Multiparticulate crystalline drug compositions having controlled release profiles

• US 20050181062A1
• Filed: 12/03/2004
• Published: 08/18/2005
• Est. Priority Date: 12/04/2003
• Status: Active Grant

• Current Assignee: Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: Lo, Julian B., Lyon, David K., Appel, Leah E., Friesen, Dwayne T., Herbig, Scott M., West, James B., McCray, Scott B., Crew, Marshall D., Ray, Roderick J.
• Granted Patent: US 7,887,844 B2
• Time in Patent Office: Days
• US Class Current: 424/489
• CPC Class Codes: A61K 31/4422 1,4-Dihydropyridines, e.g. nifedipine, nicardipine
• CPC Class Codes: A61K 31/7032 attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
• 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 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Abstract

A multiparticulate for controlled release of a drug comprises crystalline drug, a glyceride having at least one alkylate substituent of at least 16 carbon atoms, and a poloxamer, wherein at least 70 wt % of the drug in the multiparticulate is crystalline.

Claims

1. A pharmaceutical composition providing controlled release of a drug, comprising a plurality of multiparticulates, said multiparticulates comprising said drug wherein at least 70 wt % of said drug is crystalline, a poloxamer and a glyceride having at least one alkylate substituent of at least 16 carbon atoms.

2. The pharmaceutical composition of claim 1, wherein said drug is selected from the group consisting of azithromycin, amlodipine, and cetirizine.

3. The composition of claim 2 wherein said drug is azithromycin dihydrate.

4. The composition of claim 1 wherein at least 80 wt % of said drug is crystalline.

5. The composition of claim 1 wherein said alkylate substituent is selected from the group consisting of palmitate, stearate, oleate, linoleate, arachidate, behenate, lignocerate, ricinoleate and mixtures thereof.

6. The composition of claim 1 wherein said glyceride is selected from the group consisting of:

mixtures of glyceryl mono-, di-, and tribehenates;

mixtures of glyceryl tripalmitate and glyceryl tristearate;

glyceryl tri-behenates; and

mixtures thereof.

7. The composition of claim 1 wherein said poloxamer is selected from the group consisting of poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407 and mixtures thereof.

8. The composition of claim 1 wherein said poloxamer has a molecular weight of at least 4,700 daltons.

9. The composition of claim 1 wherein said poloxamer is solid at ambient temperatures.

10. The composition of claim 1 wherein said poloxamer is homogeneously distributed throughout said glyceride.

11. A process for forming multiparticulates, comprising:

(a) forming a molten mixture comprising a crystalline drug, a poloxamer and a glyceride having at least one alkylate substituent of at least 16 carbon atoms;

(b) forming droplets from said molten mixture; and

(c) solidifying said droplets to form multiparticulates

wherein at least 70 wt % of said drug in said multiparticulates is crystalline.

12. The process of claim 11 wherein said drug is selected from the group consisting of azithromycin, amlodipine, and cetirizine.

13. The process of claim 12 wherein said drug is azithromycin dihydrate.

14. The process of claim 11 wherein at least 80 wt % of said drug in said multiparticulate is crystalline.

15. The process of claim 11 wherein said molten mixture has a viscosity of less than about 10,000 cp.

16. A method for controlling the release rate of a drug from a multiparticulate, comprising:

(a) determining a desired release rate of said drug from said multiparticulate;

(b) forming multiparticulates comprising

(1) forming a molten mixture comprising a crystalline drug, a poloxamer and a glyceride having at least one alkylate substituent of at least 16 carbon atoms;

(2) forming droplets from said molten mixture; and

(3) solidifying said droplets to form multiparticulates wherein at least 70 wt % of said drug in said multiparticulates is crystalline; and

(c) prior to (b) selecting a weight ratio of said poloxamer to said glyceride to achieve said desired release rate.

17. The method of claim 16 wherein said glyceride comprises at least 20 wt % of said multiparticulate and said weight ratio of said poloxamer to said glyceride is from about 0.01 to about 0.50.

18. A pharmaceutical multiparticulate comprising a drug that is at least 70 wt % crystalline, a poloxamer and a glyceride having at least one alkylate substituent of at least 16 carbon atoms.

19. The multiparticulate of claim 18 wherein said drug is at least 80 wt % crystalline and is selected from the group consisting of azithromycin, amlodipine and cetirizine.

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

21. The multiparticulate of claim 18 wherein said glyceride is selected from the group consisting of:

mixtures of glyceryl mono-, di-, and tribehenates;

mixtures of glyceryl tripalmitate and glyceryl tristearate;

glyceryl tribehenates; and

mixtures thereof.

22. The multiparticulate of claim 21 wherein said poloxamer is selected from the group consisting of poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407 and mixtures thereof.