CA1116085A - Creamy preparation containing steroid and process for the preparation thereof - Google Patents

Abstract

Abstract:
The specification discloses a creamy preparation containing a steroid compound and having a pH of 4 to 7 and a viscosity of 10,000 to 100,000 centipoises. The preparation is applicable to the skin and, more partic-ularly, contains a steroid compound (corticosteroid), a fluid oily substance, a nonionic surfactant, and an aqueous solution of a carboxyvinyl polymer, the prep-aration having been neutralized with a basic substance.
The creamy preparation has good absorbability of the active steroid, good stability and good spreadability onto the skin and also a good feeling in use. It is therefore preferable to an ointment.

Description

Creamy preparation containing _teroid_anl~ero~Ges~ f~ the preparation thereof The present invention relates to a novel creamy preparation containing a steroid compound, which is applicable to the skin.
It is well known that some steroid compoundsl such as prednisolone, dexamethasone, cortisone, etc. have excel-lent antiinflammatory activities and are usually used as antiinflammatory agents in the form of ointments. However, ointments feel sticky and unpleasant when appiied to the skin, and furthermore, due to insufficient contact of the lO steroid with the skin, the steroid is often insufficiently absorbed by the skin. Moreover, the applied surface is often rubbed by clothes, which results in loss of the active ingdredient and also soiling of the clothes.
~esides, at high temperatures of 40C or higher, ointments 15 tend to become unstable.
In order to overcome these drawbacks of ointments, the present inventors have attempted to prepare a more desir-able substance for the topical application of steroid - compounds, and provided a transparent, gelatinous prepa-ra-20 tion which is prepared by mixing a solution of a steroid compound in crotamiton with propylene glycol and adding the resulting mixture to an aqueous solution of a carboxy- ;~
vinyl polymer and finally adding an organic amine to the resulting mixture (cf. U.S. Patent 4,008,321~.
As a result of a further studying by the present inventors, a creamy preparation of a steroid compound has ,:' , - . ,,, . , , :, ;
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According to one aspect of the present invention there is provided a creamy preparation which comprises a stexoid compound, a solvent selected f3-om crotamiton, propylene glycol and mixtures thereof, a fluid oily substance, a nonionic surfactant, and an aqueous solution of carboxy-vinyl polymer, said preparation having been neutralized with a basic substance and hav;ng a pH of 4 to 7 and a 10 viscosity of 10,000 to 100,000 centipoises at 20C, and containing said fluid oily substance in an amount of 5 to 50 % by weight, said nonionic surfactant in an amount of 0.5 to S % by weight, and carboxyvinyl polymer in an amount of 0.1 to 3.0 % by weight, based upon the total 15 weight of the preparation.
According to another aspect of the invention there is provided a process for the preparation of a creamy pre-paration of a steroid compound, which comprises dissolving a steroid compound in a solvent selected from the group 20 consisting of crotamiton, propylene glycol and mixtures thereof, adding thereto a fluid oily substance, a non-ionic surfactant, a 1 to 10 % aqueous solution o~ car-boxyviny] polymer, and then neutralizing the mixture with a basic substance to give a creamy preparation having a pH
25 of 4 to 7 and a viscosity of 10,000 to 100,000 centipoises and containing said fluid oily substance in an amount of 5 to 50 % by weight, said nonionic surfactant in an amount of 0.5 to 5 ~ by weight, and carboxyviny] polymer in an amount of 0.1 to 3.0 % by weight, based upon the total 30 weight of the preparation.
Preferably, the basic substance is water-soluble and is added while heating the mixture at about 70 to 80C.
Examples of the steroids which may be contained in --the creamy preparation include corticosteroids and esters 35 thereof, such as prednisolone, cortisone, triamcinolone, bethamethasone, hydrocortisone, dexamithasone, methyl-prednisolone, fluocinolone, fluorometholone, triamcinolone acetonide, fluocinolone-acetonide, fluocinonide, clobetasol :- ~

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17-propionate, dexamethasone valerate, betamethasone valerate, betamethasone acetate, betamethasone benzoate, flumethasone, prednisolone acetate, hydrocortisone valerate, dexamethasone valerate, betamethasone propion-ate, betachloromethasone dipropionate, , or the like.The steroid compounds are incorporated into the creamy preparation in an effective amount which varies depending on the kind of steroid, but is usually in the range of 0.001 to 1 % by weight based on the total weight of the 10 preparation.
These steroids are usually insoluble in water, but are easily soluble in crotamiton (i.e. N-crotonyl-N-ethyl-o-toluidine). In the present invention, the steroids are first dissolve~ in crotamiton or propylene glycol or a 15 mixture thereof. The steroids tend to be more soluble in crotamiton than in propylene glycol, but although crotamiton can be used alone, it is not preferable to include more than 10 % by weight of this substance in the creamy preparation. The propylene glycol may also 20 be used alone, but because of the lower solubility of steroids in propylene glycol, it is usually used alone only when the steroid compound has a comparatively high solubility in propylene glycol, for instance, in the case of dexamethasone.
~ccordingly, it is preferable in most cases to use a mixture of crotamiton and propylene glycol. The dissolu-tion of a steroid compound in a mixture of crotamiton and propylene glycol may be carried out by first dissorbing the steroid compound in either the crotamiton or the 30 propylene glycol and then adding the other one to the solution. It is preferable to use a mixture of crota-miton and propylene glycol also from the viewpoint that a "
mixture can give excellent emulsion stability and spread-ability to the preparation. When propylene glyclol is used in too Large an amount, the prepara'rion may produce undesirable irritation to the skin, and hence, it should be used in an amount of less than 20 % by weight. From .

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. ': :' the standpoint of solubility of steroids in the solvent, the prevention of crystallization of steroids in the preparation, and further emulsion stability, spread-ability and the ~eeling of the preparation, crotamiton is usually used in an amount of not more than 10 ~ by weight, usually 0.5 to 10 % by weight, preferably 2 to 10 % by weight, and propylene glycol is usually used in an amount of less than 20 % by weight, i.e. ~rom 2 to less than 20 %
by weight, preferably 5 to 10 % by weight, based upon the 10 total weight of the preparation.
The fluid oily substances to be incorporated into the creamy preparation include higher fatty alcohols, higher fatty acids and higher fatty acid esters, oil~ hydro~
carbons, and mixtures thereof. Suitable examples of the 15 fluid oily substance are fatty alcohols having 8 to 18 carbon atoms, such as octyl alcohol, capryl alcohol, nonyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, or stearly alcohol; monovalent or divalent fatty acids having 8 to 1~ carbon atoms, such as lauric acid, myristic 20 acid, palmitic acid, oleic acid, linoleic acid, sebacic acid, or stearic acid; alkyl esters of the fa~ty acids as mentioned above wherein the alkyl moiety has 1 to 18 carbon atoms, such as isopropyl myristate, diethyl sebacate, dibutyl sebacate, dioctyl sebacate, and mixtures 25 thereof.
The carboxyvinyl polymer is a hydrophilic vinyl polymer with active carboxyl groups, which is prepared by the polmerization of monomers comprising predominantly acrylic acid [cf. Chem. & Eng. News, Vol. 36, page 64 (Sept. 29, 1958)i. A11 commercially available carboxy-vinyl polymers can be used in the present invention.
Suitab]e examples are Carbopol 934, Carbopo] 940 and Carbopol 941, which are trademarks of the products of Goodrich Chemical Company. The carboxyvinyl polymer has 35 free carboxyl groups and their aqueous solution is thus acidic. When the carboxyvinyl polymer is neutralized with : ' . ', '' ~ ':

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a basic substance, a sticky gel is formed.
The basic substances to be used for the neutralization of the carbo~yvinyl polymer include organic amines, such as an alkylamine having 1 to 4 carbon atoms (e.g. methyl-amine, ethylamine, or propylamine~, a dialkylamine havingl to 4 carbon atoms in each alkyl moiety (e.g. dimethyl-amine, diethylamine, or dipropylamine), a trialkylamine having l to 4 carbon atoms in each alkyl moiety te.g.
trimethylamine, triethylamine, or tripropylamine), an lO alkanolamine having 1 to ~ carbon atoms in the a]kanol moiety (e.g. methanolamine, ethanolamine, or propanol-amine), a dialkanolamine having l to 4 carbon atoms in each alkanol moiety (e.g. dimethanolamine, diethanol-amine, dipropanolamine, or dibutanolamine), a trialkanol-15 amine having l to 4 carbon at~ms in each alkanol moiety (e.g. trimethanolamine, triethanolamine, tripropanolamine,or tributanolamine), and trimethylolaminomethane, and also includes inorganic bases such as ammonia, an aqueous solution of alkali metal hydroxides (e.g. sodium 20 hydroxi~e, or potassium hydroxide). All these basic substances can give a gel having a similar viscosity when they are used to neutralize the aqueous solution o car-boxyvinyl polymer.
The nonionic surfactants to be incorporated into the 25 creamy preparation include sorbitan sesquioleate, sorbitan trioleate, sorbitan monooleate, sorbitan monostearate, sorbitan monolaurate, polyethy]ene glycol monostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene nonylphenyl ether, 30 polyoxyethylene cetyl ether, polyoxyethylene lauryl ether, or mixtures thereof.
The creamy preparation of the present invention can be prepared in the following manner.
A steroid compound is first dissolved in crotamitron 35 or polyethylene glycol or a mixture thereof (mixed ratio of crotamiton : polyethylene glycol, 1 : lO to 5 : l by ,~, .. .. .. . ..

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weight). A Eluid oily substance, a nonionic surfactant and an aqueous solution o~ carboxyvinyl polymer are added to the solution and a water-soluble basic substance is added thereto with stirring, by which the carbox~vinyl polymer is neutralized to give a viscous gel. The above steps, i.e. the dissolution of the steroid compound in the solvent and the mixing the ingredients, may be carried out at room temperature but are preferably carried out at about 70 to 80C.
Because of the action of the nonionic surfactant, the oily phase of the mixture of a steroid compound and a fluid oily substance,~and the aqueous phase of the carboxyvinyl polymer solution become uniformly mixed to give the desired creamy preparation. The creamy prepara-15 tion thus obtained has a pH of 4 to 7, preEerably ~ to 5.5and a viscosity of 10,000 to 100,000 centipoises, prefer-ably 30,000 to 80,000 centipoises, at 20C. The creamy preparation contains 0.1 to 3.0 % by weight, preferably 0.5 to 1.2 ~ by weight, of the carboxyvinyl polymer based 20 upon the total weight of the preparation. The carboxy-vinyl polymer is usually used in the form oE a 1 to 10 %
aqueous solution, preferably 2 to 4 ~ aqueous solution, and after mixing the aqueous solution of the carboxyvinyl polymer with the mixture of a steroid compound and other ingredients, the content of the carboxyvinyl polymer in the creamy preparation is regulated in the above range by adding water thereto.
The pH of the preparation is regulated within the range 4 to 7 by controlling the amount of the basic sub-stance in the preparation. When the pH value is higherthan 7, i.e. when the preparation is alkaline, it tends to be unstable, and on the other hand, when it is lower than 4, the preparation becomes too acidic and irritative to the skin, and furthermore too large an amount of carboxy-vinyl polymer is undesirably required for increasing theviscosity thereof.

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The f]uid oily substance is usually used in an amount of 5 to 50 ~ by weight, preferably 10 to 20 % by weight, based upon the total weight of the preparation, but when crotamiton, which is also an oiLy substance, is used in a large amount, the fluid oily substance is used in a smaller amount. The nonionic surfactant is used in an amount of 0.5 to 5 ~ by weight, preferably 1 to 2 % by weight, based upon the total weight of the preparation.
The creamy prepara~ion of the present invention is a 10 uniform white cream and the viscosity thereof varies very little from high temperature (e.g. ~0C) to low tempera-ture (e.g. O~C), and also even when the preparation is kept for a long period of time. Moreover, even when the preparation is kept at a low temperature for a long period 15 of time, no crystallization of the steroid compound appears. Accordingly, the creamy preparation is very stable and does not have such drawbacks as seen in the conventional ointments, such as melting or liquefaction during summer time and hardening or solification during 20 winter time, and also separation of the oily phase and the aqueous phase.
When the creamy preparation o~ the present invention is applied to skin, it is contacted with salts, such as sodium chloride, which are contained in a very smal]
25 amount in the perspiration or are present on the surface of the skin and thereby the viscosity of the preparation is rapidly decreased, and the preparation i9 liquefied and shows good spreadability onto the skin. As a result, a film of carboxyvinyl polymer is formed on the skin, which 30 promotes the absorption o~ the active ingredient ~steroid compound) into the skin. Moreover, the film of carboxy-vinyl polymer thus formed is readily dried when contacted with air, and hence, the skin surface, to which the preparation is applied, is not sticky but rather quite smooth. Thus, the drawbacks of ointments such as soiling of clothes and unpleasant feeling, can be eliminated.

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The creamy preparatlon of the present invention may optionally incorporate other active ingredients, such as antihistaminics, analgesics, and the like.
The creamy preparation of the present invention and the method of preparation thereof are i]lustrated by the following E~amples, but the present invention is not limited thereto. In the Examples, the purified water was prepared by purifying water with an ion exchange resin, and the viscosity WAS measured at 20C by a C-type 10 viscosimeter (made by Tokyo Keilci Co., Ltd. ~apan).
Example l Dexamethasone acetate (25 mg) was dissolved in crotamiton (5 g) at about 70C, and isopropyl myristate (lO g), propylene glycol (lO g), polyoxyethylene sorbitan 15 monolaurate (l g), a 4 % aqueous solution of a carboxy-vinyl polymer (17 g), purified water (53 g) and a l %
aqueous solutlon of disodium edetate (1.2 g) were added thereto. The mixture was heated to about 70 to 80C on a water bath and a 2 % aqueous sodium hydroxide solution (2 g) was added thereto with stirring, followed by the addition of purified water until the total amount became lO0 g. The mixture was thoroughly stirred and then cooled to give a creamy preparation having a viscosity of 60,000 centipoises and a pH of 4.30.
Example 2 Fluocinonide (50 mg) was dissolved in crotamiton (7 g) with warming, and liquid paraffin (lO g~, propylene glycol (lO g), polyoxyethyelen lauryl ether (1 g), a 4 % aqueous solution of carboxyvinyl polymer (20 g), purified water (47 g) and a 1 % aqueous solution of disodium edetate (1~2 g) were added thereto. The mixture was heated to about 70 to 80C on a water bath, and a 2 ~ aqueous solution of triethanolamine ~4.68 g) was added thereto with stirring, followed by the addition of purified water 35 until the total amount became lO0 g. The mixture was thoroughly stirred and then cooled to give a creamy . .

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Example 3 Prednisolone (500 mg) was disso]ved in crotamiton (10 g) with warming, and isopropyl myristate (lO g), propylene glycol (10 g), polyoxyethylene sorbitan monostearate (1.5 g), a ~ ~ aqueous solution of carboxy-vinyl polymer (17 g), purified water (48 g) and a 1 ~
aqueous solution of ~isodium edetate (1.2 g) were added 10 thereto. The mixture was heated to about 70 to 80C on a water bath and a 2 % aqueous solution oE trieth~lamine (2.95 g) was added thereto with stirring followed by the addition of purified water until the total amount became lO0 g. The mixture was thoroughly stirred and then cooled 15 to give a creamy preparation having a viscosity of 54~,000 centipoises and a pH of 4.65.
Example 4 Dexamethasone (25 mg) was dissolved in propylene glycol (20 g) with warming, and isopropyl myristate ~o (lO g), polyoxyethylene sorbitan (l.0 g), a 4 % aqueous so~ution of carboxyvinyl polymer (13 9), purified water (57 g) and a l ~ aqueous solution of disodium edetate (1.2 9) were added thereto. The mixture was heated to about 70 to 80C on a water bath and a 2 ~ aqueous solu-25 tion of triethanolamine (5.2 9) was added thereto withstirring followed by the addition of purified water until the total amount became lO0 9. The mixture was thoroughly stirred and then cooled to give a creamy preparation having a viscosity of 43,000 centipoises 30 and a pH of 4.80.
Example 5 Hydrocortisone (500 mg) was dissolved in crotamiton (5 g) with warming, and liquid paraffin (lO g~, propylene glycol (lO g), polyoxyethylene lauryl ether (1.5 g), a ~ %
35 aqueous solution of carboxyvinyl polymer (27 g), purified water (38 g) and a 1 ~ aqueous solution of disodium . .

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~ ]~o --edetate.(1.2 g) were added thereto with stirring. The mixture was heated to about 70 to 80C on a water bath, and a 2 % aqueous sodiurn hydroxide solution (lO g) was added thereto with stirring followed by the addition of purified water until the total amount became lO0 g. The mixture was thoroughly stirred and then cooled to give a creamy preparation having a viscosity of 35,000 centi-poises and a pH of 5.30.
Examp].e 6 Triamcinolone acetonide (100 mg) was dissolved in crotmiton (7 g) with warming, and isopropyl myristate (10 g), propylene glycol (10 g), polyoxyethylene sorbitan monolaurate (l g), a 4 ~ aqueous solution of carboxyvinyl polymer (22 g), purified water (41 g) and a 1 ~ aqueous 15 solution of disodium edetate (1.2 g) were added thereto.
The mixture was heated to about 70 to 80C on a water bath and a 2 ~ aqueous solution of triethylamine (6~5 g) was added thereto with stirring followed by the addition of purified water until the total amount became 100 g. The 20 mixture was thorough].y stirred and then cooled to give a creamy preparation having a viscosity of 75,000 centi-poises and a pH of 4.53.

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Claims (5)

Claims:

1. A creamy preparation which comprises a steroid compound, a solvent selected from crotamiton, propylene glycol and mixtures thereof, a fluid oily substance, a nonionic surfactant, and an aqueous solution of carboxy-vinyl polymer, said preparation having been neutralized with a basic substance and having a pH of 4 to 7 and a viscosity of 10,000 to 100,000 centipoises at 20°C, and containing said fluid oily substance in an amount of 5 to 50 % by weight, said nonionic surfactant in an amount of 0.5 to 5 % by weight, and carboxyvinyl polymer in an amount of 0.1 to 3.0 % by weight, based upon the total weight of the preparation.

2. A creamy preparation according to claim 1, wherein the solvent is a mixture of crotamiton and propylene glycol, and said preparation contains crotamiton in an amount of 2 to 10 % by weight and propylene glycol in an amount of 2 to less than 20 % by weight based upon the total weight of the preparation.

3. A creamy preparation according to claim 1 or claim 2, wherein the steroid compound is contained in an amount of 0.001 to 1 % by weight based upon the total weight of the preparation.

4. A process for the preparation of a creamy preparation of a steroid compound, which comprises dissolving a steroid compound in a solvent selected from the group consisting of crotamiton, propylene glycol and mixtures thereof, adding thereto a fluid oily substance, a non-ionic surfactant, a 1 to 10 % aqueous solution of car-boxyvinyl polymer, and then neutralizing the mixture with a basic substance to give a creamy preparation having a pH
of 4 to 7 and a viscosity of 10,000 to 100,000 centipoises and containing said fluid oily substance in an amount of 5 to 50 % by weight, said nonionic surfactant in an amount of 0.5 to 5 % by weight, and carboxyvinyl polymer in an amount of 0.1 to 3.0 % by weight, based upon the total weight of the preparation.

5. A process according to claim 4, wherein the solvent is a mixture of crotamiton of 2 to 10 % by weight and propy-lene glycol of 2 to less than 20 % by weight, based upon the total weight of the preparation.