Use of cross-linked sodium hyaluronate injection for treatment of osteoarthritis

Abstract

Use of a cross-linked sodium hyaluronate injection in the preparation of a medicament for treating osteoarthritis. In the cross-linked sodium hyaluronate injection, divinyl sulfone is the sole cross-linking agent.

Description

Use of cross-linked sodium hyaluronate injection for treating osteoarthritis Technical Field

[0001] The present invention relates to the technical field of osteoarthritis, in particular to use of cross-linked sodium hyaluronate injection in treating osteoarthritis. Background Art

[0002] Osteoarthritis (OA) is a degenerative joint disease prevalent among the elderly worldwide. Characterized by a slow degeneration of articular cartilage and subchondral bone, accompanied by marginal osteophyte formation and low-grade inflammation, it is a chronic joint disease with an unknown etiology. Clinically, it presents with progressive joint pain, possibly accompanied by morning stiffness and joint swelling.

[0003] Sodium hyaluronic acid (HA), an important viscosupplement, is an effective treatment for osteoarthritis. Intra-articular injection of HA can significantly relieve pain, reduce the need for oral nonsteroidal anti-inflammatory drugs, and improve joint function to a certain extent. It is well tolerated by patients, with no significant serious adverse reactions. Most HA products have a short half-life, and clinical dosing regimens involve weekly injections for a course of 3-5 weeks. This frequent injection frequency increases patient pain and the risk of infection. Cross-linked sodium hyaluronate injection (cHA) chemically crosslinks part of the sodium hyaluronate into a gel, increasing its molecular weight, viscoelasticity, and the shear rate of synovial fluid. It also prolongs the in vivo degradation time of sodium hyaluronate, maintaining HA activity while reducing the frequency of clinical administration, alleviating patient pain, and lowering the risk of infection.

[0004] Currently available cross-linked sodium hyaluronate injections, such as Synvisc, are a mixture of cross-linked sodium hyaluronate polymers generated by treating sodium hyaluronate extracted from cockscombs with formaldehyde solution to induce a cross-linking reaction, and cross-linked sodium hyaluronate polymers treated with vinyl sulfone cross-linking. The cross-linking agents used are formaldehyde and vinyl sulfone. Technical issues

[0005] The present invention overcomes the deficiencies of the prior art and provides a method for treating osteoarthritis by using a cross-linked sodium hyaluronate injection, which effectively alleviates the symptoms of osteoarthritis while reducing the number of clinical administrations, alleviating the patient's pain, and lowering the risk of infection. Technical Solutions

[0006] To achieve the above object, a cross-linked sodium hyaluronate injection is designed for use in treating osteoarthritis, which is characterized in that divinyl sulfone is used as the only cross-linking agent in the cross-linked sodium hyaluronate injection.

[0007] The preparation method of the cross-linked sodium hyaluronate injection comprises the following steps:

[0008] S1, take sodium hyaluronate raw material to prepare sodium hyaluronate solution, adjust the pH to alkaline;

[0009] S2, adding divinyl sulfone to the solution of step S1 to form a modified sodium hyaluronate solution through divinyl sulfone cross-linking;

[0010] S3, taking the cross-linked sodium hyaluronate solution modified in step S2, adding an organic solvent for precipitation, and obtaining a cross-linked sodium hyaluronate injection solution cross-linked only by divinyl sulfone.

[0011] In the step S2, divinyl sulfone is added to the solution of step S1 at a weight ratio of sodium hyaluronate to divinyl sulfone dry weight of 1:1-100:1.

[0012] In the cross-linked sodium hyaluronate injection, the residual amount of the cross-linking agent is less than 2 ppm. Beneficial effects

[0013] Compared with the existing technology, the present invention uses divinyl sulfone as the sole cross-linking agent for the cross-linked sodium hyaluronate injection for the treatment of osteoarthritis. Compared with the existing injection, the number of administrations is reduced, the incidence of side effects such as inflammation and infection caused by repeated intra-articular injections is reduced, and the time of medical staff in repeated administration and other social expenditure costs are saved. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] FIG1 is a schematic diagram of the experimental results of the sham operation group and the model group in Example 1 of the present invention.

[0015] FIG2 shows the Pelletier scores of the sham operation group and the model group in Example 1 of the present invention.

[0016] FIG3 is a schematic diagram showing the experimental results of the control sample single-dose and three-dose groups of the present invention.

[0017] FIG4 shows the Pelletier scores of the control sample of the present invention in the single-dose and three-dose groups.

[0018] FIG5 is a schematic diagram of the experimental results of the single-dose and three-dose groups of the experimental sample of the present invention.

[0019] FIG6 shows the Pelletier scores of the single-dose and three-dose groups of the experimental sample of the present invention. Modes for Carrying Out the Invention

[0020] The present invention will be further described below with reference to the accompanying drawings. Example

[0021] In the cross-linked sodium hyaluronate injection of this embodiment, divinyl sulfone is used as the only cross-linking agent.

[0022] The preparation method of cross-linked sodium hyaluronate injection comprises the following steps:

[0023] S1, take sodium hyaluronate raw material to prepare sodium hyaluronate solution, adjust the pH to alkaline;

[0024] S2, adding divinyl sulfone to the solution of step S1 to form a modified sodium hyaluronate solution through divinyl sulfone cross-linking;

[0025] S3, taking the cross-linked sodium hyaluronate solution modified in step S2, adding an organic solvent for precipitation, and obtaining a cross-linked sodium hyaluronate injection solution cross-linked only by divinyl sulfone.

[0026] In step S2, divinyl sulfone is added to the solution of step S1 at a weight ratio of sodium hyaluronate to divinyl sulfone dry weight of 1:1 to 100:1.

[0027] The residual amount of the cross-linking agent in the cross-linked sodium hyaluronate injection is less than 2 ppm, and no toxic side effects caused by the cross-linking agent will be produced during the treatment of osteoarthritis.

[0028] In the present invention, the divinyl sulfone molecule contains an alkenyl group. Due to its unstable structure, the alkenyl group easily reacts with a nucleophilic reagent to form an ether bond. Sodium hyaluronate has a strong nucleophilic property and easily forms a stable structure with divinyl sulfone.

[0029] In order to verify the therapeutic effect of the cross-linked sodium hyaluronate injection of the present invention on osteoarthritis, the inventors conducted the following experiments.

[0030] First, an osteoarthritis (OA) model was established. After intraperitoneal injection of anesthesia, the left hind limb knee joint area was shaved and the skin was prepared with iodine disinfection. A 2-cm longitudinal incision was made subcutaneously on the medial side of the knee joint. The subcutaneous fascia was dissected, and the medial collateral ligament was exposed by blunt dissection. The left medial knee joint was opened, the medial collateral ligament was cut, the medial meniscus was removed, the anterior cruciate ligament was cut, and the joint capsule was sutured to establish the KOA model. In the sham-operated group, the joint cavity was opened and sutured immediately after opening, with no other treatment. After surgery, the surgical wound in each group was applied with iodine daily for 3 consecutive days. One week after surgery, the animals were trained daily on a rotarod apparatus. Six weeks later, the OA model was established.

[0031] Next, the experimental groups and drug administration were performed. After model establishment, the animals were randomly divided into the model group, the positive control group, and the experimental sample group, respectively, receiving a single dose and three doses. The three-dose animals in the positive control and experimental sample groups were dosed three times at weeks 1, 3, and 5, respectively. Both the sham-operated and model groups received normal saline. All administration routes were intra-articular injections.

[0032] The positive control group was injected with purchased Synvisc solution, and the experimental sample group was injected with the cross-linked sodium hyaluronate injection of this example.

[0033] Finally, gross observation and Pelletier scoring were performed. Six weeks after administration, animals were anesthetized and sacrificed. Knee joint specimens, including the femoral condyle and tibial plateau, were removed from the surgical side and examined intraocularly for the presence of joint effusion and synovial hyperplasia. Cartilage surface degeneration of the medial and lateral femoral condyles and medial and lateral tibial plateaus was observed under an operating microscope and scored according to Table 1.

[0034] Table 1 Pelletier general scoring criteria

[0035]

[0036] As shown in Figure 1, erosion was visible on the joint surfaces of the model group animals, with some cartilage defects extending deep into the cartilage layer. The articular cartilage darkened and lost its original luster. According to the Pelletier gross scoring standard, the Pelletier scores of the model group rats in Figure 1 were statistically significant compared with those in the normal group (P < 0.05). Figures 2 and 3 show that after injection of the relevant sodium hyaluronate injection in the sunlight control group and the experimental sample group, both a single and three doses significantly improved the Pelletier scores of the articular cartilage surface, demonstrating a significant therapeutic effect. A single dose of the cross-linked sodium hyaluronate injection in the experimental sample group was more effective than a three-dose regimen. The cross-linked sodium hyaluronate injection in the experimental sample group was more effective than the sunlight control group.

[0037] The cross-linked sodium hyaluronate injection of the present invention is a single component containing only a modified sodium hyaluronate polymer and using only one cross-linking agent. It can achieve the same therapeutic effect and has the characteristics of low toxicity. It is used to treat osteoarthritis. Compared with existing injections, it reduces the number of administrations and reduces the incidence of side effects such as inflammation and infection caused by repeated intra-articular injections, saving medical staff time for repeated administration and other social expenditure costs.

Claims

1. Use of cross-linked sodium hyaluronate injection for treating osteoarthritis, characterized by: In cross-linked sodium hyaluronate injection, divinyl sulfone is the only cross-linking agent.

2. The use of the cross-linked sodium hyaluronate injection according to claim 1 for treating osteoarthritis, characterized in that: The preparation method of the cross-linked sodium hyaluronate injection comprises the following steps: S1, take sodium hyaluronate raw material to prepare sodium hyaluronate solution, adjust the pH to alkaline; S2, adding divinyl sulfone to the solution of step S1 to form a modified sodium hyaluronate solution through divinyl sulfone cross-linking; S3, taking the cross-linked sodium hyaluronate solution modified in step S2, adding an organic solvent for precipitation, and obtaining a cross-linked sodium hyaluronate injection solution cross-linked only by divinyl sulfone.

3. Use of the cross-linked sodium hyaluronate injection according to claim 1 for treating osteoarthritis, characterized in that: In the step S2, divinyl sulfone is added to the solution of step S1 at a weight ratio of sodium hyaluronate to divinyl sulfone dry weight of 1:1-100:

1.

4. Use of the cross-linked sodium hyaluronate injection according to claim 1 or 2 for treating osteoarthritis, characterized in that: In the cross-linked sodium hyaluronate injection, the residual amount of the cross-linking agent is less than 2 ppm.

Images