Treatment of arthritis and other musculoskeletal disorders with crosslinked hyaluronic acid

a technology of crosslinked hyaluronic acid and arthritis, which is applied in the field of treatment of arthritis and other musculoskeletal disorders with crosslinked hyaluronic acid, can solve the problems of affecting the treatment effect, so as to improve the treatment time of ha in the joints, reduce the frequency of administration, and improve the effect of the treatment

Inactive Publication Date: 2007-08-30
ANIKA THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0010] With the present invention, the residence time of HA in the joints can be improved, providing longer therapeutic effect, which in turn can reduce the frequency of administration, e.g., intra-articular injections, in OA patients, but yet effecting the efficiency and safety typical of uncrosslinked HA. In particular, co-therapy of the crosslinked HA in combination with a corticosteroid can provide rapid pain relief due to the presence of the corticosteroid, and prolonged pain relief due to the presence of the crosslinked HA.

Problems solved by technology

It usually presents a pain, which worsens with exercise.
Prolonged use of NSAIDs can, however, lead to gastric ulcers, kidney damage, hearing loss and even inhibit cartilage formation.
Corticosteroids provide short-term improvement of OA symptoms with quick onset of pain relief in the arthritic joints but their repeated use is limited due to the known side-effects of steroids.

Method used

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  • Treatment of arthritis and other musculoskeletal disorders with crosslinked hyaluronic acid
  • Treatment of arthritis and other musculoskeletal disorders with crosslinked hyaluronic acid
  • Treatment of arthritis and other musculoskeletal disorders with crosslinked hyaluronic acid

Examples

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Effect test

example 1

[0083] This example illustrates an embodiment of the invention in which a biscarbodiimide, p-phenylene-bis(ethylcarbodiimide), and HA are reacted at a molar equivalent ratio of 16.7%.

[0084] A solution of HA (6.0 mg / ml; 1130-ml; 16.9 mequiv) was reacted with a solution of p-phenylene-bis(ethylcarbodiimide) (1 mg / ml in acetone; 302-ml; 1.4 mmol; 2.8 mequiv) according to a procedure described in U.S. Pat. Nos. 5,356,883, 5,502,081, 6,013,679 and 6,548,081, the teachings of which are incorporated herein by reference in their entirety. The precipitate of the cross-linked HA was separated from the solution, washed, and resuspended in saline. The suspension was stirred for 2 days in a cold room to form a water-insoluble gel of about 4 mg / ml concentration. Chloroform equal to ½ of the volume of the aqueous solution was added to the solution and contents were vigorously stirred for seven days in the cold room. The reaction mixture was then centrifuged at 4° C. and 43 k rpm for one hour to r...

example 2

[0085] This example illustrates an embodiment of the invention in which a biscarbodiimide, p-phenylene-bis(ethylcarbodiimide), and HA are reacted at a molar equivalent ratio of 5.0% in MES buffer.

[0086] A solution of HA (15.0 mg / ml; 133.3-ml; 4.99 mequiv) in MES buffer (pH 5.5) was reacted with a solution of p-phenylene-bis(ethylcarbodiimide) (15 mg / ml in acetone; 1.8-ml; 0.125 mmol; 0.25 mequiv) according to a procedure described in U.S. patent application 2005 / 0136122 A1. The reaction mixture was thoroughly mixed (mixing with either a glass rod or an overhead mechanical stirrer, e.g., for˜1 minute, results in a white paste from the clear reaction mixture), and the mixture was allowed to stand at room temperature for about 96 hours. Sodium chloride (6.5 g, to make the mixture 5% by weight of sodium chloride) was mixed into the resulting gel, which was allowed to stand for 1 hour. The crosslinked HA gel was precipitated by addition into about 1.2 L of vigorously stirred ethanol. Th...

example 3

[0087] This example illustrates an embodiment of the invention in which a biscarbodiimide, p-phenylene-bis(ethylcarbodiimide), and HA are reacted at a molar equivalent ratio of 10.0% in MES buffer.

[0088] A solution of HA (15.0 mg / ml; 133.3-ml; 4.99 mequiv) in MES buffer (pH 5.5) was reacted with a solution of p-phenylene-bis(ethylcarbodiimide) (15 mg / ml in acetone; 3.6-ml; 0.25 mmol; 0.5 mequiv) according to a procedure described in U.S. patent application Ser. No. 2005 / 0136122 A1. The reaction mixture was thoroughly mixed (mixing with either a glass rod or an overhead mechanical stirrer, e.g., for about 1 minute, results in a white paste from the clear reaction mixture), and the mixture was allowed to stand at room temperature for about 96 hours. Sodium chloride (6.5 g, to make the mixture 5% by weight of sodium chloride) was mixed into the resulting gel, which was allowed to stand for 1 hour. The crosslinked HA gel was precipitated by addition into about 1.2 L of vigorously stirr...

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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.

Description

INCORPORATION BY REFERENCE [0001] This application claims the benefit of U.S. Provisional Application Nos. 60 / 751,237; 60 / 751,381; and 60 / 751,414, all of which were filed Dec. 14, 2005. The entire teachings of the above-mentioned applications are incorporated herein by reference.BACKGROUND OF THE INVENTION [0002] Arthritis is a musculoskeletal disorder which is one of the leading causes of disability in the United States of America and the rest of the world. In particular, osteoarthritis (OA) is one of the most frequent articular pathologies in humans, and a common condition leading to total joint arthroplasty (artificial joint placement) in elderly individuals. Osteoarthritis is typically characterized by degenerative changes in the surface of the articular cartilage which results in cartilage thinning. It usually presents a pain, which worsens with exercise. Commonly affected joints are the knee, hips, spine, ankles, shoulders, fingers and toes. [0003] To date, no therapies have b...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K48/00A61K31/729A61K31/573A61K38/17A61K39/395
CPCA61K9/0024C08L5/08A61K31/573A61K31/728A61K31/729A61K35/28A61K35/32A61K38/1841A61K47/36A61L27/20A61L27/227A61L27/3817A61L27/3834A61L27/3843A61L27/48A61L27/52A61L27/56A61L2430/06A61K9/06A61K2300/00A61P19/02A61P25/00A61P29/00
Inventor SADOZAI, KHALID K.SHERWOOD, CHARLES H.BUI, KYLE X.GOODING, TAMERA B.BASSETT, MICHAEL J.KENNEDY, STEPHEN J.
Owner ANIKA THERAPEUTICS INC
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