JP2779063B2 - Skin irritation alleviating composition and transdermal external preparation containing the same - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a composition for alleviating skin irritation and a transdermal external preparation containing the same. More specifically, the present invention relates to a novel composition and a transdermal preparation for external use which have a function of promoting absorption of a pharmacologically active substance as well as reducing and alleviating skin irritation.

BACKGROUND ART Conventionally, oral administration or injection administration has been widely practiced as an administration method of pharmaceuticals, but there is a problem that there are side effects such as gastrointestinal disorders and shock. For this reason, in recent years, studies have been made on external preparations that allow transdermal administration of drugs in order to reduce the side effects of pharmaceuticals. However, at present, sufficient transdermal absorbability is often not obtained in the case of administration using an external preparation.

In order for a drug to exert its therapeutic effect to the maximum when administered by an external preparation, it is necessary for the drug to quickly migrate from the base into the skin and reach the affected area. Therefore, various measures have been made so far to enhance the transdermal absorbability of a drug dispersed or dissolved in a base in an external preparation. For example, JP-A-61-
As disclosed in JP-A-249934, two or more solvents may be mixed, or a transdermal absorption enhancer such as an azacycloalkane derivative disclosed in JP-A-62-238261 may be used. Addition methods have been proposed. However, many of them have drawbacks such as limitations on general applications and usage due to their properties as strong solvents and the strong skin irritation of the transdermal absorption enhancer itself. Therefore, various attempts have been made to solve these problems, for example, as disclosed in JP-A-58-4721, JP-A-60-56911, and JP-A-60-23312. Research is actively carried out to reduce skin irritation,
In recent years, a method of blending a non-steroidal anti-inflammatory agent disclosed in JP-A-1-299212, a method of blending an azulene derivative disclosed in JP-A-1-299217, and a method containing glycerin disclosed in JP-A-63-211241 are disclosed. Composition method, JP-A-2-96
No. 514 proposes a method of adding 2-phenyl-1-ethanol or 3-phenyl-1-propanol as a metabolic regulator. However, its practicality still has problems.

On the other hand, trialkyl citrates, especially triethyl citrate, are excellent in use feeling on skin and hair and have low skin toxicity, so Japanese Patent Publication No. 3-25403, Japanese Patent Application Laid-Open No. 64-19012,
As disclosed in JP-A-64-66107, it is widely used as a base for cosmetics, and it is also known that skin irritation of perfume can be reduced by further reducing permeation of perfume through the skin. (J.Soc.Cosmet.Chem.Japan, Vol.1
However, the application to pharmaceuticals is limited, and JP-A-1-113055, JP-A-1-113056, JP-A-2-184622, JP-A-2-237917. As shown in the gazette, addition as a plasticizer or a softener and U.S. Pat.
It is only used as a stable solvent for prostaglandins as seen in the specification of 4515810. Slightly disclosed in U.S. Pat.No. 4,666,926, JP-A-63-126832 and U.S. Pat.No. 4,814,173 are disclosed as being used as a transdermal absorption enhancing administration composition, but U.S. Pat. The specification limits the drug, and in no case describes its skin irritation at all.

Thus, various ideas and proposals for external preparations have been made, and despite the fact that transdermal topical preparations are one of the widely used preparations today and have little known about serious side effects, On the other hand, the occurrence of side effects such as irritation to the skin is on the contrary increasing steadily, and has not been solved at all.

The present invention has been made in view of the circumstances described above, and solves conventional external preparations and their drawbacks, and reduces and alleviates irritation and promotes absorption by using a specific base preparation. It is an object of the present invention to provide a new composition which can also achieve the effect, and an external preparation using the same.

DISCLOSURE OF THE INVENTION The present invention solves the above-mentioned problems by combining a trialkyl citrate, water and a lower alcohol, or blending these bases with absorption promotion to provide a transdermal composition having a very high medicinal component. An object of the present invention is to provide a composition useful for a skin external preparation characterized by realizing absorption and very low skin irritation.

That is, the inventors of the present invention have intensively studied various compositions in order to solve the above-mentioned problems, and as a result, can overcome the above-mentioned disadvantages by blending trialkyl citrate, water and a lower alcohol. I found that. Furthermore, it has been found that by blending these bases with an absorption enhancer, transdermal absorption is further promoted and skin irritation is alleviated, and the present invention has been completed.

 Hereinafter, the composition of the present invention will be specifically described.

First, the trialkyl citrate used in the present invention may be any one as long as its alkyl group is butyl, isopropyl, propyl, ethyl, methyl, or the like. Trialkyl acid is preferred. The trialkyl citrate is added in an amount of about 1 to 50% by weight, preferably 5 to 30% by weight, based on 100% by weight of the whole composition. The more preferable mixing ratio differs depending on the type of the lower alcohol to be combined.

The lower alcohol used in the present invention has 1 to 4 carbon atoms.
Any of those may be used.
Three are preferred. Specifically, methyl alcohol,
Preferred examples include ethyl alcohol, n-propyl alcohol, isopropyl alcohol, and n-butyl alcohol. These lower alcohols are used in an amount of about 1 to 70% by weight, preferably 0 to 70% by weight, based on 100% by weight of the whole composition.
20-50% by weight is blended. The more preferable mixing ratio differs depending on the type of alcohol. The water used in the present invention may be any of purified water, saline, and a buffer used for adjusting pH and the like. These waters are added in an amount of about 1 to 90% by weight, preferably 30 to 70% by weight, based on 100% by weight of the whole composition. The more preferable mixing ratio differs depending on the type of the lower alcohol to be combined.

Examples of the absorption promoter include the following terpene compounds, fatty acids, fatty acid alcohols, fatty acid esters, phenol derivatives, and azacycloalkane derivatives. First, as the terpene compound, monoterpene alcohol is usually preferred. The terpene compound may be saturated or unsaturated, and may be linear, branched, or cyclic. In the case of a ring, a monocyclic or bicyclic ring is preferred.
Examples of such monoterpene compounds include, for example, geraniol, eugenol, isoeugenol, thymol, terpineol, L-menthol, borneolol, isoborneolol, nerol, citronellol, linalool, rosinol, safrole, isosafrole, D -(+)-Limonene, pinene, d1-camphor, camphene, menthone, cimen are exemplified as preferred.

Next, as fatty acids, fatty alcohols, fatty acid esters and phenol derivatives, specifically, caprylic acid, capric acid, caproic acid, oleic acid, linoleic acid, myristic acid, salicylic acid, oleyl oleate, cetyl palmitate, cinnamic acid Preferred examples include methyl, diethyl sebacate, sorbitan sesquioleate, methyl laurate, polyethylene glycol monostearate, oleyl alcohol, myristyl alcohol, butylhydroxyanisole, and chlorcresol.

Finally, examples of the azacycloalkane derivative include, for example, 1- [2- (decylthio) ethyl] azacyclopentan-2-one or 1-n-dodecylazacycloheptan-2-one; And the compounds described in JP-A-3-500543. The above-mentioned absorption enhancer is used in an amount of 0.1% based on 100% by weight of the whole composition.
Approximately 10%, preferably 1-5%.

Furthermore, the pharmacologically active substance contained in the composition for external use of the present invention is not particularly limited as long as it is a drug that can be absorbed percutaneously, and can be a general anesthetic, a hypnotic / sedative, an anti-smoking agent, Antipyretic analgesic anti-inflammatory, stimulant, stimulant, psychiatric,
Local anesthetics, skeletal muscle relaxants, autonomic nerve agents, anticonvulsants,
Antiparkinsonian, ophthalmic, otolaryngological, antihistamine, cardiotonic, antihypertensive, vasoconstrictor, coronary vasodilator, peripheral vasodilator, cardiovascular agent, respiratory stimulant, antitussive, digestive Sexual ulcer treatment agent, bile medicine, intestinal medicine, thyroid / antithyroid hormone, narcotic, anabolic steroid, adrenocortical hormone, androgen, follicular hormone, urogenital and anal, analgesic / pruritus, Astringent and anti-inflammatory agents, agents for parasitic skin diseases, emollients, corrosives,
Vitamins, anticoagulants, addictive drugs, gout remedies, enzyme preparations, diabetic drugs, etc. are used, among which hypnotics and sedatives, antipyretic and antiphlogistic analgesics, psychiatric agents, local anesthetics, skeleton Muscle relaxants, autonomic agents, anticonvulsants, antiparkinson agents, antihistamines, cardiotonics, antihypertensives, vasoconstrictors, coronary vasodilators, peripheral vasodilators, cholerics, antithyroid hormones, narcotics, Adrenocortical hormone agents, follicular progestin agents, agents for parasitic skin diseases, gout treatment agents, diabetic agents and the like are preferred. Further, it is preferable that these drugs are water-soluble, and when the drug is acidic, the pH of the composition is 7 to 8; when the drug is basic, the pH of the composition is
Is preferably adjusted to 4 to 7. These drugs are
It may be used alone or in a mixture of two or more kinds, and if necessary, an ultraviolet absorber, an antioxidant and a preservative may be added.

Examples of the ultraviolet absorber include 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, and pyrone derivatives. , camphor derivatives, nucleic acid derivatives, allantoin derivatives, nicotinic acid derivatives, shikonin or vitamin B ₆ derivatives, and the like, in particular benzophenone derivatives, such as 2-hydroxy-4-methoxybenzophenone derivatives are preferably used. As antioxidants,
For example, ascorbic acid, stearic acid ester, sodium ascorbate, tocopherol (α-tocopherol, β-tocopherol, γ-tocopherol, δ
D-forms such as tocopherols, 1-forms and d1 forms) and their ester derivatives, nordihydroguaseletic acid, dibutylhydroxytoluene, butylhydroxyanisole,
tert-butylhydroquinone gallate (ethyl,
Esters such as propyl and isoamyl), 1-oxo-3
-Methyl-4-isopropylbenzene as well as other antioxidants. As the preservative, benzoic acid, sodium benzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate and the like are used.

These ultraviolet absorbers can be added in an amount of about 0.01 to 5% by weight, preferably 0.1 to 1% by weight, based on 100% by weight of the whole composition. The antioxidant is also about 0.01 to 5% by weight, preferably 0.1 to 1% by weight, based on 100% by weight of the whole composition, and the preservative is 0.01 to 5% by weight based on 100% by weight of the whole composition.
About 5% by weight, preferably 0.05 to 1% by weight can be added.

As described in detail above, the present invention can contain a transdermally absorbable pharmacologically active substance as an active ingredient, and is characterized by adding a trialkyl citrate, water and a lower alcohol to the active ingredient. It has both skin permeability and very low skin irritation. In a preferred embodiment, an absorption enhancer is added to the base at a specific ratio, thereby achieving both high skin permeability and extremely low skin irritation of a medicinal substance. Further, if necessary, excipients, ultraviolet absorbers, antioxidants, and preservatives can be added. Examples of the dosage form include a gel, a gel / cream, a liniment, an aerosol, a reservoir-type patch, a patch and the like.

Therefore, a formulation example of the present invention will be shown for each of the above-mentioned external preparations.

First, the gel base will be described. The gel base includes any of trimethyl citrate, triethyl citrate, triisopropyl citrate, and tributyl citrate, which are features of the present invention, and known gel bases such as lower alcohols (eg, ethanol and isopropanol), water, and gel. Agents (eg, carboxyvinyl polymer, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, etc.), neutralizing agents (eg, triethanolamine, diisopropanolamine, sodium hydroxide, etc.), and surfactants (eg, sesquiolein) Sorbitan acid, sorbitan trioleate, sorbitan monooleate, sorbitan monostearate, sorbitan monolaurate, polyethylene glycol monostearate, polyoxyethylene cet Ether, polyoxyethylene lauryl ether, etc.), absorption promoters (e.g. selected base from azacycloalkane derivative) appropriately formulated, an antioxidant if necessary, ultraviolet absorbers, blending a preservative. The gel of the present invention can be obtained by further blending a pharmacologically active substance.

 Next, one production example of a gel agent will be described for reference.

Pharmacologically active substance Appropriate amount Trialkyl citrate 30% by weight or less Water 55% by weight or less Glycols 40% by weight or less Lower alcohol 45% by weight or less Gelling agent 5% by weight or less Absorption promoter 5% by weight or less Weigh each of the above components Then, first swell the water in the gel. On the other hand, the pharmacologically active substance is dissolved or suspended in an appropriate amount of a solubilizer, and further dissolved in a mixture of glycols and trialkyl citrate, a mixture of trialkyl citrate and lower alcohol, or a mixture of these three. Subsequently, water is swollen with a gelling agent and then a neutralizing agent is added to adjust the pH to 4 to 8 to obtain the gel of the present invention. This production example is only one example, and it goes without saying that it can be produced by a known or similar method and formulation. Further, the amount is not particularly limited to each compounding amount.

Next, the gel cream is described. The cream base may be any of trimethyl citrate, triethyl citrate, triisopropyl citrate, and tributyl citrate, which are features of the present invention, and known cream bases such as white petrolatum, liquid paraffin, and higher fatty acid esters (eg, myristine). Acid esters, palmitic acid esters, ethyl sebacate, hexyl laurate, cetyl isooctanoate, etc., lower alcohols (eg, ethanol, isopropanol, etc.), emulsifiers (eg, polyoxyethylene alkyl ethers, fatty acid esters, polyethylene glycol fatty acid esters, etc.) , An absorption promoter (eg, terpene compound, azacycloalkane derivative, etc.), a gelling agent (eg, carboxyvinyl polymer,
A base selected from hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, etc.) and a neutralizing agent (for example, triethanolamine, diisopropanolamine, sodium hydroxide, etc.) is selected and appropriately blended, and if necessary, an antimicrobial agent is added. Contains oxidizing agent, ultraviolet absorber, and preservative. The gel cream of the present invention can be obtained by blending a pharmacologically active substance.

Next, one production example of a gel / cream is described for reference.

Pharmacologically active substance Appropriate amount Trialkyl citrate 20% by weight or less Higher fatty acid ester 25% by weight or less Preservative 0.5% by weight or less Emulsifier 5% by weight or less Higher alcohol 15% by weight or less Water 50% by weight or less Lower alcohol 20% by weight or less Agent 5% by weight or less Gelling agent 5% by weight or less Weigh each of the above components, first mix higher fatty acid ester, trialkyl citrate higher alcohol, emulsifier and absorption promoter, then heat and melt at 50-100 ° C. Add preservative, lower alcohol and pharmacologically active substance dissolved or suspended in pre-heated water. Thereafter, the mixture is cooled to 50 ° C., and a gelling agent is added to sufficiently disperse the mixture. Thereafter, a neutralizing agent is added to adjust the pH to 4 to 8, whereby the gel / cream preparation of the present invention can be obtained. This production example is only one example, and it goes without saying that it can be produced by a known or similar method and formulation. In addition, the amount of each compound is not limited to this.

Next, the liniment will be described. The liniment of the present invention may be a lower alcohol such as trimethyl citrate, triethyl citrate, triisopropyl citrate or tributyl citrate, which is a feature of the present invention, and a known liniment base such as lower alcohols (eg, ethanol,
Isopropanol) 10-70% by weight, water 55% by weight or less, fatty acid ester (eg, various esters of adipic acid, sepasic acid, myristic acid) 60% by weight or less, and an absorption promoter (eg, terpene compound, azacycloalkane derivative, etc.) ) And adding a pharmacologically active substance and, if necessary, 0.01 to 5% by weight of an ultraviolet absorber, 0.01 to 5% by weight of an antioxidant and 0.01 to 5% by weight of a preservative as needed to obtain a liniment agent. Can be. The above formulation examples and production examples are merely examples, and the liniment of the present invention can be naturally obtained with similar formulations. Further, in the liniment of the present invention, if necessary, a neutralizing agent for adjusting pH or a viscosity-imparting agent such as methylcellulose, carboxyvinyl polymer, or hydroxypropylcellulose can also be blended.

Next, the aerosol agent will be described. The aerosol includes 20% by weight or less of trimethyl citrate, triethyl citrate, triisopropyl citrate, and tributyl citrate, which are features of the present invention, lower alcohols (eg, ethanol and isopropanol), and 30% by weight of purified water. Hereinafter, an absorption enhancer (for example, a terpene compound or an azacycloalkane derivative), a pharmacologically active substance, and, if necessary, an inorganic substance such as talc of 5% or less, and an ultraviolet absorber 0.01
-5% by weight, antioxidant 0.01-5% by weight, preservative 0.01-5%
The aerosol composition of the present invention can be obtained by filling an aerosol container with a pressure of 20% by weight or less, 20% by weight or less of dimethyl ether and 20% by weight or less of LPG. Note that the above formulation examples and production examples are merely examples, and the aerosol of the present invention can of course be obtained with similar formulations.

Next, the reservoir type patch will be described. The composition of the reservoir portion used in this reservoir-type patch can be a composition of a pharmacologically active substance and the above-mentioned gel, gel / cream, liniment and the like. Further, the porous membrane or the polymer membrane which is the limiting membrane used here is, for example, polyethylene, polypropylene, polymethacrylate, 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. The support is made of, for example, polypropylene, polyester, polyvinylidene chloride, polyacryl, polyurethane, ethylene-vinyl acetate copolymer, cloth, nonwoven fabric, etc., and is applied to the skin via the support reservoir, a porous membrane or a polymer membrane. There may or may not be a pressure-sensitive adhesive layer on the surface to be contacted. When the pressure-sensitive adhesive layer is provided, the composition of the pressure-sensitive adhesive layer can be constituted by a patch composition containing a pharmacologically active substance. When there is no pressure-sensitive adhesive layer, the preparation of the present invention can be obtained by providing a pressure-sensitive adhesive layer based on a patch containing no pharmacologically active substance outside the porous film or polymer film which is the release surface. In addition, these manufacturing methods can be conventionally known methods.

Finally, the patch is described. This patch contains 30% by weight or less of any of trimethyl citrate, triethyl citrate, triisopropyl citrate, and tributyl citrate, which are features of the present invention, and a lower alcohol (for example,
(Ethanol, isopropanol) 10-40% by weight, water-soluble polyhydric alcohol 10-80% by weight, water 5-40% by weight, ionic unsaturated monomer 1-40% by weight, methacrylate 2-30
In addition, an absorption enhancer (for example, an azacycloalkane derivative) and a pharmacologically active substance are added to 0.05 to 1% by weight of the crosslinking component, and further, if necessary, 0.01 to 5% by weight of an ultraviolet absorber and 0.01 to 5% by weight of an antioxidant. The preservative of the present invention can be obtained by blending 0.01 to 5% by weight of a preservative and polymerizing and crosslinking in the presence of a polymerization initiator. The above-mentioned formulation examples and production examples are merely examples, and the patch of the present invention can of course be obtained with similar formulations.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the configuration and effects of the present invention will be described with reference to examples. Of course, the invention is not limited thereby.

First, as Example A, a composition composed of a trialkyl citrate, a lower alcohol and water, and a preparation in which a pharmacologically active substance is blended with this composition will be described.

[Example A]

Examples 1-A to 2-A (Comparative Examples 1-A to 2-A) Comparative Test 1-A The compositions of the present invention and the compositions for comparison were prepared as shown in Table 1-A, The primary irritation of the skin was evaluated according to the Draize method.

The results are as shown in Table 1-A, and the addition of the trialkyl citrate clearly reduced the primary irritation to the skin, which is considered to be caused by ethanol.

Comparative Test 2-A Using the solution and water having the compositions of Examples 1-A and Comparative Example 1-A, the skin permeability of the active ingredient in vitro was determined using excised skin of a hairless mouse. It was measured using a suspension of the hydrochloride. The skin permeability of the drug is the maximum flux (maximum drug permeation rate μg / cm ² /
h).

The results are as shown in Table 2-A. In Example 1-A and Comparative Example 1-A, skin penetration of the drug was almost equally promoted. However, it is clear from the results of Comparative Test 1-A that the skin irritation in Example 1-A was significantly reduced.

Example 3-A (Comparative Example 3-A) A solution having the following composition of Example 3-A and the composition of Comparative Example 3-A was prepared, and each of the solutions was in vitro using the excised skin of a hairless mouse. Was measured using the drugs shown in Table 3 below, and a skin irritation test of the drug solution was performed according to the Draize method. The skin permeability of the drug is the maximum flux (maximum drug permeation rate μ) up to 8 hours.
g / cm ² / h) and the skin irritation was compared by PII (skin irritation index).

(Example 3-A composition) Water / isopropanol / triethyl citrate / azacycloalkane derivative = 67/20/10/3 (W / W) (Comparative Example 3-A composition) Water / isopropanol / azacycloalkane derivative =
77/20/3 (W / W) The results are as shown in Table 3-A. In both cases, there was no significant change in the skin permeability of the drug, but the absorption in the solution of Example 3-A was not observed. It can be seen that the skin irritation which is considered to be caused by the accelerator (in this case, the azacycloalkane derivative) is significantly reduced.

Examples 4-A to 12-A (Comparative Examples 4-A to 12-A) Solutions having the compositions shown in Table 4-A were prepared, and for each of them,
Using the excised skin of a hairless mouse, the skin permeability of the active ingredient in vitro was measured using a morphine hydrochloride suspension,
In addition, the skin irritation of the solution was examined according to the Draize method.

The results are as shown in Table 4-A. The skin permeability of the drug was compared at the maximum Flux (maximum drug permeation rate) determined from the skin permeation test performed up to 8 hours. The combined use of a trialkyl citrate (in this case, triethyl citrate) and an absorption enhancer achieves both the same or higher skin permeability of a drug and much lower skin irritation than before. In some cases, a decrease in transmittance is observed because the blending amount of triethyl citrate is constant in this example. However, even in this case there is a much greater reduction in skin irritation than a reduction in transmittance.

Examples 13-A to 17-A (Comparative Examples 13-A to 17-A) The following Examples 13-A to 17-A and Comparative Examples 13-A to 17-A
An experiment was performed as follows for the composition of

That is, the back of a Japanese white rabbit weighing about 3 kg was shaved, and the samples of Example 13 and Comparative Example 13 (morphine hydrochloride content
30 mg) was applied to the back skin, the coated surface was covered with filter paper, and the filter paper was fixed with tape. Blood was collected at 0, 1, 2, 3, and 6 hours after application, and the morphine content was measured. Moreover, Example 13-A ~
For 17-A and Comparative Examples 13-A to 17-A, the skin irritation was evaluated according to the Draize method.

(Example 13-A gel) The following composition: morphine hydrochloride 5 azacycloalkane derivative 3 carboxyvinyl polymer 1 ethanol 20 propylene glycol 10 triethyl citrate 20 purified water 20 2-hydroxy-4-methoxybenzophenone 0.5 diisopropanolamine 1.1 Add 1 part of carboxyvinyl polymer to purified water
The mixture was swollen to 23 parts, and a mixed solution of 20 parts of ethanol, 10 parts of propylene glycol, 20 parts of triethyl citrate, 5 parts of morphine hydrochloride, and 0.5 part of 2-hydroxyl-4-methoxybenzophenone was added and stirred. Next, 3 parts of the azacycloalkane derivative and diisopropanolamine 1.
A solution obtained by dissolving 1 part in 16.4 parts of purified water was added, and the mixture was sufficiently stirred until the whole became uniform to obtain a gel.

(Comparative Example 13-A gel) The same procedure was performed as in Example 13-A, except that trichiel citrate was replaced with ethanol.

(Example 14-A liniment agent) The following composition: methyl salicylate 21-menthol 5 ethanol 25 triethyl citrate 27 isopropyl myristate 5 purified water 36 100 (% by weight) were mixed to obtain a liniment agent. .

(Comparative Example 14-A liniment agent) The procedure was the same as in Example 14-A except that triethyl citrate was replaced with ethanol.

(Example 15-A gel / cream) The following composition: silver sulfadiazine 5 geraniol 3 white petrolatum 5 cetanol 4 liquid paraffin 3 triethyl citrate 15 methyl parahydroxybenzoate 0.2 carboxyvinyl polymer 2 diisopropanolamine 1 paraoxyethylene paraoxy Propylene cetyl ether 2 Isopropanol 20 Purified water 39.8 100 (% by weight) White petrolatum, cetanol, liquid paraffin, triethyl citrate, geraniol, paraoxyethylene paraoxypropylene cetyl ether are mixed, heated and dissolved, and then heated in advance. A solution in which methyl paraoxybenzoate, isopropanol, and silver sulfadiazine were dissolved and dispersed in the purified water was added. Thereafter, the temperature was cooled to 50 ° C., the carboxyvinyl polymer was added and the mixture was sufficiently dispersed, and the mixture was added with diisopropanolamine to adjust the pH to 4 to 8 to obtain a gel cream.

(Comparative Example 15-A gel / cream) The procedure was the same as in Example 15-A except that triethyl citrate was replaced with purified water.

(Example 16-A Reservoir type patch) 1) Support polyester film 2) Drug storage layer Composition of Example 13 3) Microporous membrane Shrugard 4) Adhesive layer Acrylic adhesive (periphery of support) And a release paper was applied to the surface of the microporous adhesive layer to form a laminate.

(Comparative Example 16-A reservoir type patch) The procedure was the same as in Example 16-A except that the drug storage layer was replaced with the composition of Comparative Example 13-A.

(Example 17-A patch) 15 parts of 1-hydroxycyclohexyl phenyl ketone was dissolved in 2400 parts of 2-hydroxyethyl methacrylate,
Further, 35 parts of tetraethylene glycol dimethacrylate was added and dissolved. Separately, heat and dissolve 1900 parts of 5% saline solution and 600 parts of sulfopropyl methacrylate potassium salt,
Further, 2000 parts of glycerin, 2000 parts of isopropanol, 1100 parts of triethyl citrate, 110 parts of ketoprofen, and 300 parts of capric acid were added to obtain a uniform solution. Further, the two liquids were mixed and defoamed to obtain a uniform solution. This liquid was poured to a thickness of 300 μm on a 50 μm-thick horizontally kept PET film provided with a frame to prevent the liquid from flowing out. While keeping this in a nitrogen atmosphere,
It was placed 15 cm below the W chemical lamp, irradiated with ultraviolet rays for 5 minutes, and the cured surface was covered with a release-treated PET film to give a patch.

(Comparative Example 17-A patch) The procedure was the same as in Example 17-A except that triethyl citrate was replaced with glycerin.

The test results of the above composition are as shown in Tables 5-A and 6-A. There is no significant difference in the transfer of morphine hydrochloride into the blood between the example and the comparative example, but in the example, irritation to the skin is significantly reduced.

Next, as Example B, a composition comprising a trialkyl citrate, a lower alcohol, water and an absorption promoter of a terpene-based compound, and a preparation containing a pharmacologically active substance mixed with this composition will be described.

[Example B]

 First, the evaluation test will be described.

<Drug skin permeability test using extirpated skin of hairless mouse> Triethyl citrate, isopropanol, and water were mixed with the following composition, and each monoterpene compound as an absorption enhancer was 5% by weight with respect to 95% by weight of this mixture. To be added. The drug (ketoprofen, clonidine hydrochloride, morphine hydrochloride, eperisone hydrochloride) is then added to the mixture to a level at which the final composition is saturated at 37 ° C.

The resulting drug / percutaneous absorption preparation was subjected to a skin permeation test using skin excised from the abdomen of a hairless mouse. That is, the effect of the addition of various monoterpene compounds on the transdermal absorption of a drug was examined. The evaluation was performed for each drug by determining the maximum skin permeation rate of the drug for up to 8 hours after the start of the experiment for each additive, defining the promotion rate for the control as the penetration rate promotion rate, and comparing the values. Was.

-Sample prescription: (1) Triethyl citrate / isopropanol / water = 10/30/60 (% V / V) 95% by weight (2) Various monoterpene compounds 5% by weight 100 % in total-Control prescription: (1) Triethyl citrate / isopropanol / water = 10/30/60 (% V / V) 100% by weight-Comparative example formula: (1) Isopropanol / water = 30/70 (% V / V) 95% by weight (2) Various Monoterpene compound 5% by weight Total 100% by weight <Primary skin irritation test of base for transdermal administration containing various monoterpene compounds> 100 μl of each drug and additive-containing drug was added to a patch patch (small) at Torii. After permeation, skin irritation was evaluated according to the Draize method. For each animal, five Japanese white rabbits were shaved with an electric clipper and a shaver for each drug and used. The same composition as that of the above-mentioned skin permeation test was used for the sample composition.

The skin penetration rate promotion rate and the skin irritation index were evaluated by the above methods, and the results were shown together with Comparative Examples.

Examples 1-B to 4-B (Comparative Examples 1-B to 4-B) Skin irritation and skin permeability in each formulation when ketoprofen was used as a drug were evaluated.

The following Table 1-B and Table 2-B results were obtained. Table 1-B
In the case of the embodiment of the present invention, excellent results were obtained in both the penetration rate promotion rate and the skin irritation index.

Examples 5-B to 8-B (Comparative Examples 5-B to 8-B) Skin irritation and skin permeability in each formulation when epolizone hydrochloride was used as a drug were evaluated.

The results in Tables 3-B and 4-B below were obtained. Excellent results were obtained in the examples of the present invention.

Examples 9-B to 12-B (Comparative Examples 9-B to 12-B) The skin irritation and skin permeability of each formulation when morphine hydrochloride was used as a drug were evaluated.

The following Table 5-B and Table 6-B results were obtained. Excellent results were obtained in the examples of the present invention.

Examples 13-B to 16-B (Comparative Examples 13-B to 16-B) The skin irritation and skin permeability of each formulation when clonidine hydrochloride was used as a drug were evaluated.

The following Table 7-B and Table 8-B results were obtained. In the examples of the present invention, an excellent effect of reducing skin irritation was obtained. The permeability has not declined.

According to the evaluation by the skin irritation index summarized in the above Examples 1-B to 16-B, triethyl citrate and monoterpene compound were both used except for the comparative example in which each drug had a weak but irritating property. The containing mixture was virtually non-irritating to the skin in all cases. Moreover, it was found that transdermal absorbability was far greater than that of the control containing no monoterpene compound.

Example 17-B (Comparative Example 17-B) Based on the drug administration composition of the present invention, each formulation of gel, gel cream, liniment, reservoir-type patch, patch, and a comparison of each with the following formulation Formulations were prepared for the formulations, and the drug skin permeability and skin irritation of each formulation were evaluated in rabbits (in vivo).

(Gel formulation) Morphine hydrochloride 5 L-menthol 3 Carboxyvinyl polymer 1 Ethanol 20 Propylene glycol 15 Triethyl citrate 15 Purified water 39.4 2-Hydroxy-4-methoxybenzophenone 0.5 Diisopropanolamine 1.1 100% by weight Then, 1 part of a carboxyvinyl polymer is swollen in 23 parts of purified water, and 20 parts of ethanol, 15 parts of propylene glycol, 15 parts of triethyl citrate, 5 parts of morphine hydrochloride, and 0.5 part of 2-hydroxyl-4-methoxybenzophenone are added. Was added and stirred. Next, a solution prepared by dissolving 3 parts of L-menthol and 1.1 parts of diisopropanolamine in 16.4 parts of purified water was added, and sufficiently stirred until the whole became uniform to obtain a gel.

(Comparative prescription for gel preparation) The same procedure was performed except that ethanol was used instead of triethyl citrate in the above gel preparation.

(Gel / cream formulation) Morphine hydrochloride 5 Terpineol 3 White petrolatum 5 Cetanol 4 Liquid paraffin 3 Triethyl citrate 15 Methyl parahydroxybenzoate 0.2 Carboxyvinyl polymer 1 Diisopropanolamine 1 Paraoxyethylene paraoxy 2 Propylene cetyl ether 2 Purified water 60.8 100 (weight) %), Mixed and heated and dissolved in white petrolatum, cetanol, liquid paraffin, triethyl citrate, terpineol and paraoxyethylene paraoxypropylene cetyl ether, and then added methyl parahydroxybenzoate and methyl salicylate to purified water heated in advance. Is dissolved and dispersed, and then cooled to 50 ° C., and carboxyvinyl polymer is added and sufficiently dispersed. Then, diisopropanolamine is added to adjust pH to 4 to 8, and gel is added. Give a cream.

(Comparative prescription for gel and cream) A composition of 5 morphine hydrochloride 5 d-(+)-limonene 5 ethanol 25 triethyl citrate 30 triethyl myristate 5 purified water 30 100 (wt%) was mixed as prescribed to obtain a nilment agent. .

(Comparative prescription of liniment agent) The same procedure was carried out except that triethyl citrate was replaced with ethanol in the above liniment agent.

(Reservoir-type patch) Support Polyester film Drug storage layer Composition used in the above gel agent Microporous membrane Duragard Adhesive layer Acrylic adhesive (adhesive layer around support) Composed of An applied laminate was prepared on the adhesive layer surface of the microporous membrane.

(Comparative Example of Reservoir Patch) The procedure was the same except that the contents of the drug storage layer of the reservoir patch were replaced with the composition of the comparative gel preparation.

(Patch) 15 parts of 1-hydroxycyclohexyl phenyl ketone was dissolved in 2400 parts of 2-hydroxyethyl methacrylate,
Further, 35 parts of tetraethylene glycol dimethacrylate was added and dissolved. Separately, 1900 parts of 5% saline solution and 600 parts of sulfopropyl methacrylate potassium salt were dissolved by heating, and further 2,000 parts of glycerin, 2,000 parts of isopropanol, 1100 parts of triethyl citrate, 110 parts of morphine hydrochloride, thymol 3
By adding 00 parts, a uniform solution was obtained. Further, the two liquids were mixed and defoamed to obtain a uniform solution. This liquid was kept horizontal with a thickness of 50 μm with a frame to prevent it from flowing around
It was poured onto a PET film so as to have a thickness of 300 μm. This product was placed 15 cm below a 30 W chemical lamp while maintaining a nitrogen atmosphere, irradiated with ultraviolet rays for 5 minutes, and then the cured surface was covered with a release-treated PET film to give a patch.

(Patch comparative example) The same procedure was performed except that triethyl citrate was replaced with glycerin in the above patch preparation.

(Evaluation Test) The following test was carried out on the gel / cream formulation.

The back of a Japanese white rabbit weighing 3 kg was shaved, a gel cream and a sample of the comparative example were applied to the back skin, and the coated surface was covered with filter paper, and the filter paper was fixed with tape. After application
Blood was collected at 0, 1, 2, 3, and 6 hours and the morphine blood concentration was measured. The results are shown in Table 9-B.

The skin irritation of each formulation of morphine hydrochloride gel, gel cream, liniment, patch, and reservoir patch was evaluated according to the Draize method, including Comparative Examples. Each preparation was prepared based on the above-mentioned Examples and Comparative Examples, and subjected to comparative tests. The results are shown in Table 10-B.

Table 9-B shows that there was no significant difference in the transfer of morphine from the gel preparation into the blood between the example and the comparative example, indicating that the transdermal absorbability was maintained even by the addition of triethyl citrate. . From Table 10-B, in terms of skin irritation, the gel, gel cream, liniment, reservoir-type patch, and patch containing triethyl citrate exhibited uniform skin irritation compared to Comparative Examples. Tended to decrease.

Next, as Example C, a composition comprising an absorption enhancer selected from a trialkyl citrate, a lower alcohol, water and a fatty acid, a fatty acid alcohol, a fatty acid ester, and a phenol derivative, and a preparation prepared by mixing a pharmacologically active substance with the composition. explain.

[Example C]

Example 1-C (Temporary skin irritation of composition and effect of promoting percutaneous absorption of drug) The composition of the present invention was evaluated for its effect of temporary skin irritation and the effect of promoting percutaneous absorption of a drug. The sample solution for this purpose was 65%, 30% each of water, isopropanol and triethyl citrate.
% And 10%, and as shown in Tables 1 to 4, 5% of various absorption enhancers were added and mixed well, and a saturated amount of a physiologically active substance (pridinol mesylate, flunarizine hydrochloride,
Clonidine hydrochloride, betahistine mesylate, ketoprofen, aspirin and meperidine) were added and dissolved at 37 ° C.

The in vitro permeability of the drug was determined by sandwiching the skin of the abdominal extirpation of a female hairless mouse between horizontal 2-chamber cells, placing 2.7 ml of the sample solution in the cells on the stratum corneum side, and saline in the cells on the dermis side. 2.7 ml, and the amount of permeation of the drug from the supply tank side to the receiving tank side at 37 ° C. was evaluated over time. HP for drug quantification
The maximum permeation rate up to 8 hours was compared using LC. At the same time, perform a skin irritation test with a saturated solution of the drug.
The irritation was compared in accordance with the Draize method, and a skin irritation index (PII) was determined by comparing those prepared without triethyl citrate in each composition. Table 1-C ~
4-C.

As shown in Tables 1-C to 4-C, compared with the skin permeability when the drug was dissolved in a two-component mixture of water and isopropanol, the absorption when an absorption enhancer and triethyl citrate were added was compared. The accelerating effect was very large, and it became possible to increase the absorption of a drug having a low percutaneous absorption to a level sufficient to exert its medicinal effect. At the same time, the high skin irritation of the absorption enhancer is greatly reduced by adding triethyl citrate to the sample solution, making it possible to construct a dosage composition that is practically acceptable in both skin irritation and transdermal absorption. It became.

Example 2-C (gel) In the following case: morphine hydrochloride 5 triethyl citrate 20 caprylic acid 3 carboxyvinyl polymer 1 propylene glycol 10 isopropanol 20 2-hydroxy-4-methoxybenzophenone 0.5 diisopropanolamine 1.1 purified water 39.4 100 ( (% By weight), the carboxyvinyl polymer was swollen in half of purified water, and ethanol, propylene glycol, triethyl citrate, caprylic acid, morphine hydrochloride, and 2-hydroxy-4-methoxybenzophenone were dissolved therein. The solution was added and stirred. Next, a solution prepared by dissolving diisopropanolamine in the remaining purified water was added, and the mixture was sufficiently stirred until the whole became uniform to obtain a gel.

Comparative Example 1-C (gel) A formulation was prepared by replacing the triethyl citrate of Example 2-C with purified water.

Comparative Example 1-C (gel) A formulation was prepared by replacing the triethyl citrate and caprylic acid of Example 2-C with purified water.

Example 3-C (Liniment) The following ratio: morphine hydrochloride 1 triethyl citrate 30 methyl cinnamate 4 L-menthol 5 ethanol 25 isopropyl myristate 5 purified water 30 100 (wt%) morphine hydrochloride Menthol, ethanol, triethyl citrate, methyl cinnamate, isopropyl myristate, and purified water were mixed in predetermined amounts to obtain a liniment.

Comparative Example 2-C (Liniment) A formulation was prepared by replacing the triethyl citrate of Example 3-C with purified water.

Example 4-C (gel cream) The following proportions: morphine hydrochloride 5 linoleic acid 3 triethyl citrate 15 isopropanol 20 white petrolatum 5 cetanol 4 liquid paraffin 3 methyl paraoxybenzoate 0.2 carboxyvinyl polymer 2 diisopropanolamine 1 paraoxyl Ethylene paraoxy propylene cetyl ether 2 Purified water 39.8 100 (% by weight) White petrolatum, cetanol, liquid paraffin, triethyl citrate, linoleic acid, paraoxyethylene paraoxy propylene cetyl ether are mixed,
After heating and dissolving, dissolve and disperse methyl paraoxybenzoate, isopropanol and morphine hydrochloride in pre-heated water, add the dispersion, and then add the carboxyvinyl polymer at 50 ° C as cooling and thoroughly disperse. Diisopropanolamine was added to adjust the pH to 4 to 8 to obtain a gel cream.

Comparative Example 3-C (gel / cream) A preparation was prepared by replacing triethyl citrate with purified water in Example 4-C.

Example 5-C (Reservoir-type preparation) Using a polyester-based film as a support, an acrylic pressure-sensitive adhesive layer was formed in the drug storage layer around the support in contact with the skin containing the composition of Example 2-C, and a central portion was formed in the center. A so-called reservoir-type preparation was prepared in which a microporous membrane such as Duragard was disposed as a drug release surface, and release paper was applied to the surface of the adhesive layer of the microporous membrane.

Comparative Example 4 (Reservoir-type preparation) A preparation was prepared by replacing the drug reservoir layer of Example 5-C with the composition of Comparative example 1-C.

Example 6-C (Patch) 15 parts of 1-dihydroxycyclohexyl phenyl ketone was dissolved in 2400 parts of 2-hydroxyethyl methacrylate, and tetraethylene glycol dimethacrylate 35 was further dissolved.
Was added and dissolved. Separately heat and dissolve 1900 parts of 5% saline solution and 600 parts of sulfopropyl methacrylate potassium salt,
Further, 2000 parts of glycerin, 2000 parts of isopropanol, 1100 parts of triethyl citrate, 110 parts of morphine hydrochloride and 300 parts of chlorcresol were added to obtain a uniform solution. Further, the two liquids were mixed and defoamed to obtain a uniform solution. This liquid was poured to a thickness of 300 μm on a 50 μm-thick horizontally kept PET film provided with a frame in order to prevent the liquid from flowing out. While keeping this in a nitrogen atmosphere
It was placed 15 cm below a 30 W chemical lamp, irradiated with ultraviolet light for 5 minutes, and the cured surface was covered with a release-treated PET film to obtain a patch.

Comparative Example 5-C (Patch) A preparation was prepared by replacing triethyl citrate of Example 6-C with liquid paraffin.

Example 7-C (Evaluation of permeability and irritation) Example 2-C, Comparative Example 1-C, and Control Example 1-C described above
The following experiment was conducted for

The back of a Japanese white rabbit weighing about 3 kg was shaved, and
-C and the samples of Comparative Example 1-C and Control Example 1-C (containing 30 mg of morphine hydrochloride) were applied to the back skin, the coated surface was covered with filter paper, and the filter paper was fixed with tape. 0,1,2,3,6 after application
After an hour, blood was collected and the morphine content was measured.

In addition, Examples 2-C to 6-C and Comparative Examples 1-C to 5-
The skin irritation of C was evaluated according to the Draize method. The results are shown in Tables 5-C and 6-C.

As shown in Table 5-C, morphine was not detected in blood in Control Example 1-C containing neither triethyl citrate nor caprylic acid, and morphine hydrochloride was used in Example 2-C and Comparative Example 1-C. There is no significant difference in the transfer to the blood. However, the skin irritation shown in Table 6 was significantly reduced in the examples.

Finally, as Example D, a composition comprising a trialkyl citrate, a lower alcohol, water and an absorption enhancer of an azacycloalkane derivative, and a preparation prepared by mixing a pharmacologically active substance with this composition are described.

[Example D]

Example 1-D The following composition: water / isopropanol / triethyl citrate / 1- [2
A composition comprising-(decylthio) ethyl] azacyclopentan-2-one = 67/20/10/3 (W / W) was prepared, and its primary skin irritation was evaluated according to the Draize method. The results are shown in Table 1-D. As is clear from the comparison with the comparative example, the primary irritation to the skin, which is considered to be caused by the absorption enhancer, is clearly reduced by the addition of the trialkyl citrate.

Comparative Example 1-D The following composition: Example 1 for a composition comprising water / isopropanol / 1- [2- (decylthio) ethyl] azacyclopentan-2-one = 77/20/3 (W / W) Evaluation was performed in the same manner as for D. The results are shown in Table 1-D.

Example 2-D The following composition: water / isopropanol / triethyl citrate = 60/30 /
10 (V / V): 1-n-dodecylazacycloheptane-2-
Example 1 for a composition consisting of ON = 95: 5 (W / W)
In the same manner as in -D, the skin primary irritation was evaluated. The results are shown in Table 1-D, where the addition of the trialkyl citrate clearly reduces the possible skin primary irritation caused by the absorption enhancer.

Comparative Example 2-D The following composition: Water / isopropanol = 70/30 (V / V): 1-n-dodecylazacycloheptan-2-one = 95: 5 (W / W). Evaluation was performed in the same manner as in 1-D, and the results are shown in Table 1-D.

Examples 3-D to 9-D (Comparative Examples 3-D to 9-D) In vitro medicinal effects using the excised skin of a hairless mouse in the solutions having the compositions of Example 2-D and Comparative Example 2-D. The skin permeability of the components was measured using a drug suspension shown in Table 2-D below, and a skin irritation test of a saturated solution of the drug was performed according to the Draize method. The drug has a skin permeability of 8
Maximum Flux up to hour (Maximum drug permeation rate μg / cm ² / h)
The skin irritation was compared by PII (skin irritation index).

The results are as shown in Table 2-D. Although there was no significant change in the skin permeability of the drug in Examples of the present invention and Comparative Examples, skin irritation was significantly reduced in the compositions of Examples. Is recognized.

Example 10-D The following proportions: morphine hydrochloride 5 azacycloalkane derivative 3 carboxyvinyl polymer 1 ethanol 20 propylene glycol 10 triethyl citrate 20 purified water 39.4 2-hydroxy-4-methoxybenzophenone 0.5 diisopropanolamine 1.1 100 (weight) %), 1 part of carboxyvinyl polymer was purified water
The mixture was swollen to 23 parts, and a solution prepared by mixing 20 parts of ethanol, 10 parts of propylene glycol, 20 parts of triethyl citrate, 5 parts of morphine hydrochloride, and 0.5 part of 2-hydroxy-4-methoxybenzophenone was added and stirred. Next, 3 parts of the azacycloalkane derivative and diisopropanolamine 1.
A solution obtained by dissolving 1 part in 16.4 parts of purified water was added, and the mixture was sufficiently stirred until the whole became uniform to obtain a gel.

About this gel, together with the following Comparative Example 10-D, the back of a Japanese white rabbit weighing about 3 kg was shaved, and a sample (morphine hydrochloride content: 30 mg) was applied to the back skin, and the gel was applied to a filter paper. And the filter paper was fixed with tape. After application
Blood was collected at 0, 1, 2, 3, and 6 hours to measure morphine content. The skin irritation was determined according to the Draize method in the following Examples.
Evaluation was performed together with 11-D to 14-D and Comparative Examples 11-D to 14-D. The results are as shown in Table 3-D and Table 4-D. 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.

Comparative Example 10-D The same operation was performed as in Example 10-D except that triethyl citrate was replaced with ethanol.

Example 11-D (Liniment Agent) Morphine Hydrochloride 1 Azacycloalkane Derivative 3 L-Menthol 5 Ethanol 25 Triethyl Citrate 27 Isopropyl Myristate 5 Purified Water 34 100 (% by weight) A liniment was obtained.

The results of the skin irritation test are as shown in Table 4-D. As is clear from comparison with the following Comparative Example 11-D, the irritation was significantly reduced.

Comparative Example 11-D (Liniment) The same operation was performed as in Example 11-D except that ethanol was used instead of triethyl citrate. The results of the skin irritation test are shown in Table 4-D.

Example 12-D (Gel / cream) Morphine hydrochloride 5 Azacycloalkane derivative 3 White petrolatum 5 Cetanol 4 Liquid paraffin 3 Triethyl citrate 15 Methyl parahydroxybenzoate 0.2 Carboxyvinyl polymer 2 Diisopropanolamine 1 Paraoxyethylene paraoxy Propylene cetyl Ether 2 Isopropanol 20 Purified water 39.8 Mix 100 parts by weight of white petrolatum, cetanol, liquid paraffin, triethyl citrate, azacycloalkane derivative, paraoxyethylene paraoxypropylene cetyl ether, heat and dissolve. Dissolve and disperse methyl parahydroxybenzoate, isopropanol, and morphine hydrochloride in heated purified water, and then cool to 50 ° C, add carboxyvinyl polymer, and fully disperse After, 4 a P adding thereto diisopropanolamine
8 to obtain a gel cream.

The results of the skin irritation test are shown in Table 4-D. As is clear from the comparison in Table 4-D with Comparative Example 12-D, the skin irritation was significantly reduced.

Comparative Example 12-D (Gel / Cream) The procedure was the same as Example 12-D except that triethyl citrate was replaced with purified water.

Example 13-D (Reservoir type patch) 1) Support polyester-based film 2) Drug storage layer Composition of Example 3 3) Microporous membrane Duragard 4) Adhesive layer Acrylic adhesive (peripheral part of support) And a release paper was applied to the surface of the microporous adhesive layer to form a laminate.

The results of the skin irritation test are shown in Table 4-D. It can be seen that skin irritation is greatly reduced.

Comparative Example 13-D (Reservoir-type patch) The procedure was the same as in Example 13-D except that the drug storage layer was replaced with the composition of Comparative Example 10-D. The results of the skin irritation test are shown in Table 4-D.

Example 14-D (Patch) 15 parts of 1-hydroxycyclohexyl phenyl ketone was dissolved in 2400 parts of 2-hydroxyethyl methacrylate,
Further, 35 parts of tetraethylene glycol dimethacrylate was added and dissolved. Separately, 1900 parts of 5% saline solution and 600 parts of sulfopropyl methacrylate potassium salt were heated and dissolved, and 2,000 parts of glycerin, 2000 parts of isopropanol, 1100 parts of triethyl citrate, 110 parts of morphine hydrochloride, and 300 parts of azacycloalkane derivative were added. This gave a homogeneous solution.
Further, the two liquids were mixed and defoamed to obtain a uniform solution. 50μ thick with a frame to prevent outflow of this liquid
The film was poured onto a PET film held horizontally to a thickness of 300 μm. This product was placed under a 30 W chemical lamp 15 cm while being kept in a nitrogen atmosphere, irradiated with ultraviolet rays for 5 minutes, and then the cured surface was covered with a release-treated PET film to obtain a patch.

The results of the skin irritation test are shown in Table 4-D. It can be seen that skin irritation is greatly reduced.

Comparative Example 14-D (Patch) The procedure was the same as in Example 14-D except that triethyl citrate was replaced with glycerin.

 The results of the skin irritation test are shown in Table 4-D.

INDUSTRIAL APPLICABILITY A composition comprising a trialkyl citrate, a lower alcohol and water of the present invention, an external preparation prepared by mixing a pharmacologically active substance with this composition, and an absorption enhancer further added to these compositions The compositions and external preparations exhibited an action of significantly reducing or alleviating skin irritation, which had been a disadvantage of the prior art, and were found to have a significant effect on skin irritation, which had been a concern so far. . Therefore, it has become possible to develop various preparations for transdermal application which are very excellent in safety. At the same time, it shows a good absorption promoting effect in transdermal absorption and can be made into a preparation excellent in terms of medicinal effect. Thus, it has both a reduction in irritation and a relaxation effect and transdermal absorption. Since it can be used as an external preparation, it is very useful especially in the pharmaceutical industry as a transdermal preparation.

──────────────────────────────────────────────────続 き Continuation of the front page (31) Priority claim number Japanese Patent Application No. 3-106129 (32) Priority date Hei 3 (1991) May 10 (33) Priority claim country Japan (JP) (72) Inventor Tatsuaki Suzuki 1-25-11 Kannondai, Tsukuba, Ibaraki Pref., Tsukuba Research Laboratories Hisamitsu Pharmaceutical Co., Ltd. (72) Inventor Mitsuhiro Mizumachi 1-25-11 Kannondai, Tsukuba City, Ibaraki Pref. Inventor Hirofumi Sakaguchi 1-25-11 Kannondai, Tsukuba, Ibaraki Pref. Hisamitsu Pharmaceutical Co., Ltd. Tsukuba Research Laboratories (58) Field surveyed (Int. Cl. ⁶ , DB name) A61K 47/14, 7/00

Claims (9)

(57) [Claims] 1. A skin irritation alleviating composition comprising a trialkyl citrate, a lower alcohol and water. 2. The composition for alleviating skin irritation according to claim 1, comprising 1 to 50% by weight of trialkyl citrate, 1 to 70% by weight of lower alcohol and 1 to 90% by weight of water. (3) a trialkyl citrate, a lower alcohol,
An external preparation for transdermal use comprising water and a pharmacologically active substance. 4. The transdermal preparation according to claim 3, comprising 1 to 50% by weight of a trialkyl citrate, 1 to 70% by weight of a lower alcohol, 1 to 90% by weight of water and 0.001 to 20% by weight of a pharmacologically active substance. . 5. A composition for alleviating skin irritation characterized by further comprising an absorption enhancer in a base comprising trialkyl citrate, lower alcohol and water. 6. A base comprising 1 to 50% by weight of trialkyl citrate, 1 to 70% by weight of lower alcohol and 1 to 90% by weight of water, further containing 0.1 to 10% by weight of an absorption promoter. The composition for relieving skin irritation according to the above. 7. A composition for alleviating skin irritation characterized by further comprising an absorption enhancer and a pharmacologically active substance added to a base comprising trialkyl citrate, lower alcohol and water. 8. A base comprising 1 to 50% by weight of a trialkyl citrate, 1 to 70% by weight of a lower alcohol and 1 to 90% by weight of water, 0.1 to 10% by weight of an absorption enhancer and a pharmacologically active substance.
A transdermal external preparation characterized by containing 0.001 to 20% by weight. 9. A composition for alleviating skin irritation, wherein the absorption enhancer according to claim 5 is selected from terpene compounds, fatty acids, fatty acid alcohols, fatty acid esters, phenol derivatives and azacycloalkane derivatives. Or a transdermal topical agent.