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CN-121971374-A - Crosslinked chitosan gel for joint cavity injection and preparation method and application thereof

CN121971374ACN 121971374 ACN121971374 ACN 121971374ACN-121971374-A

Abstract

The invention provides a preparation method of crosslinked chitosan gel for joint cavity injection, which comprises the following steps of preparing a reaction solution, namely dissolving carboxymethyl chitin and amino acid in water for injection to prepare the reaction solution, adding a coupling agent into the reaction solution, adjusting the pH value of a reaction system to 6-9, performing the crosslinking reaction at 30-60 ℃ for 1-24 h, and then placing the reaction solution in 2-8 ℃ for overnight storage to obtain massive gel, and performing post-treatment on the massive gel obtained in the step 2 to obtain the crosslinked chitosan gel. The gel prepared by the invention not only can provide better viscoelastic performance to meet the movement requirement of a bone joint, but also has the advantages of good stability, good degradation resistance and the like, can reduce the injection times clinically, and can ensure the long-acting safety effect.

Inventors

  • XIONG YUFEI
  • CHEN QIANG
  • ZHU JIANFENG
  • MA SIFAN

Assignees

  • 浙江景嘉医疗科技有限公司

Dates

Publication Date
20260505
Application Date
20260127

Claims (9)

  1. 1. A method for preparing a crosslinked chitosan gel for joint cavity injection, comprising the steps of: Step 1, preparing a reaction solution, namely dissolving carboxymethyl chitin and lysine in water for injection to prepare the reaction solution; step 2, crosslinking reaction, namely adding a coupling agent into the reaction liquid, adjusting the pH value of a reaction system to 6-9, performing crosslinking reaction at 30-60 ℃ for 1-24 h, and then placing the mixture into 2-8 ℃ for overnight storage to obtain massive gel; and step 3, carrying out post-treatment on the massive gel obtained in the step 2 to obtain the crosslinked chitosan gel.
  2. 2. The preparation method according to claim 1, wherein the carboxymethyl chitin has a molecular weight of 10-30 ten thousand daltons, a degree of deacetylation of 5-20%, a degree of substitution of 80-200%, and a degree of modification of lysine crosslinking reaction of 15-30%.
  3. 3. The preparation method according to claim 1, wherein the coupling agent is 4- (4, 6-dimethoxy-triazin-2-yl) -4-methylmorpholine hydrochloride.
  4. 4. The method according to claim 1, wherein the molar ratio of carboxymethyl chitin, lysine and coupling agent in step 1 is 1 (0.5-1.5): 1-3.
  5. 5. The method of claim 1, wherein the post-treatment of step 3 comprises the steps of: (a) Dialyzing, namely cutting the gel block obtained in the step 2 into blocks, then placing the blocks in balanced salt solution for dialyzing for 24-72h, and placing the blocks in 2-8 ℃ for balancing after dialyzing to the expected mass to obtain a dialyzed gel block; (b) Homogenizing, namely homogenizing and sieving the dialysis gel block for multiple times by a sieving machine to obtain sieved gel; (c) Filling, namely uniformly stirring and mixing the sieved gel, and filling the gel into a pre-filling and sealing syringe to obtain a filling intermediate product; (d) Sterilizing, namely sterilizing the filling intermediate product by high-temperature damp heat to obtain a sterilized product; (e) Lamp inspection, namely visually observing the sterilized product under a clarity detector; (f) And packaging, namely performing blister packaging on the qualified products to obtain the final target products.
  6. 6. The preparation method according to claim 5, wherein in the step 3 (a), the balanced salt solution is prepared by dissolving sodium chloride, sodium dihydrogen phosphate and disodium hydrogen phosphate in water for injection, and the mass ratio of sodium chloride, sodium dihydrogen phosphate and disodium hydrogen phosphate is (500-1000): 10-20): 40-100.
  7. 7. A crosslinked chitosan gel for intra-articular injection prepared by the method of any one of claims 1-6.
  8. 8. The crosslinked chitosan gel according to claim 7, wherein said crosslinked chitosan gel has an elastic modulus of 100-500 Pa and a viscous modulus of 15-50 Pa.
  9. 9. Use of a crosslinked chitosan gel for intra-articular cavity injection according to claim 8, characterized in that it is used by injecting said crosslinked chitosan gel into the articular cavity to supplement intra-articular cavity viscoelastic substances, lubricate the joints, relieve pain and improve joint function.

Description

Crosslinked chitosan gel for joint cavity injection and preparation method and application thereof Technical Field The invention relates to the field of biological materials, in particular to a crosslinked chitosan gel for joint cavity injection, a preparation method and application thereof. Background Bone joint is a degenerative joint disease, often manifested as joint pain, stiffness. The main pathology of osteoarthritis is cartilage degeneration and disappearance, and bone neoplasm formation by joint marginal ligament attachment and subchondral bone reactive hyperplasia, and thereby joint pain, stiffness and dysfunction. Is frequently occurring in people over 50 years old and has more females than males. The therapeutic goal of osteoarthritis is to relieve pain, improve joint function and quality of life, and avoid toxic and side effects as much as possible. The current clinical treatments of osteoarthritis include non-drug conservation, drug therapy, surgery, etc., and require treatment schemes to be selected according to the disease stage and physical condition of the patient. The intra-articular injection medicine or biological preparation has the advantages of simple operation, high local bioavailability, less systemic adverse reaction and the like, becomes one of the conventional intervention means for treating the diseases related to the osteoarthritis, and is widely used in clinic. The application of sodium hyaluronate (also called sodium hyaluronate, HA) to perform joint cavity injection viscoelasticity supplement treatment scheme HAs become a mature treatment option of early-middle arthritis, but natural sodium hyaluronate solution is biodegraded, and the residence period in the body is shorter, so that the sodium hyaluronate injection preparation HAs a shorter curative effect, the general product needs to be injected into 3-5 needles, the curative effect is generally 3-6 months, and the discomfort of patients in medication is increased. Under the background, some macromolecular polysaccharides based on the same action mechanism of sodium hyaluronate are used for injecting and lubricating bone joint cavities, wherein carboxymethyl chitin is another macromolecular polysaccharide which is used in the market at present, and the treatment effect produced by using the carboxymethyl chitin as a viscoelastic supplement is superior to that of sodium hyaluronate due to the good lubricity and bacteriostasis. Carboxymethyl chitin is a high molecular compound whose main component is polyamino glucose after purification processing. Glucosamine is a natural amino monosaccharide, and is the main matrix in articular cartilage. Exogenous glucosamine can stimulate chondrocytes to synthesize proteoglycan, supplement lost components in cartilage matrix, and promote cartilage repair. In addition, glucosamine inhibits the release of hydrolases such as elastase and lysozyme, and reduces the hydrolytic damage to the cartilage matrix, thus allowing longer retention time in the body than sodium hyaluronate. However, carboxymethyl chitin itself has some disadvantages such as inability to terminally sterilize, small molecular weight, poor viscoelasticity, high injection frequency, etc. Currently, in order to extend the time of gel action in the joint cavity and reduce the frequency of injections, related manufacturers have attempted to achieve this by increasing the weight average molecular weight of carboxymethyl chitin and by crosslinking it. Chinese patent CN 106474569a discloses a preparation method of carboxymethyl chitin critical hydrogel, which has the characteristic that the elastic modulus and the viscous modulus are always equal, and prolongs the in vivo residual time to realize single dose injection. However, the viscoelastic modulus is low, the lubricating and buffering functions of normal joint fluid are difficult to meet, and the treatment effect is limited. In addition, in the patent, the organic solvent can cause dehydration of hydrophilic groups in the gel in the alcohol precipitation process to damage the integrity of the three-dimensional crosslinked grid, so that the degradation period of the gel in vivo is shortened. Chinese patent CN115671405A discloses a joint cavity injection gel and a preparation method thereof, wherein the gel is obtained by mixing and crosslinking polyethylene glycol active ester and carboxymethyl chitosan, and the joint cavity injection gel is prepared by mixing, sterilizing and cooling the gel after crushing and mixing with non-crosslinked carboxymethyl chitosan solution. The friction coefficient is small, the lubricating performance is good, and the safety performance is high. However, the method relies on the high molecular weight of carboxymethyl chitosan to improve the degradation resistance, and the viscoelasticity of gel cannot well meet the rheological requirements of joint synovial fluid on various forms such as walking, running and the like due to the factors such as