JP2008297212A - O/w type emulsified preparation containing prednisolone valerate acetate - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a preparation having a high stability by inhibiting the separation of an O/W type emulsified preparation containing prednisolone valerate acetate and petroleum jelly. <P>SOLUTION: This O/W type emulsified preparation contains the prednisolone valerate acetate, petroleum jelly, and hydroxypropylcellulose. The blended amount of the prednisolone valerate acetate is preferably 0.01 to 1 mass% based on the whole preparation. Thereby, it is possible to provide the prednisolone valerate acetate and petroleum jelly excellent in humectant property and use feeling, hardly causing separation over time, especially the separation under a high temperature environment and having an appearance stability. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to an O / W emulsion preparation containing prednisolone valerate acetate and a separation inhibitor thereof.

  Corticosteroid prednisolone valerate is classified as rank IV in the steroid efficacy rank classification, and it exhibits excellent anti-inflammatory activity in the affected area, but it is a highly safe drug that changes to a low active substance in the body (ante drug) It is widely used as a therapeutic agent for eczema, dermatitis, rash, insect bites, itching, rashes, hives, etc.

  Ointments, creams, emulsions and lotions are known as external preparations containing prednisolone valerate acetate. In particular, O / W emulsion preparations containing prednisolone valerate acetate blended with petrolatum as a moisturizing agent are less sticky than W / O emulsion preparations, and are widely used as pharmaceutical preparations with a high feeling of use. Even over-the-counter drugs are marketed.

  However, the O / W type emulsion formulation containing prednisolone valerate acetate and petrolatum has a problem that the emulsification system tends to become unstable, separates with time, and has poor appearance stability, particularly in a high temperature environment. there were.

  In order to solve such a problem of separation over time, various preparation studies have been made so far. For example, a skin external pharmaceutical preparation characterized by containing prednisolone valerate, diphenhydramine, an organically modified clay mineral, a nonionic surfactant having an HLB of 3 to 13, and an oil (see Patent Document 1), Prednisolone valerate acetate, polar oil is 2 to 40% by mass in the total mass of the preparation, and 10 to 50% by mass in the total oil, and one or more nonionic and / or ionic Known is a polyhydric alcohol oil-in-skin external pharmaceutical emulsion formulation (see Patent Document 2) characterized by containing a surfactant and a polyhydric alcohol having two or more hydroxyl groups in the molecule.

However, these prior arts do not describe at all the separation inhibitory action of the O / W type emulsion preparation containing prednisolone valerate acetate and petrolatum by hydroxypropylcellulose.
JP 2005-200328 A JP 2005-320257 A

  An object of the present invention is to suppress the separation of an O / W emulsion preparation containing prednisolone valerate acetate and petrolatum, and to obtain a preparation having high appearance stability.

  As a result of intensive studies in view of such circumstances, the present inventors have shown that hydroxypropyl cellulose suppresses separation over time of an O / W emulsion formulation containing prednisolone valerate acetate and petrolatum, particularly in a high-temperature environment. And when it was used, it discovered that a formulation with favorable external appearance stability could be obtained, and completed this invention.

  That is, the present invention provides an O / W emulsion formulation containing prednisolone valerate acetate, hydroxypropylcellulose and petrolatum.

  The present invention also provides a separation inhibitor for an O / W emulsion formulation containing prednisolone valerate acetate and petrolatum containing hydroxypropylcellulose as an active ingredient.

According to the present invention, an O / W type emulsified preparation containing prednisolone valerate acetate and petrolatum having excellent moisturizing property and feeling of use, segregation with time, particularly, high-temperature environment, and good appearance stability. Can be provided.
With the use of the separation inhibitor of the present invention, it is possible to prevent separation over time of an O / W emulsion formulation containing prednisolone valerate acetate and petrolatum, particularly separation in a high temperature environment, and to obtain a preparation with good appearance stability. it can.

  Prednisolone valerate acetate used in the present invention is an active ingredient of the preparation of the present invention, and the content thereof is 0.O in the amount of the O / W type emulsion preparation of the present invention in terms of effectiveness, safety and stability. 01 to 1% by mass, particularly 0.05 to 0.5% by mass is preferable.

  Vaseline used in the present invention is a component mainly blended as a humectant, and white petrolatum is preferred. The content of petrolatum is preferably from 0.1 to 30% by mass, particularly preferably from 10 to 20% by mass, in the O / W type emulsion preparation of the present invention from the viewpoint of the moisturizing effect, the feeling of use and the appearance stability.

The hydroxypropyl cellulose used in the present invention is not particularly limited, and any hydroxypropyl cellulose having different hydroxypropoxy group substitution rate, molecular weight, and viscosity may be used, or these may be used alone or in admixture of two or more. can do. The substitution rate of the hydroxypropoxy group of the hydroxypropyl cellulose is preferably in the range of 5 to 78%, more preferably in the range of 53 to 78% from the viewpoint of solubility in water. The hydroxypropoxy group substitution rate of hydroxypropylcellulose is determined according to the hydroxypropoxy group quantification method of hydroxypropylcellulose and low-substituted hydroxypropylcellulose described in the 15th revision Japanese Pharmacopoeia. Hydroxypropyl cellulose can be distinguished by the viscosity at 20 ° C. of a 2% aqueous solution (measured with a B-type viscometer), but is preferably 3 to 4000 cps, more preferably 150 to 4000 cps from the viewpoint of the effect of suppressing separation. 1000 to 4000 cps is particularly preferable. Specifically, commercially available products include, for example, HPC-SL (3.0 to 5.9 cps), HPC-L (6.0 to 10.0 cps), HPC-M (150 to 400 cps), HPC-H ( 1000-4000 cps): (Nippon Soda Co., Ltd.) and the like, and HPC-H: (Nippon Soda Co., Ltd.) is particularly preferable.
The content of hydroxypropyl cellulose is more preferably 0.01 to 3% by mass and 0.03 to 1% by mass in the O / W type emulsion preparation of the present invention from the viewpoint of separation inhibitory effect, usability and production. 0.05-0.5 mass% is especially preferable.

In the present invention, the content ratio (mass ratio) of prednisolone valerate and petrolatum is 1: 3000 to 10: 1 from the viewpoint of the medicinal effect of prednisolone valerate acetate, the moisturizing effect of petrolatum, and the dispersibility of prednisolone valerate acetate. Is preferable, and 1: 400 to 1:20 is more preferable.
The content ratio (mass ratio) of petrolatum and hydroxypropyl cellulose in the present invention is preferably 1:30 to 3000: 1, more preferably 20: 1 to 400: 1, respectively, from the viewpoint of the moisturizing effect of petrolatum and the separation stability. preferable.

  Other components of the O / W type emulsion preparation of the present invention include oils other than petrolatum, surfactants, water and the like.

The oil other than petrolatum used in the O / W type emulsion preparation of the present invention is not particularly limited as long as it is an oil-soluble substance that is usually used in the fields of pharmaceuticals, quasi drugs, cosmetics, etc. For example, hydrocarbons, fats and oils, waxes, fatty acids, higher alcohols, esters, silicone oils and the like can be mentioned, and hydrocarbons are particularly preferable, and specific examples thereof include liquid paraffin and squalane.
The content of oil other than petrolatum is not particularly limited, but is usually 0.1 to 30% by mass, and particularly preferably 1 to 20% by mass in the O / W emulsion formulation of the present invention.

  Examples of the surfactant used in the O / W type emulsion preparation of the present invention include a cationic surfactant, an anionic surfactant, an amphoteric surfactant, and a nonionic surfactant. Ionic surfactants are preferred.

  Specific examples of the nonionic surfactant include propylene glycol monofatty acid ester, ethylene glycol monofatty acid ester, glycerin monofatty acid ester, polyglycerin fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, methyl glucoside fatty acid ester, alkylpolyester. Polyhydric alcohol fatty acid ester or polyhydric alcohol alkyl ether such as glucoside; polyoxyethylene alkyl ether, polyoxyethylene alkylphenyl ether, polyoxyethylene phytosterol, polyoxyethylene phytostanol, polyoxyethylene cholesterol, polyoxyethylene cholestanol, Polyoxyethylene ethers such as polyoxyethylene polyoxypropylene alkyl ether; polyoxyethylene Mono-fatty acid ester, polyethylene glycol difatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene methyl glucoside fatty acid ester, polyoxyethylene castor oil / cured castor oil, poly Examples thereof include ether esters such as oxyethylene vegetable oil, polyoxyethylene alkyl ether fatty acid ester and polyoxyethylene polyoxypropylene glycol, and sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, and polyoxyethylene sorbitan fatty acid ester are preferable.

  The carbon number of the fatty acid in the sorbitan fatty acid ester and the polyoxyethylene sorbitan fatty acid ester is preferably 12-20, more preferably 16-20, and particularly preferably 18. The addition number of ethylene oxide in the polyoxyethylene hydrogenated castor oil is preferably 5 to 100, and more preferably 30 to 60.

  Moreover, it is preferable that HLB of a nonionic surfactant is 2-18, and it is more preferable that it is 3-17. For example, it is preferable that HLB of sorbitan fatty acid ester is 2-9, and it is more preferable that it is 3-6. It is preferable that HLB of polyoxyethylene hydrogenated castor oil is 10-17, and it is more preferable that it is 12-15. It is preferable that HLB of polyoxyethylene sorbitan fatty acid ester is 9-18, and it is more preferable that it is 14-17.

  Although it does not restrict | limit especially as content of surfactant, Usually, 0.1-10 mass% in the O / W type emulsion formulation of this invention, 1-5 mass% is preferable.

  The content of water in the O / W type emulsion preparation of the present invention varies depending on the dosage form, but is generally 35 to 95% by mass, particularly preferably 60 to 85% by mass. In addition, content of water in the case of a cream agent is 35-80 mass%, and 60-75 mass% is more preferable especially. The content of water in the case of an emulsion is preferably 45 to 90% by mass, particularly 70 to 85% by mass. The content of water in the case of lotion is preferably 50 to 95% by mass, particularly preferably 75 to 90% by mass.

The O / W type emulsion preparation of the present invention may contain various components alone or in combination of two or more, if necessary, in addition to the above components.
Such a component is not particularly limited as long as it is a component that is generally used for an external preparation in the pharmaceutical, quasi-drug or cosmetic field. For example, a base, a thickener, a preservative, a pH adjuster, a stable In addition to pharmacologically active ingredients, local anesthetics, antipruritics, anti-inflammatory agents, vitamins, antibacterial agents, antiviral agents, antifungal agents, etc. , Wound healing agents, keratin softeners, analgesics, moisturizers, whitening agents, astringents, antioxidants, hair growth inhibitors, anti-wrinkle agents and the like.

  The pH of the O / W emulsion preparation of the present invention is not particularly limited, but it is preferably 3 to 7, particularly 4 to 5 at 25 ° C. when diluted 10-fold with water.

  As the pH adjuster, for example, hydroxycarboxylic acids such as citric acid, alkyl hydroxide metal salts such as sodium hydroxide, alkyl hydroxide earth metal salts and the like can be used alone or in combination of two or more.

  The consistency of the O / W type emulsion preparation of the present invention is preferably 5 to 50 g, and more preferably 10 to 30 g. Here, the consistency is measured with a rheometer (NRM-3002D-L: manufactured by Fudo Kogyo Co., Ltd.) under a temperature condition of 25 ° C. under conditions of 1 cm sphere, 1 cm ingress, and 30 cm / min.

  Examples of the dosage form of the O / W type emulsion preparation in the present invention include creams, emulsions and lotions.

  The O / W type emulsion preparation of the present invention contains prednisolone valerate acetate, hydroxypropylcellulose and petrolatum as essential components, and optionally contains other components within the range of exhibiting the effects of the present invention. It can be manufactured by a method. For example, an aqueous phase in which hydroxypropyl cellulose is dissolved and an oil phase containing petrolatum are mixed after heating, emulsified under heating conditions such as 60 to 90 ° C., then cooled, and prednisolone acetate valerate is added. Can be manufactured.

  The separation inhibitor of the present invention comprises the above hydroxypropylcellulose as an active ingredient, and hydroxypropylcellulose can be used alone as it is, but may contain generally used ingredients.

  The separation inhibitor of the present invention stabilizes the emulsified state of an O / W emulsion formulation containing prednisolone valerate acetate and petrolatum, can suppress separation over time, and maintain the appearance stability of the formulation. Can do. In particular, it is possible to suppress separation over time at a high temperature environment of petrolatum, which is preferable from the viewpoint of moisture retention, specifically, 50 ° C. to 80 ° C.

  The blending amount of the separation inhibitor into the preparation is more preferably 0.01 to 3% by mass and 0.03 to 1% by mass as hydroxypropylcellulose mass in the preparation from the viewpoint of the effect of suppressing separation, and particularly 0.05 to 1%. 0.5 mass% is preferable.

Example 1
Petrolatum 15.0 g, liquid paraffin 5.0 g, cetanol 2.5 g, polyoxyethylene hydrogenated castor oil (50E.O.) (Nikkor HCO-50: manufactured by Nippon Surfactant Co., Ltd.) 1.0 g, poly monostearate Oxyethylenesorbitan (20E.O.) (Nikkor TS-10: Nippon Surfactant Kogyo Co., Ltd.) 1.5 g, sorbitan monostearate (Nikkor SS-10M: Nihon Surfactant Kogyo Co., Ltd.) 0.5 g, paraben 0.1 g was dissolved by heating at 75 ° C. (oil phase).

  To the purified water (total amount 100 g), 0.1 g of hydroxypropylcellulose (HPC-H: Nippon Soda Co., Ltd.), 0.01 g of sodium edetate and a pH adjuster (quenched so that the final formulation has a pH of 4.5) Acid and sodium hydroxide) were dissolved and heated to 75 ° C. (aqueous phase).

  The oil phase and the aqueous phase were mixed and emulsified at 75 ° C. After emulsification, the mixture was cooled to 50 ° C., 0.15 g of prednisolone valerate acetate (manufactured by Joko Pharmaceutical Co., Ltd.) was dispersed and mixed, and cooled to room temperature to obtain a preparation.

Comparative Example 1
A preparation was obtained in the same manner as in Example 1 except that the hydroxypropyl cellulose of Example 1 was not added.

Comparative Examples 2-6
Instead of hydroxypropylcellulose of Example 1, 0.1 g of hydroxyethylcellulose (Comparative Example 2: CF-V, manufactured by Sumitomo Seika Co., Ltd.), 0.1 g of sodium alginate (Comparative Example 3: I-1, Kimika Co., Ltd.) )), Povidone 0.3 g (Comparative Example 4: K-90, manufactured by BASF), carmellose 0.3 g (Comparative Example 5: 1350, manufactured by Daicel Chemical Industries, Ltd.), or sodium hyaluronate 0.1 g ( Comparative Example 6: A preparation was obtained in the same manner as in Example 1 except that HA12 (manufactured by Shiseido Co., Ltd.) was used. In addition, the compounding quantity of water-soluble polymer adjusted and mix | blended so that it might become the consistency with the formulation which mix | blended hydroxypropyl cellulose.

  Ingredient names and blending amounts of the preparations of Example 1 and Comparative Examples 1 to 6 are shown in Table 1.

Test Example In order to examine the appearance stability of the prepared O / W type emulsion preparation, Example 1 and Comparative Examples 1 to 6 were each filled in a glass bottle (2K bottle), and the presence or absence of separation was confirmed. The presence or absence of separation was visually evaluated. The case where separation was not observed was marked with ◯, and the case where separation occurred was marked with ×. The observation period was evaluated immediately after production and after 3 days storage at 60 ° C. The consistency was measured with a rheometer (NRM-3002D-L: manufactured by Fudo Kogyo Co., Ltd.) under a temperature condition of 25 ° C. under conditions of 1 cm sphere, 1 cm ingress, and 30 cm / min.
The results are shown in Table 1.

  Formulation excluding hydroxypropylcellulose (Comparative Example 1), hydroxyethylcellulose (Comparative Example 2), sodium alginate (Comparative Example 3), povidone (Comparative Example 4), carmellose (Comparative Example 5), hyaluron instead of hydroxypropylcellulose The O / W emulsion formulation containing prednisolone valerate acetate and petrolatum blended with sodium acid (Comparative Example 6) does not show separation immediately after production, but when stored at 60 ° C. for 3 days, Separation was also confirmed in the formulation. However, when hydroxypropylcellulose was blended with an O / W emulsion containing prednisolone valerate and petrolatum, it was confirmed that it was a stable preparation even when stored at 60 ° C. for 3 days.

Claims (4)

  O / W type emulsified preparation containing prednisolone valerate acetate, petrolatum and hydroxypropylcellulose.   The O / W emulsion formulation according to claim 1, further comprising a nonionic surfactant and water.   Separation inhibitor for O / W type emulsion preparation containing prednisolone valerate acetate and petrolatum containing hydroxypropylcellulose as active ingredients.   The separation inhibitor according to claim 3, wherein the O / W emulsion preparation further contains a nonionic surfactant and water.