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 method of treating a subject having a musculoskeletal disorder, comprising administering to a subject's articular site in need thereof an effective amount of a hyaluronic acid (HA) composition that includes a hyaluronic acid 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. 
     
     
         2 . The method of  claim 1 , wherein the hyaluronic acid (HA) composition includes a crosslinked HA gel that includes at least one crosslink represented by the following structural formula:
   HA′-U—R 2 —U—HA′
   wherein:
 each HA′ is the same or a different crosslinked HA′ molecule; 
 each U is independently an optionally substituted O-acyl isourea or N-acyl urea; and 
 each R 2  is independently a substituted or unsubstituted hydrocarbylene group optionally interrupted by one or more heteroatoms. 
   
     
     
         3 - 4 . (canceled) 
     
     
         5 . The method of  claim 1 , wherein the musculoskeletal disorder is osteoarthritis. 
     
     
         6 . The method of  claim 1 , wherein the HA composition further includes an effective amount of at least one second bioactive agent other than the HA derivative, the second bioactive agent being at least one member selected from the group consisting of cells, nucleic acids, proteins, antibodies, peptides and pharmaceuticals. 
     
     
         7 - 10 . (canceled) 
     
     
         11 . The method of  claim 6 , wherein the second bioactive agent is a corticosteroid. 
     
     
         12 . The method of  claim 2 , wherein the HA composition further includes
 an effective amount of at least one second bioactive agent other than the HA derivative, the second bioactive agent being at least one member selected from the group consisting of cells, nucleic acids, proteins, antibodies, peptides and pharmaceuticals.   
     
     
         13 - 18 . (canceled) 
     
     
         19 . The method of  claim 12 , wherein the second bioactive agent is a corticosteroid. 
     
     
         20 . A method of treating a subject having a musculoskeletal disorder, comprising the steps of:
 (a) inserting a needle into to a subject's articular site in need thereof, wherein the needle is coupled to a syringe loaded with an effective amount of hyaluronic acid (HA) composition that 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; and   (b) applying force to the syringe, whereby at least a portion of the HA composition is delivered to the articular site of the subject.   
     
     
         21 . The method of  claim 20 , wherein the hyaluronic acid composition includes a crosslinked HA gel that includes at least one crosslink represented by the following structural formula:
   HA′-U—R 2 —U—HA′
   wherein:
 each HA′ is the same or a different crosslinked HA′ molecule; 
 each U is independently an optionally substituted O-acyl isourea or N-acyl urea; and 
 each R 2  is independently a substituted or unsubstituted hydrocarbylene group optionally interrupted by one or more heteroatoms. 
   
     
     
         22 . (canceled) 
     
     
         23 . The method of  claim 20 , wherein the musculoskeletal disorder is osteoarthritis. 
     
     
         24 . The method of  claim 20 , wherein the HA composition further includes an effective amount of at least one second bioactive agent other than the HA derivative, the second bioactive agent being at least one member selected from the group consisting of cells, nucleic acids, proteins, antibodies, peptides and pharmaceuticals. 
     
     
         25 - 28 . (canceled) 
     
     
         29 . The method of  claim 24 , wherein the second bioactive agent is a corticosteroid. 
     
     
         30 - 37 . (canceled) 
     
     
         38 . 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.   
     
     
         39 . The composition of  claim 38 , comprising about 2 mg/mL to about 30 mg/mL of the HA derivative. 
     
     
         40 . The composition of  claim 38 , which has been terminally sterilized by steam sterilization. 
     
     
         41 . The composition of  claim 38 , wherein the cross-link is an intermolecular cross-link. 
     
     
         42 . The composition of  claim 38 , wherein the cross-link is an intramolecular cross-link. 
     
     
         43 . A syringe comprising the composition  claim 38 . 
     
     
         44 . The syringe of  claim 43 , comprising about 4 mL of the composition. 
     
     
         45 . The syringe of  claim 43 , which is a 5-mL syringe.