CN118078892A - External medicine for treating skin diseases and preparation method thereof - Google Patents

External medicine for treating skin diseases and preparation method thereof Download PDF

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CN118078892A
CN118078892A CN202410210773.6A CN202410210773A CN118078892A CN 118078892 A CN118078892 A CN 118078892A CN 202410210773 A CN202410210773 A CN 202410210773A CN 118078892 A CN118078892 A CN 118078892A
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skin diseases
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吴惠林
许璐洁
金蝉
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Second Affiliated Hospital of Xian Medical University
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Second Affiliated Hospital of Xian Medical University
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Abstract

The invention provides an external medicine for treating skin diseases and a preparation method thereof, and belongs to the technical field of medicines. The estradiol salicylate, the elsholtzia and the lithospermum mixed oil are prepared into a transdermal enhancer composition, and the transdermal enhancer composition is mixed with the water extracts of itraconazole/retinoic acid eutectic, dittany bark, coptis chinensis and tribulus terrestris and added into the temperature-sensitive hydrogel to prepare the external medicine for treating skin diseases. The external medicine for treating the skin diseases prepared by the invention adopts a method combining traditional Chinese medicine and western medicine, has high bioavailability, good safety, no irritation, no anaphylactic reaction, good antibacterial, skin protecting and antipruritic effects, can obviously improve and treat various skin diseases, and has wide application prospect.

Description

External medicine for treating skin diseases and preparation method thereof
Technical Field
The invention relates to the technical field of medicines, in particular to an external medicine for treating skin diseases and a preparation method thereof.
Background
Skin diseases are of a wide variety, and are mostly diseases caused by skin infection or allergy. Tinea pedis, tinea manuum, tinea cruris, tinea versicolor, onychomycosis (commonly called onychomycosis) are the most common skin diseases, the etiology comes from invasion of fungi into the epidermis of a patient, parasitic diseases in the epidermis are formed, and secondary infection can occur after the skin is broken. Taking tinea pedis as an example, the modern dermatologic therapeutics (civil military medical press, 1994 edition) divides tinea pedis into five types: 1. blister type. Clustered fire-dispersed blisters often occur at the toes and edges of the foot, with the thickness of the blisters forming annular scales after drying; 2. papular scales type. The low-grade inflammation and desquamation between the three toes and the four toes gradually spread to the foot sole, the foot margin and the heel, and the active pathological changes are erythema papules; 3. dipping erosion. The skin is usually soaked and whitened between three toes and four toes. The epidermis is stripped due to walking and friction, so that a flushing erosion surface is presented with a small amount of seepage; 4. hyperkeratosis type. Rough skin, keratinized thickening and easy chapping in winter; 5. tinea corporis type. Tinea pedis progresses toward the dorsum of the foot and appears as a semi-annular or multi-round lesion. Some patients have onychomycosis at the same time.
Common features of fungal dermatological disorders are: high incidence, infectivity, easy recurrence or reinfection. The part of refractory fungus infectious dermatoses comprises skin infection such as pustule, onychomycosis, fungus infectious granuloma, etc. in tinea capitis. At present, fungal infectious skin diseases are generally treated by oral and external antifungal agents. But has poor therapeutic responsiveness to partial refractory fungal infection such as tinea purulent, refractory onychomycosis, fungal infectious granuloma and subcutaneous fungal infection, long treatment period, easy occurrence of toxic and side effects such as drug liver injury, poor therapeutic effect and easy repetition.
Some medicines for treating skin diseases exist in the prior art, for example, chinese patent No. CN100360160C discloses a medicine for treating skin diseases and a preparation method thereof, which is prepared by adding paris rhizome, coptis root, baikal skullcap root, rhubarb, lithospermum, giant knotweed, gardenia and amur corktree bark into the raw materials according to a certain weight ratio, and preparing the raw materials into external powder, aqua, paste and ointment. Chinese patent application CN1363376A discloses a medicine for curing dermatosis. It is prepared from fungus mother, semen Cassiae without kernel, bran, bean skin, fresh orange peel and pollen through fermenting at defined temperature, activating for 17 days, immersing in water and filtering. The medicines have poor efficacy, can not exert the efficacy of the medicines on skin diseases rapidly, can not see the effect rapidly, and can not solve the pain of patients in time.
Disclosure of Invention
The invention aims to provide an external medicine for treating skin diseases and a preparation method thereof, and the prepared composition has the advantages of high bioavailability, good safety, no irritation, no anaphylactic reaction, good antibacterial, skin protecting and antipruritic effects, obvious improvement and treatment effects on various skin diseases and wide application prospect by adopting a method combining traditional Chinese medicine with western medicine.
The technical scheme of the invention is realized as follows:
The invention provides a preparation method of an external medicine for treating skin diseases, which comprises the steps of preparing a transdermal enhancer composition by using estradiol salicylate, elsholtzia and lithospermum mixed oil, mixing with water extracts of itraconazole/tretinoin eutectic crystal, cortex dictamni, coptis chinensis and tribulus terrestris, and adding the mixture into temperature-sensitive hydrogel to prepare the external medicine for treating skin diseases;
wherein the structure of the estradiol salicylate is shown as a formula I:
as a further improvement of the invention, the method comprises the following steps:
s1, preparing essential oil: drying herba Moslae and radix Arnebiae, pulverizing, and extracting with supercritical fluid to obtain essential oil;
s2, preparing a permeation enhancer composition: uniformly mixing estradiol salicylate and the essential oil prepared in the step S1 to prepare a transdermal enhancer composition;
S3, preparing a eutectic: dissolving itraconazole in dichloromethane, dissolving retinoic acid in ethanol, mixing the two solutions, volatilizing at room temperature, precipitating crystals, filtering and washing to obtain eutectic;
S4, preparation of a traditional Chinese medicine extract: cleaning cortex Dictamni Radicis, coptidis rhizoma and fructus Atriplicis Sibiricae, drying, pulverizing to obtain Chinese medicinal powder, adding into water, heating to boiling, extracting, filtering, washing, and drying to obtain Chinese medicinal extract;
S5, preparing an external medicine for treating skin diseases: dissolving chitosan in acid liquor, adding poloxamer P407 and poloxamer P188, expanding at 4 ℃, adding the transdermal enhancer composition prepared in the step S2, the eutectic prepared in the step S3 and the traditional Chinese medicine extract prepared in the step S4, and stirring and mixing uniformly to prepare the external medicine for treating skin diseases.
As a further improvement of the invention, the mass ratio of the elsholtzia to the lithospermum in the step S1 is 10-12:4-6, and the conditions of the supercritical fluid extraction are as follows: the pressure is 27-32MPa, the temperature is 32-37 ℃ and the time is 60-90min, the entrainer is ethanol, and the adding amount of the entrainer is 1.5-2.5wt%.
As a further improvement of the invention, the mass ratio of the estradiol salicylate to the essential oil in the step S2 is 1-2:5-7, and the preparation method of the estradiol salicylate is as follows: dissolving 1 molar equivalent of alpha-estradiol in toluene, adding 1-1.1 molar equivalent of salicylic acid and 0.1-0.15 molar equivalent of concentrated sulfuric acid, heating, refluxing and stirring for reaction for 5-7h, washing, removing the solvent under reduced pressure, and separating by column chromatography to obtain the estradiol salicylate.
As a further improvement of the invention, in the step S3, the mass ratio of itraconazole to dichloromethane is 2-4:100, the mass ratio of retinoic acid to ethanol is 5-7:100, and the room temperature volatilization time is 5-7d.
As a further improvement of the invention, in the step S4, the mass ratio of the cortex dictamni, the coptis chinensis and the tribulus terrestris is 3-5:2-4:7-10, the solid-liquid ratio of the traditional Chinese medicine powder and the water is 1:5-10g/mL, and the extraction time is 3-5h.
As a further improvement of the invention, the acid solution in the step S5 is 2-3wt% of acetic acid or lactic acid solution, and the mass ratio of the chitosan, the poloxamer P407 and the poloxamer P188 to the transdermal enhancer composition, the eutectic and the traditional Chinese medicine extract is 20-25:5-7:0.5-1:1-2:3-4:7-10, wherein the expansion time is 20-24h.
As a further improvement of the invention, the method specifically comprises the following steps:
S1, preparing essential oil: drying 10-12 parts by weight of elsholtzia and 4-6 parts by weight of lithospermum, crushing, and extracting by supercritical fluid to obtain essential oil;
the conditions of the supercritical fluid extraction are as follows: the pressure is 27-32MPa, the temperature is 32-37 ℃ and the time is 60-90min, the entrainer is ethanol, and the adding amount of the entrainer is 1.5-2.5wt%;
S2, preparing a permeation enhancer composition: uniformly mixing 1-2 parts by weight of estradiol salicylate and 5-7 parts by weight of essential oil prepared in the step S1 to prepare a permeation enhancer composition;
S3, preparing a eutectic: dissolving 2-4 parts by weight of itraconazole in 100 parts by weight of dichloromethane, dissolving 5-7 parts by weight of retinoic acid in 100 parts by weight of ethanol, mixing the two, volatilizing the mixture at room temperature for 5-7d, precipitating crystals, filtering and washing to obtain eutectic;
s4, preparation of a traditional Chinese medicine extract: cleaning 3-5 parts by weight of cortex dictamni, 2-4 parts by weight of coptis chinensis and 7-10 parts by weight of tribulus terrestris, drying, crushing to obtain traditional Chinese medicine powder, adding the traditional Chinese medicine powder into water, heating to boiling and extracting for 3-5 hours, filtering, washing and drying to obtain a traditional Chinese medicine extract, wherein the solid-liquid ratio of the traditional Chinese medicine powder to the water is 1:5-10 g/mL;
S5, preparing an external medicine for treating skin diseases: dissolving 20-25 parts by weight of chitosan in 500 parts by weight of acid liquor, adding 5-7 parts by weight of poloxamer P407 and 0.5-1 part by weight of poloxamer P188, expanding for 20-24 hours at 4 ℃, adding 1-2 parts by weight of the transdermal enhancer composition prepared in the step S2, 3-4 parts by weight of the eutectic prepared in the step S3 and 7-10 parts by weight of the traditional Chinese medicine extract prepared in the step S4, and uniformly stirring and mixing to prepare the external medicine for treating the skin diseases.
The invention further protects an external medicine for treating skin diseases, which is prepared by the preparation method.
The invention further provides application of the external medicine for treating skin diseases in preparing medicines for treating allergic skin diseases, skin inflammation, tinea pedis, tinea manuum, tinea cruris, sweat stain and onychomycosis.
The invention has the following beneficial effects: according to the invention, the estradiol salicylate which is a penetration-promoting compound is prepared, on one hand, the problem that salicylic acid is strong in irritation when being singly used is avoided, and meanwhile, the prepared estradiol salicylate has a good penetration-promoting effect, wherein the estradiol part can increase lipid fluidity by disturbing an intercellular lipid bilayer structure; improving the solubility of the drug, thereby changing the thermodynamic activity of the drug; the salicylate part can reduce the phase transition temperature of the lipid of the horny layer by destroying the conformational sequence of the lipid bilayer of the horny layer, so that the prepared estradiol salicylate has good transdermal absorption promoting effect.
The lithospermum volatile oil can improve excessive keratinization and hypoplastic phenomenon of plaque psoriasis, thin skin lesions and accelerate the regression of rash. The elsholtzia volatile oil contains thymol, carvacrol, p-cymene, gamma-terpene and the like, and has good antibacterial and bactericidal effects. The essential oil formed by combining the two has good effects of resisting bacteria, sterilizing and improving skin, has stronger transdermal absorption promoting capability, higher safety and small skin irritation, and can exert synergistic effect with estradiol salicylate and exert stronger treatment effect.
Itraconazole is contained in sebum in a multiple of the plasma value, high concentration can be maintained for 7 days after stopping treatment, and meanwhile, itraconazole can be firmly combined with epidermis and cutin, and is no longer present in blood circulation, so that the toxic and side effects are greatly reduced. But it is poorly water-soluble. Retinoic acid is a compound structurally similar to vitamin a that helps patients alleviate the problems associated with skin disorders. The itraconazole and the retinoic acid are mixed to prepare the eutectic, so that the solubility and the bioavailability of the itraconazole are greatly improved, the drug effect is obviously improved, and the itraconazole has obvious improvement and treatment effects on skin diseases under the synergistic effect.
The extracts of the Chinese medicinal materials of the cortex dictamni, the coptis chinensis and the tribulus terrestris have good antibacterial and skin protecting effects. The coptis extract has obvious inhibiting effect on the synthesis and renewal of the lipid of the psoriasis epidermic cells. The fructus Atriplicis Sibiricae extract has exfoliative effect of tretinoin. The cortex Dictamni Radicis extract has good antipruritic effect, and can keep skin dry, thereby inhibiting fungi and bacteria proliferation, and radically treating infectious dermatoses.
The active component is added into the temperature-sensitive hydrogel, the gel temperature of the temperature-sensitive hydrogel is about 36 ℃, so that the prepared external medicine for treating the skin diseases is in a solution state at room temperature, and can be quickly converted into a gel state after being smeared on the skin, the residence time of the external medicine for treating the skin diseases on the skin is greatly prolonged, the contact time of the medicine and the skin is greatly prolonged, the effect of delaying the release of the medicine is achieved, the action time is prolonged, the medicine effect is better exerted, and the effect is better.
The external medicine for treating the skin diseases prepared by the invention adopts a method combining traditional Chinese medicine and western medicine, has high bioavailability, good safety, no irritation, no anaphylactic reaction, good antibacterial, skin protecting and antipruritic effects, can obviously improve and treat various skin diseases, and has wide application prospect.
Detailed Description
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Preparation example 1 preparation of estradiol salicylate
The synthetic route is as follows:
The method comprises the following steps: dissolving 0.1mol of alpha-estradiol in 200mL of toluene, adding 0.1mol of salicylic acid and 0.01mol of concentrated sulfuric acid, heating, refluxing and stirring for reaction for 6 hours, washing with saturated sodium carbonate aqueous solution, taking an oil layer, removing a solvent under reduced pressure, and separating by column chromatography (ethyl acetate: petroleum ether volume ratio=1:20) to obtain the estradiol salicylate. ESI-MS calculated: c 33H35O6 (m+h) +527.24, found: 527.2, yield 42%.
Nuclear magnetic results of novel transdermal absorption enhancers ：1H NMR(300MHz,CDCl3)δ7.97(d,J＝7.5Hz,1H),7.80(d,J＝6.7Hz,1H),7.35(m,1H),7.29(m,1H),7.05(d,J＝6.0Hz,1H),6.8-6.96(m,6H),5.0(br,2H),3.89(t,1H),2.8-2.9(m,3H),1.40-1.87(m,11H),1.12-1.29(m,6H).
Example 1
The embodiment provides a preparation method of an external medicine for treating skin diseases, which specifically comprises the following steps:
s1, preparing essential oil: drying 10 parts by weight of elsholtzia and 4 parts by weight of lithospermum, crushing, and extracting by using a supercritical fluid to obtain essential oil;
The conditions of the supercritical fluid extraction are as follows: the pressure is 27MPa, the temperature is 32 ℃ and the time is 60min, the entrainer is ethanol, and the adding amount of the entrainer is 1.5wt%;
S2, preparing a permeation enhancer composition: 1 part by weight of the estradiol salicylate prepared in preparation example 1 and 5 parts by weight of the essential oil prepared in step S1 are stirred and mixed for 10 minutes to prepare a penetration enhancer composition;
S3, preparing a eutectic: 2 parts by weight of itraconazole is dissolved in 100 parts by weight of dichloromethane, 5 parts by weight of retinoic acid is dissolved in 100 parts by weight of ethanol, the two are stirred and mixed for 30min, the mixture is volatilized for 5 days at room temperature, crystals are separated out, and the mixture is filtered and washed to prepare eutectic;
S4, preparation of a traditional Chinese medicine extract: cleaning 3 parts by weight of cortex dictamni, 2 parts by weight of coptis chinensis and 7 parts by weight of tribulus terrestris, drying, crushing to obtain traditional Chinese medicine powder, adding the traditional Chinese medicine powder into water, heating to boiling for extraction for 3 hours, filtering, washing and drying to obtain a traditional Chinese medicine extract, wherein the solid-to-liquid ratio of the traditional Chinese medicine powder to the water is 1:5 g/mL;
S5, preparing an external medicine for treating skin diseases: dissolving 20 parts by weight of chitosan in 500 parts by weight of 2wt% acetic acid solution, adding 5 parts by weight of poloxamer P407 and 0.5 part by weight of poloxamer P188, expanding for 20 hours at 4 ℃, adding 1 part by weight of the transdermal enhancer composition prepared in the step S2, 3 parts by weight of the eutectic prepared in the step S3 and 7 parts by weight of the traditional Chinese medicine extract prepared in the step S4, and stirring and mixing for 30 minutes to prepare the external medicine for treating skin diseases.
Example 2
The embodiment provides a preparation method of an external medicine for treating skin diseases, which specifically comprises the following steps:
s1, preparing essential oil: drying 12 parts by weight of elsholtzia and 6 parts by weight of lithospermum, crushing, and extracting by using a supercritical fluid to obtain essential oil;
the conditions of the supercritical fluid extraction are as follows: the pressure is 32MPa, the temperature is 37 ℃ and the time is 90min, the entrainer is ethanol, and the adding amount of the entrainer is 2.5wt%;
S2, preparing a permeation enhancer composition: 2 parts by weight of the estradiol salicylate prepared in preparation example 1 and 7 parts by weight of the essential oil prepared in step S1 are stirred and mixed for 10 minutes to prepare a penetration enhancer composition;
S3, preparing a eutectic: dissolving 4 parts by weight of itraconazole in 100 parts by weight of dichloromethane, dissolving 7 parts by weight of retinoic acid in 100 parts by weight of ethanol, stirring and mixing the two for 30min, volatilizing the mixture at room temperature for 7d, precipitating crystals, filtering and washing to obtain eutectic;
S4, preparation of a traditional Chinese medicine extract: cleaning 5 parts by weight of cortex dictamni, 4 parts by weight of coptis chinensis and 10 parts by weight of tribulus terrestris, drying, crushing to obtain traditional Chinese medicine powder, adding the traditional Chinese medicine powder into water, heating to boiling for extraction for 5 hours, filtering, washing and drying, wherein the solid-to-liquid ratio of the traditional Chinese medicine powder to the water is 1:10g/mL, and obtaining the traditional Chinese medicine extract;
S5, preparing an external medicine for treating skin diseases: dissolving 25 parts by weight of chitosan in 500 parts by weight of 3wt% lactic acid solution, adding 7 parts by weight of poloxamer P407 and 1 part by weight of poloxamer P188, expanding at 4 ℃ for 24 hours, adding 2 parts by weight of the transdermal enhancer composition prepared in the step S2, 4 parts by weight of the eutectic prepared in the step S3 and 10 parts by weight of the traditional Chinese medicine extract prepared in the step S4, and stirring and mixing for 30 minutes to prepare the external medicine for treating skin diseases.
Example 3
The embodiment provides a preparation method of an external medicine for treating skin diseases, which specifically comprises the following steps:
s1, preparing essential oil: drying 11 parts by weight of elsholtzia and 5 parts by weight of lithospermum, crushing, and extracting by using a supercritical fluid to obtain essential oil;
The conditions of the supercritical fluid extraction are as follows: the pressure is 30MPa, the temperature is 35 ℃ and the time is 75min, the entrainer is ethanol, and the adding amount of the entrainer is 2wt%;
S2, preparing a permeation enhancer composition: 1.5 parts by weight of the estradiol salicylate prepared in preparation example 1 and 6 parts by weight of the essential oil prepared in step S1 are stirred and mixed for 10 minutes to prepare a penetration enhancer composition;
S3, preparing a eutectic: dissolving 3 parts by weight of itraconazole in 100 parts by weight of dichloromethane, dissolving 6 parts by weight of retinoic acid in 100 parts by weight of ethanol, stirring and mixing the two for 30min, volatilizing the mixture at room temperature for 6d, precipitating crystals, filtering and washing to obtain eutectic;
S4, preparation of a traditional Chinese medicine extract: cleaning 4 parts by weight of cortex dictamni, 3 parts by weight of coptis chinensis and 8 parts by weight of tribulus terrestris, drying, crushing to obtain traditional Chinese medicine powder, adding the traditional Chinese medicine powder into water, heating to boiling for extraction for 4 hours, filtering, washing and drying to obtain a traditional Chinese medicine extract, wherein the solid-to-liquid ratio of the traditional Chinese medicine powder to the water is 1:7 g/mL;
S5, preparing an external medicine for treating skin diseases: 22 parts by weight of chitosan is dissolved in 500 parts by weight of 2.5wt% lactic acid solution, 6 parts by weight of poloxamer P407 and 0.7 part by weight of poloxamer P188 are added, the mixture is expanded for 22 hours at 4 ℃, 1.5 parts by weight of the transdermal enhancer composition prepared in the step S2, 3.5 parts by weight of the eutectic prepared in the step S3 and 8 parts by weight of the traditional Chinese medicine extract prepared in the step S4 are added, and the mixture is stirred and mixed for 30 minutes to prepare the external medicine for treating skin diseases.
Comparative example 1
In comparison with example 3, the difference is that no arnebia root is added in step S1.
Comparative example 2
In comparison with example 3, the difference is that no elsholtzia was added in step S1.
Comparative example 3
The difference from example 3 is that no essential oil is added in step S2.
Comparative example 4
In comparison with example 3, the difference is that in step S2, estradiol salicylate was not added.
Comparative example 5
In comparison with example 3, the difference is that step S3 is not performed, and 3.5 parts by weight of the co-crystal in step S5 is replaced by a mixture of itraconazole and retinoic acid in a mass ratio of 1:2.
Comparative example 6
In comparison with example 3, the difference is that no permeation enhancer composition is added in step S5.
Comparative example 7
The difference from example 3 is that no eutectic is added in step S5.
Comparative example 8
The difference from example 3 is that no extract of the traditional Chinese medicine is added in step S5.
Comparative example 9
Compared with example 3, the difference is that the active component is not added into the temperature sensitive hydrogel in the step S5, and the preparation method is as follows:
Mixing 1.5 parts by weight of the transdermal enhancer composition prepared in the step S2, 3.5 parts by weight of the eutectic crystal prepared in the step S3 and 8 parts by weight of the traditional Chinese medicine extract prepared in the step S4, adding the mixture into 530 parts by weight of water, and stirring and uniformly mixing to prepare the external medicine for treating the skin diseases.
Test example 1 determination of the Low Critical transition temperature (LCST) of hydrogels
The LCST of the hydrogel was determined by an ultraviolet spectrophotometer and the absorbance of the dermatological agent for external use prepared in examples 1-3 was measured at a wavelength of 540nm at 25-45 ℃. LCST is defined as the temperature at which the absorbance increases by 50% compared to the initial absorbance. The results are shown in Table 1.
TABLE 1
Group of LCST(℃)
Example 1 35.2
Example 2 34.9
Example 3 35.5
As is clear from the above table, when the temperature of the external preparation for treating skin diseases prepared in examples 1 to 3 is lower than LCST, the hydrogel is in a hydrophilic state due to hydrogen bonding, and shows a transparent liquid, and the absorbance thereof is almost 0%; while as the temperature increases above LCST, hydrophobic moieties aggregate and water molecules are extruded from the polymer chains to form a gel state, the solution becomes opaque and the absorbance increases dramatically, and it can be seen that at 36 ℃ the resulting hydrogel converts to a gel state and exerts better efficacy.
Test example 2
Guinea pigs were randomly divided into 15 groups, 10 in each of control, model, positive drug, examples 1-3 and comparative examples 1-9. The other groups of guinea pigs were dehaired on both sides of the back 1d prior to the experiment, with an area of about 2cm x 2cm, except for the control group, which was shaved on the day of the experiment with Tu Zhimin, 25 μl of 5%1-chloro-2, 4-dinitrobenzene solution (olive oil as solvent). After two weeks, 100. Mu.L of 0.1% 1-chloro-2, 4-dinitrobenzene solution was applied to the inner side of the right ear of guinea pigs as a challenge, 1 time per week, four times continuously. Local swelling occurs in the coated part 48h after the last excitation, excessive hyperplasia, hyperkeratosis, erythema, scale, edema, scratch and the like can be seen in the skin after 72h, and the successful molding is indicated by the control group being coated with the same amount of physiological saline. After successful molding, the control group and the model group are coated on the skin to be given with normal saline, the positive medicine group is coated with paeonol ointment, and the corresponding prepared external medicines for treating skin diseases are respectively given in examples 1-3 and comparative examples 1-9, and the dosage is 0.2g/cm 2. The administration was continued for 7d 1 time a day.
1. Skin lesion symptom score: the last day of treatment, mice of each group were observed for skin dermatitis conditions on the back, including erythema, papules or oedema, exudation or crusting, exfoliation, dryness and lichenification, with each clinical symptom scored on a scale of 0 (none), 1 (mild), 2 (moderate) and 3 (severe).
2. Ear thickness: the last day of treatment, the thickness of the ear skin of each group of guinea pigs was measured and the thickening of the skin of each group was compared.
3. Number of scratches: the last day of treatment, the number of scratches was observed and recorded for the number of times the shaved area was scratched for 30min per group of guinea pigs over the same period of time.
TABLE 2
Annotation: * P <0.05 compared to the control group; # is P <0.05 compared to model group.
As can be seen from the above table, the external medicine for treating skin diseases prepared in the embodiments 1-3 of the invention can well relieve itching and relieve damage after skin allergy.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.

Claims (10)

1. A preparation method of an external medicine for treating skin diseases is characterized in that a transdermal enhancer composition is prepared by mixing estradiol salicylate, elsholtzia and lithospermum mixed oil, and the transdermal enhancer composition is mixed with water extracts of itraconazole/tretinoin eutectic crystal, cortex dictamni, coptis chinensis and tribulus terrestris, and then the mixture is added into temperature-sensitive hydrogel to prepare the external medicine for treating skin diseases;
wherein the structure of the estradiol salicylate is shown as a formula I:
2. the method of manufacturing according to claim 1, comprising the steps of:
s1, preparing essential oil: drying herba Moslae and radix Arnebiae, pulverizing, and extracting with supercritical fluid to obtain essential oil;
s2, preparing a permeation enhancer composition: uniformly mixing estradiol salicylate and the essential oil prepared in the step S1 to prepare a transdermal enhancer composition;
S3, preparing a eutectic: dissolving itraconazole in dichloromethane, dissolving retinoic acid in ethanol, mixing the two solutions, volatilizing at room temperature, precipitating crystals, filtering and washing to obtain eutectic;
S4, preparation of a traditional Chinese medicine extract: cleaning cortex Dictamni Radicis, coptidis rhizoma and fructus Atriplicis Sibiricae, drying, pulverizing to obtain Chinese medicinal powder, adding into water, heating to boiling, extracting, filtering, washing, and drying to obtain Chinese medicinal extract;
S5, preparing an external medicine for treating skin diseases: dissolving chitosan in acid liquor, adding poloxamer P407 and poloxamer P188, expanding at 4 ℃, adding the transdermal enhancer composition prepared in the step S2, the eutectic prepared in the step S3 and the traditional Chinese medicine extract prepared in the step S4, and stirring and mixing uniformly to prepare the external medicine for treating skin diseases.
3. The preparation method according to claim 2, wherein the mass ratio of the elsholtzia to the lithospermum in the step S1 is 10-12:4-6, and the conditions of the supercritical fluid extraction are as follows: the pressure is 27-32MPa, the temperature is 32-37 ℃ and the time is 60-90min, the entrainer is ethanol, and the adding amount of the entrainer is 1.5-2.5wt%.
4. The preparation method according to claim 2, wherein the mass ratio of the estradiol salicylate to the essential oil in the step S2 is 1-2:5-7, and the estradiol salicylate is prepared by the following steps: dissolving 1 molar equivalent of alpha-estradiol in toluene, adding 1-1.1 molar equivalent of salicylic acid and 0.1-0.15 molar equivalent of concentrated sulfuric acid, heating, refluxing and stirring for reaction for 5-7h, washing, removing the solvent under reduced pressure, and separating by column chromatography to obtain the estradiol salicylate.
5. The preparation method according to claim 2, wherein in the step S3, the mass ratio of itraconazole to dichloromethane is 2-4:100, the mass ratio of retinoic acid to ethanol is 5-7:100, and the room temperature volatilization time is 5-7d.
6. The preparation method according to claim 2, wherein in the step S4, the mass ratio of the cortex dictamni, the coptis chinensis and the tribulus terrestris is 3-5:2-4:7-10, the solid-to-liquid ratio of the traditional Chinese medicine powder and the water is 1:5-10g/mL, and the extraction time is 3-5h.
7. The preparation method according to claim 2, wherein the acid solution in step S5 is 2-3wt% acetic acid or lactic acid solution, and the mass ratio of chitosan, poloxamer P407 and poloxamer P188, the transdermal enhancer composition, the eutectic crystal, and the traditional Chinese medicine extract is 20-25:5-7:0.5-1:1-2:3-4:7-10, wherein the expansion time is 20-24h.
8. The preparation method according to claim 2, characterized by comprising the following steps:
S1, preparing essential oil: drying 10-12 parts by weight of elsholtzia and 4-6 parts by weight of lithospermum, crushing, and extracting by supercritical fluid to obtain essential oil;
the conditions of the supercritical fluid extraction are as follows: the pressure is 27-32MPa, the temperature is 32-37 ℃ and the time is 60-90min, the entrainer is ethanol, and the adding amount of the entrainer is 1.5-2.5wt%;
S2, preparing a permeation enhancer composition: uniformly mixing 1-2 parts by weight of estradiol salicylate and 5-7 parts by weight of essential oil prepared in the step S1 to prepare a permeation enhancer composition;
S3, preparing a eutectic: dissolving 2-4 parts by weight of itraconazole in 100 parts by weight of dichloromethane, dissolving 5-7 parts by weight of retinoic acid in 100 parts by weight of ethanol, mixing the two, volatilizing the mixture at room temperature for 5-7d, precipitating crystals, filtering and washing to obtain eutectic;
s4, preparation of a traditional Chinese medicine extract: cleaning 3-5 parts by weight of cortex dictamni, 2-4 parts by weight of coptis chinensis and 7-10 parts by weight of tribulus terrestris, drying, crushing to obtain traditional Chinese medicine powder, adding the traditional Chinese medicine powder into water, heating to boiling and extracting for 3-5 hours, filtering, washing and drying to obtain a traditional Chinese medicine extract, wherein the solid-liquid ratio of the traditional Chinese medicine powder to the water is 1:5-10 g/mL;
S5, preparing an external medicine for treating skin diseases: dissolving 20-25 parts by weight of chitosan in 500 parts by weight of acid liquor, adding 5-7 parts by weight of poloxamer P407 and 0.5-1 part by weight of poloxamer P188, expanding for 20-24 hours at 4 ℃, adding 1-2 parts by weight of the transdermal enhancer composition prepared in the step S2, 3-4 parts by weight of the eutectic prepared in the step S3 and 7-10 parts by weight of the traditional Chinese medicine extract prepared in the step S4, and uniformly stirring and mixing to prepare the external medicine for treating the skin diseases.
9. A medicament for external use for treating skin diseases, which is prepared by the preparation method of any one of claims 1 to 8.
10. Use of the external medicament for treating skin diseases according to claim 9 for preparing medicament for treating allergic skin diseases, skin inflammation, tinea pedis, tinea manuum, tinea cruris, sweat stain and onychomycosis.
CN202410210773.6A 2024-02-26 2024-02-26 External medicine for treating skin diseases and preparation method thereof Pending CN118078892A (en)

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