JPH05255118A - Skin irritation-relaxing composition and percutaneous external agent containing the same - Google Patents

Abstract

PURPOSE:To provide the new composition and the percutaneous external agent each having a skin irritation-reducing or relaxing action and a pharmacologically active substance absorption-accelerating action. CONSTITUTION:The skin irritation-relaxing composition contains a trialkyl citrate, a polyhydric alcohol and water. The percutaneous external agent contains the trialkyl citrate, the polyhydric alcohol, water and a pharmacologically active substance. And, the percutaneous external agent contains the trialkyl citrate, the polyhydric alcohol, water, a percutaneous absorption-accelerating substance and the pharmacologically active substance.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a skin irritation reducing composition and a transdermal external preparation containing the same. More specifically, it relates to a novel composition having a skin irritation-reducing action, a mitigating action and a pharmacologically active substance absorption-promoting action, and a transdermal external preparation.

[0002]

2. Description of the Related Art Conventionally, oral administration or administration by injection has been widely used as a method for administering pharmaceuticals, but side effects such as gastrointestinal disorders and shock have become a problem. Therefore, in recent years, in order to reduce side effects of pharmaceuticals, studies have been made on external preparations capable of transdermal administration of the drug. However, at present, in the case of administration by external preparation, sufficient transdermal absorbability is often not obtained.

In order to maximize the therapeutic effect of a drug when administered by an external preparation, it is necessary for the drug to rapidly move from the base material into the inside of the skin and reach the affected area. Therefore, in order to enhance the transdermal absorbability of the drug dispersed or dissolved in the base material in the external preparation, various efforts have been made so far. For example, as disclosed in JP-A-61-249934, two or more kinds of solvents are mixed, or percutaneous absorption such as an azacycloalkane derivative described in JP-A-62-238261. A method of adding a promoter has been proposed. However, many of them have drawbacks such as general application and usage restrictions due to their strong solvent nature and strong skin irritation of the percutaneous absorption enhancer itself. Therefore, various attempts have been made to solve these problems, for example, Japanese Patent Laid-Open Nos. 58-4721 and 60-.
As shown in JP-A-56911 and JP-A-60-23312, research on adding a specific chemical substance for reducing skin irritation has been actively carried out. A method of blending a steroidal anti-inflammatory agent, a method of blending an azulene derivative described in JP-A-1-299217, a method using a composition containing glycerin described in JP-A-63-211241, and JP-A-2
2-phenyl-as the metabolic regulator of Japanese Patent Publication No. 96514
A method of adding 1-ethanol and 3-phenyl-1-propanol has been proposed. However, there are still problems with its practicality.

On the other hand, trialkyl citrate, especially triethyl citrate, has excellent feeling on skin and hair and has low skin toxicity, so that they are disclosed in JP-A-58-180417 and 64-19012. It is widely used as a base for cosmetics as disclosed in JP-A-64-66107, and it is also known that skin irritation of a fragrance can be reduced by further reducing permeation of the fragrance into the skin. (J. Soc. Cosmet. Chem. Japan.
n, 1985).

However, its application to pharmaceuticals is limited, and the methods disclosed in Japanese Patent Application Laid-Open Nos. 1-113055 and 1-11.
No. 3056, JP-A-2-184622, JP-A-2-237917, addition as a plasticizer or a softening agent, and stability of prostaglandins as seen in US Pat. No. 4,515,810. It is only used as a solvent. U.S. Pat. No. 4,666,926 is disclosed in U.S. Pat. No. 4,666,926, Japanese Unexamined Patent Publication No. 63-126832, and U.S. Pat. No. 4,814,173. The specification limits the drugs and in each case does not describe their skin irritation.

[0006]

By the way, various ideas and proposals have been made for external preparations, and transdermal external preparations are one of the widely used preparations today, and most of them are known for serious side effects. However, the number of side effects such as irritation to the skin is increasing, and it has not been solved at all. The present invention has been made in view of the above circumstances, solves the drawbacks of the conventional external preparations and their formulations, and reduces and alleviates irritation and further absorbs them with a specific base formulation. It is an object of the present invention to provide a new composition that can also realize a promoting effect and an external preparation using the same.

[0007]

Means for Solving the Problems This invention solves the above-mentioned problems by blending trialkyl citrate, water and a polyhydric alcohol to obtain a highly effective transdermal absorbability and a very low skin. It is intended to provide a composition useful for an external preparation for skin, which is characterized by achieving irritation.
That is, the inventors of the present invention conducted extensive studies on various compositions in order to solve the above-mentioned problems, and as a result, by mixing trialkyl citrate, water, and a polyhydric alcohol in a specific ratio, The inventors have found that the above drawbacks can be overcome and completed the present invention.

The present invention will be specifically described below. The trialkyl citrate used in the present invention may be any of butyl, isopropyl, ethyl and methyl as the alkyl group, but triethyl citrate which is liquid at room temperature and has a good feeling on the skin is preferable. Trialkyl citrate is added in an amount of 1 to 50%, preferably 5 to 30%, based on 100% by weight of the entire composition. The more preferable blending ratio varies depending on the type of polyhydric alcohol to be combined.

Examples of the polyhydric alcohol used in the present invention include ethylene glycol (1,2-ethanediol), propylene glycol (1,2-propanediol), 1,3-propanediol and 1,2-butanediol. 1,3-butanediol, 1,4-butanediol, 2,3-butanediol, 1,5-pentanediol and other lower alkanediols having about 2 to 5 carbon atoms and glycerin such as glycerin having 3 to 6 carbon atoms Lower alkanetriol can be mentioned. Of these, propylene glycol and 1,3-butanediol are preferable. These polyhydric alcohols are 1 to 70% based on 100% by weight of the total composition,
Preferably 20 to 50% is blended. A more preferable blending ratio differs depending on the type of alcohol.

The water used in the present invention may be any one of purified water, saline, and a buffer solution used for adjusting pH and the like. These waters are 100% by weight of the total composition
1 to 90%, preferably 30 to 70%. A more preferable blending ratio differs depending on the type of polyhydric alcohol to be combined.

The absorption-promoting substances used in the present invention include dimethyl sulfoxide and its derivatives, aliphatic carboxylic acids, aliphatic alcohols, alcohol esters or ethers of aliphatic carboxylic acids, azacycloalkane derivatives and Azone-like structures, and pyrrolidone derivatives. , Terpene-based compounds, aromatic organic acids, aromatic alcohols and esters thereof. Aliphatic carboxylic acids, aliphatic alcohols, alcohol esters or ethers of aliphatic carboxylic acids, aromatic organic acids, aromatic alcohols and their esters may be saturated or unsaturated, and may be cyclic, linear, It may be branched. The terpene compound is preferably a monoterpene or sesquiterpene compound. Specifically, 1- [2- (decylthio) ethyl] azacyclopentan-2-one, 1-n
-Dodecylazacycloheptan-2-one, caprylic acid, capric acid, caproic acid, diethyl sebacate, oleic acid, oleyl oleate, linoleic acid, myristic acid, terpineol, borneolol, d-limonene, butylhydroxyanisole, chlor Cresol,
Cetyl palmitate, methyl cinnamate, geraniol,
Thymol, eugenol, salicylic acid, sorbitan sesquioleate, methyl laurate, polyethylene glycol monostearate, oleyl alcohol, myristyl alcohol, 1-menthol, dl-camphor, isoeugenol, isoborneolol, nerol, citronellol, linalool, rosinol, Safrole, isosaflor, pinene, camphenone, menthone, cymen, N- (2-hydroxyethyl) pyrrolidone, eucalyptol, N, N-diethyl-m-triamide, N-
Alkyl morpholine, glycerol monooleate, l
-Nonene, p-menthane, α-terpinene, n-butylcyclohexane, t-butylcyclohexane, dipentene, pinane, ethylcyclohexane, biphenyl, n
-Butylbenzene, myrcene, methylcyclopentadiene dimer, cis-1,3-dimethylcyclohexane,
Dicyclohexyl, dimethylnaphthalene, p-cymene,
Dicyclopentadiene, 1,5-cyclooctadiene,
Examples include cyclooctane, isooctane, 1-phenyl-1-cyclohexane, 1-dodecene, dimethyl sulfoxide, and the like, 1- [2- (decylthio) ethyl]
Azacyclopentan-2-one, 1-n-dodecylazacycloheptan-2-one, caprylic acid, capric acid,
Caproic acid, diethyl sebacate, oleic acid, linoleic acid, terpineol, borneolol, d-limonene, butylhydroxyanisole, chlorcresol,
Cetyl palmitate, methyl cinnamate, geraniol,
Thymol, eugenol, salicylic acid, sorbitan sesquioleate, methyl laurate, polyethylene glycol monostearate, oleyl alcohol, myristyl alcohol, 1-menthol, camphor and the like are preferable. The absorption promoting substance is added in an amount of 0.1 to 10%, preferably 1 to 5%, based on 100% by weight of the entire composition.

The pharmacologically active substance contained in the external composition of the present invention is not particularly limited as long as it is a drug which can be absorbed transdermally,
General anesthetics, hypnotics / sedatives, antispasmodics, antipyretic analgesics and anti-inflammatory agents, stimulants, stimulants, neuropsychiatric agents, local anesthetics,
Skeletal muscle relaxant, autonomic nerve agent, anticonvulsant, anti-Parkinson's agent, ophthalmic agent, otolaryngological agent, antihistamine, cardiotonic agent, antihypertensive agent, vasoconstrictor, coronary vasodilator, peripheral vasodilator, circulation Agents for organs, respiratory stimulants, antitussive agents, therapeutic agents for peptic ulcers, choleretic agents, intestinal agents, thyroid / antithyroid hormone agents, narcotics, anabolic steroids, corticosteroids, androgen agents, follicular luteum Hormonal agents, genitourinary and anal agents, analgesic / pruritic / astringent / anti-inflammatory agents, agents for parasitic skin diseases, emollients, corrosion agents, vitamins, anticoagulants, addictive agents, gout remedies ，
Enzyme preparations, diabetes drugs, etc. are used. Among them, hypnotics / sedatives, antipyretic and anti-inflammatory analgesics, neuropsychiatric agents, local anesthetics, skeletal muscle relaxants, autonomic nerve agents, anticonvulsants, antiparkinson agents, antihistamines. , Cardiotonics, antihypertensives, vasoconstrictors, coronary vasodilators, peripheral vasodilators, choleretic agents, antithyroid hormone agents, narcotics, corticosteroids, follicular progesterone agents, agents for parasitic skin diseases, gout Therapeutic agents, diabetes drugs and the like are preferable. Further, it is preferable that these drugs are water-soluble, and the pH of the composition is 7 to 8 when the drug is acidic, and the p of the composition is when the drug is basic.
It is preferable to adjust H to 4-5. These drugs may be used alone or in a mixture of two or more kinds,
UV absorbers, antioxidants, and preservatives may be added if necessary. As the ultraviolet absorber, known P-aminobenzoic acid derivatives, anthranilic acid derivatives, salicylic acid derivatives, coumarin derivatives, amino acid compounds, benzotriazole derivatives, tetrazole derivatives, imidazoline derivatives, pyrimidine derivatives, dioxane derivatives, furan derivatives, pyrone derivatives , Camphor derivatives, nucleic acid derivatives, allantoin derivatives, nicotinic acid derivatives, shikonin, vitamin B ₆ derivatives and the like, and particularly benzophenone derivatives such as 2-hydroxy-4-methoxybenzophenone derivatives. As an antioxidant,
For example, ascorbic acid, stearic acid ester, sodium ascorbate, tocopherol (α-tocopherol, β-tocopherol, γ-tocopherol, δ-
Tocopherol, etc. d-form, l-form, dl-form) and their ester derivatives, nordihydroguaselethetic acid, dibutylhydroxytoluene, butylhydroxyanisole, tert-butylhydroquinone gallate (esters such as ethyl, propyl, isoamyl) , 1-
Examples include oxo-3-methyl-4-isopropylbenzene and other antioxidants. As the preservative, benzoic acid, sodium benzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, etc. are used.

The ultraviolet absorber is 100% by weight of the total composition.
On the other hand, 0.01 to 5%, preferably 0.1 to 1% is blended. Antioxidants are also used for 100% by weight of the total composition,
0.01 to 5%, preferably 0.1 to 1% is added, and the preservative is 0.01 to 5 with respect to 100% by weight of the total composition.
%, Preferably 0.05 to 1%.

As described in detail above, the present invention can contain a percutaneously absorbable pharmacologically active substance as an active ingredient, to which trialkyl citrate, water, and a polyhydric alcohol are mixed in a specific ratio. It is characterized by high skin permeability of medicinal substances and very low skin irritation. Further, if necessary, an absorption promoting substance, an ultraviolet absorber, an antioxidant and a preservative may be added.
Examples of the dosage form include gel, gel cream, reservoir type patch, patch and the like. Here, a formulation example of the present invention is shown for each of the above-mentioned external preparations.

First, the gel base will be described. The gel base is any one of trimethyl citrate, triethyl citrate, triisopropyl citrate, and tributyl citrate, which are the features of the present invention, and a known gel base such as polyhydric alcohol, water, and a gelling agent (for example, carboxyvinyl heavy polymer). Coalesce, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, etc.) and a neutralizing agent (for example, triethanolamine, diisopropanolamine,
Sodium hydroxide, etc., surfactants (eg sorbitan sesquioleate, sorbitan trioleate, sorbitan monooleate, sorbitan monostearate, sorbitan monolaurate, polyethylene glycol monostearate, polyoxyethylene cetyl ether, polyoxyethylene) Lauryl ether, etc.), an absorption promoter (for example, an azacycloalkane derivative) are appropriately mixed, and if necessary, an antioxidant, an ultraviolet absorber,
The gel agent of the present invention can be obtained by blending a preservative and a pharmacologically active substance.

Next, one production example of the gel agent will be described and provided for reference. Pharmacologically active substance Appropriate amount Trialkyl citrate 30% by weight or less Water 55% by weight or less Polyhydric alcohols 40% by weight or less Gelling agent 5% by weight or less Absorption enhancer 5% by weight or less Weigh out the above and first gelate water And swell, while dissolving or suspending the pharmacologically active substance in an appropriate amount of a solubilizer, and further dissolving this in a mixture of polyhydric alcohols (eg 1,3-butylene glycol, propylene glycol) and trialkyl citrate. In addition to water swollen with a gelling agent, a neutralizing agent is added to adjust the pH to 4 to 8 to obtain the gelling agent of the present invention. Needless to say, this production example is only one example and can be produced by a known or similar method and formulation. Further, each compounding amount is not particularly limited.

Next, the gel cream will be described. The cream base is trimethyl citrate, triethyl citrate, triisopropyl citrate, which are the features of the present invention,
Any known tributyl citrate and cream base,
For example, white petrolatum, liquid paraffin, higher fatty acid esters (for example, myristic acid ester, palmitic acid ester, ethyl sebacate, hexyl laurate, cetyl isooctanoate, etc.), polyhydric alcohols (for example, 1, 3
-Butylene glycol, propylene glycol, etc.), emulsifiers (eg polyoxyethylene alkyl ethers,
Fatty acid ester, polyethylene glycol fatty acid ester, etc.), absorption promoter (eg, azacycloalkane derivative), gelling agent (eg, carboxyvinyl polymer, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, etc.), and neutralizing agent ( For example, a base material selected from triethanolamine, diisopropanolamine, sodium hydroxide, etc.) is selected and appropriately mixed, and if necessary, an antioxidant, an ultraviolet absorber, a preservative and a pharmacologically active substance are mixed. As a result, the gel cream of the present invention can be obtained.

Next, one production example of the gel cream will be described for reference. Appropriate amount of pharmacologically active substance Trialkyl citrate 20 wt% or less Higher fatty acid ester 25 wt% or less Preservative 0.5 wt% or less Emulsifier 5 wt% or less Higher alcohol 15 wt% or less Water 50 wt% or less Polyhydric alcohol 20 wt% Absorption accelerator 5% by weight or less Gelling agent 5% by weight or less Weigh out the above, first mix higher fatty acid ester, trialkyl citrate, higher alcohol, emulsifier and absorption accelerator, and melt by heating at 50 ° C to 100 ° C. After that, a preservative, a polyhydric alcohol and a pharmacologically active substance dissolved or suspended in water which has been heated in advance are added, and then the mixture is cooled to 50 ° C. and a gelling agent is added to sufficiently disperse the neutralizing agent. In addition p
The gel cream of the present invention can be obtained by adjusting to H4-8. In addition, it goes without saying that this production example is only one example and can be produced by a known or similar method and formulation. Further, each compounding amount is not limited to this.

Next, the reservoir type patch will be described.
As the composition of the reservoir portion used in this reservoir-type patch, the composition of the pharmacologically active substance and the gel agent, gel cream or the like can be used. Further, the porous film or polymer film which is the control film used here is, for example, polyethylene, polypropylene, polymethacrylic acid ester, polyurethane, polyester, polyvinyl alcohol-ethylene copolymer, polyvinyl alcohol, polyvinyl chloride, polyamide. , Ethylene-vinyl acetate copolymer, ethylenic copolymer gum, ethylene-methacrylic acid or ethylene-acrylic acid copolymer are used. As the support, for example, polypropylene, polyester, polyvinylidene chloride, polyacryl, polyurethane, ethylene-vinyl acetate copolymer, cloth, non-woven fabric, etc. are used, but they are applied to the skin via the support reservoir part, porous membrane or polymer membrane. There may be a case where there is an adhesive layer on the contact surface or there is no adhesive layer, but when the adhesive layer is provided, the composition of the adhesive layer is composed of a patch composition containing a pharmacologically active substance. However, in the case where there is no adhesive layer, the preparation of the present invention can be obtained by providing an adhesive layer based on a patch of a patch containing no pharmacologically active substance on the outside of the porous membrane or polymer membrane which is the release surface. It should be noted that a conventionally known method is sufficient as the manufacturing method for these.

Finally, the patch will be described. The patch of the present invention is characterized in that the present invention is characterized by trimethyl citrate, triethyl citrate, triisopropyl citrate, tributyl citrate 30% by weight or less and a polyhydric alcohol (for example, 1,3-butanediol, propylene glycol). ) 10-80 wt%, water 5-40 wt%, ionic unsaturated monomer 1-40 wt%, methacrylate 2-3
Absorption promoter (eg, azacycloalkane derivative) and pharmacologically active substance are added to 0% by weight, cross-linking component 0.05 to 1%, and if necessary, an ultraviolet absorber is added in an amount of 0.01 to 5% by weight, if necessary. The patch of the present invention can be obtained by blending 0.01 to 5% by weight of an oxidizing agent and 0.01 to 5% by weight of an antiseptic, and polymerizing and crosslinking in the presence of a polymerization initiator.
The above formulation examples and production examples are merely examples, and naturally the patch of the present invention can be obtained with a similar formulation.

[0021]

EXAMPLES Examples will be shown below to describe the effects of the present invention described above in more detail, but the present invention is not limited thereto. Example 1 Using the skin extracted from hairless mice in the solutions of Compositions 1 and 2 below, the skin permeability of the medicinal components in vitro was measured using the drugs in Table 1 below, and the skin irritation of the drug solution was also measured. The test was performed according to the Draiz method. The skin permeability of the drug is maximum by 8 hours
(Maximum drug permeation rate μg / cm / h) and skin irritation were compared by PII (skin irritation index). Composition 1 water / 1,3-BG / triethyl citrate = 50
/ 40/10 (V / V): 1-n-dodecylazacycloheptan-2-one = 95: 5 (W / W) Composition 2 Water / 1,3-BG = 60/40 (V / V): 1
-N-dodecylazacycloheptan-2-one = 95:
5 (W / W) The results are shown in Table 1, and there is no significant change in the skin permeation of the drug in Compositions 1 and 2, but in Composition 1, an absorption enhancer (in this case, an azacycloalkane derivative) It is clear that the skin irritation, which is believed to be due to

[0022]

[Table 1]

Example 2 In the solution having the composition shown in Table 2, the skin permeation of the medicinal component in vitro was measured using the excised skin of the hairless mouse, and the skin irritation of the solution was also measured. Was tested according to the Draiz method. The results are as shown in Table 2. The skin permeation of the drug was compared with the maximum flux (maximum drug permeation rate) obtained from the skin permeation test conducted up to 8 hours. By using a trialkyl citrate (triethyl citrate in this case) and an absorption enhancer together, the skin permeability of the drug which is equal to or higher than the conventional one and the skin irritation which is much lower than the conventional one are compatible. A decrease in transmittance is observed in some cases, because the compounding amount of triethyl citrate is constant in this example. However, even in this case, the reduction in skin irritation, which is much larger than the reduction in transmittance, is observed.

[0024]

[Table 2] Skin permeability and skin irritation of drugs in various compositions

Examples 3 to 6 (Comparative Examples 3 to 6) The following Examples 3 to 6 and Comparative Examples 3 to 6 were tested as follows. The back of a Japanese white rabbit weighing about 3 kg was shaved, and the samples of Example 3 and Comparative Example 3 (morphine hydrochloride content 30 mg) were applied to the back skin, the coated surface was covered with filter paper, and the filter paper was covered with tape. Fixed 0, 1, 2, after application
Blood was collected after 3 and 6 hours to measure the morphine content.
The skin irritation of Examples 3 to 6 and Comparative Examples 3 to 6 is Dra.
It evaluated according to the iz method.

Example 3 Gel Agent Morphine Hydrochloride 5 Azacycloalkane Derivative 3 Carboxyvinyl Polymer 1 Propylene Glycol 30 Triethyl Citrate 20 Purified Water 39.4 2-Hydroxy-4-methoxybenzophenone 0.5 Diisopropanolamine 1.1 100 (wt%) 1 part of carboxyvinyl polymer was swollen in 23 parts of purified water, and 30 parts of propylene glycol, 20 parts of triethyl citrate, 5 parts of morphine hydrochloride and 0.5 parts of 2-hydroxy-4-methoxybenzophenone were added thereto. The mixed solution was added and stirred. Next, 3 parts of the azacycloalkane derivative and 1.1 parts of diisopropanolamine were added to purified water 1
A solution prepared by dissolving in 6.4 parts was added, and the mixture was thoroughly stirred until a uniform mixture was obtained to obtain a gel agent.

Comparative Example 3 Gel Agent The same as in Example 3 except that propylene glycol was used instead of triethyl citrate.

Example 4 Gel Cream Cream Silver Sulfadiazine 5 Terpineol 3 White Vaseline 5 Cetanol 4 Liquid Paraffin 3 Triethyl Citrate 15 Methyl Paraoxybenzoate 0.2 Carboxyvinyl Polymer 2 Diisopropanolamine 1 Paraoxyethylene Paraoxypropylene Cetyl Ether 2 1,3-Butylene glycol 20 Purified water 39.8 100 (wt%) White petrolatum, cetanol, liquid paraffin, triethyl citrate, terpineol, paraoxyethylene paraoxypropylene cetyl ether, were mixed and heated, and then heated in advance. A solution of methyl paraoxybenzoate, 1,3-butylene glycol and silver sulfadiazine dissolved and dispersed in purified water was added, followed by cooling to 50 ° C. Then, add carboxyvinyl polymer and disperse well, then add diisopropanolamine to adjust pH to 4
~ 8 to give gel cream.

Comparative Example 4 Gel Cream The same as in Example 4 except that triethyl citrate was replaced with purified water.

Example 5 Reservoir type patch 1) Support polyester film 2) Drug storage layer Composition of Example 3 3) Microporous membrane Shuraguard 4) Adhesive layer Acrylic adhesive (peripheral part of support) 1 4, a release paper was applied to the surface of the microporous adhesive layer as shown in the figure below to prepare a laminate.

Comparative Example 5 Reservoir type patch The same operation was performed except that the composition of Comparative Example 3 was replaced in the drug storage layer of Example 5.

Example 6 Patch A 1-hydroxycyclohexyl phenyl ketone (15 parts) was dissolved in 2-hydroxyethyl methacrylate (2400 parts), and further tetraethylene glycol dimethacrylate (35 parts) was added and dissolved. Separately 5% saline 1900
Parts, 600 parts of potassium sulfopropylmethacrylate salt were dissolved by heating, and 2000 parts of glycerin, 1, 3-
Butylene glycol 2000 parts, triethyl citrate 1
100 parts, ketoprofen 110 parts, D-limonene 30
0 part was added to obtain a uniform solution. Further, the both solutions were mixed and defoamed to obtain a uniform solution. This solution was poured onto a PET film which was provided horizontally with a thickness of 50 μm and which was provided with a frame to prevent the liquid from flowing out to a thickness of 300 μm. While keeping this in a nitrogen atmosphere, place it 15 cm below a 30 W chemical lamp, irradiate it with UV rays for 5 minutes, and then release the cured surface from the PE.
The patch was covered with a T film.

Comparative Example 6 Patch The same as in Example 6 except that triethyl citrate was replaced with 1,3-butylene glycol. The results are shown in Table 3.
And as shown in Table 4. There is no significant difference in the transfer of morphine hydrochloride into the blood between the Example and the Comparative Example, but the irritation to the skin is significantly reduced in the Example.

[0034]

[Table 3]

[0035]

[Table 4]

[0036]

The trialkyl citrate of the present invention, water,
Compositions composed of polyhydric alcohols and compositions for external use in which a pharmacologically active substance or a pharmacologically active substance and an absorption-promoting substance are mixed with these compositions have a good transdermal absorption action and Remarkably reduces and alleviates the existing skin irritation. Therefore, it is possible to obtain a transdermal external preparation consisting of various preparations having extremely high safety and sufficiently exhibiting drug effects, which is particularly useful in the pharmaceutical industry.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI technical display area A61K 47/14 E 7433-4C

Claims (6)

[Claims] 1. A skin irritation reducing composition comprising a trialkyl citrate, a polyhydric alcohol and water. 2. The compounding amount of trialkyl citrate is 1 to 50% with respect to the total amount of 100% by weight, the mixing amount of polyhydric alcohol is 1 to 70% with respect to the total amount of 100% by weight, and the total amount of water is included. The amount is 1 to 90% based on 100% by weight.
The skin irritation reducing composition described. 3. A transdermal external preparation containing a trialkyl citrate, a polyhydric alcohol, water and a pharmacologically active substance. 4. The total amount of trialkyl citrate is 1 to 50%, the total amount of polyhydric alcohol is 1 to 70%, and the total amount of water is 100% by weight. The amount of the pharmacologically active substance is 0.001 to 20% with respect to 100% by weight.
%, The transdermal external preparation according to claim 3. 5. A transdermal external preparation containing a trialkyl citrate, a polyhydric alcohol, water, a substance for promoting transdermal absorption and a pharmacologically active substance. 6. The total amount of trialkyl citrate is 1
1 to 50% to 00% by weight, 1 to 70% of total amount of polyhydric alcohol to 100% by weight, 1 to 90% of total amount of water to 100% by weight, promotion of percutaneous absorption The compounding amount of the active substance is 0.1 to 1 per 100% by weight
The external preparation for transdermal application according to claim 5, wherein 0% and the compounding amount of the pharmacologically active substance are 0.001 to 20% with respect to the total amount of 100% by weight.