CN102526070A - Compound bifonazole nano-emulsion spray preparation and preparation method thereof - Google Patents

Abstract

The invention discloses a compound bifonazole nano-emulsion spray. The nano-emulsion has a particle diameter of 1nm-100nm and is made of the following raw materials in mass percentage: 30%-40% of surfactant, co-surfactant 3%～14%, oil phase 5%～10%, bifonazole 0.8%～2%, clobetasol propionate 0.02%～0.1%, cinnamaldehyde 0.01%～0.2%, the balance is deionized water , the sum of the mass percentages of the above-mentioned raw materials is 100%. The present invention has multiple effects such as fungicide, bactericide, antibacterial, antifungal, anti-inflammatory, antipruritic, etc., and can treat superficial skin fungal infection, fungal paronychia and moniliform vulvovaginitis, otitis externa, bacterial skin Infection also works. The compound nanoemulsion prepared by the invention significantly improves the activities of the three drugs, has rapid sterilization and antipruritic effects, is not easy to relapse, is simple to prepare, and has broad market prospects in the field of medicine.

Description

A kind of compound bifonazole nano-emulsion spray and preparation method thereof

technical field

The invention belongs to the field of medicine, and relates to a compound formula of an antifungal drug bifonazole for external use, and a method for preparing the compound into a new dosage form, specifically a transparent and stable oil-in-water compound bifonazole An azole nanoemulsion spray and a preparation method thereof.

Background technique

Bifonazole (Bifonazole) is an imidazole antifungal drug, and its antibacterial mechanism is a dual inhibition of fungal cell membrane ergosterol synthesis, except that it acts on P450-14a demethylation with other imidazoles, and also acts on Hydroxymethylglutamate coenzyme A reductase has a broad-spectrum antifungal effect and can inhibit 90% of pathogenic fungi. Against dermatophytes (e.g. Trichophyton, Microsporum), yeasts (e.g. Candida, Saccharomyces, Torulopsis), molds (e.g. Aspergillus), filamentous fungi, Phytophthora phyllosa, Corynebacterium tiny, etc. are effective, and are suitable for superficial skin fungal infections, such as tinea pedis, tinea corporis, jock itch, tinea versicolor, skin candidiasis, etc. Bifonazole currently has creams, suppositories, solutions, gels, etc. Bifonazole has stable chemical properties, good fat solubility, and is almost insoluble in water. The bifonazole is made into a local external dosage form, which is targeted to the treatment site and can increase the concentration of the local drug. The previous technology is to dissolve it in a fat-soluble semi-solid matrix to make a cream; or disperse it in a gel matrix to make a gel. The prepared gel is unstable after absorbing water and is easy to separate out the drug. Whether it is cream or gel, there is a problem of low transdermal absorption efficiency, which leads to long treatment time and affects the treatment effect.

Clobetasol Propionate (Clobetasol Propionate) is one of the most effective topical corticosteroids in clinical application at present. Its anti-inflammatory effect is about 112.5 times that of hydrocortisone, 2.3 times that of betamethasone sodium phosphate, and 18.7 times that of fluocinolone. It is clinically used to treat skin diseases such as psoriasis, eczema, dry and cracked feet, patchy alopecia, neurodermatitis, and palmoplantar pustulosis. This product is insoluble in water, and it is often used as a cream in clinical practice, so the transdermal absorption efficiency is limited, which undoubtedly prolongs the treatment time. Because clobetasol propionate is not suitable for long-term use, long-term medication may cause hypercorticism, thus greatly limiting its clinical application, a dosage form that can increase the transdermal absorption efficiency of clobetasol propionate seems extremely important.

Cinnamaldehyde (Cinnamaldehyde) is an aldehyde organic compound, which is a yellow viscous liquid, and exists in large quantities in plants such as cinnamon. Modern research has found that cinnamaldehyde has a significant curative effect on fungi. The antifungal effect research shows that: cinnamaldehyde is an antifungal active substance, mainly by destroying the fungal cell wall, allowing the drug to penetrate into the fungal cell and destroying the organelle to play a bactericidal effect. Escherichia coli, Bacillus subtilis and Staphylococcus aureus, Staphylococcus albus, Shigella dysenteriae, A. typhoid and paratyphoid, Pneumococcus, Bacillus aerogenes, Proteus, Bacillus anthracis, Salmonella enteritidis, Vibrio cholerae, etc. inhibition. And it has remarkable bactericidal effect on Gram-positive bacteria, and can be used to treat various diseases caused by bacterial infection. The minimum inhibitory concentration (MIC) is 0.02-0.07ul/ml, and for deep pathogenic fungi, the MIC is 0.1-0.3ul/ml. It is non-toxic or low-toxic to the human body, and can play a strong inhibitory effect on the reproduction of microorganisms. It has a strong effect on Aspergillus flavus, Aspergillus niger, Penicillium citrinum, Fusarium moniliforme, Alternaria, Geotrichum candidum, and yeast. antibacterial effect. At present, there are few reports of adding cinnamaldehyde to external antifungal infection drugs. Cinnamaldehyde is insoluble in water, which limits the transdermal absorption rate of external drugs made of it.

Contents of the invention

The purpose of the present invention is to solve the problems and defects of the prior art, and provide a compound biphenyl benzyl compound with good solubility, high transdermal absorption efficiency, high bioavailability, good bactericidal and antibacterial effects, rapid antipruritic and stable physical properties. Azole Nanoemulsion Spray.

The technical method for realizing the above invention is a compound bifonazole nano-emulsion spray, which is made of the raw materials of the following components: 30% to 40% of surfactant, 3% to 14% of cosurfactant, oil phase 5% to 10%, bifonazole 0.8% to 2%, clobetasol propionate 0.02% to 0.1%, cinnamaldehyde 0.01% to 0.2%, the balance is deionized water, the sum of the mass percentages of the above raw materials is 100%.

The preferred mass percent range of the formula for preparing the medicine of the present invention is: 30% to 36% of surfactant, 5% to 12% of cosurfactant, 6% to 9% of oil phase, 0.8% to 1.5% of bifonazole, 0.02% to 0.05% of clobetasol, 0.03% to 0.1% of cinnamaldehyde, the balance is deionized water, and the sum of the mass percentages of the above raw materials is 100%.

The optimum mass percent of the formula for preparing the medicine of the present invention is: 32% surfactant, 9.5% co-surfactant, 7.42% oil phase, 1% bifonazole, 0.03% clobetasol propionate, 0.05% cinnamaldehyde , the balance is deionized water, and the sum of the mass percentages of the above-mentioned raw materials is 100%.

The surfactant is one or a mixture of EL-40, RH-40, Tween-80 and Poloxamer 188.

The co-surfactant is one or more mixtures of absolute ethanol, 1,2-propanediol, glycerol and polyethylene glycol-400, and the non-co-surfactant of the present invention can also form clear and transparent, Nanoemulsion with good stability.

The oil phase is one or more mixtures of butyl acetate, isopropyl myristate, almond oil, wheat germ oil, triacetin and ethyl acetate.

The present invention combines bifonazole, clobetasol propionate and cinnamaldehyde for the first time to treat various diseases caused by fungal infection. Bifonazole has a broad-spectrum antifungal effect, which is mainly achieved by inhibiting the synthesis of ergosterol in the fungal cell membrane; cinnamaldehyde destroys the fungal cell wall, allows the drug to penetrate into the fungal cell, and destroys the organelle to play a bactericidal effect; the combination of the two After use, it not only has a double bactericidal effect on fungi, but also makes it easier for bifonazole to penetrate into the cytoplasm by destroying the cell wall, multiplying the antibacterial effect. Fungal infections are often accompanied by severe inflammatory reactions. The invention prevents the occurrence of severe inflammatory reactions by adding powerful anti-inflammatory drug clobetasol propionate, reduces the pain of patients, and shortens the course of treatment. The therapeutic effect of the compound medicine of the present invention is not limited to antifungal and anti-inflammation, and the active ingredient cinnamaldehyde also has a good therapeutic effect on common concurrent bacterial infections, and clobetasol propionate and cinnamaldehyde also have antipruritic effects , It also has a certain effect on the infection of mites.

In the present invention, on the basis of the compound recipe of bifonazole, clobetasol propionate, and cinnamaldehyde, these three active ingredients are made into nanoemulsion at the same time, and the transdermal absorption rate and bioavailability of the three drugs are simultaneously enhanced. Spend. This is not a simple mixing of nanoemulsions with three separate components, but the stability of the entire system, the optimal ratio of the three components, and the compatibility of the solvents used must be considered. After a series of explorations and experiments, a transparent, stable and curative compound bifonazole nano-emulsion spray was prepared.

Still another object of the present invention is to provide the preparation method of above-mentioned compound bifonazole nano-emulsion spray, it is characterized in that, comprises the following steps:

(1) Weigh the surfactant, co-surfactant, oil phase, bifonazole, clobetasol propionate, cinnamaldehyde, and deionized water in the proportion of the formula, and set aside;

(2) Mix the surfactant and co-surfactant evenly, then add the oil phase, and mix well;

(3) Add bifonazole and mix well;

(4) Add clobetasol propionate and mix well;

(5) Add cinnamaldehyde and mix well;

(6) Slowly add deionized water at room temperature, and stir while adding deionized water until a clear, transparent, colorless or yellowish liquid with low viscosity and good fluidity is formed. the

A kind of compound bifonazole nano-emulsion spray of the present invention is suitable for treating superficial skin fungal infection (such as: tinea manus, pedis, tinea corporis, jock itch, tinea versicolor, skin candidiasis, etc.) and fungal paronychia and Candidiasis vulvovaginitis, otitis externa, bacterial skin infection is also effective.

Usage: For external use, apply to the washed affected area, once in the morning and once in the evening, and continue to use the medicine for 5-10 days after the symptoms disappear to prevent recurrence.

The present invention is tested by a transmission electron microscope, the droplet diameter distribution is between 1 and 100 nm, the appearance is yellow or colorless transparent liquid, and it has good stability:

1. Stability over time

Stability over time refers to the extent to which the appearance of nanoemulsions changes over time when they are stored at room temperature under natural conditions. The compound bifonazole nanoemulsion spray is transparent for a long time, and no turbidity or precipitation is found, indicating that it has good stability over time.

2. Heat storage stability

  Put the compound bifonazole nanoemulsion spray into a test tube, seal it, and store it in a constant temperature water bath at 37°C for 14 days. The liquid looks transparent after storage.

3. Freezing stability

The compound bifonazole nanoemulsion spray was stored at -4°C for one week, and returned to room temperature after taking it out. The compound bifonazole nanoemulsion spray becomes solid at -4°C, and it returns to transparent after returning to room temperature, and remains transparent after being placed for a week, indicating that the nanoemulsion has good freezing resistance.

4. Acceleration stability

The compound bifonazole nanoemulsion spray was placed in a test tube, sealed, and centrifuged at 15,000 r/min for 20 min, without delamination and still clear and transparent.

Compared with the prior art, a kind of compound recipe bifonazole nano-emulsion spray of the present invention has the following advantages:

1) The particle size of the compound nano-emulsion droplets of the present invention is less than 100 nm, the drug has high fat solubility, and the drug can easily penetrate the cell walls of fungi and bacteria with the help of carriers, and can directly exert antibacterial or bactericidal functions in the bacteria, greatly improving the biphenyl The drug effects of benzazole, cinnamaldehyde, and clobetasol propionate shorten the onset time, thereby reducing the intake of drugs;

2) The three active ingredients encapsulated by the nanoemulsion of the present invention have a slow-release effect, not only has a fast onset of action, but also has a long duration of drug action;

3) According to the characteristics of fungal infection, the present invention has multiple functions of killing fungi, killing bacteria, anti-inflammation, relieving itching, analgesia, and inhibiting bacteria, which greatly reduces the suffering of patients;

4) Apply this product to the skin to absorb quickly, and it can be completely absorbed after gently patting, and no trace of application can be seen;

5) No greasy feeling, no stuffy feeling, no pollution to clothes, and a faint fragrance similar to cinnamon;

6) Good thermodynamic stability, high storage stability, clear and transparent appearance, no drug precipitation, and high sensory quality;

7) The preparation process is simple and suitable for large-scale production.

Detailed ways

The beneficial effect of the medicine of the present invention will be further elaborated below through pharmacodynamic tests and comparative tests. (The nanoemulsion formula used is the best mass percentage of the formula for preparing the medicine of the present invention: surfactant 32%, co-surfactant 9.5%, oil phase 7.42%, bifonazole 1%, clobetasol propionate 0.03% , cinnamaldehyde 0.05%, deionized water 50%).

Test Example 1 Rabbit Skin Administration Toxicity Test

Referring to the toxicity test and evaluation standard test method of transdermal drug administration, 24 rabbits (body weight 2.0±0.5 kg) were randomly divided into 4 groups, which were Ⅰ intact skin administration group, Ⅱ intact skin control group, and Ⅲ damaged skin administration group , IV Damaged skin control group, 6 rats in each group, half male and half male. 24 hours before the administration, the hair was depilated on the back with electric clippers, and the depilated area was about 150 cm ² . The damaged skin group was first disinfected with 75% alcohol, and then a "well" was drawn on the back hair removal area with a sterile razor blade, with the degree of bleeding. Rabbits in groups Ⅰ and Ⅲ were smeared with a compound bifonazole nano-emulsion spray of the present invention on the depilatory area, and rabbits in groups Ⅱ and Ⅳ were smeared with normal saline in the depilatory area to form a blank control, once in the morning and evening. After administration, the animals were observed continuously for 14 days, twice a day, and the animal's skin hair, diet, stool, respiration, eye and mucous membrane changes, mental state, limb activities and death were observed every day. In case of death, autopsy and naked eye observation should be carried out in time. When the lesion is visible to the naked eye, histopathological examination should be carried out. The results showed that the fur luster of the rabbits in each group was normal, and the diet, defecation, respiration, eyes and mucous membranes of the rabbits changed. The mental state and limb activities did not cause any impact. The rabbits with damaged skin began to scab on the 2nd day after administration, and the scabs were removed and recovered in about 7 days. During the observation period of 14 days, there was no acute toxic reaction, and none of the rabbits died. The results show that a compound bifonazole nanoemulsion spray of the present invention is safe and non-toxic when administered through the skin.

Test Example 2 In vitro antifungal test on guinea pigs

Take 100 guinea pigs ( ^body weight 250±50 g), ^and use electric clippers to remove hair on both sides of the back one day before the test. Blood. Apply 20 μl of ^{10 8} CFU/ml bacterial suspension of 4 common skin infection fungi (Trichophyton rubrum, Microsporum canis, Trichophyton gypsum, Candida albicans) to the skin abrasion area, and on the 7th day, select Eighty-four guinea pigs with obvious infection (local redness, swelling, oozing, and scaly skin changes) and positive local sampling results were randomly divided into 7 groups, 12 in each group, half male and half male. Group I is the compound bifonazole nano-emulsion spray group of the present invention; group II is the compound bifonazole ethanol solution group (the content of bifonazole, clobetasol propionate and cinnamaldehyde is the same as that of group I); Group III unilateral bifonazole nanoemulsion group (the content of bifonazole is the same as the present invention, self-made); Group IV unilateral clobetasol propionate nanoemulsion group (the content of clobetasol propionate is the same as the present invention, self-made) ); Group V unilateral cinnamaldehyde nanoemulsion group (the content of cinnamaldehyde is the same as that of the present invention, self-made); Group VI commercially available bifonazole cream group. In each group, 5 mg/kg of the drug was applied to the affected area twice a day for 14 consecutive days, and the condition was observed and recorded every week. Group VII was only smeared with normal saline as a positive control. Observe weekly whether there are clinical symptoms such as itching, erythema, papules, blisters, scales, keratinization, and maceration.

  According to the clinical and laboratory observation indicators, the evaluation was carried out before and after 14 days of treatment. When evaluating the curative effect: 1) The skin lesions have completely disappeared or only pigmented spots are left, the itching disappears, and the fungal microscopic examination is negative; 2) The skin lesions have disappeared ≥ 60%, the itching is significantly relieved, and the fungal microscopic examination is negative; it is markedly effective; 3 ) The cured cases and markedly effective cases are combined as effective cases, which are considered effective; 4) 20% to 60% of the skin lesions subside, the itching is mild, and the fungal microscopic examination is positive, which means improvement; 5) The skin lesions subside by less than 20% or continue to aggravate , Itching is the same as before or aggravated, fungal microscopic examination is invalid. The test results are shown in Table 1.

Table 1 A comparative test of compound bifonazole nanoemulsion spray on guinea pigs in vitro antifungal efficacy

group Number of cases/only get well markedly effective get better invalid Efficient recovery rate I 12 12 0 0 0 100% 100% II 12 8 3 1 0 91.67% 66.67% III 12 4 6 2 0 83.33% 33.33% IV 12 3 4 3 2 58.33% 25% Ⅴ 12 3 4 4 1 58.33% 25% Ⅵ 12 2 6 3 1 66.67% 16.67% VII 12 0 0 0 12 - -

The results show that: 1) a compound bifonazole nanoemulsion spray of the present invention has a good therapeutic effect in the treatment of mixed fungal infections in guinea pigs in vitro, and the effective rate and recovery rate are as high as 100%; 2) the compound is being prepared In the common dosage form, the effective rate is 37% higher than that of the commercially available bifonazole cream, which shows that the compound formula has a significant curative effect in the treatment of fungal infections; 3) each active ingredient in the present invention is made into a single nanoemulsion to treat fungal infections During the experiment, it was found that the unilateral bifonazole nanoemulsion group with fungicidal effect was better than the commercially available bifonazole cream, while the clobetapropionate with anti-inflammatory, anti-bacterial and antipruritic effects The effect of the cable and cinnamaldehyde group is equivalent to that of the common dosage form of bifonazole cream on the market. It can be seen that in the process of antifungal treatment, the synergistic effect of various drugs is required to achieve a good therapeutic effect.

Test Example 3 Antibody Culture Fungi, Bacteria and Comparative Experiments

Trichophyton rubrum, Trichophyton gypsum, Microsporum canis, Aspergillus niger, Candida albicans, Candida glabrata, Trichophyton dermatoides, Streptococcus pyogenes, and For Staphylococcus and Escherichia coli, at 37°C, slowly add 0.2%, 0.5%, 1% compound bifonazole nanoemulsion spray, compound bifonazole suspension (with 0.5% The content of bifonazole, clobetasol propionate and cinnamaldehyde in compound bifonazole nanoemulsion spray is the same), unilateral bifonazole nanoemulsion (with 0.5% compound bifonazole nanoemulsion spray The content of bifonazole is the same as that of bifonazole), and the commonly used antifungal drug miconazole nitrate (same as the content of bifonazole in 0.5% compound bifonazole nanoemulsion spray) suspension is 1 ml each, and after 12 hours of incubation, The antibacterial conditions were observed, and the results are shown in Table 1. the

Table 2 In vitro antifungal and bacterial efficacy tests and comparative tests of compound bifonazole nanoemulsion spray

The results in Table 2 show that: 1) The antibacterial activity of compound bifonazole nanoemulsion spray also increases with the increase of the concentration, and it is effective when the dose is very low. 2) The antibacterial activity of the commonly used drug miconazole nitrate at the same dose is not as good as that of compound bifonazole suspension, which shows that the drug formula of this compound has advantages in the treatment of fungal and bacterial infections, and the formula is scientific and effective. 3) The antibacterial effect of the bifonazole nanoemulsion spray of the present invention is better than that of the single bifonazole nanoemulsion, which also shows the effectiveness of the compound formula. 4) The effect of the compound bifonazole nano-emulsion spray of the same dose is far better than that of the compound bifonazole suspension, which shows that making the nano-emulsion of the present invention will undoubtedly greatly improve the efficacy and show a more superior treatment effect. 5) The efficacy of compound bifonazole nanoemulsion spray, compound bifonazole suspension and unilateral bifonazole nanoemulsion is better than that of commercially available miconazole nitrate, especially a compound bifonazole of the present invention The drug effect of the benzazole nanoemulsion spray fully demonstrates the effectiveness of the present invention and shows its broad market prospect. ("-" means invalid, "+" means valid) 

Test Example 4 Anti-inflammatory effect: Inhibition test of xylene-induced ear swelling in mice

Thirty mice, both male and female, weighing 18-25 g, were randomly divided into 5 groups. Ⅰ positive control group without administration; Ⅱ compound bifonazole nano-emulsion spray group of the present invention; Ⅲ compound bifonazole suspension group (the content of each active ingredient is the same as that of the best formula of the present invention, only it is not prepared into nanoemulsion); Ⅳ clobetasol propionate nanoemulsion group; Ⅴ dexamethasone ointment group. In each group, 0.05 ml of xylene was evenly smeared on the front and back of the right ear shell of the mice in each group to induce inflammation, and the left ear was used as a blank control. After 30 minutes, group Ⅰ was smeared with normal saline, group Ⅱ was smeared with compound bifonazole nanoemulsion spray of the present invention, group Ⅲ was smeared with compound bifonazole suspension, group Ⅳ was smeared with clobetasol propionate nanoemulsion, and group Ⅴ was smeared with Dexamethasone ointment. Mice were sacrificed 1 h later, and both ears were cut along the baseline of the auricle. Then the same part of the ear was punched with a 9 mm diameter punch, the weight of the left and right ear pieces was weighed, and the difference between the weights of the two ear pieces was used as the degree of swelling. The results are shown in Table 3.

Table 3 Inhibition test and comparative test of compound bifonazole nanoemulsion spray on xylene-induced mouse ear swelling

group quantity Left ear weight (mg) Right ear weight (mg) Degree of swelling (mg) Swelling inhibition rate (%) I 6 16.5±1.9 35.8±2.1 19.3±1.8 - II 6 15.8±2.1 16.7±0.9 0.9±1.0 95.34% III 6 16.1±1.8 19.0±1.7 2.9±2.1 84.97% IV 6 16.5±1.1 20.2±1.5 3.7±1.7 80.83% Ⅴ 6 15.9±2.1 23.5±1.1 7.6±1.7 60.62%

The results showed: 1) The compound formula preparation of the present invention has a certain anti-inflammatory effect, and the swelling inhibition rate reaches 84.97%, which is better than the common anti-inflammatory drug dexamethasone (60.62%) in the market. 2) The unilateral anti-inflammatory drug clobetasol propionate made into nanoemulsion has a better effect than dexamethasone ointment, which shows that the use of clobetasol propionate as an anti-inflammatory component in the present invention has advantages. 3) The anti-inflammatory effect of single clobetasol propionate nanoemulsion is not better than that of the common dosage form of compound bifonazole suspension, because the cinnamaldehyde added in this compound can destroy the cell wall of the bacteria, thus making the drug more effective To exert the medicinal effect, cinnamaldehyde itself also has an anti-inflammatory effect, which shows the superiority of this compound in the anti-inflammatory effect. 4) After the compound formula of the present invention is made into nanoemulsion, its anti-inflammatory effect is greatly improved, and the swelling inhibition rate reaches 95.34%, showing a good market prospect.

Test example 5 Comparative test of compound bifonazole nano-emulsion spray and other preparations in the treatment of tinea pedis

Thirty-six patients (29 males, 7 females, 27.4±10.2 years old, 45±23 months of disease duration) clinically diagnosed with fungal infection of tinea pedis were divided into 3 groups, 12 cases in each group. Ⅰ Compound bifonazole nano-emulsion spray group, Ⅱ Compound bifonazole suspension group (the active ingredients are the same as compound bifonazole nano-emulsion spray, except that it is not made into nano-emulsion), Ⅲ Bifonazole emulsion Ointment group. Apply twice in the morning and evening to the affected area. Follow-up visits were conducted before treatment, 2 weeks after treatment, when the drug was stopped, and 2 weeks after the drug was stopped. The clinical and mycological curative effects are comprehensively judged according to the 4-level criteria of cured, markedly effective, improved, and ineffective. When the clinical curative effect is inconsistent with the mycological curative effect, the clinical curative effect is subject to the mycological curative effect. Healed (clinical symptoms and signs all subsided, fungal microscopic examination and culture were all negative); markedly effective (clinical symptoms and signs subsided ≥ 60%, fungal microscopic examination and culture were all negative); improved (clinical symptoms and signs subsided within 20% to 59 %, fungal microscopic examination or culture positive); invalid (clinical symptoms and signs subside <20% or continue to aggravate, fungal microscopic examination or culture positive). The recovery rate and the marked rate are collectively referred to as the effective rate. The results are shown in Table 4.

Table 4 Compound bifonazole nanoemulsion spray in the treatment of tinea pedis and comparative test

The results showed that: 1) The compound bifonazole nanoemulsion spray of the present invention has a significant therapeutic effect in the treatment of athlete's foot caused by fungi, with an effective rate and recovery rate of up to 100%, and is not easy to relapse. 2) The effect of the bifonazole suspension prepared by this compound is better than that of the commercially available bifonazole nano-emulsion ointment, which shows that this formula is scientific and effective. 3) The curative effect of the bifonazole nano-emulsion spray of the present invention is far better than that of the commercially available bifonazole cream, and it will not recur, so it has a broad market prospect.

The preparation method of a kind of compound bifonazole nano-emulsion spray of the present invention is further described by the embodiment given by the inventor below.

Example 1

Preparation:

(1) Weigh the surfactant, co-surfactant, oil phase, bifonazole, clobetasol propionate, cinnamaldehyde, and deionized water in the proportion of the formula, and set aside;

(2) Mix the surfactant and co-surfactant evenly, then add the oil phase, and mix well;

(3) Add bifonazole and mix well;

(4) Add clobetasol propionate and mix well;

(5) Add cinnamaldehyde and mix well;

(6) Slowly add deionized water at room temperature, and stir while adding deionized water until a clear, colorless or yellowish liquid with low viscosity and good fluidity is formed, and its weight is called 100 g.

The formula is as follows: EL-40 32 g, absolute ethanol 9 g, polyethylene glycol-400 0.5 g, butyl acetate 7.42 g, bifonazole 1 g, clobetasol propionate 0.03 g, cinnamaldehyde 0.05 g , Deionized water 50 g.

Example 2

RH-40 30 g, absolute ethanol 11 g, polyethylene glycol-400 1 g, glycerin 2 g, ethyl acetate 4.5 g, almond oil 0.5 g, bifonazole 0.8 g, clobeta propionate Sodium 0.02 g, cinnamaldehyde 0.01 g, deionized water 50.17 g.

Example 3

EL-40 2 g, Tween-80 34 g, absolute ethanol 10 g, 1,2-propanediol 1.5 g, polyethylene glycol-400 0.5 g, butyl acetate 4.5 g, glyceryl triacetate 1.5 g, Benbenazole 1.5 g, clobetasol propionate 0.05 g, cinnamaldehyde 0.1 g, deionized water 44.35 g.

Example 4

EL-40 37 g, poloxamer 188 3 g, absolute ethanol 2.9 g, polyethylene glycol-400 0.1 g, butyl acetate 8 g, isopropyl myristate 2 g, bifonazole 0.8 g , clobetasol propionate 0.03 g, cinnamaldehyde 0.03 g, deionized water 46.14 g.

Example 5

EL-40 32 g, RH-40 6 g, absolute ethanol 4 g, glycerol 1 g, ethyl acetate 8 g, wheat germ oil 1 g, bifonazole 1 g, clobetasol propionate 0.06 g , cinnamaldehyde 0.15 g, deionized water 46.79 g.

Example 6

EL-40 35 g, absolute ethanol 11 g, 1,2-propanediol 1 g, butyl acetate 5 g, triacetin 0.5 g, bifonazole 2 g, clobetasol propionate 0.1 g, cinnamon Aldehyde 0.2 g, deionized water 45.2 g.

Example 7

RH-40 30 g, Tween-80 3 g, absolute ethanol 9 g, polyethylene glycol-400 1 g, butyl acetate 7 g, wheat germ oil 1 g, bifonazole 1.2 g, chlorine propionate Betasol 0.05 g, cinnamaldehyde 0.05 g, deionized water 47.7 g.

Example 8

32 g of EL-40, 3 g of Tween-80, 7.5 g of absolute ethanol, 0.5 g of glycerol, 6 g of butyl acetate, 1 g of isopropyl myristate, 1.3 g of bifonazole, chlorine propionate Betasol 0.03 g, cinnamaldehyde 0.12 g, deionized water 48.55 g.

Claims (5)

1. a compound recipe bifonazole nano-emulsion spray is characterized in that, is processed by the raw material of following mass percent:

Surfactant 30%～40%, cosurfactant 3%～14%, oil phase 5%～10%, bifonazole 0.8%～2%, clobetasol propionate 0.02%～0.1%, cinnamic aldehyde 0.01%～0.2%, surplus are deionized water, and the mass percent sum of above-mentioned raw materials is 100%;

Described surfactant is one or more the mixture in EL-40, RH-40, tween 80 and the poloxamer 188;

Described cosurfactant is a dehydrated alcohol, 1, the mixture of one or more in 2-propylene glycol, glycerin and the Polyethylene Glycol-400, and the present invention does not have cosurfactant also can form clear, the nano-emulsion of good stability;

Described oil phase is one or more a mixture of butyl acetate, isopropyl myristate, almond oil, Semen Tritici aestivi germ oil, glyceryl triacetate and ethyl acetate.

2. compound recipe bifonazole nano-emulsion spray according to claim 1 is characterized in that, is processed by the raw material of following mass percent:

Surfactant 30%～36%, cosurfactant 5%～12%, oil phase 6%～9%, bifonazole 0.8%～1.5%, clobetasol propionate 0.02%～0.05%, cinnamic aldehyde 0.03%～0.1%, surplus are deionized water, and the mass percent sum of above-mentioned raw materials is 100%.

3. compound recipe bifonazole nano-emulsion spray according to claim 1 is characterized in that, is processed by the raw material of following component:

Surfactant 32%, cosurfactant 9.5%, oil phase 7.42%, bifonazole 1%, clobetasol propionate 0.03%, cinnamic aldehyde 0.05%, surplus are deionized water, and the mass percent sum of above-mentioned raw materials is 100%.

4. a kind of compound recipe bifonazole nano-emulsion spray according to claim 1 is characterized in that the particle diameter of this nano-emulsion is 1 nm～100 nm.

5. the method for preparing of the described compound recipe bifonazole of claim 1 nano-emulsion spray is characterized in that, may further comprise the steps:

(1) take by weighing surfactant, cosurfactant, oil phase, bifonazole, clobetasol propionate, cinnamic aldehyde, the deionized water of formula proportion, subsequent use;

(2) with surfactant and cosurfactant mixing, add oil phase then, mixing;

(3) add bifonazole, mixing;

(4) add clobetasol propionate, mixing;

(5) add cinnamic aldehyde, mixing;

(6) slowly add deionized water under the room temperature, and the limit adds the deionization waterside and stirs, until form clear, colourless or little yellow, viscosity is little and the liquid of good fluidity, promptly get.