JPS62238216A - Steroid cream preparation - Google Patents

Abstract

PURPOSE:The titled preparation having improved drug releasability, obtained by blending steroid as a main drug with a solubilizer in such a way that the steroid partially exist in a crystalline state and further with a nonionic surface active agent, a carboxylvinyl polymer as a gelatinizing agent and a water-soluble basic substance. CONSTITUTION:0.01-2wt% steroid is blended with 0.5-20wt% solubilizer such as diisopropyl adipate, diethyl sebasate, etc., 0.1-5wt% nonionic surface active agent, 0.1-3wt% carboxylvinyl polymer, 0.005-1wt% water-soluble basic sub stance and purified water. The solubilizer is finely granulated and dispersed by the nonionic surface active agent, the carboxylvinyl polymer is neutralized with the water-soluble basic substance and the prepared steroid preparation is adjusted to pH 4-7. Possession of the drug in a crystalline state can except improved steroid releasability and high curing effects.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to steroid cream preparations with excellent drug release properties.

As is well known, steroids have excellent anti-inflammatory effects and are frequently used mainly in the form of oily ointments and creams. Both formulations are used depending on the condition of the skin lesion to which they are applied, such as dryness or wetness, and both are in the required formulation form.

Among these, cream formulations generally emulsify multiple oil phase components into multiple aqueous phase components, or vice versa, to create a stable semi-solid system, so cream formulations are comparatively more likely than oil-based ointment formulations to emulsify multiple oil phase components into multiple water phase components or vice versa. It has a complex composition that requires a surfactant.
It is said to tend to be highly irritating to the skin. In addition, substances that have a high affinity with the main drug, steroids, such as interfacial antioxidants, slightly polar oil phase components, and bath disintegrators, have a large effect on drug release from the base depending on their type and addition. is known to give.

Therefore, a great deal of effort is required to obtain cream preparations that have good physical properties and stability, are less irritating to the skin, and have excellent drug release properties.

By the way, as a special cream preparation, there is a certain preparation which is thickened using carboxyvinyl polymer as a gelling agent without relying on the thickening effect of emulsification as mentioned above (Japanese Patent Publication No. 58-50964). This is a mixture of a steroid dissolved in a solubilizer such as crotamiton, a fluid oily substance, a nonionic surfactant, a carboxyvinyl polymer, and an aqueous basic substance. However, since the cream formulation contains a solubilizer sufficient to dissolve the required drug, it does not have sufficient drug release properties and cannot be considered as a preferred formulation.

Means to Solve the Problems In view of the above problems, the inventor has conducted extensive research and has developed a new solution by making the composition as simple as possible with the minimum amount of additives with high drug affinity. A special type of cream formulation composition was obtained in which only the amount of solubilizing agent used changes the drug release properties.

Then, they discovered that the absorption of the main drug into the skin can be easily improved regardless of its type by having the main drug steroid moiety present in a crystalline state in this composition system, and developed the present invention. Completed j,′:.

That is, the present invention provides 0.01 to 1% of steroids, 0.5% of one or more solubilizers selected from diisopropyl adipate, diethyl sebacate, and triacetin.
~20% heavy nails, 0.1-5% nonionic surfactants,
A steroid cream containing 0.1-aia amount of carboxyvinyl polymer, 0.005 to 1% of a water-soluble basic substance, and purified water, and in which a part of the above-mentioned steroid is present in a crystalline state. Related to formulations.

In the present invention, a solubilizing agent is blended so that a part of the steroid, which is an upper drug, exists in a crystalline state in the preparation, and a nonionic surfactant, a carboxyvinyl polymer as a gelling agent, and a water-soluble basic substance are also added. This addition makes it possible to obtain a steroid preparation with excellent drug release properties. Since drugs have the highest thermodynamic activity when they are in a crystalline state, lowering the drug affinity of the base makes it easier to release the drug. However, if all of the drug is in a crystalline state, the diffusion of the drug in the base will be insufficient and good drug release properties will not be obtained. Therefore, crystalline steroids account for 10-9111% of the steroids in the formulation.
, preferably 30-9ON Kuma%, preferably 50-9%
It is best to use 80 weight and 1%. In the formulation of the present invention, good drug release properties can be obtained when the content is less than 10% by weight or more than 90% by weight.

Examples of the steroids used in the present invention include dexamethacin, dexamethacin acetate, dexamethacin valerate, dexamethacin dipropionate, betamethacin,
Betamethacin acetate, Betamethacin valerate, Betamethacin benzoate, Betamethacin dipropionate, Methylprednisolone acetate, 1q Bl/donisolone acetate, Giclolysine acetate, Prednazinolone acetonide, Triamcinolone acetonide, Fluocinolone acetonide Do,) J leodinonide, haldinonide, amcinonide, hydrocortisone butyrate, hydrocortisone valerate, hydrocortisone acetate propionate, fluoromesolone,
Corticosteroids or their esters, such as fludroxycortide, diflucortolon valerate, flumethacin bivalate, clobetasol propionate, beclomethasone propionate, diflorazone diacetate, and 6α-fluoro-
9α-chloro-16β-methylprednisolone-17,
Examples include highly fatty steroids such as 21-diacete-1. The amount of steroid mixed varies depending on the strength of its pharmacological activity, and is usually about 0.01 to 2% by volume in the preparation, especially 0.0 for 6α-fluoro-9α-chloro-16β-methylprednisolone-17,21-diacetate.
1~0.8 nails! %, preferably about 0.02 to 0.2%.

As the solubilizing agent, 1 [or 2] selected from diisopropyl adipate, diethyl sebacate, and triacetin
More than one species can be used. The solubilizing agent is mixed based on the solubility of the main ingredient in the bath dissolving agent, and in the present invention, the solubilizing agent is atomized and dispersed by using a nonionic surfactant. As the nonionic surfactant, any of the nonionic surfactants normally used in soft FF formulations can be used, such as polyoxyethylene polyoxybrobylene glycol, polyoxyethylene polyoxypropyl 1/ncetyl, etc. Ether, polyoxyethylene sorbitan tetraoleate, polyoxyethylene sorbitan trioleate, 7N lyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitol beeswax, sucrose fatty acid ester, polyglycerin fatty acid ester, polyoxyethylate/nlanolin , polyoxyethylene lanolin alcohol, polylaminated xygotylene stearamide, 1/cytin, etc., or mixtures thereof. Blend 1 of the nonionic surfactant is set within the range of about 0.1-5i% in the formulation in order to have the minimum amount necessary to disperse the above-mentioned solubilizing agent into a fine T9 in the base.

Carboxyvinyl polymer is a water-soluble vinyl polymer with carboxyl groups, and is primarily a copolymer of acrylic acid. When carboxyvinyl polymer is dispersed in water, it forms a low viscosity acidic solution, which when neutralized with a base forms a viscous gel. In the present invention, the carboxyvinyl gelimer L is neutralized with a water-soluble basic substance 'U, and the pH of the steroid preparation is adjusted once to about 4 to 7.

As the carboxyvinyl polymer, any of the various types conventionally used as gelling agents for the skin can be used. A typical example is Gudrich Chemical Co., Ltd.
1-carbobol (0arb) commercially available from Oo, )
opol) 934゜910ki and 941J, "Shunron pw-tto and PW-" commercially available from Hiki Junyakutsuji
111J, commercially available from Wako Pure Yakufu [Hibiswako-1021, 104 and IQ5J, etc. can be exemplified. The carboxyvinyl polymer is blended at 0.1% in the formulation to provide sufficient viscosity for application to affected areas of the skin.
It is best to set the amount to about 8% to 8%.

Examples of water-soluble basic substances include lower alkylamines such as methylamine, ethylamine, n-propylamine, isopropylamine, butylamine, pentylamine, and hexylamine, dimethylamine, diethylamine, and (N-methyl).

di-lower alkylamines such as N-ethyl)amine, dipropylamine, dibutylamine, dipentylamine, diethylamine, trimethylamine, triethylamine, l
- dipropylamine, trialkylamines such as (N, N-dimethyl, N-ethyl)anine, methanolamine,
Alkanolamines such as ethanolamine and propatoolamine, dimethatoolamine, dimethatoolamine,
Dialkanolamines such as dibrobanolamine, trialkanols such as trimethanolamine, triethanolamine, tripropaturamine, metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, trimethylolamino Mention may be made of methane, ammonia, etc. or mixtures thereof. The layer containing the water-soluble basic substance should be prepared so that the pH of the formulation is 4 to 7 depending on the carboxyvinyl polymer used.
It is set within a range of about 0.05 to 1% by weight.

The cream formulation of the present invention may also contain other suitable additives. Suitable additives include, for example, methylcellulose, ethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, starch, gum tragacanth, gum arabic, etc. The compounding amount may be less than 5% in the preparation. Examples of humectants include polyhydric alcohols such as propylene glycol, polyethylene glycol, sorbitol, glycerin, and 1,8-butylene gellicol, and the blending amount may be about 20 gb or less.

The method for producing the cream formulation of the present invention is not particularly limited. Generally, cream preparations are emulsified under heating, but as exemplified in Manufacturing Method-1 and Manufacturing Method-2 below, they can be manufactured without heating. can be used, and drug crystal precipitation and growth are unlikely to occur.

<Production method-1> Among the steroids contained, crystals are 10 to 90i mouseff1
．． Preferable; ノ< is 80 to 90 Kiryu%, more preferably 50
The steroid is dissolved and dispersed at room temperature in one or a mixture of formulated solubilizers, such that the steroid is present in an amount of -80%. Next, add a nonionic surfactant, add these to the carboxyvinyl polymer aqueous solution, stir thoroughly (), add the aqueous solution of the water-soluble basic substance and the remaining purified water, and phi
is adjusted to 4 to 7 to obtain the steroid preparation of the present invention.

When gummy or water-soluble polymer compounds or polyhydric alcohols are added, they can be mixed with the carboxyvinyl polymer aqueous solution, or added after adding the aqueous solution of the water-soluble basic substance.

<Production method-2> *Similarly to method-1, the steroid is dissolved and dispersed in a dissolving agent, and this is added to the mixture of the nonionic surfactant and carboxyvinyl polymer aqueous solution, and then thoroughly stirred. Then, an aqueous solution of a water-soluble basic substance and the remaining purified water are added to adjust the pH to 4 to 7 to obtain the steroid preparation of the present invention.

When gummy or water-bathable polymer compounds or polyhydric alcohols are added, they can be mixed with the carboxyvinyl polymer aqueous solution, or added after adding an aqueous solution of a water-soluble basic substance.

Effects of the Invention The cream preparation of the present invention has extremely excellent steroid release properties by simplifying the base component as much as possible and containing the drug in a crystalline state, and therefore can be expected to have a high therapeutic effect.

EXAMPLES Examples of formulations of cream preparations of the present invention and pharmacological tests showing the usefulness of the preparations of the present invention will be given to further clarify the present invention.

In the following examples, purified water means water purified using an ion exchange resin, and the viscosity is a value measured at 25°C using a BH type viscometer manufactured by Tokyo Keiki Co., Ltd.

Example 1; 6α-fluoro-9α-chloro-16β-methylprednisolone-17,21-diacetate cream 6α-fluoro-9α-chloro-16β-methylprednisolone-17,21-diacetate 0.06f diisopropyl adipate 2 .0 Tetraoleate polyoxyethylene sorbitol 0.22%
Carboxyvinyl polymer aqueous solution 50.0 Propylene glycol 10.0 Methyl paraben
0.12% sodium hydroxide aqueous solution 5.0 total
100.0f6α-fluoro-9α
-Chloro-16β-methylprednisolone-17.21
- 50 mg of diacetate diisopropyl adipate 2. A mixture of Of and polyoxyethylene sorbitol tetraoleate (0.21%) was added and subjected to ultrasonic dispersion at room temperature. To this was added 2% carboxyvinyl polymer water i[5o,
op and methylparaben 0.1f propylene glycol lO, Of/ffPe1. After adding the mixture, stir vigorously, then add 2% aqueous sodium hydroxide solution with stirring, and then add purified water to bring the total volume to 10%.
The cream formulation was heated to 0f and thoroughly stirred.

(Viscosity 56,000 centiboise, pH 4,70) Example 2; Betamexone valerate cream Betamethacin valerate 0.12 f Diisopropyl adipate 8.0 Teroxyethylene sorbitate tetraoleate 0.82% carboxyvinyl polymer water Z solution 50.0 Propylene glycol 10.0 Methyl paraben
0.12% sodium hydroxide aqueous solution 5.0 total
too, op 120mp of betamethacin valerate to diisopropyl adipate 8. Of and polyoxyethylene sorbitol tetraoleate 0.3
1 and subjected to ultrasonic dispersion at room temperature. 2 to this
% carboxyvinyl polymer aqueous solution 50. Of and methylparaben 0. IV Propylene Glycol 10. Of
After adding the solution mixture, stir vigorously and then add 2% aqueous sodium hydroxide solution with stirring5. Of was added thereto, purified water was further added to bring the total volume to 10Of, and the mixture was sufficiently stirred to obtain a cream formulation.

(Viscosity 64.500 centipoise, pH 4,72) Working side 8; 6α-fluoro-9a-chloro-16β-methylprednisolone-17,21-diacetate cream 6α-fluoro-9α-chloro-16β-methylprednisolone-17, 21-Diacetate) 0.05f
Diethyl sebacate 2.5 Polyoxyethylene polyoxypropylene cetyl ether 0.82% carboxyvinyl polymer aqueous solution 50.0 Glycerin
10.0 Methylparaben
0.12% sodium hydroxide water f
fJ liquid 5.0 total
too, or6α-fluoro-9α
-Chloro-16β-methylprednisolone-17,21
- 50 mg of diacetate to 2.5 mg of diethyl sebacate
2 and polyoxyethylene geloxypropylene cetyl ether 0.31F, and ultrasonically dispersed at room temperature.

To this, 2% carboxyvinyl polymer water aa5o.

f and methylparaben 0.1f glycerin 10. After adding the OF bath solution mixture, stir vigorously and then add 2% aqueous sodium hydroxide solution with stirring5. Of Kamaru,
Further, add purified water to bring the total volume to 100 fF.

A cream formulation was obtained by stirring thoroughly.

(Viscosity 61,000 centipoise, pH 4.66) Example 4; Dexamethacin acetate cream Dexamethacin acetate 0.19 Triacetin
5.0 Polyoxyethylene sorbitan trioleate 0.5 Carboxyvinyl polymer 1.0 Methylparaben 0.12% triethanolamine aqueous solution 7.0 total
100 mg of ioo, or dexamethacin acetate was added to a mixture of triacetin 5, oy and polyoxyethylene sorbitan trioleate 0,5f, and subjected to ultrasonication at room temperature. Methylparaben 01 to this
2% carboxyvinyl polymer aqueous solution in which 1y was dissolved 5
After adding 0.0 fI, stir vigorously and then add 2% triethanolamine water bath solution while stirring. , Of was added thereto, purified water was further added, the entire area was sealed at 1 ooi/h, and the mixture was thoroughly stirred to obtain a cream formulation.

(Viscosity 45,000 centipoise, pH 4.2g) Example 5: Fluocinolone acetonide cream Fluocinolone acetonide 0.025f! Diisopropyl adipate 0.5 Diethyl sebacate 0.5 Polyoxyethylene sorbitol tetraoleate 0.22% carboxyvinyl polymer water bath solution 50.0 Methyl paraben 0.12% sodium hydroxide aqueous solution 5.0 total
Too much or 2 byr1 g of fluocinolone acetonide was added to 0.0 g of diisopropyl adipate.
51, 0.52% of diethyl sebacate and 0.21% of poly(A-xyethylene chloride) tetraoleate, and subjected to ultrasonic dispersion at room temperature. After adding 50.01 of a 2% carboxyvinyl polymer aqueous solution in which 0.1f of methylparaben was dissolved, stir vigorously, then add 2% sodium hydroxide water bath solution 5, (111) while stirring, and then add purified water. In addition, all 1 was converted into ioog and sufficiently extracted to obtain a cream formulation.

(Viscosity 71,000 centipoise, 13.EI 4.68
) Example 6; Dekirimethasone cream Dekirimethasone 041g Diisopropyl adipate 6.0 Diethyl sebacate 2.0 Triacetin 1.0 Polyoxyethylene sorbitol tetraoleate 2.02%
Carboxyvinyl polymer water soluble [50.0 methylparaben 0.12% sodium hydroxide aqueous solution 5.0 total
ioo, or 100my of dexamethacin, diisopropyl adipate 6,(1, diethyl sebacate 2.0f1 triacetin 1.0y and polyoxyethylene sorbitol tetraoleate l-2,0
IJII, t was ultrasonically dispersed in the mixture of f at room temperature. 2% carboxyvinyl polymer water/8 solution with 0.11 methyl paraben dissolved in this 50. (Gravel with HF added, stir vigorously, then add 5.Of 2% sodium hydroxide water bath solution while stirring, add purified water to total 1 to 10 (to make HF, mix well) A cream formulation was obtained.

(viscosity + i 55,000 centipoise, pH 4,59)
Pharmacological test A cream preparation of the present invention and a conventional cream preparation having a composition similar to the product of the present invention based on the examples described in Japanese Patent Publication No. 58-50964+g' were prepared, The contraction effect was tested. Human vasoconstriction efficacy studies reflect clinical efficacy very well;
It is regarded as the most important law for determining the efficacy of steroids for use in the medical field.

[Test method] 1. Test compound (steroid) 1) 6α-fluoro-9α-chloro-16β-methylprednisolone-17,21-diacetate 2) Betamethacin valerate 2. Preparation of test sample Composition shown in Table 1 A cream formulation containing 1 m2%) and a conventional cream formulation were prepared in the following manner.

1) Manufacturing method of cream preparation of the present invention 6α-fluoro-9 is added to a mixture of diisopropyl adipate and polyoxyethylene sorbitate tetraoleate.
α-chloro-16β-methylprednisolone-17,2
A specified amount of 1-diacetate (or betamethacin valerate) was added and subjected to ultrasonic dispersion at room temperature. Add a mixture of 2% carboxyvinyl polymer aqueous solution and methylparaben propylene glycol solution to this, stir vigorously, then add 2% sodium hydroxide aqueous solution while stirring, and then add purified water to bring the total to 100V. The mixture was thoroughly stirred in hot water and used as a test sample.

Cream formulation A; viscosity 56,000 centipoise pH 4
,70 Cream formulation B; viscosity 60.000 centiboise pH 4
, 72 2) Conventional method for producing cream preparations 6a-Fluoro-9α-chloro-16β-methylprednisolone-17,21-diacetate (or betamethacin valerate) is dissolved under heating in crotamiton, and liquid paraffin (or myristic acid) is added to this. Add isopropyl acid), propylene glycol, polyoxyethylene lauryl ether (or ylioxyethylene sorbitan monostearate), 4% carboxyvinyl polymer aqueous solution, purified water, and 1% sodium edetate water f8M, and boil this on a water bath for about 70 min. Heat to ~80°C, add 2% triethanolamine aqueous solution (or 2% sulfur/lium hydroxide aqueous solution) while stirring, add purified water to make total 1 to 1ooii', and mix well. The mixture was stirred and used as a test sample.

Cream formulation C; viscosity 55.00 O centipoise pH
4,88 Cream formulation D; viscosity 62.000 7 inch poise pH 4
,40 Cream formulation E; viscosity 58,000 centipoise pH 4
,45 Cream formulation 1! '; Viscosity 60.000 centivoise p
H4,52 Next, a base was prepared for each formulation as described above, and the base was sequentially diluted 4 times by kneading using a mortar and pestle to prepare the following 7 levels of concentration samples.

That is, for cream formulations (A, O, D), ■ 0
．． 05% ■ 0.0125% ■ 0.0081
25% ■ 0.000781i3%G'i) 0.
0001953% <fi) o, o o o 048
s s% ■0.00001221% For cream formulations (B, E, F), ■0.12%
oo, oa% Q) 0.0075% (Q 0.001875%
■0.0004688% F, 15) 0.00011
72%■0.00002980% (7 levels of concentration were obtained for each type i sample, making a total of 42 samples.

8. Subjects The subjects were 10 healthy adult male volunteers aged 80 to 42 with no skin diseases.

4. For each test subject, the above 42f! All test samples of type i
Assign to random and use before patch test (
Each sample was placed on the cloth part of Torii Pharmaceutical Co., Ltd. (manufactured by Torii Yakuhin ■).
mp) and was applied to the subject's upper back. The pasting and sealing time was 4 hours, and the judgment was made before the pasting and after 2 hours and 4 hours after removing the sample.

5. Judgment method The degree of skin pallor due to vasoconstriction was judged according to the following criteria.

"No response" (-) “Weak pallor” (±) “Obvious pallor” (+) This study was conducted according to a double-blind method.

Table 2 Table 2 (Continued) In addition, the positive rate was determined using the probit method. From the above results, the vasoconstriction effect of the cream preparation of the present invention was found to be greater than that of conventional cream preparations, regardless of the type of steroid used. It is clear that he is also disappointed.

Therefore, it can be seen that the cream formulation of the present invention has excellent drug release properties.

(that's all)

Claims (1)

[Claims] (1) 0.01 to 2% by weight of steroid, one or more solubilizers selected from diisopropyl adipate, diethyl sebacate, and triacetin
．． Contains 5-20% by weight, 0.1-5% by weight of nonionic surfactant, 0.1-3% by weight of carboxyvinyl polymer, 0.005-1% by weight of water-soluble basic substance, purified water, and the above. A steroid cream preparation characterized by having a portion of the steroid exist in a crystalline state.