc. d) Anti-inflammatory agents: e.g. doxebin, etc.) Cerebral circulation improving agents: e.g. videlgin, nilgot alkaloids, iaenpronol, etc. t) Antiemetics, antitumor agents. : For example, metoclopramide, clevopride, tonbelitone, scopolamine, scopolamine hydrobromide, 5-
fluorouracil, mercaptopurine, etc.) Biopharmaceuticals: e.g. polypebutyll'M (TRI■,
derivatives of LHRl-1), Brostaglanson neck, etc.
n) Others: e.g. 7-entanyl, Novoxin, Te°
Examples include smopressin, dihydroergotamine methanesulfonic acid, nohydroergotamine tartrate, etc. One type of these drugs, or two or more types of these drugs can be used in combination as necessary.

The blending ratio of the above drug is 0.1 to 3% of the total antibacterial copolymer.
7% by weight, preferably within the range of 0.2 to 20% by weight.
It is desirable to adjust the R ratio, and if the compounding ratio of the drug is less than 0.1% by weight, the therapeutic effect will be poor, while if it exceeds 30% by weight, there will be a limit to the therapeutic effect, and crystal precipitation will cause transdermal It becomes difficult to absorb, which is a disadvantage.

Further, at this time, it is also possible to add a drug absorption enhancer to improve transdermal absorption.

Examples of such drug absorption enhancers include lower alcohols such as ethanol, glycols, polyhydric alcohols, urea, trimethyl sulfoxide, amides, imidazolinonone derivatives, noethyl sebacate, propylene carbonate, pyrrolidones, Other examples include various surfactants, and it is desirable to add at least one of these.

The blending ratio of the antibacterial copolymer (A) containing the above drug and the drug absorption enhancer (B) is 0.5 to 2.
A range of 0% by weight is desirable; if the blending ratio of (B) is less than 0.5% by weight, the effect will be poor; on the other hand, if it exceeds 20% by weight, a decrease in adhesive strength will be observed, which is undesirable. .

(e) Examples Hereinafter, the present invention will be explained in detail based on Examples, but the present invention is not limited thereto.

In the following, all parts or % mean parts by weight or % by weight.

Example 1 3-vinylsalicylic acid 10 parts isooctyl acrylate) aol vinyl acetate
10 parts azobisisobutyronitrile
0.5 part ethyl acetate 25
Four of the above formulations were placed in a Lough flask and heated to 125° C. with stirring at a temperature of 60 to 65°C under an inert gas atmosphere.
The reaction temperature was adjusted to the above range while adding 30% of ethyl acetate dropwise, and polymerization was carried out by heating for 4 hours.
After aging for a period of time, an antibacterial copolymer solution with a polymerization rate of 95.5% and a viscosity of 160 poise (temperature: 30° C.) was obtained.

Next, a solution of this antibacterial copolymer was applied to a polyethylene film so that the thickness after drying was 50 μm, and then
The antibacterial adhesive member of the present invention was obtained by drying at a temperature of 100° C. for 5 minutes.

Example 2 3-vinylsalicylic acid 15 parts Octyl acrylate 85 parts Azobisisobutyronitrile 0.5 parts Ethyl acetate
25 parts Four of the above formulations were placed in a Lough flask, and under an inert gas atmosphere, the reaction temperature was adjusted to 60 to 65°C while stirring and adding ethyl acetate for 125 seconds.
Polymerization was carried out by heating for 4 hours while controlling the temperature as described above, and further aging was carried out at a temperature of 80°C for 2 hours to obtain a solution of an antibacterial copolymer with a polymerization rate of 98.0% and a viscosity of 150 poise (temperature: 30°C). .

Next, a solution of this antibacterial copolymer was applied to a polyethylene film so that the thickness after drying was 50 μt,
The antibacterial adhesive member of the present invention was obtained by drying at a temperature of 100° C. for 5 minutes.

Example 3 An antibacterial adhesive member of the present invention was obtained in the same manner as in Example 1, except that 4-vinylsalicylic acid was used in place of 3-vinylsalicylic acid in Example 1.

Example 4 An antibacterial adhesive member of the present invention was obtained in the same manner as in Example 1, except that 5-vinylsalicylic acid was used in place of 3-vinylsalicylic acid in Example 1.

Example 5 An antibacterial adhesive member of the present invention was obtained in the same manner as in Example 1, except that methyl 3-vinylsalicylate was used in place of 3-vinylsalicylic acid in Example 1.

Example 6 The solution of the antibacterial copolymer of Example 1 had a concentration of 2 after drying.
An antibacterial adhesive member of the present invention was obtained in the same manner as in Example 1 by mixing insorbide nonitrate so that the amount was 00 parts g/cII12.

Comparative Example 1 3-vinylsalicylic acid in Example 1 was replaced with decyl acrylate, and polymerization was carried out in the same manner as in Example 1 to obtain a copolymer solution with a polymerization rate of 98% and a viscosity of 120 poise (temperature 30 ° C.),
Next, an adhesive member was obtained in the same manner as in Example 1.

Comparative Example 2 4 parts of iodine was added to 100 parts of the solid content of the copolymer solution of Comparative Example 1, and this was applied to a thickness of 50 μl after drying, and dried to obtain an adhesive member.

Comparative Example 3 Vinylpyrrolidone 10 parts Isooctyl acrylate 90 parts The above formulation was charged into a fourth flask and heated to 6 ml under an inert gas atmosphere.
While stirring at 0 to 60°C, 125 parts of ethyl acetate was added dropwise while controlling the reaction temperature within the above range, and polymerization was carried out for 4 hours, and further aged at a temperature of 80°C for 2 hours, resulting in a polymerization rate of 97.
A copolymer solution with a viscosity of 120 voids and a temperature of 30° C. was obtained.

To this, 4 parts of iodine was added, and an adhesive member was obtained in the same manner as in Comparative Example 1.

The results of each characteristic test performed on each of the above Examples and Comparative Examples are shown in Table @1.

Table 1 Test method 1, Antibacterial test (antibacterial activity test by disk method) Test bacteria: Bacillus subtilis
ilis ATCC6633), Staphylococcus
Stapl+ylocoeus aur
eus FD8 to 09P), Engineering/Nshierihiakori (E
scl+ericbiaeoli K12), Pseudomonas aeruginosa (r'seudomonas ae
ruBiniosa IFO12689).

The above test bacteria were plated by dispersing 105 to 106 cells on a meat extract agar medium, and the test pieces of each example and each comparative example were placed on top of the plate. The presence or absence of inhibition zone formation was observed.

The results of the above tests are shown in Table 1.

The rate at which inhibition zones were formed for the four types of test bacteria is shown in fractions.

2. Skin bW adhesion Each test piece in each Example and each Comparative Example (vertical 5
C-wing, horizontal Scm) was pasted on the back, and the adhesion was determined after 24 hours.

A case where 90% or more of the adhesion area was bonded was evaluated as good, and a case where all 10 volunteers were good was evaluated as ○. If the adhesive area was 90% or less even for one person, it was judged as defective X.

3. Coloring property of copolymer A copolymer having a thickness of 0.31 mm was formed on a glass plate, and the presence or absence of coloring property of the glass plate was observed with the naked eye.

4. Skin irritation Each test piece in each example and each comparative example (vertical 3
cm, m3cm) was pasted on the back, and the condition of the skin was determined 24 hours later.

Judgment method 5... Blisters 4... Edema 3... Red spots 2... Redness 1... No change Each test piece was judged by 10 volunteers, and if all of these 10 rated 2 or less, it was considered good. and the others were considered defective.

From Table 1, the antibacterial adhesive member of the present invention has excellent antibacterial properties and skin adhesion, and good results were obtained in the skin irritation test.

On the other hand, Comparative Example 1 has no antibacterial properties, and Comparative Example 2 has insufficient antibacterial properties and has problems in skin irritation tests. In this case, there was good luck in coloring with iodine, and in particular, Comparative Example 3 had a high coloring power with iodine.

(f) Effects of the Invention The antibacterial adhesive member of the present invention is made of a copolymer containing a specific vinyl salicylic acid (or its ester), and has extremely excellent antibacterial properties, and has almost no skin irritation. , does not stain the application area,
Furthermore, since it is pressure-sensitive adhesive, it is extremely easy to handle.

In addition, in the antibacterial adhesive member of the present invention, in which the antibacterial copolymer contains a transdermally absorbable drug, microorganisms such as bacteria do not grow over a long period of time, and therefore, inflammation caused by the above microorganisms does not occur. Problems such as these do not occur, and as a result, the above-mentioned drug is absorbed transdermally, resulting in more effective treatments.

Claims (5)

[Claims] (1) On a flexible support, 3-vinyl salicylic acid and its methyl ester represented by the structural formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or 4-vinyl salicylic acid and its methyl ester represented by ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ 5-50% by weight of salicylic acid or 5-vinyl salicylic acid represented by ▲There are mathematical formulas, chemical formulas, tables, etc.▼,
An antibacterial adhesive member comprising a laminated layer containing an antibacterial copolymer containing 95 to 50% by weight of (meth)acrylic acid ester as an essential component. (2) The antibacterial copolymer is 3-vinyl salicylic acid and its methyl ester represented by the structural formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or 4-vinyl salicylic acid represented by ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ 5-vinylsalicylic acid is 5 to 50% by weight,
The antibacterial adhesive member according to claim 1, comprising 95 to 50% by weight of (meth)acrylic acid ester and 10% by weight or less of a monomer copolymerizable with these or a polar monomer. (3) The antibacterial adhesive member according to claim 1 or 2, wherein the antibacterial copolymer contains a transdermally absorbable drug. (4) Content of transdermal absorbable drug is 0.1 to 30% by weight
The antibacterial adhesive member according to claim 3. (5) Content of transdermal absorbable drug is 0.2 to 20% by weight
The antibacterial adhesive member according to claim 4.