Shuanzhiotai vaginal effervescent tablet and preparation method thereof

Abstract

The invention provides a metronidazole-clotrimazole vaginal effervescent tablet and a preparation method thereof. The metronidazole-clotrimazole vaginal effervescent tablet comprises the following raw materials by weight: 180 to 220 mg of metronidazole, 120 to 200 mg of clotrimazole, 4 to 12 mg of chlorhexidine acetate, 20 to 80 mg of starch, 60 to 100 mg of sodium bicarbonate, 40 to 80 mg of an acid source, 4 to 10 mg of magnesium stearate and 40 to 60 mg of an adhesive. The adhesive is prepared from povidone K30 and an ethyl cellulose-hydroxypropyl methyl cellulose aqueous solution. An inner core of the effervescent tablet is prepared from povidone K30, metronidazole, clotrimazole, starch and sodium bicarbonate, and then on the basis of the inner core, chlorhexidine acetate, the remaining starch, an acid source and magnesium stearate in the formula are added to prepare a pill core of the effervescent tablet containing three active ingredients of metronidazole, clotrimazole and chlorhexidine acetate. And finally, adding an ethyl cellulose-hydroxypropyl methyl cellulose aqueous solution for adhesion and tabletting to obtain the metronidazole-clotrimazole vaginal effervescent tablet, which is beneficial to quickly diffusing and releasing active ingredients in the early stage, promoting the exertion of the drug effect and effectively avoiding the burst release phenomenon of the drug.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, and in particular to a mesotrione vaginal effervescent tablet and a preparation method thereof. Background Art

[0002] The vaginal effervescent tablets of metronidazole and clotrimazole are a compound preparation, the main ingredients of which include metronidazole, clotrimazole and chlorhexidine acetate. It is an external-use medicine, mainly used to treat vaginal diseases, such as bacterial vaginitis, candidal vulvovaginitis, trichomoniasis vaginitis and mixed bacterial, fungal and trichomoniasis vaginitis. Clotrimazole is a synthetic broad-spectrum antifungal drug, and its chemical name is 1-[(2-chlorophenyl)diphenylmethyl]-1H-imidazole, which can inhibit the synthesis of fungal cell membranes and affect the physiological metabolic process of fungi, and can have a certain antibacterial effect on various shallow and deep fungi. Clotrimazole has a poor oral effect, so it is mainly used as a topical medication. Clotrimazole is a poorly soluble drug, and its solubility is not high when used as a topical medication, and its efficacy is reduced. At present, vaginal effervescent tablets made by adding effervescent agents can appropriately improve the dissolution effect of clotrimazole, but the effect needs to be improved, and the controlled release effect of the drug needs to be improved. Summary of the invention

[0003] In view of this, the purpose of the present invention is to provide a mesotrione vaginal effervescent tablet and a preparation method thereof, so as to improve the controlled release rate of the active ingredient and effectively increase the solubility of the active ingredient.

[0004] The technical solution of the present invention is achieved in this way:

[0005] A dimethoate vaginal effervescent tablet comprising the following raw materials in weight proportion: 180-220 mg of metronidazole, 120-200 mg of clotrimazole, 4-12 mg of chlorhexidine acetate, 20-80 mg of starch, 60-100 mg of sodium bicarbonate, 40-80 mg of an acid source, 4-10 mg of magnesium stearate and 40-60 mg of a binder;

[0006] The binder includes povidone K30 and an ethylcellulose-hydroxypropylmethylcellulose aqueous solution.

[0007] A further solution is that the povidone K30 is a povidone K30 solution with a mass concentration of 25 to 35%;

[0008] The ethyl cellulose-hydroxypropyl methyl cellulose aqueous solution is composed of ethyl cellulose and hydroxypropyl methyl cellulose in a mass ratio of 1:2-3;

[0009] The acid source is one or more of citric acid, tartaric acid and citric acid.

[0010] A further solution is that main drug particles are prepared from the metronidazole, clotrimazole, starch, sodium bicarbonate and povidone K30, and the main drug particles are the inner core of the effervescent tablet.

[0011] A further solution is that the raw material dosage of the inner core of the effervescent tablet includes the following components in weight ratio: metronidazole 180-220 mg, clotrimazole 120-200 mg, starch 20-40 mg, sodium bicarbonate 60-100 mg and povidone K30 30-50 mg.

[0012] A further solution is to prepare total granules from the main drug granules, chlorhexidine acetate, the remaining starch in the formula, an acid source and magnesium stearate, and the total granules are the active pill cores of the effervescent tablet.

[0013] The invention selects a polyvidone K30 solution with a mass concentration of 25 to 35% and an ethyl cellulose-hydroxypropyl methylcellulose aqueous solution as an adhesive, firstly prepares an inner core of an effervescent tablet by mixing polyvidone K30 with metronidazole, clotrimazole, starch and sodium bicarbonate, and then, on the basis of the inner core, prepares a pill core of an effervescent tablet containing three active ingredients of metronidazole, clotrimazole and chlorhexidine acetate by adding chlorhexidine acetate, the remaining starch in the formula, an acid source and magnesium stearate, and finally adds an ethyl cellulose-hydroxypropyl methylcellulose aqueous solution for adhesion and tableting, so that the obtained metronidazole vaginal effervescent tablet forms a two-layer gel skeleton structure, on the one hand, the ethyl cellulose Cellulose-hydroxypropyl methylcellulose first quickly absorbs water and swells to form a gel layer, which gradually dissolves the pill core. Under the action of the gel layer, the acid source and other ingredients are first dissolved, and then the ingredients of the inner core are dissolved, so as to avoid the effervescent agent releasing a large number of bubbles to reduce the degree of bonding between the mefenamic acid vaginal effervescent tablets and the adhesive, thereby causing a sudden release phenomenon. On the other hand, ethylcellulose-hydroxypropyl methylcellulose has a fast hydration rate and is not easy to control the release rate of the active ingredient. The inner core uses povidone K30 as the adhesive material, which is used in combination with ethylcellulose-hydroxypropyl methylcellulose. With the assistance of the effervescent agent, it helps to diffuse and release the active ingredient faster in the early stage.

[0014] The present invention provides a method for preparing the above-mentioned metoprolol vaginal effervescent tablets, comprising the following preparation steps:

[0015] (1) According to the formula, metronidazole, clotrimazole, sodium bicarbonate and starch are mixed, and a polyvidone K30 solution is added to prepare a soft material, and the mixture is sheared and mixed, granulated and dried to obtain main drug granules;

[0016] (2) according to the formula, chlorhexidine acetate, the remaining starch and acid source in the formula are added to the main drug granules for premixing, and then magnesium stearate is added for total mixing to obtain total granules;

[0017] (3) The total granules are granulated, an ethylcellulose-hydroxypropylmethylcellulose aqueous solution is added, mixed, granulated, dried, and tableted to obtain metoprolol vaginal effervescent tablets.

[0018] A further solution is that in step (1), the shear mixing speed is 900-1100 rpm, the shear mixing time is 6-10 min, the drying temperature is 60-65° C., and the drying is performed until the moisture content is ≤7%.

[0019] A further solution is that in step (2), the speed of the premixing is 10-15 rpm, the time of the premixing is 3-6 min, the speed of the total mixing is 15-25 rpm, and the time of the total mixing is 3-6 min.

[0020] A further solution is that in step (3), the tabletting pressure is 4 to 7 KN.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] The invention prepares the inner core of the effervescent tablet by firstly preparing the inner core of the effervescent tablet by mixing povidone K30 with metronidazole, clotrimazole, starch and sodium bicarbonate, and then prepares the pill core of the effervescent tablet containing three active ingredients of metronidazole, clotrimazole and chlorhexidine acetate by adding chlorhexidine acetate, the remaining starch in the formula, an acid source and magnesium stearate on the basis of the inner core, and finally adds an ethyl cellulose-hydroxypropyl methylcellulose aqueous solution for adhesion and tableting. The obtained metronidazole vaginal effervescent tablet is helpful to quickly diffuse and release the active ingredients in the early stage, promotes the drug effect, and effectively avoids the sudden release of the drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 The dissolution curve of the mesotrione vaginal effervescent tablets prepared in Example 1;

[0024] Figure 2 The dissolution curve of the mesotrione vaginal effervescent tablets prepared in Example 2;

[0025] Figure 3 The dissolution curve of the mesotrione vaginal effervescent tablets prepared in Example 3;

[0026] Figure 4 The dissolution curve of the mesotrione vaginal effervescent tablets prepared in Comparative Example 1 is shown;

[0027] Figure 5 This is the dissolution curve of the metoprolol vaginal effervescent tablets prepared in Comparative Example 2. DETAILED DESCRIPTION

[0028] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0029] Unless otherwise specified, the experimental methods used in the embodiments of the present invention are all conventional methods.

[0030] Unless otherwise specified, the materials, reagents, etc. used in the embodiments of the present invention can be obtained from commercial sources.

[0031] The viscosity of ethyl cellulose is 40 to 50 mPa·s, and the viscosity of hydroxypropyl methyl cellulose is 55 to 60 mPa·s.

[0032] The dissolution determination method implemented in the present invention adopts a circulation cell device to determine the dissolution of clotrimazole vaginal effervescent tablets, using pH 4.5 phosphate buffer as the dissolution medium, the flow rate is 8 mL / min, microporous membrane filtration, methanol-water (70:30) dilution, and HPLC content determination according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV 0512), octylsilane bonded silica gel as a filler, methanol-water-triethylamine (70:30:0.3) (containing 10 mmol / L sodium heptane sulfonate, and adjusting the pH value to 4.0 with phosphoric acid) as the mobile phase, the detection wavelength is 260 nm, the injection volume is 20 μL, and the dissolution amount of each tablet (in terms of clotrimazole) is calculated by peak area according to the external standard method.

[0033] Example 1

[0034] Preparation process of dimethoate vaginal effervescent tablets:

[0035] (1) adding 30 g of povidone K30 to 100 g of purified water and stirring to prepare a binding solution, and adding 5 g of ethyl cellulose and 10 g of hydroxypropyl methyl cellulose to 100 g of purified water and stirring to prepare an ethyl cellulose-hydroxypropyl methyl cellulose aqueous solution;

[0036] (2) 200 g of metronidazole, 160 g of clotrimazole, 80 g of sodium bicarbonate and 30 g of starch were mixed, 40 g of a binding solution was added to prepare a soft material, the mixture was shear-mixed at a speed of 1000 rpm for 8 min, and after granulation, the mixture was dried at 60-65° C. until the moisture content was ≤7%, thereby obtaining main drug granules;

[0037] (3) Add 8 g of chlorhexidine acetate, 20 g of starch and 60 g of citric acid to the main drug granules for premixing, premix at a speed of 10 rpm for 5 min, then add magnesium stearate for total mixing, and mix at a speed of 15 rpm for 5 min to obtain total granules;

[0038] (4) The total granules were sized, 40 g of ethylcellulose-hydroxypropylmethylcellulose aqueous solution was added as a binder for granulation, and the granules were dried and tableted at a pressure of 5 KN to obtain metoprolol vaginal effervescent tablets.

[0039] Example 1 The surface of the dimethoate vaginal effervescent tablets prepared by the method of embodiment 1 is smooth and flat, without any cracks, stickiness or loose tablets; Figure 1 As shown, the cumulative dissolution amount of the metoprolol vaginal effervescent tablets reached more than 85%, dissolves rapidly within 100 minutes, and has good solubility.

[0040] Example 2

[0041] Preparation process of dimethoate vaginal effervescent tablets:

[0042] (1) adding 30 g of povidone K30 to 100 g of purified water and stirring to prepare a binding solution, and adding 5 g of ethyl cellulose and 10 g of hydroxypropyl methyl cellulose to 100 g of purified water and stirring to prepare an ethyl cellulose-hydroxypropyl methyl cellulose aqueous solution;

[0043] (2) 200 g of metronidazole, 160 g of clotrimazole, 80 g of sodium bicarbonate and 40 g of starch were mixed, 45 g of a binding solution was added to prepare a soft material, the mixture was shear-mixed at a speed of 1000 rpm for 8 min, and after granulation, the mixture was dried at 60-65° C. until the moisture content was ≤7%, thereby obtaining main drug granules;

[0044] (3) Add 8 g of chlorhexidine acetate, 20 g of starch and 60 g of citric acid to the main drug granules for premixing, premix at a speed of 10 rpm for 5 min, then add magnesium stearate for total mixing, and mix at a speed of 25 rpm for 3 min to obtain total granules;

[0045] (4) The total granules were sized, 40 g of ethylcellulose-hydroxypropylmethylcellulose aqueous solution was added as a binder for granulation, and the granules were dried and tableted at a pressure of 5 KN to obtain metoprolol vaginal effervescent tablets.

[0046] Example 2 The surface of the bifenthrin vaginal effervescent tablets prepared by Example 2 was smooth and flat, without any cracks, stickiness or loose tablets. Figure 2 As shown, the cumulative dissolution amount of the metoprolol vaginal effervescent tablets reached more than 85%, and the tablets dissolved rapidly within 100 minutes with good dissolution rate.

[0047] Example 3

[0048] Preparation process of dimethoate vaginal effervescent tablets:

[0049] (1) adding 30 g of povidone K30 to 100 g of purified water and stirring to prepare a binding solution, and adding 5 g of ethyl cellulose and 10 g of hydroxypropyl methyl cellulose to 100 g of purified water and stirring to prepare an ethyl cellulose-hydroxypropyl methyl cellulose aqueous solution;

[0050] (2) 200 g of metronidazole, 160 g of clotrimazole, 80 g of sodium bicarbonate and 30 g of starch were mixed, 40 g of a binding solution was added to prepare a soft material, the mixture was shear-mixed at a speed of 1000 rpm for 8 min, and after granulation, the mixture was dried at 60-65° C. until the moisture content was ≤7%, thereby obtaining main drug granules;

[0051] (3) Add 8 g of chlorhexidine acetate, 20 g of starch and 60 g of citric acid to the main drug granules for premixing, premix at a speed of 10 rpm for 5 min, then add magnesium stearate for total mixing, and mix at a speed of 15 rpm for 5 min to obtain total granules;

[0052] (4) The total granules were sized, 40 g of ethylcellulose-hydroxypropylmethylcellulose aqueous solution was added as a binder for granulation, and the granules were dried and tableted at a pressure of 5 KN to obtain metoprolol vaginal effervescent tablets.

[0053] Example 3 The surface of the bifenthrin vaginal effervescent tablets prepared by Example 3 was smooth and flat, without any cracks, stickiness or loose tablets. Figure 3 As shown, the cumulative dissolution amount of the metoprolol vaginal effervescent tablets reached more than 85%, dissolves rapidly within 100 minutes, and has good solubility.

[0054] Comparative Example 1

[0055] Preparation process of dimethoate vaginal effervescent tablets:

[0056] (1) adding 30 g of povidone K30 to 100 g of purified water and stirring to prepare a binding solution, and adding 5 g of ethyl cellulose and 10 g of hydroxypropyl methyl cellulose to 100 g of purified water and stirring to prepare an ethyl cellulose-hydroxypropyl methyl cellulose aqueous solution;

[0057] (2) 200 g of metronidazole, 160 g of clotrimazole, 80 g of sodium bicarbonate and 30 g of starch were mixed, 40 g of a binding solution was added to prepare a soft material, and granulated to obtain main drug granules;

[0058] (3) Add 5 g of chlorhexidine acetate, 20 g of starch and 60 g of citric acid to the main drug granules for premixing, premix at a speed of 10 rpm for 5 min, then add magnesium stearate for total mixing, and mix at a speed of 15 rpm for 5 min to obtain total granules;

[0059] (4) Add 40 g of ethylcellulose-hydroxypropylmethylcellulose aqueous solution as a binder to the total granules for granulation, shape the granules, dry them at 60-65° C. until the moisture content is ≤7%, and then compress them at a pressure of 5 KN to obtain metoprolol vaginal effervescent tablets.

[0060] Depend on Figure 4As shown, the cumulative dissolution amount of the metoprolol vaginal effervescent tablets is low, the dissolution rate is slow within 100 minutes, a burst release phenomenon occurs, and the solubility is poor.

[0061] Comparative Example 2

[0062] Preparation process of dimethoate vaginal effervescent tablets:

[0063] (1) 15 g of hydroxypropyl methylcellulose was added to 100 g of purified water and stirred to prepare a hydroxypropyl methylcellulose aqueous solution;

[0064] (2) 200 g of metronidazole, 160 g of clotrimazole, 80 g of sodium bicarbonate, 30 g of starch and 15 g of sodium lauryl sulfate were mixed, 40 g of hydroxypropyl methylcellulose aqueous solution was added to prepare a soft material, shear mixing was performed at a speed of 1000 rpm for 8 min, and after granulation, it was dried at 60-65° C. until the moisture content was ≤7%, to obtain the main drug granules;

[0065] (3) 5 g of chlorhexidine acetate, 20 g of lactose and 60 g of citric acid were premixed at a speed of 10 rpm for 5 min, 40 g of hydroxypropyl methylcellulose aqueous solution was added to prepare a soft material, and after granulation, the mixture was dried at 60-65° C. until the moisture content was ≤7%, thereby obtaining secondary drug granules;

[0066] (4) Mixing the main drug granules and the secondary drug granules, adding magnesium stearate for total mixing, and mixing at a speed of 15 rpm for 5 minutes to obtain total granules;

[0067] (4) The total granules are sized and compressed into tablets at a pressure of 5 KN to obtain dimethoate vaginal effervescent tablets.

[0068] Depend on Figure 5 As shown, the cumulative dissolution amount of the metoprolol vaginal effervescent tablets is low, the dissolution rate is slow within 100 minutes, and the dissolution rate is poor.

[0069] The above is a preferred embodiment of the present invention. It should be pointed out that a person skilled in the art can make several improvements and modifications without departing from the principle of the present invention. These improvements and modifications are also considered to be within the scope of protection of the present invention.

Claims

1. A mesotrione vaginal effervescent tablet, characterized in that: The invention comprises the following raw materials in weight proportion: 180-220 mg of metronidazole, 120-200 mg of clotrimazole, 4-12 mg of chlorhexidine acetate, 20-80 mg of starch, 60-100 mg of sodium bicarbonate, 40-80 mg of acid source, 4-10 mg of magnesium stearate and 40-80 mg of adhesive; The binder includes povidone K30 and an ethylcellulose-hydroxypropylmethylcellulose aqueous solution.

2. A mesotrione vaginal effervescent tablet according to claim 1, characterized in that: The povidone K30 is a povidone K30 solution with a mass concentration of 25 to 35%; The ethyl cellulose-hydroxypropyl methyl cellulose aqueous solution is composed of ethyl cellulose and hydroxypropyl methyl cellulose in a mass ratio of 1:2-3; The acid source is one or more of citric acid, tartaric acid and citric acid.

3. A mesotrione vaginal effervescent tablet according to claim 1, characterized in that: Main drug particles are prepared from the metronidazole, clotrimazole, starch, sodium bicarbonate and povidone K30, and the main drug particles are the inner core of the effervescent tablet.

4. A mesotrione vaginal effervescent tablet according to claim 3, characterized in that: The raw material dosage of the inner core of the effervescent tablet includes the following components in weight proportion: 180-220 mg of metronidazole, 120-200 mg of clotrimazole, 20-40 mg of starch, 60-100 mg of sodium bicarbonate and 30-50 mg of povidone K30.

5. A mesotrione vaginal effervescent tablet according to claim 3, characterized in that: The total granules are prepared from the main drug granules, chlorhexidine acetate, the remaining starch in the formula, an acid source and magnesium stearate, and the total granules are the active pill cores of the effervescent tablet.

6. The method for preparing a mesotrione vaginal effervescent tablet according to any one of claims 1 to 5, characterized in that: The method comprises the following preparation steps: (1) According to the formula, metronidazole, clotrimazole, sodium bicarbonate and starch are mixed, and a polyvidone K30 solution is added to prepare a soft material, and the mixture is sheared and mixed, granulated and dried to obtain main drug granules; (2) according to the formula, chlorhexidine acetate, the remaining starch and acid source in the formula are added to the main drug granules for premixing, and then magnesium stearate is added for total mixing to obtain total granules; (3) The total granules are granulated, an ethylcellulose-hydroxypropylmethylcellulose aqueous solution is added, mixed, granulated, dried, and tableted to obtain metoprolol vaginal effervescent tablets.

7. The method for preparing a mesotrione vaginal effervescent tablet according to claim 6, characterized in that: In step (1), the rotation speed of the shear mixing is 900-1100 rpm, the shear mixing time is 6-10 min, the drying temperature is 60-65° C., and the drying is performed until the moisture content is ≤7%.

8. The method for preparing a mesotrione vaginal effervescent tablet according to claim 6, characterized in that: In step (2), the speed of the premixing is 10-15 rpm, the time of the premixing is 3-6 min, the speed of the total mixing is 15-25 rpm, and the time of the total mixing is 3-6 min.

9. The method for preparing a mesotrione vaginal effervescent tablet according to claim 6, characterized in that: In step (3), the tabletting pressure is 4 to 7 KN.

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