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

1 . A method for treating a bacterial infection in a human in need thereof, which method comprises administering to said human a dosage of about 2000 mg of amoxycillin and about 125 mg of potassium clavulanate, wherein the dosage is delivered from a modified release formulation which provides a mean maximum plasma concentration (C max ) of amoxicillin of at least 12 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, and a mean plasma concentration of amoxicillin of at least 4 μg/mL for at least 4.4 hours.  
     
     
         2 - 67  (cancelled)  
     
     
         68 . The method of  claim 1  wherein the modified release formulation further provides for immediate release of the potassium clavulanate.  
     
     
         69 . The method according to  claim 68  wherein the formulation provides a mean plasma concentration of amoxycillin of 4 μg/mL for at least 4.6 hours.  
     
     
         70 . The method according to  claim 68  wherein the formulation provides a mean plasma concentration of amoxycillin of 4 μg/mL for at least 4.8 hours and a mean maximum plasma concentration (C max ) of amoxycillin of at least 16 μg/mL.  
     
     
         71 . The method according to  claim 68  wherein the formulation provides a mean plasma concentration of amoxycillin of 8 μg/mL for at least 4.4 hours.  
     
     
         72 . The method according to  claim 68  wherein the formulation provides a mean plasma concentration of amoxycillin of 8 μg/mL for at least 4.8 hours.  
     
     
         73 . The method according to  claim 68  wherein the formulation provides a mean maximum plasma concentration (C max ) of amoxycillin of at least 16 μg/mL.  
     
     
         74 . The method according to  claim 68  wherein the bacterial infection is caused by at least one of the organisms  S. pneumoniae, H. influenzae , and  M. catarrhalis.    
     
     
         75 . The method according to  claim 74  wherein the  S. pneumoniae  organism is drug resistant and penicillin resistant.  
     
     
         76 . The method according to  claim 74  wherein the bacterial infection is a respiratory tract infection.  
     
     
         77 . The method according to  claim 76  wherein the respiratory tract infection is community acquired pneumoniae (CAP), acute exacerbation of chronic bronchitis (AECB) or acute bacterial sinusitis (ABS).  
     
     
         78 . The method according to  claim 68  which further provides a dosage regimen administered over a period of 7 to 14 days.  
     
     
         79 . The method according to  claim 68  wherein the dosage is provided by two tablets each comprising about 1000/62.5 mg amoxycillin/potassium clavulanate, or four tablets of about 500/32.25 mg amoxycillin/potassium clavulanate.  
     
     
         80 . The method according to  claim 68  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.  
     
     
         81 . The method according to  claim 80  wherein the amoxycillin in the immediate release phase is amoxycillin trihydrate or a sodium amoxycillin or a combination thereof.  
     
     
         82 . The method according to  claim 80  wherein the amoxycillin in the slow release phase is sodium amoxycillin.  
     
     
         83 . The method according to  claim 82  wherein the sodium amoxycillin is crystallized sodium amoxycillin.  
     
     
         84 . The method according to  claim 68  comprising two tablets of about 1000 mg±5% amoxycillin and about 62.5 mg±5% potassium clavulanate, wherein an immediate release phase comprises about 563 mg±5% amoxycillin and about 62.5 mg±5% of potassium clavulanate, and a slow release phase comprises about 438 mg±5% of amoxycillin.  
     
     
         85 . 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 min, measured in <711> dissolution test, Apparatus 2, USP 23, 1995, at 37.0±0.5° C., using deionised water (900 mL) and a paddle speed of 75 rpm.  
     
     
         86 . The method according to  claim 85  wherein about 50% to about 75% of the amoxycillin content is dissolved within 60 minutes.  
     
     
         87 . The method according to  claim 85  wherein about 55% to about 85% of the amoxycillin content is dissolved within 120 minutes.  
     
     
         88 . The method according to  claim 85  wherein about 70% to about 95% of the amoxycillin content is dissolved within 180 minutes.  
     
     
         89 . The method according to  claim 85  wherein about 70% to about 100% of the amoxycillin content is dissolved within 240 minutes.  
     
     
         90 . The method according to  claim 89  wherein about 75% to about 100% of the amoxycillin content is dissolved within 240 minutes.  
     
     
         91 . The method according to  claim 85  wherein the formulation provides a mean plasma concentration of amoxycillin of 4 μg/mL for at least 4.4 hours.  
     
     
         92 . The method according to  claim 85  wherein the formulation provides a mean plasma concentration of amoxycillin of 4 μg/mL for at least 4.6 hours.  
     
     
         93 . The method according to  claim 85  wherein the formulation provides a mean plasma concentration of amoxycillin of 4 μg/mL for at least 4.8 hours.  
     
     
         94 . The method according to  claim 85  wherein the formulation provides a mean maximum plasma concentration (C max ) of amoxycillin of at least 12 μg/mL.  
     
     
         95 . The method according to  claim 85  wherein the formulation provides a mean maximum plasma concentration (C max ) of amoxycillin of at least 16 μg/mL.  
     
     
         96 . The method according to  claim 85  wherein the formulation provides a mean maximum plasma concentration (C max ) of amoxycillin of at least 12 μg/mL, and a mean plasma concentration of amoxicillin of at least 4 μg/mL for at least 4.4 hours.  
     
     
         97 . The method according to  claim 96  wherein the formulation provides 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.  
     
     
         98 . The method according to  claim 85  wherein the bacterial infection is caused by at least one of the organisms  S. pneumoniae, H. influenzae , and  M. catarrhalis.    
     
     
         99 . The method according to  claim 98  wherein the  S. pneumoniae  organism is drug resistant and penicillin resistant.  
     
     
         100 . The method according to  claim 98  wherein the bacterial infection is a respiratory tract infection.  
     
     
         101 . The method according to  claim 100  wherein the respiratory tract infection is community acquired pneumoniae (CAP), acute exacerbation of chronic bronchitis (AECB) or acute bacterial sinusitis (ABS).  
     
     
         102 . The method according to  claim 85  which further provides a dosage regimen administered over a period of 7 to 14 days.  
     
     
         103 . A method for 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 provides a mean maximum plasma concentration (C max ) of amoxicillin of at least 16 μg/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, and a mean plasma concentration of amoxicillin of at least 4 μg/mL for at least 4.4 hours, and which further provides for immediate release of the potassium clavulanate.  
     
     
         104 . The method according to  claim 103  wherein the formulation provides an AUC of at least 90%.  
     
     
         105 . The method according to  claim 103  wherein the formulation provides an AUC of at least 100%.  
     
     
         106 . The method according to  claim 103  wherein the formulation provides an AUC of at least 110%.  
     
     
         107 . The method according to  claim 103  wherein the formulation provides an AUC of at least 120%.  
     
     
         108 . The method according to  claim 103  wherein the formulation provides a mean plasma concentration of amoxicillin of at least 4 μg/mL for at least 4.6 hours.  
     
     
         109 . The method according to  claim 103  wherein the formulation provides a mean plasma concentration of amoxicillin of at least 4 μg/mL for at least 4.8 hours.  
     
     
         110 . The method according to  claim 103  wherein the formulation provides a mean plasma concentration of amoxicillin of at least 4 μg/mL for at least 6 hours.  
     
     
         111 . The method according to  claim 103  wherein the formulation provides a mean plasma concentration of amoxicillin of at least 8 μg/mL for at least 4.4 hours.  
     
     
         112 . The method according to  claim 103  wherein the formulation provides a mean plasma concentration of amoxicillin of at least 8 μg/mL for at least 4.8 hours.  
     
     
         113 . The method according to  claim 103  wherein the bacterial infection is caused by at least one of the organisms  S. pneumoniae, H. influenzae , and  M. catarrhalis.    
     
     
         114 . The method according to  claim 113  wherein the  S. pneumoniae  organism is drug resistant and penicillin resistant.  
     
     
         115 . The method according to  claim 113  wherein the bacterial infection is a respiratory tract infection.  
     
     
         116 . The method according to  claim 115  wherein the respiratory tract infection is community acquired pneumoniae (CAP), acute exacerbation of chronic bronchitis (AECB) or acute bacterial sinusitis (ABS).  
     
     
         117 . The method according to  claim 103  which further provides a dosage regimen administered over a period of 7 to 14 days.  
     
     
         118 . A method for 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 biphasic modified release formulation, which provides a mean maximum plasma concentration (C max ) of amoxicillin of at least 12 μg/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, and a mean plasma concentration of amoxicillin of at least 4 μg/mL for at least 4.2 hours, and which further provides for immediate release of the potassium clavulanate.  
     
     
         119 . The method according to  claim 118  wherein the formulation provides a mean plasma concentration of amoxycillin of 4 μg/mL for at least 4.6 hours.  
     
     
         120 . The method according to  claim 118  wherein the formulation provides a mean plasma concentration of amoxycillin of 4 μg/mL for at least 4.8 hours.  
     
     
         121 . The method according to  claim 118  wherein the formulation provides a mean plasma concentration of amoxicillin of at least 4 μg/mL for at least 6 hours.  
     
     
         122 . The method according to  claim 118  wherein the formulation provides a mean plasma concentration of amoxicillin of at least 8 μg/mL for at least 4.4 hours.  
     
     
         123 . The method according to  claim 118  wherein the formulation provides a mean plasma concentration of amoxicillin of at least 8 μg/mL for at least 4.8 hours.  
     
     
         124 . The method according to  claim 118  wherein the formulation provides a mean maximum plasma concentration (C max ) of amoxycillin of at least 16 μg/mL.  
     
     
         125 . The method according to  claim 118  wherein the formulation provides an AUC of at least 90%.  
     
     
         126 . The method according to  claim 118  wherein the formulation provides an AUC of at least 100%.  
     
     
         127 . The method according to  claim 118  wherein the formulation provides an AUC of at least 110%.  
     
     
         128 . The method according to  claim 118  wherein the formulation provides an AUC of at least 120%.  
     
     
         129 . The method according to  claim 118  wherein the bacterial infection is caused by at least one of the organisms  S. pneumoniae, H. influenzae , and  M. catarrhalis.    
     
     
         130 . The method according to  claim 129  wherein the  S. pneumoniae  organism is drug resistant and penicillin resistant.  
     
     
         131 . The method according to  claim 129  wherein the bacterial infection is a respiratory tract infection.  
     
     
         132 . The method according to  claim 131  wherein the respiratory tract infection is community acquired pneumoniae (CAP), acute exacerbation of chronic bronchitis (AECB) or acute bacterial sinusitis (ABS).  
     
     
         133 . The method according to  claim 118  which provides a dosage regimen administered over a period of 7 to 14 days.  
     
     
         134 . The method according to  claim 118  wherein the dosage is provided by two tablets each comprising about 1000/62.5 mg amoxycillin/potassium clavulanate, or four tablets of about 500/32.25 mg amoxycillin/potassium clavulanate.  
     
     
         135 . The method according to  claim 118  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.  
     
     
         136 . A method for 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 biphasic modified release formulation, which provides a mean maximum plasma concentration (C max ) of amoxicillin of about 17.4 μg/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, and a mean plasma concentration of amoxicillin of 4 μg/mL for at least 6 hours, and which further provides for immediate release of the potassium clavulanate.  
     
     
         137 . The method according to  claim 136  wherein the formulation provides an AUC of at least 80% of the value displayed by the biphasic formulation.  
     
     
         138 . The method according to  claim 136  wherein the formulation provides an AUC of at least 90% of the value displayed by the biphasic formulation.  
     
     
         139 . The method according to  claim 136  wherein the formulation provides an AUC of at least 100% of the value displayed by the biphasic formulation.  
     
     
         140 . The method according to  claim 136  wherein the formulation provides an AUC of at least 110% of the value displayed by the biphasic formulation.  
     
     
         141 . The method according to  claim 136  wherein the formulation provides an AUC of at least 120% of the value displayed by the biphasic formulation.  
     
     
         142 . The method according to  claim 136  wherein the biphasic modified release formulation comprises an immediate release of amoxicillin and a modified release of amoxicillin.  
     
     
         143 . The method according to  claim 142  wherein the amoxycillin in the modified release phase is sodium amoxycillin.  
     
     
         144 . The method according to  claim 143  wherein the sodium amoxycillin is crystallized sodium amoxycillin.  
     
     
         145 . The method according to  claim 142  wherein the amoxycillin in the immediate release phase is amoxycillin trihydrate.  
     
     
         146 . The method according to  claim 136  wherein the formulation provides a pharmacokinetic plasma profile for amoxycillin substantially as shown in FIG. 5, formulation A.  
     
     
         147 . The method according to  claim 136  comprising two tablets of about 1000 mg±5% amoxycillin and about 62.5 mg±5% potassium clavulanate, wherein an immediate release phase comprises about 563 mg±5% amoxycillin and about 62.5 mg±5% of potassium clavulanate, and a slow release phase comprises about 438 mg±5% of amoxycillin.  
     
     
         148 . The method according to  claim 136  wherein the bacterial infection is caused by at least one of the organisms  S. pneumoniae, H. influenzae , and  M. catarrhalis.    
     
     
         149 . The method according to  claim 148  wherein the  S. pneumoniae  organism is drug resistant and penicillin resistant.  
     
     
         150 . The method according to  claim 148  wherein the bacterial infection is a respiratory tract infection.  
     
     
         151 . The method according to  claim 150  wherein the respiratory tract infection is community acquired pneumoniae (CAP), acute exacerbation of chronic bronchitis (AECB) or acute bacterial sinusitis (ABS).  
     
     
         152 . The method according to  claim 136  which provides a dosage regimen administered over a period of 7 to 14 days.