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 - 20 . (canceled) 
     
     
         21 . A soft tissue filler having reduced viscosity under high shear rate, the soft tissue filler comprising:
 a crosslinked hyaluronic acid (HA) gel; and   an uncrosslinked HA gel combined with the crosslinked HA gel;   the uncrosslinked HA gel having a weight average molecular weight of at least about 1.0 MDa and having a HA concentration of between about 10 mg/g and about 50 mg/g,   wherein the soft tissue filler has a reduced viscosity under high shear rate relative to an otherwise identical soft tissue filler without the uncrosslinked HA gel.   
     
     
         22 . The soft tissue filler of  claim 21 , wherein the soft tissue filler has an HA concentration of about 15.0 mg/g. 
     
     
         23 . The soft tissue filler of  claim 21 , wherein the soft tissue filler has an HA concentration of about 17.5 mg/g. 
     
     
         24 . A soft tissue filler having a reduced extrusion force when delivered from a syringe, the soft tissue filler comprising:
 a crosslinked hyaluronic acid (HA) gel; and   an uncrosslinked HA gel combined with the crosslinked HA gel;   the uncrosslinked HA gel having a weight average molecular weight of at least about 1.0 MDa and having a HA concentration of between about 10 mg/g and about 50 mg/g,   wherein the soft tissue filler has a reduced extrusion force when delivered from a syringe relative to an otherwise identical soft tissue filler without the uncrosslinked HA gel.   
     
     
         25 . The soft tissue filler of  claim 24 , wherein the extrusion force is from about 5 N to about 20 N when extruded at 13.5 mm/min in a 1.0 mL syringe with a standard needle of 30 G. 
     
     
         26 . The soft tissue filler of  claim 25 , wherein the extrusion force is from about 8 N to about 15 N. 
     
     
         27 . A method of reducing viscosity of a soft tissue filler under high shear rate, the method comprising:
 providing a crosslinked hyaluronic acid (HA) gel; and   adding an uncrosslinked HA gel having a weight average molecular weight of at least about 1.0 MDa and having a HA concentration of between about 10 mg/g and about 50 mg/g to form the soft tissue filler,   wherein the addition of the uncrosslinked HA gel reduces the viscosity of the soft tissue filler under high shear rate relative to an otherwise identical soft tissue filler without the uncrosslinked HA gel.   
     
     
         28 . The method of  claim 27 , wherein the uncrosslinked HA gel is about 1.0% w/w of the soft tissue filler. 
     
     
         29 . The method of  claim 27 , wherein the soft tissue filler has a viscosity of about 50 Pa*s to about 450 Pa*s. 
     
     
         30 . The method of  claim 27 , wherein the crosslinked HA gel is crosslinked by a crosslinking agent 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. 
     
     
         31 . The method of  claim 27 , wherein the uncrosslinked HA gel has a weight average molecular weight of about 2.0 MDa. 
     
     
         32 . The method of  claim 27 , wherein the soft tissue filler has a final weight percent of between about 0.5% and about 10% uncrosslinked HA. 
     
     
         33 . The method of  claim 27 , wherein the soft tissue filler further comprises at least one anesthetic agent. 
     
     
         34 . A method of reducing an extrusion force needed to deliver a soft tissue filler from a syringe, the method comprising:
 providing a crosslinked hyaluronic acid (HA) gel; and   adding an uncrosslinked HA gel having a weight average molecular weight of at least about 1.0 MDa and having a HA concentration of between about 10 mg/g and about 50 mg/g to form the soft tissue filler,   wherein the addition of the uncrosslinked HA gel reduces the extrusion force needed to deliver the soft tissue filler from the syringe relative to an otherwise identical soft tissue filler without the uncrosslinked HA gel.   
     
     
         35 . The method of  claim 34 , wherein the extrusion force is from about 5 N to about 20 N when extruded at 13.5 mm/min in a 1.0 mL syringe with a standard needle of 30 G. 
     
     
         36 . The method of  claim 35 , wherein the extrusion force is from about 8 N to about 15 N. 
     
     
         37 . A method of making a soft tissue filler having reduced viscosity under high shear rate, the method comprising the steps of:
 preparing a crosslinked hyaluronic acid (HA) gel;   adjusting a HA concentration of the crosslinked HA gel 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 to form the soft tissue filler,   wherein the soft tissue filler has a reduced viscosity under high shear rate relative to an identical soft tissue filler without the uncrosslinked HA.   
     
     
         38 . The method of  claim 37 , wherein the soft tissue filler comprises more than about 90% by weight of the first, low molecular weight HA material. 
     
     
         39 . The method of  claim 37 , further comprising the step of combining at least one anesthetic agent with the gel. 
     
     
         40 . The method of  claim 39 , 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. 
     
     
         41 . The method of  claim 37 , further comprising the step of heat sterilizing the combined gel and solution.