A preparation method of lidocaine cream

Abstract

The present application provides a method for preparing lidocaine cream, which comprises the following steps: preparing an aqueous phase and an oil phase, wherein the aqueous phase contains polyols, water and lidocaine, and the oil phase contains an emulsifier and a grease; adding the oil phase into the aqueous phase and mixing uniformly to obtain lidocaine cream. The present application breaks through the traditional process in which lipophilic drugs can only be added to the oil phase, disperses lidocaine completely in the aqueous solution, and the prepared cream has good stability, without the phenomena of demulsification, delamination or crystallization. The product has good anesthetic effect and no adverse reactions. It solves the problems of demulsification, delamination or crystallization of lidocaine cream when the drug content is relatively high, and the prepared cream has good stability.

Description

Technical Field

[0001] This application belongs to the field of biomedicine, and specifically relates to a preparation method of lidocaine cream. Background Art

[0002] Pain has been listed as the "fifth vital sign" of the human body. However, the treatment of pain still faces great challenges clinically. Among them, neuropathic pain is a pain caused by damage or diseases of the somatic sensory system commonly seen clinically. Chronic pain not only affects the patient's sleep, work and living ability, but also increases the incidence of emotional disorders such as depression and anxiety, seriously affecting human health and quality of life. Therefore, early, sufficient and active treatment of chronic neuropathic pain can effectively relieve pain and its accompanying symptoms, restore physical function, and improve quality of life. Although there are many drugs available currently, the systemic administration method is often limited by drug adverse reactions, especially for the elderly and frail groups. While topical administration has a low systemic exposure and high safety, so topical preparations available for topical administration are increasingly valued by clinicians.

[0003] The chemical name of lidocaine is N-(2,6-dimethylphenyl)-2-(diethylamino)acetamide, which belongs to amide local anesthetics and has the effects of anesthesia and analgesia. Lidocaine cream can directly act on the skin at the pain site. Transdermal topical administration can avoid the first-pass effect of the liver, increase the local drug concentration at the pain site, reduce the systemic plasma concentration of lidocaine, and improve the drug safety and compliance of patients while reducing systemic adverse reactions. The content of lidocaine in currently clinically used lidocaine cream is generally 25 mg per gram, which can be used for cutaneous local anesthesia in needle puncture and superficial surgical operations. Due to the low drug content, problems such as prolonged anesthesia time, poor patient tolerance or too short anesthesia time often occur during clinical use. During the development of lidocaine cream, when the lidocaine content is more than 7.0 wt%, the cream prepared by the conventional process often shows unstable phenomena such as stratification and demulsification, or drug crystallization occurs during standing. Therefore, there is no cream with a high lidocaine content on the market. Summary of the Invention

[0004] In view of the above problems existing in the prior art, this application provides a preparation method of lidocaine cream.

[0005] Specifically, this application relates to the following aspects:

[0006] 1. A preparation method of lidocaine cream, characterized by comprising the following steps:

[0007] Prepare an aqueous phase and an oil phase, wherein the aqueous phase contains polyols, water and lidocaine, and the oil phase contains an emulsifier and a grease. Add the oil phase to the aqueous phase and mix evenly to obtain lidocaine cream.

[0008] 2. The preparation method according to item 1, characterized in that in the aqueous phase, the content of the polyol is 6wt%-15wt%, and the content of lidocaine is 7wt%-15wt%.

[0009] 3. The preparation method according to item 1, characterized in that in the aqueous phase, the polyol is selected from one or more of propylene glycol, pentylene glycol, butylene glycol, hexylene glycol, and glycerol.

[0010] 4. The preparation method according to item 1, characterized in that in the oil phase, the content of the emulsifier is 6wt%-15wt%, and the content of the oil and fat is 10wt%-30wt%.

[0011] 5. The preparation method according to item 1, characterized in that the emulsifier is selected from one or more of sorbitan fatty acid esters, polyglycerol fatty acid esters, polyvinyl alcohol-7-stearate, and sorbitan laurate.

[0012] 6. The preparation method according to item 1, characterized in that the oil and fat is selected from one or more of lanolin, petrolatum, cetostearyl alcohol, liquid paraffin, and beeswax.

[0013] 7. The preparation method according to item 1, characterized in that the volume ratio of the aqueous phase to the oil phase is 55:45-80:20.

[0014] 8. The preparation method according to item 1, characterized in that the oil phase is added to the aqueous phase and mixed evenly at high shear and 78°C-83°C, and the stirring rate of the high shear is 5000rpm / min-15000rpm / min.

[0015] 9. A lidocaine cream prepared by the preparation method according to any one of items 1-8.

[0016] This application changes the addition sequence of lidocaine, breaks the traditional process that fat-soluble drugs can only be added to the oil phase, completely disperses lidocaine in the aqueous solution, and after lidocaine reaches the drug melting point, the oil phase solution is slowly added to the aqueous solution under high shear conditions and maintained in the high shear state for 5-20 minutes. The prepared cream has good stability, no demulsification, delamination or crystallization phenomenon, good anesthetic effect of the product, and no adverse reactions. It solves the problems of demulsification, delamination or crystallization of lidocaine cream when the drug content is relatively high, and the prepared cream has good stability. Detailed implementation manners

[0017] The following further illustrates the present application with reference to examples. It should be understood that the examples are only used to further illustrate and explain the present application and are not used to limit the present application.

[0018] Unless otherwise defined, the technical and scientific terms used in this specification have the same meanings as those commonly understood by those skilled in the art. Although methods and materials similar or equivalent to those described herein can be used in experiments or practical applications, the materials and methods are described below. In case of conflict, the present specification, including its definitions, shall prevail. Additionally, the materials, methods, and examples are for illustrative purposes only and not restrictive. The present application will be further described below in conjunction with specific embodiments, but it is not intended to limit the scope of the present application.

[0019] The present application provides a method for preparing lidocaine cream, comprising the following steps:

[0020] Step 1: Prepare an aqueous phase and an oil phase, wherein the aqueous phase contains polyol, water, and lidocaine, and the oil phase contains an emulsifier and a grease.

[0021] Step 2: Add the oil phase to the aqueous phase and mix evenly to obtain lidocaine cream.

[0022] In Step 1, the aqueous phase contains polyol, water, and lidocaine. During the preparation of the aqueous phase, the addition order and mixing method of polyol, water, and lidocaine are not restricted, as long as polyol, water, and lidocaine are mixed evenly. In a specific embodiment, water and polyol are added first. After the temperature is raised and mixed evenly, lidocaine is added until it is completely melted. Among them, the lidocaine in the aqueous phase needs to be completely melted, so the aqueous phase needs to be maintained at 78°C - 83°C.

[0023] In a specific embodiment, the preparation of the aqueous phase comprises the following steps: Under the state of heating and stirring, polyol and water are mixed until heated to 78°C - 83°C, and then stirring is stopped. Then lidocaine is added and kept warm at 78°C - 83°C.

[0024] In a specific embodiment, in the aqueous phase, the content of the polyol is 6wt% - 15wt%, for example, it can be 6wt%, 7wt%, 8wt%, 9wt%, 10wt%, 11wt%, 12wt%, 13wt%, 14wt%, 15wt%; the content of lidocaine is 7wt% - 15wt%, for example, it can be 7wt%, 8wt%, 9wt%, 10wt%, 11wt%, 12wt%, 13wt%, 14wt%, 15wt%.

[0025] The polyol is selected from one or more of propylene glycol, pentylene glycol, butylene glycol, hexylene glycol, and glycerol.

[0026] In a specific embodiment, the polyol is a mixture of propylene glycol and glycerol, wherein the mass ratio of propylene glycol to glycerol is 1:4 - 2:3, for example, it can be 1:4, 2:5, 1:2, 2:3.

[0027] The oil phase contains an emulsifier and a grease. During the preparation of the oil phase, the addition order and mixing method of the emulsifier and the grease are not restricted, as long as the emulsifier and the grease are mixed evenly.

[0028] In a specific embodiment, the preparation of the oil phase comprises the following steps: under the state of heating and stirring, mix the emulsifier and the grease, and heat to 80°C - 85°C.

[0029] In a specific embodiment, in the oil phase, the content of the emulsifier is 6wt% - 15wt%, for example, it can be 6wt%, 7wt%, 8wt%, 9wt%, 10wt%, 11wt%, 12wt%, 13wt%, 14wt%, 15wt%; the content of the grease is 10wt% - 30wt%, for example, it can be 10wt%, 11wt%, 12wt%, 13wt%, 14wt%, 15wt%, 16wt%, 17wt%, 18wt%, 19wt%, 20wt%, 21wt%, 22wt%, 23wt%, 24wt%, 25wt%, 26wt%, 27wt%, 28wt%, 29wt%, 30wt%.

[0030] In a specific embodiment, the emulsifier is selected from one or more of sorbitan fatty acid esters, polyglycerol fatty acid esters, polyvinyl alcohol-7-stearate, and sorbitan laurate.

[0031] In a specific embodiment, the grease is selected from one or more of lanolin, petrolatum, cetostearyl alcohol, liquid paraffin, and beeswax.

[0032] In step two, the oil phase and the water phase can be mixed evenly under high shear at 78°C - 83°C, wherein the stirring rate of high shear is 5000 rpm / min - 15000 rpm / min.

[0033] During the process of adding the oil phase to the water phase and mixing evenly, in order to obtain a more stable and uniform cream, the oil phase can be slowly added to the water phase. After mixing evenly, continue to stir for 5 - 20 minutes under high shear.

[0034] In a specific embodiment, the volume ratio of the aqueous phase to the oil phase is 55:45 - 80:20, for example, it can be 55:45, 60:45, 65:45, 70:45, 75:45, 80:45, 85:45, 90:45, 95:45, 100:45, 105:45, 110:45, 115:45, 120:45, 125:45, 130:45, 135:45, 140:45, 145:45, 150:45, 155:45, 160:45, 165:45, 170:45, 175:45, 180:45.

[0035] The present application also provides lidocaine cream prepared by the above preparation method.

[0036] Example 1

[0037] (1) Preparation of aqueous phase solution: Under the state of heating and stirring, 2 g of propylene glycol, 8 g of glycerol, and 53 g of purified water are mixed together, heated to 78°C - 83°C, stirring is stopped, 7 g of lidocaine is added, and after the lidocaine is completely melted, keep warm;

[0038] (2) Preparation of oil phase solution: Under the state of heating and stirring, 12 g of polyvinyl alcohol - 7 - stearate, 6 g of cetostearyl alcohol, and 12 g of liquid paraffin are mixed together, heated to 80°C - 85°C;

[0039] (3) Under the condition of a high shear rate of 5000 r / min and the state of keeping warm, the oil phase components are slowly added to the aqueous phase components. After mixing evenly, continue to stir for 20 minutes under the high shear state;

[0040] (4) Under the state of slow stirring, the cream is cooled to room temperature by circulating condensed water and left to stand for 8 - 12 hours.

[0041] Example 2

[0042] (1) Preparation of aqueous phase solution: Under the state of heating and stirring, 4 g of propylene glycol, 10 g of glycerol, and 41 g of purified water are mixed together, heated to 78°C - 83°C, stirring is stopped, 15.0 g of lidocaine is added, and after the lidocaine is completely melted, keep warm;

[0043] (2) Preparation of oil phase solution: Under the state of heating and stirring, 12 g of polyvinyl alcohol - 7 - stearate, 6 g of cetostearyl alcohol, and 12 g of liquid paraffin are mixed together, heated to 80°C - 85°C;

[0044] (3) Under the condition of a high shear rate of 15000 r / min and the state of keeping warm, the oil phase components are slowly added to the aqueous phase components. After mixing evenly, continue to stir for 5 minutes under the high shear state;

[0045] (4) Cool the cream to room temperature with circulating condensed water under slow stirring, and let it stand for 8 to 12 hours.

[0046] Example 3

[0047] (1) Preparation of aqueous solution: Mix 6 g of propylene glycol, 9 g of glycerol, and 43 g of purified water together under heating and stirring, heat to 78°C to 83°C, stop stirring, add 12 g of lidocaine, and keep warm after the lidocaine has completely melted.

[0048] (2) Preparation of oil phase solution: Mix 12 g of polyvinyl alcohol-7-stearate, 6 g of cetostearyl alcohol, and 12 g of liquid paraffin together under heating and stirring, and heat to 80°C to 85°C.

[0049] (3) Slowly add the oil phase components to the aqueous phase components at a high shear rate of 10,000 r / min and under a heat-insulated state. After mixing evenly, continue to stir for 10 minutes under a high shear state.

[0050] (4) Cool the cream to room temperature with circulating condensed water under slow stirring, and let it stand for 8 to 12 hours.

[0051] Example 4

[0052] (1) Preparation of aqueous solution: Mix 10 g of propylene glycol and 53 g of purified water together under heating and stirring, heat to 78°C to 83°C, stop stirring, add 7 g of lidocaine, and keep warm after the lidocaine has completely melted.

[0053] (2) Preparation of oil phase solution: Mix 12 g of polyvinyl alcohol-7-stearate, 6 g of cetostearyl alcohol, and 12 g of liquid paraffin together under heating and stirring, and heat to 80°C to 85°C.

[0054] (3) Slowly add the oil phase components to the aqueous phase components at a high shear rate of 5,000 r / min and under a heat-insulated state. After mixing evenly, continue to stir for 20 minutes under a high shear state.

[0055] (4) Cool the cream to room temperature with circulating condensed water under slow stirring, and let it stand for 8 to 12 hours.

[0056] Example 5

[0057] (1) Preparation of aqueous solution: Mix 10 g of glycerol and 53 g of purified water together under heating and stirring, heat to 78°C to 83°C, stop stirring, add 7 g of lidocaine, and keep warm after the lidocaine has completely melted.

[0058] (2) Preparation of oil phase solution: Mix 12 g of polyvinyl alcohol-7-stearate, 6 g of cetostearyl alcohol, and 12 g of liquid paraffin together under heating and stirring, and heat to 80 °C - 85 °C;

[0059] (3) At a high shear rate of 5000 r / min and under the condition of heat preservation, slowly add the oil phase components to the water phase components. After mixing evenly, continue to stir for 20 minutes under high shear state;

[0060] (4) Cool the cream to room temperature with circulating condensed water under slow stirring, and let it stand for 8 - 12 hours.

[0061] Example 6

[0062] (1) Preparation of water phase solution: Mix 5 g of propylene glycol, 5 g of glycerol, and 53 g of purified water together under heating and stirring, heat to 78 °C - 83 °C, stop stirring, add 7 g of lidocaine, and keep warm after the lidocaine melts completely;

[0063] (2) Preparation of oil phase solution: Mix 12 g of sorbitan fatty acid ester and 18 g of lanolin together under heating and stirring, and heat to 80 °C - 85 °C;

[0064] (3) At a high shear rate of 5000 r / min and under the condition of heat preservation, slowly add the oil phase components to the water phase components. After mixing evenly, continue to stir for 20 minutes under high shear state;

[0065] (4) Cool the cream to room temperature with circulating condensed water under slow stirring, and let it stand for 8 - 12 hours.

[0066] Example 7

[0067] (1) Preparation of water phase solution: Mix 1.5 g of propylene glycol, 6 g of glycerol, and 41.5 g of purified water together under heating and stirring, heat to 78 °C - 83 °C, stop stirring, add 6 g of lidocaine, and keep warm after the lidocaine melts completely;

[0068] (2) Preparation of oil phase solution: Mix 15 g of polyvinyl alcohol-7-stearate, 10 g of cetostearyl alcohol, and 20 g of liquid paraffin together under heating and stirring, and heat to 80 °C - 85 °C;

[0069] (3) At a high shear rate of 5000 r / min and under the condition of heat preservation, slowly add the oil phase components to the water phase components. After mixing evenly, continue to stir for 20 minutes under high shear state;

[0070] (4) Cool the cream to room temperature with circulating condensed water under slow stirring, and let it stand for 8 - 12 hours.

[0071] Example 8

[0072] (1) Preparation of aqueous solution: Under the condition of heating and stirring, 3 g of propylene glycol, 9 g of glycerol, and 60 g of purified water were mixed together, heated to 78 °C to 83 °C, stirring was stopped, 8 g of lidocaine was added, and after the lidocaine was completely melted, it was kept warm;

[0073] (2) Preparation of oil phase solution: Under the condition of heating and stirring, 6 g of polyvinyl alcohol-7-stearate, 6 g of cetostearyl alcohol, and 8 g of liquid paraffin were mixed together and heated to 80 °C to 85 °C;

[0074] (3) Under the condition of a high shear rate of 5000 r / min and keeping warm, the oil phase components were slowly added to the aqueous phase components. After mixing evenly, stirring was continued for 20 minutes under a high shear state;

[0075] (4) Under the condition of slow stirring, the cream was cooled to room temperature using circulating condensed water and allowed to stand for 8 to 12 hours.

[0076] Example 9

[0077] (1) Preparation of aqueous solution: Under the condition of heating and stirring, 1 g of propylene glycol, 4 g of glycerol, and 28 g of purified water were mixed together, heated to 78 °C to 83 °C, stirring was stopped, 7 g of lidocaine was added, and after the lidocaine was completely melted, it was kept warm;

[0078] (2) Preparation of oil phase solution: Under the condition of heating and stirring, 24 g of polyvinyl alcohol-7-stearate, 16 g of cetostearyl alcohol, and 20 g of liquid paraffin were mixed together and heated to 80 °C to 85 °C;

[0079] (3) Under the condition of a high shear rate of 5000 r / min and keeping warm, the oil phase components were slowly added to the aqueous phase components. After mixing evenly, stirring was continued for 20 minutes under a high shear state;

[0080] (4) Under the condition of slow stirring, the cream was cooled to room temperature using circulating condensed water and allowed to stand for 8 to 12 hours.

[0081] Comparative Example 1

[0082] (1) Preparation of aqueous solution: Under the condition of heating and stirring, 2 g of propylene glycol, 8 g of glycerol, and 53 g of purified water were mixed together, heated to 78 °C to 83 °C until completely melted, stirring was stopped, and it was kept warm for standby;

[0083] (2) Preparation of oil phase solution: Under the condition of heating and stirring, 7 g of lidocaine, 12 g of polyvinyl alcohol-7-stearate, 6 g of cetostearyl alcohol, and 12 g of liquid paraffin were mixed together and heated to 80 °C to 85 °C until completely melted;

[0084] (3) Under a high shear rate of 10000 r / min and in a heat-insulated state, slowly add the oil-phase components to the water-phase components. After mixing evenly, continue stirring for 10 minutes under a high shear state;

[0085] (4) Cool the cream to room temperature using circulating condensed water under a slow stirring state, and let it stand for 8 - 12 hours.

[0086] Comparative Example 2

[0087] (1) Preparation of the water-phase solution: Mix 4 g of propylene glycol, 10 g of glycerol, and 41 g of purified water together under a heated and stirred state, heat to 78°C - 83°C until completely melted, stop stirring, and keep warm for standby;

[0088] (2) Preparation of the oil-phase solution: Mix 15 g of lidocaine, 12 g of polyvinyl alcohol-7-stearate, 6 g of cetostearyl alcohol, and 12 g of liquid paraffin together under a heated and stirred state, heat to 80°C - 85°C until completely melted;

[0089] (3) Under a high shear rate of 15000 r / min and in a heat-insulated state, slowly add the oil-phase components to the water-phase components. After mixing evenly, continue stirring for 5 minutes under a high shear state;

[0090] (4) Cool the cream to room temperature using circulating condensed water under a slow stirring state, and let it stand for 8 - 12 hours.

[0091] Comparative Example 3

[0092] (1) Preparation of the water-phase solution: Mix 6 g of propylene glycol, 9 g of glycerol, and 43 g of purified water together under a heated and stirred state, heat to 78°C - 83°C until completely melted, stop stirring, and keep warm for standby;

[0093] (2) Preparation of the oil-phase solution: Mix 12 g of lidocaine, 12 g of polyvinyl alcohol-7-stearate, 6 g of cetostearyl alcohol, and 12 g of liquid paraffin together under a heated and stirred state, heat to 80°C - 85°C until completely melted;

[0094] (3) Under a high shear rate of 10000 r / min and in a heat-insulated state, slowly add the oil-phase components to the water-phase components. After mixing evenly, continue stirring for 10 minutes under a high shear state;

[0095] (4) Cool the cream to room temperature using circulating condensed water under a slow stirring state, and let it stand for 8 - 12 hours.

[0096] Comparative Example 4 (blank matrix without drug)

[0097] (1) Preparation of aqueous solution: Mix 6 g of propylene glycol, 9 g of glycerol, and 43 g of purified water under heating and stirring, heat and stir at 78 °C - 83 °C until evenly mixed, stop stirring, and keep warm for standby;

[0098] (2) Preparation of oil phase solution: Mix 12 g of polyvinyl alcohol - 7 - stearate, 6 g of cetostearyl alcohol, and 12 g of liquid paraffin under heating and stirring, and heat to complete melting at 80 °C - 85 °C;

[0099] (3) Under the condition of a high shear rate of 10000 r / min and in a heat - preservation state, slowly add the oil - phase components to the water - phase components. After mixing evenly, continue to stir for 10 minutes under high - shear conditions;

[0100] (4) Cool the cream to room temperature using circulating chilled water under slow stirring, and let it stand for 8 - 12 hours.

[0101] The reaction conditions of the above - mentioned examples and comparative examples are shown in Table 1.

[0102] Table 1

[0103]

[0104]

[0105] Test Example 1 Stability test after the preparation of the lidocaine cream

[0106] Take about 10 g of the lidocaine creams of Examples 1 - 6 and Comparative Examples 1 - 3 above, record whether the sample crystallizes, and then place it in a centrifuge tube and centrifuge at 4000 r / min for 30 min. Observe whether the cream shows phenomena such as stratification and emulsification. The test results are shown in Table 2.

[0107] Table 2

[0108] Group Whether crystallization occurs Whether layering / demulsification occurs after centrifugation Example 1 No No Example 2 No No Example 3 No No Example 4 No No Example 5 No No Example 6 No No Example 7 No No Example 8 No No Example 9 No Yes Comparative Example 1 No Yes Comparative Example 2 Yes Yes Comparative Example 3 Yes Yes Comparative Example 4 No No

[0109] Conclusion: The cream prepared in this application has no crystallization phenomenon, and the product is stable after centrifugation.

[0110] Test Example 2 Results of the accelerated stability test of the cream

[0111] Investigation items: Appearance of the cream, whether it crystallizes, whether it stratifies after centrifugation, lidocaine content.

[0112] Test basis: Guidelines for the Stability Testing of Raw Materials and Preparations, Appendix 9001, Chinese Pharmacopoeia 2020 Edition

[0113] Test conditions: Temperature is 30 °C ± 2 °C, relative humidity is 60% ± 5%.

[0114] Sampling time: Samples were taken for testing at 0 months, 1 month, 2 months, 3 months, and 6 months respectively.

[0115] The test results are shown in Table 3.

[0116] Table 3 Test Results of Accelerated Stability Test of Lidocaine Cream

[0117]

[0118]

[0119]

[0120] Conclusion: After the accelerated stability test of the lidocaine cream of this application, there is no obvious change in the quality and appearance of the cream, no crystal precipitation phenomenon, no stratification after centrifugation, and the lidocaine content meets the requirements after detection, indicating that the product quality of this application is stable and reliable, and the production process is feasible.

Claims

1. A preparation method of lidocaine cream, characterized in that, Comprising the following steps: Preparing an aqueous phase and an oil phase, wherein the aqueous phase consists of a polyol, water and lidocaine, and the aqueous phase is maintained at 78°C - 83°C; the oil phase contains an emulsifier and a grease; the volume ratio of the aqueous phase to the oil phase is 55:45 - 80:20; adding the oil phase to the aqueous phase and mixing evenly to obtain lidocaine cream; In the aqueous phase, the content of the polyol is 6wt% - 15wt%, and the content of lidocaine is 7wt% - 15wt%; The polyol is selected from one or more of propylene glycol, pentylene glycol, butylene glycol, hexylene glycol, glycerol; In the oil phase, the content of the emulsifier is 6wt% - 15wt%, and the content of the grease is 10wt% - 30wt%.

2. The preparation method according to claim 1, characterized in that, The emulsifier is selected from one or more of sorbitan fatty acid esters, polyglycerol fatty acid esters, polyvinyl alcohol-7-stearate; 3. The preparation method according to claim 1, wherein, The grease is selected from one or more of lanolin, petrolatum, cetostearyl alcohol, liquid paraffin, beeswax; 4. The preparation method according to claim 1, characterized in that, Adding the oil phase to the aqueous phase and mixing evenly under high shear at 78°C - 83°C, and the stirring rate of the high shear is 5000rpm / min - 15000rpm / min.

5. A lidocaine cream, which is prepared by the preparation method according to any one of claims 1 - 4.

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