Abstract:
A steroid lotion formulation which has enhanced physical and chemical stability is formed of (11β,17α)-17-(ethylthio)-9α-fluoro-11β-hydroxy-17-(methylthio)androsta-1,4-diene-3-one (tipredane), and a vehicle containing as major ingredients polyethylene glycol, propylene glycol and water together with a potassium citrate buffer or tromethamine buffer, and sodium metabisulfite and butylated hydroxytoluene as antioxidants.

Description:
FIELD OF THE INVENTION 
     The present invention relates to a steroid lotion formulation which has enhanced physical and chemical stability and contains (11β,17α)-17-(ethylthio)-9α-fluoro-11β-hydroxy-17-(methylthio)-androsta-1,4-dine-3-one (tipredane) as the active ingredient. 
     BACKGROUND OF THE INVENTION 
     U.S. Pat. No. 4,361,559 to Varma discloses antinflammatory 17,17 -bis(substituted thio) androstenes of the formula ##STR1## wherein R 1  and R 2  are the same or different and each is alkyl, cycloalkyl or aryl; 
     R 3  is hydrogen, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, ##STR2##  or halogen; R 4  is hydrogen, methyl, hydroxy, ##STR3##  or halogen; R 5  is hydrogen or halogen; and 
     R 6  is carbonyl or β-hydroxymethylene. A broken line in the 1,2-, 6,7- and 15,16-position of a structural formula indicates the optional presence of ethylenic unsaturation. 
     Included among the compounds covered in the Varma patent is tipredane which has been found to be a highly effective topical antiinflammatory agent. 
     Tipredane is practically insoluble in water (less than 0.0002 mg/ml at 25° C.); 1:1 hydroalcoholic mixtures of tipredane are unstable under acidic conditions. Furthermore, tipredane itself is susceptible to oxidation. Where it has been attempted to formulate tipredane with a sodium metabisulfite anti-oxidant and a potassium buffer, it has been found that sulfate was formed by the oxidation of metabisulfite. Furthermore, the presence of excess potassium ion in the formulation could lead to the precipitation of potassium sulfate crystals. 
     Until now, attempts to prepare a stable lotion formulation containing tipredane which overcomes the above stability problems have not been successful. 
     DESCRIPTION OF THE INVENTION 
     In accordance with the present invention, a topical steroid lotion formulation is provided which contains the steroid tipredane as its active ingredient and has excellent physical and chemical stability. The lotion formulation according to the present invention contains in addition to tipredane, a carrier vehicle which is formed of polyethylene glycol, propylene glycol and water and contains a buffer to maintain the lotion pH from about 5 to about 8, such as potassium citrate, preferably in the form of the monohydrate, or tromethamine, an antioxidant such as sodium metabisulfite and an auxiliary antioxidant such as butylated hydroxytoluene, and a metal chelating agent such as dipotassium ethylene diamine tetraacetic acid preferably in the form of the dihydrate. 
     The tipredane steroid will be present in an amount within the range of from about 0.005 to about 0.15% by weight and preferably from about 0.05 to about 0.1% by weight based on the total weight of the formulation. 
     The carrier or vehicle will include polyethylene glycol in an amount within the range of from about 62 to about 70% by weight and preferably from about 65 to about 67% by weight of the total lotion formulation. The polyethylene glycol 
     
         H(OCH.sub.2 CH.sub.2).sub.n OH 
    
     will have an n value of from about 350 to about 500. 
     Propylene glycol will be present in an amount within the range of from about 10 to about 20% by weight and preferably from about 10 to about 15% by weight of the lotion formulation. 
     In addition, water will be present in an amount within the range of from about 15 to about 25% and preferably from about 18to about 22% by weight of the total lotion formulation. 
     An important feature of the lotion formulation of the invention is its excellent chemical stability and physical stability so that potassium sulfate crystals will not precipitate out even after extended periods of storage. This is achieved due to the presence of potassium citrate as a buffer in an amount within the range of from about 0.2 to about 0.5% by weight and preferably from about 0.2 to about 0.3% by weight, or the presence of tromethamine as a buffer in an amount within the range of from about 0.2 to about 1% by weight and preferably from about 0.3 to about 0.7% by weight, and sodium metabisulfite present as an antioxidant in an amount within the range of from about 0.005 to about 0.03% by weight and preferably from about 0.01 to about 0.02% by weight of the lotion formulation. 
     In order to maintain proper pH of within the range of from about 5 to about 8, the lotion formulation may include an acid such as hydrochloric acid, sulfuric acid or phosphoric acid in an amount to bring the lotion to the required pH. The acid will normally be present when tromethamine is employed as the buffer. 
     The auxiliary antioxidant will be present in an amount within the range of from about 0.01 to about 1% by weight and preferably from about 0.03 to about 0.07% by weight of the lotion. 
     Examples of antioxidants which may be employed include butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate or sodium ascorbate. 
     As the metal chelating agent, dipotassium ethylenediamine tetraacetate dihydrate is preferred. The metal chelating will be employed in an amount within the range of from about 0.001 to about 0.01% by weight and preferably from about 0.003 to about 0.006% by weight of the lotion formulation. 
     The following represents preferred lotion formulations in accordance with the present invention. 
     
         ______________________________________            Range       RangeIngredient       Percent w/w Percent w/w______________________________________Tipredane        0.05   to    0.15 0.05 to  0.15Polyethylene glycol 400            65     to    67   65   to  67Propylene glycol 10     to    15   10   to  15Potassium citrate monohydrate            0.2    to    0.3Sodium metabisulfite            0.01   to    0.02 0.01 to  0.02Dipotassium EDTA dihydrate            0.003  to    0.006                              0.003                                   to  0.006Butylated hydroxytoluene            0.03   to    0.07 0.03 to  0.07Water qs at 100% 18     to    22   18   to  22Tromethamine                       0.3  to  0.7Hydrochloric acid                  0.1  to  0.5______________________________________ 
    
     The tipredane lotion formulations of the invention may be prepared as described in the working Examples by simply mixing and dissolving the steroid in the aqueous glycol vehicle base. 
     The following Examples represent preferred embodiments of the present invention. Unless otherwise indicated, all temperatures are expressed in degrees Centigrade. 
    
    
     EXAMPLE 1 
     A 0.1% w/w tipredane lotion formulation having the following composition was prepared as described below. 
     
         ______________________________________Tipredane Lotion 0.1 W/WIngredient              Percent w/w______________________________________Tipredane powder        0.10%Polyethylene glycol 400 N.F.                   65%Propylene glycol U.S.P. 14%Butylated hydroxytoluene N.F.                   0.05%Potassium citrate monohydrate U.S.P.                   0.25%Dipotassium EDTA (edetate) dihydrate                   0.005%Sodium metabisulfite N.F.                   0.0l%Purified water          20.6%______________________________________ 
    
     Butylated hydroxytoluene (BHT) was weighed and passed through a #20 mesh stainless steel screen. Into a tared 2 liter glass beaker was weighed polyethylene glycol 400 (PEG 400). Propylene glycol was separately weighedand then added to the PEG 400 in the glass beaker. The glycol mixture was stirred and nitrogen was bubbled through the mixture. The glycol mixture was heated to about 75° C. and the batch temperature was maintainedbetween 70° C. to 75° C. for about 30  minutes. The remainingingredients: tipredane, meshed BHT, dipotassium ethylene diamine tetraacetate (edetate) dihydrate, sodium metabisulfite, potassium citrate and water were separately weighed. The glycol mixture was then allowed to cool to about 50° C. The meshed and weighed BHT was slowly added tothe batch which was mixed well to completely dissolve the BHT. The batch was cooled further to a temperature between 25° C. and 35° C. and the weighed tipredane powder was slowly added to the cooled batch. The batch was mixed well to insure complete dissolution of the steroid. The weighed dipotassium edetate dihydrate, sodium metabisulfite and potassium citrate were dissolved in the weighed water. The salt solution was slowly added to the glycol mixture containing tipredane and the batch was mixed well to assure batch homogeneity. 
     The above tipredane formulation was found to have excellent chemical and physical stability and was free of visible precipitate even after prolonged periods of storage at temperatures of 5° C., 25° C. and 40° C. 
     EXAMPLE 2 
     A 0.1% w/w tipredane lotion formulation having the following composition was prepared as described below. 
     
         ______________________________________Tipredane Lotion 0.1 W/WFormulation Using Tromethamine BufferIngredient             Percent w/w______________________________________Tipredane powder       0.10%Polyethylene glycol 400 N.F.                  67%Propylene glycol U.S.P.                  14%Butylated hydroxytoluene N.F.                  0.05%Tromethamine U.S.P.    0.50%Hydrochloric acid, ACS grade                  0.25%Dipotassium edetate dihydrate                  0.005%Sodium metabisulfite N.F.                  0.02%Purified water         15%______________________________________ 
    
     Butylated hydroxytoluene (BHT) was weighed and passed through a #20 mesh stainless steel screen. Into a tared 2 liter glass beaker was weighed polyethylene glycol 400 (PEG 400). Propylene glycol was separately weighedand then added to the PEG 400 in the glass beaker. The glycol mixture was stirred (magnetic stirring hot plate) and nitrogen was bubbled through themixture. The glycol mixture was heated to about 75° C. and the batchtemperature was maintained between 70° C. to 75° C. for about30 minutes. The remaining ingredients: tipredane, meshed BHT, dipotassium edetate dihydrate, sodium metabisulfite, tromethamine, hydrochloric acid and water were separately weighed. The glycol mixture was then allowed to cool to about 50° C. The meshed and weighed BHT was slowly added tothe glycol mixture which was mixed well to completely dissolve the BHT. Thebatch was cooled further to a temperature between 25° C. and 35° C. and the weighed tipredane powder was slowly added to the cooled batch. The batch was mixed well to insure complete dissolution of the steroid. The weighed dipotassium edetate dihydrate, sodium metabisulfite, tromethamine and HCl were added to the weighed water and allowed to dissolve with mixing. This salt solution was slowly added to the glycol mixture containing tipredane and the batch was mixed well to assure batch homogeneity. 
     The above tipredane formulation was found to have excellent chemical and physical stability and was free of visible precipitate even after prolonged periods of storage at temperatures of 5° C., 25° C. and 40° C.