Local anesthetic, and method of use

A method for providing local analgesia, local anesthesia or nerve blockade in a human comprising administering at a site in a human a unit dose of microspheres comprising a biocompatible, biodegradable carrier and bupivacaine or a pharmaceutically acceptable salt thereof, effective to provide local analgesia, local anesthesia or nerve blockade at the site of administration in a human which occurs less than about 2 hours after first administration, and a duration of local analgesia, local anesthesia or nerve blockade which lasts for at least about 1 day after first administration, wherein the mean Cmax of bupivacaine measured by microdialysis in the tissue at the site is from about 35,000 ng/ml to below a toxic concentration at the site and wherein a level of local anesthetic at the site of administration is at least 150 times the level of said local anesthetic which is absorbed systemically into blood plasma.

A method for providing local analgesia, local anesthesia or nerve blockade in a human, comprising administering a unit dose of microspheres comprising a biocompatible, biodegradable carrier and bupivacaine or a pharmaceutically acceptable salt thereof, effective to provide local analgesia, local anesthesia or nerve blockade at a site of administration in a human which occurs less than about 2 hours after first administration, and a duration of local analgesia, local anesthesia or nerve blockade which lasts for at least about 1 day after first administration, wherein the mean Tmax of bupivacaine at the tissue at the site occurs at a time point from about 10 hours to about 45 hours after first administration.

A pharmaceutical formulation comprising a plurality of controlled release microspheres comprising bupivacaine free base and a biocompatible, biodegradable polymer comprising a 65:35 DL copolymer of lactic and glycolic acid having free carboxylic acid end groups, said copolymer having a molecular weight of about 40 kDa to about 120 kDa, said microspheres comprising from about 60% to about 85% bupivacaine free base, by weight, said microspheres being contained in a pharmaceutically acceptable medium for parenteral administration, such that the formulation has a concentration of bupivacaine free base from about 2.25 mg/ml to about 36.0 mg/ml and the formulation includes a total amount of bupivacaine free base from about 45 mg to about 360 mg prior to administration.

A unit dose pharmaceutical formulation suitable for parenteral administration to humans upon reconstitution with a pharmaceutically acceptable medium for parenteral administration comprising a plurality of controlled release microspheres comprising bupivacaine free base and a biocompatible, biodegradable polymer comprising a 65:35 DL copolymer of lactic and glycolic acid having free carboxylic acid end groups, said copolymer a molecular weight of about 40 kDa to about 120 kDa, said microspheres comprising from about 60% to about 85% bupivacaine free base, by weight, said microspheres including a total amount of bupivacaine free base from about 45 mg to about 360 mg prior to administration.

A method for providing local analgesia, local anesthesia or nerve blockade in a human, comprising administering at a site in a human a unit dose of microspheres comprising a biocompatible, biodegradable carrier and a local anesthetic, effective to provide local analgesia, local anesthesia or nerve blockade at the site of administration in a human which occurs less than about 2 hours after first administration, and a duration of local analgesia, local anesthesia or nerve blockade which lasts for at least about 1 day after first administration, wherein the mean Cmax of local anesthetic measured by microdialysis in the tissue at the site is from a Cmax therapeutically equivalent to 35,000 ng/ml bupivicaine to below a toxic concentration at the site.

A method of detecting the local concentration of a local anesthetic at a site of administration comprising administering a local anesthetic at a site of a human and measuring the concentration of said local anesthetic in the tissue of said site by microdialysis at one or more time intervals.

A method of detecting the local concentration of a corticosteroid at a site of administration comprising administering a corticosteroid at a site of a human and measuring the concentration of said local anesthetic in the tissue of said site by microdialysis at one or more time intervals.

A method for preparing a local anesthetic formulation suitable for obtaining local analgesia, local anesthesia or nerve blockade in a human, comprising preparing a plurality of controlled release microspheres comprising bupivacaine free base and a biocompatible, biodegradable polymer comprising a 65:35 DL copolymer of lactic and glycolic acid having free carboxylic acid end groups, said copolymer a molecular weight of about 40 kDa to about 120 kDa, said microspheres comprising from about 60% to about 85% bupivacaine free base, by weight, and containing said microspheres in a pharmaceutically acceptable medium for parenteral administration, such that the formulation has a concentration of bupivacaine free base from about 2.25 mg/ml to about 36.0 mg/ml and the formulation includes a total amount of bupivacaine free base from about 45 mg to about 360 mg prior to administration.

A method for providing local analgesia, local anesthesia or nerve blockade in a human, comprising administering at a site in a human a formulation comprising a plurality of controlled release microspheres comprising bupivacaine free base and a biocompatible, biodegradable polymer comprising a 65:35 DL copolymer of lactic and glycolic acid having free carboxylic acid end groups, said copolymer having a molecular weight of about 40 kDa to about 120 kDa, said microspheres comprising from about 60% to about 85% bupivacaine free base, by weight, said microspheres being contained in a pharmaceutically acceptable medium for administration, said formulation having a concentration of bupivacaine free base from about 2.25 mg/ml to about 36.0 mg/ml and the formulation including a total amount of bupivacaine free base from about 45 mg to about 360 mg prior to administration, such that said formulation provides local analgesia, local anesthesia or nerve blockade at the site of administration less than about 2 hours after first administration, and a duration of local analgesia, local anesthesia or nerve blockade which lasts for at least about 1 day after first administration.

A pharmaceutical formulation comprising a unit dose of microspheres comprising a biocompatible, biodegradable carrier and bupivacaine or a pharmaceutically acceptable salt thereof, effective to provide local analgesia, local anesthesia or nerve blockade at the site of administration in a human which occurs less than about 2 hours after first administration, and a duration of local analgesia, local anesthesia or nerve blockade which lasts for at least about 1 day after first administration, said formulation providing a mean Cmax of bupivacaine measured by microdialysis in the tissue at the site from about 35,000 ng/ml to below a toxic concentration at the site and a level of local anesthetic at the site of administration at least 150 times the level of said local anesthetic absorbed systemically into blood plasma.

A pharmaceutical formulation comprising a unit dose of microspheres comprising a biocompatible, biodegradable carrier and bupivacaine or a pharmaceutically acceptable salt thereof, effective to provide local analgesia, local anesthesia or nerve blockade at a site of administration in a human which occurs less than about 2 hours after first administration, and a duration of local analgesia, local anesthesia or nerve blockade which lasts for at least about 1 day after first administration, said formulation providing a mean Tmax of bupivacaine at the tissue at the site occurs which occurs at a time point from about 10 hours to about 45 hours after first administration.