CN116650403A - Metronidazole gel and preparation method and application thereof - Google Patents
Metronidazole gel and preparation method and application thereof Download PDFInfo
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- CN116650403A CN116650403A CN202310616747.9A CN202310616747A CN116650403A CN 116650403 A CN116650403 A CN 116650403A CN 202310616747 A CN202310616747 A CN 202310616747A CN 116650403 A CN116650403 A CN 116650403A
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- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 title claims abstract description 103
- 229960000282 metronidazole Drugs 0.000 title claims abstract description 102
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 238000001879 gelation Methods 0.000 title description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims abstract description 60
- 239000004372 Polyvinyl alcohol Substances 0.000 claims abstract description 48
- 229920002451 polyvinyl alcohol Polymers 0.000 claims abstract description 48
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 38
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 27
- 229920002125 Sokalan® Polymers 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 17
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229960001631 carbomer Drugs 0.000 claims abstract description 15
- 229920002472 Starch Polymers 0.000 claims abstract description 9
- 235000019698 starch Nutrition 0.000 claims abstract description 9
- 239000008107 starch Substances 0.000 claims abstract description 9
- 208000004926 Bacterial Vaginosis Diseases 0.000 claims abstract description 7
- 238000002604 ultrasonography Methods 0.000 claims abstract description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 238000011282 treatment Methods 0.000 claims description 12
- 239000011159 matrix material Substances 0.000 claims description 11
- 239000007788 liquid Substances 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 5
- 238000010257 thawing Methods 0.000 abstract description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 12
- 229940079593 drug Drugs 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 231100000252 nontoxic Toxicity 0.000 abstract description 2
- 230000003000 nontoxic effect Effects 0.000 abstract description 2
- 231100000344 non-irritating Toxicity 0.000 abstract 1
- 239000000499 gel Substances 0.000 description 78
- 230000000052 comparative effect Effects 0.000 description 35
- 235000013772 propylene glycol Nutrition 0.000 description 15
- 235000019441 ethanol Nutrition 0.000 description 13
- 238000012360 testing method Methods 0.000 description 12
- 230000008014 freezing Effects 0.000 description 8
- 238000007710 freezing Methods 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 210000001215 vagina Anatomy 0.000 description 7
- 235000011187 glycerol Nutrition 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 5
- 238000009210 therapy by ultrasound Methods 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- 238000013329 compounding Methods 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical compound CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 description 3
- 229940082484 carbomer-934 Drugs 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 206010003693 Atrophic vulvovaginitis Diseases 0.000 description 2
- 208000003322 Coinfection Diseases 0.000 description 2
- 208000008350 Pruritus Vulvae Diseases 0.000 description 2
- 206010056530 Vulvovaginal pruritus Diseases 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 238000011056 performance test Methods 0.000 description 2
- 201000010808 postmenopausal atrophic vaginitis Diseases 0.000 description 2
- 238000011895 specific detection Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- JVTIXNMXDLQEJE-UHFFFAOYSA-N 2-decanoyloxypropyl decanoate 2-octanoyloxypropyl octanoate Chemical compound C(CCCCCCC)(=O)OCC(C)OC(CCCCCCC)=O.C(=O)(CCCCCCCCC)OCC(C)OC(=O)CCCCCCCCC JVTIXNMXDLQEJE-UHFFFAOYSA-N 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 208000036649 Dysbacteriosis Diseases 0.000 description 1
- 208000027244 Dysbiosis Diseases 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 241000289690 Xenarthra Species 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940049638 carbomer homopolymer type c Drugs 0.000 description 1
- 229940043234 carbomer-940 Drugs 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000007140 dysbiosis Effects 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 1
- 229940043351 ethyl-p-hydroxybenzoate Drugs 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 230000008717 functional decline Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000002522 swelling effect Effects 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The application relates to the technical field of medicines, and particularly discloses a metronidazole gel, a preparation method and application thereof. The metronidazole gel 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. The raw materials are added with water according to the corresponding proportion and then treated by utilizing ultrasound, wherein the ultrasonic power is 150-200W, the ultrasonic time is 50-150min, the obtained metronidazole gel has higher freeze-thawing tolerance, and after 2 times of freeze-thawing tolerance, the viscosity value of the obtained metronidazole gel is more than 18800 mPa.s, and the obtained metronidazole gel is safe, nontoxic, non-irritating and can be used in medicines for treating bacterial vaginitis, and has better effect.
Description
Technical Field
The application relates to the technical field of medicines, in particular to metronidazole gel, a preparation method and application thereof.
Background
Bacterial vaginitis is mixed infection caused by dysbacteriosis in vagina, and causes the symptoms of increased vaginal endocrine, white fishy smell, and common pruritus vulvae and burning.
In order to alleviate the discomfort associated with bacterial vaginitis, there are generally several methods: (1) The vagina is cleaned by water, so that symptoms such as pruritus vulvae and burning can be temporarily relieved, but partial bacteria also exist in the water, and the risk of secondary infection exists. (2) The metronidazole gel is clinically used for treating bacterial vaginitis. Metronidazole can inhibit the proliferation of various anaerobic bacteria, thereby reducing the number of bacteria in vagina and balancing the flora in vagina. However, when the metronidazole gel is at a lower temperature (-18 ℃ below zero) during transportation or storage and is recovered to room temperature (above 20 ℃) for use, the adhesiveness is often poor, even the metronidazole gel is water-sample, and the metronidazole gel is easy to flow out, so that the quality and the use of the metronidazole gel are seriously affected.
Therefore, a metronidazole gel with better freeze-thawing tolerance is needed, so that the quality and the use of the metronidazole gel are ensured.
Disclosure of Invention
In order to improve the freeze-thawing tolerance of the metronidazole gel, the application provides the metronidazole gel and a preparation method and application thereof.
In a first aspect, the 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.
According to the application, the metronidazole, carbomer, polyvinyl alcohol, propylene glycol, ethanol, glycerol and starch are mixed according to the corresponding parts by weight, and water is added to prepare the metronidazole gel. The viscosity value of the obtained metronidazole gel is more than 18800 mPas after 2 freeze thawing experiments (the experimental conditions are that the metronidazole gel is frozen at the temperature of minus 20 ℃ and thawed at the temperature of 25 ℃ after 20 hours), and the requirement of the viscosity value of the metronidazole gel of the application is met. The metronidazole gel obtained by the application has higher freeze-thawing tolerance, and the viscosity and the use of the metronidazole gel are not affected.
The effect of the metronidazole in the application is to inhibit the reproduction of bacteria, and effectively reduce the number of gram-negative anaerobic bacilli in vagina. The amount of metronidazole may be 7-45 parts, 7-30 parts, 7-20 parts, 7-15 parts or 10-20 parts. Illustratively, the metronidazole may be used in an amount of 7 parts, 10 parts, 15.5 parts, 20 parts, 23.4 parts, 30 parts, 35 parts, 40 parts or 45 parts.
Carbomer has higher swelling property, expands after absorbing water, and can adjust the viscosity of metronidazole gel, so that the metronidazole is better adhered to the inner wall of vagina, and plays a role in inhibiting bacteria in the vagina. Carbomers of the present application may be selected from carbomer 934, carbomer 934P, carbomer 940 or carbomer 941.
Carbomers may be used in amounts of 8-50 parts, 8-40 parts, 8-30 parts, 8-20 parts, 15-25 parts, or 30-40 parts. Illustratively, carbomers may be used in amounts of 8 parts, 10 parts, 15.2 parts, 18.5 parts, 25 parts, 30 parts, 35 parts, 40 parts
Or 50 parts.
In one embodiment, the polyvinyl alcohol is 5-10 parts by weight, the propylene glycol is 180-260 parts by weight, and the ethanol is 15-20 parts by weight.
According to the application, through mutual coordination of polyvinyl alcohol, propylene glycol and ethanol and compounding according to the weight part ratio of (5-10 parts)/(180-260 parts)/(15-20 parts), carbomer after water absorption swelling can be protected, the strength and stability of the carbomer are improved, and after 2 freeze thawing experiments, the viscosity value of the metronidazole gel is above 19000 mPa.s.
In one embodiment, the polyvinyl alcohol is 10 parts by weight, the propylene glycol is 240 parts, and the ethanol is 15 parts.
In one embodiment, the polyvinyl alcohol has a viscosity of 5 to 40mPas.
In the application, the polyvinyl alcohol can play a role only when being compounded with the propylene glycol and the ethanol, and the polyvinyl alcohol with different viscosities influences the compounding effect, so that the freeze-thawing stability of the metronidazole gel is influenced.
When other raw materials and conditions are unchanged, the viscosity of the polyvinyl alcohol is in the range of 5-40mPas, the viscosity of the polyvinyl alcohol is gradually increased, the viscosity value of the obtained metronidazole gel is firstly increased and then decreased after a freeze thawing experiment, and when the viscosity of the polyvinyl alcohol is 25mPas, the viscosity value of the obtained metronidazole gel is higher, that is, the freeze thawing stability of the metronidazole gel is better.
In one embodiment, the polyvinyl alcohol has a viscosity of 10 to 30mPas.
Further, the viscosity of the polyvinyl alcohol is 25-30mPas.
Further preferably, the viscosity of the polyvinyl alcohol is 25mPas.
In one embodiment, the polyvinyl alcohol is selected from the group consisting of pharmaceutical grade polyvinyl alcohol EG-25 and pharmaceutical grade polyvinyl alcohol EG-30.
The polyvinyl alcohol can be obtained by the market, and can be selected from pharmaceutical grade polyvinyl alcohol EG-05, and the viscosity of the polyvinyl alcohol is 5mPas; or pharmaceutical grade polyvinyl alcohol EG-25 with viscosity of 25mPas; or pharmaceutical grade polyvinyl alcohol EG-30 with viscosity of 30mPas; or the viscosity of the medical grade polyvinyl alcohol EG-40 is 40mPas.
In the application, the metronidazole gel also comprises 0.5-1.2 parts of edetate sodium and 0.6-1.5 parts of sodium hydroxide.
In a second aspect, the application provides a method for preparing metronidazole gel, comprising the following steps:
(1) Preparing a solution: preparing a carbomer solution;
(2) Preparing a gel matrix: adding sodium hydroxide into the carbomer solution to prepare a gel matrix;
(3) Preparing a liquid medicine: mixing the metronidazole, the polyvinyl alcohol, the starch, the glycerol, the propylene glycol and the ethanol to prepare a liquid medicine;
(4) And mixing the gel matrix and the liquid medicine under ultrasonic to obtain the metronidazole gel.
By adopting the technical scheme, after the ultrasonic treatment is performed, the compactness of the metronidazole gel can be improved, so that the metronidazole gel is more stable. Meanwhile, the ultrasonic wave can promote the compounding effect of the polyvinyl alcohol, the propylene glycol and the ethanol, so that the freeze-thawing tolerance of the metronidazole gel is further improved and more stable.
In one embodiment, the ultrasonic power is 100-200W.
Preferably, the ultrasonic power is 150-200W.
Further preferably, the ultrasonic power is 150W.
In the ultrasonic treatment of the application, the ultrasonic power and the ultrasonic time are two key conditions affecting the freezing and thawing tolerance of the metronidazole gel. The ultrasonic power is in the range of 100-200W, and the obtained metronidazole gel has better freeze-thawing tolerance; when the ultrasonic power is less than 100W, the freezing and thawing tolerance of the metronidazole gel cannot be effectively improved; when the ultrasonic power is more than 200W, the power is too high, and the crosslinking action of the polyvinyl alcohol, the propylene glycol and the ethanol is destroyed, so that the viscosity value of the obtained metronidazole gel is reduced.
In one embodiment, the sonication time is from 50 to 150 minutes.
Preferably, the ultrasonic time is 80-100min.
Further preferably, the ultrasound time is 90min.
In a third aspect, the application provides the use of a metronidazole gel in a medicament for the treatment of bacterial vaginitis, in particular in an senile vaginitis indication.
Senile vaginitis is commonly found in postmenopausal senile women, and is caused by ovarian function decline, estrogen level reduction, vaginal wall atrophy, mucous membrane thinning and high incidence rate, and more than 30% of people are counted to suffer from the disease. The metronidazole gel prepared by the application has higher freeze-thawing tolerance, no toxicity, no irritation and higher safety, and can be used in medicines for treating bacterial vaginitis.
In summary, the application has the following beneficial effects:
1. the application adopts the combination of the metronidazole, carbomer, polyvinyl alcohol, propylene glycol, ethanol, glycerin and starch, the prepared metronidazole gel has higher freeze thawing tolerance and higher safety, and after 2 times of freeze thawing experiments, the viscosity value is more than 18800 mPa.s, and the requirements of the viscosity value of 17000-21000 mPa.s are still met;
2. in the application, polyvinyl alcohol, propylene glycol and ethanol are preferably adopted for compounding, and the viscosity value of the obtained metronidazole gel after 2 freeze thawing experiments is more than 19000 mPa.s according to the weight part ratio of (5-10 parts)/(180-260 parts)/(15-20 parts);
3. according to the preparation method, the metronidazole gel is treated by ultrasound, wherein the ultrasonic power is 100-200W, the ultrasonic time is 50-150min, the stability of the metronidazole gel is further improved, and the difference between the viscosity values before and after 2 times of freeze thawing experiments is smaller.
Detailed Description
The present application will be described in further detail with reference to examples.
Raw and auxiliary materials
The sources of the raw materials and the auxiliary materials are shown in the table 1, and the raw materials and the auxiliary materials can be obtained through the market unless specified otherwise.
TABLE 1 sources of raw and auxiliary materials
| Names of raw and auxiliary materials | Source/specification |
| Metronidazole | CAS number: 443-48-1 |
| Propylene glycol | CAS number: 26264-14-2 |
| Glycerol | CAS number: 56-81-5 |
| Starch | CAS number: 9005-25-8 |
Examples
Example 1
The preparation of the metronidazole gel comprises the following steps:
(1) Preparing a solution: 200g of purified water and 1.2g of disodium edentate are added into a stirring tank, the stirring rotation speed is adjusted to 40Hz, then 30g of carbomer 934 is added, finally 210g of purified water is added, and after stirring for 40min, carbomer solution is prepared;
(2) Preparing a gel matrix: sucking carbomer solution in a vacuum container, adding 0.6g sodium hydroxide under stirring at 28r/min, and stirring for 120min to obtain gel matrix;
(3) Preparing a liquid medicine: 113.1g of purified water is added into a stirring container, the temperature is increased to 50 ℃, and then 20g of metronidazole, 10g of polyvinyl alcohol, 10g of starch, 7g of glycerol, 180g of propylene glycol and 15g of ethanol are added for mixing to prepare liquid medicine;
wherein the polyvinyl alcohol is medical grade polyvinyl alcohol EG-25, and the viscosity is 25mPas;
(4) And stirring and mixing the gel matrix and the liquid medicine to obtain the metronidazole gel.
Examples 2 to 10, comparative examples 1 to 6
Examples 2 to 10, comparative examples 1 to 6 are different from example 1 as shown in Table 2.
TABLE 2 parameters for the differences between examples 2-10, comparative examples 1-6 and example 1
* The polyvinyl alcohol described in example 8 is pharmaceutical grade polyvinyl alcohol EG-05; the polyvinyl alcohol described in example 9 is pharmaceutical grade polyvinyl alcohol EG-30; the polyvinyl alcohol described in example 10 is pharmaceutical grade polyvinyl alcohol EG-40.
Comparative example 7
Comparative example 7 differs from example 1 in that no starch was added in comparative example 7.
Comparative example 8
Comparative example 8 is an existing metronidazole gel comprising metronidazole 20g, carbomer 934 30g, propylene glycol 200g, disodium edetate 0.5g, polysorbate 80 2g, sodium hydroxide 0.67g, ethyl p-hydroxybenzoate 1g, purified water to 1000g.
Performance test
The above metronidazole gels prepared in examples 1 to 10 and comparative examples 1 to 8 were subjected to a freeze-thawing tolerance test to detect the viscosity values of the metronidazole gels before and after the freeze-thawing treatment.
The viscosity of the metronidazole gel is 17000-21000 mPas, and when the viscosity of the metronidazole gel is lower than 17000 mPas, the metronidazole gel cannot be effectively adhered in the actual use process; when the viscosity of the metronidazole gel is higher than 21000 mPas, the release speed of the active ingredients is slow and the dispersibility is poor in the actual use process.
Method of freeze-thaw tolerance test: 200g of the metronidazole gels prepared in examples 1 to 10 and comparative examples 1 to 8 were placed in a conical flask, covered and frozen in a refrigerator at-20℃for 20 hours, and then taken out, and thawed in a water bath at 25℃for 2 hours, which is a freeze-thawing treatment. Under the same conditions, the freezing and thawing treatment is carried out for 2 times, and specific detection results are shown in table 3.
TABLE 3 detection results (unit: mPas) for examples 1 to 10 and comparative examples 1 to 8
| Group of | Before freeze thawing tolerance test | After the freeze-thawing 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 |
As can be seen from the combination of examples 1 to 10 and comparative examples 1 to 8 and Table 3, the metronidazole gels prepared in examples 1 to 10 and comparative examples 1 to 8 are all above 20100 mPas, and meet the requirements of the application, and after 2 freeze thawing resistance tests, the metronidazole gels prepared in examples 1 to 10 of the application are above 18800 mPas, and still meet the requirements of the application, and the adhesiveness of the metronidazole gels is basically not affected.
When propylene glycol, polyvinyl alcohol and ethanol were used in the weight ratio of (120-260 parts)/(5-15 parts)/(10-20 parts) as shown in Table 3 in combination with examples 1-7 and comparative examples 1-6, the viscosity number of the obtained metronidazole gel was 19000 mPas or more after 2 freeze-thaw durability tests.
Examples 11 to 15, comparative examples 9 to 12
Example 11
Example 11 is different from example 1 in that in step (4) of example 11, the gel matrix and the drug solution are mixed by ultrasonic waves to prepare a metronidazole gel;
wherein the ultrasonic power in the ultrasonic process is 150W, and the ultrasonic time is 90min.
Examples 12 to 15, comparative examples 9 to 11 are different from example 11 as shown in Table 4.
TABLE 4 parameters for the differences between examples 11-15, comparative examples 9-11 and example 1
| Group of | Ultrasonic power/W | Ultrasonic time/min |
| Example 11 | 150 | 90 |
| Example 12 | 100 | 90 |
| Example 13 | 200 | 90 |
| Example 14 | 150 | 50 |
| Example 15 | 150 | 150 |
| Comparative example 9 | 80 | 90 |
| Comparative example 10 | 250 | 90 |
| Comparative example 11 | 150 | 180 |
Comparative example 12
Comparative example 12 is different from comparative example 8 in that the treatment with ultrasound was performed in comparative example 12, the ultrasonic power in the ultrasonic treatment was 150W, and the ultrasonic time was 90min.
Performance test
The above metronidazole gels prepared in examples 11 to 15 and comparative examples 9 to 12 were subjected to a freeze-thaw resistance test, and specific detection results are shown in table 5.
TABLE 5 detection results (unit: mPas) for examples 11 to 14 and comparative examples 9 to 12
* In table 5 "-" indicates that no detection was performed.
As can be seen from the combination of example 1 and example 11 and the combination of table 5, the freezing and thawing resistance of the metronidazole gel prepared in example 1 can be further improved by mixing the gel matrix and the liquid medicine by ultrasonic treatment, and the difference between the viscosity value of the obtained metronidazole gel after 2 times of freezing and thawing resistance tests and the difference between the viscosity value of the obtained metronidazole gel and the viscosity value of the obtained metronidazole gel before freezing and thawing resistance tests is 400mpa·s.
As can be seen from the combination of examples 11 to 15 and comparative examples 9 to 10 and the combination of Table 5, when the ultrasonic power in the ultrasonic treatment was 100 to 200W and the ultrasonic time was 50 to 150 minutes, the difference between the viscosity values before and after the test of the obtained metronidazole gel was 600 mPas or less.
Freeze-thaw resistance assay
The metronidazole gels prepared in example 1 and example 11 were subjected to a limit freeze-thaw resistance test. And (3) freezing the prepared metronidazole gel in a refrigerator at the temperature of minus 20 ℃, taking out after 20 hours, and thawing in a water bath at the temperature of 25 ℃ for 2 hours, wherein the freezing and thawing treatment is performed. Under the same condition, the times of freeze thawing treatment are respectively 2 times, 5 times, 8 times and 10 times, then the viscosity value is detected, and the experimental detection results are shown in table 6.
TABLE 6 experimental test results (unit: mPa. S)
| Number of freeze thawing treatments/times | Viscosity number of example 1 | Example 11 adhesionMetric value |
| 2 | 19800 | 19900 |
| 5 | 18500 | 18800 |
| 8 | 16900 | 17700 |
| 10 | - | 17200 |
As can be seen from a combination of examples 1 and 11 and table 6, the metronidazole gel prepared in example 11 has a high freeze-thawing resistance, and after 10 freeze-thawing treatments, the viscosity number of the obtained metronidazole gel is 17200mpa·s; in example 1, the viscosity number of the obtained metronidazole gel after 5 freeze thawing treatments was 18500 mPas, and the viscosity number of the obtained metronidazole gel after 8 freeze thawing treatments was 16900 mPas, which is lower than the requirement of the viscosity number of the application (the viscosity number is within 17000-21000 mPas).
Security detection
Safety of the Metronidazole gels prepared in examples 1-7 were tested using porcine hip endothelial cells. 10mg of each of the metronidazole gels obtained in examples 1 to 7 was added to a DMEM medium containing 10% fetal bovine serum, 100U/mL penicillin and 100U/mL streptomycin, respectively, to prepare 7 sets of culture solutions.
100. Mu.L of cells were seeded at a density of 5X 10 in 96-well plates 3 mL of cell suspension, the plates were placed at 37℃with 5% CO 2 Pre-culturing in an incubator for 24 hours; the new DMEM medium is then replaced.
The experiments were divided into experimental and control groups:
wherein the experimental components are 7 groups, 30 mu L of the obtained culture solution is added in the culture process respectively, and the incubation is continued in an incubator for 1 day. Finally, serum-free DMEM medium containing 10% CKK-8 was added to each well, and after further incubation for 1 hour, absorbance at 450nm was measured using a microplate reader,
wherein DMEM medium was used as a control group.
Experimental results: the OD values of the cells of the experimental groups 1-7 and the control group are both greater than 0.8, which indicates that the cell survival rate is high, and the metronidazole gels prepared in the examples 1-7 are nontoxic.
It is to be understood that the above embodiments are merely illustrative of the application of the principles of the present application, but not in limitation thereof. Various modifications and improvements may be made by those skilled in the art without departing from the spirit and substance of the application, and are also considered to be within the scope of the application.
Claims (10)
1. The metronidazole gel is characterized by comprising, 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.
2. The metronidazole gel as claimed in claim 1, wherein said polyvinyl alcohol is 5-10 parts by weight, said propylene glycol is 180-260 parts by weight, and said ethanol is 15-20 parts by weight.
3. The metronidazole gel as claimed in claim 2, wherein said polyvinyl alcohol is 10 parts by weight, said propylene glycol is 240 parts by weight and said ethanol is 15 parts by weight.
4. A metronidazole gel as claimed in any one of claims 1 to 3, characterized in that the polyvinyl alcohol has a viscosity of 10 to 30mPas.
5. The metronidazole gel as claimed in claim 4, characterized in that the polyvinyl alcohol has a viscosity of 25 to 30mPas.
6. The metronidazole gel as claimed in claim 5, wherein said polyvinyl alcohol is selected from the group consisting of pharmaceutical grade polyvinyl alcohol EG-25 and pharmaceutical grade polyvinyl alcohol EG-30.
7. A process for the preparation of a metronidazole gel as claimed in any one of claims 1 to 6, comprising the steps of:
(1) Preparing a solution: preparing a carbomer solution;
(2) Preparing a gel matrix: adding sodium hydroxide into the carbomer solution to prepare a gel matrix;
(3) Preparing a liquid medicine: mixing the metronidazole, the polyvinyl alcohol, the starch, the glycerol, the propylene glycol and the ethanol to prepare a liquid medicine;
(4) And mixing the gel matrix and the liquid medicine under ultrasonic to obtain the metronidazole gel.
8. The method for preparing metronidazole gel as claimed in claim 7, characterized in that said ultrasonic power is 100-200W;
preferably, the ultrasonic power is 150-200W.
9. The method for preparing metronidazole gel as claimed in claim 7, characterized in that said ultrasound time is 50-150min;
preferably, the ultrasonic time is 80-100min.
10. Use of a metronidazole gel as claimed in any one of claims 1 to 6 in a medicament for the treatment of bacterial vaginitis.
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