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)
View Patent ↗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 consisting essentially of:
a) about 31.9 mg of the compound 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,
b) about 90% of the compound particles have a particle size of greater than 10 micron but less than 90 micron;
c) the tablet is produced on a scale suitable to prepare at least about 50,000 tablets;
d) the tablet contains from about 25% to about 89% by weight of one or more excipients selected from the group consisting of microcrystalline cellulose, powdered cellulose, pregelatinized starch, starch, lactitol, mannitol, sorbitol and maltodextrin;
e) the tablet is film coated;
f) the tablet contains a disintegrant in an amount from 4% to about 12% by weight;
g) the tablet optionally contains a binder in an amount up to about 8% by weight; and
h) the tablet optionally contains a lubricant in an amount up to about 2% by weight.
2. A pharmaceutical tablet according to claim 1 wherein:
the tablet contains from about 25% to about 89% by weight of one or more excipients selected from the group consisting of microcrystalline cellulose and mannitol.
3. A process for preparing pharmaceutical tablets containing about 31.9 mg 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), which process comprises the steps of;
a) admixing:
the compound 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 about 90% of the compound particles have a particle size of greater than 10 micron but less than 90 micron; one or more excipients selected from the group consisting of microcrystalline cellulose, powdered cellulose, pregelatinized starch, starch, lactitol, mannitol, sorbitol and maltodextrin; and
further excipients;
to form a mixture;
b) compressing the mixture into tablets; and
c) applying a film coating to the tablets;
provided:
the process is carried out on a scale suitable to prepare at least about 50,000 tablets;
each tablet contains about 31.9 mg 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); and
each tablet contains from about 25% to about 89% by weight of one or more excipients selected from the group consisting of microcrystalline cellulose, powdered cellulose, pregelatinized starch, starch, lactitol, mannitol, sorbitol and maltodextrin;
each tablet contains a disintegrant in an amount from 4% to about 12% by weight;
each tablet optionally contains a binder in an amount up to about 8% by weight; and
each tablet optionally contains a lubricant in an amount up to about 2% by weight.
4. A process according to claim 3 wherein:
each tablet contains from about 25% to about 89% by weight of one or more excipients selected from the group consisting of microcrystalline cellulose and mannitol.
5. A pharmaceutical tablet consisting essentially of:
a) about 31.9 mg of the compound 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,
b) about 90% of the compound particles have a particle size of greater than 10 micron but less than 90 micron;
c) the tablet contains from about 25% to about 89% by weight of one or more excipients selected from the group consisting of microcrystalline cellulose, powdered cellulose, pregelatinized starch, starch, lactitol, mannitol, sorbitol and maltodextrin;
d) the tablet is film coated;
e) the tablet contains a disintegrant in an amount from 4% to about 12% by weight;
f) the tablet optionally contains a binder in an amount up to about 8% by weight; and
g) the tablet optionally contains a lubricant in an amount up to about 2% by weight.
6. A pharmaceutical tablet according to claim 5 wherein:
the tablet contains from about 25% to about 89% by weight of one or more excipients selected from the group consisting of microcrystalline cellulose and mannitol.
7. A process for preparing pharmaceutical tablets containing about 31.9 mg 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), which process comprises the steps of;
a) admixing:
the compound 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 about 90% of the compound particles have a particle size of greater than 10 micron but less than 90 micron; one or more excipients selected from the group consisting of microcrystalline cellulose, powdered cellulose, pregelatinized starch, starch, lactitol, mannitol, sorbitol and maltodextrin; and
further excipients;
to form a mixture;
b) compressing the mixture into tablets; and
c) applying a film coating to the tablets;
provided:
each tablet contains about 31.9 mg 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); and
each tablet contains from about 25% to about 89% by weight of one or more excipients selected from the group consisting of microcrystalline cellulose, powdered cellulose, pregelatinized starch, starch, lactitol, mannitol, sorbitol and maltodextrin;
each tablet contains a disintegrant in an amount from 4% to about 12% by weight;
each tablet optionally contains a binder in an amount up to about 8% by weight; and
each tablet optionally contains a lubricant in an amount up to about 2% by weight.
8. A process according to claim 7 wherein:
each tablet contains from about 25% to about 89% by weight of one or more excipients selected from the group consisting of microcrystalline cellulose and mannitol.
9. 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 .
10. 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 2 .
11. 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 5 .
12. 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 6 .