Liridicaine stable cream and preparation method thereof

Abstract

The invention provides a lidocaine stable cream, which relates to the field of pharmacy, and comprises lidocaine, prilocaine, sodium hyaluronate, cholesterol-PEG-biotin, butylated hydroxyanisole, an emulsifier, a humectant, a thickener, a preservative, an oil phase solvent, purified water and a pH regulator. The cream can solve the problems of poor drug permeation effect, large skin irritation, poor long-term storage stability and the like of the existing riptacaine cream; meanwhile, the prepared emulsifiable paste is high in stability and safety, stable in quality and high in permeability, can be uniformly and slowly released, and can prolong the anesthesia time and reduce the use amount of the emulsifiable paste on the premise of quickly exerting the drug effect, so that the anesthesia effect of the emulsifiable paste and the use comfort and stability of a patient are effectively improved.

Description

Technical Field

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

[0002] Liprocaine cream is a local anesthetic, the main ingredients of which include lidocaine and prilocaine. It was first developed and marketed by the Swedish company Astra in the 1980s (trade name EmLA, Enna); clinically, liprocaine cream is often used for anesthesia on the skin surface, such as: superficial anesthesia, puncture operation, laser treatment, etc. before use to relieve the patient's pain. At present, there are many schemes for improving liprocaine cream on the market, such as: Chinese patent document CN101209250A, a compound lidocaine cream preparation, Chinese patent document CN101816642A, a compound lidocaine cream and its preparation method, Chinese patent document CN106806338A, a compound lidocaine cream pharmaceutical composition and its preparation method. Although the above-mentioned improved methods have solved the defects of traditional liprocaine cream to a certain extent, they still have the following shortcomings: 1. The existing Some reprabicaine creams have poor penetration effects, resulting in a long time for the anesthesia to take effect or incomplete anesthesia effects, which in turn affects the smooth progress of subsequent surgeries or operations; second, long-term or large-area use can cause potential adverse reactions such as dry skin, itching, erythema, etc., which make it difficult for patients to tolerate and affect their comfort and acceptance of treatment; third, the existing reprabicaine creams have instability problems such as oxidative degradation or hydrolysis during long-term storage and placement, and are prone to cream stratification problems, affecting the overall use effect of the cream and product quality. Summary of the invention

[0003] In view of the problems existing in the above prior art, the object of the present invention is to provide a stable leprocaine cream, which can solve the problems of poor drug penetration, severe skin irritation, poor long-term storage stability, etc. of the existing leprocaine cream, and effectively improve the anesthetic effect of the cream, patient comfort and storage stability.

[0004] Another object of the present invention is to provide a method for preparing the above-mentioned levocaine stable cream.

[0005] The purpose of the present invention is achieved through the following technical solutions: A prilocaine stable cream comprises, by mass percentage, 2% to 5% of lidocaine, 2% to 5% of prilocaine, 0.1% to 1% of sodium hyaluronate, 0.2% to 0.6% of cholesterol-PEG-biotin, 0.3% to 0.6% of butylated hydroxyanisole, 3% to 8% of an emulsifier, 5% to 15% of a moisturizer, 0.5% to 2% of a thickener, 0.1% to 0.5% of a preservative, 20% to 30% of an oil phase solvent, 44% to 60% of purified water, and an appropriate amount of a pH regulator.

[0006] Based on the further improvement of the above scheme, the ingredients of the prilocaine stable cream are optimized as follows: 3% to 4% lidocaine, 3% to 4% prilocaine, 0.3% to 0.7% sodium hyaluronate, 0.2% to 0.6% cholesterol-PEG-biotin, 0.3% to 0.6% butylated hydroxyanisole, 4% to 6% emulsifier, 8% to 12% moisturizer, 1% to 1.5% thickener, 0.2% to 0.3% preservative, 20% to 30% oil phase solvent, 44% to 60% purified water, and an appropriate amount of pH adjuster.

[0007] Based on further optimization of the above scheme, the dosage of the pH regulator is: to ensure that the pH value of the mixed solution during the preparation of the aqueous phase is 8.0-9.5.

[0008] Based on further optimization of the above scheme, the molecular weight of PEG in the cholesterol-PEG-biotin is 1500, that is, cholesterol-PEG1500-biotin is used.

[0009] Based on further optimization of the above scheme, the emulsifier is a mixture of polyoxyethylene (23) lauryl alcohol ether and polysorbate 80 (Tween 80) or poloxamer 188, and the mass ratio of polyoxyethylene (23) lauryl alcohol ether to polysorbate 80 (Tween 80) or poloxamer 188 is 1:2-4.

[0010] Based on further optimization of the above scheme, the moisturizing agent is one or more of glycerol, propylene glycol, and butylene glycol.

[0011] Based on further optimization of the above scheme, the thickener is one or more of carbomer, hydroxypropyl methylcellulose, and sodium carboxymethyl cellulose.

[0012] Based on further optimization of the above scheme, the preservative is one or more of methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, and sodium benzoate.

[0013] Based on further optimization of the above scheme, the pH regulator is any one of triethanolamine and sodium hydroxide.

[0014] Based on further optimization of the above scheme, the oil phase solvent is either paraffin or vegetable oil.

[0015] The preparation method of the above-mentioned levocaine stable cream comprises: Step S1, preparation of oil phase: weighing the amounts of each component of the emulsifier, the thickener and the oil phase solvent in sequence according to the prescription, and adding each component of the emulsifier and the thickener to the oil phase solvent in sequence, heating and stirring evenly until all are dissolved, to obtain the oil phase for standby use; Step S2, preparation of aqueous phase: cholesterol-PEG1500-biotin, butylated hydroxyanisole, moisturizer, preservative and purified water are weighed in sequence according to the prescription; butylated hydroxyanisole is first added to the moisturizer, and the mixture is stirred evenly; then, the moisturizer mixed with butylated hydroxyanisole, cholesterol-PEG1500-biotin and preservative are sequentially added to the purified water, heated and stirred evenly until completely dissolved; finally, a pH adjuster is slowly added dropwise so that the pH value of the mixed solution after dissolution is 8.0-9.5, and an aqueous phase is obtained for standby use; Step S3, emulsification: slowly adding the water phase obtained in step S2 to the oil phase obtained in step S1 under stirring conditions, and continuously stirring for 20 min to 30 min to obtain colostrum; Step S4, adding drugs: weighing lidocaine and prilocaine according to the prescription, adding the lidocaine and prilocaine to the colostrum, stirring evenly, to obtain a mixture; Step S5, homogenization: the mixture obtained in step S4 is homogenized by a high-pressure homogenizer to obtain a stable cream.

[0016] Based on further optimization of the above scheme, the target temperature of heating in step S1 and step S2 is 70°C to 80°C.

[0017] Based on further optimization of the above scheme, the homogenization pressure is 20MPa to 30MPa, and the homogenization times are 2 to 3 times.

[0018] Based on further optimization of the above scheme, after step S5, filling is further performed, specifically: after the cream prepared in step S5 is cooled to room temperature, the quality of the cream is tested, and then aseptic filling is performed.

[0019] The following are the effects of the technical solution of the present invention: The present invention organically combines sodium hyaluronate with cholesterol-PEG1500-biotin, utilizes the penetration-promoting property of sodium hyaluronate and the skin affinity of cholesterol-PEG1500-biotin, and can effectively promote lidocaine and prilocaine to penetrate the stratum corneum of the skin, thereby shortening the anesthetic onset time and improving the anesthetic effect; at the same time, the moisturizing film formed on the skin surface by utilizing the moisturizing property of sodium hyaluronate and the sustained-release controlled-release property, uniform dispersibility and specific binding ability of cholesterol-PEG1500-biotin can not only effectively prevent the skin from experiencing adverse reactions such as dryness and irritation due to water loss, but also enhance the directional action force of the cream, so that the drug (i.e., lidocaine and prilocaine) maintains a relatively stable concentration in the skin, further avoids the occurrence of adverse reactions such as dryness, itching, erythema and the like due to excessive instantaneous concentration of the drug, prolongs the local action time of the drug on the skin, and enhances the drug effect. That is, through the organic combination of sodium hyaluronate and cholesterol-PEG1500-biotin, the cream prepared with lidocaine and prilocaine can be slowly released, quickly penetrated, and precisely acted on the skin, which not only shortens the onset time of anesthesia and improves the anesthetic effect, but also ensures the long-term effect of anesthesia, reduces the instantaneous concentration, and improves the comfort of patients.

[0020] In addition, the present invention not only effectively reduces the surface tension of the oil-water interface and improves the dispersion uniformity during the mixing of the water phase and the oil phase through the combination of cholesterol-PEG1500-biotin, butylated hydroxyanisole, and polyoxyethylene (23) lauryl alcohol ether, polysorbate 80 or poloxamer 188, but also improves the compatibility between the components, ensuring that the final cream has antioxidant properties, long-term stability and other characteristics, avoiding precipitation, deterioration, stratification and other problems caused by interaction of the components or the influence of the external environment, thereby ensuring the overall stability of the cream and facilitating long-term storage.

[0021] The preparation method of the invention is simple to operate, easy to industrialize and produce, can effectively reduce the production cost of the leprocaine cream, and has a wide range of applications. DETAILED DESCRIPTION

[0022] In order to make the purpose, technical solutions and advantages of the present invention clearer, the technical solutions of the present invention will be clearly described in the form of embodiments below; it should be clear that the following content is only an exemplary description of the scope of protection required by the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, and they should also fall within the scope of protection required by the present invention.

[0023] Embodiment 1: A prilocaine stable cream comprises, by mass percentage, 3% lidocaine, 3% prilocaine, 0.3% sodium hyaluronate, 0.2% cholesterol-PEG1500-biotin, 0.3% butylated hydroxyanisole, 4% emulsifier, 8% glycerol, 1% hydroxypropyl methylcellulose, 0.2% methyl paraben, 20% paraffin, 55% purified water, and an appropriate amount of triethanolamine, wherein the amount of triethanolamine is: to ensure that the pH value of the mixed solution during the preparation of the aqueous phase is 9.5. The emulsifier is a mixture of polyoxyethylene (23) lauryl alcohol ether and polysorbate 80 (Tween 80), and the mass ratio of them is 1:2.

[0024] A method for preparing a levocaine stable cream comprises: Step S1, preparation of oil phase: according to the prescription, the amounts of polyoxyethylene (23) lauryl alcohol ether and polysorbate 80 (Tween 80), the amount of hydroxypropyl methylcellulose and the amount of paraffin are weighed in sequence, and polyoxyethylene (23) lauryl alcohol ether, polysorbate 80 (Tween 80) and hydroxypropyl methylcellulose are added to the paraffin in sequence, heated to 70° C., and stirred evenly (the stirring speed can be 30 to 60 r / min, which can be selected according to the actual situation) until all are dissolved, to obtain the oil phase for standby use; Step S2, preparation of aqueous phase: cholesterol-PEG1500-biotin, butylated hydroxyanisole, glycerol, methyl parahydroxytoluate and purified water are weighed in sequence according to the prescription; butylated hydroxyanisole is first added to glycerol, and the mixture is stirred evenly (the stirring speed can be 30 to 60 r / min, which can be selected according to the actual situation), then glycerol, cholesterol-PEG1500-biotin and methyl parahydroxytoluate mixed with butylated hydroxyanisole are sequentially added to purified water, heated to 70° C., and stirred evenly (the stirring speed can be 30 to 60 r / min, which can be selected according to the actual situation) until completely dissolved, and finally, triethanolamine is slowly added dropwise so that the pH value of the mixed solution after dissolution is 9.5, to obtain an aqueous phase for standby use; Step S3, emulsification: under stirring conditions (the stirring speed can be 1200-2000 r / min, which can be selected according to actual conditions), slowly add the water phase obtained in step S2 to the oil phase obtained in step S1, and continue stirring for 20 minutes (the stirring speed can be 1200-2000 r / min, which can be selected according to actual conditions) to obtain colostrum; Step S4, adding drugs: weigh lidocaine and prilocaine according to the prescription, add lidocaine and prilocaine into the colostrum, and stir evenly (the stirring speed can be 1000-2000 r / min, which can be selected according to the actual situation) to obtain a mixture; Step S5, homogenization: homogenize the mixture obtained in step S4 by a high-pressure homogenizer at a pressure of 20 MPa and a homogenization frequency of 2 times to obtain a stable cream; Step S6, filling: After the cream prepared in step S5 is cooled to room temperature, the quality of the cream is tested and then aseptic filling is performed.

[0025] Embodiment 2: A prilocaine stable cream comprises, by mass percentage, 3.5% lidocaine, 3.5% prilocaine, 0.5% sodium hyaluronate, 0.4% cholesterol-PEG1500-biotin, 0.4% butylated hydroxyanisole, 5% emulsifier, 10% propylene glycol, 1.2% carbomer, 0.2% ethyl paraben, 23% vegetable oil, 49% purified water; an appropriate amount of sodium hydroxide, the amount of sodium hydroxide used is: to ensure that the pH value of the mixed solution is 8.8 during the preparation of the aqueous phase. The emulsifier is a mixture of polyoxyethylene (23) lauryl alcohol ether and polysorbate 80 (Tween 80), and their mass ratio is 1:3.

[0026] A method for preparing a levocaine stable cream comprises: Step S1, preparation of oil phase: according to the prescription, the amounts of polyoxyethylene (23) lauryl alcohol ether and polysorbate 80 (Tween 80), the amount of carbomer and the amount of vegetable oil are weighed in sequence, and polyoxyethylene (23) lauryl alcohol ether, polysorbate 80 (Tween 80) and carbomer are added to the vegetable oil in sequence, heated to 75° C., and stirred evenly (the stirring speed can be 30 to 60 r / min, which can be selected according to the actual situation) until all are dissolved, to obtain the oil phase for standby use; Step S2, preparation of aqueous phase: cholesterol-PEG1500-biotin, butylated hydroxyanisole, propylene glycol, ethyl paraben and purified water are weighed in sequence according to the prescription; butylated hydroxyanisole is first added to propylene glycol, and the mixture is stirred evenly (the stirring speed can be 30 to 60 r / min, which can be selected according to the actual situation), then propylene glycol mixed with butylated hydroxyanisole, cholesterol-PEG1500-biotin and ethyl paraben are added to purified water in sequence, heated to 75° C., and stirred evenly (the stirring speed can be 30 to 60 r / min, which can be selected according to the actual situation), until completely dissolved, and finally, sodium hydroxide is slowly added dropwise so that the pH value of the mixed solution after dissolution is 8.8, to obtain an aqueous phase for standby use; Step S3, emulsification: under stirring conditions (the stirring speed can be 1200-2000 r / min, which can be selected according to actual conditions), slowly add the water phase obtained in step S2 to the oil phase obtained in step S1, and continue stirring for 25 minutes (the stirring speed can be 1200-2000 r / min, which can be selected according to actual conditions) to obtain colostrum; Step S4, adding drugs: weigh lidocaine and prilocaine according to the prescription, add lidocaine and prilocaine into the colostrum, and stir evenly (the stirring speed can be 1000-2000 r / min, which can be selected according to the actual situation) to obtain a mixture; Step S5, homogenization: homogenize the mixture obtained in step S4 by a high-pressure homogenizer at a pressure of 25 MPa and a homogenization frequency of 2 times to obtain a stable cream; Step S6, filling: After the cream prepared in step S5 is cooled to room temperature, the quality of the cream is tested and then aseptic filling is performed.

[0027] Embodiment 3: A prilocaine stable cream comprises, by mass percentage, 4% lidocaine, 4% prilocaine, 0.7% sodium hyaluronate, 0.6% cholesterol-PEG1500-biotin, 0.6% butylated hydroxyanisole, 6% emulsifier, 12% butylene glycol, 1.5% sodium carboxymethylcellulose, 0.3% sodium benzoate, 25% paraffin, 44% purified water, and an appropriate amount of triethanolamine, wherein the amount of triethanolamine is such that the pH value of the mixed solution is 8.0 during the preparation of the aqueous phase. The emulsifier is a mixture of polyoxyethylene (23) lauryl alcohol ether and poloxamer 188, and the mass ratio of the two is 1:4.

[0028] A method for preparing a levocaine stable cream comprises: Step S1, preparation of oil phase: according to the prescription, the amounts of polyoxyethylene (23) lauryl alcohol ether and poloxamer 188, the amount of sodium carboxymethyl cellulose and the amount of paraffin are weighed in sequence, and polyoxyethylene (23) lauryl alcohol ether, poloxamer 188 and sodium carboxymethyl cellulose are added to the paraffin in sequence, heated to 80° C., and stirred evenly (the stirring speed can be 30 to 60 r / min, which can be selected according to the actual situation) until all are dissolved, to obtain the oil phase for standby use; Step S2, preparation of aqueous phase: cholesterol-PEG1500-biotin, butylated hydroxyanisole, butylene glycol, sodium benzoate and purified water are weighed in sequence according to the prescription; butylated hydroxyanisole is first added to butylene glycol, and the mixture is stirred evenly (the stirring speed can be 30 to 60 r / min, which can be selected according to the actual situation), then butylene glycol mixed with butylated hydroxyanisole, cholesterol-PEG1500-biotin and sodium benzoate are added to purified water in sequence, heated to 80° C., and stirred evenly (the stirring speed can be 30 to 60 r / min, which can be selected according to the actual situation) until completely dissolved, and finally, triethanolamine is slowly added dropwise so that the pH value of the mixed solution after dissolution is 8.0, to obtain an aqueous phase for standby use; Step S3, emulsification: under stirring conditions (the stirring speed can be 1200-2000 r / min, which can be selected according to actual conditions), slowly add the water phase obtained in step S2 to the oil phase obtained in step S1, and continue stirring for 30 minutes (the stirring speed can be 1200-2000 r / min, which can be selected according to actual conditions) to obtain colostrum; Step S4, adding drugs: weigh lidocaine and prilocaine according to the prescription, add lidocaine and prilocaine into the colostrum, and stir evenly (the stirring speed can be 1000-2000 r / min, which can be selected according to the actual situation) to obtain a mixture; Step S5, homogenization: homogenize the mixture obtained in step S4 by a high-pressure homogenizer at a pressure of 30 MPa and a homogenization frequency of 3 times to obtain a stable cream; Step S6, filling: After the cream prepared in step S5 is cooled to room temperature, the quality of the cream is tested and then aseptic filling is performed.

[0029] Comparative Example 1: A prilocaine cream comprises, by mass percentage, 3.5% lidocaine, 3.5% prilocaine, 0.5% sodium hyaluronate, 0.4% cholesterol-PEG600-biotin, 0.4% butylated hydroxyanisole, 5% emulsifier, 10% propylene glycol, 1.2% carbomer, 0.2% ethyl paraben, 23% vegetable oil, 49% purified water; an appropriate amount of sodium hydroxide, the amount of sodium hydroxide used is: to ensure that the pH value of the mixed solution is 8.8 during the preparation of the aqueous phase. The emulsifier is a mixture of polyoxyethylene (23) lauryl alcohol ether and polysorbate 80 (Tween 80), and their mass ratio is 1:3.

[0030] It can be prepared by the method described in Example 2.

[0031] Comparative Example 2: A prilocaine cream comprises, by mass percentage, 3.5% lidocaine, 3.5% prilocaine, 0.5% sodium hyaluronate, 0.4% cholesterol-PEG3000-biotin, 0.4% butylated hydroxyanisole, 5% emulsifier, 10% propylene glycol, 1.2% carbomer, 0.2% ethyl paraben, 23% vegetable oil, 49% purified water; an appropriate amount of sodium hydroxide, the amount of sodium hydroxide used is: to ensure that the pH value of the mixed solution is 8.8 during the preparation of the aqueous phase. The emulsifier is a mixture of polyoxyethylene (23) lauryl alcohol ether and polysorbate 80 (Tween 80), and their mass ratio is 1:3.

[0032] It can be prepared by the method described in Example 2.

[0033] Comparative Example 3: A prilocaine cream includes, by mass percentage, 3.5% lidocaine, 3.5% prilocaine, 0.5% sodium hyaluronate, 0.4% cholesterol-PEG1500-biotin, 0.4% butylated hydroxyanisole, 5% emulsifier, 10% propylene glycol, 1.2% carbomer, 0.2% ethyl paraben, 23% vegetable oil, 49% purified water, and an appropriate amount of sodium hydroxide, wherein the amount of sodium hydroxide is to ensure that the pH value of the mixed solution during the preparation of the aqueous phase is 8.8. The emulsifier is a mixture of polysorbate 80 (Tween 80) and poloxamer 188, and their mass ratio is 1:3.

[0034] It can be prepared by the method described in Example 2.

[0035] Comparative Example 4: A prilocaine cream includes, by mass percentage, 3.5% lidocaine, 3.5% prilocaine, 0.5% sodium hyaluronate, 0.4% cholesterol-PEG1500-biotin, 0.4% butylated hydroxyanisole, 5% emulsifier, 10% propylene glycol, 1.2% carbomer, 0.2% ethyl paraben, 23% vegetable oil, 49% purified water, and an appropriate amount of sodium hydroxide, wherein the amount of sodium hydroxide is to ensure that the pH value of the mixed solution during the preparation of the aqueous phase is 8.8. The emulsifier is a mixture of poloxamer 188 and polysorbate 80 (Tween 80), and their mass ratio is 1:3.

[0036] It can be prepared by the method described in Example 2.

[0037] Comparative Example 5: A prilocaine cream comprises, by mass percentage, 3.5% lidocaine, 3.5% prilocaine, 0.4% cholesterol-PEG1500-biotin, 0.4% butylated hydroxyanisole, 5% emulsifier, 10% propylene glycol, 1.2% carbomer, 0.2% ethyl paraben, 23% vegetable oil, 48.3% purified water, and an appropriate amount of sodium hydroxide, wherein the amount of sodium hydroxide is such that the pH value of the mixed solution is 8.8 during the preparation of the aqueous phase. The emulsifier is a mixture of polyoxyethylene (23) lauryl alcohol ether and polysorbate 80 (Tween 80), and the mass ratio of the two is 1:3.

[0038] It can be prepared by the method described in Example 2.

[0039] Comparative Example 6: A prilocaine cream comprises, by mass percentage, 3.5% lidocaine, 3.5% prilocaine, 0.5% sodium alginate, 0.4% cholesterol-PEG1500-biotin, 0.4% butylated hydroxyanisole, 5% emulsifier, 10% propylene glycol, 1.2% carbomer, 0.2% ethyl paraben, 23% vegetable oil, 49.5% purified water; an appropriate amount of sodium hydroxide, the amount of sodium hydroxide used is: to ensure that the pH value of the mixed solution is 8.8 during the preparation of the aqueous phase. The emulsifier is a mixture of polyoxyethylene (23) lauryl alcohol ether and polysorbate 80 (Tween 80), and their mass ratio is 1:3.

[0040] It can be prepared by the method described in Example 2.

[0041] Comparative Example 7: A prilocaine cream comprises, by mass percentage, 3.5% lidocaine, 3.5% prilocaine, 0.5% sodium hyaluronate, 0.4% cholesterol-PEG1500-biotin, 5% emulsifier, 10% propylene glycol, 1.2% carbomer, 0.2% ethyl paraben, 23% vegetable oil, 49% purified water, and an appropriate amount of sodium hydroxide, wherein the amount of sodium hydroxide is such that the pH value of the mixed solution is 8.8 during the preparation of the aqueous phase. The emulsifier is a mixture of polyoxyethylene (23) lauryl alcohol ether and polysorbate 80 (Tween 80), and the mass ratio of the two is 1:3.

[0042] It can be prepared by the method described in Example 2.

[0043] Comparative Example 8: A prilocaine cream comprises, by mass percentage, 3.5% lidocaine, 3.5% prilocaine, 0.6% sodium hyaluronate, 0.4% cholesterol-PEG1500-biotin, 0.45% butylated hydroxytoluene, 5.5% emulsifier, 10% propylene glycol, 1.2% carbomer, 0.3% ethyl paraben, 23% vegetable oil, 49% purified water; and an appropriate amount of sodium hydroxide, wherein the amount of sodium hydroxide is such that the pH value of the mixed solution is 8.8 during the preparation of the aqueous phase. The emulsifier is a mixture of polyoxyethylene (23) lauryl alcohol ether and polysorbate 80 (Tween 80), and the mass ratio of the two is 1:3.

[0044] It can be prepared by the method described in Example 2.

[0045] Performance Verification: The product appearance, coating conditions and placement status of the leprocaine creams obtained in Examples 1 to 3 and Comparative Examples 1 to 8 were compared, and the test results are shown in Table 1 below: Table 1

[0046] It can be clearly seen from Table 1 above that the leprocaine cream products prepared in the embodiments of the present invention (i.e., Embodiments 1 to 3) have excellent appearance, are easy to apply, and have good uniformity, and have no coating defects such as sandy feeling, sticky feeling, heavy feeling or sticky feeling. Under long-term storage conditions, the properties of the cream are highly stable, and it is not easy to have problems such as stratification and deterioration.

[0047] Franz diffusion cell was used, and three-dimensional mouse skin was used as a permeation barrier. The leprocaine cream prepared in Examples 1 to 3 and Comparative Examples 1 to 8 was applied to the skin surface, respectively. The receiving solution was a phosphate buffer solution with a pH of 7.4 and a diffusion area of ​​2.0 cm. 2 , the temperature was controlled at 37±0.5℃, stirring was continued, and the receiving solution was collected at 2h, 4h, 6h, 8h, 10h, and 12h, and an equal amount of fresh receiving solution was added. The contents of lidocaine and prilocaine in the receiving solution were determined by high performance liquid chromatography (Appendix VD of Part II of the 2010 edition of the Chinese Pharmacopoeia), and the cumulative penetration of the drugs was calculated. The specific results are shown in Table 2 below: Table 2

[0048] It can be clearly seen from Table 2 above that the cumulative permeation amounts of lidocaine and prilocaine of the leprocaine cream prepared in Example 2 of the present invention at each time point are significantly higher than those at the corresponding time points in Comparative Examples 1 to 8, indicating that the composite formula of the present invention can significantly improve the permeation effect of leprocaine.

[0049] 110 healthy adult guinea pigs were selected and randomly divided into 11 groups with 10 in each group (the guinea pigs in each group were numbered according to Example 1, Example 2, Example 3, Comparative Example 1, Comparative Example 2, Comparative Example 3, Comparative Example 4, Comparative Example 5, Comparative Example 6, Comparative Example 7, and Comparative Example 8, respectively); then, the hair on both sides of the spine of the back of the guinea pigs was removed, with an area of ​​about 3 cm×3 cm, and the corresponding leprocaine cream of Examples 1 to 3 and Comparative Examples 1 to 8 was applied to the corresponding guinea pig hair removal areas in each group, once a day for 7 consecutive days; the guinea pig skin reaction was measured every day, and the skin irritation reaction scoring standard in the Skin Irritation / Corrosion Test (GB15193.10-2014) was evaluated. The flat standard is shown in Table 3: Table 3

[0050] The experimental results of guinea pigs after 7 consecutive days of application are shown in Table 4 below: Table 4

[0051] It can be clearly seen from Table 4 above that the number of guinea pigs with irritation symptoms such as erythema on the skin in Comparative Examples 1 to 8 is significantly higher than that in Examples 1 to 3, and the average erythema scores of Comparative Examples 1 to 8 are also significantly higher than those of Examples 1 to 3, which proves that the prilocaine cream prepared in the embodiment of the present invention can effectively reduce the irritation of lidocaine, prilocaine and other substances to the skin, and has high safety.

Claims

1. A levocaine stable cream, characterized in that: Calculated by mass percentage, it includes 2% to 5% lidocaine, 2% to 5% prilocaine, 0.1% to 1% sodium hyaluronate, 0.2% to 0.6% cholesterol-PEG-biotin, 0.3% to 0.6% butylated hydroxyanisole, 3% to 8% emulsifier, 5% to 15% moisturizer, 0.5% to 2% thickener, 0.1% to 0.5% preservative, 20% to 30% oil phase solvent, 44% to 60% purified water, and an appropriate amount of pH adjuster.

2. A levulocaine stable cream according to claim 1, characterized in that: The components of the prilocaine stable cream are optimized as follows: 3% to 4% lidocaine, 3% to 4% prilocaine, 0.3% to 0.7% sodium hyaluronate, 0.2% to 0.6% cholesterol-PEG-biotin, 0.3% to 0.6% butylated hydroxyanisole, 4% to 6% emulsifier, 8% to 12% moisturizer, 1% to 1.5% thickener, 0.2% to 0.3% preservative, 20% to 30% oil phase solvent, 44% to 60% purified water, and an appropriate amount of pH regulator.

3. A levulocaine stable cream according to claim 1 or 2, characterized in that: The dosage of the pH regulator is: to ensure that the pH value of the mixed solution during the preparation of the aqueous phase is 8.0-9.

5.

4. A levulocaine stable cream according to claim 2 or 3, characterized in that: The molecular weight of PEG in the cholesterol-PEG-biotin is 1500, that is, cholesterol-PEG1500-biotin is used.

5. A levulocaine stable cream according to claim 4, characterized in that: The moisturizing agent is one or more of glycerin, propylene glycol and butylene glycol.

6. A levulocaine stable cream according to claim 4, characterized in that: The thickener is one or more of carbomer, hydroxypropyl methylcellulose and sodium carboxymethylcellulose.

7. A levulocaine stable cream according to claim 4, characterized in that: The preservative is one or more of methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate and sodium benzoate.

8. A levulocaine stable cream according to claim 4, characterized in that: The pH regulator is any one of triethanolamine and sodium hydroxide.

9. A levulocaine stable cream according to claim 4, characterized in that: The oil phase solvent is any one of paraffin or vegetable oil.

10. The method for preparing a stable levulocaine cream according to claim 4, characterized in that: include: Step S1, preparation of oil phase: weighing the amounts of each component of the emulsifier, the thickener and the oil phase solvent in sequence according to the prescription, and adding each component of the emulsifier and the thickener to the oil phase solvent in sequence, heating and stirring evenly until all are dissolved, to obtain the oil phase for standby use; Step S2, preparation of aqueous phase: cholesterol-PEG1500-biotin, butylated hydroxyanisole, moisturizer, preservative and purified water are weighed in sequence according to the prescription; butylated hydroxyanisole is first added to the moisturizer, and the mixture is stirred evenly; then, the moisturizer mixed with butylated hydroxyanisole, cholesterol-PEG1500-biotin and preservative are sequentially added to the purified water, heated and stirred evenly until completely dissolved; finally, a pH adjuster is slowly added dropwise so that the pH value of the mixed solution after dissolution is 8.0-9.5, and an aqueous phase is obtained for standby use; Step S3, emulsification: slowly adding the water phase obtained in step S2 to the oil phase obtained in step S1 under stirring conditions, and continuously stirring for 20 min to 30 min to obtain colostrum; Step S4, adding drugs: weighing lidocaine and prilocaine according to the prescription, adding the lidocaine and prilocaine to the colostrum, stirring evenly, to obtain a mixture; Step S5, homogenization: the mixture obtained in step S4 is homogenized by a high-pressure homogenizer to obtain a stable cream.

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