Preparation process of lidocaine hydrochloride gel

Abstract

The embodiment of the application discloses a preparation process of lidocaine hydrochloride gel and relates to the technical field of pharmaceutical preparations.The preparation process comprises the following steps: adding 80-98% of total volume of water for injection into a preparation tank, heating a jacket to 80-95 DEG C and keeping warm, adding lidocaine hydrochloride, hydroxybenzyl methyl ester and hydroxybenzyl propyl ester, adding hydroxypropyl methyl cellulose under stirring after dissolution, continuing to stir until the material is in a uniformly dispersed state, and obtaining the suspension liquid by sequentially adjusting a pH value, sterilizing and reducing temperature to obtain the lidocaine hydrochloride gel.The lidocaine hydrochloride gel can form a uniform, transparent and flocculent-free gel product, obviously shortens the process time and production cycle, reduces energy consumption, effectively controls the production cost, greatly reduces the bacterial contamination risk after sterilization, further improves the drug safety of the product, and has a good industrial application prospect.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, specifically to a process for preparing lidocaine hydrochloride gel. Background Technology

[0002] Lidocaine hydrochloride gel is an amide-based transdermal local anesthetic. It stabilizes neuronal membranes by inhibiting the ion flux generated by impulse initiation and conduction, thus producing analgesia after transdermal administration. This product is mainly used domestically and internationally for local anesthesia during transurethral examinations and treatments, as well as for mucosal anesthesia during thoracoscopic examinations or laparoscopic surgery, effectively relieving discomfort and pain during these procedures.

[0003] In existing preparation technologies, lidocaine hydrochloride gel typically uses hydroxypropyl methylcellulose (HMCMC) as the matrix material. HMCMC, as an excellent thickener and gelling agent, is widely used in the pharmaceutical industry. It not only imparts appropriate viscosity to the gel but also enables slow drug release, thereby prolonging the duration of drug efficacy and reducing the frequency of administration. However, due to the inherent physicochemical properties of HMCMC, its aqueous solution flocculates and precipitates at temperatures exceeding 50°C. As the temperature decreases, the formed clumps can redissolve and disperse back into the solution system. This unique thermoinduced phase transition behavior leads to batch-to-batch variability and quality instability in lidocaine hydrochloride gel products. The finished product often contains flocculent matter, directly affecting the overall performance of the product and the safety and reliability of patient medication.

[0004] The applicant's previous research, CN119564503B, disclosed a preparation process for lidocaine hydrochloride gel. This process employs a stepped cooling procedure after ingredient preparation and sterilization, effectively ensuring the uniformity and stability of product quality across batches and solving problems such as unstable product quality and the occurrence of flocculation in traditional processes. However, this technology has significant limitations: the process is too time-consuming, with the cooling step after sterilization alone requiring 7-19 hours (usually controlled at around 12 hours in production), leading to a prolonged overall production cycle, higher production costs, and ultimately increasing the economic burden on patients.

[0005] Based on the above situation, further optimization and improvement of the preparation process of lidocaine hydrochloride gel is of great practical significance and research value. Summary of the Invention

[0006] Therefore, embodiments of the present invention provide a process for preparing lidocaine hydrochloride gel to solve the problem of excessively long process time in the prior art.

[0007] To achieve the above objectives, the embodiments of the present invention provide the following technical solutions:

[0008] A process for preparing lidocaine hydrochloride gel, the process comprising:

[0009] Add 80-98% of the total volume of water for injection to the preparation tank, heat the jacket to 80-95℃ and keep it warm, add lidocaine hydrochloride, methylparaben and propylparaben, and after dissolving, add hydroxypropyl methylcellulose under stirring, and continue stirring until the material is uniformly dispersed. The resulting suspension is then subjected to pH adjustment, sterilization and cooling to obtain the lidocaine hydrochloride gel.

[0010] In the conventional production process of lidocaine hydrochloride gel, the materials must first be cooled to room temperature or below during the mixing stage to form a transparent gel. Then, pH adjustment, replenishment of water for injection, and moist heat sterilization are performed sequentially. The slow, stepwise cooling process disclosed in patent CN119564503B is then required to obtain a homogeneous gel. This entire process is time-consuming. In response, the applicant unexpectedly discovered through process optimization that the suspension obtained in the mixing step, without cooling to form a transparent gel, can directly undergo conventional pH adjustment, replenishment of water for injection, and moist heat sterilization, followed by rapid cooling to room temperature or below, to form a homogeneous, transparent, and flocculent gel. This optimized process eliminates the slow, stepwise cooling step required by patent CN119564503B, significantly shortening the process time and reducing energy consumption. Furthermore, rapid cooling after sterilization greatly reduces the risk of contamination. While ensuring product quality, it effectively controls production and operating costs, ultimately helping to alleviate the economic burden of medication for patients.

[0011] Furthermore, the stirring speed is 30-300 rpm, and the stirring time is 10-60 min. Further research by the applicant revealed that the stirring speed during the addition of hydroxypropyl methylcellulose, as well as the continuous stirring time after addition, both affect the quality of the final gel product. If the stirring speed is too fast, it easily leads to drug splashing, and a large amount of hydroxypropyl methylcellulose residue adheres to the wall, which not only disrupts the homogeneity of the system but also affects gel performance (such as causing a decrease in viscosity). If the stirring speed is too slow, hydroxypropyl methylcellulose is difficult to disperse evenly in the system, thus affecting its distribution consistency in the material and ultimately impairing gel performance. Within the above parameter range, a uniform gel product free of flocculent matter can be prepared. In some preferred embodiments, the stirring speed is 100-200 rpm, and the stirring time is 20-30 min. Under these preferred process conditions, the prepared lidocaine hydrochloride gel has superior product quality, higher system homogeneity, smaller batch-to-batch differences, and better safety and reliability of medication.

[0012] Furthermore, the specific process of adjusting the pH value is as follows: under the condition of heat preservation in the preparation tank, sodium hydroxide solution is added to the preparation tank and stirred to adjust the pH to 6.0-7.0, and water for injection is added.

[0013] Furthermore, the specific sterilization process is as follows: steam is introduced into the jacket of the preparation tank, stirred and heated to 121°C, and kept at this temperature for 15-30 minutes for moist heat sterilization.

[0014] Furthermore, the specific cooling process is as follows: the sterilized suspension is cooled to 30°C or below within 0.1-7 hours under stirring.

[0015] Furthermore, the cooling conditions are: a stirring speed of 30-100 rpm and a cooling rate of 0.5-10℃ / min. In some preferred embodiments, the cooling conditions are: a stirring speed of 50-100 rpm and a cooling rate of 5-10℃ / min. Through repeated experimental research, the applicant has found that under the above-mentioned preferred cooling conditions, the materials in the system can achieve uniform heat dissipation and thorough mixing, effectively avoiding gel structure defects caused by excessive local temperature differences. The resulting gel product has higher uniformity and better overall quality, better meeting the performance requirements of clinical applications. At the same time, the cooling time is shorter, which helps to shorten the process time, reduce production costs, and significantly reduce the risk of bacterial contamination of the sterilized drug solution.

[0016] Furthermore, the preparation process also includes filling, specifically: the lidocaine hydrochloride gel is aseptically filled using a filling machine in a B+A environment under GMP conditions.

[0017] Further, the lidocaine hydrochloride gel comprises the following raw materials by weight percentage: 2-2.2% lidocaine hydrochloride, 1-4% hydroxypropyl methylcellulose, 0.03-0.1% methylparaben, 0.03-0.1% propylparaben, an appropriate amount of sodium hydroxide solution to adjust the pH to 6.0-7.0, and the balance being water for injection.

[0018] Furthermore, the concentration of the sodium hydroxide solution is 1-12 wt%.

[0019] The embodiments of the present invention have the following advantages:

[0020] This invention provides a process for preparing lidocaine hydrochloride gel. In this process, the suspension formed during the ingredient preparation process can be directly subjected to conventional pH adjustment and moist heat sterilization without cooling to form a transparent gel. Subsequently, it is rapidly cooled to room temperature or below to form a homogeneous, transparent gel product free of flocculent matter. This process eliminates the need for ingredient cooling, sterilization heating (from room temperature to 80-95°C), reducing energy consumption, and the slow, stepwise cooling process after sterilization. This simplifies operation, significantly shortens process time and production cycle, effectively controls production costs, and greatly reduces the risk of post-sterilization contamination, further improving the product's medication safety and demonstrating promising prospects for industrial application. Detailed Implementation

[0021] The following specific embodiments illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0022] Example 1

[0023] This embodiment provides a process for preparing lidocaine hydrochloride gel, including the following steps:

[0024] (1) Ingredients: First, add 90 kg of water for injection to the preparation tank, heat it to 85°C under jacket and keep it warm. Add 2 kg of lidocaine hydrochloride, 0.06 kg of methylparaben and 0.03 kg of propylparaben under stirring, dissolve and continue stirring for 15 min; then adjust the stirring speed to 100 rpm, add 2.25 kg of hydroxypropyl methylcellulose to the preparation tank under the condition of keeping it warm and stirring, and stir for 30 min;

[0025] (2) Adjust pH value: Under the condition of heat preservation, add an appropriate amount of 10wt% sodium hydroxide solution to the preparation tank and stir to adjust the pH to 6.5, and add water for injection to make the total mass 100kg;

[0026] (3) Sterilization: Steam is introduced into the jacket of the preparation tank, stirred and heated to 121°C, and kept at this temperature for 20 minutes for wet heat sterilization;

[0027] (4) Cooling: After sterilization, the temperature was reduced to 25°C at a cooling rate of 10°C / min under the condition of stirring speed of 50 rpm to obtain lidocaine hydrochloride gel.

[0028] (5) Filling: The lidocaine hydrochloride gel is aseptically filled in a B+A environment under GMP conditions using a filling machine.

[0029] Examples 2-9

[0030] Examples 2-9 provide a process for preparing lidocaine hydrochloride gel.

[0031] The difference between the above embodiments and Embodiment 1 is that the amount of water for injection, temperature, stirring speed and stirring time in the preparation steps are as shown in Table 1 below.

[0032] Table 1

[0033]

[0034] Examples 10-13

[0035] Examples 10-13 provide a process for preparing lidocaine hydrochloride gel.

[0036] The difference between the above embodiments and Embodiment 1 is that the concentration of sodium hydroxide solution and the pH value of the system in the pH adjustment step are shown in Table 2 below.

[0037] Table 2

[0038]

[0039] Examples 14-21

[0040] Examples 14-21 each provide a process for preparing lidocaine hydrochloride gel.

[0041] The difference between the above embodiments and Embodiment 1 is that the cooling rate and stirring speed in the cooling step are as shown in Table 3 below.

[0042] Table 3

[0043]

[0044] Comparative Example 1

[0045] Comparative Example 1 provides a preparation process for lidocaine hydrochloride gel.

[0046] The difference between the above comparative example and Example 1 is that a cooling process was performed in the preparation step. Specifically, the suspension was cooled to 25°C at a stirring speed of 100 rpm to form a gel, then 10 wt% sodium hydroxide solution was added to adjust the pH to 6.5, water for injection was added, and then the temperature was raised to 121°C for sterilization. Finally, the temperature was cooled to 25°C at a stirring speed of 100 rpm.

[0047] Performance testing

[0048] The uniformity and appearance quality of the lidocaine hydrochloride gels prepared in Examples 1-21 and Comparative Example 1 were tested, and the results are shown in Table 4 below.

[0049] (1) Uniformity: After cooling, take one sample from the upper, middle and lower layers of the system and test the content of hydroxypropyl methylcellulose and lidocaine hydrochloride in the sample. The content of lidocaine hydrochloride was detected by high performance liquid chromatography-ultraviolet detection (HPLC-UV), and hydroxypropyl methylcellulose was detected by high performance liquid chromatography-evaporative light scattering (HPLC-ELSD).

[0050] (2) Appearance quality: Observe whether the liquid medicine is separated into layers and whether hydroxypropyl methylcellulose is aggregated into clumps.

[0051] Table 4

[0052]

[0053] The results showed that the lidocaine hydrochloride gels obtained in Examples 1-21 were homogeneous and transparent gels, with lidocaine hydrochloride content of 18.5-21.5 mg / g and hydroxypropyl methylcellulose content of 21.0-23.5 mg / g in the upper, middle, and lower layers. Examples 1, 4-7, and 15-17 not only had shorter cooling times but also yielded lidocaine hydrochloride gels with lidocaine hydrochloride content of 19.7-20.4 mg / g and hydroxypropyl methylcellulose content of 22.1-22.7 mg / g in the upper, middle, and lower layers, exhibiting superior uniformity. The lidocaine hydrochloride gels obtained in Examples 10-13 had lidocaine hydrochloride content of 19.2-20.5 mg / g and hydroxypropyl methylcellulose content of 22.0-22.8 mg / g in the upper, middle, and lower layers. The sodium hydroxide solution concentration and pH value of the gel, also exhibiting good uniformity, indicate that the concentration of sodium hydroxide solution and the pH value of the system have virtually no impact on the performance of the gel product during the pH adjustment step. In contrast, the lidocaine hydrochloride gel obtained in Comparative Example 1 showed obvious stratification, with hydroxypropyl methylcellulose agglomerated. The lidocaine hydrochloride content in the upper, middle, and lower layers ranged from 16.2 to 22.8 mg / g, and the hydroxypropyl methylcellulose content ranged from 16.8 to 23.5 mg / g. These results demonstrate that the process of this invention can obtain a highly uniform, colorless, and transparent lidocaine hydrochloride gel, significantly improving the safety and reliability of medication use. Furthermore, the production time of the above preparation process is significantly shortened, greatly reducing the risk of bacterial contamination, and it possesses good prospects for industrial application.

[0054] Although the present invention has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. A process for preparing lidocaine hydrochloride gel, characterized in that, The preparation process includes: Add 80-98% of the total volume of water for injection to the preparation tank, heat the jacket to 80-95℃ and keep it warm, add lidocaine hydrochloride, methylparaben and propylparaben, and after dissolving, add hydroxypropyl methylcellulose under stirring, and continue stirring until the material is uniformly dispersed. The resulting suspension is then subjected to pH adjustment, sterilization and cooling to obtain the lidocaine hydrochloride gel. The stirring speed is 100-200 rpm, and the stirring time is 20-30 min. The specific cooling process is as follows: the sterilized suspension is cooled to 30°C or below within 0.1-7 hours under stirring. The cooling conditions are: stirring speed of 50-100 rpm and cooling rate of 5-10℃ / min; The lidocaine hydrochloride gel comprises the following raw materials by weight percentage: 2-2.2% lidocaine hydrochloride, 1-4% hydroxypropyl methylcellulose, 0.03-0.1% methylparaben, 0.03-0.1% propylparaben, appropriate amount of sodium hydroxide solution to adjust pH to 6.0-7.0, and the balance being water for injection.

2. The process for preparing lidocaine hydrochloride gel according to claim 1, characterized in that, The specific process for adjusting the pH value is as follows: under the condition of heat preservation in the preparation tank, sodium hydroxide solution is added to the preparation tank and stirred to adjust the pH to 6.0-7.0, and water for injection is added.

3. The process for preparing lidocaine hydrochloride gel according to claim 1, characterized in that, The specific sterilization process is as follows: steam is introduced into the jacket of the preparation tank, stirred and heated to 121°C, and kept at this temperature for 15-30 minutes for moist heat sterilization.

4. The process for preparing lidocaine hydrochloride gel according to claim 1, characterized in that, The preparation process also includes filling, specifically: lidocaine hydrochloride gel is aseptically filled using a filling machine in a B+A environment under GMP conditions.

5. The process for preparing lidocaine hydrochloride gel according to claim 1, characterized in that, The concentration of the sodium hydroxide solution is 1-12 wt%.

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