Novel pharmaceutical composition

Abstract

Disclosed are novel pharmaceutical compositions containing 3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid bis-(monoethanolamine) (eltrombopag olamine) and processes for preparing the same.

1 . A pharmaceutical tablet comprising 3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid bis-(monoethanolamine) wherein the tablet is made using a diluent or diluents that are substantially free of coordinating metals and/or that are substantially free of reducing sugars. 
   
   
       2 . A pharmaceutical tablet comprising 3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid bis-(monoethanolamine) wherein the tablet is made on a commercial scale, by a wet granulation process using a diluent or diluents that are substantially free of coordinating metals and/or that are substantially free of reducing sugars. 
   
   
       3 . A pharmaceutical tablet according to  claim 1 , wherein about 90% of the drug particles have a particle size greater than 10 micron but less than 90 micron. 
   
   
       4 . Pharmaceutical tablets according to  claim 2 , wherein about 90% of the drug particles have a particle size greater than 10 micron but less than 90 micron. 
   
   
       5 . Pharmaceutical tablets according to  claim 2 , wherein about 90% of the drug particles have a particle size greater than 20 micron but less than 50 micron. 
   
   
       6 . Pharmaceutical tablets according to  claim 2 , wherein about 50% of the drug particles have a particle size greater than 5 micron but less than 50 micron. 
   
   
       7 . Pharmaceutical tablets according to  claim 2 , wherein about 50% of the drug particles have a particle size greater than 5 micron but less than 20 micron. 
   
   
       8 . A pharmaceutical tablet according to  claim 1  comprising:
 a) from about 2% to about 65% eltrombopag olamine;   b) from about 25% to about 89% of diluent;   c) up to about 8% binder;   d) up to about 2% of lubricant; and   e) from 4% to about 12% of disintegrant.   
   
   
       9 . A pharmaceutical tablet according to  claim 1  comprising:
 a) from about 2% to about 65% eltrombopag olamine;   b) from about 25% to about 89% of diluent;   c) up to about 8% of binder;   d) up to about 2% of lubricant; and   e) from to about 6% to about 10% of disintegrant.   
   
   
       10 . A pharmaceutical tablet according to  claim 1  comprising:
 a) from about 2% to about 65% eltrombopag olamine;   b) from about 25% to about 89% of diluent;   c) up to about 8% of binder;   d) up to about 2% of lubricant; and   e) from to about 7% to about 9% of disintegrant.   
   
   
       11 . A pharmaceutical tablet according to  claim 4  comprising:
 a) from about 2% to about 65% eltrombopag olamine;   b) from about 25% to about 89% of diluent;   c) up to about 8% binder;   d) up to about 2% of lubricant; and   e) from 4% to about 12% of disintegrant.   
   
   
       12 . A pharmaceutical tablet according to  claim 4  comprising:
 a) from about 2% to about 65% eltrombopag olamine;   b) from about 25% to about 89% of diluent;   c) up to about 8% of binder;   d) up to about 2% of lubricant; and   e) from to about 6% to about 10% of disintegrant.   
   
   
       13 . A pharmaceutical tablet according to  claim 4  comprising:
 a) from about 2% to about 65% eltrombopag olamine;   b) from about 25% to about 89% of diluent;   c) up to about 8% of binder;   d) up to about 2% of lubricant; and   e) from to about 7% to about 9% of disintegrant.   
   
   
       14 .- 16 . (canceled) 
   
   
       17 . A pharmaceutical tablet according to  claim 8  wherein the diluent component comprises a non-reducing sugar and microcrystalline cellulose. 
   
   
       18 . A pharmaceutical tablet according to  claim 17  wherein the non-reducing sugar is Mannitol, the binder is polyinylpyrolidone, the disintegrant is sodium starch glycolate and the lubricant is magnesium stearate. 
   
   
       19 . A pharmaceutical tablet according to  claim 11  wherein the diluent component comprises a non-reducing sugar and microcrystalline cellulose. 
   
   
       20 . A pharmaceutical tablet according to  claim 19  wherein the non-reducing sugar is mannitol, the binder is polyinylpyrolidone, the disintegrant is sodium starch glycolate, and the lubricant is magnesium stearate. 
   
   
       21 .- 22 . (canceled) 
   
   
       23 . Pharmaceutical tablets according to  claim 18  prepared on a commercial scale. 
   
   
       24 . A pharmaceutical tablet according to  claim 1  wherein the tablet is made by a wet granulation process using a diluent or diluents that are substantially free of coordinating metals and/or that are substantially free of reducing sugars. 
   
   
       25 . A method of treating thrombocytopenia in a human in need thereof which comprises administering to such human a therapeutically effective amount of a pharmaceutical tablet according to  claim 1 . 
   
   
       26 . A method of agonizing the TPO receptor in a human in need thereof which comprises administering to such human a therapeutically effective amount of a pharmaceutical tablet according to  claim 1 . 
   
   
       27 . A method of  claim 25  further comprising co-administering a therapeutically effective amount of an agent selected from the group consisting of: a colony stimulating factor, cytokine, chemokine, interleukin or cytokine receptor agonist or antagonists, soluble receptors, receptor agonists or antagonist antibodies, or small molecules or peptides that act by the same mechanisms as one or more of said agents. 
   
   
       28 . A solid oral pharmaceutical dosage form comprising 3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid bis-(monoethanolamine) wherein the solid oral pharmaceutical dosage form is made using a diluent or diluents that are substantially free of coordinating metals and/or that are substantially free of reducing sugars. 
   
   
       29 . A solid oral pharmaceutical dosage form comprising 3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid bis-(monoethanolamine) wherein the solid oral pharmaceutical dosage form is made on a commercial scale, using a diluent or diluents that are substantially free of coordinating metals and/or that are substantially free of reducing sugars. 
   
   
       30 . A solid oral pharmaceutical dosage form according to  claim 28 , wherein about 90% of the drug particles have a particle size greater than 10 micron but less than 90 micron. 
   
   
       31 . A solid oral pharmaceutical dosage form according to  claim 28  comprising:
 a) from about 2% to about 65% eltrombopag olamine;   b) from about 25% to about 89% of diluent;   c) up to about 8% binder;   d) up to about 2% of lubricant; and   e) from 4% to about 12% of disintegrant.   
   
   
       32 . Solid oral pharmaceutical dosage forms according to  claim 31  prepared on a commercial scale. 
   
   
       33 . A method of treating thrombocytopenia in a human in need thereof which comprises administering to such human a therapeutically effective amount of a solid oral pharmaceutical dosage form according to  claim 32 . 
   
   
       34 . A method of agonizing the TPO receptor in a human in need thereof which comprises administering to such human a therapeutically effective amount of a solid oral pharmaceutical dosage form according to  claim 32 . 
   
   
       35 . A method of  claim 33  further comprising co-administering a therapeutically effective amount of an agent selected from the group consisting of: a colony stimulating factor, cytokine, chemokine, interleukin or cytokine receptor agonist or antagonists, soluble receptors, receptor agonists or antagonist antibodies, or small molecules or peptides that act by the same mechanisms as one or more of said agents. 
   
   
       36 . A pharmaceutical capsule comprising 3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid bis-(monoethanolamine) wherein the capsule is made using a diluent or diluents that are substantially free of coordinating metals and/or that are substantially free of reducing sugars. 
   
   
       37 . A pharmaceutical capsule comprising 3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid bis-(monoethanolamine) wherein the capsule is made on a commercial scale, using a diluent or diluents that are substantially free of coordinating metals and/or that are substantially free of reducing sugars. 
   
   
       38 . A pharmaceutical capsule according to  claim 36 , wherein about 90% of the drug particles have a particle size greater than 10 micron but less than 90 micron. 
   
   
       39 . A pharmaceutical capsule according to  claim 36  comprising:
 a) from about 2% to about 65% eltrombopag olamine;   b) from about 25% to about 89% of diluent;   c) up to about 8% binder;   d) up to about 2% of lubricant; and   e) from 4% to about 12% of disintegrant.   
   
   
       40 . Pharmaceutical capsules according to  claim 39  prepared on a commercial scale. 
   
   
       41 . A method of treating thrombocytopenia in a human in need thereof which comprises administering to such human a therapeutically effective amount of a pharmaceutical capsule according to  claim 40 . 
   
   
       42 . A method of agonizing the TPO receptor in a human in need thereof which comprises administering to such human a therapeutically effective amount of a pharmaceutical capsule according to  claim 40 . 
   
   
       43 . A method of  claim 41  further comprising co-administering a therapeutically effective amount of an agent selected from the group consisting of: a colony stimulating factor, cytokine, chemokine, interleukin or cytokine receptor agonist or antagonists, soluble receptors, receptor agonists or antagonist antibodies, or small molecules or peptides that act by the same mechanisms as one or more of said agents. 
   
   
       44 . Pharmaceutical granules comprising 3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid bis-(monoethanolamine) wherein the granules are made using a diluent or diluents that are substantially free of coordinating metals and/or that are substantially free of reducing sugars. 
   
   
       45 . Pharmaceutical granules comprising 3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid bis-(monoethanolamine) wherein the granules are made on a commercial scale, using a diluent or diluents that are substantially free of coordinating metals and/or that are substantially free of reducing sugars. 
   
   
       46 . A process for preparing solid oral pharmaceutical dosage forms containing a diluent or diluents that are substantially free of coordinating metals and/or that are substantially free of reducing sugars and a therapeutically effective amount of 3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid bis-(monoethanolamine) as described in  claim 1 , which process comprises bringing the compound of  claim 1  into association with the diluent or diluents.