Lidocaine hydrochloride gel and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and relates to lidocaine hydrochloride gel and a preparation method thereof, and the preparation method comprises the following steps: 1) dissolving and dispersing a bacteriostatic agent and a gel matrix with water, and sterilizing to obtain a gel solution; 2) dissolving lidocaine hydrochloride with water, adjusting the pH value of the solution, and performing rapid heating and cooling sterilization to obtain a lidocaine hydrochloride solution; and (3) adding a lidocaine hydrochloride solution into the gel solution under a sterile condition, and stirring and mixing the lidocaine hydrochloride solution and the gel solution. By adjusting and changing the production and preparation process of lidocaine hydrochloride, the exposure time of lidocaine under a high-temperature condition is reduced, the degradation of lidocaine is further reduced, the content level of 2, 6-dimethylaniline is effectively reduced, the stability and quality of the product are improved, and toxic and side effects on patients are reduced; and the production process is simple and convenient to operate, the production time of the lidocaine hydrochloride gel is shortened, the working efficiency is improved, and the cost is saved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology and relates to a lidocaine hydrochloride gel and its preparation method. Background Technology

[0002] Local anesthetics alter the permeability of the nerve endometrium, reducing the entry of sodium ions into the endometrium, thereby affecting nerve impulse conduction and action potentials, resulting in anesthesia and pain relief. Lidocaine is a commonly used amide-type local anesthetic in clinical practice, widely used in local surgery, chronic pain management, puncture and catheterization, postoperative pain relief, and neuropathic pain. It is characterized by strong penetration, easy diffusion, rapid onset of action, low toxicity and irritation, and short duration of action. In cosmetic surgery and puncture and catheterization, it can quickly provide analgesia and local anesthesia.

[0003] 2,6-Dimethylaniline is a degradation product of lidocaine. On October 27, 2017, the International Agency for Research on Cancer (IARC) of the World Health Organization listed it as a Group 2B carcinogen. 2,6-Dimethylaniline is produced during production, storage, and use. Factors that trigger the formation of this degradation product include strong light exposure and prolonged exposure to high temperatures.

[0004] The gel matrix material for lidocaine hydrochloride gel is often high-viscosity hydroxypropyl methylcellulose (HMCMC). HMCMC dissolves in cold water to form a viscous colloidal solution, but at higher temperatures, it precipitates out of the solution again to form a suspension. This poses a significant challenge to the preparation of aseptic gels containing HMCMC. Furthermore, the preparation of aseptic gels inevitably involves high-temperature sterilization. Due to the inherent properties of HMCMC, the viscosity of the HMCMC solution decreases sharply at high temperatures, exhibiting a low-viscosity state, before reverting to a high-viscosity gel state as the temperature decreases. However, uneven local temperatures during the cooling process of hydroxypropyl methylcellulose after sterilization can lead to partial aggregation. Aggregation often requires 2-4 hours or longer to completely dissolve, with the longest dissolution time exceeding 20 hours. During the cooling process in product preparation, lidocaine is exposed to high temperatures in a molecular state for an extended period, which greatly increases the content of degradation products, including 2,6-dimethylaniline. This poses unavoidable risks to product stability and patient safety.

[0005] Therefore, in the preparation of lidocaine hydrochloride gel, it is necessary to consider not only the smooth preparation process and the qualified inspection of product quality, but also the further improvement of product quality during the preparation of lidocaine. Summary of the Invention

[0006] The main objective of this invention is to overcome the deficiencies in the prior art and provide a lidocaine hydrochloride gel and its preparation method.

[0007] To achieve the above objectives, the specific technical solution is as follows: This invention provides a method for preparing lidocaine hydrochloride gel, comprising the following steps: 1) After dissolving and dispersing the antibacterial agent and gel matrix in water, the gel solution is obtained after sterilization; 2) Dissolve lidocaine hydrochloride in water, adjust the pH of the solution to 5.0-8.0, rapidly heat to 115-125℃, sterilize for 10-20 minutes, and then rapidly cool to below 30℃ to obtain lidocaine hydrochloride solution; preferably sterilize at 121℃ for 15 minutes. The rapid heating rate is not less than 10℃ / min; the rapid cooling rate is not less than 10℃ / min. 3) Under aseptic conditions, add lidocaine hydrochloride solution to the gel solution and stir to mix evenly.

[0008] This invention employs a two-step solution preparation and stepwise sterilization method. Lidocaine hydrochloride only needs to undergo sterilization once after dissolution. By using rapid heating and rapid cooling, the entire heating, sterilization, and cooling process is completed in a short time, avoiding prolonged exposure of lidocaine hydrochloride to high temperatures and effectively reducing the content of the genotoxic impurity 2,6-dimethylaniline. At the same time, it effectively shortens the total production time, reduces energy consumption and production costs, and further makes the lidocaine hydrochloride gel mix more uniform and has better stability.

[0009] Preferably, in step 2), the heating rate of the rapid heating is 15°C / min; the cooling rate of the rapid cooling is 15°C / min. Further, in step 1), the specific method for dissolving and dispersing the antibacterial agent and gel matrix in water is as follows: first, dissolve and disperse the antibacterial agent in a small amount of room temperature water, then add it to preheated water and stir to dissolve to obtain an antibacterial agent aqueous solution; add the gel matrix to the antibacterial agent aqueous solution, stir to disperse, then cool to dissolve the matrix, and sterilize to obtain a mixed solution.

[0010] The above-described dissolution method of the present invention can effectively shorten the total production time, thereby effectively reducing energy consumption and production costs.

[0011] Furthermore, in step 1), the amount of water used to dissolve and disperse the antibacterial agent is 15-30 times the mass of the antibacterial agent; the amount of water used for preheating is 60%-80% of the total water volume.

[0012] Further, in step 1), the sterilization is carried out by high-temperature sterilization, the sterilization temperature is 115-125℃, the sterilization time is 10-20min, and the temperature is cooled to below 30℃ after sterilization; preferably, the sterilization temperature is 121℃ and the sterilization time is 15min.

[0013] Further, in step 1), after sterilization, the mixture is rapidly cooled down under stirring, with a cooling rate of not less than 10°C / min; more preferably, the cooling rate is 15°C / min.

[0014] The present invention uses stirring and cooling at high temperature to avoid the aggregation of gel matrices such as hydroxypropyl methylcellulose, so that they can be easily redissolved after cooling.

[0015] Further, in step 1), after high-temperature sterilization, under stirring conditions, the temperature is first cooled from 115-125℃ to 100℃, then heated from 100℃ to 110℃, then cooled from 110℃ to 90℃, then heated from 90℃ to 100℃, and this heating and cooling process is repeated until the temperature drops below 30℃. The preferred heating rate is not less than 10℃ / min, and the cooling rate is not less than 10℃ / min; More preferably, the heating rate is 15°C / min and the cooling rate is 15°C / min.

[0016] In particular, the high-viscosity gel matrix hydroxypropyl methylcellulose is in a gel state at low temperatures in the solution. When the temperature is higher than 60°C or even higher, hydroxypropyl methylcellulose will re-precipitate in the solution, and the solution will become a suspension again. Based on the properties of gel matrices such as hydroxypropyl methylcellulose, under stirring conditions, a regular rapid heating and cooling cycle is adopted to ensure that hydroxypropyl methylcellulose is fully dissolved and swollen within a limited time. The overall cooling time can be controlled within 2 hours.

[0017] Further, the antibacterial agent is methylparaben and / or propylparaben; in step 1), the temperature of the preheated water is not lower than 80°C, preferably 80°C.

[0018] The antibacterial agent of the present invention uses methylparaben and / or propylparaben. The preheating temperature of the water described above can ensure that the antibacterial agents methylparaben and / or propylparaben are fully dissolved and dispersed.

[0019] Further, in step 2), the reagent for adjusting the pH value of the solution is an inorganic salt solution, wherein the inorganic salt is selected from sodium hydroxide or potassium hydroxide.

[0020] Furthermore, in step 3), the lidocaine hydrochloride solution is transferred to the gel solution in a closed manner to ensure a closed and sterile environment.

[0021] Further, by weight, the lidocaine hydrochloride gel comprises 0.2-5 parts lidocaine hydrochloride, 0.01-0.5 parts methylparaben and / or propylparaben, 1-5 parts gel matrix, and 85-99 parts water.

[0022] In one specific embodiment of the present invention, the lidocaine hydrochloride gel comprises, by weight, 0.2-5 parts lidocaine hydrochloride, 0.01-0.15 parts methylparaben, 0.01-0.35 parts propylparaben, 1-5 parts hydroxypropyl methylcellulose, and 85-99 parts water.

[0023] The antibacterial agent of this invention is a mixture of methylparaben and propylparaben. The synergistic effect of methylparaben and propylparaben can achieve a highly efficient antibacterial and antiseptic effect, thus ensuring the stability of the formulation.

[0024] More preferably, by weight, the lidocaine hydrochloride gel comprises 1.5-2.5 parts lidocaine hydrochloride, 0.01-0.10 parts methylparaben, 0.05-0.15 parts propylparaben, 2-5 parts hydroxypropyl methylcellulose, and 92-97 parts water.

[0025] The present invention also provides a lidocaine hydrochloride gel, which is prepared by the above-described method for preparing lidocaine hydrochloride gel.

[0026] The lidocaine hydrochloride gel of this invention has a pH value of 5.0-8.0 and a viscosity of 2300-5000 mPa·s.

[0027] Compared with the prior art, the present invention has the following significant advantages: This invention provides a method for preparing lidocaine hydrochloride gel. By adjusting and modifying the production process of lidocaine hydrochloride, the exposure time of lidocaine under high temperature conditions is reduced, further reducing the degradation of lidocaine hydrochloride, effectively reducing the content level of 2,6-dimethylaniline, improving product stability and quality, and reducing toxic side effects on patients. Moreover, the production process is simple and easy to operate, shortening the production time of lidocaine hydrochloride gel, improving work efficiency, and saving costs. Detailed Implementation

[0028] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of this invention, not all embodiments. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0029] Unless otherwise specified in the embodiments of the present invention, the techniques or conditions described in the literature in this field or the product instructions shall be followed; if the manufacturers of the reagents or instruments used are not specified, they are all conventional products that can be purchased through legitimate channels.

[0030] Example 1 This embodiment provides a method for preparing lidocaine hydrochloride gel, wherein the lidocaine hydrochloride gel, by mass percentage, comprises 2.0% lidocaine hydrochloride, 0.03% methylparaben, 0.07% propylparaben, 2.3% hydroxypropyl methylcellulose, and purified water adjusted to 100%. The specific preparation method is as follows: 1) Heat approximately 70% of the purified water in the composition to 80°C and keep it at that temperature for later use; 2) Add the solution obtained by dispersing methylparaben and propylparaben in purified water at a volume 20 times that of the antibacterial agent to the hot water in step 1), and stir thoroughly to dissolve it; 3) Add hydroxypropyl methylcellulose to the solution in step 2) and stir thoroughly to disperse the hydroxypropyl methylcellulose. 4) Transfer the solution from step 3) to a sterile container and sterilize it at 121°C for 15 min. After sterilization, rapidly cool the solution while stirring at a rate of 15°C / min to allow the solution to fully gel and cool it to below 30°C to obtain a gel solution for later use. 5) Add lidocaine hydrochloride to the remaining purified water under stirring to dissolve it. Adjust the pH of the solution to 7.0±0.5, then rapidly heat to 121℃ and maintain this temperature for 15 min. After that, rapidly cool to below 30℃. The heating rate is 15℃ / min and the cooling rate is 15℃ / min to obtain a lidocaine hydrochloride solution for later use. 6) Transfer the lidocaine hydrochloride solution from step 5) to the gel solution from step 4). Keep the preparation tank and the sterile tank sealed during the transfer process. After the transfer is complete, turn on the sterile tank and stir to mix the two solutions.

[0031] Example 2 This embodiment provides a method for preparing lidocaine hydrochloride gel. The difference between this embodiment and registered example 1 is that in step 4), the solution from step 3) is transferred to a sterile container by sterile compressed air and sterilized at 121°C for 15 minutes. After sterilization, under stirring, the temperature is first lowered from 121°C to 100°C, then raised from 100°C to 110°C, then lowered from 110°C to 90°C, and then raised from 90°C to 100°C. This heating and cooling process is repeated until the temperature drops below 30°C to obtain a gel solution for later use. The rest is the same as in example 1 and will not be repeated here.

[0032] The high-viscosity gel matrix hydroxypropyl methylcellulose is in a gel state at low temperatures in solution. When the temperature is above 60°C or even higher, hydroxypropyl methylcellulose will recrystallize in the solution, and the solution will become a suspension again. Based on the above properties of hydroxypropyl methylcellulose, this embodiment adopts a regular rapid heating and cooling cycle under stirring conditions after high-temperature sterilization, which can better ensure that hydroxypropyl methylcellulose is fully dissolved and swollen.

[0033] Comparative Example 1 This comparative example provides a method for preparing lidocaine hydrochloride gel, wherein the composition of the lidocaine hydrochloride gel is the same as that in Example 1; The specific preparation method is as follows: 1) Heat approximately 70% of the purified water in the composition to 80°C and keep it at that temperature for later use; 2) Add the solution obtained by dispersing methylparaben and propylparaben evenly with 20 times the amount of purified water as the antibacterial agent to the hot water in step 1), and stir thoroughly to dissolve it; 3) Add hydroxypropyl methylcellulose to the solution in step 2), stir thoroughly to disperse, and cool down while continuing to stir until the hydroxypropyl methylcellulose is redissolved. 4) Under stirring conditions, add lidocaine hydrochloride to the solution in step 3) to dissolve it, and adjust the pH of the solution to 7.0±0.5; 5) Add the remaining purified water and stir thoroughly. 6) Transfer the solution to a sterile container and sterilize it at 121°C for 15 minutes. After sterilization, keep it at 90°C for 2 hours with a stirring speed of 40 rpm. Then keep it at 60°C for 2 hours with a stirring speed of 40 rpm. Finally, let it stand at 40°C for 15 hours until the hydroxypropyl methylcellulose is completely dissolved and swollen.

[0034] Comparative Example 2 This comparative example provides a lidocaine hydrochloride gel, which is a sterile lidocaine hydrochloride gel formulation (2%) manufactured by Aspen Company.

[0035] The stability of lidocaine hydrochloride gels from the examples and comparative examples was investigated.

[0036] The method for detecting impurities is high performance liquid chromatography.

[0037] Table 1 Comparison of Experimental Data

[0038] Note: Impurity A is 2,6-dimethylaniline, and ND means not detected.

[0039] As can be seen from the data in Table 1, the level of impurity A in the embodiments of the present invention is much lower than that of impurity A and other impurities in the conventional preparation method or commercial products of the comparative example.

[0040] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A method for preparing lidocaine hydrochloride gel, characterized in that, Includes the following steps: 1) After dissolving and dispersing the antibacterial agent and gel matrix in water, the gel solution is obtained after sterilization and cooling. 2) Dissolve lidocaine hydrochloride in water, adjust the pH of the solution to 5.0-8.0, rapidly heat to 115-125℃, sterilize for 10-20 min, and then rapidly cool to below 30℃ to obtain a lidocaine hydrochloride solution; the heating rate of the rapid heating is not less than 10℃ / min; the cooling rate of the rapid cooling is not less than 10℃ / min; 3) Under aseptic conditions, add lidocaine hydrochloride solution to the gel solution and stir to mix.

2. The method for preparing lidocaine hydrochloride gel according to claim 1, characterized in that, In step 1), the specific method for dissolving and dispersing the antibacterial agent and the gel matrix is ​​as follows: first, dissolve and disperse the antibacterial agent with water, then add it to preheated water and stir to dissolve it to obtain an antibacterial agent aqueous solution; add the gel matrix to the antibacterial agent aqueous solution, stir to disperse it, and then cool it down until the matrix dissolves.

3. The method for preparing lidocaine hydrochloride gel according to claim 2, characterized in that, In step 1), the amount of water used to dissolve and disperse the antibacterial agent is 15-30 times the mass of the antibacterial agent. And / or, the amount of water preheated is 60%-80% of the total water volume.

4. The method for preparing lidocaine hydrochloride gel according to any one of claims 1-3, characterized in that, In step 1), the sterilization is carried out using a high-temperature sterilization method. The sterilization temperature is 115-125℃, the sterilization time is 10-20 minutes, and the temperature is cooled to below 30℃ after sterilization. Preferably, the sterilization temperature is 121℃ and the sterilization time is 15 minutes. And / or, after sterilization, rapidly cool down under stirring, with a cooling rate of not less than 10℃ / min.

5. The method for preparing lidocaine hydrochloride gel according to claim 4, characterized in that, In step 1), after high-temperature sterilization, under stirring conditions, the temperature is first cooled from 115-125℃ to 100℃, then heated from 100℃ to 110℃, then cooled from 110℃ to 90℃, and then heated from 90℃ to 100℃. This heating and cooling process is repeated until the temperature drops below 30℃. Preferably, the heating rate is not less than 10℃ / min and the cooling rate is not less than 10℃ / min; more preferably, the heating rate of the rapid heating is 15℃ / min and the cooling rate of the rapid cooling is 15℃ / min.

6. The method for preparing lidocaine hydrochloride gel according to any one of claims 1-3, characterized in that, The antibacterial agent is methylparaben and / or propylparaben; in step 1), the temperature of the preheated water is not lower than 80°C, preferably 80°C.

7. The method for preparing lidocaine hydrochloride gel according to any one of claims 1-3, characterized in that, In step 2), the reagent used to adjust the pH of the solution is an inorganic salt solution, wherein the inorganic salt is selected from sodium hydroxide or potassium hydroxide.

8. The method for preparing lidocaine hydrochloride gel according to any one of claims 1 to 7, characterized in that, By weight, the lidocaine hydrochloride gel comprises 0.2-5 parts lidocaine hydrochloride, 0.01-0.5 parts methylparaben and / or propylparaben, 1-5 parts gel matrix, and 85-99 parts water.

9. The method for preparing lidocaine hydrochloride gel according to claim 8, characterized in that, The lidocaine hydrochloride gel comprises 0.2-5 parts lidocaine hydrochloride, 0.01-0.15 parts methylparaben, 0.01-0.35 parts propylparaben, 1-5 parts hydroxypropyl methylcellulose, and 85-99 parts water.

10. A lidocaine hydrochloride gel, prepared by the method for preparing lidocaine hydrochloride gel according to any one of claims 1 to 9.

Images