CN113332280B

CN113332280B - Method for pretreating raw materials of nifuratel nysfungin vaginal soft capsule and preparation method of preparation

Info

Publication number: CN113332280B
Application number: CN202110537358.8A
Authority: CN
Inventors: 刘镇; 段月晓; 张泽; 刘畅; 陈冲; 李小臣; 彭艳
Original assignee: Beijing Jincheng Taier Pharmaceutical Co ltd
Current assignee: Beijing Jincheng Taier Pharmaceutical Co ltd
Priority date: 2021-05-18
Filing date: 2021-05-18
Publication date: 2023-01-24
Anticipated expiration: 2041-05-18
Also published as: CN113332280A

Abstract

The invention provides a method for pretreating nifuratel, which comprises a pretreatment step of granulating nifuratel by a wet method to prepare high-dispersion fine powder particles. The preparation method of the nifuratel high-dispersion fine powder particles comprises the following steps: carrying out wet granulation and drying on nifuratel and an additive solution to obtain high-dispersion fine powder particles, wherein the additive solution comprises a surfactant or a wetting agent. The invention also provides a nifuratel medicinal preparation prepared by the method. The preparation process includes mixing fine nifuratel powder and nystatin to prepare suspension, and pelletizing to prepare soft capsule containing nifuratel. The nifuratel medicinal preparation prepared by the preparation method has the advantages of obviously reduced amount of related substances, good dissolution property and stability, high bioavailability, improved wettability and content uniformity of insoluble medicines, simple operation, low cost, no need of special equipment and easy application to industrial production.

Description

Method for pretreating raw materials of nifuratel nysfungin vaginal soft capsule and preparation method of preparation

Technical Field

The disclosure belongs to the fields of pharmacology and pharmacy, particularly relates to a pharmaceutical preparation and a preparation method thereof, and particularly relates to a raw material pretreatment method and a preparation method of a nifuratel nysfungin vaginal soft capsule.

Background

Suspension refers to a heterogeneous dispersion of a poorly soluble solid drug in a liquid medium in the form of microparticles. It has the advantages of large drug-loading rate, prevention of drug oxidation and hydrolysis, covering up the unpleasant odor of the drug, easy swallowing, etc., and is a drug form with simple preparation and wide application. However, as a thermodynamically unstable system, a suspension has problems such as ion aggregation and precipitation. The stability of a suspension depends on the sedimentation of the particles, the crystalline state, the wetting of the particles, the potential, the rheology of the preparation. The stable suspension has high viscosity and is not layered, so a suspending agent, a flocculating agent and a deflocculating agent are added. The surfactant is used as a suspending agent and is one of important auxiliary materials for keeping the physical stability of the suspension. It forms a solvating film and the same charge at the interface of two phases, so that the suspension particles are stable; meanwhile, the method can reduce the interfacial tension between a dispersed phase and a solvent so as to facilitate the wetting and dispersion of the hydrophobic drug. Surfactants have a wetting effect in addition to a suspending effect in such applications. If the ibuprofen suspension is prepared by taking hydroxypropyl methylcellulose (HPMC) as a suspending agent, the ibuprofen suspension is determined to be pseudoplastic fluid by a Hakke viscometry instrument, and the drug content is stable. In addition, the research shows that the suspending agent of beeswax and lecithin can be used as the stabilizer in acanthopanax suspension.

The nifuratel nysfungin vaginal soft capsule is a common gynecological medicine, is applicable to bacterial vaginosis, trichomonas vaginitis, monilial vulvovaginitis and mixed vaginal infection, and contains a dispersion suspension containing nifuratel and nysfungin. At present, the method for adding the surfactant or the wetting agent into the suspension is to add the surfactant or the wetting agent into soybean oil for mixing, for example, glycerol and tween 80 are added into the soybean oil for hot melt mixing treatment, but the dispersion effect on the insoluble raw material with strong hydrophobicity, such as nifuratel, is still poor, and the phenomenon of aggregation and agglomeration exists, so that the stability of the medicine is reduced, and the medicine effect is influenced.

Disclosure of Invention

In order to solve the technical problems, the present disclosure aims to provide a nifuratel nysfungin vaginal soft capsule with uniformly dispersed contents, stable preparation properties and improved curative effect.

Specifically, the present disclosure provides the following technical solutions:

the present disclosure provides a method for pre-treating nifuratel, comprising a step of wet granulation of nifuratel with an additive solution comprising a surfactant or wetting agent and a solvent, for the preparation of nifuratel nysfungin soft vaginal capsules.

Preferably, the method comprises the steps of pre-treating nifuratel by wet granulation using an additive solution comprising a surfactant or wetting agent and a solvent, preparing a dispersion suspension, preparing a capsule shell and pelleting.

Preferably, wherein the surfactant or wetting agent is selected from one or more of PEG, tween, glycerol, SDS.

Preferably, the solvent is selected from one or more of ethanol and water.

The present disclosure also provides a method for preparing nifuratel nysfungin vaginal soft capsules, the method comprising the steps of:

step (1), nifuratel pretreatment: carrying out wet granulation on nifuratel by using an additive solution to obtain nifuratel granules, wherein the additive solution is prepared by adding a surfactant or a wetting agent into a solvent to completely dissolve the surfactant or the wetting agent;

step (2) preparing a dispersion liquid: adding vegetable oil into the suspension, and mixing uniformly to obtain a dispersion;

step (3) preparation of a dispersion suspension: adding a preservative, nysfungin and the nifuratel granules obtained in the step (1) into the dispersion liquid obtained in the step (2), and uniformly dispersing to obtain a dispersion suspension;

step (4), preparing a capsule shell;

and (5) pelleting.

Preferably, before the step (1), a crushing step of crushing nifuratel, a preservative and nysfungin can be further included; preferably, the milling is micronization;

preferably, in the nifuratel pretreatment of step (1), the micronized preservative and nifuratel may be mixed and then subjected to wet granulation.

Preferably, wherein the surfactant or wetting agent is selected from one or more of PEG, tween, glycerol, SDS, preferably glycerol and/or SDS.

Preferably, the solvent is selected from one or more of ethanol and water.

Preferably, the vegetable oil comprises soybean oil.

Preferably, the suspension agent is selected from one or more of white vaseline and yellow vaseline, preferably white vaseline.

Preferably, the preservative is selected from one or more of ethylparaben and methylparaben, preferably ethylparaben.

Preferably, wherein the preparation step of the method comprises:

(1) Crushing raw materials: pulverizing nifuratel, antiseptic and nystatin until the particle diameter D90 is less than 30 μm;

(2) Nifuratel pretreatment: adding surfactant or humectant glycerol and/or SDS into solvent water to completely dissolve to obtain additive solution;

(3) And (3) wet granulation: adding nifuratel and micronized ethylparaben into a high-shear wet granulation pot or a fluidized bed granulation pot, performing wet granulation by using the additive solution, and drying to obtain nifuratel high-dispersion fine powder particles;

(4) Preparation of the dispersion: adding white vaseline into soybean oil, and mixing to obtain a dispersion;

(5) Preparation of the dispersion suspension: sequentially adding the preservative, the nystatin and the nifuratel high-dispersion fine powder particles into the dispersion liquid, and uniformly dispersing by using a dispersion machine to obtain a dispersion suspension;

(6) Preparing a capsule shell: the capsule comprises 2000-3000 parts of gelatin, 800-1200 parts of glycerol, 2000-3000 parts of water, 5-15 parts of titanium dioxide, 3-5 parts of sunset yellow and 1-5 parts of optional preservative, preferably 2500 parts of gelatin, 1000 parts of glycerol, 2500 parts of water, 8 parts of titanium dioxide, 4 parts of sunset yellow and 2 parts of preservative, and the capsule shell is prepared by a conventional method;

(7) Pelleting: pressing the dispersion suspension and the capsule shell to obtain capsule preparations, wherein the content in each pill contains 300-600mg of nifuratel, 10-40 ten thousand units of nysfungin, 984-995mg of soybean oil, 5-16mg of white vaseline and 1-5mg of preservative;

preferably, in the step (4), the mixing condition of adding white vaseline into the soybean oil is that the soybean oil is heated to 35-40 ℃ and stirred for 90-120 minutes;

preferably, in the step (5), after the preservative is added, nysfungin is added at the temperature of 35-40 ℃ and stirred for 30 minutes;

preferably, in the step (5), after the nifuratel high-dispersion fine powder particles are added, stirring for at least 150 minutes to disperse uniformly;

preferably, the dispersion suspension is further ground to obtain content liquid medicine, and the content liquid medicine and the capsule shell are used for pelleting to prepare a capsule preparation;

preferably, the method further comprises (8) a quality detection step, preferably, the content of nifuratel in each capsule preparation is within the range of 30.20-34.74%, the titer of the nysfungin is within the range of 121-139 IU/mg, and the pH value of the liquid medicine is 6.2-7.0, namely the quality is qualified.

Preferably, the nifuratel nysfungin vaginal soft capsule comprises the following raw materials in parts by weight: each pill contains 500mg of nifuratel, 20 ten thousand units of nysfungin, 990mg of soybean oil, 10mg of white vaseline and 2mg of ethylparaben.

Compared with the prior art, the method disclosed by the invention has the advantages that the raw material and the additive solution containing the surfactant or the wetting agent are subjected to wet granulation and then dried for pretreatment, so that the interfacial tension between the nifuratel raw material and the dispersion liquid is reduced, the hydrophobic nifuratel wetting and dispersion are facilitated, the wettability of nifuratel and the content uniformity of suspension are improved, the amount of related substances in the obtained nifuratel nysfungin vaginal soft capsule is obviously reduced, the dissolution characteristic and the stability are good, and the bioavailability is high. Meanwhile, the method is simple and convenient to operate, low in cost, free of special equipment and easy to apply to industrial production, and particularly the method eliminates the influence of the form of the raw material medicine on the preparation process.

Drawings

FIG. 1A shows a photomicrograph (X50) of a dispersion suspension prepared from nifuratel drug substance without surface modification

FIG. 1B shows a photomicrograph (20) of a dispersed suspension prepared from nifuratel drug substance surface-modified with glycerol

FIG. 1C shows a photomicrograph (20) of a dispersion suspension prepared from an SDS surface-modified nifuratel drug substance

FIG. 2 shows a photomicrograph (X50) of the dispersion of nifuratel drug substance in the content liquid after surface modification with mixed glycerol and SDS

Detailed Description

Based on the above disclosure, other modifications, substitutions and alterations can be made without departing from the basic technical concept of the present disclosure as it is known and customary in the art.

I. Definition of

Throughout the specification and claims, unless explicitly stated otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element or component but not the exclusion of any other element or component.

The term "medicament" or "pharmaceutical composition" is designed for use in animals and humans and can be administered via all routes of administration. Preferred routes of administration are injection, oral, pulmonary, nasal, rectal, parenteral. Such pharmaceutical compositions and unit dosage forms thereof may contain conventional or novel ingredients in conventional or special proportions, with or without additional active compounds or ingredients, and such unit dosage forms may contain any suitable effective amount of the active ingredient to be employed commensurate with the intended daily dosage range.

The pharmaceutical formulations of the present disclosure are for vaginal administration, and primarily include vaginal capsules.

The trichomonas vaginitis, bacterial Vaginosis (BV) and vulvovaginal candidiasis are the most common vaginal infectious diseases of women of childbearing age, are vaginal inflammations caused by trichomonas vaginalis and candida albicans infection, and BV is a syndrome without vaginal mucosal inflammation expression caused by various pathogens (mainly anaerobic bacteria). Trichomonas vaginitis, BV and vulvovaginal candidiasis can cause infection of the upper genital tract and many complications such as amniocytosis, premature rupture of membranes, premature delivery, postpartum endometritis, post-cesarean section and infection after total hysterectomy. Therefore, attention should be paid to the diagnosis and treatment of trichomonas vaginitis, BV and vulvovaginal candidiasis.

Nifuratel is 5- [ (methylthio) methyl ] -3- [ [ (5-nitro-2-furanmethylene ] amino ] -2-oxazolidinone, belongs to nitrofuran derivatives, is a broad-spectrum antibiotic, and is effective on bacteria, trichomonas and candida which cause female reproductive system infection.

"nystatin" is a polyene antifungal drug with broad-spectrum antifungal effect and high antibacterial activity against candida, and cryptococcus neoformans, aspergillus, mucor, microsporum, capsular histoplasma bacteria, dermatitis blastomyces and dermatophyte are usually sensitive to the product. Nystatin belongs to a special variety in China, is not on the market abroad, and is a multicomponent antibiotic.

Description of the preferred embodiments

In a first aspect of the disclosure, a method of pretreatment of nifuratel, the method comprising a pretreatment step of wetting the nifuratel with an additive solution.

In one embodiment, the nifuratel is used for preparing nifuratel nystatin soft vaginal capsules.

In a second aspect of the disclosure, a method for preparing the contents of the nifuratel nysfungin vaginal soft capsule comprises the steps of carrying out pretreatment on nifuratel, preparing a dispersion liquid, preparing a dispersion suspension, preparing a capsule shell and pelleting and the like, wherein the pretreatment is to wet the nifuratel by using an additive solution, and the additive solution comprises a surfactant or a wetting agent and a solvent.

A third aspect of the present disclosure relates to a method for preparing a nifuratel nysfungin soft capsule, which comprises the following steps:

preparing a dispersion liquid in step (2): adding vegetable oil into the suspension, and mixing uniformly to obtain a dispersion;

step (3) preparation of a dispersion suspension: adding a preservative, nysfungin and the nifuratel granules obtained in the step (2) into the dispersion liquid obtained in the step (4), and uniformly dispersing to obtain a dispersion suspension;

step (5), preparing a capsule shell;

and (6) pelleting.

In one embodiment, before the step (1), a crushing step can be further included, wherein the crushing step is to crush nifuratel, preservative and nystatin; preferably, the milling is micronization;

in one embodiment, in the nifuratel pretreatment of step (1), the micronized preservative may be mixed with nifuratel followed by wet granulation.

In one embodiment, the additive solution includes a surfactant or wetting agent and a solvent.

In a particular embodiment, the surfactant or wetting agent is selected from one or more of PEG, tween, glycerol, SDS, preferably glycerol and/or SDS.

In a particular embodiment, the solvent is selected from one or more of ethanol, water.

In a particular embodiment, the vegetable oil is selected from one or more of soybean oil, peanut oil, soybean oil, linseed oil, castor oil, rapeseed oil, and the like, preferably soybean oil.

In a particular embodiment, the suspension agent is selected from one or more of white petrolatum, yellow petrolatum, preferably white petrolatum.

In a specific embodiment, the preservative is selected from one or more of ethylparaben and methylparaben, preferably ethylparaben.

In a specific embodiment, the nifuratel nysfungin vaginal soft capsule comprises the following raw materials in parts by weight: each pill contains 300-600mg of nifuratel, 10-40 ten thousand units of nysfungin, 984-995mg of vegetable oil, 5-16mg of suspension and 1-5mg of preservative.

In one embodiment, the capsule shell comprises 2000-3000 parts of gelatin, 800-1200 parts of glycerol, 2000-3000 parts of water, 5-15 parts of titanium dioxide, 3-5 parts of sunset yellow and optionally 1-5 parts of a preservative.

Example III

Example 1: nifuratel pretreatment method

(1) Adding surfactant or humectant glycerol and/or SDS into solvent water, and dissolving completely to obtain additive solution.

(2) Adding nifuratel into a high-shear wet granulation pot or a fluidized bed granulation pot, performing wet granulation for a period of time by adopting an additive solution to modify the surface of the hydrophobic raw material, and drying to obtain the nifuratel high-dispersion powder particles. The wetting and dispersing effects of the nifuratel in the suspension can be improved by using the nifuratel high-dispersion fine powder particles.

Example 2: preparation of nifuratel nysfungin Dispersion suspensions

(1) Preparation of the dispersion: adding the suspension into the vegetable oil, heating to 38 ℃, stirring for 90-120 minutes, and uniformly mixing to obtain dispersion.

(2) Preparation of the dispersion suspension: adding antiseptic into the dispersion, adding nystatin at 38 deg.C, stirring for 30min to disperse uniformly, adding nifuratel high-dispersion powder into the dispersion, stirring for 150 min with a dispersion machine to disperse uniformly to obtain dispersion suspension.

Example 3: preparation method of nifuratel nysfungin vaginal soft capsule

(1) Adding one of surfactant or humectant glycerol and/or SDS into solvent ethanol, and dissolving completely to obtain additive solution.

(2) Adding nifuratel into a high-shear wet granulation pot, performing wet granulation by using the additive solution for a period of time to modify the surface of the hydrophobic raw material, and then drying to obtain the nifuratel high-dispersion powder particles.

(3) Adding white vaseline into soybean oil, and mixing.

(4) And sequentially adding ethylparaben, nysfungin and nifuratel high-dispersion powder particles into the dispersion liquid, and uniformly dispersing by using an emulsifying machine to obtain a dispersion suspension.

(5) Preparing a capsule shell: preparing gelatin, glycerol, water, titanium dioxide, sunset yellow and ethylparaben into capsule shell by conventional method.

(6) Pelleting: the capsule preparation is obtained, wherein the content of each pill contains 300-600mg of nifuratel, 10-40 ten thousand units of nysfungin, 984-995mg of soybean oil, 5-16mg of white vaseline and 1-5mg of ethylparaben.

Example 4: preparation method of nifuratel nysfungin vaginal soft capsule

(1) The nifuratel, the preservative and the nystatin are crushed until the particle size D90 is less than 30 microns, and the nystatin is micronized by airflow at high temperature sensitivity.

(2) Adding surfactant or wetting agent selected from glycerol alone, SDS alone and glycerol and SDS in mixture into solvent water to dissolve completely to obtain additive solution.

(3) Adding nifuratel and micronized ethylparaben into a fluidized bed granulation pot, performing wet granulation for a period of time by adopting an additive solution to modify the surface of the hydrophobic raw material, and then drying to obtain nifuratel high-dispersion fine powder particles.

(4) Preparation of the dispersion: adding vegetable oil such as soybean oil into suspension such as white vaseline, heating to 35 deg.C, stirring for 90-120 min, and mixing to obtain dispersion.

(5) Preparation of the dispersion suspension: adding antiseptic into the dispersion, adding nystatin at 35 deg.C, stirring for 30min to disperse uniformly, adding nifuratel fine powder into the dispersion, stirring for 150 min with a dispersing machine to disperse uniformly to obtain a dispersion suspension.

(6) Grinding: when the dispersed suspension is cooled to room temperature, grinding the dispersed suspension once by using a colloid mill, and sieving by using a 80-mesh sieve to obtain the content liquid medicine of the nifuratel nysfungin vaginal soft capsule, wherein the content liquid medicine is yellow viscous oily matter, and has no bubbles and black point impurities on the surface;

(7) Preparing a capsule shell: according to the proportion of 2500 parts of gelatin, 1000 parts of glycerol, 2500 parts of water, 8 parts of titanium dioxide, 4 parts of sunset yellow and 2 parts of optional preservative, capsule shell is prepared by a conventional method.

(8) Pelleting: thus obtaining the capsule preparation, wherein the content in each pill contains 500mg of nifuratel, 20 ten thousand units of nysfungin, 990mg of soybean oil, 10mg of white vaseline and 2mg of ethylparaben.

(9) And (3) quality detection: the content of nifuratel is within the range of 30.20-34.74%, the titer of the nysfungin is within the range of 121-139 IU/mg, and the pH value of the liquid medicine is 6.2-7.0, namely the quality is qualified.

Example 5 Nifuratel nysfungin vaginal Soft Capsule Dispersion suspension stability assay of the present disclosure

In the experiment, under the process parameters, the centrifugal stability and the volume sedimentation ratio of the dispersion suspension prepared by the unmodified nifuratel bulk drug and the content liquid medicine obtained in example 4 are considered:

1. the preparation method comprises the following steps:

experimental example: in the method of example 4, additive solutions were prepared from glycerol, SDS, glycerol, and SDS, respectively.

Comparative example: the process of example 4 above, but omitting the example steps (1) - (3).

2. The detection method comprises the following steps:

(1) The particle distribution of the prepared dispersion suspension is observed by a microscope.

(2) Centrifugal stability: centrifuging at 1000rpm of 30min by TD5A-WS desk-top low-speed centrifuge, recording the height H of the liquid medicine in the initial centrifuge tube, and inspecting the height H of the suspension after centrifugation ₁ Drug solution stability = H ₁ /H。

(3) Volume sedimentation ratio: filling the liquid medicine into a 50ml measuring cylinder, sealing, shaking for 1min, and recording the dehumidification height H of the suspension ₀ Standing for 3H, recording the final height H of the suspension, and settling volume ratio = H/H ₀ The detection result should be greater than 0.9.

As a result:

(1) Observation with a microscope

As can be seen from fig. 1A to C and fig. 2, when the surface modification is performed by adding the surfactant or wetting agent to the process of preparing the drug solution, it can be seen from the observation of the drug solution under a microscope that there is electrostatic adsorption between the batches of the drug solution prepared from the raw material without surface modification (fig. 1A), and the drug solution prepared from the raw material with surface modification is significantly better dispersed and the adsorption between the raw materials is less (fig. 1B to C, fig. 2).

(2) Formulation stability

TABLE 1 stability assay results for Nifuratel nysfungin vaginal soft capsule dispersion suspensions of the present disclosure

As can be seen from the data in Table 1, the centrifugal stability and the volume sedimentation ratio parameter of the modified dispersion suspension are obviously improved compared with the dispersion suspension before modification under the same particle size, which shows that the dispersion suspension for preparing the nifuratel nysfungin vaginal soft capsule content liquid medicine prepared by the method is beneficial to wetting and dispersing hydrophobic nifuratel by reducing the interfacial tension between nifuratel raw materials and the dispersion liquid, improves the wettability of nifuratel and the content uniformity of the suspension, and further improves the stability and the bioavailability of the content liquid medicine.

Meanwhile, the stability of the modified preparation prepared from nifuratel raw material medicines with different particle sizes is visible, and the smaller the particle size is, the better the stability of the preparation such as centrifugal stability and sedimentation ratio is. In the case of micronizing nifuratel and nystatin crude drugs at the same time and modifying nifuratel by using a surfactant or wetting agent, the centrifugal stability and the mentioned sedimentation ratio are remarkably improved (the centrifugal stability is improved from 0.69 to 1.00, and the mentioned sedimentation ratio is improved from 70% to 99.7%).

Claims

1. A preparation method of nifuratel nysfungin vaginal soft capsules is characterized by comprising the following steps: step (1), nifuratel pretreatment: carrying out wet granulation on nifuratel by using an additive solution to obtain nifuratel granules,

the additive solution is prepared by adding a wetting agent into a solvent to completely dissolve the wetting agent; the wetting agent is glycerol; the solvent is selected from one or more of ethanol and water;

preparing a dispersion liquid in step (2): adding the suspension white vaseline into soybean oil, and mixing to obtain a dispersion;

step (4), preparing a capsule shell;

pelleting;

before the step (1), a crushing step is further included, wherein the crushing step is to crush nifuratel, a preservative and nystatin, and the crushing is micronization.

2. The method according to claim 1, wherein in the nifuratel pretreatment of step (1), the micronized preservative is mixed with nifuratel and then wet granulated.

3. The method according to claim 1, wherein the preservative is selected from one or more of ethylparaben and methylparaben.

4. The method of claim 3, wherein the preservative is ethylparaben.

5. The method of claim 1, wherein the method is prepared by:

(1) Crushing raw materials: grinding nifuratel, preservative and nystatin until the particle size D90 is less than 30 microns;

(2) Nifuratel pretreatment: adding a wetting agent glycerol into a solvent to obtain an additive solution, wherein the solvent is water;

(5) Preparation of the dispersion suspension: sequentially adding the preservative, nysfungin and nifuratel high-dispersion fine powder particles into the dispersion liquid, and dispersing by using a dispersion machine to obtain a dispersion suspension;

(6) Preparing a capsule shell: comprises 2000-3000 parts of gelatin, 800-1200 parts of glycerol, 2000-3000 parts of water, 5-15 parts of titanium dioxide, 3-5 parts of sunset yellow and 1-5 parts of optional preservative, and the capsule shell is prepared by a conventional method;

(7) Pelleting: and (3) pelleting the dispersion suspension and the capsule shell to obtain a capsule preparation, wherein the content in each pill contains 300-600mg of nifuratel, 10-40 ten thousand units of nystatin, 984-995mg of soybean oil, 5-16mg of white vaseline and 1-5mg of a preservative.

6. The method according to claim 5, wherein the mixing condition of the soybean oil with the white petrolatum in the step (4) is heating to 35 to 40 ℃, and stirring for 90 to 120 minutes.

7. The method according to claim 5, wherein in the step (5), after the addition of the preservative, nystatin is added at a temperature of 35 to 40 ℃ and stirred for 30 minutes.

8. The process according to claim 5, wherein in step (5), the nifuratel highly dispersed fine powder particles are added and stirred for at least 150 minutes.

9. The process according to claim 5, wherein the dispersion suspension is further subjected to a milling process to obtain a content liquid and the content liquid is used to press the content liquid with the capsule shell to obtain a capsule preparation.

10. The method according to any one of claims 1 to 9, wherein the method further comprises (8) a quality detection step, wherein the nifuratel content in each capsule preparation is within a range of 30.20-34.74%, the nystatin titer is within a range of 121-139 IU/mg, and the pH value of the liquid medicine is 6.2-7.0, namely the quality is qualified.

11. The method according to any one of claims 1 to 9, wherein the nifuratel vaginal soft capsule comprises the following raw materials in parts by weight: each pill contains 500mg of nifuratel, 20 ten thousand units of nysfungin, 990mg of soybean oil, 10mg of white vaseline and 2mg of ethylparaben.