CN103520089A - Metronidazole expandable vaginal suppository, and preparation method and detection method thereof - Google Patents

Abstract

The invention relates to a metronidazole expandable vaginal suppository, and a preparation method and a detection method thereof. The expandable vaginal suppository comprises metronidazole, a matrix and an expansion carrier. The drug-containing matrix also includes a resin; a resin compound formed by the resin with metronidazole can improve stability of the suppository and cooperate with an acidifier to prolong effect time of metronidazole on the vagina, extend therapeutic effect and maintain the specific acid environment and self-cleaning function of the vagina; and the chitosan can promote the absorption of metronidazole by the vagina and improve the bioavailability of the suppository. The metronidazole expandable vaginal suppository employs seven unique technologies and has beneficial effects of prevention of outflow liquid and secondary infection.

Description

Metronidazole vagina expansible plug and preparation method thereof and detection method

Technical field

The invention belongs to vaginal suppository field, particularly a kind of metronidazole vagina expansible plug and preparation method thereof and detection method.

Background technology

Metronidazole, chemistry Metronidazole by name, its structure is as follows:

Metronidazole poorly soluble, slightly molten in ethanol, slightly soluble in water, the clinical trichomonal vaginitis that is mainly used in; Common formulations comprises oral formulations, injection and suppository etc., but oral and injection, 15-30% case occurs take that digestive tract is as main untoward reaction; And metronidazole suppository is rectally, has overcome the untoward reaction of oral or injection, and do not had liver first-pass effect.

2010 editions one quality standard that discloses metronidazole suppository of Chinese Pharmacopoeia, also discloses the compound metronidazole suppository of pastille metronidazole in " Ministry of Public Health new drug become a full member standard " the 11st; Prior art also has some reports about metronidazole suppository to be exemplified below:

Xu Ziyou (Xu Ziyou, Chen Jiyue, Li Qiaoyun, Deng. the experimentation of vaginea suppository of metronidazole [J], Chinese Hospitals pharmacy impurity, 1994,14 (9): 387-388) disclose the sponge suppository of being made by metronidazole, gelatin, formalin and distilled water; Lin Biying (Lin Biying. two kinds of different substrates metronidazole suppository tablets in vitros contrasts [J], Strait Pharmaceutical Journal, 2002,14 (3): 12-13) disclose the ordinary suppository of being made by metronidazole and semi-synthetic fatty acid glyceride or glycerin gelatine; The poorly water-soluble of metronidazole in above suppository, it is undesirable in intravaginal absorption, affects its curative effect; And existing metronidazole suppository also exists not easy to clean as follows, easily pollution clothes active medicine and people's contact level are little, cause absorbing insufficient, do not bring into play the optimum curative effect of prescription; The technical problems such as drug effect is fast, and effective administration time is short.

Summary of the invention

In order to solve the problems of the technologies described above, give full play to the curative effect of metronidazole, the present invention has studied a kind of metronidazole vagina expansible plug and preparation method thereof; A kind of science detection method that can control above-mentioned metronidazole 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 metronidazole vagina expansible plug, described expansible plug comprises metronidazole, substrate and expandable expansion carrier, described metronidazole 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; The parts by weight of described each composition of expansible plug are:

Metronidazole 2.5-20

Substrate 50-220

Expansion carrier 50-400

Described substrate comprises one or more in Acrawax, natural acid ester, lipoidis substrate, water-soluble base, hydrogenated oil and fat, glyceride, distillate oil, wax work, stearate or colloidal compound;

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 lipoidis substrate comprises lanoline or lanonol;

Described 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;

Described hydrogenated oil and fat comprises one or more in hydrogenated vegetable oil, hydrogenated groundnut, castor oil hydrogenated or cotmar;

Described 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 Base 299, Wecobee W, Wecobee K, Wecobee S, Wecobee M, Wecobee ES, Massuppol, Massuppol 15, 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, Tegester Triglyceride Bases-57, tripalmitin, glycerol tristearate, one or more in Gan You behenic acid ester or lauric acid triglyceride,

Described distillate oil comprises fractional distillation Petiolus Trachycarpi oil or fractionated coconut oil;

Described wax work comprises one or more in Brazil wax, spermaceti, cationic emulsified wax, Cera Flava or Cera Flava;

Described stearate comprises one or more in xylitan monostearate, stearic acid Petiolus Trachycarpi glyceride, polyethylene glycol mono stearate, ethylene glycol monostearate or glyceryl monostearate;

Described colloidal compound comprises one or more in arabic gum, gelatin or pectin.

The substrate of English name of the present invention include in " industrial pharmacy theory and practice " book (J.L. card Buddhist nun is uncommon for L. La Heman, H.A. profit Berman. 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 described 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, the parts by weight of described each composition of expansible plug are:

Metronidazole 5-15

Substrate 80-168

Expansion carrier 100-250

Described substrate is the mixture of Acrawax, lipoidis substrate and hydrogenated oil and fat, and the parts by weight of described Acrawax, hydrogenated oil and fat and lipoidis substrate are 6-10:1-4:1; Described mixed-matrix has overcome the low-melting technical problem of fat-soluble substrate, can increase the stability of suppository.

Further, described Acrawax is mixed fatty glycerides, and described hydrogenated oil and fat is hydrogenated groundnut, and described lipoidis substrate is lanoline, and the parts by weight of described each composition of expansible plug are:

Preferably, the pastille substrate of metronidazole vagina expansible plug of the present invention also comprises resin, described metronidazole and resin formation metronidazole resin complexes, and the ratio of weight and number of described metronidazole and resin is 1:1-3, described resin is selected from iRP-64,

iRP-69 or

one or more in IRP-88; Described resin complexes, has not only increased the stability of metronidazole, and then improves the stability of suppository, and metronidazole is can embedded resin inner, plays the effect that metronidazole discharges that delays, and increases the action time of suppository to vagina, the curative effect that extends suppository.

Further preferably, pastille substrate of the present invention also comprises that weight portion is the chitosan of 2-10 part; Described chitosan can promote the absorption of vagina to metronidazole, improves its bioavailability.

Curative effect for further prolong drug, make " prolonged drug layering release ", pastille substrate of the present invention also comprises that weight portion is the acidulant of 1-5 part, described acidulant is selected from one or more in polyacrylic acid, alginic acid, polylactic acid or polyuronic acid, described acidulant can guarantee the specific sour environment of intravaginal synergistically with resin, guarantee vagina self cleaning function, and can also with the resin action time of prolong drug to vagina synergistically, extend curative effect, within one day, be administered once, drug effect reaches 24 hours, improves patient compliance.

The swell value of expansion carrier of the present invention after saturated water suction is greater than 1.5, and described swell value is swell value radially; Described 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 the front end 1/5-4/5 place that Semi surrounding type is coated in described expansion carrier, according to " human engineering suppository " shape, is designed to the shapes such as duckbill, spherical, avette or bullet shaped, torpedo, cylindrical, taper shape or clavate.

The rear end of the expansion carrier of metronidazole vagina expansible plug of the present invention is connected with bracing wire, stype 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 is also pulled 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 metronidazole vagina expansible plug of the present invention, meet the effect that water can expand rapidly, after described expansion carrier water suction, 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 metronidazole of the present invention meets the feature that water expand and make to expand insufficient; When water absorption is too high, expansion carrier is understood too much absorption ingredient and is limited its diffusion.Therefore, water absorption is too low or too high, is not the desired expansion carrier of the present invention.

The invention provides the preparation method of metronidazole vagina expansible plug, 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. metronidazole is pulverized, crossed 80-100 mesh sieve, be dissolved in ethanol, make ethanol, under stirring, resin is joined in ethanol, mix homogeneously, dry, make metronidazole resin complexes;

C. metronidazole resin complexes is mixed homogeneously with chitosan, acidulant, make mixture;

D. by the fused mass of the mixture of c step and a step, mix homogeneously, makes pastille substrate;

2) pastille substrate is poured in bolt mould, inserted expansion carrier, cooling and shaping, makes suppository.

The preparation method of metronidazole 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 described metronidazole vagina expansible plug on the other hand, and described detection method comprises swell value assay method, weight differential detection method, assay etc.

Wherein said swell value assay method comprises:

A. along radially the choosing a bit or some points of described metronidazole vagina expansible plug end face, measure the initial length H of described expansion carrier;

B. after the saturated water suction of described metronidazole vagina expansible plug, be determined at the rear length h of selected location place's expansion carrier expansion in a step;

While c. calculating described swell value, according to I formula, calculate;

$p=\frac{h}{H}$

（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:

A. along described metronidazole vagina expansible plug axially choose a place or some positions, measure the initial diameter R of described expansion carrier;

B. after the saturated water suction of described metronidazole vagina expansible plug, be determined at the rear diameter r of selected location place's expansion carrier expansion in a step;

While c. calculating described swell value, press II formula and calculate;

$P=\frac{r}{R}$

（II）

Wherein, P represent swell value, r radially represent to expand after diameter, R represent initial diameter;

Described weight differential assay method comprises:

A. get described metronidazole vagina expansible plug, take weight M;

B. get the expansion carrier in the described metronidazole 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 metronidazole 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 metronidazole 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 metronidazole vagina expansible plug melts after the detection of change time limit, is determined at the rear length h of selected location place's 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;

$\mathrm{pi}=\frac{\mathrm{hi}}{\mathrm{Hi}}$

（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:

A. first an angle along described metronidazole 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;

B. described metronidazole vagina expansible plug melts after the detection of change time limit, is determined at the rear diameter r of selected location place's expansion carrier expansion in a step; The different angles of rolling are again measured several times, ask the rear average diameter ri that expands;

While c. calculating described swell value, press II formula and calculate;

$P_i=\frac{\mathrm{ri}}{\mathrm{Ri}}$

（II）

Wherein, Pi represent swell value, ri radially represent to expand after average diameter, Ri represent to put down

Equal initial diameter.

The wherein said change time limit assay method (two appendix of existing Chinese Pharmacopoeia) that melts comprising: gets 3 of described metronidazole 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.Except as otherwise herein provided, said apparatus is dipped vertically into respectively in the container that fills 37.0 ± 0.5 ℃ of water that are no less than 4L, its upper end position should fill a rot at 90mm place, underwater 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:

A. get described metronidazole vagina expansible plug, take weight M;

B. 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 metronidazole vagina expansible plug of the present invention, 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 metronidazole 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; Above-mentioned 3 bolts are used for melting and become after the time limit measures and finish, 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 three positions again, each cotton sliver obtains six data altogether, obtains 6 meansigma methods r of mensuration _i, calculate the swell value P of every _i, the swell value of three bolts all should be greater than 1.5.

2) weight differential assay method:

Get 10 of described metronidazole vagina expansible plugs, the accurately weighed weight of difference, 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, the accurately weighed cotton sliver weight of difference, 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 metronidazole 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 metronidazole vagina expansible plug of the present invention of state-promulgated pharmacopoeia appendix weight differential, substrate need be scraped off, the scraping degree of grasping due to operator is different, 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 described weight differential assay method is more convenient stable.

Described content assaying method is according to Chinese Pharmacopoeia appendix V D high effective liquid chromatography for measuring.

Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler; The methanol-water (20:80) of take is mobile phase; Detection wavelength is 320nm.Number of theoretical plate calculates and is not less than 2000 by metronidazole peak.

Algoscopy is got described metronidazole vagina expansible plug, accurately weighed, is cut into broken end, precision takes in right amount (being approximately equivalent to metronidazole 25mg), puts in 100ml measuring bottle, adds mobile phase appropriate, heated water bath heating is dissolved metronidazole, lets cool, and by mobile phase, is diluted to scale, put in ice bath cooling 1 hour, after taking-up, filter immediately, treat that subsequent filtrate puts to room temperature, precision measures subsequent filtrate 10 μ l, injection liquid chromatography, records chromatogram; Separately get metronidazole reference substance appropriate, accurately weighed, add mobile phase and dissolve and quantitatively dilute and make the solution that approximately contains 0.25mg in every 1ml, be measured in the same method, by external standard method, with calculated by peak area, obtain.

Metronidazole vagina expansible plug provided by the present invention has good effect, the high beneficial effect that waits of stability, and this metronidazole vagina expansible plug has adopted seven leading technologies of original creation, expansion carrier in described metronidazole vagina expansible plug add " the disposable fill of stype is integrally formed " technology of having applied original creation, " 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 metronidazole vagina expansible plug fully contact with vaginal walls, and prevent medicinal liquid outflow, also there is the effect that cleaning vagina prevents superinfection, the resin complexes that described resin and metronidazole form can improve suppository stability, and applied " prolonged drug layering release " technology with acidulant, extend the action time of metronidazole to vagina, the curative effect of prolong drug, guarantee intravaginal specific acid environment simultaneously, keep the self-cleaning function of vagina, described chitosan can promote the absorption of vagina to metronidazole, improves the bioavailability of suppository.

Accompanying drawing explanation

The vitro release result of the test of metronidazole vagina expansible plug described in Fig. 1 embodiment 2-8;

The schematic diagram of Fig. 2 and Fig. 3 swell value assay method.

The specific embodiment

Embodiment 1

Preparation method:

1) preparation of pastille substrate:

A. mixed fatty glycerides, hydrogenated groundnut and lanoline are placed in to water-bath heating and melting, make fused mass;

B. the metronidazole that takes recipe quantity is pulverized, and crosses 100 mesh sieves, with the fused mass of a step, mix homogeneously, makes pastille substrate;

2) pastille substrate is poured in bolt mould, inserted cotton sliver, cooling and shaping, makes 100 pieces of cylindrical suppositorys, every piece of heavily about 3.3g.

Embodiment 2

Preparation method:

1) preparation of pastille substrate:

A. propylene glycol stearate, hydrogenated vegetable oil and lanonol are placed in to water-bath heating and melting, make fused mass;

B. take the metronidazole of recipe quantity, pulverize, cross 80 mesh sieves, be dissolved in ethanol, make ethanol, will under stirring

iRP-64 joins in ethanol, and mix homogeneously is dry, makes metronidazole resin complexes;

C. the metronidazole resin complexes of b step is added in a step, mix homogeneously, makes pastille substrate;

2) pastille substrate is poured in bolt mould, inserted cotton sliver, cooling and shaping, makes 100 pieces of spherical suppositorys, every piece of heavily about 1.4g.

Embodiment 3

Preparation method: make 100 pieces of avette suppositorys by embodiment 2 methods, every piece of heavily about 3.2g.

Embodiment 4

Preparation method:

1) preparation of pastille substrate:

A. Witepsol, semi-synthetic fat glycerides, castor oil hydrogenated and lanoline are placed in to water-bath heating and melting, make fused mass;

B. metronidazole is pulverized, crossed 80 mesh sieves, be dissolved in ethanol, make ethanol, will under stirring

iRP-88 and

iRP-69 joins in ethanol, and mix homogeneously is dry, makes metronidazole resin complexes;

C. metronidazole resin complexes is mixed homogeneously with chitosan, make mixture;

D. the mixture of c step is added in a step, mix homogeneously, makes pastille substrate;

2) 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 4.6g.

Embodiment 5

Preparation method: make 100 pieces of conical suppositorys by embodiment 4 methods, every piece of heavily about 2.4g.

Embodiment 6

Preparation method:

1) preparation of pastille substrate:

A. mixed fatty glycerides, hydrogenated groundnut and lanoline are placed in to water-bath heating and melting, make fused mass;

B. metronidazole is pulverized, crossed 80 mesh sieves, be dissolved in ethanol, make ethanol, will under stirring

iRP-64 and

iRP-69 joins in ethanol, and mix homogeneously is dry, makes metronidazole resin complexes;

C. metronidazole resin complexes is mixed homogeneously with chitosan and alginic acid, make mixture;

D. by the fused mass of the mixture of c step and a step, mix homogeneously, makes pastille substrate;

2) pastille substrate is poured in bolt mould, inserted cotton sliver, cooling and shaping, makes 100 pieces of duckbill suppositorys, every piece of heavily about 3.5g.

Embodiment 7

Preparation method: make 100 pieces of torpedo suppositorys by embodiment 6 methods, every piece of heavily about 5.0g.

Embodiment 8

Preparation method: make 100 pieces of avette suppositorys by embodiment 6 methods, every piece of heavily about 3.9g.

Embodiment 9

Preparation method: mixed aliphatic ester is placed in to water-bath heating and melting, adds metronidazole mix homogeneously under stirring, make mixture, mixture is poured in bolt mould, cooling and shaping, makes 100, piece bullet shaped suppository, every piece of heavily about 3.3g.

Test example 1 stability test

1. accelerated test

Get metronidazole vagina expansible plug described in embodiment 1-8 and the common metronidazole suppository of embodiment 9, all at 30 ℃ ± 2 ℃ of constant temperature, relative humidity is to place 6 months under 65% ± 5% constant humidity condition, duration of test 1 month, 2 months, 3 months, sample respectively once 6 the end of month, press the regulation in Chinese Pharmacopoeia, detect the character of expansible plug, labelled amount (%) containing metronidazole, melt and become time limit and metronidazole related substance (%), the accelerated test of the metronidazole vagina expansible plug described in embodiment 1-6 the results are shown in Table 1, the accelerated test of the metronidazole vagina expansible plug described in embodiment 7-8 and the metronidazole suppository of embodiment 9 the results are shown in Table 2,

The accelerated test result of metronidazole vagina expansible plug described in table 1 embodiment 1-6

The accelerated test result of the metronidazole suppository of metronidazole vagina expansible plug and embodiment 9 described in table 2 embodiment 7-8

Metronidazole vagina expansible plug described in embodiment of the present invention 1-8, under the environment of constant temperature high humidity, places after 6 months as can be seen from the table, the color of described expansible plug, the labelled amount that contains metronidazole, melts and becomes the time limit and obvious variation does not occur related substance; And metronidazole ordinary suppository suppository described in embodiment 9 places after 2 months under high humidity, suppository color changes, and speckle appears in suppository surface, part suppository generation fracture phenomena; And the content of metronidazole significantly declines in described metronidazole suppository, to melt and become time limit significant prolongation, the amount of metronidazole related substance significantly increases; Show that metronidazole vagina expansible plug of the present invention compares stability with metronidazole suppository and significantly improve.

2. long term test

Get metronidazole vagina expansible plug described in embodiment 1-8 and the metronidazole suppository of embodiment 9, 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, labelled amount (%) containing metronidazole, melt and become time limit and metronidazole 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, the long-term test results of the metronidazole vagina expansible plug described in embodiment 1-3 is in Table 3, the long-term test results of the metronidazole vagina expansible plug described in embodiment 4-7 is in Table 4, the long-term test results of the metronidazole vagina expansible plug described in embodiment 8 and the metronidazole suppository of embodiment 9 is in Table 5,

The long-term test results of metronidazole vagina expansible plug described in table 3 embodiment 1-3

The long-term test results of the metronidazole vagina expansible plug of table 4 embodiment 4-7

The long-term test results of the metronidazole vagina expansible plug of table 5 embodiment 8 and the metronidazole suppository of embodiment 9

Metronidazole vagina expansible plug described in embodiment of the present invention 1-8, under the environment of constant temperature high humidity, places after 36 months as can be seen from the table, the color of described expansible plug, the labelled amount that contains metronidazole, melts and becomes the time limit and obvious variation does not occur related substance; And common metronidazole suppository described in embodiment 9 places after 3 months under high humidity, suppository color changes, and places after 9 months, and speckle appears in suppository surface, part suppository generation fracture phenomena; And the content of metronidazole significantly declines in described metronidazole suppository, to melt and become time limit significant prolongation, the amount of related substance significantly increases, and shows that metronidazole vagina expansible plug of the present invention compares stability with metronidazole suppository and significantly improve.

Test example 2 vitro release determination tests

The drug release rate of suppository detects: with reference to 2010 editions " Chinese Pharmacopoeia " appendix XIXD vitro drug release degree, check.

Get respectively the metronidazole vagina expansible plug described in above embodiment 2-8, put in medicament dissolution instrument, in 1h, 2h, 4h, 6h, 12h, 16h, 24h, sample respectively, by high performance liquid chromatography, detect stripping percentage rate, and calculate the cumulative release percentage rate of medicine, the results are shown in Figure 1.

As can be seen from the figure described in embodiment 2-8, metronidazole vagina expansible plug medicine slowly discharges in 24h; Illustrate that resin can extend the action time of expansion suppository to vagina, extends curative effect.

Test example 3 swell value determination tests

Method one

Get 3 of described metronidazole 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; Above-mentioned 3 bolts are used for melting and become after the time limit measures and finish, 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 three positions again, each cotton sliver obtains six data altogether, obtains 6 meansigma methods r of mensuration _i, calculate the swell value P of every _i, the swell value of three bolts is all greater than 1.5.

As shown in table 6 according to the swell value of metronidazole vagina expansible plug described in above-mentioned swell value assay method mensuration embodiment 1-8;

The swell value of table 6 embodiment 1-8 metronidazole vagina expansible plug

Embodiment	Average diameter (mm) before expanding	Average diameter (mm) after expanding	Swell value (doubly)	Result
					Embodiment 1	12.13	20.58	1.70	Qualified
Embodiment
	2	12.08	22.33	1.85	Qualified
Embodiment 3						11.96	19.87	1.66	Qualified
	Embodiment
4		12.33	22.36	1.81	Qualified
	Embodiment 5					12.24	21.78	1.78	Qualified
Embodiment
	6	12.18	22.54	1.85	Qualified
Embodiment 7						12.27	20.96	1.71	Qualified
	Embodiment
8		12.11	21.42	1.77	Qualified

Method two

As shown in Figures 2 and 3:

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-points of C5 along described vagina expansible plug end face are measured after initial length H4, H5, the H6 of described expansion carrier with slide gauge, ask the meansigma methods Hi of H1, H2, H3, H4, H5 and H6;

B. described vagina expansible plug melts after the detection of change time limit, with slide gauge, is determined at selected C1, C2 in a step, C3 tri-expansions of position expansion carriers rear length h1, h2, h3; Roll again 90 °, with slide gauge, be determined at selected C1, C4 in a step, C5 tri-expansions of position expansion carriers rear length h4, h5, h6, ask the average length of h1, h2, h3, h4, h5 and h6, be the rear average length hi that expands;

While c. calculating described swell value, according to I formula, calculate;

$\mathrm{pi}=\frac{\mathrm{hi}}{\mathrm{Hi}}$

（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, press II formula and calculate;

$P_i=\frac{\mathrm{ri}}{\mathrm{Ri}}$

（II）

Wherein, Pi represent swell value, ri radially represent to expand after average diameter, Ri represent average initial diameter.

Test example 4 weight differential determination tests

Get 10 of described metronidazole vagina expansible plugs, the accurately weighed weight of difference, gently scrape pastille substrate (must not lose cotton sliver), 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, the accurately weighed cotton sliver weight of difference, 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 metronidazole vagina expansible plug described in embodiment 1-8, the equal conformance with standard of its weight differential.

Test example 5 clinical trials

One, research method

(1) research approach is formulated with reference to relevant " clinical verification of the department of obstetrics and gynecology urogenital tract infection local application " content of Ministry of Health of the People's Republic of China's new drug clinical guidance principle.

(2) diagnostic criteria

1, symptom: thin cystose leucorrhoea grow in quantity and pruritus vulvae, can, with burn feeling, pain and sexual anhedonia, during as companion's urinary tract infection, have frequent micturition, urgent micturition, dysurea or hematuria;

2, gynecologial examination: vaginal mucosa and ectocervical are obviously congested, and have petechia, intravaginal to have a large amount of leucorrhea, is yellow-white, the faint yellow thin foam sample secretions of ash;

3, lab testing: visible infusorian under microscope;

(3) test case standard

Include case history standard in: in 21-50 year, meet the married woman of bacteriodiagnosis.

(4) Therapeutic Method

1, treatment group: the metronidazole vagina expansible plug described in the use embodiment of the present invention 6 is treated, and one of every day, 7 days is a course for the treatment of.

2, matched group: using metronidazole suppository treatment, one of every day, 7 days is a course for the treatment of.

(5) observation item

Therapeutic is observed

(1) symptom: vaginitis symptom, the amount of secretions, color, abnormal smells from the patient;

(2) gynecologial examination: comprise pudendum and vaginal secretions inspection;

(3) lab testing: comprise under mirror and checking.

(6) curative effect determinate standard

1, recovery from illness: transference cure, gynecologial examination and lab testing are normal;

2, effective: symptom obviously alleviates, gynecologial examination and lab testing are clearly better;

3, effective: symptom alleviates to some extent, gynecologial examination and lab testing take a turn for the better;

4, invalid: unchanged before and after treatment.

Two, therapeutic outcome

(1) two group of therapeutic effect to trichomonal vaginitis is relatively in Table 7;

Table 7 liang group is to the comparison of trichomonal vaginitis therapeutic effect

Group	Case load	Disease more	Effective	Effectively	Invalid	Effective percentage (%)
							Treatment group	42	34	4	2	2	95.2
Matched group	19	12	1	2	4	78.9

Two groups of curative effect comparison treatment groups are better than matched group.

Three, conclusion

Metronidazole vagina expansible plug reaches 95.2% to the effective percentage of trichomonal vaginitis, and curative effect is better than matched group; In its curative effect process of checking, do not find toxic and side effects, safe and reliable, evident in efficacy.

Claims (11)

1. a metronidazole vagina expansible plug, it is characterized in that, described expansible plug comprises metronidazole, substrate and expandable expansion carrier, described metronidazole and substrate formed pastille substrate are coated in expansion carrier surface, the swell value of described expansion carrier after saturated water suction is greater than 1.1, and the parts by weight of described each composition of expansible plug are:

Metronidazole 2.5-20

Substrate 50-220

Expansion carrier 50-400

Described substrate comprises one or more in Acrawax, natural acid ester, lipoidis substrate, water-soluble base, hydrogenated oil and fat, glyceride, distillate oil, wax work or colloidal compound;

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 lipoidis substrate comprises lanoline or lanonol;

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;

Described hydrogenated oil and fat comprises one or more in hydrogenated vegetable oil, hydrogenated groundnut, castor oil hydrogenated or cotmar;

Described glyceride comprises one or more in tripalmitin, glycerol tristearate, Gan You behenic acid ester or lauric acid triglyceride;

Described distillate oil comprises fractional distillation Petiolus Trachycarpi oil or fractionated coconut oil;

Described wax work comprises one or more in Brazil wax, spermaceti, cationic emulsified wax, Cera Flava or Cera Flava;

Described colloidal compound comprises one or more in arabic gum, gelatin or pectin.

2. metronidazole vagina expansible plug as claimed in claim 1, is characterized in that, the parts by weight of described each composition of expansible plug are:

Metronidazole 5-15

Substrate 80-168

Expansion carrier 100-250

Described substrate is the mixture of Acrawax, lipoidis substrate and hydrogenated oil and fat, and the parts by weight of described Acrawax, hydrogenated oil and fat and lipoidis substrate are 6-10:1-4:1.

3. metronidazole vagina expansible plug as claimed in claim 2, is characterized in that, described Acrawax is mixed fatty glycerides, and described hydrogenated oil and fat is hydrogenated groundnut, and described lipoidis substrate is lanoline, and the parts by weight of described each composition of expansible plug are:

4. metronidazole vagina expansible plug as claimed in claim 1, is characterized in that, described pastille substrate also comprises resin, described metronidazole and resin formation metronidazole resin complexes, and the total amount portion rate of described metronidazole and resin is 1:1-3, described resin is selected from

iRP-64,

iRP-69 or

one or more in IRP-88.

5. metronidazole vagina expansible plug as claimed in claim 4, is characterized in that, described pastille substrate also comprises that weight portion is the chitosan of 2-10 part.

6. metronidazole vagina expansible plug as claimed in claim 5, is characterized in that, described pastille substrate also comprises that weight portion is the acidulant of 1-5 part, and described acidulant is selected from one or more in polyacrylic acid, alginic acid, polylactic acid or polyuronic acid.

7. the metronidazole vagina expansible plug as described in as arbitrary in claim 1-6, 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 the front end 1/5-4/5 place that Semi surrounding type is coated in 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.

8. the preparation method of metronidazole 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. metronidazole is pulverized, crossed 80-100 mesh sieve, be dissolved in ethanol, make ethanol, under stirring, resin is joined in ethanol, mix homogeneously, dry, make metronidazole resin complexes;

C. metronidazole resin complexes is mixed homogeneously with chitosan, acidulant, make mixture;

D. the mixture of c step is added in a step, mix homogeneously, makes pastille substrate;

2) pastille substrate is poured in bolt mould, inserted expansion carrier, cooling and shaping, makes suppository.

9. as the detection method of the metronidazole vagina expansible plug of claim 1-6 or 8 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 metronidazole vagina expansible plug end face, measure the initial length H of described expansion carrier;

B. after the saturated water suction of described metronidazole vagina expansible plug, be determined at the rear length h of selected location place's expansion carrier expansion in a step;

While c. calculating described swell value, according to I formula, calculate;

$p=\frac{h}{H}$

（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:

A. along described metronidazole vagina expansible plug axially choose a place or some positions, measure the initial diameter R of described expansion carrier;

B. after the saturated water suction of described metronidazole vagina expansible plug, be determined at the rear diameter r of selected location place's expansion carrier expansion in a step;

While c. calculating described swell value, press II formula and calculate;

$P=\frac{r}{R}$

（II）

Wherein, P represent swell value, r radially represent to expand after diameter, R represent initial diameter;

2) weight differential assay method:

A. get described metronidazole vagina expansible plug, take weight M;

B. get the expansion carrier in the described metronidazole 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）。

10. the detection method of metronidazole vagina expansible plug as claimed in claim 9, 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 metronidazole 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 metronidazole vagina expansible plug melts after the detection of change time limit, is determined at the rear length h of selected location place's 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;

$\mathrm{pi}=\frac{\mathrm{hi}}{\mathrm{Hi}}$

（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:

A. first an angle along described metronidazole 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;

B. described metronidazole vagina expansible plug melts after the detection of change time limit, is determined at the rear diameter r of selected location place's expansion carrier expansion in a step; The different angles of rolling are again measured several times, ask the rear average diameter ri that expands;

While c. calculating described swell value, press II formula and calculate;

$P_i=\frac{\mathrm{ri}}{\mathrm{Ri}}$

（II）

Wherein, Pi represent swell value, ri radially represent to expand after average diameter, Ri represent average initial diameter;

2) weight differential assay method:

A. get described metronidazole vagina expansible plug, take weight M;

B. 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 11. metronidazole vagina expansible plugs as claimed in claim 10, 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 metronidazole 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; Above-mentioned 3 bolts are used for melting and become after the time limit measures and finish, 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 three positions again, each cotton sliver obtains six data altogether, obtains 6 meansigma methods r of mensuration _i, calculate the swell value P of every _i, the swell value of three bolts all should be greater than 1.5;

2) weight differential assay method:

Get 10 of described metronidazole vagina expansible plugs, the accurately weighed weight of difference, 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, the accurately weighed cotton sliver weight of difference, 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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