JPH0341445B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to a patch provided with a pressure-sensitive adhesive layer containing a drug and a method for producing the same. (Prior Art) Many patches having an adhesive layer containing a drug such as an anti-inflammatory agent have already been manufactured for the purpose of obtaining local or systemic effects through transdermal absorption of the drug. For example, Japanese Patent Publication No. 52-31405 discloses a patch having an acrylic adhesive layer in which steroids are uniformly dispersed. However, when the drug is present in the adhesive in a dispersed state without being dissolved, the release rate of the drug from the patch is poor. On the other hand, if the drug is uniformly dissolved in the adhesive, the drug release rate will be high, but the drug cannot be dissolved beyond the saturation solubility of the adhesive, and therefore, the drug generally contains a high concentration of drug. It is difficult to obtain a patch that does. A method has also been proposed in which a highly polar polymer capable of dissolving a high concentration of drug is used as an adhesive; however, the interaction between the drug and the polymer is large, such as the drug being adsorbed to the polymer, so it is difficult for the drug to pass through the skin. absorption is poor. In order to improve drug release properties, Japanese Patent Application Laid-Open No. 57-42619 discloses an adhesive tape in which a particulate pressure-sensitive adhesive layer containing a drug is formed on a carrier. In such tapes, the gaps between the adhesive particles are filled with a drug, or the gaps between the adhesive particles are filled with a solution or suspension of the drug. Such adhesive tapes are prepared by forming a particulate pressure-sensitive adhesive layer on a carrier and then coating and absorbing a drug-containing solution or suspension, so the manufacturing process is complicated and the drug may not stick. Difficult to uniformly disperse within the agent layer. Another drawback is that drugs tend to precipitate during storage of the resulting tape. (Problems to be Solved by the Invention) The present invention solves the above-mentioned conventional drawbacks, and its purpose is to have an adhesive layer uniformly containing a drug at a high concentration, and An object of the present invention is to provide a patch that has good absorption through the skin, in other words, a high bioavailability, and a method for producing the same. Another object of the present invention is to provide a patch in which the drug does not precipitate on the surface of the adhesive layer even when it contains a high concentration of drug, and a method for producing the same. Still another object of the present invention is to
The object of the present invention is to provide a method for easily producing a patch having the above characteristics. (Means for Solving the Problems) The patch of the present invention has an acrylic pressure-sensitive adhesive layer provided on the surface of the support, and the acrylic pressure-sensitive adhesive has fine particles of an acrylic polymer dispersed therein. The acrylic polymer matrix contains a drug in an amount equal to or higher than the saturation solubility of the acrylic polymer, thereby achieving the above object. Furthermore, the method for producing the patch of the present invention includes a step of adding a drug having a saturation solubility or higher of the acrylic polymer to a solution of the acrylic polymer having a hydrophilic group; A step of adding and mixing a poor solvent to precipitate a part of the acrylic polymer as fine particles, and applying a suspension containing the drug and the fine particles of the acrylic polymer to the surface of the support. The method includes a step of forming a pressure-sensitive adhesive layer, thereby achieving the above object. The acrylic polymer used in the acrylic pressure-sensitive adhesive of the present invention is a copolymer containing (meth)acrylic acid ester as a main component and a monomer having a hydrophilic group as a copolymerization component. Examples of the (meth)acrylic esters include methyl acrylate, ethyl acrylate, propyl acrylate, isopropyl acrylate, butyl acrylate, isobutyl acrylate, hexyl acrylate, octyl acrylate, 2-ethylhexyl acrylate, Examples include decyl acrylate, isodecyl acrylate, lauryl acrylate, methyl methacrylate, ethyl methacrylate, propyl methacrylate, butyl methacrylate, and 2-ethylhexyl methacrylate. The hydrophilic group possessed by the monomer to be copolymerized includes, for example, an amide group, a hydroxyl group, an ether group, a carboxyl group, and the like. Examples of monomers having an amide group include alkyl (meth)acrylic acid amides such as acrylamide, dimethylacrylamide and diethylacrylamide; alkyl ether methylol (meth)acrylamides such as butoxymethylacrylamide and ethoxymethylacrylamide. Other monomers such as diacetone acrylamide and vinylpyrrolidone are also used. Examples of monomers having hydroxyl groups include hydroxyalkyl (meth)acrylates and hydroxypolyalkyl (meth)acrylates such as 2-hydroxyethyl (meth)acrylate and hydroxypropyl (meth)acrylate. Monomers having a carboxyl group include α-β unsaturated carboxylic acids such as acrylic acid and methacrylic acid, maleic acid, and maleic anhydride;
Monoalkyl maleate esters such as butyl maleate; coumaric acid, crotonic acid, etc. These acid compounds may be, for example, salts of alkali metals such as sodium and potassium, and alkaline earth metals such as magnesium, barium, and calcium. When such a copolymer having a hydrophilic group is used in the preparation of an acrylic pressure-sensitive adhesive, it becomes easy to produce the acrylic polymer fine particles described below. The compatibility between the adhesive and the drug is also improved. The monomer having a hydrophilic group is 0.1 to 90 mol% as a copolymerization component,
It is preferably contained in the copolymer in a proportion of 1 to 60 mol%. As a copolymer component, radically polymerizable monomers other than those mentioned above, such as vinyl esters such as vinyl acetate and vinyl butyrate; styrene, α-methylstyrene, acrylonitrile, vinyl chloride, ethylene,
α-olefins such as propylene; butadiene,
A diene monomer such as isoprene may also be contained. The drug used in the present invention is not particularly limited, and any drug commonly used in adhesive patches can be used. Examples include hypnotics such as phenobarbital, amobarbital, cyclobarbital, barbital; cortisone, cortisone acetate, hydrocortisone, prednisolone, prednisolone acetate, fludroxycortisone, triamcinolone, dexamethasone, betamethasone, sodium salicylate, mefenamic acid;
Anti-inflammatory drugs such as flufenamic acid, indomethacin, diclofenac, flurbiprofen, and aspirin; psychotropic drugs such as diazepam, nitrazepam, and chloropromazine; central stimulants such as theophylline, caffein, and theobromine; and lidocaine, benzocaine, and procaine. Local anesthetics; cholinergic agonists such as acetylcholine and pilocarpine; anticholinergic agonists such as scopolamine and atropine; adrenergic agonists such as noradrenaline, adrenaline, and ephedrine; adrenergic receptor blockers such as deipenamine and phenoxybenzamine; tetraethylammonium ,
Ganglion blockers such as hexamethonium, pentrium, chloroisondamine; nitroglycerin,
Anginal drugs such as isosorbide dinitrate, dipyridamole, pentaerythritol tetranitrate, erythritol tetranitrate, and nifedipine; antiarrhythmic drugs such as propranolol; clonidine,
Antihypertensive drugs such as kallikrein; diuretics such as bendroflumethiazide, hydrothiazide, and cyclopenthiazide; anticoagulants such as heparin sodium and warfarin sodium; antihistamines such as diphenhydramine and diphenylimidazole Examples include. When a water-soluble drug is used, a patch with particularly high initial release properties can be obtained. Water-soluble drugs include diclofenac sodium, sodium salicylate, sodium goldthiomaleate, acetylcholine, scopolamine, atropine, tetraethylammonium, hexamethonium, pentolinium, heparin sodium, and warfarin sodium. The amount of drug to be used is determined as appropriate depending on the type of drug, the purpose of use of the patch, etc., but the amount is usually 0.1 to 200 parts by weight per 100 parts by weight of the acrylic polymer. The adhesive may contain an absorption aid in order to promote transdermal absorption of the drug. Examples of absorption aids include isopropyl myristate,
diethyl sebacate, squalene, squalane,
Liquid paraffin, propylene glycol, polypropylene glycol, ethylene glycol, polyethylene glycol, glycerin, water, octyloxystearate, lanolin alcohol, cecyl alcohol, stearyl alcohol, dimethyl sulfoxide, dimethyl formamide, ethylene glycol monoethyl ether, etc. . The amount of absorption aid used is an amount sufficient to dissolve the drug used, and the amount of acrylic polymer
The proportion is preferably 1 to 100 parts by weight, particularly 2 to 25 parts by weight, per 100 parts by weight. When preparing a patch, first, the acrylic polymer, which is the above copolymer, is dissolved in a suitable solvent. As the solvent, ester solvents such as ethyl acetate and methyl acetate; ketone solvents such as acetone and methyl ethyl ketone; and hydrocarbon solvents such as toluene, xylene and hexane are used. The drug and, if necessary, additives such as absorption aids are added to this acrylic polymer solution. However, these may be added at the same time as the poor solvent is added, which will be described later, or after precipitation of the acrylic polymer fine particles. A poor solvent for the acrylic polymer is added to the obtained acrylic polymer solution. Here, the term "poor solvent" refers to a solvent that does not dissolve the acrylic polymer in the present invention, or even if it can dissolve a small amount of it, it does not dissolve most of it and only swells it. Such poor solvents include alcohols such as methanol, ethanol, and isopropanol;
Water etc. are used. When a poor solvent is added, a portion of the dissolved acrylic polymer precipitates against the dissolving action of the initially used solvent, such as ethyl acetate or toluene. It is thought that the precipitated acrylic polymer has a relatively large molecular weight and is easily insolubilized by poor solvents. The amount of the poor solvent added varies depending on the type of poor solvent and the type and molecular weight of the acrylic polymer, but it causes some of the acrylic polymer in the solution to coagulate and precipitate, and even after mixing, it does not cause precipitation in the solution. The amount may be sufficient as long as the amount is sufficient to allow the aggregated fine particles to exist without being dissolved again. usually,
1 to 80 for the total amount of solvent and poor solvent in the solution
It is added in % by weight, preferably 5-50% by weight.
When the mixture of the poor solvent and the acrylic polymer solution is stirred under mechanical shear stress using, for example, a stirrer, the precipitated acrylic polymer becomes fine particles and is dispersed in the solution. These fine particles are formed by diluting the solvent with a poor solvent.
Even when stirred, it does not dissolve again and is uniformly dispersed.
Formation of fine particles can be confirmed by cloudiness of the mixed solution after addition of the poor solvent, decrease in light transmittance, microscopic observation, etc. The particle size of the fine particles is 0.1 to 500 μm, preferably 0.5 to 50 μm. In this way, a drug-containing acrylic polymer suspension containing the drug and in which a portion of the acrylic polymer is dispersed in the form of fine particles is obtained. An acrylic pressure-sensitive adhesive layer is formed on the surface of the support using this drug-containing acrylic polymer suspension. Usually, an adhesive layer is formed by applying the suspension onto the surface of a support and drying it. During drying, heating is performed as necessary to evaporate and remove the solvent and poor solvent. The support on which the adhesive layer is formed includes polyethylene, polypropylene, ethylene-vinyl acetate copolymer, polyvinyl chloride, polyvinylidene chloride, vinyl acetate-vinyl chloride copolymer, polyamide, polyester, polyurethane, acrylic resin. Examples include films of polymer materials such as cellulose acetate, ethyl cellulose, and cellophane; metal foils such as aluminum foil; paper; nonwoven fabrics; woven fabrics. Since the support is used by being attached to the skin, a flexible and drug-impermeable support is preferred. The surface of the support may be subjected to corona discharge treatment or the like for the purpose of improving adhesion to the adhesive or imparting moisture permeability. The acrylic pressure-sensitive adhesive of the patch thus obtained consists of a homogeneous polymer layer formed by removing the solvent from the solution portion of the drug-containing acrylic polymer suspension, and a homogeneous polymer layer dispersed within the homogeneous polymer layer. This is an acrylic polymer matrix composed of acrylic polymer fine particles. Because of the presence of microscopic gaps around the microparticles, the drug contained in the matrix can diffuse much more easily than in a dissolved state in a polymer layer that does not contain microparticles. Therefore, when the patch is applied to the skin surface, the drug can easily move to the skin surface. On the other hand, when fine particles are produced, a part of the drug may be contained in the particles, or the drug may be adsorbed on the surface of the produced fine particles. Therefore, the amount of drug that is greater than the saturation solubility of the acrylic polymer can be present in the matrix, making it possible to prepare a patch containing a large amount of drug. Due to the presence of the polymer fine particles, the drug is released in a bypass manner, and therefore the drug release is sustained well. Drug retention in the acrylic polymer matrix is also good;
Even if the patch is stored for a long time, the drug will not be deposited on the surface of the adhesive layer. Since it is possible to stably contain a drug with a saturation solubility or higher, the acrylic polymer used may be one with low polarity that would normally not be able to dissolve a large amount of drug. Acrylic polymers with low polarity have the advantage of a high drug release rate because of their small interaction with drugs. Therefore, a patch with a high drug transfer rate to the skin, in other words, a high bioavailability can be obtained. (Example) The present invention will be described below with reference to Examples. Example 1 A 25% ethyl acetate solution of a copolymer consisting of 55 mol% butyl acrylate, 10 mol% 2-ethylhexyacrylate, 30 mol% 2-ethylhexyl methacrylate, and 5 mol% diacetone acrylamide was prepared. To 400 parts by weight of this ethyl acetate solution, 300 parts by weight of a methanol solution in which 10 parts by weight of sodium dichlorofenac was dissolved was added, and the mixture was stirred for 20 minutes at 7000 rpm using a dissolver to form a milky white cloudy mixture containing fine particles of the copolymer dispersed therein. An acrylic polymer suspension was obtained. This suspension was applied onto release paper to a dry thickness of 50 μm, dried at 70° C. for 20 minutes, and then transferred to a polystyrene-vinyl acetate copolymer film to obtain a patch. A water elution test was conducted using this patch. The results are shown in Table 1.
A water dissolution test was performed on the patch after it had been stored at 60°C for one month, but there was almost no change in dissolution properties, and no changes in appearance such as drug precipitation were observed. In addition, in the water elution tests in Examples 1 to 3 and Comparative Examples 1 to 3, the patch was cut into a circle with a diameter of 50.5 mm,
The dissolution rate of the drug was measured when it was immersed in water at 20°C. Comparative Example 1 400 parts by weight of a copolymer having the same composition as Example 1,
10 parts by weight of diclofenac sodium, 100 parts by weight of ethanol, and 30 parts by weight of isopropanol were added to obtain a transparent homogeneous solution. This was applied onto release paper, dried at 70°C for 20 minutes, and then transferred to a polyethylene-vinyl acetate copolymer film to determine the thickness of the adhesive layer.
A 50 μm patch was obtained. The drug in the adhesive layer of the patch after drying was not uniformly dissolved, and drug crystals were dispersed. The obtained patch was subjected to a water elution test in the same manner as in Example 1. The results are shown in Table 1.

[Table] The saturated solubility of diclofenac sodium in the copolymer used in Example 1 and Comparative Example 1 was 5 parts by weight or less, and in both Example 1 and Comparative Example 1, diclofenac sodium had a saturated solubility or higher. It is a patch containing. From the above results, the usual method of forming an adhesive layer from a homogeneous solution of a copolymer,
Although drug precipitation is observed on the surface of the adhesive layer, it is clear that the adhesive of the copolymer matrix obtained by the present invention can stably contain a drug with a saturation solubility or higher. Furthermore, the patch obtained in Example 1 has excellent drug release properties.
It is known that the greater the water release property, the greater the absorption from the skin when applied, and it can be seen that the patch of the present invention has high drug absorption. Example 2 A 25% ethyl acetate solution of a copolymer consisting of 61 mol% butyl acrylate, 30 mol% 2-ethylhexyl methacrylate, and 9 mol% diacetone acrylamide was prepared. To 400 parts by weight of this ethyl acetate solution, 8 parts by weight of indomethacin and 200 parts by weight of methanol.
Add weight part and 20 at 7000rpm by dissolver
The mixture was stirred for several minutes to obtain an acrylic polymer suspension in which fine copolymer particles were dispersed. This suspension was applied onto release paper so that the thickness after drying was 50 μm,
After drying at 70℃ for 20 minutes, the polyethylene film was
A patch was obtained by transfer. A water elution test was conducted in the same manner as in Example 1, and the results are shown in Table 2. A water dissolution test was conducted after the patch had been stored at room temperature for 6 months, but there was no change in its dissolution properties, and no changes in appearance such as drug precipitation were observed. Comparative Example 2 To 400 parts by weight of a 25% ethyl acetate solution of a copolymer having the same composition as in Example 2, 8 parts by weight of indomethacin was added to obtain a transparent homogeneous solution. Using this, a patch was obtained in the same manner as in Example 2. Table 2 shows the results of the water elution test immediately after the patch was manufactured. When the patch was stored at room temperature for 6 months, drug precipitation was observed in the adhesive layer of the patch. When a water elution test was conducted on the adhesive in which the drug had precipitated, the water elution rate was significantly lower than that immediately after manufacture.

[Table] The saturated solubility of indomethacin in the copolymer used in Example 2 and Comparative Example 2 was 6 parts by weight or less. From the above results, it is clear that according to the present invention, it is possible to prepare a patch that contains a drug with a saturation solubility or higher without being precipitated and has a high drug release property. Example 3 25% of a copolymer consisting of 65 mol% 2-ethylhexyl acrylate and 35 mol% vinylpyrrolidone
An ethyl acetate solution was prepared. This ethyl acetate solution
To 400 parts by weight, add a solution consisting of 10 parts by weight of diclofenac sodium and 450 parts by weight of methanol,
The mixture was stirred for 10 minutes at 3000 rpm using a dissolver to obtain a milky white acrylic polymer suspension in which fine copolymer particles were dispersed. Coat this on release paper so that the thickness after drying is 50 μm, and heat it for 20 minutes at 70℃.
After drying for a minute, it was transferred to a polyethylene-vinyl acetate copolymer film to obtain a patch. A water elution test was conducted and the results are shown in Table 3. There was no change in dissolution after the patch was stored at 60°C for one month, and no changes in appearance such as drug precipitation were observed. Comparative Example 3 10 parts by weight of diclofenac sodium, 100 parts by weight of ethanol, and 30 parts by weight of isopropyl alcohol were added to 400 parts by weight of a copolymer solution having the same composition as in Example 3 to obtain a transparent and uniform solution. Using this solution, a patch was obtained according to Example 3. When the obtained patch was stored at 60°C for one month, drug precipitation was observed. Table 3 shows the results of the water elution test immediately after the patch was manufactured. In addition, Example 3 and Comparative Example 3
The saturation solubility of the drug in the copolymer used was less than 10%.

[Table] (Effects of the Invention) According to the present invention, a patch having a pressure-sensitive adhesive layer that uniformly and stably contains a drug having a saturation solubility or higher can be obtained by a simple method. Therefore, a patch containing a desired drug concentration, particularly a high concentration, can be obtained. The bioavailability of the drug in the patch is high, and the medicinal effect lasts for a long time when applied to the skin surface. Even when the drug is contained in a high concentration, the drug does not precipitate during storage of the patch, and the drug does not deteriorate during storage.

Claims (1)

[Claims] 1. An acrylic pressure-sensitive adhesive layer is provided on the surface of the support, and the acrylic pressure-sensitive adhesive is an acrylic polymer matrix in which fine particles of an acrylic polymer are dispersed; A patch in which the acrylic polymer matrix contains a drug in an amount equal to or higher than the saturation solubility of the acrylic polymer. 2. The adhesive patch according to claim 1, wherein the acrylic polymer is a copolymer containing (meth)acrylic acid ester as a main component and a monomer having a hydrophilic group as a copolymerization component. . 3. Adding a drug having a saturation solubility or higher of the acrylic polymer to an acrylic polymer solution having a hydrophilic group; Adding and mixing a poor solvent for the acrylic polymer to the acrylic polymer solution; a step of precipitating a part of the acrylic polymer as fine particles; and a step of forming a pressure-sensitive adhesive layer on the surface of the support using a suspension containing the drug and the fine particles of the acrylic polymer. A method for producing a patch containing the product. 4. Claim 3, wherein the acrylic polymer having a hydrophilic group is a copolymer containing (meth)acrylic acid ester as a main component and a monomer having a hydrophilic group as a copolymerization component. The method described in.