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 0-acyl isourea, or both N-acylurea and 0-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 . The method of  claim 1 , wherein the hyaluronic acid composition is administered to the subject by an intra-articular injection.  
   
   
       4 . The method of  claim 1 , wherein the musculoskeletal disorder is arthritis.  
   
   
       5 . The method of  claim 4 , 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 . The method of  claim 6 , wherein the second bioactive agent includes at least one member selected from the group consisting of growth and differentiation factors, antibiotics, analgesics, anesthetics, steroidal and non-steroidal anti-inflammatory agents, chondroregenerative agents, chondroprotective agents, matrix metalloproteinase inhibitors, tissue inhibitors of matrix metalloproteinase, bone protective agents, bone regenerating agents, bone anabolic agents, bone resorption inhibitors, and bone osteoclast inhibiting agents.  
   
   
       8 . The method of  claim 7 , wherein the second bioactive agent is an anti-inflammatory drug, a chondroprotective agent or a chondroregenerative agent.  
   
   
       9 . The method of  claim 8 , wherein the second bioactive agent is a steroidal anti-inflammatory drug.  
   
   
       10 . The method of  claim 8 , wherein the second bioactive agent is a non-steroidal anti-inflammatory drug.  
   
   
       11 . The method of  claim 9 , wherein the bioactive agent is a corticosteroid.  
   
   
       12 . A method of treating a subject having a musculoskeletal disorder, comprising co-administering to a subject's articular site in need thereof: 
 (a) an effective amount of a hyaluronic acid (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) 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 . The method of  claim 12 , wherein the HA 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.    
   
   
       14 . The method of  claim 12 , wherein the HA derivative is administered to the subject by an intra-articular injection.  
   
   
       15 . The method of  claim 12 , wherein the second bioactive agent includes at least one member selected from the group consisting of growth factors, antibiotics, analgesics, anesthetics, steroidal and non-steroidal anti-inflammatory agents, chondroregenerative agents, chondroprotective agents, matrix metalloproteinase inhibitors, tissue inhibitors of matrix metalloproteinase, bone protective agents, bone regenerating agents, bone anabolic agents, bone resorption inhibitors, and bone osteoclast inhibiting agents.  
   
   
       16 . The method of  claim 15 , wherein the second bioactive agent is an anti-inflammatory drug, a chondroprotective agent or a chondroregenerative agent.  
   
   
       17 . The method of  claim 16 , wherein the bioactive agent is a steroidal anti-inflammatory drug.  
   
   
       18 . The method of  claim 16 , wherein the bioactive agent is a non-steroidal anti-inflammatory drug.  
   
   
       19 . The method of  claim 17 , wherein the 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 . The method of  claim 20 , wherein the musculoskeletal disorder is arthritis.  
   
   
       23 . The method of  claim 22 , 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 . The method of  claim 24 , wherein the second bioactive agent includes at least one member selected from the group consisting of growth factors, antibiotics, analgesics, anesthetics, steroidal and non-steroidal anti-inflammatory agents, chondroregenerative agents, chondroprotective agents, matrix metalloproteinase inhibitors, tissue inhibitors of matrix metalloproteinase, bone protective agents, bone regenerating agents, bone anabolic agents, bone resorption inhibitors, and bone osteoclast inhibiting agents.  
   
   
       26 . The method of  claim 25 , wherein the second bioactive agent is an anti-inflammatory drug, a chondroprotective agent or a chondroregenerative agent.  
   
   
       27 . The method of  claim 26 , wherein the bioactive agent is a steroidal anti-inflammatory drug.  
   
   
       28 . The method of  claim 26 , wherein the bioactive agent is a non-steroidal anti-inflammatory drug.  
   
   
       29 . The method of  claim 27 , wherein the bioactive agent is a corticosteroid.  
   
   
       30 . 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 crosslinked HA gel, wherein the crosslinked HA is prepared by reacting an uncrosslinked HA with a biscarbodiimide in the presence of a pH buffer in a range of between about 4 and about 8.  
   
   
       31 . The method of  claim 30 , wherein the hyaluronic acid composition is administered to the subject by an intra-articular injection.  
   
   
       32 . The method of  claim 30 , wherein the musculoskeletal disorder is arthritis.  
   
   
       33 . The method of  claim 32 , wherein the musculoskeletal disorder is osteoarthritis.  
   
   
       34 . The method of  claim 30 , wherein the HA composition further includes an effective amount of at least one second bioactive agent other than the crosslinked HA gel, the second bioactive agent being at least one member selected from the group consisting of cells, nucleic acids, proteins, antibodies, peptides and pharmaceuticals.  
   
   
       35 . The method of  claim 34 , wherein the second bioactive agent includes at least one member selected from the group consisting of growth and differentiation factors, antibiotics, analgesics, anesthetics, steroidal and non-steroidal anti-inflammatory agents, chondroregenerative agents, chondroprotective agents, bone protective agents, matrix metalloproteinase inhibitors, tissue inhibitors of matrix metalloproteinase, bone protective agents, bone regenerating agents, bone anabolic agents, bone resorption inhibitors, and bone osteoclast inhibiting agents.  
   
   
       36 . The method of  claim 35 , wherein the second bioactive agent is a steroidal anti-inflammatory drug.  
   
   
       37 . The method of  claim 36 , wherein the second bioactive agent is a corticosteroid.