CN103751094A - Ornidazole vaginal expansion suppository and preparation and detection methods thereof - Google Patents
Ornidazole vaginal expansion suppository and preparation and detection methods thereof Download PDFInfo
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Abstract
The invention relates to an ornidazole vaginal expansion suppository and preparation and detection methods thereof. The expansion suppository comprises a medicated substrate and an expansion carrier, wherein the medicated substrate consists of ornidazole and a substrate; the medicated substrate also comprises bitriglycerol monostearate, propylene glycol diacetate, an oil phase, sodium alginate, methylparaben and propylparaben. The ornidazole vaginal expansion suppository has the beneficial effects of high bioavailability, high stability, and difficulty in rancidifying; in addition, Due to the adoption of six unique leading technologies, the ornidazole vaginal expansion suppository realizes the beneficial effects of preventing outflow of liquid medicine, and preventing superinfection, etc.
Description
Technical field
The invention belongs to vaginal suppository field, particularly a kind of ornidazole vagina expansible plug and preparation method thereof and detection method.
Background technology
Ornidazole, the chemistry chloro-2-hydroxypropyl of 1-(3-by name)-2-5-nitro imidazole, its structural formula is as follows:
Ornidazole is white or micro-yellow crystalline powder; Odorless, bitter in the mouth, meets photochromic gradual change Huang, easily molten in ethanol, slightly molten in water.
The curative effect of ornidazole is better than metronidazole, is slightly better than tinidazole; Be mainly used in clinically trichomonal vaginitis; The preparation of ornidazole mainly comprises tablet, capsule, injection, suppository etc.; But because Tablet and Capsula is after taking medicine, absorbs and enter blood through gastrointestinal, then reach focus by blood, the amount that reaches the effective ingredient of focus reduces greatly, and there will be the gastrointestinal side effects such as nauseating, vomiting; Injection administration easily adds the burden of heavy patient liver, kidney, affects its application; So based on the feature of suppository, it is widely used; CN101632658 discloses a kind of ornidazole type of effervescent suppository, and this type of effervescent suppository comprises ornidazole, sodium bicarbonate, citric acid monohydrate, semi-synthetic fatty acid glyceride and polyoxyethylene sorbitan monoleate; The sphere of action of this type of effervescent suppository is wide, and curative effect can reach vagina depths or fold place; But the bioavailability of this type of effervescent suppository is poor, and stability is low, further affects its curative effect; (the Ji Cunyuan such as Ji Cunyuan, Yang Qiuli etc. Ornidazole Suppository Study on Preparation [J], northwest pharmaceutical journal, 2006,21 (2): 73-74) disclose a kind of Ornidazole Suppository preparation technology, the water-soluble base of applying in its suppository has very strong zest to vagina; And common Ornidazole Suppository also exist not easy to clean, easily pollution clothes; Active component and people's contact level are little, cause absorbing insufficient, do not bring into play the technical problems such as the optimum curative effect of prescription.
Summary of the invention
In order to solve the problems of the technologies described above, improve the stability of Ornidazole Suppository, give full play to curative effect, the invention provides a kind of ornidazole vagina expansible plug and preparation method thereof; A kind of science detection method that can control above-mentioned ornidazole vagina expansible plug product quality is also provided simultaneously.
The concrete technical scheme of the present invention is as follows:
The invention provides a kind of ornidazole vagina expansible plug, this expansible plug comprises that weight portion is the ornidazole of 25-60 part, weight portion is that substrate and the weight portion of 65-200 part is the expandable expansion carrier of 60-400 part, ornidazole and substrate formed pastille substrate are coated in expansion carrier surface, and the swell value of expansion carrier after saturated water suction is greater than 1.1;
Wherein, substrate comprises one or more in Acrawax, natural acid ester, lipoidis substrate, water-soluble base, hydrogenated oil and fat, glyceride, distillate oil or colloidal compound;
Acrawax comprises one or more in mixed fatty glycerides, propylene glycol stearate, fixed oil, semi-synthetic fatty acid glyceride, semi-synthetic cocos nucifera oil ester, Witepsol, semi-synthetic Petiolus Trachycarpi grease or semi-synthetic Fructus Litseae ester;
Natural acid ester comprises one or more in oleum sapii, Oleum Linderae, Fructus Foeniculi fat, Ke Kemu fat or cocoa butter;
Lipoidis substrate comprises lanoline or lanonol;
Water-soluble base comprises one or more in PEG400, polyethylene glycol 1500, Macrogol 4000, polyethylene glycol 6000, glycerin gelatine, polysorbate60, polysorbate65, polyoxyethylene condensation substance Idropostal, polyoxyethylene monostearate or poloxamer;
Hydrogenated oil and fat comprises one or more in hydrogenated vegetable oil, hydrogenated groundnut, castor oil hydrogenated or cotmar;
Glyceride comprises Adeps Solidus, Massa Estarinum A, Massa Estarinum AS, Massa Estarinum B, Massa Estarinum C, Massa Estarinum D, Massa Estarinum E, Massa Estarinum I, Massa Estarinum T, Massa Mf13, Suppository Base W, Suppository Base AB, Suppository Base A, Suppository Base B, Suppository Base BC, Suppository Base BD, Suppository Base BBC, Suppository Base E, Suppository Base BCF, Suppository Base C, Suppository Base D, Suppository Base299, Wecobee W, Wecobee K, Wecobee S, Wecobee M, Wecobee ES, Massuppol, Massuppol15, Suppocire OSI, Suppocire OSIx Suppocire A, Suppocire B, Suppocire C, Suppocire D, Suppocire DM, Suppocire H, Suppocire L, Tegester Triglyceride Bases-9, Tegester Triglyceride Bases-MA, one or more in Tegester Triglyceride Bases-57,
Distillate oil comprises fractional distillation Petiolus Trachycarpi oil or fractionated coconut oil;
Colloidal compound comprises one or more in arabic gum, gelatin or pectin;
Preferably, substrate comprises one or more in Acrawax, natural acid ester or water-soluble base.
The substrate of English name of the present invention is included (L. La Heman in < < industrial pharmacy theory and practice > > book, H.A. sharp Berman, J.L. block Buddhist nun uncommon. industrial pharmacy theory and practice, Chemical Industry Press, second edition: 215-217).
The present invention has adopted original creation " intravaginal sticking type medicine-feeding technology ", and this technology by adding expansion carrier to realize in suppository.Ordinary suppository is due to the relation of gravity, no matter user be standing, sitting posture or lie under formula position, always have vagina can not or the less pastille substrate that touches, after expansion carrier expands, pastille substrate can be 360 ° and contact with vaginal walls, fully administration, 6 times of administration enlarged areas, medicine directly attaches to lesions position, makes the position that originally cannot contact medicine also can obtain effectively attaching treatment; And due to the buffer action that stype plays in the middle of vagina, make no longer to contact with each other between wound surface, thereby avoid superinfection, it is shown effect no longer repeatedly.In addition, " anti-side leakage key " design concept has been applied in the introducing of expansion carrier, because the expansion of expansion carrier tail end (non-pastille substrate) can be close to vaginal wall, and then prevent the outflow of medicine and substrate, reduce the pollution of medicated clothing and keep the valid density of medicine; And by " inner core coefficient of expansion control technology ", the swell value of carrier after saturated water suction that can make to expand is greater than 1.1.
Further improve, the substrate in this expansible plug is the mixture of natural acid ester and water-soluble base, and wherein, the ratio of weight and number of natural acid ester and water-soluble base is 25-29:1.
Preferably, natural acid ester is Fructus Foeniculi fat, and water-soluble base is PEG400, and the ratio of weight and number of Fructus Foeniculi fat and PEG400 is 27.5:1.The mixing of natural acid ester and water-soluble base can improve melting of expansible plug and become the time limit, can reduce the zest of water-soluble base simultaneously.
In order to improve dissolution and the bioavailability of ornidazole vagina expansible plug, in pastille substrate of the present invention, also comprise that weight portion is the two triglycerol monostearates of 15-30, weight portion is that propylene glycol diacetate and the weight portion of 15-30 part is the oil phase of 3-10 part; Oil phase comprises one or more in ethyl lactate, ethyl oleate or isopropyl palmitate; Preferably, oil phase is ethyl lactate.
In order to improve the stability of expansible plug, the present invention also comprises that in pastille substrate weight portion is the sodium alginate of 2-6 part.
For the stability of expansible plug is further provided, prevent from becoming sour, pastille substrate of the present invention also comprises that weight portion is the methyl hydroxybenzoate of 1-3 part and the propylparaben of 0.2-0.5 part.
Further improve, the parts by weight of the each composition of ornidazole vagina expansible plug are preferably:
Ornidazole vagina expansible plug bioavailability provided by the invention is high, stable in properties, and little to the zest of vagina, safe and reliable.
Preferably, the swell value of expansion carrier of the present invention after saturated water suction is greater than 1.5, and swell value is swell value radially; Expansion carrier includes but not limited to cotton sliver, also can comprise the sterilizable material that other can expand, as non-woven fabrics, elastic fiber etc.
Pastille substrate of the present invention is Semi surrounding type and is coated in the front end 1/5-4/5 place of expansion carrier, according to " human engineering suppository " shape, is designed to the shapes such as duckbill, spherical, avette, bullet shaped, torpedo, cylindrical, taper shape or clavate.
The expansion carrier rear end of ornidazole vagina expansible plug of the present invention is connected with bracing wire, suppository after expansion, by the rear end bracing wire of tractive expansion carrier, the dead bark that be adsorbed on the virus being killed on expansion carrier, toxin, comes off also pulls out external in the lump, change dressings at every turn and just equal to do once thoroughly clean to vagina, fundamentally prevention of inflammation recurs again, and this expansible plug belongs to " integrated dosage form is cleaned in treatment ".
In order to reach ornidazole vagina expansible plug of the present invention, meet the effect that water can expand rapidly, after the water suction of expansion carrier, the maximum water absorption of every is not less than 1.5 milliliters; Suitable water absorption, can guarantee suitable swell value, and too low or too high water absorption all can cause bad impact.When water absorption is too low, can not guarantee that ornidazole vagina expansible plug of the present invention meets the feature that water expand and make to expand insufficient; When water absorption is too high, the absorption ingredient that expansion carrier can be too much and limit its diffusion; Therefore, water absorption is too low or too high, is not the desired expansion carrier of the present invention.
The present invention provides the preparation method of ornidazole vagina expansible plug on the other hand, and the method comprises the steps:
1) preparation of pastille substrate:
A. substrate is placed in to water-bath heating and melting, makes fused mass;
B. ornidazole is pulverized, crossed 80-100 mesh sieve, under stirring, be distributed in oil phase, continue to stir, then add two triglycerol monostearate and propylene glycol diacetates, mix homogeneously, makes emulsion; C. the emulsion of step b and sodium alginate and methyl hydroxybenzoate and propylparaben are mixed homogeneously,
Make mixture;
D. the mixture of step c is added in the fused mass of step a, mix homogeneously, makes pastille substrate;
2) preparation of expansible plug: pastille substrate is poured in bolt mould, inserted expansion carrier, cooling and shaping, makes suppository.
The preparation method of ornidazole vagina expansible plug of the present invention has adopted " the integrally formed technology of the disposable fill of stype ".
The present invention also provides the detection method of ornidazole vagina expansible plug on the other hand, and this detection method comprises swell value assay method, weight differential detection method, assay etc.
Wherein swell value assay method comprises:
A. along radially the choosing a bit or some points of described ornidazole vagina expansible plug end face, measure the initial length H of described expansion carrier;
B. after the saturated water suction of described ornidazole vagina expansible plug, be determined at the rear length h of place, selected location expansion carrier expansion in a step;
While c. calculating described swell value, according to I formula, calculate;
（I）
Wherein, p represent axial swell value, h represent to expand after length, H represent initial length;
Or described swell value assay method is as follows:
D. along described ornidazole vagina expansible plug axially choose a place or some positions, measure the initial diameter R of described expansion carrier;
E. after the saturated water suction of described ornidazole vagina expansible plug, be determined at the rear diameter r of place, selected location expansion carrier expansion in d step;
While f. calculating described swell value, by II formula, calculate;
（II）
Wherein, P represent swell value, r radially represent to expand after diameter, R represent initial diameter; Described weight differential assay method comprises:
G. get described ornidazole vagina expansible plug, take weight M;
H. get the expansion carrier in the described ornidazole vagina expansible plug that scrapes pastille substrate, dry, take weight m, according to the weight X of pastille substrate as described in calculating as III formula:
X=M-m
（Ⅲ）。
Further, in the detection method of ornidazole vagina expansible plug of the present invention, melt and become after time limit detection, then carry out following at least one detection method:
1) swell value assay method is as follows:
A. first along radially the choosing a bit or some points of described ornidazole vagina expansible plug end face, measure after the initial length H of described expansion carrier, then the different angles of rolling measure several times, Hi averages;
B. described ornidazole vagina expansible plug melts after the detection of change time limit, is determined at the rear length h of place, selected location expansion carrier expansion in a step; The different angles of rolling are again measured several times, ask the rear average length hi that expands;
While c. calculating described swell value, according to I formula, calculate;
（I）
Wherein, pi represent axial swell value, hi represent to expand after average length, Hi represent average initial length;
Or described swell value assay method is as follows:
D. first an angle along described ornidazole vagina expansible plug axially choose a place or some positions, measure after the initial diameter R of described expansion carrier, then the different angles of rolling measure several times, Ri averages;
E. described ornidazole vagina expansible plug melts after the detection of change time limit, is determined at the rear diameter r of place, selected location expansion carrier expansion in d step; The different angles of rolling are again measured several times, ask the rear average diameter ri that expands;
While f. calculating described swell value, by II formula, calculate;
（II）
Wherein, Pi represent swell value, ri radially represent to expand after average diameter, Ri represent average initial diameter.
The wherein said change time limit assay method (two appendix of existing Chinese Pharmacopoeia) that melts comprising: gets 3 of described ornidazole vagina expansible plugs, in room temperature, places after 1 hour, be placed on respectively on lower floor's plectane of 3 metal rack, pack in sleeve pipe separately, and fixing with hook.Unless otherwise specified, said apparatus is dipped vertically into respectively and is filled in the container of 37.0 ± 0.5 ℃ of water that is no less than 4L, its upper end position should, at 90mm place, underwater, fill a rot in container, every 10 minutes, overturn this device once in solution.Above numerical range should not be construed as limitation of the present invention, and the technical scheme in above-mentioned numerical range is not in protection scope of the present invention yet.
2) weight differential assay method:
G. get described ornidazole vagina expansible plug, take weight M;
H. scrape pastille substrate, expansion carrier is placed in to 20-90 ℃ of organic solvent, take out, in 50-150 ℃ of dry 1-10h, take weight m, according to the weight X of pastille substrate as described in the calculating of III formula
X=M-m（Ⅲ）
Wherein, described organic solvent is selected from one or more in ethanol, methanol or isopropyl alcohol.
Further, in the detection method of ornidazole vagina expansible plug of the present invention, expansion carrier is cotton sliver, and detection method comprises following at least one method:
1) swell value assay method:
Get 3 of ornidazole vagina expansible plugs, with slide gauge, survey its afterbody cotton sliver diameter, roll approximately 90 ° and survey once again, survey twice for every, obtain 2 meansigma methods Ri of every mensuration; By above-mentioned 3 bolts be used for melting become the time limit measure finish after, take out immediately residue cotton sliver, treat disconnected of water, all gently be placed on glass plate, with slide gauge, measure two ends and middle three positions of each cotton sliver, roll after approximately 90 ° and measure again three positions, each cotton sliver obtains six data altogether, 6 meansigma methods ri that obtain mensuration, calculate the swell value Pi of every, and the swell value of three bolts all should be greater than 1.5.
2) weight differential assay method:
Get 10 of ornidazole vagina expansible plugs, accurately weighed weight respectively, gently scrape pastille substrate (must not lose cotton sliver), cotton sliver is placed in to the 200-400ml ethanol of 50-80 ℃, preferably, cotton sliver is placed in to the 300ml ethanol of 60-70 ℃, and 80khz frequency ultrasonic cleaning 5 minutes, the remaining stromatolysis in cotton sliver surface is removed, taking out cotton sliver firmly extracts, with filter paper, inhale 3 times again, in 105 ℃, be dried 2 hours, take out, room temperature was placed after 1 hour, accurately weighed cotton sliver weight respectively, obtain every pastille substrate weight and average pastille substrate weight, every pastille substrate weight and average pastille substrate weight ratio are, what exceed average pastille substrate weight ± 10% must not be more than 2, and must not there is 1 times of 1 overrun.
The assay method of the swell value of ornidazole vagina expansible plug provided by the present invention adopts repeatedly measuring method of multi-angle, has improved the accuracy of measuring, and has increased the operability of measuring, and method is easier to judgement; When carrying out the standard detection ornidazole vagina expansible plug of the present invention of state-promulgated pharmacopoeia appendix weight differential, substrate need be scraped off, due to the scraping degree difference of operator's grasp, cause every scraping degree difference larger, so the present invention adopts the substrate on dissolution with solvents expansible plug surface, through verification experimental verification, when adopting hot ethanol to clean the substrate on expansible plug surface, result is better, and repeatability is higher, and weight differential assay method is more convenient stable.
Content assaying method is according to Chinese Pharmacopoeia appendix V D high effective liquid chromatography for measuring.
It is high that ornidazole vagina expansible plug provided by the present invention has bioavailability, the high beneficial effect that waits of stability, and this ornidazole vagina expansible plug has adopted six leading technologies of original creation, in described ornidazole vagina expansible plug, expand and applied " the disposable fill of stype is integrally formed " technology of original creation adding of carrier, " control of the inner core coefficient of expansion " technology, " human engineering bolt type " technology, " treatment is clean integrated " dosage form, " administration of intravaginal sticking type " technology, " anti-side leakage key design " six technology, this expansion carrier can make the pastille substrate of ornidazole vagina expansible plug fully contact with vaginal walls, and prevent medicinal liquid outflow, also there is the effect that cleaning vagina prevents superinfection, select special substrate to reduce the zest of ornidazole vagina expansible plug to vagina, in pastille substrate, add two triglycerol monostearates, propylene glycol diacetate and oil phase ornidazole can be made to microemulsion, the dissolubility that it has increased ornidazole, has improved the bioavailability of ornidazole, the sodium alginate simultaneously adding in pastille substrate and methyl hydroxybenzoate and propylparaben have improved the stability of ornidazole vagina expansible plug, and make this expansible plug be difficult for becoming sour.
Accompanying drawing explanation
The schematic diagram of Fig. 1 and Fig. 2 swell value assay method.
The specific embodiment
Embodiment 1
Preparation method:
1) preparation of pastille substrate:
A. semi-synthetic fatty acid glyceride is placed in to water-bath heating and melting, makes fused mass;
B. take the ornidazole of recipe quantity, pulverize, cross 80 mesh sieves, add the fused mass mix homogeneously of step a, make pastille substrate;
2) preparation of expansible plug: pastille substrate is poured in bolt mould, inserted cotton sliver, cooling and shaping, makes 100 pieces of spherical suppositorys, every piece of heavily about 3.2g.
Embodiment 2
Preparation method: make 100 pieces of torpedo suppositorys by the method for embodiment 1, every piece of heavily about 5.0g.
Embodiment 3
Preparation method:
1) preparation of pastille substrate:
A. Ke Kemu fat, polyoxyethylene monostearate and polysorbate60 are placed in to water-bath heating and melting, make fused mass;
B. take the ornidazole of recipe quantity, pulverize, cross 100 mesh sieves, under stirring, be distributed in ethyl lactate, continue to stir, then add two triglycerol monostearate and propylene glycol diacetates, mix homogeneously, makes emulsion;
C. the emulsion of step b is added in the fused mass of step a, mix homogeneously, makes pastille substrate;
2) preparation of expansible plug: pastille substrate is poured in bolt mould, inserted cotton sliver, cooling and shaping, makes 100 pieces of bullet shaped suppositorys, every piece of heavily about 2.7g.
Embodiment 4
Preparation method: make 100 pieces of cylindrical suppositorys by the method for embodiment 3, every piece of heavily about 3.5g.
Embodiment 5
Preparation method:
1) preparation of pastille substrate:
A. Oleum Linderae and glycerin gelatine are placed in to water-bath heating and melting, make fused mass;
B. take the ornidazole of recipe quantity, pulverize, cross 90 mesh sieves, under stirring, be distributed in isopropyl palmitate, continue to stir, then add two triglycerol monostearate and propylene glycol diacetates, mix homogeneously, makes emulsion;
C. the emulsion of step b is mixed homogeneously with sodium alginate, make mixture;
D. the mixture of step c is added in the fused mass of step a, mix homogeneously, makes pastille substrate;
2) preparation of expansible plug: pastille substrate is poured in bolt mould, inserted cotton sliver, cooling and shaping, makes 100 pieces of duckbill suppositorys, every piece of heavily about 3.6g.
Embodiment 6
Preparation method: make 100 pieces of avette suppositorys by the method for embodiment 5, every piece of heavily about 3.5g.
Embodiment 7
Preparation method:
1) preparation of pastille substrate:
A. Fructus Foeniculi fat and PEG400 are placed in to water-bath heating and melting, make fused mass;
B. take the ornidazole of recipe quantity, pulverize, cross 100 mesh sieves, under stirring, be distributed in ethyl lactate, continue to stir, then add two triglycerol monostearate and propylene glycol diacetates, mix homogeneously, makes emulsion;
C. the emulsion of step b and sodium alginate and methyl hydroxybenzoate and propylparaben are mixed homogeneously, make mixture;
D. the mixture of step c is added in the fused mass of step a, mix homogeneously, makes pastille substrate;
2) preparation of expansible plug: pastille substrate is poured in bolt mould, inserted cotton sliver, cooling and shaping, makes 100 pieces of clavate suppositorys, every piece of heavily about 4.4g.
Embodiment 8
Preparation method: make 100 conical suppositorys by the method for embodiment 7, every piece of heavily about 1.8g.
Embodiment 9
Preparation method: make 100 clavate suppositorys by the method for embodiment 7, every piece of heavily about 4.2g.
Embodiment 10(CN101632658)
Preparation method: be prepared into 100 pieces of duckbill suppositorys by disclosed method in CN101632658, every piece of heavily about 2.1g.
Test example 1
The outward appearance of the ornidazole vagina expansible plug that embodiment of the present invention 1-9 provides, containing the amount (labelled amount %) of ornidazole, melt the amount that becomes time limit, related substance testing result in Table 1;
The testing result of the ornidazole vagina expansible plug indices of table 1 embodiment 1-9
Test example 2 stability tests
1. accelerated test
Get the ornidazole vagina expansible plug of embodiment 7, be divided into 3 batches, be numbered respectively sample 1, sample 2 and sample 3, get the Ornidazole Suppository product in contrast of embodiment 10, by sample and reference substance all at 25 ℃ ± 2 ℃, relative humidity is to place 6 months under 65% ± 5% condition, at duration of test, sample respectively once 1 month, 2 months, 3 months, 6 the end of month, by the regulation in Chinese Pharmacopoeia, detect the character of expansible plug, containing the amount (labelled amount %) of ornidazole, melt the amount that becomes time limit and related substance, result of the test is in Table 2;
Three batch samples of table 2 embodiment 7 and the accelerated test result of reference substance
Ornidazole vagina expansible plug provided by the present invention as can be seen from the table, under the environment of constant temperature high humidity, places after 6 months, the color of described expansible plug, the amount that contains ornidazole, all significantly variations of generation of amount of melting change time limit and related substance; And the ornidazole suppository of embodiment 10 is placed after 6 months under high humidity, suppository flavescence, there is speckle in surface, fracture phenomena occurs, and the content of ornidazole significantly declines, and melts change duration, the amount of related substance significantly increases; Show that ornidazole vagina expansible plug of the present invention stability compared with ornidazole suppository significantly improves.
2. long term test
Get the ornidazole vagina expansible plug of embodiment 7, be divided into 3 batches, be numbered respectively sample 1, sample 2 and sample 3, get the Ornidazole Suppository product in contrast of embodiment 10, by sample and reference substance all at 25 ℃ ± 2 ℃ of temperature, relative humidity is to place 36 months under 60% ± 10% condition, sampling in every 3 months once, respectively at 0 month, 3 months, 6 months, 9 months, sampling in 12 months, detect the character of expansible plug, containing the amount (labelled amount %) of ornidazole, melt the amount that becomes time limit and related substance, after 12 months, still need to continue to investigate index of correlation, respectively at 18 months, 24 months, sampling in 36 months detects, and testing result and comparison in 0 month, result of the test is in Table 3,
Three batch samples of table 3 embodiment 7 and the long-term test results of reference substance
Ornidazole vagina expansible plug provided by the invention as can be seen from the table, under the environment of constant temperature high humidity, places after 36 months, the color of described expansible plug, the amount that contains ornidazole, all significantly variations of generation of amount of melting change time limit and related substance; And the ornidazole suppository of embodiment 10 was placed after 9 months, suppository darkens, and speckle appears in surface, places after 12 months, and fracture phenomena occurs on suppository surface; And the content of ornidazole significantly declines in ornidazole suppository, to melt and become time limit significant prolongation, the amount of related substance significantly increases; Show that ornidazole vagina expansible plug of the present invention stability compared with ornidazole suppository significantly improves; And the holding time is long.
Test example 3 swell values are measured
Method one
Get 3 of ornidazole vagina expansible plugs, with slide gauge, survey its afterbody cotton sliver diameter, roll approximately 90 ° and survey once again, survey twice for every, obtain 2 meansigma methods Ri of every mensuration; By above-mentioned 3 bolts be used for melting become the time limit measure finish after, take out immediately residue cotton sliver, treat disconnected of water, all gently be placed on glass plate, with slide gauge, measure two ends and middle three positions of each cotton sliver, roll after approximately 90 ° and measure again three positions, each cotton sliver obtains six data altogether, 6 meansigma methods ri that obtain mensuration, calculate the swell value Pi of every, and the swell value of three bolts is all greater than 1.5.
As shown in table 4 according to the swell value of the ornidazole vagina expansible plug of above-mentioned swell value assay method mensuration embodiment 1-9;
The swell value of table 4 embodiment 1-9 ornidazole vagina expansible plug
Method two
As depicted in figs. 1 and 2:
1) swell value assay method:
A. first along described vagina expansible plug end face, radially choose C1, C2, tri-points of C3, with slide gauge, measure after initial length H1, H2, the H3 of described expansion carrier, the 90 ° of measurements of rolling again, radially choose C1, C4, tri-some slide gaugies of C5 along described vagina expansible plug end face are measured after initial length H4, the H5 of described expansion carrier, H6, ask the meansigma methods Hi of H1, H2, H3, H4, H5 and H6;
B. described vagina expansible plug melts and becomes after the time limit detects, length h1, h2, h3 after being determined at selected C1, C2 in a step, tri-position expansion carriers of C3 and expanding with slide gauge; Roll 90 °, length h4, h5, h6 after being determined at selected C1, C4 in a step, tri-position expansion carriers of C5 and expanding with slide gauge, ask the average length of h1, h2, h3, h4, h5 and h6 again, be expand after average length hi;
While c. calculating described swell value, according to I formula, calculate;
（I）
Wherein, pi represent axial swell value, hi represent to expand after average length, Hi represent average initial length;
Or, swell value assay method:
D. first an angle, along described vagina expansible plug, axially choose A1, A2 and tri-points of A3, with slide gauge, measure after initial diameter R1, the R2 and R3 of described expansion carrier, roll again 90 °, along described vagina expansible plug, axially choose B1, B2 and tri-points of B3, with slide gauge, measure after initial diameter R4, the R5 and R6 of described expansion carrier, ask the meansigma methods Ri of R1, R2, R3, R4, R5 and six initial diameters of R6;
E. described vagina expansible plug melts and becomes after the time limit detects, and after being determined in d step selected A1, A2 and A3 position expansion carrier and expanding, diameter is respectively r1, r2 and r3; Roll again 90 ° measure in d step selected B1, B2 and B3 position expansion carrier and expand after diameter be respectively r4, r5 and r6, ask the meansigma methods of r1, r2, r3, r4, r5 and r6, average diameter ri afterwards must expand;
While f. calculating described swell value, by II formula, calculate;
（II）
Wherein, Pi represent swell value, ri radially represent to expand after average diameter, Ri represent to put down
All initial diameters.
Test example 4 weight differential determination tests
Get 10 of ornidazole vagina expansible plugs, accurately weighed weight respectively, gently scrape pastille substrate (must not lose cotton sliver), cotton sliver is placed in to the 300ml ethanol of 60-70 ℃, if (substrate comprises glycerin gelatine, cotton sliver is placed in to the 300ml water of 60-70 ℃), and 80khz frequency ultrasonic cleaning 5 minutes, the remaining stromatolysis in cotton sliver surface is removed, taking out cotton sliver firmly extracts, with filter paper, inhale 3 times again, in 105 ℃, be dried 2 hours, take out, room temperature was placed after 1 hour, accurately weighed cotton sliver weight respectively, obtain every pastille substrate weight and average pastille substrate weight, every pastille substrate weight and average pastille substrate weight ratio are, what exceed average pastille substrate weight ± 10% must not be more than 2, and must not there is 1 times of 1 overrun,
Repeat aforesaid operations, detect the ornidazole vagina expansible plug of embodiment 1-9, the equal conformance with standard of its weight differential.
The therapeutic effect of test example 5 to trichomonal vaginitis
1. physical data: accept trichomonal vaginitis patient 40 examples for medical treatment, be Status of Married Child-bearing aged Women, age 26-55 year, patient's clinical manifestation is mainly that vaginal secretions increases and pruritus vulvae, or have scorching hot, pain, sexual anhedonia etc., secretions feature is thin purulence, cystose, frowziness, vaginal mucosa hyperemia is shown in inspection, and severe patient has petechia, the visible infusorian of vaginal secretions microscopy;
2. grouping and drug treatment method:
40 routine patients are divided into treatment group 24 example and matched group 16 examples at random;
Treatment group: cleaning after pudendum before sleeping every night, give the ornidazole vagina expansible plug of embodiment 7, every day 1 time, 7 days is a course for the treatment of; Finish rear 5-7 days further consultation the course for the treatment of;
Matched group: cleaning after pudendum before sleeping every night, give commercially available Ornidazole Suppository, every day 1 time, 7 days is a course for the treatment of; Finish rear 5-7 days further consultation the course for the treatment of;
3. criterion of therapeutical effect:
Recovery from illness: the transference cures such as frequent micturition, dysurea, pruritus vulvae, leucorrhea disappears, and pudendum, vagina are without hyperemia, and it is normal that vaginal mucosa recovers, and microscopy is without infusorian;
Effective: the transference cures such as frequent micturition, dysurea, pruritus vulvae, leucorrhea is treated front obvious minimizing, and vaginal mucosa is congested to be reduced more than 2/3, and microscopy is without infusorian;
Effective: the symptoms such as frequent micturition, dysurea, pruritus vulvae alleviate, and leucorrhea is treated front minimizing, vaginal mucosa is congested reduces 1/2, and microscopy has infusorian;
Invalid: after treatment, symptom, sign, vagina cleanness degree are not improved, and microscopy has infusorian;
4. therapeutic outcome
Treatment group and matched group compare in Table 5 the therapeutic effect of trichomonal vaginitis;
Table 5 liang group is to the comparison of trichomonal vaginitis therapeutic effect
| Group | Case load | Disease more | Effective | Effectively | Invalid | Effective percentage (%) | Relapse rate (%) |
| Treatment group | 26 | 21 | 3 | 2 | 0 | 100 | 0 |
| Matched group | 14 | 9 | 1 | 2 | 2 | 85.7 | 7.1 |
Two groups of curative effect comparison treatment groups and the matched group property of there are differences (P ﹤ 0.05);
5. conclusion
Ornidazole vagina expansible plug reaches 100% to the effective percentage of trichomonal vaginitis, and curative effect is better than matched group.
The irritation test of test example 6 ornidazole vagina expansible plugs to rabbit vagina mucosa
1. animal and material
10 of rabbit, scale of construction 2.0-3.0kg, is in a good state of health;
The disclosed Ornidazole Suppositories such as the ornidazole vagina expansible plug of embodiment 7 and Ji Cunyuan;
2. test method
By 10 rabbit, be divided at random 5 of 5 for the treatment of groups and matched groups, in the rabbit vagina for the treatment of group, give 1 piece of the ornidazole vagina expansible plug of embodiment 7; The rabbit of matched group gives 1 piece of the disclosed Ornidazole Suppository such as Ji Cunyuan; Before each administration, by warm water by clean the vagina cleaning of rabbit; Two groups of equal successive administrations 7 days; Every day, observed and recorded vaginal mucosa had or not redness, congested situation, and observed and recorded rabbit general status, body weight, diet etc.; After last administration, 24h puts to death rabbit, gets rabbit vagina tissue, and utilizes 10% formalin to be fixed, and carries out histopathologic examination;
3. result of the test
Treatment group and matched group the results are shown in Table 6 to the irritation test of rabbit mucosa;
The irritation test of table 6 liang group to rabbit vagina mucosa
4. conclusion:
Ornidazole vagina expansible plug of the present invention is to the effect of rabbit vagina mucosa nonirritant.
Claims (12)
1. an ornidazole vagina expansible plug, it is characterized in that, described expansible plug comprises that weight portion is the ornidazole of 25-60 part, weight portion is that substrate and the weight portion of 65-200 part is the expandable expansion carrier of 60-400 part, described ornidazole and substrate formed pastille substrate are coated in expansion carrier surface, and the swell value of described expansion carrier after saturated water suction is greater than 1.1;
Described substrate comprises one or more in Acrawax, natural acid ester or water-soluble base;
Described Acrawax comprises one or more in mixed fatty glycerides, propylene glycol stearate, fixed oil, semi-synthetic fatty acid glyceride, semi-synthetic cocos nucifera oil ester, Witepsol, semi-synthetic Petiolus Trachycarpi grease or semi-synthetic Fructus Litseae ester;
Described natural acid ester comprises one or more in oleum sapii, Oleum Linderae, Fructus Foeniculi fat, Ke Kemu fat or cocoa butter;
Described water-soluble base comprises one or more in PEG400, polyethylene glycol 1500, Macrogol 4000, polyethylene glycol 6000, glycerin gelatine, polysorbate60, polysorbate65, polyoxyethylene monostearate or poloxamer.
2. ornidazole vagina expansible plug as claimed in claim 1, is characterized in that, described substrate is the mixture of natural acid ester and water-soluble base, and the ratio of weight and number of described natural acid ester and water-soluble base is 25-29:1.
3. ornidazole vagina expansible plug as claimed in claim 2, is characterized in that, described natural acid ester is Fructus Foeniculi fat, and described water-soluble base is PEG400, and the ratio of weight and number of described Fructus Foeniculi fat and PEG400 is 27.5:1.
4. ornidazole vagina expansible plug as claimed in claim 1, is characterized in that, described pastille substrate also comprises that weight portion is the two triglycerol monostearates of 15-30, and weight portion is that propylene glycol diacetate and the weight portion of 15-30 part is the oil phase of 3-10 part; Described oil phase comprises one or more in ethyl lactate, ethyl oleate or isopropyl palmitate; Preferably, described oil phase is ethyl lactate.
5. ornidazole vagina expansible plug as claimed in claim 4, is characterized in that, described pastille substrate also comprises that weight portion is the sodium alginate of 2-6 part.
6. ornidazole vagina expansible plug as claimed in claim 5, is characterized in that, described pastille substrate also comprises that weight portion is the methyl hydroxybenzoate of 1-3 part and the propylparaben of 0.2-0.5 part.
7. ornidazole vagina expansible plug as claimed in claim 6, is characterized in that, the parts by weight of the each composition of described expansible plug are:
8. the ornidazole vagina expansible plug as described in as arbitrary in claim 1-7, is characterized in that, the swell value of described expansion carrier after saturated water suction is greater than 1.5, and described swell value is swell value radially; Described expansion carrier is cotton sliver; Described pastille substrate is Semi surrounding type and is coated in the front end 1/5-4/5 place of described expansion carrier, and the rear end of described expansion carrier is connected with bracing wire; After described expansion carrier water suction, the maximum water absorption of every is not less than 1.5 milliliters.
9. the preparation method of ornidazole vagina expansible plug as claimed in claim 6, is characterized in that, described method comprises the steps:
1) preparation of pastille substrate:
A. substrate is placed in to water-bath heating and melting, makes fused mass;
B. ornidazole is pulverized, crossed 80-100 mesh sieve, under stirring, be distributed in oil phase, continue to stir, then add two triglycerol monostearate and propylene glycol diacetates, mix homogeneously, makes emulsion;
C. the emulsion of step b and sodium alginate and methyl hydroxybenzoate and propylparaben are mixed homogeneously, make mixture;
D. the mixture of step c is added in the fused mass of step a, mix homogeneously, makes pastille substrate;
2) preparation of expansible plug: pastille substrate is poured in bolt mould, inserted expansion carrier, cooling and shaping, makes suppository.
10. as the detection method of the ornidazole vagina expansible plug of claim 1-7 or 9 as described in arbitrary, it is characterized in that, described detection method comprises following at least one method:
1) swell value assay method is as follows:
A. along radially the choosing a bit or some points of described ornidazole vagina expansible plug end face, measure the initial length H of described expansion carrier;
B. after the saturated water suction of described ornidazole vagina expansible plug, be determined at the rear length h of place, selected location expansion carrier expansion in a step;
While c. calculating described swell value, according to I formula, calculate;
（I）
Wherein, p represent axial swell value, h represent to expand after length, H represent initial length;
Or swell value assay method is as follows:
D. along described ornidazole vagina expansible plug axially choose a place or some positions, measure the initial diameter R of described expansion carrier;
E. after the saturated water suction of described ornidazole vagina expansible plug, be determined at the rear diameter r of place, selected location expansion carrier expansion in d step;
While f. calculating described swell value, by II formula, calculate;
（II）
Wherein, P represent swell value, r radially represent to expand after diameter, R represent initial diameter;
2) weight differential assay method:
G. get described ornidazole vagina expansible plug, take weight M;
H. get the expansion carrier in the described ornidazole vagina expansible plug that scrapes pastille substrate, dry, take weight m, according to the weight X of pastille substrate as described in calculating as III formula:
X=M-m
（Ⅲ）。
The detection method of 11. ornidazole vagina expansible plugs as claimed in claim 10, is characterized in that, melts and becomes after time limit detection, then carry out following at least one detection method:
1) swell value assay method is as follows:
A. first along radially the choosing a bit or some points of described ornidazole vagina expansible plug end face, measure after the initial length H of described expansion carrier, then the different angles of rolling measure several times, Hi averages;
B. described ornidazole vagina expansible plug melts after the detection of change time limit, is determined at the rear length h of place, selected location expansion carrier expansion in a step; The different angles of rolling are again measured several times, ask the rear average length hi that expands;
While c. calculating described swell value, according to I formula, calculate;
（I）
Wherein, pi represent axial swell value, hi represent to expand after average length, Hi represent average initial length;
Or swell value assay method is as follows:
D. first an angle along described ornidazole vagina expansible plug axially choose a place or some positions, measure after the initial diameter R of described expansion carrier, then the different angles of rolling measure several times, Ri averages;
E. described ornidazole vagina expansible plug melts after the detection of change time limit, is determined at the rear diameter r of place, selected location expansion carrier expansion in d step; The different angles of rolling are again measured several times, ask the rear average diameter ri that expands;
While f. calculating described swell value, by II formula, calculate;
（II）
Wherein, Pi represent swell value, ri radially represent to expand after average diameter, Ri represent average initial diameter;
2) weight differential assay method:
G. get described ornidazole vagina expansible plug, take weight M;
H. scrape pastille substrate, expansion carrier is placed in to 20-90 ℃ of organic solvent, take out, in 50-150 ℃ of dry 1-10h, take weight m, according to the weight X of pastille substrate as described in the calculating of III formula
X=M-m（Ⅲ）
Wherein, described organic solvent is selected from one or more in ethanol, methanol or isopropyl alcohol.
The detection method of 12. ornidazole vagina expansible plugs as claimed in claim 11, is characterized in that, described expansion carrier is cotton sliver, and described detection method comprises following at least one method:
1) swell value assay method:
Get 3 of described ornidazole vagina expansible plugs, with slide gauge, survey its afterbody cotton sliver diameter, roll approximately 90 ° and survey once again, survey twice for every, obtain 2 meansigma methods Ri of every mensuration; By above-mentioned 3 bolts be used for melting become the time limit measure finish after, take out immediately residue cotton sliver, treat disconnected of water, all gently be placed on glass plate, with slide gauge, measure two ends and middle three positions of each cotton sliver, roll after approximately 90 ° and measure again three positions, each cotton sliver obtains six data altogether, 6 meansigma methods ri that obtain mensuration, calculate the swell value Pi of every, and the swell value of three bolts all should be greater than 1.5;
2) weight differential assay method:
Get 10 of described ornidazole vagina expansible plugs, accurately weighed weight respectively, gently scrape pastille substrate (must not lose cotton sliver), cotton sliver is placed in to the 200-400ml ethanol of 50-80 ℃, preferably, cotton sliver is placed in to the 300ml ethanol of 60-70 ℃, and 80khz frequency ultrasonic cleaning 5 minutes, the remaining stromatolysis in cotton sliver surface is removed, taking out cotton sliver firmly extracts, with filter paper, inhale 3 times again, in 105 ℃, be dried 2 hours, take out, room temperature was placed after 1 hour, accurately weighed cotton sliver weight respectively, obtain every pastille substrate weight and average pastille substrate weight, every pastille substrate weight and average pastille substrate weight ratio are, what exceed average pastille substrate weight ± 10% must not be more than 2, and must not there is 1 times of 1 overrun.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113908114A (en) * | 2021-10-29 | 2022-01-11 | 宁波第二激素厂 | Flugesterone acetate vaginal sponge |
| CN113975226A (en) * | 2021-10-29 | 2022-01-28 | 宁波第二激素厂 | Preparation method of fluoprogesterone acetate vaginal sponge |
| CN115837046A (en) * | 2022-11-23 | 2023-03-24 | 哈尔滨誉衡制药有限公司 | Ornidazole pessary and preparation method thereof |
| CN116327679A (en) * | 2023-04-23 | 2023-06-27 | 郑州大学第一附属医院 | Ornidazole suppository and preparation method thereof |
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| CN101069686A (en) * | 2006-05-12 | 2007-11-14 | 南京圣和药业有限公司 | Laevo-ornidazole vagina administration preparation, its preparing method and use |
| CN103181889A (en) * | 2012-11-29 | 2013-07-03 | 哈尔滨欧替药业有限公司 | Expandable vaginal suppository |
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2013
- 2013-12-31 CN CN201310750221.6A patent/CN103751094B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101069686A (en) * | 2006-05-12 | 2007-11-14 | 南京圣和药业有限公司 | Laevo-ornidazole vagina administration preparation, its preparing method and use |
| CN103181889A (en) * | 2012-11-29 | 2013-07-03 | 哈尔滨欧替药业有限公司 | Expandable vaginal suppository |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113908114A (en) * | 2021-10-29 | 2022-01-11 | 宁波第二激素厂 | Flugesterone acetate vaginal sponge |
| CN113975226A (en) * | 2021-10-29 | 2022-01-28 | 宁波第二激素厂 | Preparation method of fluoprogesterone acetate vaginal sponge |
| CN113908114B (en) * | 2021-10-29 | 2024-02-09 | 宁波第二激素厂 | Fluogesterone acetate vaginal sponge |
| CN113975226B (en) * | 2021-10-29 | 2024-02-09 | 宁波第二激素厂 | Preparation method of fluogesterone acetate vaginal sponge |
| CN115837046A (en) * | 2022-11-23 | 2023-03-24 | 哈尔滨誉衡制药有限公司 | Ornidazole pessary and preparation method thereof |
| CN116327679A (en) * | 2023-04-23 | 2023-06-27 | 郑州大学第一附属医院 | Ornidazole suppository and preparation method thereof |
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| CN103751094B (en) | 2016-02-24 |
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