Controlled Delivery System

Abstract

The present invention relates to novel anesthetic compositions containing a non-polymeric carrier material and an anesthetic, where the compositions are suitable for providing a sustained local anesthesia without an initial burst and having a duration for about 24 hours or longer. Certain compositions are also provided that include a first anesthetic and a second anesthetic. In such compositions, the second anesthetic is a solvent for the first anesthetic and provides an initial anesthetic effect upon administration to a subject. The non-polymeric carrier may optionally be a high viscosity liquid carrier material such as a suitable sugar ester. The compositions can further include one or more additional ingredients including active and inactive materials. Methods of using the compositions of the invention to produce a sustained anesthetic effect at a site in a subject are also provided.

1 . A composition comprising an anesthetic and a pharmaceutically acceptable non-polymeric carrier, wherein the non-polymeric carrier controls release of the anesthetic to provide an anesthetic effect characterized by sustained local anesthesia after administration to a subject without an initial burst and having a duration of at least about 24 hours after administration. 
     
     
         2 . The composition of  claim 1 , wherein the non-polymeric carrier is sufficient to provide either a first order controlled-release profile of the anesthetic, or a pseudo-zero order release profile of said anesthetic. 
     
     
         3 . The composition of  claim 1 , wherein the anesthetic provides sustained local anesthesia for at least about 36 to 48 hours after administration to a subject. 
     
     
         4 . The composition of  claim 3 , wherein the anesthetic provides sustained local anesthesia for at least about 48 to 72 hours after administration to a subject. 
     
     
         5 . The composition of  claim 1 , wherein the anesthetic is a local anesthetic. 
     
     
         6 . The composition of  claim 5 , wherein the anesthetic is an amide- or ester-type local anesthetic. 
     
     
         7 . The composition of  claim 6 , wherein the anesthetic is bupivacaine. 
     
     
         8 . The composition of  claim 1 , wherein the anesthetic is present in free base form. 
     
     
         9 . The composition of  claim 1 , wherein the non-polymeric carrier is substantially insoluble in water or aqueous biological systems. 
     
     
         10 . The composition of  claim 9  further comprising a solvent that is dispersible, soluble or miscible in water or in an aqueous system. 
     
     
         11 . The composition of  claim 10 , wherein the solvent is an organic solvent. 
     
     
         12 . The composition of  claim 11 , wherein the solvent is capable of dissipating, diffusing or leaching away from the composition upon placement within a biological system, whereby the non-polymeric carrier can coagulate or precipitate to form a solid implant in situ. 
     
     
         13 . The composition of  claim 9 , wherein the non-polymeric carrier is a liquid. 
     
     
         14 . The composition of  claim 13 , wherein the non-polymeric carrier is a high viscosity liquid carrier material (“HVLCM”) having a viscosity of at least about 5,000 cP at 37° C. that does not crystallize neat under ambient or physiological conditions. 
     
     
         15 . The composition of  claim 14  further comprising a solvent in which the non-polymeric carrier is soluble. 
     
     
         16 . The composition of  claim 15 , wherein the solvent is selected from the group consisting of ethanol, dimethyl sulfoxide, triethyl citrate, ethyl lactate, ethyl acetate, benzyl benzoate, benzyl alcohol, triacetin, N-methylpyrrolidone, propylene carbonate, polyethylene glycol, glycerol, glycofurol, 2-pyrrolidone, tetrafluoroethane, esters of caprylic and/or capric acids with glycerol or alkylene glycols, and combinations thereof. 
     
     
         17 . The composition of  claim 15 , wherein the solvent is sufficient to lower to viscosity of the HVLCM. 
     
     
         18 . The composition of  claim 15 , wherein the solvent is a second anesthetic agent. 
     
     
         19 .- 166 . (canceled) 
     
     
         167 . A method for providing an anesthetic effect at a site in a subject, said method comprising administering a composition at, near, in, or adjacent to the site, wherein the composition comprises an anesthetic and a pharmaceutically acceptable non-polymeric carrier, and further wherein the non-polymeric carrier controls release of the anesthetic to provide an anesthetic effect characterized by sustained local anesthesia after administration to the subject without an initial burst and having a duration of at least about 24 hours after administration. 
     
     
         168 . A method for providing an anesthetic effect at a site in a subject, said method comprising administering a composition at, near, in, or adjacent to the site, wherein the composition comprises an anesthetic and a pharmaceutically acceptable non-polymeric carrier, and further wherein the non-polymeric carrier controls release of the anesthetic to provide an anesthetic effect characterized by sustained local anesthesia after administration to the subject, and the composition is capable of providing a sustained mean steady state plasma concentration (C ss ) of the anesthetic of at least about 200 ng/mL for a period of at least about 24 hours when said composition is administered subcutaneously. 
     
     
         169 .- 181 . (canceled)