Lidocaine hydrochloride-containing sodium hyaluronate gel for injection and preparation method of lidocaine hydrochloride-containing sodium hyaluronate gel

Abstract

The invention discloses lidocaine hydrochloride-containing sodium hyaluronate gel for injection and a preparation method of the lidocaine hydrochloride-containing sodium hyaluronate gel, and belongs to the technical field of sodium hyaluronate gel. Comprising the following steps: preparing an alkaline sodium hyaluronate composite solution, a cross-linking agent composite solution and a gel block, dialyzing, granulating to obtain gel particles, preparing a lidocaine composite solution, and mixing to obtain the lidocaine hydrochloride-containing sodium hyaluronate gel for injection. According to the lidocaine hydrochloride-containing sodium hyaluronate gel for injection, the lidocaine hydrochloride can quickly reach 3.3 mu g / mL or above within 10 min after administration, the concentration can be stably maintained for 8 h or above, the peak concentration lasting time reaches 5 h or above, the single administration concentration does not need to be increased or the administration frequency does not need to be increased, and the lidocaine hydrochloride-containing sodium hyaluronate gel for injection can be used for injection. The requirements of clinical injection operation and local analgesia within a period of postoperative time can be met.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of sodium hyaluronate gel, in particular to a kind of lidocaine hydrochloride injection containing sodium hyaluronate gel and preparation method thereof. BACKGROUND

[0002] Sodium hyaluronate gel for injection in clinical application, not only will be due to injection operation process instrument stimulation, gel and human tissue direct interaction leads to patient produces local pain, 12 hours after injection can also be due to tissue stress response, slight inflammation and other factors cause pain, therefore, adding lidocaine hydrochloride in sodium hyaluronate gel formula to realize local analgesia, has become the common technical means to improve the problem.

[0003] However, lidocaine hydrochloride has weak retention in vivo, after contacting human tissue, it is easily affected by physiological environment such as body fluid circulation, tissue fluid exchange, quickly diffuses and dilutes, which makes it difficult for lidocaine hydrochloride to exist stably in the target action area, and unable to maintain effective concentration for a long time.

[0004] In order to ensure the expected auxiliary effect during the whole operation process, make up for the problem of insufficient concentration caused by rapid loss of drug, it is often necessary to adjust by increasing the concentration of single dose or increasing the frequency of administration in practical application. Although this adjustment method can maintain short-term effect to some extent, it directly leads to the increase of total amount of lidocaine hydrochloride, and the excess drug not only causes waste due to insufficient utilization, but also increases the total amount of drug entering systemic circulation.

[0005] Based on this, the present application designs a kind of lidocaine hydrochloride injection containing sodium hyaluronate gel and preparation method thereof to solve the above problems. SUMMARY

[0006] In view of the above-mentioned shortcomings of the prior art, the present application provides a preparation method of lidocaine hydrochloride injection containing sodium hyaluronate gel, comprising the following steps: S1. Add 40-50℃, 85-95 parts by weight of water for injection to the liquid preparation tank, add 0.8-1.2 parts by weight of sodium hydroxide solid, and stir to obtain a sodium hydroxide solution; filter, and extract 2.0-2.5 parts by weight of the solution as a crosslinking agent diluent for standby; To the remaining sodium hydroxide solution, add 18-22 parts by weight of sodium hyaluronate dry powder while stirring, add 0.05-0.15 parts by weight of trehalose, high-speed shear dispersion, reduce the speed, swell for 2-4h under nitrogen atmosphere and 25-30℃, to obtain an alkaline sodium hyaluronate composite solution; S2. Take 2.0-2.5 parts by weight of the sodium hydroxide solution reserved in S1, add 0.30-0.38 parts by weight of 1,4-butanediol diglycidyl ether, and add 0.01-0.03 parts by weight of vitamin E polyethylene glycol succinate, homogenize to obtain a crosslinking agent emulsion, and add the crosslinking agent emulsion to the basic sodium hyaluronate composite solution prepared in S1 while stirring to obtain a crosslinking agent composite solution; S3. Inject the crosslinking agent composite solution into a tray, and first perform a first-stage crosslinking at 4-8℃ for 120-144h under nitrogen protection, then raise the temperature to 38-43℃, and perform a second-stage high-temperature curing for 4-6h, and cool to obtain a gel sheet, and cut the gel sheet into gel blocks; S4. Perform dialysis on the gel blocks using a phosphate buffer as a dialysis medium to obtain purified gel blocks; and granulate to obtain gel particles; S5. Add 80-90 parts by weight of a phosphate buffer to a solution preparation tank, add 2.0-3.0 parts by weight of lidocaine hydrochloride, 0.5-1.0 parts by weight of sodium chloride, and 0.1-0.3 parts by weight of glycine, stir, add 1.5-2.5 parts by weight of sodium hyaluronate dry powder, and stir and filter to obtain a lidocaine composite solution; S6. Mix the gel particles and the lidocaine composite solution at a mass ratio of 65-75:25-35 to obtain a finished gel and fill the finished gel into a container; S7. Sterilize to obtain a sodium hyaluronate gel containing lidocaine hydrochloride for injection.

[0007] Further, S1 is specifically: add 85-95 parts by weight of water for injection to a solution preparation tank, control the water temperature at 40-50℃, add 0.8-1.2 parts by weight of sodium hydroxide solid, and stir at 120-150r / min for 15-20min to obtain a sodium hydroxide solution; Pass the sodium hydroxide solution through a delivery pump, pre-filter through a 0.45μm folding filter, and then terminal filter through a 0.22μm polyether sulfone sterilization filter, and deliver to an intermediate storage tank; and take 2.0-2.5 parts by weight of the solution in the intermediate storage tank as a crosslinking agent diluent for standby use; While stirring, add 18-22 parts by weight of sodium hyaluronate dry powder to the remaining sodium hydroxide solution, and simultaneously add 0.05-0.15 parts by weight of trehalose, high-speed shear disperse at 2800-3200r / min for 20-30min, reduce the speed to 60-80r / min, and swell at 25-30℃ in a nitrogen atmosphere for 2-4h to obtain a basic sodium hyaluronate composite solution.

[0008] Further, S2 is specifically: taking 2.0-2.5 parts by weight of sodium hydroxide solution reserved in S1, adding 0.30-0.38 parts by weight of 1,4-butanediol diglycidyl ether, and adding 0.01-0.03 parts by weight of vitamin E polyethylene glycol succinate, homogenizing for 5-10 min at 1500-2000 r / min to form emulsion droplets of the oil-soluble crosslinking agent in the aqueous phase, to obtain a crosslinking agent emulsion, adding the crosslinking agent emulsion to the basic sodium hyaluronate composite solution prepared in S1 at a rate of 0.5 parts by weight / min under stirring at 40-60 r / min, and stirring for another 30-40 min under a nitrogen atmosphere to obtain a crosslinking agent composite solution.

[0009] Further, S3 is specifically: delivering the crosslinking agent composite solution to a sterile tank through a pipeline, prepositioning a polytetrafluoroethylene tray that has been sterilized in a temperature-controlled reaction cabinet, controlling the spacing between the tray racks to be 10 cm, injecting the crosslinking agent composite solution into the tray, and controlling the thickness of the liquid layer in each tray to be 3.5-5.5 mm, first performing a first-stage crosslinking at 4-8℃ for 120-144 h under nitrogen protection, then increasing the temperature to 38-43℃ at a rate of 3-5℃ / h, and performing a second-stage high-temperature curing for 4-6 h, and naturally cooling the gel sheet to room temperature to obtain a gel square, and cutting the gel sheet into square gel blocks with a side length of 0.6-0.8 cm.

[0010] Further, S4 is specifically: placing the gel blocks in a dialysis bag, sealing the dialysis bag, and placing the dialysis bag in a dialysis barrel, using a phosphate buffer with a pH value of 7.0-7.4 as the dialysis medium, controlling the liquid-solid ratio to be 20-30:1, and dialyzing for 48-72 h, replacing the dialysis liquid every 0.5-2 h during the dialysis, and obtaining purified gel blocks. Loading the purified gel blocks into a granulator, connecting nitrogen that has been sterilized and filtered, installing a titanium alloy microporous screen plate with a pore size of 480-520 μm at the discharge port of the granulator, performing primary granulation and collecting the granules, replacing the screen plate with a pore size of 250-400 μm, and performing secondary granulation on the primary granulation collected granules to obtain gel granules.

[0011] Further, S5 is specifically: adding 80-90 parts by weight of a phosphate buffer to a solution preparation tank, adding 2.0-3.0 parts by weight of lidocaine hydrochloride, 0.5-1.0 parts by weight of sodium chloride, and 0.1-0.3 parts by weight of glycine, stirring at 100-120 r / min for 20-30 min, then adding 1.5-2.5 parts by weight of sodium hyaluronate dry powder, continuing to stir for 60-90 min, and then performing two-stage sterilization filtration through 0.45 μm and 0.22 μm filter cartridges to obtain a lidocaine composite solution.

[0012] Further, S6 is specifically: the gel particles and the lidocaine complex liquid are put into a mixer at a mass ratio of 65-75:25-35, mixed at 60-80 r / min for 30-45 min, and the finished gel is obtained after mixing is completed and is filled.

[0013] A lidocaine hydrochloride-containing sodium hyaluronate gel for injection prepared according to the method.

[0014] Compared with the prior art, the present application has the following beneficial effects: 1. The lidocaine hydrochloride-containing sodium hyaluronate gel for injection prepared by the present application can make the concentration of lidocaine hydrochloride reach more than 3.3 μg / mL within 10 min after administration, and the concentration can be stably maintained for more than 8 h, and the peak concentration (more than 5.2 μg / mL) can be maintained for more than 5 h, without the need to increase the concentration of single administration or increase the frequency of administration.

[0015] 2. The present application adds trehalose and vitamin E polyethylene glycol succinate in the formula, and uses a two-stage crosslinking process, thereby improving the structural stability and drug release controllability of the gel, reducing the rapid diffusion and dilution of lidocaine hydrochloride in the body, reducing the total amount of drug, and avoiding the waste caused by excessive drug and the risk of increasing the total amount of circulating drug.

[0016] 3. The gel prepared by the present application has a light transmittance of more than 99% in the wavelength range of 300-800 nm, a pH value of 7.0-7.3, and an osmotic pressure of 320-330 mOsmol / kg, which meets the industry general standard, has good physicochemical stability, and meets the requirements of clinical injection. BRIEF DESCRIPTION OF DRAWINGS

[0017] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the following will briefly introduce the drawings needed to be used in the embodiments or the prior art description. Obviously, the drawings in the following description are only some embodiments of the present application, and other drawings can be obtained by those skilled in the art without creative labor.

[0018] Figure 1 The figure is a graph of the change of lidocaine concentration in the rat plasma of each embodiment and the comparative example of the present application with time; Figure 2 The figure is a high-performance liquid chromatogram for detecting the concentration of lidocaine hydrochloride in the plasma of Example 3 of the present application at 10 min; Figure 3 The figure is a high-performance liquid chromatogram for detecting the concentration of lidocaine hydrochloride in the plasma of Example 3 of the present application at 2 h; Figure 4The high performance liquid chromatogram for detecting the concentration of lidocaine hydrochloride in the plasma at 12 h of Example 3 of the present application. DETAILED DESCRIPTION

[0019] In order to make the objectives, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be described clearly and completely below with reference to the drawings in the embodiments of the present application. Obviously, the described embodiments are some but not all of the embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by a person of ordinary skill in the art without creative work fall within the protection scope of the present application.

[0020] Example 1: This embodiment provides a preparation method of a hyaluronic acid sodium gel for injection containing lidocaine hydrochloride, comprising the following steps: S1. 85 parts by weight of water for injection was added to a solution preparation tank, the water temperature was controlled at 40℃, 0.8 parts by weight of sodium hydroxide solid was added, and stirring was carried out at 120 r / min for 15 min to obtain a sodium hydroxide solution; The sodium hydroxide solution was pre-filtered through a 0.45 μm folding filter, and then terminal filtered through a 0.22 μm polyether sulfone sterilization filter, and then delivered to an intermediate storage tank, and 2.0 parts by weight of the solution was taken from the intermediate storage tank as a crosslinking agent diluent for standby; While stirring, 18 parts by weight of sodium hyaluronate dry powder (molecular weight 1800-2200 kDa) was added to the remaining sodium hydroxide solution, and 0.05 parts by weight of trehalose was added, and high-speed shearing dispersion was carried out at 2800 r / min for 20 min, the speed was reduced to 60 r / min, and swelling was carried out at 25℃ in a nitrogen atmosphere for 2 h to obtain an alkaline sodium hyaluronate composite solution; S2. 2.0 parts by weight of sodium hydroxide solution reserved in S1 was taken, 0.30 parts by weight of 1,4-butanediol diglycidyl ether was added, and 0.01 parts by weight of vitamin E polyethylene glycol succinate was added, and homogenization was carried out at 1500 r / min for 5 min to form emulsion droplets of oil-soluble crosslinking agent in the water phase to obtain a crosslinking agent emulsion, and the crosslinking agent emulsion was added to the alkaline sodium hyaluronate composite solution prepared in S1 at a rate of 0.5 parts by weight / min while stirring at 40 r / min, and after all the addition was completed, stirring was carried out under a nitrogen atmosphere for another 30 min to obtain a crosslinking agent composite solution; S3. The crosslinking agent composite solution is transported through a pipeline into a sterile tank, a sterilized polytetrafluoroethylene tray is prearranged in a temperature-controlled reaction cabinet, the tray shelf spacing is controlled to be 10 cm, the crosslinking agent composite solution is injected into the tray, the liquid layer thickness of each tray is 3.5 mm, under the protection of nitrogen, a first-stage crosslinking at 4℃ for 120 h is performed, then the temperature is raised to 38℃ at a rate of 3℃ / h, a second-stage high-temperature curing for 4 h is performed, and the gel sheet is naturally cooled to room temperature to obtain a gel sheet, the gel sheet is cut into square gel blocks with a side length of 0.6 cm; S4. The gel blocks are placed in a dialysis bag with a molecular weight cut-off of 8000 Da, the dialysis bag is sealed and then placed in a dialysis barrel, a phosphate buffer solution with a pH value of 7.0-7.4 (sodium chloride concentration 7.75±0.25‰, sodium dihydrogen phosphate concentration 0.15±0.01‰, disodium hydrogen phosphate concentration 0.8±0.2‰ and injection water) is used as the dialysis medium, the liquid-solid ratio is 20:1, the dialysis time is 48 h, the dialysis is completed, and the dialysate is replaced every 0.5 h during the dialysis to obtain purified gel blocks; The purified gel blocks are loaded into a granulator (screw extrusion granulator), nitrogen filtered by sterilization is connected at 2℃, a titanium alloy microporous screen plate with a pore size of 480 μm is installed at the discharge port of the granulator, the granulation is performed once and the particles are collected, the screen plate with a pore size of 250 μm is replaced, and the particles collected after the first granulation are subjected to second granulation, the length of the particles is 0.5-1 cm, and gel particles are obtained; S5. 80 parts by weight of the phosphate buffer solution, 2.0 parts by weight of lidocaine hydrochloride, 0.5 parts by weight of sodium chloride and 0.1 parts by weight of glycine are added into a liquid preparation tank, stirred at 100 r / min for 20 min, then 1.5 parts by weight of sodium hyaluronate dry powder is added, and stirred for another 60 min, and then subjected to two-stage sterilization filtration through 0.45 μm and 0.22 μm filter cartridges in sequence to obtain a lidocaine compound solution; S6. The gel particles and the lidocaine compound solution are put into a mixer at a mass ratio of 65:25, mixed at 60 r / min for 30 min, and then the finished gel is obtained and filled; S7. The filled finished gel is sterilized by radiation sterilization, and the finished gel containing lidocaine hydrochloride for injection is obtained by irradiation with γ rays generated by Co-60, and the absorption dose is set to 25 kGy.

[0021] Embodiment 2: A preparation method of a sodium hyaluronate gel containing lidocaine hydrochloride for injection is provided, which comprises the following steps: S1. 95 parts by weight of injection water is added into a liquid preparation tank, the water temperature is controlled at 50℃, 1.2 parts by weight of sodium hydroxide solid is added, and stirred at 150 r / min for 20 min to obtain a sodium hydroxide solution; The sodium hydroxide solution was pre-filtered through a 0.45 μm folded filter cartridge and then terminal filtered through a 0.22 μm polyether sulfone bacteria-removing filter cartridge by a delivery pump, and delivered into an intermediate storage tank. 2.5 parts by weight of the solution was drawn from the intermediate storage tank as a crosslinking agent diluent for standby use; While stirring, 22 parts by weight of sodium hyaluronate dry powder and 0.15 parts by weight of trehalose were added into the remaining sodium hydroxide solution, and then high-speed shearing dispersion was performed at 3200 r / min for 30 min. The rotation speed was reduced to 80 r / min, and swelling was performed at 30°C under a nitrogen atmosphere for 4 h to obtain an alkaline sodium hyaluronate composite solution. S2. 0.38 parts by weight of 1,4-butanediol diglycidyl ether and 0.03 parts by weight of vitamin E polyethylene glycol succinate were added into 2.5 parts by weight of the sodium hydroxide solution reserved in S1, and then homogenization was performed at 2000 r / min for 10 min to form oil-soluble crosslinking agent emulsion droplets in the aqueous phase. The crosslinking agent emulsion was added into the alkaline sodium hyaluronate composite solution prepared in S1 at a rate of 0.5 parts by weight / min under stirring at 60 r / min. After the addition was completed, stirring was performed under a nitrogen atmosphere for 30-40 min to obtain a crosslinking agent composite solution. S3. The crosslinking agent composite solution was delivered into a sterile tank through a pipeline, and a sterilized polytetrafluoroethylene tray was prearranged in a temperature-controlled reaction cabinet. The tray was arranged with a layer spacing of 10 cm. The crosslinking agent composite solution was injected into the tray, and the liquid layer thickness of each tray was 5.5 mm. Under nitrogen protection, one-stage crosslinking was performed at 8°C for 144 h, and then two-stage high-temperature curing was performed at a temperature increasing rate of 5°C / h to 43°C for 6 h. The gel sheet was naturally cooled to room temperature to obtain a gel square with a side length of 0.8 cm. S4. The gel square was placed in a dialysis bag with a molecular weight cut-off of 8000 Da. After the dialysis bag was sealed, it was placed in a dialysis barrel. Phosphate buffer solution with a pH value of 7.0-7.4 (sodium chloride concentration of 7.75±0.25‰, sodium dihydrogen phosphate concentration of 0.15±0.01‰, disodium hydrogen phosphate concentration of 0.8±0.2‰, and injection water) was used as the dialysis medium. The liquid-solid ratio was 30:1, and the dialysis time was 72 h. The dialysate was replaced every 2 h during the dialysis to obtain a purified gel square. The purified gel square was loaded into a granulator (screw extrusion granulator). Nitrogen filtered by sterilization was connected at 8°C. A titanium alloy microporous screen plate with a pore size of 520 μm was installed at the discharge port of the granulator. After one-time granulation, the particles were collected. After replacing the screen plate with a pore size of 400 μm, the particles collected after the first-time granulation were subjected to second-time granulation. The length of the particles was 1 cm to obtain gel particles. S5. Add 80-90 parts by weight of phosphate buffer to the liquid preparation tank, add 3.0 parts by weight of lidocaine hydrochloride, 1.0 part by weight of sodium chloride, and 0.3 parts by weight of glycine, stir at 120 r / min for 30 min, then add 2.5 parts by weight of sodium hyaluronate dry powder, continue to stir for 90 min, and then perform two-stage sterilization filtration through 0.45 μm and 0.22 μm filter cartridges in sequence to obtain a lidocaine compound solution; S6. Put the gel particles and the lidocaine compound solution into a mixer at a mass ratio of 75:35, mix at 80 r / min for 45 min, and obtain the finished gel after mixing is completed and then fill it; S7. Sterilize the filled finished gel by radiation sterilization method, irradiate using γ-rays generated by Co-60, set the absorption dose to 25 kGy, and obtain a sodium hyaluronate gel containing lidocaine hydrochloride for injection.

[0022] Embodiment 3: The embodiment provides a preparation method of a sodium hyaluronate gel containing lidocaine hydrochloride for injection, which comprises the following steps: S1. Add 92 parts by weight of water for injection to the liquid preparation tank, control the water temperature at 46℃, add 0.9 parts by weight of solid sodium hydroxide, and stir at 130 r / min for 18 min to obtain a sodium hydroxide solution; Pass the sodium hydroxide solution through a delivery pump, pre-filter it through a 0.45 μm folding filter cartridge, and then perform terminal filtration through a 0.22 μm polyether sulfone sterilization filter cartridge, and deliver it to an intermediate storage tank. Take 2.5 parts by weight of the solution from the intermediate storage tank as a crosslinking agent diluent for standby use; While stirring, add 19 parts by weight of sodium hyaluronate dry powder and 0.08 parts by weight of trehalose to the remaining sodium hydroxide solution, and disperse them at a high speed of 2800 r / min for 24 min. Reduce the speed to 65 r / min, swell in a nitrogen atmosphere at 30℃ for 4 h, and obtain an alkaline sodium hyaluronate compound solution; S2. Take 2.2 parts by weight of the sodium hydroxide solution reserved in S1, add 0.32 parts by weight of 1,4-butanediol diglycidyl ether, and add 0.02 parts by weight of vitamin E polyethylene glycol succinate, and homogenize at 1800 r / min for 7 min to form oil droplets of the oil-soluble crosslinking agent in the water phase, and obtain a crosslinking agent emulsion. Add the crosslinking agent emulsion to the alkaline sodium hyaluronate compound solution prepared in S1 at a rate of 0.5 parts by weight / min while stirring at 47 r / min, and after all the crosslinking agent emulsion is added, stir for another 37 min in a nitrogen atmosphere to obtain a crosslinking agent compound solution; S3. The crosslinking agent composite solution is delivered through a pipeline into a sterile tank, a sterilized polytetrafluoroethylene tray is prearranged in a temperature-controlled reaction cabinet, the tray shelf spacing is controlled to be 10 cm, the crosslinking agent composite solution is injected into the tray, the liquid layer thickness of each tray is 5 mm, under the protection of nitrogen, a first-stage crosslinking at 6℃ for 130 h is performed, the temperature of the reaction kettle is increased to 42℃ at a rate of 4℃ / h, a second-stage high-temperature curing for 4 h is performed, and the gel sheet is naturally cooled to room temperature to obtain a gel square; S4. The gel square is placed in a dialysis bag with a molecular weight cut-off of 8000 Da, the dialysis bag is sealed and then placed in a dialysis barrel, a phosphate buffer solution with a pH value of 7.0-7.4 (sodium chloride concentration 7.75±0.25‰, sodium dihydrogen phosphate concentration 0.15±0.01‰, disodium hydrogen phosphate concentration 0.8±0.2‰ and injection water) is used as the dialysis medium, the liquid-solid ratio is 22:1, and the dialysis time is 52 h, after which the dialysis is completed, and the dialysis liquid is replaced every 1 h during the dialysis to obtain a purified gel square; The purified gel square is loaded into a granulator (screw extrusion granulator), nitrogen filtered by sterilization is connected at 4℃, a titanium alloy microporous sieve plate with a pore size of 500μm is installed at the discharge port of the granulator, and the granulation is performed once and the particles are collected, the sieve plate with a pore size of 400μm is replaced, and the particles collected after the first granulation are subjected to second granulation, and the length of the particles is 0.5cm to obtain gel particles; S5. 88 parts by weight of the phosphate buffer solution, 2.3 parts by weight of lidocaine hydrochloride, 0.7 parts by weight of sodium chloride and 0.3 parts by weight of glycine are added into a liquid preparation tank, stirred at 120 r / min for 27 min, then 1.9 parts by weight of sodium hyaluronate dry powder is added, and stirred for another 66 min, and then subjected to two-stage sterilization filtration through 0.45μm and 0.22μm filter cartridges in sequence to obtain a lidocaine compound solution; S6. The gel particles and the lidocaine compound solution are put into a mixer at a mass ratio of 72:30, and mixed at 75 r / min for 40 min to obtain the finished gel which is then filled; S7. The filled finished gel is sterilized by radiation sterilization method, and irradiated by γ-rays generated by Co-60, and the absorption dose is set to 25kGy to obtain the sodium hyaluronate gel containing lidocaine hydrochloride for injection.

[0023] Comparative Example 1: The difference between this comparative example and Example 3 is that in S5, the amount of lidocaine hydrochloride added is 1 part by weight.

[0024] Comparative Example 2: The difference between this comparative example and Example 3 is that in S2, vitamin E polyethylene glycol succinate is not added.

[0025] Comparative Example 3: The difference between this comparative example and Example 3 is that no trehalose was added in S1.

[0026] Comparative Example 4: This comparative example differs from Example 3 in that trehalose was not added in S1 and vitamin E polyethylene glycol succinate was not added in S2.

[0027] Experimental Example 1: Local Concentration Detection Experiment in Vivo; 120 SD rats (half male and half female) were randomly divided into 8 groups of 15 rats each, corresponding to Examples 1-3 and Comparative Examples 1-4, respectively. The administration method was to remove hair from the back of rats (area 2cm×2cm), disinfect the area, and inject 0.2g of gel into each rat in each group in the examples and comparative examples; Blood samples of 0.2 mL were drawn subcutaneously from the administration site using a microsyringe at 10 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 12 h after administration. The concentration of lidocaine hydrochloride in plasma was determined by HPLC, and the concentration of each group was recorded. The HPLC detection conditions are as follows: Chromatographic column: Agilent ZORBAX SB-C18 column (4.6 mm × 250 mm, 5 μm); Mobile phase: methanol - 5 mmol / L ammonium acetate = 55:45 (volume ratio); Column temperature 30℃; flow rate 0.5mL / min; injection volume 10μL.

[0028] It should be noted that, Figures 2-4 Only the first 9 minutes containing lidocaine hydrochloride were captured.

[0029] The data is shown in Table 1; Table 1: From Table 1 and Figure 1 It can be seen that in Examples 1-3, the concentration reached 3.35-3.45 μg / mL within 10 minutes after administration, the peak concentration reached 5.74-5.84 μg / mL at 2 hours, and remained at a stable level of 2.20-2.32 μg / mL for 12 hours; while in Comparative Example 1, the lidocaine hydrochloride was reduced to 1 part by weight, and the concentration was significantly lower than that in Examples throughout the entire process, which could not meet the long-term analgesic needs; In Examples 1-3, the peak concentration (above 5.2 μg / mL) was maintained for 6 hours, and remained above 4 μg / mL for 8 hours. In Comparative Example 2 (without vitamin E polyethylene glycol succinate), the peak concentration was approximately 4.93 μg / mL, and dropped below 4 μg / mL after 5 hours, with the peak duration shortened to 3 hours. In Comparative Example 3 (without trehalose), the peak concentration was approximately 4.24 μg / mL, falling below 4 μg / mL after 4 hours, with the peak duration less than 2 hours. In Comparative Example 4, the peak concentration was 4.25 μg / mL, and the concentration rapidly declined after 3 hours, with the peak duration only 1 hour. This indicates that trehalose enhances the structural stability of the gel and reduces drug leakage at peak concentrations, while vitamin E polyethylene glycol succinate optimizes the dispersion uniformity of the cross-linking agent, resulting in a smoother drug release. The synergistic effect of these two components significantly prolongs the duration of peak concentration.

[0030] Experimental Example 2: According to YY / T 0308-2015, the transmittance (%), pH, and osmotic pressure (mOsmol / kg) in the wavelength range of 300-800nm ​​were detected. The results are shown in Table 2; Table 2: Item Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Transmittance % 99.4 99.3 99.5 98.7 98.8 99.1 99.2 pH 7.2 7.2 7.2 6.9 7.1 7.1 7.3 Osmolarity mOsmol / kg 320 326 325 302 314 318 322 The sodium hyaluronate gel containing lidocaine hydrochloride for injection prepared by this invention has a transmittance of >99% in the wavelength range of 300-800nm, a pH that is stable in the range of 7.0-7.3, and an osmotic pressure in the range of 320-330mOsmol / kg, which meets the general industry standards.

[0031] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions will not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a lidocaine hydrochloride containing sodium hyaluronate gel for injection, characterized in that, Comprise the following steps: S1. Add 40-50℃, 85-95 parts by weight of water for injection to the liquid preparation tank, add 0.8-1.2 parts by weight of sodium hydroxide solid, and stir to obtain a sodium hydroxide solution; filter, and extract 2.0-2.5 parts by weight of the solution as a crosslinking agent diluent for standby; To the remaining sodium hydroxide solution, add 18-22 parts by weight of sodium hyaluronate dry powder while stirring, add 0.05-0.15 parts by weight of trehalose, and disperse at high speed, reduce the speed, swell for 2-4h under nitrogen atmosphere at 25-30℃, and obtain a basic sodium hyaluronate composite solution; S2. Take 2.0-2.5 parts by weight of the sodium hydroxide solution reserved in S1, add 0.30-0.38 parts by weight of 1,4-butanediol diglycidyl ether, and add 0.01-0.03 parts by weight of vitamin E polyethylene glycol succinate, and homogenize to obtain a crosslinking agent emulsion; add the crosslinking agent emulsion to the basic sodium hyaluronate composite solution prepared in S1 while stirring, and stir to obtain a crosslinking agent composite solution; S3. Inject the crosslinking agent composite solution into a tray, and under nitrogen protection, first perform a first-stage crosslinking at 4-8℃ for 120-144h, then increase the temperature to 38-43℃, and perform a second-stage high-temperature curing for 4-6h, cool to obtain a gel sheet, and cut the gel sheet into gel blocks; S4. Use a phosphate buffer as a dialysis medium to dialyze the gel blocks, and obtain purified gel blocks; granulate to obtain gel particles; S5. Add 80-90 parts by weight of a phosphate buffer to the liquid preparation tank, add 2.0-3.0 parts by weight of lidocaine hydrochloride, 0.5-1.0 parts by weight of sodium chloride, and 0.1-0.3 parts by weight of glycine, stir, add 1.5-2.5 parts by weight of sodium hyaluronate dry powder, and stir and filter to obtain a lidocaine composite solution; S6. Mix the gel particles and the lidocaine composite solution at a mass ratio of 65-75:25-35 to obtain a finished gel and fill it; S7. Sterilize to obtain a sodium hyaluronate gel containing lidocaine hydrochloride for injection.

2. The method for preparing the lidocaine hydrochloride-containing sodium hyaluronate gel for injection according to claim 1, characterized by, S1 is specifically: add 85-95 parts by weight of water for injection to the liquid preparation tank, control the water temperature at 40-50℃, add 0.8-1.2 parts by weight of sodium hydroxide solid, and stir at 120-150r / min for 15-20min to obtain a sodium hydroxide solution; The sodium hydroxide solution is pre-filtered through a 0.45μm folded filter, then terminal filtered through a 0.22μm polyether sulfone sterilization filter, and delivered to an intermediate storage tank, from which 2.0-2.5 parts by weight of the solution is extracted as a crosslinking agent diluent for standby; To the remaining sodium hydroxide solution, add 18-22 parts by weight of sodium hyaluronate dry powder while stirring, add 0.05-0.15 parts by weight of trehalose, and disperse at high speed for 20-30min at 2800-3200r / min, reduce the speed to 60-80r / min, swell for 2-4h under nitrogen atmosphere at 25-30℃, and obtain a basic sodium hyaluronate composite solution.

3. The method for preparing the lidocaine hydrochloride-containing sodium hyaluronate gel for injection according to claim 1, characterized by, S2 is specifically: taking 2.0-2.5 parts by weight of sodium hydroxide solution reserved in S1, adding 0.30-0.38 parts by weight of 1,4-butanediol diglycidyl ether, and adding 0.01-0.03 parts by weight of vitamin E polyethylene glycol succinate, homogenizing for 5-10 min at 1500-2000 r / min to form emulsion droplets of the oil-soluble crosslinking agent in the aqueous phase, obtaining a crosslinking agent emulsion, adding the crosslinking agent emulsion to the basic sodium hyaluronate composite solution prepared in S1 at a rate of 0.5 parts by weight / min under stirring at 40-60 r / min, and stirring for another 30-40 min under a nitrogen atmosphere to obtain a crosslinking agent composite solution.

4. The method of claim 1, wherein the lidocaine HCl containing sodium hyaluronate gel for injection is prepared by, S3 is specifically: the crosslinking agent composite solution is delivered to a sterile tank through a pipeline, a polytetrafluoroethylene tray subjected to sterilization is prearranged in a temperature-controlled reaction cabinet, the tray shelf spacing is controlled to be 10 cm, the crosslinking agent composite solution is injected into the tray, the liquid layer thickness of each tray is 3.5-5.5 mm, and a first-stage crosslinking at 4-8℃ for 120-144 h is performed under nitrogen protection, then the temperature is raised to 38-43℃ at a rate of 3-5℃ / h, a second-stage high-temperature curing for 4-6 h is performed, and a gel sheet is obtained by natural cooling to room temperature, the gel sheet is cut into square gel blocks with a side length of 0.6-0.8 cm.

5. The method of claim 1, wherein the lidocaine HCl containing sodium hyaluronate gel for injection is prepared by, S4 is specifically: the gel blocks are placed in a dialysis bag, the dialysis bag is sealed and then placed in a dialysis barrel, a phosphate buffer with a pH value of 7.0-7.4 is used as a dialysis medium, the liquid-solid ratio is 20-30:1, the dialysis time is 48-72 h, the dialysis is ended, and the dialysis liquid is replaced every 0.5-2 h during the dialysis to obtain purified gel blocks. The purified gel blocks are loaded into a granulator, nitrogen subjected to sterilization filtration is connected under 2-8℃, a titanium alloy microporous screen plate with a pore size of 480-520 μm is installed at the discharge port of the granulator, and the granulation is performed once to collect the granules, the screen plate with a pore size of 250-400 μm is replaced, and the collected granules after the first granulation are subjected to second granulation to obtain gel granules.

6. The method of claim 1, wherein the lidocaine HCl containing sodium hyaluronate gel for injection is prepared by, S5 is specifically: 80-90 parts by weight of a phosphate buffer, 2.0-3.0 parts by weight of lidocaine hydrochloride, 0.5-1.0 parts by weight of sodium chloride, and 0.1-0.3 parts by weight of glycine are added to a solution preparation tank, stirred at 100-120 r / min for 20-30 min, 1.5-2.5 parts by weight of sodium hyaluronate dry powder is further added, and stirred for another 60-90 min, and then subjected to two-stage sterilization filtration through 0.45 μm and 0.22 μm filter cartridges in sequence to obtain a lidocaine composite solution.

7. The method of claim 1, wherein the lidocaine HCl containing sodium hyaluronate gel for injection is prepared by, S6 is specifically: the gel granules and the lidocaine composite solution are put into a mixer at a mass ratio of 65-75:25-35, mixed at 60-80 r / min for 30-45 min, and then the finished product gel is obtained and filled.

8. A sodium hyaluronate gel containing lidocaine hydrochloride for injection prepared by the method according to any one of claims 1-7.

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