Pharmaceutical formulae for thyroid hormones and procedures for obtaining them

• US 20040219218A1
• Filed: 12/23/2003
• Published: 11/04/2004
• Est. Priority Date: 12/27/2002
• Status: Active Grant

• Current Assignee: Altergon SA
• Original Assignee: Altergon SA
• Inventors: Martino, Alessandro Di, Marchiorri, Maurizio, Garavani, Alberto, Mateo, Angel
• Granted Patent: US 7,691,411 B2
• Time in Patent Office: Days
• US Class Current: 424/488
• CPC Class Codes: A61K 9/2063 Proteins, e.g. gelatin
• CPC Class Codes: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4

Abstract

The present invention provides pharmaceutical formulation for thyroid hormones which allow safe and stable administration by mouth within the ambit of the narrow therapeutic index prescribed in the case of thyroid dysfunctions, as well as procedures for obtaining

Claims

1. Pharmaceutical composition of thyroid hormones, preferably of T3 and/or T4 or their salts, in a pharmaceutically efficacious concentration, preferably 0.001-1% in weight, in a uniform matrix of soft-gel which can be taken by mouth without chewing, in which the matrix has the form and dimensions of a tablet or capsule, the pharmaceutical composition comprising, in the dried state, 30%-68% in weight of gelatine of bovine, pig or fish origin, and characterised in that it comprises, in the dried state, 31-60% in weight of glycerol and 1-10% in weight of water.

4. Pharmaceutical composition according to claim 1, wherein the gelatine has a pH between 3 and 10.

7. Pharmaceutical composition according to claim 1, characterised in that it comprises 0.5-5% in weight of ethanol.

8. Pharmaceutical composition according to claim 1, characterised in that it comprises, in the dried state, 3-10% in weight of other polyhydroxy or polyether alcohols, preferably chosen from the group that comprises sorbitol/sorbitans, 1,2-propylenglycol, polyethylenglycols and mannitol or mixtures therof.

12. Pharmaceutical composition according to claim 1, characterised in that it comprises excipients, for example solid additives that modify the characteristics of the release of thyroid hormones from the uniform matrix of soft-gel, or preservatives and/or colouring agents.

16. Pharmaceutical composition according to claim 1, provided on the outside with enteric layers and/or layers to facilitate ingestion.

20. Procedure for obtaining pharmaceutical compositions as in claim 1 comprising the following steps:

preparation of a medicated gelatinous mixture comprising 10-50% in weight of type A or B gelatine of bovine, pig or fish origin, 10-50% in weight of glycerol, 0-10% in weight of ethanol, 20-80% in weight of water and 0.001-1% in weight of T3 and/or T4 or their salts,

melting of the medicated gelatinous mixture at a temperature between 30° and

55°

C., preferably between 35° and

45°

C.,

feeding of the medicated gelatinous mixture into the cavities of the shaping cylinders of a “

Rotary Die”

type machine for forming capsules,

cutting and taking the pharmaceutical composition in a uniform matrix of soft-gel thus formed from the “

Rotary Die”

machine, and

drying of the pharmaceutical composition in a uniform matrix of soft-gel.

21. Procedure for obtaining pharmaceutical compositions as in claim 1 comprising the following steps:

preparation of a medicated gelatinous mixture comprising 10-50% in weight of type A or B gelatine of bovine, pig or fish origin, 5-45% in weight of glycerol, 0-10% in weight of ethanol and 20-60% in weight of water,

melting of the medicated gelatinous mixture at a temperature between 300 and 80°

C., preferably between 40° and

65°

C.,

when it is completely melted, lowering of the temperature of the gelatinous mixture to 45±

5°

C. and addition of a medicated mixture comprising T3 and/or T4 or their salts as required and glycerol, the quantity of the medicated mixture corresponding to 5%-10% in weight of the gelatinous mixture, obtaining a medicated gelatinous mixture,

feeding of the medicated gelatinous mixture into the cavities of the shaping cylinders of a “

Rotary Die”

type machine for forming capsules,

cutting and taking the pharmaceutical composition in a uniform matrix of soft-gel thus formed from the “

Rotary Die”

machine, and

drying of the pharmaceutical composition in a uniform matrix of soft-gel.

22. Procedure for obtaining pharmaceutical compositions as in claim 1 comprising the following steps:

preparation of a gelatinous mixture comprising 10-50% in weight of type A or B gelatine of bovine, pig or fish origin, 10-50% in weight of glycerol, 0-10% in weight of ethanol, and 20-80% in weight of water,

melting of the gelatinous mixture at a temperature between 30-80°

C. preferably between 40-65°

C.,

feeding of the gelatinous mixture into the cavities of the shaping cylinders of a “

Rotary Die”

type machine for forming capsules;

injection, at the time of closing the cavity, by means of the special injector, of a quantity of medicated injected material corresponding to from 1% to 50% in weight, preferably to 5-30% in weight, of the quantity of gelatinous mixture placed in the cavity, said medicated injected material comprising

30-95% in weight of glycerol,

0-50% in weight of ethanol,

0-50% in weight of water,

0-50% in weight of gelatine

as much as necessary in weight of T3 and/or T4,

cutting and taking the pharmaceutical composition in a uniform matrix of soft-gel thus formed from the “

Rotary Die”

machine, and

drying of the pharmaceutical composition in a uniform matrix of soft-gel.

23. Procedure as in claim 22 wherein the medicated injected substance comprises 50%-90% in weight of glycerol, 0%-30% in weight of ethanol, 0%-45% in weight of water, 5%-20% in weight of gelatine and as much as necessary in weight of T3 and/or T4.

2. Pharmaceutical composition according to the first claim, characterised in that it comprises, in the dried state, 32-55% in weight of glycerol and 1-10% in weight of water.

3. Pharmaceutical composition according to claim 2, characterised in that it comprises, in the dried state, 32.5%-50% in weight of glycerol and 1-10% in weight of water.

5. Pharmaceutical composition according to claim 2, wherein the gelatine has a pH between 3 and 10.

6. Pharmaceutical composition according to claim 3, wherein the gelatine has a pH between 3 and 10.

9. Pharmaceutical composition according to claim 2, characterised in that it comprises, in the dried state, 3-10% in weight of other polyhydroxy or polyether alcohols, preferably chosen from the group that comprises sorbitol/sorbitans, 1,2-propylenglycol, polyethylenglycols and mannitol or mixtures therof.

10. Pharmaceutical composition according to claim 3, characterised in that it comprises, in the dried state, 3-10% in weight of other polyhydroxy or polyether alcohols, preferably chosen from the group that comprises sorbitol/sorbitans, 1,2-propylenglycol, polyethylenglycols and mannitol or mixtures therof.

11. Pharmaceutical composition according to claim 5, characterised in that it comprises, in the dried state, 3-10% in weight of other polyhydroxy or polyether alcohols, preferably chosen from the group that comprises sorbitol/sorbitans, 1,2-propylenglycol, polyethylenglycols and mannitol or mixtures therof.

13. Pharmaceutical composition according to claim 2, characterised in that it comprises excipients, for example solid additives that modify the characteristics of the release of thyroid hormones from the uniform matrix of soft-gel, or preservatives and/or colouring agents.

14. Pharmaceutical composition according to claim 3, characterised in that it comprises excipients, for example solid additives that modify the characteristics of the release of thyroid hormones from the uniform matrix of soft-gel, or preservatives and/or colouring agents.

15. Pharmaceutical composition according to claim 5, characterised in that it comprises excipients, for example solid additives that modify the characteristics of the release of thyroid hormones from the uniform matrix of soft-gel, or preservatives and/or colouring agents.

17. Pharmaceutical composition according to claim 2, provided on the outside with enteric layers and/or layers to facilitate ingestion.

18. Pharmaceutical composition according to claim 3, provided on the outside with enteric layers and/or layers to facilitate ingestion.

19. Pharmaceutical composition according to claim 5, provided on the outside with enteric layers and/or layers to facilitate ingestion.

24. Pharmaceutical composition of thyroid hormones, preferably of T3 and/or T4 or their salts, in a pharmaceutically efficacious concentration, preferably 0.001-1% in weight, in a uniform matrix of soft-gel which can be taken by mouth without chewing, in which the matrix has the form and dimensions of a tablet or capsule, the pharmaceutical composition comprising, in the dried state, 30%-70% in weight of gelatine of bovine, pig or fish origin, and characterised in that it comprises, in the dried state, 20-60% in weight of sorbitol/sorbitans, and 1-10% in weight of water.

25. Pharmaceutical composition according to claim 24, characterised in that it comprises, in the dried state, 25-55% in weight of sorbitol/sorbitans and 1-10% in weight of water.

26. Pharmaceutical composition according to claim 25, characterised in that it comprises, in the dried state, 25%-50% in weight of sorbitol/sorbitans and 1-10% in weight of water.

27. Pharmaceutical composition according to claim 24, wherein the gelatine has a pH between 3 and 10.

28. Pharmaceutical composition according to claim 25, wherein the gelatine has a pH between 3 and 10.

29. Pharmaceutical composition according to claim 26, wherein the gelatine has a pH between 3 and 10.

30. Pharmaceutical composition according to claim 24, characterised in that it comprises 0.5-5% in weight of ethanol.

31. Pharmaceutical composition according to claim 25, characterised in that it comprises 0.5-5% in weight of ethanol.

32. Pharmaceutical composition according to claim 26, characterised in that it comprises 0.5-5% in weight of ethanol.

33. Pharmaceutical composition according to claim 24, characterised in that it comprises, in the dried state, 1-10% in weight of other polyhydroxy or polyether alcohols, preferably chosen from the group that comprises glycerol, 1,2-propylenglycol, polyethylenglycols and mannitol or mixtures thereof.

34. Pharmaceutical composition according to claim 25, characterised in that it comprises, in the dried state, 1-10% in weight of other polyhydroxy or polyether alcohols, preferably chosen from the group that comprises glycerol, 1,2-propylenglycol, polyethylenglycols and mannitol or mixtures thereof.

35. Pharmaceutical composition according to claim 26, characterised in that it comprises, in the dried state, 1-10% in weight of other polyhydroxy or polyether alcohols, preferably chosen from the group that comprises glycerol, 1,2-propylenglycol, polyethylenglycols and mannitol or mixtures thereof.

36. Pharmaceutical composition according to claim 30, characterised in that it comprises, in the dried state, 1-10% in weight of other polyhydroxy or polyether alcohols, preferably chosen from the group that comprises glycerol, 1,2-propylenglycol, polyethylenglycols and mannitol or mixtures thereof.

37. Pharmaceutical composition according to claim 24, characterised in that it comprises excipients, for example solid additives that modify the characteristics of the release of thyroid hormones from the uniform matrix of soft-gel, or preservatives and/or colouring agents.

38. Pharmaceutical composition according to claim 25, characterised in that it comprises excipients, for example solid additives that modify the characteristics of the release of thyroid hormones from the uniform matrix of soft-gel, or preservatives and/or colouring agents.

39. Pharmaceutical composition according to claim 26, characterised in that it comprises excipients, for example solid additives that modify the characteristics of the release of thyroid hormones from the uniform matrix of soft-gel, or preservatives and/or colouring agents.

40. Pharmaceutical composition according to claim 30, characterised in that it comprises excipients, for example solid additives that modify the characteristics of the release of thyroid hormones from the uniform matrix of soft-gel, or preservatives and/or colouring agents.

41. Pharmaceutical composition according to claim 24, provided on the outside with enteric layers and/or layers to facilitate ingestion.

42. Pharmaceutical composition according to claim 25, provided on the outside with enteric layers and/or layers to facilitate ingestion.

43. Pharmaceutical composition according to claim 26, provided on the outside with enteric layers and/or layers to facilitate ingestion.

44. Pharmaceutical composition according to claim 30, provided on the outside with enteric layers and/or layers to facilitate ingestion.

45. Procedure for obtaining pharmaceutical compositions as in claim 24 comprising the following steps:

preparation of a medicated gelatinous mixture comprising 10-50% in weight of type A or B gelatine of bovine, pig or fish origin, 10-50% in weight of sorbitol/sorbitans solution, 0-10% in weight of ethanol, 20-80% in weight of water and 0.001-1% in weight of T3 and/or T4 or their salts,

melting of the medicated gelatinous mixture at a temperature between 30° and

55°

C., preferably between 35° and

45°

C.,

feeding of the medicated gelatinous mixture into the cavities of the shaping cylinders of a “

Rotary Die”

type machine for forming capsules,

cutting and taking the pharmaceutical composition in a uniform matrix of soft-gel thus formed from the “

Rotary Die”

machine, and

drying of the pharmaceutical composition in a uniform matrix of soft-gel.

46. Procedure for obtaining pharmaceutical compositions as in claim 24 comprising the following steps:

preparation of a medicated gelatinous mixture comprising 10-50% in weight of type A or B gelatine of bovine, pig or fish origin, 10-50% in weight of sorbitol/sorbitans solution, 0-10% in weight of ethanol and 20-60% in weight of water,

melting of the medicated gelatinous mixture at a temperature between 30° and

80°

C., preferably between 40° and

65°

C.,

when it is completely melted, lowering of the temperature of the gelatinous mixture to 45°

+5°

C. and addition of a medicated mixture comprising T3 and/or T4 or their salts as required and glycerol, the quantity of the medicated mixture corresponding to 1%-5% in weight of the gelatinous mixture, obtaining a medicated gelatinous mixture,

feeding of the medicated gelatinous mixture into the cavities of the shaping cylinders of a “

Rotary Die”

type machine for forming capsules,

cutting and taking the pharmaceutical composition in a uniform matrix of soft-gel thus formed from the “

Rotary Die”

machine, and

drying of the pharmaceutical composition in a uniform matrix of soft-gel.

47. Procedure for obtaining pharmaceutical compositions as in claim 24 comprising the following steps:

preparation of a gelatinous mixture comprising 10-50% in weight of type A or B gelatine of bovine, pig or fish origin, 10-50% in weight of sorbitol/sorbitans solution, 0-10% in weight of ethanol, and 20-80% in weight of water,

melting of the gelatinous mixture at a temperature between 30-80°

C. preferably between 40-65°

C.,

feeding of the gelatinous mixture into the cavities of the shaping cylinders of a “

Rotary Die”

type machine for forming capsules;

injection, at the time of closing the cavity, by means of the special injector, of a quantity of medicated injected material corresponding to 1-30% in weight, preferably to 5-15% in weight, of the quantity of gelatinous mixture placed in the cavity, said medicated injected material comprising

25-95% in weight of glycerol,

0-50% in weight of ethanol,

0-50% in weight of water,

0-50% in weight of gelatine

as much as necessary in weight of T3 and/or T4,

cutting and taking the pharmaceutical composition in a uniform matrix of soft-gel thus formed from the “

Rotary Die”

machine, and

drying of the pharmaceutical composition in a uniform matrix of soft-gel.

48. Procedure as in claim 47 wherein the medicated injected substance comprises 50%-90% in weight of glycerol, 0%-30% in weight of ethanol, 5%-45% in weight of water, 0%-20% in weight of gelatine and as much as necessary in weight of T3 and/or T4.