JPH10316564A - Antipruritic and analgesic medicine for external use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject medicine showing high treatment effects against itching, ache and inflammations of the skin by including a local anesthetic, vitamin E and squalene. SOLUTION: This medicine contains 0.01 to 30 wt.% of a local anesthetic, 1.0 to 99.8 wt.% of vitamin E and 0.1 to 98 wt.% of squalene. It may be further incorporated with at least one type of percutaneous absorption accelerator selected from the group consisting of N-acylsarcosine (salt), a higher fatty acid ester as the product of the reaction between a 10-18C higher fatty acid and 1-20C alcohol, 2-10C dicarboxylic acid (salt), hydroxycarboxylic acid ester as the product of the reaction between a 3-6C hydroxycarboxylic acid and 1-20C alcohol, and aliphatic ethanol amide. The medicine is administered to the affected part at 0.1 to 10 g a day in several times. Presence of vitamin E and squalene can reduce content of the local anesthetic required for sufficient treatment effects. As a result, the medicine shows high and safe treatment effects, while controlling the side effects of the anesthetic, e.g. hives, edema and anthema.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an antipruritic and analgesic external preparation having a high therapeutic effect on itching, pain and inflammation of the skin.

[0002]

2. Description of the Related Art Conventionally, preparations containing a local anesthetic have been frequently used for itching and pain of the skin (Naoshi Ishida et al., Kidney and Dialysis, 36, 1135-1139, 19).
1994). However, as a side effect of local anesthetics,
Since there are urticaria, edema, rash, pruritus, etc. (13th revised edition of the Japanese Pharmacopoeia, Hirokawa Shoten), it is important for treatment to reduce these side effects and further increase the effect.

[0003]

SUMMARY OF THE INVENTION The present invention has been made in view of the above,
It is an object of the present invention to provide an antipruritic and analgesic external preparation having a sufficient therapeutic effect by using a low dose of a local anesthetic in order to reduce side effects when using a local anesthetic in the treatment of skin diseases.

[0004]

The topical antipruritic agent according to claim 1 is characterized by containing a local anesthetic, vitamin E and squalane.

The topical antipruritic agent according to claim 2 has a local anesthetic content of 0.01 to 30% by weight, a vitamin E content of 1.0 to 99.8% by weight and a squalane content of 2. The composition according to claim 1, wherein the content is 0.1 to 98% by weight.
It is an antipruritic analgesic external preparation described in the above.

The topical antipruritic analgesic according to claim 3, further comprising N-acylsarcosine (salt), a higher fatty acid ester which is a reaction product of a higher fatty acid having 10 to 18 carbon atoms and an alcohol having 1 to 20 carbon atoms. A dicarboxylic acid (salt) having 2 to 10 carbon atoms, a hydroxycarboxylic acid ester which is a reaction product of a hydroxycarboxylic acid having 3 to 6 carbon atoms and an alcohol having 1 to 20 carbon atoms, and a fatty acid ethanolamide. The antipruritic and analgesic external preparation according to claim 1 or 2, which comprises at least one transdermal absorption enhancer selected.

The above local anesthetics include ethyl aminobenzoate, tetracaine hydrochloride, procaine hydrochloride, dibucaine hydrochloride, lidocaine hydrochloride, lidocaine hydrochloride / epinephrine hydrochloride, oxybuprocaine hydrochloride, thecaine, bupivacaine hydrochloride, mepivacaine hydrochloride, propitocaine hydrochloride, hydrochloric acid Propitocaine / epinephrine, oxesazein, ethyl piperidinoacetylaminobenzoate, pyridoxine hydrochloride, dimethisoquine hydrochloride, bromoxine hydrochloride, lidocaine, benzocaine, procaine, dibucaine, piperocaine hydrochloride, hexothiocaine hydrochloride, benzyl alcohol, thecaine hydrochloride, cocaine hydrochloride, catacaine hydrochloride
Butanicain hydrochloride, Oxybutanican hydrochloride, Mebrylbutanican hydrochloride, Piperocaine hydrochloride, Chlorobutanol, Meprilcaine hydrochloride, Epilocaine hydrochloride, Amylokine hydrochloride, Isobucaine hydrochloride, Chloroprocaine hydrochloride,
Examples include, but are not limited to, tricaine hydrochloride, parethoxycaine hydrochloride, pirocaine hydrochloride, prilocaine hydrochloride, procaine amide hydrochloride, propalacaine hydrochloride, propoxycaine hydrochloride, hexylcaine hydrochloride, metabutetamine hydrochloride, metabutoxycaine hydrochloride, xylocaine.

[0008] The above-mentioned vitamin E refers to tocopherol (vitamin E) and its derivatives. Examples of those listed in the Japanese Pharmacopoeia include dl-α-tocopherol, tocopherol acetate (vitamin E acetate), and succinic acid. Acid tocopherol (vitamin E succinate) and the like. Those not listed in the Japanese Pharmacopoeia include, for example, d-α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, tocopherol nicotinate (vitamin E nicotinate), tocopherol phosphate (vitamin E phosphate) ).

[0009] The above-mentioned squalane is fish in the deep sea, especially in shark liver oil or vegetable oil such as olive oil,
It is a saturated hydrocarbon obtained by reducing squalene which is an unsaturated hydrocarbon present in rice bran oil, wheat germ oil, sesame oil, cottonseed oil and the like.

[0010] The transdermal absorption enhancer is at least one selected from the group consisting of N-acyl sarcosine (salt), higher fatty acid ester, dicarboxylic acid (salt), hydroxycarboxylic acid ester, and fatty acid ethanolamide.

The N-acyl sarcosine includes, for example, N-lauroyl sarcosine, N-oleoyl sarcosine, N-palmitoyl sarcosine, coconut oil fatty acid sarcosine, and the like. Sodium salt, potassium salt, magnesium salt, calcium salt, aluminum salt and the like.

The above higher fatty acid ester is a reaction product of a higher fatty acid and an alcohol. The carbon number of the higher fatty acid is 10 to 18 since the higher fatty acid ester of the product becomes easier to volatilize when it becomes smaller, and the percutaneous absorption effect decreases when it becomes larger, and the carbon number of the alcohol is
If it becomes larger, the percutaneous absorption effect decreases, so it is 1 to 20. Examples of the higher fatty acid having 10 to 18 carbon atoms include saturated aliphatic monocarboxylic acids such as capric acid, lauric acid, myristic acid, palmitic acid, and stearic acid;
Unsaturated aliphatic monocarboxylic acids such as palmitoleic acid, oleic acid, vaccenic acid, linoleic acid, and linolenic acid; and saturated aliphatic dicarboxylic acids such as sebacic acid.

The alcohol having 1 to 20 carbon atoms includes, for example, methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, tertiary butyl alcohol, pentyl alcohol, hexyl alcohol, heptyl alcohol, octyl alcohol. , Caprylic alcohol, nonyl alcohol, decyl alcohol,
Examples include aliphatic saturated alcohols such as lauryl alcohol, myristyl alcohol, palmityl alcohol, and stearyl alcohol. Examples of the higher fatty acid ester include isopropyl myristate, isopropyl palmitate, isopropyl laurate, and isopropyl stearate.

If the carbon number of the dicarboxylic acid (salt) is too small or too large, the percutaneous absorption effect is reduced.
It is 10. Examples of the dicarboxylic acids having 2 to 10 carbon atoms include, for example, saturated aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, and suberic acid; and fumaric acid and maleic acid. Saturated aliphatic dicarboxylic acids; aromatic dicarboxylic acids such as phthalic acid, isophthalic acid, and terephthalic acid; and the salts thereof include, for example, sodium, potassium, magnesium, calcium, and aluminum salts of the above dicarboxylic acids. And the like.

The above hydroxycarboxylic acid ester is
It is a reaction product of a hydroxycarboxylic acid and an alcohol. When the number of carbon atoms of the hydroxycarboxylic acid is small, the hydroxycarboxylic acid ester of the product is liable to volatilize. When the carbon number is large, the transdermal absorption effect is reduced.
In addition, the carbon number of the alcohol is 1 to 20 because the effect of transdermal absorption decreases as the alcohol number increases.

Examples of the hydroxycarboxylic acids having 3 to 6 carbon atoms include monocarboxylic acids such as lactic acid and glyceric acid, and dicarboxylic acids such as malic acid and tartaric acid. As the alcohol having 1 to 20 carbon atoms,
The same as those used in the reaction of the above higher fatty acid ester can be used. Examples of the hydroxycarboxylic acid esters include myristyl lactate and cetyl lactate.

As the fatty acid ethanolamide, fatty acid monoethanolamide or fatty acid diethanolamide, and an alkylene oxide adduct thereof can be used. As the fatty acid ethanolamide,
For example, lauric acid monoethanolamide, lauric acid diethanolamide, lauroyl monoethanolamide, palmitic acid monoethanolamide, palmitic acid diethanolamide, myristic acid monoethanolamide, myristic acid diethanolamide, lauric acid / myristic acid monoethanolamide, coconut Oil fatty acid monoethanolamide, coconut oil fatty acid diethanolamide, polyoxyethylene added lauroyl monoethanolamide, polyoxyethylene added coconut oil fatty acid monoethanolamide and the like can be mentioned.

As the transdermal absorption enhancer, N-lauroyl sarcosine, isopropyl myristate, isopropyl palmitate, fumaric acid, maleic acid, myristyl lactate, cetyl lactate, lauric acid diethanolamide are particularly preferable. In addition, as a transdermal absorption enhancer,
The above-mentioned ones are preferable, but not limited thereto, and conventionally known ones can be used.

If the amount of the local anesthetic in the antipruritic and analgesic external preparation of the present invention is too small, the enhancement of the effect with vitamin E and squalane is weakened. To 30% by weight, preferably 0.1 to 1%.
0% by weight is more preferred.

When the content of vitamin E in the antipruritic and analgesic external preparation of the present invention decreases, the therapeutic effect becomes insufficient, and even if it increases, the effect does not increase remarkably according to the content. To 99.8% by weight, preferably 2 to 8%.
0% by weight is more preferable, and 5 to 30% by weight is most preferable.

When the content of squalane in the antipruritic and analgesic external preparation of the present invention decreases, the therapeutic effect becomes insufficient, and when it increases, the effect does not increase significantly depending on the content. 98% by weight is preferred, and 0.2 to 8
0 wt% is more preferable, and 10 to 30 wt% is most preferable.

The preferred combination of the content of each component in the antipruritic and analgesic external preparation of the present invention is 0.01 to 30% for local anesthetics.
%, 1.0 to 99.8% by weight of vitamin E and 0.1 to 98% by weight of squalane, and a particularly preferred combination is 0.1 to 10% by weight of a local anesthetic, vitamin E5 to 5%.
30% by weight and 10-30% by weight of squalane.

When the percutaneous absorption enhancer is contained in the antipruritic and analgesic external preparation of the present invention, the percutaneous absorption promoting effect decreases as the content decreases, and if the content increases, the skin irritation is expressed, In some cases, it may be difficult to maintain the dosage form depending on the base (described later) due to excessively high properties. Therefore, the total of the local anesthetic, vitamin E, squalane, and the base (described below) is 1
0.1 to 25 parts by weight is preferable with respect to 00 parts by weight,
1 to 12 parts by weight is more preferred.

The dosage form of the antipruritic and analgesic external preparation of the present invention is not particularly limited. For example, the above-mentioned local anesthetic, vitamin E, squalane and, if necessary, a transdermal absorption enhancer in a base Dissolving or mixing and dispersing into cream, paste, jelly, gel, emulsion, liquid, etc. forms (ointments, liniments, lotions, etc.); , Vitamin E, squalane and, if necessary, a percutaneous absorption enhancer dissolved or mixed and dispersed, spread on a support (such as a cataplasm), the above-mentioned local anesthetic agent in an adhesive, and vitamin E , Squalane, and, if necessary, a solution obtained by dissolving or mixing and dispersing a transdermal absorption enhancer and the like, spread on a support (a plaster agent, a tape agent, etc.).

As the base, any pharmaceutically acceptable base may be used, and those conventionally known as bases for ointments, liniments, lotions and the like can be used. For example, sodium alginate, gelatin, Corn starch, tragacanth gum, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, dextrin, carboxymethyl starch, polyvinyl alcohol, sodium polyacrylate, methoxyethylene
Polymers such as maleic anhydride copolymer, polyvinyl ether and polyvinylpyrrolidone; beeswax, olive oil, cocoa oil, sesame oil, soybean oil, camellia oil, peanut oil, beef oil, pork oil, lanolin, etc .; white petrolatum; paraffin Gelled hydrocarbons (for example, trade name Plastibase, manufactured by Bristol-Myers Squibb);
Higher fatty acids such as stearic acid; higher alcohols such as cetyl alcohol and stearyl alcohol; polyethylene glycol; surfactants;

Examples of the surfactant include lecithin derivatives, propylene glycol fatty acid esters, glycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyglycerin fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, and polyoxyethylene. Sorbit fatty acid ester, polyoxyethylene alkylphenyl formaldehyde condensate, polyoxyethylene castor oil / hardened castor oil, polyoxyethylene sterol / hydrogenated sterol, polyethylene glycol fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene alkyl Ether, polyoxyethylene alkyl phenyl ether, polyoxyethylene lanolin / lano Emissions alcohol beeswax derivatives, polyoxyethylene alkyl amines, fatty acid amides, polyoxyethylene alkyl ether phosphoric acid-phosphate, but such polymeric emulsifiers include, but are not limited thereto.

Among the above surfactants, polyoxyethylene sorbitan fatty acid esters (for example, POE (20) sorbitan monopalmitate), polyoxyethylene castor oil and hydrogenated castor oil, which have been confirmed to be highly safe, include: Particularly suitable for the present invention.

Further, if necessary, inorganic fillers such as kaolin, bentonite, zinc oxide and titanium oxide; viscosity modifiers; antioxidants; pH regulators; humectants such as glycerin and propylene glycol; buffers; , A fragrance or the like may be added.

The above-mentioned support is appropriately selected according to the dosage form, but is preferably a flexible material which is impermeable or hardly permeable to the active ingredient and is, for example, cellulose acetate, ethyl cellulose, polyethylene, polypropylene, polyvinyl chloride. ,
Vinyl acetate-vinyl chloride copolymer, ethylene-vinyl acetate copolymer, ethylene-vinyl acetate-carbon monoxide copolymer, ethylene-butyl acrylate-carbon monoxide copolymer, polyvinylidene chloride, polyurethane, nylon, polyethylene Resin films such as terephthalate and polybutylene terephthalate; aluminum sheets, woven fabrics, non-woven fabrics and the like; and laminated sheets thereof.

The pressure-sensitive adhesive may be any one which is pharmaceutically acceptable, and conventionally known ones can be used. For example, acrylic pressure-sensitive adhesives, rubber-based pressure-sensitive adhesives, silicone-based pressure-sensitive adhesives, urethane-based pressure-sensitive adhesives Agents and the like, and acrylic pressure-sensitive adhesives and rubber pressure-sensitive adhesives are preferably used. When the adhesive is spread on the support, the properties of the adhesive include solvent-based,
Any type such as an emulsion type and a hot melt type can be used.

Examples of the acrylic pressure-sensitive adhesive include pressure-sensitive adhesives mainly composed of polyalkyl (meth) acrylate obtained by copolymerizing alkyl (meth) acrylate. A copolymer with a functional monomer or another vinyl monomer may be used.

Examples of the above alkyl (meth) acrylate include 2-ethylhexyl (meth) acrylate, dodecyl (meth) acrylate and the like.
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. And the like.

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 and the like. A tackifier such as rosin, rosin ester, terpene resin, terpene phenol resin, petroleum resin, cumarone resin, and cumarone-indene resin is added.

[0034] The amount of the antipruritic and analgesic external preparation of the present invention varies depending on the type of the disease, the degree of the symptoms, the size of the affected part, etc., but is preferably 0.1 to 10 g per day. Apply to affected area in different times.

The diseases to be treated with the antipruritic and analgesic external preparations of the present invention include, for example, hot flashes, sores, insect bites, diaper rash, hives, eczema, allergic dermatitis, razor defeat, genital anal pruritus And skin diseases such as shoe slips, contact dermatitis, atopic dermatitis, palm keratosis and senile pruritus, and pruritus due to chronic renal failure and the like.

[0036]

The topical antipruritic agent of the present invention contains a local anesthetic, vitamin E and squalane, and has a sufficient therapeutic effect even in a preparation containing a low dose of a local anesthetic.
It can suppress side effects of local anesthetics such as urticaria, edema and rash, and has a safe and high therapeutic effect. further,
When the specific transdermal absorption enhancer is contained, the medicinal components (local anesthetic, vitamin E, squalane) are easily absorbed by the skin, and the therapeutic effect can be further improved.

[0037]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited to only these examples.

Examples 1-4 and Comparative Examples 1-3 Predetermined amounts (% by weight) of ethyl 4-aminobenzoate (Sigma), lidocaine hydrochloride (Sigma), vitamin E shown in Table 1 [Tocopherol acetate (manufactured by BASF)], squalane (manufactured by Maruha), gelled hydrocarbon (trade name, Plastibase, manufactured by Bristol-Myers Squibb) and isopropyl myristate (manufactured by Nacalai Tesque) are supplied to a mortar, An ointment was obtained by kneading until the whole became uniform.

Using the ointment obtained above as a sample, a test was conducted by the following method. A 6-week-old male ddY strain mouse was subcutaneously injected with a compound 48/80 (manufactured by Sigma) saline solution at 100 μg / mouse on the back to induce pruritus. The sample was administered by impregnating the sample with a lint cloth of a patch test plaster,
pound 48/80 was applied to the site of administration.
The control group used only gelled hydrocarbon as a sample. Each sample was tested using 5 mice and 15
The number of pruritus movements per minute was measured, and the average value of the five mice is shown in Table 1.

[0040]

[Table 1]

From Table 1, it can be seen that the addition of vitamin E and squalane is more effective in suppressing pruritus than the case where only a low concentration of local anesthetic was administered.
Therefore, the topical antipruritic agent of the present invention is useful for treating the above-mentioned diseases.

[0042]

The composition of the topical antipruritic and analgesic composition according to claim 1 is as described above and contains vitamin E and squalane, so that even a preparation containing a low dose of a local anesthetic has a sufficient therapeutic effect. Therefore, side effects of local anesthetics such as urticaria, edema and rash can be suppressed, and it has a safe and high therapeutic effect.

The composition of the antipruritic analgesic external preparation according to claim 2 comprises:
As described above, since vitamin E, squalane and a local anesthetic are contained in a specific range, even a preparation containing a low dose of a local anesthetic has a sufficient therapeutic effect, such as urticaria, edema, rash, etc. Can suppress the side effects of local anesthetics, and has a safe and high therapeutic effect.

The composition of the antipruritic and analgesic external preparation according to claim 3 comprises:
As described above, since the transdermal absorption enhancer is contained in the antipruritic and analgesic external preparation according to claim 1 or 2, the medicinal component is easily absorbed into the skin, and the therapeutic effect can be further improved.

Claims (3)

[Claims] 1. An antipruritic and analgesic external preparation comprising a local anesthetic, vitamin E and squalane. 2. The content of the local anesthetic is 0.01 to 30% by weight, the content of vitamin E is 1.0 to 99.8% by weight, and the content of squalane is 0.1 to 98% by weight. The topical antipruritic and analgesic preparation according to claim 1, characterized in that: 3. An N-acyl sarcosine (salt),
Higher fatty acid esters which are reaction products of higher fatty acids having 10 to 18 carbon atoms and alcohols having 1 to 20 carbon atoms, dicarboxylic acids (salts) having 2 to 10 carbon atoms, hydroxycarboxylic acids having 3 to 6 carbon atoms and carbon 3. The composition according to claim 1, further comprising at least one transdermal absorption enhancer selected from the group consisting of a hydroxycarboxylic acid ester, which is a reaction product with an alcohol of Formulas 1 to 20, and a fatty acid ethanolamide. 4. Topical antipruritic agent.