Multiparticulate compositions with improved stability

• US 20050186285A1
• Filed: 12/03/2004
• Published: 08/25/2005
• Est. Priority Date: 12/04/2003
• Status: Active Grant

• Current Assignee: Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: Ray, Rodrick J., Appel, Leah E., Friesen, Dwayne T., Crew, Marshall D.
• Granted Patent: US 7,736,672 B2
• Time in Patent Office: Days
• US Class Current: 424/489
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Abstract

A process is described for producing drug-containing multiparticulates with improved stability, characterized by an improvement in one or more of chemical stability, physical stability, or dissolution stability.

Claims

1. A process for making drug-containing multiparticulates comprising the steps:

(a) forming multiparticulates comprising a drug, a pharmaceutically acceptable carrier, and an optional dissolution enhancer, said carrier having a melting point of T_m°

C.; and

(b) treating said multiparticulates of step (a) by at least one of (i) heating said multiparticulates to a temperature of at least about 35°

C. and less than about (T_m°

C.-10°

C.), and (ii) exposing said multiparticulates to a mobility-enhancing agent, to form a post-treated multiparticulate;

wherein step (b) is conducted for a period of time sufficient to achieve a degree of crystallinity of said drug in said multiparticulates that is greater than the crystallinity of said drug in a control composition consisting essentially of the untreated multiparticulates of step (a).

2. The process of claim 1 wherein said multiparticulates of step (a) is treated by exposing said multiparticulates to a mobility-enhancing agent, to form a post-treated multiparticulate.

3. The process of claim 1, wherein said multiparticulates comprise a drug, a pharmaceutically acceptable carrier, an optional dissolution enhancer, and a mobility-enhancing agent;

and said multiparticulates are treated to a temperature of at least about 35°

C. and less than about (T_m°

C.-10°

C.) to form a post-treated multiparticulate.

4. The process of claim 1 wherein said drug in said post-treated multiparticulate has an improvement in stability relative to said drug in said control composition.

5. The process of claim 4 wherein said improvement in stability comprises a relative degree of improvement in drug crystal form of at least 1.25 relative to said control composition.

6. The process of claim 4 wherein said improvement in stability comprises an improvement in dissolution performance of at least 1.25 relative to said control composition.

7. The process of claim 4 wherein said improvement in stability comprises an improvement in chemical stability of at least 1.25 relative to said control composition.

8. The process of claim 1 wherein step (b) comprises both heating said multiparticulates and exposing said multiparticulates to said mobility-enhancing agent.

9. The process of claim 1 wherein said mobility-enhancing agent is selected from the group consisting of water, methanol, ethanol, propanol and its isomers, butanol and its isomers, acetone, methyl ethyl ketone, methyl iso-butyl ketone, ethyl acetate, tetrahydrofuran, acetonitrile, cyclohexane, formic acid, acetic acid and mixtures thereof.

10. The process of claim 9 wherein said mobility-enhancing agent is water in the form of water vapor comprising greater than about 10% relative humidity.

11. The process of claim 1 wherein step (b) comprises heating said multiparticulates at a temperature of 40°

to 50°

C. in an atmosphere of at least about 50% relative humidity for about 30 days or less.

12. The process of claim 3 wherein step (b) comprises the steps:

(i) placing said multiparticulates in a sealed container; and

(ii) heating said sealed container at a temperature of not more than about (T_m-10°

C.) for a time sufficient to achieve a degree of drug crystallinity of at least 95%.

13. The process of claim 3 wherein step (a) comprises the steps:

(i) forming a preblend feed comprising said drug, said carrier and said mobility-enhancing agent;

(ii) forming a molten mixture of said preblend feed in an extruder;

(iii) delivering said molten mixture to atomizing means to form droplets from said mixture; and

(iv) congealing said droplets to form said multiparticulates.

14. The process of claim 3 wherein step (a) comprises the steps:

(i) forming in an extruder a first molten mixture comprising said drug and said carrier;

(ii) delivering said mobility-enhancing agent to said extruder to form a second molten mixture comprising said drug, said carrier and said mobility-enhancing agent;

(iii) delivering said second molten mixture to atomizing means to form droplets; and

(iv) congealing said droplets to form said multiparticulates.

15. The process of claim 14 wherein step (b) comprises the steps:

(i) placing said multiparticulates in a sealed container; and

(ii) heating said sealed container at a temperature of not more than about (T_m-10°

C.) for a time sufficient to achieve a degree of drug crystallinity of at least 95%.

16. The process of claim 15 wherein said sealed container is heated at a temperature of from 40°

to 50°

C. for about 5 to about 21 days.

17. The process of claim 15 wherein said mobility-enhancing agent is water.

18. The process of claim 17 wherein said water is in a form selected from a liquid and a vapor.

19. The process of claim 1 wherein said drug is azithromycin.

20. The process of claim 19 wherein said drug is azithromycin dihydrate.

21. The process of claim 19 wherein said carrier is selected from the group consisting of long-chain alcohols, long-chain fatty acid esters, waxes, ether-substituted cellulosics, ester-substituted cellulosics, acid-functionalized polymethacrylates and polyacrylates, ester-functionalized polymethacrylates and polyacrylates and mixtures thereof.

22. The process of claim 21 wherein said carrier is selected from the group consisting of stearyl alcohol, cetyl alcohol, polyethylene glycol, glyceryl monooleate, glyceryl monostearate, glyceryl palmitostearate, polyethoxylated castor oil derivatives, hydrogenated vegetable oils, mono-, di-, and trialkyl glycerides, glyceryl mono-, di-, and tribehenates, synthetic wax, microcrystalline wax, paraffin wax, carnauba wax, white and yellow beeswax, microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethylcellulose, cellulose acetate, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate succinate, acid-functionalized polymethacrylates and polyacrylates, ester-functionalized polymethacrylates and polyacrylates and mixtures thereof.

23. The process of claim 21 wherein said carrier is a mixture of glyceryl mono-, di-, and tribehenates.

24. The process of claim 19 wherein said dissolution enhancer is selected from the group consisting of alcohols, surfactants, sugars, salts, amino acids, and mixtures thereof.

25. The process of claim 24 wherein said dissolution enhancer is selected from the group consisting of stearyl alcohol, cetyl alcohol, polyethylene glycol, poloxamers, docusate salts, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polysorbates, polyoxyethylene alkyl esters, sodium lauryl sulfate, sorbitan monoesters, glucose, sucrose, xylitol, sorbitol, maltitol, sodium chloride, potassium chloride, lithium chloride, calcium chloride, magnesium chloride, sodium sulfate, potassium sulfate, sodium carbonate, magnesium sulfate, potassium phosphate, alanine, glycine, and mixtures thereof.

26. The process of claim 24 wherein said dissolution enhancer is a surfactant.

27. The process of claim 26 wherein said dissolution enhancer is a poloxamer.

28. The process of claim 19 wherein said carrier is a mixture of glyceryl mono-, di-, and tribehenates and said dissolution enhancer is a poloxamer.

29. The product of the process of claim 1.

30. The product of claim 29 wherein said drug is azithromycin, said carrier comprises a glyceride having at least one alkylate substituent of at least 16 carbon atoms and said dissolution enhancer is a poloxamer.

31. The product of claim 30 wherein azithromycin is present in an amount of from about 20 to about 75 wt %.

32. The product of claim 30 wherein azithromycin is present in an amount of from about 35 to about 55 wt %, said glyceride is present in an amount of from about 40 to about 65 wt % and said poloxamer is present in an amount of from about 0.1 to about 15 wt %.

33. The product of claim 32 wherein said azithromycin is azithromycin dihydrate.