JP2005320257A - Emulsified skin care preparation for external use and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an emulsion-type skin care preparation for external use compounded with prednisolone valerate acetate and having excellent drug stability and usability. <P>SOLUTION: This oil-in-polyhydric alcohol type emulsified preparation contains (a) the prednisolone valerate acetate, (b) an oil component containing a polar oil in an amount of 2-40 mass% based on the total mass of the preparation and 10-50 mass% based on the total oil component, (c) one or more nonionic and/or ionic surfactants and (d) a polyhydric alcohol having ≥2 hydroxyl groups in one molecule. An O/W-type emulsion preparation is produced by slowly adding the oil-in-polyhydric alcohol type emulsion to (e) an aqueous phase component. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to an external pharmaceutical emulsion preparation containing prednisolone valerate acetate and a method for producing the same, and more particularly to an external pharmaceutical emulsion preparation excellent in preparation stability while using an emulsifying base and a method for producing the same.

  In the treatment of skin diseases such as eczema and dermatitis, external preparations for steroids are 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 activity. It is a drug with high safety and relatively few side effects.

  On the other hand, petrolatum ointment and water-in-oil emulsification systems have been used as the base for prednisolone valerate acetate (see Patent Documents 1 to 5). However, the preparation using prednisolone valerate acetate as a drug has good stability when petrolatum ointment is used. was there. Further, in the emulsified system, prednisolone valerate acetate is ester-decomposed to generate odor of valeric acid, and it has been difficult to make a preparation with good temporal stability.

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 present inventors have found that an emulsion prepared from a nonionic and / or ionic surfactant and a polyhydric alcohol having two or more hydroxyl groups in the molecule is valeric acid. It has been found that even when prednisolone acetate is added, the preparation / drug has good stability over time, and there is no off-flavor, and the usability can be improved. The present invention has been completed.

  That is, the present invention comprises (a) prednisolone valerate acetate, (b) an oil containing 2 to 40% by weight of a polar oil based on the total weight of the formulation, and 10 to 50% by weight based on the total oil, (c (1) one or more nonionic and / or ionic surfactants and (d) a polyhydric alcohol-in-oil type comprising a polyhydric alcohol having two or more hydroxyl groups in the molecule It is a pharmaceutical emulsified preparation for external use on the skin.

  The production method also includes (a) prednisolone acetate valerate and (b) an oil component containing 2 to 40% by mass of a polar oil based on the total mass of the preparation and 10 to 50% by mass based on the total oil. The oil phase is converted into a polyhydric alcohol phase containing (c) one or more nonionic and / or ionic surfactants and (d) a polyhydric alcohol having two or more hydroxyl groups in the molecule. It is characterized by producing an oil-in-polyol emulsified preparation by gradually adding.

  Furthermore, according to the present invention, (a) prednisolone acetate valerate and (b) an oil component containing 2 to 40% by mass of a polar oil component with respect to the total mass of the preparation and 10 to 50% by mass with respect to the total oil component, (C) a polyhydric alcohol-in-oil emulsion containing one or more nonionic and / or ionic surfactants and (d) a polyhydric alcohol having two or more hydroxyl groups in the molecule, (E) Provided is a method for producing an oil-in-water type external pharmaceutical emulsion preparation, characterized in that an oil-in-water type emulsion preparation is produced by gradually adding it to an aqueous phase component.

  ADVANTAGE OF THE INVENTION According to this invention, it is an emulsification type external skin pharmaceutical formulation which mix | blended prednisolone valerate acetate, Comprising: Usability, The external pharmaceutical emulsification formulation with favorable time-dependent stability of a formulation and a medicine can be provided. Furthermore, by adding an aqueous phase component to this emulsion, it is possible to obtain an emulsion having a good formulation / drug stability over time, and having a cream-like to emulsion-like appearance and a lotion-like appearance. It is possible to use properly depending on the taste of the.

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

  Examples of the (b) oil used in the present invention include solid oil, semi-solid oil, and liquid oil. Among these, typical examples of the solid oil include microcrystalline wax, ceresin, bees wax, and higher alcohol, and examples of the semi-solid oil include petrolatum, medium-chain fatty acid triglyceride, and the like. Liquid oils include liquid polar oils and liquid nonpolar oils.

  Among liquid oils, 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, isostearic acid Examples include medicinal components such as fatty acid monoesters such as hexadecyl and cetyl isooctanoate, triglycerides such as glyceryl triisooctanoate, crotamiton, and diphenhydramine.

  Among liquid oils, examples of liquid nonpolar oils include liquid paraffin, squalane, dimethylpolysiloxane, and cyclic silicone.

  In the present invention, the blending amount of (b) oil is, for example, 10 to 85% by mass, more preferably 12 to 80% by mass, based on the total mass of the preparation.

  The polar oil content is, for example, 2 to 40% by mass, more preferably 4 to 30% by mass, based on the total mass of the preparation. Moreover, it is preferable to contain 10-50 mass% with respect to the total oil content. If there is too much polar oil in the total oil, the polarity of the oil will increase and a good emulsion cannot be obtained. If there is too little polar oil in the total oil, prednisolone valerate acetate cannot be dissolved.

In the present invention, (c) one or more nonionic and / or ionic surfactants are used.
Nonionic surfactants include those represented by the following (I) to (VI).
(I) Lanolin and lanolin fatty acid, lanolin alcohol ethylene oxide 15-80 mol adduct, cholesterol and cholestanol ethylene oxide 15-60 mol adduct,
(II) A product obtained by further adding 20 to 80 mol of ethylene oxide to 1 to 12 mol of propylene oxide adduct of cetanol, cholesterol and cholestanol,
(III) 30-100 mol ethylene oxide adduct of castor oil and hydrogenated castor oil,
(IV) A product obtained by further adding 30 to 80 mol of ethylene oxide to an adduct of 1 to 12 mol of propylene oxide of castor oil and hydrogenated castor oil,
(V) ethylene oxide 20-100 mol adduct of oleic acid monoglyceride and stearyl glyceryl ether,
(VI) A product obtained by further adding 20 to 80 mol of ethylene oxide to 1 to 12 mol of propylene oxide adduct of oleic acid monoglyceride and stearyl glyceryl ether.

  On the other hand, examples of ionic surfactants include alkyl sulfates typified by sodium cetyl sulfate, sodium salts of acylated glutamic acid and triethanolamine salts (for example, Amisoft HS-11 manufactured by Ajinomoto Co., Inc.), acylated hydrolyzed proteins Potassium salts (for example, promois manufactured by Seiwa Kasei Co., Ltd.), fatty acid salts represented by potassium stearate, and the like.

Particularly preferred among the components (c) are the nonionic surfactants (II) and (III).
(C) 1 type, or 2 or more types of nonionic and / or ionic surfactant of this invention are 0.1-10 mass% with respect to the total mass of a formulation, More preferably, 0.5- It is appropriate to add 8% by mass.

Examples of the polyhydric alcohol having two or more hydroxyl groups in the molecule used in the present invention include dihydric alcohols such as ethylene glycol, propylene glycol, 1,3-butylene glycol and hexylene glycol, and 3 such as glycerin. Polyhydric alcohols, tetrahydric alcohols such as pentaerythritol, pentahydric alcohols such as xylitol, hexahydric alcohols such as sorbitol and mannitol, polyhydric alcohol polymers such as diethylene glycol, dipropylene glycol, diglycerin and polyethylene glycol, ethylene glycol monomethyl Examples include dihydric alcohol alkyl ethers such as ether, ethylene glycol dibutyl ether, and diethylene glycol monomethyl ether, which are used alone or in combination of two or more.
Particularly preferred are propylene glycol, 1,3-butylene glycol, dipropylene glycol, polyethylene glycol 300, polyethylene glycol 400, and glycerin.

  The polyhydric alcohol having two or more hydroxyl groups in the molecule (d) of the present invention is, for example, 0.5 to 50% by mass, more preferably 1 to 45% by mass, based on the total mass of the preparation. Is appropriate.

  In the present invention, in addition to the polyhydric alcohol, ethanol, dimethyl ether of a polyoxyethylene / polyoxypropylene random polymer, and the like can also be blended.

Furthermore, in the case of a polyhydric alcohol oil-in-the-oil external pharmaceutical emulsion preparation, a better emulsion can be obtained by using a small amount of purified water in combination with the polyhydric alcohol.
In addition, in the case of an oil-in-water type external pharmaceutical emulsion formulation, (e) an aqueous phase component is included. (E) In addition to water, the water phase component may include diphenhydramine hydrochloride, various thickeners, chelating agents, preservatives, lower alcohols, and other raw materials blended in conventional cosmetics and pharmaceutical preparations. A preferable blending amount of water is 3 to 80% by mass.

The oil-in-oil type external pharmaceutical emulsified preparation of the present invention comprises (a) prednisolone acetate valerate and (b) polar oil in an amount of 2 to 40% by mass relative to the total mass of the formulation and 10% of the total oil. An oil phase containing an oil content of ˜50% by mass, (c) one or more nonionic and / or ionic surfactants, and (d) a polyvalent having two or more hydroxyl groups in the molecule. It is produced by gradually adding to a polyhydric alcohol phase containing alcohol.
In the oil-in-polyhydric oil-based external pharmaceutical emulsion preparation of the present invention, a surfactant is first added to the polyhydric alcohol, and an oil phase is added thereto to produce a fine polyhydric alcohol-in-oil emulsion. This is an emulsified state in which oil is dispersed in a surfactant and a polyhydric alcohol solution.

The oil-in-water type external pharmaceutical emulsion preparation of the present invention comprises (a) prednisolone acetate valerate and (b) 2 to 40% by mass of the polar oil based on the total mass of the formulation and 10 to 50 based on the total oil. A polyhydric compound containing an oil component containing by mass%, (c) one or more nonionic and / or ionic surfactants, and (d) a polyhydric alcohol having two or more hydroxyl groups in the molecule. It is produced by gradually adding an oil-in- alcohol emulsion to the (e) water phase component.
The oil-in-water external skin pharmaceutical emulsion preparation of the present invention can be made into an oil-in-water external skin emulsion by adding the oil-in-polyhydric oil emulsion to the aqueous phase component.
Both the polyhydric alcohol oil-in-water emulsion and the oil-in-water emulsion are uniform and fine emulsions having an emulsified particle size of 1 μm or less.

Next, examples of the present invention will be described.
Examples 1 and 2 and Comparative Example 1
A preparation was prepared according to the formulation shown in Table 1 below, the emulsified particle size was measured, and storage stability and odor evaluation after one month were performed. Moreover, the remaining amount of prednisolone valerate acetate and diphenhydramine hydrochloride after one month was quantified. The quantitative method is a liquid chromatography method. The results are shown in Table 1. As for storage stability and odor evaluation, “stable” and “no off-flavor” were defined as those having a stability or no off-flavor for all of 0 ° C. to 50 ° C. The same applies to the following evaluations.

From Table 1 above, it can be seen that the pharmaceutical preparation for external use of the skin of the present invention is excellent in preparation / drug and odor stability.
Examples 1 and 2 are oil emulsified preparations for external use in the skin of polyhydric alcohol. When the preparation method is shown based on Example 1, the oil phase is No. 1. 1 to 8 are heated and dissolved uniformly, while the polyhydric alcohol phase is No.1. It is obtained by heating 9 to 15 to dissolve uniformly and gradually adding the oil phase to the polyhydric alcohol phase while homogenizing.
The emulsion thus prepared had very fine and uniform emulsion particles. For comparison, an attempt was made to prepare a preparation with the formulation of Comparative Example 1, but it was separated immediately after preparation because it contained a large amount of polar oil including crotamiton.

(Examples 3 to 5, Comparative Example 2)
A preparation was prepared according to the formulation shown in Table 2 below, the emulsified particle size and viscosity were measured, and storage stability and odor were evaluated after one month. Moreover, the remaining amount of prednisolone valerate acetate and diphenhydramine hydrochloride after one month was quantified. The quantitative method is a liquid chromatography method. The results are shown in Table 2.

From Table 2, it can be seen that the external skin pharmaceutical emulsion preparation of the present invention is excellent in preparation / drug and odor stability.
Examples 3 to 5 are oil-in-water type skin external pharmaceutical emulsion preparations obtained by diluting a polyhydric alcohol-in-oil emulsion into an aqueous phase component. When the preparation method is shown based on Example 3, the oil phase is No. 1 as the first step. 1 to 8 are heated and dissolved uniformly, while the polyhydric alcohol phase is No.1. 9 and 10 parts 5 and 11 are heated and dissolved uniformly, and the oil phase is gradually added to the polyhydric alcohol phase while homogenizing to obtain a polyhydric alcohol-in-oil emulsion.

  The emulsion thus obtained has very fine and uniform emulsion particles. As the second stage, the polyhydric alcohol-in-oil emulsion obtained in the first stage is No. No. 10 in the balance of No. 10. It is an oil-in-water emulsion obtained by adding and diluting to the water phase which melt | dissolved 12-16 while stirring. In particular, Example 5 is a skin lotion containing alcohol having substantially no viscosity, and is particularly excellent in convenience and usability during application.

In Comparative Example 2, the same formulation as in Example 3 was used as a normal emulsification method, that is, as an oil phase instead of the preparation method of the present invention. 1 to 8 are heated and dissolved uniformly, while the aqueous phase is No. 1. 9 to 15 were similarly heated and dissolved uniformly, and the oil phase was gradually added to the aqueous phase and homogenized. As is apparent from Table 2, the emulsion prepared by such a normal emulsification method has a large emulsified particle size and a wide particle size distribution, and the emulsified state is not good, resulting in poor storage stability. It was.

Claims (3)

  (A) prednisolone acetate valerate, (b) oil containing 2 to 40% by weight of polar oil with respect to the total weight of the formulation and 10 to 50% by weight with respect to the total oil, and (c) one or two kinds A non-ionic and / or ionic surfactant as described above, and (d) a polyhydric alcohol having two or more hydroxyl groups in the molecule, and an oil-in-oil external pharmaceutical emulsion preparation characterized by comprising .   (C) an oil phase comprising (a) prednisolone valerate acetate and (b) an oil component containing 2 to 40% by weight of a polar oil based on the total weight of the preparation and 10 to 50% by weight based on the total oil. By gradually adding to a polyhydric alcohol phase comprising one or more nonionic and / or ionic surfactants and (d) a polyhydric alcohol having two or more hydroxyl groups in the molecule. A method for producing an oil-in-polyhydric oil-in-oil external pharmaceutical emulsion preparation, characterized by producing an oil-in-polyhydric oil-in-water emulsion preparation. (A) prednisolone acetate valerate, (b) oil containing 2 to 40% by weight of polar oil with respect to the total weight of the formulation and 10 to 50% by weight with respect to the total oil, and (c) one or two kinds A polyhydric alcohol-in-oil emulsion containing the above nonionic and / or ionic surfactant and (d) a polyhydric alcohol having two or more hydroxyl groups in the molecule; A method for producing an oil-in-water type external skin pharmaceutical emulsion, characterized in that an oil-in-water type emulsion formulation is produced by gradually adding to an oil.