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What is claimed:
1. An isolated compound of the formula:
<IMG>
2. A composition comprising a compound of the formula:
<IMG>
wherein the composition is free of rosiglitazone
maleate.
3. A composition comprising a compound having the
formula(I):
<IMG>
in an amount of at least 0.2% based on the weight of
the composition, and a carrier.
-38-
4. The composition of claim 3 comprising at least 1.5% of
the compound of the formula (I), based on the weight
of the composition.
5. The composition of claim 4 comprising at least 50% of
the compound of the formula (I), based on the weight
of the composition.
6. The composition of claim 3 comprising from more than 0
to 99.8% by weight of rosiglitazone maleate, based on
the combined weight of the compound of the formula (I)
and the rosiglitazone maleate.
7. The composition of claim 3 comprising from more than 0
to 98.5% by weight of rosiglitazone maleate, based on
the combined weight of the compound of the formula (I)
and the rosiglitazone maleate.
8. The composition of claim 6, which is a pharmaceutical
composition and the carrier is a pharmaceutically
acceptable carrier.
9. The pharmaceutical composition of claim 8, wherein the
compound of formula (I) is present in an amount
between 0.20% and 5.0% based on the combined weight of
the compound of formula (I) and rosiglitazone maleate
in the composition.
10. The pharmaceutical composition of claim 9, wherein the
compound of formula (I) is present in an amount
between 0.20% and 3.0% based on the combined weight of
the compound of formula (I) and rosiglitazone maleate
in the composition.
11. The pharmaceutical composition of claim 10, wherein
the compound of formula (I) is present in an amount
-39-
between 0.25% and 2.0% based on the combined weight of
the compound of formula (I) and rosiglitazone maleate
in the composition.
12. The pharmaceutical composition of claim 11, wherein
the compound of formula (I) is present in an amount
between 0.70% and 2.0% based on the combined weight of
the compound of formula (I) and rosiglitazone maleate
in the composition.
13. The pharmaceutical composition of claim 12, wherein
the compound of formula (I) is present in an amount
between 1.10% and 2.0% based on the combined weight of
the compound of formula (I) and rosiglitazone maleate
in the composition.
14. A pharmaceutical composition comprising a granulate of
a mixture of:
a) rosiglitazone maleate;
b) at least one pharmaceutically acceptable carrier;
and
c) less than 0.1% of the compound of the formula (I):
<IMG>
based on the combined weight of the compound of the
formula (I) and rosiglitazone maleate.
15. The pharmaceutical composition of claim 14, wherein
the compound of formula (I) is present in an amount
less than 0.1% based on the combined weight of the
compound and rosiglitazone maleate.
-40-
16. The pharmaceutical composition of claim 14 or 15,
wherein the granulate is a product of wet granulation
in an aqueous solution.
17. The pharmaceutical composition of any of claims 14-16,
wherein the granulate is a milled granulate.
18. The pharmaceutical composition of any of claims 8-17,
further comprising at least one disintegrant and at
least one binder.
19. The pharmaceutical composition of claim 18, wherein
the disintegrant is croscarmellose sodium, and the
binder is povidone.
20. The pharmaceutical composition of any of claims 8-17,
further comprising a biguanide antidiabetic compound.
21. The pharmaceutical composition of claim 20, wherein
the biguanide antidiabetic compound is a
pharmaceutically acceptable salt of metformin.
22. The pharmaceutical composition of claim 21, wherein
the pharmaceutically acceptable salt of metformin is
metformin hydrochloride.
23. The pharmaceutical composition of any of claims 8-22,
further comprising a sulfonyl urea antidiabetic
compound.
24. The pharmaceutical composition of claim 23, wherein
the sulfonyl urea antidiabetic compound is glimepride
or glipizide.
25. The pharmaceutical composition of any of claims 8-24
in the form of a tablet.
-41-
26. The pharmaceutical composition of claim 25, wherein
the tablet comprises a tablet core, the tablet core
comprising, by weight, between 1% and 4%
rosiglitazone maleate, 6% croscarmellose sodium, 2%
povidone, between 0.5% and 1% magnesium stearate and
between 87% and 90% filler, the filler consisting of
lactose and microcrystalline cellulose.
27. The pharmaceutical composition of claim 25, wherein
the tablet comprises a tablet core, the tablet core
comprising, by weight, between 75% and 76% metformin
HCl, between 0.2% and 1% rosiglitazone maleate,
between 5% and 6% povidone, between 1% and 2%
croscarmellose sodium, between 4% and 5% starch, and
between 0.5% and 1% magnesium stearate.
28. A sealed package comprising the composition of any of
claims 2-7 or the pharmaceutical composition of any
one of claims 8-27.
29. The sealed package of claim 28, further comprising a
desiccant.
30. The sealed package of claim 29, wherein the desiccant
is silica gel.
31. The sealed package of any of claims 28-30, which is a
HDPE bottle.
32. The sealed package of any of claims 28-31, wherein a
net increase of the total content of a compound of the
formula (I):
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<IMG>
based on the combined weight of the compound of the
formula (I) and rosiglitazone maleate in the
pharmaceutical composition, is 0.7% or less after
storage of the sealed package at 75% relative humidity
and 40°C for 3 months.
33. A sealed package comprising the pharmaceutical
composition of any one of claims 14-27, wherein the
pharmaceutical composition contains less than 1.0% of
a compound of the formula (I):
<IMG>
based on the combined weight of the compound of the
formula (I) and rosiglitazone maleate in the
pharmaceutical composition, after storage of the
sealed package at 75% relative humidity and 40°C for 3
months.
-43-
34. A sealed package comprising:
a pharmaceutical composition comprising rosiglitazone
maleate and at least one pharmaceutically acceptable
carrier; and
a desiccant.
35. The sealed package of claim 34, wherein the
pharmaceutical composition further comprises a
compound of the formula (I):
<IMG>
in an amount of 1.0% or below, based on the combined
weight of the compound of the formula (I) and
rosiglitazone maleate in the pharmaceutical
composition.
36. The sealed package of claim 35, wherein the compound
of the formula (I):
<IMG>
is present in the pharmaceutical composition in an
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amount of less than 0.1%, based on the combined weight
of the compound of the formula (I) and rosiglitazone
maleate.
37. The sealed package of any of claims 34-36, wherein the
pharmaceutical composition contains less than 1.0% of
a compound of the formula (I):
<IMG>
based on the combined weight of the compound of the
formula (I) and rosiglitazone maleate in the
pharmaceutical composition, after storage of the
sealed package at 75% relative humidity and 40°C for 3
months.
38. The sealed package of any of claims 34-36, wherein a
net increase of the total content of a compound of the
formula (I):
<IMG>
based on the combined weight of the compound of the
formula (I) and rosiglitazone maleate in the
pharmaceutical composition, is 0.7% or less after
-45-
storage of the sealed package at 75% relative humidity
and 40°C for 3 months.
39. The sealed package of any of claims 34-38, wherein the
pharmaceutical composition further comprises at least
one disintegrant and at least one binder.
40. The sealed package of claim 39, wherein the
disintegrant is croscarmellose sodium, and the binder
is povidone.
41. The sealed package of any of claims 34-40, wherein the
pharmaceutical composition further comprises a
biguanide antidiabetic compound.
42. The sealed package of any of claims 41, wherein the
biguanide antidiabetic compound is a pharmaceutically
acceptable salt of metformin.
43. The sealed package of claim 42, wherein the
pharmaceutically acceptable salt of metformin is
metformin HC1.
44. The sealed package of any of claims 34-43, wherein the
pharmaceutical composition further comprises a
sulfonyl urea antidiabetic compound.
45. The sealed package of claim 44, wherein the sulfonyl
urea antidiabetic compound is glimepride or glipizide.
46. The sealed package of any of claims 34-45, wherein the
pharmaceutical composition is in the form of a tablet.
47. The sealed package of claim 46, wherein the tablet
comprises a tablet core, the tablet core comprising,
by weight, between 1% and 4% rosiglitazone maleate,
6% croscarmellose sodium, 2% povidone, between 0.5%
-46-
and 1% magnesium stearate and between 87% and 90%
filler, the filler consisting of lactose and
microcrystalline cellulose.
48. The sealed package of claim 46, wherein the tablet
comprises a tablet core, the tablet core comprising,
by weight, between 75% and 76% metformin HCl, between
0.2% and 1% rosiglitazone maleate, between 5% and 6%
povidone, between 1% and 2% croscarmellose sodium,
between 4% and 5% starch, and between 0.5% and 1%
magnesium stearate.
49. The sealed package of any of claims 34-48, wherein the
desiccant is silica gel.
50. The sealed package of any of 34-49, wherein the
pharmaceutical composition is prepared by wet
granulation with water.
51. The sealed package of any of claims 34-50, wherein the
sealed package is a HDPE bottle.
52. A process for making the pharmaceutical composition of
claim 26, comprising
a) granulating in the presence of water a mixture of
rosiglitazone maleate, croscarmellose sodium, povidone
and a filler to obtain a granualte;
b) drying the granulate;
c) milling the granulate to obtain a milled granulate;
d) mixing the milled granulate with magnesium stearate
to obtain a final blend; and
e) compressing the final blend into a tablet core.
53. The process of claim 52, wherein steps c) - e) are
performed in an atmosphere having a relative humidity
of 30% or less.
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54. A process for making the pharmaceutical composition of
claim 27, comprising
a) granulating in the presence of an aqueous povidone
solution a mixture comprising rosiglitazone maleate
and metformin to obtain a granulate;
b) drying the granulate;
c) milling the granulate to obtain a milled granulate;
d) mixing the milled granulate with croscarmellose
sodium and starch to obtain an first blend;
e) mixing the first blend with magnesium stearate to
obtain a final blend; and
f) compressing the final blend into a tablet core.
55. The process of claim 54, wherein steps c) - f) are
performed in an atmosphere having a relative humidity
of 30% or less.
56. The process of any of claims 52-55, further comprising
coating the tablet core with a film coating.
57. A process for preparing the pharmaceutical composition
of any one of claims 14-27 or the sealed package of
any one of claims 28-33, comprising:
a. obtaining rosiglitazone maleate drug substance;
b. determining the total amount of 2-N-{5-[[4-[2-
(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-
2,4-thiazolidinedione}-butanedioic acid present
in the rosiglitazone maleate drug substance; and
c. including the rosiglitazone maleate drug
substance in the preparation of the
pharmaceutical composition only if the drug
substance is determined to have less than 0.10%
by weight of 2-N-{5-[[4-[2-(methyl-2-
pyridinylamino)ethoxy]phenyl]methyl]-2,4-
thiazolidinedione}-butanedioic acid.
58. The process of claim 57, wherein the pharmaceutical
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composition is prepared by wet granulation in an
aqueous solution.
59. A process for preparing a pharmaceutical composition
comprising rosiglitazone maleate and a
pharmaceutically acceptable carrier, wherein the
pharmaceutical composition comprises less than 1.2% of
2-N-{5-[[4-[2-(methyl-2-pyridinylamino)
ethoxy]phenyl]methyl]-2,4-thiazolidinedione}
butanedioic acid, based on the combined weight of 2-N-
{5-[[4-[2-(methyl-2-pyridinylamino)
ethoxy]phenyl]methyl]-2,4-thiazolidinedione}
butanedioic acid and rosiglitazone maleate,
comprising:
a. obtaining rosiglitazone maleate drug substance;
b. determining the total amount of 2-N-{5-[[4-[2-
(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-
2,4-thiazolidinedione}-butanedioic acid present
in the rosiglitazone maleate drug substance; and
c. including the rosiglitazone maleate drug
substance in the preparation of the
pharmaceutical composition only if the drug
substance is determined to have less than 0.10%
by weight of 2-N-{5-[[4-[2-(methyl-2-
pyridinylamino)ethoxy]phenyl]methyl]-2,4-
thiazolidinedione}-butanedioic acid.
60. The process of claim 59, wherein the pharmaceutical
composition is prepared by wet granulation in an
aqueous solution.
61. A process for validating a batch of a pharmaceutical
composition containing rosiglitazone maleate and at
least one pharmaceutically acceptable carrier for
distribution comprising:
a. determining the total amount of 2-N-{5-[[4-[2-
(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-
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2,4-thiazolidinedione}-butanedioic acid in a
sample of the batch after stability testing; and
b. validating the batch for distribution only if the
sample of the batch is determined in step a) to
contain less than 1.2% by weight of 2-N-{5-[[4-
[2-(methyl-2-pyridinylamino)
ethoxy]phenyl]methyl]-2,4-thiazolidinedione}
butanedioic acid.
62. The process of claim 61, wherein the batch is
validated for distribution only if the sample of the
batch is determined in step a) to contain less than
1.0% by weight of 2-N-{5-[[4-[2-(methyl-2-
pyridinylamino)ethoxy]phenyl]methyl]-2,4-
thiazolidinedione}-butanedioic acid.
63. The process of claim 62, wherein the batch is
validated for distribution only if the sample of the
batch is determined in step a) to contain less than
0.5% by weight of 2-N-{5-[[4-[2-(methyl-2-
pyridinylamino)ethoxy]phenyl]methyl]-2,4-
thiazolidinedione}-butanedioic acid.
64. A process for making the isolated compound of claim
1, comprising:
a. contacting rosiglitazone maleate with water at
a temperature of 40-100°C, and
b. isolating the compound from the reaction mixture
of step a).
65. The method of claim 64, wherein the compound is
isolated from the mixture via chromatography.
66. The method of claim 64, wherein the compound is
isolated from the mixture via recrystallization.
67. A method for increasing insulin sensitivity in a human
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subject comprising administering to the human subject
the pharmaceutical composition of any one of claims 8-
27.
68. Use of the composition of any of claims 2-7 or the
pharmaceutical composition of any one of claims 8-27
for manufacturing a medicament for increasing insulin
sensitivity in a human subject.
69. The pharmaceutical composition of any one of claims 8-
27 for increasing insulin sensitivity in a human
subject.
