Pharmaceutical formulations containing poorly soluble drug substances

• US 6,197,787 B1
• Filed: 10/01/1999
• Issued: 03/06/2001
• Est. Priority Date: 03/03/1997
• Status: Expired due to Term

• Current Assignee: Sanofi-Synthelabo Incorporated (Sanofi )
• Original Assignee: Sanofi-Synthelabo Incorporated (Sanofi )
• Inventors: Franson, Nancy M., Rocco, William L., Laughlin, Sharon M., Guillot, Micael A.
• Primary Examiner(s): Spivack, Phyllis G.
• Application Number:
  US09/410,600
• Time in Patent Office: 522 Days
• Field of Search: 514/313, 514/569, 514/23, 514/723
• US Class Current: 514/313
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds

Abstract

A method for preparing pharmaceutical formulations of poorly soluble drug substances in the form of concentrated solutions for filling soft gelatin capsules and solid dispersions and suspensions for filling hard gelatin capsules and compressing into tablets is provided. Pharmaceutical formulations of poorly soluble drug substances are also disclosed. The formulations include the sodium salt of the poorly soluble drug substance, a conversion aid such as PEG, polysorbate, a sugar alcohol (e.g. mannitol or xylitol), propylene glycol or transcutol, and, in some cases an excipient, such as dicalcium phosphate dihydrate, lactose monohydrate, or microcrystalline cellulose.

Claims

1. A pharmaceutical formulation in the form of a solid dispersion comprising:

a) a poorly soluble organic acid drug substance selected from the group consisting of;

analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytic sedatives, astringents, beta-adrenoceptor blocking agents, cardiac inotropic agents, contrast media, corticosteroids, cough suppressants, diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics, haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin, prostaglandins, radio-pharmaceuticals, sex hormones, anti-allergic agents, stimulants, anoretics, sympathomimetics, thyroid agents, vasodilators and xanthines;

b) propylene glycol;

c) a sufficient quantity of a solid diluent selected from the group consisting of xylitol, dicalcium phosphate dihydrate, and lactose monohydrate/microcrystalline cellulose to provide a solid dispersion.

2. The pharmaceutical formulation of claim 1 wherein said drug substance is SR48692.

3. The pharmaceutical formulation of claim 1 further comprising a base.

4. The pharmaceutical formulation of claim 1 wherein said drug substance is Naproxyn.

5. The pharmaceutical formulation of claim 4 further comprising a base.

6. The pharmaceutical formulation of claim 1 further comprising a base.

7. A process of preparing a pharmaceutical formulation in the form of a solid dispersion comprising the steps of:

a) dissolving a poorly soluble organic acid drug substance in aqueous sodium hydroxide/propylene glycol mixture to form a solution wherein said poorly soluble drug substance is selected from the group consisting of;

analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytic sedatives, astringents, beta-adrenoceptor blocking agents, cardiac inotropic agents, contrast media, corticosteroids, cough suppressants, diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics, haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin, prostaglandins, radio-pharmaceuticals, sex hormones, anti-allergic agents, stimulants, anoretics, sympathomimetics, thyroid agents, vasodilators and xanthines; and

b) adding the solution to a sufficient quantity of a solid diluent selected from the group consisting of xylitol, dicalcium phosphate dihydrate, and lactose monohydrate and/or microcrystalline cellulose to provide a solid dispersion.

8. The process of claim 7 further comprises adding water or aqueous xylitol to said sodium hydroxide/propylene glycol mixture in step (a).

9. The process of claim 7 wherein said drug substance is SR48692.

10. The process of claim 7 wherein said drug substance is Naproxyn.

11. A concentrated drug solution for soft gelatin capsule filling consisting essentially of:

a) a poorly soluble organic acid drug selected from the group consisting of analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytic sedatives, astringents, beta-adrenoceptor blocking agents, cardiac inotropic agents, contrast media, corticosteroids, cough suppressants, diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics, haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin, prostaglandins, radio-pharmaceuticals, sex hormones, anti-allergic agents, stimulants, anoretics, sympathomimetics, thyroid agents, vasodilators and xanthines;

b) propylene glycol;

c) sodium hydroxide; and

d) water;

wherein the mole equivalent of sodium hydroxide per mole equivalent of the poorly soluble drug is at least 1.1.

12. The concentrated drug solution of claim 11 wherein said poorly soluble drug is SR48692.

13. The concentrated drug solution of claim 12 wherein the ratio of mole equivalents of sodium hydroxide per mole equivalent of SR48692 is at least 1.2.

14. The concentrated drug solution of claim 11 wherein said poorly soluble drug is Naproxyn.

15. The concentrated drug solution of claim 14 wherein the ratio of mole equivalents of sodium hydroxide per mole equivalent of Naproxyn is at least 1.2.

16. The concentrated drug solution of claim 11 wherein the ratio of mole equivalents of sodium hydroxide per mole equivalent of said poorly soluble drug is at least 1.2.

17. A pharmaceutical formulation in a highly concentrated suspension form for a hard gelatin capsule filling comprising:

0.1 to 40% by weight of SR48692;

0.1 to 40% by weight propylene glycol;

0.1 to 99% by weight of a diluent selected from the group consisting of starch;

microcrystalline cellulose and lactose;

sodium hydroxide and water, wherein the mole equivalents of sodium hydroxide per mole equivalents of the poorly soluble drug substance is from 0.5 to 1.5.

18. The pharmaceutical formulation of claim 17 wherein SR48692 is present in an amount of 1 to 30% by weight.

19. The pharmaceutical formulation of claim 17 further including polyethylene glycol.

20. The pharmaceutical formulation of claim 17 wherein the water is present in an amount from 0.1 to 20% by weight.

21. A pharmaceutical formulation consisting essentially of:

a) a poorly soluble drug substance;

b) xylitol; and

c) Transcutol.

22. The pharmaceutical formulation of claim 21 further comprising a base.

23. A method of preparing the pharmaceutical formulation of claim 21 comprising the steps of:

a) dissolving a poorly soluble drug substance in Transcutol; and

b) adding the solution to xylitol.

24. A method for preparing the sodium salt of a poorly soluble organic acid drug for use in solid formulations, comprising

(a) bringing said poorly soluble organic acid drug into intimate contact with a conversion aid to provide a drug/aid mix;

(b) adding a concentrated aqueous solution containing at least one equivalent of sodium hydroxide to said drug/aid mix;

(c) mixing said sodium hydroxide and drug/aid mix until said drug is greater than 95% in the form of its sodium salt;

said conversion aid chosen from the group consisting of PEG, mannitol and polysorbate, said method allowing conversion of said poorly soluble organic acid drug into its sodium salt substantially in the solid phase.

25. A method according to claim 24 wherein said poorly soluble organic acid drug is SR48692.

26. A method according to claim 25 wherein said conversion aid is chosen from the group consisting of PEG 400, mannitol and polysorbate 20.

27. A method according to claim 26 wherein said conversion aid is from 5 to 35 parts of mannitol to 40 to 60 parts by weight of SR48692 and from 1.001 to 1.15 equivalents of sodium hydroxide is added.

28. A method according to claim 26 wherein said conversion aid is from 0.5 to 15 parts of polysorbate 20 to 35 to 55 parts by weight of SR48692 and from 1.001 to 1.1 equivalents of sodium hydroxide is added.

29. A method according to claim 26 wherein said conversion aid is from 2 to 60 parts of PEG 400 to 40 to 60 parts by weight of SR48692 and from 1.001 to 1.1 equivalents of sodium hydroxide is added.

30. A method according to any one of claims 24 to 29 further comprising the steps of

(d) adding sufficient water to prepare a slurry;

(e) adding excipients to form a wetted powder; and

(f) drying to less than 15% by wt water.

31. A method according to claim 30 further comprising forming said solid into a tablet.

32. A method according to claim 30 further comprising filling said solid into a capsule.

33. A pharmaceutical formulation comprising

(a) from about 40 parts by weight to about 60 parts by weight of the reaction product of SR48692

with more than 1.0 equivalent of NaOH;

(b) from 2 to 60 parts by weight of polyethylene glycol of molecular weight 200-800; and

(c) less than 15 wt % water.

34. The formulation of claim 33 wherein the polyethylene glycol has a nominal molecular weight of 400.

35. A pharmaceutical formulation according to claim 33 comprising

(a) from about 40 wt % to about 60 wt % of the reaction product of SR48692 with more than 1.0 equivalent of NaOH;

(b) from 2 to 60 wt % polyethylene glycol of molecular weight 200-800; and

(c) less than 15 wt % water.

40. A hard gelatin capsule filled with a pharmaceutical formulation according to any one of claims 33-39.

41. A pharmaceutical formulation according to any one of claims 33-39 in the form of a tablet.

36. A pharmaceutical formulation comprising

(a) from about 40 parts by weight to about 60 parts by weight of the reaction product of SR48692

with more than 1.0 equivalent of NaOH;

(b) from 5 to 35 parts by weight of mannitol; and

(c) less than 15 wt % water.

37. A pharmaceutical formulation comprising

(a) from about 40 wt % to about 60 wt % of the reaction product of SR48692 with more than one equivalent of NaOH

(b) from 5 to 35 wt % mannitol;

and

(c) less than 15 wt % water.

38. A pharmaceutical formulation comprising

(a) from about 35 parts by weight to about 55 parts by weight of the reaction product of SR48692

with more than one equivalent of NaOH;

(b) from 0.5 to 15 parts by weight of polysorbate 20; and

(c) less than 15 wt % water.

39. A pharmaceutical formulation according to claim 38 comprising

(a) from about 35 wt % to about 55 wt % of the reaction product of SR48692 with more than one equivalent of NaOH;

(b) from 0.5 to 15 wt % polysorbate 20; and

(c) less than 15 wt % water.

42. A pharmaceutical formulation comprising

(a) from about 35 to about 55 parts by weight of the sodium salt of SR48692

(b) from 0.5 to 15 parts by weight of polysorbate 20;

and

(c) less than 15 wt % water.

43. A pharmaceutical formulation according to claim 42 comprising

(a) from about 35 wt % to about 55 wt % of the sodium salt of SR48692

(b) from 0.5 to 15 wt % polysorbate 20; and

(c) less than 15 wt % water.

49. A hard gelatin capsule filled with a pharmaceutical formulation according to any one of claims 42-48.

50. A pharmaceutical formulation according to any one of claims 42-48 in the form of a tablet.

44. A pharmaceutical formulation comprising

(a) from about 40 to about 60 parts by weight of the sodium salt of SR48692

(b) from 2 to 60 parts by weight of polyethylene glycol of molecular weight 200-800;

and

(c) less than 15 wt % water.

45. A pharmaceutical formulation according to claim 44 comprising

(a) from about 40 wt % to about 60 wt % of the sodium salt of SR48692;

(b) from 2 to 60 wt % polyethylene glycol of molecular weight 200-800; and

(c) less than 15 wt % water.

46. The formulation of claim 44 wherein the polyethylene glycol has a nominal molecular weight of 400.

47. A pharmaceutical formulation comprising

(a) from about 40 to about 60 parts by weight of the sodium salt of SR48692

(b) from 5 to 35 parts by weight mannitol;

and

(c) less than 15 wt % water.

48. A pharmaceutical formulation according to claim 47 comprising

(a) from about 40 wt % to about 60 wt % of the sodium salt of SR48692;

(b) from 5 to 35 wt % mannitol; and

(c) less than 15 wt % water.