Lidocaine cream and preparation method thereof

Abstract

The invention relates to lidocaine emulsifiable paste and a preparation method thereof, and belongs to the technical field of biological medicine, the lidocaine emulsifiable paste comprises a main medicine solution, an oil phase component, a water phase component, a preservative and an antioxidant; the preparation method comprises the following steps: adding a prepared thickener solution into a water phase, stirring and swelling, and shearing by using a high-shear dispersion machine; slowly adding the oil-phase component into the water-phase component, keeping the temperature, dispersing by using a high-shear dispersion machine while adding to prepare primary emulsion, dripping the main medicine solution into the primary emulsion to obtain paste containing the main medicine, and finally adding the preservative and the antioxidant. No pH regulator is added, the formula composition is simple, and the prepared cream is good in stability and low in cost. In the preparation process, a high-shear dispersion machine is used for shearing twice, so that the prepared finished product is brighter in appearance, finer and smoother in texture and good in glossiness, the particle size of liquid drops is smaller, the stability of the prepared finished product is improved, and the prepared finished product is not prone to layering during centrifugation.

Description

Technical Field

[0001] The invention relates to the technical field of biomedicine, and in particular to a lidocaine cream and a preparation method thereof. Background Art

[0002] Lidocaine is a local anesthetic and antiarrhythmic drug. It is a derivative of cocaine, but it does not have the hallucination-producing and addictive components of cocaine. Lidocaine hydrochloride is a white crystalline powder that is very slightly soluble in water. It has a strong and lasting local anesthetic effect and good surface penetration. It can be injected or used as a surface anesthesia. It was used to treat arrhythmias in 1963. It is a drug for preventing and treating acute myocardial infarction and various heart diseases complicated by rapid ventricular arrhythmias. It is the first choice for ventricular premature beats, ventricular tachycardia and ventricular fibrillation in acute myocardial infarction.

[0003] In addition to intramuscular injection, intravenous injection, and intravenous drip, lidocaine can also be made into creams, mouthwashes, aerosols, etc. for external administration. When lidocaine is applied as a cream for external administration, it is applied to undamaged skin or mucous membrane surfaces to release lidocaine to the cortex or subcutaneous layer, and accumulates in the cortical pain receptors and nerve endings to play an anesthetic role in the cortex. It can also be used to relieve pain and itching. Lidocaine cream is often used to relieve symptoms such as anal pain and anal itching. The ones on the market in China are compound lidocaine creams, with lidocaine and prilocaine as active ingredients. Currently, there is no lidocaine cream with a single active ingredient on the market in China.

[0004] Patent CN110585312A in the prior art discloses lidocaine deoxygenation cream and its preparation method and use, including two active ingredients of lidocaine and phenylephrine hydrochloride, and also includes the following excipients: aloe extract, benzyl alcohol, carbomer 934P, cholesterol, hydrogenated phosphatidylcholine, isopropyl myristate, polysorbate 80 (Tween-80), propylene glycol, triethanolamine, α-tocopherol acetate, grape skin extract and water in appropriate amounts. The medicine disclosed in the patent contains two active ingredients, and the prescription ingredients are complex, and aloe extract and grape skin extract are additionally added. The carbomer 934P excipient used in it needs to use a type of solvent benzene in the production process, because benzene is in the list of Class 1 carcinogens and has low safety; at the same time, the antioxidant in the preparation process of the cream is added too early in the early preparation process of the oil phase component, and after multiple high-temperature heating, it is easy to degrade, thereby weakening the antioxidant effect.

[0005] Therefore, it is necessary to develop a lidocaine cream with simple ingredients, only one active ingredient, higher safety and better stability. Summary of the invention

[0006] The object of the present invention is to provide a lidocaine cream and a preparation method thereof, which improves the safety of the product, and the prepared finished product has good glossiness, fine texture, small droplet size, high stability, and is not easy to separate after centrifugation, thereby solving the problems of complex product ingredients, low safety, and poor stability in the prior art. To achieve this object, the present invention adopts the following technical solutions:

[0007] The first aspect of the present invention provides a lidocaine cream, comprising a main drug solution, an oil phase component, an aqueous phase component, a preservative and an antioxidant; the lidocaine cream does not contain a pH regulator;

[0008] The main drug solution is lidocaine and a solvent; the oil phase components are an oil phase and a surfactant; and the water phase components are a water phase, an emulsifier, a dispersant and a thickener.

[0009] As an embodiment of the present invention, the solvent includes one or more of ethanol, 1,3-butanediol, and diethylene glycol monobutyl ether.

[0010] The oil phase includes cholesterol and medium chain triglycerides; the surfactant includes one or more of soybean lecithin, hydrogenated soybean lecithin, and hydrogenated palm oil glyceride.

[0011] The aqueous phase includes purified water; the emulsifier includes one of polysorbate 80, polysorbate 60, and polysorbate 20; the dispersant is ethanol; and the thickener includes one of carbomer 980P, carbomer 974P, and carbomer 940P.

[0012] The preservative includes one or more of benzyl alcohol, benzoic acid, and potassium sorbate.

[0013] The antioxidant includes one or more of tocopherol and butylated hydroxyanisole.

[0014] In the main drug solution, alcohol or ether is added as a solvent to dissolve and disperse lidocaine; in the oil phase component, soybean lecithin, hydrogenated soybean lecithin, and hydrogenated palm oil glyceride are low in price, which is conducive to reducing costs; in the water phase component, carbomer 980P, carbomer 974P, and carbomer 940P are used, which do not contain benzene residues and improve the safety of the finished product. Adding preservatives such as benzyl alcohol can act as a local anesthetic, which is conducive to synergizing lidocaine with analgesia and relieving itching; tocopherol and the like are used for antioxidant effects and are low in price.

[0015] As an embodiment of the present invention, the weight content of each component of the lidocaine cream is: in the main drug solution, lidocaine 6.2-10.4 parts, solvent 6.5-26.5 parts;

[0016] The oil phase components include 4.6-30 parts of oil phase and 1-2 parts of surfactant;

[0017] The aqueous phase components include 130-150 parts of aqueous phase, 0.4-24 parts of emulsifier, 3.5-13.5 parts of dispersant, and 0.8-2 parts of thickener;

[0018] 1-2 parts of the preservative;

[0019] The antioxidant is 0.02-0.1 part.

[0020] As an embodiment of the present invention, the mass concentration of lidocaine is 1.5-6.6%, further such as 2%, 3%, 4%, 5% or 6%.

[0021] As an embodiment of the present invention, the ratio of the preservative to the antioxidant is 20-50:1, which is conducive to uniform mixing of the preservative and the antioxidant.

[0022] As an embodiment of the present invention, the weight content of each component of the lidocaine cream is: in the main drug solution, 8 parts of lidocaine and 24 parts of ethanol;

[0023] The oil phase ingredients include 2 parts of cholesterol, 2 parts of soybean lecithin, and 12 parts of medium-chain triglycerides;

[0024] The aqueous phase comprises 140 parts of purified water, 1.3 parts of polysorbate 80, 7 parts of ethanol, and 1.6 parts of carbomer 980P;

[0025] 2 parts of benzyl alcohol;

[0026] 0.1 part of the tocopherol; and a lidocaine cream with a mass concentration of 4% is prepared.

[0027] A second aspect of the present invention provides a method for preparing lidocaine cream, the preparation method comprising:

[0028] Preparation of the main drug solution: mixing lidocaine with a solvent, and heating and dissolving to form a main drug solution;

[0029] Preparation of the oil phase component: heating and melting the oil phase and the surfactant to form the oil phase component;

[0030] Preparation of aqueous phase components: After the thickener, emulsifier and dispersant are mixed with the aqueous phase, they are stirred and swelled, sheared with a high shear disperser, and heated to dissolve and keep warm to prepare the aqueous phase components; when the thickener solution swells, shearing with a high shear disperser is used, which is conducive to the preparation of a finished product with a brighter appearance, finer texture and better gloss.

[0031] Preparation of colostrum: slowly add the oil phase components into the water phase components and keep them warm, and use a high shear disperser to disperse them to obtain colostrum; when the water and oil phase components are mixed, high shear dispersion is introduced to improve the emulsification effect, make the droplet size smaller, improve the stability of the prepared product, and make it difficult to separate by centrifugation.

[0032] The main drug solution is dripped into the colostrum to obtain a paste containing the main drug with a pH value of 8.7-9.7;

[0033] Finally, preservatives and antioxidants are added into the paste containing the main drug to prepare a cream.

[0034] Adding preservatives and antioxidants in the last step of the preparation process can prevent the antioxidants from being affected by high temperatures and becoming ineffective.

[0035] In the above preparation process, the preparation order of the main drug solution, the oil phase component and the water phase component can be exchanged successively.

[0036] As an embodiment of the present invention, the heating and / or heat preservation temperature during the preparation of the main drug solution, oil phase components, water phase components and colostrum is 75-85°C, preferably 80°C.

[0037] In the preparation of the aqueous phase component, the stirring and swelling rotation speed is 200-600rpm, preferably 400rpm; the stirring time is 8-12min, preferably 10min; the shearing time of the high shear disperser is 5-15min, preferably 10min; the rotation speed of the high shear disperser is 8000-12000rpm, preferably 10000rpm.

[0038] As an embodiment of the present invention, in the preparation of colostrum, the shearing time of the high shear disperser is 1-5 min, preferably 2 min; the rotation speed of the high shear disperser is 3000-6000 rpm, preferably 5000 rpm.

[0039] As an embodiment of the present invention, the main drug solution is dripped into the colostrum, and the pH value is controlled to be 9.2, which is conducive to the acidic thickener being neutralized by the alkaline lidocaine to present the best viscosity of the cream. During the dripping process, the stirring time is controlled to be 10-20 minutes, preferably 15 minutes; the stirring speed is 50-100 rpm, preferably 60 rpm.

[0040] Compared with the prior art solutions, the present invention has the following beneficial effects:

[0041] 1. The components of the present invention include a main drug solution, an oil phase component, an aqueous phase component, a preservative and an antioxidant; wherein, in the main drug solution, an alcohol or ether solvent is added to dissolve and disperse lidocaine; in the oil phase component, soybean lecithin, hydrogenated soybean lecithin, and hydrogenated palm oil glyceride are low in price, which is conducive to reducing costs; in the aqueous phase component, carbomer 980P, carbomer 974P, and carbomer 940P are used, which do not contain benzene residues and improve the safety of the finished product. Adding a preservative can play the role of a local anesthetic, which is conducive to synergizing lidocaine with analgesia and relieving itching; tocopherol and butylated hydroxyanisole are used for antioxidant effects, which are low in price and save production costs. The present invention unexpectedly found that it is not necessary to add an additional pH regulator, and the pH value can be adjusted by utilizing the alkaline property of lidocaine itself, that is, the carbomer thickener is acidic after being configured into a solution, and the alkaline lidocaine is used to neutralize the acidic carbomer thickener, so that the pH is controlled within the range of 8.7-9.7, which can greatly increase the viscosity of the carbomer thickener solution, make it present the optimal viscosity, and finally make the prepared cream have the best viscosity. The present invention does not need to add an additional pH regulator, has low cost, simple prescription composition, and better safety.

[0042] 2. The high shear disperser is used twice in the preparation process of the present invention. The first time, when the thickener solution is swollen, the high shear disperser is used for shearing, which is conducive to the finished product having a brighter appearance, good gloss and finer texture. The second time, when the oil phase component is slowly added to the water phase component, high shear dispersion is introduced to improve the emulsification effect, make the droplet size smaller, and centrifugal separation is not easy, thereby improving the stability of the prepared finished product.

[0043] 3. The present invention uses a preservative to dilute an antioxidant, and adds the diluted antioxidant to the prepared colostrum. Antioxidants (such as tocopherol) are relatively viscous, and the use of a preservative (such as benzyl alcohol) to dilute the antioxidant can avoid the occurrence of uneven mixing of the antioxidant and colostrum, improve the stability of the finished product, and have a good antioxidant effect. The present invention adds the preservative and antioxidant in the last step of the preparation process, which can avoid the antioxidant being added too early and being affected by high temperature and becoming ineffective. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 is a graph of lidocaine content after 6 months of storage in Example 1;

[0045] Figure 2 This is a graph of lidocaine content in comparative example 1 after 6 months of storage;

[0046] Figure 3 This is a graph of lidocaine content in comparative example 2 after 6 months of storage;

[0047] Figure 4 It is a graph of lidocaine content in the reference solution. DETAILED DESCRIPTION

[0048] The present invention is further described below in conjunction with examples, but the embodiments of the present invention are not limited thereto.

[0049] The equipment or other reagents / materials used in the examples can be purchased through commercial channels.

[0050] The centrifugal stability of the present invention is observed after centrifugation in a high-speed centrifuge.

[0051] The particle size was measured by a transdermal cream particle size analyzer.

[0052] Example 1

[0053] The present embodiment provides a lidocaine cream and a preparation method thereof, the preparation method comprising the following steps:

[0054] Step 1: Mix 8 parts of lidocaine with 24 parts of ethanol, and heat to dissolve to form a main drug solution;

[0055] Step 2: Mix 2 parts of cholesterol, 2 parts of soybean lecithin and 12 parts of medium-chain triglycerides to form an oil phase component, heat to 80°C and keep warm;

[0056] Step 3: Mix 7 parts of ethanol, 1.3 parts of polysorbate 80 and 1.6 parts of carbomer 980P, add 140 parts of purified water after wetting, stir and swell, the stirring speed is 400 rpm, and the stirring time is 10 minutes; use a high shear disperser to shear, the speed is 10000 rpm, and the shear time is 10 minutes; heat to 80°C to fully dissolve and then keep warm to prepare an aqueous phase component;

[0057] Step 4: slowly add the oil phase component to the water phase component and keep it at 80°C, while adding, use a high shear disperser to disperse it at a speed of 5000rpm and a shear time of 2min to obtain colostrum;

[0058] Step 5: dripping the main drug solution into the colostrum to obtain a paste containing the main drug with a pH value of 9.2;

[0059] Step 6: Use 2 parts of benzyl alcohol to dilute 0.1 parts of tocopherol, add the diluted tocopherol to the paste prepared in step 5, stir evenly to prepare a cream with a lidocaine concentration of 4%, and fill it after cooling to room temperature.

[0060] Example 2

[0061] The present embodiment provides a lidocaine cream and a preparation method thereof, the preparation method comprising the following steps:

[0062] Step 1: Mix 6.2 parts of lidocaine with 6.5 parts of ethanol, and heat to dissolve to form a main drug solution;

[0063] Step 2: Mix 0.6 parts of cholesterol, 1 part of soybean lecithin and 4 parts of medium-chain triglycerides to form an oil phase component, heat to 80°C and keep warm;

[0064] Step 3: Mix 3.5 parts of ethanol, 0.4 parts of polysorbate 80 and 0.8 parts of carbomer 980P, add 130 parts of purified water after wetting, stir and swell, the stirring speed is 400 rpm, and the stirring time is 10 minutes; use a high shear disperser to shear, the speed is 10000 rpm, the shear time is 10 minutes, heat to 80°C to fully dissolve, and then keep warm to prepare an aqueous phase component;

[0065] Step 4: slowly add the oil phase component to the water phase component and keep it at 80°C, while adding, use a high shear disperser to disperse it at a speed of 5000rpm and a shear time of 2min to obtain colostrum;

[0066] Step 5: dripping the main drug solution into the colostrum to obtain a paste containing the main drug with a pH value of 9.7;

[0067] Step 6: dilute 0.02 parts of tocopherol with 1 part of benzyl alcohol, add the diluted tocopherol to the paste prepared in step 5, stir evenly to prepare a cream with a lidocaine concentration of 4%, and fill it after cooling to room temperature.

[0068] Example 3

[0069] The present embodiment provides a lidocaine cream and a preparation method thereof, the preparation method comprising the following steps:

[0070] Step 1: Mix 10.4 parts of lidocaine with 26.5 parts of ethanol, and heat to dissolve to form a main drug solution;

[0071] Step 2: Mix 10 parts of cholesterol, 2 parts of soybean lecithin and 20 parts of medium-chain triglycerides to form an oil phase component, heat to 80°C and keep warm;

[0072] Step 3: Mix 13.5 parts of ethanol, 24 parts of polysorbate 80 and 2 parts of carbomer 980P, add 150 parts of purified water after wetting, stir and swell, the stirring speed is 400 rpm, and the stirring time is 10 minutes; use a high shear disperser to shear, the speed is 10000 rpm, the shear time is 10 minutes, heat to 80°C to fully dissolve, and then keep warm to prepare an aqueous phase component;

[0073] Step 4: slowly add the oil phase component to the water phase component and keep it at 80°C, while adding, use a high shear disperser to disperse it at a speed of 5000rpm and a shear time of 2min to obtain colostrum;

[0074] Step 5: dripping the main drug solution into the colostrum to obtain a paste containing the main drug with a pH value of 9.3;

[0075] Step 6: Use 1.5 parts of benzyl alcohol to dilute 0.05 parts of tocopherol, add the diluted tocopherol to the paste prepared in step 5, stir evenly to prepare a cream with a lidocaine concentration of 4%, and fill it after cooling to room temperature.

[0076] Example 4

[0077] The present embodiment provides a lidocaine cream and a preparation method thereof, the preparation method comprising the following steps:

[0078] Step 1: Mix 8 parts of lidocaine with 24 parts of 1,3-butanediol, and heat to dissolve to form a main drug solution;

[0079] Step 2: Mix 2 parts of cholesterol, 2 parts of hydrogenated soy lecithin and 12 parts of medium chain triglycerides to form an oil phase component, heat to 80°C and keep warm;

[0080] Step 3: Mix 7 parts of ethanol, 1.3 parts of polysorbate 60 and 1.6 parts of carbomer 974P, add 140 parts of purified water after wetting, stir and swell, the stirring speed is 400 rpm, and the stirring time is 10 minutes; use a high shear disperser to shear, the speed is 10000 rpm, the shear time is 10 minutes, heat to 80°C to fully dissolve, and then keep warm to prepare an aqueous phase component;

[0081] Step 4: slowly add the oil phase component to the water phase component and keep it at 80°C, while adding, use a high shear disperser to disperse it at a speed of 5000rpm and a shear time of 2min to obtain colostrum;

[0082] Step 5: dripping the main drug solution into the colostrum to obtain a paste containing the main drug with a pH value of 9.1;

[0083] Step 6: Use 2 parts of benzoic acid to dilute 0.1 parts of butyl hydroxyanisole, add the diluted butyl hydroxyanisole to the paste prepared in step 5, stir evenly to prepare a cream with a lidocaine mass concentration of 4%, and then cool to room temperature before filling.

[0084] Example 5

[0085] The present embodiment provides a lidocaine cream and a preparation method thereof, the preparation method comprising the following steps:

[0086] Step 1: Mix 8 parts of lidocaine with 24 parts of diethylene glycol monobutyl ether, and heat to dissolve to form a main drug solution;

[0087] Step 2: Mix 2 parts of cholesterol, 2 parts of hydrogenated palm glyceride and 12 parts of medium chain triglyceride to form an oil phase component, heat to 80°C and keep warm;

[0088] Step 3: Mix 7 parts of ethanol, 1.3 parts of polysorbate 20 and 1.6 parts of carbomer 940P, add 140 parts of purified water after wetting, stir and swell, the stirring speed is 400 rpm, and the stirring time is 10 minutes; use a high shear disperser to shear, the speed is 10000 rpm, the shear time is 10 minutes, heat to 80°C to fully dissolve, and then keep warm to prepare an aqueous phase component;

[0089] Step 4: slowly add the oil phase component to the water phase component and keep it at 80°C, while adding, use a high shear disperser to disperse it at a speed of 5000rpm and a shear time of 2min to obtain colostrum;

[0090] Step 5: dripping the main drug solution into the colostrum to obtain a paste containing the main drug with a pH value of 9.3;

[0091] Step 6: Use 2 parts of potassium sorbate to dilute 0.1 parts of tocopherol, add the diluted tocopherol to the paste prepared in step 5, stir evenly to prepare a cream with a lidocaine concentration of 4%, and then cool to room temperature before filling.

[0092] Example 6

[0093] The present embodiment provides a lidocaine cream and a preparation method thereof, the preparation method comprising the following steps:

[0094] Step 1: Mix 8 parts of lidocaine with 24 parts of ethanol, and heat to dissolve to form a main drug solution;

[0095] Step 2: Mix 2 parts of cholesterol, 2 parts of soybean lecithin and 12 parts of medium-chain triglycerides to form an oil phase component, heat to 75°C and keep warm;

[0096] Step 3: Mix 7 parts of ethanol, 1.3 parts of polysorbate 80 and 1.6 parts of carbomer 980P, add 140 parts of purified water after wetting, stir and swell, the stirring speed is 200 rpm, and the stirring time is 12 minutes; use a high shear disperser to shear, the speed is 8000 rpm, the shear time is 15 minutes, heat to 75°C to fully dissolve, and then keep warm to prepare an aqueous phase component;

[0097] Step 4: slowly add the oil phase component to the water phase component and keep it at 75°C, while adding, use a high shear disperser to disperse it at a speed of 3000 rpm and a shear time of 5 minutes to obtain colostrum;

[0098] Step 5: dripping the main drug solution into the colostrum to obtain a paste containing the main drug with a pH value of 8.7;

[0099] Step 6: dilute 0.1 part of tocopherol with 2 parts of benzyl alcohol, add the diluted tocopherol to the paste prepared in step 5, stir evenly to prepare a cream with a lidocaine concentration of 4%, and fill it after cooling to room temperature.

[0100] Example 7

[0101] The present embodiment provides a lidocaine cream and a preparation method thereof, the preparation method comprising the following steps:

[0102] Step 1: Mix 8 parts of lidocaine with 24 parts of ethanol, and heat to dissolve to form a main drug solution;

[0103] Step 2: Mix 2 parts of cholesterol, 2 parts of soybean lecithin and 12 parts of medium-chain triglycerides to form an oil phase component, heat to 85°C and keep warm;

[0104] Step 3: Mix 7 parts of ethanol, 1.3 parts of polysorbate 80 and 1.6 parts of carbomer 980P, add 140 parts of purified water after wetting, stir and swell, the stirring speed is 600 rpm, and the stirring time is 8 minutes; use a high shear disperser to shear, the speed is 12000 rpm, the shear time is 5 minutes, heat to 85°C to fully dissolve, and then keep warm to prepare an aqueous phase component;

[0105] Step 4: slowly add the oil phase component to the water phase component and keep it at 85°C, while adding, use a high shear disperser to disperse it at a speed of 6000 rpm and a shear time of 1 minute to obtain colostrum;

[0106] Step 5: dripping the main drug solution into the colostrum to obtain a paste containing the main drug with a pH value of 9.4;

[0107] Step 6: dilute 0.1 part of tocopherol with 2 parts of benzyl alcohol, add the diluted tocopherol to the paste prepared in step 5, stir evenly to prepare a cream with a lidocaine concentration of 4%, and fill it after cooling to room temperature.

[0108] Comparative Example 1

[0109] This embodiment provides a lidocaine cream and a preparation method thereof. The preparation method refers to CN110585312A and comprises the following steps:

[0110] Step 1: Mix 8 parts of lidocaine with 24 parts of ethanol, and heat to dissolve to form a main drug solution;

[0111] Step 2: Mix 2 parts of cholesterol, 12 parts of medium chain triglycerides, 2 parts of benzyl alcohol, and 0.1 parts of tocopherol to form an oil phase component, heat it to 80°C and keep it warm;

[0112] Step 3: Mix 10 parts of ethanol, 1.3 parts of polysorbate 80 and 1.6 parts of carbomer 980P, add 140 parts of purified water after wetting, stir and swell, the stirring speed is 400 rpm, the stirring time is 10 minutes, heat to 80°C to fully dissolve and keep warm to prepare the water phase component;

[0113] Step 4: Slowly add the oil phase component to the water phase component and keep it warm at 80°C. Stir while adding until it becomes a homogeneous solution, then slowly add it to the heated emulsifier, add triethanolamine (adjust the pH value to 9.2), 2 parts of hydrogenated phosphatidylcholine, turn on the emulsifier, speed 400rpm, duration 2min, to obtain colostrum;

[0114] Step 5: Heat to 80°C, turn on the emulsifier, and drip the main drug solution into the colostrum at a stirring speed of 300 rpm;

[0115] Step 6: Stir evenly to prepare a lidocaine cream with a mass concentration of 4%, and then fill it after cooling to room temperature.

[0116] Comparative Example 2

[0117] The present embodiment provides a lidocaine cream and a preparation method thereof, the preparation method comprising the following steps:

[0118] Step 1: Mix 8 parts of lidocaine with 24 parts of ethanol, and heat to dissolve to form a main drug solution;

[0119] Step 2: Mix 2 parts of cholesterol, 2 parts of soybean lecithin and 12 parts of medium-chain triglycerides to form an oil phase component, heat to 80°C and keep warm;

[0120] Step 3: Mix 7 parts of ethanol, 1.3 parts of polysorbate 80 and 1.6 parts of carbomer 980P, add 140 parts of purified water after wetting to prepare a thickener solution; stir and swell the prepared thickener solution at a stirring speed of 400 rpm for 10 minutes; heat to 80°C to fully dissolve and then keep warm to prepare an aqueous phase component;

[0121] Step 4: slowly add the oil phase component into the water phase component, stir normally and keep warm at 80°C to obtain colostrum;

[0122] Step 5: dripping the main drug solution into the colostrum to obtain a paste containing the main drug with a pH value of 9.2;

[0123] Step 6: dilute 0.1 part of tocopherol with 2 parts of benzyl alcohol, add the diluted tocopherol to the paste prepared in step 5, stir evenly to prepare a cream with a lidocaine concentration of 4%, and fill it after cooling to room temperature.

[0124] The lidocaine creams obtained in Examples 1-7 and Comparative Examples 1-2 were placed at 25°C for 24 months to examine the change in particle size. The lidocaine content in Examples 1-7, Comparative Examples 1 and 2 was examined at 25°C for 6 months, as shown in Table 1.

[0125] Table 1 Particle size of lidocaine cream

[0126]

[0127]

[0128] Conclusion: The lidocaine cream prepared by the method of the present invention, when sheared by a high shear disperser, has a particle size value compared with that of comparative examples 1 and 2, and the values ​​of Examples 1 to 7 are better than those of comparative examples 1 and 2, indicating that the particle size of the lidocaine cream prepared by the present invention has a small change range after being placed for 24 months, and has higher stability. 50 and D 90 The smaller the particle size, the more stable the emulsion.

[0129] The present invention adopts liquid chromatography to measure the content of lidocaine cream, specifically:

[0130] (1) Prepare solution A: Dissolve 2.73 g potassium dihydrogen phosphate in 630 mL water, adjust the pH to 7.20 ± 0.02, and dilute to 1 L with acetonitrile.

[0131] Prepare solution B: Dissolve 2.73 g potassium dihydrogen phosphate in 900 mL water, adjust pH to 7.20 ± 0.02, and dilute to 1 L with acetonitrile.

[0132] Prepare reference solution: Accurately weigh USP lidocaine reference and dilute quantitatively with solution A to make a 0.2 mg / mL solution.

[0133] Prepare the test solution: Take the cream containing 20 mg of lidocaine in Example 1, Comparative Example 1 and Comparative Example 2 respectively, disperse the cream and mix well, add 5 mL of 5N hydrochloric acid and dilute with solution A, shake well. After filtering, discard the initial filtrate and use the subsequent filtrate.

[0134] (2) In a liquid chromatograph, solution A and solution B are used for gradient elution, and the filtered and degassed solution A and solution B are used as mobile phases. 50 μL of the reference solution and 50 μL of the test solution (50 μL each of Example 1, Comparative Examples 1 and 2) are respectively injected into the liquid chromatograph, the chromatogram is recorded, and the lidocaine peak response is measured. The labeled content of lidocaine in the cream is calculated according to the following formula:

[0135] 100C(rU / rS)(V / W)(100 / L)

[0136] Wherein, C is the concentration of USP lidocaine reference in the reference solution (mg / mL), rU and rS are the peak responses of lidocaine in the test solution and the reference solution, respectively; V is the dilution volume of the test solution (mL); W is the amount of cream weighed when the test solution is prepared (mg); and L is the labeled amount of lidocaine (%).

[0137] According to the quality standard of lidocaine cream formulated by our company, its content range should be 90-110%. After the finished products prepared in comparative examples 1 and 2 were placed for 6 months, the content was greater than 110%, which exceeded the standard range. When the lidocaine cream formula was adjusted by introducing two high shear disperser shearing conditions, the lidocaine content in the cream was within the standard range after being placed for 6 months. It can be seen that the lidocaine cream prepared by the present invention has higher stability after being placed for 6 months.

[0138] The lidocaine creams obtained in Examples 1-7 and Comparative Examples 1-2 were placed at 25° C. for 24 months to examine centrifugal stability and appearance changes, as shown in Table 2.

[0139] Table 2 Centrifugal stability and appearance changes of lidocaine cream

[0140]

[0141]

[0142]

[0143] Conclusion: The lidocaine cream prepared by the method of the present invention has no stratification phenomenon, fine texture and glossy texture, and no stratification is observed under centrifugation at 5000 rpm for 30 min. The product has excellent stability and good quality.

Claims

1. A lidocaine cream, characterized in that: It comprises a main drug solution, an oil phase component, an aqueous phase component, a preservative and an antioxidant; the lidocaine cream does not contain a pH regulator; The main drug solution is lidocaine and a solvent; the oil phase components are an oil phase and a surfactant; and the water phase components are a water phase, an emulsifier, a dispersant and a thickener.

2. The lidocaine cream according to claim 1, characterized in that: The solvent includes one or more of ethanol, 1,3-butanediol, and diethylene glycol monobutyl ether; The oil phase includes cholesterol and medium chain triglycerides; the surfactant includes one or more of soybean lecithin, hydrogenated soybean lecithin, and hydrogenated palm oil glyceride; The aqueous phase includes purified water; the emulsifier includes one of polysorbate 80, polysorbate 60, and polysorbate 20; the dispersant is ethanol; the thickener includes one of carbomer 980P, carbomer 974P, and carbomer 940P; The preservative includes one or more of benzyl alcohol, benzoic acid, and potassium sorbate; The antioxidant includes one or more of tocopherol and butylated hydroxyanisole.

3. The lidocaine cream according to any one of claims 1 to 2, characterized in that The weight content of each component of the lidocaine cream is: in the main drug solution, lidocaine 6.2-10.4 parts, solvent 6.5-26.5 parts; The oil phase components include 4.6-30 parts of oil phase and 1-2 parts of surfactant; The aqueous phase components include 130-150 parts of aqueous phase, 0.4-24 parts of emulsifier, 3.5-13.5 parts of dispersant, and 0.8-2 parts of thickener; 1-2 parts of the preservative; The antioxidant is 0.02-0.1 part.

4. The lidocaine cream according to claim 1-2, characterized in that: The mass concentration of lidocaine is 1.5-6.6%, preferably 4%.

5. The lidocaine cream according to claim 1-2, characterized in that: The ratio of the preservative to the antioxidant is 20-50:

1.

6. The lidocaine cream according to claim 3, characterized in that: The weight content of each component of the lidocaine cream is as follows: 8 parts of lidocaine and 24 parts of ethanol in the main drug solution; The oil phase ingredients include 2 parts of cholesterol, 2 parts of soybean lecithin, and 12 parts of medium-chain triglycerides; The aqueous phase comprises 140 parts of purified water, 1.3 parts of polysorbate 80, 7 parts of ethanol, and 1.6 parts of carbomer 980P; 2 parts of benzyl alcohol; The tocopherol is 0.1 part.

7. A method for preparing the lidocaine cream according to any one of claims 1 to 6, characterized in that: The preparation method comprises: Preparation of the main drug solution: mixing lidocaine with a solvent, and heating and dissolving to form a main drug solution; Preparation of the oil phase component: heating and melting the oil phase and the surfactant to form the oil phase component; Preparation of water phase components: mixing thickener, emulsifier, dispersant and water phase, stirring and swelling, shearing with a high shear disperser, heating and dissolving, and then keeping warm to prepare water phase components; Preparation of colostrum: slowly add the oil phase component to the water phase component and keep it warm, and use a high shear disperser to disperse it to obtain colostrum; The main drug solution is dripped into the colostrum to obtain a paste containing the main drug with a pH value of 8.7-9.7; Finally, preservatives and antioxidants are added into the paste containing the main drug to prepare a cream.

8. The method for preparing lidocaine cream according to claim 7, characterized in that: The heating and / or insulation temperature is 75-85°C, preferably 80°C.

9. The method for preparing lidocaine cream according to claim 7, characterized in that: In the preparation of the aqueous phase component, the stirring and swelling speed is 200-600 rpm, preferably 400 rpm; the stirring time is 8-12 min, preferably 10 min; the shearing time of the high shear disperser is 5-15 min, preferably 10 min; the speed of the high shear disperser is 8000-12000 rpm, preferably 10000 rpm; In the colostrum preparation, the shearing time of the high shear disperser is 1-5 min, preferably 2 min; the rotation speed of the high shear disperser is 3000-6000 rpm, preferably 5000 rpm.

10. The method for preparing lidocaine cream according to claim 7, characterized in that: The pH value was controlled at 9.2.

Images