Claims for Patent: 6,878,386

Summary for Patent: 6,878,386

Title:	Method of treating a bacterial infection comprising amoxycillin and potassium clavulanate
Abstract:	Bacterial infections may be treated using a high dosage regimen of amoxycillin and potassium clavulanate. 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 (Pte) Limited (Jurong, SG)
Application Number:	09/544,019
Patent Claims:	1. A method for treating a bacterial infection in a human in need thereof, which method comprises administering to said human, at a dosage regimen interval of about 12 hours, a dosage of about 2000 mg of amoxicillin and about 125 mg potassium clavulanate, in which the dosage is delivered from a modified release formulation, adapted to provide a mean maximum plasma concentration (C.sub.max) of amoxicillin of at least 12 .mu.g/ml, an Area under the Curve (AUC) value of amoxicillin which is at least 80% 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 amoxicillin of at least 4 .mu.g/ml for at least 4.2 hours, and further adapted to provide for immediate release of the potassium clavulanate. 2. The method 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 and a mean maximum plasma concentration (C.sub.max) of amoxycillin of at least 12 .mu.g/mL. 3. The method according to claim 2 wherein the formulation provides a mean plasma concentration of amoxycillin of 4 .mu.g/mL for at least 4.8 hours and a mean maximum plasma concentration (C.sub.max) of amoxycillin of at least 16 .mu.g/mL. 4. The method according to claim 1 wherein the formulation provides a mean plasma concentration of amoxycillin of 8 .mu.g/mL for at least 4.4 hours. 5. The method according to claim 1 in which the bacterial infection is caused by at least one of the organisms S. pneumoniae, H. influenzae, and M. catarrhalis. 6. The method according to claim 1 wherein the formulation provides a mean maximum plasma concentration (C.sub.max) of amoxycillin of at least 16 .mu.g/mL. 7. The method according to claim 1 wherein the formulation provides a mean plasma concentration of amoxycillin of 8 .mu.g/mL for at least 4.8 hours. 8. The method according to claim 1 wherein the formulation provides a mean maximum plasma concentration (C.sub.max) of amoxycillin of at least 16 .mu.g/mL. 9. A method of treating a bacterial infection in a human in need thereof, which method comprises administering to said human, at a dosage regimen interval of about 12 hours, a dosage of about 2000 mg of amoxicillin and about 125 mg potassium clavulanate, wherein the dosage is delivered from a modified release formulation which has an in vitro dissolution profile wherein about 45% to about 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 deionised water (900 mL) and a paddle speed of 75 rpm. 10. The method according to claim 9 wherein about 50% to about 75% of the amoxycillin content is dissolved within 60 minutes. 11. The method according to claim 9 wherein about 55% to about 85% of the amoxycillin content is dissolved within 120 minutes. 12. The method according to claim 9 wherein about 70% to about 95% of the amoxycillin content is dissolved within 180 minutes. 13. The method according to claim 9 wherein about 70% to about 100% of the amoxycillin content is dissolved within 240 minutes. 14. The method according to claim 13 wherein about 75% to about 100% of the amoxycillin content is dissolved within 240 minutes. 15. The method according to claim 9 wherein the formulation is adapted to provide a mean plasma concentration of amoxycillin of 4 .mu.g/mL for at least 4.2 hours. 16. The method according to claim 9 wherein the formulation is adapted to provide a mean plasma concentration of amoxycillin of 4 .mu.g/mL for at least 4.4 hours. 17. The method according to claim 9 wherein the formulation is adapted to provide a mean plasma concentration of amoxycillin of 4 .mu.g/mL for at least 4.8 hours. 18. The method according to claim 9 wherein the formulation is adapted to provide a mean maximum plasma concentration (C.sub.max) of amoxycillin of at least 12 .mu.g/mL. 19. The method according to claim 9 wherein the formulation is adapted to provide a mean maximum plasma concentration (C.sub.max) of amoxycillin of at least 16 .mu.g/mL. 20. The method according to claim 9 wherein the formulation is adapted to provide over the dosage regimen a mean maximum plasma concentration (C.sub.max) of amoxycillin of at least 12 .mu.g/mL, and a mean plasma concentration of amoxicillin of at least 4 .mu.g/ml for at least 4.2 hours. 21. The method according to claim 20 wherein the formulation is adapted to provide an Area under the Curve (AUC) value of amoxicillin which is at least 80% of that of the same amount if taken as an immediate release formulation over the same dosage regimen interval. 22. The method according to claim 9 wherein the bacterial infection is caused by at least one of the organisms S. pneumoniae, H. infiuenzae, and M. catarrhalis. 23. The method according to claim 22 wherein the S. pneumoniae organism is drug resistant and penicillin resistant. 24. The method according to claim 9 which has a dosage regimen administered over a period of 7 to 14 days. 25. A method of treating a bacterial infection in a human in need thereof, which method comprises administering to said human a dosage of about 2000 mg of amoxicillin and about 125 mg potassium clavulanate, wherein the dosage is delivered from a modified release formulation which has an in vitro dissolution profile wherein about 45% to about 65% of the amoxycillin content is dissolved within 30 minutes; about 50% to about 75% of the amoxycillin content is dissolved within 60 minutes; about 55% to about 85% of the amoxycillin content is dissolved within 120 minutes; about 70% to about 95% of the amoxycillin content is dissolved within 180 minutes; and about 70% to about 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 deionised water (900 mL) and a paddle speed of 75 rpm. 26. The method according to claim 25 wherein the bacterial infection caused by at least one of the organisms S. pneumoniae, H. influenzae, and M. catarrhalis. 27. The method according to claim 26 wherein the S. pneumoniae organism is drug resistant and penicillin resistant. 28. A method for treating a bacterial infection in a human in need thereof, which method comprises administering to said human, at a dosage regimen interval of about 12 hours, a dosage of about 2000 mg of amoxicillin and about 125 mg potassium clavulanate, wherein the dosage is delivered from a modified release formulation, adapted to provide a mean maximum plasma concentration (Cmax) of amoxicillin of at least 16 .mu.g/ml, an Area under the Curve (AUC) value of amoxicillin which is at least 80% 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 amoxicillin of at least 4 .mu.g/ml for at least 4.2 hours, and further adapted to provide for immediate release of the potassium clavulanate. 29. The method according to claim 28 wherein the formulation provides an AUC of at least 90%. 30. The method according to claim 28 wherein the formulation provides an AUC of at least 100%. 31. The method according to claim 28 wherein the formulation provides an AUC of at least 110%. 32. The method according to claim 28 wherein the formulation provides an AUC of at least 120%. 33. The method according to claim 28 wherein the formulation provides a mean plasma concentration of amoxicillin of at least 4 micrograms/ml for at least 4.4 hours. 34. The method according to claim 28 wherein the formulation provides a mean plasma concentration of amoxicillin of at least 4 micrograms/ml for at least 4.8 hours. 35. The method according to claim 28 wherein the formulation provides a mean plasma concentration of amoxicillin of at least 4 micrograms/ml for about 6 hours. 36. The method according to claim 28 wherein the formulation provides a mean plasma concentration of amoxicillin of at least 8 micrograms/ml for at least 4.4 hours. 37. The method according to claim 28 wherein the formulation provides a mean plasma concentration of amoxicillin of at least 8 micrograms/ml for at least 4.8 hours. 38. The method according to claim 28 wherein the bacterial infection is caused by at least one of the organisms S. pneumoniae, H. influenzae, and M. catarrhalis. 39. The method according to claim 38 wherein the S. pneumoniae organism is drug resistant and penicillin resistant. 40. A method for treating a bacterial infection in a human in need thereof, which method comprises administering to said human, at a dosage regimen interval of about 12 hours, a dosage of about 2000 mg of amoxicillin and about 125 mg potassium clavulanate, wherein the dosage is delivered from a biphasic modified release formulation, adapted to provide a mean maximum plasma concentration (Cmax) of amoxicillin of at least 12 .mu.g/ml, an Area under the Curve (AUC) value of amoxicillin which is at least 80% 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 amoxicillin of at least 4 .mu.g/ml for at least 4.2 hours, and further adapted to provide for immediate release of the potassium clavulanate. 41. The method according to claim 40 wherein the bacterial infection is caused by at least one of the organisms S. pneumoniae, H. infiuenzae, and M. catarrhalis. 42. The method according to claim 41 wherein the S. pneumoniae organism is drug resistant and penicillin resistant. 43. The method according to claim 40 wherein the formulation provides a mean plasma concentration of amoxycillin of 4 .mu.g/mL for at least 4.4 hours. 44. The method according to claim 40 wherein the formulation provides a mean plasma concentration of amoxycillin of 4 .mu.g/mL for at least 4.8 hours. 45. The method according to claim 40 wherein the formulation provides a mean plasma concentration of amoxicillin of at least 4 micrograms/ml for about 6 hours. 46. The method according to claim 40 wherein the formulation provides a mean plasma concentration of amoxicillin of at least 8 micrograms/ml for at least 4.4 hours. 47. The method according to claim 40 wherein the formulation provides a mean plasma concentration of amoxicillin of at least 8 micrograms/ml for at least 4.8 hours. 48. The method according to claim 40 wherein the formulation provides a mean maximum plasma concentration (C.sub.max) of amoxycillin of at least 16 .mu.g/mL. 49. The method according to claim 40 wherein the formulation provides an AUC of at least 90%. 50. The method according to claim 40 wherein the formulation provides an AUC of at least 100%. 51. The method according to claim 40 wherein the formulation provides an AUC of at least 110%. 52. The method according to claim 40 wherein the formulation provides an AUC of at least 120%. 53. The method according to claim 41 wherein the bacterial infection is a respiratory tract infection. 54. The method according to claim 53 wherein the respiratory tract infection is community acquired pneumoniae (CAP), acute exacerbation of chronic bronchitis (AECB) or acute bacterial sinusitis (ABS). 55. The method according to claim 40 wherein the dosage regimen is administered over 7 to 14 days. 56. The method according to claim 40 wherein the dosage is provided by two tablets each comprising about 1000/62.5 mg amoxycillin/potassium clavulanate, or four tablets of 500/32.25 mg amoxycillin/potassium clavulanate. 57. The method according to claim 40 wherein all of the potassium clavulanate and a first part of amoxycillin are formulated with at least one pharmaceutically acceptable excipient which allows for immediate release of the potassium clavulanate and the first part of amoxycillin, to form an immediate release phase, and wherein a second part of amoxycillin is formulated with at least one pharmaceutically acceptable excipient to allow for slow release of the second part of amoxycillin, to form a slow release phase. 58. A method for treating a bacterial infection in a human in need thereof which method comprises administering to said human, at a dosage regimen interval of about 12 hours, a dosage of about 2000 mg of amoxicillin and about 125 mg potassium clavulanate, wherein the dosage is delivered from a biphasic modified release formulation, adapted to provide a mean maximum plasma concentration (Cmax) of amoxicillin of about 17.4 .mu.g/ml, an Area under the Curve (AUC) value of amoxicillin 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 amoxicillin of at least 4 .mu.g/ml for about 6 hours, and further adapted to provide for immediate release of the potassium clavulanate. 59. The method according to claim 58 wherein the formulation provides an AUC of at least 80% of the value displayed by the biphasic formulation. 60. The method according to claim 58 wherein the formulation provides an AUC of at least 90% of the value displayed by the biphasic formulation. 61. The method according to claim 58 wherein the formulation provides an AUC of at least 100% of the value displayed by the biphasic formulation. 62. The method according to claim 58 wherein the formulation provides an AUC of at least 110% of the value displayed by the biphasic formulation. 63. The method according to claim 58 wherein the formulation provides an AUC of at least 120% of the value displayed by the biphasic formulation. 64. The method according to claim 58 wherein the biphasic modified release formulation comprises an immediate release of amoxicillin and a modified release of amoxicillin. 65. The method according to claim 58 wherein the bacterial infection caused by at least one of the organisms S. pneumoniae, H. influenzae, and M. catarrhalis. 66. The method according to claim 65 wherein the S. pneumoniae organism is drug resistant and penicillin resistant. 67. The method according to claim 58 wherein the formulation provides a pharmacokinetic plasma profile for amoxycillin substantially as shown in FIG. 5, formulation A. 68. The method according to claim 58 comprising two tablets of about 1000 mg.+-.5% amoxycillin and about 62.5 mg.+-.5% potassium clavulanate, wherein the immediate release phase comprises about 563 mg.+-.5% amoxycillin and about 62.5 mg.+-.5% of potassium clavulanate, and the slow release phase comprises about 438 mg.+-.5% of amoxycillin. 69. The method according to claim 64 wherein the amoxycillin in the modified release phase is sodium amoxycillin. 70. The method according to claim 69 wherein the sodium amoxycillin is crystallized sodium amoxycillin. 71. The method according to claim 64 wherein the amoxycillin in the immediate release phase is amoxycillin trihydrate. 72. The method according to claim 65 wherein the bacterial infection is a respiratory tract infection. 73. The method according to claim 72 wherein the respiratory tract infection is community acquired pneumoniae (CAP), acute exacerbation of chronic bronchitis (AECB) or acute bacterial sinusitis (ABS). 74. The method according to claim 58 wherein the dosage regimen is administered over 7 to 14 days. 75. The method according to claim 1 wherein the dosage is provided by two tablets each comprising about 1000/62.5 mg amoxycillin/potassium clavulanate, or four tablets of 500/32.25 mg amoxycillin/potassium clavulanate. 76. The method according to claim 1 wherein all of the potassium clavulanate and a first part of amoxycillin are formulated with at least one pharmaceutically acceptable excipient which allows for immediate release of the potassium clavulanate and the first part of amoxycillin, to form an immediate release phase, and wherein a second part of amoxycillin is formulated with at least one pharmaceutically acceptable excipient to allow for slow release of the second part of amoxycillin, to form a slow release phase. 77. The method according to claim 76 wherein the amoxycillin in the immediate release phase is amoxycillin trihydrate or a sodium amoxycillin or a combination thereof. 78. The method according to claim 76 wherein the amoxycillin in the slow release phase is sodium amoxycillin. 79. The method according to claim 78 wherein the sodium amoxycillin is crystallized sodium amoxycillin. 80. The method according to claim 1 comprising two tablets of about 1000 mg.+-.5% amoxycillin and about 62.5 mg.+-.5% potassium clavulanate, wherein the immediate release phase comprises about 563 mg.+-.5% amoxycillin and about 62.5 mg.+-.5% of potassium clavulanate, and the slow release phase comprises about 438 mg.+-.5% of amoxycillin. 81. The method according to claim 5 wherein the S. pneumoniae organism is drug resistant and penicillin resistant. 82. The method according to claim 1 wherein the dosage regimen is administered over 7 to 14 days. 83. The method according to claim 5 wherein the bacterial infection is a respiratory tract infection. 84. The method according to claim 83 wherein the respiratory tract infection is community acquired pneumoniae (CAP), acute exacerbation of chronic bronchitis (AECB) or acute bacterial sinusitis (ABS). 85. The method according to claim 22 wherein the bacterial infection is a respiratory tract infection. 86. The method according to claim 85 wherein the respiratory tract infection is community acquired pneumoniae (CAP), acute exacerbation of chronic bronchitis (AECB) or acute bacterial sinusitis (ABS). 87. The method according to claim 22 wherein the dosage regimen is administered over 7 to 14 days. 88. The method according to claim 26 wherein the bacterial infection is a respiratory tract infection. 89. The method according to claim 88 wherein the respiratory tract infection is community acquired pneumoniae (CAP), acute exacerbation of chronic bronchitis (AECB) or acute bacterial sinusitis (ABS). 90. The method according to claim 26 wherein the dosage regimen is administered over 7 to 14 days. 91. The method according to claim 38 wherein the bacterial infection is a respiratory tract infection. 92. The method according to claim 91 wherein the respiratory tract infection is community acquired pneumoniae (CAP), acute exacerbation of chronic bronchitis (AECB) or acute bacterial sinusitis (ABS). 93. The method according to claim 38 wherein the dosage regimen is administered over 7to 4days.