High-purity composition comprising (7alpha, 17alpha)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one and a process for purifying (7alpha, 17alpha)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one

Abstract

The invention pertains to a process for the preparation of a high-purity composition of (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one. The process provides for a composition with less than 0.5% of (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-4-en-20-yn-3-one. This composition can be used as a source for the preparation of stable pharmaceutical dosage units.

What is claimed is:  
     
         1 . A process for purifying (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one (tibolone), comprising: 
 aging crystals of tibolone for at least 24 hours in the presence of water; and  
 drying the crystals of tibolone after the at least 24 hours of aging, wherein the tibolone contains less than 0.5% by weight of (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-4-en-20-yn-3-one as an impurity relative to the tibolone after the drying.  
 
     
     
         2 . The process of  claim 1 , wherein the drying is carried out after at least 3 days of aging the crystals of tibolone.  
     
     
         3 . The process of  claim 1 , wherein the (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-4-en-20-yn-3-one is present at less than 0.25% by weight relative to the tibolone.  
     
     
         4 . The process of  claim 1 , wherein the (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-4-en-20-yn-3-one is present at less than 0.1% by weight relative to the tibolone.  
     
     
         5 . A dosage unit comprising a pharmaceutically suitable solid carrier and (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-5 (10)-en-20-yn-3-one (tibolone), prepared by a process comprising: 
 preparing the tibolone according to the process of  claim 1;  and  
 converting the tibolone to the dosage unit.  
 
     
     
         6 . The dosage unit of  claim 5 , wherein the dosage unit includes 2.50 mg of tibolone.  
     
     
         7 . The dosage unit of  claim 6 , wherein the dosage unit is a tablet.  
     
     
         8 . The dosage unit of  claim 6 , wherein the dosage unit is a capsule.  
     
     
         9 . The dosage unit of  claim 5 , wherein the dosage unit includes 1.25 mg of tibolone.  
     
     
         10 . The dosage unit of  claim 9 , wherein the dosage unit is a tablet.  
     
     
         11 . The dosage unit of  claim 9 , wherein the dosage unit is a capsule.  
     
     
         12 . The dosage unit of  claim 5 , wherein the dosage unit includes 0.625 mg of tibolone.  
     
     
         13 . The dosage unit of  claim 12 , wherein the dosage unit is a tablet.  
     
     
         14 . The dosage unit of  claim 12 , wherein the dosage unit is a capsule.  
     
     
         15 . The dosage unit of  claim 5 , wherein converting comprises: 
 granulating a diluent, a disintegrant, and a binder to obtain a granulate;    sieving the granulate;    mixing part of the granulate with tibolone and ascorbyl palmitate;    mixing the part of the granulate, tibolone, and ascorbyl palmitate with the remainder of the granulate and a lubricant; and    compressing the granulate.    
     
     
         16 . The dosage unit of  claim 15 , wherein the diluent is lactose.  
     
     
         17 . The dosage unit of  claim 15 , wherein the binder is potato starch mucilage.  
     
     
         18 . The dosage unit of  claim 15 , wherein the disintegrant is potato starch.  
     
     
         19 . The dosage unit of  claim 15 , wherein the lubricant is magnesium stearate.  
     
     
         20 . The dosage unit of  claim 5 , wherein the dosage unit further comprises lactose, potato starch, potato starch mucilage, ascorbyl palmitate, and magnesium stearate.  
     
     
         21 . A dosage unit comprising a pharmaceutically suitable solid carrier and 1.25 mg of (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one (tibolone), wherein the dosage unit contains less than 3% by weight of (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-4-en-20-yn-3-one relative to the tibolone after storage at a temperature of 25° C. and a relative humidity of 60% for two years.  
     
     
         22 . The dosage unit of  claim 21 , wherein the dosage unit is a tablet.  
     
     
         23 . The dosage unit of  claim 21 , wherein the dosage unit is a capsule.  
     
     
         24 . The dosage unit of  claim 21 , wherein the dosage unit further comprises lactose, potato starch, potato starch mucilage, ascorbyl palmitate and magnesium stearate.  
     
     
         25 . A dosage unit comprising a pharmaceutically suitable solid carrier and 0.625 mg of (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one (tibolone), wherein the dosage unit contains less than 4.9% by weight of (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-4-en-20-yn-3-one relative to the tibolone after storage at a temperature of 25° C. and a relative humidity of 60% for two years.  
     
     
         26 . The dosage unit of  claim 25 , wherein the dosage unit is a tablet.  
     
     
         27 . The dosage unit of  claim 25 , wherein the dosage unit is a capsule.  
     
     
         28 . The dosage unit of  claim 25 , wherein the dosage unit further comprises lactose, potato starch, potato starch mucilage, ascorbyl palmitate and magnesium stearate.  
     
     
         29 . A dosage unit comprising a pharmaceutically suitable solid carrier and 1.25 mg of (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one (tibolone), wherein the dosage unit has about a two times increase in (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-4-en-20-yn-3-one after storage for six months.  
     
     
         30 . The dosage unit of  claim 29 , wherein the dosage unit has less than about a 2.2 times increase in (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-4-en-20-yn-3-one after storage for six months.