A kind of preparation process of lidocaine hydrochloride gel

Abstract

The present application relates to the field of pharmaceutical preparation technology, and specifically discloses a preparation process of lidocaine hydrochloride gel. The preparation process of lidocaine hydrochloride gel provided by the present application, comprising the following steps: batching, sterilization, step-by-step cooling; the specific process of the step-by-step cooling is: the first stage: first, keep warm at 90-60°C for 1-2h, and the stirring speed is 10-60rpm; the second stage: then keep warm at 60-40°C for 1-2h, and the stirring speed is 10-60rpm; the third stage: finally stand and keep warm at 40-10°C for 5-15h. The preparation process of lidocaine hydrochloride gel provided by the present application can obtain colorless and transparent lidocaine hydrochloride gel with high uniformity and good stability, greatly improving the practical reliability and safety of lidocaine hydrochloride gel.

Description

Technical Field

[0001] The present application relates to the technical field of pharmaceutical preparations, and in particular to a preparation process of lidocaine hydrochloride gel. Background Art

[0002] As a commonly used local anesthetic transdermal preparation, lidocaine hydrochloride gel is widely used in the medical field, especially in transurethral examination and treatment, thoracoscopic examination and abdominal surgery. The drug achieves analgesic effect by inhibiting ion flux on neuronal membranes, greatly improving patient comfort and safety. In recent years, with the rapid development of the pharmaceutical industry and technological progress, the application scope of lidocaine hydrochloride gel has been continuously expanded, and the market demand has been growing. In order to meet this demand, many pharmaceutical companies have invested resources to improve the quality and stability of their products.

[0003] At present, the preparation process of lidocaine hydrochloride gel mainly includes the steps of batching, mixing, sterilization, cooling, etc. In the batching stage, the water for injection is usually first mixed evenly with lidocaine hydrochloride, preservatives and other raw materials, and then hydroxypropyl methylcellulose is added and fully stirred to completely dissolve it to form a gel matrix; then the mixed liquid is sterilized by high temperature and wet heat, and finally cooled and filled. However, in the actual production process, due to the influence of the physical and chemical properties of hydroxypropyl methylcellulose itself, flocculation will occur when the temperature of the aqueous solution exceeds 50°C, and as the temperature drops, these clumps that have been formed can be dispersed and dissolved back into the solution system again. This unique thermal phase transition behavior causes more or less flocs in lidocaine hydrochloride gel products, and there are batch differences and unstable quality in the products, which not only increases the difficulty of quality control, but also reduces the safety and reliability of patients' medication.

[0004] Therefore, it is urgent to develop a new preparation process for lidocaine hydrochloride gel to improve the uniformity of the product and ensure that each batch of products can meet high quality standards, thereby reducing batch differences in drugs and improving the safety and reliability of medication. Summary of the invention

[0005] In order to overcome the problems of unstable quality and the presence of a small amount of flocs in existing lidocaine hydrochloride gel products, the present application provides a preparation process of lidocaine hydrochloride gel.

[0006] The preparation process of lidocaine hydrochloride gel provided in the present application adopts the following technical scheme:

[0007] A preparation process of lidocaine hydrochloride gel comprises the following steps: batching, sterilization, and step-by-step cooling; the specific process of the step-by-step cooling is:

[0008] Stage 1: First, keep warm at 90-60℃ for 1-2h, with a stirring speed of 10-60rpm;

[0009] The second stage: then keep warm at 60-40℃ for 1-2h, stirring at 10-60rpm;

[0010] The third stage: Finally, let it stand and keep warm at 40-10℃ for 5-15h.

[0011] The present application provides a preparation process of lidocaine hydrochloride gel. The cooling stage of the preparation process adopts three-stage stepped cooling. By controlling the temperature and stirring conditions of each stage within the above range, a colorless and transparent lidocaine hydrochloride gel with high uniformity and good stability can be obtained. The above preparation process effectively avoids the problems of floc formation and product stratification caused by rapid cooling in traditional methods, significantly improves the quality stability of lidocaine hydrochloride gel products, reduces batch-to-batch differences in products, greatly improves production reliability and safety, and meets strict medical standard requirements.

[0012] The inventors of the present application discovered through experimental research that if the temperature is lowered directly after sterilization, the drug solution will be stratified. No matter whether the stirring time is extended or the stirring speed is increased, a uniform lidocaine hydrochloride gel cannot be obtained, and the hydroxypropyl methylcellulose in the system will still flocculate or aggregate into clumps; if the speed is too fast during the cooling process, a large number of bubbles will be generated in the system, which will extend the defoaming time and increase the risk of bacterial contamination; if there are too many insulation stages and the insulation time is too long, the production cycle will be too long, which will still increase the risk of bacterial contamination.

[0013] In some embodiments, the temperature of the first stage may be 60-70°C, 60-80°C, 60-90°C, 70-80°C, 70-90°C, or 80-90°C.

[0014] In a specific embodiment, the temperature of the first stage may also be 60°C, 70°C, 80°C or 90°C.

[0015] In some embodiments, the temperature of the second stage may be 40-50°C or 50-60°C.

[0016] In a specific embodiment, the temperature of the second stage may also be 40°C, 50°C or 60°C.

[0017] In some embodiments, the temperature of the third stage may be 10-20°C, 10-30°C, 10-40°C, 20-30°C, 20-40°C, or 30-40°C.

[0018] In a specific embodiment, the temperature of the third stage may also be 10°C, 20°C, 30°C or 40°C.

[0019] In some embodiments, the stirring speed of the first stage and the second stage can be 10-20rpm, 10-30rpm, 10-40rpm, 10-50rpm, 10-60rpm, 20-30rpm, 20-40rpm, 20-50rpm, 20-60rpm, 30-40rpm, 30-50rpm, 30-60rpm, 40-50rpm, 40-60rpm or 50-60rpm.

[0020] In a specific embodiment, the stirring speeds of the first stage and the second stage may be 10 rpm, 20 rpm, 30 rpm, 40 rpm, 50 rpm or 60 rpm.

[0021] Optionally, the temperature of the first stage is 90-70°C, and the temperature of the third stage is 30-10°C.

[0022] Optionally, the temperature of the first stage is 80°C, the temperature of the second stage is 50°C, and the temperature of the third stage is 20°C.

[0023] Optionally, the stirring speed of the first stage and the second stage is 20-40 rpm.

[0024] Optionally, the cooling rate v1 from the first stage to the second stage is 5-12°C / min, and the cooling rate v2 from the second stage to the third stage is 3-8°C / min.

[0025] Optionally, the cooling rate v1 from the first stage to the second stage is 5-10°C / min, and the cooling rate v2 from the second stage to the third stage is 3-5°C / min.

[0026] In the present application, the cooling rate v1 from the first stage to the second stage and the cooling rate v2 from the second stage to the third stage will affect the uniformity of the lidocaine hydrochloride gel. The present application has found through experimental research that by further controlling the cooling rate v1 from the first stage to the second stage and the cooling rate v2 from the second stage to the third stage within the above range, the uniformity of the lidocaine hydrochloride gel obtained is higher.

[0027] In some embodiments, the cooling rate v1 from the first stage to the second stage may be 5-8°C / min, 5-10°C / min, 5-12°C / min, 8-10°C / min, 8-12°C / min or 10-12°C / min.

[0028] In a specific embodiment, the cooling rate v1 from the first stage to the second stage may also be 5°C / min, 8°C / min, 10°C / min or 12°C / min.

[0029] In some embodiments, the cooling rate v2 from the second stage to the third stage may be 3-5°C / min or 5-8°C / min.

[0030] In a specific embodiment, the cooling rate v2 from the second stage to the third stage can also be 3°C / min, 5°C / min or 8°C / min.

[0031] Optionally, the specific steps of the preparation are: first, add about 90% of the total volume of water for injection into the preparation tank, heat the jacket to 80-90°C, add lidocaine hydrochloride, methylparaben and propylparaben thereto under stirring, dissolve and continue stirring for at least 15 minutes; then add hydroxypropyl methylcellulose to the preparation tank under heat preservation and stirring conditions, stir for 30-40 minutes, and then cool to room temperature; finally, add sodium hydroxide solution to the preparation tank and stir, adjust the pH to 6.0-7.0, and replenish water for injection to obtain a mixture.

[0032] In the present application, the concentration of the sodium hydroxide solution is 2-10wt%.

[0033] Optionally, the specific steps of sterilization are: filtering the mixture into a sterilization tank, introducing steam into the jacket, stirring and heating to 121° C., and keeping the temperature for 15-30 minutes for wet heat sterilization.

[0034] Optionally, the preparation process further comprises filling, and the specific steps are: aseptically filling the lidocaine hydrochloride gel with a filling machine in a B+A environment under GMP conditions.

[0035] Optionally, the lidocaine hydrochloride gel has a formula by mass of: 2-2.2% lidocaine hydrochloride, 1-4% hydroxypropyl methylcellulose, 0.03-0.1% methylparaben, 0.03-0.1% propylparaben, 0.6-1% sodium hydroxide solution, and the balance is water.

[0036] In summary, this application has the following beneficial effects:

[0037] 1. The present application provides a preparation process of lidocaine hydrochloride gel. The cooling stage of the preparation process adopts a three-stage stepped cooling process, which can improve the uniformity of lidocaine hydrochloride gel and reduce the generation of stratification and floccules on the one hand, and shorten the production time and reduce the risk of contamination on the other hand, and has a good prospect for industrial application.

[0038] 2. In the present application, the temperature and stirring speed of each cooling stage are further controlled within the following range: the temperature of the first stage is 90-70°C, the temperature of the second stage is 60-40°C, the temperature of the third stage is 30-10°C, the stirring speed of the first and second stages is 20-40rpm, the cooling rate v1 from the first stage to the second stage is 5-10°C / min, and the cooling rate v2 from the second stage to the third stage is 3-5°C / min. The obtained lidocaine hydrochloride gel has higher uniformity, smaller batch-to-batch differences, and better safety and reliability of medication. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 This is a process flow chart of the preparation of lidocaine hydrochloride gel provided in this application. DETAILED DESCRIPTION

[0040] The present application provides a preparation process of lidocaine hydrochloride gel, comprising the following steps:

[0041] (1) Preparation: First, add about 90% of the total volume of water for injection into the preparation tank, heat the jacket to 80-90°C, add lidocaine hydrochloride, methylparaben and propylparaben thereto under stirring, dissolve and continue stirring for at least 15 minutes; then add hydroxypropyl methylcellulose into the preparation tank under heat preservation and stirring conditions, stir for 30-40 minutes, and then cool to room temperature; finally, add 2-10wt% sodium hydroxide solution into the preparation tank and stir, adjust the pH to 6.0-7.0, and replenish water for injection to obtain a mixture;

[0042] (2) Sterilization: Filter the mixture into a sterilization tank, introduce steam into the jacket, stir and heat to 121°C, and keep warm for 15-30 minutes for wet heat sterilization;

[0043] (3) Step-by-step cooling: After sterilization, step-by-step cooling is performed to obtain lidocaine hydrochloride gel; the step-by-step cooling process is as follows:

[0044] The first stage: first, keep warm at 90-60°C for 1-2h, with a stirring speed of 10-60rpm; then cool down at a cooling rate v1 of 5-10°C / min; further, the first stage of the heat preservation temperature is 90-70°C, and the stirring speed is 20-40rpm;

[0045] The second stage: then keep warm at 60-40°C for 1-2h, with a stirring speed of 10-60rpm; then cool at a cooling rate v2 of 3-5°C / min; further, the stirring speed of the second stage is 20-40rpm;

[0046] The third stage: finally, standing and keeping warm at 40-10°C for 5-15h; further, the keeping warm temperature of the third stage is 30-10°C;

[0047] (4) Filling: Aseptically fill the lidocaine hydrochloride gel in a B+A environment under GMP conditions using a filling machine.

[0048] The raw materials, reagents, solvents, etc. used in this application can be obtained commercially.

[0049] The present application is further described in detail below in combination with embodiments, performance testing and accompanying drawings. Example 1

[0050] Embodiment 1 provides a preparation process of lidocaine hydrochloride gel, comprising the following steps:

[0051] (1) Preparation: First, add about 90% of the total volume of water for injection into the preparation tank, heat the jacket to 85°C, add lidocaine hydrochloride, methylparaben and propylparaben thereto under stirring, dissolve and continue stirring for at least 15 minutes; then add hydroxypropyl methylcellulose into the preparation tank under heat preservation and stirring conditions, stir for 30 minutes, and then cool to room temperature; finally, add 10wt% sodium hydroxide solution into the preparation tank and stir, adjust the pH to 6.5, and replenish water for injection to obtain a mixture;

[0052] The formula of the lidocaine hydrochloride gel is: 2kg of lidocaine hydrochloride, 2.25kg of hydroxypropyl methylcellulose, 0.06kg of methylparaben, 0.03kg of propylparaben, 0.6kg of 10wt% sodium hydroxide solution, and water for injection to a total mass of 100kg;

[0053] (2) Sterilization: Filter the mixture into a sterilization tank, pass steam into the jacket, stir and heat to 121°C, and keep warm for 20 minutes for moist heat sterilization;

[0054] (3) Step cooling: After sterilization, the temperature was cooled in a step-by-step manner. First, the temperature was kept at 80°C for 1.5 h, with a stirring speed v1 of 30 rpm; then the temperature was cooled to 50°C at a cooling rate of 8°C / min and kept for 1.5 h, with a stirring speed v2 of 30 rpm; finally, the temperature was cooled to 20°C at a cooling rate of 3°C / min and kept for 10 h to obtain lidocaine hydrochloride gel;

[0055] (4) Filling: Aseptically fill the lidocaine hydrochloride gel in a B+A environment under GMP conditions using a filling machine.

[0056] Example 2-14

[0057] Examples 2-14 respectively provide a preparation process of lidocaine hydrochloride gel.

[0058] The difference between the above embodiment and embodiment 1 is that the temperature, time and rotation speed in the step-by-step cooling are specifically shown in Table 1 below;

[0059] Table 1 Temperature, time and rotation speed of each stage in step cooling in Examples 2-14

[0060]

[0061] Examples 15-19

[0062] Examples 15-19 respectively provide a preparation process of lidocaine hydrochloride gel.

[0063] The difference between the above embodiment and embodiment 1 is that the cooling rate in the step-by-step cooling is specifically shown in Table 2 below;

[0064] Table 2 Cooling rate in step cooling in Example 1 and Examples 15-19

[0065] Comparative Example 1

[0066] Comparative Example 1 provides a preparation process of lidocaine hydrochloride gel.

[0067] The difference between the comparative example and Example 1 is that the step-by-step cooling is replaced by direct cooling, and the specific steps are: after the sterilization is completed, the temperature is directly and rapidly cooled to 20° C. to obtain lidocaine hydrochloride gel. Comparative Example 2

[0068] Comparative Example 2 provides a preparation process of lidocaine hydrochloride gel.

[0069] The difference between the comparative example and Example 1 is that the step-by-step cooling process is: first, keep warm at 50°C for 1.5 hours, with a stirring speed v1 of 30 rpm; then cool to 20°C at a cooling rate of 3°C / min, and keep warm for 10 hours to obtain lidocaine hydrochloride gel.

[0070] Performance testing

[0071] The uniformity and appearance quality of the lidocaine hydrochloride gel obtained in Example 1-19 and Comparative Example 1-2 were tested, and the results are shown in Table 1 below.

[0072] (1) Uniformity: After cooling, take a sample from each of the upper, middle and lower layers of the system, and test the contents of hydroxypropyl methylcellulose and lidocaine hydrochloride in the sample; lidocaine hydrochloride content is tested by high performance liquid chromatography ultraviolet detection (HPLC-UV), and hydroxypropyl methylcellulose is tested by high performance liquid chromatography-evaporative light scattering (HPLC-ELSD).

[0073] (2) Appearance quality: Observe whether the drug solution is stratified and whether the hydroxypropyl methylcellulose is aggregated.

[0074] Table 3 Uniformity and appearance quality test results of lidocaine hydrochloride gel

[0075]

[0076] According to the test results in Table 3, the lidocaine hydrochloride gels obtained in Examples 1-19 have high uniformity, no stratification or flocs, and the lidocaine hydrochloride content in the upper, middle and lower layers is 18.2-21.0 mg / g, and the hydroxypropyl methylcellulose content is 21.4-23.0 mg / g; while the lidocaine hydrochloride gel obtained in Comparative Example 1 has obvious stratification, and the hydroxypropyl methylcellulose is aggregated into agglomerates, and the lidocaine hydrochloride content in the upper, middle and lower layers is 15.4-22.6 mg / g, and the hydroxypropyl methylcellulose content is 17.3-23.2 mg / g; a small amount of hydroxypropyl methylcellulose is aggregated into flocs in the lidocaine hydrochloride gel obtained in Comparative Example 2, and the lidocaine hydrochloride content in the upper, middle and lower layers is 15.5-20.2 mg / g, and the hydroxypropyl methylcellulose content is 19.1-23.2 mg / g. Therefore, it is shown that the three-stage cooling process adopted in the present application can obtain a colorless and transparent lidocaine hydrochloride gel with high uniformity and good stability, which greatly improves the safety and reliability of medication. In addition, the production time of the above preparation process is short, which greatly reduces the risk of bacterial contamination and is conducive to industrial production.

[0077] The test results of Examples 1-14 show that in the upper, middle and lower layers of the lidocaine hydrochloride gel obtained in Examples 2, 9-10 and 13-14, the content of hydroxypropyl methylcellulose and lidocaine hydrochloride is quite different, and there are a small amount of bubbles in the lidocaine hydrochloride gel of Examples 13-14; while in the upper, middle and lower layers of the lidocaine hydrochloride gel obtained in Examples 1, 3-8 and 11-12, the content of lidocaine hydrochloride is 19.2-20.2 mg / g, and the content of hydroxypropyl methylcellulose is 22.1-22.7 mg / g, and the difference in the content range is small. Therefore, it is explained that the present application further controls the temperature of the first stage within the range of 90-70°C, the temperature of the second stage within the range of 60-40°C, the temperature of the third stage within the range of 30-10°C, the stirring speed of the first stage and the second stage is 20-40rpm, and the uniformity of the lidocaine hydrochloride gel obtained is higher.

[0078] The test results of Example 1 and Examples 15-19 show that in the upper, middle and lower layers of the lidocaine hydrochloride gel obtained in Examples 15-16 and Example 18, the content of lidocaine hydrochloride is 19.5-20.3 mg / g, and the content of hydroxypropyl methylcellulose is 22.2-22.6 mg / g, and the difference in the content range is small. Therefore, it is explained that the present application further controls the cooling rate v1 from the first stage to the second stage within the range of 5-10°C / min, and the cooling rate v2 from the second stage to the third stage within the range of 3-5°C / min, and the uniformity of the lidocaine hydrochloride gel obtained is higher.

[0079] Although the present invention has been described in detail above with general descriptions and specific embodiments, it is obvious to those skilled in the art that some modifications or improvements may be made thereto based on the present invention. Therefore, these modifications or improvements made without departing from the spirit of the present invention all fall within the scope of protection claimed by the present invention.

Claims

1. A preparation process of lidocaine hydrochloride gel, characterized in that: The following steps are involved: Mixing, sterilization, step-by-step cooling; the specific process of the step-by-step cooling is: Stage 1: First, keep warm at 90-60℃ for 1-2h, with a stirring speed of 10-60rpm; The second stage: then keep warm at 60-40℃ for 1-2h, stirring at 10-60rpm; The third stage: Finally, let it stand and keep warm at 40-10℃ for 5-15h.

2. The preparation process of lidocaine hydrochloride gel according to claim 1, characterized in that: The temperature of the first stage is 90-70°C, and the temperature of the third stage is 30-10°C.

3. The preparation process of lidocaine hydrochloride gel according to claim 1, characterized in that: The temperature of the first stage is 80°C, the temperature of the second stage is 50°C, and the temperature of the third stage is 20°C.

4. The preparation process of lidocaine hydrochloride gel according to claim 1, characterized in that: The stirring speed of the first stage and the second stage is 20-40 rpm.

5. The preparation process of lidocaine hydrochloride gel according to claim 1, characterized in that: The cooling rate v1 from the first stage to the second stage is 5-10°C / min, and the cooling rate v2 from the second stage to the third stage is 3-5°C / min.

6. The preparation process of lidocaine hydrochloride gel according to claim 1, characterized in that: The specific steps of the preparation are: first, adding about 90% of the total volume of water for injection into a preparation tank, heating the jacket to 80-90°C, adding lidocaine hydrochloride, methylparaben and propylparaben thereto under stirring, dissolving and continuously stirring for at least 15 minutes; then, adding hydroxypropyl methylcellulose into the preparation tank under heat preservation and stirring conditions, stirring for 30-40 minutes, and then cooling to room temperature; finally, adding sodium hydroxide solution into the preparation tank and stirring, adjusting the pH to 6.0-7.0, and replenishing water for injection to obtain a mixture.

7. The preparation process of lidocaine hydrochloride gel according to claim 1, characterized in that: The specific steps of the sterilization are: filtering the mixed material into a sterilization tank, introducing steam into the jacket, stirring and heating to 121° C., and keeping the temperature for 15-30 minutes for wet heat sterilization.

8. The process for preparing lidocaine hydrochloride gel according to any one of claims 1 to 7, characterized in that: The preparation process also includes filling, and the specific steps are: aseptically filling the lidocaine hydrochloride gel with a filling machine in a B+A environment under GMP conditions.

9. The process for preparing lidocaine hydrochloride gel according to any one of claims 1 to 7, characterized in that: The lidocaine hydrochloride gel has a formula of 2-2.2% lidocaine hydrochloride, 1-4% hydroxypropyl methylcellulose, 0.03-0.1% methylparaben, 0.03-0.1% propylparaben, 0.6-1% sodium hydroxide solution, and the balance is water.

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