JP2001072603A - External preparation containing prednisolone valerate and basic local anesthetic - Google Patents

Abstract

(57) [Summary] (Problems corrected) [PROBLEMS] To provide an external preparation comprising prednisolone acetate valerate and a basic local anesthetic, wherein prednisolone acetate valerate is stable even after long-term storage. SOLUTION: An external preparation containing prednisolone acetate valerate and a basic local anesthetic is adjusted to pH 3-7. In particular, the basic local anesthetic is lidocaine, dibucaine or tetracaine, which is mixed with citric acid, lactic acid, phosphoric acid, malic acid, tartaric acid, acetic acid, sorbic acid, hydrochloric acid or a salt thereof for pH adjustment, and cream Agent or emulsion,
An external preparation for skin that stabilizes prednisolone valerate for a long time.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an external preparation comprising prednisolone acetate valerate and a basic local anesthetic, and more particularly, valeric acid which can stably combine prednisolone acetate valerate for a long period of time. The present invention relates to an external preparation containing prednisolone acetate and a basic local anesthetic.

[0002]

2. Description of the Related Art In recent years, skin diseases typified by atopic dermatitis have become widespread, and research on therapeutic agents therefor has rapidly progressed. Steroid drugs have been applied to these skin diseases accompanied by inflammation. Prednisolone acetate valerate acts as a steroid with a high anti-inflammatory effect on the affected area of the skin surface, is decomposed when absorbed into the body, and its side effects are weakened.It is a so-called anti-drug steroid drug, eczema, dermatitis, rash, heat It is widely used as an external treatment for urticaria. In addition, a local anesthetic is used in an external preparation for the purpose of suppressing pain, itching, hot flashes and the like in the affected area. Therapeutic agents for skin diseases represented by atopic dermatitis include eczema, dermatitis, rash,
However, in addition to skin diseases such as urticaria, external preparations that can treat diseases involving pain, itching, hot flashes, etc. in the affected area with a single agent are desired. Preparation of external preparations containing a steroid and a local anesthetic at the same time However, no external preparation combining a prednisolone acetate valerate and a basic local anesthetic at the same time has been known.

[0003]

However, when an external preparation containing prednisolone acetate valerate and a basic local anesthetic at the same time is prepared, the prednisolone acetate valerate in the preparation becomes unstable with time, and particularly, A stable topical formulation containing prednisolone acetate valerate and a basic local anesthetic at the same time, because the formulation becomes unstable over time when the formulation is a cream or emulsion with a relatively high water content. Was extremely difficult to prepare.

[0004]

Means for Solving the Problems The present inventor has made intensive studies in view of the above facts and found that an external preparation prepared by mixing prednisolone acetate valerate and a basic local anesthetic was adjusted to a specific pH to obtain an external preparation. The present inventors have found that prednisolone acetate valerate in the solution can be stabilized with time, and thus completed the present invention.

[0005] That is, the present invention is to adjust the pH of the suspension when the external preparation containing prednisolone acetate valerate and the basic local anesthetic simultaneously diluted 10 times with purified water to the range of 3-7. Thus, the present invention provides an external preparation which stabilizes prednisolone valerate and a method for stabilizing the same. The external preparation of the present invention is used for the treatment of skin diseases such as eczema, dermatitis, rash, rash, soreness and urticaria of prednisolone acetate valerate, and for the treatment of diseases associated with pain, itching and hot flashes in the affected area with local anesthetics. It is useful as an external preparation that has an action and can be stored for a long time.

[0006] The external preparation of the present invention includes ointments, emulsions and creams, and includes both oil-in-water and water-in-oil preparations. Of these, creams and emulsions are particularly preferred.

The basic local anesthetic used in the external preparation of the present invention includes lidocaine, dibucaine, tetracaine, oxydibucaine, bupivacaine, mepivacaine, propitocaine, diethylaminoethyl parabutylaminobenzoate and the like. Dibucaine and tetracaine are preferred, and lidocaine is particularly preferred.

The base used in the external preparation of the present invention includes petrolatum, plastibase, paraffin, liquid paraffin,
Oily bases such as light liquid paraffin, beeswax, behenyl alcohol, stearyl alcohol, cetanol, stearic acid, behenic acid, silicone oil; water,
Solvents such as macrogol, ethanol, methyl ethyl ketone, cottonseed oil, olive oil, peanut oil, etc .; polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene alkyl ether, sorbitan fatty acid ester Emulsifiers such as nonionic surfactants such as polyoxyethylene polyoxypropylene glycol or ionic surfactants such as sodium lauryl sulfate and sodium cetyl sulfate; polyvinylpyrrolidone, carboxymethylcellulose, colloidal hydrous aluminum silicate, xanthan gum, Thickeners such as locust bean gum, tragacanth gum, guar gum, gelatin, gum arabic, alginic acid, albumin; oxybenzo , Dibutylhydroxytoluene, stabilizers such as sodium edetate; sodium hyaluronate, sodium chondroitin sulfate, glycerin,
1,3-butylene glycol, propylene glycol,
Moisturizers such as urea, sucrose, erythritol, sorbitol; preservatives such as methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, propyl paraoxybenzoate, sodium dehydroacetate, p-cresol, etc. Select and use as appropriate.

The external preparation of the present invention can be adjusted so that the suspension when diluted 10-fold with purified water has a pH of 3 to 7. To adjust the pH, citric acid, lactic acid,
One or more of acids such as phosphoric acid, malic acid, tartaric acid, acetic acid, sorbic acid and hydrochloric acid or water-soluble acids such as sodium salt, potassium salt and calcium salt thereof or salts thereof are used. Preferred are citric acid, lactic acid and malic acid. The amount of the acid or a salt thereof may be any amount as long as the object of the present invention can be achieved. preferable.

The mixing ratio of prednisolone acetate valerate and basic local anesthetic is 0.1 to 100 parts by weight, preferably 3 to 20 parts by weight of basic local anesthetic per 1 part by weight of prednisolone acetate valerate. .

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The external preparation of the present invention is prepared as follows.

For example, a cream or emulsion is prepared by separately heating and dissolving a lipophilic component such as prednisolone acetate valerate and lidocaine and a hydrophilic component such as citric acid, lactic acid and malic acid in a suitable base. The mixture is added to the former, emulsified with stirring using a homomixer or the like, and cooled to room temperature to produce the mixture.

The external preparation of the present invention may contain the following active ingredients in addition to prednisolone acetate valerate and a basic local anesthetic. For example, anti-inflammatory analgesics such as bufexamac, diclofenac, ketoprofen, indomethacin, glycyrrhetinic acid; antihistamines such as diphenhydramine hydrochloride, diphenylpyramine hydrochloride, chlorpheniramine maleate; astringents such as zinc oxide; sterilization such as isopropylmethylphenol and chlorhexidine hydrochloride Agent: sodium ascorbate, pyridoxine hydrochloride,
Vitamin preparations such as tocopherol and tocopherol acetate; antipruritics such as crotamiton; antifungal agents such as tolnaftate, bifonazole and miconazole nitrate; vasoconstrictors such as naphazoline hydrochloride; wound healing agents such as allantoin; menthol, borneol, camphor and peppermint oil And the like, but not limited thereto.

Since the thus obtained external preparation of the present invention has excellent stability over time, prednisolone valerate acetate in the preparation does not become unstable even during long-term storage, and stable prednisolone acetate valerate and It is possible to provide a formulation containing a basic local anesthetic.

[0015]

EXAMPLES The present invention will be described in detail below with reference to examples and comparative examples, but the present invention is not limited to these examples.

Example 1 Prednisolone acetate valerate 0.15 g, lidocaine 2
g, propyl paraoxybenzoate 0.1 g, polyoxyethylene (2) cetyl ether 3.9 g, polyoxyethylene (23) cetyl ether 3.1 g, cetanol 9
g, 8 g of paraffin, 2.5 g of light liquid paraffin, and 3.5 g of lanolin were dissolved by heating. To this solution was added hot water in which 1.5 g of citric acid, 0.5 g of sodium edetate and 0.3 g of xanthan gum were added to make 100 g, then emulsified using a homomixer, cooled to room temperature, and creamed (water Oil type). In addition, this cream was diluted 10-fold with purified water, and the pH of the stirred suspension was 4.3.

Example 2 0.15 g of prednisolone valerate acetate, lidocaine 1
g, 0.1 g of methyl paraoxybenzoate, 0.1 g of propyl paraoxybenzoate, 25 g of white petrolatum, 20 g of stearyl alcohol, 4 g of polyoxyethylene (60) hydrogenated castor oil and 1 g of glycerin monostearate were dissolved by heating. 0.6 g of 90% lactic acid was added to this solution,
Add 1 g of allantoin, 0.5 g of sodium edetate and 12 g of propylene glycol to add hot water and add 10 g
Then, the same operation as in Example 1 was performed to obtain a cream (oil-in-water type). In addition, this cream was diluted 10 times with purified water, and the pH of the stirred suspension was 5.4.

Example 3 0.15 g of prednisolone valerate acetate, 0.1 g of lidocaine.
5 g, 0.025 g of methyl parahydroxybenzoate, 0.015 g of propyl paraoxybenzoate, 2.5 g of stearyl alcohol and 25 g of light liquid paraffin were heated and dissolved. To this solution was added hot water in which 0.3 g of malic acid, 0.5 g of sodium edetate, 1 g of sodium lauryl sulfate and 10 g of glycerin were dissolved to make 100 g,
Next, the mixture was emulsified using a homomixer and cooled to room temperature to obtain an emulsion (oil-in-water type). The emulsion was purified water 10 times.
The pH of the diluted suspension and stirred was 6.0.

Example 4 0.15 g of prednisolone valerate acetate, lidocaine 3
g, tocopherol acetate 0.5 g, ethyl paraoxybenzoate 0.1 g, butyl paraoxybenzoate 0.1 g,
40 g of white petrolatum, 10 g of cetanol, 5 g of beeswax, 5 g of sorbitan sesquioleate (sorbitan sesquioleate) and 0.5 of lauromacrogol (polyoxyethylene (8) lauryl ether) 0.5
g was dissolved by heating. To this solution was added hot water in which 1 g of citric acid, 0.7 g of malic acid and 0.5 g of sodium edetate were dissolved to make 100 g, and then the same operation as in Example 1 was performed to prepare a cream (water-in-oil type). Obtained. The cream was diluted 10-fold with purified water, and the pH of the stirred suspension was 4.0.

Comparative Examples In Examples 1 to 4, preparations were prepared in which the pH of each cream and emulsion was varied, and these were used as comparative examples.

COMPARATIVE EXAMPLE 1 The same operation as in Example 1 was carried out except that citric acid was not added. The cream was diluted 10-fold with purified water and the pH of the stirred suspension was 8.8. Obtained.

Comparative Example 2 The same operation as in Example 2 was carried out except that 90% lactic acid was not added. The cream was diluted 10-fold with purified water and the pH of the stirred suspension was 8.5. I got

Comparative Example 3 The same operation as in Example 3 was carried out except that malic acid was not added, and the emulsion was diluted 10-fold with purified water and the pH of the stirred suspension was 8.2. Was.

Comparative Example 4 The same operation as in Example 4 was carried out except that citric acid and malic acid were not added. The suspension was diluted 10-fold with purified water, and the pH of the stirred suspension was 9.0. A cream was obtained.

Stability test of prednisolone acetate valerate Preparations prepared in each of Examples and Comparative Examples were tested at 50 ° C. and 40 ° C.
Each sample was stored at a relative humidity of 75% for a certain period of time, and prednisolone valerate acetate was quantified. The test results are shown in Tables 1 and 2.

The amount of prednisolone acetate valerate was determined by high performance liquid chromatography under the following conditions. Detector: UV absorption spectrophotometer (measuring wavelength: 243 nm) Column: TSK gel ODS-80TS (Tosoh Corporation)
Mobile phase: Methanol / water (10: 3) mixed solution

[0027]

[Table 1]

[0028]

[Table 2]

As is clear from Tables 1 and 2, it was confirmed that prednisolone valerate in the preparations of Examples was more stable than the preparations of Comparative Examples.

[0030]

The external preparation of the present invention comprises prednisolone acetate valerate, eczema, dermatitis, rash, hot flashes, soreness,
It is useful as a long-term preservable external preparation that has a therapeutic effect on skin diseases such as urticaria and a therapeutic effect on diseases associated with local anesthetics, such as pain, itching, and hot flashes.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/47 A61K 31/47 31/573 31/573 47/04 47/04 47/12 47/12 A61P 17/00 A61P 17/00 (72) Inventor Hidetomo Sakurai Oshikiri, Ogata, Konan-cho, Osato-gun, Saitama 251-2-1 Inside the Central Research Laboratory of Zeria Shinyaku Kogyo Co., Ltd. 2512-1 Numakami 1 Zeria Shinyaku Kogyo Co., Ltd. Central Research Laboratory F term (reference) 4C076 AA07 AA16 BB31 CC01 CC04 CC18 DD22Z DD26Z DD41Z DD43Z FF61 FF63 GG45 4C084 AA19 AA27 MA02 MA05 MA22 MA28 MA63 NA03 ZA212 ZA890 ZB01 MA034 MA21 MA28 MA63 NA03 ZA21 ZA89 ZB11 4C206 AA01 FA37 GA19 GA31 MA03 MA05 MA21 MA41 MA48 MA83 NA03 ZA21 ZA89 ZB11

Claims (6)

[Claims] 1. An external preparation comprising prednisolone acetate valerate and a basic local anesthetic, wherein the pH of the suspension is 3 to 7 when the external preparation is diluted 10-fold with purified water.
An external preparation, characterized in that: 2. The external preparation according to claim 1, wherein the basic local anesthetic is one or more selected from lidocaine, dibucaine and tetracaine. 3. The method according to claim 1, wherein one or more selected from citric acid, lactic acid, phosphoric acid, malic acid, tartaric acid, acetic acid, sorbic acid, hydrochloric acid or salts thereof are added for adjusting the pH. Or the external preparation according to 2. 4. The external preparation according to claim 1, which is a cream or an emulsion. 5. A method of adjusting the pH of a suspension obtained by diluting an external preparation comprising prednisolone valerate acetate and a basic local anesthetic, which is diluted 10-fold with purified water, to 3 to 7. A method for stabilizing prednisolone valerate acetate. 6. The method according to claim 5, wherein one or more selected from citric acid, lactic acid, phosphoric acid, malic acid, tartaric acid, acetic acid, sorbic acid, hydrochloric acid or salts thereof are added for adjusting the pH. Stabilization method as described.