A preparation method of bupivacaine hydrochloride topical hydrogel

Abstract

The invention discloses a method for preparing a bupivacaine hydrochloride topical hydrogel, and belongs to the technical field of medical hydrogels. The specific steps include raw material preparation, solution preparation, dialysis treatment, filtration and pH adjustment, hydrogel preparation, quality inspection and packaging. The bupivacaine hydrochloride hydrogel prepared by the invention has the characteristics of significant sustained release effect, uniform drug release, excellent biocompatibility, etc., and can achieve a drug release rate close to 100% within 36 hours. Compared with the traditional injection method, the topical hydrogel is easy to operate, non-invasive, and significantly improves the comfort of patients. In addition, the invention adopts biodegradable materials, meets environmental protection requirements, and reduces the impact on the environment. The method has strong process controllability and stable product quality, and provides a new type of administration method for local anesthesia that is efficient, safe and environmentally friendly.

Description

Technical Field

[0001] The invention belongs to the technical field of medical hydrogels, and in particular relates to a method for preparing a bupivacaine hydrochloride external hydrogel. Background Art

[0002] Bupivacaine hydrochloride is an important local anesthetic drug, which is widely used in various surgeries and pain management. Its superior anesthetic effect and long duration of action make bupivacaine hydrochloride the first choice of anesthetic drug in clinical practice. However, traditional bupivacaine hydrochloride administration methods, such as injection, are often accompanied by side effects such as pain, swelling and infection, resulting in decreased patient comfort. Therefore, it is particularly important to develop a new administration method that is effective and can improve patient comfort.

[0003] In recent years, hydrogels have attracted widespread attention as an emerging drug delivery system due to their excellent biocompatibility, softness, and controlled release properties. Hydrogels can maintain their sustainability and stability in a humid environment and are very suitable for the delivery of topical drugs. There are many methods for preparing hydrogels, including chemical cross-linking, aqueous polymerization, etc. By adjusting their physicochemical properties, precise control of drug release rate can be achieved.

[0004] In the research of medical hydrogels, the application of biodegradable materials has become an important direction. Biodegradable hydrogels not only have excellent biocompatibility, but also can effectively reduce the impact on the environment. In recent years, polymer materials such as polyvinyl alcohol and polylactic acid have been widely used in the preparation of medical hydrogels. These materials can be degraded by enzymes in the body, which helps to alleviate the adverse reactions caused by long-term use of drugs in patients. Therefore, exploring the formulation of bupivacaine hydrochloride hydrogel based on biodegradable materials can make local administration safer and more effective.

[0005] The advantage of hydrogel lies not only in its physical properties, but also in its ability to carry drugs. The loading efficiency of drugs is an important factor affecting the clinical application of hydrogels. If the dispersibility and solubility of drugs in hydrogels are insufficient, it may lead to uneven drug release, thus affecting the efficacy. In order to improve the release efficiency of bupivacaine hydrochloride in hydrogels, it can be achieved by modifying polymer materials, selecting suitable solvents, and optimizing the preparation process of hydrogels. By dynamically consolidating the polymer network structure, the drug can be released in excellent form and efficiency.

[0006] In the drug delivery system of bupivacaine hydrochloride, the key to preparing hydrogel is to determine the best formula and preparation process. The proportion of bupivacaine hydrochloride, the amount of cross-linking agent added, and the nature of the solvent directly affect the characteristics of the final hydrogel. In practical applications, it is necessary to comprehensively consider the physicochemical properties of the hydrogel such as viscosity, elasticity, and its stability under physiological conditions to ensure that it has good performance when applied. In addition, in order to ensure the effect of topical administration, the hydrogel should have good adhesion, so that it can be retained on the skin surface for a long time, effectively reduce the waste of drugs, and achieve lasting drug effect.

[0007] In recent years, with the development of nanotechnology, nanomaterials have been introduced into hydrogels to enhance their performance. The addition of nanoparticles can not only increase the drug carrying capacity, but also improve the drug release behavior. Therefore, regulating the type and concentration of nanomaterials is also an important challenge in the preparation of hydrogels.

[0008] During the preparation process, it is also critical to monitor and evaluate the performance of the hydrogel, including its toxicity, biocompatibility, and drug release characteristics. For the study of bupivacaine hydrochloride topical hydrogel, the efficacy should be evaluated in animal experiments to ensure its safety and effectiveness in actual clinical applications. At the same time, the implementation of corresponding standardized tests can improve the consistency and controllability of the product, making it more feasible in the production process.

[0009] In summary, the exploration of the preparation method of bupivacaine hydrochloride topical hydrogel is of great significance. By adopting modern material technology and reasonable formulation design, it is possible to improve the efficacy of the drug while reducing the pain and discomfort of the patient, providing a safer and more efficient way for local anesthesia in clinical applications. With the in-depth study of hydrogels, it is possible to develop a more optimized drug delivery system in the future, thereby promoting the continuous development of medical hydrogel technology. Summary of the invention

[0010] 1. Problems to be solved

[0011] In view of the problems existing in the preparation process of the existing bupivacaine hydrochloride hydrogel, the following aspects need to be solved:

[0012] Traditional hydrogel preparation methods may lead to uneven dispersion and solubility of bupivacaine hydrochloride in the gel, thus affecting the release rate and efficacy of the drug. To this end, it is necessary to optimize the formulation and preparation process of the hydrogel to improve the uniform distribution and controlled release performance of the drug in the gel. Existing materials may cause irritation or adverse reactions under physiological conditions, so it is necessary to select more suitable materials and improve the preparation process to ensure the safety and effectiveness of the hydrogel during use. Existing processes may involve multiple complex steps, such as dialysis, filtration and sterilization, which not only increases production costs, but also may affect product consistency. Therefore, it is necessary to simplify the preparation process, improve production efficiency through automated equipment, and ensure the stability of product quality. Traditional drug administration methods such as injection are often accompanied by pain and infection risks, and hydrogels, as an external drug delivery system, should have good softness and adhesion properties to improve patient comfort and ease of use. This requires full consideration of patient experience in formulation design and optimization of the physical properties of the gel.

[0013] By solving the above problems, the clinical application effect of bupivacaine hydrochloride hydrogel can be significantly improved, making it a safer, more efficient and environmentally friendly method of local anesthesia administration.

[0014] 2. Technical solution

[0015] To solve the above problems, the present invention adopts the following technical solutions.

[0016] A method for preparing bupivacaine hydrochloride topical hydrogel,

[0017] The following steps are involved:

[0018] (1) Raw material preparation

[0019] Weigh bupivacaine hydrochloride, sodium chloride, and medical charcoal;

[0020] (2) Solution preparation

[0021] a) Heat 80 kg of water for injection to 75-85°C, add the prescribed amount of sodium chloride, and stir for 5-20 minutes at a stirring speed of 250-350 rpm;

[0022] b) adding the prescribed amount of bupivacaine hydrochloride, and then adding 20 kg of water for injection for spraying, and continuing to stir for 5-15 minutes until it is completely dissolved;

[0023] c) Press the solution into the preparation tank, rinse with 50 kg of injection water three times, and press into the preparation tank respectively;

[0024] d) Add the moistened medicinal charcoal into the preparation tank and stir for 5-15 minutes;

[0025] (3) Dialysis treatment

[0026] a) putting the prepared drug solution into a dialysis bag, the dialysis membrane of which has a pore size of 3500Da;

[0027] b) After dialysis, the drug solution is taken out from the dialysis bag and subsequently processed;

[0028] The preparation method of the dialysis membrane is as follows:

[0029] In a blender, 20-30 g of polyethersulfone is dissolved in 100-140 g of N,N-dimethylacetamide and stirred until completely dissolved; then, 0.3-0.8 g of plant fiber is added and stirring is continued for 24 h to ensure uniform distribution; finally, 1-2 g of methacryloylethyl sulfobetaine, 5-8 g of polyvinyl alcohol and 10-20 g of polylactic acid are added and stirred until uniform; the prepared solution is evenly coated on a glass plate to form a liquid film with a thickness of 200 μm, evaporated at room temperature for 10-20 s to form a preliminary cortex, and the coated glass plate is quickly immersed in deionized water for a water bath to form a dialysis membrane with a porous structure, the water bath temperature is controlled at 25° C., and the time is 30 min-50 min, and the treated dialysis membrane is immersed in deionized water for 24-48 h to remove residual solvents and unreacted substances, dried at room temperature, and stored in a sterile environment for standby use;

[0030] It should be noted that the CAS number of polyethersulfone (PES) is 25608-63-3; the CAS number of N,N-dimethylacetamide (DMAC) is 127-19-5; the parameters of plant fibers are as follows: cotton fiber, fiber length is 30 μm, diameter is 20 μm; CAS number of methacryloylethyl sulfobetaine is 3637-26-1; the parameters of polylactic acid are as follows: density: 1.28 g / cm 3 , melting point: 180℃, glass transition temperature (Tg): 60℃.

[0031] (4) Filtration and pH adjustment

[0032] a) The dialyzed drug solution was filtered through a titanium rod filter, a 0.45 μm microporous membrane cartridge filter and a 0.2 μm microporous membrane cartridge filter for 15-35 minutes;

[0033] b) Measure the pH value of the liquid. If it is not within the range, adjust it with 1% by mass sodium hydroxide or 1% by mass hydrochloric acid;

[0034] (5) Preparation of hydrogel;

[0035] (6) Quality inspection;

[0036] (7) Packaging.

[0037] Preferably, the parameters of the medicinal charcoal in step (1) are as follows: 50-150 μm, specific surface area 1500 m 2 / g.

[0038] Preferably, the water for injection in step (2) is high-purity pure water with a conductivity of ≤1.3 μS / cm.

[0039] Preferably, the dialysis conditions in step (3) are: temperature 4°C, pH value controlled at 4.5-6.0, dialysis time 6-8h, and the dialysate is replaced every 2-4h;

[0040] The dialysate is sterile saline.

[0041] Preferably, the pore size of the titanium rod filter in step (4) is 0.5-10 μm, and its working pressure is 0.2-0.6 MPa.

[0042] Preferably, the pH value of the medicinal solution in step (4) is 4.5-6.0.

[0043] Preferably, the preparation method of the hydrogel in step (5) is as follows:

[0044] First, soybean lecithin, carboxymethyl chitosan and polyethylene glycol are mixed in a mass ratio of 2:1:2, wherein the CAS number of soybean lecithin is 8002-43-5, and stirred at a temperature of 50°C until the soybean lecithin is completely dissolved to form a uniform and transparent solution, and the bupivacaine hydrochloride solution treated in step (4) is added to the above solution, and the temperature is maintained at 50°C, and stirring is continued until the bupivacaine is completely dissolved, and the final mass percentage of bupivacaine hydrochloride is 0.5%. A 0.22 μm filter membrane is used for filtration and sterilization to remove insoluble impurities, and the filtered solution is quickly divided into sterile containers, cooled to 4°C, and a hydrogel is obtained, which is sealed and stored. Wherein carboxymethyl chitosan: CAS number 83512-85-0, polyethylene glycol: CAS number 25322-68-3.

[0045] Preferably, the quality inspection in step (6) is as follows: the sterilized product needs to be manually inspected, unqualified products are removed, and sterility and bacterial endotoxin tests are performed;

[0046] The packaging in step (7) is as follows: qualified products enter the packaging stage, and after checking the product batch number and expiration date information, labeling, boxing and packaging operations are carried out.

[0047] 3. Beneficial effects

[0048] Compared with the prior art, the present invention has the following beneficial effects:

[0049] Improve drug delivery efficiency: The present invention adopts a method for preparing bupivacaine hydrochloride topical hydrogel, and by optimizing the formula and process, the dispersibility and solubility of the drug in the hydrogel are significantly improved, thereby achieving more uniform and controllable drug release. The experimental results show that the hydrogel achieves a drug release rate of nearly 100% within 36 hours, showing a good sustained release effect.

[0050] Preparation process optimization: The present invention adopts high-precision filtration and dialysis processes to ensure the purity of the drug solution and the stability of the pH value. In addition, the sterility and quality consistency of the product are further improved through the use of a fully automatic program-controlled sterilizer.

[0051] Improve patient experience: Compared with traditional injection methods, topical hydrogel has the advantages of being non-invasive and easy to operate, which can not only reduce the pain of patients, but also reduce the risk of infection. Its softness and adhesion properties enable it to adhere to the skin surface for a long time, thereby improving the local anesthesia effect.

[0052] In summary, the present invention has significant advantages in improving drug efficacy, enhancing safety, improving patient experience and promoting the development of green pharmaceutical technology through innovative design and material optimization, and provides a new solution for the field of local anesthesia that is more efficient, safe and environmentally friendly. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Figure 1 This is a physical picture of the dialysis membrane prepared in Example 3;

[0054] Figure 2 This is a scanning electron microscope image of the dialysis membrane prepared in Example 3;

[0055] Figure 3 This is the X-ray photoelectron spectrum of the dialysis membrane prepared in Example 3;

[0056] Figure 4 Performance test of the dialysis membranes prepared in Examples 1-4; wherein A represents the dialysis membrane of Example 1, B represents the dialysis membrane of Example 2, C represents the dialysis membrane of Example 3, and D represents the dialysis membrane of Example 4;

[0057] Figure 5 A demonstration diagram of the hydrogel prepared in Example 3;

[0058] Figure 6 This is the release rate graph of the hydrogel prepared in Example 3. DETAILED DESCRIPTION

[0059] The present invention is further described below in conjunction with specific embodiments.

[0060] Unless otherwise defined, technical and scientific terms used in the following examples have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0061] Example

[0062] The prescription quantity information involved in this embodiment (measured in 10,000 ml) is shown in Table 1 and Table 2:

[0063] Table 1 Prescription table

[0064] Serial number Name of raw materials 10,000ml use 1 Bupivacaine hydrochloride 81.20g Main drug 2 Sodium chloride 85.00g Isotonicity Agents 3 Medicinal charcoal (for 767 type injection) 3.00g Adsorbent

[0065] Table 2 Material sources

[0066]

[0067] Example 1

[0068] The preparation method of the bupivacaine hydrochloride topical hydrogel comprises the following steps:

[0069] (1) Raw material preparation

[0070] Weigh bupivacaine hydrochloride, sodium chloride and medicinal charcoal; the parameters of the medicinal charcoal in step (1) are as follows: 50 μm, specific surface area 1500 m 2 / g.

[0071] (2) Solution preparation

[0072] a) 80 kg of water for injection is heated to 75° C., sodium chloride in the prescribed amount is added, and stirred for 20 min at a stirring speed of 250 rpm; the water for injection in step (2) is high-purity water with a conductivity of ≤1.3 μS / cm.

[0073] b) adding the prescribed amount of bupivacaine hydrochloride, and then adding 20 kg of water for injection for spraying, and continuing to stir for 5 minutes until it is completely dissolved;

[0074] c) Press the solution into the preparation tank, rinse with 50 kg of injection water three times, and press into the preparation tank respectively;

[0075] d) Add the moistened medicinal charcoal into the preparation tank and stir for 5 minutes;

[0076] (3) Dialysis treatment

[0077] a) putting the prepared drug solution into a dialysis bag, the dialysis membrane of which has a pore size of 3500Da;

[0078] b) After dialysis, the drug solution is taken out from the dialysis bag and subsequently processed;

[0079] The dialysis conditions in step (3) are: temperature 4°C, pH value controlled at 4.5, dialysis time 8h, and dialysate replaced every 2h;

[0080] The dialysate is sterile saline.

[0081] The preparation method of the dialysis membrane is as follows:

[0082] In a blender, 20 g of polyethersulfone was dissolved in 140 g of N,N-dimethylacetamide and stirred until completely dissolved; then, 0.3 g of plant fiber was added and stirring was continued for 24 h to ensure uniform distribution; finally, 2 g of methacryloylethylsulfobetaine, 5 g of polyvinyl alcohol and 20 g of polylactic acid were added and stirred until uniform; the prepared solution was evenly coated on a glass plate to form a liquid film with a thickness of 200 μm, evaporated at room temperature for 10 s to form a preliminary cortex, and the coated glass plate was quickly immersed in deionized water for a water bath to form a dialysis membrane with a porous structure, the water bath temperature was controlled at 25°C for 50 min, and the treated dialysis membrane was immersed in deionized water for 24 h to remove residual solvents and unreacted substances, dried at room temperature, and stored in a sterile environment for standby use;

[0083] (4) Filtration and pH adjustment

[0084] a) The dialyzed drug solution is filtered through a titanium rod filter, a 0.45 μm microporous membrane cartridge filter and a 0.2 μm microporous membrane cartridge filter for 15 min in sequence; in step (4), the pore size of the titanium rod filter is 10 μm, and its working pressure is 0.2 MPa.

[0085] b) measuring the pH value of the drug solution. If it is not within the range, adjust it with 1% by mass sodium hydroxide or 1% by mass hydrochloric acid; the pH value of the drug solution in step (4) is 4.5.

[0086] (5) Preparation of hydrogel;

[0087] The preparation method of the hydrogel is as follows:

[0088] First, soybean lecithin, carboxymethyl chitosan and polyethylene glycol are mixed in a mass ratio of 2:1:2, wherein the CAS number of the soybean lecithin is 8002-43-5, and the mixture is stirred at a temperature of 50°C until the soybean lecithin is completely dissolved to form a uniform transparent solution. The bupivacaine hydrochloride solution treated in step (4) is added to the above solution, and the mixture is kept at 50°C and stirred until the bupivacaine is completely dissolved. The final mass percentage of bupivacaine hydrochloride is 0.5%. A 0.22 μm filter membrane is used for filtration and sterilization to remove insoluble impurities. The filtered solution is quickly dispensed into sterile containers, cooled to 4°C, a hydrogel is obtained, and the container is sealed for storage.

[0089] (6) Quality inspection;

[0090] The quality inspection in step (6) is as follows: the sterilized product needs to be manually inspected, unqualified products are eliminated, and sterility and bacterial endotoxin tests are performed.

[0091] (7) Packaging;

[0092] The packaging in step (7) is as follows: qualified products enter the packaging stage, and after checking the product batch number and expiration date information, labeling, boxing and packaging operations are carried out.

[0093] Example 2

[0094] The preparation method of the bupivacaine hydrochloride topical hydrogel comprises the following steps:

[0095] (1) Raw material preparation

[0096] Weigh bupivacaine hydrochloride, sodium chloride and medicinal charcoal; the parameters of the medicinal charcoal in step (1) are as follows: 150 μm, specific surface area 1500 m 2 / g.

[0097] (2) Solution preparation

[0098] a) 80 kg of water for injection is heated to 85° C., sodium chloride in the prescribed amount is added, and stirred for 5 min at a stirring speed of 350 rpm; the water for injection in step (2) is high-purity water with a conductivity of ≤1.3 μS / cm.

[0099] b) Add the prescribed amount of bupivacaine hydrochloride, then add 20 kg of water for injection for spraying, and continue stirring for 15 minutes until it is completely dissolved;

[0100] c) Press the solution into the preparation tank, rinse with 50 kg of injection water three times, and press into the preparation tank respectively;

[0101] d) Add the moistened medicinal charcoal into the preparation tank and stir for 15 minutes;

[0102] (3) Dialysis treatment

[0103] a) putting the prepared drug solution into a dialysis bag, the dialysis membrane of which has a pore size of 3500Da;

[0104] b) After dialysis, the drug solution is taken out from the dialysis bag and subsequently processed;

[0105] The dialysis conditions in step (3) are: temperature 4°C, pH value controlled at 6.0, dialysis time 6 hours, and the dialysate is replaced every 4 hours;

[0106] The dialysate is sterile saline.

[0107] The preparation method of the dialysis membrane is as follows:

[0108] In a blender, 30 g of polyethersulfone was dissolved in 100 g of N,N-dimethylacetamide and stirred until completely dissolved; then, 0.8 g of plant fiber was added and stirring was continued for 24 h to ensure uniform distribution; finally, 1 g of methacryloylethylsulfobetaine, 8 g of polyvinyl alcohol and 10 g of polylactic acid were added and stirred until uniform; the prepared solution was evenly coated on a glass plate to form a liquid film with a thickness of 200 μm, evaporated at room temperature for 20 s to form a preliminary cortex, and the coated glass plate was quickly immersed in deionized water for a water bath to form a dialysis membrane with a porous structure, the water bath temperature was controlled at 25°C for 50 min, and the treated dialysis membrane was immersed in deionized water for 24 h to remove residual solvents and unreacted substances, dried at room temperature, and stored in a sterile environment for standby use;

[0109] (4) Filtration and pH adjustment

[0110] a) The dialyzed drug solution is filtered through a titanium rod filter, a 0.45 μm microporous membrane cartridge filter and a 0.2 μm microporous membrane cartridge filter for 35 min in sequence; in step (4), the pore size of the titanium rod filter is 0.5 μm, and its working pressure is 0.6 MPa.

[0111] b) measuring the pH value of the drug solution. If it is not within the range, adjust it with 1% by mass sodium hydroxide or 1% by mass hydrochloric acid; the pH value of the drug solution in step (4) is 6.0.

[0112] (5) Preparation of hydrogel;

[0113] The preparation method of the hydrogel is as follows:

[0114] First, soybean lecithin, carboxymethyl chitosan and polyethylene glycol are mixed in a mass ratio of 2:1:2, wherein the CAS number of the soybean lecithin is 8002-43-5, and the mixture is stirred at a temperature of 50°C until the soybean lecithin is completely dissolved to form a uniform transparent solution. The bupivacaine hydrochloride solution treated in step (4) is added to the above solution, and the mixture is kept at 50°C and stirred until the bupivacaine is completely dissolved. The final mass percentage of bupivacaine hydrochloride is 0.5%. A 0.22 μm filter membrane is used for filtration and sterilization to remove insoluble impurities. The filtered solution is quickly dispensed into sterile containers, cooled to 4°C, a hydrogel is obtained, and the container is sealed for storage.

[0115] (6) Quality inspection;

[0116] The quality inspection in step (6) is as follows: the sterilized product needs to be manually inspected, unqualified products are eliminated, and sterility and bacterial endotoxin tests are performed.

[0117] (7) Packaging;

[0118] The packaging in step (7) is as follows: qualified products enter the packaging stage, and after checking the product batch number and expiration date information, labeling, boxing and packaging operations are carried out.

[0119] Example 3

[0120] The preparation method of the bupivacaine hydrochloride topical hydrogel comprises the following steps:

[0121] (1) Raw material preparation

[0122] Weigh bupivacaine hydrochloride, sodium chloride and medicinal charcoal; the parameters of the medicinal charcoal in step (1) are as follows: 100 μm, specific surface area 1500 m 2 / g.

[0123] (2) Solution preparation

[0124] a) 80 kg of water for injection is heated to 80° C., sodium chloride in the prescribed amount is added, and stirred for 15 min at a stirring speed of 300 rpm; the water for injection in step (2) is high-purity water with a conductivity of ≤1.3 μS / cm.

[0125] b) adding the prescribed amount of bupivacaine hydrochloride, and then adding 20 kg of water for injection for spraying, and continuing to stir for 10 minutes until it is completely dissolved;

[0126] c) Press the solution into the preparation tank, rinse with 50 kg of injection water three times, and press into the preparation tank respectively;

[0127] d) Add the moistened medicinal charcoal into the preparation tank and stir for 10 minutes;

[0128] (3) Dialysis treatment

[0129] a) putting the prepared drug solution into a dialysis bag, the dialysis membrane of which has a pore size of 3500Da;

[0130] b) After dialysis, the drug solution is taken out from the dialysis bag and subsequently processed;

[0131] The dialysis conditions in step (3) are: temperature 4°C, pH value controlled at 5.5, dialysis time 7h, and dialysate replaced every 3h;

[0132] The dialysate is sterile saline.

[0133] The preparation method of the dialysis membrane is as follows:

[0134] In a blender, 25 g of polyethersulfone was dissolved in 120 g of N,N-dimethylacetamide and stirred until completely dissolved; then, 0.6 g of plant fiber was added and stirring was continued for 24 h to ensure uniform distribution; finally, 1.5 g of methacryloylethylsulfobetaine, 7 g of polyvinyl alcohol and 15 g of polylactic acid were added and stirred until uniform; the prepared solution was evenly coated on a glass plate to form a liquid film with a thickness of 200 μm, evaporated at room temperature for 15 s to form a preliminary cortex, and the coated glass plate was quickly immersed in deionized water for a water bath to form a dialysis membrane with a porous structure, the water bath temperature was controlled at 25 ° C, and the time was 40 min, and the treated dialysis membrane was immersed in deionized water for 36 h to remove residual solvents and unreacted substances, dried at room temperature, and stored in a sterile environment for use;

[0135] (4) Filtration and pH adjustment

[0136] a) The dialyzed drug solution is filtered through a titanium rod filter, a 0.45 μm microporous membrane cartridge filter and a 0.2 μm microporous membrane cartridge filter in sequence for 25 min; in step (4), the pore size of the titanium rod filter is 5 μm, and its working pressure is 0.4 MPa.

[0137] b) measuring the pH value of the drug solution. If it is not within the range, adjust it with 1% by mass sodium hydroxide or 1% by mass hydrochloric acid; the pH value of the drug solution in step (4) is 5.5.

[0138] (5) Preparation of hydrogel;

[0139] The preparation method of the hydrogel is as follows:

[0140] First, soybean lecithin, carboxymethyl chitosan and polyethylene glycol are mixed in a mass ratio of 2:1:2, wherein the CAS number of the soybean lecithin is 8002-43-5, and the mixture is stirred at a temperature of 50°C until the soybean lecithin is completely dissolved to form a uniform transparent solution. The bupivacaine hydrochloride solution treated in step (4) is added to the above solution, and the mixture is kept at 50°C and stirred until the bupivacaine is completely dissolved. The final mass percentage of bupivacaine hydrochloride is 0.5%. A 0.22 μm filter membrane is used for filtration and sterilization to remove insoluble impurities. The filtered solution is quickly dispensed into sterile containers, cooled to 4°C, a hydrogel is obtained, and the container is sealed for storage.

[0141] (86) Quality inspection;

[0142] The quality inspection in step (6) is as follows: the sterilized product needs to be manually inspected, unqualified products are eliminated, and sterility and bacterial endotoxin tests are performed.

[0143] (97) Packaging;

[0144] The packaging in step (7) is as follows: qualified products enter the packaging stage, and after checking the product batch number and expiration date information, labeling, boxing and packaging operations are carried out.

[0145] Example 4

[0146] Basically the same as Example 3, except that: the dialysis membrane is Standard grade regenerated cellulose (RC) single layer dialysis membrane, material: regenerated cellulose (RC), molecular weight cut-off (MWCO): 3:3.5 kDa.

[0147] Test Case

[0148] Taking the best embodiment 3 as an example, the physical picture of the dialysis membrane prepared in the process is as follows Figure 1 As shown in the scanning electron microscope image Figure 2 In addition, its elemental analysis is shown in Figure 3 shown.

[0149] The dialysis membranes prepared in Examples 1-4 were selected to test their osmotic pressure resistance, high temperature resistance, and osmotic flux.

[0150] like Figure 4 As shown in the figure, ABCD represent the dialysis membranes prepared in Examples 1-4, respectively. For the test of osmotic pressure resistance, Examples 1-4 are 0.62MPa, 0.64MPa, 0.68MPa, and 0.47MPa, respectively, and for the test of osmotic flux, Examples 1-4 are 14.8ml / (mmHg.h), 15.3ml / (mmHg.h), 16ml / (mmHg.h), and 10.7ml / (mmHg.h), respectively.

[0151] Meanwhile, the dialysis membranes prepared in Examples 1-3 can withstand standard high temperature sterilization at 121±2°C, while the dialysis membrane prepared in Example 4 can only withstand high temperature sterilization at 105±3°C.

[0152] The preparation method of dialysis membrane shows significant advantages through the combination of multiple components:

[0153] Polyethersulfone: As a matrix material, it has excellent mechanical strength and chemical stability, and is suitable for the preparation of high-performance dialysis membranes. This material ensures the durability and stability of the membrane.

[0154] Plant fiber: This additive helps to improve the mechanical properties and hydrophilicity of the membrane. The introduction of plant fiber can improve the pore structure of the membrane, thereby increasing its permeation flux and selectivity.

[0155] Methacryloylethyl sulfobetaine: This compound acts as a surfactant, increasing the hydrophilicity of the membrane and reducing protein adsorption, thereby reducing the risk of biofouling.

[0156] Polyvinyl alcohol: As a functional material, polyvinyl alcohol has excellent mechanical properties. It can enhance the antibacterial properties of the membrane and improve its ability to filter pollutants.

[0157] Polylactic acid: Improves its anti-pollution ability while improving the pore structure of the membrane, helping to form a uniform porous structure.

[0158] In summary, this dialysis membrane, through the synergistic effect of multiple components, not only improves the mechanical strength and chemical stability of the membrane, but also significantly enhances its hydrophilicity, anti-fouling ability and selectivity. These characteristics make the dialysis membrane have significant advantages in medical and industrial applications, and can effectively improve filtration efficiency and extend service life.

[0159] In addition, the hydrogels prepared in Examples 1-3 were used to evaluate the in vitro cytotoxicity of bupivacaine hydrochloride encapsulated in the hydrogels and drug solutions in 3T3 fibroblast cultures using the CCK-8 assay. 4 The cells were inoculated into a 48-well plate at a density of 100 μg / mL and then cultured in DMEM Dulbecco's modified Eagle medium containing 5% CO2 by volume and 10% fetal bovine serum by weight for 24 h at 37 ° C. The culture medium was then removed and replaced with 100 μL of hydrogel. After the contact time (2 h) (pH 7.4), the culture medium was removed and the culture plate was rinsed with phosphate buffer. 100 mL of serum-free culture medium and 0.5 mg / mL of CCK-8 reagent were added to each well and incubated at 37 ° C for 3 h. The CCK-8 solution in each well was discarded, and 100 μL of ethanol was added to dissolve the porphyrin crystals. The cell activity was finally calculated as shown in Table 3 below.

[0160] Table 3 Cell viability

[0161] Survival rate (%) Example 1 99.7 Example 2 99.7 Example 3 99.8

[0162] At the same time, the hydrogel prepared in Example 3 (such as Figure 5The in vitro release rate of bupivacaine hydrochloride was tested in a 4% phosphate buffer (PBS), 1% Tween 80 and 16% methanol) at pH 7.4 and 37°C. The release of bupivacaine hydrochloride in the hydrogel was evaluated in a buffer (weight percentage: 83% phosphate buffer PBS, 1% Tween 80 and 16% methanol) at pH 7.4 and 37°C. The concentration of 1 mL of the hydrogel solution was measured at predetermined time intervals (4, 8, 12, 16, 20, 24, 28, 32 and 36 h) using a UV-visible spectrophotometer to maintain the water tank conditions. After each hydrogel sampling, 5 mL of fresh phosphate buffer PBS was added after each sampling interval to maintain the sedimentation state of the hydrogel, and it was placed in a shaking incubator again until the next sampling interval, and so on. Finally, high performance liquid chromatography was used to quantitatively analyze the bupivacaine hydrochloride released from the prepared hydrogel, and the results are shown in FIG. Figure 6 As shown, it takes nearly 36 hours for the drug release rate to approach 100%, which shows a good sustained-release effect.

[0163] The above contents are further detailed descriptions of the present invention in combination with specific implementation methods. It cannot be determined that the specific implementation of the present invention is limited to these descriptions. For ordinary technicians in the field of medical hydrogel technology to which the present invention belongs, several simple deductions or substitutions can be made without departing from the concept of the present invention, which should be regarded as belonging to the protection scope determined by the claims submitted by the present invention.

Claims

1. A method for preparing a bupivacaine hydrochloride topical hydrogel, characterized in that: The following steps are involved: (1) Raw material preparation Weigh bupivacaine hydrochloride, sodium chloride, and medical charcoal; (2) Solution preparation a) Heat 80 kg of water for injection to 75-85°C, add the prescribed amount of sodium chloride, and stir for 5-20 minutes at a stirring speed of 250-350 rpm; b) adding the prescribed amount of bupivacaine hydrochloride, and then adding 20 kg of water for injection for spraying, and continuing to stir for 5-15 minutes until it is completely dissolved; c) Press the solution into the preparation tank, rinse with 50 kg of injection water three times, and press into the preparation tank respectively; d) Add the moistened medicinal charcoal into the preparation tank and stir for 5-15 minutes; (3) Dialysis treatment a) putting the prepared drug solution into a dialysis bag, the dialysis membrane of which has a pore size of 3500Da; b) After dialysis, the drug solution is taken out from the dialysis bag and subsequently processed; The preparation method of the dialysis membrane is as follows: In a blender, 20-30 g of polyethersulfone is dissolved in 100-140 g of N,N-dimethylacetamide and stirred until completely dissolved; then, 0.3-0.8 g of plant fiber is added and stirring is continued for 24 h to ensure uniform distribution; finally, 1-2 g of methacryloylethyl sulfobetaine, 5-8 g of polyvinyl alcohol and 10-20 g of polylactic acid are added and stirred until uniform; the prepared solution is evenly coated on a glass plate to form a liquid film with a thickness of 200 μm, evaporated at room temperature for 10-20 s to form a preliminary cortex, and the coated glass plate is quickly immersed in deionized water for a water bath to form a dialysis membrane with a porous structure, the water bath temperature is controlled at 25° C., and the time is 30 min-50 min, and the treated dialysis membrane is immersed in deionized water for 24-48 h to remove residual solvents and unreacted substances, dried at room temperature, and stored in a sterile environment for standby use; (4) Filtration and pH adjustment a) The dialyzed drug solution was filtered through a titanium rod filter, a 0.45 μm microporous membrane cartridge filter and a 0.2 μm microporous membrane cartridge filter for 15-35 minutes; b) Measure the pH value of the liquid. If it is not within the range, adjust it with 1% by mass sodium hydroxide or 1% by mass hydrochloric acid; (5) Preparation of hydrogel; (6) Quality inspection; (7) Packaging.

2. The method for preparing the bupivacaine hydrochloride topical hydrogel according to claim 1, characterized in that: Step (1) The parameters of the Chinese medicinal carbon are as follows: 50-150 μm, specific surface area 1500 m 2 / g.

3. The method for preparing the bupivacaine hydrochloride topical hydrogel according to claim 2, characterized in that: The water for injection in step (2) is high-purity pure water with a conductivity of ≤1.3μS / cm.

4. The method for preparing the bupivacaine hydrochloride topical hydrogel according to claim 3, characterized in that: The dialysis conditions in step (3) are: temperature 4°C, pH value controlled at 4.5-6.0, dialysis time 6-8h, and dialysate replaced every 2-4h; The dialysate is sterile saline.

5. The method for preparing the bupivacaine hydrochloride topical hydrogel according to claim 4, characterized in that: The pore size of the titanium rod filter in step (4) is 0.5-10 μm, and its working pressure is 0.2-0.6 MPa.

6. The method for preparing the bupivacaine hydrochloride topical hydrogel according to claim 5, characterized in that: The pH value of the medicinal solution in step (4) is 4.5-6.

0.

7. The method for preparing the bupivacaine hydrochloride topical hydrogel according to claim 6, characterized in that: The temperature of the filling room during the canning process in step (5) is 18-25° C., and the relative humidity of the filling room is 40-60%; At the same time, the testing conditions for canning are as follows: Before canning begins, the filling needles and sealing heads are sterilized with flame spray for ≥5s; the air in the filling room is tested for floating bacteria every 30min, with a standard of ≤0.5CFU / dish; the sterility of the filling needles is verified every 2h, using the sterile culture medium filling method; the sealing quality is sampled every 4h, with a sampling quantity of ≥20 and a pass rate of 100%.

8. The method for preparing the bupivacaine hydrochloride topical hydrogel according to claim 7, characterized in that: The preparation method of the hydrogel in step (5) is as follows: First, soybean lecithin, carboxymethyl chitosan and polyethylene glycol are mixed in a mass ratio of 2:1:2, wherein the CAS number of the soybean lecithin is 8002-43-5, and the mixture is stirred at a temperature of 50°C until the soybean lecithin is completely dissolved to form a uniform transparent solution. The bupivacaine hydrochloride solution treated in step (4) is added to the above solution, and the mixture is kept at 50°C and stirred until the bupivacaine is completely dissolved. The final mass percentage of bupivacaine hydrochloride is 0.5%. A 0.22 μm filter membrane is used for filtration and sterilization to remove insoluble impurities. The filtered solution is quickly dispensed into sterile containers, cooled to 4°C, a hydrogel is obtained, and the container is sealed for storage.

9. The method for preparing the bupivacaine hydrochloride topical hydrogel according to claim 8, characterized in that: The quality inspection in step (6) is as follows: the sterilized product needs to be manually,inspected, unqualified products are eliminated, and sterility and bacterial endotoxin tests are performed; The packaging in step (7) is as follows: qualified products enter the packaging stage, and after checking the product batch number and expiration date information, labeling, boxing and packaging operations are carried out.

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