Granted Patent B2

US 8,487,002 · App. 11/111,996 · Granted Jul 16, 2013

Abstract

Claims (36)

1. A solid dosage formulation comprising:

a core comprising tramadol dispersed in a first controlled-release matrix comprising cross-linked high amylose starch; and

a compression coat formed over the core and comprising tramadol dispersed in a second controlled-release matrix comprising a mixture of polyvinyl acetate and polyvinylpyrrolidone at a weight ratio of about 8:2 such that the mixture comprises from about 30% to about 65% by weight of the coat, wherein the initial rate of release of tramadol from the second controlled-release matrix is at least twice the initial rate of release of tramadol from the first controlled release matrix when measured separately for each matrix material in a USP Type I apparatus in 50 mM phosphate, pH 6.8, and stirring between 50 and 150 rpm.

2. The formulation of claim 1 , wherein the tramadol is present in the formulation as an ionic salt.

3. The formulation of claim 1 , wherein the rate of release of tramadol from the second controlled-release matrix is between three and nine times the rate of release of tramadol from the first controlled-release matrix.

4. The formulation of claim 1 , wherein the rate of release of tramadol from the second controlled-release matrix is at least three times the rate of release of tramadol from the first controlled-release matrix.

5. The formulation of claim 1 , wherein between 10% and 30% of tramadol present at 0 hours is released between 0 and 2 hours when tested in vitro using a USP Type I apparatus in 50 mM phosphate, pH 6.8, and stirring between 50 and 150 rpm.

6. The formulation of claim 1 , wherein between 10% and 40% of the tramadol is released from the formulation between 0 and about 2 hours, between about 30% and 60% of the tramadol is released from the formulation between 2 and about 7 hours, between about 50% and 80% of the tramadol is released from the formulation between 7 and about 12 hours, and between about 80% and 100% of the tramadol is released from the formulation after about 20 hours.

7. The formulation of claim 1 , wherein the ratio of the core to the coat (w/w) is between about 1 and about 0.1.

8. The formulation of claim 1 , wherein the ratio of the tramadol in the core to the tramadol in the coat (w/w) is between about 0.6 and about 2.

9. The formulation of claim 1 , wherein the coat is between about 5% and about 90% by weight tramadol.

10. The formulation of claim 1 , wherein the ratio of the matrix of the coat to the tramadol of the coat (w/w) is between about 0.7 and about 4.

11. The formulation of claim 1 , wherein the ratio of the matrix of the core to the tramadol of the core (w/w) is between about 0.1 and about 10.

12. The formulation of claim 1 , wherein the coat further comprises a binding agent.

13. The formulation of claim 12 , wherein the binding agent is xanthan gum.

14. The formulation of claim 1 , wherein the formulation is a tablet, and wherein the cross-linked high amylose starch comprises a chemically-modified, cross-linked high amylose starch prepared by a method comprising:

(a) cross-linking high amylose starch, followed by

(b) chemically modifying the cross-linked high amylose starch by hydroxypropylating the cross-linked high amylose starch, followed by

(c) gelatinization, and

(d) drying to obtain a powder of the controlled release excipient;

wherein the cross-linked high amylose starch is characterized in that upon solubilization in 90% DMSO at 80° C. for about three days and gel permeation chromatography, the height of the peak corresponding to amylose in the cross-linked high amylose starch is at least 90% of that of the peak corresponding to amylose in the high amylose starch prior to (a).

15. The formulation of claim 1 , wherein the core further comprises a lubricant.

16. The formulation of claim 1 , wherein the coat further comprises a lubricant.

17. The formulation of claim 1 , wherein the formulation is a tablet formulated for oral administration.

18. A controlled released tablet comprising:

a compressed core comprising cross-linked high amylose starch and tramadol, or a salt thereof; and

a coat formed over the core by compression, and comprising a mixture of polyvinyl acetate, polyvinylpyrrolidone, a binder, and tramadol; and wherein:

the ratio of the core/coat (w/w) is between about 0.2 and 0.6;

the ratio of the tramadol in the core to the tramadol in the coat is between about 0.7 and about 1;

the ratio of polyvinyl acetate/polyvinylpyrrolidone (w/w) is about 8:2; and

the rate of release of tramadol from the coat is at least twice the rate of release of tramadol from the core when measured by a USP Type I apparatus in 50 mM phosphate, pH 6.8, and between 50 and 150 rpm.

19. A method of administering a pharmacological agent, the method comprising administering to a patient a solid dosage formulation as defined in claim 1 or 18 .

20. The formulation of claim 18 , wherein the polyvinyl acetate has a molecular weight in the range from about 100,000 to about 1,000,000.

21. The formulation of claim 18 , wherein the polyvinylpyrrolidone has a molecular weight in the range from about 10,000 to about 100,000.

22. The formulation of claim 18 , wherein the formulation is a once daily oral pharmaceutical composition for controlled release of tramadol or a salt thereof, wherein the composition, upon initial administration of one dose, provides a mean plasma concentration of at least 100 ng/mL within two hours of administration and continues to provide a mean plasma concentration of at least 100 ng/mL for at least 22 hours after administration.

23. The formulation of claim 22 , wherein the maximum mean plasma concentration is less than 2.2 times the mean plasma concentration obtained 24 hours after administration.

Assignments (18)