JPH046166B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a member for external use that is applied directly to the skin of the body to exhibit pharmacological effects and treat diseases.

Conventionally, this type of externally used member has been divided into rubber-based types and acrylic-based types, and the forming methods for both include mixing drugs into adhesive polymeric substances.
Generally, a drug-containing adhesive layer is provided by dissolving the drug, or a drug solution dissolved in an appropriate solvent is applied to the surface of a previously formed adhesive layer for impregnation.

However, among these external use parts, rubber-based external use parts do not have tackiness only with the main rubber component, so it is necessary to add a tackifying resin.
Due to the combination of such resins, drug stability and release properties are poor.

Furthermore, because of insufficient moisture permeability, when applied to the skin of the body, it causes skin irritation and causes phenomena such as rashes. On the other hand, although the above-mentioned problems have been considerably improved with acrylic external members, the following various problems still remain.

In other words, if an organic solvent is used during the synthesis of the acrylic pressure-sensitive adhesive and the drug-containing composition is in the form of an organic solvent solution before the formation of the external use part, workers may be inhaled when the organic solvent evaporates during the formation of the external use part. There are various problems such as toxicity and fire danger caused by organic solvents, increased capital investment for installing solvent recovery equipment, and environmental pollution.Furthermore, when external parts are applied to the skin of the body, residual organic solvents may cause skin irritation, There are also inherent problems such as absorption toxicity. In order to eliminate these problems, the use of solvent-free products has progressed, and emulsion-type external parts have also come into use, but in general, large amounts of surfactants are used in emulsion polymerization of acrylic monomers. It is impossible to completely remove the surfactant used when applying the pressure-sensitive adhesive layer, resulting in decreased water resistance (e.g. sweat resistance) and problems such as blooming on the surface. This phenomenon has adverse effects such as reduced skin adhesion. Furthermore, since commonly used surfactants have highly reactive functional groups, there is a problem in that they lack drug stability. For this purpose, surfactants for pharmacopoeia products, food additives, and cosmetic raw material standards are used due to skin irritation and other concerns, but these surfactants have weak surfactant ability, so When used in polymerization, a polymer with sufficient properties could not be obtained.

As a result of extensive research from this point of view, the present inventors found that a monomer mixture of an acrylic monomer and a polar group-containing monomer copolymerizable therewith in an aqueous medium in the absence of a surfactant. For external use, it consists of a laminate of a carrier and a drug-containing pressure-sensitive adhesive layer formed by adding a drug and, if necessary, a drug release promoting substance to an emulsion copolymer (emulsion) obtained by polymerizing the drug. It was discovered that the material has excellent drug stability, release properties, and skin adhesion.

That is, the present invention has a laminated form of a layer containing a drug in an acrylic pressure-sensitive adhesive that is sticky at room temperature and a carrier, and the acrylic pressure-sensitive adhesive is used in the absence of a surfactant. An emulsion obtained by copolymerizing an acrylic unsaturated monomer and a polar group-containing monomer copolymerizable therewith in an aqueous medium with a particle size of 0.05
The present invention provides an external member characterized by using an emulsion copolymer of ~1 μm.

According to the present invention, the emulsion copolymer is produced by producing a polymer in an aqueous medium without using any surfactant or organic solvent, so it does not have the above-mentioned problems such as skin irritation and toxicity. To provide a member for external use that is completely free of.

In addition, unlike solution copolymers using organic solvents, we use a heterogeneous polymerization method in an aqueous medium, so the emulsion copolymers produced have emulsion particle sizes of 0.05 μm to 1 μm, which is relatively high. When a copolymer of fine particles with a narrow particle size distribution is obtained and used as a drug-containing pressure-sensitive adhesive layer for external use, ultramicroscopic drug transfer paths exist between the particles in the adhesive layer, and the drug Contributes to improved release properties. Furthermore, unlike a solution copolymer, the molecular weight of the copolymer increases from several times to more than ten times, so it has excellent internal cohesive force, that is, it has excellent skin adhesion, and an external member without adhesive residue can be obtained. In addition, since drug transfer occurs both through diffusion within the polymer copolymer and through ultrafine paths between fused emulsion particles, in the case of a solution copolymer, drug movement occurs only within the copolymer. It has a fast-acting and sustained drug release compared to other drugs.

In other words, when the external member of the present invention is applied to the skin of the body, sweat secreted from the sweat glands fills the channels (gaps) between emulsion particles due to capillary action and becomes a medium for drug transfer. Therefore, the rapid effect is enhanced. Next, the drug diffuses and moves through the copolymer, which absorbs moisture and swells to increase its travel distance, thereby maintaining sustained release.

The acrylic unsaturated monomer used in the present invention is intended to impart tackiness to the pressure-sensitive adhesive layer, and is mainly composed of commonly used acrylic acid alkyl esters. . Specifically, butyl acrylate, pentyl acrylate, hexyl acrylate, isooctyl acrylate, 2-ethylhexyl acrylate, nonyl acrylate, decyl acrylate, dodecyl acrylate, and stearyl acrylate. One or a combination of two or more monomers such as esters can be used, and if necessary, a modifying monomer can be added thereto. The above-mentioned modifying monomers include (meth)acrylic acid methyl ester, (meth)acrylic acid ethyl ester, acrylic acid 2-methoxyethyl ester, acrylic acid 2-butoxyethyl ester, acrylic acid cyclohexyl ester, vinyl acetate, and propion. Examples include monomers such as vinyl acid.

The greater the hydrophobicity of the acrylic unsaturated monomer, the better the skin adhesion. Specifically, in the case of acrylic acid alkyl ester, monomers in which the alkyl group has 5 or more carbon atoms are optimal, and the amount added is preferably between 40% and 98% by weight.
If it is added in an amount of 98% by weight or more, the cohesiveness of the pressure-sensitive adhesive layer will be insufficient, resulting in adhesive residue when used as a patch, and there is a risk of contaminating the skin surface to which it is applied.

In addition, the polar group-containing monomers that can be copolymerized with the above monomers are components intended to impart cohesive properties to the pressure-sensitive adhesive layer, and specifically include acrylic acid, methacrylic acid, maleic acid, , itaconic acid, maleic anhydride, acrylic acid hydroxyethyl ester, acrylic acid hydroxypropyl ester, acrylonitrile, acrylic acid NN-dimethylaminoethyl ester, methacrylic acid NN-dimethylaminoethyl ester, acrylic acid N-tert
Examples include monomers such as -butylaminoethyl ester, acrylamide, methacrylamide, and N-methylolacrylamide.

A method for producing a pressure-sensitive adhesive from the above monomer in an aqueous medium in the absence of a surfactant is as follows:
There are various methods, but for example, the monomer mixture is mixed all at once (or dropped) in an aqueous medium, stirred, and dispersed, and then a water-soluble polymerization initiator is added to start the copolymerization reaction. A method of growing a polymerization reaction using a water-insoluble copolymer as a reactant as a core particle, and a multi-stage addition of a monomer mixture (at once or dropwise)
A method for obtaining an emulsion copolymer by carrying out a reaction can be used, and the method can be arbitrarily selected depending on the type and purpose of the monomers and the mixed composition of the monomers.

Such an emulsion copolymer is in the form of a milky white emulsion with low viscosity and has a relatively narrow particle size distribution of 0.05 μm to 1 μm. As a result, a drug-containing acrylic pressure-sensitive adhesive layer can be obtained. On the surface and inside of the pressure-sensitive adhesive layer obtained in this way, there are ultramicroscopic drug transfer paths (gaps) formed by the fusion of emulsion particles, and the drug release properties and Particularly effective for fast-acting.

The external member of the present invention has a laminated form of the above-mentioned acrylic pressure-sensitive adhesive layer and a carrier, and carriers used here include various plastic films, nonwoven fabrics, woven fabrics, papers, Metal foil, a laminated film of this and a plastic film, etc. can be used as desired depending on the purpose.

The drug used in the present invention is not particularly limited as long as it is a medicinal ingredient that can be absorbed through the skin to a therapeutically effective concentration, and examples include the following drugs.

(b) Corticosteroids: For example, hydrocortisone, prednisolone, paramethasone, peclomethasone propionate, flumethasone, petamethasone, beclomethasone propionate,
Dexamethasone, triamcinolone, triamcinolone acetonide, fluocinolone, fluocinolone acetonide, fluocinolone acetonide acetate, clobetasol propionate, etc. (b) Analgesic and anti-inflammatory agents: for example, acetaminophen, mefenamic acid, flufenamic acid, indomethacin, diclofenac, Arklovenatsk,
Oxyphenbutazone, phenylbutazone, ibuprofen, flurbiprofen, salicylic acid, l-menthol, camphor and combinations thereof, etc. (c) Hypnosedatives: for example, barbitals such as phenobarbital, amobarbital, cyclobarbital, etc. Scopolamine, scopolamine hydrobromide, etc.(d) Tranquilizers: For example, fluphenazine, thioridazine, benzodiazepines (e.g. diazepam,
lorazepam, flunitrazepam), chlorpromazine, etc. (e) Antihypertensive agents: e.g. clonidine, kallikrein, etc. (f) Antihypertensive diuretics: e.g. hydrothiazide,
Bendroflumethiazide, etc. (g) Antibiotics: e.g. β-lacdam antibiotics (penicillins, cephalosporins), oxytetracycline, fradiomycin sulfate, erythromycin, chloramphenicol, etc. (h) Anesthetics: e.g. lidocaine , penzocaine,
(l) Antibacterial substances such as nitrofurazone, nystatin, acetosulfamine, clotrimazole, etc. (n) Antifungal substances such as pentamycin, amphotericin B, virolnitrine, clotrimazole, etc. (l) Vitamin preparations: e.g. vitamin A, ergocalciferol, cholecalciferol, octothiamine, riboflavin butyrate, etc. (e) Antiepileptic drugs: e.g. nitrazepam, mepropamate, etc. (w) Coronary vasodilators: e.g. glycerin,
Nifedipine, dipyridamole, isosorbite dinitrate, erythritose tetranitrate, pentaerytose tetranitrate, etc. (f) Antihistamines: such as diphenhydramine hydrochloride, chlorpheniramine, diphenylimidazole, etc. These drugs are necessary. Two or more types can be used in combination depending on the situation.

After the external member of the present invention is applied to the skin surface,
The drug contained therein is effectively released with immediate and sustained action, and exhibits sufficient pharmacological effects as expected.
Furthermore, drug solubility is also good. In addition, it has good skin adhesion when applied to the skin surface and does not peel off or fall off during use. Moreover, when the external member is removed, all or part of the pressure-sensitive adhesive does not remain on the skin surface to which it is applied, and does not cause any contamination.

EXAMPLES The present invention will be explained in more detail below with reference to Examples, but the present invention is not limited to these Examples, and various applications are possible without departing from the technical idea of the present invention.

Example 1 A mixture consisting of 93 parts by weight of acrylic acid 2-ethylhexyl ester, 7 parts by weight of acrylic acid, and 250 parts by weight of water was stirred and after sufficient nitrogen substitution,
0.5 parts by weight of ammonium persulfate was added as a polymerization initiator, and polymerization was carried out at 70°C for 10 hours to obtain the desired emulsion copolymer.

Scopolamine was added to and mixed with the emulsion copolymer thus obtained, and the mixture was coated on the surface of a polyethylene film to a dry thickness of 50 μm and dried to obtain a drug-containing member for external use. The amount of scopolamine used in this example was set to 400 μg/cm ² .

The solubility of scopolamine in the obtained external use material was good, no undissolved matter or crystal precipitation was observed, and the stability over time was good, with almost no decomposition reaction occurring (after 1 month at 50°C). Survival rate after storage: 97
%). Furthermore, when applied as a patch on the skin, the skin adhesion and drug release properties were good, reaching an effective plasma concentration in about 20 minutes after application, and the pharmacological effect lasted for about 24 hours. Furthermore, after application and use, when the external member was peeled off and removed, no adhesive remained on the applied skin surface or skin irritation such as rash was observed.

Example 2 A monomer aqueous solution consisting of 20 parts by weight of acrylic acid 2-methoxyethyl ester and 250 parts by weight of water was stirred,
After sufficient nitrogen substitution, 0.8 parts by weight of a redox initiator consisting of potassium persulfate and sodium hydrogen sulfite was added as a polymerization initiator, and the temperature was raised to 60°C and polymerization was carried out for 3 hours. 50 parts by weight of acrylic acid nonyl ester and vinyl acetate in the cloudy polymer
Complete the dropping of the mixture with 30 parts by weight in 4 hours,
The temperature was further raised to 80°C and polymerization was carried out for 5 hours to obtain the desired emulsion copolymer.

Isosorbite dinitrate was added and mixed to the emulsion copolymer thus obtained, and the surface of a laminated film of polyethylene-polyvinyl acetate (EVA) and polyethylene was coated to a thickness of 30 μm after drying.
The mixture was applied and dried to obtain a drug-containing external member. The amount of isosorbite dinitrate used in this example was set to 200 μg/cm ² .

The solubility of isosorbite dinitrate in the obtained external use material was good, no undissolved matter or crystal precipitation was observed, and the stability of the drug over time was extremely good (50℃ , survival rate after 1 month storage
98.5%). Furthermore, when applied to the skin, the skin adhesion and drug release properties are good, and approximately
Effective plasma concentrations were reached in 15 minutes, and pharmacological effects lasted for 20 hours. Furthermore, after application and use, when the external member was peeled off and removed, no adhesive remained on the applied skin surface or skin irritation such as rash was observed.

Claims (1)

[Claims] 1 It has a laminated form of a layer containing a drug in an acrylic pressure-sensitive adhesive that is sticky at room temperature and a carrier, and the acrylic pressure-sensitive adhesive can be used in an aqueous medium in the absence of a surfactant. An external member characterized by using an emulsion copolymer having an emulsion particle size of 0.05 to 1 μm, which is obtained by copolymerizing an acrylic unsaturated monomer and a polar group-containing monomer copolymerizable with the monomer.