Treatment of Arthritis and Other Musculoskeletal Disorders With Crosslinked Hyaluronic Acid

Abstract

A method of treating a subject having a musculoskeletal disorder includes administering to a subject's articular site in need thereof an effective amount of a hyaluronic acid (HA) composition. In one embodiment, the HA composition includes an HA derivative, wherein carboxyl functionalities of the hyaluronic acid derivative are each independently derivatized to include an N-acylurea or O-acyl isourea, or both N-acylurea and O-acyl isourea. In another embodiment, the HA composition includes a crosslinked HA gel that is prepared by reacting an uncrosslinked HA with a biscarbodiimide in the presence of pH buffer in a range of between about 4 and about 8. The composite can optionally include at least one second bioactive agent other than the HA derivative, such as a steroid.

1 . A sterile pharmaceutical composition comprising: (a) an effective amount of triamcinolone hexacetonide; and (b) an effective amount of a hyaluronic acid (HA) derivative, wherein the HA derivative comprises a cross-linked HA gel, wherein the cross-linked HA gel comprises at least one cross-link represented by the following structural formula:
   HA′-U—R 2 —U-HA′
   wherein   each HA′ is a hyaluronic acid that is the same or a different;   each U is independently an optionally substituted O-acyl isourea or N-acyl urea;   each R 2  is independently a substituted or unsubstituted hydrocarbylene group optionally interrupted by one or more heteroatoms;   between about 1% and about 10% by mol of the carboxy functionalities of the HA gel is cross-linked; and   wherein the composition is formulated for administration as an intra-articular injection.   
     
     
         2 . The composition of  claim 1 , comprising about 2 mg/mL to about 30 mg/mL of the HA derivative. 
     
     
         3 . The composition of  claim 1 , which provides rapid and prolonged pain relief. 
     
     
         4 . The composition of  claim 1 , which provides pain relief for about 4-6 months. 
     
     
         5 . The composition of  claim 1 , which has been terminally sterilized by steam sterilization. 
     
     
         6 . A syringe comprising the composition of any one of  claims 1 - 5 . 
     
     
         7 . The syringe of  claim 6 , comprising about 4 mL of the composition. 
     
     
         8 . The syringe of  claim 6 , which is a 5-mL syringe. 
     
     
         9 . The composition of  claim 1 , wherein the cross-link is an intermolecular cross-link. 
     
     
         10 . The composition of  claim 1 , wherein the cross-link is an intramolecular cross-link.