PHARMACEUTICAL FORMULATIONS COMPRISING NITROCATECHOL DERIVATIVES AND METHODS OF MAKING THE SAME

• US 20100256194A1
• Filed: 03/31/2010
• Published: 10/07/2010
• Est. Priority Date: 04/01/2009
• Status: Abandoned Application

• Current Assignee: BIAL Portela & Ca, SA
• Original Assignee: BIAL Portela & Ca, SA
• Inventors: Cardoso de Vasconcelos, Teófilo, Cerdeira de Campos Costa, Rui, Miguel da Costa Barrocas, Pedro, Jorge dos Santos Lima, Ricardo, Sofia de Castro Pereira, Ligia
• Application Number:
  US12/750,957
• Publication Number:
  US 20100256194A1
• Time in Patent Office: Days
• US Class Current: 514/340
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 7/10 Antioedematous agents; Diuretics
• CPC Class Codes: A61P 9/12 Antihypertensives

Abstract

The present disclosure relates to compositions and pharmaceutical formulations comprising at least one active pharmaceutical ingredient chosen from nitrocatechol derivatives of formula I as defined herein and salts, esters, hydrates, solvates and other derivatives thereof and methods of making the same.

Claims

1. A stable composition comprising:

at least one active pharmaceutical ingredient (API) chosen from 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide and 5-[3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol and salts, esters, hydrates, solvates and other derivatives thereof;

at least one filler; and

at least one binder;

wherein at least the at least one active pharmaceutical ingredient is present in the composition in granular form.

2. The stable composition of claim 1, wherein the at least one API is a combination of 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide and 5-[3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol.

3. The stable composition of claim 1, wherein less than 10% of the API decomposes over 15 days of storage at 70°

C. and uncontrolled humidity, over 6 months at 40°

C. and 75% relative humidity, and/or over 3 years at 60% relative humidity and 30°

C. or 25°

C.

7. The stable composition of claim 1, wherein the increase in total impurities is less than 5% over 15 days of storage at 70°

C. and uncontrolled humidity, over 6 months at 40°

C. and 75% relative humidity, and/or over 3 years at 60% relative humidity and 30°

C. or 25°

C.

11. The stable composition of claim 1, wherein the at least one filler is chosen from lactose, maize starch and microcrystalline cellulose.

12. The stable composition of claim 1, wherein the at least one binder is chosen from hypromellose, hydroxypropyl cellulose, methyl- or ethyl-cellulose, pregelatinized maize starch and gelatin.

13. The stable composition of claim 1, wherein the granules further comprise the at least one filler and/or at least one binder.

14. The stable composition of claim 1, further comprising at least one additional excipient chosen from disintegrants, glidants, and lubricants.

15. The stable composition of claim 1, wherein the composition exhibits improved bulk density.

16. The stable composition of claim 15 wherein the composition exhibits a bulk density of greater than 0.1 g/ml.

121. The stable composition of claim 1, wherein the at least one filler is not a phosphate-derivative;

and

wherein the at least one binder is not a PVP derivative compound.

122. The stable composition of claim 1, wherein the active pharmaceutical ingredient is present in a therapeutically effective amount.

123. The stable composition of claim 1, wherein the composition further comprises an additional active pharmaceutical ingredient.

124. The stable composition of claim 121, wherein the composition further comprises at least one additional excipient chosen from disintegrants, glidants, and lubricants.

4-6. -6. (canceled)

8-10. -10. (canceled)

17-22. -22. (canceled)

23. A pharmaceutical formulation comprising a stable composition comprising:

at least one active pharmaceutical ingredient (API) chosen from 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide and 5-[3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol and salts, esters, hydrates, solvates and other derivatives thereof;

at least one filler; and

at least one binder;

wherein at least the at least one active pharmaceutical ingredient is present in the composition in granular form.

24. The pharmaceutical formulation of claim 23, wherein the formulation is in the dosage form of a tablet or capsule.

25. The pharmaceutical formulation of claim 23, wherein the pharmaceutical formulation is stable.

26. The pharmaceutical formulation of claim 25, wherein less than 10% of the API decomposes over 15 day of storage at 70°

C. and uncontrolled humidity, over 6 months at 40°

C. and 75% relative humidity, and/or over 3 years at 60% relative humidity and 30°

C. or 25°

C.

125. The pharmaceutical formulation of claim 23, wherein the at least one filler is not a phosphate-derivative;

and

wherein the at least one binder is not a PVP derivative compound.

126. The pharmaceutical formulation of claim 23, wherein the granules further comprise the at least one filler and/or at least one binder.

127. The pharmaceutical formulation of claim 23, wherein the composition exhibits improved apparent density.

128. The pharmaceutical formulation of claim 127, wherein the composition exhibits an apparent density greater than 0.1 g/ml.

129. The pharmaceutical formulation of claim 23, wherein the at least one active pharmaceutical ingredient is a combination of 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide and 5-[3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol.

130. The pharmaceutical formulation of claim 25, wherein the increase in total impurities is less than 5% over 15 days of storage at 70°

C. and uncontrolled humidity, over 6 months at 40°

C. and 75% relative humidity, and/or over 3 years at 60% relative humidity and 30°

C. or 25°

C.

27-29. -29. (canceled)

30. A method of manufacturing a stable pharmaceutical formulation, said method comprising:

granulating at least one active pharmaceutical ingredient (API) chosen from 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide and 5-[3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol and salts thereof to form granules;

mixing at least one filler with the at least one active pharmaceutical ingredient before, during or after granulation;

mixing at least one binder with the at least one active pharmaceutical ingredient before, during or after granulation; and

preparing a pharmaceutical formulation in the form of a dosage form.

31. The method of claim 30, wherein the at least one API is a combination of 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide and 5-[3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol.

32. The method of claim 30, wherein the at least one filler is chosen from lactose, maize starch and microcrystalline cellulose.

33. The method of claim 30 wherein the at least one binder is chosen from hypromellose, hydroxypropyl cellulose, methyl- or ethyl-cellulose, pregelatinized maize starch and gelatin.

34. The method of claim 30, wherein less than 10% of the API in the dosage form decomposes over 15 days of storage at 70°

C. and uncontrolled humidity, over 6 months at 40°

C. and 75% relative humidity, and/or over 3 years at 60% relative humidity and 30°

C. or 25°

C.

38. The method of claim 30 wherein the increase in total impurities is less than 5% over 15 days of storage at 70°

C. and uncontrolled humidity, over 6 months at 40°

C. and 75% relative humidity, and/or over 3 years at 60% relative humidity and 30°

C. or 25°

C.

43. The method of claim 30, wherein the granulation process is wet granulation.

48. The method of claim 30, wherein the granules and/or composition exhibit improved bulk density.

49. The method of claim 48, wherein the granules and/or composition exhibit a bulk density greater than 0.1 g/ml.

35-37. -37. (canceled)

39-42. -42. (canceled)

44-47. -47. (canceled)

50-120. -120. (canceled)