CN114404548A - Antifungal transdermal absorption ointment - Google Patents

Antifungal transdermal absorption ointment Download PDF

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CN114404548A
CN114404548A CN202210109207.7A CN202210109207A CN114404548A CN 114404548 A CN114404548 A CN 114404548A CN 202210109207 A CN202210109207 A CN 202210109207A CN 114404548 A CN114404548 A CN 114404548A
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transdermal absorption
mixing
antifungal
drying
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李保健
黄沃林
周斌华
彭爱云
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Shenzhen Yulaiman Biotechnology Co ltd
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Abstract

The invention discloses an antifungal transdermal absorption ointment. The antifungal transdermal absorption ointment comprises the following steps: extracting Curcuma rhizome, radix Cyathulae, and Moschus, filtering, adding stearic acid, glycerol, oleum ricini, ethylparaben, triethanolamine, water, and liquid paraffin, concentrating to obtain ointment, adding glycyrrhetinic acid, skin penetration enhancer, laurocapram, and urea, and mixing to obtain antifungal skin penetration ointment. The antifungal percutaneous absorption ointment of the invention is beneficial to the absorption of functional components, and simultaneously, the polysaccharide nanocrystal is used as a stabilizer of the percutaneous absorption enhancer to improve the thermal stability and the anti-coalescence stability of the emulsion in the preparation process. The invention has the effects of promoting blood circulation by removing blood stasis, diminishing inflammation and relieving pain and has excellent antifungal effect.

Description

Antifungal transdermal absorption ointment
Technical Field
The invention relates to the technical field of traditional Chinese medicine preparations, in particular to an antifungal transdermal absorption ointment.
Background
Glycyrrhetinic acid has effects of treating dermatogic diseases such as neurodermatitis, chronic eczema, chronic urticaria, alopecia areata, etc., and has no serious adverse reaction. The ointment preparation prepared by using the compound formula of the turmeric, the medicinal cyathula root, the musk and the glycyrrhetinic acid has mild effect and low irritation, can relieve skin pruritus and discomfort caused by mosquito bite, eczema and the like, but also has the technical problem of difficult storage, and has the defects of low efficacy of medicinal active ingredients and difficult exertion of the ideal antifungal effect due to poor stability.
Patent CN 109223941 a discloses an antifungal ointment, which uses dogliver, feather cockscomb seed, yam, perilla frutescens, longan seed, wintercherry, ledebouriella root, fig and potentilla chinensis to make prescription to improve antibacterial effect and reduce side effect. Patent CN 107095845A provides an antifungal ointment, which is composed of active ingredients and pharmaceutic adjuvants, wherein the active ingredients are aucubin and asiaticoside, and the antifungal ointment has the effects of better antifungal effect and low recurrence rate. None of the above patents optimizes and improves the transdermal effect and stability of the ointment, and there may be a technical problem of reduced efficacy due to poor stability in practical application.
Disclosure of Invention
In view of the defects of disordered raw materials, weak efficacy and easy allergy of the traditional Chinese medicine ointment in the prior art, the invention aims to solve the technical problem that 2-nitroimidazole is pretreated by polyethylene glycol methyl ether methacrylate and then subjected to fluoroalkylation reaction with ethyl difluorobromoacetate, and the fluoroalkylation product prepared by further oxidizing polypyrrole is combined with a Chinese herbal medicine extract to form the antifungal transdermal absorption ointment.
In order to achieve the aim, the basic formula of the antifungal transdermal absorption ointment provided by the invention is as follows: turmeric, medicinal cyathula root, musk, glycyrrhetinic acid, stearic acid, glycerin, castor oil, ethylparaben, triethanolamine, water, liquid paraffin, a transdermal absorption enhancer, laurocapram and urea.
Preferably, the antifungal transdermal absorption ointment is prepared from the following raw materials in parts by weight: 4-8 parts of turmeric, 2-6 parts of medicinal cyathula root, 1-5 parts of musk, 2-6 parts of glycyrrhetinic acid, 10-20 parts of stearic acid, 4-8 parts of glycerol, 2-7 parts of castor oil, 0.01-0.2 part of ethylparaben, 1-3 parts of triethanolamine, 50-80 parts of water, 1-5 parts of liquid paraffin, 4-8 parts of transdermal absorption enhancer, 1-3 parts of laurocapram and 1-3 parts of urea.
Further preferably, the antifungal transdermal absorption ointment is prepared from the following raw materials in parts by weight: 6 parts of turmeric, 4 parts of medicinal cyathula root, 3 parts of musk, 3 parts of glycyrrhetinic acid, 15 parts of stearic acid, 6 parts of glycerol, 5 parts of castor oil, 0.1 part of ethylparaben, 2 parts of triethanolamine, 60 parts of water, 3 parts of liquid paraffin, 6 parts of a transdermal absorption enhancer, 2 parts of laurocapram and 2 parts of urea.
The invention also discloses a preparation method of the antifungal transdermal absorption ointment, which comprises the following steps:
step 1, cleaning turmeric, medicinal cyathula root and musk by using water, and then drying; then grinding into powder, sieving, and mixing uniformly to prepare mixed powder;
step 2, adding the mixed powder prepared in the step 1 into an ethanol aqueous solution for mixing, performing reflux extraction, and filtering an extracting solution after the reflux is finished to obtain a mixed filtrate; heating the mixed filtrate, adding stearic acid and triethanolamine into the mixed filtrate, mixing, adding glycerol, castor oil, ethylparaben and liquid paraffin into the mixed filtrate, evaporating and concentrating to obtain paste, adding glycyrrhetinic acid into the paste, adding transdermal absorption enhancer, laurocapram and urea, and stirring to obtain the antifungal transdermal absorption ointment.
Further preferably, the antifungal transdermal absorption ointment is prepared by the following steps of:
step 1, washing turmeric, medicinal cyathula root and musk with water for 2-3 times, and then drying at 40-60 ℃; then grinding into powder, sieving with a 50-200 mesh sieve, and uniformly mixing to prepare mixed powder;
step 2, adding the mixed powder prepared in the step 1 into 200-400 parts of 85-95 wt% ethanol aqueous solution for mixing, performing reflux extraction for 2-3 times at the temperature of 60-80 ℃, wherein the reflux time is 2-3 hours each time, and filtering an extracting solution by using a 0.1-0.3 mu m microporous filter membrane after the reflux is finished to obtain a mixed filtrate; heating the mixed filtrate to 80-90 ℃ by adopting water bath heating, adding 10-20 parts of stearic acid and 4-8 parts of triethanolamine into the mixed filtrate, uniformly mixing, then adding 4-8 parts of glycerol, 2-7 parts of castor oil, 0.02-0.5 part of ethylparaben and 1-5 parts of liquid paraffin into the mixed filtrate, evaporating and concentrating in a water bath at 40-50 ℃ to obtain a paste with the relative density of 1.15-1.35, adding 1-5 parts of glycyrrhetinic acid into the paste, adding 5-10 parts of transdermal absorption enhancer, 1-5 parts of laurocapram and 1-5 parts of urea, and fully stirring to obtain the antifungal transdermal absorption ointment.
Preferably, the urea is hydroxyethyl urea.
Preferably, the preparation steps of the transdermal absorption enhancer are as follows:
s1, dissolving fatty acid methyl ester sodium sulfonate in water, adding dimethyl sulfoxide and N-methyl pyrrolidone, and mixing to prepare a mixed solution;
s2, adding cyanamide and acetaldehyde into the mixed solution prepared in the step S1, stirring, then adding a sodium chloride aqueous solution and an ethanol aqueous solution to prepare a reaction solution, centrifuging, collecting precipitates, dissolving the precipitates in water, filtering to obtain a mixed filtrate, and freeze-drying the obtained mixed filtrate to obtain functional powder;
s3, adding the functional powder prepared in the step S2 into water, then adding 3-indoleacetamide for mixing, adding 1, 3-butanediol and an emulsifier, heating and stirring, finally adding potassium hydroxide and isopropyl adipate, and mixing to obtain the transdermal absorption enhancer.
Further preferably, the preparation steps of the transdermal absorption enhancer are as follows, and the parts are all parts by weight:
s1, dissolving 1-2 parts of fatty acid methyl ester sodium sulfonate in 30-50 parts of water, adding 15-30 parts of dimethyl sulfoxide and 1-5 parts of N-methyl pyrrolidone, and mixing for 10-20 min to prepare a mixed solution;
s2, adding 20-30 parts of cyanamide and 1-10 parts of acetaldehyde into the mixed solution prepared in the step S1, stirring for 4-6 hours by using a stirrer, then adding 40-60 parts of 30-35 wt% sodium chloride aqueous solution and 10-30 parts of 70-80 wt% ethanol aqueous solution to prepare a reaction solution, centrifuging at a speed of 3500-5000 r/min for 8-15 min, collecting precipitates, dissolving the precipitates in 40-60 parts of water, filtering by using a 0.1-0.3 mu m microporous filter membrane to obtain a mixed filtrate, and freeze-drying the obtained mixed filtrate to obtain functional powder;
s3, adding the functional powder prepared in the step S2 into 70-100 parts of water, then adding 3-8 parts of 3-indoleacetamide, mixing for 10-20 min at room temperature, adding 1-3 parts of 1, 3-butanediol and 0.2-1 part of emulsifier, mixing for 10-30 min at the temperature of 60-70 ℃ and the stirring speed of 400-600 r/min, finally adding 0.01-0.2 part of potassium hydroxide and 0.1-2 parts of isopropyl adipate, mixing for 20-40 min at the speed of 800-1200 r/min, and obtaining the transdermal absorption enhancer.
In practical applications, the inventors found that the skin penetration enhancer has a merit of promoting the absorption of the pharmaceutically active ingredient into the skin, but has a technical problem of difficulty in storage, and the efficacy of the pharmaceutically active ingredient is lowered due to poor stability, and it is difficult to exert an antifungal effect. Therefore, the inventor makes further optimization, and uses the polysaccharide nanocrystal as a stabilizer of the transdermal absorption enhancer to improve the thermal stability and the anti-coalescence stability of the emulsion; the size and aspect ratio of the polysaccharide nanocrystals impart their ability to stabilize emulsions, facilitating the formation of a single or multi-layered interface at the surface of oil droplets, which in turn forms a network in the continuous phase to stabilize the emulsion.
Preferably, the preparation step of the transdermal absorption enhancer can also be as follows:
s1, dissolving 1-2 parts of fatty acid methyl ester sodium sulfonate in 30-50 parts of water, adding 15-30 parts of dimethyl sulfoxide and 1-5 parts of N-methyl pyrrolidone, and mixing for 10-20 min to prepare a mixed solution;
s2, adding 20-30 parts of cyanamide and 1-10 parts of acetaldehyde into the mixed solution prepared in the step S1, stirring for 4-6 hours by using a stirrer, then adding 40-60 parts of 30-35 wt% sodium chloride aqueous solution and 10-30 parts of 70-80 wt% ethanol aqueous solution to prepare a reaction solution, centrifuging at a speed of 3500-5000 r/min for 8-15 min, collecting precipitates, dissolving the precipitates in 40-60 parts of water, filtering by using a 0.1-0.3 mu m microporous filter membrane to obtain a mixed filtrate, and freeze-drying the obtained mixed filtrate to obtain functional powder;
s3, adding the functional powder prepared in the step S2 into 70-100 parts of water, then adding 3-8 parts of 3-indoleacetamide, mixing for 10-20 min at room temperature, adding 1-3 parts of 1, 3-butanediol and 0.2-1 part of emulsifier, mixing for 10-30 min at the temperature of 60-70 ℃ and the stirring speed of 400-600 r/min, finally adding 0.01-0.2 part of potassium hydroxide, 0.1-2 parts of isopropyl adipate and 0.05-0.2 part of nanocrystalline stabilizer, mixing for 20-40 min at the speed of 800-1200 r/min, and obtaining the transdermal absorption enhancer.
Preferably, the lyophilization parameters in step S2 are as follows: pre-freezing for 3-5 h at-32 to-38 ℃, and vacuumizing and drying after freezing, wherein the drying conditions are as follows: the vacuum degree is 2-5 Pa, a primary sublimation method is adopted to gradually heat the product, the freeze-drying box plate layer is respectively kept for 2-3 hours at 0 ℃, 5 ℃, 10 ℃ and 15 ℃ to make the ice crystals of the product disappear, and then the temperature is raised to 26-30 ℃ of the drying chamber and kept for 2-3 hours.
Preferably, the emulsifier in step S3 is one of isomeric dodecyl alcohol polyoxyethylene ether and fatty alcohol polyoxyethylene ether.
Preferably, the preparation method of the nanocrystal stabilizer in the step S3 is as follows, in parts by weight:
mixing 1-3 parts of cellulose and 20-30 parts of 1.5-4 wt% potassium chloride solution at 65-75 ℃, adjusting the pH of the mixed solution to 4-5 by using 1-2 mol/L hydrochloric acid, mixing for 3-5 h, and after the mixture is finished, centrifugally separating solids and freeze-drying to obtain freeze-dried powder A; mixing 20-30 parts of 5-8 wt% potassium hydroxide aqueous solution with the freeze-dried powder, treating for 4-8 h, and after the treatment, performing centrifugal separation on solids and freeze-drying to obtain freeze-dried powder B; mixing the freeze-dried powder B with 5-15 parts of 60-70 wt% sulfuric acid aqueous solution for 5-10 min, and then carrying out ultrasonic treatment on the mixture for 15-30 min at 550-850W and 28-40 kHz; and after the ultrasonic treatment is finished, performing centrifugal separation on solids and freeze-drying to obtain the nanocrystalline stabilizer.
Cyathula root, radix Cyathulae is neutral in nature, slightly bitter and sweet in taste. Removing blood stasis, dredging channels, promoting joint movement, and inducing diuresis for treating stranguria. Belongs to the blood-activating and menstruation-regulating herbs classified under the blood-activating and stasis-resolving herbs.
Turmeric root, rhizoma Curcumae Longae, warm in nature, bitter and pungent in flavor. Break blood and move qi, dredge meridians to stop pain. Belongs to the category of blood-activating and stasis-resolving herbs.
Musk, warm in nature and pungent in flavor. Inducing resuscitation, refreshing mind, promoting blood circulation, dredging channels, and relieving swelling and pain. Belongs to the field of resuscitation inducing medicine.
Glycyrrhetinic acid can reduce phospholipase activity to exert its antiinflammatory effect, inhibit beta-hydroxysteroid dehydrogenase expression, reduce glucocorticoid degradation, and regulate PI3K pathway to restore glucocorticoid sensitivity. Physiological effects include inhibition of angiogenesis, as well as effects in skin development, proliferation, differentiation and regeneration, increasing the level of ceramides and similar molecules in the stratum corneum, thereby reducing water loss.
The stratum corneum is the outermost layer of the skin and is the largest barrier. It consists of dead anucleated keratinocytes and intercellular lipids. Many compounds permeate into the skin through intercellular lipids, and the intercellular lipid gaps of the stratum corneum are narrow; the transcellular pathway through the cell will penetrate the cell membrane at least twice. In general, lipophilic compounds have greater skin permeability than hydrophilic compounds. If lipophilic compounds are present in the permeation pathway (intercellular pathway), it is possible to improve skin permeation. Glycyrrhetinic acid is a water-soluble polymer having a high adsorption capacity to keratinocytes, so that it does not penetrate deeply into the skin and stays on the surface. The interaction between the skin penetration enhancer formed by chemical reaction of fatty acid methyl ester sodium sulfonate, cyanamide and 3-indoleacetamide and lipid is strong, thereby enhancing the permeability of skin. Glycyrrhetinic acid can only enter skin through intracellular route, and transdermal absorption enhancer can enter skin through intercellular route. Therefore, the invention changes the skin permeation path under the action of the transdermal absorption enhancer by converting the glycyrrhetinic acid into the nano particles.
The invention adopts polyion complexation method to prepare the transdermal absorption enhancer so as to improve the permeability of the skin. First, the percutaneous absorption enhancer contains a surfactant, an oil-and-fat polyol, water and other compounds, and improves the spreadability of the ointment on the skin. The formation of glycyrrhetinic acid nanoparticles can alter the water solubility of the polymer, allowing it to penetrate into the skin via a more osmotic route. When applied to the skin, glycyrrhetinic acid exists in the form of nanoparticles, and glycyrrhetinic acid is released from the nanoparticles after penetrating into the skin to form free molecules. Furthermore, the transdermal absorption enhancer is used, and the transdermal absorption enhancer can be adsorbed to a living cell membrane after passing through the stratum corneum. The stratum corneum has a low calcium ion concentration and the calcium ion concentration increases in the direction of the dermis. Therefore, the transdermal absorption enhancer is not rapidly decomposed after being applied to the skin, and is slowly decomposed after penetrating into the dermis, and the glycyrrhetinic acid can enter the skin at a high concentration.
Due to the adoption of the technical scheme, compared with the prior art, the antifungal transdermal absorption ointment and the preparation method thereof have the advantages that: 1) the traditional Chinese medicine is used for 'treatment based on syndrome differentiation', and is scientifically decocted and concentrated into ointment through turmeric, medicinal cyathula root and musk, so that discomfort such as skin itch of patients can be effectively relieved; 2) the scientific proportion enhances the treatment effect of the ointment, saves the cost and reduces the side effect; 3) the skin penetration enhancer is formed by chemical reaction of fatty acid methyl ester sodium sulfonate, cyanamide and 3-indoleacetamide, enhances the skin permeability, is beneficial to the absorption of high-dose functional components, and has the functions of promoting blood circulation, removing blood stasis, diminishing inflammation and relieving pain; 4) the polysaccharide nanocrystal is used as a stabilizer of the transdermal absorption enhancer, so that the technical problem of low efficacy of active ingredients of the medicine due to poor stability is solved.
Detailed Description
Sources of the main raw materials in the examples:
turmeric: ou City of Ou province, Fujian province.
Radix cyathulae: the Yunan Wenshan Zhuang seedling family in the producing area is autonomous.
Musk: gansu Min county of origin.
Glycyrrhetinic acid: kunshancheng bioscience and technology limited, molecular formula: C30H46O4, molecular weight: 470.68, CAS number: 471-53-4.
Ethyl paraben: hubei hongtao bioengineering Limited, molecular formula: C9H10O3, molecular weight: 166.1739, CAS number: 120-47-8.
Sodium fatty acid methyl ester sulfonate: hubei Kovode chemical Co., Ltd, CAS number: 93348-22-2.
N-methylpyrrolidone: shandong Deno New Material science and technology, molecular weight: 99.13106, CAS number: 872-50-4.
Cyanamide: shandong Xuchen chemical science and technology Co., Ltd, melting point 46 ℃, boiling point 83 ℃, CAS number: 420-04-2.
3-indoleacetamide: southern Tong Runfeng petrochemical company, molecular weight: 174.1992, CAS number: 879-37-8.
Laurone: jinan Hui Jingchuan chemical company, molecular formula: C18H35NO, molecular weight: 281.4766, CAS number: 2078-71-9.
Hydroxyethyl urea: hubei Kovode chemical Co., Ltd., molecular weight: 104.113, CAS number: 59227-89-3.
Example 1
A method for preparing antifungal percutaneous absorption ointment comprises the following steps:
step 1, cleaning 0.6kg of turmeric, 0.4kg of medicinal cyathula root and 0.3kg of musk by water for 3 times, and then drying at 50 ℃; then grinding into powder, sieving with a 100-mesh sieve, and uniformly mixing to prepare mixed powder;
step 2, adding the mixed powder prepared in the step 1 into 30kg of 90 wt% ethanol aqueous solution for mixing, performing reflux extraction for 3 times at 70 ℃, wherein the reflux time is 2 hours each time, and filtering the extracting solution by using a 0.2-micrometer microporous filter membrane after the reflux is finished to obtain a mixed filtrate; heating the mixed filtrate to 85 ℃ by adopting water bath heating, adding 1.5kg of stearic acid and 0.6kg of triethanolamine into the mixed filtrate, uniformly mixing, then adding 0.6kg of glycerol, 0.5kg of castor oil, 0.01kg of ethylparaben and 0.3kg of liquid paraffin into the mixed filtrate, evaporating and concentrating in 45 ℃ water bath to obtain a paste with the relative density of 1.2, adding 0.3kg of glycyrrhetinic acid into the paste, adding 0.6kg of transdermal absorption enhancer, 0.2kg of laurocapram and 0.2kg of hydroxyethyl urea, and fully stirring to obtain the antifungal transdermal absorption ointment.
The preparation steps of the transdermal absorption enhancer in the step 2 are as follows:
s1, weighing 0.125kg of fatty acid methyl ester sodium sulfonate, dissolving the fatty acid methyl ester sodium sulfonate in 4kg of water, adding 2kg of dimethyl sulfoxide and 0.3kg of N-methylpyrrolidone, and mixing for 15min to prepare a mixed solution;
s2, adding 2.5kg of cyanamide and 0.5kg of acetaldehyde into the mixed solution prepared in the step S1, stirring for 5 hours by using a stirrer at the stirring speed of 300r/min, then adding 5kg of 35 wt% sodium chloride aqueous solution and 2kg of 75 wt% ethanol aqueous solution to prepare a reaction solution, centrifuging the reaction solution for 10 minutes at the speed of 4000r/min, collecting precipitates, dissolving the precipitates in 5kg of water, filtering by using a 0.2-micron microporous filter membrane to obtain a mixed filtrate, freeze-drying the obtained mixed filtrate, pre-freezing for 4 hours at-35 ℃, vacuumizing and drying after freezing, wherein the drying conditions are as follows: the vacuum degree is 3Pa, a one-time sublimation method is adopted to gradually heat the product, the freeze-drying box plate layer is respectively kept at 0 ℃, 5 ℃, 10 ℃ and 15 ℃ for 2.5h to ensure that the ice crystals of the product disappear, and then the temperature is raised to 28 ℃ in a drying chamber and kept for 3h to obtain functional powder;
s3, adding the functional powder prepared in the step S2 into 8kg of water, then adding 0.5kg of 3-indoleacetamide, mixing for 15min at room temperature, adding 0.2kg of 1, 3-butanediol and 0.05kg of fatty alcohol-polyoxyethylene ether, mixing for 20min at 65 ℃ and at the stirring speed of 500r/min, finally adding 0.01kg of potassium hydroxide and 0.1kg of isopropyl adipate, and mixing for 30min at 1000r/min to obtain the transdermal absorption enhancer.
Example 2
A method of preparing an antifungal transdermal absorption ointment, substantially the same as in example 1, with the only difference that: the preparation method of the transdermal absorption enhancer in the step 2 is inconsistent.
The preparation steps of the transdermal absorption enhancer in the step 2 are as follows:
s1, adding 2kg of dimethyl sulfoxide and 0.3kg of N-methyl pyrrolidone into 4kg of water, and mixing for 15min to prepare a mixed solution;
s2, adding 2.5kg of cyanamide and 0.5kg of acetaldehyde into the mixed solution prepared in the step S1, stirring for 5 hours by using a stirrer at the stirring speed of 300r/min, then adding 5kg of 35 wt% sodium chloride aqueous solution and 2kg of 75 wt% ethanol aqueous solution to prepare a reaction solution, centrifuging the reaction solution for 10 minutes at the speed of 4000r/min, collecting precipitates, dissolving the precipitates in 5kg of water, filtering by using a 0.2-micron microporous filter membrane to obtain a mixed filtrate, freeze-drying the obtained mixed filtrate, pre-freezing for 4 hours at-35 ℃, vacuumizing and drying after freezing, wherein the drying conditions are as follows: the vacuum degree is 3Pa, a one-time sublimation method is adopted to gradually heat the product, the freeze-drying box plate layer is respectively kept at 0 ℃, 5 ℃, 10 ℃ and 15 ℃ for 2.5h to ensure that the ice crystals of the product disappear, and then the temperature is raised to 28 ℃ in a drying chamber and kept for 3h to obtain functional powder;
s3, adding the functional powder prepared in the step S2 into 8kg of water, then adding 0.5kg of 3-indoleacetamide, mixing for 15min at room temperature, adding 0.2kg of 1, 3-butanediol and 0.05kg of fatty alcohol-polyoxyethylene ether, mixing for 20min at 65 ℃ and at the stirring speed of 500r/min, finally adding 0.01kg of potassium hydroxide and 0.1kg of isopropyl adipate, and mixing for 30min at 1000r/min to obtain the transdermal absorption enhancer.
Example 3
A method of preparing an antifungal transdermal absorption ointment, substantially the same as in example 1, with the only difference that: the preparation method of the transdermal absorption enhancer in the step 2 is inconsistent.
The preparation steps of the transdermal absorption enhancer in the step 2 are as follows:
s1, weighing 0.125kg of fatty acid methyl ester sodium sulfonate, dissolving the fatty acid methyl ester sodium sulfonate in 4kg of water, adding 2kg of dimethyl sulfoxide and 0.3kg of N-methylpyrrolidone, and mixing for 15min to prepare a mixed solution;
s2, adding 0.5kg of acetaldehyde into the mixed solution prepared in the step S1, stirring for 5 hours by using a stirrer at the stirring speed of 300r/min, then adding 5kg of 35 wt% sodium chloride aqueous solution and 2kg of 75 wt% ethanol aqueous solution to prepare a reaction solution, centrifuging the reaction solution at the speed of 4000r/min for 10 minutes, collecting precipitates, dissolving the precipitates in 5kg of water, filtering by using a 0.2-micron microporous filter membrane to obtain a mixed filtrate, carrying out freeze drying on the obtained mixed filtrate, carrying out pre-freezing at-35 ℃ for 4 hours, and carrying out vacuum drying after freezing, wherein the drying conditions are as follows: the vacuum degree is 3Pa, a one-time sublimation method is adopted to gradually heat the product, the freeze-drying box plate layer is respectively kept at 0 ℃, 5 ℃, 10 ℃ and 15 ℃ for 2.5h to ensure that the ice crystals of the product disappear, and then the temperature is raised to 28 ℃ in a drying chamber and kept for 3h to obtain functional powder;
s3, adding the functional powder prepared in the step S2 into 8kg of water, then adding 0.5kg of 3-indoleacetamide, mixing for 15min at room temperature, adding 0.2kg of 1, 3-butanediol and 0.05kg of fatty alcohol-polyoxyethylene ether, mixing for 20min at 65 ℃ and at the stirring speed of 500r/min, finally adding 0.01kg of potassium hydroxide and 0.1kg of isopropyl adipate, and mixing for 30min at 1000r/min to obtain the transdermal absorption enhancer.
Example 4
A method of preparing an antifungal transdermal absorption ointment, substantially the same as in example 1, with the only difference that: the preparation method of the transdermal absorption enhancer in the step 2 is inconsistent.
The preparation steps of the transdermal absorption enhancer in the step 2 are as follows:
s1, weighing 0.125kg of fatty acid methyl ester sodium sulfonate, dissolving the fatty acid methyl ester sodium sulfonate in 4kg of water, adding 2kg of dimethyl sulfoxide and 0.3kg of N-methylpyrrolidone, and mixing for 15min to prepare a mixed solution;
s2, adding 2.5kg of cyanamide and 0.5kg of acetaldehyde into the mixed solution prepared in the step S1, stirring for 5 hours by using a stirrer at the stirring speed of 300r/min, then adding 5kg of 35 wt% sodium chloride aqueous solution and 2kg of 75 wt% ethanol aqueous solution to prepare a reaction solution, centrifuging the reaction solution for 10 minutes at the speed of 4000r/min, collecting precipitates, dissolving the precipitates in 5kg of water, filtering by using a 0.2-micron microporous filter membrane to obtain a mixed filtrate, freeze-drying the obtained mixed filtrate, pre-freezing for 4 hours at-35 ℃, vacuumizing and drying after freezing, wherein the drying conditions are as follows: the vacuum degree is 3Pa, a one-time sublimation method is adopted to gradually heat the product, the freeze-drying box plate layer is respectively kept at 0 ℃, 5 ℃, 10 ℃ and 15 ℃ for 2.5h to ensure that the ice crystals of the product disappear, and then the temperature is raised to 28 ℃ in a drying chamber and kept for 3h to obtain functional powder;
s3, adding the functional powder prepared in the step S2 into 8kg of water, then adding 0.2kg of 1, 3-butanediol and 0.05kg of fatty alcohol-polyoxyethylene ether, mixing for 20min at 65 ℃ and at the stirring speed of 500r/min, finally adding 0.01kg of potassium hydroxide and 0.1kg of isopropyl adipate, and mixing for 30min at 1000r/min to obtain the transdermal absorption enhancer.
Example 5
A method for preparing antifungal percutaneous absorption ointment comprises the following steps:
step 1, cleaning 0.6kg of turmeric, 0.4kg of medicinal cyathula root and 0.3kg of musk by water for 3 times, and then drying at 50 ℃; then grinding into powder, sieving with a 100-mesh sieve, and uniformly mixing to prepare mixed powder;
step 2, adding the mixed powder prepared in the step 1 into 30kg of 90 wt% ethanol aqueous solution for mixing, performing reflux extraction for 3 times at 70 ℃, wherein the reflux time is 2 hours each time, and filtering the extracting solution by using a 0.2-micrometer microporous filter membrane after the reflux is finished to obtain a mixed filtrate; heating the mixed filtrate to 85 ℃ by adopting water bath heating, adding 1.5kg of stearic acid and 0.6kg of triethanolamine into the mixed filtrate, uniformly mixing, then adding 0.6kg of glycerol, 0.5kg of castor oil, 0.01kg of ethylparaben and 0.3kg of liquid paraffin into the mixed filtrate, evaporating and concentrating in 45 ℃ water bath to obtain a paste with the relative density of 1.2, adding 0.3kg of glycyrrhetinic acid into the paste, adding 0.6kg of transdermal absorption enhancer, 0.2kg of laurocapram and 0.2kg of hydroxyethyl urea, and fully stirring to obtain the antifungal transdermal absorption ointment.
The preparation steps of the transdermal absorption enhancer in the step 2 are as follows:
s1, weighing 0.125kg of fatty acid methyl ester sodium sulfonate, dissolving the fatty acid methyl ester sodium sulfonate in 4kg of water, adding 2kg of dimethyl sulfoxide and 0.3kg of N-methylpyrrolidone, and mixing for 15min to prepare a mixed solution;
s2, adding 2.5kg of cyanamide and 0.5kg of acetaldehyde into the mixed solution prepared in the step S1, stirring for 5 hours by using a stirrer at the stirring speed of 300r/min, then adding 5kg of 35 wt% sodium chloride aqueous solution and 2kg of 75 wt% ethanol aqueous solution to prepare a reaction solution, centrifuging the reaction solution for 10 minutes at the speed of 4000r/min, collecting precipitates, dissolving the precipitates in 5kg of water, filtering by using a 0.2-micron microporous filter membrane to obtain a mixed filtrate, freeze-drying the obtained mixed filtrate, pre-freezing for 4 hours at-35 ℃, vacuumizing and drying after freezing, wherein the drying conditions are as follows: the vacuum degree is 3Pa, a one-time sublimation method is adopted to gradually heat the product, the freeze-drying box plate layer is respectively kept at 0 ℃, 5 ℃, 10 ℃ and 15 ℃ for 2.5h to ensure that the ice crystals of the product disappear, and then the temperature is raised to 28 ℃ in a drying chamber and kept for 3h to obtain functional powder;
s3, adding the functional powder prepared in the step S2 into 8kg of water, then adding 0.5kg of 3-indoleacetamide, mixing for 15min at room temperature, adding 0.2kg of 1, 3-butanediol and 0.05kg of fatty alcohol-polyoxyethylene ether, mixing for 20min at 65 ℃ and at the stirring speed of 500r/min, finally adding 0.01kg of potassium hydroxide, 0.1kg of isopropyl adipate and 0.01kg of nanocrystalline stabilizer, and mixing for 30min at 1000r/min to obtain the transdermal absorption enhancer.
The preparation method of the nanocrystalline stabilizer in the step S3 is as follows:
mixing 1kg of cellulose and 20kg of potassium chloride solution with the concentration of 4 wt% at 65 ℃, adjusting the pH of the mixed solution to 5 by using hydrochloric acid with the concentration of 1mol/L, mixing for 3h, and after the mixture is finished, performing centrifugal separation on solids and freeze-drying to obtain freeze-dried powder A; mixing 20kg of 8 wt% potassium hydroxide aqueous solution with the freeze-dried powder, treating for 4-8 h, and after the treatment, performing centrifugal separation on solids and freeze-drying to obtain freeze-dried powder B; mixing the lyophilized powder B with 7.5kg of 65 wt% aqueous sulfuric acid solution for 5min, followed by sonication at 550W, 28kHz for 15 min; and after the ultrasonic treatment is finished, performing centrifugal separation on solids and freeze-drying to obtain the nanocrystalline stabilizer.
Comparative example 1
A method of preparing an antifungal transdermal absorption ointment, substantially the same as in example 1, with the only difference that: the preparation method of the transdermal absorption enhancer in the step 2 is inconsistent.
The preparation steps of the transdermal absorption enhancer in the step 2 are as follows:
s1, adding 2kg of dimethyl sulfoxide and 0.3kg of N-methyl pyrrolidone into 4kg of water, and mixing for 15min to prepare a mixed solution;
s2, adding 0.5kg of acetaldehyde into the mixed solution prepared in the step S1, stirring for 5 hours by using a stirrer at the stirring speed of 300r/min, then adding 5kg of 35 wt% sodium chloride aqueous solution and 2kg of 75 wt% ethanol aqueous solution to prepare a reaction solution, centrifuging the reaction solution at the speed of 4000r/min for 10 minutes, collecting precipitates, dissolving the precipitates in 5kg of water, filtering by using a 0.2-micron microporous filter membrane to obtain a mixed filtrate, carrying out freeze drying on the obtained mixed filtrate, carrying out pre-freezing at-35 ℃ for 4 hours, and carrying out vacuum drying after freezing, wherein the drying conditions are as follows: the vacuum degree is 3Pa, a one-time sublimation method is adopted to gradually heat the product, the freeze-drying box plate layer is respectively kept at 0 ℃, 5 ℃, 10 ℃ and 15 ℃ for 2.5h to ensure that the ice crystals of the product disappear, and then the temperature is raised to 28 ℃ in a drying chamber and kept for 3h to obtain functional powder;
s3, adding the functional powder prepared in the step S2 into 8kg of water, then adding 0.2kg of 1, 3-butanediol and 0.05kg of fatty alcohol-polyoxyethylene ether, mixing for 20min at 65 ℃ and at the stirring speed of 500r/min, finally adding 0.01kg of potassium hydroxide and 0.1kg of isopropyl adipate, and mixing for 30min at 1000r/min to obtain the transdermal absorption enhancer.
Comparative example 2
A method of preparing an antifungal transdermal absorption ointment, substantially the same as in example 1, with the only difference that: in the step 2, no percutaneous absorption enhancer is added.
Test example 1
Cumulative release amount test
Referring to the test method of the modern journal of food science and technology (preparation of glycyrrhetinic acid cream and lipolysis research, author: zu ling, university of wuhan, institute of medicine, 2009), 6 treated rat skins of the same thickness were fixed to a diffusion cell and coated with 2g of each of the samples of examples and comparative examples. The receiving solution is a physiological saline solution containing 40 wt% of ethanol, is subjected to constant-temperature water bath at 37 ℃, is rotated at 50r/min, is continuously stirred, is taken for three times at 6h, is 2.0mL each time, is respectively subjected to absorbance measurement at a wavelength of 253nm, and is averaged. A glycyrrhetinic acid solution for control was prepared with a physiological saline solution containing 40% ethanol, and its absorbance was measured at 253 nm. The receiver concentration was calculated as follows:
V＝(Treceiving liquid/TControl solution)×VControl solution
V is the receiving liquid concentration
VControl solutionAs the concentration of the control solution
TReceiving liquidIs the ultraviolet absorbance of the receiving solution
TControl solutionAs the ultraviolet absorbance of the control solution
The test statistics are shown in table 1.
Table 1, 6h cumulative release
Experimental protocol Cumulative burst size (μ g/mL)
Example 1 165
Example 2 143
Example 3 141
Example 4 146
Comparative example 1 121
Comparative example 2 119
As can be seen from the test results in Table 1, the most cumulative release amount of example 1 indicates the best transdermal effect, probably because glycyrrhetinic acid is a water-soluble polymer having a high adsorption capacity to keratinocytes, and glycyrrhetinic acid can enter the skin only through intracellular pathways, and thus it does not penetrate into the skin and stays on the surface. The interaction between the skin penetration enhancer formed by chemical reaction of fatty acid methyl ester sodium sulfonate, cyanamide and 3-indoleacetamide and lipid is strong by polyion complexation, and the skin penetration enhancer contains surfactant, oil polyol, water and other compounds and can enter skin through intercellular route. Through converting glycyrrhetinic acid into nano particles, the skin permeation path is changed under the action of a transdermal absorption enhancer. When applied to the skin, glycyrrhetinic acid exists in the form of nanoparticles, and glycyrrhetinic acid is released from the nanoparticles after penetrating into the skin to form free molecules. Furthermore, the transdermal absorption enhancer is used, and the transdermal absorption enhancer can be adsorbed to a living cell membrane after passing through the stratum corneum. The stratum corneum has a low calcium ion concentration and the calcium ion concentration increases in the direction of the dermis. Therefore, the transdermal absorption enhancer is not rapidly decomposed after being applied to the skin, and is slowly decomposed after penetrating into the dermis, and glycyrrhetinic acid can enter the skin at a high concentration, thereby enhancing the permeability of the skin.
Test example 2
Obesity degree test of mice
60 mice were randomly divided into 6 groups, and the abdomen of the mice was depilated corresponding to examples and comparative examples. 0.2g of the corresponding drug was uniformly applied to the gauze and fixed to the lower abdomen of the mouse with an adhesive tape. The dressing change was made at the same time every other day, and the weight, body length and food amount of the mice were recorded for 28 d. Mice were evaluated for obesity by Lee's index (L).
Figure BDA0003494530290000151
The test results are shown in Table 2
TABLE 2 Lee's index Change Rate
Figure BDA0003494530290000152
As can be seen from the test results in table 2, the rate of change of body weight and the rate of change of Lee's index in example 1 are the smallest, probably because glycyrrhetinic acid can exert its anti-inflammatory effect by reducing the activity of phospholipase, and glycyrrhetinic acid can also inhibit the expression of beta-hydroxysteroid dehydrogenase, thereby reducing the degradation of glucocorticoid, increasing the glucocorticoid content, and the effect of inhibiting body weight gain is more significant, thereby also indicating that the permeability of glycyrrhetinic acid in example 1 is the best.
Test example 3
Lipolysis Effect test
Selecting common experimental mice, quickly taking out epididymal fat pads, cutting fat tissues into pieces, weighing 200 mg/part, randomly dividing 42 parts into 7 groups, arranging a blank control group, placing the blank control group in a clean six-hole plate, mixing a culture solution by 0.5g and 3.5g of antifungal transdermal absorption ointment of examples and comparative examples, and mixing a culture solution of the blank group by 4g of water. Placing the six-hole plate in a shaking table, shaking and culturing at 37 deg.C for 90min, collecting 2.0mL each culture solution, centrifuging, collecting supernatant, measuring free fatty acid content with a kit, and evaluating the lipolysis effect of glycyrrhetinic acid.
The content of free amino acid in the blank group is 115.3 +/-14.2 mu mol/L, and the content of free amino acid in the examples and the comparative examples is more than 200 mu mol/L, which shows that the glycyrrhetinic acid in the antifungal transdermal absorption ointment prepared in the examples and the comparative examples can promote the release of in vitro fatty acid and has better lipolysis effect.
Test example 4
The bacteriostasis test is carried out according to the specific requirements of WS/T650-2019 'evaluation method for antibacterial and bacteriostasis effects'. The fungus used in the test was Candida albicans (ATCC 10231), said strain being provided by Northo Biotech, Inc. of Shanghai. The diluent adopts 0.03mol/L phosphate buffer solution with the pH value of 7.2; candida albicans was cultured using Sabouraud's agar medium. The Candida albicans is cultured for 72h, the final result is observed, the experiment is repeated for 3 times, and the result is averaged. The results of the bacteriostatic tests are shown in table 3.
TABLE 3
Bacteriostatic ratio (%)
Example 1 86
Example 5 97
The higher the bacteriostasis rate is, the better the bacteriostasis effect is, according to the definition in the WS/T650 plus 2019 'evaluation method of antibacterial and bacteriostasis effect' result judgment, the bacteriostasis rate is more than or equal to 50-90 percent, and the judgment has the bacteriostasis effect; the bacteriostasis rate is more than or equal to 90 percent, and the antibacterial effect is stronger. As can be seen from the comparison of the above examples, example 5 has a strong bacteriostatic action on Candida albicans, and the bacteriostatic action is superior to that of example 1. The reason for this may be that the polysaccharide nanocrystals act as stabilizers of the transdermal absorption enhancers to improve the thermal stability and anti-coalescence stability of the emulsion; the size and the aspect ratio of the polysaccharide nanocrystals endow the polysaccharide nanocrystals with the ability of stabilizing the emulsion, which is beneficial to forming a single-layer or multi-layer interface on the surface of oil drops, and further forming a network in a continuous phase to stabilize the emulsion, thereby solving the problem of low efficacy of active ingredients of the medicament due to poor stability.

Claims (6)

1. The antifungal transdermal absorption ointment is characterized by being prepared from the following raw materials in parts by weight: 4-8 parts of turmeric, 2-6 parts of medicinal cyathula root, 1-5 parts of musk, 2-6 parts of glycyrrhetinic acid, 10-20 parts of stearic acid, 4-8 parts of glycerol, 2-7 parts of castor oil, 0.01-0.2 part of ethylparaben, 1-3 parts of triethanolamine, 50-80 parts of water, 1-5 parts of liquid paraffin, 4-8 parts of transdermal absorption enhancer, 1-3 parts of laurocapram and 1-3 parts of urea;
the preparation method of the transdermal absorption enhancer comprises the following steps of:
s1, dissolving 1-2 parts of fatty acid methyl ester sodium sulfonate in 30-50 parts of water, adding 15-30 parts of dimethyl sulfoxide and 1-5 parts of N-methyl pyrrolidone, and mixing for 10-20 min to prepare a mixed solution;
s2, adding 20-30 parts of cyanamide and 1-10 parts of acetaldehyde into the mixed solution prepared in the step S1, stirring for 4-6 hours by using a stirrer, then adding 40-60 parts of 30-35 wt% sodium chloride aqueous solution and 10-30 parts of 70-80 wt% ethanol aqueous solution to prepare a reaction solution, centrifuging at a speed of 3500-5000 r/min for 8-15 min, collecting precipitates, dissolving the precipitates in 40-60 parts of water, filtering by using a 0.1-0.3 mu m microporous filter membrane to obtain a mixed filtrate, and freeze-drying the obtained mixed filtrate to obtain functional powder;
s3, adding the functional powder prepared in the step S2 into 70-100 parts of water, then adding 3-8 parts of 3-indoleacetamide, mixing for 10-20 min at room temperature, adding 1-3 parts of 1, 3-butanediol and 0.2-1 part of emulsifier, mixing for 10-30 min at the temperature of 60-70 ℃ and the stirring speed of 400-600 r/min, finally adding 0.01-0.2 part of potassium hydroxide, 0.1-2 parts of isopropyl adipate and 0.05-0.2 part of nanocrystalline stabilizer, mixing for 20-40 min at the speed of 800-1200 r/min, and obtaining the transdermal absorption enhancer;
the preparation method of the nanocrystalline stabilizer in the step S3 comprises the following steps of:
mixing 1-3 parts of cellulose and 20-30 parts of 1.5-4 wt% potassium chloride solution at 65-75 ℃, adjusting the pH of the mixed solution to 4-5 by using 1-2 mol/L hydrochloric acid, mixing for 3-5 h, and after the mixture is finished, centrifugally separating solids and freeze-drying to obtain freeze-dried powder A; mixing 20-30 parts of 5-8 wt% potassium hydroxide aqueous solution with the freeze-dried powder, treating for 4-8 h, and after the treatment, performing centrifugal separation on solids and freeze-drying to obtain freeze-dried powder B; mixing the freeze-dried powder B with 5-15 parts of 60-70 wt% sulfuric acid aqueous solution for 5-10 min, and then carrying out ultrasonic treatment on the mixture for 15-30 min at 550-850W and 28-40 kHz; and after the ultrasonic treatment is finished, performing centrifugal separation on solids and freeze-drying to obtain the nanocrystalline stabilizer.
2. The antifungal transdermal absorption ointment of claim 1, which is prepared from the following raw materials in parts by weight: 6 parts of turmeric, 4 parts of medicinal cyathula root, 3 parts of musk, 3 parts of glycyrrhetinic acid, 15 parts of stearic acid, 6 parts of glycerol, 5 parts of castor oil, 0.1 part of ethylparaben, 2 parts of triethanolamine, 60 parts of water, 3 parts of liquid paraffin, 6 parts of a transdermal absorption enhancer, 2 parts of laurocapram and 2 parts of urea.
3. The antifungal transdermal absorption ointment of claim 1 or 2, wherein: the urea is hydroxyethyl urea.
4. The antifungal transdermal absorption ointment of claim 1 or 2, wherein: the lyophilization parameters in step S2 are as follows: pre-freezing for 3-5 h at-32 to-38 ℃, and vacuumizing and drying after freezing, wherein the drying conditions are as follows: the vacuum degree is 2-5 Pa, a primary sublimation method is adopted to gradually heat the product, the freeze-drying box plate layer is respectively kept for 2-3 hours at 0 ℃, 5 ℃, 10 ℃ and 15 ℃ to make the ice crystals of the product disappear, and then the temperature is raised to 26-30 ℃ of the drying chamber and kept for 2-3 hours.
5. The antifungal transdermal absorption ointment of claim 1 or 2, wherein: and in the step S3, the emulsifier is one of isomeric dodecyl alcohol polyoxyethylene ether and fatty alcohol polyoxyethylene ether.
6. The antifungal transdermal absorption ointment according to any one of claims 1 to 5, which is prepared by the following method, wherein the parts are all parts by weight:
step 1, cleaning turmeric, medicinal cyathula root and musk by using water, and then drying; then grinding into powder, sieving, and mixing uniformly to prepare mixed powder;
step 2, adding the mixed powder prepared in the step 1 into an ethanol aqueous solution for mixing, performing reflux extraction, and filtering an extracting solution after the reflux is finished to obtain a mixed filtrate; heating the mixed filtrate, adding stearic acid and triethanolamine into the mixed filtrate, mixing, adding glycerol, castor oil, ethylparaben and liquid paraffin into the mixed filtrate, evaporating and concentrating to obtain paste, adding glycyrrhetinic acid into the paste, adding transdermal absorption enhancer, laurocapram and urea, and stirring to obtain the antifungal transdermal absorption ointment.
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Application publication date: 20220429