Solid pharmaceutical dispersions with enhanced bioavailability

• US 20030219489A1
• Filed: 06/09/2003
• Published: 11/27/2003
• Est. Priority Date: 08/11/1997
• Status: Active Grant

• Current Assignee: Bend Research Inc. (Lonza Group AG)
• Original Assignee: Pfizer Inc.
• Inventors: Herbig, Scott M., Curatolo, William J., Nightingale, James A. S.
• Granted Patent: US 8,257,741 B2
• Time in Patent Office: Days
• US Class Current: 424/488
• CPC Class Codes: A61J 3/02 into the form of powders pulverising in general B02C
• CPC Class Codes: A61K 47/38 Cellulose; Derivatives thereof
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: B01J 2/02 by dividing the liquid material into drops, e.g. by spraying, and solidifying the drops
• CPC Class Codes: B01J 8/005 Separating solid material from the gas/liquid stream separation processes per se B01D

Abstract

Spray dried solid dispersions comprising a sparingly soluble drug and hydroxypropylmethylcellulose acetate succinate (HPMCAS) provide increased aqueous solubility and/or biavailability in a use environment.

Claims

1. A composition comprising a spray dried solid dispersion, which dispersion comprises a sparingly water-soluble drug and HPMCAS, said dispersion providing a maximum concentration of said drug in a use environment that is higher by a factor of at least 1.5 relative to a control composition comprising an equivalent quantity of undispersed drug.

2. A composition as decribed in claim 1, wherein said drug has a dose to aqueous solubility ratio greater than 100.

3. A composition as defined in claim 1, wherein said drug is crystalline when undispersed.

4. A composition as defined in claim 1, wherein said drug is amorphous when undispersed.

5. A composition as defined in claim 1, wherein said use environment is the gastrointestinal tract.

6. A composition as defined in claim 1, wherein said use environment is MFD.

22. A composition as defined in claim 1, wherein the concentration of drug in MFD falls to no less than 25% of the maximum supersaturated concentration during the 15 minutes following the time at which the maximum supersaturated concentration is reached.

23. A composition as defined in claim 1, wherein said dispersion is in the form of particles less than 100 μ

m in diameter.

27. A composition as defined in claim 1, wherein the drug to HPMCAS weight ratio is from 1/0.2 to 1/100.

28. A composition as defined in claims 1, 7, 11, or 15, wherein said compound is a glycogen phosphorylase inhibitor.

29. A composition as defined in claims 1, 7, 11, or 15, wherein said compound is

30. A composition as defined in claims 1, 7, 11, or 15, wherein said compound is

31. A composition as defined in claims 1, 7, 11, or 15, wherein said compound is a 5-lipoxygenase inhibitor.

32. A composition as defined in claims 1, 7, 11, or 15, wherein said compound is

33. A composition as defined in claims 1, 7, 11, or 15, wherein said compound is a CRH inhibitor.

34. A composition as defined in claims 1, 7, 11, or 15, wherein said compound is

35. A composition as defined in claims 1, 7, 11, or 15, wherein said compound is

36. A composition as defined in claims 1, 7, 11, or 15, wherein said compound is an antipsychotic.

37. A composition as defined in claims 1, 7, 11, or 15, wherein said compound is ziprasidone.

38. A composition as defined in claims 1, 7, 11, or 15, wherein said compound is selected from griseofulvin, nifedipine, and phenytoin.

7. A composition of matter comprising a spray-dried solid dispersion, which dispersion comprises a sparingly soluble drug and HPMCAS, said dispersion exhibiting a maximum supersaturated concentration in MFD which is higher by a factor of at least 1.5 relative to the equilibrium concentration exhibited by a control composition comprising an equivalent quantity of undispersed drug.

8. A composition as decribed in claim 7, wherein said drug has a dose to aqueous solubility ratio greater than 100.

9. A composition as defined in claim 7, wherein said drug is crystalline when undispersed.

10. A composition as defined in claim 7, wherein said drug is amorphous when undispersed.

24. A composition as defined in claim 7, wherein said dispersion is in the form of particles less than 100 μ

m in diameter.

11. A composition comprising a spray dried solid dispersion, which dispersion comprises a sparingly water-soluble drug and HPMCAS, said dispersion effecting, in vivo, a maximal observed blood drug concentration (C_max ) that is higher by a factor of at least 1.25 relative to a control composition comprising an equivalent quantity of undispersed drug.

12. A composition as defined in claim 11, wherein said drug is crystalline when undispersed.

13. A composition as defined in claim 11, wherein said drug is amorphous when undispersed.

14. A composition as decribed in claim 11, wherein said drug has a dose to aqueous solubility ratio greater than 100.

25. A composition as defined in claim 11, wherein said dispersion is in the form of particles less than 100 μ

m in diameter.

15. A composition comprising a spray dried solid dispersion, which dispersion comprises a sparingly water-soluble drug and HPMCAS, said dispersion effecting, in vivo, an AUC that is higher by a factor of at least 1.25 relative to a control composition comprising an equivalent quantity of undispersed drug.

16. A composition as defined in claim 15, wherein said drug is crystalline when undispersed.

17. A composition as defined in claim 15, wherein said drug is amorphous when undispersed.

18. A composition as decribed in claim 15, wherein said drug has a dose to aqueous solubility ratio greater than 100.

26. A composition as defined in claim 15, wherein said dispersion is in the form of particles less than 100 μ

m in diameter.

19. A process for making a spray dried solid dispersion comprising

A. forming a solution comprising (i) HPMCAS, (ii) a sparingly water-soluble drug, and (iii) a solvent in which both (i) and (ii) are soluble;

and

B. spray drying said solution, thereby forming spray dried particles having an average diameter less than 100 μ

m.

20. A process as defined in claim 19, wherein the concentration of drug in said solvent is less than 20 g/100 g of solvent.

21. A process as defined in claim 19, wherein the spray-drying is conducted under conditions whereby said droplets solidify in less than 20 seconds.