Preparation method of high-stability metronidazole suppository

Abstract

The invention provides a preparation method of a high-stability metronidazole suppository, and relates to the technical field of metronidazole suppository preparation. The high-stability metronidazole suppository is prepared from metronidazole, ginseng stem and leaf saponin, vitamin E, a polyethylene glycol composition, polyoxyethylene stearate, distilled water and vitamin C palmitate, and the high-stability metronidazole suppository is prepared by the following steps: dissolving the vitamin E, the polyethylene glycol composition, the polyoxyethylene stearate and the distilled water as matrixes; the metronidazole suppository is obtained by mixing metronidazole and ginseng stem and leaf saponin with vitamin C palmitate, then mixing the mixture with part of the matrix, dropwise adding the remaining matrix in a nitrogen atmosphere, and then performing stirring treatment by adopting carbon dioxide to obtain the final metronidazole suppository. The metronidazole suppository overcomes the defects in the prior art, the disintegration time of the metronidazole suppository in a human body can be effectively shortened, meanwhile, the stability of the metronidazole suppository is improved, and the safety of medicine storage is guaranteed.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of preparation of metronidazole suppositories, in particular to a preparation method of high-stability metronidazole suppositories. BACKGROUND

[0002] Metronidazole suppositories are an external antibacterial drug, mainly used for the treatment of vaginal infectious diseases, and the main active ingredient is metronidazole. In the development process of the prior art, panax notoginseng saponins are also added to enhance immune function, promote mucosal repair and reduce inflammatory response, and at the same time improve the local microcirculation of the vagina, thereby assisting to improve the overall treatment effect.

[0003] Due to the use characteristics of metronidazole suppositories, it is required to disintegrate within 5 minutes to 1 hour in the human body environment. In order to consider the comfort of drug use, the faster the disintegration speed is, the better. However, the faster the disintegration is, the poorer the stability of the metronidazole suppository is. The metronidazole suppository with faster disintegration has a risk of softening in a natural environment. Metronidazole suppositories are sensitive to high temperatures. If they are exposed to an environment above 30°C for a long time, they may soften, deform or even melt, affecting drug release and drug efficacy. The metronidazole suppository with faster disintegration is prone to loss of active ingredients when stored due to slight temperature rise. Therefore, how to improve the storage stability of metronidazole suppositories while ensuring the disintegration efficiency of metronidazole suppositories is an important research direction at the present stage. SUMMARY

[0004] In view of the deficiencies of the prior art, the present application provides a preparation method of high-stability metronidazole suppositories, which can effectively shorten the disintegration time of metronidazole suppositories in the human body and at the same time improve the stability thereof, thereby ensuring the safety of drug storage.

[0005] To achieve the above object, the present application is implemented by the following technical scheme: A preparation method of high-stability metronidazole suppositories, comprising the following steps: S1. Preparing materials according to the following weight parts: metronidazole 40-60 parts, panax notoginseng saponins 2-3 parts, vitamin E 3-5 parts, polyethylene glycol composition 120-180 parts, polyoxyethylene stearate 80-100 parts, distilled water 40-60 parts, and vitamin C palmitate 10-12 parts; S2. The polyethylene glycol composition mixed with distilled water is placed in a water bath and stirred to melt. After complete melting, vitamin E and polyoxyethylene stearate are added and continue to be stirred and dissolved to obtain a mixed base for standby; S3. The panax notoginseng saponins and metronidazole are mixed, ground and crushed, and then the vitamin C palmitate is added and stirred uniformly to obtain a main material for standby; S4. The main material is added to an equal amount of the mixed base, and after being stirred thoroughly, the remaining mixed base is added dropwise under a nitrogen atmosphere and stirred. After the dropwise addition is completed, a mixed material is obtained for standby. S5, after the mixed material is kept warm, carbon dioxide is pumped into the mixed material for mixing and stirring treatment, and then vacuum degassing is conducted, so that the prefabricated material is obtained for use; S6, the prefabricated material is injected into a plug mold coated with liquid paraffin in advance, and after being cooled at room temperature for 5-10 min, it is placed at a temperature of 2-5 DEG C for continuous solidification and then demolded, so that the metronidazole suppository is obtained.

[0006] Preferably, the polyethylene glycol composition is a mass mixture of polyethylene glycol 6000, polyethylene glycol 4000 and polyethylene glycol 400.

[0007] Preferably, the temperature of the stirring and melting in the water bath kettle in step S2 is 60-65 DEG C.

[0008] Preferably, the ginsenoside and metronidazole are mixed and ground through an 80-mesh sieve in step S3.

[0009] Preferably, the temperature of the mixed matrix is controlled at 60-65 DEG C in step S4, and the temperature of the mixed matrix during the dropping is controlled at 65-70 DEG C.

[0010] Preferably, the dropping speed is 2-5 mL / s in step S4, and the stirring speed is 120-200 r / min during the dropping.

[0011] Preferably, the pumping amount of carbon dioxide is 8-10 L / min in step S5, and the stirring time is 10-15 min.

[0012] Preferably, the vacuum degassing time is 20-30 min in step S5.

[0013] Preferably, the temperature of the plug mold before use is controlled at 35-40 DEG C in step S6.

[0014] The present application provides a preparation method of a high-stability metronidazole suppository. The present application uses a polyethylene glycol composition, polyoxyethylene stearate dissolved in distilled water as a drug matrix, and a part of the matrix is mixed with vitamin C palmitate, metronidazole and ginsenoside, and the remaining matrix is added dropwise in a nitrogen atmosphere, so as to promote the dispersion of the effective components, and then carbon dioxide is pumped in for vacuum degassing, so as to effectively improve the stability of the drug, prevent the oxidation of the drug, and enable the whole system to be quickly disintegrated in the human vaginal environment and have high stability during natural storage. DETAILED DESCRIPTION

[0015] In order to make the purposes, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be described clearly and completely below in conjunction with the embodiments of the present application. Obviously, the described embodiments are only some of the embodiments of the present application, rather than all the embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative work fall within the scope of protection of the present application.

[0016] The polyethylene glycol composition in the following embodiments is obtained by mixing polyethylene glycol 6000, polyethylene glycol 4000, polyethylene glycol 400, etc. in equal amounts.

[0017] Embodiment 1 Preparation of metronidazole suppositories (1) Prepare the following ingredients by weight: metronidazole 40 parts, ginsenoside 2 parts, vitamin E 3 parts, polyethylene glycol composition 120 parts, polyoxyethylene stearate 80 parts, distilled water 40 parts, and vitamin C palmitate 10 parts; (2) Put the polyethylene glycol composition mixed with distilled water in a 60°C water bath and stir to melt. After complete melting, add vitamin E and polyoxyethylene stearate and continue to stir to dissolve to obtain a mixed base for standby; (3) Mix metronidazole and ginsenoside and grind through an 80-mesh sieve. Then mix with vitamin C palmitate and stir evenly to obtain a main material for standby; (4) Add the main material to an equal amount of 60°C mixed base, stir thoroughly, and place in a nitrogen atmosphere. Warm the remaining mixed base to 65°C, and add dropwise at a rate of 2 mL / s while stirring at a speed of 120 r / min. After complete addition, obtain a mixed material for standby; (5) After keeping the mixed material at 60°C, pump it into carbon dioxide at a rate of 8 L / min for 10 min of mixing and stirring, and then vacuum degas for 20 min to obtain a pre-prepared material for standby; (6) Inject the pre-prepared material into a suppository mold coated with liquid paraffin in advance (the mold temperature is preheated to 35°C). After cooling at room temperature for 5 min, continue to solidify at a temperature of 2°C, and then demold to obtain metronidazole suppositories.

[0018] Embodiment 2 Preparation of metronidazole suppositories (1) Prepare the following ingredients by weight: metronidazole 60 parts, ginsenoside 3 parts, vitamin E 5 parts, polyethylene glycol composition 180 parts, polyoxyethylene stearate 100 parts, distilled water 60 parts, and vitamin C palmitate 12 parts; (2) Put the polyethylene glycol composition mixed with distilled water in a 65°C water bath and stir to melt. After complete melting, add vitamin E and polyoxyethylene stearate and continue to stir to dissolve to obtain a mixed base for standby; (3) Mix metronidazole and ginsenoside through 80 mesh sieve, then mix vitamin C palmitate and stir to be uniform, to obtain main material for standby; (4) Add the main material into equal quality of 65℃ mixed base, stir fully, then place in nitrogen atmosphere, heat the rest of the mixed base to 70℃, drop at a speed of 5mL / s and stir at a speed of 200r / min, after the drop is completed, obtain mixed material for standby; (5) After the mixed material is kept at 60℃, pump carbon dioxide into the mixed material at a rate of 10L / min, stir for 15min, then vacuum degas for 30min, to obtain preform for standby; (6) Inject the preform into a suppository mold coated with liquid paraffin in advance (mold temperature preheated at 40℃), then cool at room temperature for 10min, then continue to solidify at 5℃, then demold, to obtain metronidazole suppository.

[0019] Comparative Example 1: Preparation of metronidazole suppository: (1) Prepare the following weight parts: metronidazole 60 parts, ginsenoside 3 parts, vitamin E 5 parts, polyethylene glycol composition 180 parts, polyoxyethylene stearate 100 parts, distilled water 60 parts; (2) Place the polyethylene glycol composition mixed with distilled water in a 65℃ water bath and stir to melt, then add vitamin E and polyoxyethylene stearate to continue stirring and dissolve, to obtain mixed base for standby; (3) Mix metronidazole and ginsenoside through 80 mesh sieve, to obtain main material for standby; (4) Add the main material into equal quality of 65℃ mixed base, stir fully, then place in nitrogen atmosphere, heat the rest of the mixed base to 70℃, drop at a speed of 5mL / s and stir at a speed of 200r / min, after the drop is completed, obtain mixed material for standby; (5) After the mixed material is kept at 60℃, pump carbon dioxide into the mixed material at a rate of 10L / min, stir for 15min, then vacuum degas for 30min, to obtain preform for standby; (6) Inject the preform into a suppository mold coated with liquid paraffin in advance (mold temperature preheated at 40℃), then cool at room temperature for 10min, then continue to solidify at 5℃, then demold, to obtain metronidazole suppository.

[0020] Comparative Example 2: Preparation of metronidazole suppository: (1) Prepare the following weight parts: metronidazole 60 parts, ginsenoside 3 parts, vitamin E 5 parts, polyethylene glycol composition 180 parts, polyoxyethylene stearate 100 parts, distilled water 60 parts, vitamin C palmitate 12 parts; (2) The polyethylene glycol composition mixed distilled water is placed in a 65°C water bath and stirred to melt, and after complete melting, vitamin E and polyoxyethylene stearate are added and stirred to dissolve, to obtain a mixed base for standby; (3) Metronidazole and ginsenoside are mixed and ground through an 80-mesh sieve, and then mixed with vitamin C palmitate and stirred uniformly to obtain a main material for standby; (4) The main material is added to the 65°C mixed base, and after being stirred and dissolved, a mixed material is obtained for standby; (5) The mixed material is kept at 60°C, and then pumped into carbon dioxide at a rate of 10L / min for mixing and stirring for 15 min, and then vacuum degassed for 30 min, to obtain a preform for standby; (6) The preform is injected into a suppository mold coated with liquid paraffin in advance (the mold temperature is preheated to 40°C), and then cooled at room temperature for 10 min, and then placed at 5°C for further solidification, and then demolded, to obtain a metronidazole suppository.

[0021] Comparative Example 3: Preparation of a metronidazole suppository: (1) The following weight parts are prepared: metronidazole 60 parts, ginsenoside 3 parts, vitamin E 5 parts, polyethylene glycol composition 180 parts, polyoxyethylene stearate 100 parts, distilled water 60 parts, and vitamin C palmitate 12 parts; (2) The polyethylene glycol composition mixed distilled water is placed in a 65°C water bath and stirred to melt, and after complete melting, vitamin E and polyoxyethylene stearate are added and stirred to dissolve, to obtain a mixed base for standby; (3) Metronidazole and ginsenoside are mixed and ground through an 80-mesh sieve, and then mixed with vitamin C palmitate and stirred uniformly to obtain a main material for standby; (4) The main material is added to the 65°C mixed base, and after being stirred and dissolved, a mixed material is obtained for standby; (5) The mixed material is kept at 60°C, and then pumped into carbon dioxide at a rate of 10L / min for mixing and stirring for 15 min, and then vacuum degassed for 30 min, to obtain a preform for standby; (6) The preform is injected into a suppository mold coated with liquid paraffin in advance (the mold temperature is preheated to 40°C), and then cooled at room temperature for 10 min, and then placed at 5°C for further solidification, and then demolded, to obtain a metronidazole suppository.

[0022] Detection: 1. The disintegration efficiency of the metronidazole suppositories in each group under simulated human environment is as follows: The artificial vaginal fluid is configured as follows: 0.8% sodium chloride + 1.5% mucin + 0.02% calcium chloride, the rest being distilled water, and the pH is adjusted to 4.0 using lactic acid; A container simulating a vaginal environment is constructed using silica gel, the inner wall simulating the roughness of the vaginal mucosa, and is equipped with a temperature control system to maintain a constant temperature of 37°C. Artificial vaginal fluid is injected into the container to cover the bottom of the container, and then metronidazole suppositories in each group are placed at the bottom of the container. The disintegration is observed and recorded every 5 minutes, and the disintegration rate is calculated (the simulated vaginal fluid is filtered with filter paper, the undissolved residue is collected and dried in a 35°C oven to constant weight, weighed and the disintegration rate is calculated: disintegration rate = 1 - residue mass / initial drug mass). The disintegration rates at 5 min, 15 min and 45 min are recorded respectively (since there is a residue of artificial vaginal fluid, i.e. it is considered completely disintegrated when the disintegration rate is more than 99%), and the specific results are shown in Table 1 below: Table 1 As can be seen from the above table, the disintegration rates of Example 1, Example 2 and Comparative Example 1 are all high at 5 min, and they are basically completely disintegrated at 15 min.

[0023] 2. Drug stability test of each group of metronidazole suppositories: The content of metronidazole in each group of prepared metronidazole suppositories is set to 100%, and the relative content of metronidazole in the metronidazole suppositories after multiple melting and solidification tests is detected. The specific melting and solidification experiment is as follows: Each group of metronidazole suppositories is sealed and melted at 45°C water bath temperature for 1h, and then solidified at 2°C environment for 1h. This is one melting and solidification. The relative content of metronidazole after 20, 40 and 60 times of melting and solidification treatment is calculated respectively, and the specific results are shown in Table 2 below: Table 2 Due to the loss of other components in the melting and solidification experiment, the relative content of metronidazole detected is not completely decreasing, for example, in Example 1-2, after 20 times of melting and solidification, the loss of metronidazole is less than that of other components, and the relative content of metronidazole is slightly improved. In Comparative Example 1, due to the reduction of vitamin C palmitate, a higher loss of metronidazole occurs after 20 times of melting and solidification. Overall, the stability of the metronidazole suppositories of Example 1-2 is the highest.

[0024] The above examples are only used to illustrate the technical solutions of the present application, and are not intended to limit the present application; although the present application has been described in detail with reference to the foregoing examples, those skilled in the art should understand that the technical solutions recorded in the foregoing examples can be modified, or some technical features can be replaced by equivalent features; and these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present application.

Claims

1. A method for preparing a high-stability metronidazole suppository, characterized by, The preparation method comprises the following steps: S1, according to the following weight parts, prepare materials: metronidazole 40-60 parts, ginseng stem and leaf saponin 2-3 parts, vitamin E 3-5 parts, polyethylene glycol composition 120-180 parts, polyoxyethylene stearate 80-100 parts, distilled water 40-60 parts, vitamin C palmitate 10-12 parts; S2, the polyethylene glycol composition mixed distilled water is placed in a water bath for stirring and melting, and after complete melting, vitamin E, polyoxyethylene stearate is added for continuous stirring and dissolution, and a mixed matrix is obtained for standby; S3, the ginseng stem and leaf saponin and metronidazole are mixed, ground and crushed, and then mixed with vitamin C palmitate for uniform stirring, and a main material is obtained for standby; S4, the main material is added to an equal amount of mixed matrix, and after sufficient stirring, the remaining mixed matrix is added dropwise under a nitrogen atmosphere and stirred, and after complete dropwise addition, a mixed material is obtained for standby; S5, after the mixed material is kept warm, carbon dioxide is pumped into the mixed material for mixing and stirring treatment, and then vacuum degassing is performed, and a pre-prepared material is obtained for standby; S6, the pre-prepared material is injected into a plug mold coated with liquid paraffin in advance, and after room temperature cooling for 5-10 min, it is placed at a temperature of 2-5℃ for continuous solidification and then demolded, and a metronidazole suppository is obtained.

2. The method of claim 1, wherein: The polyethylene glycol composition is a mixture of polyethylene glycol 6000, polyethylene glycol 4000 and polyethylene glycol 400 in equal amounts.

3. The method of claim 1, wherein: In step S2, the temperature of the water bath for stirring and melting is 60-65℃.

4. The method of claim 1, wherein: In step S3, the ginseng stem and leaf saponin and metronidazole are mixed, ground and crushed through an 80-mesh sieve.

5. The method of claim 1, wherein: In step S4, the temperature of the mixed matrix is controlled at 60-65℃, and the temperature of the mixed matrix during dropwise addition is controlled at 65-70℃.

6. The method of claim 1, wherein: In step S4, the dropwise addition speed is 2-5 mL / s, and the stirring speed during dropwise addition is 120-200 r / min.

7. The method of claim 1, wherein: In step S5, the pump-in amount of carbon dioxide is 8-10 L / min, and the stirring time is 10-15 min.

8. The method of claim 1, wherein: In step S5, the vacuum degassing time is 20-30 min.

9. The method of claim 1, wherein: In step S6, the temperature of the plug mold before use is controlled at 35-40℃.

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