Method of Providing Sustained Analgesia With Buprenorphine

Abstract

A method of effectively treating pain in humans is achieved by administering buprenorphine in accordance with first order kinetics over an initial three-day dosing interval, such that a maximum plasma concentration from about 20 pg/ml to about 1052 pg/ml is attained, and thereafter maintaining the administration of buprenorphine for at least an additional two-day dosing interval in accordance with substantially zero order kinetics, such that the patients experience analgesia throughout the at least two-day additional dosing interval.

1 - 67 . (canceled) 
     
     
         68 . A method of treating pain in a human patient, comprising
 administering buprenorphine base transdermally to said human patient by applying a transdermal delivery system to the skin of a patient, and maintaining said transdermal delivery system in contact with the patient's skin for a seven day dosing interval, said transdermal delivery system maintaining a mean relative release rate of from about 3 ug/hr to about 86 ug/hr and providing a substantially first order plasma level increase of buprenorphine from the initiation of the dosing interval until about 72 hours after the initiation of the dosing interval; and a mean relative release rate of about 0.3 ug/hr to about 9 ug/hr and providing a substantially zero order plasma level fluctuation of buprenorphine from about 72 hours after the initiation of the dosing interval until the end of the seven-day dosing interval, such that the following mean plasma concentrations are achieved:   a mean plasma concentration from about 0.3 to about 113 pg/ml at about 6 hours after initiation of the dosing interval;   a mean plasma concentration from about 3 to about 296 pg/ml at about 12 hours after initiation of the dosing interval;   a mean plasma concentration from about 7 to about 644 pg/ml at about 24 hours after initiation of the dosing interval;   a mean plasma concentration from about 13 to about 753 pg/ml at about 36 hours after initiation of the dosing interval;   a mean plasma concentration from about 16 to about 984 pg/ml at about 48 hours after initiation of the dosing interval;   a mean plasma concentration from about 20 to about 984 pg/ml at about 60 hours after initiation of the dosing interval;   a mean plasma concentration from about 21 to about 1052 pg/ml at about 72 hours after initiation of the dosing interval;   a mean plasma concentration from about 23 to about 1052 pg/ml at about 96 hours after initiation of the dosing interval;   a mean plasma concentration from about 23 to about 1052 pg/ml at about 120 hours after initiation of the dosing interval;   a mean plasma concentration from about 22 to about 970 pg/ml at about 144 hours after initiation of the dosing interval; and   a mean plasma concentration from about 19 to about 841 pg/ml at about 168 hours after initiation of the dosing interval.   
     
     
         69 . The method of  claim 68  wherein the Tmax occurs from about 3 to about 5 days after application of the transdermal delivery system. 
     
     
         70 . The method of  claim 68  wherein the transdermal delivery system comprises an adhesive reservoir layer comprising the buprenorphine base. 
     
     
         71 . The method of  claim 70  wherein the adhesive reservoir layer comprises about 10 to about 98 weight percent polymeric material, about 0.1 to about 40 weight percent softener and about 0.1 to about 30 weight percent buprenorphine base. 
     
     
         72 . The method of  claim 71  wherein the adhesive reservoir layer further comprises about 0.1 to about 30 weight percent of solvent for the buprenorphine base. 
     
     
         73 . The method of  claim 70  wherein the adhesive reservoir layer comprises about 10 weight percent buprenorphine base, about 10 to about 15 weight percent acid, about 10 weight percent softener, about 55 to about 70 weight percent polyacrylate and 0 to about 10 weight percent polyvinylpyrrolidone. 
     
     
         74 . The method of  claim 73  wherein the acid is levulinic acid. 
     
     
         75 . The method of  claim 74  wherein the softener is oleyl oleate. 
     
     
         76 . A method of treating pain in a human patient, comprising
 administering buprenorphine base transdermally to said human patient for a seven day dosing interval such that mean relative release rates are achieved over the dosing interval as follows:   a mean relative release rate of from about 3 ug/hr to about 86 ug/hr from the initiation of the dosing interval until about 72 hours after the initiation of the dosing interval; and   a mean relative release rate of about 0.3 ug/hr to about 9 ug/hr from about 72 hours after the initiation of the dosing interval until the end of the seven day dosing interval.   
     
     
         77 . The method of  claim 76  wherein the Tmax occurs from about 3 to about 5 days after application of the transdermal delivery system. 
     
     
         78 . The method of  claim 76  wherein the transdermal delivery system comprises an adhesive reservoir layer comprising the buprenorphine base. 
     
     
         79 . The method of  claim 78  wherein the adhesive reservoir layer comprises about 10 to about 98 weight percent polymeric material, about 0.1 to about 40 weight percent softener and about 0.1 to about 30 weight percent buprenorphine base. 
     
     
         80 . The method of  claim 79  wherein the adhesive reservoir layer further comprises about 0.1 to about 30 weight percent of solvent for the buprenorphine base. 
     
     
         81 . The method of  claim 78  wherein the adhesive reservoir layer comprises about 10 weight percent buprenorphine base, about 10 to about 15 weight percent acid, about 10 weight percent softener, about 55 to about 70 weight percent polyacrylate and 0 to about 10 weight percent polyvinylpyrrolidone. 
     
     
         82 . The method of  claim 82  wherein the acid is levulinic acid. 
     
     
         83 . The method of  claim 83  wherein the softener is oleyl oleate. 
     
     
         84 . A method of treating pain in a human patient, comprising
 applying a transdermal delivery system containing buprenorphine base as the active ingredient onto the skin of said human patient to provide a substantially first order plasma level increase of buprenorphine over a first three-day dosing interval, such that a mean plasma concentration from about 21 to about 1052 pg/ml is attained about 72 hours after application of said transdermal delivery system; and maintaining said transdermal delivery system on the skin of said human patient for an additional four-day dosing interval, such that a mean relative release rate from about 0.3 μg/hr to about 9 μg/hr is maintained over said four-day additional dosing interval and said transdermal delivery system provides a therapeutic effect to said human patient throughout the four-day additional dosing interval.   
     
     
         85 . The method of  claim 84  wherein the Tmax occurs from about 3 to about 5 days after application of the transdermal delivery system. 
     
     
         86 . The method of  claim 84  wherein the transdermal delivery system comprises an adhesive reservoir layer comprising the buprenorphine base. 
     
     
         87 . The method of  claim 86  wherein the adhesive reservoir layer comprises about 10 to about 98 weight percent polymeric material, about 0.1 to about 40 weight percent softener and about 0.1 to about 30 weight percent buprenorphine base. 
     
     
         88 . The method of  claim 87  wherein the adhesive reservoir layer further comprises about 0.1 to about 30 weight percent of solvent for the buprenorphine base. 
     
     
         89 . The method of  claim 86  wherein the adhesive reservoir layer comprises about 10 weight percent buprenorphine base, about 10 to about 15 weight percent acid, about 10 weight percent softener, about 55 to about 70 weight percent polyacrylate and 0 to about 10 weight percent polyvinylpyrrolidone. 
     
     
         90 . The method of  claim 89  wherein the acid is levulinic acid. 
     
     
         91 . The method of  claim 90  wherein the softener is oleyl oleate. 
     
     
         92 . A method of treating pain in a human patient, comprising
 applying a transdermal delivery system containing buprenorphine base onto the skin of said human patient to provide a first order release rate of buprenorphine over a three-day dosing interval, such that a maximum buprenorphine plasma concentration from about 20 pg/ml to about 1052 pg/ml is attained, and   maintaining said transdermal delivery system on the skin of said human patient for an additional four-day dosing interval during which said transdermal delivery system provides substantially zero order kinetics, such that said transdermal delivery system provides a therapeutic effect to said human patient throughout the four-day additional dosing interval.   
     
     
         93 . The method of  claim 92  wherein the Tmax occurs from about 3 to about 5 days after application of the transdermal delivery system. 
     
     
         94 . The method of  claim 92  wherein the transdermal delivery system comprises an adhesive reservoir layer comprising the buprenorphine base. 
     
     
         95 . The method of  claim 94  wherein the adhesive reservoir layer comprises about 10 to about 98 weight percent polymeric material, about 0.1 to about 40 weight percent softener and about 0.1 to about 30 weight percent buprenorphine base. 
     
     
         96 . The method of  claim 95  wherein the adhesive reservoir layer further comprises about 0.1 to about 30 weight percent of solvent for the buprenorphine base. 
     
     
         97 . The method of  claim 94  wherein the adhesive reservoir layer comprises about 10 weight percent buprenorphine base, about 10 to about 15 weight percent acid, about 10 weight percent softener, about 55 to about 70 weight percent polyacrylate and 0 to about 10 weight percent polyvinylpyrrolidone. 
     
     
         98 . The method of  claim 97  wherein the acid is levulinic acid. 
     
     
         99 . The method of  claim 98  wherein the softener is oleyl oleate. 
     
     
         100 . A method of treating a human patient suffering from moderate to severe pain by applying a transdermal delivery system containing an active ingredient, wherein the active ingredient consists essentially of buprenorphine base, onto the skin of the human patient and maintaining the transdermal delivery system in contact with the skin for a 3 day dosing interval, the transdermal delivery system containing an amount of buprenorphine sufficient to maintain an adequate relative release rate to provide a therapeutic effect in the patient for approximately only 3 days, comprising maintaining the transdermal delivery system in contact with the human patient's skin for 4 additional days beyond said 3 day dosing interval, such that the human patient continues to receive a therapeutic effect from said transdermal buprenorphine delivery system. 
     
     
         101 . The method of  claim 100 , wherein the active ingredient consists of buprenorphine base. 
     
     
         102 . The method of  claim 100  wherein the Tmax occurs from about 3 to about 5 days after application of the transdermal delivery system. 
     
     
         103 . The method of  claim 100  wherein the transdermal delivery system comprises an adhesive reservoir layer comprising the buprenorphine base. 
     
     
         104 . The method of  claim 103  wherein the adhesive reservoir layer comprises about 10 to about 98 weight percent polymeric material, about 0.1 to about 40 weight percent softener and about 0.1 to about 30 weight percent buprenorphine base. 
     
     
         105 . The method of  claim 104  wherein the adhesive reservoir layer further comprises about 0.1 to about 30 weight percent of solvent for the buprenorphine base. 
     
     
         106 . The method of  claim 103  wherein the adhesive reservoir layer comprises about 10 weight percent buprenorphine base, about 10 to about 15 weight percent acid, about 10 weight percent softener, about 55 to about 70 weight percent polyacrylate and 0 to about 10 weight percent polyvinylpyrrolidone. 
     
     
         107 . The method of  claim 106  wherein the acid is levulinic acid. 
     
     
         108 . The method of  claim 107  wherein the softener is oleyl oleate. 
     
     
         109 . A method of treating pain in a human patient comprising transdermally administering an active ingredient, wherein the active ingredient comprises an opioid base, to said human patient by applying a transdermal delivery system comprising an opioid base to the skin of a patient, and maintaining said transdermal delivery system in contact with the skin of said patient for 7 days, said transdermal delivery system providing a substantially first order plasma level increase of said opioid from the initiation of the dosing interval until about 72 hours after the initiation of the dosing interval and providing a substantially zero order plasma level fluctuation of said opioid from about 72 hours after the initiation of the dosing interval until the end of the seven-day dosing interval. 
     
     
         110 . The method of  claim 109  wherein the Tmax occurs from about 3 to about 5 days after application of the transdermal delivery system. 
     
     
         111 . The method of  claim 110  wherein the transdermal delivery system comprises an adhesive reservoir layer comprising the opioid base. 
     
     
         112 . The method of  claim 111  wherein the opioid base is buprenorphine base. 
     
     
         113 . The method of  claim 112  wherein the adhesive reservoir layer comprises about 10 to about 98 weight percent polymeric material, about 0.1 to about 40 weight percent softener and about 0.1 to about 30 weight percent buprenorphine base. 
     
     
         114 . The method of  claim 113  wherein the adhesive reservoir layer further comprises about 0.1 to about 30 weight percent of solvent for the buprenorphine base. 
     
     
         115 . The method of  claim 112  wherein the adhesive reservoir layer comprises about 10 weight percent buprenorphine base, about 10 to about 15 weight percent acid, about 10 weight percent softener, about 55 to about 70 weight percent polyacrylate and 0 to about 10 weight percent polyvinylpyrrolidone. 
     
     
         116 . The method of  claim 115  wherein the acid is levulinic acid. 
     
     
         117 . The method of  claim 116  wherein the softener is oleyl oleate. 
     
     
         118 . The method of  claim 112  wherein the active ingredient consists essentially of buprenorphine base. 
     
     
         119 . The method of  claim 118  wherein the adhesive reservoir layer comprises about 10 to about 98 weight percent polymeric material, about 0.1 to about 40 weight percent softener and about 0.1 to about 30 weight percent buprenorphine base. 
     
     
         120 . The method of  claim 119  wherein the adhesive reservoir layer further comprises about 0.1 to about 30 weight percent of solvent for the buprenorphine base. 
     
     
         121 . The method of  claim 118  wherein the adhesive reservoir layer comprises about 10 weight percent buprenorphine base, about 10 to about 15 weight percent acid, about 10 weight percent softener, about 55 to about 70 weight percent polyacrylate and 0 to about 10 weight percent polyvinylpyrrolidone. 
     
     
         122 . The method of  claim 121  wherein the acid is levulinic acid. 
     
     
         123 . The method of  claim 122  wherein the softener is oleyl oleate. 
     
     
         124 . The method of  claim 112  wherein the active ingredient consists of buprenorphine base. 
     
     
         125 . The method of  claim 124  wherein the adhesive reservoir layer comprises about 10 to about 98 weight percent polymeric material, about 0.1 to about 40 weight percent softener and about 0.1 to about 30 weight percent buprenorphine base. 
     
     
         126 . The method of  claim 125  wherein the adhesive reservoir layer further comprises about 0.1 to about 30 weight percent of solvent for the buprenorphine base. 
     
     
         127 . The method of  claim 124  wherein the adhesive reservoir layer comprises about 10 weight percent buprenorphine base, about 10 to about 15 weight percent acid, about 10 weight percent softener, about 55 to about 70 weight percent polyacrylate and 0 to about 10 weight percent polyvinylpyrrolidone. 
     
     
         128 . The method of  claim 127  wherein the acid is levulinic acid. 
     
     
         129 . The method of  claim 128  wherein the softener is oleyl oleate. 
     
     
         130 . A method of effectively treating pain in a human patient, comprising
 administering buprenorphine base transdermally to said human patient by applying a transdermal delivery system to the skin of a patient, and maintaining said transdermal delivery system in contact with the patient's skin for 7 days, such that the following mean plasma concentrations are achieved over a 168 hour dosing interval:   a mean plasma concentration from about 0.3 to about 113 pg/ml at about 6 hours after initiation of the dosing interval;   a mean plasma concentration from about 3 to about 296 pg/ml at about 12 hours after initiation of the dosing interval;   a mean plasma concentration from about 7 to about 644 pg/ml at about 24 hours after initiation of the dosing interval;   a mean plasma concentration from about 13 to about 753 pg/ml at about 36 hours after initiation of the dosing interval;   a mean plasma concentration from about 16 to about 984 pg/ml at about 48 hours after initiation of the dosing interval;   a mean plasma concentration from about 20 to about 984 pg/ml at about 60 hours after initiation of the dosing interval;   a mean plasma concentration from about 21 to about 1052 pg/ml at about 72 hours after initiation of the dosing interval;   a mean plasma concentration from about 23 to about 1052 pg/ml at about 96 hours after initiation of the dosing interval;   a mean plasma concentration from about 23 to about 1052 pg/ml at about 120 hours after initiation of the dosing interval;   a mean plasma concentration from about 22 to about 970 pg/ml at about 144 hours after initiation of the dosing interval; and   a mean plasma concentration from about 19 to about 841 pg/ml at about 168 hours after initiation of the dosing interval.   
     
     
         131 . The method of  claim 130 , further comprising maintaining a mean relative release rate from about 3 ug/hr to about 86 ug/hr from the initiation of the 168 hour dosing interval until about 72 hours after the initiation of the dosing interval; and a mean relative release rate from about 0.3 ug/hr to about 9 ug/hr from about 72 hours after the initiation of the dosing interval until the end of dosing interval. 
     
     
         132 . The method of  claim 130  wherein the Tmax occurs from about 3 to about 5 days after application of the transdermal delivery system. 
     
     
         133 . The method of  claim 132  wherein the transdermal delivery system comprises an adhesive reservoir layer comprising the buprenorphine base. 
     
     
         134 . The method of  claim 133  wherein the adhesive reservoir layer comprises about 10 to about 98 weight percent polymeric material, about 0.1 to about 40 weight percent softener and about 0.1 to about 30 weight percent buprenorphine base. 
     
     
         135 . The method of  claim 134  wherein the adhesive reservoir layer further comprises about 0.1 to about 30 weight percent of solvent for the buprenorphine base. 
     
     
         136 . The method of  claim 133  wherein the adhesive reservoir layer comprises about 10 weight percent buprenorphine base, about 10 to about 15 weight percent acid, about 10 weight percent softener, about 55 to about 70 weight percent polyacrylate and 0 to about 10 weight percent polyvinylpyrrolidone. 
     
     
         137 . The method of  claim 136  wherein the acid is levulinic acid. 
     
     
         138 . The method of  claim 137  wherein the softener is oleyl oleate. 
     
     
         139 . The method of  claim 130  wherein the active ingredient consists essentially of buprenorphine base. 
     
     
         140 . The method of  claim 139  wherein the Tmax occurs from about 3 to about 5 days after application of the transdermal delivery system. 
     
     
         141 . The method of  claim 140  wherein the transdermal delivery system comprises an adhesive reservoir layer comprising the buprenorphine base. 
     
     
         142 . The method of  claim 141  wherein the adhesive reservoir layer comprises about 10 to about 98 weight percent polymeric material, about 0.1 to about 40 weight percent softener and about 0.1 to about 30 weight percent buprenorphine base. 
     
     
         143 . The method of  claim 142  wherein the adhesive reservoir layer further comprises about 0.1 to about 30 weight percent of solvent for the buprenorphine base. 
     
     
         144 . The method of  claim 141  wherein the adhesive reservoir layer comprises about 10 weight percent buprenorphine base, about 10 to about 15 weight percent acid, about 10 weight percent softener, about 55 to about 70 weight percent polyacrylate and 0 to about 10 weight percent polyvinylpyrrolidone. 
     
     
         145 . The method of  claim 144  wherein the acid is levulinic acid. 
     
     
         146 . The method of  claim 145  wherein the softener is oleyl oleate. 
     
     
         147 . The method of  claim 130  wherein the active ingredient consists of buprenorphine base. 
     
     
         148 . The method of  claim 147  wherein the Tmax occurs from about 3 to about 5 days after application of the transdermal delivery system. 
     
     
         149 . The method of  claim 148  wherein the transdermal delivery system comprises an adhesive reservoir layer comprising the buprenorphine base. 
     
     
         150 . The method of  claim 149  wherein the adhesive reservoir layer comprises about 10 to about 98 weight percent polymeric material, about 0.1 to about 40 weight percent softener and about 0.1 to about 30 weight percent buprenorphine base. 
     
     
         151 . The method of  claim 150  wherein the adhesive reservoir layer further comprises about 0.1 to about 30 weight percent of solvent for the buprenorphine base. 
     
     
         152 . The method of  claim 149  wherein the adhesive reservoir layer comprises about 10 weight percent buprenorphine base, about 10 to about 15 weight percent acid, about 10 weight percent softener, about 55 to about 70 weight percent polyacrylate and 0 to about 10 weight percent polyvinylpyrrolidone. 
     
     
         153 . The method of  claim 152  wherein the acid is levulinic acid. 
     
     
         154 . The method of  claim 153  wherein the softener is oleyl oleate.