Details for Patent: 6,660,299

Title:	Modified release pharmaceutical formulation comprising amoxycillin
Abstract:	Bacterial infections may be treated using a high dosage regimen of amoxycillin. Preferably, the dosage is provided by a bilayer tablet.
Inventor(s):	Conley; Creighton P. (Bristol, TN), Roush; John A. (Kingsport, TN), Storm; Kevin H. (Bristol, TN)
Assignee:	Beecham Pharmaceuticals Limited (Jurong, SG)
Filing Date:	Jul 24, 2001
Application Number:	09/911,905
Claims:	1. A modified release pharmaceutical formulation comprising about 2000 mg of amoxycillin in an immediate release phase and a slow release phase; the immediate release phase comprising a first part of amoxycillin formulated with one or more pharmaceutically acceptable excipients which allows for immediate release of the first part of amoxycillin, and the slow release phase comprising a second part of amoxycillin formulated with one or more release modifying pharmaceutically acceptable excipients, wherein the ratio of amoxycillin in the immediate and slow release phase is from 3:1 to 1:3, and wherein the AUC value is at least 80% of that of the corresponding dosage of amoxycillin taken as an immediate release tablet or tablets, over the same dosage period. 2. The pharmaceutical formulation according to claim 1 which is tablet formulation. 3. The pharmaceutical formulation according to claim 1 in which the amoxycillin of the slow release phase consists essentially of crystallised sodium amoxycillin. 4. The pharmaceutical formulation according to claim 1 which is a layered tablet comprising an immediate release layer comprising amoxycillin and a slow release layer comprising amoxycillin and a release retarding excipient, which tablet: (a) is a bilayered tablet; or (b) comprises at least three layers, including an immediate release and a slow release layer, and comprising at least 275 mg of amoxycillin in the immediate release layer phase; or (c) comprises at least three layers, including an immediate release and a slow release layer, and in which the release retarding excipient in the slow release layer comprises xanthan gum and/or a pharmaceutically acceptable organic acid, or (d) comprises at least three layers, including an immediate release and a slow release layer, and in which the amoxycillin is provided as a mixture of amoxycillin trihydrate and sodium amoxycillin, in a ratio of 3:1 to 1:3. 5. The layered tablet according to claim 4 in which the slow release layer comprises one or more release retarding excipients which are selected from a pH sensitive polymer; a release-retarding polymer which has a high degree of swelling in contact with water or aqueous media; a polymeric material which forms a gel on contact with water or aqueous media; a polymeric material which has both swelling and gelling characteristics in contact with water or aqueous media; a hydrocolloid; carbohydrate-based substances, proteinaceous substances, or a mixture thereof. 6. The layered tablet according to claim 5 in which the release retarding gellable polymer is selected from methylcellulose, carboxymethylcellulose, low-molecular weight hydroxypropylmethylcellulose, low-molecular weight polyvinylalcohols, polyoxyethyleneglycols, and non-cross linked polyvinylpyrrolidone, or xanthan gum. 7. The layered tablet according to claim 5 in which the release retarding excipient is xanthan gum and is present in an amount of about 1 to 25% by weight of the layer. 8. The layered tablet according to claim 4 in which the slow release layer comprises from 70 to 80% of amoxycillin, from 1 to 25% of xanthan gum, from 10 to 20% of fillers/compression aids, and from 1 to 2.5% by weight of a lubricant. 9. The layered tablet according to claim 4 in which the slow release phase comprises sodium amoxycillin and in which the slow release layer comprises a pharmaceutically acceptable organic acid present in a molar ratio of from 100:1 to 1:10 of amoxycillin salt to organic acid. 10. The layered tablet according to claim 9 in which the pharmaceutically acceptable acid is citric acid present in a molar ratio of about 50:1 to 1:2. 11. The layered tablet according to claim 10 further comprising a release retarding gellable polymer. 12. The layered tablet according to claim 11 in which the release retarding gellable polymer is xanthan gum. 13. The layered tablet according to claim 12 in which xanthan gum is present in from 0.5 to 8% by weight of the slow release layer. 14. The pharmaceutical formulation according to claim 1 in which the immediate release phase is formed from immediate release granules comprising amoxycillin and the slow release phase is formed from slow release granules comprising amoxycillin. 15. The pharmaceutical formulation according to claim 14 which is a single dose sachet, a capsule, a monolith tablet, a dispersible tablet, a chewable tablet, effervescent chewable tablet, or an effervescent dispersible tablet. 16. The pharmaceutical formulation according to claim 14 comprising slow release compacted granules comprising amoxycillin, a diluent/compression aid, and an organic acid (if amoxycillin is present as a soluble salt thereof) or a release retarding polymer or a mixture thereof, and further immediate release compacted granules comprising amoxycillin. 17. The formulation according to claim 1 having an AUC, C.sub.max, and t.sub.max substantially according to FIG. 4, formulation VI or VII. 18. A formulation which is bioequivalent to the formulation of claim 17. 19. The formulation according to claim 1 wherein the release profile is biphasic. 20. The formulation according to claim 1 comprising two tablets of about 1000 mg.+-.5% amoxycillin, wherein the immediate release phase comprises about 563 mg.+-.5% amoxycillin, and the slow release phase comprises about 438 mg.+-.5% of amoxycillin. 21. A modified release pharmaceutical formulation comprising about 2000 mg of amoxycillin in an immediate release phase and a slow release phase; the immediate release phase comprising a first part of amoxycillin formulated with one or more pharmaceutically acceptable excipients which allows for immediate release of the first part of amoxycillin, and the slow release phase comprising a second part of amoxycillin formulated with one or more release modifying pharmaceutically acceptable excipients, wherein the ratio of amoxycillin in the immediate and slow release phase is from 3:1 to 1:3, such that the formulation has an in vitro dissolution profile wherein 45 to 65% of the amoxycillin content is dissolved within 30 min, measured in <711> dissolution test, Apparatus 2, USP 23, 1995, at 37.0.+-.0.5.degree. C., using 900 mL of deionised water and a paddle speed of 75 rpm. 22. The formulation according to claim 21 wherein the release profile is biphasic. 23. The formulation according to claim 21 comprising two tablets of about 1000 mg.+-.5% amoxycillin, wherein the immediate release phase comprises about 563 mg.+-.5% amoxycillin, and the slow release phase comprises about 438 mg.+-.5% of amoxycillin. 24. The formulation according to claim 21 wherein 50 to 75% of the amoxycillin content is dissolved within 60 minutes. 25. The formulation according to claim 21 wherein 55 to 85% of the amoxycillin content is dissolved within 120 minutes. 26. The formulation according to claim 21 wherein 70 to 95% of the amoxycillin content is dissolved within 180 minutes. 27. The formulation according to claim 21 wherein 70 to 100% of the amoxycillin content is dissolved within 240 minutes. 28. The formulation according to claim 27 wherein 75 to 100% of the amoxycillin content is dissolved within 240 minutes. 29. The formulation according to claim 1 wherein the formulation provides a mean plasma concentration of amoxycillin of 4 .mu.g/mL for at least 4.2 hours. 30. The formulation according to claim 1 wherein the formulation provides a mean plasma concentration of amoxycillin of 4 .mu.g/mL for at least 4.4 hours. 31. The formulation according to claim 1 wherein the formulation provides a mean plasma concentration of amoxycillin of 4 .mu.g/mL for at least 4.8 hours. 32. The formulation according to claim 21 wherein the formulation provides a mean C.sub.max of amoxycillin of at least 12 .mu.g/mL. 33. The formulation according to claim 21 wherein the formulation provides a mean C.sub.max of amoxycillin of at least 16 .mu.g/mL. 34. The formulation according to claim 21 wherein the formulation provides a mean C.sub.max of amoxycillin of at least 12 .mu.g/mL, and a mean plasma concentration of amoxycillin of at least 4 .mu.g/mL for at least 4.2 hours. 35. A modified release formulation comprising about 2000 mg of amoxycillin in an immediate release phase and a slow release phase; the immediate release phase comprising a first part of amoxycillin formulated with one or more pharmaceutically acceptable excipients which allows for immediate release of the first part of amoxycillin, and the slow release phase comprising a second part of amoxycillin formulated with one or more release modifying pharmaceutically acceptable excipients, wherein the ratio of amoxycillin in the immediate and slow release phase is from 3:1 to 1:3, such that the amoxycillin has an in vitro dissolution profile wherein 45 to 65% of the amoxycillin content is dissolved within 30 minutes; 50 to 75% of the amoxycillin content is dissolved within 60 minutes; 55 to 85% of the amoxycillin content is dissolved within 120 minutes; 70 to 95% of the amoxycillin content is dissolved within 180 minutes; and 70 to 100% of the amoxycillin content is dissolved within 240 minutes, measured in the <711> dissolution test, Apparatus 2, USP 23, 1995, at 37.0.+-.0.5.degree. C., using 900 mL of deionised water and a paddle speed of 75 rpm. 36. The formulation according to claim 35 wherein the release profile is biphasic. 37. The formulation according to claim 35 comprising two tablets of about 1000 mg.+-.5% amoxycillin, wherein the immediate release phase comprises about 563 mg.+-.5% amoxycillin, and the slow release phase comprises about 438 mg.+-.5% of amoxycillin. 38. A modified release pharmaceutical formulation comprising about 2000 mg of amoxycillin in an immediate release phase and a slow release phase; the immediate release phase comprising a first part of amoxycillin formulated with one or more pharmaceutically acceptable excipients which allows for immediate release of the first part of amoxycillin, and the slow release phase comprising a second part of amoxycillin formulated with one or mare release modifying pharmaceutically acceptable excipients, wherein the ratio of amoxycillin in the immediate and slow release phase is from 3:1 to 1:3, such that the formulation provides a mean C.sub.max of amoxycillin of at least 16 .mu.g/mL, an AUC value of amoxycillin which is at least 80% of that of the same amount if taken as an immediate release formulation, and a mean plasma concentration of amoxycillin of at least 4 .mu.g/mL for at least 4.2 hours. 39. The formulation according to claim 38 wherein the release profile is biphasic. 40. The formulation according to claim 38 comprising two tablets of about 1000 mg.+-.5% amoxycillin, wherein the immediate release phase comprises about 563 mg.+-.5% amoxycillin, and the slow release phase comprises about 438 mg.+-.5% of amoxycillin. 41. The formulation according to claim 38 wherein the AUC is at least 90%. 42. The formulation according to claim 38 wherein the AUC is at least 100%. 43. The formulation according to claim 38 wherein the AUC is at least 110%. 44. The formulation according to claim 38 wherein the AUC is at least 120%. 45. The formulation according to claim 38 wherein the mean plasma concentration of amoxicillin is at least 4 micrograms/mL for at least 4.4 hours. 46. The formulation according to claim 38 wherein the mean plasma concentration of amoxicillin is at least 4 micrograms/mL for at least 4.8 hours. 47. A modified release formulation comprising about 2000 mg of amoxycillin in an immediate release phase and a slow release phase; the immediate release phase comprising a first part of amoxycillin formulated with one or more pharmaceutically acceptable excipients which allows for immediate release of the first part of amoxycillin, and the slow release phase comprising a second part of amoxycillin formulated with one or more release modifying pharmaceutically acceptable excipients, wherein the ratio of amoxycillin in the immediate and slow release phase is from 3:1 to 1:3, such that the amoxycillin provides a mean C.sub.max of amoxycillin of about 17.4 .mu.g/mL, an AUC value of amoxycillin which is at least 74.9% of that of the same amount if taken as an immediate release formulation over the same dosage regimen interval, and a mean plasma concentration of amoxycillin of at least 4 .mu.g/mL for about 6 hours. 48. The formulation according to claim 47 wherein the release profile is biphasic. 49. The formulation according to claim 47 which corresponds to the pharmacokinetic profile for amoxycillin plasma as shown in FIG. 4 formulation A. 50. The formulation according to claim 47 comprising two tablets of about 1000 mg.+-.5% amoxycillin, wherein the immediate release phase comprises about 563 mg.+-.5% amoxycillin, and the slow release phase comprises about 438 mg.+-.5% of amoxycillin. 51. The formulation according to claim 47 wherein the amoxycillin in the slow release phase is sodium amoxycillin. 52. The formulation according to claim 51 wherein the sodium amoxycillin is crystallized sodium amoxycillin. 53. The formulation according to claim 52 which consists of a layered tablet and in which the immediate and slow release phases are provided for as separate layers of the layered tablet. 54. The formulation according to claim 1 wherein the ratio of amoxycillin in the immediate and slow phase is selected from 2:1 to 2:3 or 3:2 to 1:1. 55. The formulation according to claim 1 wherein the ratio of amoxycillin in the immediate and slow phase is selected from 2:1 to 2:3 or 3:2 to 1:1. 56. The formulation according to claim 35 wherein the ratio of amoxycillin in the immediate and slow phase is selected from 2:1 to 2:3 or 3:2 to 1:1. 57. The formulation according to claim 38 wherein the ratio of amoxycillin in the immediate and slow phase is selected from 2:1 to 2:3 or 3:2 to 1:1. 58. The formulation according to claim 47 wherein the ratio of amoxycillin in the immediate and slow phase is selected from 2:1 to 2:3 or 3:2 to 1:1.