JP2005200328A - Skin care medicine preparation for external use - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a skin care medicine preparation for external use, which is obtained by formulating prednisolone valerate acetate with diphenhydramine, has excellent usability, emits no offensive smell with time and has excellent stability. <P>SOLUTION: This skin care medicine preparation for external use is obtained by formulating (a) prednisolone valerate acetate with (b) diphenhydramine or its salt, (c) organic modified clay mineral, (d) a nonionic surfactant having HLB 3-13 and (e) oil. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a pharmaceutical preparation for external use containing prednisolone valerate acetate, and more particularly to a pharmaceutical preparation for external application using an oily gel base and excellent in formulation stability.

In the treatment of skin diseases such as eczema and dermatitis, topical steroid preparations have been widely used, exhibiting excellent effects on these symptoms, and many synthetic steroids have been developed. Among them, prednisolone valerate acetate is classified as rank III (strong) in the steroid potency rank classification, and exhibits excellent local anti-inflammatory action, but is rapidly metabolized to a less active compound after absorption in the blood. It is a drug with high safety and relatively few side effects.
Furthermore, since prednisolone valerate acetate does not have sufficient antipruritic action, it has been practiced in combination with prednisolone valerate acetate and an antihistamine to provide antipruritic and anti-inflammatory effects in itch-related skin diseases (patented) Reference 1).

  On the other hand, as a base for these medicinal substances, petrolatum ointment and water-in-oil type emulsification systems have been conventionally used (Patent Documents 2 to 6). However, a preparation using prednisolone valerate acetate as a drug has a drawback that although the preparation stability is good when petrolatum ointment is used, the drug is dispersed in the form of crystals and the absorbability is poor. On the other hand, in the emulsified system, prednisolone valerate acetate is ester-decomposed and the smell of valeric acid is generated, and it is difficult to make a preparation with good stability over time.

JP 2002-356430 A JP-A-6-72850 JP-A 63-255227 Japanese Patent Laid-Open No. 2001-151662 JP 2001-181166 A Japanese Patent Laid-Open No. 9-249547

  As a result of intensive studies, the inventors of the present invention dissolved an oil-based gel base prepared with an organically modified clay mineral, a specific nonionic surfactant, and an oil to dissolve the prednisolone valerate acetate drug, In addition, the inventors have found that the stability over time can be improved, and have completed the present invention.

  The present invention comprises (a) prednisolone valerate acetate, (b) diphenhydramine, (c) an organically modified clay mineral, (d) a nonionic surfactant having an HLB of 3 to 13, and (e) an oil component. Is a pharmaceutical preparation for external use on the skin.

ADVANTAGE OF THE INVENTION According to this invention, it is an external skin pharmaceutical formulation which mix | blended prednisolone valerate acetate and diphenhydramine, Comprising: Usability, The generation | occurrence | production of off-flavor does not generate | occur | produce with time, The skin external pharmaceutical formulation excellent in stability can be provided.
In particular, in the conventional combination with diphenhydramine, the odor stability was poor in the system containing water, but by using this oily gel base, there is no off-flavor and stable, and the drug is the base. Since it was dissolved, a product with good absorbability was obtained.

Hereinafter, the present invention will be described in detail.
(A) Prednisolone valerate acetate used in the present invention is suitably blended in an amount of 0.01 to 1% by mass, more preferably 0.1 to 0.3% by mass, based on the total mass of the preparation.

  (B) The diphenhydramine of this invention is 0.01-3.0 mass% with respect to the total mass of a formulation, for example, More preferably, it is suitable to mix | blend 0.1-2.0 mass%.

(C) The organically modified clay mineral blended in the present invention is a kind of colloidal hydrous aluminum silicate having a three-layer structure, and is generally a quaternary ammonium salt type clay mineral represented by the following general formula (1) It is modified with a cationic surfactant. The mixing ratio of the quaternary ammonium salt type cationic surfactant to the clay mineral is 60 to 120 meq, preferably 80 to 100 meq, of the quaternary ammonium salt type cationic surfactant with respect to 100 g of the clay mineral.

  (However, X = Al, Fe (III), Mn (III), Cr (III), Y = Mg, Fe (II), Ni, Zn, Li, Z = K, Na, Ca)

  Specifically, there are montmorillonite groups of natural or synthetic (in this case, the (OH) group in the formula is substituted with fluorine) such as montmorillonite, saponite, hectorite, etc. (commercially available products are bee gum, kunipia, laponite, etc.). ) And synthetic mineral mica known as sodium silicic mica and sodium or lithium teniolite (commercially available products include Dimonite: Topy Industries, Ltd.) and quaternary ammonium salt type cationic surfactants. Is obtained by processing.

  The quaternary ammonium salt type cationic surfactant used here is represented by the following general formula (2).

Wherein R ¹ is an alkyl group having 10 to 22 carbon atoms or a benzyl group, R ² is a methyl group or an alkyl group having 10 to 22 carbon atoms, R ³ and R ⁴ are alkyl groups having 1 to 3 carbon atoms or hydroxy An alkyl group, X represents a halogen atom or a methyl sulfate residue)

  Examples of the quaternary ammonium salt type cationic surfactant include dodecyltrimethylammonium chloride, myristyltrimethylammonium chloride, cetyltrimethylammonium chloride, stearyltrimethylammonium chloride, aralkyltrimethylammonium chloride, behenyltrimethylammonium chloride, myristyldimethylethylammonium. Chloride, cetyldimethylethylammonium chloride, stearyldimethylethylammonium chloride, aralkyldimethylethylammonium chloride, behenyldimethylethylammonium chloride, myristyldiethylmethylammonium chloride, cetyldiethylmethylammonium chloride, stearyldiethylmethylammonium chloride, arachi Diethylmethylammonium chloride, behenyldiethylmethylammonium chloride, benzyldimethylmyristylammonium chloride, benzyldimethylcetylammonium chloride, benzyldimethylstearylammonium chloride, benzyldimethylbehenylammonium chloride, benzylmethylethylcetylammonium chloride, benzylmethylethylstearylammonium chloride, di Examples include stearyldimethylammonium chloride, dibehenyl dihydroxyethylammonium chloride, and corresponding bromides, and dipalmitylpropylethylammonium methyl sulfate. In carrying out the present invention, one or more of these are arbitrarily selected.

  Representative examples of the organically modified clay mineral include dimethylalkylammonium hectorite, benzyldimethylstearylammonium hectorite, distearyldimethylammonium chloride-treated aluminum magnesium silicate, and the like. Benton 27 (benzyldimethylstearyl ammonium chloride-treated hectorite: manufactured by National Red) and Benton 38 (distearyldimethylammonium chloride-treated hectorite: manufactured by National Red) are preferable as commercial products.

  The blending amount of the (c) organically modified clay mineral blended in the present invention is 5 to 20% by mass, more preferably 8 to 18% by mass. If the amount of the organically modified clay mineral is less than 5% by mass, sufficient hardness cannot be obtained and the stability is poor, and if it exceeds 20% by mass, the hardness is excessive and preparation is very difficult.

The nonionic surfactant (d) having an HLB of 3 to 13 of the present invention more preferably has an HLB of 6 to 10.
Examples of such nonionic surfactants include the following.
(1) Polyoxyethylene cetyl ether, polyoxyethylene isocetyl ether, polyoxyethylene oleyl ether, polyoxyethylene stearyl ether, polyoxyethylene isostearyl ether, polyoxyethylene dodecyl ether, polyoxyethylene tetradecyl ether, polyoxy Polyoxyethylene higher alcohol ethers such as ethylene octyldodecyl ether and polyoxyethylene behenyl ether (2) Polyoxyethylene oleic acid ester, polyoxyethylene stearic acid ester, polyoxyethylene isostearic acid ester, polyoxyethylene behenic acid ester Polyoxyethylene higher fatty acid monoesters such as polyethylene glycol diisostearate, polyethylene glycol Polyethylene glycol fatty acid diester such as oleate (4) Polyoxyethylene polyoxypropylene decyl ether (5) Monoglyceryl stearate, monoglyceryl polyoxyethylene stearate, glyceryl polyoxyethylene monoisostearate, glyceryl polyoxyethylene triisostearate, etc. (6) Ether esters such as stearic acid polyoxyethylene cetyl ether and stearic acid polyoxyethylene stearyl ether (7) polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil

  Of these, polyethylene glycol diisostearate, polyethylene glycol dioleate, polyoxyethylene dodecyl ether, and polyoxyethylene triisostearate glyceryl are particularly preferable.

  The nonionic surfactant (d) having an HLB of 3 to 13 of the present invention is, for example, 0.5 to 6.0% by mass, more preferably 0.8 to 5.4% by mass with respect to the total mass of the preparation. % Is suitable.

  Further, the blending ratio of (d) a nonionic surfactant having an HLB of 3 to 13 and (c) an organically modified clay mineral is (d) a nonionic surfactant having an HLB of 3 to 13 / (c ) The organically modified clay mineral is 0.1 / 1 to 0.3 / 1, preferably 0.15 / 1 to 0.25 / 1, more preferably 0.2 / 1. At these ratios, the oily gel has the highest hardness and stability.

Examples of the oil (e) used in the present invention include solid oil, semi-solid oil, and liquid oil. Among these, typical examples of solid oils include microcrystalline wax, higher alcohols, and semi-solid oils include petrolatum, medium-chain fatty acid triglycerides, and the like.
Liquid oils include liquid polar oils and liquid nonpolar oils.
Among these, liquid polar oils include dicarboxylic acid diesters such as diethyl sebacate, diisopropyl sebacate, diisopropyl adipate, diisobutyl adipate, dioctyl adipate, octyldodecyl myristate, isopropyl myristate, myristyl myristate, hexadecyl isostearate. , Fatty acid monoesters such as cetyl isooctanoate, triglycerides such as glycerin triisooctanoate, crotamiton and the like. Examples of the liquid nonpolar oil include liquid paraffin, squalane, dimethylpolysiloxane, and cyclic silicone.

(E) The blending amount of the oil is, for example, 74 to 95% by mass, more preferably 76 to 92% by mass, based on the total mass of the preparation. In order to give an appropriate hardness to the preparation, there is an optimum amount and ratio of the organically modified clay mineral and the nonionic surfactant, and the total mass is 100% in terms of oil or the like.
Further, in order to dissolve prednisolone valerate acetate, it is desirable to blend 27% by mass or more of polar oil in the total oil.

  Next, examples of the present invention will be described. Prior to the examples, the presence or absence of crystallization of the drug due to the difference in the type of oil when (a) prednisolone valerate acetate and (b) diphenhydramine were used as the drug was measured. The results are shown in Table 1. The units in Table 1 are parts by mass. It can be seen from Table 1 that the drug dissolves when the polar oil is 27 parts by mass or more.

Example 1 and Comparative Example 1
A preparation was prepared according to the formulation shown in Table 2 below, and the remaining amounts of prednisolone valerate and diphenhydramine after one month were quantified. The quantitative method is a liquid chromatography method. The results are also shown in Table 2. In the table, “out of quantification range (about 20%)” means outside the calibration curve range.
The HLB of the polyethylene glycol 600 di-isostearate, which is a nonionic surfactant, is 7.

  From Table 2, it can be seen that the pharmaceutical preparation for external application of the present invention is excellent in stability.

  Next, odor evaluation after leaving the pharmaceutical preparation for external use of Example 1 and Comparative Example 1 at RT, 40 ° C. and 50 ° C. for one month was performed according to the following criteria. The results are shown in Table 3.

Evaluation criteria 1: No change 2: Almost no change 3: Some change 4: Large change (with a strange odor)

Claims (3)

  (A) Prednisolone valerate acetate, (b) diphenhydramine, (c) an organically modified clay mineral, (d) a nonionic surfactant having an HLB of 3 to 13, and (e) an oil component. A pharmaceutical preparation for external application to the skin.   2. The external preparation for skin according to claim 1, wherein the component (d) is a nonionic surfactant having an HLB of 6 to 10. 2. The external preparation for skin according to claim 1, wherein the oil component contains 27% by mass or more of a polar oil component in the total oil component.