CN101890003B - Method for preparing novel chlorhexidine acetate cream - Google Patents
Method for preparing novel chlorhexidine acetate cream Download PDFInfo
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- CN101890003B CN101890003B CN2009102126889A CN200910212688A CN101890003B CN 101890003 B CN101890003 B CN 101890003B CN 2009102126889 A CN2009102126889 A CN 2009102126889A CN 200910212688 A CN200910212688 A CN 200910212688A CN 101890003 B CN101890003 B CN 101890003B
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Abstract
The invention provides a method for preparing chlorhexidine acetate cream. The novel chlorhexidine acetate cream is prepared by adopting the micronization treatment technique, the content uniformity and the limit of impurities are better controlled, and the chlorhexidine acetate preparation having the advantages of high efficiency, quick effect and high stability and safety is provided by the method of the invention.
Description
Technical field
The present invention relates to a kind of preparation method of chlorhexidine acetate cream, belong to field of pharmaceutical preparations.
Background technology
The health that infusorian, anaerobe mycete and other bacillary common gynecological disease have endangered numerous women.Two azoles Thailand has the effects such as anaerobe resistant, anti-trichomonal, anti-ameba, antifungal, anti-aerobe, and the curative effect that is used for the treatment of bacteria mixed infection vaginitis, colpitis mycotica and trichomonal vaginitis has obtained fully certainly clinically.
The safe preparation of the two azoles that gone on the market has suppository, water-soluble ointment agent and vagina effervescence.Suppository easily runs off after meeting the body temperature melting, affects the treatment, and pollution clothes, the patient has sense of discomfort, and the drug delivery position is shallow, does not reach position and lessens the curative effect and substrate can not dissolved substance and affect the absorption of solid drugs.The safe water-soluble ointment of two azoles, owing to there being the shortcomings such as drug deposition, gathering, dispersion be inhomogeneous, and metronidazole facile hydrolysis in water, cause its poor stability, and affect its clinical use.Metronidazole effervescence patch is the poor defect of existence and stability also, and standing time, length can cause its gas release to descend gradually, and effervescent tablet need to absorb moisture content and can cause local desiccation, solid particle is difficult to be absorbed, and foreign body sensation is arranged, and drug level is inhomogeneous, bioavailability is not high, thereby affects its curative effect.
In ointment, because the drop dispersion is large, the performance of drug absorption and drug effect is fast, and bioavailability is high.In addition, ointment can guarantee that again dosage is accurate, and easy to use.The present invention relates to the preparation method of chlorhexidine acetate cream, adopt metronidazole and the clotrimazole crude drug of micronization processes, overcome the deficiency of existing kind, provide a kind of efficient, quick-acting, good stability, bioavailability is high, compliance is good two azoles Thailand preparation.Said preparation has been controlled the limit of the uniformity and impurity well, has guaranteed the quality of medicine.
Summary of the invention
The active constituents of medicine of two azoles Thailand is metronidazole, clotrimazole and chlorhexidine acetate.Metronidazole is nitro glyoxaline compound, except being used for anti-trichomonal and anti-ameba, also is widely used in recent years anti anaerobic bacteria infection.Metronidazole is white or little yellow crystal or crystalline powder, and is slightly molten in ethanol, and slightly soluble in water or chloroform is atomic molten in ether.Clotrimazole is the broad-spectrum antifungal medicine, and is water-soluble hardly, is soluble in methanol or chloroform, is dissolved in ethanol or acetone.Chlorhexidine acetate all has killing action to gram positive bacteria, gram negative bacteria and fungus, and slightly soluble in water, dissolve in ethanol.
Consumption is little in this product due to chlorhexidine acetate, and in water slightly soluble, in it can being soluble in the aqueous phase when preparing chlorhexidine acetate cream.Yet metronidazole and clotrimazole are insoluble in water, and metronidazole easily decomposes in water.Evidence, it is also poor that metronidazole and clotrimazole prepare in the oil phase of ointment dissolubility in routine.Use the preparation method of conventional ointment to prepare the safe emulsifiable paste of two azoles, the uniformity of its medicine and granularity be more difficult reaches requirement.
The object of the present invention is to provide the preparation method of chlorhexidine acetate cream.The present invention adopts joining in oil phase after metronidazole and clotrimazole crude drug micronization, and it is uniformly dispersed, facile hydrolysis not, and good stability, do not degrade, do not deposit, do not assemble, both kept curative effect, guaranteed again the stable of its quality.
The prescription of ointment of the present invention contains: metronidazole 200mg, clotrimazole 160mg, chlorhexidine acetate 8mg, emulsifiable paste matrix are appropriate.
Wherein emulsifiable paste matrix is receivable emulsion bases pharmaceutically, oil phase, water, emulsifying agent three parts, consists of.
The preparation method of ointment of the present invention follows these steps to carry out:
(1) with after metronidazole, clotrimazole crude drug micronization processes, standby;
(2) after the chlorhexidine acetate crude drug is crossed 100 mesh sieves, standby;
(3) water of emulsifiable paste matrix, oil phase are heated respectively, emulsifying agent is scattered in water or oil phase;
(4) metronidazole after micronization, clotrimazole are joined in oil phase and be uniformly mixed, chlorhexidine acetate joins aqueous phase and stirs and fully dissolve;
(5) with oil phase and the emulsifying of water mix and blend, homogenate is cooling;
(6) divide the threading flexible pipe with cooling good emulsifiable paste, obtain.
The provided by the invention pair of safe cream formulation science of azoles, technical maturity, and efficiently quick-acting, overcome the deficiencies in the prior art.Compare with metronidazole,clotrimazole and chlorhexidine acetate suppositories agent, vagina effervescence, water-soluble ointment, ointment uniformity of dosage units difference provided by the invention is little, and granularity is little, the content of total impurities and single impurity is lower, good stability, and non-stimulated to vaginal mucosa, skin is not irritated.
The specific embodiment
Following representative instance is used for illustrating the present invention, within simple replacement that those skilled in the art do the present invention or improvement etc. all belong to the technical scheme that the present invention protects.
Embodiment 1:
Preparation prescription of the present invention is comprised of following component by weight:
Metronidazole 200g
Clotrimazole 160g
Chlorhexidine acetate 8g
Liquid paraffin,light 300g
White vaseline 200g
Hexadecanol 200g
Stearic acid 50g
Sodium lauryl sulphate 25g
Glyceryl monostearate 300g
Propylene glycol 800g
Purified water adds to 4000g
Make 1000
Preparation technology:
(1) with standby after metronidazole, the processing of clotrimazole micropowder, it is standby that chlorhexidine acetate is crossed 100 mesh sieves.
(2) liquid paraffin,light of recipe quantity, white vaseline, hexadecanol, stearic acid, glyceryl monostearate are mixed, after being heated to 70 ℃～80 ℃ meltings, add metronidazole, clotrimazole, be uniformly mixed, obtain oil phase.
(3) get the approximately purified water of 80% recipe quantity and the mixed with propylene glycol of recipe quantity, add the chlorhexidine acetate stirring and dissolving after being heated to 70 ℃～80 ℃, obtain water.
(4) oil phase and water are mixed, add sodium lauryl sulphate, stirring and emulsifying, purified water adds to full dose, and homogenate is cooling, and packing obtains.
Embodiment 2:
Preparation prescription of the present invention is comprised of following component by weight:
Metronidazole 200g
Clotrimazole 160g
Chlorhexidine acetate 8g
Liquid paraffin,light 800g
Hexadecanol 200g
Glyceryl monostearate 340g
Glycerol 300g
Tween 80 120g
Purified water adds to 4000g
Make 1000
Preparation technology:
(1) with standby after metronidazole, the processing of clotrimazole micropowder, it is standby that chlorhexidine acetate is crossed 100 mesh sieves.
(2) liquid paraffin,light of recipe quantity, hexadecanol, glyceryl monostearate are mixed, after being heated to 70 ℃～80 ℃ meltings, add metronidazole, clotrimazole, be uniformly mixed, obtain oil phase.
(3) get the purified water of about 80% recipe quantity and glycerol, the tween 80 of recipe quantity and mix, after being heated to 70 ℃～80 ℃, add chlorhexidine acetate, stirring and dissolving, obtain water.
(4) with oil phase and water mixing and emulsifying, water adds to full dose, and homogenate is cooling, and packing obtains.
Embodiment 3:
Preparation prescription of the present invention is comprised of following component by weight:
Metronidazole 200g
Clotrimazole 160g
Chlorhexidine acetate 8g
Liquid paraffin,light 250g
White vaseline 32g
Stearic acid 500g
Triethanolamine 30g
Glyceryl monostearate 150g
Purified water adds to 4000g
Make 1000
Preparation technology:
(1) with standby after metronidazole, the processing of clotrimazole micropowder, it is standby that chlorhexidine acetate is crossed 100 mesh sieves.
(2) with the liquid paraffin,light of recipe quantity, white vaseline, stearic acid, glyceryl monostearate, after Hybrid Heating to 70 ℃～80 ℃ melting, add metronidazole, clotrimazole, be uniformly mixed, obtain oil phase.
(3) get the purified water of about 80% recipe quantity and the triethanolamine of recipe quantity and mix, add chlorhexidine acetate after being heated to 70 ℃～80 ℃, stirring and dissolving, obtain water.
(4) with oil phase and water mixing and emulsifying, water adds to full dose, and homogenate is cooling, and packing obtains.
Embodiment 4:
Preparation prescription of the present invention is comprised of following component by weight:
Metronidazole 200g
Clotrimazole 160g
Chlorhexidine acetate 8g
Liquid paraffin,light 2000g
White vaseline 250g
Tween 80 200g
Purified water adds to 4000g
Make 1000
Preparation technology:
(1) with standby after metronidazole, the processing of clotrimazole micropowder, it is standby that chlorhexidine acetate is crossed 100 mesh sieves.
(2) liquid paraffin,light of recipe quantity, white vaseline are mixed, after being heated to 70 ℃～80 ℃ meltings, add metronidazole, clotrimazole, be uniformly mixed, obtain oil phase.
(3) get the purified water of about 80% recipe quantity and the tween 80 of recipe quantity and mix, add chlorhexidine acetate after being heated to 70 ℃～80 ℃, stirring and dissolving, obtain water.
(4) with oil phase and water mixing and emulsifying, water adds to full dose, and homogenate is cooling, and packing obtains.
Embodiment 5:
The uniformity of dosage units of chlorhexidine acetate cream provided by the invention obviously is better than suppository, vagina effervescence and water-soluble ointment, and demonstration test is as follows:
Get suppository, melt and get different parts 5 times, vagina effervescence adds a small amount of water and gets different parts 5 times, the water-soluble ointment agent is got different parts 5 times, and by the sample that the formula of implementing 2 prepares, get different parts 5 times, and add mobile phase appropriate, put shake well 10min in hot bath, test sample is dissolved, let cool, add mobile phase and be diluted to scale, make and shake up, put in ice bath cooling 2 hours, take out rapidly and filter, subsequent filtrate is placed to room temperature, precision measures need testing solution 20 μ l, method test according to assay, record chromatogram.Calculate content by external standard method.Its result is as shown in table 1 below.
The method of assay is as follows:
Measure according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2005).
Chromatographic condition and system suitability are packed column with octyl silane group silica gel; Be mobile phase with methanol-water-triethylamine (70: 30: 0.3) (containing sodium heptanesulfonate 10mmol/L, with phosphoric acid adjust pH to 4.0); Flow velocity 0.8ml/min, detect wavelength 260nm.Number of theoretical plate calculates and is not less than 2500 by the clotrimazole peak, and the separating degree at metronidazole, clotrimazole, chlorhexidine acetate peak should meet the requirements.
The algoscopy precision takes test sample appropriate (approximately being equivalent to metronidazole 20mg), puts in the 100ml measuring bottle, adds mobile phase appropriate, put shake well 10min in hot bath, test sample is dissolved, let cool, add mobile phase and be diluted to scale, shake up, put in ice bath cooling 2 hours, and took out rapidly and filter, subsequent filtrate is placed to room temperature, precision measures 20 μ l injection liquid chromatographies, records chromatogram.Another precision takes chlorhexidine acetate reference substance 50mg, puts in the 50ml measuring bottle, adds mobile phase and dissolves and be diluted to scale, shakes up, as the chlorhexidine acetate storing solution; Precision takes metronidazole reference substance 50mg, clotrimazole reference substance 40mg, put in the 25ml measuring bottle, then precision measures chlorhexidine acetate storing solution 2ml, be set up and state in the 25ml measuring bottle, add mobile phase and be diluted to scale, shake up, precision measures 5ml, put in the 50ml measuring bottle, add mobile phase and be diluted to scale, shake up, product solution in contrast, be measured in the same method, by the appearance method,, with calculated by peak area, obtain.
Table 1 Determination of Content Uniformity result
Embodiment 6:
The related substance of chlorhexidine acetate cream provided by the invention obviously is better than suppository, vagina effervescence and water-soluble ointment, and demonstration test is as follows:
Get suppository, vagina effervescence, water-soluble ointment and by the sample of the formula preparation of embodiment 2, according to the inspection assay method of related substance, check related substance, its result is as shown in table 2.
Related substance checks that assay method is as follows:
(1) inspection of clotrimazole related substance: get test sample appropriate (approximately being equivalent to clotrimazole 200mg), put in 50ml tool plug conical flask, accurately add chloroform 10ml to put shake well 10min in hot bath, test sample is dissolved, shake up, put in ice bath cooling 2 hours, take out, filter rapidly, get subsequent filtrate as need testing solution.Get need testing solution 1ml, put in the 100ml measuring bottle, add chloroform and be diluted to scale, shake up, in contrast solution.According to thin layer chromatography (two appendix VB of Chinese Pharmacopoeia version in 2005) test, draw each 10 μ l of above-mentioned two kinds of solution, put respectively on same silica gel g thin-layer plate, take dimethylbenzene-normal propyl alcohol-liquor ammoniae fortis (180: 20: 1) as developing solvent, launch, dry, put in iodine vapor and develop the color.Need testing solution, as aobvious impurity speckle, compares with the reference substance solution principal spot.
(2) inspection of 2-5-nitro imidazole: precision weighing test sample appropriate (approximately being equivalent to metronidazole 50mg) is put in the 50ml measuring bottle, adds water appropriate, puts shake well 10min in hot bath, let cool, be diluted with water to scale, shake up, filter, precision measures subsequent filtrate 1ml, puts in the 10ml measuring bottle, adds mobile phase and is diluted to scale, shake up, put in ice bath cooling 2 hours, and took out rapidly and filter, get subsequent filtrate as need testing solution; Separately get approximately 25mg of 2-5-nitro imidazole reference substance, accurately weighed, put in the 100ml measuring bottle, add dissolve with methanol and be diluted to scale, shake up, precision measures in right amount, makes 1ml with mobile phase and contains the solution of 1 μ g, in contrast product solution.Measure according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2005), be packed column with octadecylsilane chemically bonded silica, take methanol-water (20: 80) as mobile phase, the detection wavelength is 300nm, number of theoretical plate calculates and is not less than 2000 by the metronidazole peak, and the separating degree at metronidazole and 2-5-nitro imidazole peak should meet the requirements.Get reference substance solution 20 μ l injection liquid chromatographies, regulate detection sensitivity, the peak height that makes the main constituent chromatographic peak is 20% of full scale; Precision measures each 20 μ l of need testing solution and reference substance solution, and injection liquid chromatography respectively records to main constituent peak retention time 2 times of chromatogram.In the chromatogram of need testing solution, as 2-5-nitro imidazole peak occurring, the main peak Area comparison of its peak area and reference substance calculates content.
The measurement result of table 2 related substance
| Related substance | Suppository | Vagina effervescence | Water-soluble ointment | Ointment |
| The clotrimazole related substance | ＜1.0％ | ＜1.0％ | ＜1.0％ | ＜1.0％ |
| The 2-5-nitro imidazole | 0.3％ | 0.2％ | 0.4％ | 0.02％ |
Get suppository, lotion, vagina effervescence, water-soluble ointment and, by the sample of the formula preparation of embodiment 2, place sampling in 10 days under 60 ℃ of conditions, according to the inspection assay method of related substance, check related substance, its result is as shown in table 3.
Place the measurement result of related substance after 10 days under table 360 ℃ condition
| Related substance | Suppository | Vagina effervescence | Water-soluble ointment | Ointment |
| The clotrimazole related substance | ＞1.0％ | ＞1.0％ | ＞1.0％ | ＜1.0％ |
| The 2-5-nitro imidazole | 0.6％ | 0.7％ | 0.8％ | 0.02％ |
Embodiment 7:
The granularity of the insoluble granule of chlorhexidine acetate cream provided by the invention obviously is better than suppository, vagina effervescence and water-soluble ointment.Get suppository, lotion, vagina effervescence, water-soluble ointment and, by the sample of the formula preparation of embodiment 2, after 10ml water mixes, adopt the granularity of microscopic method mensuration insoluble granule, result of the test is as shown in table 4.
The testing result of the granularity of table 4 insoluble granule
| Check item | Suppository | Vagina effervescence | Water-soluble ointment | Ointment |
| Particle size range (μ m) | 53～185 | 56～207 | 27～168 | 8～18 |
| Particle size distribution (10～97%) (μ m) | 57.7～171.2 | 78.9～194.3 | 38.9～140.6 | 10.2～13.3 |
[0115]Embodiment 8:
Get the sample by the formula preparation of embodiment 2, carry out medicine stability test, verify that chlorhexidine acetate cream provided by the invention is stay-in-grade.Result of the test such as table 5, table 6 and table 7.
The safe emulsifiable paste of the two azoles of test sample source: the development of Jiangsu pharmaceutcal corporation, Ltd of Ya Bang Johnson ﹠ Johnson, lot number: 041103,041201,041202,041203.
Reference substance: metronidazole, lot number: 100191-200305; Clotrimazole, lot number: 100037-200306; Chlorhexidine acetate, lot number: 100183-199902; The calibrating of Chinese biological drug inspection provides
Table 5 influence factor tests and investigates result (lot number: 041103)
Table 6 accelerated test is investigated result
Table 7 long term test is investigated result
According to pharmacopeia regulation, with under the safe emulsifiable paste influence factor of two azoles conditions, under acceleration environment, character, the uniformity, lamination, related substance, content are investigated, with 0 day as a result the comparison indices have no significant change.Long-term placement was respectively investigated the project indicator in 24 months and is had no significant change.
Embodiment 9:
Get the sample by the formula preparation of embodiment 2, carry out the drug safety test, verify that chlorhexidine acetate cream provided by the invention is safe, result of the test is as follows.
1, the safe emulsifiable paste Vaginal mucosa irritation test of two azoles
1.1, test objective:
Observe the local excitation reaction that produces after the administration of the safe emulsifiable paste rabbit vagina of two azoles, for data for clinical drug use provides foundation.
1.2, tested medicine:
The safe emulsifiable paste of two azoles, lot number: 041201, developed by Jiangsu pharmaceutcal corporation, Ltd of Ya Bang Johnson ﹠ Johnson.Character: white emulsifiable paste.
Specification: 4g/ props up (containing metronidazole 0.2g, clotrimazole 0.16g, chlorhexidine acetate 8mg).Preservation condition: lucifuge, sealing are preserved.Administering mode: vagina administration.
The substrate sample: for not containing the excipient emulsifiable paste of medicine, pharmaceutcal corporation, Ltd of Ya Bang Johnson ﹠ Johnson provides by Jiangsu.
1.3, animal subject:
12 of Female rabbits, body weight 2.17～2.31kg,, without pregnant, provided by Beijing section space animal cultivation center, the quality certification number: SCXK (capital) 2002-0005, laboratory animal occupancy permit number: SYXK (army) 2002-020.Raising condition: temperature: 22 ± 2 ℃; Humidity: 40-70%; Illumination: 12 hours light and shades alternately; 1, every cage; Feed with the grains dedicated feedstuff of rabbit, be aided with fresh vegetables.Drinking water for animals before experiment, feed is normal, and is in good condition.
1.4, test method
12 of female healthy rabbits, weigh, and numbering, divide 3 groups at random.First group is the blank group, and second group is the substrate matched group, and the 3rd group is the safe emulsifiable paste group (being subjected to the reagent group) of two azoles.Smear gently in the rabbit vagina depths and be subjected to reagent or substrate 0.5g every day respectively, fully contact with its mucosa, until drug absorption, every day 1 time, SM 7 days.Duration of test is observed the general signs of animal every day, comprises that appetite, the water yield, hair color, gait, mental status and vaginal orifice have or not the phenomenons such as hyperemia, edema, hemorrhage, ulcer, erosion and abnormal secretion thing.Test and put to death rabbit on the 8th day, take out vagina tissue, the perusal mucosa has or not hyperemia, edema, hemorrhage, ulcer or the phenomenon such as rotten to the corn, result with-(reactionless) ,+(mild reaction), ++ (than significant reaction), +++(significant reaction), ++ ++ (very significant reaction) expression.And carry out histopathological examination.
1.5, conclusion (of pressure testing):
The safe emulsifiable paste of two azoles repeatedly after vagina administration, does not have obvious local irritant effect to the rabbit vagina mucosa.
2, the safe emulsifiable paste skin anaphylactic test of two azoles
2.1, experiment purpose
After the observation guinea pig skin repeated to contact the safe emulsifiable paste of two azoles, the performance of human body immune system response on skin, for data for clinical drug use provided foundation.
2.2, tested medicine
The safe emulsifiable paste of two azoles, lot number: 041201, developed by Jiangsu pharmaceutcal corporation, Ltd of Ya Bang Johnson ﹠ Johnson.Character: white emulsifiable paste.Specification: 4g/ props up (containing metronidazole 0.2g, clotrimazole 0.16g, chlorhexidine acetate 8mg).Preservation condition: lucifuge, sealing are preserved.Administering mode: skin is smeared.
Negative control thing: substrate sample: for not containing the excipient emulsifiable paste of medicine, pharmaceutcal corporation, Ltd of Ya Bang Johnson ﹠ Johnson provides by Jiangsu.
Positive drug: 2,4-dinitro fluorine oxygen (DNFB), lot number: 040623, provided by medical supply station, the Academy of Medical Sciences, Beijing.Facing the used time prepares with 95% ethanol.
2.3, animal subject
30 of Cavia porcelluss, male and female half and half, body weight 274～299g, provided by Beijing section space animal cultivation center, the quality certification number: SCXK (capital) 2002-0005, laboratory animal occupancy permit number: SYXK (army) 2002-020.Raising condition: temperature: 22 ± 2 ℃; Humidity: 40-70%; Illumination: 12 hours light and shades alternately; 3, every cage; Feed with the grains dedicated feedstuff of Cavia porcellus, be aided with fresh vegetables.Drinking water for animals before experiment, feed is normal, and is in good condition.
2.4, test method
30 of Cavia porcelluss, be divided into negative control thing (matrix group), the safe emulsifiable paste group of two azoles and positive controls (being the DNFB group) at random, every group of each 10 animals, and male and female half and half, 24h is approximately 3*3cm to back part of animal left side depilation area before test
2.Experiment day is applied to substrate (0.5ml/ only), the safe emulsifiable paste of two azoles (0.5ml/ only) and 1%DNFB (0.2ml/ only) respectively the depilation district in guinea pig back left side, with suitable method, fixes, and continues 6hr.Once, method is identical for the 7th day, the 14th day each repeated trials.
After last sensitization the 13rd day (test the 27th day), with a some razor, back part of animal right side hair is taken off unhairing area 3*3cm
2.After last sensitization the 14th day (test the 28th day), substrate after preparing respectively, the safe emulsifiable paste and 0.1%2 of two azoles, 4-dinitrofluorobenzene (each 0.1mol/ only) is applied to depilation district, right side, back and attacks, and with suitable method, fixes, and removes medicine after 6 hours.Observe and attack the irritated situation of rear 6hr, 24hr, 48hr, 72hr and 96hr animal skin, and by " new drug (Western medicine) preclinical study guideline compilation (pharmacy, pharmacology, toxicology) ", mark.The scoring mark is in Table 8, and the sensitization rate is classified in Table 9.
Table 8 skin allergy standards of grading
The classification of table 9 sensitization
| Sensitization rate (%) | Classification | Response strength |
| 0～8 | I | Weak sensitization |
| 9～28 | II | Slight sensitization |
| 29～64 | III | Moderate sensitization |
| 65～80 | IV | Strong sensitization |
| 81～100 | V | Extremely strong sensitization |
After pressing table 8 scoring, by the classification of table 9, judge its sensitization rate, computing formula is: reaction meansigma methods=(erythema forms total points+edema and forms total points)/add up to number of animals.Sensitization rate=occur skin erythema or edema (no matter degree weight) animal number of cases/animal subject sum.
2.5, experiment conclusion
Under this experimental condition, the safe emulsifiable paste of two azoles and substrate all do not cause the obvious skin allergy of Cavia porcellus.
Claims (1)
1. the preparation method of a chlorhexidine acetate cream, step is as follows:
Preparation technology:
(1) with standby after metronidazole, clotrimazole micronization processes, it is standby that chlorhexidine acetate is crossed 100 mesh sieves;
(2) liquid paraffin,light of recipe quantity, hexadecanol, glyceryl monostearate are mixed, after being heated to 70 ℃～80 ℃ meltings, add metronidazole, clotrimazole, be uniformly mixed, obtain oil phase;
(3) get the purified water of 80% recipe quantity and glycerol, the tween 80 of recipe quantity and mix, after being heated to 70 ℃～80 ℃, add chlorhexidine acetate, stirring and dissolving, obtain water;
(4) with oil phase and water mixing and emulsifying, water adds to full dose, and homogenate is cooling, and packing obtains.
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|---|---|---|---|
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| CN104800148A (en) * | 2015-04-20 | 2015-07-29 | 程伟智 | Clotrimazole emulsifiable paste and preparation method thereof |
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| CN1326737A (en) * | 2000-06-02 | 2001-12-19 | 金生银 | External use medicine for curing sexual disease and its preparing process |
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