CN112007030A - Oil-in-water type compound ketoconazole nano-medicament and preparation method thereof - Google Patents

Abstract

The invention discloses an oil-in-water type compound ketoconazole nano-medicament, which has the particle size of 1-100 nm and consists of the following raw materials in percentage by mass: 0.01-8.0 percent of ketoconazole, 0.01-10 percent of eugenol, 0.001-5.0 percent of clobetasol propionate, 25.0-45.0 percent of surfactant, 0-10.0 percent of cosurfactant, 0.1-25.0 percent of oil and the balance of distilled water. The medicine can be used for treating intractable dermatophytosis, candidiasis, chronic mucocutaneous candidiasis, dermatitis blastomycosis, coccidioidomycosis, histoplasmosis, pigmented mycosis, paracoccidioidomycosis, dermatomycosis, tinea versicolor and tinea due to dermatophyte and yeast, skin inflammation and pruritus. The medicine has the advantages of strong permeability, good stability, good wettability, lasting action time, obvious effect, low cost, simple preparation method and convenient popularization and application.

Description

Oil-in-water type compound ketoconazole nano-medicament and preparation method thereof

Technical Field

The invention belongs to the field of medicines, relates to a novel compound formulation of ketoconazole, eugenol and clobetasol propionate, and particularly relates to an oil-in-water compound ketoconazole nano-drug and a preparation method thereof.

Background

At present, the medicines for clinically treating skin diseases mainly comprise compound ointment, injection and oral dosage forms, but most of the medicines only aim at mycosis, acariasis or eczema, the diseases are frequently simultaneously attacked, and the medicines for treating the skin diseases are rarely reported. Although the oral preparation is easy to dissolve in gastric acid and absorb, the distribution is wide after absorption, the blood concentration fluctuation is large, many adverse reactions such as nausea, vomiting, abdominal pain, headache and the like are brought, and liver damage and anaphylactic reaction are occasionally caused. Although ointment and other external preparations can alleviate adverse reactions and expand the clinical application range, the ointment and other external preparations have the defects of unsatisfactory transdermal effect, poor stability and low bioavailability, and the skin penetration enhancers such as azone, DMF, DMSO and the like are required to be used for increasing the transdermal absorption effect.

Disclosure of Invention

Aiming at the problems and the defects in the prior art, the invention aims to provide the oil-in-water type compound ketoconazole nano-medicament which has the advantages of good transdermal absorption effect, high bioavailability, high medicament stability, high solubility, good sustained release property, good treatment effect and ideal medicament loading rate, treats common main skin diseases of pets, and can meet the clinical requirement.

The technical scheme for realizing the aim of the invention is that the oil-in-water compound ketoconazole nano-medicament has the particle size of 1-100 nm and consists of the following raw materials in percentage by mass:

0.01-8.0 percent of ketoconazole, 0.01-10 percent of eugenol, 0.001-5.0 percent of clobetasol propionate, 25.0-45.0 percent of surfactant, 0-10.0 percent of cosurfactant, 0.1-25.0 percent of oil and the balance of distilled water, wherein the sum of the mass percentages of the raw materials is 100 percent.

The surfactant involved in the medicine of the invention is nonionic surfactant, the surfactant mainly comprises natural surfactant and synthetic surfactant, the natural surfactant is non-toxic and cheap, but has batch difference and is very unfavorable for large-scale production, and the capability of reducing interfacial tension of the natural surfactant is not strong. The synthetic surfactants are classified into ionic surfactants and nonionic surfactants, and the ionic surfactants include amine or quaternary ammonium salts, fatty acid salts, fatty alcohol sulfonates, and the like, which are strongly hemolytic and are limited in use by pH. The nonionic surfactant can be used in combination with various cosurfactants, while the ionic surfactant has strong hydrophilicity and needs to be used in combination with the cosurfactant of the clear oil to enhance the compatibilization of the ionic surfactant and the cosurfactant. The nonionic surfactant is suitable for the pH value of 3-10, is slightly influenced by ionic strength, inorganic salt, acid and alkali, has low toxicity and irritation, can be compatible with most medicaments, and is most widely applied. The surfactant with the HLB value of 4-7 can be used for preparing W/O type nano-drugs, the surfactant with the HLB value of 8-18 can be used for preparing O/W type nano-drugs, and in consideration of the easiness in formation and stability of the nano-drugs, the selected surfactant is a nonionic surfactant with the HLB of 10-16 or is compounded with the nonionic surfactant with the HLB of less than 10. The surfactant can be selected from one or two of polyoxyethylene castor oil (Cremophor ELHLB ═ 13.5), polyoxyethylene hydrogenated castor oil (Cremophor RH40HLB ═ 14-16), polyoxyethylene sorbitol oleate (Tween-80HLB ═ 11), polyoxyethylene triglyceride (Tagat TO HLB ═ 11.3), polyethylene glycol-8-glyceryl caprylate/caprate (Labrasol HLB ═ 14), coconut oil C8/C10 polyethylene glycol glyceride (Labrafac CM10HLB ═ 10), polyethylene glycol lauric glyceride (Gelucire44/14HLB ═ 14) and sorbitan monostearate (Span-80HLB ═ 4.3).

The selection of the oil phase needs to consider the solubility and self-emulsibility of the drug, and in principle, the smaller the volume of the oil phase molecules is, the stronger the dissolving power is, and the overlong molecular chains of the oil phase cannot form the nano drug. In order to improve the solubility of the main drug in the oil phase and enlarge the formation area of the nano-drug, the short-chain oil phase is selected. The invention selects 2-phenethyl alcohol, eugenol and any one or a mixture of IPM, ethyl acetate, vitamin E oil, almond oil, wheat germ oil, glyceryl triacetate, isopropyl laurate, soybean oil and olive oil as the oil phase, and can also only use 2-phenethyl alcohol and eugenol as the oil phase.

The invention can select absolute ethyl alcohol and 1, 2-propylene glycol as cosurfactant, the cosurfactant is not an essential component for forming the oil-in-water compound nano-medicament, and the oil-in-water compound nano-medicament can be formed under the condition that the cosurfactant component is zero.

The invention also aims to provide a preparation method of the compound ketoconazole nano-drug, which comprises the following steps:

1) weighing ketoconazole, eugenol, clobetasol propionate, a surfactant, a cosurfactant, oil and distilled water for later use;

2) adding ketoconazole and clobetasol propionate into oil, uniformly stirring, adding cosurfactant and eugenol, and stirring until the cosurfactant and the eugenol are completely dissolved;

3) adding a surfactant into the solution prepared in the step 2), and uniformly stirring;

4) rapidly stirring the solution prepared in the step 3) at room temperature, slowly dripping distilled water while stirring, and continuously stirring to obtain transparent and clear liquid, namely the compound nanoemulsion drug.

The ketoconazole, the clobetasol propionate and the eugenol are used as the combination of the invention because the ketoconazole has antibacterial effects on deep infection fungi such as candida, chromomycosis, coccidioidomycosis, histoplasma, sporotrichosis and the like, also has antibacterial activity on trichophyton and the like, and can treat various skin tinea and skin candidiasis. The clobetasol propionate is one of the high-efficiency externally-applied corticosteroid traditional Chinese medicines which are clinically applied at present, has the effect of treating skin inflammation and pruritus, such as neurodermatitis, contact dermatitis, seborrheic dermatitis, eczema, local pruritus and the like, has a synergistic effect when being matched with ketoconazole, and has a better effect than that when being used alone. The eugenol has the functions of resisting bacteria, diminishing inflammation, anaesthetizing, relieving pain, clearing away heat, reducing temperature and resisting parasites, and has strong killing power on mites. The compatibility of the three medicines has better treatment effect on the skin diseases of pets. The nanometer medicinal preparation has the advantages of reduced side effects and irritation to skin, improved stability, sustained release, and prolonged action time.

The specific use method of the invention comprises the following steps:

is sprayed or smeared on the surface of the affected part once a day.

Compared with the prior art, the compound ketoconazole nano-medicament has the following advantages:

1. the preparation method is simple, high in safety and convenient to popularize.

2. The composition has the advantages of stable system, good clarity and transparency, good fluidity, good wettability, strong permeability, and capability of penetrating into skin to exert drug effect, and can be adjusted according to the need every year.

3. Can be made into spray and liniment according to its function.

4. Has wide application range, can be used for treating pet skin diseases of dogs, cats and the like, can also be used for treating rabbit skin diseases, and contributes to the breeding industry.

5. The medicine has the function of treating common clinical fungal, bacterial and parasitic skin diseases and eczema of pets, and the compatibility treatment of the three medicines is more thorough than the treatment of other medicines only aiming at one disease.

Drawings

FIG. 1 is an electron microscope image of the oil-in-water compound ketoconazole nano-drug of the invention.

The beneficial effects of the drug of the present invention are further illustrated by the following test examples, which include the drug stability test and the clinical efficacy test of the present invention.

Test example 1 stability test

1) Test for appearance stability

The diameter distribution of the liquid drops is 1-100 nm detected by a transmission electron microscope of northwest agriculture and forestry science and technology university, and an electron microscope photo is shown in figure 1. The nano-drug is yellow, light yellow or colorless transparent liquid in appearance, is uniformly dispersed, is transparent and clear after being placed at room temperature for a long time, and has stable form and no phenomena of turbidity, layering and precipitation.

2) Centrifugal acceleration test

Taking a proper amount of the compound nano-medicament prepared by the method of example 1, putting the compound nano-medicament into a centrifuge tube, sealing the tube opening, putting the centrifuge tube into a high-speed centrifuge, and centrifuging the compound nano-medicament for 30min at the rotating speed of 4000r/min, wherein the compound nano-medicament liquid still keeps clear and transparent, and the phenomenon of medicament precipitation is not found at the bottom of the centrifuge tube.

3) Light stability test

Filling appropriate amount of compound nanometer medicinal solution and blank nanometer medicinal solution into penicillin glass bottle, irradiating in sunlight for 10 days, and sampling at 1d, 3d, 5d, and 10 d. The result shows that the compound nano-drug liquid still keeps clear and transparent, and the color is yellow and has no change. The blank nano-drug solution is still clear and transparent, is yellow, and has no unstable phenomena such as layering, turbidity and the like.

4) Temperature stability test

The compound nanometer medicine is taken and packaged into a plurality of glass bottles, sealed and placed in a refrigerator for 30 days under the three temperature conditions of 4 ℃, 25 ℃ and 37 ℃, and observed once every 5 days. The results show that the compound nano-medicament can keep clear and transparent appearance for a long time under three conditions without instability.

Test example 2 toxicology test

1. Skin irritation test

1.1 test methods

20 healthy female rabbits were randomly divided into two groups, namely intact skin and damaged skin groups, of 10 per group, by body weight. Symmetrically depilating two sides of the spine of rabbit with sodium sulfide aqueous solution, depilating at 5cm × 5cm area, feeding for 24 hr, sterilizing the depilated part of the damaged skin group with iodine tincture, and slightly oozing blood with sterile needle. Uniformly applying 0.5g of compound nanometer medicinal liquid to depilated skin of one side of 5 rabbits in each group, uniformly applying 0.5g of blank nanometer medicinal liquid to depilated skin of one side of the other 5 rabbits in each group, covering with sterile gauze, fixing with non-irritant adhesive plaster, and feeding in single cage. The other side was coated with the same dose of distilled water as a control. The application time is at least 4h after the medicine is applied, the medicine is removed after the application is finished, and the administration part is cleaned by warm water. The same method is applied 1 time per day for 7 days.

The skin reactions were observed in the natural light during the test period, and the occurrence and regression times of skin erythema, edema, pigmentation, bleeding spots, and skin roughness were observed and recorded before removing the test substance for 1 hour each time and reapplying the test substance. After the last application, the skin reaction condition was observed and recorded at 1h, 24h, 48h and 72h after the removal of the test object, the scoring criteria are given as table 1, and the skin irritation intensity evaluation is performed as table 2. The test results are shown in Table 3.

TABLE 1 evaluation criteria for skin reaction intensity

TABLE 2 evaluation criteria for skin irritation intensity

1.2 test results

TABLE 3 rabbit skin irritation test results

The results show that after the intact skin and the damaged skin of the rabbit are contacted with the compound nano-drug and the blank nano-drug with the same dose, the animals do not have the conditions of local erythema, edema, pigmentation, bleeding spots, rough skin or thin skin and the like at different times, and do not have abnormal reactions on the left side and the right side of the same body.

2. Skin allergy test

2.1 test methods

30 guinea pigs were randomly divided into 3 groups of 10 animals each based on body weight and sex. Depilating two sides of vertebral column of guinea pig with 1% sodium sulfide solution, removing hair area of 3cm × 3cm, feeding for 24 hr, and administering. Group 1 is blank control group, and blank nano-drug is administered in an amount of 0.2 g; the group 2 is an administration group, and 0.2g of compound nano-medicine is administered; group 3 was a positive control group, and 0.2ml of 1% 2, 4-dinitrochlorobenzene was given. The test substances of each group are respectively coated on the left unhairing part and fixed for 6h by using sterile gauze and non-irritant adhesive plaster. The administration was carried out once on day 7 and day 14 in the same manner, and the administration was triggered on day 28, and the corresponding test substance was applied to the right depilation region in the same manner as described above, and the positive control group was changed to 0.1% 2, 4-dinitrochlorobenzene, which was fixed for 6 hours in the same manner. After application, the drug is removed and washed with warm water.

The skin reaction was observed under natural light during the test. Skin reactions were observed and recorded immediately after removal of the test article and at 24h, 48h, 72 h. Skin erythema and edema were scored according to table 4 and the mean response and sensitization rate were counted; sensitization was judged as in Table 5. And simultaneously observing whether the animal has allergic reactions such as asthma, unstable standing or shock and the like. The test results are shown in Table 6.

TABLE 4 skin allergy Scoring criteria

TABLE 5 evaluation criteria for skin sensitization

2.2 test results

TABLE 6 sensitization intensity in the groups of test animals

The results show that 6h, 12h, 24h and 72h after the compound nano-drug liquid and the blank nano-drug are contacted, no guinea pig skin adverse reaction is caused, no allergic reactions such as asthma, restlessness in standing, shock and the like exist, and the sensitization rate is 0. While the positive control group showed significant edema and erythema.

Test example 3 pharmacodynamic test

1. Observation test of mite-killing effect of rabbit

1.1 test methods

30 diseased rabbits infected with fungi are randomly divided into I, II, III, IV, V and VI 6 groups, and each group has 5 rabbits with unlimited characters. The treatment comprises respectively smearing nanometer medicine containing 1% of eugenol, spraying nanometer medicine containing 0.5% of eugenol, smearing 300 times diluted miticide aqueous solution, spraying 600 times diluted miticide aqueous solution, injecting 10mg/ml avermectin subcutaneously, and smearing blank nanometer medicine. The medicine is taken once a day for two days in the groups I and III, and is taken once after 7 days; the medicine is taken once in group II and IV at interval of 7 days; group V one injection of 0.3mg/kg was given at 7d intervals. After the test, the appetite, drinking water, mental status and pathological changes of the sick rabbits were observed and recorded every day. The mites on the affected part are stuck by a transparent adhesive tape method 5 days after the application of the acaricide, the mites are inspected by a microscope, the total number, the death number and the survival number of the mites are recorded, and the average acaricidal rate is calculated. The test results are shown in Table 7.

1.2 test results

TABLE 7 Rabbit body mite killing Effect

Note: indicating no calculation

The results show that the effect of the abamectin is the best when the abamectin is taken for the first time, and the effect of the group I after the abamectin is taken for the second time is the best and is slightly superior to that of the group which is injected with the abamectin.

2 Observation test of in vitro antifungal Effect of Guinea pig

2.1 test methods

Taking a common-grade guinea pig, removing 5 x 6cm of back hair by using a sodium sulfide solution, wiping the depilated part by using 75% alcohol for 24h, after the residual alcohol on the depilated part is volatilized and dried, marking a # shape on the bacteria-coated part by using a sterile needle, wherein the area is 2 x 2cm, taking the condition that the epidermis is scratched and blood does not seep out as the standard, dripping 0.5ml of prepared bacterial liquid, uniformly coating, exposing in the air after the completion, and observing the skin infection condition every day. After 5-7 days, selecting guinea pigs with similar skin tinea symptoms (such as local red swelling, exudation and scale-like change of skin) at the inoculated parts, carrying out microscopic examination to obtain positive results, and determining that the infection succeeds and then starting test treatment within 48 h. The test was divided into 6 groups of 10 individuals. The 1 st, 2 nd and 3 rd groups are compound nanometer medicinal liquid groups, and the nanometer medicinal liquid groups are coated with 0.1g/cm nanometer medicine containing 1% of ketoconazole and 0.05% of clobetasol propionate according to the body surface area²，0.2g/cm²，0.4g/cm²Once daily. Group 4 is a positive control 1% ketoconazole lotion group, once daily, with a dosage of 0.2g/cm². Group 5 was a blank control group and was not administered. The blank group was not treated for any time within 14 days. The medicine is applied to the infected area once a day for 7 days before the groups 1,2, 3 and 4. The application is stopped 7 days later. The results were observed and compared. The treatment conditions of the fungus on skin infection are divided into two types of cured and uncured, wherein the cured state means that scales on a pathological change part completely fall off and disappear, and the skin is restored to be flat and smooth; the unhealed disease refers to the condition that the diseased part is in a white scale shape or spreads, the diseased part gradually spreads to the periphery, and the curative effect is judged by fungus microscopic examination and fungus culture after the treatment course is finished. The test results are shown in Table 8.

2.2 test results

TABLE 8 in vitro antifungal Effect of guinea pigs

The result shows that the nano-drug of the drug composition has better therapeutic effect on the fungal dermatosis and is superior to lotion with the same amount.

3 Observation of treatment Effect of Guinea pig eczema

3.1 test methods

25 healthy female guinea pigs (the center of experimental animals in this school) with the age of 4-5 weeks were taken, the weight was 232.4 + -32.95 g, and hair was removed at 4 places on both sides of the back of each mouse, and the area was 2cm × 3 cm/place. Performing intraperitoneal injection anesthesia according to the body weight of the pentobarbital; OVA 10. mu.g + Al (OH) 30.5 mg was injected intradermally at the site of hair removal; after 1 week, using 3cm × 4cm gauze, coating 10% OVA, 10% SDS, 30% vaseline and 50% water, and sticking the mixture on the unhaired part for 48 hours; after 3 weeks of intradermal injection, a 3cm × 4cm gauze is coated with 10% OVA, 5% SDS, 37% vaseline and 48% water, and the mixture is stuck to the shaved part and kept for 48 hours; resting for 1 week, spreading 10% OVA, 20% water and 70% vaseline on 1cm × 1cm double-layer gauze, and sticking on the unhaired part for 24 hr for antigen exciting reaction. Erythema, edema, and scratch were scored after 48h, and total scores were calculated.

The total number of samples is 100, and the samples are randomly divided into five groups of A, B, C, D and E, and each group comprises 20 samples. The administration is started after the excitation, and the compound nano-medicine liquid medicine (wherein the concentration of clobetasol propionate is 0.10 percent, 0.05 percent and 0.025 percent respectively) is administered to the groups A, B and C once a day; d, clobetasol propionate ointment is given twice a day; e is blank control. The treatment effect of each group is evaluated 48h, 1,2 and 3 weeks after the administration. The evaluation criteria are shown in Table 9.

3.2 test results Table 9 Guinea pig eczema response Scoring Standard

Eczematous reaction appeared 48h after OVA challenge in guinea pig back, manifested as diffuse erythema, edema, scratch with bloody scab, unclear border, a few papules on it, and partial exudation. On the 5 th day of administration, the cavy in groups A, B, C and D had pale-back erythema, mild edema, and slight scratch and blood crust; in group E, erythema on the back is diffuse, unclear, mild edema, obvious scratch blood crust, miliary papule and exudation tendency. On the 7 th day of administration, erythema of A, B, C and D groups is reduced, edema is subsided, a little crust skin is formed, and scratch is old; there was no improvement in group E symptoms. After continuous administration for 15 days, erythema of groups A, B and C is faded, pigment is deepened, epidermis is basically recovered to be normal, compared with clobetasol propionate ointment, the symptom of group E is still not improved.

4 Observation of in vitro bacteriostatic Effect

4.1 test methods

Staphylococcus aureus, Escherichia coli and streptococcus are selected for experiments, and the bacteriostatic effect of the medicine is determined by measuring the Minimum Inhibitory Concentration (MIC). The nutrient broth culture medium is prepared from peptone 1%, meat extract 1%, sodium chloride 0.5%, and distilled water 100mL, and has pH of 7.4, transferring seed from the strain tube, transferring 2 times in the broth tube, using 18-24 h culture as the strain, and diluting the bacteria concentration to 1 × 10⁸one/mL as bacterial suspension. Diluting the compound medicinal composition nano-medicament into test solution with the concentration of 0.1 mg/mL-10 mg/mL in a double concentration series by using distilled water, and adding 1mL of the test solution with each diluted concentration into a test tube containing 1mL of double concentration nutrient broth. 0.1mL of the bacterial suspension was inoculated into each of the above test tubes to prepare a test group sample. Bacteria were inoculated in tubes of nutrient broth without drug solution in the same manner as negative control samples. The bacteria and nutrient broth containing blank nano-drug were inoculated in the same manner in a test tube as a blank control sample. Bacteria were inoculated in nutrient broth tubes containing the dragon tiger brand essential balm in the same manner as a positive control sample. And taking the bacteriostatic concentration corresponding to the highest dilution of the aseptic growth of each test group as the minimum bacteriostatic concentration of the corresponding test bacteria of the sample. The test results are shown in Table 10.

4.2 test results

TABLE 10 minimum inhibitory concentrations in vitro

Note: p < 0.01 compared to positive control group; comparison with blank Nanoparticulate group^▲p＜0.01

The results show that the nano-drug group of the compound drug composition has obvious difference compared with a positive control group and has obvious inhibition effect on three bacteria.

Example 1

1) Weighing 0.77g of 2-phenethyl alcohol, 0.23g of eugenol, 0.166g of ketoconazole, 0.01g of clobetasol propionate, 1.809 g of Tween-and 14.000g of distilled water for later use;

2) adding ketoconazole and clobetasol propionate into 2-phenethyl alcohol, uniformly stirring, adding eugenol, and stirring until the eugenol is completely dissolved;

3) adding Tween-80 into the solution prepared in the step 2) and uniformly stirring;

4) rapidly stirring the solution prepared in the step 3) at room temperature, slowly dripping distilled water while stirring, and continuously stirring to obtain transparent and clear liquid, namely the compound nanoemulsion drug.

Example 2

The composition comprises Tween-808.000 g, ketoconazole 0.500g, 2-phenethyl alcohol 1.000g, IPM0.100g, clobetasol propionate 0.300g, eugenol 0.300g, absolute ethyl alcohol 2.000g and distilled water 12.000 g.

Example 3

Consists of EL407.000g, ketoconazole 0.840g, 2-phenethyl alcohol 0.900g, vitamin E oil 0.060g, clobetasol propionate 0.012g, eugenol 0.240g and distilled water 13.750 g.

Example 4

Consists of Span-807.000 g, ketoconazole 0.600g, 2-phenethyl alcohol 0.600g, almond oil 0.090g, clobetasol propionate 0.200g, eugenol 0.200g and distilled water 12.800 g.

Example 5

Comprises RH407.500g, Span-801.500g, 2-phenethyl alcohol 0.700g, wheat germ oil 0.070g, eugenol 0.230g, ketoconazole 0.220g, clobetasol propionate 0.112g and distilled water 13.000 g.

Example 6

The composition comprises Tween-804.500g, 2-phenethyl alcohol 0.250g, eugenol 0.125g, IPM 0.125g, ketoconazole 0.050g clobetasol propionate 0.003g and distilled water 14.000 g.

Example 7

Consists of RH406.800g, 0.890g of 2-phenethyl alcohol, 0.010g of glyceryl triacetate, 0.300g of eugenol, 1.000g of 1, 2-propylene glycol, 0.500g of ketoconazole, 0.015g of clobetasol propionate and 5.000g of distilled water.

Example 8

Consists of EL409.000g, 0.800g of 2-phenethyl alcohol, 0.060g of isopropyl laurate, 0.140g of eugenol, 0.040g of ketoconazole, 0.012g of clobetasol propionate and 13.750g of distilled water.

Example 9

Consists of RH406.800g, 0.880g of 2-phenethyl alcohol, 0.020g of olive oil, 0.300g of eugenol, 1.000g of glycerol, 0.500g of ketoconazole, 0.015g of clobetasol propionate and 5.000g of distilled water.

Claims (5)

1. The oil-in-water compound ketoconazole nano-drug is characterized in that the particle size of the nano-drug is 1-100 nm, and the nano-drug is composed of the following raw materials in percentage by mass:

0.01-8.0 percent of ketoconazole, 0.01-10 percent of eugenol, 0.001-5.0 percent of clobetasol propionate, 25.0-45.0 percent of surfactant, 0-10.0 percent of cosurfactant, 0.1-25.0 percent of oil and the balance of distilled water, wherein the sum of the mass percentages of the raw materials is 100 percent;

the surfactant is any one or a mixture of two of Tween-80, RH40, EL40 and Span-80;

the cosurfactant is any one or a mixture of more of absolute ethyl alcohol, 1, 2-propylene glycol and glycerol;

the oil is one or more of 2-phenylethyl alcohol, IPM, ethyl acetate, vitamin E oil, almond oil, wheat germ oil, glyceryl triacetate, isopropyl laurate, soybean oil and olive oil.

2. The oil-in-water compound ketoconazole nano-drug as claimed in claim 1, which is characterized by comprising the following raw materials in percentage by mass:

0.1-7.0 percent of ketoconazole, 0.1-8.0 percent of eugenol, 0.01-4.0 percent of clobetasol propionate, 28-42.0 percent of surfactant, 1-8.0 percent of cosurfactant, 1.0-24.0 percent of oil and the balance of distilled water, wherein the sum of the mass percentages of the components is 100 percent.

3. The oil-in-water compound ketoconazole nano-drug as claimed in claim 1, which is characterized by comprising the following raw materials in percentage by mass:

1 to 6.0 percent of ketoconazole, 0.5 to 7.5 percent of eugenol, 0.1 to 3.8 percent of clobetasol propionate, 30.0 to 40.0 percent of surfactant, 1.5 to 7.5 percent of cosurfactant, 1.5 to 23.0 percent of oil and the balance of distilled water, wherein the sum of the mass percentages of the components is 100 percent.

4. The oil-in-water compound ketoconazole nano-drug as claimed in claim 1, wherein the weight ratio of the surfactant to the oil phase is 24: 1-1.5: 1.

5. The preparation method of the oil-in-water compound ketoconazole nano-drug as claimed in claim 1, which is characterized by comprising the following steps:

1) weighing ketoconazole, eugenol, clobetasol propionate, a surfactant, a cosurfactant, oil and distilled water for later use;

2) adding ketoconazole and clobetasol propionate into oil, uniformly stirring, adding cosurfactant and eugenol, and stirring until the cosurfactant and the eugenol are completely dissolved;

3) adding a surfactant into the solution prepared in the step 2), and uniformly stirring;

4) rapidly stirring the solution prepared in the step 3) at room temperature, slowly dripping distilled water while stirring, and continuously stirring to obtain transparent and clear liquid, namely the compound nanoemulsion drug.

Images