Hyaluronic acid based formulations

Abstract

Disclosed herein are soft tissue fillers, for example, dermal and subdermal fillers, based on low molecular weight hyaluronic acids and pharmaceutically acceptable salts thereof, and methods of manufacturing same.

What is claimed is: 
     
         1 . A stable, sterile, injectable soft tissue filler comprising:
 a crosslinked hyaluronic acid (HA) gel comprising a crosslinked mixture of (i) a first, low molecular weight HA material having a weight average molecular weight of between 0.20 about MDa and about 0.99 MDa and (ii) a second high molecular weight HA material having a weight average molecular weight of between about 1.0 MDa and about 4.0 MDa, wherein the weight average molecular weight of the second, high molecular weight HA material is at least twice that of the first, low molecular weight HA material;   an uncrosslinked HA gel comprising HA or a salt thereof having a weight average molecular weight of at least about 1.0 MDa, the uncrosslinked HA gel being added to the crosslinked gel in an amount of between about 0.5% and about 5.0% w/w;   wherein the crosslinking is achieved by use of a crosslinking agent;   wherein the HA concentration is between about 15 mg/g and about 20 mg/g.   
     
     
         2 . The filler of  claim 1  wherein the uncrosslinked HA gel comprises a HA having a weight average molecular weight of about 2.0 MDa. 
     
     
         3 . The filler of  claim 1  wherein the weight average molecular weight of the first, low molecular weight HA material is at least about 500,000 Da. 
     
     
         4 . The filler of  claim 1  wherein the weight average molecular weight of the second, high molecular weight HA material is at least about 1.0M Da. 
     
     
         5 . The filler of  claim 1  wherein the weight average molecular weight of the first, low molecular weight HA material is about 800,000 Da. 
     
     
         6 . The filler of  claim 1  wherein the mixture contains about 50% by weight of the first, low molecular weight HA material. 
     
     
         7 . The filler of  claim 1  wherein the mixture contains at least about 70% by weight of the first, low molecular weight HA material. 
     
     
         8 . The filler of  claim 1  wherein the mixture contains about 90% by weight of the first, low molecular weight HA material. 
     
     
         9 . The filler of  claim 1  wherein the crosslinking agent is selected from the group consisting of 1,4-butanediol diglycidyl ether (BDDE), 1,4-bis(2,3-epoxypropoxy)butane, 1,4-bisglycidyloxybutane, 1,2-bis(2,3-epoxypropoxy)ethylene and 1-(2,3-epoxypropyl)-2,3-epoxycyclohexane. 
     
     
         10 . The filler of  claim 1  wherein the HA concentration is about 15.0 mg/g. 
     
     
         11 . The filler of  claim 1  wherein the HA concentration is about 17.5 mg/g. 
     
     
         12 . The filler of  claim 1  wherein the uncrosslinked HA gel is added to the crosslinked gel in an amount of less than about 1.0% w/w. 
     
     
         14 . The filler of  claim 1  further comprising at least one anesthetic agent combined with said HA gels. 
     
     
         15 . The filler of  claim 14  wherein the anesthetic agent is lidocaine. 
     
     
         16 . A method of making a soft tissue filler comprising the steps of:
 preparing a crosslinked hyaluronic acid (HA) gel comprising a mixture of a first, low molecular weight HA material and a second, high molecular weight HA material, the second, high molecular weight HA material having a weight average molecular weight of at least twice that of the first, low molecular weight material, the mixture comprising more than about 50% by weight of the first, low molecular weight HA material, wherein the HA materials are hyaluronic acid or one or more salts thereof;   adjusting the HA concentration to a HA concentration of between about 15.0 mg/g and about 20.0 mg/g;   preparing a solution of uncrosslinked HA having a HA concentration of between about 10 mg/g and about 50 mg/g, the solution comprising HA having a weight average molecular weight of between at least about 1.0 MDa and about 4.0 MDa; and   combining the gel with the solution.   
     
     
         17 . The method of  claim 15  wherein the mixture comprises more than about 90% by weight of the first, low molecular weight HA material. 
     
     
         18 . The method of  claim 15  further comprising the step of combining at least one anesthetic agent with the gel. 
     
     
         19 . The method of  claim 17  wherein the step of combining at least one anesthetic agent with the gel is performed prior to the step of combining the gel with the solution. 
     
     
         20 . The method of  claim 15  further comprising the step of heat sterilizing the combined gel and solution.