阅读说明：本技术 一种盐酸奈康唑组合物、其制剂和制备方法 (Nalconazole hydrochloride composition, preparation and preparation method thereof ) 是由 任亚东 夏春森 欧志展 姚远航 蔡乐 刘志强 袁海成 于 2020-12-18 设计创作，主要内容包括：本发明提供一种盐酸奈康唑组合物、其制剂及制备方法。所述组合物包含作为活性成分的盐酸奈康唑或其水合物,以及药用辅料；所述活性成分与药用辅料的重量比为1:(50-200)；所述药用辅料包括基质、增黏剂、乳化剂、络合剂、防腐剂、pH调节剂和溶剂中的一种或多种；所述药用辅料中至少含有聚氧乙烯烷基醚。本发明组合物中各辅料组分与活性成分盐酸奈康唑相互作用,得到的盐酸奈康唑组合物和其制剂具有优异的稳定性和用药安全性,以及良好的杀菌和抗菌性,其可用于治疗和/或预防与真菌相关的疾病(尤其是足癣),还具有抑制与真菌相关疾病复发的作用。(The invention provides a nyconazole hydrochloride composition, a preparation and a preparation method thereof. The composition comprises the nerconazole hydrochloride or hydrate thereof as an active ingredient and pharmaceutic adjuvant; the weight ratio of the active ingredient to the pharmaceutic adjuvant is 1 (50-200); the pharmaceutic adjuvant comprises one or more of a matrix, a tackifier, an emulsifier, a complexing agent, a preservative, a pH regulator and a solvent; the pharmaceutical excipients at least contain polyoxyethylene alkyl ether. The auxiliary material components in the composition interact with the active component, namely the naphthoconazole hydrochloride, so that the obtained naphthoconazole hydrochloride composition and the preparation thereof have excellent stability, medication safety and good sterilization and antibacterial properties, can be used for treating and/or preventing diseases (especially tinea pedis) related to fungi, and also have the effect of inhibiting the relapse of the diseases related to the fungi.)

1. A composition of nyconazole hydrochloride, characterized in that the composition comprises nyconazole hydrochloride or hydrate thereof as an active ingredient, and a pharmaceutical excipient;

the weight ratio of the active ingredient to the pharmaceutic adjuvant is 1 (50-200);

the pharmaceutic adjuvant comprises one or more of a matrix, a tackifier, an emulsifier, a complexing agent, a preservative, a pH regulator and a solvent.

2. The composition of claim 1, wherein the active ingredient is nyconazole hydrochloride.

3. The composition of claim 1 or 2, wherein the base is selected from at least one of petrolatum, paraffin, silicone, lanolin, beeswax and spermaceti; preferably, the mass ratio of the matrix to the active ingredient is (2-10): 1.

Preferably, the tackifier is selected from at least one of glycerol ester of saturated fatty acid, solid fatty alcohol, ester of saturated fatty alcohol and saturated fatty acid, saturated hydrocarbon, mixture of polyoxyethylene derivative of fatty alcohol and sorbitan fatty acid ester, polyethylene glycol; preferably, the mass ratio of the tackifier to the active ingredient is (2-10): 1.

4. The composition according to any one of claims 1 to 3, wherein the emulsifier is at least one selected from the group consisting of polyoxyethylene alkyl ethers, polyoxyethylene ethers, polyoxypropylene ethers, block copolymers of ethylene oxide and propylene oxide, and polyol fatty acid esters;

preferably, the mass ratio of the emulsifier to the active ingredient is (3-35) to 1;

preferably, the emulsifier comprises a first emulsifier and a second emulsifier; preferably, the weight ratio of the first emulsifier to the second emulsifier is (1-6): 1;

preferably, the first emulsifier is selected from glyceryl mono-and distearate; the second emulsifier is selected from polyoxyethylene cetyl ether.

5. The composition of any of claims 1-4, wherein the complexing agent is selected from at least one of ethylenediaminetetraacetic acid and its sodium salt, and dicarboxylic acid compounds;

preferably, the mass ratio of the complexing agent to the active ingredient is (1-10): 100.

Preferably, the solvent includes an aqueous phase solvent and an oil phase solvent. For example, the aqueous phase solvent is selected from at least one of water, ethanol and glycol; for example, the oil phase solvent is a medium chain fatty acid ester.

Preferably, the mass ratio of the aqueous phase solvent to the active ingredient is (50-100): 1.

Preferably, the mass ratio of the oil phase solvent to the active ingredient is (6-20): 1.

Preferably, the preservative is selected from at least one of benzoic acid and salts thereof and parabens, preferably parabens preservative, such as at least one of methyl hydroxybenzoate, ethyl hydroxybenzoate, propyl hydroxybenzoate and butyl hydroxybenzoate;

preferably, the mass ratio of the preservative to the active ingredient is (1-5): 10;

preferably, the pH adjusting agent is selected from weakly basic compounds, preferably triethanolamine. Preferably, the mass ratio of the triethanolamine to the active ingredient is (0.2-1): 1.

Preferably, the pharmaceutical excipient optionally further comprises a flavoring agent;

preferably, the composition of the nyconazole hydrochloride is in the form of a paste;

preferably, the pH of the composition of nyconazole hydrochloride is 5-7;

preferably, the content of total impurities in the composition of the nerconazole hydrochloride is not more than 2%;

preferably, the content of Z isomer in the composition of nyconazole hydrochloride is not more than 0.2%.

6. The composition of any one of claims 1 to 5, wherein the composition of nyconazole hydrochloride comprises the following components in parts by weight: 1 part of nyconazole hydrochloride, 2-10 parts of vaseline, 2-10 parts of octadecanol, 6-20 parts of medium-chain triglyceride, 2-5 parts of glycerin monostearate and distearate, 1-4 parts of polyoxyethylene cetyl ether, 0.1-0.5 part of preservative, 0.01-0.05 part of complexing agent, 0.2-1 part of triethanolamine and 50-100 parts of water.

7. Use of the composition of nyconazole hydrochloride as claimed in any of claims 1 to 6 for the preparation of a formulation of nyconazole hydrochloride.

8. A formulation of nyconazole hydrochloride comprising the composition of nyconazole hydrochloride according to any of claims 1 to 6.

9. A process for the preparation of the composition of nerconazole hydrochloride as claimed in any of claims 1-6, comprising the steps of: mixing the active ingredient water solution, the oil phase and the water phase, and carrying out an emulsification reaction to obtain the naphthoconazole hydrochloride composition;

the oil phase comprises a substrate, a tackifier, an emulsifier, medium chain triglyceride and a preservative which are mixed according to a ratio; the water phase comprises a complexing agent, a pH regulator, a preservative and water which are mixed according to a ratio.

Preferably, the preparation method of the nyconazole hydrochloride preparation of claim 8 comprises the following steps: sterilizing, filling and sealing the nyconazole hydrochloride composition of any one of claims 1 to 6 to obtain the nyconazole hydrochloride preparation.

10. Use of the composition of nyconazole hydrochloride as claimed in any of claims 1 to 6 for the preparation of a medicament. Preferably, the medicament is for the prevention or treatment of a fungal related disease.

Technical Field

The invention belongs to the field of pharmaceutical compositions, and particularly relates to a neconazole hydrochloride composition, a preparation and a preparation method thereof.

Background

The chemical name of the nyconazole hydrochloride (CAS No.130773-02-3) is as follows: (E) -1- [ 2-methylsulfanyl-1- [2- (pentyloxy) phenyl ] vinyl ] -1H-imidazole hydrochloride having the structure shown in formula I:

the neconazole hydrochloride is a novel imidazole antifungal drug and has double effects of antibiosis and sterilization. It has broad antibacterial spectrum, and has broad-spectrum antibacterial effect on yeast-like fungus, dermatophyte, tinea versicolor fungus, coloring fungus and other filamentous fungi. The preparation of nyconazole hydrochloride is developed by Japanese SS pharmaceutical company, and is firstly marketed in Japan in 1993, and is clinically used for treating dermatophytosis (tinea pedis, tinea corporis and tinea cruris), cutaneous candidiasis (interdigital erosion and intertrigo) and tinea versicolor.

At present, the pharmaceutical composition of nyconazole hydrochloride with good antifungal effect, and the characteristics of safety and/or stability of the drug during the period of validity, etc. is still paid extensive attention by pharmaceutical researchers, and needs to be studied further.

Disclosure of Invention

The invention provides a nyconazole hydrochloride composition which comprises nyconazole hydrochloride or hydrate thereof serving as an active ingredient and pharmaceutic adjuvant; the weight ratio of the active ingredient to the pharmaceutical excipient is 1: 50-200, e.g., 1: 70-160, e.g., 1: 90-120, illustratively 1: 90, 1: 95, 1: 99, 1: 100, 1: 105, 1: 110.

According to the invention, the active ingredient is nyconazole hydrochloride.

According to the present invention, the pharmaceutical excipients may include one or more of a base, a tackifier, an emulsifier, a complexing agent, a preservative, a pH adjuster, and a solvent.

Wherein, the base may be selected from at least one of vaseline, paraffin, silicone, lanolin, beeswax, spermaceti wax and the like, for example, at least one selected from white vaseline, yellow vaseline, liquid paraffin, solid paraffin, lanolin, exemplarily selected from white vaseline. Further, the mass ratio of the matrix to the active ingredient is (2-10) to 1, such as (3-7) to 1, illustratively 3.5: 1, 4: 1, 5: 1, 6: 1.

Wherein the tackifier may be selected from at least one of a glyceride of a saturated fatty acid, a solid fatty alcohol, an ester of a saturated fatty acid and a saturated fatty alcohol, a saturated hydrocarbon, a mixture of a fatty alcohol and a polyoxyethylene derivative of a sorbitan fatty acid ester, polyethylene glycol, and the like, and may be selected from at least one of a glyceride of a saturated fatty acid, a solid fatty alcohol, and stearyl alcohol and/or cetyl alcohol as an example. Further, the mass ratio of the tackifier to the active ingredient is (2-10) to 1, such as (2.5-7) to 1, illustratively 3: 1, 4: 1, 5: 1, 6: 1.

According to the present invention, the emulsifier may be at least one selected from among polyoxyethylene alkyl ethers, polyoxyethylene ethers, polyoxypropylene ethers, ethylene oxide and propylene oxide block copolymers, polyol fatty acid esters, and the like, for example, at least one selected from among polyoxyethylene alkyl ethers and polyol fatty acid esters, and illustratively at least one selected from among mono-, di-and polyoxyethylene cetyl ethers.

Further, the mass ratio of the emulsifier to the active ingredient is (3-35):1, such as (5-30): 1, illustratively 3: 1, 5: 1, 10: 1, 11: 1, 14: 1, 16: 1, 17.465: 1, 18: 1, 19: 1. Further, the emulsifier may include a first emulsifier and a second emulsifier; for example, the weight ratio of the first emulsifier to the second emulsifier is (1-6) to 1, such as (1.5-5) to 1, illustratively 1.5: 1, 2: 1, 3: 1, 3.7: 1, 4: 1. For example, the first emulsifier is glyceryl mono-and distearate; the second emulsifier is polyoxyethylene cetyl ether.

According to the present invention, the complexing agent may be selected from at least one of ethylenediaminetetraacetic acid and its sodium salt, and a dicarboxylic acid compound; for example, the ethylene diamine tetraacetic acid sodium salt is ethylene diamine tetraacetic acid disodium salt or ethylene diamine tetraacetic acid calcium sodium salt, and the dicarboxylic acid compound is tartaric acid or citric acid; illustratively, the complexing agent is disodium ethylenediaminetetraacetate (disodium edetate). Further, the mass ratio of the complexing agent to the active ingredient is (1-10) to 100, such as (1.5-5) to 100, illustratively 1: 50.

According to the present invention, the solvent includes an aqueous phase solvent and an oil phase solvent. For example, the aqueous phase solvent may be selected from at least one of water, ethanol, ethylene glycol, and the like, preferably water, such as purified water. For example, the oil phase solvent is a medium chain fatty acid ester, preferably a medium chain triglyceride.

Further, the mass ratio of the aqueous solvent to the active ingredient is (50-100) to 1, such as (60-80) to 1, illustratively 70: 1, 72: 1, 75: 1.

Further, the mass ratio of the oil phase solvent to the active ingredient is (6-20) to 1, such as (8-15) to 1, illustratively 9: 1, 10: 1, 11: 1, 12: 1.

According to the invention, the preservative can be selected from at least one of benzoic acid and salts thereof and parabens, preferably a paraben preservative, such as at least one of methylparaben, ethylparaben, propylparaben and butylparaben, exemplified by methylparaben and butylparaben. Further, the mass ratio of the preservative to the active ingredient is (1-5) to 10, such as (2-4) to 10, illustratively 1: 10, 2: 10, 3: 10.

According to the invention, the pH adjusting agent may be selected from weakly basic compounds, such as triethanolamine. Further, the mass ratio of the triethanolamine to the active ingredient is (0.2-1) to 1, e.g. (0.3-0.6) to 1, exemplary 0.4: 1, 0.465: 1, 0.5: 1.

According to the present invention, the pharmaceutical excipient may also optionally include a flavoring agent. For example, the aromatic agent may be selected from at least one of natural flavors such as at least one of lemon, anise, peppermint oil, and the like, and artificial flavors such as at least one of apple essence, orange essence, banana essence, and the like.

According to the invention, the composition of the nerconazole hydrochloride comprises the following components in parts by weight: 1 part of nyconazole hydrochloride, 2-10 parts of vaseline, 2-10 parts of octadecanol, 6-20 parts of medium-chain triglyceride, 2-5 parts of glycerin monostearate and distearate, 1-4 parts of polyoxyethylene cetyl ether, 0.1-0.5 part of preservative, 0.01-0.05 part of complexing agent, 0.2-1 part of triethanolamine and 50-100 parts of water. For example, the composition of the nyconazole hydrochloride comprises 1 part of nyconazole hydrochloride, 3-7 parts of white vaseline, 2.5-7 parts of octadecanol, 8-15 parts of medium-chain triglyceride, 2.5-4 parts of glycerin monostearate and distearate, 1.5-3 parts of polyoxyethylene cetyl ether, 0.1-0.2 part of methylparaben, 0.1-0.3 part of butyl hydroxybenzoate, 0.02-0.04 part of disodium edetate, 0.3-0.6 part of triethanolamine and 60-80 parts of water. Illustratively, when the nyconazole hydrochloride is 1 part, 2, 3, 4, 5, 6, 7, 8, 9 and 10 parts of vaseline can be selected, 1, 2, 3 and 4 parts of polyoxyethylene cetyl ether can be selected, 0.1, 0.2, 0.3, 0.4 and 0.5 part of preservative can be selected, 0.01, 0.02, 0.03, 0.04 and 0.05 part of complexing agent can be selected, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 and 1 part of triethanolamine can be selected; illustratively, the composition of the nyconazole hydrochloride comprises 1 part of nyconazole hydrochloride, 5 parts of white vaseline, 4 parts of octadecanol, 11 parts of medium-chain triglyceride, 3 parts of glycerin monostearate and distearate, 2 parts of polyoxyethylene cetyl ether, 0.2 part of methyl hydroxybenzoate, 0.1 part of oxybenzene butyl ester, 0.02 part of disodium edetate, 0.465 part of triethanolamine and 72.215 parts of water; or the composition of the nyconazole hydrochloride comprises 1 part of nyconazole hydrochloride, 4 parts of white vaseline, 6 parts of octadecanol, 11 parts of medium-chain triglyceride, 3 parts of glycerin monostearate and distearate, 2 parts of polyoxyethylene cetyl ether, 0.2 part of methylparaben, 0.1 part of butyl hydroxybenzoate, 0.02 part of disodium edetate, 0.465 part of triethanolamine and 72.215 parts of water.

According to the invention, the composition of the nyconazole hydrochloride is in the form of a paste, i.e. a non-flowing pasty liquid.

According to the invention, the pH of the composition of nyconazole hydrochloride is 5-7, such as 5.2-6.5, exemplary 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9.

According to the present invention, the content of total impurities in the composition of nyconazole hydrochloride is not more than 2%, for example not more than 1.5%, as well as not more than 1.0%, preferably not more than 0.5%, more preferably not more than 0.35%, and exemplarily the content of total impurities may be 0.10%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%.

According to the invention, the content of the Z isomer in the nyconazole hydrochloride composition is not more than 0.2%, wherein the Z isomer ((Z) -1- (2- (methylthio) -1- (2- (pentyloxy) phenyl) vinyl) -1H-imidazole) has a structure shown in formula (II):

preferably, the Z isomer is present in the composition in an amount of no more than 0.15%, more preferably, no more than 0.12%, illustratively, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%.

The invention also provides application of the nerconazole hydrochloride composition in preparation of a nerconazole hydrochloride preparation. For example, the formulation of the nyconazole hydrochloride can be in the form of external ointment, such as ointment, cream, plaster, gel or ointment-like formulation (such as paste or film coating agent), preferably cream. For example, the packaging container of the nyconazole hydrochloride preparation does not have physicochemical effects on the active ingredient and/or the pharmaceutical excipients, and can be made of aluminum, plastic or backing materials (such as non-woven fabrics), such as aluminum pharmaceutical cream tubes.

The invention also provides a nyconazole hydrochloride preparation which contains the nyconazole hydrochloride composition. Wherein the formulation of the nyconazole hydrochloride preparation has the meaning as described above. Wherein the packaging container of the nyconazole hydrochloride preparation also has the meaning as described above.

The invention also provides a preparation method of the composition of the nyconazole hydrochloride, which comprises the following steps: mixing the active ingredient water solution, the oil phase and the water phase, and carrying out an emulsification reaction to obtain the naphthoconazole hydrochloride composition;

the oil phase comprises a substrate, a tackifier, an emulsifier, medium chain triglyceride and a preservative which are mixed according to the mixture ratio; the water phase comprises a complexing agent, a pH regulator preservative and water which are mixed according to the proportion.

Preferably, the emulsifier has the meaning and amount as described above. Preferably at least one of polyoxyethylene cetyl ether and glyceryl mono-and distearate.

For example, the preparation method of the composition of the nyconazole hydrochloride comprises the following steps:

(1) dissolving the naphthoconazole hydrochloride in water to obtain an active ingredient solution:

(2) uniformly mixing a substrate, a tackifier, medium-chain triglyceride, a first emulsifier, a second emulsifier and a first preservative, and heating until the mixture is completely melted to obtain an oil phase;

preferably, white vaseline, octadecanol, medium-chain triglyceride, glyceryl monostearate, glyceryl distearate, polyoxyethylene cetyl ether and butyl hydroxybenzoate are uniformly mixed and heated to be molten to obtain an oil phase;

(3) uniformly mixing a complexing agent, a pH regulator, a second preservative and water, and heating for dissolving to obtain a water phase;

preferably, disodium edetate, triethanolamine, methylparaben and water are uniformly mixed and heated to be dissolved to obtain a water phase;

(4) and mixing the active ingredient solution, the oil phase and the water phase, and carrying out an emulsification reaction to obtain the naphthoconazole hydrochloride composition.

According to the invention, in step (1), the weight ratio of the nyconazole hydrochloride to the water is 1: 1-8, such as 1: 2-5, and is exemplarily 1: 2.5.

According to the invention, in step (2), the heating is carried out at a temperature of 70 to 80 ℃, such as 72 to 78 ℃, illustratively 73 ℃, 75 ℃, 77 ℃.

According to the invention, in step (4), the oil phase and the aqueous phase have the same temperature, for example a temperature of 70 to 80 ℃, for example 72 to 78 ℃, exemplarily 73 ℃, 75 ℃, 77 ℃ before being mixed with the active ingredient solution.

According to the invention, in step (4), the mixing order of the active ingredient solution, the oil phase and the water phase is: the oil phase, the aqueous phase and the active ingredient solution are added sequentially to an emulsifying device (e.g., a vacuum emulsification homogenizer). Further, the emulsifying device may be supplemented with a prescribed amount of 1.0-2% water, for example 1.5% water.

According to the invention, in step (4), the temperature of the emulsification reaction is 65-75 ℃, such as 68-73 ℃, exemplary 66 ℃, 67 ℃, 68 ℃, 69 ℃, 70 ℃, 71 ℃, 72 ℃, 73 ℃, 74 ℃. The time of the emulsification reaction is 15-30min, such as 20-25min, exemplary 21min, 22min, 23min, 24 min. The emulsification reaction is carried out under stirring and homogenizing conditions, preferably under alternate stirring and homogenizing conditions, for example, stirring for 2-4 minutes, homogenizing for 7-10 minutes, stopping homogenizing, stirring for 4-6 minutes, and homogenizing for 7-10 minutes; illustratively, homogenization is stopped after 3 minutes of stirring for 8 minutes, followed by stirring for 5 minutes and then for 8 minutes. For example, the homogenization speed is 2000-2100 r/min.

According to the present invention, the step (4) may further comprise cooling the reactants to room temperature after the emulsification reaction is completed. For example, the room temperature is 15 to 40 ℃, preferably 20 to 35 ℃.

The invention also provides a preparation method of the nerconazole hydrochloride preparation, which comprises the following steps: and sterilizing, filling and sealing the neconazole hydrochloride composition or the neconazole hydrochloride composition obtained by the preparation method to obtain the neconazole hydrochloride preparation.

The invention also provides application of the composition of the nyconazole hydrochloride in preparation of medicines. Preferably, the medicament is for the prevention or treatment of a fungal related disease; for example, the fungus is a yeast-like fungus, dermatophyte, tinea versicolor, chromofungus, and other filamentous fungus, such as at least one of: candida glabrata, Trichophyton rubrum, Trichophyton mentagrophytes, Microsporum canis, Microsporum gypseum, Epidermophyton floccosum, Candida albicans, Malassezia, etc.; for example, the fungal-related disease may be at least one of dermatophytosis (e.g., tinea pedis, tinea corporis, tinea cruris), cutaneous candidiasis (e.g., interdigital erosion, intertrigo), tinea versicolor, and the like.

The invention also provides application of the composition of the nyconazole hydrochloride or the preparation thereof in preventing or treating diseases related to fungi.

The invention also provides application of the composition of the nyconazole hydrochloride or the preparation thereof in inhibiting recurrence of diseases related to fungi.

The present invention also provides a method for preventing or treating a fungal-related disease comprising administering a therapeutically effective amount of the pharmaceutical composition to a patient in need thereof.

Definition and description of terms

Unless otherwise indicated, the definitions of groups and terms described in the specification and claims of the present application, including definitions thereof as examples, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. The definitions of the groups and the structures of the compounds in such combinations and after the combination are within the scope of the present specification.

The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound of the present invention sufficient to effect the intended use, including but not limited to the treatment of a disease as defined below. The therapeutically effective amount may vary depending on the following factors: the intended application (in vitro or in vivo), or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition and the mode of administration, etc., can be readily determined by one of ordinary skill in the art. The specific dosage will vary depending on the following factors: the particular compound selected, the dosage regimen to be followed, whether to administer it in combination with other compounds, the timing of administration, the tissue to be administered and the physical delivery system carried.

The term "patient" refers to a patient in need of a targeted prevention or treatment of a disease associated with fungi, wherein the patient is a mammal, e.g. selected from rodents, cows, pigs, dogs, cats and primates, in particular humans.

The term "expiration date" means a period of time during which the quality of a pharmaceutical product can meet the specified requirements under the specified storage conditions, for example, 36 months.

Advantageous effects

The auxiliary material components in the composition interact with the active component, namely the naphthoconazole hydrochloride, so that the obtained naphthoconazole hydrochloride composition and the preparation thereof have excellent stability, medication safety and good sterilization and antibacterial properties, can be used for treating and/or preventing diseases (especially tinea pedis) related to fungi, and also have the effect of inhibiting the relapse of the diseases related to the fungi.

Detailed Description

The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.

Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.

Example 1 cream of nyconazole hydrochloride

Prescription

Active ingredients: nalconazole hydrochloride 100mg

Auxiliary materials:

in total: 10 g.

Specification: 10g/0.1 g.

Example 2 cream of nyconazole hydrochloride (pilot test)

Prescription

Active ingredients: 1.0kg of Nalconazole hydrochloride

Auxiliary materials:

in total: 100 kg;

batch production: 1 ten thousand.

The production process of the nyconazole hydrochloride emulsifiable paste comprises the following steps: weighing, oil phase preparation, water phase preparation, main drug solution preparation, emulsification homogenization, cooling, filling, external packaging and other links, wherein the production processes of weighing (raw materials), main drug solution preparation, emulsification homogenization, cooling, filling and the like need to be protected from light or use weak red light. The preparation process comprises the following steps:

1. weighing machine

Weighing the auxiliary materials and the raw material medicines according to the prescription amount for later use.

2. Cream preparation

2.1. Preparation of the oil phase

Taking the prescribed amount of medium-chain triglyceride, octadecanol, butyl hydroxybenzoate, white vaseline, glyceryl monostearate, glyceryl distearate and polyoxyethylene cetyl ether, adding the mixture into an oil phase tank, heating to 70-80 ℃, and stirring to completely melt the mixture to obtain an oil phase.

2.2. Preparation of aqueous phase

Adding purified water with the prescription amount of 95% into an aqueous phase tank, taking methyl hydroxybenzoate, edetate disodium and triethanolamine with the prescription amount, adding into the aqueous phase tank, heating to 70-80 deg.C, and stirring until the materials are completely dissolved (colorless transparent liquid) to obtain aqueous phase.

2.3. Preparation of main drug solution

And taking the nyconazole hydrochloride with the prescription amount, adding purified water with the prescription amount of 3.5 wt%, and stirring until the mixture is dissolved for later use.

2.4. Emulsifying and homogenizing

Starting vacuum, controlling stirring speed to be 28-32r/min, sequentially pumping and filtering the oil phase, the water phase and the main drug solution into an emulsification tank (a vacuum emulsification homogenizer), and adding purified water with the amount of 1.5 wt% of the prescription amount. Controlling the temperature at 65-75 ℃, homogenizing at the speed of 2000-2100r/min, and controlling the time at 20-25 min: after stirring for 3 minutes, homogenizing for 8 minutes, stopping homogenizing, stirring for 5 minutes, and continuing homogenizing for 8 minutes.

2.5. Cooling down

Cooling water is introduced, stirring is maintained, and discharging is carried out after the temperature in the emulsification tank body is reduced to 30 ℃. Sampling and detecting the intermediate product.

3. Filling

And encapsulating and sealing the tail according to the loading amount of 10 g/piece.

4. External packing

And packaging to obtain the finished product.

Wherein, the content of the naphthoconazole hydrochloride is converted into pure according to the requirement of feeding, and when the content of the raw materials exceeds 100%, the raw materials are fed according to the conversion of 100 percent:

selecting three batches of the nyconazole hydrochloride cream obtained by the preparation method, and respectively recording the three batches of the nyconazole hydrochloride cream as an S1 sample, an S2 sample and an S3 sample.

The S1, S2, and S3 samples were all white creams.

Example 3 stability test of Nalconazole hydrochloride cream

(I) accelerated test

Accelerated experiments were performed on samples from S1 to S3 under the following conditions: 40 ℃ plus or minus 2 ℃ and RH75 percent plus or minus 5 percent. The results of the experiments are shown in tables 1-3.

TABLE 1 accelerated test results for S1 sample

TABLE 2 accelerated test results of S2 sample

TABLE 3 accelerated test results of S3 sample

The results show that: three batches of pilot samples S1-S3 of the neticonazole hydrochloride emulsifiable paste accelerate the examination for 6 months under the conditions of 40 ℃ plus or minus 2 ℃ and RH75 percent plus or minus 5 percent, the properties, the identification, the loading, the acidity, the content, the methyl hydroxybenzoate and the butyl hydroxybenzoate have no obvious change, and the microbial limit meets the regulation. The Z isomer of the S1 sample is increased by 0.06 percent, and the maximum single impurity is increased by 0.04 percent; the Z isomer of the S2 sample is increased by 0.04 percent, and the maximum single impurity is increased by 0.02 percent; the Z isomer of the S3 sample is increased by 0.04%, the maximum single impurity is increased by 0.08%, and the total impurity is increased by 0.13%, but all the Z isomers are within the limit range.

In summary, the following steps: three pilot samples of the nyconazole hydrochloride cream, S1-S3, were affected by the acceleration condition of higher temperature, and the acidity was slightly reduced when the test was examined for 6 months, but still within the limit range; the overall impurity is somewhat increasing, but within limits.

(II) Long term experiments

Long-term experiments were performed on samples from S1 to S3 under the following experimental conditions: 25 ℃ plus or minus 2 ℃ and RH60 percent plus or minus 10 percent. The results of the experiments are shown in tables 4-6.

(III) intermediate test

Intermediate experiments were performed on samples S1-S3, with experimental conditions: 30 ℃ plus or minus 2 ℃ and RH65 percent plus or minus 5 percent. The results of the experiments are shown in tables 7-9.

Tables 4-6 the results show that: three batches of pilot samples of the neticonazole hydrochloride emulsifiable paste S1-S3 are examined for 36 months under the conditions of long-term 25 +/-2 ℃ and RH60 +/-10%, the properties, identification, loading, content, methyl hydroxybenzoate, butyl hydroxybenzoate, Z isomer, maximum single impurity and total impurity of the three batches of pilot samples of the neticonazole hydrochloride emulsifiable paste S1-S3 have no obvious change, the microbial limit meets the regulation, the acidity is in a descending trend, but is in a limit range.

Tables 7-9 the results show that: three batches of pilot test samples of the neticonazole hydrochloride emulsifiable paste S1-S3 are examined for 33 months under the conditions of 30 +/-2 ℃ and RH65 +/-5 percent, the properties, the identification, the loading amount and the content of the three batches of pilot test samples of the neticonazole hydrochloride emulsifiable paste, the hydroxybenzene methyl ester, the hydroxybenzene butyl ester and the Z isomer are not obviously changed, the microbial limit meets the regulation, and the maximum single impurity increase of the S1 sample is 0.08 percent; the maximum single impurity growth of the S2 sample is 0.12%; the maximum single impurity increase of the S3 sample is 0.14 percent, but all the single impurity increases are within the limit range; the acidity is in a downward trend, and is still within the limit range before 24 months, but is reduced to 4.9 by 33 months, and is beyond the limit range.

In summary, the following steps: the test sample of the nyconazole hydrochloride cream is placed for 36 months under long-term conditions (25 +/-2 ℃ and RH60 +/-10 percent), all indexes are within the limit range, and the quality is controllable; however, when the product is placed for 33 months under the intermediate conditions (30 ℃ plus or minus 2 ℃, H65 plus or minus 5%), the acidity changes remarkably, and the temperature has certain influence on the acidity of the product, so the product should be prevented from being placed under the condition of high temperature (above 30 ℃) for a long time and should be stored at room temperature.

The detection method of the related substances comprises the following steps:

the measurement is carried out according to high performance liquid chromatography (China pharmacopoeia 2015 edition of the general rules 0512 in four parts).

(1) Chromatographic conditions and System suitability test

Octadecylsilane bonded silica gel as a filler (Agilent Eclipse XDB-C18, 250X 4.6mm, 5 μm or equivalent column); methanol-0.05 mol/L sodium hydrogen tartrate solution (65: 35) is taken as a mobile phase; isocratic elution for 30 min; the flow rate is 1.0 ml/min; the column temperature was 40 ℃; the detection wavelength was 286 nm.

Taking about 25mg of reference product of the nyconazole hydrochloride, adding a mobile phase for dissolving and diluting to 50ml, and setting the total illumination (namely the sum of the illumination after illuminating for a plurality of hours under certain illumination) of the solution to be about 10⁵Breaking under Lux hr illumination, collecting 5ml of the solution, adding 0.1% oxybenzone butyl ester ethanol solution 5ml, mixing, precisely measuring 10 μ l, injecting into liquid chromatograph, and sequentially flowing oxybenzone butyl ester, naphthoconazole, and Z isomer with separation degree not less than 1.5. The number of theoretical plates is not less than 2000 calculated according to the peak of the naphthoconazole.

(2) Assay method

And (4) avoiding light. Taking about 0.5g (about equivalent to 5mg of the naphthoconazole hydrochloride) of a cream sample, precisely weighing, placing the cream sample in a 100ml measuring flask, adding a proper amount (about 60ml) of ethanol, placing the cream sample in a 70 ℃ water bath, shaking to dissolve the naphthoconazole hydrochloride, cooling, diluting with the ethanol to a scale, shaking up, cooling in an ice bath for 1 hour, taking out, filtering immediately, taking out a subsequent filtrate, placing the subsequent filtrate to the room temperature, precisely measuring 10 mu l of the subsequent filtrate, injecting the subsequent filtrate into a liquid chromatograph, and recording a chromatogram; taking another appropriate amount of reference product of the nyconazole hydrochloride, precisely weighing, adding ethanol for dissolving, quantitatively diluting to prepare a solution containing about 50 mug in each 1ml, shaking up, and measuring by the same method. Calculating according to the peak area by an external standard method to obtain the product.

Methylparaben, butylparaben: taking a test sample solution under the content determination item as a test sample solution; weighing appropriate amount of methyl hydroxybenzoate and butyl hydroxybenzoate as control, precisely weighing, dissolving in ethanol, and quantitatively diluting to obtain solution containing methyl hydroxybenzoate 10 μ g and butyl hydroxybenzoate 5 μ g per 1ml as control solution. Measuring according to chromatographic conditions under content measurement items, and calculating according to peak area by an external standard method to obtain the product. The content of methylparaben in the product is 0.16% (g/g) to 0.24% (g/g), and the content of butylparaben is 0.08% (g/g) to 0.12% (g/g).

Example 4 clinical trials of Neconazole hydrochloride cream

The test has 422 patients randomly, wherein 211 patients are in the test group, and 211 patients are in the control group; the number of cases completing the test is 384, 191 in the test group and 193 in the control group; the number of cases exiting the test in advance is 38, accounting for 9.00% of the total cases entering the test group, wherein the number of cases in the test group is 20, and the number of cases in the control group is 18.

Among all the subjects who completed the test, the number of cases not included in the PPS analysis due to protocol violation was 37, which accounted for 8.77% of the total cases included in the group, 17 in the test group, and 20 in the control group.

According to the definition of an analysis data set, 422 cases are finally subjected to FAS analysis, 211 cases are subjected to a test group, and 211 cases are subjected to a control group; the number of cases subjected to PPS analysis is 351, 177 in the experimental group and 174 in the control group; the number of cases subjected to SS analysis was 422, 211 in the test group, and 211 in the control group.

1. The test process comprises the following steps:

the purpose of the test is as follows: the efficacy and safety of the cream of the nyconazole hydrochloride for treating the tinea pedis are evaluated by taking the cream of the bifonazole as a contrast.

And (3) experimental design: the test is designed as a multicenter, randomized, double-blind, positive drug parallel-control, non-inferiority clinical test.

Number of subjects: 422 patients were actually grouped, 422 cases were entered into FAS and SS, and 351 cases were entered into PPS.

Indications are as follows: patients with tinea pedis.

Test drugs:

test drugs: a sample of the nyconazole hydrochloride cream S1 (specification 10 g: 0.1g) prepared in example 1.

Control drug: bifonazole cream (specification: 10 g: 0.1g, trade name: Meike), manufactured by Bayer pharmaceuticals, health promotion Co., Ltd.

The administration scheme is as follows: it is applied externally. The affected part is cleaned before sleeping every day, a proper amount of the medicine is uniformly coated on the affected part and the skin of the peripheral area, the skin lesions are covered and the medicine is gently kneaded to permeate into the skin, and the treatment is continued for 4 weeks.

And (3) test period: the treatment period was 4 weeks, the follow-up period was 2 weeks, and the test period was 6 weeks in total.

2. Main efficacy analysis:

(1) FAS analysis showed: the clinical efficacy test group at drug withdrawal (4 weeks post-dose) was 80.09% (95% CI (74.71,85.48)) and the control group was 72.04% (95% CI (65.98,78.09)), the difference between the two rates: 8.05(-0.06, 16.16)%, the two comparisons had no statistical significance (P ═ 0.0676).

The two-sided 95% confidence limit of the difference between the effective rates of the test group and the control group is-0.06 > -10%, which indicates that the test group is not inferior to the control group;

(2) PPS analysis showed: clinical effective rate when stopping taking the medicine (4 weeks after taking the medicine): the test group was 83.62% (95% CI: (78.16,89.07)), the control group was 79.89% (95% CI: (73.93,85.84)), and the difference between the two values: 3.73(-4.34, 11.80)%, the two comparisons had no statistical significance (P ═ 0.4079).

The two-sided 95% confidence limit of the difference between the effective rates of the test group and the control group is-4.34 > -10%, which indicates that the test group is not inferior to the control group;

FAS and PPS agree, indicating that the test group is not inferior to the control group.

According to the specification of the original medicine of the nyconazole hydrochloride cream (Atolant nyconazole hydrochloride cream), the effective rate of treating tinea pedis is 76.1%, and the clinical effective rate of the experimental group is more excellent.

3. Secondary efficacy analysis:

(1) mycological effect when stopping (4 weeks after administration): FAS showed no statistical significance for the two group comparisons, PPS showed the test group to be superior to the control group.

(2) Mycological effect 2 weeks after drug withdrawal: FAS and PPS both showed that the test group outperformed the control group.

(3) The comprehensive curative effect is as follows when stopping taking the medicine (4 weeks after taking the medicine): FAS and PPS both showed no statistical significance for both comparisons.

(4) 2 weeks after drug withdrawal combined therapeutic effect: FAS and PPS both showed no statistical significance for both comparisons.

(5) Clinical efficacy 2 weeks after drug withdrawal: FAS and PPS both showed no statistical significance for both comparisons.

The mycological curative effect of the test group and the control group when the medicine is stopped (4 weeks after the medicine is taken) is similar to the mycological cure rate of 60-91 percent described in the expert consensus on tinea pedis diagnosis and treatment.

Through analysis and comparison, the clinical curative effect and the comprehensive curative effect of the test group and the control group are not obviously different; the mycological efficacy test group at withdrawal was higher than the control group (FAS showed no statistical significance for the two group comparisons, PPS showed statistical significance for the two group comparisons); the mycological curative effects FAS and PPS after 2 weeks of drug withdrawal show that the test group is superior to the control group (P is less than 0.05), which shows that the test group has advantages in eliminating fungi and inhibiting disease recurrence, and the long-term curative effect has a trend superior to that of the control group.

Analysis of MIC assay results:

results of the range of results of the MIC determination of 294 strains of the baseline fungus show that:

(1) the MIC range of the test drug, namely the naphthoconazole hydrochloride, is 0.019-1.00 mu g/ml; mean value: 0.055 μ g/ml; MIC₅₀＝0.030μg/ml；MIC₉₀0.060 μ g/ml. The MIC results of the test drugs are basically consistent with the descriptions in the literature reports and the specification.

(2) The MIC range of the positive control drug bifonazole is 0.030-1.0 mu g/ml; mean value: 0.083 μ g/ml; MIC₅₀＝0.060μg/ml；MIC₉₀＝0.125μg/ml。

5. And (3) safety analysis:

occurrence of adverse events: in the 211 patients of the test group, 46 patients experienced adverse events, and the occurrence rate was 21.80%, and in the 211 patients of the control group, 59 patients experienced adverse events, and the occurrence rate was 27.96%. Adverse reaction occurrence conditions: the test group has 18 adverse reactions, the incidence rate is 8.53%, and the control group has 19 adverse reactions, the incidence rate is 9.00%. Serious adverse event occurrence: the test group had 1 severe adverse event with an incidence of 0.47%, and the control group had 4 severe adverse events with an incidence of 1.90%.

Serious adverse event occurrence associated with drugs: the test group had 0 cases with severe adverse events at 0.00%, and the control group had 0 cases with severe adverse events at 0.00%.

Through analysis and comparison, the adverse events and the adverse reaction incidence rate of the test group and the control group have no statistical difference (P is more than 0.05), the adverse reactions are the common adverse reactions of the cream preparation, the reaction at the administration part is taken as the main reaction, and the incidence rate is similar to the previous research result.

6. Conclusion

The secondary blindness uncovering result of the clinical test is as follows: group A is the test group and group B is the control group.

The clinical test result prompts: the clinical curative effect and the comprehensive curative effect of the nyconazole hydrochloride cream provided by the invention are equivalent to those of the bifonazole cream which is generally recognized in curative effect on the market (the clinical effective rate of FAS when the medicine is stopped is 80.09%, the control group is 72.04%, the difference between the two values is 8.05, and the P is 0.0676, the two groups have no statistical significance, the test group is not inferior to the control group, the clinical effective rate of PPS when the medicine is stopped is 83.62%, the control group is 79.89%, the difference between the two values is 3.73%, the P is 0.4079, the two groups have no statistical significance, and the test group is not inferior to the control group, and the FAS and the PPS result are consistent); the mycological curative effect shows that the nyconazole hydrochloride emulsifiable paste has advantages in the aspects of eliminating fungi and inhibiting disease recurrence, and the long-term curative effect has a trend superior to that of the bifonazole emulsifiable paste; in the aspect of the incidence rate of adverse reactions, the two medicines have no significant difference. The cream of the nyconazole hydrochloride provided by the invention is an effective and safe medicine for treating tinea pedis, and is worthy of clinical popularization and application.

The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.