CN1444938A - Metronidazole, Clotrimazole and Chlorhexidime Acetate preparation and its preparing method - Google Patents
Metronidazole, Clotrimazole and Chlorhexidime Acetate preparation and its preparing method Download PDFInfo
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Abstract
A medicine "Shuangzuotai" in the form of soft capsule and its preparing process are disclosed. It is the improvement to original suppository. Its advantages are high curative effect, high stability and disintegration speed, and no damage to vagina.
Description
Technical field
The invention belongs to the dosage form of pharmacopeia product metronidazole,clotrimazole and chlorhexidine acetate suppositories and the reform of dosage, be specially safe preparation of two azoles and preparation method thereof.
Background technology
2000 editions two metronidazole,clotrimazole and chlorhexidine acetate suppositorieses that record of Chinese Pharmacopoeia through clinical application for many years, prove that metronidazole,clotrimazole and chlorhexidine acetate suppositories is clear and definite to treatment bacteria mixed infection, mycotic, trichomonal vaginitis curative effect.But existing pharmacopeia metronidazole,clotrimazole and chlorhexidine acetate suppositories is a low dosage formulation, can not accomplish assault amount quick sterilization, and the course of treatment is longer relatively, easily produces drug resistance.And because the plastid of metronidazole,clotrimazole and chlorhexidine acetate suppositories is harder, its preparation technology through cold contraction makes the very not regular slyness of its external form again, sends into regular meeting's damage vagina in the vagina process; And it is frangible that this suppository becomes fragile winter, then easily melts summer, sticking hands; Both used inconvenience, and can not guarantee to send into the accurate of the interior dosage of body again, what finally affect the treatment is stable.The domestic people of having has developed the safe water-soluble ointment agent of two azoles, but bad because of its stability, influence is used.
Summary of the invention
The technical problem to be solved in the present invention is to improve the dosage and the dosage form of two azoles Thailands, especially higher than normal dose agent of high dose metronidazole,clotrimazole and chlorhexidine acetate suppositories and soft capsule preparation, screening can either keep former side's curative effect, can make the principal agent long-term stability again, do not degrade, do not deposit, do not build up, be uniformly dispersed, the little adjuvant of local irritation, and this adjuvant simultaneously should not hinder the content assaying method of pharmacopeia regulation.
The present invention also will be by the good soft capsule of suitable prepared disintegration, makes them can quick-acting sterilizations when high dose, reduces issuable drug resistance as far as possible; And its smooth surface, the pliable and tough degree of having of utricule, having reduced when the medication damage to vagina, can't because of weather or temperature effect key special rational can, not broken, do not split, tack-free, can easily complete dosage be sent in the body.
For addressing the above problem, the invention provides following technical scheme.
The safe preparation of the two azoles of high dose, in the safe per thousand parts of monomer formulations of two azoles, contain crude drug metronidazole＞200g to 1200g, clotrimazole＞160g～960g, chlorohaxanpyridine acetate＞8g～48g, that is: crude drug metronidazole＞200g is to metronidazole=1200g, and clotrimazole＞160g is to clotrimazole=960g, chlorohaxanpyridine acetate＞8g is to chlorohaxanpyridine acetate=48g, and pharmaceutically acceptable conventional adjuvant.Pharmacological testing of the present invention proves: the preparation that the metronidazole of high power amount, clotrimazole, chlorohaxanpyridine acetate are made, more can effectively kill the pathogen in the vagina, the principal agent of high power amount mixes with the pharmacy adjuvant, can make suppository, unguentum, gel or the effervescent tablet of high multiple dose according to a conventional method.
A kind of soft capsule, in its per thousand, soft capsule content is basically by crude drug metronidazole 200～1200g, clotrimazole 160～960g, chlorohaxanpyridine acetate 8～48g, with adjuvant vaseline and/or stearic acid 100～350g, single stearic acid glyceride and/or span 30～90g, liquid Paraffin 500～1500g forms; Its outer wrapping rubber is made up of gelatin, glycerol, water and ethyl hydroxybenzoate and titanium dioxide basically routinely.Sorbester p18 or sorbester p17 are better.Rubber is basically by 1 part in 1 part in gelatin, glycerol 0.35-0.40 part, water, and 5 ‰ ethyl hydroxybenzoates and 4% titanium dioxide are formed.
Described soft capsule, per thousand soft capsules are made up of following raw material medicaments and adjuvant basically: metronidazole 400～1000g, clotrimazole 320～640g, chlorohaxanpyridine acetate 16～32g, vaseline and/or stearic acid 200～280g, single stearic acid glyceride and/or span 50～70g, liquid Paraffin 980～1330g.
Described soft capsule, per thousand soft capsules are made up of following raw material medicaments and adjuvant basically: metronidazole 800g, clotrimazole 640g, chlorohaxanpyridine acetate 32g, vaseline and/or stearic acid 200～220g, single stearic acid glyceride and/or span 50～60g, liquid Paraffin 980g.
Described soft capsule, per thousand soft capsules are made up of following raw material medicaments and adjuvant basically: metronidazole 400g, clotrimazole 320g, chlorohaxanpyridine acetate 16g, vaseline 160g, stearic acid 60g, single stearic acid glyceride 36g, Arlacel-80 is 20g, liquid Paraffin 988g.
Described soft capsule, per thousand soft capsules are made up of following raw material medicaments and adjuvant basically: metronidazole 200g, clotrimazole 160g, chlorohaxanpyridine acetate 8g, vaseline 160g, stearic acid 80g, single stearic acid glyceride 36g, Arlacel-60 is 20g, liquid Paraffin 1336g.
Aforementioned preparation of soft capsule method, it can comprise the following steps:
Get crude drug metronidazole 200～1200g, clotrimazole 160～960g, chlorohaxanpyridine acetate 8～48g mixing, get the crude drug mixture;
Get adjuvant vaseline and/or stearic acid 100～350g, single stearic acid glyceride and/or span 30～90g, liquid Paraffin 500～1500g Hybrid Heating makes dissolving, the adjuvant mixture;
Above-mentioned raw materials medicine mixture and adjuvant mixture are merged, use the colloid mill mixing, get soft capsule content;
Get gelatin, glycerol, water, count 1 part by weight: 0.35～0.40 part: 1 part, ethyl hydroxybenzoate is for counting 5 ‰ by weight, mix the glue of preparation soft capsule rubber;
Soft capsule content and glue are suppressed in encapsulating machine.
Described preparation of soft capsule method is that crude drug mixture and adjuvant mixture are merged, behind the colloid mill mixing, temperature reduce to 25～35 ℃ standby.Gelatin, glycerol, water, ethyl hydroxybenzoate dissolve under 80～100 ℃ of conditions, make the glue of preparation soft capsule rubber in 0.5 hour at-0.06 Mpa-0.10Mpa evacuation.Oils and fats with ethanol flush away soft gelatin capsule surface; Under 24 ℃～30 ℃ temperature, relative humidity below 60% with capsule drying 18～24 hours.
The safe soft capsule of two azoles is the compound preparation that metronidazole, clotrimazole and three kinds of principal agents of chlorohaxanpyridine acetate are formed.The present invention adopts orthogonal experiment to select suitable adjuvant, and wherein single stearic acid glyceride both had been a thickening agent, was all surfactant with span again.The present invention has screened and can either keep former side's curative effect, can make the principal agent long-term stability again, does not degrade, does not deposit, does not build up, is uniformly dispersed, and the little adjuvant of local irritation, and this adjuvant does not simultaneously hinder the content assaying method of pharmacopeia regulation.
The present invention is by the good soft capsule of suitable prepared disintegration, even it is at the high dose also quick-acting sterilizations of disintegrate rapidly, thereby needs repeatedly the issuable drug resistance of medication repeatedly because the efficacy of a drug is not enough to reduce as far as possible; And its smooth surface, the pliable and tough degree of having of utricule has reduced when medication the damage to vagina, capsule shell melts under body temperature, is unguinosus content and is distributed in intravaginal equably under the pressure in abdominal cavity, and medicine is discharged rapidly, play quick-acting sterilization effects, brought into play curative effect more fully; And not can because of weather or temperature effect key special rational can, not broken, do not split, tack-free, can easily complete dosage be sent in the body.
The selected adjuvant of the present invention had both kept former side's curative effect, guaranteed the stability of three flavor principal agents again, also accelerated the release of medicine, proved through local excitation test, acute toxicity test and long-term stable experiment, this medicine does not have part or general toxic reaction, and is safe in utilization effective.Contain lanoline in the substrate of pharmacopeia product metronidazole,clotrimazole and chlorhexidine acetate suppositories agent, this composition of evidence is meeting and the effect of principal agent chlorohaxanpyridine acetate in storage process, reduces the content of this principal agent.And not containing lanoline in the safe soft capsule prescription of two azoles, other selected substrate do not influence the content of each principal agent yet.The present invention is sealed in medicine in the soft capsule, is not subjected to the influence of external condition substantially at the storage process Chinese medicine, and the suitable adjuvant that is in addition screened has guaranteed stability of drug.The safe soft capsule of the two azoles of the present invention also specially designs the high dose specification, and dosage wherein is two times of former prescription, can reach three times, four times of former prescription even.Purpose is to be used for assault amount quick sterilization, shortens the course of treatment, prevents to produce drug resistance.
One, stability test
(1) accelerated test
Test method: 3 aluminum-plastic packaged batch samples are placed on temperature: 30 ℃ ± 2 ℃, relative humidity: 60% ± 5% (NaNO
2Saturated solution) in the calorstat, the 1st, 2,3,6 sampling at the end of month, detects respectively by relevant study on the stability project.The results are shown in Table 1.
(2) long-term stable experiment
Test method: 3 aluminum-plastic packaged batch samples are placed on 25 ℃ ± 2 ℃ of temperature, relative humidity 60% ± 10% (NaNO
2Saturated solution) in the calorstat, the 1st, 2,3,6,9,12 sampling at the end of month, detects respectively by relevant study on the stability project.The results are shown in Table 2.
Table 1, accelerated test
| Lot number | Period of storage (moon) | The investigation project | ||||||
| Outward appearance | The content character | Catabolite | Disintegration (branch) | Content (%) | ||||
| Metronidazole | Clotrimazole | Chlorohaxanpyridine acetate | ||||||
| 020901 | ?0 ?1 ?2 ?3 ?6 | Olive shape olive shape olive shape olive shape olive shape | The even mastic of the even mastic milky of the even mastic milky of the even mastic milky of the even mastic milky of milky | Do not have | ?20 ?18 ?19 ?17 ?18 | ?96.11 ?96.27 ?95.37 ?94.69 ?94.28 | ?98.63 ?95.31 ?97.92 ?96.87 ?95.36 | ?110.09 ?107.68 ?105.27 ?107.69 ?106.12 |
| ?020902 | ?0 ?1 ?2 ?3 ?6 | Olive shape olive shape olive shape olive shape olive shape | The even mastic of the even mastic milky of the even mastic milky of the even mastic milky of the even mastic milky of milky | Do not have | ?21 ?19 ?20 ?20 ?18 | ?95.18 ?96.28 ?95.73 ?94.79 ?94.17 | ?97.96 ?95.37 ?96.28 ?96.12 ?95.21 | ?108.28 ?107.53 ?105.29 ?106.57 ?108.11 |
| ?020903 | ?0 ?1 ?2 ?3 ?6 | Olive shape olive shape olive shape olive shape olive shape | The even mastic of the even mastic milky of the even mastic milky of the even mastic milky of the even mastic milky of milky | Do not have | ?19 ?16 ?18 ?20 ?19 | ?98.31 ?97.63 ?97.82 ?96.21 ?95.77 | ?96.87 ?95.89 ?95.38 ?94.67 ?94.28 | ?103.12 ?102.36 ?101.98 ?101.12 ?102.53 |
Table 2, long-term stable experiment
| Lot number | Period of storage (moon) | The investigation project | ||||||
| Outward appearance | The content character | Catabolite | Disintegration (branch) | Content (%) | ||||
| Metronidazole | Clotrimazole | Chlorohaxanpyridine acetate | ||||||
| 020901 | ?0 ?1 ?2 ?3 ?6 | Olive shape olive shape olive shape olive shape olive shape | The even mastic of the even mastic milky of the even mastic milky of the even mastic milky of the even mastic milky of milky | Do not have | ?20 ?19 ?20 ?17 ?18 | ?96.11 ?96.29 ?95.37 ?95.29 ?95.22 | ?98.63 ?98..37 ?97.89 ?97.17 ?97.17 | ?110.09 ?108.29 ?106.28 ?105.19 ?104.29 |
| ?020902 | ?0 ?1 ?2 ?3 ?6 | Olive shape olive shape olive shape olive shape olive shape | The even mastic of the even mastic milky of the even mastic milky of the even mastic milky of the even mastic milky of milky | Do not have | ?21 ?19 ?18 ?19 ?17 | ?95.18 ?95.22 ?94.37 ?94.13 ?94.11 | ?97.96 ?97.31 ?96.28 ?96.37 ?95.27 | ?108.28 ?107.66 ?105.89 ?105.21 ?105.17 |
| ?020903 | ?0 ?1 ?2 ?3 ?6 | Olive shape olive shape olive shape olive shape olive shape | The even mastic of the even mastic milky of the even mastic milky of the even mastic milky of the even mastic milky of milky | Do not have | ?19 ?20 ?17 ?15 ?16 | ?98.31 ?98.11 ?97.12 ?97.81 ?96.25 | ?96.87 ?96.79 ?96.21 ?95.21 ?95.13 | ?103.12 ?102.37 ?102.17 ?101.19 ?101.81 |
Above stability test result shows that this medicine is stable in properties under aluminum-plastic packaged, room temperature, drying condition.Therefore effect duration is decided to be 2 years.
Two, detect adjuvant to the influence of principal agent mensuration, the degree of degradation and tlc determination catabolite feasibility () metronidazole of principal agent
Lamellae: get silica gel G F
254Plate
Developing solvent: ethyl acetate-isopropyl alcohol-water-ammonia water (15: 7: 3: 1)
Get metronidazole 0.2g and add methanol 20ml and make dissolving, as solution (1); Other gets metronidazole 0.2g, after soda acid adds heat damage, adds methanol 20ml and makes dissolving, as solution (2).Get above-mentioned solution (1), (2) each 10 μ l, put in same silica gel G F respectively
254On the lamellae, with ethyl acetate-isopropyl alcohol-water-ammonia water (15: 7: 3: 1) be developing solvent, after launching to dry, put under the uviol lamp (254nm) and inspect that the result shows and do not detect catabolite.Sensitivity test result shows that the limit of identification of this method is 5 μ g.Interference test result shows: the not detection of principal spot in the disturbed specimen of this method adjuvant.Sample detection result shows: amount of degradation products is less than 1% in the sample.(2) chlorohaxanpyridine acetate
Lamellae: get silica gel G F
2548g adds sodium formate 1g, adds water 22ml, and mediation is made.
Developing solvent: chloroform-dehydrated alcohol-formic acid (7: 3: 0.9)
Get chlorohaxanpyridine acetate 50mg, add methanol 10ml and make dissolving, as solution (1); Other gets chlorohaxanpyridine acetate 50mg, after soda acid adds heat damage, adds methanol 10ml and makes dissolving, as solution (2).Get above-mentioned solution (1), (2) each 10 μ 1, put in same silica gel G F respectively
254On the lamellae, be developing solvent, after launching to dry, put under the uviol lamp (254nm) and inspect that the result shows to also have two catabolite speckles except that getting the chlorohaxanpyridine acetate principal spot with chloroform-dehydrated alcohol-formic acid (7: 3: 0.9).Sensitivity test result shows that the limit of identification of this method is 5 μ g.Interference test result shows the not detection of principal spot in the disturbed specimen of this method adjuvant.Sample detection result shows: amount of degradation products is less than 1% in the sample.(3) clotrimazole
Lamellae: silica gel G plate
Developing solvent: dimethylbenzene-n-butyl alcohol-strong aqua ammonia (80: 20: 1)
Get clotrimazole 0.5g, add chloroform 5ml, make dissolving, as solution (1); Other gets clotrimazole 0.5g, after soda acid adds thermal degradation, adds chloroform 5ml, makes dissolving, as solution (2).Getting each 10 μ l of above-mentioned solution (1), (2), put respectively on same silica gel g thin-layer plate, be to dry after developing solvent launches with dimethylbenzene-n-butyl alcohol-strong aqua ammonia (80: 20: 1), smokes with behind the iodine steam, inspects immediately, and the result shows and do not detect catabolite.Sensitivity test result shows that the limit of identification of this method is 10 μ g.Interference test result shows: the not detection of principal spot in the disturbed specimen of this method adjuvant.Sample detection result shows: amount of degradation products is less than 1% in the sample.
Three, the research of assay
Effective ingredient is clotrimazole, metronidazole, chlorohaxanpyridine acetate in the safe soft capsule of two azoles.Recipe quantity is: every contains metronidazole 400mg, clotrimazole 320mg, chlorohaxanpyridine acetate 16mg; Metronidazole 200mg, clotrimazole 160mg, two kinds of specifications of chlorohaxanpyridine acetate 8mg.Wherein the adjuvant of two middle metronidazole,clotrimazole and chlorhexidine acetate suppositorieses of the composition of adjuvant and Chinese Pharmacopoeia version in 2000 is close is liposoluble substance, and content assaying method is tested and set with relevant kind and to the method for this product with reference to metronidazole,clotrimazole and chlorhexidine acetate suppositories.Clotrimazole adopts perchloric acid titration liquid (0.1mol/L) titrimetry, and metronidazole adopts ultraviolet spectrophotometry, and chlorohaxanpyridine acetate adopts colorimetry.Through test, the response rate of various component content assay methods is reliable, and linear relationship is good, and method is feasible.
Four, local excitation and acute toxicity test
The safe soft capsule of two azoles is on the basis of the safe ointment of former pair of azoles, increases medicament contg to reach the new Western medicine unguentum that use part convenient and the raising therapeutic efficiency.For understanding its local application to the acute toxicity effect of vaginal mucosa, corresponding genitals and absorption back to whole body, we adopt rabbit and rat is local excitation and the acute toxicity test that laboratory animal has been carried out the safe soft capsule of two azoles, for clinical practice provides the rationale foundation.
Be subjected to the reagent thing: the safe soft capsule content of two azoles contains the medicine composition, metronidazole 400mg/2g, clotrimazole 320mg/2g, chlorohaxanpyridine acetate 16mg/2g in the content.Every gram content contains medicine composition 0.386g.
Positive control: metronidazole,clotrimazole and chlorhexidine acetate suppositories agent
Negative control: the excipient of the safe soft capsule ointment of two azoles.
Dosage: the heavy dose of group of the safe soft capsules of two azoles: administration every day of every rabbit 1.0g, single administration 0.5g, the next day once, ingredient 0.386g, average 0.1472g/kg is 20 times of people's consumption.Every rat single administration 0.2g, the next day once (about 0.2g), ingredient 0.0736g, average 0.2944g/kg is 40 times of people's consumption.
Dosage group in the safe soft capsule of two azoles: every rabbit single administration 0.5g, the next day once, ingredient 0.184g, average 0.0736g/kg is 9.5 times of people's consumption.Every rat single administration 0.1g, the next day once, ingredient 0.0368g, average 0.1472g/kg is 20 times of people's consumption.
The safe soft capsule small dose group of two azoles: every rabbit single administration 0.2g, the next day once, contain medicine composition 0.0736g, average 0.02944g/kg is 3.8 times of people's consumption.Every rat single administration 0.05g, the next day once, contain medicine composition 0.0184g, average 0.0736g/kg is 9.5 times of people's consumption.
Positive control: the metronidazole,clotrimazole and chlorhexidine acetate suppositories agent, every contains medicine metronidazole 0.2g, clotrimazole 0.16g, chlorohaxanpyridine acetate 0.008g.Contain medicine 0.368g altogether.Each 0.5 of rabbit, the next day once, average out to 0.0736g/kg is 10 times of people's consumption.
Rat is 0.1, contains medication amount 0.0368g, and average out to 0.1472g/kg is 20 times of people's consumption, the next day once.This used metronidazole,clotrimazole and chlorhexidine acetate suppositories agent is that Chinese-foreign joint Tianyang Pharmaceutical Co., Ltd., Anhui Prov. produces, No. (2001) the * 005730, the accurate word of Anhui medicine, and batch number: 020717, valid until 2005 06 month.
Negative control: substrate contrast, main component is a semi-synthetic fatty acid glyceride, rabbit is 1.0g/ day, the next day twice, rat is 0.2g, the next day once.
Animal: Female rabbits, body weight 2.25-2.55kg, the female 0.235-0.260kg of rat is provided by Chinese Medical Sciences University's second clinical hospital clinical Animal Lab., the experimental animal quality certification number: No. (2000) 015, distant real kinoplaszm word.
Test method: 20 Female rabbits, 30 female rat are divided into 5 groups at random, every group of 4 rabbit, 6 rat.Metronidazole,clotrimazole and chlorhexidine acetate suppositories agent group, 1/2 of rabbit one time, once/next day.1/10 of rat, once/next day, vagina administration.Reagent group and matrix group are injected medicine with the 1ml syringe to intravaginal.The heavy dose of group of rabbit give twice/next day, administration is 4 times altogether, observes 7 days.MAIN OUTCOME MEASURES: the activity of animal, feed, defecation, fur, the vagina outward appearance, it is no abnormal etc. to have or not edema, hyperemia, ulceration and secretions to have.
After the last administration next day sacrificed by exsanguination rabbit, rat is put to death in cervical vertebra dislocation.1. dissect pelvic cavity perusal reproductive system and the surrounding tissue organ has or not abnormal phenomenas such as edema, hyperemia, erosion.2. dissect variations such as vagina perusal vaginal walls color, edema, hyperemia, erosion, ulcer, secretions be unusual.3. win part animal vagina and carry out the pathological section making, and observe, take a picture.
Result of the test:
1. general reaction: administration and viewing duration, all no abnormal findings such as reagent group and matched group five treated animal activities, feed, defecation, fur, body weight, breathing, heart rate and matched group ratio, all Non Apparent Abnormality.
2. vagina is dissected perusal: do not have abnormal findings such as hyperemia, swelling and surrounding tissue adhesion.
3. vagina pathology histological observation: select experimental group animal vagina to do pathological section at random, carry out histological examination, the no abnormal pathological change of its result.
Conclusion: the safe soft capsule capsule of two azoles maximal dose group is 40 times (rat) of people's consumption, 20 times (rabbit); Middle dosage group is 20 times (rat) of people's consumption, 9.5 times (rabbit); 9.5 times (rat) of small dose group behaviour consumption, 3.8 times (rabbit).The administration next day of vagina continuous 4 times, was observed its result, the local excitation reaction and the symptom of not seeing vagina and other genitals 8 days.Matrix group and metronidazole,clotrimazole and chlorhexidine acetate suppositories positive controls are not seen vagina local excitation symptom yet.
Five, the long term toxicity test of the safe soft capsule vagina of two azoles local application
Be subjected to the reagent thing: the same
Dosage: heavy dose of group: every rat single administration 0.2ml (about 0.2g), the next day once, ingredient 0.0736g, average 0.2944g/kg is 40 times of people's consumption.
In the dosage group: every rat single administration 0.1g, the next day once, ingredient 0.0368g, average 0.1472g/kg is 20 times of people's consumption.
Small dose group: every rat single administration 0.05g, the next day once, contain medicine composition 0.0184g, average 0.0736g/kg is 9.5 times of people's consumption.
Positive control: the metronidazole,clotrimazole and chlorhexidine acetate suppositories agent, every contains medicine metronidazole 0.2g, clotrimazole 0.16g, chlorohaxanpyridine acetate 0.008g.Contain medicine 0.368g altogether.Rat is 0.1, contains medication amount 0.0368g, and average out to 0.1472g/kg is 20 times of people's consumption, the next day once.
Conclusion: the safe soft capsule heavy dose of two azoles is 40 times (rat) of people's consumption; 20 times (rat) of middle dosage behaviour consumption; Low dose is 9.5 times (rat) of people's consumption.Be administered once the next day of three dosage groups, observed continuously 28 days, repeated experiments three times, its result: animal whole body and vagina part there is no toxic reaction and local irritation, the substrate matched group, the metronidazole,clotrimazole and chlorhexidine acetate suppositories positive controls is not seen whole body and local toxicity reaction yet.
Four, pathologic finding report
Censorship material: drug study rabbit vagina tissue, heavy dose of group, small dose group, matrix group and normal control group, every group each 2, all be elongated tubular, size is 3.6 * 1.6 * 1.3 centimetres, rough surface, and central authorities are an irregular cavity, by mucosal fold is full of, intracavity does not have hyperemia, no hemorrhage or inflammatory exudate.
Inspection method: above-mentioned tissue is fixed with 10% formlinata aquae concentratac, draws materials in the transverse section, and cured film-making is soaked in the conventional dehydration of pathology, H, E dyeing, microscopic examination.The censorship material has heavy dose of group, small dose group and matrix group, does not see that medicine and substrate have pathogenic effects to each layer of vagina.
The specific embodiment
Embodiment 1
Metronidazole 400g
Clotrimazole 320g
Chlorohaxanpyridine acetate 16g
Vaseline 160g
Single stearic acid glyceride 40g
Arlacel-80 20g
Stearic acid 60g
Liquid Paraffin adds to 2000g
Make 1000
1. take by weighing recipe quantity metronidazole, clotrimazole, three kinds of crude drug mix homogeneously of chlorohaxanpyridine acetate, sieving for standby.
2. get recipe quantity adjuvant vaseline, single stearic acid glyceride, Arlacel-80, stearic acid, liquid Paraffin in water-bath, heat make be dissolved to clear and bright.
3. mix, stir above-mentioned 1,2, cross colloid mill and be mixed, when temperature was reduced to 25 ℃～35 ℃, it was standby to be rare paste.
4. with gelatin, glycerol, water (1: 0.35～0.4: 1), in 5 ‰ ethyl hydroxybenzoates, the 4% titanium dioxide addingization glue jar, under 80 ℃ of-100 ℃ of temperature, dissolved, stir, mix 1 hour,, make glue-0.06Mpa-0.10Mpa evacuation 0.5 hour.
5. be pressed into soft gelatin capsule with above-mentioned 3,4 at encapsulating machine.
6. use the oils and fats on ethanol flush away soft gelatin capsule surface.
7. under 24 ℃～30 ℃ temperature, relative humidity went out ball with soft gelatin capsule in 18～24 hours in rotating cage internal rotation, forced air drying below 60%.(can suitably adjust drying time according to season, condition.)
Embodiment 2
Metronidazole 200g
Clotrimazole 160g
Chlorohaxanpyridine acetate 8g
Vaseline 160g
Single stearic acid glyceride 40g
Arlacel-60 20g
Stearic acid 80g
Liquid Paraffin adds to 2000g
Make 1000
Preparation method is the same.
Embodiment 3
Metronidazole 400g
Clotrimazole 320g
Chlorohaxanpyridine acetate 16g
Single hard acid glyceride 160g
Paraffin 240g
Semi-synthetic fatty acid substrate 1000g
Make 1000 suppositorys
Suppository preparation method preparation routinely.According to the situation in season, supplementary product consumption can appropriate resize ratio, and the model of semi-synthetic fatty acid substrate also can be adjusted.
Embodiment 4
Metronidazole 800g
Clotrimazole 640g
Chlorohaxanpyridine acetate 32g
White vaseline 320g
Single hard acid glyceride 80g
Sorbester p17 40g
Stearic acid 160g
Liquid paraffin adds to 3000g
Make 1000 suppositorys
Suppository preparation method preparation routinely.
Embodiment 5 (one) physicochemical properties
1. character: this product rubber adds titanium dioxide (opacifier) by glycerol, gelatin, water to be made, and content be white or the milky unguentum of being made up of metronidazole, chlorohaxanpyridine acetate, clotrimazole and adjuvant, and making behind the preparation is white olive shape soft capsule.
2. content uniformity: 20 of sample thiefs, measure its loading amount respectively, see the following form.
| Sample number | 1 | ?2 | ?3 | ?4 | ?5 | ?6 | ?7 | ?8 | ?9 | ?10 |
| Loading amount (g) | 2.002 | ?2.013 | ?2.025 | ?2.118 | ?1.986 | ?1.991 | ?2.079 | ?1.988 | ?2.079 | ?2.095 |
| Sample number | 1 | ?2 | ?3 | ?4 | ?5 | ?6 | ?7 | ?8 | ?9 | ?10 |
| Loading amount (g) | 1.967 | ?1.986 | ?2.079 | ?2.018 | ?2.026 | ?2.089 | ?2.016 | ?2.021 | ?1.987 | ?1.976 |
| Average loading amount=2.027g | ||||||||||
As seen from the above table, this product content uniformity is all in ± 7.5% limit, and is up to specification.Content uniformity is relevant with adjuvant selection, drug ratio and preparation technology.
(2). differentiate
Formulate this product down according to two middle metronidazole,clotrimazole and chlorhexidine acetate suppositorieses discriminating items of Chinese Pharmacopoeia version in 2000 and differentiate item, meet standards of pharmacopoeia.
(3). disintegration
Get 10 batches of samples, press the inspection of 2000 editions appendix XA of Chinese Pharmacopoeia inspection technique disintegration respectively, the result is as follows:
| Sample number | ??1 | ???2 | ????3 | ????4 | ????5 | ????6 | ????7 | ????8 | ????9 | ????10 |
| Disintegration time (min) | ??12 | ???18 | ????15 | ????13 | ????19 | ????13 | ????16 | ????11 | ????16 | ????18 |
| Average disintegration time=15.1min | ||||||||||
As seen from the above table, this product meets the regulation of soft capsule all in disintegrate in a hour.Disintegration is relevant with adjuvant selection, drug ratio and preparation technology.
Claims (10)
1, the safe preparation of the two azoles of high dose is characterized in that: in the safe per thousand parts of monomer formulations of two azoles, contain crude drug metronidazole＞200g to 1200g, clotrimazole＞160g～960g, chlorohaxanpyridine acetate＞8g～48g, and pharmaceutically acceptable conventional adjuvant.
2, a kind of soft capsule, it is characterized in that: per thousand soft capsules, its capsule 's content is basically by crude drug metronidazole 200～1200g, clotrimazole 160～960g, chlorohaxanpyridine acetate 8～48g, with adjuvant vaseline and/or stearic acid 100～350g, single stearic acid glyceride and/or span 30～90g, liquid Paraffin 500～1500g forms; Its outer wrapping rubber is made up of gelatin, glycerol, water and ethyl hydroxybenzoate and titanium dioxide basically routinely.
3, according to the described soft capsule of claim 1, it is characterized in that per thousand soft capsules are made up of following raw material medicaments and adjuvant basically: metronidazole 400～1000g, clotrimazole 320～640g, chlorohaxanpyridine acetate 16～32g, vaseline and/or stearic acid 200～280g, single stearic acid glyceride and/or span 50～70g, liquid Paraffin 980～1330g.
4, according to the described soft capsule of claim 3, it is characterized in that per thousand soft capsules are made up of following raw material medicaments and adjuvant basically: metronidazole 800g, clotrimazole 640g, chlorohaxanpyridine acetate 32g, vaseline and/or stearic acid 200～220g, single stearic acid glyceride and/or span 50～60g, liquid Paraffin 980g.
5, according to the described soft capsule of claim 3, it is characterized in that per thousand soft capsules are made up of following raw material medicaments and adjuvant basically: metronidazole 400g, clotrimazole 320g, chlorohaxanpyridine acetate 16g, vaseline 160g, stearic acid 60g, single stearic acid glyceride 36g, Arlacel-80 is 20g, liquid Paraffin 988g.
6, according to the described soft capsule of claim 3, it is characterized in that per thousand soft capsules are made up of following raw material medicaments and adjuvant basically: metronidazole 200g, clotrimazole 160g, chlorohaxanpyridine acetate 8g, vaseline 160g, stearic acid 80g, single stearic acid glyceride 36g, Arlacel-60 is 20g, liquid Paraffin 1336g.
7, the described preparation of soft capsule method of claim 1, it comprises the following steps:
Get crude drug metronidazole 200～1200g, clotrimazole 160～960g, chlorohaxanpyridine acetate 8～48g mixing, get the crude drug mixture;
Get adjuvant vaseline and/or stearic acid 100～350g, single stearic acid glyceride and/or span 30～90g, liquid Paraffin 500～1500g Hybrid Heating makes dissolving, the adjuvant mixture;
Above-mentioned raw materials medicine mixture and adjuvant mixture are merged, use the colloid mill mixing, get soft capsule content;
Get gelatin, glycerol, water, count 1 part by weight: 0.35～0.40 part: 1 part, ethyl hydroxybenzoate is for counting 5 ‰ by weight, mix the glue of preparation soft capsule rubber;
Soft capsule content and glue are suppressed in encapsulating machine.
8, according to the described preparation of soft capsule method of claim 7, it is characterized in that: crude drug mixture and adjuvant mixture are merged, behind the colloid mill mixing, temperature reduce to 25～35 ℃ standby.
9, according to the described preparation of soft capsule method of claim 7, it is characterized in that: gelatin, glycerol, water, ethyl hydroxybenzoate dissolve under 80～100 ℃ of conditions, make the glue of preparation soft capsule rubber in 0.5 hour at-0.06Mpa-0.10Mpa evacuation.
10, according to the described preparation of soft capsule method of claim 7, it is characterized in that: with the oils and fats on ethanol flush away soft gelatin capsule surface; Under 24 ℃～30 ℃ temperature, relative humidity below 60% with capsule drying 18～24 hours.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 03113292 CN1197571C (en) | 2003-04-25 | 2003-04-25 | Metronidazole, Clotrimazole and Chlorhexidime Acetate preparation and its preparing method |
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| CN 03113292 CN1197571C (en) | 2003-04-25 | 2003-04-25 | Metronidazole, Clotrimazole and Chlorhexidime Acetate preparation and its preparing method |
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| CN1197571C CN1197571C (en) | 2005-04-20 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100496488C (en) * | 2006-07-14 | 2009-06-10 | 西安正清医药科技开发有限公司 | Tinidazole vaginal soft capsule and its preparing method |
| CN1785180B (en) * | 2005-11-17 | 2011-05-25 | 贵州神奇集团控股有限公司 | Method for detecting compound bismuth potassium citrate metronidazole |
| CN104127412A (en) * | 2014-08-07 | 2014-11-05 | 江西九华药业有限公司 | Metronidazole suppository and preparation method thereof |
| CN110507630A (en) * | 2019-09-29 | 2019-11-29 | 陈汝霖 | A kind of portable cavity sterilization soft capsule |
-
2003
- 2003-04-25 CN CN 03113292 patent/CN1197571C/en not_active Expired - Lifetime
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1785180B (en) * | 2005-11-17 | 2011-05-25 | 贵州神奇集团控股有限公司 | Method for detecting compound bismuth potassium citrate metronidazole |
| CN100496488C (en) * | 2006-07-14 | 2009-06-10 | 西安正清医药科技开发有限公司 | Tinidazole vaginal soft capsule and its preparing method |
| CN104127412A (en) * | 2014-08-07 | 2014-11-05 | 江西九华药业有限公司 | Metronidazole suppository and preparation method thereof |
| CN110507630A (en) * | 2019-09-29 | 2019-11-29 | 陈汝霖 | A kind of portable cavity sterilization soft capsule |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1197571C (en) | 2005-04-20 |
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