CN101406463B - Metronidazole, clotrimazole and chlorhexidime vaginal effervescent tablet and preparation method - Google Patents
Metronidazole, clotrimazole and chlorhexidime vaginal effervescent tablet and preparation method Download PDFInfo
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- CN101406463B CN101406463B CN2008100492829A CN200810049282A CN101406463B CN 101406463 B CN101406463 B CN 101406463B CN 2008100492829 A CN2008100492829 A CN 2008100492829A CN 200810049282 A CN200810049282 A CN 200810049282A CN 101406463 B CN101406463 B CN 101406463B
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- clotrimazole
- metronidazole
- effervescent tablet
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Abstract
The invention relates to a method for preparing a new gynecological anti-bacterial anti-inflammatory drug, namely dithiazole vaginal effervescent tablet and a method for quality control. The dithiazole vaginal effervescent tablet is used for treating gynecopathy, anorectal diseases and skin commonly-encountered diseases such as pelvic inflammatory disease, cervical erosion, vaginitis and the like caused by anaerobic bacteria, aerobic bacteria, trichomoniasis, pure or mixed fungal infections. The dithiazole vaginal effervescent tablet is characterized in that lactic acid and a calcium lactate buffer system are added to the formulation so that the PH value of the drug is between 3.5 and 4.0 similar to the vaginal physiological PH and is advantageous to remove pathogen and infusorian, provide living conditions suitable for vaginal beneficial bacterium group of lactic acid bacteria, and promote the illness rehabilitation. Besides, the dithiazole vaginal effervescent tablet uses pharmaceutical acceptable water-soluble polymer materials such as water-soluble polymer polyethylene glycol, polyvidone K30 and the like to enwrap acidic or alkaline components of an effervescent disintegrant so as to avoid the occurrence of hidden spots or even collapsing phenomenon on the surface of the tablet caused by gas production reaction resulted from small amount of water in the storage process, and uses a ethanol solution with adhesives and surface-active agents for granulation so that the hydrolysis of clotrimazole can be prevented, the infiltration of moisture is promoted in use, the uniform collapse is accelerated, and gas bubbles are homogeneous and stable.
Description
Technical field
The present invention relates to new drug metronidazole, clotrimazole and chlorhexidime acetate vaginal effervescent tablet method for making and the method for quality control of a kind of gynecological with anti-inflammation.
Background technology
At present, infusorian, anaerobe, mycete and other bacterial infection gynaecopathia serious threat WomanHealths.Although the Amino-Cerv kind is a lot of, use and treat all to have certain problem; In addition, number of patent application is that 94113652 patent has been described a kind of metronidazole, clotrimazole and chlorhexidime acetate vaginal effervescent tablet, existing at present listing; Exist storage moisture absorption aerogenesis to influence storage-stable, gas production is unstable during use, PH fluctuation big (4.0～6.0) after its disintegrate; Not only influence the vagina physiological PH value; It is inhomogeneous that also influence presses down the problem and the foam size of killing the pathogen effect, and drug dispersion is not enough, and the part medicine does not carry out the problem of assay.
The objective of the invention is to overcome the deficiency of existing kind, the novel vagina effervescence preparation of a kind of spectrum, efficient, quick-acting, stable, good patient compliance is provided and method of quality control is provided.
Summary of the invention
The present invention is a kind of medicine that is mainly used in gynecological infection; Vagina effervescence is than suppository, washing liquid, easy-to-use, direct, rapid, and after medicine contacted with focus is local, micro-physiological secretions made vagina effervescence moistening disintegrate; Fill the air distribution; Directly contact, immerse in its cell, give full play to the killing microorganisms effect with the focus pathogenic microorganism.The safe prescription element of two azoles has anaerobe resistant, anti-trichomonal, anti-ameba, antifungal, mycete; Effects such as anti-aerobe can be used for anaerobe, aerobe, infusorian, the gynecological that the simple or mixed infection of mycete causes; Anorectal, the skin commonly encountered diseases, like pelvic inflammatory disease, cervical erosion, vaginitis etc.Easy to use, clean, do not influence routine work study.
The invention has the advantages that tract local application, avoid or reduce the possible untoward reaction of systemic administration that the diseased region medicine effective concentration is high; Help bringing into play therapeutical effect, say from physiological angle, the suitable PH condition of microorganism is 4.0～9.0; Compared with prior art; The lactic acid that adds in these article prescription, calcium lactate buffer system make the PH of medicine close with vagina physiology PH 3.5～4.0 between, help the removing of pathogenic bacterium and infusorian; And provide vagina profitable strain lactobacillus suitable conditions of existence, promote rehabilitation.In addition, these article use pharmacy can accept water-soluble polymer Polyethylene Glycol, 30 POVIDONE K 30 BP/USP
30Acidic components or basic component Deng water-soluble high-molecular substance parcel gas-producing disintegrant; Latent speckle of tablet surface even the disintegration phenomenon of avoiding micro-moisture in the storage process to cause that air-generating reaction causes take place; The alcoholic solution of use adhesive and surfactant is granulated and can be prevented the hydrolysis of clotrimazole; And can impel the infiltration of moisture when using, quicken even disintegrate, the bubble stable homogeneous.
The present invention is achieved in that
(1) these article prescription is (1000 preparation units): metronidazole 100～600g, and clotrimazole 80～480g, chlorhexidine acetate 4～24g, gas-producing disintegrant, water-soluble high-molecular substance, PH buffer substance and pharmacy acceptable auxiliary 300g～3500g process.
The characteristic of these article is to contain the PH buffer substance in the adjuvant, and its contained cushion mass-energy makes the medicine of 1 preparation unit be dissolved in PH in the 100ml water between 3.5～4.0.Buffer substance can mainly be selected from but be not limited only to lactic acid/calcium lactate, citric acid/citrate, fumaric acid/fumarate, phosphoric acid/phosphate, acetic acid/acetate, tartaric acid/tartrate.
The characteristic of these article is that the gas-producing disintegrant consumption of 1000 preparation units should be able to produce 0.5～2 moles of gas; Its alkaline constituents is selected from but is not limited only to calcium carbonate, magnesium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and acid constituents is selected from but is not limited only to citric acid, tartaric acid, potassium hydrogen tartrate, fumaric acid, adipic acid, malic acid.The equivalent point consumption of acidic components amount ratio acid-base reaction many 1～10%.
The characteristic of these article is to use the acid or the alkaline constituents of water-soluble high-molecular substance parcel gas-producing disintegrant in the prescription; The consumption of water-soluble high-molecular substance is 30～120% of the composition weight that is wrapped, and mainly is selected from but is not limited only to polyvinylpyrrolidone, Macrogol 4000 and 6000, gelatin, Carmomer, polyvinyl alcohol, polyacrylate, sodium carboxymethyl cellulose.
Can add filler starch, lactose, sucrose, glucose, dextrin, mannitol, Nulomoline, calcium hydrogen phosphate according to circumstances in these article prescription; Fluidizer lubricant silicon dioxide, stearic acid and salt thereof, refining hydrogenated vegetable oil, liquid paraffin,light, Pulvis Talci, lauryl sulfate, short infiltration draw humectant such as tween 80, Arlacel-60, bromination cetyl potassium ammonium.
Metronidazole, clotrimazole and chlorhexidime acetate vaginal effervescent tablet optimization prescription is: metronidazole 200g, clotrimazole 160g, chlorhexidine acetate 8g, starch 50.0g, calcium lactate 60g, lactic acid 82g, fumaric acid 100g, sodium bicarbonate 120g, Macrogol 4000 60g, silicon dioxide 20.0g, 30 POVIDONE K 30 BP/USP
304g, tween 80 0.3g, magnesium stearate 4.0g process 1000
The method for preparing of these article is:
A is melt and dissolved with water-soluble high-molecular substance, adds the basic component parcel, and cooling was pulverized 80～100 mesh sieves in case of necessity, or polymer substance is processed solution, with the coating method parcel, volatilizes solvent and processes basic component.
B draws humectant with granulation binders and short infiltration and adds an amount of dissolve with ethanol and process solution, is used to prepare the particulate binding agent of acid constituents.
C adds mix homogeneously in the mixer with recipe quantity metronidazole, clotrimazole, chlorhexidine acetate, PH buffer substance, the acid constituents of gas-producing disintegrant, filler, puts in the wet granulator; Add binding agent (B) and process wet granular; 50～60 ℃ of oven dry, granulate, the acidic components granule.
D is with basic component granule, acidic components granule, silicon dioxide and recipe quantity magnesium stearate mix homogeneously.
E is with suitable punch die, through the tablet machine tabletting.
Similar acidic components among the above preparation technology and basic component can be exchanged under the situation of necessity, surfactant can before tabletting, add without prejudice to the improvement of essence of the present invention and improve and also belong to category of the present invention.
(2) quality standard of these article mainly comprises: 1. acidity is got these article an amount of (being equivalent to 1 preparation unit's medicine), and porphyrize adds water 100ml, and (two appendix VI of Chinese Pharmacopoeia version in 2005 H) measured in jolting in accordance with the law after 10 minutes, and pH value should be 3.5～4.0.
2. 10 in scale test tube (internal diameter 1.5cm) is measured in foaming, and each precision adds water 2ml, puts 37 ℃ ± 1 ℃ water-bath after 5 minutes; Drop into 1 preparation unit's medicine of these article respectively in each pipe; Observe the volume of maximum gas release in 20 minutes, on average should be less than 6ml, and be less than 3ml must not be above 2.
3. [assay] is according to HPLC (two appendix V of Chinese Pharmacopoeia version in 2005 D)
Chromatographic condition and system suitability test use octadecylsilane chemically bonded silica or amino bonded silica gel to be filler; (get potassium dihydrogen phosphate 4.35g with methanol-acetonitrile-phosphate solution; In the 1000ml measuring bottle; Thin up is to scale, with phosphoric acid regulating ph value to 2.8) (55: 10: 35) or methanol-phosphate buffer (get phosphoric acid 5ml, add 50% methanol solution and be diluted to 1000ml; Regulate pH value to 3.8 with triethylamine) (40: 60) or second eyeball: the 0.016mol/L potassium dihydrogen phosphate: dodecyl sodium sulfate (28: 31: 31, regulate pH value 8.0 with ammonia) is a mobile phase; The detection wavelength is 260nm.Number of theoretical plate calculates by the clotrimazole peak and is not less than 2000.
Algoscopy is got 10 preparation units of these article, and accurate the title decides, porphyrize, and precision takes by weighing in right amount (being equivalent to metronidazole 100mg approximately); Put in the 50ml measuring bottle, add methanol and make dissolving and be diluted to scale, shake up, filter; Precision is measured subsequent filtrate 5ml, puts in the 100ml measuring bottle, adds mobile phase and is diluted to scale; Shake up, get 20 μ l and inject chromatograph of liquid, the record chromatogram; It is an amount of that precision takes by weighing the chlorhexidine acetate reference substance in addition, adds methanol and process the solution that contains 80 μ g among every 1ml approximately; Precision takes by weighing metronidazole, clotrimazole in right amount in the 100ml measuring bottle again; Add chlorhexidine acetate reference substance solution 5ml and make dissolving with an amount of methanol; Add mobile phase and be diluted to scale; Shake up, every 1ml contains the solution that metronidazole, clotrimazole, chlorhexidine acetate are respectively 100 μ g, 80 μ g, 4 μ g, measure with method.Press external standard method with C in the calculated by peak area test sample
6H
9N
3O
3, C
22H
17CIN
2With C
22H
30C
12N
102C
2H
4O
2Content, three kinds of compositions indicate content all should be in 90.0～110.0% limits.
The specific embodiment
Embodiment: (1) metronidazole 200g, clotrimazole 160g, chlorhexidine acetate 8g, starch 50.0g, calcium lactate 60g, lactic acid 82g, fumaric acid 100g, sodium bicarbonate 120g, Macrogol 4000 60g, silicon dioxide 20.0g, 30 POVIDONE K 30 BP/USP
304g, tween 80 0.3g, magnesium stearate 4.0g process 1000
The method for preparing of these article is:
A is melt and dissolved with Macrogol 4000, adds the sodium bicarbonate parcel, and 80～100 mesh sieves were pulverized in cooling, processed basic component.
B is with 30 POVIDONE K 30 BP/USP
30Add an amount of dissolve with ethanol with tween 80 and process solution, be used to prepare the particulate binding agent of acid constituents.
C adds mix homogeneously in the mixer with recipe quantity metronidazole, clotrimazole, chlorhexidine acetate, starch, calcium lactate, lactic acid, fumaric acid, puts in the wet granulator; Add binding agent (B) and process wet granular; 50～60 ℃ of oven dry, granulate, the acidic components granule.
D is with basic component granule, acidic components granule, silicon dioxide and recipe quantity magnesium stearate mix homogeneously.
E is with suitable punch die, through the tablet machine tabletting.
Stability test
1, main test apparatus
High performance liquid chromatograph SPD-10ATVP island Tianjin LC-10ATVP
Tianjin, analytical balance AY120 island
Ultraviolet-uisible spectrophotometer FWZ800-D3B island Tianjin UV-2450
2, medicine
Supply test agent: metronidazole, clotrimazole and chlorhexidime acetate vaginal effervescent tablet self-control lot number is: 07,060 1,070,602 070603
Reference substance: metronidazole: Metronidazole, lot number: 100191-200305
Reference substance: clotrimazole: Clotrimazole, lot number: 100037-200306
Reference substance: chlorhexidine acetate: Chlorhexidine Acetate, lot number: 100183-199902
3, accelerated stability test method
With the two aluminum packings of metronidazole, clotrimazole and chlorhexidime acetate vaginal effervescent tablet (070,601 070,602 070603) (commercially available back on the plan); 40 ± 2 ℃ of temperature; The condition held of relative humidity 75% ± 5% (saturated aqueous common salt) 6 months; Respectively at 0 month, 1 the end of month, 2 the end of month, 3 the end of month, sampling in 6 months once, detect by stable high spot reviews project (character, related substance, content).
4, long-term stable experiment method
The two aluminum of metronidazole, clotrimazole and chlorhexidime acetate vaginal effervescent tablet (070,601 070,602 070603) are packed (plan commercially available back) 25 ± 2 ℃ of temperature, the condition held of relative humidity 60% ± 10%.Respectively at 0 month, 3 the end of month, 6 the end of month, detect by stable high spot reviews project (character, related substance, content).
5, stability test result
Metronidazole, clotrimazole and chlorhexidime acetate vaginal effervescent tablet accelerated test (relative humidity 75% ± 5%, 40 ℃ ± 2 ℃ of temperature) is test down, long term test (relative humidity 60% ± 10%; 25 ℃ ± 2 ℃ of temperature) observed 6 months continuously respectively; It detects projects such as character, related substance, content, and 0 month, June the foot couple microbial limit investigate, have no significant change; The regulation that meets quality standard; The metronidazole, clotrimazole and chlorhexidime acetate vaginal effervescent tablet steady quality, packaging material do not have influence to quality, expect that effect duration is 24 months.
6, influence factor's test
Stipulate according to Chinese Pharmacopoeia version appendix in 2005 XIXC " medicine stability test guideline "; Adopt a collection of sample (lot number: 070601) make an experiment of pilot product; Experimental condition is respectively 60 ℃ of high temperature, high humidity 90% (25 ℃), high light (4500Lx ± 500Lx); Measure respectively at sampling in 5,10 days, compare with 0 day mensuration result.
(1) hot test
These article of getting place culture dish in right amount, put in 60 ℃ of calorstats and place 10 days, respectively at the 5th, 10 day sampling and measuring, compare with 0 day mensuration result.
(2) high wet test
Sample thief is put in the culture dish in right amount, and accurate the title decided weight, is placed in the container of constant humidity again, and 25 ℃ of temperature, the condition held of relative humidity 90% in 5,10 days sampling and measuring, is compared with 0 day mensuration result.
(3) strong illumination
Get an amount of sample and spread out in culture dish, be placed on 4500 ± 500Lx illumination and place, and, compare with 0 day mensuration result in 5,10 days sampling and measuring.
Result: according to the pharmacopeia regulation; With metronidazole, clotrimazole and chlorhexidime acetate vaginal effervescent tablet exposed placement 10 days under high temperature, high humidity, strong illumination; And, content heavy to character, sheet at the 5th day, 10 days investigates, compare with 0 day result, except that sheet heavy with high humidity environment tablet moisture absorption down collapse diffusing the weightening finish; Related substance and content do not have significant change, meet the regulation of quality standard.Metronidazole, clotrimazole and chlorhexidime acetate vaginal effervescent tablet is steady quality under high temperature, high humidity, strong illumination.
Safety testing
1, metronidazole, clotrimazole and chlorhexidime acetate vaginal effervescent tablet mucomembranous pungency test
1.1 test objective:
After the observation metronidazole, clotrimazole and chlorhexidime acetate vaginal effervescent tablet is repeatedly inserted the rabbit vagina, to the IR situation that the rabbit vagina mucosa produces, untoward reaction such as the inflammation that mucosa possibly occur after the prompting clinical drug was used, tissue degeneratiaon.
1.2 test material
1.2.1 receive the reagent thing
The metronidazole, clotrimazole and chlorhexidime acetate vaginal effervescent tablet lot number: 070601, negative control article: except that not containing the medicine all the other same metronidazole, clotrimazole and chlorhexidime acetate vaginal effervescent tablets.
1.2.2 laboratory animal
Animal varieties: Japan large ear rabbit, the unit of providing: science and technology exchange centre in Henan Province's provides credit number: scxk2005-0002, the animal rank: regular grade, body weight, sex: 2.0～2.5kg, female, no pregnant.Number of animals: 12
Raising condition: regular grade Animal House, 1 in every cage, temperature: 20 ± 3 ℃; Humidity: 50%-70%; Light application time: 12 hours.Free diet.Laboratory observation 3 days, no abnormality seen.
1.3 test method
Animal is divided into 2 groups immediately, 6 every group, is respectively medication group and negative control group.With special instrument, slowly metronidazole, clotrimazole and chlorhexidime acetate vaginal effervescent tablet is inserted the rabbit vagina deep, negative control group is used the same procedure administration.Administration every day 1 time, successive administration 7 days.The last administration was put to death Half animals respectively in 24 hours, 48 hours, cut vagina open, and warm water washes away residue, observed administration place mucosa situation of change and also drew materials, put in 10% the formaldehyde fixing after, carry out histopathologic examination.
1.4 result of the test
During the administration, it is good that each organizes the rabbit overall health of patients, animal activity freely, hair luster, the feed and defecation normal, the no abnormal secretions in vaginal orifice place is not seen obvious abnormal response; Each is organized the perusal of rabbit vagina mucous membrane tissue and is not seen phenomenons such as hyperemia, redness, breakage and erosion, the result of histopathologic examination, and each routine vaginal mucosa organizational structure of medication group and negative control group is complete, does not see hemorrhage, inflammation and necrosis, and the result sees table 1.
Behind the table 1 metronidazole, clotrimazole and chlorhexidime acetate vaginal effervescent tablet topical rabbit vaginal mucosa is organized naked eyes and histological examination result
1.5 estimate and conclusion
Under this experimental condition, metronidazole, clotrimazole and chlorhexidime acetate vaginal effervescent tablet is to the effect of animal subject vaginal mucosa nonirritant.
2 metronidazole, clotrimazole and chlorhexidime acetate vaginal effervescent tablet skin allergy tests
2.1 test objective
After repeating contact and tried thing through animal skin, observe body immune system and be reflected at the performance on the skin.
2.2 test material
2.2.1 receive the reagent thing: metronidazole, clotrimazole and chlorhexidime acetate vaginal effervescent tablet lot number: 070601; Test medication:,, use preceding preparation with 0.9% sodium chloride injection furnishing pasty state (concentration about 40%) with the metronidazole, clotrimazole and chlorhexidime acetate vaginal effervescent tablet grind into fine powder; Reference substance: 0.9% sodium chloride injection, 06081625, Henan bamboo grove all living creatures pharmaceutical Co. Ltd provides.
2.2.2 laboratory animal
Animal varieties: healthy Hartley Cavia porcellus.The unit of providing: science and technology exchange centre in Henan Province's provides.Body weight, sex: 300～350g, male and female half and half.Number of animals: 40
Raising condition: regular grade Animal House, 5 in every cage, temperature: 20 ± 3 ℃; Humidity: 30%-70%; Light application time: 12 hours, free diet.Laboratory observation 5 days, no abnormality seen.
Positive sensitizer: 2,4-dinitro-chloro-benzene (DNCB), Tianjin recovery fine chemistry industry institute is produced lot number: 20030217.
Sensitization: be made into 1% solution for standby with 70% ethanol.
Excite: will go up liquid and be diluted to 0.1% subsequent use.
2.3 test method
2.3.1 test is divided into groups: Cavia porcellus is divided into three groups at random by the body weight sex, first group 20, tried the thing metronidazole, clotrimazole and chlorhexidime acetate vaginal effervescent tablet, second group 10, be blank (giving normal saline), the 3rd group 10, positive thing matched group (giving DNCB).
2.3.2 test key step:
2.3.2.1. tried preceding 24 hours of thing the guinea pig back diamond wool is removed about 4 * 6 square centimeters of the every side of QUMAO scope with shaver in giving.
2.3.2.2. sensitization contact: get metronidazole, clotrimazole and chlorhexidime acetate vaginal effervescent tablet pastel 0.2ml and be evenly coated in depilation district, animal left side.Cover with thin film, the external application gauze is then fixed with rubberized fabric adhere, continues 6 hours.The 7th day and the 14th day, in kind repeat once.The blank group is given normal saline 0.2ml; Positive controls is given 1% dinitro-chloro-benzene 0.2ml, and method is the same.
2.3.2.3 excite contact: in last give tried thing sensitization after 14 days; Metronidazole, clotrimazole and chlorhexidime acetate vaginal effervescent tablet pastel 0.2ml is applied to depilation district, guinea pig back right side; With 0.1% dinitro-chloro-benzene 0.2ml, medication is the same with normal saline 0.2ml, positive controls for the blank group.Remove after 6 hours and tried thing, observe at once, observed the skin allergy situation once more in 24,48,72 hours then, press table 1 scoring.
Table 1 skin allergy standards of grading
Reaction meansigma methods=(erythema forms total points+edema and forms total points)/total number of animals
2.4, the result judges and estimate:
According to the difference of test group and the reaction of matched group guinea pig skin, press table 1 and judge that metronidazole, clotrimazole and chlorhexidime acetate vaginal effervescent tablet is to skin allergy character.The result: after the sensitization 6 hours first, to observe after removing covering, normal saline matched group, medication treated animal skin do not have significant change, and positive controls has 7 had slight erythema, disappears gradually after 72 hours; After the sensitization, normal saline matched group, medication treated animal skin do not have significant change for the second time, and positive controls has 54 had slight edema of moderate erythema to occur; After the sensitization, normal saline matched group, medication treated animal skin do not have significant change for the third time, and positive controls has 73 edema of moderate erythema to occur.Excite the back different time to observe, normal saline matched group, medication treated animal skin do not have erythema and edema, no skin allergy; Positive group different time observed result is seen table 2
Table 2 metronidazole, clotrimazole and chlorhexidime acetate vaginal effervescent tablet skin anaphylactic test reaction evaluating
2.5 conclusion: after the administration, medication group, normal saline group all do not have erythema and edema to form to each treated animal as stated above, and the metronidazole, clotrimazole and chlorhexidime acetate vaginal effervescent tablet skin allergy is negative.
Claims (2)
1. metronidazole, clotrimazole and chlorhexidime acetate vaginal effervescent tablet is characterized in that these article prescription is: metronidazole 200g, clotrimazole 160g, chlorhexidine acetate 8g, starch 50.0g, calcium lactate 60g, lactic acid 82g, fumaric acid 100g, sodium bicarbonate 120g, Macrogol 4000 60g, silicon dioxide 20.0g, 30 POVIDONE K 30 BP/USP
304.0g, tween 80 0.3g, magnesium stearate 4.0g process 1000.
2. the method for preparing of the described metronidazole, clotrimazole and chlorhexidime acetate vaginal effervescent tablet of claim 1 the steps include:
A adds the sodium bicarbonate parcel with the Macrogol 4000 fusion, and 80～100 mesh sieves were pulverized in cooling, processed basic component;
B is with 30 POVIDONE K 30 BP/USP
30Add an amount of dissolve with ethanol with tween 80 and process solution, be used to prepare the particulate binding agent of acidic components;
C adds mix homogeneously in the mixer with recipe quantity metronidazole, clotrimazole, chlorhexidine acetate, starch, calcium lactate, lactic acid, fumaric acid, puts in the wet granulator; The binding agent that adding step B processes is processed wet granular; 50-60 ℃ of oven dry, granulate, the acidic components granule;
D is with basic component granule, acidic components granule, silicon dioxide and recipe quantity magnesium stearate mix homogeneously;
E is with suitable punch die, through the tablet machine tabletting.
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| CN102038679B (en) * | 2010-12-07 | 2012-05-23 | 沈文立 | Metronidazole, clotrimazole and chlorhexidine acetate vagina gel and preparation method thereof |
| CN102048708A (en) * | 2010-12-08 | 2011-05-11 | 赵磊 | Tinidazole vaginal effervescent tablet and preparation method thereof |
| RU2013150323A (en) * | 2011-05-02 | 2015-06-10 | Апталис Фарматек, Инк. | COMPOSITIONS IN THE FORM OF QUICK DISPLACEMENT TABLETS FOR VAGINAL INTRODUCTION |
| CN102379870B (en) * | 2011-08-23 | 2013-03-06 | 南京瑞尔医药有限公司 | Preparation method of metronidazole clotrimazole and chlorhexidine acetate vaginal effervescent tablet |
| CN102836139A (en) * | 2012-09-20 | 2012-12-26 | 山东方明药业集团股份有限公司 | Compound ketoconazole vaginal effervescent tablet and preparation method thereof |
| CN104257624A (en) * | 2014-09-10 | 2015-01-07 | 天津爱勒易医药材料有限公司 | Novel effervescent and disintegrative premix and preparation method thereof |
| CN104666273B (en) * | 2015-02-09 | 2017-12-05 | 尹克春 | A kind of metronidazole vagina effervescent tablet agent and its preparation technology |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1038557C (en) * | 1994-12-09 | 1998-06-03 | 赵存梅 | Diazoletan efferrescent tablets and preparing method thereof |
| CN1319394A (en) * | 2000-01-28 | 2001-10-31 | 王西民 | Easy effervescent, moistureproof antiseptic antiphlogistic tablet and preparation process thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1038557C (en) * | 1994-12-09 | 1998-06-03 | 赵存梅 | Diazoletan efferrescent tablets and preparing method thereof |
| CN1319394A (en) * | 2000-01-28 | 2001-10-31 | 王西民 | Easy effervescent, moistureproof antiseptic antiphlogistic tablet and preparation process thereof |
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