A pharmaceutical composition for treating fungal infection and its preparation method and application

Abstract

The present invention belongs to the field of pharmaceutical preparation technology, and specifically relates to a pharmaceutical composition for treating fungal infections, and a preparation method and application thereof. The pharmaceutical composition of the present invention comprises the following components: bifonazole, osthole, flavonoids, industrial hemp extract, ethanol and water. The present invention combines bifonazole with osthole and flavonoids to prepare a pharmaceutical composition, and through the synergistic coordination between the components of bifonazole, osthole and flavonoids, the effects of strong antibacterial activity, wide antibacterial spectrum, low toxicity and side effects, and not easy to cause the body to produce drug resistance are achieved, and it can effectively prevent and treat bacterial infectious diseases such as dermatophytosis and its secondary infectious diseases. The pharmaceutical composition of the present invention has simple components and easy-to-obtain raw materials, so that patients have good compliance when taking the medicine, and the preparation process is simple, which is suitable for wide production and application.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicine preparation, and in particular relates to a medicine composition for treating fungal infection and a preparation method and application thereof. Background Art

[0002] Bifonazole is an imidazole derivative with a broad antibacterial spectrum, inhibiting 90% of pathogenic fungi. It can inhibit a variety of skin fungi (such as Trichophyton, Microsporum), yeast (such as Candida, Flask-shaped yeast, and Toruloplasma), mold (such as Aspergillus) and various fungi (such as Coccidioides, Blastomyces, and Histoplasma). It also has activity against certain Gram-positive bacteria (such as Staphylococcus, Streptococcus, etc.). The antibacterial mechanism of bifonazole is: at low concentrations, it prevents the synthesis of ergosterol, a lipid component of the cell membrane; at high concentrations, it changes the properties of the cell membrane lipid-specific binding membrane, causing disorders in the cell membrane structure and function, thereby showing antifungal effects. Some superficial fungal diseases commonly treated with bifonazole topical preparations are tinea cruris, tinea pedis, tinea manuum, candidiasis, pityriasis versicolor, and onychomycosis.

[0003] At present, the treatment of skin fungal infections mainly includes systemic treatment with oral antibacterial drugs and local treatment with topical drugs or a combination of the two. Among oral preparations, pure Western medicine preparations account for a large proportion, and Chinese medicine preparations are rare. After years of clinical application, the shortcomings of Western medicine preparations have gradually emerged. The efficacy is not ideal, and it is easy to relapse after discontinuation of medication. Long-term use has certain toxic side effects or irritation. Topical preparations are mainly concentrated in ointments, liniments, tinctures and patches based on compound Chinese medicines, supplemented by steroid hormones. Tinctures and patches are easily affected by the external environment during use, and the active ingredients are less attached, resulting in the local drug failing to reach an effective concentration or the effective maintenance time is too short, and the transdermal absorption effect is poor.

[0004] For example, Chinese invention patent invention CN109316552A provides a pharmaceutical composition for treating tinea pedis. The invention provides a pharmaceutical composition for treating tinea pedis, the sum of the mass parts of each component is 100 parts, and the composition is composed of the following components: 0.5-5 parts of azole antifungal drugs, 0.1-10 parts of schizonepeta tenuifolia, 0.1-10 parts of Sophora flavescens, 0.1-10 parts of Polygonatum sibiricum, 0.1-5 parts of Dictamni, 0.1-5 parts of mint, 0.1-2 parts of cloves, 0.1-2 parts of Artemisia argyi, 0.1-2 parts of alum, and the remainder is auxiliary materials and water, which achieves the effect of treating both the symptoms and the root cause of tinea pedis under the joint action of antifungal drugs and traditional Chinese medicine.

[0005] Another Chinese invention patent CN110898151A provides a pharmaceutical composition for treating fungal skin infections and a preparation process thereof, comprising the following components: azole antifungal drugs, Sophora flavescens, Cnidium monnieri, Brassica juncea, Angelica dahurica, Forsythia suspensa, Atractylodes macrocephala, Clematis chinensis, Smilax glabra, Acer truncatum, Galla chinensis, Dictamni cortex, Phellodendron chinense, Rhubarb, and excipients. The pharmaceutical composition for treating fungal skin infections provided by the invention and a preparation process thereof adopt the theory of combining traditional Chinese and Western medicine. The selected Western medicine has an antifungal effect, and the selected traditional Chinese medicine has the effect of clearing away heat and drying dampness, thereby being able to treat both the symptoms and the root cause, having a wide treatment range, significant clinical efficacy, small toxic and side effects, being convenient and safe to use, and having a simple and easy preparation process.

[0006] The disadvantages of the above-mentioned composition are that the ingredients are complex, the mechanism of action is unclear, multiple medications lead to poor compliance of patients, the cost of raw materials is high, and the preparation process is relatively complicated.

[0007] In view of this, there is an urgent need in the art for a pharmaceutical composition for treating fungal infections that can solve the above technical problems. Summary of the invention

[0008] In view of the problems existing in the prior art, the present invention provides a pharmaceutical composition for treating fungal infection and a preparation method and application thereof.

[0009] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0010] A pharmaceutical composition for treating fungal infection comprises the following components: bifonazole, osthole, flavonoids, industrial hemp extract, ethanol and water.

[0011] Preferably, the following components are included by weight: 0.1-10 parts of bifonazole, 10-30 parts of osthole, 10-30 parts of flavonoids, 2-6 parts of industrial hemp extract, 200-300 parts of ethanol, and 50-80 parts of water.

[0012] More preferably, the following components are included by weight: 6-10 parts of bifonazole, 15-25 parts of osthole, 15-25 parts of flavonoids, 4-6 parts of industrial hemp extract, 230-260 parts of ethanol, and 55-70 parts of water.

[0013] Further preferably, the following components are included by weight: 8 parts of bifonazole, 20 parts of osthole, 20 parts of flavonoids, 5 parts of industrial hemp extract, 250 parts of ethanol, and 60 parts of water.

[0014] Preferably, the volume concentration of the ethanol is 90-95%.

[0015] More preferably, the volume concentration of ethanol is 95%.

[0016] Preferably, the dosage form of the pharmaceutical composition is a solution.

[0017] The present invention also provides a method for preparing the above-mentioned pharmaceutical composition, comprising the following steps: first, by weight, ultrasonically mixing bifonazole, osthole and ethanol to obtain solution 1; then, mixing calendula, industrial hemp extract and water to obtain solution 2; and finally, mixing solutions 1 and 2 evenly to obtain the pharmaceutical composition.

[0018] The present invention also provides a product for preventing and / or treating diseases caused by fungi, comprising the above pharmaceutical composition or the pharmaceutical composition prepared by the above preparation method.

[0019] The present invention also provides the use of the above-mentioned pharmaceutical composition or the pharmaceutical composition obtained by the above-mentioned preparation process in preparing products for preventing and / or treating diseases caused by fungi.

[0020] Preferably, the disease is an infection caused by fungi.

[0021] The present invention also provides the use of the above-mentioned pharmaceutical composition or the pharmaceutical composition obtained by the above-mentioned preparation process in preparing a product for inhibiting the growth and / or reproduction of fungi.

[0022] Preferably, the fungus is selected from one or more of Trichophyton rubrum, Trichophyton mentagrophytes, Candida albicans, yeast and Epidermophyton floccosum.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] (1) The pharmaceutical composition of the present invention combines bifonazole with osthole and palmatum, and through the synergistic cooperation among the components of bifonazole, osthole and palmatum, it achieves the effects of strong antibacterial activity, broad antibacterial spectrum, low toxicity and side effects, and is not easy to cause the body to develop drug resistance, and can effectively prevent and treat bacterial infectious diseases such as dermatophytosis and its secondary infectious diseases.

[0025] (2) The pharmaceutical composition of the present invention is a solution preparation for external use, which acts directly on the pathogenic bacteria, has a strong effect, few toxic and side effects, a mild dosage form, is easy to use, and avoids causing contact dermatitis.

[0026] (3) The pharmaceutical composition of the present invention has simple components and readily available raw materials, which improves patient compliance when taking the medicine. The preparation process is simple and suitable for widespread production and application. DETAILED DESCRIPTION

[0027] It is worth noting that the raw materials used in the present invention are all common commercial products, among which osthole, purity 99%, was purchased from Aladdin; flavonoids, purity ≥97%, was purchased from Aladdin; industrial hemp extract, reference invention patent CN111388529A; Trichophyton Rubrum, ATCC 28188, purchased from China Industrial Microbiological Culture Collection Administration Center; Candida Albicans, CMCC 98001, purchased from China Microbiological Culture Collection Center; Saccharomyces Sp., ATCC 764, purchased from China Microbiological Culture Collection Center; Epidermophyton Floccosum, ATCC 26072, purchased from China Microbiological Culture Collection Center.

[0028] Example 1

[0029] A pharmaceutical composition for treating fungal infection is composed of the following raw materials in parts by weight: 8 parts of bifonazole, 20 parts of osthole, 20 parts of flavonoids, 5 parts of industrial hemp extract, 250 parts of ethanol with a volume concentration of 95%, and 60 parts of water.

[0030] A preparation method of a pharmaceutical composition for treating fungal infections is as follows: by weight, firstly, bifonazole, osthole and ethanol are ultrasonically mixed for 30 minutes, the ultrasonic power is set to 100W, and the ultrasonic temperature is set to 50°C to obtain solution 1; then, flavonoids, industrial hemp extract and water are mixed at 60°C for 30 minutes to obtain solution 2; finally, solutions 1 and 2 are mixed at room temperature to obtain the composition.

[0031] Example 2

[0032] A pharmaceutical composition for treating fungal infection is composed of the following raw materials in parts by weight: 0.1 parts of bifonazole, 10 parts of osthole, 10 parts of flavonoids, 2 parts of industrial hemp extract, 200 parts of ethanol with a volume concentration of 90%, and 50 parts of water.

[0033] A preparation method of a pharmaceutical composition for treating fungal infections is as follows: by weight, firstly, bifonazole, osthole and ethanol are ultrasonically mixed for 30 minutes, the ultrasonic power is set to 100W, and the ultrasonic temperature is set to 50°C to obtain solution 1; then, flavonoids, industrial hemp extract and water are mixed at 60°C for 30 minutes to obtain solution 2; finally, solutions 1 and 2 are mixed at room temperature to obtain the composition.

[0034] Example 3

[0035] A pharmaceutical composition for treating fungal infection is composed of the following raw materials in parts by weight: 10 parts of bifonazole, 30 parts of osthole, 30 parts of flavonoids, 6 parts of industrial hemp extract, 300 parts of ethanol with a volume concentration of 95%, and 80 parts of water.

[0036] A preparation method of a pharmaceutical composition for treating fungal infections is as follows: by weight, firstly, bifonazole, osthole and ethanol are ultrasonically mixed for 30 minutes, the ultrasonic power is set to 100W, and the ultrasonic temperature is set to 50°C to obtain solution 1; then, flavonoids, industrial hemp extract and water are mixed at 60°C for 30 minutes to obtain solution 2; finally, solutions 1 and 2 are mixed at room temperature to obtain the composition.

[0037] Comparative Example 1

[0038] The same as Example 1, except that bifonazole is not added to the formula.

[0039] A pharmaceutical composition for treating fungal infection is composed of the following raw materials in parts by weight: 24 parts of osthole, 24 parts of flavonoids, 5 parts of industrial hemp extract, 250 parts of ethanol with a volume concentration of 95%, and 60 parts of water.

[0040] A preparation method of a pharmaceutical composition for treating fungal infections is as follows: first, by weight, osthole and ethanol are ultrasonically mixed for 30 minutes, the ultrasonic power is set to 100 W, and the ultrasonic temperature is set to 50° C., to obtain solution 1; then, pyrantel, industrial hemp extract and water are mixed at 60° C. for 30 minutes to obtain solution 2; finally, solutions 1 and 2 are mixed at room temperature to obtain.

[0041] Comparative Example 2

[0042] The same as Example 1, the only difference is that osthole and flavonoids are not added into the formula.

[0043] A pharmaceutical composition for treating fungal infection is composed of the following raw materials in parts by weight: 48 parts of bifonazole, 5 parts of industrial hemp extract, 250 parts of ethanol with a volume concentration of 95%, and 60 parts of water.

[0044] A preparation method of a pharmaceutical composition for treating fungal infections is as follows: by weight, firstly, bifonazole and ethanol are ultrasonically mixed for 30 minutes, the ultrasonic power is set to 100W, and the ultrasonic temperature is set to 50°C, to obtain solution 1; then, industrial hemp extract and water are mixed at 60°C for 30 minutes to obtain solution 2; finally, solutions 1 and 2 are mixed at room temperature to obtain.

[0045] Comparative Example 3

[0046] The same as Example 1, the only difference is that the formula does not contain flavonoids.

[0047] A pharmaceutical composition for treating fungal infection is composed of the following raw materials in parts by weight: 8 parts of bifonazole, 40 parts of osthole, 5 parts of industrial hemp extract, 250 parts of ethanol with a volume concentration of 95%, and 60 parts of water.

[0048] A preparation method of a pharmaceutical composition for treating fungal infection is as follows: by weight, firstly, bifonazole, osthole and ethanol are ultrasonically mixed for 30 minutes, the ultrasonic power is set to 100W, and the ultrasonic temperature is set to 50°C, to obtain solution 1; then, industrial hemp extract and water are mixed at 60°C for 30 minutes to obtain solution 2; finally, solutions 1 and 2 are mixed at room temperature to obtain.

[0049] Comparative Example 4

[0050] The same as Example 1, the only difference is that osthole is not added into the formula.

[0051] A pharmaceutical composition for treating fungal infection is composed of the following raw materials in parts by weight: 8 parts of bifonazole, 40 parts of flavonoids, 5 parts of industrial hemp extract, 250 parts of ethanol with a volume concentration of 95%, and 60 parts of water.

[0052] A preparation method of a pharmaceutical composition for treating fungal infections is as follows: by weight, firstly ultrasonically mix bifonazole and ethanol for 30 minutes, setting the ultrasonic power to 100 W and the ultrasonic temperature to 50° C. to obtain solution 1; then, mix calendula, industrial hemp extract and water at 60° C. for 30 minutes to obtain solution 2; finally, mix solutions 1 and 2 at room temperature to obtain the product.

[0053] Comparative Example 5

[0054] The same as Example 1, the only difference is the number of components in the formula.

[0055] A pharmaceutical composition for treating fungal infection is composed of the following raw materials in parts by weight: 20 parts of bifonazole, 5 parts of osthole, 5 parts of flavonoids, 8 parts of industrial hemp extract, 300 parts of ethanol with a volume concentration of 95%, and 60 parts of water.

[0056] A preparation method of a pharmaceutical composition for treating fungal infections is as follows: by weight, firstly, bifonazole, osthole and ethanol are ultrasonically mixed for 30 minutes, the ultrasonic power is set to 100W, and the ultrasonic temperature is set to 50°C to obtain solution 1; then, flavonoids, industrial hemp extract and water are mixed at 60°C for 30 minutes to obtain solution 2; finally, solutions 1 and 2 are mixed at room temperature to obtain the composition.

[0057] Experimental Example 1

[0058] Under sterile conditions, 100 μL of fungi with a density of 10 5CFU / mL of Trichophyton rubrum, Candida albicans, yeast and Epidermophyton floccosum were transferred into potato dextrose agar (PDA) medium and cultured continuously for 24 hours in an incubator (T=25±2°C, L / D=12h / 12h). Then, the bacterial solution and agar medium were injected into a flat plate, mixed and allowed to coagulate. When the culture plate was about 2 / 3 of the plate, 6 holes with a diameter of 6 mm were punched on the agar plate with a sterile puncher.

[0059] The agar in the wells was picked out, and then the pharmaceutical compositions prepared in Examples 1-3 and Comparative Examples 1-5, which were diluted 2 times, were added respectively. Sterile water was used as the control group. About 20 μL was added to each well. The mixture was cultured at 25°C for 24 h. The diameter of each colony was measured by the cross method. The EC was calculated by the colony diameter method. 50 , take the average, and calculate the inhibition rate according to the formula.

[0060] The calculation formula of the antibacterial rate is as follows:

[0061]

[0062] The experimental results are shown in Table 1. The pharmaceutical compositions prepared in Examples 1-3 of the present invention have strong antibacterial and bactericidal effects on four pathogenic fungi, namely Trichophyton rubrum, Candida albicans, yeast and Epidermophyton floccosum. It can be seen from Example 1 and Comparative Examples 1-4 that the synergistic effect of bifonazole, osthole and flavonoids significantly enhances the antibacterial effect (P<0.01).

[0063] Table 1 Antibacterial effect

[0064]

[0065]

[0066] Note: Compared with Comparative Example 1, * indicates P < 0.05, ** Indicates P<0.01.

[0067] Experimental Example 2

[0068] A total of 160 cases of tinea pedis and tinea manuum were divided into 8 groups according to the time of consultation, with 20 cases in each group. Medication: After local cleaning, the pharmaceutical composition solutions prepared in Examples 1-3 and Comparative Examples 1-5 were evenly applied to the affected area, once a day, and any other treatment was stopped during the treatment. Treatment course: 4 weeks for tinea pedis and tinea manuum. The comprehensive efficacy evaluation results are shown in Table 2.

[0069] Clinical efficacy evaluation: There are four levels of evaluation: basic cure (basic recovery), marked effect, improvement, and ineffectiveness; among which, the percentage of improvement of symptom / sign indicators (efficacy index) a = (pre-treatment score - post-treatment score) / pre-treatment score × 100%.

[0070] Basic recovery: The improvement rate of symptoms / signs is ≥90%;

[0071] Significant effect: 60%≤a<90%;

[0072] Improvement: 20%≤a<60%;

[0073] Ineffective: a<20% or continues to worsen.

[0074] Clinical effective rate = (number of clinically effective cases + number of cured cases) / total number of cases × 100%.

[0075] The experimental results show that the therapeutic effects of the pharmaceutical compositions prepared in Examples 1-3 of the present invention on tinea pedis are higher than those in Comparative Examples 1-5, wherein bifonazole, osthole and flavonoids synergistically promote the therapeutic effect on tinea pedis and tinea manuum.

[0076] Table 2 Comprehensive efficacy evaluation results

[0077]

[0078]

[0079] In summary, the pharmaceutical composition of the present invention can directly reach the lesion site, have antibacterial and anti-inflammatory effects, promote blood circulation and detoxify, have significant therapeutic effects, and have little irritation and no recurrence.

[0080] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A pharmaceutical composition for treating fungal infection, characterized in that: The invention is composed of the following components by weight: 0.1-10 parts of bifonazole, 10-30 parts of osthole, 10-30 parts of flavonoids, 2-6 parts of industrial hemp extract, 200-300 parts of ethanol and 50-80 parts of water.

2. The pharmaceutical composition according to claim 1, characterized in that The invention is composed of the following components by weight: 6-10 parts of bifonazole, 15-25 parts of osthole, 15-25 parts of flavonoids, 4-6 parts of industrial hemp extract, 230-260 parts of ethanol and 55-70 parts of water.

3. The pharmaceutical composition according to any one of claims 1 to 2, characterized in that The volume concentration of the ethanol is 90-95%.

4. The pharmaceutical composition according to claim 3, characterized in that The dosage form of the pharmaceutical composition is a solution.

5. A method for preparing the pharmaceutical composition according to any one of claims 1 to 4, characterized in that: The method comprises the following steps: firstly, by weight, ultrasonically mixing bifonazole, osthole and ethanol to obtain solution 1; then, mixing calendula, industrial hemp extract and water to obtain solution 2; and finally, mixing solutions 1 and 2 evenly to obtain the solution.

6. A medicine for preventing and / or treating diseases caused by fungi, characterized in that: The medicine is the pharmaceutical composition according to any one of claims 1 to 4 or the pharmaceutical composition prepared by the preparation method according to claim 5.

7. Use of the pharmaceutical composition according to any one of claims 1 to 4 or the pharmaceutical composition prepared by the preparation method according to claim 5 in the preparation of medicines for preventing and / or treating diseases caused by fungi, characterized in that: The disease is an infection caused by fungi.

8. Use of the pharmaceutical composition according to any one of claims 1 to 4 or the pharmaceutical composition prepared by the preparation method according to claim 5 in the preparation of a medicine for inhibiting the growth and / or reproduction of fungi.

9. The use according to any one of claims 7-8, characterized in that: The fungus is selected from one or more of Trichophyton rubrum, Trichophyton mentagrophytes, Candida albicans, yeast and Epidermophyton floccosum.

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