CN103768006A - Triaconazole vagina expansion suppository as well as preparation method and detection method thereof - Google Patents

Abstract

The invention relates to a triaconazole vagina expansion suppository as well as a preparation method and a detection method thereof. The triaconazole vagina expansion suppository comprises a drug-containing matrix, a drug-containing mucous layer and an expansion carrier, wherein the drug-containing matrix is formed by triaconazole and a matrix, the drug-containing mucous layer is formed by the triaconazole and a mucosa agent, and an emulsifying agent and urotropin in the drug-containing matrix are capable of improving solubility of the triaconazole, absorption of the triaconazole in human bodies and bioavailability of the drug; and the drug-containing mucous layer can be adsorbed to the vagina skin and is capable of promoting absorption of the drug in human bodies and further improving bioavailability of the drug. The triaconazole vagina expansion suppository provided by the invention is prepared by adopting six ingenious leading technologies and has the beneficial effects of prevention of external flow of liquid medicine, good absorption in human bodies, high bioavailability, lasting curative effect, prevention of secondary infection and the like.

Description

Terconazole (triaconazole) vagina expansible plug and preparation method thereof and detection method

Technical field

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

Background technology

Terconazole (triaconazole), belongs to triazole antifungal agent, is soluble in chloroform, water-soluble hardly; Terconazole (triaconazole) has antibacterial action also to have antibacterial action to some antibacterial to candidiasis, perhaps epidermophyton and other funguses; Be mainly used in the treatment of vulvovaginal candidiasis.Prior art, to the research of terconazole (triaconazole) suppository few, simultaneously because terconazole (triaconazole) itself is not soluble in water, is made after suppository, and the absorbed amount of vagina administration is few, and bioavailability is low; And common terconazole (triaconazole) suppository also exists 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, increase the dissolubility of terconazole (triaconazole), give full play to curative effect, the present invention has studied a kind of terconazole (triaconazole) vagina expansible plug and preparation method thereof; A kind of science detection method that can control above-mentioned terconazole (triaconazole) 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 terconazole (triaconazole) vagina expansible plug, described expansible plug comprises terconazole (triaconazole), substrate and expandable expansion carrier; Described terconazole (triaconazole) 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, and the parts by weight of the each composition of described expansible plug are:

Terconazole (triaconazole) 2-20

Substrate 70-250

Expansion carrier 80-350

Described substrate comprises one or more in Acrawax, natural acid ester, lipoidis substrate, water-soluble base, gel-type vehicle, hydrogenated oil and fat, glyceride, distillate oil 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, 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, methyl oleate 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 gel-type vehicle comprises one or more in sodium carboxymethyl cellulose, hypromellose, carbomer, alginic acid or sodium alginate;

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, SuppositoryBase 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, 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, 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 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, the 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 the each composition of described expansible plug are:

Terconazole (triaconazole) 3-12

Substrate 100-200

Expansion carrier 12 0-250

Described substrate is the mixture of natural acid ester and lipoidis substrate, and the ratio of weight and number of described natural acid ester and lipoidis substrate is 2-6:1.

Further, described natural acid ester is Oleum Linderae, and described lipoidis substrate is lanonol, and the parts by weight of the each composition of described expansible plug are:

Preferably, terconazole (triaconazole) vagina expansible plug of the present invention, described pastille substrate also comprises that weight portion is the hexamethylenamine of 5-30 part.Because terconazole (triaconazole) is almost water-fast material of one, add hexamethylenamine can increase the dissolubility of terconazole (triaconazole), improve the bioavailability of terconazole (triaconazole), here, hexamethylenamine does solubilizing agent and cosolvent simultaneously.

Terconazole (triaconazole) vagina expansible plug of the present invention, described pastille substrate also comprises that weight portion is the emulsifying agent of 5-20 part, described emulsifying agent is one or more in casein, month sodium silicate, chitose, emulsifing wax, pectin, loose glue.Emulsifying agent also can further increase the dissolubility of terconazole (triaconazole), improves bioavailability.

Terconazole (triaconazole) vagina expansible plug of the present invention, described pastille substrate outside is also with one deck pastille mucous layer, described pastille mucous layer comprises that weight portion is that terconazole (triaconazole) and the weight portion of 2-5 part is the mucous membrane agent of 5-20 part, and described mucous membrane agent comprises one or more in acetyl tributyl citrate, acetyltriethyl citrate.

Because mucous membrane agent acetyl tributyl citrate or acetyltriethyl citrate are when the local application, can form mucosa, in use, pastille mucous layer just can be adsorbed on vagina skin, promotes the absorption of skin, further improves the bioavailability of medicine.

Terconazole (triaconazole) vagina expansible plug of the present invention, described pastille mucous layer is discontinuous lamellar and distributes.

Due to the plasticization of mucous membrane agent acetyl tributyl citrate or acetyltriethyl citrate, can cause the poor ductility of pastille mucous layer, and being designed to be discontinuous lamellar, pastille mucous layer distributes, can overcome well this shortcoming, improve the ductility of pastille mucous layer, further improve the bioavailability of medicine.

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.

Substrate of the present invention is Semi surrounding type and is coated in the front end 1/5-4/5 place of described 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 rear end of expansion carrier 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 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 ".

Meet in order to reach terconazole (triaconazole) vagina expansible plug of the present invention 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 terconazole (triaconazole) 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 terconazole (triaconazole) vagina expansible plug on the other hand, and 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. get the water that hexamethylenamine adds 2-7 doubly to measure, be fully ground to water quantities and be less than 5% pastel, under grinding, add terconazole (triaconazole), mix homogeneously, makes the first mixture;

C. the first mixture is mixed homogeneously with emulsifying agent, make the second mixture;

D. by the fused mass of the second 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 pastille substrate bolt core;

3) preparation of pastille mucous membrane agent:

Terconazole (triaconazole) is mixed homogeneously with mucous membrane agent, make pastille mucous membrane agent;

4) by the pastille mucous membrane agent in step 3) with discontinuous Sprayable spray attachment in step 2) on the pastille substrate bolt core that makes, on substrate bolt core, form one deck pastille mucous layer, make described terconazole (triaconazole) vagina expansible plug.

The preparation method of terconazole (triaconazole) 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 terconazole (triaconazole) 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 terconazole (triaconazole) vagina expansible plug end face, measure the initial length H of described expansion carrier;

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

C., while calculating described swell value, calculate according to I formula;

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

（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 terconazole (triaconazole) 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 terconazole (triaconazole) vagina expansible plug, be determined at the rear diameter r of selected location place expansion carrier expansion in a step;

C., while calculating described swell value, calculate by II formula;

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

（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 terconazole (triaconazole) vagina expansible plug, take weight M;

B. get the expansion carrier in the described terconazole (triaconazole) vagina expansible plug that scrapes pastille substrate and pastille mucous layer, dry, take weight m, the gross weight X according to pastille substrate and pastille mucous layer as described in the calculating of III formula:

X=M-m

（Ⅲ）。

Further, in the detection method of described terconazole (triaconazole) vagina expansible plug, 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 terconazole (triaconazole) 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 terconazole (triaconazole) vagina expansible plug melts after the detection of change time limit, is determined at the rear length h of selected location place expansion carrier expansion in a step; The different angles of rolling are again measured several times, ask the rear average length hi that expands;

C., while calculating described swell value, calculate according to I formula;

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

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

C., while calculating described swell value, calculate by II formula;

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

（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 terconazole (triaconazole) vagina expansible plug, take weight M;

B. scrape pastille substrate and pastille mucous layer, 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 gross weight X of pastille substrate and pastille mucous layer as described in the calculating of III formula

X=M-m（Ⅲ）

Wherein, described organic solvent comprises one or more in ethanol, methanol or isopropyl alcohol.

Further, in the detection method of described terconazole (triaconazole) vagina expansible plug, described expansion carrier is cotton sliver, and described detection comprises following at least one method:

1) swell value assay method:

Get 3 of described terconazole (triaconazole) vagina expansible plugs, survey its afterbody cotton sliver diameter with slide gauge, 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, measure two ends and middle three positions of each cotton sliver with slide gauge, 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 terconazole (triaconazole) vagina expansible plugs, accurately weighed weight respectively, gently scrape pastille substrate and pastille mucous layer (must not lose cotton sliver), cotton sliver is placed in to 200-400ml ethanol (if the substrate glycerin gelatine of 50-80 ℃, cotton sliver is placed in to twice of the water repeated washing of 60 ℃), 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, inhale 3 times with filter paper again, be dried 2 hours in 105 ℃, take out, room temperature was placed after 1 hour, accurately weighed cotton sliver weight respectively, obtain the gross weight of every pastille substrate and pastille mucous layer and average pastille substrate and pastille mucous layer gross weight with respect to total number, and the two is compared, what exceed average gross 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 terconazole (triaconazole) 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; In the time carrying out the standard detection terconazole (triaconazole) vagina of the present invention expansible plug of state-promulgated pharmacopoeia appendix weight differential, pastille substrate and pastille mucous layer 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, in the time 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.

It is high that terconazole (triaconazole) vagina expansible plug provided by the present invention has stability, the beneficial effects such as good effect, and this terconazole (triaconazole) vagina expansible plug has adopted six leading technologies of original creation, expansion carrier in described terconazole (triaconazole) 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 mucous layer of terconazole (triaconazole) vagina expansible plug fully contact with vaginal walls, and prevent medicinal liquid outflow, also there is effect that cleaning vagina prevents superinfection, selected emulsifying agent and hexamethylenamine, improved the dissolubility of terconazole (triaconazole), improved its bioavailability, described mucous membrane agent mixes the pastille mucous layer making and just can be adsorbed on vagina skin with terconazole (triaconazole), promote the absorption of skin, further improves the bioavailability of medicine.

Accompanying drawing explanation

Fig. 1 is the structural representation of terconazole (triaconazole) vagina expansible plug of the present invention, and 1 is pastille mucous layer, and 2 is pastille substrate, and 3 is expansion carrier, and 4 is bracing wire;

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

The specific embodiment

Embodiment 1

Preparation method:

1) preparation of pastille substrate:

A. Oleum Linderae, lanonol are placed in to water-bath heating and melting, make fused mass;

B. by the fused mass of terconazole (triaconazole) 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 cylindrical suppositorys, every piece of 2.7g.

Embodiment 2

Preparation method:

1) preparation of pastille substrate:

A. Oleum Linderae, lanonol are placed in to water-bath heating and melting, make fused mass;

B. get the water that hexamethylenamine adds 2 times of amounts, be fully ground to water quantities and be less than 5% pastel, under grinding, add terconazole (triaconazole), mix homogeneously, makes mixture;

C. by the fused mass of the mixture of b 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 spherical suppositorys, every piece of 3.3g.

Embodiment 3

Preparation method:

1) preparation of pastille substrate:

A. methyl oleate, lanoline are placed in to water-bath heating and melting, make fused mass;

B. get the water that hexamethylenamine adds 4 times of amounts, be fully ground to water quantities and be less than 5% pastel, under grinding, add terconazole (triaconazole), mix homogeneously, makes the first mixture;

C. the first mixture is mixed homogeneously with casein, make the second mixture;

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

2) pastille substrate is poured in bolt mould, inserted elastic fiber, cooling and shaping, makes 100 pieces of avette suppositorys, every piece of 2.3g.

Embodiment 4

Preparation method: make 100 pieces of conical suppositorys by embodiment 3 methods, every piece of heavily about 4.7g.

Embodiment 5

Preparation method:

1) preparation of pastille substrate:

A. lauric acid triglyceride, glycerin gelatine are placed in to water-bath heating and melting, make fused mass;

B. get the water that hexamethylenamine adds 7 times of amounts, be fully ground to water quantities and be less than 5% pastel, under grinding, add terconazole (triaconazole), mix homogeneously, makes the first mixture;

C. the first mixture is mixed homogeneously with a month sodium silicate, make the second mixture;

D. by the fused mass of the second 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 bullet shaped pastille substrate bolt cores;

3) preparation of pastille mucous membrane agent:

Terconazole (triaconazole) is mixed homogeneously with acetyl tributyl citrate, make pastille mucous membrane agent;

4) by the pastille mucous membrane agent in step 3) with discontinuous Sprayable spray attachment in step 2) on the pastille substrate bolt core that makes, on substrate bolt core, form one deck pastille mucous layer, make 100 pieces of bullet shaped suppositorys, every piece of heavily about 4.6g.

Embodiment 6

Preparation method: make 100 pieces of torpedo suppositorys by embodiment 5 methods, every piece of heavily about 4.8g.

Embodiment 7

Preparation method: make 100 pieces of spherical suppositorys by embodiment 5 methods, every piece of heavily about 3g.

Embodiment 8

Preparation method: make 100 pieces of avette suppositorys by embodiment 5 methods, every piece of heavily about 4g.

Test example 1 stability test

1. accelerated test

Get terconazole (triaconazole) vagina expansible plug described in embodiment 2-8 and commercially available terconazole (triaconazole) vaginal suppository, all at 25 ℃ ± 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, by the regulation in Chinese Pharmacopoeia, detect the character of expansible plug, containing the labelled amount (%) of terconazole (triaconazole), melt and become the time limit, the accelerated test of the terconazole (triaconazole) vagina expansible plug described in embodiment 2-5 the results are shown in Table 1, terconazole (triaconazole) vagina expansible plug described in embodiment 6-8 and the accelerated test of terconazole (triaconazole) suppository the results are shown in Table 2.

The accelerated test result of terconazole (triaconazole) vagina expansible plug described in table 1 embodiment 2-5

The accelerated test result of terconazole (triaconazole) vagina expansible plug and terconazole (triaconazole) vaginal suppository described in table 2 embodiment 6-8

Terconazole (triaconazole) vagina expansible plug described in embodiment of the present invention 2-8 as can be seen from the table, under the environment of constant temperature high humidity, place after 6 months, the color of described expansible plug does not change, described expansible plug smooth surface, do not occur speckle, the phenomenon of breaking, in described expansible plug there is not obvious variation in the labelled amount of terconazole (triaconazole), melts and become yet significantly prolongation of generation of time limit; And terconazole (triaconazole) vaginal suppository is placed after 1 month under high humidity, it is coarse that suppository surface just becomes, and places after 6 months, and suppository breaks, and it is more and more darker that color becomes; And the content of described terconazole (triaconazole) significantly declines, melt and become time limit significant prolongation; Show that terconazole (triaconazole) vagina expansible plug of the present invention stability compared with terconazole (triaconazole) vaginal suppository significantly improves.

2. long term test

Get terconazole (triaconazole) vagina expansible plug described in embodiment 2-8 and commercially available terconazole (triaconazole) vaginal suppository, 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, contain the labelled amount (%) of terconazole (triaconazole) and melt and become the time limit, 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 terconazole (triaconazole) vagina expansible plug described in embodiment 2-6 is in table 3, the long-term test results of embodiment 7-8 and terconazole (triaconazole) vaginal suppository is in table 4.

The long-term test results of terconazole (triaconazole) vagina expansible plug described in table 3 embodiment 2-6

The long-term test results of terconazole (triaconazole) vagina expansible plug and terconazole (triaconazole) vaginal suppository described in table 4 embodiment 7-8

Terconazole (triaconazole) vagina expansible plug described in embodiment of the present invention 2-8 as can be seen from the table, in the long term test of 36 months, the color of described expansible plug does not change, described suppository smooth surface, there is not speckle, the phenomenon of breaking, in described expansible plug there is not obvious variation in the labelled amount of terconazole (triaconazole), melts and become yet significantly prolongation of generation of time limit; And terconazole (triaconazole) vaginal suppository was placed after 3 months, it is coarse that suppository surface just becomes, and places after 36 months, and suppository breaks, and it is more and more darker that color becomes; And the content of described terconazole (triaconazole) significantly declines, melt and become time limit significant prolongation; Show that terconazole (triaconazole) vagina expansible plug of the present invention stability compared with terconazole (triaconazole) vaginal suppository significantly improves.

Test example 2 swell value determination tests

Method one

Get 3 of described terconazole (triaconazole) vagina expansible plugs, survey its afterbody cotton sliver diameter with slide gauge, 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, measure two ends and middle three positions of each cotton sliver with slide gauge, 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 5 according to the swell value of terconazole (triaconazole) vagina expansible plug described in above-mentioned swell value assay method mensuration embodiment 1-8.

The swell value of table 5 embodiment 1-8 terconazole (triaconazole) vagina expansible plug

Embodiment	Average diameter (mm) before expanding	Average diameter (mm) after expanding	Swell value (doubly)	Result
					Embodiment 1	12.18	21.38	1.76	Qualified
Embodiment
	2	11.93	20.07	1.68	Qualified
Embodiment
	3	12.29	19.99	1.62	Qualified

Embodiment 4	12.29	22.53	1.83	Qualified
					Embodiment 5	12.15	22.47	1.85	Qualified
Embodiment 6	12.05	22.39	1.86	Qualified
					Embodiment 7	12.37	23.42	1.90	Qualified
Embodiment 8	12.23	22.68	1.86	Qualified

Method two

As shown in Figures 2 and 3, the detection method of vagina expansible plug:

1) swell value assay method:

A. first radially choose C1, C2, tri-points of C3 along described vagina expansible plug end face, measure with slide gauge 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;

C., while calculating described swell value, calculate according to I formula;

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

（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 axially choose A1, A2 and tri-points of A3 an angle along described vagina expansible plug, measure with slide gauge after initial diameter R1, the R2 and R3 of described expansion carrier, roll again 90 °, axially choose B1, B2 and tri-points of B3 along described vagina expansible plug, measure with slide gauge 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;

F., while calculating described swell value, calculate by II formula;

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

（II）

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

All initial diameters.

Test example 3 weight differential determination tests

Get 10 of described terconazole (triaconazole) vagina expansible plugs, accurately weighed weight respectively, gently scrape pastille substrate and pastille mucous layer (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, inhale 3 times with filter paper again, be dried 2 hours in 105 ℃, take out, room temperature was placed after 1 hour, accurately weighed cotton sliver weight respectively, obtain the gross weight of every pastille substrate and pastille mucous layer and average pastille substrate and pastille mucous layer gross weight with respect to total number, and the two is compared, what exceed average gross weight ± 10% must not be more than 2, and must not there is 1 times of 1 overrun.

Repeat aforesaid operations, detect the terconazole (triaconazole) vagina expansible plug described in embodiment 1-8, the equal conformance with standard of its weight differential.

Test example 4 clinical trials

One, research method

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

(2) diagnostic criteria

1, vulvovaginal candidiasis symptom: pruritus vulvae, having more white bean dregs sample leucorrhea is this sick cardinal symptom, can be with pudendum burn feeling, urgent micturition, dysurea and sexual anhedonia;

2, gynecologial examination: swelling of external genitals, epidermis can strip off, and can have scratch, and nympha inner side and vaginal mucosa, with white membranoid substance, are wiped rear visible vaginal mucosa redness or rotten to the corn face and shallow table ulcer, and leucorrhea is white, grumeleuse shape and bean dregs sample, slightly stink;

3, lab testing: smear detects, and looks for pseudohypha under microscope, and positive rate can reach 60%.

(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 terconazole (triaconazole) vagina expansible plug described in the use embodiment of the present invention 7 is treated, and one of every day, 7 days is a course for the treatment of.

2, matched group: using the treatment of terconazole (triaconazole) vaginal suppository, 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, plate coating 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 to the therapeutic effect of vulvovaginal candidiasis relatively in table 6;

The therapeutic effect comparison of table 6 liang group to vulvovaginal candidiasis

Group	Case load	Disease more	Effective	Effectively	Invalid	Effective percentage (%)
							Treatment group	31	27	2	1	1	96.7
Matched group	20	12	2	2	4	80.0

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

Three, conclusion

Terconazole (triaconazole) vagina expansible plug reaches 96.7% to the effective percentage of vulvovaginal candidiasis, 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 (12)

1. a terconazole (triaconazole) vagina expansible plug, is characterized in that, described expansible plug comprises terconazole (triaconazole), substrate and expandable expansion carrier; Described terconazole (triaconazole) 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, and the parts by weight of the each composition of described expansible plug are:

Terconazole (triaconazole) 2-20

Substrate 70-250

Expansion carrier 80-350

Described substrate comprises one or more in Acrawax, natural acid ester, lipoidis substrate, water-soluble base, gel-type vehicle, hydrogenated oil and fat, glyceride, distillate oil 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, 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, methyl oleate 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 gel-type vehicle comprises one or more in sodium carboxymethyl cellulose, hypromellose, carbomer, alginic acid or sodium alginate;

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

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

Terconazole (triaconazole) 3-12

Substrate 100-200

Expansion carrier 12 0-250

Described substrate is the mixture of natural acid ester and lipoidis substrate, and the ratio of weight and number of described natural acid ester and lipoidis substrate is 2-6:1.

3. terconazole (triaconazole) vagina expansible plug as claimed in claim 2, is characterized in that, described natural acid ester is Oleum Linderae, and described lipoidis substrate is lanonol, and the parts by weight of the each composition of described expansible plug are:

4. terconazole (triaconazole) vagina expansible plug as claimed in claim 1, is characterized in that, described pastille substrate also comprises that weight portion is the hexamethylenamine of 5-30 part.

5. terconazole (triaconazole) vagina expansible plug as claimed in claim 4, it is characterized in that, described pastille substrate also comprises that weight portion is the emulsifying agent of 5-20 part, and described emulsifying agent is one or more in casein, month sodium silicate, chitose, emulsifing wax, pectin, loose glue.

6. terconazole (triaconazole) vagina expansible plug as claimed in claim 5, it is characterized in that, described pastille substrate outside is also with one deck pastille mucous layer, described pastille mucous layer comprises that weight portion is that terconazole (triaconazole) and the weight portion of 2-5 part is the mucous membrane agent of 5-20 part, and described mucous membrane agent comprises one or more in acetyl tributyl citrate, acetyltriethyl citrate.

7. terconazole (triaconazole) vagina expansible plug as claimed in claim 6, is characterized in that, described pastille mucous layer is discontinuous lamellar and distributes.

8. the terconazole (triaconazole) 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 terconazole (triaconazole) 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. get the water that hexamethylenamine adds 2-7 doubly to measure, be fully ground to water quantities and be less than 5% pastel, under grinding, add terconazole (triaconazole), mix homogeneously, makes the first mixture;

C. the first mixture mixture is mixed homogeneously with emulsifying agent, make the second mixture;

D. by the fused mass of the second 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 pastille substrate bolt core;

3) preparation of pastille mucous membrane agent:

Terconazole (triaconazole) is mixed homogeneously with mucous membrane agent, make pastille mucous membrane agent;

4) by the pastille mucous membrane agent in step 3) with discontinuous Sprayable spray attachment in step 2) on the pastille substrate bolt core that makes, on substrate bolt core, form one deck pastille mucous layer, make described terconazole (triaconazole) vagina expansible plug.

10. as the detection method of the terconazole (triaconazole) 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 terconazole (triaconazole) vagina expansible plug end face, measure the initial length H of described expansion carrier;

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

C., while calculating described swell value, calculate according to I formula;

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

（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 terconazole (triaconazole) 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 terconazole (triaconazole) vagina expansible plug, be determined at the rear diameter r of selected location place expansion carrier expansion in a step;

C., while calculating described swell value, calculate by II formula;

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

（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 terconazole (triaconazole) vagina expansible plug, take weight M;

B. get the expansion carrier in the described terconazole (triaconazole) vagina expansible plug that scrapes pastille substrate and pastille mucous layer, dry, take weight m, the gross weight X according to pastille substrate and pastille mucous layer as described in the calculating of III formula:

X=M-m

（Ⅲ）。

The detection method of 11. terconazole (triaconazole) 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 terconazole (triaconazole) 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 terconazole (triaconazole) vagina expansible plug melts after the detection of change time limit, is determined at the rear length h of selected location place expansion carrier expansion in a step; The different angles of rolling are again measured several times, ask the rear average length hi that expands;

C., while calculating described swell value, calculate according to I formula;

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

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

C., while calculating described swell value, calculate by II formula;

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

（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 terconazole (triaconazole) vagina expansible plug, take weight M;

B. scrape pastille substrate and pastille mucous layer, 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 gross weight X of pastille substrate and pastille mucous layer as described in the calculating of III formula

X=M-m（Ⅲ）

Wherein, described organic solvent comprises one or more in ethanol, methanol or isopropyl alcohol.

The detection method of 12. terconazole (triaconazole) vagina expansible plugs as claimed in claim 11, its feature exists

In, described expansion carrier is cotton sliver, described detection comprises following at least one method:

1) swell value assay method:

Get 3 of described terconazole (triaconazole) vagina expansible plugs, survey its afterbody cotton sliver diameter with slide gauge, 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, measure two ends and middle three positions of each cotton sliver with slide gauge, 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 terconazole (triaconazole) vagina expansible plugs, accurately weighed weight respectively, gently scrape pastille substrate and pastille mucous layer (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, inhale 3 times with filter paper again, be dried 2 hours in 105 ℃, take out, room temperature was placed after 1 hour, accurately weighed cotton sliver weight respectively, obtain the gross weight of every pastille substrate and pastille mucous layer and average pastille substrate and pastille mucous layer gross weight with respect to total number, and the two is compared, what exceed average gross weight ± 10% must not be more than 2, and must not there is 1 times of 1 overrun.

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