CA1040534A

CA1040534A - Stabilized steroid formulations

Info

Publication number: CA1040534A
Application number: CA227,942A
Authority: CA
Inventors: James W. Mcginity; John A. Hill
Original assignee: ER Squibb and Sons LLC
Current assignee: ER Squibb and Sons LLC
Priority date: 1974-06-13
Filing date: 1975-05-28
Publication date: 1978-10-17
Also published as: BE830239A; GB1497836A; PH14507A; YU152175A; IE41417L; IE41417B1; ZA753429B; DE2526251A1; FR2274310B1; FR2274310A1; AU8168175A; JPS5126216A; NL7506872A; JPS5747971B2

Abstract

ABSTRACT

This invention describes a stabilized steroid composition comprising from 0.01% to 0.5% by weight of the steroid 9.alpha.-fluoro-21-chloro-11.beta.,16.alpha.,17.alpha.-trihydroxypregn-4-ene-3,20-dione, 16,17-acetonide, 0.005 to 0.2% by weight of an antioxidant selected from the group consisting of propyl gallate, butylated hydroxy-toluene, butylated hydroxyanisole, sodium bisulfite, sodium metabi-sulfite, and ascorbic acid, and polyethylene glycol or a poly-ethylene glycol ester, said polyethylene glycol or polyethylene glycol ester having a polyethylene glycol molecular weight of from 200 to 7500 and, optionally, including an oleaginous material.
This composition is useful in the treatment of various dermatoses.

Description

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This invention relates to novel stable steroid compositions which are useful in the treatment of a variety of dermatoses.
The present invention provides a stabilized steroid composition comprising from 0.01% to 0.5% by weight of the steroid 9a-fluoro-21-chloro~ ,16a,17a-trihydroxypregn-4-ene-3,20-dione, 16,17-acetonide, 0.005 to 0.2% by weight of an antioxidant selected from the group consisting of propyl gallate, butylated hydroxytoluene, butylated hydroxyanisole, sodium bisulfite, sodium metabisul~ite, and ascorbic acid, and polyethylene glycol or a polyethylene glycol ester, said polyethylene glycol or polyethylene glycol ester having a polyethylene glycol molecular weight of from 200 to 7500.
The present invention further provides a process for preparing a ~tabilized steroid composition which comprises dissolving from 0.01% to 0.5% by weight of the steroid 9a-fluoro-21-chloro-11~, 16a,17a-trihydroxypregn-4-ene-3,20-dione, 16,17-acetonide and from 0.005 to 0.2% by weight of an antioxidant selected from t~ group consisting of propyl gallate, butylated hydroxytoluene, butylated h~droxyanisole, sodium bisulfite, sodium metabisulfite and ascorbic acid in polyethylene glycol or polyethylene glycol ester, said ~ , polyethylene glycol or polyethylene glycol ester having a polyethylene glycol molecular weight of from 200 to 7500v 9a-Fluoro-21-chloro-11~,16a,17a-trihydroxypregn-4-ene-3,20-dione, 16,17-acetonide is a known corticosteroid that can be used for the treatment of inflammatory diseases of the skin and for the treatment of psoriasis.
It has been found that polyethylene glycol and polyethylene glycol esters are effective vechicles for the formulation of solubilized 9a-fluoro-21-chloro-11~,16a,17a-trihydroxypregn-4- ;
ene-3,20-dione, 16,17-acetoni~e as a lotion or as an ointment.
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In ageing tests, however~ the concentration of active steroid component in a polyethylene glycol-type vehicle is found to decrease. This loss of activity occurs at elevated temperatures, room temperature, and a~ refrigerated temperatures.
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Analysis shows that higher-molecular weight polyethylene glycols and polyethylene glycol esters often contain peroxide - impurities. Furthermore, it has now been found that as a composition comprising 9a-fluoro-21-chloro-11~,16~,17~-tri-; hydroxypregn-4-ene-3,20-dione, 16,17-acetonide and a polyethylene glycol or polyethylene glycol ester ages, the level of activity of the ~teroid decreases.
The problem of stabilizing a composition comprising 9~-fluoro-21-chloro~ ,16~,17a-trihydroxypregn-4-ene-3,20-dione, 16,17-acetonide in a polyethylene glycol or a polyethylene glycol ester is a two-fold problem, Polyethylene glycol-type vehicles usually contain peroxide impurities. Furthermore, after formulation, ; polyethylene glycol-type vehicles continue to generate peroxides. ;
It is, therefore, desirable to prevent 1) the peroxides present `' in the polyethylene glycol-type vehicle from adversely affecting 20 the activity of the active component in the formulation and 2) ~-the generation of additional peroxides in the polyethylene glycol- `~
type vehicle. `;
In the formulations of this invention the active steroid -component can be present in an amount of from about 0.01% to about -; -; 0.5% by weight, preferably from about 0.025% to about 0.2% ?
by weight, based on the total composition weight. The poly-ethylene glycol-type vehicle can be present in an amount of ; fro~ about 1 to 99O/o by weight~ Lotions can contain about 50%

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~O~S34 to about 99% by weight of a polyethylene glycol-type vehicle, preferably about 80% to about 90% by weight~ Ointments can contain about 1% to about 35% by weight of a polyethylene glycol-type vehicle, preferably about 2.5% to about 25% by ~ -weight.
The polyethylene glycol-type vehicle used in the composition of this invention may be a polyethylene glycol or a polyethylene glycol ester and should have a polyethylene glycol molecular weight ranging from about 200 to 7500, preferably 300 to 6000. The term "polyethylene glycol ester"
refers to mono- or di- fatty acid esters of a polymer of ethylene oxide and water. The fatty acid moiety will have about 16 to 18 carbon atoms. Exemplary of polyethylene glycol esters that may be used as vehicles are polyethylene glycol 4000 and 6000 monostearate and polyethylene glycol 4000 and 6000 distearate. A vehicle may be made up of more than one polyethylene glycol or polyethylene glycol ester having vary-ing molecular weights.
The antioxidants used to prevent oxidative degradation of the active steroid component are propyl gallate, butylated hydroxytoluene, butylated hydroxyanisole, sodium bi~ulfite, sodium metabisulfite, and ascorbic acid. Amounts of anti-oxidant ranging from 0.005 to 0.2% by weight of the compo-sition can be used concentrations of from 0~01 to 0.2% by weight are preferred. The antioxidants may be used either sin~ly or in combination in ehe composition of this invention.

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. It is a preferred embodiment of this invention that the composition contain, in addition to an antioxidant, a - chelating agent, e.q., ethylenediaminetetraacetic acid (EDTA) or a salt thereof (alkali metal salts, alkaline earth metal . ~ .
salts, ammonium salts, amine salts, etc.), diethylenetri-aminepentaacetic acid (DTPA) or a salt thereof (alkali metal salts, alkaline earth metal salts, ammonium salts, amine salts, etc.), citric acid, phosphoric acid, and tartaric acid; di-sodium edetate is preferred. The weight ratio of antioxid-dant to chelating agent can range from about 50:1 to 1:1, and is preferably about 10:1. The chelating agents have a dual effect. First, they prevent the reaction of trace metals in the vehicle with the antioxidant, thus preventing the dis-coloration of the product. Secondly, they potentiate the antioxidants.
It is also a preferred embodiment of this invention to include water in the composition in an amount of from about 0.1 to 40% by weight of the composition preferably 0.1 to 2%

by weight for ointments and 10 to 40% by weight for lotions.
The water aids in preventing or retarding peroxide formation on a~eing. ~`
In a preferred embodiment of this invention an oint-: . . .
ment is prepared wherein the polyethylene glycol-type vehicle is dispersed in an oleaginous material after the steroid, antioxidant, chelating agent, etc. are first dissolved in the polyethylene glycol. The polyethylene glycol preferably contains at least about 80~ of that amount of steroid required to form a saturated solution of the steroid in the polyethylene glycol. Most preferably, the polyethylene glycol solution of '' ~ .
''' ' ` ~4~534 the steroid is a saturated solution~ Bxemplary of oleaginous materials that can be used in the formulations of this invention are white petrolatum and mineral oil thickened with polyethylene; mineral oil thickened with polyethylene is the preferred oleaginous material. A description of the thicken-ing of mineral oil with polyethylene can be found in United States Patents 2,627,938, 2,628,187, and 2,628,205. The weight ratio of polyethylene glycol or polyethylene glycol ester to oleaginous material can range from 1:99 to 35:~5, but will preferably be from 2.5:97.5 to 25:75.

In addition to that portion of the steroid dissolved in the polyethylene glycol-type vehicle a portion of the steroid can be suspended in the oleaginous material, thus pro-viding a resevoir of steroiid to replenish the steroid removed from the glycol phase during topical application.
The compositions of this invention comprising a poly-ethylene glycol-type vehicle dispersed in white petrolatum can be prepared by first dissolving the steroid, antioxidant, chelating agent, etc. in the polyethylene glycol-type vehicle with heating and agitation. The white petrolatum, which has been separately melted, is then added to the polyethylene glycol solution of the steroid and the resulting formulation is allowed to cool while agitation is continued until con-gealing begins. Alternatively, the above process can be ~-reversed, i.e., the glycol phase can be added to the melted oleaginous material.
Still another process for preparing the compositions of this invention wherein the polyethylene glycol-type vehicle is dispersed in white petrolatum comprises first dissolving , 1~)4~1S34 the steroid, antioxidant, chelating agent, etc. in a heated polyethylene glycol-type vehicle and then allowing this solution to cool with continued agitation until it becomes unctuous. The polyethylene glycol phase is then mixed, preferably in a planetary type mixer, with about 10-20% of the desired quantity of oleaginous material and the mixture is passed through a roll mill. The remainder of the oleaginous material is then added to the milled mixture and mixed until ~-uniform.
10The compositions of this invention comprising a poly-ethylene glycol-type vehicle dispersed in mineral oil thickened with polyethylene can be prepared by first dissolving the ; steroid, antioxidant, chelating agent, etc. in the poly- ;
ethylene glycol-type vehi~le with heating and agitation. The hot steroid solution is added slowly to the mineral oil gelled with polyethylene while mixing in a planetary type mixer and the material is then passed through a static mixer using a high capacity low shear screw type pump and allcwed to cool to room temperature.
Alternatively, the compositionsof this invention wherein the polyethylene glycol-type vehicle is dispersed in minexal oil thickened with polyethylene can be prepared by first mixing the oleaginous material in a planetary mixer in the presence of a dispersing modifier such as hydroxylated lanolin or polysorbate 65 ~ween 65)u The steroid, anti-oxidant, chelating agent, etc. are dissolved in the poly-ethylene glycol-type vehicle with heating and agitation and the hot soLution is added slowly to the oleaginous material with mixing and allowed to cool to room temperature. -The following examples are specific embodiments of this invention.
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*Trade Mark . ,f ~

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LOTION
:
9 ~Fluoro-2l-chloro-ll~rl6a,l7a - -trihydroxypregn-4-ene-3,20-dione, 16,17-acetonide . . . . . . . . . . . . . . 100 mg.
Disodium edetate, U.S.P. . . . . . . . . . 5 mg.
Butylated hydroxytoluene . . . . . . . . . 50 mg.
Distilled w~ter . . . . . . . . . . . . . . 10 ml.
; Polyethylene glycol, 300 . . q.s. . . . . 100 ml.
A lotion is prepared by adding 10% of the antioxidant to 80 ml o polyethylene glycol 300. The disodium edetate is dissolved in the distilled water and added to the glycol vehicle. High shear mechanical stirring and heat (80 to 90C) ; are used to obtain full solution of the dispersed ingredients.
Heating and stirring are continued for approximately 45 minutes. After cooling the solution, the remaining antioxi-dant and the steroid are dissolved therein. The solution is adjusted to the proper volume.
Exa~ple 2 LOTION
9~-Fluoro-2l-chloro-~ l6all7a -trihydroxypregn-4-ene-3,20-dione, 16,17-acetonide . . . . . . . . . . . . . . . 100 mg.
Disodium edetate, U.S.P. . . . . . . . . . . 10 mg.
Propyl gallate ................................ SOmg.
Distilled water ............................... lOml.
Polyethylene glycol, 300 . . . q.s. . . . . 100 ml.
A lotion is prepared with the above formulation follow-

3~ ing the procedure set forth in Example 1.
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~Q4~)534 Example 3 ~ -LOTION

9a-Fluoro-21-chloro-11~,16a,17~

-trihydroxypregn-4-ene-3,20-dione, 16,17-acetonide . . . . . . . . . . . . . . . 100 mg.

Disodium edetate, U.S.P. . . . . . . . . . . 5 mg.

Propyl gallate . . . . . . . . . . . . . . . 25 mg.

Butylated hydroxyanisole . . . . . . . . . . 25 mg.

Distilled water . . . . . . . . . . . . . . . 10 ml.

Polyethylene glycol, 300 . . q.s. . . . . . 100 ml.

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A lotion is prepared with the above formulation following the procedure set forth in Example 1.
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Example 4 LOTION
9a-Fluoro-21-chloro-11~,16a,17~ ;--trihydroxypregn-4-ene-3,20-dione, 16,17-acetonide . . . . . . . . . . . . . . . 100 mg.
Disodium edetate, U.S.P. . . . . . . . . . . 5 mg.

Citric acid ............................ 100 mg.
Butylated hydroxyanisole . . ~ . . . . . . . 50 mg.
Distilled water ........................ 10 ml.
Polyethylene glycol, 300 . . q.s. . . . . . 100 ml.

A lotion is prepared with the above formulation following the procedure set forth in Example 1.

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4~534 . Example 5 LOTION
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9~-Fluoro-21-chloro-11~,16~,17~
-trihydroxypregn-4-ene-3,20-dione, 16,17-acetonide . . . . . . . . . . . . . . . 25 mg.
Disodium edetate, U.S.P. . . . . . ~ . . . . 10 mg.
Sodium metabisulfite . . . . . . . . . . . . 50 mg.
Distilled water ........................... 20 ml.
Polyethylene glycol, 300 . . q.s. . . . . . 100 ml.
10' A lotion is prepared by first dissolving the sodium metabisulfite and disodium edetate in the water and slowly adding the solution, with stirring, to 70 ml of the poly-ethylene glycol 300. The~steroid is then dissolved in the solution. The solution is adjusted to volume with poly-ethylene glycol 300.

Example 6 OINTMENT
9a-Fluoro-21-chloro-11~,16a,17~
-trihydroxypregn-4-ene-3,20-dione, 16,17-acetonide . . . . . . . . . . . . . . . 10~ mg.
Polyethylene glycol, 400 . . . . . . . . . . 10 g.
; Polyethylene glycol,- 1,500 . . . . . . . . . 10 g.
Polyethylene glycol, 6000 distearate . . . . . . . . . . . . . . . . . 2 g.
Butylated hydroxytoluene . . . . . . . . . . 50 mg.
White petrolatum . . . q.s. . . . . . . . . 100 g.
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. The butylated hydroxytoluene i5 added to the glycols which have been mixed together and heated to 60C. ~fter the antioxidant is dissolved in the glycol solution, the steroid is then dissolved. The white petrolatum (at 60C) is then admixed with the molten glycol solution (at 60C) and dispersed by mechanical agitation. The resulting dis-persion is cooled by agitation to the congealing point. The -resulting ointment has the white petrolatum as the continuous .
phase and the polyethylene glycol (having the steroid dis-solved therein) as the discontinuous phase.
, Example 7 OINTMENT
9a-Fluoro-21-chlor~ ,16~,17~
-trihydroxypregn-4-ene-3,20-dione, 16,17-acetonide . . . . . . . . . . . . . . . 100 mg.
Polyethylene glycol, 400 . . . . . . . . . . 10 g. `~
Polyethylene glycol, 1,500 . . . . . . . . . 10 g.
; Polyethylene glycol 6000 distearate ................................. 2 g.
Propyl gallate ............................ 50 mg. `
Distilled water . . . . . . . . . . . . . . . 0.1 ml.
Disodium edetate, U.S.P. . . . . . . . . . . 1.1 mg.
White petrolatum . . . . . q.s. . . . . . . 100 g.
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The disodium edetate is dissolved in water, and the resulting solution, along with the propyl gallate, is added r to a mixture of the glycols which is already at a temperature of 60C. After the steroid is dissolved in the glycol ... - , . . . .. . .

~041~534 . solution, the white petrolatum at 60C is then admixed with the molten glycol solution (at 60C) and dispersed by mechanical agitation. The resulting dispersion is cooled with agitation to the congealing point. The resulting oint-ment has the petrolatum as the continuous phase and the poly-ethylene glycol (having the steroid dissolved therein) as the discontinuous phase.

Example 8 OINTMENT
9a-Fluoro-21-chloro-llR,16a,17~
-trihydroxypregn-4-ene-3,20-dione, 16,17-acetonide ~ . . . . . . . . . . . . . . . 100 mg.
Polyethylene glycol, 400 . . . . . . . . . . . 5 g.
Polyethylene glycol, 1,500 . . . . . . . . . . 5 g.
Polyethylene glycol 6000 distearate . . . . . . 1 g.
Butylated hydroxytoluene . . . . . . . . . . . 25 mg.
*Plastibase 50W (mineral oil gelled - with polyethylene) . . . . . . . . . . . . . . 83.875 g.
Polysorbate 65 (~ween 65) (dispersing modifier) . 5 g.

The glycols are melted together by heating to 65C.
The butylated hydroxytoluene is dissolved in the mixture of glycols with stirring followed by the dissolution of 50 mg of steroid in the solution.
The polysorbate 65 is melted separately.
About 90~ of the Plastibase 50W is mixed at slow speed in a planetary mixer and the polysorbate 65 is added, followed by the addition of the molten glycol solution with continued stirring. The mixture is cooled to about 30C.

' *Trade Mark P ~
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~ 4~534 . A concentrate of the remaining steroid is prepared by mixing with a portion of*Piastibase 50W in a planetar~
mixer. The concentrate is passed through a three roll mill and diluted with the remaining*Plastibase 50W in a planetary mixer. After about 10 minutes of mixing, the concentrate is added to the main batch and mixed for about 15 minutes to yield an ointment.
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Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A stabilized steroid composition comprising from 0.1%
to 0.5% by weight of the steroid 9.alpha.-fluoro-21-chloro-11.beta.,16.alpha., 17.alpha., trihydroxypregn-4-ene-3,20-dione, 16,17 acetonide, 0.005 to 0.2% by weight of an antioxidant selected from the group consisting of propyl gallate, butylated hydroxytoluene, butylated hydroxyanisole, sodium bisulfite, sodium metabi-sulfite, and ascorbic acid, and polyethylene glycol or a polyethylene glycol ester said polyethylene glycol or poly-ethylene glycol ester having a polyethylene glycol molecular weight of from 200 to 7500.

2. A composition in accordance with claim 1 further comprising an oleaginous material.

3. A composition in accordance with claim 2 wherein said oleaginous material is mineral oil thickened with poly-ethylene.

4. A composition in accordance with claim 2 wherein said oleaginous material is white petrolatum.

5. A composition in accordance with claim 1 further comprising a chelating agent.

6. A composition in accordance with claim 5 wherein said chelating agent is disodium ethylenediaminetetraacetic acid.

7. A composition in accordance with claim 1 or 2 further comprising water in an amount of from 0.1 to 40% by weight.

8. A composition in accordance with claim 1 or 2 wherein the antioxidant is present in an amount of from 0.01 to 0.2%
by weight.

9. A composition in accordance with claim 2 wherein the weight ratio of polyethylene glycol or polyethylene glycol ester to the oleaginous material is from 1:99 to 35:65.

10. A composition in accordance with claim 5 wherein the ratio of antioxidant to chelating agent is from 50:1 to 1:1.

11. Process for preparing a stabilized steroid composition which comprises dissolving from 0.01% to 0.5%
by weight of the steroid 9.alpha.-fluoro-21-chloro-11.beta.,16.alpha.,17.alpha.-trihydroxypregn-4-ene-3,20-dione,16,17-acetonide and from 0.005 to 0.2% by weight of an antioxidant selected from the group consisting of propyl gallate, butylated hydroxytoluene, butylated hydroxyanisole, sodium bisulfite, sodium metabisulfite and ascorbic acid in polyethylene glycol or polyethlene glycol ester, said polyethylene glycol or polyethylene glycol ester having a polyethylene glycol molecular weight of from 200 to 7500.

12. The process of claim 11 which comprises combining the polyethylene glycol or polyethylene glycol ester solution with an oleaginous material.

13. The process of claim 12 wherein the oleaginous material is mineral oil thickened with polyethylene.

14. The process of claim 12 wherein the oleaginous material is white petrolatum.

15. The process of claim 11 wherein a chelating agent is added to the polyethene glycol or polyethylene glycol ester.

16. The process of claim 15 wherein the chelating agent is disodium ethylenediaminetetraacetic acid.

17. The process of claim 11 or 12 wherein water in an amount of from 0.1 to 40% by weight is included in the polyethylene glycol or polyethylene glycol ester solution.

18. The process of claim 11 or 12 wherein the antioxidant is present in an amount of from 0.01 to 0.2% by weight.

19. The process of claim 12 wherein the weight ratio of polyethylene glycol or polyethylene glycol ester to the oleaginous material is from 1:99 to 35:65.

20. The process of claim 15 wherein the ratio of antioxidant to chelating agent is from 50:1 to 1:1.