JPH09169635A - Transdermal formulation - Google Patents

Abstract

(57) Abstract: To provide a percutaneous absorption preparation which achieves high drug absorption and high utilization rate and has low irritation. A percutaneous absorption preparation containing a drug, a percutaneous absorption promoter for the drug and a stabilizer in a base (eg, olive oil, cocoa butter, etc.), wherein the percutaneous absorption promoter is carbon. Alcohol of several 10 to 14 (eg, lauryl alcohol,
(Myristyl alcohol, etc.) and its content in the preparation is 0.1 to 30% by weight. Further, an adhesive containing a drug, the above-mentioned percutaneous absorption enhancer and a stabilizer on one side of the support (eg, vinylpyrrolidone.2-
An ethylhexyl acrylate copolymer) layer-provided tape preparation, wherein the content of the percutaneous absorption enhancer in the pressure-sensitive adhesive layer is 0.1 to 30% by weight.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a transdermal preparation.

[0002]

2. Description of the Related Art Conventionally, there are many drugs that cannot be sufficiently absorbed by oral administration unless they are administered in a large amount because of their low absorption in the digestive tract. In general, when a large amount of a drug is administered, the blood concentration becomes too high immediately after the administration, which causes a problem that side effects are likely to occur. Especially in female hormone agents such as estradiol,
Side effects such as fraudulent bleeding and increased incidence of cancer were observed.

Transdermal preparations have been developed to solve this problem. For example, in the case of estradiol, Japanese Patent Laid-Open No. 154122/1982 proposes a transdermal preparation comprising a multi-layered patch. This percutaneous absorption preparation comprises a support, a drug-enhancing agent-containing layer, a diffusion film layer, and a pressure-sensitive adhesive layer, which are sequentially laminated. The drug-enhancing agent-containing layer is formed by gelling ethanol with hydroxypropylcellulose or the like. The gel-like substance is composed of a drug-containing gel containing estradiol, and the diffusion film layer functions as a drug release controlling film. This percutaneous absorption preparation is said to have high percutaneous absorption and appropriate drug release, but a large administration area is required to obtain sufficient percutaneous absorption, and it is bulky because of its structure. There is a problem that it is difficult.

Further, Japanese Patent Application Laid-Open No. 2-237926 proposes a transdermal patch of estradiol, and according to this proposal, a hollow fiber is produced in an acrylic pressure-sensitive adhesive layer containing estradiol and polyvinylpyrrolidone. It is said that by laminating fibers, a patch having high stability and low skin irritation can be obtained. However, since the compatibility between polyvinylpyrrolidone and the acrylic pressure-sensitive adhesive is not good, it is difficult to manufacture, a certain quality cannot be obtained, and the transdermal absorption amount is not high.

A similar patch is disclosed in Japanese Patent Laid-Open No. 5-1481.
No. 45 has been proposed, but similarly, there is a problem that the amount of percutaneous absorption is insufficient.

In order to solve these problems, a percutaneous absorption preparation containing a percutaneous absorption promoter has been proposed.
For example, in JP-A-61-249934, a drug,
A percutaneous absorption preparation is proposed by combining a lower alcohol, an alcohol having 7 to 20 carbon atoms and water, and it is said that an effective percutaneous absorption preparation can be obtained in a small amount by increasing the percutaneous absorption of various drugs. ing. However, in this case, since water is essential, a drug unstable to water cannot be used, and since the volatile component is the main component, its transdermal absorption promoting effect is lost in a short time. There is a problem.

[0007] Further as a preparation having improved transdermal absorbability,
There are ointments, gels, and poultices, which are formulations in which the fluidity of the base is increased to improve the transdermal absorbability. As examples of these, for example, JP-A-2-237383 proposes a percutaneous absorption preparation comprising an acrylate polymer, a liquid component compatible with the polymer, and estradiol. However, since this formulation has poorer adhesiveness than the patch, the blood concentration varies from person to person, and there is a problem in terms of efficacy and safety.

[0008]

SUMMARY OF THE INVENTION The present invention is intended to solve the above problems, and an object thereof is to provide a percutaneous absorption preparation which achieves high drug absorption and high utilization rate and is low in irritation. It is to be.

[0009]

The transdermal absorption preparation according to claim 1 is a transdermal preparation containing a drug, a transdermal absorption enhancer of the drug and a stabilizer in a base, The transdermal absorption enhancer is an alcohol having 10 to 14 carbon atoms, and its content in the preparation is 0.1 to 30% by weight.

The percutaneous absorption preparation according to claim 2 is a tape preparation in which a pressure-sensitive adhesive layer containing a drug, the percutaneous absorption enhancer and a stabilizer is provided on one surface of a support, The content of the absorption promoter in the adhesive layer is 0.1 to 30% by weight.
The percutaneously absorbable preparation according to claim 1.

The drug used in the percutaneous absorption preparation of the present invention may be a pharmacologically active substance, such as a drug that acts by incorporating the drug into blood or a drug that locally acts on the administration site. Any type of drug can be used regardless of its type, for example, general anesthetics, hypnotics / analgesics, antiepileptics, antipyretic analgesics / antiphlogistics, stimulants / stimulants, antidepressants, psychotropic drugs, and local anesthesia. Drugs, muscle relaxants, antispasmodics, anti-Parkinson's agents, antihistamines, cardiotonics, antiarrhythmic agents, diuretics, antihypertensive agents (eg clonidine hydrochloride),
Vasoconstrictor, coronary vasodilator, peripheral vasodilator, anti-arteriosclerotic drug, antitussive expectorant, anti-peptic ulcer drug, hormone drug, corticosteroid (eg dexamethasone), hemorrhoid drug, wound protectant, Astringent, antipruritic, anthelmintic, emollient, vitamin, anticoagulant, toxic antidote, gout remedy,
Examples include enzyme agents, antidiabetic agents, antineoplastic agents, antibiotics, chemotherapeutic agents, antiprotozoal agents, cytokine-like substances, narcotics, antisense RNA, and the like.

The above drug is preferably contained in the preparation in an amount of 0.01 to 30% by weight. This percentage is
Formulations such as ointments and creams, which do not have a support, show the content relative to the whole formulation, and for formulations such as tapes and poultices, which have a support,
The content relative to the drug-containing layer (adhesive layer) is shown. The same applies to the contents of percutaneous absorption enhancers and stabilizers described below. When the drug concentration is low, sufficient drug absorbency cannot be obtained, and when it is high, the drug does not dissolve in the remaining components after the volatile components in the base have volatilized, and it precipitates on the body surface as drug crystals. Becomes extremely bad.

As the percutaneous absorption enhancer contained in the percutaneous absorption preparation of the present invention, an alcohol having 10 to 14 carbon atoms is used. Examples thereof include lauryl alcohol, decyl alcohol, undecyl alcohol, tridecyl alcohol and myristyl. Examples thereof include alcohols, and lauryl alcohol is particularly preferable.

If the amount of the above-mentioned alcohol having 10 to 14 carbon atoms is reduced, the effect of promoting percutaneous absorption of the drug cannot be obtained, and if the amount is increased, the percutaneously absorbable preparation becomes sticky and the feeling of use becomes poor. It is contained in a proportion of 1 to 30% by weight, preferably 0.5 to 4% by weight in the formulation for ointments, creams and the like, and 1 to 10% by weight in the adhesive layer for tapes and the like. . In the case of ointments, creams, etc., the alcohol having 10 to 14 carbon atoms remains on the skin after volatilization of the volatile component in the base, dissolves the drug and quickly penetrates the skin, or acts on the skin. The structure of the lipophilic part of the skin is disturbed, which gives the preparation high absorbability.In the case of tapes, etc., the drug is dissolved from the adhesive layer and quickly penetrates the skin, or acts on the skin. , Disturbs the structure of the lipophilic part of the skin, which gives the formulation high absorbency.

The transdermal preparation of the present invention further contains a stabilizer. Examples of the stabilizer include butylhydroxytoluene.

The dosage form of the percutaneous absorption preparation of the present invention is not particularly limited, and for example, the above-mentioned drug, percutaneous absorption enhancer, stabilizer and the like are dissolved or mixed and dispersed in a base and paste. , Cream, jelly, gel, emulsion, liquid, etc. (ointments, creams, gels, liniments, lotions, tinctures, etc.), the above drug in a base, Dissolved or mixed dispersion of percutaneous absorption enhancer and stabilizer, etc. spread on a support (such as poultice), and the above drug, percutaneous absorption enhancer and stabilizer are dissolved in adhesive. Alternatively, a mixture (dispersion product) spread on a support (tape preparation, plaster preparation, etc.) and the like can be mentioned.

As the base used in the above ointment, synthetic resins such as macrogol and hydrocarbon gel ointment (for example, trade name Plastibase, manufactured by Taisho Pharmaceutical Co., Ltd.); paraffins such as white petrolatum and hydrophilic petrolatum; olive oil, Examples include natural oils and fats such as cocoa butter, beeswax, and refined lanolin. In addition, as a base used in the cream, stearic acid, stearyl alcohol, fats and oils such as purified lanolin and water, an aqueous solvent such as propylene glycol are surfactants (for example, alkylamine salts and quaternary ammonium salts). Cationic surfactants, alkyl sulfates, acylated amino acids, higher fatty acid salts, polyoxyethylene phosphates, anionic surfactants such as alkyl ether carboxylic acids, polyoxyethylene alkyl ethers, polyoxyethylene fatty acid esters , Nonionic surfactants such as fatty acid alkanolamides, sorbitan fatty acid esters, and sucrose fatty acid esters). Further, as the base of the gel agent, carboxyvinyl polymer, polyacrylic acid, polyvinylpyrrolidone, alginic acid, gelatin, corn starch, tragacanth gum, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, dextrin, polyvinyl alcohol, methoxyethylene-anhydrous. Hydrophilic polymers such as maleic acid copolymers and polyvinyl ethers; salts of said hydrophilic polymers; aluminum silicate,
Examples thereof include those obtained by gelling a silicate such as magnesium silicate with an organic solvent, water, or an aqueous solvent such as propylene glycol. In addition, a neutralizing component such as triethanolamine may be added to the gel agent, if necessary. Further, examples of the base of the liniment agent include phenol / zinc white liniment, lime liniment, soap camphur liniment, and camphur liniment. Examples of the base of the lotion include water, glycerin, ethyl alcohol, isopropyl alcohol and the like.

As the base of the poultice, the same bases as the above gels can be mentioned.

The support is appropriately selected according to its dosage form (eg, poultice, tape, plaster, etc.), but is preferably impermeable or poorly permeable to the drug, and its shape is Generally, a film-shaped one is used, but the shape is not limited as long as it can be fixed on the body surface. As the material of the support, any of those conventionally used for tape preparations can be used, and the material varies depending on the drug used, but for example, polyethylene terephthalate film, aluminum vapor-deposited polyethylene film, polypropylene film, poly Examples thereof include vinylidene chloride film.

The above-mentioned pressure-sensitive adhesive is not particularly limited as long as it can dissolve a drug and can be adhered to the body surface. For example, acrylic pressure-sensitive adhesive, silicon-based pressure-sensitive adhesive, rubber-based pressure-sensitive adhesive, urethane-based pressure-sensitive adhesive. Examples thereof include adhesives. Further, when spread on the support, the properties of the adhesive are:
Any solvent type, emulsion type, hot melt type or the like can be used.

Examples of the acrylic pressure-sensitive adhesive include pressure-sensitive adhesives mainly composed of polyalkyl (meth) acrylate obtained by copolymerization of alkyl (meth) acrylate, which are copolymerizable with polyalkyl (meth) acrylate. It may be a copolymer with a polyfunctional monomer or another vinyl monomer.

Examples of the alkyl (meth) acrylate include 2-ethylhexyl (meth) acrylate and dodecyl (meth) acrylate. Examples of the polyfunctional monomer include 1,6-hexane glycol dimethacrylate and tetraethylene glycol diacrylate, and examples of the other vinyl monomer include N-vinyl-2-pyrrolidone and vinyl acetate. Is mentioned.

Examples of the rubber-based pressure-sensitive adhesive include pressure-sensitive adhesives mainly composed of natural rubber, styrene-isoprene-styrene block copolymer, styrene-olefin-styrene block copolymer, etc. Generally, rosin and hydrogenated A tackifier such as rosin, rosin ester, terpene resin, terpene phenol resin, petroleum resin, coumarone resin, coumarone-indene resin is added.

To produce the transdermal preparation of the present invention, in the case of an ointment, cream, gel, liniment, lotion, tincture, etc., the drug and the transdermal agent in the base are used. The absorption promoter and the stabilizer may be dissolved or mixed and dispersed to form paste, cream, jelly, gel, emulsion, liquid or the like.

In the case of a poultice, the drug, the percutaneous absorption enhancer, the stabilizer and the like dissolved or mixed and dispersed in the above base may be spread on a support.

In the case of a tape agent, various coating methods such as a solvent coating method, a hot melt coating method and an electron beam curing emulsion coating method can be used to form the pressure-sensitive adhesive layer. Among them, a solvent coating method is suitably used. To form the pressure-sensitive adhesive layer by the solvent coating method, for example, the pressure-sensitive adhesive is diluted with an appropriate solvent, and the drug, the percutaneous absorption enhancer, the stabilizer and, if necessary, other compounding agents are added thereto. In addition, the mixture is uniformly mixed, and the obtained solution is applied to the surface of the support and dried. Instead of directly applying the solution to the surface of the support, the solution may be applied onto a release paper coated with a silicone resin or the like, dried and then brought into close contact with the support. Such release paper is used to protect the surface of the pressure-sensitive adhesive layer of the tape agent until the time of use.

[0027]

Next, embodiments of the present invention will be described. (Examples 1 to 17 and Comparative Examples 1 to 12) Predetermined amounts (parts by weight) of a base, a percutaneous absorption enhancer and a drug shown in Tables 1 and 2 were blended at 80 ° C, and the mixture was further stirred for 10 minutes. The resulting solution was dissolved uniformly to produce a percutaneous absorption preparation.

The gel base material in the base material column in the table has the following composition. Ethanol 35 parts Propylene glycol 30 parts Water 34 parts Carboxyvinyl polymer 1 part Triethanolamine 0.05 parts

A percutaneous absorption preparation using a gel base was manufactured by the following method. Ethanol, propylene glycol and carboxyvinyl polymer are homogenized using a homomixer (made by Tokushu Kika Kogyo Co., Ltd.) at 25 ° C.
It was rotated and stirred for 30 minutes. Then, the drug and the percutaneous absorption enhancer were put into the liquid and further stirred at 25 ° C. for 10 minutes. Finally, water in which triethanolamine was dissolved was added, and this was rotated and stirred at 25 ° C for 30 minutes to produce an ointment.

The types and sources of the base, transdermal absorption enhancer and drug used are as follows. -Base olive oil: manufactured by Maruishi Pharmaceutical Co., Ltd. Cocoa butter: manufactured by Maruishi Pharmaceutical Co., Ltd.
White vaseline: manufactured by Maruishi Pharmaceutical Co., Ltd. Ethanol: manufactured by Wako Pure Chemical Industries. Propylene glycol: manufactured by Wako Pure Chemical Industries. Carboxyvinyl polymer: manufactured by Wako Pure Chemical Industries. Triethanolamine: manufactured by Tokyo Chemical Industry.

Transdermal absorption promoter Lauryl alcohol: manufactured by Wako Pure Chemical Industries. Myristyl alcohol: manufactured by Wako Pure Chemical Industries. Octyl alcohol: manufactured by Wako Pure Chemical Industries. Stearyl alcohol: manufactured by Wako Pure Chemical Industries.・ Drug dexamethasone: manufactured by Wako Pure Chemical Industries. Clonidine hydrochloride: manufactured by Sigma.

[0032]

[Table 1]

[0033]

[Table 2]

(Examples 18 to 28 and Comparative Examples 13 to 1)
8) Predetermined amount (parts by weight) of the adhesive solution shown in Table 3, solvent (ethyl acetate was used for the vinylpyrrolidone-2-ethylhexyl acrylate copolymer ethyl acetate solution, and tetrahydrofuran was used for Silascon 355) ,
A transdermal absorption enhancer and a drug were mixed and stirred with a homomixer to form a uniform solution, which was then coated on a polyethylene terephthalate film (thickness: 35 μm) treated with a silicone-based release agent with a knife coater. Coating was performed so that the thickness after drying was 60 μm, and this was dried for 30 minutes by a dryer heated to 60 ° C. to form a film. Then, a polyethylene film (thickness 75 μm) was laminated as a support.

The types and sources of the adhesive solution, solvent, percutaneous absorption promoter and drug used are as follows. -Adhesive solution Ethyl acetate solution of vinylpyrrolidone-2-ethylhexyl acrylate copolymer (solid content 35%) (in the table,
Abbreviated as VP-EHA): manufactured by Sekisui Chemical Co., Ltd. Silicone adhesive solution (solid content 10%) (abbreviated as SI in the table): Dow Corning Co., Ltd., trade name "Silascon 35"
5 ”. -Solvent Ethyl acetate: manufactured by Wako Pure Chemical Industries. Tetrahydrofuran: manufactured by Wako Pure Chemical Industries.

Transdermal absorption promoter Lauryl alcohol: manufactured by Wako Pure Chemical Industries. Myristyl alcohol: manufactured by Wako Pure Chemical Industries. Octyl alcohol: manufactured by Wako Pure Chemical Industries. Stearyl alcohol: manufactured by Wako Pure Chemical Industries.・ Drug dexamethasone: manufactured by Wako Pure Chemical Industries. Clonidine hydrochloride: manufactured by Sigma.

[0037]

[Table 3]

Experimental Example 1 A drug permeability test was conducted on the preparations of Examples and Comparative Examples as follows. A diffusion cell 10 shown in FIG. 1 was prepared. The diffusion cell 10 has a cylindrical bottomed receptor tank 1 and a cylindrical bottomed donor tank 2 having an opening 21 at the bottom. The donor tank 2 is stacked above the receptor tank 1 airtightly and concentrically via a pair of O-rings 31 and 32. The receptor tank 1 has a sampling port 11 protruding laterally on its side. O
The skin 4 used for the test is sandwiched between the rings 31 and 32, and the opening 21 of the donor tank 2 is entirely covered with the skin 4.

Hairless mouse (Hos / hr-1, male, 6 weeks old)
Was killed by cervical dislocation, the skin was peeled off, the subcutaneous adipose tissue and blood vessels were removed, and a skin piece of about 5 cm × 5 cm was obtained.
The above-mentioned preparation was added to this, Examples 1-17 and Comparative Examples 1-12.
The contact area of the formulation of No. ¹ was 7.1 cm ² , and the tape preparations of Examples 18 to 28 and Comparative Examples 13 to 18 were each applied with an application area of 7.1 cm ² .
At the time of application, the polyethylene terephthalate film that had been treated with a silicone-based release agent was peeled off so that the surface that was in contact with the film was in contact with the skin piece.)
Then, it was set between both O-rings 31 and 32 of the diffusion cell 10. The receptor tank 1 was filled with the following receptor liquid, and the receptor liquid was stirred by the stirrer 12.

Receptor solution preparation method: NaH ₂ PO _{4 in} distilled water
The pH was adjusted to 7.2 by adding an aqueous NaOH solution to a buffer containing 5 × 10 ⁻⁴ M, Na ₂ HPO ₄ 2 × 10 ⁻⁴ M, NaCl 1.5 × 10 ⁻¹ M and gentamicin sulfate 10 μg / ml. 800 ml of this buffer
On the other hand, 200 ml of polyethylene glycol 400 (manufactured by Tokyo Chemical Industry Co., Ltd.) was added to prepare a receptor solution.

The entire diffusion cell 10 was placed in a constant temperature bath maintained at 37 ° C. 1,3,6,18,24 after starting the test
After a lapse of time, 1 ml of the receptor liquid was sampled from the sampling port 11 and replaced with 1 m of fresh receptor liquid.
l was replenished. The drug permeated through the skin is dissolved in the collected receptor liquid. The drug concentration in the collected receptor solution was measured by high performance liquid chromatography, and the drug permeation amount (unit: μg / 7.1 cm ² ) was calculated.
~ 6.

[0042]

[Table 4]

[0043]

[Table 5]

[0044]

[Table 6]

[0045]

The composition of the percutaneous absorption preparation according to claim 1 is as described above, and the transdermal absorption enhancer contained in the preparation dissolves or permeates the drug or promotes percutaneous absorption. When the agent acts on the skin, a percutaneous absorption preparation having high drug absorption can be obtained. As a result, drugs that have been poorly permeable to the skin can now be used as transdermal preparations. Further, according to the present invention, it has a high absorbency at the beginning,
A transdermal preparation having stable absorbability over a long period of time was obtained. The constitution of the percutaneous absorption preparation according to claim 2 is as described above, and the permeation absorption enhancer contained in the pressure-sensitive adhesive layer dissolves or permeates the drug, or the percutaneous absorption enhancer acts on the skin. By acting on, a tape preparation having high drug absorption can be obtained. As a result, drugs that have been poorly permeable to the skin can now be used as tapes. Further, according to the present invention, a tape preparation having high absorbency at the beginning and stable absorbability over a long period of time was obtained.

[Brief description of the drawings]

FIG. 1 is a perspective view showing a diffusion cell for testing drug permeability.

Claims (2)

[Claims] 1. A percutaneous absorption preparation containing a drug, a percutaneous absorption promoter for the drug and a stabilizer in a base, wherein the percutaneous absorption promoter is an alcohol having 10 to 14 carbon atoms. ,
A percutaneous absorption preparation characterized in that the content in the preparation is 0.1 to 30% by weight. 2. A tape preparation having a pressure-sensitive adhesive layer containing a drug, the percutaneous absorption enhancer and a stabilizer on one surface of a support, wherein the pressure-sensitive adhesive layer of the percutaneous absorption enhancer comprises: The transdermal preparation according to claim 1, wherein the content is 0.1 to 30% by weight.