Preparation process of crotamiton and external preparation applied by crotamiton

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a preparation process of crotamiton and an external preparation applied by the crotamiton. Comprising the following steps: step 1, slowly dropwise adding 2-butenoyl chloride into N-ethyl-o-toluidine, and controlling the reaction temperature at 10-30 DEG C; after the reaction is finished, heating to 45-55 DEG C, and reacting for 2-4 hours to obtain a product A; adding purified water for dilution, adding a demulsifier, and adding ethyl acetate for extraction to obtain an organic phase; 2, washing the organic phase with a hydrochloric acid solution and a sodium hydroxide solution in sequence, performing liquid separation, performing reduced pressure distillation, collecting fractions at the temperature of 152-155 DEG C and the pressure of-0.096 to-0.1 Mpa, performing refined filtration with a 0.2-0.24 [mu] m filter element in sequence, performing filling, performing capping, and performing packaging; and thus, the crotamiton is obtained. And preparing a medicine solution from crotamiton and other substances, and combining the medicine solution with the pre-gel solution to obtain the external preparation of crotamiton.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations, in particular to a preparation process of crotamiton and an external preparation used therein. Background Art

[0002] With the continuous development of medical technology, the research and development of anti-scabies drugs has received increasing attention. Crotamiton, as a highly effective and broad-spectrum anti-scabies drug, has a local anesthetic effect, can treat various types of pruritus, and has a specific killing effect on scabies, so it is widely used in the field of dermatology.

[0003] However, in the prior art, the preparation process of crotamiton involves the reaction of 2-butenoyl chloride and N-ethyl-o-toluidine at a specific temperature, followed by extraction and reduced pressure distillation. However, emulsification often occurs in this process, which has a significant impact on the yield and purity of crotamiton.

[0004] As for the topical preparations of crotamiton, they are mainly in the form of creams on the market. Although this preparation has a certain effect on fighting scabies, it is irritating to the skin and has a low transdermal absorption rate. More importantly, the scabies targeted by the topical preparations of crotamiton often appear on the flexor side of the upper limbs, the elbows, the front of the armpits, under the breasts, the waist, the lower abdomen, the gluteal groove, the external genitalia, the inner thighs, etc. Therefore, special attention should be paid to avoid contact with clothing during the use of the cream, otherwise the drug will be stained with clothing, which will cause inconvenience to the patient and reduce the drug properties.

[0005] In summary, it is of great significance to prepare a high-yield, high-purity crotamiton and to prepare an external preparation of crotamiton that can reduce skin irritation, promote drug absorption and utilization, improve skin adhesion, and effectively prevent drug contact with clothing. Summary of the invention

[0006] The purpose of the present invention is to provide a preparation process of crotamiton and an external preparation thereof, so as to solve the problems raised in the above background technology.

[0007] In order to solve the above technical problems, the present invention provides the following technical solutions:

[0008] A preparation process of crotamiton comprises the following steps:

[0009] Step 1: slowly drop 2-butenoyl chloride into N-ethyl-o-toluidine, and control the reaction temperature at 10-30°C; after the reaction is completed, heat to 45-55°C and react for 2-4 hours to obtain product A; add purified water to dilute, add a demulsifier, and add ethyl acetate to extract to obtain an organic phase;

[0010] Step 2: The organic phase is washed with hydrochloric acid solution and sodium hydroxide solution in sequence, separated, and distilled under reduced pressure to collect the fractions at 152-155° C. and -0.096--0.1 Mpa, and then filtered through a 0.2-0.24 μm filter element, filled, capped, and packaged to produce crotamiton.

[0011] More optimally, the product A comprises 2-butenoyl chloride and N-ethyl-o-toluidine in a mass ratio of 1:1.1-1.3.

[0012] More optimally, the amount of ethyl acetate added accounts for 25-50wt% of product A.

[0013] More optimally, the amount of the demulsifier added is 0.5-1.5wt% of the product A.

[0014] More optimally, the demulsifier includes sodium chloride, calcium chloride, and polyethylene glycol 2000 in a mass ratio of 1:0.5-0.8:2-2.5.

[0015] Among them, in the extraction process for preparing crotamiton, a specific demulsifier is added to combine the organic demulsifier with the inorganic demulsifier. The organic demulsifier (polyethylene glycol 2000) has a low surface tension and good wetting properties, and can be quickly adsorbed to the oil / water interface, thereby reducing the interfacial tension and interfacial film strength. The inorganic demulsifier (sodium chloride, calcium chloride) can further destroy the structure of the emulsion through its ion effect or adsorption, accelerate the demulsification process of the emulsion, and the combination of the two produces mutual synergy and significantly improves the demulsification efficiency;

[0016] In a further solution, the addition of a demulsifier can effectively avoid the problem of reduced yield and purity of crotamiton due to emulsification during the preparation process. Its main function is to promote oil-water separation by destroying the emulsion structure formed in the reaction system, thereby ensuring the smooth progress of the subsequent ethyl acetate extraction step. This not only meets the demand for high-purity crotamiton in the fields of medicine and pesticides, but also ensures the quality and stability of the final product.

[0017] More optimally, the hydrochloric acid solution is an 8-12 wt % hydrochloric acid solution; the sodium hydroxide solution is an 8-12 wt % sodium hydroxide solution.

[0018] More optimally, the cromiton prepared by the cromiton preparation process is described.

[0019] More optimally, crotamiton is used to prepare crotamiton external preparations.

[0020] More optimally, the preparation of the topical preparation of crotamiton comprises the following steps:

[0021] Step 1: adding crotamiton, mometasone furoate, poloxamer 407, cocoyl glyceride and glycerin to purified water and diethylene glycol monoethyl ether and mixing them at 30-40° C. to obtain a drug solution;

[0022] Step 2: (1) adding polyvinyl alcohol to purified water to prepare a 25-35 wt% polyvinyl alcohol solution; filtering the 25-35 wt% polyvinyl alcohol solution to obtain a filtrate for later use; (2) adding γ-(glycidyloxypropyl)trimethoxysilane and D-lactic acid to the polyvinyl alcohol filtrate to react at 55-65° C. for 1-2 hours, then raising the temperature to 80-90° C. for 2-3 hours to obtain a pre-gel solution;

[0023] Step 3: Add polyvinyl pyrrolidone, poloxamer 407 and drug solution to the pre-gel solution and stir to react at 25-35° C. for 4-5 hours, and then place at 25-35° C. for 8-12 hours to obtain a topical preparation of crotamiton.

[0024] Among them, Poloxamer 407 was added twice in the preparation of crotamiton external preparation, and the two played different roles.

[0025] The first addition of poloxamer 407 is to prevent the amide bond of crotamiton from breaking due to hydrolysis when preparing the drug solution, which greatly affects the content of crotamiton and the performance of the overall drug;

[0026] The second addition of poloxamer 407 is when preparing the topical preparation. The hydrophilic part of the triblock structure of poloxamer 407 can interact with hydrophilic polymers such as polyvinyl alcohol and polyvinyl pyrrolidone to form a more stable structure, thereby increasing the stability of the overall gel.

[0027] In addition, the hydrophobic part of Poloxamer 407, POP, can form hydrophobic microdomains in the gel, which can act as "cross-linking points" and increase the viscosity of the gel, making it easier to apply on the skin;

[0028] More importantly, Poloxamer 407 has a solubilizing effect that can improve the solubility of the drug, and can also produce similar compatibility with Poloxamer 407 in the drug solution, further enhancing the solubility of the drug solution and the pregel solution, and promoting the release and absorption of the drug.

[0029] Among them, a topical preparation of crotamiton was prepared, in which polyvinyl alcohol was used as a matrix, γ-(glycidyloxypropyl)trimethoxysilane was used as an inorganic modifier to further modify the polyvinyl alcohol, and finally polyvinyl pyrrolidone and poloxamer 407 were added as treating agents. Glycerol in the drug solution was used as a plasticizer to further make it compatible with poloxamer 407, so that the drug was completely integrated into the pre-gel solution, further generating a biogel film.

[0030] More optimally, the drug solution comprises the following components: by mass, 4 to 5 parts of crotamiton, 0.2 to 0.25 parts of mometasone furoate, 20 to 25 parts of poloxamer 407, 10 to 12 parts of diethylene glycol monoethyl ether, 6 to 7 parts of cocoyl glyceride, 20 to 25 parts of glycerol, and 25 to 32 parts of purified water;

[0031] The pre-gel solution comprises the following components: by mass, 6 to 8 parts of γ-(glycidyloxypropyl)trimethoxysilane, 0.5 to 1 part of D-lactic acid, and 30 to 40 parts of polyvinyl alcohol filtrate;

[0032] The external preparation of crotamiton comprises the following components: by weight, 0.5 to 1.5 parts of polyvinyl pyrrolidone, 0.05 to 0.1 parts of poloxamer 407, 18 to 20 parts of drug solution, and 18 to 22 parts of pre-gel solution.

[0033] Compared with the prior art, the present invention has the following beneficial effects:

[0034] 1. In the scheme, in the preparation of crotamiton, adding an emulsifier can effectively avoid the problems of reduced yield and reduced purity of crotamiton due to emulsification during the preparation process.

[0035] 2. In the scheme, in the preparation of the topical preparation of crotamiton, poloxamer 407 is added twice, which not only protects crotamiton from being hydrolyzed, but also produces similar compatibility with poloxamer 407 added to the pre-gel solution subsequently, further protecting the drug performance, enhancing the gel stability, improving the drug solubility, and promoting drug release and skin absorption.

[0036] 3. In the scheme, the topical preparation of crotamiton is a new type of biogel membrane, which can significantly improve the bioavailability of the drug, reduce the frequency of medication for patients, stabilize the dosage spectrum, and improve the therapeutic effect. Compared with traditional cream preparations, the new biogel membrane has higher permeability and is easy to use, which can reduce skin irritation and thus increase the release of the drug. In addition, it also has excellent film-forming properties, processability, biocompatibility and non-toxicity, which can significantly enhance the hygroscopicity and chemical resistance of the drug, ensure that the drug does not leave a greasy feeling at the application site, improve the efficacy and safety of the drug, and provide patients with a more comfortable and convenient treatment option. DETAILED DESCRIPTION

[0037] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0038] It should be noted that the following parts are by mass, and all raw materials involved in the present invention are purchased from manufacturers without any special restrictions. Examples include: In the following embodiments, γ-(glycidyloxypropyl)trimethoxysilane has a purity of 97%, CAS No. 2530-83-8, and is purchased from Shanghai Koraman Reagent Co., Ltd.; Poloxamer 407 is purchased from Wuhan Xindadi Environmental Protection Materials Co., Ltd.; and Polyethylene glycol 2000 is purchased from Yishen Biotechnology (Shanghai) Co., Ltd.

[0039] In the following embodiments, it is particularly noted that the relevant material parameters are as follows:

[0040] The demulsifier includes sodium chloride, calcium chloride and polyethylene glycol 2000 in a mass ratio of 1:0.6:2.3.

[0041] Embodiment 1: A process for preparing crotamiton, comprising the following steps:

[0042] Step 1: slowly drop 2-butenoyl chloride into N-ethyl-o-toluidine, control the reaction temperature at 20°C, and the mass ratio of 2-butenoyl chloride to N-ethyl-o-toluidine is 1:1.2; after the reaction is completed, heat to 50°C for 3 hours to obtain product A; add purified water for dilution, add demulsifier, and add ethyl acetate for extraction, wherein the amount of ethyl acetate added accounts for 35wt% of product A, and the amount of demulsifier added accounts for 0.8wt% of product A, to obtain an organic phase;

[0043] Step 2: The organic phase is washed with 10 wt % hydrochloric acid solution and 10 wt % sodium hydroxide solution in sequence, separated, and distilled under reduced pressure to collect the fraction at 153° C. and −0.098 MPa. The fraction is filtered through a 0.22 μm filter element, filled, capped, and packaged in a workshop 102 production line (C-grade environment) to produce crotamiton.

[0044] Embodiment 2: A process for preparing crotamiton, comprising the following steps:

[0045] Step 1: slowly drop 2-butenoyl chloride into N-ethyl-o-toluidine, control the reaction temperature at 20°C, and the mass ratio of 2-butenoyl chloride to N-ethyl-o-toluidine is 1:1.2; after the reaction is completed, heat to 50°C for 3 hours to obtain product A; add purified water for dilution, add demulsifier, and add ethyl acetate for extraction, the amount of ethyl acetate added accounts for 35wt% of product A, and the amount of demulsifier added accounts for 0.5wt% of product A, to obtain an organic phase;

[0046] Step 2: The organic phase is washed with 10 wt % hydrochloric acid solution and 10 wt % sodium hydroxide solution in sequence, separated, and distilled under reduced pressure to collect the fraction at 152° C. and −0.098 MPa. The fraction is filtered through a 0.22 μm filter element, filled, capped, and packaged in a workshop 102 production line (C-grade environment) to produce crotamiton.

[0047] Embodiment 3: A process for preparing crotamiton, comprising the following steps:

[0048] Step 1: slowly drop 2-butenoyl chloride into N-ethyl-o-toluidine, control the reaction temperature at 20°C, and the mass ratio of 2-butenoyl chloride to N-ethyl-o-toluidine is 1:1.2; after the reaction is completed, heat to 50°C for 3 hours to obtain product A; add purified water for dilution, add demulsifier, and add ethyl acetate for extraction, the amount of ethyl acetate added accounts for 35wt% of product A, and the amount of demulsifier added accounts for 1.5wt% of product A, to obtain an organic phase;

[0049] Step 2: The organic phase is washed with 10 wt % hydrochloric acid solution and 10 wt % sodium hydroxide solution in sequence, separated, and distilled under reduced pressure, and the fractions at 155° C. and −0.098 MPa are collected. The fractions are filtered through a 0.22 μm filter element, filled, capped, and packaged in a workshop 102 production line (C-grade environment) to produce crotamiton.

[0050] Comparative Example 1: Based on Example 1, no demulsifier was added, and the other processes remained unchanged, specifically:

[0051] Step 1: slowly drop 2-butenoyl chloride into N-ethyl-o-toluidine, control the reaction temperature at 20°C, and the mass ratio of 2-butenoyl chloride to N-ethyl-o-toluidine is 1:1.2; after the reaction is completed, heat to 50°C for 3 hours to obtain product A; add purified water to dilute, add ethyl acetate to extract, the amount of ethyl acetate added accounts for 35wt% of product A, and obtain an organic phase;

[0052] Step 2: The organic phase is washed with 10 wt % hydrochloric acid solution and 10 wt % sodium hydroxide solution in sequence, separated, and distilled under reduced pressure to collect the fraction at 153° C. and −0.098 MPa. The fraction is filtered through a 0.22 μm filter element, filled, capped, and packaged in a workshop 102 production line (C-grade environment) to produce crotamiton.

[0053] Comparative Example 2: Based on Example 1, sodium chloride was added alone as a demulsifier, and the rest of the process remained unchanged, specifically:

[0054] Step 1: slowly drop 2-butenoyl chloride into N-ethyl-o-toluidine, control the reaction temperature at 20°C, and the mass ratio of 2-butenoyl chloride to N-ethyl-o-toluidine is 1:1.2; after the reaction is completed, heat to 50°C for 3 hours to obtain product A; add purified water for dilution, add sodium chloride, and add ethyl acetate for extraction, wherein the amount of ethyl acetate added accounts for 35wt% of product A, and the amount of sodium chloride added accounts for 0.8wt% of product A, to obtain an organic phase;

[0055] Step 2: The organic phase is washed with 10 wt % hydrochloric acid solution and 10 wt % sodium hydroxide solution in sequence, separated, and distilled under reduced pressure to collect the fraction at 153° C. and −0.098 MPa. The fraction is filtered through a 0.22 μm filter element, filled, capped, and packaged in a workshop 102 production line (C-grade environment) to produce crotamiton.

[0056] Detection experiment: The crotamiton prepared in Examples 1 to 3 and Comparative Examples 1 to 2 was subjected to performance testing: (1) Yield test: The yield of the crotamiton prepared in Examples 1 to 3 and Comparative Examples 1 to 2 was measured, and the results are shown in Table 1; (2) Purity test: The crotamiton prepared in Examples 1 to 3 and Comparative Examples 1 to 2 was measured by high performance liquid chromatography (HPLC), and the results are shown in Table 1;

[0057]

[0058] Table 1

[0059] Result analysis: According to the data analysis in Table 1, it can be seen that the demulsification efficiency is significantly improved by combining the use of organic demulsifiers (such as polyethylene glycol 2000) and inorganic demulsifiers (such as sodium chloride and calcium chloride) in the extraction process of preparing crotamiton. This combination method utilizes the wetting properties and ability of organic demulsifiers to quickly adsorb to the oil / water interface, as well as the ionic effect or adsorption of inorganic demulsifiers, to jointly destroy the emulsion structure and accelerate the demulsification process. This demulsification strategy effectively avoids the problem of reduced yield and purity of crotamiton due to emulsification during the preparation process, meets the demand for high-purity crotamiton in the fields of medicine and pesticides, and ensures the quality and stability of the final product.

[0060] Example 4: An external preparation for application of crotamiton, comprising the following steps:

[0061] Step 1: 4.5 parts of crotamiton, 0.23 parts of mometasone furoate, 22.6 parts of poloxamer 407, 6.8 parts of cocoyl glyceride, and 22.5 parts of glycerol are added to 28 parts of purified water and 11 parts of diethylene glycol monoethyl ether and mixed at 35° C. to obtain a drug solution;

[0062] Step 2: (1) adding polyvinyl alcohol to purified water to prepare a 30 wt% polyvinyl alcohol solution; filtering the 30 wt% polyvinyl alcohol solution to obtain a filtrate for later use; (2) adding 7 parts of γ-(glycidyloxypropyl)trimethoxysilane and 0.7 parts of D-lactic acid to 35 parts of the polyvinyl alcohol filtrate and reacting at 60° C. for 1.5 hours, then raising the temperature to 85° C. and reacting for 2.5 hours to obtain a pregel solution;

[0063] Step 3: Add 1 part of polyvinyl pyrrolidone, 0.07 parts of poloxamer 407 and 19 parts of the drug solution to 20 parts of the pre-gel solution, stir and react at 30°C for 4.5 hours, and then place at 30°C for 10 hours to obtain a topical preparation of crotamiton.

[0064] Example 5: An external preparation for application of crotamiton, comprising the following steps:

[0065] Step 1: 4 parts of crotamiton, 0.2 parts of mometasone furoate, 20 parts of poloxamer 407, 6 parts of cocoyl glyceride, and 20 parts of glycerol are added to 25 parts of purified water and 10 parts of diethylene glycol monoethyl ether and mixed at 35° C. to obtain a drug solution;

[0066] Step 2: (1) adding polyvinyl alcohol to purified water to prepare a 30 wt% polyvinyl alcohol solution; filtering the 30 wt% polyvinyl alcohol solution to obtain a filtrate for later use; (2) adding 7 parts of γ-(glycidyloxypropyl)trimethoxysilane and 0.7 parts of D-lactic acid to 35 parts of the polyvinyl alcohol filtrate and reacting at 60° C. for 1.5 hours, then raising the temperature to 85° C. and reacting for 2.5 hours to obtain a pregel solution;

[0067] Step 3: Add 0.5 parts of polyvinyl pyrrolidone, 0.05 parts of poloxamer 407 and 18 parts of the drug solution to 18 parts of the pre-gel solution, stir and react at 30°C for 4.5 hours, and then place at 30°C for 10 hours to obtain an external preparation of crotamiton.

[0068] Example 6: An external preparation for application of crotamiton, comprising the following steps:

[0069] Step 1: 5 parts of crotamiton, 0.25 parts of mometasone furoate, 25 parts of poloxamer 407, 7 parts of cocoyl glyceride, and 25 parts of glycerol are added to 32 parts of purified water and 12 parts of diethylene glycol monoethyl ether and mixed at 35° C. to obtain a drug solution;

[0070] Step 2: (1) adding polyvinyl alcohol to purified water to prepare a 30 wt% polyvinyl alcohol solution; filtering the 30 wt% polyvinyl alcohol solution to obtain a filtrate for later use; (2) adding 7 parts of γ-(glycidyloxypropyl)trimethoxysilane and 0.7 parts of D-lactic acid to 35 parts of the polyvinyl alcohol filtrate and reacting at 60° C. for 1.5 hours, then raising the temperature to 85° C. and reacting for 2.5 hours to obtain a pregel solution;

[0071] Step 3: Add 1.5 parts of polyvinyl pyrrolidone, 0.1 parts of poloxamer 407 and 20 parts of the drug solution to 22 parts of the pre-gel solution, stir and react at 30°C for 4.5 hours, and then place at 30°C for 10 hours to obtain a topical preparation of crotamiton.

[0072] Comparative Example 3: Based on Example 4, poloxamer 407 was not added when preparing the drug solution, and the other processes remained unchanged, specifically:

[0073] Step 1: 4.5 parts of crotamiton, 0.23 parts of mometasone furoate, 6.8 parts of cocoyl glyceride, and 22.5 parts of glycerol are added to 28 parts of purified water and 11 parts of diethylene glycol monoethyl ether and mixed at 35° C. to obtain a drug solution;

[0074] Step 2: (1) adding polyvinyl alcohol to purified water to prepare a 30 wt% polyvinyl alcohol solution; filtering the 30 wt% polyvinyl alcohol solution to obtain a filtrate for later use; (2) adding 7 parts of γ-(glycidyloxypropyl)trimethoxysilane and 0.7 parts of D-lactic acid to 35 parts of the polyvinyl alcohol filtrate and reacting at 60° C. for 1.5 hours, then raising the temperature to 85° C. and reacting for 2.5 hours to obtain a pregel solution;

[0075] Step 3: Add 1 part of polyvinyl pyrrolidone, 0.07 parts of poloxamer 407 and 19 parts of the drug solution to 20 parts of the pre-gel solution, stir and react at 30°C for 4.5 hours, and then place at 30°C for 10 hours to obtain a topical preparation of crotamiton.

[0076] Comparative Example 4: Based on Example 4, poloxamer 407 was not added when preparing the external preparation, and the other processes remained unchanged, specifically:

[0077] Step 1: 4.5 parts of crotamiton, 0.23 parts of mometasone furoate, 22.6 parts of poloxamer 407, 6.8 parts of cocoyl glyceride, and 22.5 parts of glycerol are added to 28 parts of purified water and 11 parts of diethylene glycol monoethyl ether and mixed at 35° C. to obtain a drug solution;

[0078] Step 2: (1) adding polyvinyl alcohol to purified water to prepare a 30 wt% polyvinyl alcohol solution; filtering the 30 wt% polyvinyl alcohol solution to obtain a filtrate for later use; (2) adding 7 parts of γ-(glycidyloxypropyl)trimethoxysilane and 0.7 parts of D-lactic acid to 35 parts of the polyvinyl alcohol filtrate and reacting at 60° C. for 1.5 hours, then raising the temperature to 85° C. and reacting for 2.5 hours to obtain a pregel solution;

[0079] Step 3: Add 1 part of polyvinyl pyrrolidone and 19 parts of the drug solution to 20 parts of the pre-gel solution, stir and react at 30°C for 4.5 hours, and then place at 30°C for 10 hours to obtain a topical preparation of crotamiton.

[0080] Comparative Example 5: The external preparation of crotamiton prepared by the prior art is:

[0081] Step 1: Heat 20 parts of stearic acid and 10 parts of glyceryl monostearate to melt at 75°C to obtain an oil phase;

[0082] Step 2: Grind 20 parts of crotamiton, 1 part of mometasone furoate, 10 parts of glycerol and 139 parts of purified water at 75° C., add to the oil phase, stir and cool to obtain an external preparation of crotamiton.

[0083] Testing experiment: The performance of the crotamiton external preparation prepared in Examples 4 to 6 and Comparative Examples 3 to 4 was tested: (1) Viscosity test: The main shaft of the crotamiton external preparation prepared in Examples 4 to 6 and Comparative Examples 3 to 4 was set to rotate at a speed of 10 r / min to measure the viscosity. The results are shown in Table 2; (2) Water vapor permeability test: A sample with a diameter of 2 cm was cut from the crotamiton external preparation prepared in Examples 4 to 6 and Comparative Examples 3 to 4 and placed in 10 g of distilled liquor, and the temperature was maintained at 37° C. for 1 day. The results are shown in Table 2;

[0084]

[0085]

[0086] Table 2

[0087] Result analysis: According to the data analysis in Table 2, it can be seen that in the preparation of the topical preparation of crotamiton in the scheme, by adding poloxamer 407 twice, not only crotamiton is protected from hydrolysis, but also similar compatibility with poloxamer 407 added to the pre-gel solution subsequently can be achieved, further protecting the drug performance, enhancing gel stability, improving drug solubility, and promoting drug release and skin absorption.

[0088] Testing experiment: The performance of the external preparation of crotamiton prepared in Example 4 and Comparative Example 5 was tested: Efficacy experiment: 50 patients with scabies were selected as research subjects, and 30g of the external preparation of crotamiton prepared in Example 4 and Comparative Example 5 were taken for use by 50 patients, 25 patients used the external preparation of crotamiton prepared in Example 4, and 25 patients used the external preparation of crotamiton prepared in Comparative Example 5, and 24 hours was set as a medication cycle, that is, once a day. At the 2nd and 4th weeks after medication, the efficacy of the patients was evaluated, and the evaluation results were divided into three levels: recovery, marked effect and ineffectiveness, and the results are shown in Table 3 below.

[0089]

[0090] Table 3

[0091] Results analysis: According to the data analysis in Table 3, it can be seen that the prepared topical preparation of crotamiton is a new type of biogel membrane, which significantly improves bioavailability by optimizing drug delivery, prolongs the drug action time, thereby reducing the frequency of medication and improving treatment compliance, ensures the consistency and stability of drug release to optimize the treatment effect, and at the same time, with its higher permeability and enhanced skin penetration ability, the drug can act more effectively on the affected area and accelerate the recovery process. In addition, the preparation also reduces skin irritation. The biogel membrane can effectively reduce drug loss and increase drug release. It has excellent film-forming properties, processability, biocompatibility, non-toxicity, and enhanced hygroscopicity and chemical resistance. It is refreshing and non-greasy after application, providing patients with a more efficient, safe, comfortable and convenient treatment option.

[0092] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above and that the present invention can be implemented in other specific forms without departing from the spirit or essential features of the present invention. Therefore, the embodiments should be considered exemplary and non-restrictive in all respects, and the scope of the present invention is defined by the appended claims rather than the above description, and it is intended that all changes falling within the meaning and scope of the equivalent elements of the claims be included in the present invention.

Claims

1. A process for preparing crotamiton, characterized in that: The following steps are involved: Step 1: slowly drop 2-butenoyl chloride into N-ethyl-o-toluidine, and control the reaction temperature at 10-30°C; after the reaction is completed, heat to 45-55°C and react for 2-4 hours to obtain product A; add purified water to dilute, add a demulsifier, and add ethyl acetate to extract to obtain an organic phase; Step 2: The organic phase is washed with hydrochloric acid solution and sodium hydroxide solution in sequence, separated, and distilled under reduced pressure to collect the fractions at 152-155° C. and -0.096--0.1 Mpa, and then filtered through a 0.2-0.24 μm filter element, filled, capped, and packaged to produce crotamiton.

2. A process for preparing crotamiton according to claim 1, characterized in that: The product A comprises 2-butenoyl chloride and N-ethyl-o-toluidine in a mass ratio of 1:1.1-1.

3.

3. A process for preparing crotamiton according to claim 1, characterized in that: The amount of ethyl acetate added is 25-50 wt % of the product A.

4. A process for preparing crotamiton according to claim 1, characterized in that: The amount of the demulsifier added is 0.5-1.5 wt % of the product A.

5. A process for preparing crotamiton according to claim 3, characterized in that: The demulsifier comprises sodium chloride, calcium chloride and polyethylene glycol 2000 in a mass ratio of 1:0.5-0.8:2-2.

5.

6. A process for preparing crotamiton according to claim 1, characterized in that: The hydrochloric acid solution is 8-12 wt % of hydrochloric acid solution; the sodium hydroxide solution is 8-12 wt % of sodium hydroxide solution.

7. Crotamiton prepared according to the process for preparing crotamiton according to any one of claims 1 to 6.

8. An external preparation for application of crotamiton, characterized in that: The crotamiton prepared according to claim 7 is used to prepare an external preparation of crotamiton.

9. The external preparation for application of crotamiton according to claim 8, characterized in that: The preparation of the external preparation of crotamiton comprises the following steps: Step 1: adding crotamiton, mometasone furoate, poloxamer 407, cocoyl glyceride and glycerin to purified water and diethylene glycol monoethyl ether and mixing them at 30-40° C. to obtain a drug solution; Step 2: (1) adding polyvinyl alcohol to purified water to prepare a 25-35 wt% polyvinyl alcohol solution; filtering the 25-35 wt% polyvinyl alcohol solution to obtain a filtrate for later use; (2) adding γ-(glycidyloxypropyl)trimethoxysilane and D-lactic acid to the polyvinyl alcohol filtrate to react at 55-65° C. for 1-2 hours, then raising the temperature to 80-90° C. for 2-3 hours to obtain a pre-gel solution; Step 3: Add polyvinyl pyrrolidone, poloxamer 407 and drug solution to the pre-gel solution and stir to react at 25-35° C. for 4-5 hours, and then place at 25-35° C. for 8-12 hours to obtain a topical preparation of crotamiton.

10. The external preparation for use of crotamiton according to claim 9, characterized in that: The drug solution comprises the following components: by mass, 4 to 5 parts of crotamiton, 0.2 to 0.25 parts of mometasone furoate, 20 to 25 parts of poloxamer 407, 10 to 12 parts of diethylene glycol monoethyl ether, 6 to 7 parts of cocoyl glyceride, 20 to 25 parts of glycerol, and 25 to 32 parts of purified water; The pre-gel solution comprises the following components: by mass, 6 to 8 parts of γ-(glycidyloxypropyl)trimethoxysilane, 0.5 to 1 part of D-lactic acid, and 30 to 40 parts of polyvinyl alcohol filtrate; The external preparation of crotamiton comprises the following components: by weight, 0.5 to 1.5 parts of polyvinyl pyrrolidone, 0.05 to 0.1 parts of poloxamer 407, 18 to 20 parts of drug solution, and 18 to 22 parts of pre-gel solution.

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