JPH0353286B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides a sticky steroid composition, more specifically, a novel sticky anti-inflammatory agent that contains corticosteroids dissolved in an oily solvent as an active ingredient and is capable of inhibiting the growth of microorganisms when applied topically. The present invention relates to a drug composition. The present invention is in the form of a sticky composition and is based on a corticosteroid completely dissolved in an oily medium and the growth of microorganisms on the surface of the sticky composition and its transfer from one application area to another. A topical corticosteroid formulation is provided that contains antimicrobial compounds to inhibit the spread of microorganisms and can be used as an anti-inflammatory agent. More specific to the foregoing, the present invention provides an effective amount of at least one corticosteroid, one or more oily solvents to completely dissolve the corticosteroid, impart tackiness and stiffness. one or more waxes and specific antimicrobial compounds (such as steroids) to inhibit the growth of microorganisms and the spread of microorganisms from one area of application of the adhesive composition to another. The present invention provides novel adhesive anti-inflammatory compositions having as active ingredients corticosteroids present in an amount of about 1-25% by weight of the composition. Topically administered corticosteroid preparations are widely used in the treatment of skin disorders such as dermatitis. In order to facilitate the desired subcutaneous absorption of the active ingredient and increase its therapeutic effect, the active ingredient should be in a molecularly dispersed state, and subcutaneous absorption is particularly important for enhancing the therapeutic effect in the treatment of psoriasis. . Commonly administered medications such as ointments, creams, lotions, etc. for applying effective steroids to the skin may require application to the patient's fingers. It is not desirable to apply and expose steroids to the fingers. A large proportion of skin disease patients are elderly or institutionalized, and many of these people rely on a third party (attendant, nurse, etc.) to administer steroids to the affected area. people, etc.). Particularly advantageous agents for overcoming and eliminating these difficulties and inconveniences are adhesive compositions that are solid at room temperature. Such adhesive compositions do not expose the active steroid when applied to the finger, thus eliminating the possibility of eye contamination, and are satisfactory for third-party treatment. It can be attached directly to the executive to mark it, and it does not leave any stains. Various steroids in the form of conventional adhesive compositions are described in US Pat.
No.). Adhesive drugs come into direct contact with the affected skin area while being attached to the skin, and it has become recognized that they may contain certain types of microorganisms. Preservatives commonly useful in creams or lotions, such as parabens, chlorocresol, benzoic acid and chlorobutanol, may also be used in adhesive compositions to prevent the growth and spread of such microorganisms. began to be suggested. Unfortunately, however, it has been found that these cream or lotion preservatives are virtually ineffective in solid, viscous pharmaceuticals at room temperature. The present invention is directed to a topical adhesive steroid preparation that is capable of inhibiting the contamination and proliferation of germs, which is made by blending an antibacterial agent into an adhesive steroid preparation to effectively retain its bactericidal effect. It is. According to the invention, in order to inhibit the growth of microorganisms on the surface of the adhesive composition and to exclude the spread of said microorganisms from one part of the application area to another, it is possible to Even in the presence of an oily solvent, the antibacterial compound can still be effectively contained and retained. The adhesive composition of the present invention consists of two systems: (a) an oily solvent for dissolving the corticosteroids; and (b) a wax for imparting stickiness and hardness to the composition; A room-temperature solid product containing an antibacterial compound that exhibits a bactericidal effect even in an oil-based sticky substance, and, if necessary, a liquid softener or softener, an antioxidant, and/or an opacifying agent. . Surprisingly, it has been found that propylene glycol and 1,3-butylene glycol, which are immiscible in oily solvents, are particularly effective for inhibiting the growth and spread of microorganisms in sticky materials such as the present invention. Ta. Such an effect is a useful effect that could not have been expected at the beginning. Unlike conventional topical formulations that contain corticosteroids in solid dispersion, all of the corticosteroids in the adhesive compositions of the present invention are retained solubilized for the most effective biological absorption. Availability can be guaranteed. Solvents suitable for this purpose should be mutually miscible with the steroids and miscible with the waxes so that separation and syneresis do not occur at the concentrations used. The preferred amount of solvent used should be just enough to dissolve the entire amount of corticosteroid used in the composition, ie, ideally the concentration of dissolved steroid should be a saturated solution. It is undesirable if the solution contains an amount of steroid above saturation because the excess steroid will crystallize. If the solution falls below saturation, the excess solvent will increase the affinity for the substrate (wax) instead of the steroid, thus retarding the rate of steroid release. The solvent used for addition has a low intrinsic viscosity, so
After the wax matrix is destroyed during application, the solvent can easily penetrate into the skin. For this reason, when castor oil or mineral oil is used, it is preferred to dilute these solvents with dibutyl sebacate or diisopropyl sebacate to reduce their intrinsic viscosity. Therefore, as discussed below, a low intrinsic viscosity solvent may be used to form the necessary saturated solution, while a cooperative solvent may be used with the primary oily solvent to dissolve the steroid. Typically, the solubility of the steroid component in such cooperative solvents is low, and such processing methods result in the formation of a solvent system that has a low intrinsic viscosity and constitutes a saturated solution that essentially equilibrates at the point of saturation. Examples of oily solvents that can be used in the present invention are listed below.
These are given by way of example and not in a limiting sense: castor oil, mineral oil, isostearyl alcohol, isopropyl palmitate, isopropyl myristate, dibutyl sebacate, diisopropyl sebacate and mixtures thereof. The type of these solvents depends on the selective solubility of the steroid in the solvent and the intrinsic viscosity of the solvent. For example, castor oil is a good oily solvent for hallucinonide, and to complete the solvent system, equilibrate castor oil with isostearyl alcohol (which is not as good a solvent for hallucinonide as castor oil is). let In this way, solvent mixtures with favorable solubility (for example 0.100 g of halcinonide in 60 g of the solvent mixture) can be formed. Such steroid-solvent mixtures can be mixed with waxes and antimicrobial agents (sticky 100%
0.1% halucinonide composition can be manufactured by formulating the same with halcinonide (formulated in g). Useful mixtures other than those mentioned above include isostearyl alcohol and dibutyl sebacate or diisopropyl sebacate, and castor oil and dibutyl sebacate or diisopropyl sebacate. These can be mixed with all waxes in the desired concentration. However, castor oil and mineral oil are not miscible, so this combination should be avoided. Generally oily solvent mixtures are about 45 to 85% sticky composition.
% by weight, preferably in an amount of about 50-80% by weight. In particularly preferred embodiments, the weight ratio of isostearyl alcohol to castor oil is from about 3 to 0.8:1, preferably from about 2.5 to 1:1, and the weight ratio of isostearyl alcohol to dibutyl sebacate is from about 3 to 0.8:1, depending on the steroid present. about 0.5 to 2:1, preferably about 0.8 to
1.5:1, the weight ratio of castor oil to dibutyl sebacate from about 0.5 to 1.5:1, preferably from about 0.8 to
Use at 1.2:1. The selection of waxes is important for making the adhesive composition of the present invention appropriate. In a preferred embodiment, waxes with a wide range of melting points are used to avoid agglomeration phenomena in the adhesive composition. Waxes also have minimal solubility in oily solvents, and therefore easily form gel structures.
It is preferable not to substantially increase the intrinsic viscosity. Waxes with certain emulsifying properties, such as glyceryl monostearate,
It is used for this reason, reducing the interfacial tension between moist skin and oily solvents. Examples of suitable waxes for use in the present invention include carnauba wax, white wax, ozokerite, beeswax, candelilla wax, cetyl alcohol, petrolatum, mineral oil enriched with polyethylene (U.S. Pat.
2627938, 2628187, 2628205, and 3733403) and various mixtures of at least two of these. Waxes typically have adhesive compositions of about 10 to 40
% by weight, preferably about 15-30% by weight. The antibacterial compound (antibacterial agent) used in the adhesive composition of the present invention is about 1 to 25% of the total weight of the adhesive composition.
Preferably it may be present in an amount of about 2-10%, optimally about 3-8%. Suitable antibacterial agents for use in the present invention include propylene glycol, 1,3
-Butylene glycol and mixtures thereof may be mentioned. 1 to 3 in the adhesive composition of the present invention.
Propylene glycol or 1,3-butylene glycol in concentrations of 6% or more kills fungi, and at concentrations of 6% or more kills 99.9% of fungi originally present in the composition.
% can be sterilized. Glycols not only function as antibacterial agents, but also as permeability enhancers. Given the fact that antimicrobial agents such as those described above are generally not miscible with the oily substances required in the adhesive compositions of the present invention, such antimicrobial agents may be incorporated into the adhesive compositions of the present invention to achieve effectiveness. The fact that it can appear is actually amazing. The present inventors believe that when using the antibacterial agent in the amount specified above, the antibacterial agent is uniformly dispersed (not dissolved) in the adhesive composition without separating. found that it was retained. The active steroid ingredient used in the compositions of the present invention is about 0.001 to 3% of the total weight of the composition, preferably about
Preferably, the steroid is present in an amount ranging from 0.025 to 0.2%. The specific amount used depends on the type of steroid and its solubility in the oily solvent. Examples of steroids that can be used in the present invention include acetonide derivatives of pregnane steroids disclosed in US Pat. No. 3,048,581 and US Pat. No. 3,937,720. Examples of steroids include triamcinolone acetonide and halucinonide, which are disclosed in the former of the above-mentioned US patents. In addition, the steroids used in the adhesive composition of the present invention are disclosed in US Pat.
No. 3994935, No. 4018757, No. 4116978, No.
No. 4018774, No. 4091036, No. 4094840, No.
No. 4133811, No. 4146538, No. 4160772 and No.
4164504). These steroids are described merely as examples, and the steroids used in the present invention are described in the sense that the steroids used in the present invention are limited to specific steroids or specific steroid groups among locally active anti-inflammatory steroids. Emphasize that you didn't do it. The adhesive composition of the present invention optionally contains an opacifying agent, such as titanium dioxide, which acts as an indicator of uniformity of dispersion, based on the total weight of the composition.
It may be present in an amount of 0.2-1%, preferably about 0.3-0.8%. In addition, if necessary, an antioxidant may be added in an amount of about 0.005 to 0.1%, preferably about 0.01 to 0.1% of the total weight of the composition.
It may be contained in an amount of 0.03%. Next, specific examples of preferred compositions of the adhesive steroid composition of the present invention will be shown. The composition of the present invention is not limited to these. Hallucinonide 0.025% adhesive composition: - 0.020-0.03 g of finely powdered hallucinonide; 30-45 g of isostearyl alcohol; 15-35 g of castor oil;
6-25 g of propylene glycol or 1,3-butylene glycol; 2-6 g of white wax; 3-7 g of ozokerite; 1-3 g of candelilla wax; 2-4 g of carnauba wax; 2-4 g of glyceryl stearate; 5 g of cetyl alcohol ~9g. Hallucinonide 0.1% sticky composition: - 0.09-0.11 g of finely powdered hallucinonide; 30-45 g of isostearyl alcohol; 15-35 g of castor oil; 6-25 g of propylene glycol or 1,3-butylene glycol; 2-6 g of white wax; ozokerite 3-7 g; candelilla wax 1-3 g; carnauba wax 2-4 g; glyceryl stearate 2-4 g; cetyl alcohol 5-9 g. Kenalog 0.025% adhesive composition: - Finely powdered triamcinolone acetonide (Kenalog) 0.02-0.03 g; Isostearyl alcohol 30
~45g; castor oil 15-35g; propylene glycol or 1,3-butylene glycol 6-25g;
White wax 2~6g; Ozokerite 3~7g; Candelilla wax 1~3g; Carnauba wax 2~
4g; glyceryl stearate 2-4g; cetyl alcohol 5-9g. Kenalog 0.1% adhesive composition: - Finely powdered triamcinolone acetonide (Kenalog) 0.09-0.11 g; Isostearyl alcohol 30
~45g; castor oil 15-35g; propylene glycol or 1,3-butylene glycol 6-25g;
White wax 2~6g; Ozokerite 3~7g; Candelilla wax 1~3g; Carnauba wax 2~
4 g; glyceryl stearate 2-4 g; cetyl alcohol 5-9 g. Adhesive composition containing 0.1% of steroid A or B below: - The composition is shown in Table 1. Steroid A...21-(acetyloxy)-9-
Fluoro-1′,2′,3′,4′-tetrahydro-11β-
Hydroxypregna-1,4-dieno [16α, 17
-b] Naphthalene-3,20-dione Steroid B...21-chloro-9-fluoro-
1',2',3',4'-tetrahydro-11β-hydroxypregna-1,4-dieno[16α,17-b]naphthalene-3,20-dione

[Table] Next, a method for producing a preferred anti-inflammatory composition of the present invention will be specifically explained with reference to Examples. Examples 1 to 11 Using the ingredients shown in Table 2, a lipophilic adhesive composition of the present invention is produced by the following method. Oil-based solvent (i.e. secondary
Gently heat the isostearyl alcohol, castor oil and dibutyl sebacate shown in the table,
Steroids (steroids A and B are as shown below) are dissolved in this. This solution (90
Add the molten mixture of the remaining ingredients to the temperature (°C). The resulting mixture was poured into a mold and rapidly cooled to solidify the mixture to obtain an adhesive composition. Steroid A...21-(acetyloxy)-9-
Fluoro-1′,2′,3′,4′-tetrahydro-11β-
Hydroxypregna-1,4-dieno [16α, 17
-b] Naphthalene-3,20-dione Steroid B...21-chloro-9-fluoro-
1',2',3',4'-tetrahydro-11β-hydroxypregna-1,4-dieno[16α,17-b]naphthalene-3,20-dione.

[Table] Each of the above lipophilic adhesive compositions contains its steroid component completely dissolved in a saturated solution form in an oily solvent mixture having a low intrinsic viscosity. These adhesive compositions have therapeutic effects as anti-inflammatory agents and contain antibacterial agents (i.e. propylene glycol or 1,3-butylene glycol) to prevent microbial growth on the surface of the composition and application. It has been confirmed that the spread of microorganisms from one part of the area to another can be prevented.

Claims (1)

[Scope of Claims] 1. An effective amount of at least one corticosteroid, one or more oily solvents that completely dissolve the corticosteroid, and one or more waxes for imparting stickiness and hardness. Above, and 1. Growth of microorganisms on the surface of sticky materials and application area.
The antimicrobial compound consists of propylene glycol or 1,3-butylene glycol to inhibit the spread of microorganisms from one site to another, and the antimicrobial compound is present in an amount of about 1 to 25% by weight of the composition. A sticky steroid composition characterized by: 2. The composition of claim 1, wherein one or more oily solvents are present in an amount of about 45-85% by weight of the composition. 3. The composition of claim 1 or 2, wherein the oily solvent includes isostearyl alcohol, mineral oil, castor oil, dibutyl sebacate, diisopropyl sebacate, or mixtures thereof. 4 Corticosteroids include halcinonide, triamcinolone acetonide, 21-(acetyloxy)-
9-Fluoro-1',2',3',4'-tetrahydro-
11β-hydroxypregna-1,4-dieno[16α,17-b]naphthalene-3,20-dione or 21-chloro-9-fluoro-1′,2′,3′,
4′-tetrahydro-11β-hydroxypregna-
1,4-dieno[16α,17-b]naphthalene-
A composition according to claim 1, 2 or 3 which is a 3,20-dione. 5. A composition according to any one of claims 1 to 4, wherein the antimicrobial compound is present in an amount of about 2 to 10% by weight of the composition. 6. A composition according to any one of claims 1 to 5, wherein the antimicrobial compound is present in an amount of about 3 to 8% by weight of the composition. 7. Add corticosteroid to approximately 0.05 to 0.05 of the weight of the composition.
Claims 1 to 1 present in an amount of 0.6%
The composition according to any one of Item 6. 8. The composition according to any one of claims 1 to 7, wherein the waxes are present in an amount of about 10 to 40% of the weight of the composition. 9. The composition according to any one of claims 1 to 8, wherein the wax is white wax, ozokerite, candelilla wax, carnauba wax, glyceryl stearate, cetyl alcohol, or a mixture thereof. 10. The composition according to any one of claims 1 to 9, wherein the corticosteroid is hallucinonide and the oily solvent includes a mixture of isostearyl alcohol and castor oil. 11. Claims 1 to 1, wherein the corticosteroid is triamcinolone acetonide and the oily solvent is a mixture of castor oil and dibutyl sebacate.
9. The composition according to any one of Item 9. 12 The corticosteroid is 21-(acetyloxy)-9-fluoro-1',2',3',4'-tetrahydro-11β-hydroxypregna-1,4-dieno[16α,17-b]naphthalene- 3,20-dione,
10. A composition according to any of claims 1 to 9, wherein the oily solvent comprises a mixture of isostearyl alcohol and dibutyl sebacate. 13 Corticosteroids are 21-chloro-9-fluoro-1',2',3',4'-tetrahydro-11β-hydroxypregna-1,4-dieno[16α,17-
b] Naphthalene-3,20-dione, the composition according to any one of claims 1 to 9, wherein the oily solvent comprises a mixture of castor oil and dibutyl sebacate.