An intra-articular preparation containing a chitosan-based lidocaine and a method for preparing the same

Abstract

This invention discloses a chitosan-based lidocaine formulation for intra-articular use and its preparation method. Belonging to the field of pharmaceutical formulation technology, the formulation is prepared from chitosan, carboxymethyl chitosan, lidocaine, chitosan-PNIPAM microspheres, sulfated trehalose, and excipients. The chitosan-PNIPAM used in this invention exhibits dual temperature and pH response. With temperature changes, PNIPAM possesses both hydrophobic contractile and hydrophilic swelling states, thereby controlling the lidocaine release rate. Simultaneously, when the pH decreases, chitosan repels PNIPAM, further disintegrating the microspheres to release the drug, thus achieving targeted analgesia. Sulfated trehalose, as a cartilage matrix synthesis promoter, can activate intracellular signaling pathways in chondrocytes, promoting the synthesis of type II collagen and proteoglycans. Simultaneously, the sulfate groups can form electrostatic complexes with the amino groups of chitosan, enhancing drug retention. The formulation of this invention can inhibit synovial cells, release cytokines, and synergistically with carboxymethyl chitosan, increase the inhibition rate of inflammatory factors by 40%-50%.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically referring to a joint intra-articular preparation containing chitosan lidocaine and its preparation method. Background Technology

[0002] Joint diseases are prevalent among middle-aged and elderly people, with an incidence rate exceeding 30% in people over 60 years of age worldwide. The pathological mechanisms revolve around degenerative damage to articular cartilage, synovial inflammation, and abnormal viscoelasticity of synovial fluid. The loss of type II collagen and proteoglycans in the cartilage matrix leads to cartilage thinning and wear. Inflammatory factors released by synovial cells cause joint swelling, and the decrease in hyaluronic acid content in synovial fluid leads to loss of lubrication function. Ultimately, this manifests as joint pain and limited mobility, and in severe cases, it can lead to joint deformities, significantly reducing the patient's quality of life. While current clinical treatments targeting the joint cavity have developed into a system, they all have significant limitations: Glucocorticoid injections, represented by dexamethasone and triamcinolone, rapidly relieve symptoms by inhibiting the synthesis of inflammatory factors in synovial cells. However, the drugs have a half-life of only 12-36 hours within the joint cavity, and long-term use can inhibit chondrocyte proliferation and accelerate cartilage matrix degradation. Clinical studies show that patients who received more than three consecutive injections had a 15%-20% reduction in cartilage thickness compared to those who did not receive injections, and their risk of joint degeneration increased threefold. Sodium hyaluronate injections, as a supplement to the natural components of synovial fluid, can improve the viscoelasticity of synovial fluid and reduce mechanical friction damage to cartilage. However, its analgesic effect is slow, and its pain control effect is poor in the acute inflammatory phase, making it only suitable for patients in the chronic stable phase. Simple local anesthetic injections, such as lidocaine... Caine, as the primary anesthetic, provides rapid analgesia by blocking sodium ion channels in nerve endings within the joint cavity. However, due to the diluting effect of synovial fluid and the drug's rapid diffusion characteristics, its half-life within the joint cavity is only 1-2 hours, resulting in an analgesic duration of less than 4 hours. This necessitates 2-3 aspiration injections per week to maintain efficacy, increasing patient discomfort and raising the risk of joint infection from 0.1% with a single injection to 0.8%-1.5% with multiple injections. It may also damage the joint capsule and synovial tissue. Traditional chondroprotective agents, such as glucosamine and chondroitin sulfate, require oral administration through the gastrointestinal tract to reach the joint cavity, resulting in bioavailability of less than 10% and low local concentrations, making them ineffective. Topical chondroprotective patches have even more limited effectiveness due to the thick stratum corneum of the joint cavity skin and poor drug permeability. Chitosan, an aminopolysaccharide extracted from natural sources such as shrimp and crab shells, has become a research hotspot in the field of articular cartilage protection in recent years due to its excellent biocompatibility, biodegradability, and tissue adhesion. The free amino groups in its molecular structure can form hydrogen bonds with the hydroxyl and carboxyl groups on the surface of the cartilage matrix, forming a transparent protective film on the cartilage surface and reducing further damage to damaged cartilage caused by mechanical friction. Simultaneously, in vitro cell experiments have confirmed that chitosan can delay the degenerative process of cartilage by activating the PI3K / Akt signaling pathway within chondrocytes, inhibiting chondrocyte apoptosis, and promoting the synthesis of type II collagen and proteoglycans.

[0003] However, the application of chitosan alone in intra-articular preparations has significant drawbacks: First, poor solubility. Chitosan is only soluble in acidic environments (pH < 6.0), while the normal pH of synovial fluid in the joint cavity is 7.3-7.5. In pathological conditions, the pH may drop to 6.8-7.2 due to synovial inflammation, which still cannot meet the solubility requirements of chitosan. Direct injection easily forms flocculent material, which not only affects drug diffusion but may also block the joint cavity and worsen the limitation of movement. Second, limited function. Chitosan can only play a cartilage protection role and cannot relieve the most urgent pain symptoms of patients with joint diseases. It needs to be used in combination with analgesic components to meet the needs of comprehensive clinical treatment. Third, short retention time. Unmodified chitosan is easily degraded by lysozyme in synovial fluid in the joint cavity, with a half-life of only 6-8 hours. Frequent injections are required to maintain efficacy, facing similar clinical pain points as lidocaine alone. To address the solubility issue of chitosan, researchers have developed water-soluble derivatives such as carboxymethyl chitosan and hydroxypropyl chitosan. Among these, carboxymethyl chitosan is the most widely used due to its simple modification process and low cost. By introducing carboxymethyl groups into the chitosan molecular chain, its water solubility is significantly improved, allowing it to dissolve stably within a pH range of 4.0-10.0, perfectly adapting to the synovial fluid environment of the joint cavity. Simultaneously, the introduction of carboxymethyl groups enhances the hydrophilicity and negative charge of the molecular chain, enabling it to form electrostatic adsorption with positively charged proteins on the surface of the synovial tissue in the joint cavity, prolonging the drug's retention time in the joint cavity to 12-24 hours. Furthermore, carboxymethyl chitosan also possesses certain anti-inflammatory activity, reducing the release of inflammatory factors and helping to alleviate joint swelling by inhibiting the activation of the NF-κB signaling pathway in synovial cells. Even so, current technologies have yet to develop an integrated solution for intra-articular treatment that combines analgesia, cartilage protection, and anti-inflammation. Some studies have simply mixed chitosan and lidocaine, but due to the lack of synergistic effect, lidocaine still diffuses rapidly, and the duration of analgesia is only extended to 6-8 hours, failing to meet clinical expectations. Other studies have combined carboxymethyl chitosan with sodium hyaluronate, which improves the viscoelasticity of synovial fluid, but still cannot solve the problem of immediate analgesia. Therefore, developing a composite formulation that can be stably dissolved in the intra-articular environment, possesses both rapid analgesia and long-lasting cartilage protection functions, and reduces the frequency of injections has become a pressing technical challenge in the current pharmaceutical field. Summary of the Invention

[0004] The purpose of this invention is to provide a chitosan-based lidocaine formulation for intra-articular use and its preparation method. The chitosan-PNIPAM used in this invention exhibits dual temperature and pH responsiveness. With temperature changes, PNIPAM possesses both a hydrophobic contractile state and a hydrophilic swelling state, thereby controlling the lidocaine release rate. Simultaneously, when the pH decreases, chitosan repels PNIPAM, causing the microspheres to further disintegrate and release the drug, thus achieving targeted analgesia. Sulfated trehalose, as a cartilage matrix synthesis promoter, can activate intracellular signaling pathways in chondrocytes, promoting the synthesis of type II collagen and proteoglycans. Furthermore, the sulfate groups can form electrostatic complexes with the amino groups of chitosan, enhancing drug retention. The formulation of this invention can inhibit synovial cells, release cytokines, and synergistically with carboxymethyl chitosan, increase the inhibition rate of inflammatory factors by 40%-50%.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows: a joint cavity preparation containing chitosan-based lidocaine and its preparation method, wherein the preparation comprises the following components in parts by weight: 50-80 parts chitosan, 40-70 parts carboxymethyl chitosan, 30-60 parts lidocaine, 10-30 parts chitosan-PNIPAM microspheres, 5-30 parts sulfated trehalose, and 1-20 parts excipients.

[0006] Preferably, the formulation comprises the following components in parts by weight: 60-80 parts chitosan, 50-60 parts carboxymethyl chitosan, 30-40 parts lidocaine, 10-20 parts chitosan-PNIPAM microspheres, 10-16 parts sulfated trehalose, and 2-6 parts excipients.

[0007] Preferably, the chitosan-PNIPAM microspheres are temperature- and pH-responsive microspheres.

[0008] Preferably, the chitosan has a deacetylation rate greater than 85% and a molecular weight of 50kDa-200kDa; the degree of substitution of carboxymethyl chitosan is greater than 0.8.

[0009] Preferably, the sulfated trehalose is selected from sulfated trehalose with a degree of sulfate substitution of 2.1-2.6 and a molecular weight of 3kDa-5kDa.

[0010] Preferably, the excipients include 1% sodium chloride, 0.02% disodium edetate, 0.04% mannitol, and water for injection.

[0011] This invention also provides a method for preparing a chitosan-based lidocaine formulation for intra-articular use, the preparation method comprising the following steps: (1) Dissolve sodium chloride and disodium edetate in water for injection, then add chitosan, adjust the pH to 5.2, and stir for 30 min to dissolve; (2) Add carboxymethyl chitosan and sulfated trehalose, and stir for 20 minutes; (3) Add chitosan-PNIPAM microspheres containing lidocaine and free lidocaine, stir for 15 min, and adjust the pH to 7.2; (4) Filtering, filling, and sealing.

[0012] Further, the chitosan-PNIPAM microspheres are prepared according to the following steps: chitosan-PNIPAM copolymer is dissolved in N,N-dimethylformamide, lidocaine is added, and the mixture is sonicated to form an oil phase; then liquid paraffin is measured as the aqueous phase and placed in a three-necked flask; the oil phase is added dropwise to the aqueous phase and stirred for 30 min to form a reverse emulsion; glutaraldehyde is added, and the mixture is heated to react for 2 h to solidify the microspheres; the microspheres are collected by centrifugation, washed three times with anhydrous ethanol, and freeze-dried for later use.

[0013] The beneficial effects of the present invention using the above structure are as follows: (1) The chitosan-PNIPAM used in the present invention has dual temperature and pH response. As the temperature changes, PNIPAM has a hydrophobic contraction state and a hydrophilic swelling state, thereby controlling the release rate of lidocaine. At the same time, when the pH decreases, chitosan and PNIPAM repel each other, and the microspheres further disintegrate to release the drug, thereby achieving targeted analgesia; (2) The sulfated trehalose used in the present invention, as a cartilage matrix synthesis promoter, can activate the signaling pathway in chondrocytes and promote the synthesis of type II collagen and proteoglycans. At the same time, the sulfate group can form an electrostatic complex with the amino group of chitosan, thereby enhancing the drug retention effect; (3) The formulation of the present invention can inhibit synovial cells, release cytokines, and synergistically with carboxymethyl chitosan, increase the inhibition rate of inflammatory factors by 40%-50%. Attached Figure Description

[0014] Figure 1 The effect of a chitosan-based lidocaine formulation for intra-articular use on TNF-α concentration.

[0015] The accompanying drawings are provided to further illustrate the invention and form part of the specification. They are used together with the embodiments of the invention to explain the invention and do not constitute a limitation thereof. Detailed Implementation

[0016] The technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to this invention. The preferred embodiments and materials described herein are for illustrative purposes only and do not limit the scope of this application.

[0018] Unless otherwise specified, the experimental methods used in the following examples are conventional methods; unless otherwise specified, the experimental materials and test strains used in the following examples were purchased from commercial channels. Example

[0019] A chitosan-based lidocaine formulation for intra-articular use and its preparation method The formulation comprises the following components in parts by weight: 60 parts chitosan, 60 parts carboxymethyl chitosan, 30 parts lidocaine, 20 parts chitosan-PNIPAM microspheres, 10 parts sulfated trehalose, and 6 parts excipients.

[0020] The chitosan-PNIPAM microspheres are temperature- and pH-responsive microspheres.

[0021] The chitosan has a deacetylation rate greater than 85% and a molecular weight of 50kDa-200kDa; the carboxymethyl chitosan has a degree of substitution greater than 0.8.

[0022] The sulfated trehalose is selected from sulfated trehalose with a degree of sulfate substitution of 2.1-2.6 and a molecular weight of 3kDa-5kDa.

[0023] The excipients include 1% sodium chloride, 0.02% disodium edetate, 0.04% mannitol, and water for injection.

[0024] This invention also provides a method for preparing a chitosan-based lidocaine formulation for intra-articular use, the preparation method comprising the following steps: (1) Dissolve sodium chloride and disodium edetate in water for injection, then add chitosan, adjust the pH to 5.2, and stir for 30 min to dissolve; (2) Add carboxymethyl chitosan and sulfated trehalose, and stir for 20 minutes; (3) Add chitosan-PNIPAM microspheres containing lidocaine and free lidocaine, stir for 15 min, and adjust the pH to 7.2; (4) Filtering, filling, and sealing.

[0025] The chitosan-PNIPAM microspheres are prepared according to the following steps: chitosan-PNIPAM copolymer is dissolved in N,N-dimethylformamide, lidocaine is added, and the mixture is sonicated to form an oil phase; then liquid paraffin is measured as the aqueous phase and placed in a three-necked flask; the oil phase is added dropwise to the aqueous phase and stirred for 30 min to form a reverse emulsion; glutaraldehyde is added, and the mixture is heated for 2 h to solidify the microspheres; the microspheres are collected by centrifugation, washed three times with anhydrous ethanol, and freeze-dried for later use. Example

[0026] A chitosan-based lidocaine formulation for intra-articular use and its preparation method The formulation comprises the following components in parts by weight: 80 parts chitosan, 50 parts carboxymethyl chitosan, 40 parts lidocaine, 10 parts chitosan-PNIPAM microspheres, 16 parts sulfated trehalose, and 2 parts excipients.

[0027] The chitosan-PNIPAM microspheres are temperature- and pH-responsive microspheres.

[0028] The chitosan has a deacetylation rate greater than 85% and a molecular weight of 50kDa-200kDa; the carboxymethyl chitosan has a degree of substitution greater than 0.8.

[0029] The sulfated trehalose is selected from sulfated trehalose with a degree of sulfate substitution of 2.1-2.6 and a molecular weight of 3kDa-5kDa.

[0030] The excipients include 1% sodium chloride, 0.02% disodium edetate, 0.04% mannitol, and water for injection.

[0031] The present invention also provides a method for preparing a joint intra-articular formulation containing chitosan lidocaine, wherein the preparation method is performed in accordance with Example 1. Example

[0032] A chitosan-based lidocaine formulation for intra-articular use and its preparation method The formulation comprises the following components in parts by weight: 70 parts chitosan, 55 parts carboxymethyl chitosan, 35 parts lidocaine, 15 parts chitosan-PNIPAM microspheres, 13 parts sulfated trehalose, and 4 parts excipients.

[0033] The chitosan-PNIPAM microspheres are temperature- and pH-responsive microspheres.

[0034] The chitosan has a deacetylation rate greater than 85% and a molecular weight of 50kDa-200kDa; the carboxymethyl chitosan has a degree of substitution greater than 0.8.

[0035] The sulfated trehalose is selected from sulfated trehalose with a degree of sulfate substitution of 2.1-2.6 and a molecular weight of 3kDa-5kDa.

[0036] The excipients include 1% sodium chloride, 0.02% disodium edetate, 0.04% mannitol, and water for injection.

[0037] The present invention also provides a method for preparing a joint intra-articular formulation containing chitosan lidocaine, wherein the preparation method is performed in accordance with Example 1.

[0038] Experimental Example 1 Forty New Zealand white rabbits suffering from osteoarthritis were randomly divided into four groups of ten each, designated as Groups 1-3 and the control group. The preparations described in Examples 1-3 of this invention were used as experimental drugs, while the control group received pure lidocaine injection. The concentration of TNF-α in the synovial fluid of the rabbits in each group was measured 24 hours after administration.

[0039] Results analysis: such as Figure 1 As shown, 24 hours after administration, the TNF-α concentration in groups 1-3 was much lower than that in the control group, with the lowest TNF-α concentration in group 3.

[0040] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

[0041] The present invention and its embodiments have been described above. This description is not restrictive, and the accompanying drawings are only one embodiment of the present invention; the actual structure is not limited thereto. In conclusion, if those skilled in the art are inspired by this description and design similar structures and embodiments without departing from the spirit of the invention, such designs should fall within the protection scope of the present invention.

Claims

1. A joint preparation containing chitosan-based lidocaine, characterized in that: The formulation comprises the following components in parts by weight: 50-80 parts chitosan, 40-70 parts carboxymethyl chitosan, 30-60 parts lidocaine, 10-30 parts chitosan-PNIPAM microspheres, 5-30 parts sulfated trehalose, and 1-20 parts excipients.

2. The intra-articular formulation containing chitosan-based lidocaine according to claim 1, characterized in that: The formulation comprises the following components in parts by weight: 60-80 parts chitosan, 50-60 parts carboxymethyl chitosan, 30-40 parts lidocaine, 10-20 parts chitosan-PNIPAM microspheres, 10-16 parts sulfated trehalose, and 2-6 parts excipients.

3. The intra-articular formulation containing chitosan-based lidocaine according to claim 2, characterized in that: The chitosan-PNIPAM microspheres are temperature and pH responsive microspheres.

4. The intra-articular formulation containing chitosan-based lidocaine according to claim 3, characterized in that: The chitosan has a deacetylation rate greater than 85% and a molecular weight of 50kDa-200kDa; the degree of substitution of carboxymethyl chitosan is greater than 0.

8.

5. A joint intra-articular formulation containing chitosan-based lidocaine according to claim 4, characterized in that: The sulfated trehalose is selected from sulfated trehalose with a degree of sulfate substitution of 2.1-2.6 and a molecular weight of 3kDa-5kDa.

6. A joint intra-articular formulation containing chitosan-based lidocaine according to claim 5, characterized in that: The excipients include 1% sodium chloride, 0.02% disodium edetate, 0.04% mannitol, and water for injection.

7. A method for preparing a chitosan-containing lidocaine formulation for intra-articular use according to claim 6, characterized in that: The preparation method includes the following steps: (1) Dissolve sodium chloride and disodium edetate in water for injection, then add chitosan, adjust the pH to 5.2, and stir for 30 min to dissolve; (2) Add carboxymethyl chitosan and sulfated trehalose, and stir for 20 minutes; (3) Add chitosan-PNIPAM microspheres containing lidocaine and free lidocaine, stir for 15 min, and adjust the pH to 7.2; (4) Filtering, filling, and sealing.

8. The method for preparing a chitosan-based lidocaine formulation for intra-articular use according to claim 7, characterized in that: The chitosan-PNIPAM microspheres were prepared according to the following steps: chitosan-PNIPAM copolymer was dissolved in N,N-dimethylformamide, lidocaine was added, and the mixture was sonicated to form an oil phase; then liquid paraffin was measured as the aqueous phase and placed in a three-necked flask; the oil phase was added dropwise to the aqueous phase and stirred for 30 min to form a reverse emulsion; glutaraldehyde was added, and the mixture was heated to react for 2 h to solidify the microspheres; the microspheres were collected by centrifugation, washed three times with anhydrous ethanol, and freeze-dried for later use.

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