阅读说明：本技术 一种克霉唑***片组合物及其制备方法 (Clotrimazole vaginal tablet composition and preparation method thereof ) 是由 张辉 李林波 常海容 张俊杰 于 2020-07-22 设计创作，主要内容包括：本发明涉及一种克霉唑乳杆活菌组合物及其制备方法,属于药物制剂技术领域。本发明所述克霉唑乳杆活菌阴道片,含有克霉唑500mg；乳杆菌粉1mg；乳酸20mg～30mg；乳酸钙8mg～12mg；淀粉6mg～12mg；纤维素乳糖C80 200mg～300mg；尤特奇?RL30D 66mg～180mg；乳糖225mg～314mg；微晶维素170mg～225mg；交联聚维酮70mg；胶态二氧化硅20mg；硬脂酸镁10mg。本发明提供了一种克霉唑乳杆活菌阴道片。(The invention relates to a live clotrimazole lactobacillus composition and a preparation method thereof, belonging to the technical field of pharmaceutical preparations. The clotrimazole lactobacillus viable bacteria vaginal tablet contains 500mg of clotrimazole; 1mg of lactobacillus powder; 20 mg-30 mg of lactic acid; 8-12 mg of calcium lactate; 6mg to 12mg of starch; cellulose lactose C80200 mg-300 mg; yttky RL30D 66mg to 180 mg; 225mg to 314mg of lactose; 170-225 mg of microcrystalline vitamin; 70mg of crospovidone; 20mg of colloidal silica; magnesium stearate 10 mg. The invention provides a clotrimazole lactobacillus viable bacteria vaginal tablet.)

1. A clotrimazole vaginal tablet composition, wherein a unit dose of the composition comprises 500mg of clotrimazole; 1mg of lactobacillus powder; 20 mg-30 mg of lactic acid; 8-12 mg of calcium lactate; 6mg to 12mg of starch; cellulose lactose C80200 mg-300 mg; yttky RL30D 80 mg-180 mg; 225mg to 310mg of lactose; 170 mg-221 mg of microcrystalline cellulose; 70mg of crospovidone; 20mg of colloidal silica; 10mg of magnesium stearate, wherein the starch is used in the form of starch slurry with the mass ratio of 3-6%.

2. The clotrimazole vaginal tablet composition of claim 1, wherein the unit dose of the composition comprises 500mg of clotrimazole; 1mg of lactobacillus powder; 22-28 mg of lactic acid; 9mg to 11mg of calcium lactate; 8-11 mg of starch; cellulose lactose C80200 mg-300 mg; yttky RL30D 80 mg-180 mg; 225mg to 310mg of lactose; 170 mg-221 mg of microcrystalline cellulose; 70mg of crospovidone; 20mg of colloidal silica; magnesium stearate 10 mg.

3. A method of preparing a clotrimazole vaginal tablet composition of claim 1, comprising the steps of:

preparing bacterial liquid in the first step:

adding a prescription amount of starch into boiled purified water for pulping to prepare 3% -6% concentration starch pulp, cooling to room temperature, adding lactobacillus powder, mixing uniformly, adding a prescription amount of lactic acid and calcium lactate, and keeping the pH value of the solution within the range of 2.5-3.0 for later use;

and (2) second step of strain solidification, adsorption and coating:

spraying the bacterial liquid prepared in the first step to the surface of cellulose lactose C80 by adopting a fluidized bed bottom spraying coating technology, then coating by Yttrium RL30D, increasing the weight of the coating by 8-15%, drying, and sieving the granules by a 30-mesh sieve for later use;

and a third step of mixing:

uniformly mixing the strain granules prepared in the second step with the formula amounts of clotrimazole, lactose, microcrystalline cellulose and crospovidone in a hopper mixer, and then uniformly mixing with colloidal silicon dioxide and magnesium stearate;

and fourthly, tabletting and double-aluminum packaging.

4. The method for preparing clotrimazole vaginal tablet composition of claim 3, wherein the temperature of the inlet air of the second granulation fluidized bed granulation coating machine is 35-45 ℃; the air flow is 20-30 HZ, the atomization pressure is 0.3-0.6 mpa, the material temperature is 30-40 ℃, and the liquid spraying speed is 15-30 ml/min.

Technical Field

A clotrimazole vaginal tablet composition and a preparation method thereof.

Background

Candidal vaginitis is a common gynecological disease and is caused by candida infection, and the clinical manifestations of the candidal vaginitis are that external pruritus and leucorrhea are white and like, which seriously affect the quality of life of women.

The candida also called as candida albicans, is most suitable for breeding environments, has a pH value of 5.5-6.5, is adhered to organism tissues, secretes adenosine to block neutrophils from releasing oxygen free radicals, generates aspartic protease to degrade extracellular matrix, increases glycogen and acidity in vagina, causes tissue damage and causes inflammation.

Normally, the pH value in the vagina of a woman is maintained within 3.8-4.4, and the woman inhabits microorganisms which have no harm to the human body and are called normal microbial flora or normal microbial flora; under the condition, the normal flora, the host and the environment are in a dynamic balance state, and a system which is interdependent and mutually restricted is formed. When the acidity value in the vagina is increased, candida is bred and grows in a proper breeding environment, the flora balance is damaged, the number of lactobacillus is reduced, and glycogen is not decomposed in time, so that the acidity of lactic acid in the cavity is increased, hydrogen peroxide is reduced, and candida albicans vaginitis is initiated.

Antifungal drugs are mostly used for treating candidal vaginitis, such as: "Daktarin" suppository 1/day 3d, clotrimazole vaginal tablet 1/3 d, or fix planting probiotics, such as: the lactobacillus capsule has 1 time/day for 10 days, has obvious effect of inhibiting the moniliatic vaginitis, but is easy to relapse.

Clinical literature reports on the synergistic combination of clotrimazole and lactobacillus, such as: the observation of the curative effect of the combination of clotrimazole and lactobacillus active preparation on the treatment of gestational vulvovaginal candidiasis [ Zhangjuan, health study [ J ].2014.10,34(5): 510-; the clotrimazole vaginal tablet and the lactobacillus capsule have the influence on the change of the vaginal pH value of a patient with gestational complicated candida vaginitis [ depending on foot, clinical medicine [ J ].2015,28(4):56-57 ]. Compared with single administration, the combined administration can effectively reduce the pH value of the vagina and improve the clinical symptoms of patients, but the combined administration has a plurality of defects, such as the need of multiple administrations by the patients, inconvenient application and poor patient compliance. If the clotrimazole and lactobacillus compound tablet can be provided, the compound tablet is greatly convenient for patients to use, and the compliance of the patients is improved.

Clotrimazole is an imidazole broad-spectrum antifungal drug, is almost insoluble in water, has poor stability in an acidic environment, and is a first-line drug for monilial vulvovaginitis, infection caused by yeast and double infection caused by sensitive bacteria.

Lactic acid is a pH regulator of Kenyin of original Kenyazole vaginal tablets (producer: German Bayer). Lactic acid is also a main metabolite of lactobacillus, is used for regulating the vaginal microecological pH environment in vivo, maintaining the bacterial state balance, inhibiting the growth of harmful bacterial colonies in the cavity, promoting the reproduction and growth of viable lactobacillus, and improving gynecological inflammation, and has the functions of sterilization and antisepsis.

The vaginal viable lactobacillus is one or more of Lactobacillus reuteri, Lactobacillus delbrueckii, Lactobacillus crispatus and Lactobacillus acidophilus, which form vaginal microorganism state, and has balanced inhibition on growth of Candida albicans, and the number of viable lactobacillus capsule for vaginal use is not less than 2.5 × 10⁵cfu/granule. The lactobacillus is most suitable for breeding environment with the pH value of 5.5-5.8, is acid-resistant, can survive in the environment with the pH value of 3.8-4.4 of the vagina and keeps balance with harmful bacteria, but the number of the viable bacteria is gradually reduced along with the reduction of the pH value in the environment with the pH value lower than 3.0.

Disclosure of Invention

The invention aims to provide a clotrimazole vaginal tablet composition and a preparation method thereof.

At present, the market has no published documents for preparing the live clotrimazole and lactobacillus compound vaginal tablets.

To achieve the object of the invention, we have worked from the following aspects:

method one, after lactic acid is separately granulated, the lactic acid and clotrimazole are mixed and tableted;

in the second method, the micro encapsulation of the lactobacillus can resist the damage of the extreme environment to the activity of the lactobacillus;

the three active ingredients are respectively granulated or isolated independently, and then mixed and tableted or filled into capsules.

The results prove that: the first method and the second method can not reflect that the lactic acid can simultaneously meet requirements of clotrimazole degradation, lactobacillus activity and preparation acidity, and the third method can combine three active substances by a three-unit release model and meet requirements of vaginal tablets, but the production process is complex in operation, time and resource cost are high, mixing uniformity of live bacteria in the lactobacilli is difficult to guarantee, and the requirements on the intermediate standard of each release unit are extremely strict.

Therefore, how to prepare the clotrimazole, the lactic acid and the live lactobacillus into a compound preparation ensures uniform mixing, ensures the stability of the clotrimazole, the activity of the live lactobacillus, the acidity of the vaginal tablets, the melting time limit and other characteristic requirements in the production and storage processes, meets the industrial production with simple production process and low cost, and becomes a key technical problem to be solved at present.

The core problem to be solved by the invention is as follows:

1) under the condition that the pH value of the vaginal tablet is 3.0-4.5, the clotrimazole acid is prevented from being degraded;

2) during the production process, viable lactobacillus is kept inactive or relatively static at room temperature;

3) the viable bacteria of the lactobacillus can ensure the quantity of the viable bacteria in the production process of the preparation and under the condition of room temperature storage;

4) 500 portions of clotrimazole and 1 portion of lactobacillus powder are evenly mixed.

In order to solve the technical problems, the technical scheme provided by the invention is as follows:

starch slurry of 5-25% (W/W) is generally selected as an adhesive in a tablet formula, and the product experiment shows that the starch slurry of 3-6% (W/W) can prevent the inactivation of live lactobacillus under the environment of pH2.5-3.0, so that the coexistence of high-concentration lactic acid and lactobacillus is realized, the porous fiber three-dimensional structure of cellulose lactose is utilized for adsorption, solidification and isolation, the uneven mixing and degradation risk of clotrimazole and live lactobacillus are reduced, the acidity requirement of the preparation is met, and the compound vaginal tablet of live clotrimazole is prepared. The reason why the lactobacillus achieves the uniform mixing and non-inactivation is presumed to be: the low-concentration starch slurry is easier to dissolve and disperse lactobacillus powder uniformly, a starch slurry buffer layer is formed on the surface of lactobacillus, the influence of an acid environment with the pH value of 2.5-3.0 can be resisted, certain adhesiveness is achieved during adsorption and solidification, lactobacillus can be adsorbed uniformly, the increase of the particle size is not influenced remarkably, the uniform mixing with clotrimazole and an excipient is further ensured, and the acidity requirement of a finished product with the pH value of 3.0-4.5 is met.

The clotrimazole vaginal tablet composition provided by the invention contains 500mg of clotrimazole in a unit dose of the composition; 1mg of lactobacillus powder; 20 mg-30 mg of lactic acid; 8-12 mg of calcium lactate; 6mg to 12mg of starch; cellulose lactose C80200 mg-300 mg; yttky RL30D 80 mg-180 mg; 225mg to 310mg of lactose; 170 mg-221 mg of microcrystalline cellulose; 70mg of crospovidone; 20mg of colloidal silica; magnesium stearate 10mg, wherein the starch is used in the form of 3-6% (W/W) starch slurry.

Preferably, the clotrimazole vaginal tablet composition of the invention contains 500mg of clotrimazole; 1mg of lactobacillus powder; 22-28 mg of lactic acid; 9mg to 11mg of calcium lactate; 8-11 mg of starch; cellulose lactose C80200 mg-300 mg; yttky RL30D 80 mg-180 mg; 225mg to 310mg of lactose; 170 mg-221 mg of microcrystalline cellulose; 70mg of crospovidone; 20mg of colloidal silica; magnesium stearate 10mg, wherein the starch is used in the form of 4% to 5.5% (W/W) starch slurry.

The preparation method of the clotrimazole vaginal tablet composition comprises the following steps:

preparing bacterial liquid in the first step.

Adding a prescription amount of starch into boiled purified water for pulping to prepare 3% -6% concentration starch pulp, cooling to room temperature, adding lactobacillus powder, mixing uniformly, adding a prescription amount of lactic acid and calcium lactate, and keeping the pH value of the solution within the range of 2.5-3.0 for later use;

second step strain solidifying adsorption coating

Spraying the bacterial liquid prepared in the first step to the surface of cellulose lactose C80 by adopting a fluidized bed bottom spraying coating technology, then coating by Yttrium RL30D, increasing the weight of the coating by 8-15%, drying, and sieving the granules by a 30-mesh sieve for later use;

the technological parameters are as follows: the air inlet temperature of the fluidized bed granulation coating machine is 35-45 ℃; the air flow is 20-30 HZ, the atomization pressure is 0.3-0.6 mpa, the material temperature is 30-40 ℃, and the liquid spraying speed is 15-30 ml/min.

The third step of mixing

Uniformly mixing the strain granules prepared in the second step with the formula amounts of clotrimazole, lactose, microcrystalline cellulose and crospovidone in a hopper mixer, and then uniformly mixing with colloidal silicon dioxide and magnesium stearate;

and fourthly, tabletting and double-aluminum packaging.

The activity of the live lactobacillus in the starch slurry with the pH value of 2.5-3.0 is kept relatively static, so that the live lactobacillus can coexist with lactic acid at a lower pH value; adsorbing the bacterial liquid to cellulose lactose into granules by a fluidized bed bottom spraying coating technology, and compounding the granules with the Yttva RL30D coated and sieved into a vaginal tablet preparation; the risk of incompatibility of the clotrimazole, the live lactobacillus and the lactic acid is overcome, the content uniformity of the live lactobacillus in a unit preparation and the activity of the live lactobacillus solid preparation in the storage process are improved, the production process is simple and feasible, the cost is lower, the antibacterial activity is greatly improved, the combined synergistic medication of the clotrimazole and the live lactobacillus can be met, and the compliance of patients is improved.

The invention adopts starch and boiling water for size mixing to prepare 3-6% of starch size, and utilizes the characteristic that starch forms non-Newtonian fluid when meeting hot water to dissolve and disperse lactobacillus powder in the starch, so that a uniform protective layer is formed on the surface of live lactobacillus, and the influence of acid environment on the live lactobacillus is reduced, wherein the weight ratio of the live lactobacillus to the starch is 1: 6-12.

According to the clotrimazole vaginal tablet composition, lactic acid and calcium lactate in a formula can form a buffer system, the pH value of starch slurry bacteria liquid can be adjusted to be in a range of 2.5-3.0, a proper coexistence system is provided for live lactobacillus and lactic acid, the live lactobacillus is uniformly dispersed, the activity of the live lactobacillus is inhibited, and the prior art is improved, wherein the weight ratio of the live lactobacillus to the lactic acid to the calcium lactate is 1: 20-30: 8-12.

The method adopts cellulose lactose C80 as an adsorption carrier of the live lactobacillus in the bacterial liquid, utilizes the regular porous fiber spatial configuration of cellulose lactose C80, adopts a fluidized bed bottom spraying coating technology to quickly adsorb the bacterial liquid to the carrier, reduces the influence of long-term exposure of the lactobacillus to an extremely low pH environment generated by water volatilization, and gradually adsorbs the lactobacillus and lactic acid on the dried carrier, wherein the weight ratio of the lactobacillus powder to the carrier cellulose lactose C80 is 1: 200-300, the air inlet temperature of the fluidized bed bottom spraying coating parameter is 35-45 ℃, and the material temperature is 30-40 ℃.

According to the invention, the live lactobacillus particles are coated and isolated by Yttrium RL30D, the weight of the coating is increased by 8-15%, and the internal migration of the moisture and oxygen of an added excipient auxiliary material is overcome, so that live lactobacillus and lactic acid coexist without reducing the activity; the risks of the migration of lactic acid in the particles and the degradation of clotrimazole acid are avoided.

The invention prepares clotrimazole, live lactobacillus and lactic acid into vaginal tablets by compounding, and selects regular porous fibrous cellulose lactose C80 as an adsorption carrier of live lactobacillus; selecting starch slurry with the concentration of 3-6% as a protective agent and an adhesive of the viable lactobacillus; lactic acid and calcium lactate in the composition not only inhibit the activity of viable lactobacillus, but also serve as a finished product pH regulator to control the pH of the bacterial liquid to be 2.5-3.0.

Advantageous effects

The invention provides the clotrimazole vaginal tablet, which enhances the bacteriostatic property of a single prescription, reduces the times of combined medication, can improve the compliance of patients, and has the advantages of simple prescription preparation process, low cost, and exact quality and curative effect.

The invention realizes the coexistence of lactobacillus, clotrimazole and lactic acid, not only stabilizes the activity of the lactobacillus, but also realizes the requirements of even acidity and content of the preparation, and simultaneously reduces the risk of instability in clotrimazole acid; the whole production process is simple and convenient to operate, is suitable for continuous and stable technological production, and realizes the synergistic application of multiple treatment modes.

Detailed Description

The present invention will be further described with reference to the following examples.