Topical formulation for a jak inhibitor

Abstract

This invention relates to pharmaceutical formulations for topical skin application comprising (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, and use in the treatment of skin disorders.

1 . A pharmaceutical formulation for topical skin application, comprising:
 an oil-in-water emulsion; and   a therapeutically effective amount of a therapeutic agent which is (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof   
     
     
         2 . A pharmaceutical formulation according to  claim 1 , wherein the emulsion comprises water, an oil component, and an emulsifier component. 
     
     
         3 - 4 . (canceled) 
     
     
         5 . A pharmaceutical formulation according to  claim 2 , wherein the oil component is present in an amount of about 20% to about 27% by weight of the formulation. 
     
     
         6 . (canceled) 
     
     
         7 . A pharmaceutical formulation according to  claim 2 , wherein the oil component comprises one or more substances independently selected from white petrolatum, cetyl alcohol, stearyl alcohol, light mineral oil, medium chain triglycerides, and dimethicone. 
     
     
         8 . A pharmaceutical formulation according to  claim 2 , wherein the oil component comprises an occlusive agent component. 
     
     
         9 . (canceled) 
     
     
         10 . A pharmaceutical formulation according to  claim 8 , wherein the occlusive agent component is present in an amount of about 5% to about 10% by weight of the formulation. 
     
     
         11 . (canceled) 
     
     
         12 . A pharmaceutical formulation according to  claim 8 , wherein the occlusive agent component comprises white petrolatum. 
     
     
         13 . A pharmaceutical formulation according to  claim 2 , wherein the oil component comprises a stiffening agent component. 
     
     
         14 - 15 . (canceled) 
     
     
         16 . A pharmaceutical formulation according to  claim 13 , wherein the stiffening agent component is present in an amount of about 4% to about 7% by weight of said formulation. 
     
     
         17 - 18 . (canceled) 
     
     
         19 . A pharmaceutical formulation according to  claim 13 , wherein the stiffening agent component comprises one or more substances independently selected from C 16-18  fatty alcohols. 
     
     
         20 . (canceled) 
     
     
         21 . A pharmaceutical formulation according to  claim 2 , wherein the oil component comprises an emollient component. 
     
     
         22 . (canceled) 
     
     
         23 . A pharmaceutical formulation according to  claim 21 , wherein the emollient component is present in an amount of about 7% to about 13% by weight of the formulation. 
     
     
         24 - 25 . (canceled) 
     
     
         26 . A pharmaceutical formulation according to  claim 21 , wherein the emollient component comprises one or more substances independently selected from light mineral oil, medium chain triglycerides, and dimethicone. 
     
     
         27 - 28 . (canceled) 
     
     
         29 . A pharmaceutical formulation according to  claim 2 , wherein the water is present in an amount of about 45% to about 55% by weight of the formulation. 
     
     
         30 - 32 . (canceled) 
     
     
         33 . A pharmaceutical formulation according to  claim 2 , wherein the emulsifier component is present in an amount of about 4% to about 7% by weight of the formulation. 
     
     
         34 . (canceled) 
     
     
         35 . A pharmaceutical formulation according to  claim 2 , wherein the emulsifier component comprises one or more substances independently selected from glyceryl fatty esters and sorbitan fatty esters. 
     
     
         36 . (canceled) 
     
     
         37 . A pharmaceutical formulation according to  claim 1 , wherein said pharmaceutical formulation further comprises a stabilizing agent component. 
     
     
         38 - 39 . (canceled) 
     
     
         40 . A pharmaceutical formulation according to  claim 37 , wherein the stabilizing agent component is present in an amount of about 0.3 to about 0.5% by weight of the formulation. 
     
     
         41 . (canceled) 
     
     
         42 . A pharmaceutical formulation according to  claim 37 , wherein the stabilizing agent component comprises xanthan gum. 
     
     
         43 . A pharmaceutical formulation according to  claim 1 , wherein said pharmaceutical formulation further comprises a solvent component. 
     
     
         44 - 45 . (canceled) 
     
     
         46 . A pharmaceutical formulation according to  claim 43 , wherein the solvent component is present in an amount of about 20% to about 25% by weight of the formulation. 
     
     
         47 . A pharmaceutical formulation according to  claim 43 , wherein the solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols. 
     
     
         48 . (canceled) 
     
     
         49 . A pharmaceutical formulation according to  claim 1 , wherein the therapeutic agent is present in an amount of about 0.5% to about 1.5% by weight of the formulation on a free base basis. 
     
     
         50 . A pharmaceutical formulation according to  claim 1 , wherein said therapeutic agent is present in an amount of about 0.5% by weight of the formulation on a free base basis. 
     
     
         51 . A pharmaceutical formulation according to  claim 1 , wherein said therapeutic agent is present in an amount of about 1% by weight of the formulation on a free base basis. 
     
     
         52 . A pharmaceutical formulation according to  claim 1 , wherein said therapeutic agent is present in an amount of about 1.5% by weight of the formulation on a free base basis. 
     
     
         53 . A pharmaceutical formulation according to  claim 1 , wherein said therapeutic agent is (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile phosphoric acid salt. 
     
     
         54 . A pharmaceutical formulation according to  claim 1 , comprising:
 from about 35% to about 65% of water by weight of the formulation;   from about 10% to about 40% of an oil component by weight of the formulation;   from about 1% to about 9% of an emulsifier component by weight of the formulation;   from about 10% to about 35% of a solvent component by weight of the formulation;   from about 0.05% to about 5% of a stabilizing agent component by weight of the formulation; and   from about 0.5% to about 1.5% of (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, by weight of the formulation on a free base basis.   
     
     
         55 . A pharmaceutical formulation according to  claim 1 , comprising:
 from about 40% to about 60% of water by weight of the formulation;   from about 15% to about 30% of an oil component by weight of the formulation;   from about 2% to about 6% of an emulsifier component by weight of the formulation;   from about 15% to about 30% of a solvent component by weight of the formulation;   from about 0.1% to about 2% of a stabilizing agent component by weight of the formulation; and   from about 0.5% to about 1.5% of (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, by weight of the formulation on a free base basis.   
     
     
         56 . A pharmaceutical formulation according to  claim 1 , comprising:
 from about 45% to about 55% of water by weight of the formulation;   from about 17% to about 27% of an oil component by weight of the formulation;   from about 3% to about 5% of an emulsifier component by weight of the formulation;   from about 20% to about 25% of a solvent component by weight of the formulation;   from about 0.3% to about 0.5% of a stabilizing agent component by weight of the formulation; and   from about 0.5% to about 1.5% of (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, by weight of the formulation on a free base basis.   
     
     
         57 . A pharmaceutical formulation according to  claim 1 , comprising:
 from about 45% to about 55% of water by weight of the formulation;   from about 17% to about 27% of an oil component by weight of the formulation;   from about 4% to about 7% of an emulsifier component by weight of the formulation;   from about 20% to about 25% of a solvent component by weight of the formulation;   from about 0.3% to about 0.5% of a stabilizing agent component by weight of the formulation; and   from about 0.5% to about 1.5% of (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, by weight of the formulation on a free base basis.   
     
     
         58 . A pharmaceutical formulation according to  claim 54 , wherein:
 the oil component comprises one or more substances independently selected from petrolatums, fatty alcohols, mineral oils, triglycerides, and dimethicones;   the emulsifier component comprises one or more substances independently selected from glyceryl fatty esters and sorbitan fatty esters;   the solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols; and   the stabilizing agent component comprises one or more substances independently selected from polysaccharides.   
     
     
         59 . A pharmaceutical formulation according to  claim 54 , wherein:
 the oil component comprises one or more substances independently selected from white petrolatum, cetyl alcohol, stearyl alcohol, light mineral oil, medium chain triglycerides, and dimethicone;   the emulsifier component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20;   the solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol; and   the stabilizing agent component comprises xanthan gum.   
     
     
         60 . A pharmaceutical formulation according to  claim 1 , comprising:
 from about 35% to about 65% of water by weight of the formulation;   from about 2% to about 15% of an occlusive agent component by weight of the formulation;   from about 2% to about 8% of a stiffening agent component by weight of said formulation;   from about 5% to about 15% of an emollient component by weight of the formulation;   from about 1% to about 9% of an emulsifier component by weight of the formulation;   from about 0.05% to about 5% of a stabilizing agent component by weight of the formulation;   from about 10% to about 35% of a solvent component by weight of the formulation; and   from about 0.5% to about 1.5% of (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, by weight of the formulation on a free base basis.   
     
     
         61 . A pharmaceutical formulation according to  claim 1 , comprising:
 from about 40% to about 60% of water by weight of the formulation;   from about 5% to about 10% of an occlusive agent component by weight of the formulation;   from about 2% to about 8% of a stiffening agent component by weight of said formulation;   from about 7% to about 12% of an emollient component by weight of the formulation;   from about 2% to about 6% of an emulsifier component by weight of the formulation;   from about 0.1% to about 2% of a stabilizing agent by weight of the formulation;   from about 15% to about 30% of a solvent component by weight of the formulation; and   from about 0.5% to about 1.5% of (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, by weight of the formulation on a free base basis.   
     
     
         62 . A pharmaceutical formulation according to  claim 1 , comprising:
 from about 45% to about 55% of water by weight of the formulation;   from about 5% to about 10% of an occlusive agent component by weight of the formulation;   from about 3% to about 6% of a stiffening agent component by weight of said formulation;   from about 7% to about 13% of an emollient component by weight of the formulation;   from about 3% to about 5% of an emulsifier component by weight of the formulation;   from about 0.3% to about 0.5% of a stabilizing agent component by weight of the formulation;   from about 20% to about 25% of a solvent component by weight of the formulation; and   from about 0.5% to about 1.5% of (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, by weight of the formulation on a free base basis.   
     
     
         63 . A pharmaceutical formulation according to  claim 1 , comprising:
 from about 45% to about 55% of water by weight of the formulation;   from about 5% to about 10% of an occlusive agent component by weight of the formulation;   from about 4% to about 7% of a stiffening agent component by weight of said formulation;   from about 7% to about 13% of an emollient component by weight of the formulation;   from about 4% to about 7% of an emulsifier component by weight of the formulation;   from about 0.3% to about 0.5% of a stabilizing agent component by weight of the formulation;   from about 20% to about 25% of a solvent component by weight of the formulation; and   from about 0.5% to about 1.5% of (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, by weight of the formulation on a free base basis.   
     
     
         64 . A pharmaceutical formulation according to  claim 1 , comprising:
 from about 45% to about 55% of water by weight of the formulation;   about 7% of an occlusive agent component by weight of the formulation;   from about 4.5% to about 5% of a stiffening agent component by weight of said formulation;   about 10% of an emollient component by weight of the formulation;   from about 4% to about 4.5% of an emulsifier component by weight of the formulation;   about 0.4% of a stabilizing agent component by weight of the formulation;   about 22% of a solvent component by weight of the formulation; and   from about 0.5% to about 1.5% of (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, by weight of the formulation on a free base basis.   
     
     
         65 . A pharmaceutical formulation according to  claim 60 , wherein the combined amount of the stiffening agent component and the emulsifier component is at least about 8% by weight of the formulation. 
     
     
         66 . A pharmaceutical formulation according to  claim 60 , wherein:
 the occlusive agent component comprises a petrolatum;   the stiffening agent component comprises one or more substances independently selected from one or more fatty alcohols;   the emollient component comprises one or more substances independently selected from mineral oils and triglycerides;   the emulsifier component comprises one or more substances independently selected from glyceryl fatty esters and sorbitan fatty esters;   the stabilizing agent component comprises one or more substances independently selected from polysaccharides; and   the solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols.   
     
     
         67 . A pharmaceutical formulation according to  claim 60 , wherein:
 the occlusive agent component comprises white petrolatum;   the stiffening agent component comprises one or more substances independently selected from cetyl alcohol and stearyl alcohol;   the emollient component comprises one or more substances independently selected from light mineral oil, medium chain triglycerides, and dimethicone;   the emulsifier component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20;   the stabilizing agent component comprises xanthan gum; and   the solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol.   
     
     
         68 - 74 . (canceled) 
     
     
         75 . A method of treating a skin disorder in a patient in need thereof, comprising applying a pharmaceutical formulation according to  claim 1  to an area of skin of said patient. 
     
     
         76 . The method of  claim 75 , wherein the skin disorder is a topic dermatitis or psoriasis. 
     
     
         77 . The method of  claim 75 , wherein the skin disorder is psoriasis. 
     
     
         78 . The method of  claim 75 , wherein said skin disorder is skin sensitization, skin irritation, skin rash, contact dermatitis or allergic contact sensitization. 
     
     
         79 . The method of  claim 75 , wherein said skin disorder is a bullous skin disorder. 
     
     
         80 . The method of  claim 79 , wherein said bullous skin disorder is pemphigus vulgaris (PV) or bullous pemphigoid (BP). 
     
     
         81 - 82 . (canceled)