A kind of compound lidocaine cream and its preparation method and application

Abstract

The invention provides a compound lidocaine cream and a preparation method and application thereof, and relates to the technical field of pharmaceutical preparations. The compound lidocaine cream of the invention comprises components, by weight, including: 18-32.5 parts of lidocaine, 18-32.5 parts of prilocaine, 6-11 parts of isopropyl myristate, 7.3-13.5 parts of polyoxyethylene hydrogenated castor oil, 16-30 parts of carbomer 934, 5-12 parts of trehalose, 8-15 parts of vitamin E, 1-2 parts of dimethicone, 20-45 parts of oleic acid, 1.8-2.5 parts of sodium hydroxide, 6-15 parts of ethanol and 660-1140 parts of water; each component is reasonably matched, and the compound lidocaine cream prepared under a specific preparation method has high stability and safety, stable cream quality, fast drug release, high transdermal absorption capacity, high safety, and significant superficial anesthesia, prolonged penile erection time, and lubrication effects.

Description

Technical Field

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

[0002] Local anesthetics refer to drugs that can temporarily and reversibly block the generation and conduction of nerve fiber impulses within a limited range of the body without causing the patient to lose consciousness. Common local anesthetics are divided into amide and lipid anesthetics. Among them, compound lidocaine cream prepared from lidocaine and prilocaine is widely used in local anesthesia. The advantages of local anesthetics are: they have anesthesia and analgesia effects for some surgeries or pain that do not require whole-body exposure, and have few side effects. However, when local anesthetic drugs are applied to the skin, they are usually limited by the interaction between the main drug and the excipients, which affects the epidermal penetration and the effect of the drug.

[0003] Compound lidocaine cream is a compound cream preparation obtained by compounding lidocaine and prilocaine. It is a local anesthetic, originally developed and marketed by Swedish Astra Company (trade name EmLA). This drug is an effective surface anesthetic that can penetrate intact skin, which can solve the problem that existing anesthetics are difficult to penetrate the stratum corneum and epidermis of intact skin, and are not easy to enter the dermis where the nerve endings that sense pain are located to exert an analgesic effect.

[0004] In order to improve the transdermal penetration effect, the existing compound lidocaine cream often adds a penetrant such as Tween 80 in the formula. Chinese invention patent CN101209250A provides a compound lidocaine cream, whose auxiliary materials include carbomer 934, Tween 80, and azone, a penetration enhancer; the preparation steps include: preparing lidocaine prilocaine eutectic, swell carbomer 934 with purified water and stir evenly into a transparent colloid, adjust the pH to 8-10 with sodium hydroxide solution, add Tween 80 and stir evenly, then add the eutectic and azone, stir until emulsified evenly, and finally add water and stir until emulsified evenly. The mechanism of action of Tween 80 is to increase the subcutaneous penetration effect by destroying the epidermal tissue of the skin. When the cream is applied to the skin, it is easy to cause irritation to the skin.

[0005] Chinese invention patent CN106806338A provides a compound lidocaine cream pharmaceutical composition and a preparation method thereof, wherein the pharmaceutical composition is prepared from an effective amount of lidocaine and prilocaine as main drug raw materials, polyoxyethylene hydrogenated castor oil, carbomer, sodium hydroxide and purified water. The preparation method comprises the steps of: preparing a 0.5%-2% carbomer aqueous solution, stirring to obtain an aqueous phase; melting lidocaine and prilocaine at 40-50°C, then adding the melted polyoxyethylene hydrogenated castor oil, stirring to obtain an oil phase; adding water to the oil phase for stirring and emulsification, the emulsification time is not less than 12 minutes, and obtaining an emulsion; finally, adding the aqueous phase to the emulsion, stirring, and slowly adding a 5%-40% sodium hydroxide solution after the emulsion is hung on the wall.

[0006] The current preparation methods of compound lidocaine cream often have the following defects: long production cycle, high energy consumption and high cost required for temperature change; difficulty in process control causes product instability, and excessive impurities in the cream affect product quality and stability. In addition, compound lidocaine cream also has the problems of poor uniformity of preparation texture and poor lubricity in the application of drugs for prolonging sexual intercourse time.

[0007] Therefore, further research is needed on the raw and auxiliary materials and preparation process of the compound lidocaine cream to improve the safety and stability of the cream product; at the same time, the cream product should have good transdermal penetration effect, and the lubricity and superficial anesthetic effect during use should be improved through the interaction of the components. Summary of the invention

[0008] The present invention aims at the problems existing in the prior art and provides a compound lidocaine cream and a preparation method and application thereof. The compound lidocaine cream of the present invention reasonably combines lidocaine, prilocaine, isopropyl nutmeg, polyoxyethylene hydrogenated castor oil, carbomer, trehalose, vitamin E, dimethyl silicone oil, oleic acid, sodium hydroxide, ethanol and water. The prepared compound lidocaine cream has high stability and safety, stable cream quality, fast drug release and high transdermal absorption capacity, high safety, superficial anesthesia and the effect of prolonging penile erection time, and remarkable lubrication effect.

[0009] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0010] On the one hand, the present invention provides a compound lidocaine cream, which comprises the following components in parts by weight: 18-32.5 parts of lidocaine, 18-32.5 parts of prilocaine, 6-11 parts of isopropyl myristate, 7.3-13.5 parts of polyoxyethylene hydrogenated castor oil, 16-30 parts of carbomer 934, 5-12 parts of trehalose, 8-15 parts of vitamin E, 1-2 parts of dimethicone, 20-45 parts of oleic acid, 1.8-2.5 parts of sodium hydroxide, 6-15 parts of ethanol and 660-1140 parts of water;

[0011] The polyoxyethylene hydrogenated castor oil is selected from at least one of polyoxyethylene 100 hydrogenated castor oil and polyoxyethylene 200 hydrogenated castor oil.

[0012] Preferably, the compound lidocaine cream comprises the following components, measured in parts by weight: 23-28 parts of lidocaine, 23-28 parts of prilocaine, 7.2-10.5 parts of isopropyl myristate, 8-12 parts of polyoxyethylene hydrogenated castor oil, 18-25 parts of carbomer 934, 7-11 parts of trehalose, 10-13 parts of vitamin E, 1.2-1.8 parts of dimethicone, 30-40 parts of oleic acid, 2-2.3 parts of sodium hydroxide, 8-13 parts of ethanol and 800-905 parts of water.

[0013] Further preferably, the compound lidocaine cream comprises the following components, in parts by weight: 25 parts of lidocaine, 25 parts of prilocaine, 8 parts of isopropyl myristate, 10 parts of polyoxyethylene hydrogenated castor oil, 20 parts of carbomer 934, 8 parts of trehalose, 11 parts of vitamin E, 1.5 parts of dimethicone, 35 parts of oleic acid, 2.2 parts of sodium hydroxide, 10 parts of ethanol and 844.3 parts of water.

[0014] Preferably, the polyoxyethylene hydrogenated castor oil is a mixture of polyoxyethylene 100 hydrogenated castor oil and polyoxyethylene 200 hydrogenated castor oil, and the weight ratio of polyoxyethylene 100 hydrogenated castor oil to polyoxyethylene 200 hydrogenated castor oil is 2-6:1.

[0015] Further preferably, the weight ratio of the polyoxyethylene 100 hydrogenated castor oil to the polyoxyethylene 200 hydrogenated castor oil is 4:1.

[0016] Preferably, the weight ratio of isopropyl myristate, polyoxyethylene hydrogenated castor oil and carbomer 934 is 7.2-10.5:8-12:18-25; further preferably, the weight ratio of isopropyl myristate, polyoxyethylene hydrogenated castor oil and carbomer 934 is 8:10:20.

[0017] Preferably, the weight ratio of trehalose, vitamin E, dimethicone and oleic acid is 7-11:10-13:1.2-1.8:30-40; further preferably, the weight ratio of trehalose, vitamin E, dimethicone and oleic acid is 8:11:1.5:35.

[0018] On the other hand, the present invention provides a method for preparing the above-mentioned compound lidocaine cream, comprising the steps of:

[0019] (1) preparing an ethanol solution and a sodium hydroxide solution with water respectively for standby use; wherein the volume concentration of the ethanol solution is 3%-6%;

[0020] (2) Preparation of aqueous phase: Carbomer, trehalose and water are mixed, stirred until dissolved, and continued to be stirred and swollen at 50-65° C. to obtain an aqueous phase;

[0021] (3) Preparation of oil phase: polyoxyethylene hydrogenated castor oil, vitamin E, dimethyl silicone oil, oleic acid and the ethanol solution of step (1) are stirred and mixed, and then stirred and mixed with isopropyl myristate to obtain an oil phase;

[0022] (4) Preparation of a eutectic: After lidocaine and prilocaine are mixed, the mixture is heated to 50-65° C. under stirring to obtain a eutectic of lidocaine and prilocaine;

[0023] (5) mixing: adding the eutectic of lidocaine and prilocaine of step (4) to the oil phase of step (3) in batches under heat preservation conditions; and then mixing with the water phase of step (2) to obtain a mixture;

[0024] (6) Emulsification: stirring and scraping the mixture from step (5), emulsifying at a rotation speed of 2200-3400 r / min for 2-3 min, repeating the emulsification 3-5 times to obtain an emulsion;

[0025] (7) Add the sodium hydroxide solution of step (1) dropwise to the emulsion of step (6), and stir to obtain a compound lidocaine cream.

[0026] Preferably, in step (1), the mass concentration of the sodium hydroxide solution is 5%-8%; further preferably, the mass concentration of the sodium hydroxide solution is 6%.

[0027] Preferably, in step (1), the volume concentration of the ethanol solution is 4%-5%; further preferably, the volume concentration of the ethanol solution is 4%.

[0028] Preferably, in step (2), the stirring and swelling refers to swelling for 2-5 hours under stirring conditions of 40-60 r / min and a temperature of 50-60°C.

[0029] More preferably, the stirring and swelling refers to swelling for 3 hours under stirring conditions of 50 r / min and a temperature of 55°C.

[0030] Preferably, step (3) is carried out under stirring conditions at a rotation speed of 40-60 r / min.

[0031] Preferably, in step (4), the temperature is increased under stirring conditions, specifically: the stirring speed is 40-60 r / min, and the temperature is increased to 50-60°C.

[0032] More preferably, the temperature is increased under stirring conditions, specifically: the rotation speed is 50 r / min and the temperature is increased to 55° C.

[0033] Preferably, in step (5), under the insulation conditions, the insulation temperature is 50-65°C; further preferably, the insulation temperature is 50-60°C; further preferably, the insulation temperature is 55°C.

[0034] Preferably, step (5) is specifically as follows: under the condition of keeping warm at 50-65° C., adding the low eutectic of lidocaine and prilocaine in step (4) to the oil phase in step (3) in 3-6 portions, stirring while adding, to obtain a premix; then adding the premix to the water phase in step (2) in 3-6 portions, stirring while adding, to obtain a mixture; the stirring speed of step (5) is 40-60 r / min.

[0035] Further preferably, step (5) is specifically as follows: under the condition of keeping warm at 50-60° C., adding the low eutectic of lidocaine and prilocaine of step (4) into the oil phase of step (3) in four portions, stirring while adding, to obtain a premix; then adding the premix into the water phase of step (2) in four portions, stirring while adding, to obtain a mixture; the stirring speed of step (5) is 50 r / min.

[0036] Preferably, step (6) is specifically as follows: stirring the mixture of step (5) at a rotation speed of 40-60 r / min, scraping the wall for 5-10 min, and emulsifying at 2400-3000 r / min for 2-3 min; repeating the above emulsification step 2-4 times to obtain an emulsion.

[0037] Further preferably, step (6) is specifically as follows: stirring the mixture of step (5) at a rotation speed of 50 r / min, scraping the wall for 5-10 min, emulsifying at 2800 r / min for 2.5 min, repeating the above emulsification step 3 times to obtain an emulsion.

[0038] Preferably, step (7) is specifically as follows: dripping the sodium hydroxide solution of step (1) into the emulsion of step (6), dripping while stirring, the dripping time is controlled at 10-35 min, and the stirring speed is 40-60 r / min.

[0039] Further preferably, step (7) is specifically as follows: adding the sodium hydroxide solution of step (1) dropwise to the emulsion of step (6), adding dropwise while stirring, the adding time is controlled within 20-30 min, and the stirring speed is 50 r / min; further preferably, the adding time is controlled within 30 min.

[0040] Finally, the present invention provides the use of the compound lidocaine cream in preparing medicines for superficial anesthesia or treatment of premature ejaculation.

[0041] Compared with the prior art, the present invention has the following beneficial effects:

[0042] 1. The compound lidocaine cream of the present invention is obtained by using auxiliary materials with specific ingredients and proportions; wherein the polyoxyethylene hydrogenated castor oil is selected from at least one of polyoxyethylene 100 hydrogenated castor oil and polyoxyethylene 200 hydrogenated castor oil, so that the compound lidocaine cream has better coating performance, good skin feel when used, and high stability under accelerated test placement conditions; isopropyl myristate, polyoxyethylene hydrogenated castor oil and carbomer 934 cooperate with each other to improve the stability and uniformity of the cream, fast drug release and high transdermal penetration efficiency, improve the efficacy of superficial anesthesia, reduce the sensitivity of the glans penis through superficial anesthesia, prolong the ejaculation time, and is loved by men who need to prolong the erection time or patients with premature ejaculation; in addition, the trehalose, vitamin E, dimethyl silicone oil and oleic acid of the present invention produce a synergistic effect, so that the lubrication performance is significantly improved, the smoothness of both parties is improved, and the stimulation is reduced.

[0043] 2. In the compound lidocaine cream of the present invention, the use of ethanol solution further improves the uniformity of the compound lidocaine cream. The compound lidocaine cream has a low impurity content after long-term storage and good stability. It is non-irritating when acting on the skin, has no redness, swelling and sensitization risks, has high safety, and improves the quality of the cream.

[0044] 3. The present invention adopts a specific preparation method to prepare the compound lidocaine cream, and the preparation method is simple and controllable; the main drug is evenly dispersed in the auxiliary material matrix, the cream is evenly applied and easily absorbed, and the transdermal effect is significantly improved. DETAILED DESCRIPTION

[0045] The following non-limiting examples can enable those skilled in the art to more fully understand the present invention, but do not limit the present invention in any way. The following content is merely an exemplary description of the scope of the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, which should also fall within the scope of the present invention.

[0046] When the embodiments give numerical ranges, it should be understood that, unless otherwise specified in the present invention, both endpoints of each numerical range and any numerical value between the two endpoints can be selected. Unless otherwise defined, all technical and scientific terms used in the present invention have the same meanings as those generally understood by those of ordinary skill in the art to which the present invention belongs.

[0047] The present invention is further described below by way of specific examples. Unless otherwise specified, the various chemical reagents used in the examples of the present invention are obtained through conventional commercial channels.

[0048] In the following examples, the CAS number of lidocaine is 137-58-6; the CAS number of prilocaine is 721-50-6; the CAS number of isopropyl myristate is 110-27-0; and the CAS number of carbomer 934 is 9007-16-3.

[0049] For the above components, products from different manufacturers have no significant effect on the effects.

[0050] Example 1

[0051] A compound lidocaine cream consists of the following components in parts by weight: 25 parts of lidocaine, 25 parts of prilocaine, 8 parts of isopropyl myristate, 8 parts of polyoxyethylene 100 hydrogenated castor oil, 2 parts of polyoxyethylene 200 hydrogenated castor oil, 20 parts of carbomer 934, 8 parts of trehalose, 11 parts of vitamin E, 1.5 parts of dimethicone, 35 parts of oleic acid, 2.2 parts of sodium hydroxide, 10 parts of ethanol and 844.3 parts of water.

[0052] The preparation method of the compound lidocaine cream comprises the steps of:

[0053] (1) preparing an ethanol solution and a sodium hydroxide solution with water respectively for standby use; wherein the volume concentration of the ethanol solution is 4%, and the mass concentration of the sodium hydroxide solution is 6%;

[0054] (2) Preparation of aqueous phase: Carbomer, trehalose and water are mixed and stirred until dissolved, and then stirred and swollen at 50 rpm for 3 h at 55°C to obtain an aqueous phase;

[0055] (3) Preparation of oil phase: polyoxyethylene 100 hydrogenated castor oil, polyoxyethylene 200 hydrogenated castor oil, vitamin E, dimethyl silicone oil, oleic acid and the ethanol solution of step (1) were stirred and mixed at 50 r / min, and then stirred and mixed with isopropyl myristate at 50 r / min to obtain an oil phase;

[0056] (4) Preparation of a eutectic: After lidocaine and prilocaine are mixed, the mixture is heated to 55° C. under stirring at 50 rpm to obtain a eutectic of lidocaine and prilocaine;

[0057] (5) Mixing: under the condition of keeping warm at 55° C., the eutectic of lidocaine and prilocaine in step (4) is added into the oil phase in step (3) in 4 batches, stirring (50 r / min) while adding, to obtain a premix; then the premix is ​​added into the water phase in step (2) in 4 batches, stirring (50 r / min) while adding, to obtain a mixture; the time of step (5) is controlled within 25 min;

[0058] (6) Emulsification: The mixture of step (5) was stirred and scraped at a rotation speed of 50 r / min for 8 min, and then emulsified at 2800 r / min for 2.5 min;

[0059] Repeat the above emulsification step 3 times to obtain an emulsion;

[0060] (7) Add the sodium hydroxide solution of step (1) dropwise to the emulsion of step (6) while stirring, the dropping time is controlled within 30 min, and the stirring speed is 50 r / min, to obtain a compound lidocaine cream.

[0061] Example 2

[0062] A compound lidocaine cream consists of the following components in parts by weight: 23 parts of lidocaine, 23 parts of prilocaine, 7.2 parts of isopropyl myristate, 6.4 parts of polyoxyethylene 100 hydrogenated castor oil, 1.6 parts of polyoxyethylene 200 hydrogenated castor oil, 18 parts of carbomer 934, 7 parts of trehalose, 10 parts of vitamin E, 1.2 parts of dimethicone, 30 parts of oleic acid, 2 parts of sodium hydroxide, 8 parts of ethanol and 800 parts of water.

[0063] The preparation method of the compound lidocaine cream is the same as that of Example 1.

[0064] Example 3

[0065] A compound lidocaine cream consists of the following components in parts by weight: 28 parts of lidocaine, 28 parts of prilocaine, 10.5 parts of isopropyl myristate, 9.6 parts of polyoxyethylene 100 hydrogenated castor oil, 2.4 parts of polyoxyethylene 200 hydrogenated castor oil, 25 parts of carbomer 934, 11 parts of trehalose, 13 parts of vitamin E, 1.8 parts of dimethicone, 40 parts of oleic acid, 2.3 parts of sodium hydroxide, 13 parts of ethanol and 905 parts of water.

[0066] The preparation method of the compound lidocaine cream is the same as that of Example 1.

[0067] Example 4

[0068] A compound lidocaine cream consists of the following components in parts by weight: 18 parts of lidocaine, 18 parts of prilocaine, 6 parts of isopropyl myristate, 5.84 parts of polyoxyethylene 100 hydrogenated castor oil, 1.46 parts of polyoxyethylene 200 hydrogenated castor oil, 16 parts of carbomer 934, 5 parts of trehalose, 8 parts of vitamin E, 1 part of dimethicone, 20 parts of oleic acid, 1.8 parts of sodium hydroxide, 6 parts of ethanol and 660 parts of water.

[0069] The preparation method of the compound lidocaine cream is the same as that of Example 1.

[0070] Example 5

[0071] A compound lidocaine cream, comprising the following components by weight: 32.5 parts of lidocaine, 32.5 parts of prilocaine, 11 parts of isopropyl myristate, 10.8 parts of polyoxyethylene 100 hydrogenated castor oil, 2.7 parts of polyoxyethylene 200 hydrogenated castor oil, 30 parts of carbomer 934, 12 parts of trehalose, 15 parts of vitamin E, 2 parts of dimethicone, 45 parts of oleic acid, 2.5 parts of sodium hydroxide, 15 parts of

[0072] ethanol and 1140 parts of water.

[0073] The preparation method of the compound lidocaine cream is the same as that of Example 1.

[0074] Comparative Example 1

[0075] The difference from Example 1 is that polyoxyethylene 100 hydrogenated castor oil and polyoxyethylene 200 hydrogenated castor oil are replaced by polyoxyethylene 40 hydrogenated castor oil.

[0076] The compound lidocaine cream is composed of the following components, according to weight parts: 25 parts of lidocaine, 25 parts of prilocaine, 8 parts of isopropyl myristate, 10 parts of polyoxyethylene 40 hydrogenated castor oil, 20 parts of carbomer 934, 8 parts of trehalose, 11 parts of vitamin E, 1.5 parts of dimethicone, 35 parts of oleic acid, 2.2 parts of sodium hydroxide, 10 parts of ethanol and 844.3 parts of water.

[0077] Comparative Example 2

[0078] The difference from Example 1 is that trehalose is replaced by chitosan.

[0079] The rest are the same as in Example 1.

[0080] Comparative Example 3

[0081] The difference from Example 1 is that isopropyl myristate is replaced by peppermint oil.

[0082] The compound lidocaine cream is composed of the following components by weight: 25 parts of lidocaine, 25 parts of prilocaine, 8 parts of peppermint oil, 8 parts of polyoxyethylene 100 hydrogenated castor oil, 2 parts of polyoxyethylene 200 hydrogenated castor oil, 20 parts of carbomer 934, 8 parts of trehalose, 11 parts of vitamin E, 1.5 parts of dimethicone, 35 parts of oleic acid, 2.2 parts of sodium hydroxide, 10 parts of ethanol and 844.3 parts of water. The rest is the same as that of Example 1.

[0083] Comparative Example 4

[0084] The difference from Example 1 is that oleic acid is replaced by glycerol. The rest is the same as Example 1.

[0085] Comparative Example 5

[0086] The difference from Example 1 is that the proportions of the ingredients in the cream are different, specifically the weight ratios of isopropyl myristate, polyoxyethylene hydrogenated castor oil and carbomer 934 are different. The rest are the same as Example 1.

[0087] A compound lidocaine cream consists of the following components in parts by weight: 25 parts of lidocaine, 25 parts of prilocaine, 2 parts of isopropyl myristate, 25 parts of polyoxyethylene 100 hydrogenated castor oil, 5 parts of polyoxyethylene 200 hydrogenated castor oil, 6 parts of carbomer 934, 8 parts of trehalose, 11 parts of vitamin E, 1.5 parts of dimethicone, 35 parts of oleic acid, 2.2 parts of sodium hydroxide, 10 parts of ethanol and 844.3 parts of water.

[0088] Comparative Example 6

[0089] The difference from Example 1 is that the ingredients in the cream are different. Trehalose, vitamin E, dimethicone and oleic acid are not used, and the rest are the same as Example 1.

[0090] A compound lidocaine cream consists of the following components, measured by weight: 25 parts of lidocaine, 25 parts of prilocaine, 8 parts of peppermint oil, 8 parts of polyoxyethylene 100 hydrogenated castor oil, 2 parts of polyoxyethylene 200 hydrogenated castor oil, 20 parts of carbomer 934, 2.2 parts of sodium hydroxide, 10 parts of polyethylene glycol 400 and 844.3 parts of water.

[0091] Comparative Example 7

[0092] Different from Example 1, the compound lidocaine cream has different components, and dimethicone and vitamin E are not used;

[0093] A compound lidocaine cream consists of the following components in parts by weight: 25 parts of lidocaine, 25 parts of prilocaine, 8 parts of isopropyl myristate, 8 parts of polyoxyethylene 100 hydrogenated castor oil, 2 parts of polyoxyethylene 200 hydrogenated castor oil, 20 parts of carbomer 934, 8 parts of trehalose, 35 parts of oleic acid, 2.2 parts of sodium hydroxide, 10 parts of ethanol and 844.3 parts of water.

[0094] Comparative Example 8

[0095] Different from Example 1, the components of the compound lidocaine cream are different, and trehalose and oleic acid are not used;

[0096] A compound lidocaine cream consists of the following components in parts by weight: 25 parts of lidocaine, 25 parts of prilocaine, 8 parts of isopropyl myristate, 8 parts of polyoxyethylene 100 hydrogenated castor oil, 2 parts of polyoxyethylene 200 hydrogenated castor oil, 20 parts of carbomer 934, 11 parts of vitamin E, 1.5 parts of dimethicone, 2.2 parts of sodium hydroxide, 10 parts of ethanol and 844.3 parts of water.

[0097] Comparative Example 9

[0098] The difference from Example 1 is that the preparation method of the compound lidocaine cream is different, specifically, the volume concentration of the ethanol solution in step (1) is different; this comparative example does not prepare the ethanol solution.

[0099] (1) Prepare a sodium hydroxide solution with a mass concentration of 6% using water;

[0100] (2) Preparation of aqueous phase: Carbomer, trehalose and water are mixed and stirred until dissolved, and then stirred and swollen at 50 rpm for 3 h at 55°C to obtain an aqueous phase;

[0101] (3) Preparation of oil phase: Polyoxyethylene 100 hydrogenated castor oil, polyoxyethylene 200 hydrogenated castor oil, vitamin E, dimethicone, oleic acid and ethanol were stirred and mixed at 50 r / min, and then stirred and mixed with isopropyl myristate at 50 r / min to obtain an oil phase;

[0102] (4)-(7) are the same as in Example 1.

[0103] Test 1: Comparison of cream performance

[0104] The compound lidocaine creams prepared in Examples 1 to 5 and Comparative Examples 1 to 9 were compared in terms of product appearance and coating uniformity.

[0105] The performance comparison results are shown in Table 1.

[0106] Table 1

[0107] Characteristics Coating situation Example 1-Example 5 White cream, moist and suitable appearance Easy to apply, no sandy feeling, no heavy feeling Comparative Example 1 White cream, moist paste The coating is normal, no sand feeling Comparative Example 2 White cream, moist paste The coating is average, no sandy feeling, and has a heavy feeling Comparative Example 3 White cream, moist paste The coating is average, no sandy feeling, and has a heavy feeling Comparative Example 4 White cream, sticky and wet The coating is normal, no sandy feeling, with a heavy and sticky feeling Comparative Example 5 White cream, moist paste The coating is average, no sandy feeling, and has a heavy feeling Comparative Example 6 White cream, moist paste Easier to apply, no gritty feeling Comparative Example 7 White cream, dry paste Difficult to apply, feels sandy and heavy, and demulsification occurs Comparative Example 8 White cream, dry paste The coating is average, no sandy feeling, and has a heavy feeling Comparative Example 9 White cream, dry paste The coating is average, no sandy feeling, and has a heavy feeling

[0108] As can be seen from Table 1, the compound lidocaine cream prepared by the present invention has excellent product appearance, uniform properties, uniform coating, easy to spread, good skin feel, and no sandy or heavy feeling.

[0109] Experiment 2: Stability Study

[0110] The compound lidocaine cream prepared in Examples 1 to 5 and Comparative Examples 1 to 9 was placed under accelerated long-term test conditions (40±2°C, relative humidity 75%±5% for 6 months) to conduct an accelerated long-term stability test. The results of the related substances and the maximum unknown single impurity content after 6 months are shown in Table 2.

[0111] At the same time, the properties of the compound lidocaine cream were observed, and the test results of the properties of the compound lidocaine cream after 6 months of accelerated long-term stability test are shown in Table 2.

[0112] The properties meet the specified standards: uniform color, fine texture, no rancidity, discoloration, hardening, oil-water separation or stratification. Take an appropriate amount of cream, add mobile phase to dissolve, and make a solution containing 100μg of lidocaine and 100μg of prilocaine per milliliter as the test solution. After dilution, use high performance liquid chromatography (Appendix VD of Part II of the 2010 edition of the Chinese Pharmacopoeia) for determination. Use octadecylsilane bonded silica gel as the filler, acetonitrile: water: sodium dihydrogen phosphate: sodium dodecyl sulfate (300mL: 200mL: 1.7g: 0.85g) as the mobile phase, and the flow rate is 1mL / min.

[0113] Table 2

[0114]

[0115] As shown in Table 2, after the accelerated long-term stability test of the compound lidocaine cream of each embodiment was investigated for 6 months, the content of the related substance o-toluidine was between 0.10% and 0.13%, the maximum unknown single impurity was between 0.02% and 0.03%, and other known impurities were not detected. The compound lidocaine cream prepared by the present invention has low impurity content and high stability; after being placed in the accelerated long-term test for 6 months, the paste properties are still stable and meet the property specification standards.

[0116] Test 3: Lubrication performance test

[0117] The composite lidocaine creams prepared in Example 1, Comparative Example 2, Comparative Example 4, Comparative Example 6-Comparative Example 8 were tested for friction coefficient using condoms as coating carriers. The test results of the dynamic friction coefficient are shown in Table 3.

[0118] The detection method is GB 10006-88.

[0119] Table 3

[0120] Example 1 Comparative Example 2 Comparative Example 4 Comparative Example 6 Comparative Example 7 Comparative Example 8 Dynamic friction coefficient 0.0046 0.0073 0.0064 0.0137 0.0090 0.0122

[0121] As can be seen from Table 3, the average friction coefficient of the compound lidocaine cream of Example 1 is significantly lower than that of the comparative example, indicating that trehalose, vitamin E, dimethyl silicone oil and oleic acid work synergistically to significantly improve the lubrication performance. The compound lidocaine cream of the present invention has excellent lubrication performance; it can be used by men who need to prolong erection time or patients with premature ejaculation to significantly reduce the sensitivity of the glans penis and prolong the ejaculation time.

[0122] Test 4 Safety Evaluation

[0123] Test samples: compound lidocaine cream prepared in Examples 1 to 3, Comparative Example 1 and Comparative Example 9.

[0124] 48 SD rats were randomly divided into 8 groups. 24 hours before the test, the hair on both sides of the spine was shaved without damaging the epidermis. The hair removal range was 2 cm×2 cm on each side. 24 hours later, 3 groups of rats were subjected to skin scratching and damage, and were respectively recorded as the skin scratching group of Example 1, the skin scratching group of Comparative Example 1, and the skin scratching group of Comparative Example 9. The rest were respectively recorded as the blank group, the skin non-injury groups of Examples 1 to 3, and the skin non-injury group of Comparative Example 1.

[0125] Take 0.5g of the test sample and apply it directly on the skin, cover it with four layers of gauze (2.5cm×2.5cm) and one layer of cellophane, and then fix it with non-irritating adhesive tape and bandage. Use a closed test with a 4h application time. After the test, remove the remaining test sample with warm water. Observe for 7 days. Perform irritation scores at 1h, 24h, 48h and 72h after removing the test sample.

[0126] The skin reaction scoring criteria are shown in Table 4.

[0127] Table 4

[0128]

[0129]

[0130] The skin irritation intensity classification standard is shown in Table 5.

[0131] Table 5

[0132] Integral mean (the highest integral mean at the observation point) Strength classification 0-0.5 (excluding 0.5) Non-irritating 0.5-2.0 (excluding 2.0) Mild irritant 2.0-6.0 (excluding 6.0) Moderate irritation ≥6.0 Strong irritation

[0133] The results of the skin irritation test on rats in each group are shown in Table 6.

[0134] Table 6

[0135] Number of rats Erythema and eschar Edema Total score Mean Blank group 6 0 0 0 0 Example 1 Skin scratch group 6 0 1 1 0.17 Example 1 Skin No Damage Group 6 0 0 0 0 Example 2 Skin No Damage Group 6 0 0 0 0 Example 3 Skin No Damage Group 6 0 0 0 0 Comparative Example 1 Skin scratch group 6 24 20 44 7.33 Comparative Example 1: Skin without damage group 6 10 8 18 3.00 Comparative Example 9 Skin Scratching Group 6 9 8 17 2.83

[0136] It can be seen from Table 6 that the compound lidocaine cream of the embodiment of the present invention has no irritation to intact skin and damaged skin and is highly safe.

[0137] Test 5: Transdermal Diffusion Test

[0138] 1. Test drug

[0139] The compound lidocaine cream prepared in Example 1, Comparative Example 1, Comparative Example 3 and Comparative Example 5.

[0140] 2. Experimental methods

[0141] The abdominal skin of 8-week-old rats was peeled off and the dermis side served as the receiving layer. pH 7.0 phosphate buffer was used as the transdermal medium. The sampling time points were 0 min, 30 min, 60 min, 90 min, 120 min, 180 min, 240 min, and 360 min. Other experimental conditions and detection methods were consistent with the in vitro release.

[0142] The Franz diffusion cell method was used: the injection hole diameter of the diffusion cell was 15 mm, the medium temperature was 32°C ± 0.5°C, the medium volume was 12 mL, and the sample amount was 300 mg of cream.

[0143] The permeation amount of each drug (lidocaine, prilocaine) was measured and the drug release properties were compared. The cumulative permeation amount test results are shown in Table 7.

[0144] Table 7

[0145]

[0146] As can be seen from Table 7, the compound lidocaine cream prepared in the embodiment of the present invention has various auxiliary materials that cooperate with each other to promote the penetration of the active ingredients of the medicine into the skin, increase the permeation amount of the active ingredients of the medicine, and has a significant permeation promoting effect, thereby having a rapid and high superficial anesthetic effect.

[0147] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A compound lidocaine cream, characterized in that: The composition comprises the following components in parts by weight: 18-32.5 parts of lidocaine, 18-32.5 parts of prilocaine, 6-11 parts of isopropyl myristate, 7.3-13.5 parts of polyoxyethylene hydrogenated castor oil, 16-30 parts of carbomer 934, 5-12 parts of trehalose, 8-15 parts of vitamin E, 1-2 parts of dimethicone, 20-45 parts of oleic acid, 1.8-2.5 parts of sodium hydroxide, 6-15 parts of ethanol and 660-1140 parts of water; The polyoxyethylene hydrogenated castor oil is a mixture of polyoxyethylene 100 hydrogenated castor oil and polyoxyethylene 200 hydrogenated castor oil in a weight ratio of 2-6:

1.

2. The compound lidocaine cream according to claim 1, characterized in that The invention comprises the following components in parts by weight: 23-28 parts of lidocaine, 23-28 parts of prilocaine, 7.2-10.5 parts of isopropyl myristate, 8-12 parts of polyoxyethylene hydrogenated castor oil, 18-25 parts of carbomer 934, 7-11 parts of trehalose, 10-13 parts of vitamin E, 1.2-1.8 parts of dimethicone, 30-40 parts of oleic acid, 2-2.3 parts of sodium hydroxide, 8-13 parts of ethanol and 800-905 parts of water.

3. The compound lidocaine cream according to claim 2, characterized in that: The composition comprises the following components in parts by weight: 25 parts of lidocaine, 25 parts of prilocaine, 8 parts of isopropyl myristate, 10 parts of polyoxyethylene hydrogenated castor oil, 20 parts of carbomer 934, 8 parts of trehalose, 11 parts of vitamin E, 1.5 parts of dimethicone, 35 parts of oleic acid, 2.2 parts of sodium hydroxide, 10 parts of ethanol and 844.3 parts of water.

4. The compound lidocaine cream according to claim 1, characterized in that: The weight ratio of the isopropyl myristate, polyoxyethylene hydrogenated castor oil and carbomer 934 is 7.2-10.5:8-12:18-25.

5. The compound lidocaine cream according to claim 1, characterized in that: The weight ratio of trehalose, vitamin E, dimethicone and oleic acid is 7-11:10-13:1.2-1.8:30-40.

6. The method for preparing the compound lidocaine cream according to any one of claims 1 to 5, characterized in that: Includes steps: (1) Prepare ethanol solution and sodium hydroxide solution with water respectively and set aside; wherein the volume concentration of the ethanol solution is 3%-6%; (2) Preparation of aqueous phase: Carbomer, trehalose and water are mixed and stirred until dissolved, and the mixture is further stirred and swelled at 50-65°C to obtain an aqueous phase; (3) Preparation of oil phase: polyoxyethylene hydrogenated castor oil, vitamin E, dimethyl silicone oil, oleic acid and the ethanol solution of step (1) are stirred and mixed, and then stirred and mixed with isopropyl myristate to obtain an oil phase; (4) Preparation of a eutectic mixture: After lidocaine and prilocaine are mixed, the mixture is heated to 50-65° C. under stirring to obtain a eutectic mixture of lidocaine and prilocaine; (5) Mixing: adding the eutectic of lidocaine and prilocaine from step (4) to the oil phase from step (3) in batches under heat preservation conditions; and then mixing with the water phase from step (2) to obtain a mixture; (6) Emulsification: stirring and scraping the mixture from step (5), emulsifying at a rotation speed of 2200-3400 r / min for 2-3 min, repeating the emulsification 3-5 times to obtain an emulsion; (7) Add the sodium hydroxide solution of step (1) dropwise to the emulsion of step (6), and stir to obtain a compound lidocaine cream.

7. The preparation method according to claim 6, characterized in that: In step (1), the mass concentration of the sodium hydroxide solution is 5%-8%; the volume concentration of the ethanol solution is 4%-5%.

8. The preparation method according to claim 6, characterized in that: In step (2), the stirring and swelling refers to swelling for 2-5 hours under stirring conditions of 40-60 r / min and a temperature of 50-60°C.

9. The preparation method according to claim 6, characterized in that: Step (3) is carried out under stirring conditions at a rotation speed of 40-60 r / min.

10. The preparation method according to claim 6, characterized in that: In step (4), the temperature is increased under stirring conditions, specifically: the stirring speed is 40-60r / min, and the temperature is increased to 50-60°C.

11. The preparation method according to claim 6, characterized in that: Step (5) specifically comprises: adding the eutectic of lidocaine and prilocaine in step (4) to the oil phase in step (3) in 3-6 portions under the condition of keeping warm at 50-65° C., stirring while adding, to obtain a premix; then adding the premix to the water phase in step (2) in 3-6 portions, stirring while adding, to obtain a mixture.

12. The preparation method according to claim 6, characterized in that: Step (6) is specifically as follows: stirring the mixture of step (5) at a rotation speed of 40-60 r / min, scraping the wall for 5-10 min, and emulsifying at 2400-3000 r / min for 2-3 min; repeating the above emulsification step 2-4 times to obtain an emulsion.

13. The preparation method according to claim 12, characterized in that: Step (6) is specifically as follows: stirring the mixture of step (5) at a rotation speed of 50 r / min and scraping the wall for 5-10 min, then emulsifying at 2800 r / min for 2.5 min, repeating the above emulsification step 3 times to obtain an emulsion.

14. Use of compound lidocaine cream in the preparation of drugs for superficial anesthesia or treatment of premature ejaculation, characterized in that: The compound lidocaine cream is the compound lidocaine cream described in any one of claims 1 to 5 or the compound lidocaine cream prepared by the preparation method described in any one of claims 6 to 13.

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