JPS62273913A - Production of percutaneously absorbable preparation - Google Patents

Abstract

PURPOSE:To obtain the titled preparation wherein a drug is uniformly dispersed in a pressure-sensitive adhesive agent layer at >=saturated solubility, by adding a solution of a drug in a good solvent for the drug to a solution of a polymer in a poor solvent for the drug, applying the prepared dispersion of drug fine particles to a substrate and drying. CONSTITUTION:A solution of a drug in a good solvent (e.g. THF, acetone or methanol) for the drug is added to a solution of a polymer in a poor solvent (e.g. n-hexane or toluene) for the drug to give a dispersion wherein drug fine particles having <=30mum, especially <=15mum average particle diameter are uniformly dispersed. The dispersion is applied to a substrate (e.g. synthetic resin film or fibrous sheet) and dried. The kinds of the solvents, drug concentration and the blending ratio of the drug solution and the polymer solution are determined in such ranges as to precipitate drug crystallite and not to form reprecipitation of the polymer. The preparation has improved drug releasability and good release durability.

Description

DETAILED DESCRIPTION OF THE INVENTION 3. Small daily dose i''■ (Field of industrial application) The present invention relates to a method for producing a transdermal drug preparation with excellent transdermal absorption of drugs.

(Prior Art) In order to obtain systemic or local medicinal effects, drugs (physiologically active substances) are absorbed through the skin using transdermal absorbable preparations. A transdermal absorption preparation has a flexible support and an adhesive layer containing a drug. The adhesive layer is made of a polymer such as natural rubber, synthetic rubber, or acrylic resin.

The amount of drug contained in the adhesive layer is usually less than the saturation solubility of the polymer. However, if the amount of drug is less than the saturation solubility, the amount of drug absorbed by the human body is small, and therefore sufficient medicinal efficacy cannot be obtained. Increasing the thickness of the adhesive layer or increasing the size of the preparation in order to increase the amount of drug absorption increases the cost and gives the user a sense of discomfort.

In order to solve these drawbacks, transdermal absorbable preparations have been proposed in which the adhesive layer contains a drug having a saturated solubility or higher than that of the dipolymer. If the polymer contains a drug with a saturation solubility or higher, as the drug is absorbed transdermally into the human body, the drug in undissolved form B (dispersed form B) will be sequentially dissolved in the polymer and replenished. , drug absorption increases. Sustained drug absorption can also be achieved. In particular, it is preferable to form the drug into fine particles because the drug can be easily redissolved and the amount of drug absorbed by the human body can be increased. The above-mentioned transdermal absorbable preparations include 1, for example, as disclosed in Japanese Patent Application Laid-Open No. 185713/1983,
There is a preparation in which a drug with a saturation solubility or higher is dispersed in a polymer in the form of recrystallized fine particles. This formulation dissolves the drug and polymer in a good drug solvent.

It is manufactured by applying this solution to a support and drying it.

However, in this method, the drug recrystallizes into fine particles by drying, so the drug that is not completely crystallized dissolves in the adhesive layer in a supersaturated state, and this gradually precipitates out to form huge recrystallized particles. . Due to the volatilization of the solvent during the drying process, recrystallized drug particles are unevenly distributed on the surface of the adhesive layer (drug floating phenomenon), resulting in a decrease in adhesiveness. Moreover, the particle size of the recrystallized drug particles and their distribution state in the adhesive layer change depending on the drying conditions, making it difficult to obtain a formulation in which the drug in the form of 'R1 particles is uniformly dispersed in the adhesive layer. be.

Also disclosed is a method of mixing a drug dispersion with a poor drug solvent and a polymer solution with a good drug solvent. Fine drug particles are dispersed in the drug dispersion liquid.

However, in this method, drug particles tend to coalesce and form giant particles due to mixing. Moreover, drug particles cannot be uniformly dispersed in the adhesive layer.

(Problems to be Solved by the Invention) The present invention solves the above-mentioned conventional problems, and its purpose is to provide transdermal absorption in which fine particulate drugs are uniformly dispersed in the adhesive layer. An object of the present invention is 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 the adhesive layer contains a drug with a saturation solubility or higher.

(Means for Solving the Problems) The method for producing a transdermal preparation of the present invention is a method for producing a transdermal preparation having a support and an adhesive layer containing a drug having a saturation solubility or higher. the step of adding a drug solution of a drug good solvent to a polymer solution of a drug poor solvent to obtain a dispersion of drug fine particles; and a step of applying the dispersion to the support and drying the dispersion. The above objective is achieved.

Journal
of Pharmaceutical 5science
s (JPS)+50+847+(1961);
JPS, 52.1145. (1963) ; J
our own of the 5ociety o
f cos+wetic chemists, Dan,
85° (1960); JPS, 64.1643.
(1975) and others. Jr'S, 5
4.1459 (1965) describes the particle size of drug particles in the adhesive layer. In order to improve the permeability of drugs into the skin, it is desirable to incorporate drugs with a saturation solubility or higher into fine particles in the adhesive layer from the viewpoint of thermodynamic activity (Monthly Pharmaceutical Affairs, Benefits, Patient 2). (198
3), Ryoji Konishi).

The present invention was completed based on these findings.

Examples of good drug solvents include tetrahydrofuran.

These include ethyl acetate, acetone, methanol, methylene chloride, chloroform, and ether. Examples of poor drug solvents include n-hexane and cyclohexane.

There's toluene. However, drug good solvents and drug poor solvents vary depending on the drug used, e.g.

Tetrahydrofuran, ethyl acetate, etc. can be poor drug solvents. The drug good solvent and drug poor solvent used in the present invention are not particularly limited, but the type of solvent, drug concentration, and drug solution and polymer solution can be adjusted as long as the drug microcrystals precipitate and the polymer does not re-precipitate. The blending ratio of is determined.

Fine particulate drugs are uniformly dispersed in a drug dispersion obtained by adding a drug solution to a polymer solution. The average particle size of the drug fine particles is 30 μm or less, preferably 15 μm or less. Since this particulate drug is easily redissolved in the adhesive layer, transdermal preparations containing this drug in the adhesive layer have excellent drug release properties. As a result, if this is applied to the human body, the amount of drug absorbed will increase. Moreover, since the adhesive layer contains the drug at a saturation solubility or higher, sustained drug absorption can be achieved.

The drug contained in the transdermal absorbable preparation of the present invention.

It is a drug that is absorbed transdermally and exerts its medicinal effects.

For example, hydrocortiscin, prednisolone.

Heclomethasone pionate, flumethacin.

Corticosteroids such as hetamethasone, triamcinolone, triamcinolone acetonide, fluocinolone, fluocinolone acetonide, fluocinolone acetonide acetate, clobetasol propionate; acetaminophen, mefenamic acid, flufenamic acid, indomethacin, diclofenac, diclofenac sodium; Analgesic and anti-inflammatory agents such as alclofenac, oxyphenbutacin, phenylbutacin, ibuprofen, flurbuprofen, salicylic acid, methyl salicylate, 1-menthol, camphor, sulindac, tolmetin sodium, naproxen, fenbufen; phenobarbital, amol Barbital, cyclobarbital, toluazolam.

Hypnotic sedatives such as nitrazepam, lorazepam, haloperidol; fluphenazine, thioridazine.

Diazepam, fludiazepam, fludiazepam.

Tranquilizers such as chlorpromazine; clonidine.

Clonidine hydrochloride, pindolol, propranolol, propranolol hydrochloride, pufranol, indenolol,
Antihypertensive agents such as nivadipine, lofedixin, nipradilol, bucumolol, nifedipine; antihypertensive diuretics such as hydrothiazide, bendroflumeshiazide, cyclopenthiazide; penicillin, tetracycline, oxytetracycline, fradiomycin sulfate.

Antibiotics such as erythromycin, chloramphenicol; anesthetics such as lidocaine, pensicaine, ethyl aminobenzoate; antibacterial substances such as benzalkonium chloride, nitrofurazone, nyscutin, acetosulfamine, clotrimazole; pentamycin, amphotericin B Antifungal substances such as , pyrrolenidrine, and clotrimazole; vitamins such as vitamin A, ergocalciferol, cholecalciferol, octothiamine, and riboflavin butyrate; antiepileptic agents such as nitrazepam, mepropamate, and clonazepam; isosorbide dinitrate Coronary vasodilators, such as , erythridose-stetranitrate, pentaerydose-stetranitrate, propyl nitrate; antihistamines, such as diphenhydramine hydrochloride, chlorpheniramine, diphenylimidasol; dextromethorphan, terbutaline.

Ephedrine, ephedrine salbutamol hydrochloride.

Antitussives such as isoprotenol; borogesterone.

Sex hormones such as estradiol; anti-agents such as doxepin; 5-fluorouracil, dihydroergotamine, fentanyl, desmopressin.

Other drugs include digoxin, metoclopraside, domperid, scopolamine, scopolamine hydrobromide, and prostaglandins.

Examples of polymers forming the adhesive layer include polyvinyl alkyl ether, poly(meth)acrylate, 2-ethylhexyl acrylate-2-ethylhexyl methacrylate copolymer, 2-ethylhexyl acrylate-vinylpyrrolidone copolymer, and polyurethane. , styrene-isoprene-
There are styrene block copolymers, polyisobutylene rubber, polyisoprene rubber, butyl rubber, natural rubber, silicone resins, and terpene resins. Known tackifiers are used to impart pressure-sensitive adhesive properties to these polymers.

Softeners, fillers, anti-aging agents, etc. may be added.

The support is provided to provide self-supporting properties to the transdermal preparation and to prevent volatilization and migration of the drug in the adhesive layer.For example, the support is made of polyethylene.

Polypropylene, boria, krylic, polyurethane.

Films or sheets made of polyester, polyvinyl alcohol, polyvinyl chloride, polyvinylidene chloride, polyamide, ethylenic copolymers; laminated films of these; porous films or sheets made of rubber and/or synthetic resins; nonwoven fabrics.

Fibrous film or sheet such as woven paper; metal foil;
There is a film or sheet of metal foil that has a metal vapor deposited surface. Among these materials, a material that has 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 percutaneously absorbable preparation of the present invention in order to promote percutaneous absorption of the drug. Absorption enhancers include 2, for example, 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;
Isopropyl myristate, isopropyl palmitate.

Higher fatty acid esters such as diethyl sebacate.

These include higher fatty acid triglycerides; fatty acid (mono)jetanolamide; salicylic acid; and salicylic acid esters. The absorption enhancer may be used alone or in combination of two or more, and is contained in the adhesive layer in an amount of 30% by weight or less.

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

In the Examples and Comparative Examples, the drug blood concentration of isosorbide dinitrate was measured by gas chromatography, and the drug blood concentration of indomethacin was measured by liquid chromatography.

Isosorbide was added to 100 parts by weight of a 21% by weight cyclohexane solution of 2-ethylhexyl acrylate-2-ethylhexyl methacrylate copolymer (containing 25 parts by weight of 2-ethylhexyl methacrylate based on 75 parts by weight of 2-functional tylhexyl acrylate) on charcoal. 12.35 parts by weight of a 30% by weight methylene chloride solution of dinitrate (ISDN) was added and mixed uniformly using a discer.

The obtained dispersion of l5DNfi crystals was applied onto a polyethylene terephthalate (PET) film (one side treated with a silicone release agent, thickness 45 μm), and
The adhesive layer was formed by drying at ℃ for 30 minutes. A PET film (thickness: 10 μm) was laminated on this adhesive layer.

A transdermal absorbable preparation was obtained. Observation using a polarizing microscope revealed that needle-shaped drug microcrystals with an average particle size of about 6 μm were uniformly dispersed in the adhesive layer. The thickness of the adhesive layer was 50 μm, and the drug concentration in the adhesive layer was 15% by weight.

The transdermal absorbable preparation I Q cal thus obtained
of.

It was applied to the backs of Japanese domestic rabbits that had been subjected to hair removal treatment, and the changes over time in the blood concentrations of the two drugs were measured. These results are shown in Table 1.

Carbonation 1 Instead of a 21% by weight cyclohexane solution of 2-ethylhexyl acrylate-2-ethylhexyl methacrylate copolymer, a 10% by weight cyclohexane solution of a mixture of 55 parts by weight of natural rubber and 45 parts by weight of terpene resin was used, and isosorbide was added. Except that 3.704 parts by weight of a 30% by weight methylene chloride solution of dinitrate (ISDN) was added.
A transdermal absorbable preparation was obtained in the same manner as in Example 1.

Observation using a polarizing microscope revealed that needle-shaped drug microcrystals with an average particle size of 3 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.

10 cd of the transdermal absorbable preparation thus obtained.

It was applied to the backs of Japanese domestic rabbits that had undergone hair removal treatment, and changes in blood drug concentration over time were measured. These results are shown in Table 1.

Contains 15 parts by weight of vinylpyrrolidone for 85 parts by weight of 2-ethylhexyl acrylate-vinylpyrrolidone hexyl acrylate instead of 21% by weight cyclohexane (21% by weight 2-ethylhexyl acrylate-2-ethylhexyl methacrylate copolymer). ) using a 15ml 1% cyclohexane solution. Instead of a 30% by weight solution of isosorbide dinitrate in methylene chloride. A transdermal preparation was obtained in the same manner as in Example 1, except that 30 parts by weight of a 15% by weight solution of indomethacin in tetrahydrofuran was added.

In the adhesive layer of this transdermal absorption preparation. Observation using a polarizing microscope revealed that needle-shaped drug microcrystals with an average particle size of 7 μm were uniformly dispersed. The thickness of the adhesive layer was 50 μm. The drug concentration in the adhesive layer was 23% by weight.

30 cal of the transdermal absorbable preparation thus obtained.

It was applied to the backs of Japanese domestic rabbits that had undergone hair removal treatment, and changes in blood drug concentrations over time were measured. These results are shown in Table 2.

] 1.3 of a mixture of 50 parts by weight of styrene-isoprene-styrene block copolymer and 50 parts by weight of terpene resin instead of a 21% by weight cyclohexane solution of 2-ethylhexyl acrylate-2-ethylhexyl methacrylate copolymer.
Using a 0% by weight cyclohexane solution, replacing the 30% by weight methylene chloride solution of isosorbide dinitrate with a 15% by weight solution of indomethacin in tetrahydrofuran 20
A transdermal absorbable preparation was obtained in the same manner as in Example 1, except that part by weight was added.

Observation using a polarizing microscope revealed that needle-shaped drug microcrystals with an average particle size of 2 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.

30 cal of the transdermal absorbable preparation thus obtained.

It was applied to the backs of Japanese domestic rabbits that had undergone hair removal treatment, and changes in blood drug concentration over time were measured. These results are shown in Table 2.

Using a 10% by weight cyclohexane solution of a highly reliable 2-ethylhexyl acrylate-2-ethylhexyl methacrylate copolymer (containing 25 parts by weight of 2-ethylhexyl methacrylate to 75 parts by weight of 2-ethylhexyl acrylate), isosorbidinite was used. (ISDN) in 30% by weight methylene chloride solution.

A transdermal preparation was obtained in the same manner as in Example 1, except that 14.29 parts by weight of a 7% by weight acetone/methanol mixed solvent solution of prednisolone (171 volume ratio) was added.

Observation using a polarizing microscope revealed that needle-shaped drug microcrystals with an average particle size of 12 μm were uniformly dispersed in the adhesive layer of this transdermal preparation. The thickness of the adhesive layer is 50 μm,
The drug concentration in the adhesive layer was 10%.

A transdermal preparation was obtained in the same manner as in Example 1, except that ethyl acetate (good drug solvent) was used in place of cyclohexane (poor drug solvent). The drug was supersaturated in the adhesive layer, and no crystal precipitation was observed even when observed using a polarizing microscope. This preparation was left at room temperature for 2 days.

Husband-like giant crystals with an average particle size of about 80 μm were precipitated over the entire surface of the preparation.

10 cffl of the skin-absorbable preparation in which the crystals had precipitated was applied to the back of a Japanese domestic rabbit that had undergone hair removal treatment, and the change in blood drug concentration over time was measured. These results are shown in Table 1.

Except that tetrahydrofuran (a good drug solvent) was used instead of cyclohexane (a poor drug solvent).

A transdermal absorbable preparation was obtained in the same manner as in Example 2. The drug was supersaturated in the adhesive layer, and no crystal precipitation was observed even when observed using a polarizing microscope. When this preparation was left at room temperature for 2 days, giant needle-like crystals with an average particle size of 60 μm spread out radially on a part of the side surface of the preparation. After being left at room temperature for one month, precipitated crystals were observed over the entire surface of the preparation.

The transdermal absorption preparation LocIA in which the crystals were precipitated was applied to the back of a Japanese domestic rabbit that had been subjected to hair removal treatment, and the change in blood drug concentration over time was measured. These results are shown in Table 1.

A transdermal preparation was obtained in the same manner as in Example 3, except that ethyl acetate (good drug solvent) was used in place of dichlorohexane (poor drug solvent). The drug was supersaturated in the adhesive layer, and no crystal precipitation was observed even when observed using a polarizing microscope. This preparation was left at room temperature for 2 days.

Husband-like giant crystals with an average particle size of 70 μm were precipitated in a part of the preparation. After being left at room temperature for 3 months, the precipitated crystals were applied to the backs of molded Japanese domestic rabbits, and changes in blood drug concentration over time were measured. These results are shown in Table 2.

Except that tetrahydrofuran (a good drug solvent) was used instead of cyclohexane (a poor drug solvent).

A transdermal absorbable preparation was obtained in the same manner as in Example 4. The drug was supersaturated in the adhesive layer, and no crystal precipitation was observed even when observed using a polarizing microscope. When this preparation was allowed to stand at room temperature for 2 days, giant acicular crystals with an average particle size of 40 μm precipitated over the entire surface of the preparation. This crystal was spread out in a circular shape around the nucleus.

10 cal of the transdermal preparation in which the crystals were precipitated was applied to the back of a Japanese domestic rabbit that had undergone hair removal treatment, and the change in blood drug concentration over time was measured. These results are shown in Table 2.

(Blank below) This Mjt product was manufactured in the same manner as in Example 5 except that ethyl acetate (good drug solvent) was used instead of cyclohexane (poor drug solvent). However, Giant crystals with an average particle size of approximately 200 μm are precipitated on the surface of the adhesive layer (
drug floating phenomenon), and could not be laminated onto a support due to low adhesion.

As is clear from the Examples and Comparative Examples, according to the method for manufacturing a transdermal preparation of the present invention, drug fine particles can be uniformly dispersed in the adhesive layer. For this purpose, this transdermal absorbable preparation is applied to the skin.

A high level of drug concentration in the blood can be obtained, and the persistence of the drug concentration in the blood can be improved. According to the conventional method for manufacturing transdermal preparations in which a drug and a polymer are dissolved in a good drug solvent, the solution is applied to a support, and then dried, large particles of the drug are precipitated in the adhesive layer.

Therefore, if this transdermal absorbable preparation is applied to the skin,
The drug concentration in the blood is low, and its durability is also lacking.

(Effects of the Invention) According to the present invention, a transdermal preparation in which fine particulate drugs are uniformly dispersed in the adhesive layer can be obtained. This transdermal absorption preparation has excellent drug release properties. Sustained drug release is also obtained. As a result, if this transdermal absorbable preparation is applied to the skin.

High levels of drug blood concentration are obtained. It also has excellent sustainability of drug blood concentration.

that's all

Claims (1)

[Claims] 1. A method for producing a transdermal preparation having an adhesive layer and a support that contain a drug having a saturation solubility or higher, the method comprising: converting a drug solution in a good drug solvent into a polymer in a drug poor solvent; A method for producing a percutaneously absorbable preparation comprising the steps of: adding the drug to a solution to obtain a dispersion of fine drug particles; and applying the dispersion to the support and drying it. 2. The method for producing a transdermal preparation according to claim 1, wherein the average particle size of the drug fine particles is in the range of 30 μm or less.