Hyaluronic acid-based gels including lidocaine

Abstract

Disclosed herein are soft tissue fillers, for example, dermal and subdermal fillers, based on hyaluronic acids and pharmaceutically acceptable salts thereof. Some of the hyaluronic acid-based compositions can include a therapeutically effective amount of at least one anesthetic agent, for example, lidocaine. Compared to conventional compositions that include lidocaine, some of the hyaluronic acid-based compositions disclosed herein can have an enhanced stability, for example, when subjected to sterilization techniques or when stored for long periods of time. Methods and processes of preparing such compositions are also provided.

1 - 20 . (canceled) 
     
     
         21 . A soft tissue filler composition comprising:
 crosslinked hyaluronic acid (HA) present in the composition at a concentration of between about 20 mg/ml and about 30 mg/ml, wherein the HA is crosslinked at a degree of crosslinking between about 2% and about 20%,   soluble form HA present in the composition in an amount at least about 10% by weight of the HA in the composition,   lidocaine in an amount effective to mitigate pain upon injection of the mixture, wherein the lidocaine is freely released in vivo, and   wherein the pH of the composition is about 7.0.   
     
     
         22 . The soft tissue filler composition of  claim 21 , wherein the crosslinked HA concentration is between about 22 mg/mL and about 24 mg/mL. 
     
     
         23 . The soft tissue filler composition of  claim 21 , wherein the crosslinked HA comprises particles of HA of about uniform size and shape. 
     
     
         24 . The soft tissue filler composition of  claim 23 , wherein the particles of HA crosslinked with BDDE have an average size of at least about 200 μm. 
     
     
         25 . The soft tissue filler composition of  claim 21 , wherein the HA is crosslinked with 1,4-butanediol diglycidyl ether (BDDE). 
     
     
         26 . The soft tissue filler composition of  claim 21 , wherein the lidocaine is present in the composition at a concentration of between about 0.1% and about 5% by weight of said composition. 
     
     
         27 . The soft tissue filler composition of  claim 21 , wherein the soft tissue filler composition is contained in a syringe. 
     
     
         28 . The soft tissue filler composition of  claim 21 , wherein the composition is heat sterilized. 
     
     
         29 . The soft tissue filler composition of  claim 21 , wherein the composition has a viscosity of between about 5 Pa*s and about 450 Pa*s when measured at about 5 Hz. 
     
     
         30 . The soft tissue filler composition of  claim 21 , wherein the extrusion force of the composition is between about 10 N and about 13 N at an extrusion rate of about 12.5 mm/minute. 
     
     
         31 . A method of preparing a HA-based soft tissue filler composition comprising the steps of:
 (a) combining a crosslinked HA component and an uncrosslinked HA component,
 wherein the crosslinked HA component comprises between 20 mg/ml and 30 mg/ml HA crosslinked with BDDE, and wherein the crosslinked HA component has a degree of crosslinking between about 2% and about 20%, and 
 wherein the uncrosslinked HA component is present at a concentration of at least about 10% of the weight of the HA component, 
   (b) adjusting the pH of the combined HA components to an adjusted pH above about 7.2; and   (c) adding a solution containing lidocaine to obtain a HA-based soft tissue filler that is stable after being subjected to heat sterilization.   
     
     
         32 . The method of  claim 31 , further comprising a step of heat sterilizing the HA-based composition. 
     
     
         33 . The method of  claim 31 , wherein the pH is adjusted to an adjusted pH above about 8.0. 
     
     
         34 . The method of  claim 31 , wherein the HA-based soft tissue filler comprises particles of HA of about uniform size and shape. 
     
     
         35 . The method of  claim 34 , wherein the particles have an average size of at least about 200 μm. 
     
     
         36 . The method of  claim 31 , further comprising introducing the HA-based composition into a syringe. 
     
     
         37 . The method of  claim 36 , wherein the syringe has a needle gauge of between about 27 G and about 32 G. 
     
     
         38 . A soft tissue filler composition comprising:
 crosslinked hyaluronic acid (HA) present in the composition at a concentration of between about 20 mg/ml and about 24 mg/ml, wherein the HA is crosslinked at a degree of crosslinking between about 2% and about 20%,   soluble form HA present in the composition in an amount at least about 10% by weight of the HA in the composition,   lidocaine at about 0.3% by weight of the composition, wherein the lidocaine is freely released in vivo, and   wherein the pH of the composition is about 7.0.   
     
     
         39 . The soft tissue filler composition of  claim 38 , wherein the soft tissue filler composition is contained in a syringe. 
     
     
         40 . The soft tissue filler composition of  claim 39 , wherein the composition and the syringe are heat sterilized.