Levothyroxine pharmaceutical compositions, methods of making and methods of administration
First Claim
1. A stabilized solid pharmaceutical composition comprising a levothyroxine salt and a pharmaceutically acceptable carrier, wherein at least about 85% of the levothyroxine dissolves in aqueous solution in less than about 20 minutes as determined by a standard dissolution test.
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Abstract
The present invention generally relates to stable pharmaceutical compositions, and methods of making and administering such compositions. In one aspect, the invention features stabilized pharmaceutical compositions that include pharmaceutically active ingredients such as levothyroxine (T4) sodium and liothyronine (T3) sodium (thyroid hormone drugs), preferably in an immediate release solid dosage form. Also provided are methods for making and using such immediate release and stabilized compositions.
21 Citations
151 Claims
- 1. A stabilized solid pharmaceutical composition comprising a levothyroxine salt and a pharmaceutically acceptable carrier, wherein at least about 85% of the levothyroxine dissolves in aqueous solution in less than about 20 minutes as determined by a standard dissolution test.
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5. The composition of claim 5, wherein the microcrystalline β
- -cellulose, has a bulk density of between from about 0.10 g/cm3 to about 0.35 g/cm3.
- View Dependent Claims (6)
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8. The composition of claim 8, wherein tablet has a total hardness of between from about 6 to about 14 KP as determined by a standard hardness test.
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12. A stabilized pharmaceutical composition in tablet form comprising levothyroxine sodium, the composition comprising:
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a) between from about 1 μ
g/tablet to about 1000 μ
g/tablet levothyroxine sodium (USP),b) between from about 100 mg/tablet to about 110 mg/tablet of microcrystalline β
-cellulose. NF (Ceolus) having a bulk density of between from about 0.10 g/cm3 to about 0.35 g/cm3,c) between from about 25 mg/tablet to about 50 mg/tablet of croscarmellose sodium, NF (Ac-di-sol); and
d) between from about 0.5 mg/tablet to about 5 mg/tablet of magnesium stearate, NF.
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- 13. An immediate released solid pharmaceutical composition comprising a levothyroxine salt and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition loses less than 0.7% of its activity per month for up to 18 months.
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19. A stabilized pharmaceutical composition comprising a levothyroxine salt, wherein the composition features a levothyroxine (T4) plasma AUC (0-t) of between from about 450 μ
- g-hour/dl to about 600 μ
g-hour/dl. - View Dependent Claims (20, 21, 22)
- g-hour/dl to about 600 μ
- 23. A non-granulated sugar-free, starch-free stabilized pharmaceutical composition comprising levothyroxine and a pharmaceutically acceptable carrier, in tablet form.
- 30. A non-granulated sugar-free, starch-free immediate release pharmaceutical composition comprising levothyroxine and a pharmaceutically acceptable carrier, in tablet form.
- 37. A method of administering a levothyroxine pharmaceutical composition to a patient, comprising placing a stabilized levothyroxine pharmaceutical tablet in an aqueous medium, dispersing the levothyroxine composition in the aqueous medium for less than ten minutes, and administering the aqueous medium to the patient.
- 40. A stabilized pharmaceutical composition comprising a levothyroxine salt, wherein the composition features a triiodothyronine (T3) AUC (0-t) of between from about 10 ng-hour/mL to about 100 ng-hour/mL
- 42. A stabilized pharmaceutical composition comprising a levothyroxine salt, wherein the composition features a triiodothyronine (T3) AUC (0-t) of between from about 10 ng-hour/mL to about 100 ng-hour/mL.
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46. A stabilized pharmaceutical composition comprising a levothyroxine salt, wherein the composition exhibits a levothyroxine (T4) plasma Cmax of between from about 10 μ
- g/dl to about 20 μ
g/dl as determined by a standard Cmax test. - View Dependent Claims (47, 48, 49)
- g/dl to about 20 μ
- 50. A stabilized pharmaceutical composition comprising a levothyroxine salt, wherein the composition exhibits a levothyroxine (T4) plasma Tmax of between from about 0.5 hours to about 5 hours as determined by a standard Tmax test.
- 52. A stabilized pharmaceutical composition comprising a levothyroxine salt, wherein the composition exhibits a triiodothyronine (T3) plasma Tmax of between from about 10 hours to about 20 hours as determined by the standard Tmax test.
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54. An immediate release solid pharmaceutical composition comprising a levothyroxine salt, wherein the composition is essentially sugar free.
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55. A stabilized solid pharmaceutical composition comprising a levothyroxine salt, wherein the composition is essentially sugar free.
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56. An immediate release solid pharmaceutical composition comprising a levothyroxine salt, wherein the composition is essentially non-granular.
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57. A stabilized solid pharmaceutical composition comprising a levothyroxine salt, wherein the composition is essentially non-granular.
- 58. An immediate release pharmaceutical composition comprising a levothyroxine salt, wherein the composition is formulated as a tablet.
- 61. An immediate release solid pharmaceutical composition comprising a levothyroxine salt, wherein the composition is formulated as a tablet.
- 64. A stabilized solid pharmaceutical composition comprising a levothyroxine salt, wherein the composition is formulated as a tablet.
- 67. An immediate release pharmaceutical composition comprising a levothyroxine salt, wherein the tablet is configured to increase heat transfer away from the tablet.
- 81. A stabilized solid pharmaceutical composition comprising a levothyroxine salt, wherein the tablet is configured to increase heat transfer away from the tablet.
- 97. An immediate release solid pharmaceutical composition comprising a levothyroxine salt, wherein the composition features less than about 10% total impurities as determined by a standard impurity test.
- 105. A stabilized solid pharmaceutical composition comprising a levothyroxine salt, wherein the composition features less than about 10% total impurities as determined by a standard impurity test.
- 113. An immediate release solid pharmaceutical composition comprising a levothyroxine salt, wherein the composition comprises a pharmaceutically acceptable croscarmellose salt.
- 115. A stabilized solid pharmaceutical composition comprising a levothyroxine salt, wherein the composition comprises a pharmaceutically acceptable croscarmellose salt.
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117. An immediate release pharmaceutical composition in tablet form comprising levothyroxine sodium, the composition comprising:
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a) between from about 0.01 mg/tablet to about 500 mg/tablet levothyroxine sodium (USP), b) between from about 100 mg/tablet to about 110 mg/tablet of microcrystalline β
-cellulose, NF (Ceolus) having a bulk density of between from about 0.10 g/cm3 to about 0.35 g/cm3,c) between from about 25 mg/tablet to about 50 mg/tablet of croscarmellose sodium, NF (Ac-di-sol); and
d) between from about 0.5 mg/tablet to about 5 mg/tablet of magnesium stearate, NF. - View Dependent Claims (118)
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119. A stabilized pharmaceutical composition in tablet form comprising levothyroxine sodium, the composition comprising:
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a) between from about 0.01 mg/tablet to about 500 mg/tablet levothyroxine sodium (USP), b) between from about 100 mg/tablet to about 110 mg/tablet of microcrystalline β
-cellulose, NF (Ceolus) having a bulk density of between from about 0.10 g/cm3 to about 0.35 g/cm3,c) between from about 25 mg/tablet to about 50 mg/tablet of croscarmellose sodium, NF (Ac-di-sol); and
d) between from about 0.5 mg/tablet to about 5 mg/tablet of magnesium stearate, NF. - View Dependent Claims (120)
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- 121. An immediate release pharmaceutical aqueous liquid comprising a levothyroxine salt.
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123. A method of making an immediate release pharmaceutical composition comprising a levothyroxine salt, the method comprising
a) mixing a levothyroxine salt with microcrystalline β - -cellulose and a croscarmellose salt to make a blend; and
b) compressing the blend in a ratio of initial volume to final volume of between from about 2;
1 to about 5;
1 to make the composition. - View Dependent Claims (124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138)
- -cellulose and a croscarmellose salt to make a blend; and
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139. A method of making a stabilized pharmaceutical composition comprising a levothyroxine salt, the method comprising
a) mixing a levothyroxine salt with microcrystalline β - -cellulose and a crosscarmellose salt to make a blend; and
b) compressing the blend in a ratio of initial volume to final volume of between from about 2;
1 to about 5;
1 to make the composition. - View Dependent Claims (140, 141, 142, 143, 144, 145, 146, 147)
- -cellulose and a crosscarmellose salt to make a blend; and
-
148. A method of instructing a human to take an immediate release pharmaceutical composition in tablet form comprising levothyroxine, said method comprising:
instructing the human to take a certain number of the immediate release pharmaceutical levothyroxine tablets at a selected number of times daily to treat reduced or absent thyroid function. - View Dependent Claims (149)
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150. A method of instructing a human to take a stabilized pharmaceutical composition in tablet form comprising levothyroxine, said method comprising:
instructing the human to take a certain number of the immediate release pharmaceutical levothyroxine tablets at a selected number of times daily to treat reduced or absent thyroid function. - View Dependent Claims (151)
Specification