A kind of metronidazole gel and preparation method thereof, application

Abstract

The present application relates to the field of medical technology, and specifically discloses a metronidazole gel and a preparation method thereof, and application. The metronidazole gel, by weight, includes 7-45 parts of metronidazole, 8-50 parts of carbomer, 5-15 parts of polyvinyl alcohol, 120-260 parts of propylene glycol, 10-20 parts of ethanol, 5-10 parts of glycerol, and 8-15 parts of starch. After the above-mentioned raw materials are added with water in corresponding proportions, they are processed by ultrasound, wherein the ultrasound power is 150-200W, and the ultrasound time is 50-150min, and the obtained metronidazole gel has a higher freeze-thaw tolerance. After 2 freeze-thaw tolerances, the viscosity value of the obtained metronidazole gel is more than 18800mPa·s, and it is safe and non-toxic, non-irritating, and can be used in the treatment of bacterial vaginitis drugs, and the effect is better.

Description

Technical Field

[0001] The present application relates to the field of medical technology, and more specifically to a metronidazole gel and a preparation method and application thereof. Background Art

[0002] Bacterial vaginosis is a mixed infection caused by the imbalance of normal vaginal flora, which leads to increased vaginal secretions, fishy odor of leucorrhea, and is often accompanied by symptoms such as vulvar itching and burning.

[0003] In order to relieve the discomfort caused by bacterial vaginitis, there are generally the following methods: (1) Using water to clean the vagina can temporarily relieve symptoms such as vulvar itching and burning, but some bacteria also exist in the water, and there is a risk of secondary infection. (2) Metronidazole gel is used clinically to treat bacterial vaginitis. Metronidazole can inhibit the reproduction of a variety of anaerobic bacteria, thereby reducing the number of bacteria in the vagina, thereby keeping the vaginal flora in balance. However, if metronidazole gel is at a low temperature (below -18°C) during transportation or storage, and then returned to room temperature (above 20°C) for use, the adhesion of the gel often deteriorates, and it may even become watery and easy to flow out, which seriously affects the quality and use of the metronidazole gel.

[0004] Therefore, a metronidazole gel with good freeze-thaw tolerance is needed to ensure the quality and use of the metronidazole gel. Summary of the invention

[0005] In order to improve the freeze-thaw tolerance of metronidazole gel, the present application provides a metronidazole gel and a preparation method and application thereof.

[0006] In a first aspect, the present application provides a metronidazole gel, which comprises, by weight, 7-45 parts of metronidazole, 8-50 parts of carbomer, 5-15 parts of polyvinyl alcohol, 120-260 parts of propylene glycol, 10-20 parts of ethanol, 5-10 parts of glycerol, and 8-15 parts of starch.

[0007] In the present application, metronidazole, carbomer, polyvinyl alcohol, propylene glycol, ethanol, glycerol and starch are mixed according to the corresponding parts by weight, and then water is added to obtain metronidazole gel. After two freeze-thaw experiments (the experimental conditions are: freezing at -20°C, thawing at 25°C after 20 hours), the viscosity value of the obtained metronidazole gel is above 18800mPa·s, which meets the requirement of the viscosity value of the metronidazole gel of the present application at 17000-210000mPa·s. It is shown that the metronidazole gel obtained in the present application has a high freeze-thaw tolerance and does not affect the viscosity and use of the metronidazole gel.

[0008] The effect of metronidazole in the present application is to inhibit the reproduction of bacteria, effectively reducing the number of Gram-negative anaerobic bacilli in the vagina. The dosage of metronidazole can be 7-45 parts, 7-30 parts, 7-20 parts, 7-15 parts or 10-20 parts. Exemplarily, the dosage of metronidazole can be 7 parts, 10 parts, 15.5 parts, 20 parts, 23.4 parts, 30 parts, 35 parts, 40 parts or 45 parts.

[0009] Carbomer has high swelling capacity and expands after absorbing water, which can adjust the viscosity of metronidazole gel, so that metronidazole can better adhere to the inner wall of the vagina and play an inhibitory role in the vagina. The carbomer of the present application can be selected from carbomer 934, carbomer 934P, carbomer 940 or carbomer 941.

[0010] The amount of carbomer can be 8-50 parts, 8-40 parts, 8-30 parts, 8-20 parts, 15-25 parts or 30-40 parts. Exemplarily, the amount of carbomer can be 8 parts, 10 parts, 15.2 parts, 18.5 parts, 25 parts, 30 parts, 35 parts, 40 parts

[0011] or 50 copies.

[0012] In one embodiment, by weight, the polyvinyl alcohol is 5-10 parts, the propylene glycol is 180-260 parts, and the ethanol is 15-20 parts.

[0013] In the present application, by combining polyvinyl alcohol, propylene glycol and ethanol and compounding them according to the weight ratio of (5-10 parts) / (180-260 parts) / (15-20 parts), the carbomer can be protected after swelling by water absorption, and the strength and stability of the carbomer can be increased. After two freeze-thaw experiments, the viscosity of the metronidazole gel is above 19000mPa·s.

[0014] In one embodiment, based on weight parts, the polyvinyl alcohol is 10 parts, the propylene glycol is 240 parts, and the ethanol is 15 parts.

[0015] In one embodiment, the viscosity of the polyvinyl alcohol is 5-40 mPas.

[0016] In the application, polyvinyl alcohol needs to be compounded with propylene glycol and ethanol to work, and polyvinyl alcohol of different viscosities affects the compounding effect, which in turn affects the freeze-thaw stability of metronidazole gel.

[0017] When other raw materials and conditions remain unchanged, the viscosity of polyvinyl alcohol is in the range of 5-40mPas. As the viscosity of polyvinyl alcohol gradually increases, the viscosity of the obtained metronidazole gel increases first, then decreases after the freeze-thaw experiment. When the viscosity of polyvinyl alcohol is 25mPas, the viscosity of the obtained metronidazole gel is higher, that is to say, the freeze-thaw stability of the metronidazole gel is better.

[0018] In one embodiment, the viscosity of the polyvinyl alcohol is 10-30 mPas.

[0019] Furthermore, the viscosity of the polyvinyl alcohol is 25-30 mPas.

[0020] Further preferably, the viscosity of the polyvinyl alcohol is 25 mPas.

[0021] In one embodiment, the polyvinyl alcohol is selected from pharmaceutical grade polyvinyl alcohol EG-25 and pharmaceutical grade polyvinyl alcohol EG-30.

[0022] The polyvinyl alcohol in the present application can be obtained commercially, and the polyvinyl alcohol can be selected from pharmaceutical grade polyvinyl alcohol EG-05, whose viscosity is 5mPas; or pharmaceutical grade polyvinyl alcohol EG-25, whose viscosity is 25mPas; or pharmaceutical grade polyvinyl alcohol EG-30, whose viscosity is 30mPas; or pharmaceutical grade polyvinyl alcohol EG-40, whose viscosity is 40mPas.

[0023] In the present application, the metronidazole gel further comprises 0.5-1.2 parts of sodium edetate and 0.6-1.5 parts of sodium hydroxide.

[0024] In a second aspect, the present application provides a method for preparing a metronidazole gel, comprising the following steps:

[0025] (1) Preparing solution: preparing carbomer solution;

[0026] (2) preparing a gel matrix: adding sodium hydroxide to the carbomer solution to prepare a gel matrix;

[0027] (3) preparing a pharmaceutical solution: mixing the metronidazole, the polyvinyl alcohol, the starch, the glycerol, the propylene glycol and the ethanol to prepare a pharmaceutical solution;

[0028] (4) Mixing the gel matrix and the drug solution under ultrasound to prepare metronidazole gel.

[0029] By adopting the above technical solution, after ultrasonic treatment, the compactness of metronidazole gel can be improved, making it more stable. At the same time, ultrasound can promote the compounding effect of polyvinyl alcohol, propylene glycol and ethanol, so that the freeze-thaw tolerance of metronidazole gel is further improved and more stable.

[0030] In one embodiment, the ultrasonic power is 100-200W.

[0031] Preferably, the ultrasonic power is 150-200W.

[0032] Further preferably, the ultrasonic power is 150W.

[0033] In the ultrasonic treatment of this application, ultrasonic power and ultrasonic time are two key conditions that affect the freeze-thaw tolerance of metronidazole gel. When the ultrasonic power is in the range of 100-200W, the obtained metronidazole gel has good freeze-thaw tolerance; when the ultrasonic power is less than 100W, the freeze-thaw tolerance of metronidazole gel is not effectively improved; when the ultrasonic power is greater than 200W, the power is too large, which destroys the cross-linking effect of polyvinyl alcohol, propylene glycol and ethanol, thereby reducing the viscosity value of the obtained metronidazole gel.

[0034] In one embodiment, the ultrasonic time is 50-150 min.

[0035] Preferably, the ultrasonic time is 80-100 min.

[0036] More preferably, the ultrasonic time is 90 min.

[0037] In a third aspect, the present application provides an application of metronidazole gel in a drug for treating bacterial vaginitis, especially in the indication of senile vaginitis.

[0038] Senile vaginitis is common in postmenopausal women. Due to the decline of ovarian function, the decrease of estrogen level, the atrophy of vaginal wall and the thinning of mucosa, the incidence rate is high. According to statistics, more than 30% of people will suffer from this disease. The metronidazole gel prepared in this application has high freeze-thaw tolerance, is non-toxic, non-irritating, and has high safety. It can be used in drugs for the treatment of bacterial vaginitis.

[0039] In summary, this application has the following beneficial effects:

[0040] 1. The present application adopts a compound of metronidazole, carbomer, polyvinyl alcohol, propylene glycol, ethanol, glycerol and starch. The prepared metronidazole gel has high freeze-thaw tolerance and high safety. After two freeze-thaw experiments, the viscosity value is above 18800 mPa·s, which still meets the requirement of a viscosity value of 17000-21000 mPa·s;

[0041] 2. In the present application, polyvinyl alcohol, propylene glycol and ethanol are preferably compounded in a weight ratio of (5-10 parts) / (180-260 parts) / (15-20 parts), and the viscosity value of the obtained metronidazole gel after two freeze-thaw tests is above 19000 mPa·s;

[0042] 3. The preparation method of the present application is treated by ultrasound, wherein the ultrasound power is 100-200 W and the ultrasound time is 50-150 min, which further improves the stability of the metronidazole gel, and the difference in viscosity values ​​before and after the two freeze-thaw experiments is small. DETAILED DESCRIPTION

[0043] The present application is further described in detail below with reference to the embodiments.

[0044] Raw materials

[0045] The sources of the raw and auxiliary materials described in this application are shown in Table 1. Unless otherwise specified, they can all be obtained from the market.

[0046] Table 1 Sources of raw materials and auxiliary materials

[0047] Name of raw materials Source / Specifications Metronidazole CAS No.: 443-48-1 Propylene glycol CAS No.: 26264-14-2 glycerin CAS No.: 56-81-5 starch CAS No.: 9005-25-8

[0048] Example

[0049] Example 1

[0050] The preparation of metronidazole gel comprises the following steps:

[0051] (1) Preparation of solution: Add 200 g of purified water and 1.2 g of edetate disodium into a stirring tank, adjust the stirring speed to 40 Hz, then add 30 g of Carbomer 934, and finally add 210 g of purified, stir for 40 min, and prepare a Carbomer solution;

[0052] (2) Preparation of gel matrix: In a vacuum container, the carbomer solution was sucked in, and 0.6 g of sodium hydroxide was added at a stirring speed of 28 r / min, and stirred for 120 min to obtain a gel matrix;

[0053] (3) Preparing a liquid medicine: Add 113.1 g of purified water into a stirring container, raise the temperature to 50° C., and then add 20 g of metronidazole, 10 g of polyvinyl alcohol, 10 g of starch, 7 g of glycerol, 180 g of propylene glycol and 15 g of ethanol and mix them to prepare a liquid medicine;

[0054] The polyvinyl alcohol is pharmaceutical grade polyvinyl alcohol EG-25 with a viscosity of 25 mPas;

[0055] (4) stirring and mixing the gel matrix and the drug solution to prepare a metronidazole gel.

[0056] Examples 2-10, Comparative Examples 1-6

[0057] The differences between Examples 2-10, Comparative Examples 1-6 and Example 1 are shown in Table 2.

[0058] Table 2 Parameters of Examples 2-10, Comparative Examples 1-6 and Example 1

[0059]

[0060]

[0061] *The polyvinyl alcohol described in Example 8 is medical grade polyvinyl alcohol EG-05; the polyvinyl alcohol described in Example 9 is medical grade polyvinyl alcohol EG-30; the polyvinyl alcohol described in Example 10 is medical grade polyvinyl alcohol EG-40.

[0062] Comparative Example 7

[0063] The difference between Comparative Example 7 and Example 1 is that no starch is added in Comparative Example 7.

[0064] Comparative Example 8

[0065] Comparative Example 8 is an existing metronidazole gel, including 20 g of metronidazole, 30 g of carbomer 934, 200 g of propylene glycol, 0.5 g of disodium ethylenediaminetetraacetate, 2 g of polysorbate 80, 0.67 g of sodium hydroxide, 1 g of ethyl parahydroxybenzoate, and purified water added to 1000 g.

[0066] Performance testing

[0067] The metronidazole gels prepared in Examples 1-10 and Comparative Examples 1-8 were subjected to freeze-thaw tolerance tests to detect the viscosity values ​​of the metronidazole gels before and after freeze-thaw treatment.

[0068] The present application requires that the viscosity of the metronidazole gel be 17000 to 21000 mPa·s. When the viscosity of the metronidazole gel is lower than 17000 mPa·s, it cannot be effectively adhered during actual use; when the viscosity of the metronidazole gel is higher than 21000 mPa·s, the release rate of the active ingredient is slow and the dispersibility is poor during actual use.

[0069] Freeze-thaw tolerance test method: 200 g of metronidazole gel prepared in Examples 1-10 and Comparative Examples 1-8 were placed in conical bottles, covered and frozen in a -20°C refrigerator, taken out after 20 hours, and thawed in a 25°C water bath for 2 hours, which was one freeze-thaw treatment. Under the same conditions, freeze-thaw treatment was performed twice, and the specific test results are shown in Table 3.

[0070] Table 3 Test results of Examples 1-10 and Comparative Examples 1-8 (unit: mPa·s)

[0071] Group Before freeze-thaw tolerance test After freeze-thaw tolerance test Example 1 20500 19800 Example 2 20300 19200 Example 3 20600 19400 Example 4 20700 19100 Example 5 20400 19600 Example 6 20200 19200 Example 7 20800 19000 Example 8 20300 18800 Example 9 20500 19500 Example 10 20600 19100 Comparative Example 1 20700 16300 Comparative Example 2 20100 16100 Comparative Example 3 20200 15200 Comparative Example 4 20600 16400 Comparative Example 5 20400 14600 Comparative Example 6 20600 15700 Comparative Example 7 20700 15900 Comparative Example 8 20900 13400

[0072] Combining Examples 1-10 and Comparative Examples 1-8 and Table 3, it can be seen that the metronidazole gels prepared in Examples 1-10 and Comparative Examples 1-8 are all above 20100 mPa·s, which meet the requirements of the present application. After two freeze-thaw tolerance tests, the metronidazole gels prepared in Examples 1-10 of the present application are above 18800 mPa·s, which still meet the requirements of the present application, and have little effect on the adhesion of the metronidazole gel.

[0073] Combining Examples 1-7 and Comparative Examples 1-6 with Table 3, it can be seen that when the weight ratio of propylene glycol, polyvinyl alcohol and ethanol is (120-260 parts) / (5-15 parts) / (10-20 parts), the viscosity value of the obtained metronidazole gel after two freeze-thaw tolerance tests is above 19000 mPa·s.

[0074] Examples 11-15, Comparative Examples 9-12

[0075] Embodiment 11

[0076] The difference between Example 11 and Example 1 is that in step (4) of Example 11, the gel matrix and the drug solution are mixed by ultrasound to prepare the metronidazole gel;

[0077] The ultrasonic power during the ultrasonic process is 150W and the ultrasonic time is 90min.

[0078] The differences between Examples 12-15, Comparative Examples 9-11 and Example 11 are shown in Table 4.

[0079] Table 4 Parameters of Examples 11-15, Comparative Examples 9-11 and Example 1

[0080] Group Ultrasonic power / W Ultrasonic time / min Embodiment 11 150 90 Example 12 100 90 Example 13 200 90 Embodiment 14 150 50 Embodiment 15 150 150 Comparative Example 9 80 90 Comparative Example 10 250 90 Comparative Example 11 150 180

[0081] Comparative Example 12

[0082] The difference between Comparative Example 12 and Comparative Example 8 is that in Comparative Example 12, ultrasound treatment is used, the ultrasound power is 150 W, and the ultrasound time is 90 min.

[0083] Performance testing

[0084] The metronidazole gels prepared in Examples 11-15 and Comparative Examples 9-12 were subjected to freeze-thaw tolerance tests. The specific test results are shown in Table 5.

[0085] Table 5 Test results of Examples 11-14 and Comparative Examples 9-12 (unit: mPa·s)

[0086]

[0087]

[0088] *“-” in Table 5 means no test was performed.

[0089] Combining Example 1 and Example 11 with Table 5, it can be seen that the gel matrix and the drug solution are mixed by ultrasonic treatment to prepare the metronidazole gel, which can further improve the freeze-thaw tolerance of the metronidazole gel prepared in Example 1. After two freeze-thaw tolerance tests, the viscosity value of the obtained metronidazole gel is slightly different from that before the freeze-thaw tolerance test, and the difference is 400 mPa·s.

[0090] Combining Examples 11-15 and Comparative Examples 9-10 and Table 5, it can be seen that when the ultrasonic power is 100-200 W and the ultrasonic time is 50-150 min during ultrasonic treatment, the difference in viscosity before and after the test of the obtained metronidazole gel is less than 600 mPa·s.

[0091] Freeze-thaw tolerance test

[0092] The metronidazole gel prepared in Example 1 and Example 11 was subjected to an extreme freeze-thaw tolerance test. The prepared metronidazole gel was placed in a -20°C refrigerator and frozen, taken out after 20 hours, and thawed in a 25°C water bath for 2 hours, which was a freeze-thaw treatment. Under the same conditions, the freeze-thaw treatment times were 2 times, 5 times, 8 times, and 10 times, respectively, and then the viscosity value was tested. The experimental test results are shown in Table 6.

[0093] Table 6 Experimental test results (unit: mPa·s)

[0094] Freeze-thaw treatment times / times Viscosity value of Example 1 Viscosity values ​​of Example 11 2 19800 19900 5 18500 18800 8 16900 17700 10 - 17200

[0095] Combining Examples 1 and 11 and Table 6, it can be seen that the metronidazole gel prepared in Example 11 has a high freeze-thaw tolerance. After 10 freeze-thaw treatments, the viscosity of the obtained metronidazole gel is 17200 mPa·s; while in Example 1, after 5 freeze-thaw treatments, the viscosity of the obtained metronidazole gel is 18500 mPa·s, and the viscosity of the obtained metronidazole gel after 8 freeze-thaw treatments is 16900 mPa·s, which is lower than the viscosity value requirement of the present application (the viscosity value is in the range of 17000-21000 mPa·s).

[0096] Safety Testing

[0097] The safety of the metronidazole gels prepared in Examples 1 to 7 was tested using porcine hip endothelial cells. 10 mg of each of the metronidazole gels prepared in Examples 1 to 7 were added to DMEM culture media containing 10% fetal bovine serum, 100 U / mL penicillin and 100 U / mL streptomycin to prepare 7 groups of culture fluids.

[0098] In a 96-well plate, 100 μL of cells were seeded at a density of 5 × 10 3 mL of cell suspension, place the culture plate in a 37°C, 5% CO2 incubator for pre-culture for 24 h; then replace with new DMEM culture medium.

[0099] The experiment was divided into an experimental group and a control group:

[0100] The experimental group was divided into 7 groups, and 30 μL of the obtained culture solution was added to each well during the culture process, and the cells were incubated in the incubator for 1 day. Finally, serum-free DMEM medium containing 10% CKK-8 was added to each well, and the cells were incubated for another 1 hour, and the absorbance at 450 nm was measured using an enzyme marker.

[0101] DMEM culture medium was used as the control group.

[0102] Experimental results: The OD values ​​of the cells in the experimental groups 1-7 and the control group were all greater than 0.8, indicating that the cell survival rate was high and the metronidazole gel prepared in Examples 1-7 was non-toxic.

[0103] It is to be understood that the above embodiments are merely exemplary embodiments used to illustrate the principles of the present application, but the present application is not limited thereto. For those skilled in the art, various modifications and improvements can be made without departing from the spirit and essence of the present application, and these modifications and improvements are also considered to be within the scope of protection of the present invention.

Claims

1. A metronidazole gel, characterized in that The invention comprises, by weight, 7-45 parts of metronidazole, 8-50 parts of carbomer 934, 5-15 parts of polyvinyl alcohol, 120-260 parts of propylene glycol, 10-20 parts of ethanol, 5-10 parts of glycerol and 8-15 parts of starch; the polyvinyl alcohol is one of polyvinyl alcohol EG-05, polyvinyl alcohol EG-25, polyvinyl alcohol EG-30 and polyvinyl alcohol EG-40.

2. A metronidazole gel according to claim 1, characterized in that: In terms of weight, the polyvinyl alcohol is 5-10 parts, the propylene glycol is 180-260 parts, and the ethanol is 15-20 parts.

3. A metronidazole gel according to claim 2, characterized in that: In terms of weight, the polyvinyl alcohol is 10 parts, the propylene glycol is 240 parts, and the ethanol is 15 parts.

4. A metronidazole gel according to any one of claims 1 to 3, characterized in that The viscosity of the polyvinyl alcohol is 10-30 mPas.

5. A metronidazole gel according to claim 4, characterized in that: The viscosity of the polyvinyl alcohol is 25-30 mPas.

6. A metronidazole gel according to claim 5, characterized in that: The polyvinyl alcohol is selected from pharmaceutical grade polyvinyl alcohol EG-25 and pharmaceutical grade polyvinyl alcohol EG-30.

7. A method for preparing the metronidazole gel according to any one of claims 1 to 6, characterized in that: The following steps are involved: (1) Solution preparation: prepare carbomer solution; (2) preparing a gel matrix: adding sodium hydroxide to the carbomer solution to prepare a gel matrix; (3) preparing a pharmaceutical solution: mixing the metronidazole, the polyvinyl alcohol, the starch, the glycerol, the propylene glycol and the ethanol to prepare a pharmaceutical solution; (4) Mixing the gel matrix and the drug solution under ultrasound to prepare metronidazole gel.

8. The method for preparing a metronidazole gel according to claim 7, characterized in that: The ultrasonic power is 100-200W.

9. The method for preparing a metronidazole gel according to claim 7, characterized in that: The ultrasonic time is 50-150 min.

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