CN120695028A - A butylene glycol cross-linked sodium hyaluronate gel and its composition and preparation method - Google Patents

Abstract

The invention discloses a sodium hyaluronate gel of D Gan Jiaolian and a composition and a preparation method thereof, wherein the sodium hyaluronate gel is a gel mixture formed by swelling gel of crosslinked hyaluronic acid and salt thereof in sodium chloride phosphate physiological buffer solution, wherein the gel of the crosslinked hyaluronic acid and salt thereof is prepared by crosslinking hyaluronic acid or salt thereof with a crosslinking agent, and the D50 particle size distribution range of the gel mixture is 300-3000 mu m, so that the physical properties of healthy joint synovial fluid can be better simulated under the condition of the same gel molecular weight and storage elastic modulus, more effective lubrication and buffering effects are provided, thereby reducing joint friction and pain and improving the curative effect of the crosslinked sodium hyaluronate maintained in vivo.

Description

Di Gan Jiaolian sodium hyaluronate gel, and composition and preparation method thereof

Technical Field

The invention relates to the field of pharmaceutical compositions, in particular to a sodium butyrate Gan Jiaolian hyaluronate gel, a composition and a preparation method thereof.

Background

Osteoarthritis (Osteoarthritis, OA) is a common degenerative joint disease, which is mainly manifested by destruction of articular cartilage, hyperosteogeny and periarticular inflammation. It is the most common type of arthritis, most common in the middle-aged and elderly, but may also occur in advance due to joint damage, obesity or genetic factors.

The therapeutic principle of osteoarthritis mainly comprises three aspects of relieving pain, inhibiting inflammatory reaction and promoting cartilage repair. Common methods of treatment encompass physical therapy (e.g., exercise therapy, weight management, massage, etc.), medication, surgical treatment, and nutritional support, among others. In drug therapy, anti-inflammatory drugs are common analgesic and anti-inflammatory means for doctors, and among them, non-steroidal anti-inflammatory drugs (NSAIDs) are the first drugs, and although NSAIDs have remarkable effects in relieving pain and anti-inflammatory, they cannot radically treat diseases or reverse joint injuries. In addition, prolonged use of NSAIDs may cause adverse reactions to the gastrointestinal tract (e.g., gastric ulcers, bleeding, etc.), and may also potentially harm the cardiovascular system and kidney function, and thus should be carefully used.

Hyaluronic acid is a key component of joint synovial fluid and is critical to maintaining normal function of the joint. It not only gives good viscoelasticity to synovial fluid, but also protects articular cartilage, so that it maintains ideal cushioning properties. However, in osteoarthritis patients, clear abnormalities in hyaluronic acid in joint synovial fluid occur, manifested by reduced molecular weight, reduced concentration and reduced viscoelasticity.

The commercial product Ding Gan of LG company, namely the crosslinked sodium hyaluronate injection (trade name: hyruan ONE), is a medicament for treating osteoarthritis, can lubricate joint parts, reduce inflammation and relieve pain, and is characterized by long acting time and capability of maintaining curative effect in vivo for up to 6 months. However, in practical application, most patients need to re-inject the medicine within 6 months for relieving symptoms such as pain.

In order to improve the therapeutic effect of the osteoarthritis injection drug maintained in vivo, further research on the drug is necessary.

Disclosure of Invention

The invention aims to provide Ding Gan crosslinked sodium hyaluronate gel with controllable particle size, stable curative effect and small side effect.

The technical scheme of the invention is as follows:

The invention provides a crosslinked hyaluronic acid gel, which is prepared by crosslinking hyaluronic acid or salt thereof with a crosslinking agent, wherein the D50 particle size distribution range of the crosslinked hyaluronic acid gel is 300-800μm、500-1000μm、750-1250μm、1000-1500μm、1250-1750μm、1500-2000μm、1750-2250μm、2000-2500μm、2250-2750μm、2500-3000μm.

The invention provides a composition for injection containing crosslinked hyaluronic acid gel, which is a gel mixture formed by swelling gel of crosslinked hyaluronic acid and salt thereof in physiological buffer solution of sodium phosphate, wherein the gel of the crosslinked hyaluronic acid and salt thereof is prepared by crosslinking hyaluronic acid or salt thereof with a crosslinking agent, the concentration of the hyaluronic acid or salt thereof is 15-25g/L, the physiological buffer solution of sodium phosphate comprises 6-12g/L of sodium chloride, 0.01-0.1g/L of potassium dihydrogen phosphate or sodium dihydrogen phosphate, 0.1-0.5g/L of disodium hydrogen phosphate or potassium dihydrogen phosphate, and water for injection as a solvent, wherein the D50 particle size distribution range of the gel mixture is 300-800μm、500-1000μm、750-1250μm、1000-1500μm、1250-1750μm、1500-2000μm、1750-2250μm、2000-2500μm、2250-2750μm、2500-3000μm.

In some embodiments, the molecular weight of the hyaluronic acid or salt thereof is 200-400 Da and the storage elastic modulus of the crosslinked hyaluronic acid or salt thereof gel is 100-600pa, preferably 200-500pa.

In some embodiments, the hyaluronic acid or salt thereof is selected from one or a combination of hyaluronic acid, sodium hyaluronate, potassium hyaluronate, calcium hyaluronate, magnesium hyaluronate, ammonium hyaluronate, tetrabutylammonium hyaluronate, bismuth hyaluronate, and zinc hyaluronate. Sodium hyaluronate is preferred.

In some embodiments, the cross-linking agent is selected from 1, 4-butanediol diglycidyl ether, glycerol triglycidyl ether, resorcinol diglycidyl ether, allyl glycidyl ether, ethylene glycol diglycidyl ether, 1, 6-hexanediol diglycidyl ether, or neopentyl glycol diglycidyl ether, preferably 1, 4-butanediol diglycidyl ether.

In some embodiments, when potassium dihydrogen phosphate is 0.01 to 0.1g/L, disodium hydrogen phosphate is 0.1 to 0.5g/L.

In other embodiments, the dipotassium phosphate is 0.1-0.5g/L when the sodium phosphate monobasic is 0.01-0.1 g/L.

The invention also provides a preparation method of the crosslinked hyaluronic acid gel, which comprises the following steps:

(1) Mixing sodium hyaluronate with molecular weight of 200-400 Da with alkaline solution, adding 0.5-5% crosslinking agent and sodium hyaluronate solution, and mixing, wherein the mass ratio of sodium hyaluronate to alkaline solution is (0.1-1): 1;

(2) Crosslinking treatment, namely crosslinking the mixture obtained in the step (1) at 20-60 ℃ for 10-50 hours to obtain crosslinked sodium hyaluronate gel, wherein the alkaline solution is one of sodium hydroxide aqueous solution, potassium hydroxide aqueous solution or ammonia water, and the crosslinking agent is any one of 1, 4-butanediol diglycidyl ether, glycerol triglycidyl ether, resorcinol diglycidyl ether, allyl glycidyl ether, ethylene glycol diglycidyl ether, 1, 6-hexanediol diglycidyl ether or neopentyl glycol diglycidyl ether;

(3) Washing, namely preparing a sodium phosphate physiological buffer solution, adding hydrochloric acid solution equivalent to the alkaline solution, adding the crosslinked sodium hyaluronate gel obtained in the step (2) into the sodium phosphate physiological buffer solution, standing for 1-20h, then discarding supernatant, and repeatedly flushing the solution to pH 7-10 by adopting the sodium phosphate physiological buffer solution, wherein the sodium phosphate physiological buffer solution comprises 6-12g/L of sodium chloride, 0.01-0.1g/L of potassium dihydrogen phosphate or sodium dihydrogen phosphate, 0.1-0.5g/L of disodium hydrogen phosphate or potassium dihydrogen phosphate, and the balance of water for injection;

(4) Swelling, namely standing and swelling the crosslinked sodium hyaluronate gel washed in the step (3) for 6-20h to obtain a gel mixture;

(5) Crushing, namely crushing the gel mixture obtained by swelling in the step (4) into crosslinked sodium hyaluronate gel particles, wherein the crushing mode of the gel mixture with the D50 particle size distribution range of 300-800μm、500-1000μm、750-1250μm、1000-1500μm、1250-1750μm、1500-2000μm、1750-2250μm、2000-2500μm、2250-2750μm、2500-3000μm; of the particle size of the crosslinked sodium hyaluronate gel particles comprises, but is not limited to, cutting and crushing, stirring and crushing, wet crushing, low-temperature crushing, extrusion sieving and the like;

(6) Sterilizing, namely stirring and homogenizing the crushed crosslinked sodium hyaluronate gel particles in the step (5), and then carrying out damp-heat sterilization at 121 ℃ for 10-30min to obtain the crosslinked sodium hyaluronate gel.

The invention also provides a preparation method of the injection composition containing the crosslinked hyaluronic acid gel, which comprises the following steps:

(1) Mixing sodium hyaluronate with molecular weight of 200-400 Da with alkaline solution, adding 0.5-5% crosslinking agent and sodium hyaluronate solution, and mixing, wherein the mass ratio of sodium hyaluronate to alkaline solution is (0.1-1): 1;

(2) Crosslinking treatment, namely crosslinking the mixture obtained in the step (1) at 20-60 ℃ for 10-50 hours to obtain crosslinked sodium hyaluronate gel, wherein the alkaline solution is one of sodium hydroxide aqueous solution, potassium hydroxide aqueous solution or ammonia water, and the crosslinking agent is any one of 1, 4-butanediol diglycidyl ether, glycerol triglycidyl ether, resorcinol diglycidyl ether, allyl glycidyl ether, ethylene glycol diglycidyl ether, 1, 6-hexanediol diglycidyl ether or neopentyl glycol diglycidyl ether;

(3) Washing, namely preparing a sodium phosphate physiological buffer solution, adding hydrochloric acid solution equivalent to the alkaline solution, adding the crosslinked sodium hyaluronate gel obtained in the step (2) into the sodium phosphate physiological buffer solution, standing for 1-20h, then discarding supernatant, and repeatedly flushing the solution to pH 7-10 by adopting the sodium phosphate physiological buffer solution, wherein the sodium phosphate physiological buffer solution comprises 6-12g/L of sodium chloride, 0.01-0.1g/L of potassium dihydrogen phosphate or sodium dihydrogen phosphate, 0.1-0.5g/L of disodium hydrogen phosphate or potassium dihydrogen phosphate, and the balance of water for injection;

(4) Swelling, namely standing and swelling the crosslinked sodium hyaluronate gel washed in the step (3) for 6-20h to obtain a gel mixture;

(5) Crushing, namely crushing the gel mixture obtained by swelling in the step (4) into crosslinked sodium hyaluronate gel particles, wherein the crushing mode of the gel mixture with the D50 particle size distribution range of 300-800μm、500-1000μm、750-1250μm、1000-1500μm、1250-1750μm、1500-2000μm、1750-2250μm、2000-2500μm、2250-2750μm、2500-3000μm; of the particle size of the crosslinked sodium hyaluronate gel particles comprises, but is not limited to, cutting and crushing, stirring and crushing, wet crushing, low-temperature crushing, extrusion sieving and the like;

(6) Sterilizing, namely stirring and homogenizing the crushed crosslinked sodium hyaluronate gel particles in the step (5), and then carrying out damp-heat sterilization for 10-30min at 121 ℃;

(7) And (3) filling, namely filling the crosslinked sodium hyaluronate gel particles sterilized in the step (6) by a prefilled syringe, and performing damp-heat sterilization at 121 ℃ for 10-30min to obtain the crosslinked sodium hyaluronate gel injection.

The Ding Gan crosslinked sodium hyaluronate gel and the injection composition thereof are applied to relieving osteoarthritis. Further, the injectable composition or the crosslinked sodium hyaluronate gel injection is administered by injection through the cavity of a bone joint. Further, the bone joint is in particular a knee bone joint.

Compared with the prior art, the application has the beneficial effects that the crosslinked sodium hyaluronate gel is crushed to 300-3000 mu m particle size after being swelled in the physiological buffer solution of sodium phosphate, so that the particle size distribution of the crosslinked sodium hyaluronate gel can be effectively controlled, the physical properties of the healthy joint synovial fluid can be better simulated under the condition of the same gel molecular weight and storage elastic modulus, more effective lubrication and buffering effect can be provided, thereby reducing joint friction and pain and improving the curative effect of the crosslinked sodium hyaluronate maintained in vivo.

Detailed Description

The application is further illustrated by the following specific examples. It is to be understood that the examples of the present application are intended to be illustrative of the present application and are not to be construed as limiting the present application. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. The raw materials of specific origin are not noted in the following examples, and are generally commercially available conventional products. The technical scheme obtained by simply improving the application or adopting conventional means or components to perform equivalent substitution on the basis of the technical scheme of the application belongs to the protection scope of the application.

Example 1

A method for preparing a composition for injection of a butyro Gan Jiaolian hyaluronic acid gel, comprising the steps of:

(1) Mixing sodium hyaluronate with molecular weight of 200-400 Da with alkaline solution, adding 0.5-5% crosslinking agent and sodium hyaluronate solution, and mixing, wherein the mass ratio of sodium hyaluronate to alkaline solution is (0.1-1): 1;

(2) Crosslinking treatment, namely crosslinking the mixture obtained in the step (1) for 10-50 hours at 20-60 ℃ to prepare crosslinked sodium hyaluronate gel (the storage elastic modulus is 100-600 pa), wherein the alkaline solution is one of sodium hydroxide aqueous solution, potassium hydroxide aqueous solution or ammonia water, and the crosslinking agent is 1, 4-butanediol diglycidyl ether;

(3) Washing, namely preparing a sodium phosphate physiological buffer solution, adding hydrochloric acid solution equivalent to the alkaline solution, adding the crosslinked sodium hyaluronate gel obtained in the step (2) into the sodium phosphate physiological buffer solution, standing for 1-20h, discarding supernatant, and repeatedly flushing the solution to pH 7-10 by adopting the sodium phosphate physiological buffer solution, wherein the concentration of hyaluronic acid or salt thereof is 20g/L, the sodium phosphate physiological buffer solution comprises 6-12g/L of sodium chloride, 0.01-0.1g/L of sodium dihydrogen phosphate, 0.1-0.5g/L of potassium dihydrogen phosphate and the balance of water for injection;

(4) Swelling, namely standing and swelling the crosslinked sodium hyaluronate gel washed in the step (3) for 6-20h to obtain a gel mixture;

(5) Crushing, namely crushing the gel mixture obtained by swelling in the step (4) into crosslinked sodium hyaluronate gel particles in a squeezing and sieving mode, wherein the D50 particle size distribution range of the particle size of the crosslinked sodium hyaluronate gel particles is 300-800 mu m;

(6) Sterilizing, namely stirring and homogenizing the crushed crosslinked sodium hyaluronate gel particles in the step (5), and then carrying out damp-heat sterilization for 10-30min at 121 ℃;

(7) And (3) filling, namely filling the crosslinked sodium hyaluronate gel particles sterilized in the step (6) by a prefilled syringe, and performing damp-heat sterilization at 121 ℃ for 10-30min to obtain the crosslinked sodium hyaluronate gel injection.

Examples 2 to 10

Examples 2 to 10 are substantially the same as example 1 except that the crosslinked sodium hyaluronate gel particles of examples 2 to 10 have a D50 particle size distribution ranging in order from 500-1000μm、750-1250μm、1000-1500μm、1250-1750μm、1500-2000μm、1750-2250μm、2000-2500μm、2250-2750μm、2500-3000μm.

Comparative examples 1 to 2

Comparative examples 1-2 were substantially the same as example 1 except that the particle size D50 of the crosslinked sodium hyaluronate gel particles of comparative examples 1-2 was distributed in a range of 50-250 μm, 4000-4500 μm in order.

Comparative example 3

Comparative example 3 is commercially available product Hyruan ONE.

Experimental example 1 Rabbit joint Chamber local irritation experiment

Taking 13 samples of the invention in examples 1-10 and comparative examples 1-3, respectively injecting into the knee joint of a rabbit for 2 times, and taking samples for histological examination after 48h of the second injection at intervals of 0.2 ml/time, and comparing the irritation of the two samples to joint tissues. Wherein, the samples of examples 1-10 and comparative examples 1-3 were all found to be obviously reddish and swelling after being injected into the knee joint of the rabbit.

Test example 2 human body Effect experiment

1. Experimental method

70 Cases of outpatient knee joint inflammation patients are selected and randomly divided into 14 groups, 5 persons in each group are respectively a blank control group, an example 1-10 group and a comparative example 1-3 group, wherein each of the example 1-10 group and the comparative example 1-3 group is injected with each group of medicines (specification: 3ml, 60mg according to sodium hyaluronate) into knee joint cavities, and the blank control group is injected with 3ml of physiological saline. The average WOMAC arthritis index score and VAS pain score scale are used to evaluate the improvement of clinical symptoms and the change of the structure and function of the articular cartilage before and after each intervention, and the statistical analysis is carried out

A visual simulation scoring method (visual analogue scale, VAS) VAS was used to evaluate the pain degree index based on a score of 2.57.+ -. 1.04 for the average of mild pain, 5.18.+ -. 1.41 for the average of moderate pain and 8.41.+ -. 1.35 for the average of severe pain.

The VAS scores before and after subject intervention are compared to table 1 and the WOMAC knee scores before and after subject intervention are compared to table 2.

Table 1 comparison of VAS scores before and after subject intervention

Remarks: -representing no significant difference (P > 0.05) from the pre-injection comparison to the placebo group, # representing significant difference (P < 0.05) from the pre-injection comparison to the present group of patients, & representing very significant difference (P < 0.01) from the pre-injection comparison to the present group of patients.

As is clear from Table 1, the pain results were not reduced after 1 month, 2 months, 3 months, 4 months, 5 months and 6 months of injection, but the pain of the patients after injection of the medicines of examples 1 to 10 of the present invention was significantly reduced as compared with the pain before injection of the medicines and could be maintained for 6 months. Comparative example 1 showed significant pain relief after 1 month and 2 months of drug injection, but gradually increased after 3-6 months. Comparative example 2 the pain-alleviating effect was not as remarkable as examples 1 to 10 after 1 month, 2 months, 3 months, 4 months, 5 months, 6 months of drug injection. Comparative example 3 (commercially available product Hyruan ONE) maintained a mild pain index for a further 1-4 months, but scored higher than the contemporaneous examples 1-10 after 5-6 months, i.e., the pain value was higher.

While the foregoing is directed to the preferred embodiments of the present invention, it will be appreciated by those skilled in the art that various modifications and adaptations can be made without departing from the principles of the present invention, and such modifications and adaptations are intended to be comprehended within the scope of the present invention.

Claims (10)

1. A crosslinked hyaluronic acid gel obtained by crosslinking hyaluronic acid or a salt thereof with a crosslinking agent, characterized in that the crosslinked hyaluronic acid gel has a D50 particle size distribution range of 300-800μm、500-1000μm、750-1250μm、1000-1500μm、1250-1750μm、1500-2000μm、1750-2250μm、2000-2500μm、2250-2750μm、2500-3000μm.

2. An injection composition containing crosslinked hyaluronic acid gel is a gel mixture formed by swelling gel of crosslinked hyaluronic acid and salt thereof in a sodium phosphate physiological buffer solution, wherein the gel of the crosslinked hyaluronic acid and salt thereof is prepared by crosslinking hyaluronic acid or salt thereof with a crosslinking agent, the concentration of the hyaluronic acid or salt thereof is 15-25g/L, and the sodium phosphate physiological buffer solution comprises 6-12g/L of sodium chloride, 0.01-0.1g/L of potassium dihydrogen phosphate or sodium dihydrogen phosphate, 0.1-0.5g/L of disodium hydrogen phosphate or potassium dihydrogen phosphate and water for injection as a solvent;

Characterized in that the D50 particle size distribution of the gel mixture is within the range of 300-800μm、500-1000μm、750-1250μm、1000-1500μm、1250-1750μm、1500-2000μm、1750-2250μm、2000-2500μm、2250-2750μm、2500-3000μm.

3. The crosslinked hyaluronic acid gel according to claim 1 or2, characterized in that the molecular weight of the hyaluronic acid or salt thereof is 200-400 Da and the storage elastic modulus of the crosslinked hyaluronic acid or salt thereof gel is 100-600pa.

4. The crosslinked hyaluronic acid gel of claim 1 or 2 or 3, wherein the hyaluronic acid or salt thereof is selected from one or a combination of hyaluronic acid, sodium hyaluronate, potassium hyaluronate, calcium hyaluronate, magnesium hyaluronate, ammonium hyaluronate, tetrabutylammonium hyaluronate, bismuth hyaluronate, and zinc hyaluronate.

5. The crosslinked hyaluronic acid gel according to claim 1 or 2, characterized in that the crosslinking agent is selected from 1, 4-butanediol diglycidyl ether, glycerol triglycidyl ether, resorcinol diglycidyl ether, allyl glycidyl ether, ethylene glycol diglycidyl ether, 1, 6-hexanediol diglycidyl ether or neopentyl glycol, glycol diglycidyl ether.

6. The composition for injection according to claim 2, wherein the disodium hydrogen phosphate is 0.1 to 0.5g/L when the potassium dihydrogen phosphate is 0.01 to 0.1g/L, or the dipotassium hydrogen phosphate is 0.1 to 0.5g/L when the sodium dihydrogen phosphate is 0.01 to 0.1 g/L.

7. A method for preparing a crosslinked hyaluronic acid gel, comprising the steps of:

(1) Mixing sodium hyaluronate with molecular weight of 200-400 Da with alkaline solution, adding 0.5-5% crosslinking agent and sodium hyaluronate solution, and mixing, wherein the mass ratio of sodium hyaluronate to alkaline solution is (0.1-1): 1;

(2) Crosslinking treatment, namely crosslinking the mixture obtained in the step (1) at 20-60 ℃ for 10-50 hours to obtain crosslinked sodium hyaluronate gel, wherein the alkaline solution is one of sodium hydroxide aqueous solution, potassium hydroxide aqueous solution or ammonia water, and the crosslinking agent is any one of 1, 4-butanediol diglycidyl ether, glycerol triglycidyl ether, resorcinol diglycidyl ether, allyl glycidyl ether, ethylene glycol diglycidyl ether, 1, 6-hexanediol diglycidyl ether or neopentyl glycol diglycidyl ether;

(3) Washing, namely preparing a sodium phosphate physiological buffer solution, adding hydrochloric acid solution equivalent to the alkaline solution, adding the crosslinked sodium hyaluronate gel obtained in the step (2) into the sodium phosphate physiological buffer solution, standing for 1-20h, then discarding supernatant, and repeatedly flushing the solution to pH 7-10 by adopting the sodium phosphate physiological buffer solution, wherein the sodium phosphate physiological buffer solution comprises 6-12g/L of sodium chloride, 0.01-0.1g/L of potassium dihydrogen phosphate or sodium dihydrogen phosphate, 0.1-0.5g/L of disodium hydrogen phosphate or potassium dihydrogen phosphate, and the balance of water for injection;

(4) Swelling, namely standing and swelling the crosslinked sodium hyaluronate gel washed in the step (3) for 6-20h to obtain a gel mixture;

(5) Crushing, namely crushing the gel mixture obtained by swelling in the step (4) into crosslinked sodium hyaluronate gel particles, wherein the D50 particle size distribution range of the particle size of the crosslinked sodium hyaluronate gel particles is 300-800μm、500-1000μm、750-1250μm、1000-1500μm、1250-1750μm、1500-2000μm、1750-2250μm、2000-2500μm、2250-2750μm、2500-3000μm;

(6) Sterilizing, namely stirring and homogenizing the crushed crosslinked sodium hyaluronate gel particles in the step (5), and then carrying out damp-heat sterilization at 121 ℃ for 10-30min to obtain the crosslinked sodium hyaluronate gel.

8. A method for preparing an injectable composition comprising a crosslinked hyaluronic acid gel, comprising the steps of:

(1) Mixing sodium hyaluronate with molecular weight of 200-400 Da with alkaline solution, adding 0.5-5% crosslinking agent and sodium hyaluronate solution, and mixing, wherein the mass ratio of sodium hyaluronate to alkaline solution is (0.1-1): 1;

(2) Crosslinking treatment, namely crosslinking the mixture obtained in the step (1) at 20-60 ℃ for 10-50 hours to obtain crosslinked sodium hyaluronate gel, wherein the alkaline solution is one of sodium hydroxide aqueous solution, potassium hydroxide aqueous solution or ammonia water, and the crosslinking agent is any one of 1, 4-butanediol diglycidyl ether, glycerol triglycidyl ether, resorcinol diglycidyl ether, allyl glycidyl ether, ethylene glycol diglycidyl ether, 1, 6-hexanediol diglycidyl ether or neopentyl glycol diglycidyl ether;

(3) Washing, namely preparing a sodium phosphate physiological buffer solution, adding hydrochloric acid solution equivalent to the alkaline solution, adding the crosslinked sodium hyaluronate gel obtained in the step (2) into the sodium phosphate physiological buffer solution, standing for 1-20h, then discarding supernatant, and repeatedly flushing the solution to pH 7-10 by adopting the sodium phosphate physiological buffer solution, wherein the sodium phosphate physiological buffer solution comprises 6-12g/L of sodium chloride, 0.01-0.1g/L of potassium dihydrogen phosphate or sodium dihydrogen phosphate, 0.1-0.5g/L of disodium hydrogen phosphate or potassium dihydrogen phosphate, and the balance of water for injection;

(4) Swelling, namely standing and swelling the crosslinked sodium hyaluronate gel washed in the step (3) for 6-20h to obtain a gel mixture;

(5) Crushing, namely crushing the gel mixture obtained by swelling in the step (4) into crosslinked sodium hyaluronate gel particles, wherein the D50 particle size distribution range of the particle size of the crosslinked sodium hyaluronate gel particles is 300-800μm、500-1000μm、750-1250μm、1000-1500μm、1250-1750μm、1500-2000μm、1750-2250μm、2000-2500μm、2250-2750μm、2500-3000μm;

(6) Sterilizing, namely stirring and homogenizing the crushed crosslinked sodium hyaluronate gel particles in the step (5), and then carrying out damp-heat sterilization for 10-30min at 121 ℃;

(7) And (3) filling, namely filling the crosslinked sodium hyaluronate gel particles sterilized in the step (6) by a prefilled syringe, and performing damp-heat sterilization at 121 ℃ for 10-30min to obtain the crosslinked sodium hyaluronate gel injection.

9. Use of the crosslinked hyaluronic acid gel or the injectable composition according to any of claims 1-8 for alleviating osteoarthritis.

10. The use according to claim 9, wherein the injectable composition or the cross-linked sodium hyaluronate gel injection is administered by injection through the osteoarticular cavity.