JPH0699299B2 - Method for manufacturing transdermal preparations - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing a percutaneous absorption preparation having excellent percutaneous absorption of a drug.

(Prior Art) In order to obtain a drug effect systemically or locally, a transdermal drug is used to absorb a drug (physiologically active substance) through the skin. The transdermal preparation has a flexible support and an adhesive layer containing a drug. The pressure-sensitive adhesive layer is made of a polymer such as natural rubber, synthetic rubber or acrylic resin.

The amount of drug contained in the pressure-sensitive adhesive layer is usually set to be equal to or lower than the saturated solubility of the polymer. However, if the amount of drug is less than the saturated solubility, the amount of drug absorbed by the human body is small, and thus sufficient drug effect cannot be obtained. If the thickness of the pressure-sensitive adhesive layer is increased or the size of the preparation is increased in order to increase the amount of drug absorbed, the cost becomes high and the user feels uncomfortable.

In order to solve such a drawback, a transdermal preparation in which a drug having a saturated solubility of a polymer or more is contained in an adhesive layer has been proposed. If a drug having a saturated solubility or higher is contained in the polymer, the drug in a non-dissolved state (dispersed state) is sequentially dissolved and replenished in the polymer due to percutaneous absorption of the drug into the human body. The absorption amount increases. Prolonged drug absorption is also obtained. In particular, it is preferable that the drug is in the form of fine particles because the drug is easily redissolved and the amount of the drug absorbed by the human body increases. The above-mentioned transdermal preparations include, for example, JP
As disclosed in JP-A-60-185713, there is a preparation in which a drug having a saturated solubility or higher is dispersed in a polymer in a recrystallized fine particle state. This preparation is manufactured by dissolving a drug and a polymer in a good drug solvent, applying this solution to a support, and drying. However, in this method, the drug is recrystallized into fine particles by drying, so that the drug that is not completely crystallized dissolves in the adhesive layer in a supersaturated state and gradually precipitates to form huge recrystallized particles. . Due to the evaporation of the solvent in the drying step, recrystallized particles of the drug are unevenly distributed on the surface of the pressure-sensitive adhesive layer (drug floating phenomenon), and thus the adhesiveness is reduced. Moreover, the particle size of the drug recrystallized particles and the distribution of the drug recrystallized particles in the pressure-sensitive adhesive layer change depending on the drying conditions, so that it is difficult to obtain a drug product in which fine-particle drug is uniformly dispersed in the pressure-sensitive adhesive layer. A method of mixing a drug dispersion of a poor drug solvent and a polymer solution using a good drug solvent is also disclosed. Fine drug particles are dispersed in the drug dispersion liquid. However, in this method, the drug particles are likely to coalesce to become giant particles by mixing. Moreover, the drug particles cannot be uniformly dispersed in the adhesive layer.

(Problems to be Solved by the Invention) The present invention is intended to solve the above-mentioned conventional problems, and it is an object of the present invention to provide a transdermal absorption in which a fine particle drug is uniformly dispersed in an adhesive layer. To provide a method for producing a sex preparation. Another object of the present invention is to provide a method for producing a transdermal preparation in which a drug having a saturated solubility or higher is contained in an adhesive layer.

(Means for Solving Problems) The method for producing a percutaneously absorbable preparation of the present invention has a pressure-sensitive adhesive layer containing a drug having a saturated solubility or higher in the form of fine particles having an average particle size of 30 μm or less, and a support. A method for producing a percutaneously absorbable preparation, comprising: adding a drug solution of a good drug solvent to a polymer solution of a poor drug solvent having a boiling point higher than that of the good drug solvent to obtain a drug solution; A step of obtaining a dispersion of fine drug particles by distilling off a good drug solvent under a reduced pressure of 300 to 700 mmHg until a drug crystal is precipitated from the solution, and coating the dispersion on the support and drying the adhesive layer To form the above-mentioned object, whereby the above object is achieved.

The drug release behavior of percutaneously absorbable preparations containing a drug having a saturated solubility or higher in a crystalline state in the adhesive layer is described in the Journal of Pharmacology.
ceutical Sciences (JPS), 50 , 847, (1961); JPS, 52 , 1
145, (1963); Journal of of the society of cosmetic
chemists, 11 , 85, (1960); JPS, 64 , 1643, (1975). JPS, 54 , 1459 (1965) describes the particle size of drug particles in the adhesive layer. In order to improve the permeability of the drug to the skin, it is desirable from the viewpoint of thermodynamic activity that the drug having a saturated solubility or higher is made into fine particles and contained in the adhesive layer (Monthly Pharmaceutical Affairs, 25 , NO. 2,
(1983), Ryoji Konishi). The present invention has been completed based on these findings.

Examples of the good drug solvent include tetrahydrofuran, ethyl acetate, acetone, methanol, methylene chloride, chloroform and ether. Drug poor solvents include, for example, n-hexane, cyclohexane, and toluene. However, the drug good solvent and the drug poor solvent differ depending on the drug used, and for example, tetrahydrofuran, ethyl acetate, etc. can be the drug poor solvent. The drug good solvent and drug poor solvent used in the present invention are not particularly limited as long as the drug poor solvent is a combination having a higher boiling point than the drug good solvent, but the drug good solvent is partially removed. The solvent type, the drug concentration, and the mixing ratio of the drug solution and the polymer solution are determined within the range where the drug microcrystals are precipitated and the polymer is not reprecipitated.

The drug is uniformly dissolved in the drug solution obtained by adding the drug solution to the polymer solution. From this drug solution, the good drug solvent is distilled off under reduced pressure of 300 to 700 mmHg. Examples of the apparatus used at this time include a vacuum emulsion mixing apparatus. Then, the drug good solvent is distilled off under reduced pressure to obtain a dispersion of drug fine particles. The average particle size of the drug fine particles is 30 μm or less, preferably 15 μm or less. Since the drug in the form of fine particles is easily redissolved in the pressure-sensitive adhesive layer, a transdermal preparation containing the drug in the pressure-sensitive adhesive layer is excellent in drug release. As a result, when it is attached to the human body, the amount of drug absorbed increases. Moreover, since the adhesive layer contains a drug having a saturated solubility or higher, the drug absorption can be maintained.

The drug contained in the percutaneously absorbable preparation of the present invention is a drug that is transdermally absorbed and exerts a medicinal effect, and examples thereof include hydrocortisone, prednisolone, beclomethasone propionate, flumethasone, betamethasone, triamcinolone, triamcinolone acetolone. Corticosteroids such as nido, fluocinolone, fluocinolone acetonide, fluocinolone acetonide acetate, clobetasol propionate; acetaminophen, mefenamic acid, flufenamic acid, indomethacin, diclofenac, diclofenac sodium, alclofenac, oxyphene Butazone, phenylbutazone, ibuprofen, flurbuprofen, salicylic acid, methyl salicylate, l-menthol, camphor, sulindac,
Analgesic and anti-inflammatory agents such as tolmetin sodium, naproxen and fenbufen; hypnotic sedatives such as phenobarbital, amorbarbital, cyclobarbital, toluazolam, nitrazepam, lorazepam, haloperidol;
Fluentazine, thioridazine, diazepam, fludiazepam, flunitrazepam, chlorpromazine, and other tranquilizers; clonidine, clonidine hydrochloride, pindolol, propranolol, propranolol hydrochloride, bufanol, indenolol, nivadipine, rofedixine, nibradirol, bucumolol, antihypertensive, etc .; Antihypertensive diuretics such as hydrothiazide, bendroflumesiazide, cyclopenthiazide; antibiotics such as penicillin, tetracycline, oxytetracycline, fradiomycin sulfate, erythromycin, chloramphenicol; lidocaine, benzocaine, ethyl aminobenzoate, etc. Anesthetic: benzalkonium chloride, nitrofurazone, nystatin, acetosulfamine, croto Antibacterial substances such as Mazoru;
Pentamycin, amphotericin B, pyrrolenitrin,
Antifungal substances such as clotrimazole; vitamins such as vitamin A, ergocalciferol, cholecalciferol, octothiamine, riboflavin butyrate; antiepileptics such as nitrazepam, mepropamate, clonazepam; isosorbide dinitrate, erythritol. Coronary vasodilators such as tetranitrate, pentaerytose tetranitrate, propatil nitrate;
Antihistamines such as diphenhydramine hydrochloride, chlorpheniramine, diphenylimidazole; antitussives such as dextromethorphan, terbutaline, ephedrine, ephedrine salbutamol hydrochloride, isoprotenol; sex hormones such as borogesterone and estradiol; antidepressants such as doxepin; 5-fluorouramin, dihydroeramine, dihydroeramine , Fentanyl, desmopressin, digoxin, metoclopramide, domperide, scopolamine, scopolamine hydrobromide, and prostaglandin.

Examples of the polymer forming the adhesive layer include polyvinyl alkyl ether, poly (meth) acrylate, 2-ethylhexyl acrylate-2-ethylhexyl methacrylate copolymer, 2-ethylhexyl acrylate-vinylpyrrolidone copolymer, polyurethane, styrene. -Isoprene-styrene block copolymer, polyisobutylene rubber, polyisoprene rubber, butyl rubber, natural rubber, silicone resin, and terpene resin. Known tackifiers, softeners, fillers, antioxidants, etc. may be added to these polymers in order to impart pressure-sensitive adhesiveness.

The support is provided to impart self-supporting properties to the transdermal preparation and to prevent volatilization and migration of the drug in the adhesive layer, such as polyethylene, polypropylene, polyacryl, polyurethane, polyester, polyvinyl alcohol. , Polyvinyl chloride, polyvinylidene chloride, polyamide, film or sheet made of ethylenic copolymer; laminated film thereof; porous film or sheet made of rubber and / or synthetic resin; non-woven fabric, woven fabric,
There are fibrous films or sheets of paper and the like; metal foils; films or sheets of metal foil having metal vapor deposition on the surface. Among these materials, a material having a conformability to the skin surface is used. The thickness of the support is 500 μm or less, preferably 5 to 150 μm.

If necessary, an absorption enhancer may be added to the percutaneous absorption preparation of the present invention in order to promote percutaneous absorption of the drug. Examples of the absorption enhancer include glycols such as diethylene glycol, propylene glycol and polyethylene glycol; fats and oils such as olive oil and squalene lanolin; urea derivatives such as urea and allantoin;
Higher fatty acid esters such as isopropyl myristate, isopropyl palmitate and diethyl sebacate, higher fatty acid triglycerides; fatty acid (mono) diethanolamides; salicylic acid; salicylates.
Absorption enhancers may be used alone or in combination of two or more,
It is contained in the adhesive layer in an amount of 30% by weight or less.

(Examples) The present invention will be described below with reference to Examples.

In the Examples and Comparative Examples, the drug blood concentrations of isosorbide dinitrate and nifedipine were measured by gas chromatography. When measuring the drug blood concentration of nifedipine, the application site was shielded from light.

Example 1 100 parts by weight of a 20% by weight cyclohexane solution of 2 ethylhexyl acrylate / 2 ethylhexyl methacrylate copolymer (containing 2 parts by weight of 2 ethylhexyl methacrylate for 75 parts by weight of 2 ethylhexyl acrylate) in isosorbidogenite 35.29 parts by weight of a 10% by weight methylene chloride solution of ISDN was added and stirred using a vacuum emulsification mixing device to obtain a drug solution in which the drug was uniformly dissolved. While stirring this solution, the pressure was reduced to 500 mmHg by a vacuum pump, and the solvent was partially distilled off. The methylene chloride recovered in the solvent trap was 22 parts by weight, and the cyclohexane was 10 parts by weight. A dispersion of ISDN microcrystals was obtained by distilling off the solvent. This dispersion was applied onto a polyethylene terephthalate (PET) film (one side treated with a silicone release agent, thickness: 45 μm) and dried at 70 ° C. for 30 minutes to form an adhesive layer. PET film (thickness 1
0 μm) was laminated to obtain a transdermal preparation. In the adhesive layer, an average particle size of about 5μ was observed by a polarizing microscope.
m needle-shaped drug crystallites were uniformly dispersed. The thickness of the adhesive layer is 50 μm, and the drug concentration in the adhesive layer is 15% by weight.
Met.

The percutaneously absorbable preparation (10 cm ²⁾ thus obtained was applied to the back of a dehaired Japanese white rabbit and the time-dependent change in drug blood concentration was measured. The results are shown in Table 1.

Example 2 Instead of a 20 wt% cyclohexane solution of a 2-ethylhexyl acrylate / 2-ethylhexyl methacrylate copolymer, a 10 wt% cyclohexane solution of a mixture of 55 parts by weight of natural rubber and 45 parts by weight of a terpene resin was used, and isosorbide dinitrate was used. 5 wt% methylene chloride solution of rate (ISDN)
A transdermal preparation was obtained in the same manner as in Example 1 except that 22.22 parts by weight was added. The methylene chloride recovered in the solvent trap was 17 parts by weight and the cyclohexane was 7 parts by weight.

Observation with a polarizing microscope revealed that needle-shaped drug microcrystals having an average particle size of 4 μm were uniformly dispersed in the adhesive layer of this transdermal preparation. The thickness of the adhesive layer was 50 μm, and the drug concentration in the adhesive layer was 10% by weight.

The percutaneously absorbable preparation (10 cm ²⁾ thus obtained was applied to the back of a dehaired Japanese white rabbit and the time-dependent change in drug blood concentration was measured. The results are shown in Table 1.

Example 3 Instead of a 20 wt% cyclohexane solution of a 2-ethylhexyl acrylate / 2-ethylhexyl methacrylate copolymer, a 2-ethylhexyl acrylate-vinylpyrrolidone copolymer (85 parts by weight of 2-ethylhexyl acrylate,
(Containing 15 parts by weight of vinylpyrrolidone) in a 10% by weight cyclohexane solution, isosorbide dinitrate
Instead of 10% by weight methylene chloride solution, nifedipine 10
A transdermal preparation was obtained in the same manner as in Example 1, except that 53.846 parts by weight of a acetone solution of wt% was added. Acetone recovered in the solvent trap was 42 parts by weight, and cyclohexane was 17 parts by weight.

Observation with a polarization microscope revealed that needle-shaped drug microcrystals having an average particle diameter of 6 μm were uniformly dispersed in the pressure-sensitive adhesive layer of this transdermal preparation. The thickness of the adhesive layer was 50 μm, and the drug concentration in the adhesive layer was 35% by weight.

The percutaneously absorbable preparation (10 cm ²⁾ thus obtained was applied to the back of a dehaired Japanese white rabbit and the time-dependent change in drug blood concentration was measured. The results are shown in Table 2.

Example 4 A styrene-isoprene-styrene block copolymer was used instead of a 20 wt% cyclohexane solution of a 2-ethylhexyl acrylate-diethylhexyl methacrylate copolymer.
A 15 wt% cyclohexane solution of a mixture of 50 parts by weight and 50 parts by weight of a terpene resin was used, and 100 parts by weight of a 5% by weight tetrahydrofuran solution of nifedipine was added instead of a 10% by weight methylene chloride solution of isosorbide dinitrate. In the same manner as in Example 1, a transdermal preparation was obtained. Tetrahydrofuran recovered in the solvent trap was 80 parts by weight, and cyclohexane was 50 parts by weight.

Observation with a polarizing microscope revealed that needle-shaped drug microcrystals having an average particle size of 10 μm were uniformly dispersed in the adhesive layer of this transdermal preparation. The thickness of the adhesive layer was 50 μm, and the drug concentration in the adhesive layer was 25% by weight.

The percutaneously absorbable preparation (10 cm ²⁾ thus obtained was applied to the back of a dehaired Japanese white rabbit and the time-dependent change in drug blood concentration was measured. The results are shown in Table 2.

Example 5 Isosorbide dinitrate was prepared by using a 10 wt% cyclohexane solution of a 2-ethylhexyl acrylate / 2-ethylhexyl methacrylate copolymer (containing 25 parts by weight of 2-ethylhexyl methacrylate for 75 parts by weight of 2-ethylhexyl acrylate). A transdermal preparation was obtained in the same manner as in Example 1 except that 100 parts by weight of a 1 wt% tetrahydrofuran solution of prednisolone was added in place of the 10 wt% methylene chloride solution of (ISDN). Tetrahydrofuran recovered in the solvent trap was 80 parts by weight, and cyclohexane was 50 parts by weight.

Observation with a polarizing microscope revealed that needle-shaped drug microcrystals having an average particle size of 10 μm were uniformly dispersed in the adhesive layer of this transdermal preparation. The thickness of the adhesive layer was 50 μm, and the drug concentration in the adhesive layer was 9.09% by weight.

Comparative Example 1 In the same manner as in Example 1 except that ethyl acetate (good solvent for drug) was used in place of cyclohexane (poor solvent for drug), and 12.35 parts by weight of a 30 wt% ethylene chloride solution of isosorbide dinitrate was added. A drug solution was obtained. This solution was applied onto a PET film in the same manner as in Example 1 to obtain a transdermal preparation. The drug was supersaturated in the pressure-sensitive adhesive layer, and no crystal precipitation was observed by observation with a polarizing microscope. When this formulation was left at room temperature for 2 days, the average particle size was about 80μ over the entire surface of the formulation.
Large whiskers of m were deposited.

A 10 cm ² percutaneous absorption preparation in which crystals were deposited was attached to the back of a dehaired Japanese white rabbit, and the time-dependent change in drug blood concentration was measured. The results are shown in Table 1.

Comparative Example 2 A drug was prepared in the same manner as in Example 2 except that tetrahydrofuran (good solvent for drug) was used instead of cyclohexane (poor solvent for drug), and 3.704 parts by weight of a 30 wt% methylene chloride solution of isosorbide dinitrate was added. A solution was obtained.
This solution was applied onto a PET film in the same manner as in Example 1 to obtain a transdermal preparation. The drug was supersaturated in the pressure-sensitive adhesive layer, and no crystal precipitation was observed by observation with a polarizing microscope. When this formulation was left to stand at room temperature for 2 days, part of the side of the formulation
Giant needle-like crystals with an average particle size of 60 μm that spread radially were deposited. After standing for 1 month at room temperature, precipitated crystals were observed on the entire surface of the preparation.

A 10 cm ² percutaneous absorption preparation in which crystals were deposited was attached to the back of a dehaired Japanese white rabbit, and the time-dependent change in drug blood concentration was measured. The results are shown in Table 1.

Comparative Example 3 25 parts by weight of a copolymer solution of ethyl acetate (a good drug solvent) was used in place of the 10% by weight copolymer solution of cyclohexane (a poor drug solvent), and a 10% by weight acetone solution of nifedipine was added to the solution.
A drug solution was obtained in the same manner as in Example 3 except that 4.62 parts by weight was added. This solution was applied onto a PET film in the same manner as in Example 1 to obtain a transdermal preparation.
The drug was supersaturated in the pressure-sensitive adhesive layer, and no crystal precipitation was observed by observation with a polarizing microscope.
When this preparation was allowed to stand at room temperature for 2 days, plate-like giant crystals with an average particle size of 45 μm were precipitated in a part of the preparation. After standing for 2 months at room temperature, precipitated crystals were observed on the entire surface of the preparation.

A 10 cm ² percutaneous absorption preparation in which crystals were deposited was attached to the back of a dehaired Japanese white rabbit, and the time-dependent change in drug blood concentration was measured. The results are shown in Table 2.

Comparative Example 4 25% by weight of a copolymer solution of tetrahydrofuran (drug good solvent) was used instead of the 15% by weight copolymer solution of cyclohexane (drug poor solvent), and 83.325 parts by weight of a 10% by weight tetrahydrofuran solution of nifedipine was added. A drug solution was obtained in the same manner as in Example 4 except for the above. This solution was applied onto a PET film in the same manner as in Example 1 to obtain a transdermal preparation. Observation with a polarizing microscope revealed that plate-like crystals with an average particle size of about 55 μm were partially observed in the adhesive layer. When this preparation was allowed to stand at room temperature for 1 month, plate-like giant crystals were deposited on the entire surface of the preparation.

A 10 cm ² percutaneous absorption preparation in which crystals were deposited was attached to the back of a dehaired Japanese white rabbit, and the time-dependent change in drug blood concentration was measured. The results are shown in Table 2.

Comparative Example 5 Except that ethyl acetate (good drug solvent) was used in place of cyclohexane (drug poor solvent), 14.29 parts by weight of a 7 wt% acetone / methanol mixed solvent solution of prednisolone (volume ratio 1/1) was added. A drug solution was obtained in the same manner as in Example 5. This solution was applied onto a PET film in the same manner as in Example 1 to try to produce a percutaneously absorbable preparation, but giant crystals with an average particle size of about 200 μm were deposited on the surface of the adhesive layer. (Drug floating phenomenon) and could not be laminated on the support because of low adhesiveness.

As is clear from Examples and Comparative Examples, according to the method for producing a percutaneously absorbable preparation of the present invention, fine drug particles can be uniformly dispersed in the adhesive layer. Therefore, when this transdermal absorbable connection is applied to the skin, a high level of drug blood concentration can be obtained, and the drug blood concentration characteristic is improved. According to the conventional method for producing a percutaneously absorbable preparation in which a drug and a polymer are dissolved in a good drug solvent, and the solution is applied to a support and dried, giant particles of the drug are deposited in the adhesive layer. Therefore, if this percutaneous absorption preparation is applied to the skin, the blood concentration of the drug will be low, and its sustainability will be lacking.

(Effects of the Invention) According to the present invention, a percutaneous absorption preparation in which a drug in the form of fine particles is uniformly dispersed in an adhesive layer is thus obtained. This percutaneously absorbable preparation is excellent in drug release. A sustained drug release is also obtained. As a result, when this percutaneously absorbable preparation is applied to the skin, a high level of drug concentration in the blood can be obtained. It also excels in the sustainability of drug concentration in blood.

Claims (2)

[Claims] 1. A drug having a saturated solubility or higher and an average particle size of 30 μm.
A method for producing a percutaneously absorbable preparation having the following adhesive layer containing fine particles and a support, wherein a drug solution of a good drug solvent is mixed with a heavy solvent of a poor drug solvent having a boiling point higher than that of the good drug solvent. Step of adding drug solution to coalesced solution to obtain drug solution, until drug crystals precipitate from the drug solution 30
A step of distilling off a good drug solvent under reduced pressure of 0 to 700 mmHg to obtain a dispersion of fine drug particles, and a step of coating the dispersion on the support and drying to form an adhesive layer. Method for manufacturing transdermal preparations. 2. The method for producing a percutaneously absorbable preparation according to claim 1, wherein the vacuum distillation is performed by a vacuum emulsification mixing device.