Claims for Patent: 6,783,773

Summary for Patent: 6,783,773

Title:	Composition comprising amoxicillin and potassium clavulanate
Abstract:	Bacterial infections may be treated using a high dosage regimen of amoxicillin and potassium clavulanate. Preferably, the dosage is provided by a bilayer tablet.
Inventor(s):	Storm; Kevin H. (Bristol, TN), Conley; Creighton P. (Bristol, TN), Roush; John A. (Kingsport, TN)
Assignee:	Beecham Pharmaceuticals (Pte) Limited (Jurong, SG)
Application Number:	09/971,560
Patent Claims:	1. A composition comprising amoxicillin and potassium clavulanate, the composition being in a solid form and comprising a first release phase and a second release phase; the first release phase comprising potassium clavulanate and a first amount of the amoxicillin; the second release phase comprising a second amount of the amoxicillin-, said second amount of amoxicillin being a pharmaceutically acceptable soluble salt of amoxicillin, and at least one pharmaceutically acceptable organic acid which are admixed, as solids, in intimate contact at a ratio of from about 20:1 to about 1:2. 2. A composition according to claim 1 wherein the ratio of the pharmaceutically acceptable soluble salt of amoxicillin to the at least one pharmaceutically acceptable organic acid in the second release phase is from about 2:1 to about 1:1.2. 3. A composition according to claim 1 wherein the ratio of the amoxicillin in the first release phase to the amoxicillin in the second release phase is from about 3:1 to about 1:3. 4. A composition according to claim 1, wherein the ratio of the amoxicillin in the first release phase to the amoxicillin in the second release phase is from about 2:1 to about 2:3. 5. A composition according to claim 2 wherein the ratio of the amoxicillin in the first release phase to the amoxicillin in the second release phase is from about 2:1 to about 2:3. 6. A composition according to claim 1 wherein the ratio of the amoxicillin in the first release phase to the amoxicillin in the second release phase is from about 3:2 to about 1:1. 7. A composition according to claim 2 wherein the ratio of the amoxicillin in the first release phase to the amoxicillin in the second release phase is from about 3:2 to about 1:1. 8. A composition according to claim 1 wherein the ratio of the amoxicillin in the first release phase to the amoxicillin in the second release phase is about 9:7. 9. A composition according to claim 1 wherein the at least one pharmaceutically acceptable organic acid is selected from pharmaceutically acceptable monocarboxylic and polycarboxylic acids having from 2 to 25 carbon atoms, pharmaceutically acceptable monocyclic aryl and polycyclic aryl acids, and pharmaceutically acceptable monohydrogen and dihydrogen metal salts of any of the foregoing muti-valent acids. 10. A composition according to claim 1 wherein the at least one pharmaceutically acceptable organic acid is selected from pharmaceutically acceptable monocarboxylic and polycarboxylic acids having from 2 to 10 carbon atoms and an acidic salt of any of the foregoing. 11. A composition according to claim 2 wherein the at least one pharmaceutically acceptable organic acid is selected from pharmaceutically acceptable monocarboxylic and polycarboxylic acids having from 2 to 10 carbon atoms and an acidic salt of any of the foregoing. 12. A composition according to claim 6 wherein the at least one pharmaceutically acceptable organic acid is selected from pharmaceutically acceptable monocarboxylic and polycarboxylic acids having from 2 to 10 carbon atoms and an acidic salt of any of the foregoing. 13. A composition according to claim 1 wherein the at least one pharmaceutically acceptable organic acid is selected from C.sub.(2-10) alkyl- and C.sub.(2-10) alkenyl-carboxylic acids having one, two, or three carboxylic acid groups, and optionally at least one hydroxy substituent, and optionally at least one --CO group in the carbon chain and an acidic salt of any of the foregoing. 14. A composition according to claim 1 wherein the at least one pharmaceutically acceptable organic acid is selected from malonic acid, succinic acid, fumaric acid, malic acid, adipic acid, lactic acid, levulinic acid, sorbic acid, tartaric acid, malic acid, ascorbic acid, citric acid, and an acidic salt of any of the foregoing. 15. A composition according to claim 2 wherein the at least one pharmaceutically acceptable organic acid is selected from malonic acid, succinic acid, fumaric acid, maleic acid, adipic acid, lactic acid, levulinic acid, sorbic acid, tartaric acid, malic acid, ascorbic acid, citric acid, and an acidic salt of any of the foregoing. 16. A composition according to claim 6 wherein the at least one pharmaceutically acceptable organic acid is selected from malonic acid, succinic acid, fumaric acid, maleic acid, adipic acid, lactic acid, levulinic acid, sorbic acid, tartaric acid, malic acid, ascorbic acid, citric acid, and an acidic salt of any of the foregoing. 17. A composition according to claim 1 wherein the at least one pharmaceutically acceptable organic acid is citric acid. 18. A composition according to claim 2 wherein the at least one pharmaceutically acceptable organic acid is citric acid. 19. A composition according to claim 6 wherein the at least one pharmaceutically acceptable organic acid is citric acid. 20. A composition according to claim 1 wherein the at least one pharmaceutically acceptable organic acid is citric acid anhydrous. 21. A composition according to claim 1 wherein the pharmaceutically acceptable soluble salt of amoxicillin is sodium amoxicillin. 22. A composition according to claim 2 wherein the pharmaceutically acceptable soluble salt of amoxicillin is sodium amoxicillin. 23. A composition according to claim 6 wherein the pharmaceutically acceptable soluble salt of amoxicillin is sodium amoxicillin. 24. A composition according to claim 16 wherein the pharmaceutically acceptable soluble salt of amoxicillin is sodium amoxicillin. 25. A composition according to claim 19 wherein the pharmaceutically acceptable soluble salt of amoxicillin is sodium amoxicillin. 26. A composition according to claim 1 wherein the pharmaceutically acceptable soluble salt of amoxicillin is crystallized sodium amoxicillin. 27. A composition according to claim 19 wherein the pharmaceutically acceptable soluble salt of amoxicillin is crystallized sodium amoxicillin. 28. A composition according to claim 1 wherein the ratio of the amount of amoxicillin in the composition to the amount of potassium clavulanate is from about 2:1 to about 20:1. 29. A composition according to claim 1 wherein the ratio of the amount of amoxicillin in the composition to the amount of potassium clavulanate is from about 12:1 to about 20:1. 30. A composition according to claim 1 wherein the ratio of the amount of amoxicillin in the composition to the amount of potassium clavulanate is from about 14:1 to about 16:1. 31. A composition according to claim 2 wherein the ratio of the amount of amoxicillin in the composition to the amount of potassium clavulanate is from about 14:1 to about 16:1. 32. A composition according to claim 6 wherein the ratio of the amount of amoxicillin in the composition to the amount of potassium clavulanate is from about 14:1 to about 16:1. 33. A composition according to claim 19 wherein the ratio of the amount of amoxicillin in the composition to the amount of potassium clavulanate is from about 14:1 to about 16:1. 34. A composition according to claim 28 wherein the pharmaceutically acceptable soluble salt of amoxicillin is crystallized sodium amoxicillin and the at least one pharmaceutically acceptable organic acid is citric acid anhydrous. 35. A composition according to claim 1 wherein all of the potassium clavulanate of the composition is present in the first release phase. 36. A composition according to claim 15 wherein all of the potassium clavulanate of the composition is present in the first release phase. 37. A composition according to claim 25 wherein all of the potassium clavulanate of the composition is present in the first release phase. 38. A composition according to claim 1 wherein the first release phase comprises at least one pharmaceutically acceptable soluble salt of amoxicillin, amoxicillin trihydrate, or a mixture thereof. 39. A composition according to claim 36 wherein the first release phase comprises at least one pharmaceutically acceptable soluble salt of amoxicillin, amoxicillin trihydrate, or a mixture thereof. 40. A composition according to claim 1 wherein the amount of amoxicillin in the composition is from about 700 mg to about 2600 mg. 41. A composition according to claim 30 wherein the amount of amoxicillin in the composition is from about 700 mg to about 2600 mg. 42. A composition according to claim 1 wherein the amount of amoxicillin in the composition is from about 700 mg to about 1300 mg. 43. A composition according to claim 30 wherein the amount of amoxicillin in the composition is from about 700 mg to about 1300 mg. 44. A composition according to claim 37 wherein the amount of amoxicillin in the composition is from about 700 mg to about 1300 mg. 45. A composition according to claim 1 wherein the amount of amoxicillin in the composition is from about 950 mg to about 1300 mg. 46. A composition according to claim 33 wherein the amount of amoxicillin in the composition is from about 950 mg to about 1300 mg. 47. A composition according to claim 1 wherein the amount of amoxicillin in the composition is from about 1400 mg to about 2600 mg. 48. A composition according to claim 33 wherein the amount of amoxicillin in the composition is from about 1400 mg to about 2600 mg. 49. A composition according to claim 1 wherein the amount of amoxicillin in the composition is from about 1900 mg to about 2600 mg. 50. A composition according to claim 37 wherein the amount of amoxicillin in the composition is from about 1900 mg to about 2600 mg. 51. A composition according to claim 1 wherein the amount of amoxicillin in the composition is about 1000 mg or about 2000 mg. 52. A composition according to claim 39 wherein the amount of amoxicillin in the composition is about 1000 mg or about 2000 mg. 53. A composition according to claim 1 wherein the amount of amoxicillin in the composition is about 2000 mg. 54. A composition according to claim 1 wherein the amount of amoxicillin in the second release phase is from about 60% to about 80% by weight of the second release phase. 55. A composition according to claim 36 wherein the amount of amoxicillin in the second release phase is from about 60% to about 80% by weight of the second release phase. 56. A composition according to claim 44 wherein the amount of amoxicillin in the second release phase is from about 60% to about 80% by weight of the second release phase. 57. A composition according to claim 50 wherein the amount of amoxicillin in the second release phase is from about 60% to about 80% by weight of the second release phase. 58. A composition according to claim 1 wherein the amount of amoxicillin in the first release phase is about 563 mg+/-5% and the amount of amoxicillin in the second release phase is about 438 mg+/-5%. 59. A composition according to claim 19 wherein the amount of amoxicillin in the first release phase is about 563 mg+/-5% and the amount of amoxicillin in the second release phase is about 438 mg+/-5%. 60. A composition according to claim 34 wherein the amount of amoxicillin in the first release phase is about 563 mg+/-5% and the amount of amoxicillin in the second release phase is about 438 mg+/-5%. 61. A composition according to claim 37 wherein the amount of amoxicillin in the first release phase is about 563 mg+/-5% and the amount of amoxicillin in the second release phase is about 438 mg+/-5%. 62. A composition according to claim 1 wherein the composition comprises multiple dosage units. 63. A composition according to claim 41 wherein the composition comprises multiple dosage units. 64. A composition according to claim 47 wherein the composition comprises multiple dosage units. 65. A composition according to claim 41 wherein the amoxicillin is present in at least two of the multiple dosage units. 66. A composition according to claim 48 wherein the amoxicillin is present in at least two of the multiple dosage units. 67. A composition according to claim 62 wherein the amoxicillin is present in at least two of the multiple dosage units. 68. A composition according to claim 65 wherein the first release phase is in at least one dosage unit and the second release phase is in at least one other dosage unit. 69. A composition according to claim 37 wherein the first release phase is in at least one dosage unit and the second release phase is in at least one other dosage unit. 70. A composition according to claim 48 wherein the first release phase is in at least one dosage unit and the second release phase is in at least one other dosage unit. 71. A composition according to claim 56 wherein the first release phase is in at least one dosage unit and the second release phase is in at least one other dosage unit. 72. A composition according to claim 1 wherein the composition is in the form of a compressed tablet. 73. A composition according to claim 72 wherein the composition is in the form of a monolith tablet. 74. A composition according to claim 5 wherein the composition is in the form of a compressed tablet. 75. A composition according to claim 16 wherein the composition is in the form of a compressed tablet. 76. A composition according to claim 24 wherein the composition is in the form of a compressed tablet. 77. A composition according to claim 76 wherein the composition is in the form of a monolith tablet. 78. A composition according to claim 34 wherein the composition is in the form of a compressed tablet. 79. A composition according to claim 46 wherein the composition is in the form of a compressed tablet. 80. A composition according to claim 61 wherein the composition is in the form of a compressed tablet. 81. A composition according to claim 72 wherein the compressed tablet comprises at least two layers. 82. A composition according to claim 75 wherein the compressed tablet comprises at least two layers. 83. A composition according to claim 78 wherein the compressed tablet comprises at least two layers. 84. A composition according to claim 74 wherein all of the first release phase is in a first layer and all of the second release phase is in a second layer. 85. A composition according to claim 75 wherein all of the first release phase is in a first layer and all of the second release phase is in a second layer. 86. A composition according to claim 76 wherein all of the first release phase is in a first layer and all of the second release phase is in a second layer. 87. A composition according to claim 72 wherein the second release phase of the tablet further comprises at least one release retarding excipient which is selected from pH sensitive polymers, release-retarding polymers which exhibit swelling characteristics when in an aqueous environment, polymeric materials which exhibit gelling characteristics when in an aqueous environment, and polymeric materials which exhibit both swelling and gelling characteristics when in an aqueous environment. 88. A composition according to claim 87 wherein the at least one release retarding excipient is selected from methylcelluloses, carboxymethylcelluloses, low-molecular weight hydroxypropylmethylcelluloses, low-molecular weight polyvinylalcohols, polyoxyethyleneglycols, and noncross-linked polyvinylpyrrolidones. 89. A composition according to claim 16 wherein the second release phase of the tablet further comprises at least one release retarding excipient which is selected from pH sensitive polymers, release-retarding polymers which exhibit swelling characteristics when in an aqueous environment, polymeric materials which exhibit gelling characteristics when in an aqueous environment, and polymeric materials which exhibit both swelling and gelling characteristics when in an aqueous environment. 90. A composition according to claim 24 wherein the second release phase of the tablet further comprises at least one release retarding excipient which is selected from pH sensitive polymers, release-retarding polymers which exhibit swelling characteristics when in an aqueous environment, polymeric materials which exhibit gelling characteristics when in an aqueous environment, and polymeric materials which exhibit both swelling and gelling characteristics when in an aqueous environment. 91. A composition according to claim 34 wherein the second release phase of the tablet further comprises at least one release retarding excipient which is selected from pH sensitive polymers, release-retarding polymers which exhibit swelling characteristics when in an aqueous environment, polymeric materials which exhibit gelling characteristics when in an aqueous environment, and polymeric materials which exhibit both swelling and gelling characteristics when in an aqueous environment. 92. A composition according to claim 87 wherein the at least one release retarding excipient is xanthan gum. 93. A composition according to claim 89 wherein the at least one release retarding excipient is xanthan gum. 94. A composition according to claim 90 wherein the at least one release retarding excipient is xanthan gum. 95. A composition according to claim 91 wherein the at least one release retarding excipient is xanthan gum. 96. A composition according to claim 92 wherein the xanthan gum is present in an amount from about 0.5% to about 8% by weight of the second release phase. 97. A composition according to claim 94 wherein the xanthan gum is present in an amount from about 0.5% to about 8% by weight of the second release phase. 98. A composition according to claim 92 wherein the xanthan gum is pharmaceutical grade xanthan gum, 200 mesh. 99. A composition according to claim 94 wherein the xanthan gum is pharmaceutical grade xanthan gum, 200 mesh. 100. A composition according to claim 96 wherein the xanthan gum is pharmaceutical grade xanthan gum, 200 mesh. 101. A composition according to claim 1 wherein the pharmaceutically acceptable soluble salt of amoxicillin and the at least one pharmaceutically acceptable organic acid of the second release phase are admixed in intimate contact such that upon exposure to an aqueous environment they interact such that the rate of release of amoxicillin from the solid form of the second release phase is reduced compared to the rate of release of amoxicillin from the solid form of the first release phase. 102. A composition according to claim 25 wherein the sodium amoxicillin and the at least one pharmaceutically acceptable organic acid of the second release phase are admixed in intimate contact such that upon exposure to an aqueous environment they interact such that the rate of release of amoxicillin from the solid form of the second release phase is reduced compared to the rate of release of amoxicillin from the solid form of the first release phase. 103. A composition according to claim 34 wherein the sodium amoxicillin and the at least one pharmaceutically acceptable organic acid of the second release phase are admixed in intimate contact such that upon exposure to an aqueous environment they interact such that the rate of release of amoxicillin from the solid form of the second release phase is reduced compared to the rate of release of amoxicillin from the solid form of the first release phase. 104. A composition according to claim 1 wherein the in vitro dissolution rate profile of the composition is such that about 45% to about 65% of the total amoxicillin is dissolved within 30 minutes, as determined by the <711> Dissolution Test, Apparatus 2, provided in USP 23, 1995, in 900 mL of deionized water, at a paddle speed of 75 rpm. 105. A composition according to claim 34 wherein the in vitro dissolution rate profile of the composition is such that about 45% to about 65% of the total amoxicillin is dissolved within 30 minutes, as determined by the <711> Dissolution Test, Apparatus 2, provided in USP 23, 1995, in 900 mL of deionized water, at a paddle speed of 75 rpm. 106. A composition according to claim 1 wherein the in vitro dissolution rate profile of the composition is such that about 50% to about 75% of the total amoxicillin is dissolved within 60 minutes, as determined by the <711> Dissolution Test, Apparatus 2, provided in USP 23, 1995, in 900 mL of deionized water, at a paddle speed of 75 rpm. 107. A composition according to claim 1 wherein the in vitro dissolution rate profile of the composition is such that about 55% to about 85% of the total amoxicillin is dissolved within 120 minutes, as determined by the <711> Dissolution Test, Apparatus 2, provided in USP 23, 1995, in 900 mL of deionized water, at a paddle speed of 75 rpm. 108. A composition according to claim 1 wherein the in vitro dissolution rate profile of the composition is such that about 70% to about 95% of the total amoxicillin is dissolved within 180 minutes, as determined by the <711> Dissolution Test, Apparatus 2, provided in USP 23, 1995, in 900 mL of deionized water, at a paddle speed of 75 rpm. 109. A composition according to claim 1 wherein the in vitro dissolution rate profile of the composition is such that about 70% to about 100% of the total amoxicillin is dissolved within 240 minutes, as determined by the <711> Dissolution Test, Apparatus 2, provided in USP 23, 1995, in 900 mL of deionized water, at a paddle speed of 75 rpm. 110. A composition according to claim 1 wherein the in vitro dissolution rate profile of the composition is such that the amount of amoxicillin released over thirty minutes is in the range about 45% to about 65% of the total amoxicillin content, over sixty minutes is in the range about 50% to about 75% of the total amoxicillin content, over two hours is in the range about 55% to about 85% of the total amoxicillin content, over 180 minutes is in the range about 70% to about 95% of the total amoxicillin content and over 240 minutes is in the range about 70% to about 100% of the total amoxicillin content, as tested by the USP Dissolution Test, Apparatus 2, method at 37 degrees C., a paddle speed of 75 rpm and in 900 mL deionized water. 111. A composition according to claim 53 wherein, upon administration to a human, provides a mean maximum plasma concentration (C.sub.max) of amoxicillin of at least 12 ug/mL. 112. A composition according to claim 53 which, upon administration to a human, provides a mean maximum plasma concentration (C.sub.max) of amoxicillin of at least 16 ug/mL. 113. A composition according to claim 57 which, upon administration to a human, provides a mean plasma concentration of amoxicillin of at least 4 ug/mL for at least 4.4 hours. 114. A composition according to claim 111 which, upon administration to a human, provides a mean plasma concentration of amoxicillin of at least 4 ug/mL for at least 4.4 hours. 115. A composition according to claim 53 which, upon administration to a human, provides a mean plasma concentration of amoxicillin of at least 4 ug/mL for at least 4.8 hours. 116. A composition according to claim 115 which, upon administration to a human, provides a mean maximum plasma concentration (C.sub.max) of amoxicillin of at least 16 ug/mL. 117. A composition according to claim 53 which, upon administration to a human, provides an area under the curve (AUC) of the total amount of amoxicillin in the composition that is at least 80% of the corresponding dosage of amoxicillin taken as an immediate release formulation over the same dosage period. 118. A composition according to claim 53 which, upon administration to a human, provides an area under the curve (AUC) of the total amount of amoxicillin in the composition that is at least 90% of the corresponding dosage of amoxicillin taken as an immediate release formulation, over the same dosage period. 119. A composition according to claim 53 which, upon administration to a human, provides an area under the curve (AUC) of the total amount of amoxicillin in the composition that is at least 100% of the corresponding dosage of amoxicillin taken as an immediate release formulation over the same dosage period. 120. A composition according to claim 53 which, upon administration to a human, provides an area under the curve (AUC) of the total amount of amoxicillin in the composition that is at least 110% of the corresponding dosage of amoxicillin taken as an immediate release formulation over the same dosage period. 121. A composition according to claim 53 which, upon administration to a human, provides an area under the curve (AUC) of the total amount of amoxicillin in the composition that is at least 120% of the corresponding dosage of amoxicillin taken as an immediate release formulation over the same dosage period. 122. A composition according to claim 53 which provides, upon administration to a human, an AUC, C.sub.max, and T.sub.max substantially according to FIG. 5, profile A (Formulation VI). 123. A composition according to claim 4 which provides, upon administration to a human, an AUC, C.sub.max, and T>MIC at about the values according to FIG. 5, profile A (Formulation VI). 124. A composition according to claim 53 which provides, upon administration to a human, an AUC, C.sub.max, and T.sub.max substantially according to FIG. 5, profile B (Formulation VII). 125. A composition according to claim 53 which provides, upon administration to a human, an AUC, C.sub.max, and T>MIC at about the values according to FIG. 5, profile B (Formulation VII). 126. A composition according to claim 1 wherein the ratio of amoxicillin to organic acid in the second phase is about 1:1. 127. A composition according to claim 2 wherein the ratio of amoxicillin in the first release phase to amoxicillin in the second release phase is about 9:7. 128. A composition according to claim 126 wherein the ratio of amoxicillin in the first release phase to amoxicillin in the second release phase is about 9:7. 129. A composition according to claim 17 wherein the citric acid is citric acid anhydrous. 130. A composition according to claim 20 wherein the pharmaceutically acceptable soluble salt of amoxicillin is crystallized sodium amoxicillin. 131. A composition according to claim 1 wherein the amount of amoxicillin in the composition is in a unit dosage form of two tablets of about 1000 mg. 132. A composition in solid dosage form comprising amoxicillin and potassium clavulanate in a weight ratio of amoxicillin to potassium clavulanate from about 2:1 to about 20:1, the amount of amoxicillin is in the range of about 1950 to about 2550 mg; and the dosage regimen interval is about 12 hours, such that the amount of amoxicillin released over thirty minutes is in the range about 45% to about 65% of the total amoxicillin content, over sixty minutes is in the range about 50% to about 75% of the total amoxicillin content, over two hours is in the range about 55-% to about 85% of the total amoxicillin content, over 180 minutes is in the range about 70-% to about 95% of the total amoxicillin content and over 240 minutes is in the range about 70% to about 100% of the total amoxicillin content, as tested by the USP Dissolution Test, Apparatus 2, method at 37 degrees C., a paddle speed of 75 rpm and in 900 ml deionized water, over a period of 8 hours; and which provides a mean maximum plasma concentration (C.sub.max) that is at least 12 micrograms/ml and a mean time that the plasma concentration exceeds 4 micrograms/ml for at least 4.4 hours, when tested in a group of at least 7 healthy humans, based on blood sampling at half hourly intervals for the first two hours and thereafter at hourly intervals. 133. A composition in solid dosage form comprising amoxicillin and potassium clavulanate, such that the amount of amoxicillin is about 2000 mg and comprising a first release phase and a second release phase; the first release phase comprising potassium clavulanate and a first portion of the amoxicillin; the second release phase comprising a second portion of amoxicillin, which is a pharmaceutically acceptable soluble salt of amoxicillin, and at least one pharmaceutically acceptable organic acid which are admixed in intimate contact at a ratio of from about 20:1 to about 1:2; such that the weight ratio of amoxicillin to potassium clavulanate is from about 2:1 to about 20:1, and the solid dosage is administered at a regimen interval of about 12 hours, and wherein the solid dosage is such that the amount of amoxicillin released over thirty minutes is in the range about 45% to about 65% of the total amoxicillin content, over sixty minutes is in the range about 50% to about 75% of the total amoxicillin content, over two hours is in the range about 55-% to about 85% of the total amoxicillin content, over 180 minutes is in the range about 70-% to about 95% of the total amoxicillin content and over 240 minutes is in the range about 70% to about 100% of the total amoxicillin content, as tested by the USP Dissolution Test, Apparatus 2, method at 37 degrees C., a paddle speed of 75 rpm and in 900 ml deionized water, over a period of 8 hours; and which provides a mean maximum plasma concentration (C.sub.max) that is at least 12 micrograms/ml and a mean time that the plasma concentration exceeds 4 micrograms/ml for at least 4.4 hours, when tested in a group of at least 7 healthy humans, based on blood sampling at half hourly intervals for the first two hours and thereafter at hourly intervals.