Solid pharmaceutical dispersions with enhanced bioavailability

• US 8,257,741 B2
• Filed: 06/09/2003
• Issued: 09/04/2012
• Est. Priority Date: 08/11/1997
• Status: Expired due to Fees

• Current Assignee: Bend Research Inc. (Lonza Group AG)
• Original Assignee: Bend Research Inc. (Lonza Group AG)
• Inventors: Curatolo, William J., Herbig, Scott M., Nightingale, James A. S.
• Primary Examiner(s): FUBARA, BLESSING M
• Application Number:
  US10/458,840
• Publication Number:
  US 20030219489A1
• Time in Patent Office: 3,375 Days
• Field of Search: 424/465, 424/488, 424/468, 424/486, 424/484, 424/473, 424/475, 424/401, 424/464, 424/487, 424/501, 424/499, 424/457, 424/497, 424/564, 514/312, 514/57, 514/345, 514/414, 514/575, 514/177, 514/338, 514/419
• US Class Current: 424/489
• 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 process for making a solid dispersion consisting of a sparingly water-soluble drug and hydroxypropyl methyl cellulose acetate succinate (HPMCAS), said drug being molecularly dispersed and amorphous in said dispersion, said process consisting essentially of the steps of:

(a) providing a solution consisting of a sparingly water-soluble drug, HPMCAS, and a solvent, said solvent being an organic compound in which said drug and HPMCAS are mutually soluble, said solution having a ratio of said drug to HPMCAS of from 1 to 0.4 to 1 to 20;

(b) breaking up said solution into small droplets, wherein said droplets range in size from 1 to 500 μ

m;

(c) directing said droplets and a drying gas into a drying chamber to cause evaporation of a sufficient amount of said solvent from said droplets to cause solidification of said droplets in less than 5 seconds to form said solid dispersion

wherein said drug has a dose to aqueous solubility ratio greater than 100 mL.

3. The process of claim 1 or 2, wherein HPMCAS is present in an amount in said solution that constitutes at least 50 wt % of said solid dispersion.

4. The process of claim 1 or 2, wherein said solvent has a boiling point of less than 150°

C.

5. The process of claim 1 or 2, wherein the pressure in said drying chamber is at a partial vacuum.

6. The process of claim 1 or 2, wherein said drying gas is heated.

7. The process of claim 5, wherein said drying gas is heated.

8. The process of claim 1 or 2, wherein said solvent is selected from the group consisting of alcohols and ketones.

9. The process of claim 1 or 2, wherein said solvent is selected from the group consisting of methanol and acetone.

10. The process of claim 1 or 2, wherein said solidification occurs in less than 2 seconds.

11. The process of claim 1 or 2, wherein said particles have a diameter of less than 50 μ

m.

12. The process of claim 1 or 2, wherein said particles have a diameter of less than 25 μ

m.

13. The process of claim 1 or 2, further comprising the step of evaporating solvent from said dispersion following solidification.

14. The process of claim 1 or 2, wherein said solid dispersion has a residual solvent content of less than 2 wt %.

15. The process of claim 1 or 2, wherein the concentration of drug in said solvent is less than 20 g/100 g of said solvent.

2. A process for making a solid dispersion consisting of a sparingly water-soluble drug and hydroxypropyl methyl cellulose acetate succinate (HPMCAS), said drug being molecularly dispersed and amorphous in said dispersion, said process consisting essentially of the steps of:

(a) providing a solution consisting of a sparingly water-soluble drug, HPMCAS, and a solvent, said solvent being an organic compound in which drug and HPMCAS are mutually soluble, said solution having a ratio of said drug to HPMCAS of from 1 to 0.4 to 1 to 20;

(b) breaking up said solution into small droplets, wherein said droplets range in size from 1 to 500 μ

m;

(c) directing said droplets and a drying gas into a drying chamber to cause evaporation of a sufficient amount of said solvent from said droplets to cause solidification of said droplets in less than 5 seconds to form particles of said solid dispersion

wherein said drug is crystalline when undispersed.

16. A process for making a solid dispersion consisting of a sparingly water-soluble drug and hydroxypropyl methyl cellulose acetate succinate (HPMCAS), said drug being molecularly dispersed and amorphous in said dispersion, said process consisting essentially of the steps of:

(a) providing a solution consisting of a sparingly water-soluble drug, HPMCAS, and a solvent, said solvent being an organic compound in which the drug and HPMCAS are mutually soluble, said solution having a ratio of said drug to HPMCAS of from 1 to 0.4 to 1 to 20, and the concentration of said drug in said solvent is less than 20 g/100 g of solvent;

(b) breaking up said solution into small droplets, wherein said droplets range in size from 1 to 500 μ

m;

(c) directing said droplets and a drying gas into a drying chamber to cause evaporation of a sufficient amount of said solvent from said droplets to cause solidification of said droplets in less than 5 seconds to form said solid dispersion.