JPH0339484B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Technical Field) The present invention relates to a method for manufacturing a patch preparation provided with a pressure-sensitive adhesive drug-releasing matrix. (Prior art) Patches have traditionally been applied to the body to treat diseased areas of the skin or to continuously administer drugs to affected areas, the circulatory system, and other organs within the body via the skin. For example, those in which an acrylic pressure-sensitive adhesive layer containing a drug is provided on one surface of a base material are disclosed in Japanese Patent Publication No. 52-31405, Japanese Patent Application Laid-open No. 18813-1982, and Japanese Patent Application Laid-open No. 45412-1989. However, in these methods, the drug contained in the pressure-sensitive adhesive layer is difficult to diffuse and move, and the solubility of the drug in the adhesive layer is insufficient. It is difficult to release an effective amount of drug in a timely manner, resulting in delayed onset of effect and difficulty in transdermal absorption of an effective amount of drug. In order to solve the above-mentioned drawbacks, a particulate pressure-sensitive adhesive layer is formed as shown in Japanese Patent Application Laid-Open No. 57-42619, and the gaps between the adhesive are filled with a drug. However, since the drug is filled in the gaps between the particulate pressure-sensitive adhesive layer formed by suspension polymerization on one side of the base material, the drug may precipitate over time even during storage. Furthermore, during use, the drug is released in a short period of time, resulting in a lack of sustainability.Furthermore, the adhesion of the adhesive layer is also unsatisfactory. (Object of the invention) In view of the above-mentioned drawbacks of conventional patch preparations, the object of the present invention is to provide a patch preparation that has excellent initial release properties, long-lasting efficacy, and excellent storage stability. As a result of research, we have discovered a method that can easily produce such excellent patch preparations. (Structure of the Invention) The gist of the present invention is to mechanically add a poor solvent for these polymers and a drug to a mixed solution of an acrylic polymer having a hydrophilic group in the molecule and a (meth)acrylic acid alkyl ester polymer. A drug-containing liquid material is prepared by mixing under stress and agglomerating some of these polymers to form a state in which agglomerated fine particles are dispersed in the mixed solution. The present invention relates to a method for producing a patch preparation, which is characterized by forming a drug-releasing matrix on one surface. The acrylic polymer having a hydrophilic group in the molecule used in the present invention refers to one or more acrylic esters or methacrylic esters and a hydrophilic group such as a hydroxyl group, an ether group, a carboxyl group, or an amide group. means a copolymer with a monomer having And, as the monomer having the above hydroxyl group, 2
-Hydroxyalkyl (meth)acrylates such as hydroxyethyl (meth)acrylate and hydroxypropyl (meth)acrylate are exemplified,
Examples of monomers having a carboxyl group include α-β unsaturated carboxylic acids such as acrylic acid, methacrylic acid, maleic acid, maleic anhydride, monoalkyl maleic esters such as butyl maleate, coumaric acid, crotonic acid, etc. These acid compounds are treated with alkali metals such as sodium and potassium, magnesium, barium,
It may be neutralized with an alkaline earth metal such as calcium, and in that case, it is preferable to neutralize so that 80 mol% or more of the carboxyl groups contained in the copolymer are converted into salt. In addition, examples of monomers having an amide group include acrylamide, alkyl (meth)acrylamides such as dimethylacrylamide and diethylacrylamide, alkyl ether methylol (meth)acrylamides such as butoxymethylacrylamide and ethoxymethylacrylamide, diacetone acrylamide, vinylpyrrolidone, etc. monomers are mentioned. One or more of the above monomers having a hydrophilic group, and acrylic esters such as ethyl acrylate, butyl acrylate, 2-ethylhexyl acrylate, lauryl acrylate, methyl methacrylate, butyl methacrylate, and methacrylate. acid 2-
Copolymers of methacrylic esters such as ethylhexyl and lauryl methacrylate with one or more types of (meth)acrylic esters are commonly used as acrylic polymers having hydrophilic groups in the molecule, but other than the above. Radically polymerizable monomers such as vinyl esters such as vinyl acetate and vinyl butyrate, styrene, α-methylstyrene, acrylonitrile, vinyl chloride, α-olefins such as ethylene and propylene, and diene monomers such as butadiene and isoprene. It is also possible to contain it as a copolymerization component. The proportion of the monomer having a hydrophilic group in the acrylic polymer is preferably 0.1 to 90 mol%, particularly 1 to 60 mol%. Next, the (meth)acrylic acid alkyl ester polymer used in the present invention is a polymer of one or more types of acrylic acid or methacrylic acid alkyl ester, and as the acrylic acid alkyl ester, the number of carbon atoms in the alkyl group portion thereof is is 4 to 12, and as a methacrylic acid alkyl ester, the number of carbon atoms in the alkyl group is 1 to 12.
Each is preferably. In addition, in order to produce the acrylic polymer having a hydrophilic group in the molecule and the above-mentioned (meth)acrylic acid alkyl ester, a conventional method for producing acrylic polymers, such as solution polymerization, is carried out using appropriate monomers. Polymerization may be carried out in accordance with the law. In addition, in these polymerizations, if the weight average molecular weight of the resulting polymer is lower than that, it tends to cause adhesive residue and stringiness, and if it is higher than that, the tack value decreases and it tends to gel, making it difficult to coat. It is preferable to set it at 200,000 to 2,000,000 because the workability may be reduced. In the present invention, two types of polymers are used: an acrylic polymer having a hydrophilic group in the molecule and a (meth)acrylic acid alkyl ester polymer, and a mixed solution is prepared. Although it depends somewhat on the content of hydrophilic groups and the composition of these polymers, it seems that acrylic polymers having hydrophilic groups in the molecule are present in the range of 5 to 99% by weight in the total amount of both. It is preferable to use it for. In addition, to make a mixed solution, these polymers can be dissolved and mixed by adding them to a solvent such as ethyl acetate or toluene, or one or both of the two polymers can be prepared using a solution polymerization method in a solvent system. Generally, polymers are prepared in a solution state and then added to form a mixed solution. The solid content concentration in the mixed solution is 15 to 38% by weight, preferably 18%.
It is best to adjust the content to be in the range of ~25% by weight. Next, the drugs used in the present invention are not particularly limited, and any drug that can be used as a patch preparation can be used. ;cortisone,
Anti-inflammatory drugs such as cortisone acetate, hydrocortisone, prednisolone, prednisolone acetate, fludroxycortisone, triamcinolone, dexamethasone, betamethasone, sodium salicylate, mefenamic acid, flufenamic acid, indomethacin, diclofenac, flurbiprofen, aspirin; diapipam, nitrazebam, chloro Psychotropic drugs such as promazine; central stimulants such as theophylline, caffeein, and theobromine; local anesthetics such as lidocaine, benzocaine, and procaine; cholinergic drugs such as acetihacholine and pilocarpine; anticholinergic drugs such as scopolamine and atropine; norepinephrine , adrenaline,
Adrenergic agonists such as ephedrine; adrenergic receptor blockers such as deibenamine and phenoxybenzamine; ganglion blockers such as tetraethylammonium, hexamethonium, pentrium, and chloroisondamine; = troglycerin, isolylbidedinite Anti-angina drugs such as Lato, dipyridamole, pentaerythritol tetranitrate, erythritol tetranitrate, nifedipine;
Antiarrhythmic drugs such as propranolol; antihypertensive drugs such as clonidine and kallikrein; diuretics such as bendroflumethiazide, hydrothiazide, and cyclopenthiazide; anticoagulants such as hevarin sodium and warfarin sodium; diphenhydra Antihistamines such as amine, diphenylimidazole, etc. may be mentioned. In addition, water-soluble drugs such as diclofenac sodium, sodium salicylate, sodium goldthiomaleate, acetylcholine, scopolamine, atropine, tetraethylammonium, hexamethonium, pentolinium, sodium peparin, and sodium waluaarin can be applied to the patch of the present invention. When used in preparations, among the various effects based on the present invention, particularly high initial release properties can be obtained. In addition, the amount of the drug used in the present invention is appropriately determined depending on the type of drug and the purpose of application, but it is 0.1 to 0.1 to 100 parts by weight of the commonly used polymer.
It is best to choose from a range of 200 parts by weight. Furthermore, in the present invention, it is also possible to use an absorption aid having the effect of promoting transdermal absorption of the drug together with the above drug, and the amount used is an amount sufficient to dissolve the drug used. and 1 to 100 parts by weight, especially 2 to 25 parts by weight per 100 parts by weight of the polymer used.
It is preferable to set it as the range of parts by weight. 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, cecil alcohol, Examples include stearyl alcohol, dimethyl sulfoxide, dimethyl formamide, and ethylene glycol monoethyl ether. In the production of the patch preparation according to the present invention, the above-mentioned 2
The main feature is that when adding and mixing the drug and, if necessary, the absorption aid to a mixed solution of different types of polymers, a poor solvent for these polymers is added, and the poor solvent is first added. By mixing under mechanical stress, some of these polymers are aggregated, and a drug-containing liquid material in which aggregated fine particles are dispersed in the mixed solution is prepared. The timing of addition of drugs and absorption aids added as necessary may be before, at the same time, or after the addition of the poor solvent. It is sufficient to ensure that the drug, etc. is contained uniformly. Therefore, as a poor solvent, a solvent that does not dissolve the acrylic polymer and the (meth)acrylic acid alkyl ester polymer that have a hydrophilic group in the molecule, or may dissolve a small amount but do not dissolve the majority of them. A liquid that only causes swelling is used, and suitable examples include alcohols such as methanol, ethanol, and isopropanol, and water. By being added to the mixed solution, the poor solvent acts to agglomerate some of the polymers in the mixed solution against the dissolving action of the solvent such as ethyl acetate or toluene already present in the mixed solution. By mixing under mechanical stress, for example by means of a stirrer, the agglomerated polymer is finely divided and dispersed in the mixed solution. The amount of the poor solvent to be added varies depending on the poor solvent, the type of solvent, the type and molecular weight of the polymer, etc., but the key is to coagulate and precipitate a portion of the polymer in the mixed solution, so that even after mixing, The amount may be sufficient as long as the aggregated fine particles are present in the mixed solution without being redissolved, and is generally 1 to 80% by weight, particularly 5 to 80% by weight, based on the total amount of the solvent in the mixed solution and the poor solvent added.
It is preferable to select it within a range of 50% by weight. As mentioned above, by adding and mixing a poor solvent to the mixed solution, aggregated fine particles are generated and dispersed. Parts that are easily insolubilized by poor solvents, such as parts with the highest molecular weight, coagulate and precipitate when they come into contact with poor solvents, and even if stirred by mechanical stress, they will not be able to dissolve again at a solvent concentration diluted by poor solvents. This is thought to be because the particles are not dissolved and are uniformly dispersed as fine particles. The formation of fine particles can be confirmed by clouding of the mixed solution after addition of the poor solvent, decrease in light transmittance, microscopic observation, etc. Further, the size of the fine particles is 0.1 to 500 μm, preferably 0.5 to 500 μm.
It is in the range of 50 μm. Thus, a drug-containing liquid is prepared in which a portion of the polymer used is made into agglomerated fine particles and is dispersed in a solution in which the other portion of the polymer is dissolved. Next, the drug-containing liquid material is formed into a layer and dried to form a drug-releasing matrix on one surface of the substrate.More specifically, the drug-containing liquid material is applied to one surface of the substrate. Generally, a patch preparation is manufactured by forming a drug-containing pressure-sensitive adhesive polymer layer by evaporating the solvent and poor solvent in the liquid and drying it by heating etc. according to a conventional method. Adopted. Substrates used in the present invention include polyethylene, polypropylene, ethylene-vinyl acetate copolymer, polyvinyl chloride, polyvinylidene chloride, vinyl acetate-vinyl chloride copolymer, polyamide, polyester, cellulose acetate, ethyl cellulose, cellophane, etc. Films of polymeric materials, metal foils such as aluminum foils, paper, nonwoven fabrics, woven fabrics, etc. are used, and since they are used by pasting them on the skin, those with flexibility and drug impermeability are preferable.
Further, the base material may be subjected to corona discharge treatment or other treatments for the purpose of improving adhesion to the drug-releasing matrix or imparting moisture permeability. The patch preparation manufactured by the method of the present invention as described above has a drug-releasing matrix formed by layering and drying the drug-containing liquid material on one surface of a base material, and the drug-releasing matrix is formed on one surface of a base material. Basically, it consists of a homogeneous polymer layer formed by drying a polymer solution and aggregated fine particles dispersed therein. Not only is the release property improved by facilitating the movement of the drug to the drug, but also the formation of a bypassed drug flow path by the agglomerated fine particles and the fact that a portion of the drug is contained or adsorbed inside or around the particles. As a result, the sustainability of drug release is also good, and excellent therapeutic effects can be expected. moreover,
The adhesive preparation according to the present invention has good drug retention in the matrix, and has excellent storage stability without precipitation of drug on the surface even after long-term storage. As described above, according to the present invention, a patch preparation having excellent performance as described above can be manufactured and provided by simple operations without requiring complicated steps. (Examples) Hereinafter, the present invention will be explained based on Examples.
Note that in the following, parts mean parts by weight. Example 1 80 parts of a copolymer of 30.3 mol% 2-ethylhexyl methacrylate, 60.6 mol% butyl acrylate, 9.1 mol% diacetone acrylamide, and 15 mol% 2-ethylhexyl acrylate. , butyl acrylate 53 mol%, 2-ethylhexyl methacrylate 32 mol% copolymer 20 parts solids content 23% by weight
of ethyl acetate, 10 parts of diclofenac sodium and 1.5 parts of diclofenac sodium per 100 parts of solid content of the solution
of magnesium oxide was added thereto, and methanol was added in an amount of 28% by weight based on the total amount of ethyl acetate and methanol added in the above solution, and the mixture was stirred for 30 minutes in a closed system stirrer. The drug-containing liquid thus obtained was one in which aggregated fine particles produced by addition of a poor solvent were uniformly dispersed in the polymer solution phase. The drug-containing liquid material was applied to an ethylene-vinyl acetate copolymer film and dried in a gear oven at 70°C for 30 minutes to obtain a patch having a 50 μm thick drug-containing pressure-sensitive adhesive layer. The drug dissolution rate in water of the thus obtained patch preparation was measured, and it was 68% after immersion for 1 hour and 87% after 24 hours, and the skin transfer rate was 14.8 after 2 hours of application.
%, it was 35.4% after 6 hours of application. In addition, when a test was performed in which the product was stored at 60°C for 2 months (hereinafter referred to as the "severe test"), no changes in performance such as a decrease in the drug content, denaturation or precipitation of the drug were observed. The details of each of the above test methods are as follows. Drug elution rate with water: Punch out a sample in a certain area, immerse it in water, and elute at 25° room temperature while stirring. After a predetermined period of time, the eluate is sampled and quantified using a spectrophotometer. The drug dissolution rate is calculated using the following formula. Drug elution rate (%) = Amount of drug eluted/Amount of drug contained in sample x
100 Skin transfer rate: Remove hair from the rabbit's back with a hair removal agent. Four hours after hair removal, a sample containing a known amount of drug is pasted on the back. After a predetermined period of time, the sample is peeled off, extracted with a methanol solution, and the amount of drug remaining in the sample is determined using high performance liquid chromatography. The skin transfer rate is calculated using the following formula. Skin transfer rate (%) = Amount of drug contained in the sample - Amount of remaining drug / Amount of drug contained in the sample x 100 Severity test: Wrap the sample in aluminum foil and heat at 60℃
After 2 months in a constant temperature room, they were taken out and their condition after storage was examined. Comparative Example 1 A drug-containing liquid material was prepared in the same manner as in Example 1, except that methanol was not added in Example 1, and a patch preparation was prepared and tested in the same manner as in Example 1. Note that the polymer in the drug-containing liquid material was a homogeneous solution, and no aggregated fine particles were present. The results showed that the drug dissolution rate by water was 4.8% after 1 hour immersion and 15.1% after 24 hours, and the skin transfer rate was 1.9% after 2 hours application and 2.9% after 6 hours. Example 2 90 parts of a copolymer of 10 mol% 2-ethylhexyl acrylate, 53 mol% butyl acrylate, 32 mol% 2-ethylhexyl methacrylate, 5 mol% diacetone acrylamide and 15 mol% 2-ethylhexyl acrylate. , butyl acrylate 53 mol%,
In an ethyl acetate solution having a solid content of about 23% with 10 parts of a copolymer of 32 mol% 2-ethylhexyl methacrylate, 1.5 parts of magnesium oxide, 3 parts of propylene glycol, 10 of diclofenac sodium was added, and methanol was added in an amount of 28% by weight based on the total amount of ethyl acetate and methanol added in the above solution. A drug-containing liquid material in which particles were uniformly dispersed in a polymer solution phase was prepared, and a patch preparation was prepared in the same manner. Regarding this, a test similar to that in Example 1 was conducted, and the results showed that the drug dissolution rate with water was 71 after immersion for 1 hour.
% in 24 hours, and the skin transfer rate was 18.6% after 2 hours of application and 36.4% after 6 hours. Further, as in Example 1, no change in performance was observed after the two-month severe test. Comparative Example 2 Solid content of a copolymer of 50 mol% 2-ethylhexyl acrylate, 40 mol% butyl acrylate, and 10 mol% 2-ethylhexyl methacrylate, about 23%.
To the ethyl acetate solution of Example 2, the same amounts of magnesium oxide, propylene glycol, and diclofenac sodium were added, and the same proportion of methanol was added, and a patch preparation was prepared in the same manner as in Example 2. I conducted a test. The results showed that the drug dissolution rate with water was 1 hour immersion.
20.1%, 29.4% in 24 hours, and the skin transfer rate is 2.
The rate was 4.7% for hourly application and 12.8% for 6 hours. In addition, the results of the severe test showed that the drug in the adhesive layer tends to precipitate on the surface. Example 3 80 parts of a copolymer of 70 mol% 2-ethylhexyl acrylate and 30 mol% vinylpyrrolidone, 15 mol% 2-ethylhexyl acrylate, 53 mol% butyl acrylate, and 32 mol% 2-ethylhexyl methacrylate. A solution of 20 parts of the copolymer in ethyl acetate (solid content concentration 23% by weight) was added with 10 parts of diclofenac sodium and 1.5 parts per 100 parts of the solid content of the solution.
Example 1 A patch preparation was prepared in the same manner as above, and the same test was conducted. The results showed that the drug elution rate with water was 52% after 1 hour immersion and 89% after 24 hours, and the skin transfer rate was 12.2% after 2 hours of application and 31.8% after 6 hours. Further, as in Example 1, no change in performance was observed after the two-month severe test. Comparative Example 3 A patch preparation was prepared and tested in the same manner as in Example 3, except that methanol was not added in Example 3, so that no aggregated fine particles were precipitated. The results showed that the drug dissolution rate with water was 1 hour immersion.
4.6%, 16.2% in 24 hours, skin transfer rate is 2.
The rate was 1.7% for hourly application and 3.2% for 6 hours. Example 4 75 parts of a copolymer of 30.3 mol% 2-ethylhexyl methacrylate, 60.6 mol% butyl acrylate, and 9.1 mol% diacetone acrylamide, 20 mol% 2-ethylhexyl acrylate, 50 mol% butyl acrylate, In an ethyl acetate solution (solid concentration 23% by weight) with 25 parts of a copolymer of 30 mol% 2-ethylhexyl methacrylate, 4 parts of indomethacin and 10 parts of diethyl sebacate were added to 100 parts of the solid content of the solution. was added, and further methanol was added in an amount of 30% by weight based on the total amount of ethyl acetate and methanol added in the above solution. A uniformly dispersed drug-containing liquid was prepared, and a patch preparation was prepared in the same manner. When the same test as in Example 1 was conducted, the drug elution rate with water was 37% after 2 hours of immersion and 88% after 24 hours, and the skin transfer rate was 22.7% after 2 hours of application and 36.1% after 24 hours. It was %. Further, no change in performance was observed after the two-month severe test, indicating good storage stability. Comparative Example 4 A drug-containing liquid material was prepared in the same manner as in Example 4, except that methanol was not added in Example 4, so that aggregated fine particles were not precipitated, and a patch preparation was prepared in the same manner as in Example 4. I created it and tested it. The results showed that the drug elution rate with water was 23.2% after 2-hour immersion and 72.8% after 24 hours, and the skin transfer rate was 13.3% after 2-hour application and 21.8% after 24 hours. Example 5 10 mol% acrylic acid as resin component of mixed solution
90 parts of a copolymer of 90 mol% of butyl acrylate and 70 mol% of butyl acrylate and 2-methacrylic acid
A patch preparation was prepared in the same manner as in Example 1 except that 10 parts of a 30 mol% ethylhexyl copolymer was used, and a drug elution test was conducted. The results were as shown in Table 1. Comparative Example 5 Example 5 except that methanol was not added to the mixed solution and therefore no aggregated fine particles were precipitated.
I did the same thing. The results were as shown in Table 1. Example 6 35 mol% vinyl acetate as resin component of mixed solution
Example except that 80 parts of a copolymer of 65 mol% of butyl acrylate and 20 parts of a copolymer of 20 mol% of 2-ethylhexyl acrylate, 50 mol% of butyl acrylate and 30 mol% of 2-ethylhexyl methacrylate were used. A patch preparation was prepared in the same manner as in 1, and a drug elution test was conducted. The results were as shown in Table 1. Comparative Example 6 Example 6 except that only 100 parts of a copolymer of 20 mol% 2-ethylhexyl acrylate, 50 mol% butyl acrylate, and 30 mol% 2-ethylhexyl methacrylate was used as the resin component of the mixed solution.
A patch preparation was prepared in the same manner as above. Alcohol was added to the ethyl acetate solution of the above resin, and after mixing, the resin components in the coating solution were a little separated, and the adhesive coating after coating had noticeable unevenness and a tendency for drug precipitation. Ta. Example 7 As resin components of the mixed solution, 90 parts of a copolymer of 10 mol% hydroxyethyl methacrylate and 90 mol% of butyl acrylate and 10 parts of a copolymer of 80 mol% of butyl acrylate and 20 mol% of 2-ethylhexyl methacrylate were used. A patch preparation was prepared in the same manner as in Example 1, except that the following procedure was used, and a drug solubility test was conducted. The results were as shown in Table 1. Comparative Example 7 Example 7 except that methanol was not added to the mixed solution and therefore no aggregated fine particles were precipitated.
I did the same thing. The results were as shown in Table 1. 【table】

Claims (1)

[Claims] 1. A poor solvent for these polymers and a drug are mixed under mechanical stress into a mixed solution of an acrylic polymer having a hydrophilic group in the molecule and a (meth)acrylic acid alkyl ester polymer. Then, a drug-containing liquid material is prepared by agglomerating some of these polymers to form a state in which the agglomerated fine particles are dispersed in a mixed solution, and this is formed into a layer and dried. A method for producing a patch preparation, which comprises forming a release matrix. 2 The solid content concentration in the mixed solution is 15 to 38% by weight
A method for producing a patch preparation according to claim 1. 3. The method for producing a patch preparation according to claim 1, wherein the amount of the poor solvent used is 1 to 80% by weight based on the total amount of the solvent in the mixed solution and the poor solvent.