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.

1 . A soft tissue filler composition comprising:
 (1) a crosslinked hyaluronic acid (HA) component 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;   wherein the HA materials are hyaluronic acid or one or more salts thereof;   wherein the crosslinked HA component has a HA concentration of between about 15.0 mg/g and about 20.0 mg/g; and   wherein the crosslinking is achieved by use of a crosslinking agent; and   (2) an uncrosslinked HA component which is HA or a salt thereof, and which has a weight average molecular weight of at least about 1.0 MDa and is present in the composition in an amount of less than about 5.0% w/w   
     
     
         2 . The composition of  claim 1  wherein the uncrosslinked HA component has a weight average molecular weight of at least about 2.0 MDa. 
     
     
         3 . The composition 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 composition 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 composition of  claim 1  wherein the weight average molecular weight of the first, low molecular weight HA material is about 800,000 Da. 
     
     
         6 . The composition of  claim 1  wherein the mixture contains about 50% by weight of the first, low molecular weight HA material. 
     
     
         7 . The composition of  claim 1  wherein the mixture contains at least about 70% by weight of the first, low molecular weight HA material. 
     
     
         8 . The composition of  claim 1  wherein the mixture contains about 90% by weight of the first, low molecular weight HA material. 
     
     
         9 . The composition 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, and 1,4-butanediol diglycidyl ether. 
     
     
         10 . The composition of  claim 1  wherein the crosslinked HA component has a HA concentration of about 15.0 mg/g. 
     
     
         11 . The composition of  claim 1  wherein the crosslinked HA component has a HA concentration of about 17.5 mg/g. 
     
     
         12 . The composition of  claim 1  wherein the uncrosslinked HA component is present in an amount of less than about 1.0% w/w. 
     
     
         13 . The composition of  claim 1  wherein the uncrosslinked HA component has a HA concentration of between about 10.0 mg/g and about 50.0 mg/g. 
     
     
         14 . The composition of  claim 1  further comprising at least one anesthetic agent combined with said crosslinked HA component. 
     
     
         15 . A soft tissue filler composition comprising:
 a crosslinked hyaluronic acid (HA) component comprising a mixture of a first, low molecular weight HA material and a second, high molecular weight HA material, the materials being hyaluronic acid or salts thereof and being crosslinked with a crosslinking agent, the crosslinked HA component having a HA concentration of between about 15 mg/g and about 20 mg/g, and the mixture containing at least 50% by weight of the low molecular weight HA material;   the weight average molecular weight of the second, high molecular weight HA material being at least twice that of the weight average molecular weight of the first, low molecular weight HA material;   an uncrosslinked hyaluronic acid component or salt thereof, having a weight average molecular weight of at least about 2.4 M Da and an HA concentration of between about 10 mg/g and about 50 mg/g;   the uncrosslinked HA component being present in an amount of less than about 5.0% w/w; and   at least one anesthetic agent combined with said crosslinked HA component.   
     
     
         16 . The composition of  claim 15  wherein the mixture contains at least 70% by weight of the first, low molecular weight HA material. 
     
     
         17 . The composition of  claim 15  wherein the mixture contains about 90% by weight of the first, low molecular weight HA material. 
     
     
         18 . A method of making a soft tissue filler composition 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 in the crosslinked HA gel to a HA concentration of between about 15.0 mg/g and about 20.0 mg/g;   preparing a solution comprising an uncrosslinked HA material or a salt thereof having a weight average molecular weight of between at least about 1.0 MDa and about 4.0 MDa and a concentration of between about 10 mg/g and about 50 mg/g; and   combining the gel with the solution.   
     
     
         19 . The method of  claim 18  wherein the mixture comprises more than about 70% by weight of the first, low molecular weight HA material. 
     
     
         20 . The method of  claim 18  wherein the mixture comprises more than about 90% by weight of the first, low molecular weight HA material. 
     
     
         21 . The method of  claim 18  further comprising the step of combining at least one anesthetic agent with the gel. 
     
     
         22 . The method of  claim 21  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.