Multi-component synovitis therapeutic composition based on repairing cartilage tissue and use thereof

Abstract

The present invention discloses a multi-component synovitis therapeutic composition based on cartilage tissue repair and a use thereof, relating to the technical field of biomedicine. The composition comprises glucosamine hydrochloride, chondroitin sulfate, dimethyl sulfone, and graded molecular weight sodium hyaluronate. By compounding these components in precise parts by weight, the present invention constructs a gradient sustained-release and targeted delivery system for synovitis lesions. Dimethyl sulfone specifically inhibits hyaluronidase activity in the inflamed joint cavity, significantly reducing sodium hyaluronate degradation and prolonging the retention time of each active ingredient at the lesion site. High molecular weight sodium hyaluronate rapidly forms a lubricating protective film to achieve immediate analgesia and relieve ankylosis, while medium- and low-molecular-weight sodium hyaluronate penetrates the synovial barrier and carries cartilage repair components to the cartilage defect area, thereby achieving synergistic enhancement and comprehensively improving synovitis treatment efficacy.

Description

[0001] DESCRIPTION

[0002] Multi-component synovitis therapeutic composition based on repairing cartilage tissue and use thereof

[0003] TECHNICAL FIELD

[0004] The present invention relates to the technical field of biomedicine, specifically to a multi-component synovitis therapeutic composition based on repairing cartilage tissue and a use thereof.

[0005] BACKGROUND

[0006] Synovitis is an inflammatory lesion of the joint synovium triggered by various physical, chemical, biological, and other factors. It is a clinically common high-incidence joint disease in orthopedics, often affecting weight-bearing joints such as knees and hips. Upon onset, the synovium exhibits pathological manifestations such as congestion, edema, and secretory dysfunction, leading to symptoms like joint effusion, pain, stiffness, and limited mobility. If the condition persists, irreversible changes such as synovial hyperplasia and thickening may occur. Effective treatment of synovitis holds significant clinical and social importance. If inflammation is not controlled promptly, the persistent inflammatory microenvironment continuously damages articular cartilage, causing cartilage matrix degradation and chondrocyte apoptosis, ultimately progressing to osteoarthritis. This severely reduces patients' limb mobility and quality of life, and increases the consumption of social medical resources. Therefore, researching and developing efficient treatments for synovitis is crucial for protecting joint function and delaying joint degeneration. Repairing cartilage tissue plays a central and critical role in synovitis treatment. Cartilage tissue itself lacks blood vessels and nerves, resulting in extremely poor repair capacity. Pro-inflammatory factors produced in synovitis accelerate the degradation of proteoglycans and type II collagen in the cartilage matrix. Conversely, cartilage damage further stimulates synovial inflammation, forming a pathological vicious cycle of "synovial inflammation - cartilage damage - aggravated inflammation". Repairing damaged cartilage tissue can fundamentally break this cycle, improve the pathological state of synovitis, enhance the long-term efficacy of treatment, and prevent recurrence.

[0007] In the prior art, compositions for treating synovitis are mostly single active ingredients or simple compound preparations. Sodium hyaluronate is often used in a single molecular weight form, suffering from short retention time in the joint cavity and poor targeting of active ingredients to the lesion. They cannot simultaneously achieve immediate relief of joint pain and stiffness symptoms and long-term cartilage tissue repair. Furthermore, a synergistic targeted delivery system is not formed among the components. Hyaluronidase in the inflamed joint cavity easily degrades sodium hyaluronate rapidly, and cartilage repair components such as glucosamine and chondroitin cannot effectively accumulate in the cartilage defect lesion area. This ultimately limits the therapeutic effect for synovitis, making it impossible to fundamentally break the pathological vicious cycle of synovitis and cartilage damage. Therefore, developing a multi-component synovitis therapeutic composition based on repairing cartilage tissue and its use is of great significance.

[0008] SUMMARY

[0009] An objective of the present invention is to address the shortcomings of the prior art by providing a multi-component synovitis therapeutic composition based on repairing cartilage tissue and a use thereof. It constructs a gradient sustained-release and targeted delivery system for synovitis lesions by compounding graded molecular weight sodium hyaluronate with glucosamine hydrochloride, chondroitin sulfate, and dimethyl sulfone in precise parts by weight. Dimethyl sulfone is utilized to specifically inhibit the activity of hyaluronidase in the inflamed joint cavity, significantly reducing the degradation of sodium hyaluronate and prolonging the retention time of each active ingredient at the lesion site. High molecular weight sodium hyaluronate rapidly forms a lubricating protective film to achieve immediate analgesia and relieve ankylosis, while medium-low molecular weight sodium hyaluronate penetrates the synovial barrier, carrying cartilage repair components to enrich the cartilage defect area, thereby achieving synergistic enhancement of the components.

[0010] To solve the above technical problems, the present invention provides the following technical solutions: A multi-component synovitis therapeutic composition based on repairing cartilage tissue, characterized in that the composition consists of glucosamine hydrochloride, chondroitin sulfate, dimethyl sulfone, and graded molecular weight sodium hyaluronate;

[0011] The components comprise, in parts by weight: 100-200 parts by weight of glucosamine hydrochloride, 50-100 parts by weight of chondroitin sulfate, 30-80 parts by weight of dimethyl sulfone, and 10-50 parts by weight of graded molecular weight sodium hyaluronate;

[0012] The graded molecular weight sodium hyaluronate is compounded from high molecular weight sodium hyaluronate and medium-low molecular weight sodium hyaluronate, wherein the weight ratio of high molecular weight sodium hyaluronate to medium-low molecular weight sodium hyaluronate is 2: 1-3:1, the molecular weight of the high molecular weight sodium hyaluronate is 1500-2000 kDa, and the molecular weight of the medium-low molecular weight sodium hyaluronate is 100-800 kDa.

[0013] Further, the purity of the glucosamine hydrochloride is not less than 98%, it is pharmaceutical grade glucosamine hydrochloride, its raw material is crystalline glucosamine hydrochloride with a crystal water content of 1-2, and the fine powder particle size D50 of the glucosamine hydrochloride after grinding is 30-50 pm. Glucosamine hydrochloride with this particle size specification exhibits good physical compatibility with other components in the composition, preventing layering or agglomeration during mixing, while ensuring stable dispersibility in subsequent formulation processes.

[0014] Furthermore, the chondroitin sulfate is chondroitin sulfate sodium salt, extracted from shark cartilage tissue, with a purity of not less than 90%, a sulfate group content of 35-40%, and a molecular weight of 50-150 kDa. Chondroitin sulfate in this molecular weight range is the main effective component form present in natural cartilage matrix. When combined with glucosamine hydrochloride, it forms structurally matched cartilage repair components. Moreover, this chondroitin sulfate is free from other animal-derived impurity residues, meeting the impurity control requirements for pharmaceutical raw materials.

[0015] Furthermore, the dimethyl sulfone is pharmaceutical grade dimethyl sulfone with a purity of not less than 99%, its crystal form is orthorhombic, and the fine powder particle size D90 after grinding is 40-60 pm. This crystal form of dimethyl sulfone is chemically stable and does not undergo crystal form transformation under normal temperature and pressure. Dimethyl sulfone with this particle size achieves uniform dispersion when mixed with other components, preventing a decrease in the homogeneity of the mixed system due to particle size differences, while ensuring stable dissolution performance in subsequent applications.

[0016] Furthermore, the medium-low molecular weight sodium hyaluronate is compounded from low molecular weight sodium hyaluronate and medium molecular weight sodium hyaluronate, wherein the weight ratio of low molecular weight sodium hyaluronate to medium molecular weight sodium hyaluronate is 1:1, the molecular weight of the low molecular weight sodium hyaluronate is 100-400 kDa, and the molecular weight of the medium molecular weight sodium hyaluronate is 400-800 kDa. The medium-low molecular weight sodium hyaluronate prepared by this compounding method forms a gradient molecular weight distribution, which, compared to a single molecular weight medium-low molecular sodium hyaluronate, better cooperates with high molecular weight sodium hyaluronate to form a graded sodium hyaluronate component system.

[0017] Furthermore, the molecular weight of the high molecular weight sodium hyaluronate is 1600-1900 kDa, its purity is not less than 95%, it is sodium hyaluronate prepared by a microbial fermentation method using Streptococcus zooepidemicus as the fermentation strain. The high molecular weight sodium hyaluronate prepared by this process has a narrow molecular weight distribution, no chemical modification residues, and its glucuronic acid content is 45-50%, consistent with the structure of sodium hyaluronate in natural joint synovial fluid. The purity of the high molecular weight sodium hyaluronate in the graded molecular weight sodium hyaluronate is consistent with that of the medium-low molecular weight sodium hyaluronate, ensuring the uniformity of the graded sodium hyaluronate component. Furthermore, the glucosamine hydrochloride, chondroitin sulfate, dimethyl sulfone, and graded molecular weight sodium hyaluronate are all 80-mesh standard fine powders after grinding, the particle size D90 of all component fine powders is not greater than 100 pm, the particle size distribution span is not greater than 50 pm, and the bulk density of the fine powder of each component is 0.4-0.6 g / cm3. The fine powders of each component within this bulk density range achieve density matching during mixing, avoiding gravitational layering due to bulk density differences. Meanwhile, the 80-mesh standard fine powder specification ensures sufficient contact area among components during mixing, achieving uniform mixing.

[0018] Furthermore, the preparation method of the composition comprises the following steps:

[0019] 51. Weighing the raw material components of glucosamine hydrochloride, chondroitin sulfate, dimethyl sulfone, and graded molecular weight sodium hyaluronate respectively according to the parts by weight ratio, grinding all raw material components separately using a grinder, and passing through an 80-mesh standard sieve after grinding to obtain the corresponding fine powder of each raw material for later use;

[0020] 52. Putting the glucosamine hydrochloride fine powder, chondroitin sulfate fine powder, and dimethyl sulfone fine powder into a three-dimensional mixer, adjusting the rotation speed of the three-dimensional mixer to 150-200 r / min, and continuously mixing at this speed for 15-25 min to obtain a uniformly mixed premix powder;

[0021] S3. Adding the graded molecular weight sodium hyaluronate fine powder to the premix powder obtained in S2, adjusting the rotation speed of the three-dimensional mixer to 100-150 r / min, and continuously mixing at this speed for 20-30 min; after mixing is completed, discharging to obtain the composition.

[0022] Furthermore, the grinder used in SI is a universal grinder, the spindle speed of the universal grinder during grinding is 2000-3000 r / min, the grinding time for a single component is 5-10 min, air cooling is used for cooling during the grinding process, the temperature of the raw material components during grinding does not exceed 40°C, sieving uses a standard metal sieve mesh, the sieve mesh size deviation is not greater than ±2 mesh, the ratio of the rotation speed of the mixing drum to the revolution speed of the three-dimensional mixer in S2 and S3 is 1 :3-1 :5, and an intermittent stirring method is used during the mixing process, with stirring paused for 1 min after every 5 min of continuous mixing, before continuing mixing.

[0023] Use of a multi-component synovitis therapeutic composition based on repairing cartilage tissue, applicable to the above-mentioned multi-component synovitis therapeutic composition based on repairing cartilage tissue, characterized in that the composition is used for preparing a medicament for treating acute or chronic synovitis, the medicament takes the composition as the core active ingredient, and the composition is compounded with pharmaceutically acceptable excipients to prepare conventional pharmaceutical dosage forms, the dosage forms being one or more of granules, capsules, tablets, and injections.

[0024] Compared with the prior art, this multi-component synovitis therapeutic composition based on repairing cartilage tissue and its use have the following beneficial effects:

[0025] The present invention constructs a gradient sustained-release and targeted delivery system for synovitis lesions by compounding graded molecular weight sodium hyaluronate with glucosamine hydrochloride, chondroitin sulfate, and dimethyl sulfone in precise parts by weight. Dimethyl sulfone is utilized to specifically inhibit the activity of hyaluronidase in the inflamed joint cavity, significantly reducing the degradation of sodium hyaluronate and prolonging the retention time of each active ingredient at the lesion site. High molecular weight sodium hyaluronate rapidly forms a lubricating protective film to achieve immediate analgesia and relieve ankylosis, while medium-low molecular weight sodium hyaluronate penetrates the synovial barrier, carrying cartilage repair components to enrich the cartilage defect area, thereby achieving synergistic enhancement of the components. It solves the technical problems of existing compositions, such as poor targeting, short lesion retention time, and inability to simultaneously achieve immediate symptom relief and long-term cartilage repair, fundamentally breaking the pathological vicious cycle of synovitis and cartilage damage, enhancing the therapeutic effect for synovitis, and improving the utilization efficiency of active ingredients, providing a new effective solution for the clinical treatment of synovitis.

[0026] Other advantages, objectives, and features of the present invention will be set forth in part in the following description, and in part will become apparent to those skilled in the art upon examination of the following or may be learned from practice of the invention.

[0027] BRIEF DESCRIPTION OF DRAWINGS

[0028] To explain the technical solutions in the embodiments of the present invention or the prior art more clearly, the following briefly introduces the drawings required for describing the embodiments or the prior art. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without inventive effort.

[0029] Figure 1 is a flow chart of the preparation method of the multi-component synovitis therapeutic composition based on repairing cartilage tissue;

[0030] Figure 2 is a flow block diagram of the preparation method of the multi-component synovitis therapeutic composition based on repairing cartilage tissue.

[0031] DETAILED DESCRIPTION

[0032] To further elaborate on the technical means and effects adopted by the present invention to achieve the intended invention objectives, the following, in conjunction with the accompanying drawings and preferred embodiments, provides a detailed description of the specific implementation, structure, features, and effects of the present invention.

[0033] The present invention discloses a multi-component synovitis therapeutic composition based on repairing cartilage tissue and a use thereof. Aiming at the technical problems of existing synovitis therapeutic compositions, such as poor targeting, short retention time in the joint cavity, and inability to simultaneously achieve immediate symptom relief and long-term cartilage repair, it constructs a gradient sustained-release and targeted delivery system for synovitis lesions, fundamentally breaking the pathological vicious cycle of synovial inflammation and cartilage damage, providing a new clinical solution for acute and chronic synovitis.

[0034] The composition is compounded from glucosamine hydrochloride, chondroitin sulfate, dimethyl sulfone, and graded molecular weight sodium hyaluronate. Each component has a defined parts by weight range. The graded molecular weight sodium hyaluronate is compounded from high molecular weight and medium-low molecular weight sodium hyaluronate in a specific ratio, and the medium-low molecular weight sodium hyaluronate is further compounded by mixing low and medium molecular weight sodium hyaluronate in equal proportions, with strict definitions for each molecular weight range. Simultaneously, the present invention provides detailed requirements for the specifications of each raw material. Glucosamine hydrochloride is pharmaceutical grade and crystalline. Chondroitin sulfate is extracted from shark cartilage and is in the sodium salt form. Dimethyl sulfone is pharmaceutical grade with an orthorhombic crystal form. High molecular weight sodium hyaluronate is prepared by fermentation with Streptococcus zooepidemicus . All components are 80-mesh fine powders after grinding, maintaining a uniform standard in particle size and bulk density to ensure mixing homogeneity.

[0035] The present invention also specifies the preparation method of the composition. First, each raw material is weighed according to the parts by weight, ground using a universal grinder, and passed through an 80-mesh sieve to obtain fine powder. Then, the glucosamine hydrochloride, chondroitin sulfate, and dimethyl sulfone fine powders are placed into a three-dimensional mixer and mixed at a specific speed to prepare a premix powder. Finally, the graded molecular weight sodium hyaluronate fine powder is added, and mixing continues at an adjusted speed. The entire process has standardized requirements for grinding and mixing equipment parameters, operation methods, and time.

[0036] The composition can be used as the core active ingredient, compounded with pharmaceutically acceptable excipients, to prepare various dosage forms such as granules, capsules, tablets, and injections for treating acute or chronic synovitis. By utilizing dimethyl sulfone to inhibit hyaluronidase activity in the inflamed joint cavity, it reduces sodium hyaluronate degradation and prolongs the retention time of active ingredients at the lesion. High molecular weight sodium hyaluronate rapidly forms a lubricating protective film for immediate analgesia and ankylosis relief, while medium-low molecular weight sodium hyaluronate penetrates the synovial barrier, carrying cartilage repair components to enrich the cartilage defect area, achieving synergistic enhancement of the components, effectively improving the therapeutic effect for synovitis and the utilization efficiency of active ingredients.

[0037] Embodiment 1

[0038] This embodiment selects the optimal intermediate parts by weight for component compatibility, uses raw materials that meet pharmaceutical standards and have matching physicochemical properties, and strictly follows the professional preparation process of gradient mixing to prepare a multi-component synovitis therapeutic composition based on repairing cartilage tissue. This composition possesses the dual effects of immediate analgesia and long-term cartilage repair, with significant synergistic effects among the active ingredients, and can specifically improve various pathological symptoms of acute and chronic synovitis, making it suitable for the treatment of clinical moderate to severe synovitis.

[0039] Composition components and raw material specifications: By parts by weight, the components are 150 parts of glucosamine hydrochloride, 75 parts of chondroitin sulfate, 55 parts of dimethyl sulfone, and 30 parts of graded molecular weight sodium hyaluronate.

[0040] Glucosamine hydrochloride is pharmaceutical grade crystalline, with a purity of 99%, a crystal water content of 1.5, and a fine powder particle size D50 of 40 pm after grinding, without agglomeration, exhibiting excellent physical compatibility. Chondroitin sulfate is in the sodium salt form extracted from shark cartilage tissue, with a purity of 95%, a sulfate group content of 38%, a molecular weight of 100 kDa, free from other animal-derived impurity residues, meeting the impurity control requirements for pharmaceutical raw materials. Dimethyl sulfone is pharmaceutical grade ii with an orthorhombic crystal form, a purity of 99.5%, a fine powder particle size D90 of 50 pm after grinding, chemically stable, with no crystal form transformation under normal temperature and pressure. In the graded molecular weight sodium hyaluronate, the weight ratio of high molecular weight to medium-low molecular weight is 2.5: 1. The high molecular weight sodium hyaluronate is prepared by microbial fermentation with Streptococcus zooepidemicus, with a molecular weight of 1800 kDa, a purity of 96%, a glucuronic acid content of 48%, a narrow molecular weight distribution, and no chemical modification residues. The medium-low molecular weight sodium hyaluronate is compounded from low molecular weight and medium molecular weight in a 1:1 ratio, with the low molecular weight range being 100-400 kDa and the medium molecular weight range being 400-800 kDa, both with a purity of 96%, forming a gradient molecular weight distribution. All components are 80-mesh standard fine powders after grinding, with a particle size D90 < 100 pm, a particle size distribution span < 50 pm, and a bulk density of 0.5 g / cm3for each component fine powder, ensuring density matching during mixing.

[0041] Referring to Figure 1 and Figure 2, the preparation method of the composition in this embodiment is as follows:

[0042] SI . Accurately weigh the raw material components of glucosamine hydrochloride, chondroitin sulfate, dimethyl sulfone, and graded molecular weight sodium hyaluronate according to the above parts by weight. Grind each raw material component separately using a universal grinder. Set the spindle speed of the universal grinder to 2500 r / min during grinding, with a grinding time of 7 min for a single component. Continuously use air cooling for cooling during the grinding process, strictly controlling the temperature of the raw material components to <38°C. After grinding, sieve using a vibrating method through an 80-mesh standard metal sieve, ensuring the sieve mesh size deviation is ±1 mesh to guarantee the passing rate of the fine powder. Obtain the corresponding fine powder of each raw material and seal for later use.

[0043] 52. Put the glucosamine hydrochloride fine powder, chondroitin sulfate fine powder, and dimethyl sulfone fine powder into a three-dimensional mixer at once. Adjust the overall rotation speed of the three-dimensional mixer to 180 r / min, with the ratio of the mixing drum rotation speed to the revolution speed being 1:4. Use an intermittent stirring method, pausing stirring for 1 min after every 5 min of continuous mixing. Continue mixing under these parameters for 20 min to obtain a uniformly mixed premix powder.

[0044] 53. Slowly add the graded molecular weight sodium hyaluronate fine powder to the premix powder obtained in S2 to avoid agglomeration. Reduce the rotation speed of the three-dimensional mixer to 120 r / min, maintaining the mixing drum rotation to revolution speed ratio at 1:4. Continue using the same intermittent stirring method, mixing under these parameters for 25 min. After mixing, collect the material from the discharge port to obtain the multi-component synovitis therapeutic composition based on repairing cartilage tissue.

[0045] In summary, the synovitis therapeutic composition prepared in this embodiment selects raw materials balancing specification compliance and physicochemical property compatibility. The particle size and bulk density of each component are highly uniform. The preparation process precisely controls grinding and mixing parameters, following standardized procedures throughout. The resulting composition shows no layering or agglomeration, achieving excellent component mixing uniformity. When this composition is compounded with pharmaceutically acceptable excipients to prepare an injection for use in a rat synovitis model experiment, the results show that the analgesic onset time of the injection is 15 min, ankylosis symptoms are significantly relieved within 30 min, and the retention time of each active ingredient at the joint lesion site can reach 72 h. After 14 days of continuous administration to model rats, the joint effusion resolution rate is 95%, and the repair rate of cartilage matrix and chondrocytes in the cartilage defect area reaches 92%, fundamentally breaking the pathological vicious cycle of synovial inflammation-cartilage damage. Simultaneously, the active ingredient utilization efficiency of this composition reaches over 90% without significant side effects, exhibiting excellent therapeutic effects for acute and chronic synovitis, making it a preferred preparation for clinical treatment of moderate to severe synovitis.

[0046] Embodiment 2

[0047] This embodiment selects parts by weight with a relatively high proportion of cartilage repair and anti-inflammatory active ingredients. The raw materials meet pharmaceutical grade specification requirements, and each index parameter fits the need for component synergy. By fine-tuning the mixing speed and mixing time of the preparation process, the bonding state between components is optimized to prepare a multi-component synovitis therapeutic composition. This composition exhibits outstanding gradient sustained-release effects at the joint lesion, with excellent long-term cartilage repair performance, making it suitable for treating chronic synovitis with a longer disease course and accompanying synovial hyperplasia.

[0048] Composition components and raw material specifications: By parts by weight, the components are 180 parts of glucosamine hydrochloride, 90 parts of chondroitin sulfate, 70 parts of dimethyl sulfone, and 45 parts of graded molecular weight sodium hyaluronate.

[0049] Glucosamine hydrochloride is pharmaceutical grade crystalline, with a purity of 98.5%, a crystal water content of 2, and a fine powder particle size D50 of 45 pm after grinding, exhibiting stable dispersibility. Chondroitin sulfate is the sodium salt extracted from shark cartilage, with a purity of 93%, a sulfate group content of 39%, a molecular weight of 120 kDa, being the main effective component form in natural cartilage matrix, forming structurally matched cartilage repair components when combined with glucosamine hydrochloride. Dimethyl sulfone is pharmaceutical grade with an orthorhombic crystal form, a purity of 99.2%, a fine powder particle size D90 of 55 pm after grinding, achieving uniform dispersion when mixed with other components, with stable dissolution performance. In the graded molecular weight sodium hyaluronate, the weight ratio of high molecular weight to medium-low molecular weight is 3:1. The high molecular weight sodium hyaluronate is prepared by fermentation with Streptococcus zooepidemicus, with a molecular weight of 1900 kDa, a purity of 95%, a glucuronic acid content of 49%, consistent with the structure of sodium hyaluronate in natural joint synovial fluid. The medium-low molecular weight sodium hyaluronate is compounded from low and medium molecular weight in a 1 : 1 ratio, with low molecular weight 100-400 kDa and medium molecular weight 400-800 kDa, both with a purity of 95%, capable of efficiently penetrating the synovial barrier. All components are 80-mesh standard fine powders after grinding, with D90 < 100 pm, particle size distribution span < 50 pm, and a bulk density of 0.55 g / cm3for each component fine powder, meeting density matching requirements during mixing.

[0050] Referring to Figure 1 and Figure 2, the preparation method of the composition in this embodiment is as follows:

[0051] 51. Accurately weigh each raw material component according to the above parts by weight. Grind each raw material separately using a universal grinder, setting the grinder spindle speed to 2800 r / min, with a grinding time of 9 min for a single component. Continuously cool with air during grinding, controlling the raw material temperature to <39 °C. After grinding, sieve through an 80-mesh standard metal sieve with a sieve mesh size deviation of ±2 mesh, using vibration sieving to ensure fine powder quality. Obtain each raw material fine powder and seal away from light for later use.

[0052] 52. Put the glucosamine hydrochloride fine powder, chondroitin sulfate fine powder, and dimethyl sulfone fine powder into a three-dimensional mixer. Adjust the mixer rotation speed to 190 r / min, with the ratio of mixing drum rotation speed to revolution speed being 1:5. Use an intermittent stirring method, pausing for 1 min after every 5 min of mixing, and continue mixing for 23 min to obtain a uniformly mixed premix powder, periodically observing the mixing state during the process to ensure no local caking.

[0053] S3. Add the graded molecular weight sodium hyaluronate fine powder in batches to the premix powder, stirring at low speed while adding. Adjust the three-dimensional mixer rotation speed to 140 r / min, maintaining the mixing drum rotation to revolution speed ratio at 1:5. Use the same intermittent stirring method, continue mixing for 28 min. After mixing, discharge the material and pass it through a sieve a second time to remove a small amount of agglomerates, obtaining the synovitis therapeutic composition.

[0054] In summary, the synovitis therapeutic composition prepared in this embodiment has a component ratio with relatively high content of cartilage repair components like glucosamine hydrochloride and chondroitin sulfate, and the anti-inflammatory component dimethyl sulfone, suitable for the pathological characteristics of chronic synovitis. The preparation process appropriately increases mixing speed and time, further optimizing the uniformity of component mixing. The secondary sieving operation also ensures the quality of the finished composition. When this composition is compounded with pharmaceutical excipients to prepare capsules for use in a rabbit chronic synovitis model experiment, the results show that after oral administration, the analgesic onset time is 20 min, and the retention time of active ingredients at the joint lesion site reaches 60 h, demonstrating outstanding sustained-release effects. After 21 days of continuous administration to model rabbits, the joint effusion resolution rate is 90%, synovial hyperplasia is significantly improved, and the repair rate in the cartilage defect area reaches 88%, effectively delaying the degradation rate of cartilage matrix. The active ingredient utilization efficiency of this composition reaches over 85%, with high oral bioavailability, exhibiting good therapeutic effects for chronic synovitis, suitable for long-term medication in patients with a longer disease course.

[0055] Embodiment 3

[0056] This embodiment selects the basic effective parts by weight of each active ingredient for compounding. Raw materials meeting basic pharmaceutical grade specifications are chosen. The preparation process strictly follows the basic parameters of the standardized process, optimizing the basic procedures of raw material grinding and mixing to prepare a multi-component synovitis therapeutic composition. The raw material preparation cost of this composition is lower, the production operation is simpler, and the analgesic onset is fast, capable of quickly improving typical symptoms of acute synovitis. It is suitable for treating milder acute synovitis and is convenient for promotion and use in primary clinical settings.

[0057] Composition components and raw material specifications: By parts by weight, the components are 120 parts of glucosamine hydrochloride, 60 parts of chondroitin sulfate, 40 parts of dimethyl sulfone, and 15 parts of graded molecular weight sodium hyaluronate.

[0058] Glucosamine hydrochloride is pharmaceutical grade crystalline, with a purity of 98%, a crystal water content of 1, and a fine powder particle size D50 of 35 pm after grinding, exhibiting good physical compatibility with other components. Chondroitin sulfate is the sodium salt extracted from shark cartilage, with a purity of 90%, a sulfate group content of 36%, a molecular weight of 60 kDa, free from animal-derived impurities, meeting basic pharmaceutical raw material requirements. Dimethyl sulfone is pharmaceutical grade with an orthorhombic crystal form, a purity of 99%, a fine powder particle size D90 of 45 pm after grinding, exhibiting good uniform dispersibility. In the graded molecular weight sodium hyaluronate, the weight ratio of high molecular weight to medium-low molecular weight is 2:1. The high molecular weight sodium hyaluronate is prepared by fermentation with Streptococcus zooepidemicus, with a molecular weight of 1600 kDa, a purity of 95%, a glucuronic acid content of 46%, capable of rapidly forming a joint lubricating protective film. The medium-low molecular weight sodium hyaluronate is compounded from low and medium molecular weight in a 1:1 ratio, with low molecular weight 100-400 kDa and medium molecular weight 400-800 kDa, both with a purity of 95%. The gradient molecular weight distribution facilitates carrying cartilage repair components to enrich the cartilage defect area. All components are 80-mesh standard fine powders after grinding, with D90 < 100 pm, particle size distribution span < 50 pm, and a bulk density of 0.45 g / cm3for each component fine powder, achieving gravity balance during mixing with no risk of layering.

[0059] Referring to Figure 1 and Figure 2, the preparation method of the composition in this embodiment is as follows:

[0060] 51. Accurately weigh each raw material component according to the above parts by weight. Grind each raw material separately using a universal grinder, setting the grinder spindle speed to 2200 r / min, with a grinding time of 6 min for a single component. Cool with air during grinding, strictly controlling the raw material temperature to <37 °C to prevent property changes due to high temperature. After grinding, sieve through an 80-mesh standard metal sieve with a sieve mesh size deviation of ±1 mesh. Obtain each raw material fine powder and seal in a moisture-proof container for later use.

[0061] 52. Put the glucosamine hydrochloride fine powder, chondroitin sulfate fine powder, and dimethyl sulfone fine powder into a three-dimensional mixer. Adjust the mixer rotation speed to 160 r / min, with the ratio of mixing drum rotation speed to revolution speed being 1:3. Use an intermittent stirring method, pausing for 1 min after every 5 min of mixing. Continue mixing under these parameters for 18 min to obtain a uniformly mixed premix powder.

[0062] S3. Add the graded molecular weight sodium hyaluronate fine powder to the premix powder. Adjust the three-dimensional mixer rotation speed to 110 r / min, maintaining the mixing drum rotation to revolution speed ratio at 1:3. Continue using the intermittent stirring method, mixing for 22 min. After mixing, discharge the material to obtain the synovitis therapeutic composition. The finished product is sealed and packaged for storage.

[0063] In summary, the synovitis therapeutic composition prepared in this embodiment selects the basic effective parts by weight of each active ingredient for compounding, significantly reducing raw material costs. The preparation process uses standardized basic parameters, is simple to operate, and easy to scale up for production, suitable for the production conditions of primary pharmaceutical enterprises. When this composition is compounded with pharmaceutical excipients to prepare granules for use in a mouse acute synovitis model experiment, the results show that after dissolution and administration, the analgesic onset time is 25 min, ankylosis symptoms are effectively relieved within 40 min, and the retention time of active ingredients at the joint lesion site reaches 56 h. After 7 days of continuous administration to model mice, the joint effusion resolution rate is 88%, and the repair rate in the cartilage defect area reaches 85%, quickly improving typical symptoms such as joint pain and effusion caused by acute synovitis. Moreover, the granules are convenient to take and have good palatability. The active ingredient utilization efficiency of this composition reaches over 80%, the treatment cost is low, and the overall therapeutic effect is good. It is suitable for patients with milder acute synovitis, especially for groups such as children and elderly patients with difficulty swallowing, and has high value for promotion in primary clinical settings.

[0064] Comparative Example This comparative example uses a conventional synovitis therapeutic composition formula from the prior art. Dimethyl sulfone is omitted, the graded molecular weight sodium hyaluronate is replaced with single high molecular weight sodium hyaluronate, no unified control is applied to the bulk density and particle size distribution of the raw materials, and a common continuous stirring mixing process is used to prepare a comparative composition, thereby verifying the scientific nature of the formula design, the necessity of raw material specification control, and the superiority of the preparation process of the composition of the present invention.

[0065] Comparative Example Composition Components and Raw Material Specifications: By parts by weight, the components are 150 parts of glucosamine hydrochloride, 75 parts of chondroitin sulfate, and 30 parts of single high molecular weight sodium hyaluronate, with no dimethyl sulfone added. The basic raw material specifications of glucosamine hydrochloride, chondroitin sulfate, and single high molecular weight sodium hyaluronate are consistent with Embodiment 1, but no unified control is applied to the bulk density and particle size distribution span of each component. The bulk density of each component fine powder varies by 0.2-0.6 g / cm3, the particle size distribution span reaches 80 pm, and there is no clear unified standard.

[0066] Preparation method is as follows:

[0067] SI . Weigh each raw material component according to the above parts by weight. Grind all raw materials together using a universal grinder and pass through an 80-mesh sieve without separate grinding, obtaining a mixed fine powder for later use. S2. Put all the mixed fine powder into an ordinary horizontal mixer, adjust the mixer speed to 200 r / min, use continuous stirring without intermittent operation, stir continuously for 30 min, and discharge directly after stirring to obtain the comparative synovitis composition.

[0068] In summary, the comparative composition prepared in this comparative example, due to the absence of dimethyl sulfone, cannot inhibit hyaluronidase activity in the joint cavity, leading to rapid degradation of sodium hyaluronate. Using single molecular weight sodium hyaluronate cannot achieve gradient sustained-release and targeted delivery. The preparation process is simple stirring mixing, resulting in slight agglomeration and layering of components. When this composition is prepared as an injection and tested in the same rat synovitis model as in Embodiment 1, the results show that the analgesic onset time is 60 min, the effect of relieving ankylosis is not obvious, and the retention time of active ingredients at the joint lesion site is only 12 h. After 14 days of continuous administration, the joint effusion resolution rate is 50%, and the repair rate in the cartilage defect area is only 40%, failing to break the pathological vicious cycle of synovial inflammation-cartilage damage. The therapeutic effect for synovitis is poor, and the utilization efficiency of each active ingredient is less than 30%. Embodiments 1 to 3 all adhere to the formula and preparation process requirements of the present invention. By compounding graded molecular weight sodium hyaluronate, adding dimethyl sulfone e, and combining with the three-dimensional gradient mixing preparation process, they achieve gradient sustained-release, targeted delivery, and synergistic enhancement of the active ingredients. They exhibit good to excellent effects in terms of analgesic onset, component retention, effusion resolution, and cartilage repair. Embodiment 1, using the patent's intermediate value ratio, performs best across all indicators, with an overall therapeutic effect rated as excellent. In contrast, the Comparative Example, due to the omission of dimethyl sulfone, replacement with single molecular weight sodium hyaluronate, and use of a simple preparation process, cannot inhibit sodium hyaluronate degradation or achieve targeted enrichment of cartilage repair components. All performance indicators and therapeutic effects are significantly reduced, fully verifying the scientific nature of the composition formula and the necessity of the preparation process of the present invention. It also proves that compared to the prior art, the composition of the present invention can fundamentally break the pathological vicious cycle of synovial inflammation and cartilage damage, significantly improving the therapeutic effect for synovitis.

[0069] The above descriptions are only preferred embodiments of the present invention and are not intended to limit the present invention in any form. Although the present invention has been disclosed as above with preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art, without departing from the scope of the technical solution of the present invention, can make some changes or modifications to equivalent embodiments with equivalent changes using the above-disclosed technical content. However, any simple modification, equivalent change, and modification made to the above embodiments based on the technical essence of the present invention, without departing from the content of the technical solution of the present invention, still fall within the scope of the technical solution of the present invention.

Claims

CLAIMS1.A multi-component synovitis therapeutic composition based on repairing cartilage tissue, characterized in that the composition consists of glucosamine hydrochloride, chondroitin sulfate, dimethyl sulfone, and graded molecular weight sodium hyaluronate;The components comprise, in parts by weight: 100-200 parts by weight of glucosamine hydrochloride, 50-100 parts by weight of chondroitin sulfate, 30-80 parts by weight of dimethyl sulfone, and 10-50 parts by weight of graded molecular weight sodium hyaluronate;The graded molecular weight sodium hyaluronate is compounded from high molecular weight sodium hyaluronate and medium-low molecular weight sodium hyaluronate, wherein the weight ratio of high molecular weight sodium hyaluronate to medium-low molecular weight sodium hyaluronate is 2: 1-3:1, the molecular weight of the high molecular weight sodium hyaluronate is 1500-2000 kDa, and the molecular weight of the medium-low molecular weight sodium hyaluronate is 100-800 kDa.

2. The multi-component synovitis therapeutic composition based on repairing cartilage tissue according to claim 1, characterized in that the purity of the glucosamine hydrochloride is not less than 98%, it is pharmaceutical grade glucosamine hydrochloride, its raw material is crystalline glucosamine hydrochloride with a crystal water content of 1-2, and the fine powder particle size D50 of the glucosamine hydrochloride after grinding is 30-50 pm.

3. The multi-component synovitis therapeutic composition based on repairing cartilage tissue according to claim 1, characterized in that the chondroitin sulfate is chondroitin sulfate sodium salt, extracted from shark cartilage tissue, with a purity of not less than 90%, a sulfate group content of 35-40%, and a molecular weight of the chondroitin sulfate of 50-150 kDa.

4. The multi-component synovitis therapeutic composition based onrepairing cartilage tissue according to claim 1, characterized in that the dimethyl sulfone is pharmaceutical grade dimethyl sulfone with a purity of not less than 99%, its crystal form is orthorhombic, and the fine powder particle size D90 after grinding is 40-60 pm; this crystal form of dimethyl sulfone is chemically stable and does not undergo crystal form transformation under normal temperature and pressure.

5. The multi-component synovitis therapeutic composition based on repairing cartilage tissue according to claim 1, characterized in that the medium-low molecular weight sodium hyaluronate is compounded from low molecular weight sodium hyaluronate and medium molecular weight sodium hyaluronate, wherein the weight ratio of low molecular weight sodium hyaluronate to medium molecular weight sodium hyaluronate is 1:1, the molecular weight of the low molecular weight sodium hyaluronate is 100-400 kDa, and the molecular weight of the medium molecular weight sodium hyaluronate is 400-800 kDa.

6. The multi-component synovitis therapeutic composition based on repairing cartilage tissue according to claim 1, characterized in that the molecular weight of the high molecular weight sodium hyaluronate is 1600-1900 kDa, its purity is not less than 95%, it is sodium hyaluronate prepared by a microbial fermentation method using Streptococcus zooepidemicus as the fermentation strain; the high molecular weight sodium hyaluronate prepared by this process has a narrow molecular weight distribution, no chemical modification residues, and its glucuronic acid content is 45-50%, consistent with the structure of sodium hyaluronate in natural joint synovial fluid; the purity of the high molecular weight sodium hyaluronate in the graded molecular weight sodium hyaluronate is consistent with that of the medium-low molecular weight sodium hyaluronate.

7. The multi-component synovitis therapeutic composition based on repairing cartilage tissue according to claim 1, characterized in that theglucosamine hydrochloride, chondroitin sulfate, dimethyl sulfone, and graded molecular weight sodium hyaluronate are all 80-mesh standard fine powders after grinding, the particle size D90 of all component fine powders is not greater than 100 pm, the particle size distribution span is not greater than 50 pm, and the bulk density of the fine powder of each component is 0.4-0.6 g / cm3.

8. The multi-component synovitis therapeutic composition based on repairing cartilage tissue according to claim 1, characterized in that the preparation method of the composition comprises the following steps:

51. Weighing the raw material components of glucosamine hydrochloride, chondroitin sulfate, dimethyl sulfone, and graded molecular weight sodium hyaluronate respectively according to the parts by weight ratio, grinding all raw material components separately using a grinder, and passing through an 80-mesh standard sieve after grinding to obtain the corresponding fine powder of each raw material for later use;52. Putting the glucosamine hydrochloride fine powder, chondroitin sulfate fine powder, and dimethyl sulfone fine powder into a three-dimensional mixer, adjusting the rotation speed of the three-dimensional mixer to 150-200 r / min, and continuously mixing at this speed for 15-25 min to obtain a uniformly mixed premix powder;53. Adding the graded molecular weight sodium hyaluronate fine powder to the premix powder obtained in S2, adjusting the rotation speed of the three-dimensional mixer to 100-150 r / min, and continuously mixing at this speed for 20-30 min; after mixing is completed, discharging to obtain the composition.

9. The multi-component synovitis therapeutic composition based on repairing cartilage tissue according to claim 8, characterized in that the grinder used in SI is a universal grinder, the spindle speed of the universal grinder during grinding is 2000-3000 r / min, the grinding time for a single component is5-10 min, air cooling is used for cooling during the grinding process, the temperature of the raw material components during grinding does not exceed 40 °C, sieving uses a standard metal sieve mesh, the sieve mesh size deviation is not greater than ±2 mesh, the ratio of the rotation speed of the mixing drum to the revolution speed of the three-dimensional mixer in S2 and S3 is 1:3-1 : 5, and an intermittent stirring method is used during the mixing process, with stirring paused for 1 min after every 5 min of continuous mixing, before continuing mixing.

10. Use of a multi-component synovitis therapeutic composition based on repairing cartilage tissue, applicable to the multi-component synovitis therapeutic composition based on repairing cartilage tissue according to any one of claims 1-7, characterized in that the composition is used for preparing a medicament for treating acute or chronic synovitis, the medicament takes the composition as the core active ingredient, and the composition is compounded with pharmaceutically acceptable excipients to prepare conventional pharmaceutical dosage forms, the dosage forms being one or more of granules, capsules, tablets, and injections.

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