Preparation process of menthol ointment

Abstract

The invention discloses a menthol ointment preparation process, which belongs to the technical field of ointment, and adopts polyhydroxyethyl methacrylate and quaternary ammonium salt modified cyclodextrin as a carrier to wrap menthol molecules to enhance the stability of the menthol ointment. The added hydroxyethyl polymethylacrylate can be used as a thickening agent and a stabilizing agent, so that the physical stability of the ointment is improved, and meanwhile, hydrogen-bond interaction is formed between the hydroxyethyl polymethylacrylate and menthol molecules; quaternary ammonium salt has broad-spectrum antibacterial activity and can effectively inhibit growth of bacteria, fungi and some viruses, and dispersity of cyclodextrin is further improved through mutual exclusion among cations. The modified structure can prevent menthol from volatilizing, reduce loss and prevent menthol from reacting with air and other substances, so that the stability of menthol is improved; the release time can be controlled, so that the cool feeling of menthol is slowly and enduringly released in the use process, and the use effect is prolonged; the pungent smell is covered, so that the product is easier to accept.

Description

Technical Field

[0001] The invention belongs to the technical field of ointments, and particularly relates to a preparation process of menthol ointment. Background Art

[0002] In today's medical field, skin topical preparations have a wide range of application needs. As the largest organ of the human body, the skin often faces various problems, such as mosquito bites, skin itching, mild sunburn, dryness and cracking, etc. Menthol ointment has long been widely used as a classic topical skin preparation. Menthol is extracted from the leaves and stems of mint and can be used as a flavoring agent for toothpaste, perfume, beverages and candies. It is used as a stimulant in medicine, acting on the skin or mucous membranes, with a cooling and antipruritic effect. It can be taken orally as a wind-repellent for headaches and inflammation of the nose, pharynx and throat. Menthol can selectively stimulate the cold receptors of human skin or mucous membranes, produce cold reflexes and cold sensations, cause blood vessels in the skin and mucous membranes to contract (in fact, the skin remains normal), and also cause blood vessels in deep tissues to contract, resulting in therapeutic effects. When used externally, it can reduce inflammation, relieve pain, relieve itching, promote blood circulation, and reduce edema.

[0003] However, the preparation process of menthol ointment in the early days was relatively crude, and a simple mixing method was mostly used to directly stir menthol with vaseline or other matrices. This resulted in uneven dispersion of menthol, poor stability of the ointment, and greatly reduced efficacy.

[0004] There are many ways to stabilize ointments, including using carriers to encapsulate drugs, such as nanoparticle encapsulation, microemulsion encapsulation, and liposome encapsulation. All of the above methods may have disadvantages to varying degrees. For example, the surface properties of nanoparticles in the nanoparticle encapsulation method may affect their interaction with the biomembrane, thereby affecting the absorption and distribution of the drug; the surfactants and co-surfactants in the microemulsion encapsulation method may irritate the skin; the liposome encapsulation preparation process is complex and costly, and the physical stability of liposomes is poor, which makes them prone to aggregation, fusion, and leakage during storage and use. Therefore, it is still necessary to develop a menthol ointment preparation process with good dispersibility and stability. Summary of the invention

[0005] In order to overcome the above-mentioned deficiencies of the prior art, the present invention provides a preparation process of menthol ointment, which uses polyhydroxyethyl methacrylate and quaternary ammonium salt-modified cyclodextrin as carriers to encapsulate menthol molecules, thereby enhancing the stability of menthol ointment and solving the above-mentioned problems.

[0006] The technical solution for achieving the purpose of the present invention is as follows:

[0007] A method for preparing menthol ointment comprises the following steps:

[0008] S1. Weigh 282-300 parts of a mixed solution of glycerol and deionized water and 100-108 parts of lanolin in a beaker, heat to 40-60°C and stir evenly;

[0009] S2. Then add 10 to 12 parts of modified cyclodextrin-encapsulated menthol and stir evenly;

[0010] S3. Cool and discharge the product, and check whether the appearance, texture and smell of the mint ointment meet the requirements;

[0011] The preparation method of the modified cyclodextrin-encapsulated menthol is as follows:

[0012] Dispersing 1 part of menthol and 3 to 6 parts of modified cyclodextrin in a mixed solution of water and ethanol, stirring until uniform dispersion, and freeze-drying to obtain menthol coated with modified cyclodextrin;

[0013] The menthol wrapped in the modified cyclodextrin is obtained by polymerizing polyhydroxyethyl methacrylate and methacryloyloxyethyl trimethyl ammonium chloride and grafting cyclodextrin.

[0014] Preferably, the preparation method of the modified cyclodextrin is as follows:

[0015] 1) After mixing 4 to 6 parts of cyclodextrin and 8 to 10 parts of triethylamine with 20 to 25 parts of toluene, 6 to 8 parts of 3-chloropropionyl chloride were gradually added under vigorous stirring at 0°C, the reaction was heated to room temperature and stirred overnight, washed with cold water and brine, dried with sodium sulfate solid, and the solvent was removed under reduced pressure to obtain product A;

[0016] 2) Disperse 1 part of the product A obtained in step 1) in 25-30 parts of anhydrous tetrahydrofuran, ultrasonicate for 20-30 minutes, transfer to a reactor, add 10-15 parts of hydroxyethyl methacrylate, 1-2 parts of methacryloyloxyethyl trimethyl ammonium chloride and 0.01-0.03 parts of cuprous bromide, freeze-thaw degassing three times, add 0.15-0.22 parts of N,N,Nˋ,Nˋ,Nˋˋ-pentamethyldiethylenetriamine ligand under an inert atmosphere, heat to 50-60° C. and stir for 8-16 hours; introduce oxygen to terminate the polymerization reaction; concentrate by rotary evaporation, filter, purify by column chromatography, and dry the modified cyclodextrin.

[0017] Preferably, the optimal mass ratio of the mixed solution of glycerol and deionized water is 1:2 to 3:1.

[0018] Preferably, gradually adding 3-chloropropionyl chloride means that the 3-chloropropionyl chloride is added completely within 10 to 20 minutes.

[0019] Preferably, the inert atmosphere is argon or nitrogen.

[0020] Preferably, the cyclodextrin is one or more of α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin.

[0021] Another object of the present invention is to protect a menthol ointment prepared by the preparation method of the menthol ointment.

[0022] Beneficial Effects

[0023] The present invention has the following beneficial effects:

[0024] 1. The addition of polyhydroxyethyl methacrylate can be used as a thickener and stabilizer to improve the physical stability of the ointment and prevent the components from being stratified or separated; at the same time, the addition of polyhydroxyethyl methacrylate can form hydrogen bonds with menthol molecules on the outside of cyclodextrin, thereby achieving a sustained-release effect of gradually releasing menthol molecules.

[0025] 2. Quaternary ammonium salts have broad-spectrum antibacterial activity and can effectively inhibit the growth of bacteria, fungi and certain viruses.

[0026] 3. The menthol molecules wrapped by modified cyclodextrin are stable and can be evenly dispersed in the ointment, which improves the quality stability and consistency of the product's efficacy. This structure can prevent menthol from volatilizing and reducing losses, and can also prevent menthol from reacting with air and other substances, thereby improving the stability of menthol; it can control the release time, so that the cooling feeling of menthol is slowly and persistently released during use, prolonging the effect of use; it can cover up the pungent smell and make the product more acceptable.

[0027] 4. The menthol ointment prepared by this process has a fine and uniform texture, is easy to apply, and has good skin affinity. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 The process of modifying cyclodextrin.

[0029] Figure 2 Infrared spectra of cyclodextrin and modified cyclodextrin. DETAILED DESCRIPTION

[0030] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. 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.

[0031] In the examples, the experimental methods used are conventional methods unless otherwise specified, and the materials, reagents, etc. used are all commercially available unless otherwise specified.

[0032] The raw materials and equipment used in the embodiments and comparative examples are described as follows:

[0033] Menthol: Product No. BD 137401, purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd.;

[0034] γ-Cyclodextrin: Product No. BD131847, purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd.;

[0035] 3-Chloropropionyl chloride: Product No. BD41878, purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd.;

[0036] Methacryloyloxyethyl trimethylammonium chloride: Product No. BD137604, purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd.;

[0037] Hydroxyethyl methacrylate: Product No. BD22916, purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd.;

[0038] N,N,Nˋ,Nˋ,Nˋˋ-Pentamethyldiethylenetriamine: Product No. BD52200, purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd.;

[0039] Lanolin: Product No. JX443963, purchased from Anhui Zesheng Technology Co., Ltd.;

[0040] Glycerol: Product No. BD132150, purchased from Shanghai BiDe Pharmaceutical Technology Co., Ltd.;

[0041] Ethanol: Product No. A040857, purchased from Anhui Zesheng Technology Co., Ltd.;

[0042] Acetonitrile: Product No. A011968, purchased from Anhui Zesheng Technology Co., Ltd.;

[0043] Phosphoric acid: Product No. M0113801, purchased from Anhui Zesheng Technology Co., Ltd.;

[0044] 2-3 month old Bama pig skin for the experiment: purchased from Linxi County Jingde Agricultural Products Sales Co., Ltd.;

[0045] Modified cyclodextrin: homemade.

[0046] The following is the test method of the performance parameters involved in the present invention:

[0047] (1) HPLC parameters: Instrument: ThermoFisher UV3000; Column: Core-shell Ascentis Express C 18 ,5μm,4.6x 150mm,mobile phase: 0.1% volume concentration of phosphoric acid solution-acetonitrile (60:40),column temperature 30℃;flow rate 1.0mL / min;detection wavelength is 254nm.

[0048] (2) Sustained-release effect test: In order to study the sustained-release effect of menthol and ensure the conditions of simulating human skin, pig skin was used to simulate human skin and observe its sustained-release effect. The test method is as follows:

[0049] Prepare 4 x 4 cm pieces numbered 1 to 6 2 The pig skin was smeared with the ointments of Examples 1 to 6 in thicknesses of 0.5, 0.7, and 1.0 mm, respectively, and the temperature was maintained at 36.8 to 37.1° C. The sustained-release effects of the ointments of the three thicknesses in each example were tested using high performance liquid chromatography every 2 h for a total of 8 h, as shown in Table 3.

[0050] (3) Antibacterial effect test: Detection method: Escherichia coli and Staphylococcus aureus were selected, and the antibacterial experiment was carried out with reference to Appendix C4 of GB159779-2002. The specific results are shown in Table 4.

[0051] The present invention will be further described below in conjunction with the embodiments.

[0052] Modified cyclodextrin 1

[0053] 1) After mixing 4 parts of cyclodextrin and 10 parts of triethylamine with 25 parts of toluene, 8 parts of 3-chloropropionyl chloride were gradually added under vigorous stirring at 0°C, the reaction was heated to room temperature and stirred overnight, washed with cold water and brine, dried with sodium sulfate solid, and the solvent was removed under reduced pressure to obtain product A;

[0054] 2) Disperse 1 part of the product A obtained in step S1 in 30 parts of anhydrous tetrahydrofuran, and after ultrasonic treatment for 20 minutes, transfer to a reactor, add 15 parts of hydroxyethyl methacrylate, 2 parts of methacryloyloxyethyl trimethyl ammonium chloride and 0.03 parts of cuprous bromide, freeze-thaw degassing three times, add 0.15-0.22 parts of N,N,N`,N`,N``-pentamethyldiethylenetriamine ligand under an inert atmosphere, heat to 60° C. and stir for 16 hours; introduce oxygen to terminate the polymerization reaction; concentrate by rotary evaporation, filter, purify by column chromatography, and dry the modified cyclodextrin.

[0055] Modified Cyclodextrin 2

[0056] Compared with the preparation method of modified cyclodextrin 1, the difference is that 2 parts of methacryloyloxyethyltrimethylammonium chloride in step 2) are replaced by 2 parts of hydroxyethyl methacrylate.

[0057] The preparation method of modified cyclodextrin-encapsulated menthol is as follows: menthol, ethanol and deionized water are mixed, modified cyclodextrin or cyclodextrin is added, and freeze-drying is performed to obtain modified cyclodextrin-encapsulated menthol. Table 1 shows formulas 1 to 8 for preparing cyclodextrin-encapsulated menthol. The modified cyclodextrin-encapsulated menthol is obtained by polymerizing polyhydroxyethyl methacrylate and methacryloyloxyethyl trimethylammonium chloride and grafting cyclodextrin.

[0058] Table 1 Cyclodextrin-encapsulated menthol formula 1-8 (g)

[0059]

[0060] The preparation method of menthol ointment is as follows:

[0061] Weigh the menthol wrapped in modified cyclodextrin, the mixed solution of glycerol and deionized water, and lanolin; place the mixed solution of glycerol and deionized water in a ratio of 1:1 and lanolin in a beaker, heat and stir evenly; add the menthol wrapped in modified cyclodextrin to the mixture and stir evenly; cool and discharge, and check whether the appearance, texture and smell of the mint ointment meet the requirements. Table 2 shows the formulas of Examples 1 to 4 and Comparative Examples 1 to 4.

[0062] Table 2 Menthol ointment Examples 1 to 4, Comparative Examples 1 to 4 (g)

[0063]

[0064] Stability test

[0065] In order to study the sustained-release effect of menthol and ensure the conditions of simulating human skin, pig skin was used to simulate human skin and observe its sustained-release effect.

[0066] The menthol ointments of Examples 1 to 4 and Comparative Examples 1 to 4 were applied to the skin layer side of the pig skin;

[0067] The temperature of the pigskin test was 36.8-37.1°C;

[0068] The pigskin is the skin of 2-3 month old Bama Xiang pigs for testing;

[0069] Table 3 Cumulative release rate of menthol ointment in Examples 1 to 4 and Comparative Examples 1 to 4

[0070]

[0071]

[0072] It can be seen from Table 3 that when the ointment is applied at a thickness of 0.5 to 0.7 mm, it has a better sustained-release effect.

[0073] Antibacterial effect test of the ointment of the present invention

[0074] Table 4 Antibacterial effects of Examples 1 to 4 and Comparative Examples 1 to 4

[0075] Antibacterial rate against Escherichia coli (%) Antibacterial rate against Staphylococcus aureus (%) Example 1 87.1 79.8 Example 2 89.9 81.6 Example 3 92.2 83.4 Example 4 94.6 85.1 Comparative Example 1 49.9 49.2 Comparative Example 2 98.9 97.2 Comparative Example 3 50.2 49.5 Comparative Example 4 50.1 49.1

[0076] As can be seen from the above table, the ointment provided by the invention has obvious antibacterial effect and can effectively prevent skin infections caused by Staphylococcus aureus and Escherichia coli.

[0077] From the above experiments, it can be seen that in Examples 1 to 4, the sustained release effect increases successively, and the antibacterial effect increases successively; in Comparative Example 1, the sustained release effect and the antibacterial effect are the worst; in Comparative Example 2, the sustained release effect is too strong and the release amount is too small; the sustained release effect of Comparative Example 3 is slightly better than that of Example 2, but the antibacterial effect is poor; Comparative Example 4 has a certain sustained release effect, but the antibacterial effect is poor; the results show that the addition of polyhydroxyethyl methacrylate in the modified cyclodextrin can form hydrogen bonds between the outside of the cyclodextrin and the menthol molecules, thereby achieving a sustained release effect of gradually releasing the menthol molecules; the addition of quaternary ammonium salt can effectively inhibit bacterial growth.

[0078] The preferred embodiments of the present invention disclosed above are only used to help illustrate the present invention. The preferred embodiments do not describe all the details in detail, nor do they limit the invention to the specific implementation methods described. Obviously, many modifications and changes can be made according to the content of this specification. This specification selects and specifically describes these embodiments in order to better explain the principles and practical applications of the present invention, so that those skilled in the art can understand and use the present invention well. The present invention is limited only by the claims and their full scope and equivalents.

Claims

1. A method for preparing menthol ointment, characterized in that: The steps include: S1. Weigh 282 to 300 parts of a mixed solution of glycerol and deionized water and 100 to 108 parts of lanolin, heat to 40 to 60 ° C and stir evenly; S2. Then add 10 to 12 parts of modified cyclodextrin-encapsulated menthol and stir evenly; S3. Cool and discharge the product, and check whether the appearance, texture and smell of the mint ointment meet the requirements; The preparation method of the modified cyclodextrin-encapsulated menthol is as follows: Dispersing 1 part of menthol and 3 to 6 parts of modified cyclodextrin in a mixed solution of water and ethanol, stirring until the mixture is evenly dispersed, and freeze-drying to obtain menthol coated with modified cyclodextrin; The modified cyclodextrin-encapsulated menthol is obtained by grafting cyclodextrin with a copolymer of hydroxyethyl methacrylate and methacryloyloxyethyl trimethyl ammonium chloride.

2. The method for preparing the menthol ointment according to claim 1, wherein the method for preparing the modified cyclodextrin is as follows: 1) After mixing 4 to 6 parts of cyclodextrin and 8 to 10 parts of triethylamine with 20 to 25 parts of toluene, 6 to 8 parts of 3-chloropropionyl chloride were gradually added under vigorous stirring at 0°C, the reaction was heated to room temperature and stirred overnight, washed with cold water and brine, dried with sodium sulfate solid, and the solvent was removed under reduced pressure to obtain product A; 2) Disperse 1 part of the product A obtained in step 1) in 25-30 parts of anhydrous tetrahydrofuran, and after ultrasonic treatment for 20-30 minutes, transfer to a reaction kettle, add 10-15 parts of hydroxyethyl methacrylate, 1-2 parts of methacryloyloxyethyl trimethyl ammonium chloride and 0.01-0.03 parts of cuprous bromide, freeze-thaw degassing three times, add 0.15-0.22 parts of N,N,Nˋ,Nˋ,Nˋˋ-pentamethyldiethylenetriamine ligand under an inert atmosphere, heat to 50-60° C. and stir for 8-16 hours; introduce oxygen to terminate the polymerization reaction, concentrate by rotary evaporation, filter, purify by column chromatography, and dry the modified cyclodextrin.

3. The method for preparing menthol ointment according to claim 1, characterized in that: The mass ratio of the mixed solution of glycerol and deionized water is 1:2 to 3:

1.

4. The method for preparing menthol ointment according to claim 1, characterized in that: The volume ratio of the mixed solution of water and ethanol is 1:1-1:2; the mass of the mixed solution of water and ethanol is 40-50 parts.

5. The method for preparing menthol ointment according to claim 2, characterized in that: The stepwise addition of 3-chloropropionyl chloride means that the 3-chloropropionamide is added completely within 10 to 20 minutes.

6. The method for preparing the menthol ointment according to claim 2, characterized in that: The inert atmosphere is argon or nitrogen.

7. The method for preparing the menthol ointment according to claim 1, characterized in that: The cyclodextrin is one or more of α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin.

8. A menthol ointment, characterized in that: The menthol ointment is prepared by the preparation method of any one of claims 1 to 7.

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