CN103768006B - Terconazole (triaconazole) vaginal expansion plug and preparation method thereof and detection method - Google Patents
Terconazole (triaconazole) vaginal expansion plug and preparation method thereof and detection method Download PDFInfo
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Abstract
The present invention relates to a kind of terconazole (triaconazole) vaginal expansion plug and preparation method thereof and detection method, described expansible plug includes terconazole (triaconazole) and substrate formed pastille substrate, terconazole (triaconazole) and the pastille mucous layer of mucous membrane agent formation, expandable carrier；Emulsifying agent in described pastille substrate and hexamethylenamine, improve the dissolubility of terconazole (triaconazole), adds the human body absorption to it, improves the bioavailability of medicine；Pastille mucous layer can adsorb on vagina skin, promotes the absorption of skin, further increases the bioavailability of medicine.And terconazole (triaconazole) vaginal expansion plug provided by the present invention have employed six leading technologies of original creation, has and prevents medicinal liquid from outflowing, and absorption of human body is good, bioavailability is high, and curative effect is lasting, prevents the beneficial effects such as superinfection.
Description
Technical field
The invention belongs to vaginal suppository field, particularly to a kind of terconazole (triaconazole) vaginal expansion plug and preparation method thereof and detection
Method.
Background technology
Terconazole (triaconazole), belongs to triazole antifungal agent, is soluble in chloroform, is practically insoluble in water；Terconazole (triaconazole) to candidiasis, permitted
Epidermophyton and other funguses have antibacterial action that some antibacterial is also had antibacterial action；It is mainly used in vulvovaginal candidiasis
Treatment.Prior art is the most few to the research of terconazole (triaconazole) suppository, simultaneously because terconazole (triaconazole) itself is not readily dissolved in water, makes suppository
After, the absorbed amount of vagina administration is few, and bioavailability is low；And commonly terconazole (triaconazole) suppository there is also the most easy to clean, easily dirty
Dye medicated clothing；Active component is little with human contact face, causes absorbing insufficient, and the technology such as optimum curative effect not playing prescription is asked
Topic.
Summary of the invention
In order to solve above-mentioned technical problem, increasing the dissolubility of terconazole (triaconazole), give full play to curative effect, the present invention have studied one
Terconazole (triaconazole) vaginal expansion plug and preparation method thereof；Additionally provide one simultaneously and can control above-mentioned terconazole (triaconazole) vaginal expansion plug product
The science detection method of quality.
The concrete technical scheme of the present invention is as follows:
The present invention provides a kind of terconazole (triaconazole) vaginal expansion plug, and described expansible plug includes terconazole (triaconazole), substrate and expandable swollen
Swollen carrier；Described terconazole (triaconazole) and substrate formed pastille substrate are coated in expandable carrier surface, and described expandable carrier is in saturated suction
Swell value after water is more than 1.1, and the parts by weight of each composition of described expansible plug are:
Terconazole (triaconazole) 2-20
Substrate 70-250
Expandable carrier 80-350
Described substrate include Acrawax, natural acid ester, lipoidis substrate, water-soluble base, gel-type vehicle,
One or more in hydrogenated oil and fat, glyceride, distillate oil or colloidal compound；
Described Acrawax includes mixed fatty glycerides, propylene glycol stearate, fixed oil, semi-synthetic fat
One or more in acid glyceride, semi-synthetic cocos nucifera oil ester, semi-synthetic Petiolus Trachycarpi grease or semi-synthetic Fructus Litseae ester；
Described natural acid ester include the one in oleum sapii, Oleum Linderae, Fructus Foeniculi fat, methyl oleate or cocoa butter or
Multiple；
Described lipoidis substrate includes lanoline or lanonol；
Described water-soluble base include PEG400, polyethylene glycol 1500, Macrogol 4000, polyethylene glycol 6000,
One or more in glycerin gelatine, polysorbate60, polysorbate65, polyoxyethylene monostearate or poloxamer；
Described gel-type vehicle includes in sodium carboxymethyl cellulose, hypromellose, carbomer, alginic acid or sodium alginate
One or more；
Described hydrogenated oil and fat include the one in hydrogenated vegetable oil, hydrogenated groundnut, castor oil hydrogenated or cotmar or
Multiple；
Described glyceride include 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, glycerol behenic acid ester or the moon
One or more in cinnamic acid triglyceride；
Described distillate oil includes fractionating palm oil or fractionated coconut oil；
Described colloidal compound includes one or more in arabic gum, gelatin or pectin.
The substrate of English name of the present invention be embodied in " industrial pharmacy theory and practice " book (L. La Heman,
H.A. profit Berman, J.L. card Buddhist nun wishes. industrial pharmacy theory and practice, Chemical Industry Press, the second edition: 215-217).
Present invention employs " the intravaginal sticking type medicine-feeding technology " of original creation, this technology carries by adding to expand in suppository
Body realizes.Ordinary suppository 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 expandable carrier expands, pastille substrate can contact with vaginal walls in 360 °,
Fully being administered, be administered enlarged areas 6 times, medicine is directly attached to lesions position, makes the position that originally cannot contact medicine also can
Effectively attached treatment；And the buffer action played in the middle of vagina due to stype, makes no longer to contact with each other between wound surface,
Thus avoid superinfection so that it is no longer recurrent exerbation.Additionally, the introducing of expandable carrier applies " lateral leakage protection key " design reason
Read, because the expansion of expandable carrier tail end (non-pastille substrate), can be close to vaginal wall, and then prevent outside medicine and substrate
Stream, reduces the pollution of medicated clothing and keeps the valid density of medicine.And by " the inner core coefficient of expansion controls technology ", expansion can be made
Carrier swell value after saturated water suction is more than 1.1.
Further, the parts by weight of each composition of described expansible plug are:
Terconazole (triaconazole) 3-12
Substrate 100-200
Expandable carrier 120-250
Described substrate is natural acid ester and the mixture of lipoidis substrate, described natural acid ester and lipoidis base
The ratio of weight and number of matter is 2-6:1.
Further, described natural acid ester is Oleum Linderae, and described lipoidis substrate is lanonol, and described expansible plug is each
The parts by weight of composition are:
Preferably, the terconazole (triaconazole) vaginal expansion plug of the present invention, described pastille substrate also includes the black Lip river that weight portion is 5-30 part
Tropine.Owing to terconazole (triaconazole) is a kind of material being practically insoluble in water, add hexamethylenamine and can increase the dissolubility of terconazole (triaconazole), carry
The bioavailability of high terconazole (triaconazole), here, hexamethylenamine does solubilizing agent and cosolvent simultaneously.
The terconazole (triaconazole) vaginal expansion plug of the present invention, described pastille substrate also includes the emulsifying agent that weight portion is 5-20 part, institute
Stating emulsifying agent is one or more in casein, moon sodium silicate, chitose, emulsifing wax, pectin, pine glue.Emulsifying agent can also
Increase the dissolubility of terconazole (triaconazole) further, improve bioavailability.
The terconazole (triaconazole) vaginal expansion plug of the present invention, is accompanied by one layer of pastille mucous layer outside described pastille substrate, described contain
Medicine mucous layer includes the terconazole (triaconazole) that weight portion is 2-5 part and the mucous membrane agent that weight portion is 5-20 part, and described mucous membrane agent includes acetyl
One or more in tributyl citrate, acetyltriethyl citrate.
Owing to mucous membrane agent acetyl tributyl citrate or acetyltriethyl citrate are when local application, can be formed viscous
Film, in use, pastille mucous layer just can adsorb on vagina skin, promotes the absorption of skin, improves medicine further
Bioavailability.
The terconazole (triaconazole) vaginal expansion plug of the present invention, described pastille mucous layer is that discontinuous lamellar is distributed.
Due to mucous membrane agent acetyl tributyl citrate or the plasticization of acetyltriethyl citrate, pastille mucosa can be caused
The poor ductility of layer, and be designed as pastille mucous layer being distributed in discontinuous lamellar, this shortcoming can be overcome well, carry
The ductility of high pastille mucous layer, improves the bioavailability of medicine further.
The expandable carrier of the present invention swell value after saturated water suction is more than 1.5, and described swell value is expansion radially
Value；Described expandable carrier includes but not limited to cotton sliver, may also include other sterilizable materials that can expand, such as non-woven fabrics, elasticity
Fiber etc..
Substrate of the present invention is that Semi surrounding type is coated at the front end 1/5-4/5 of described expandable carrier, according to " human body work
Cheng Xue suppository " shape, it is designed to the shapes such as duckbill, spherical, avette, bullet shaped, torpedo, cylinder, cone or rod.
The rear end of expandable carrier of the present invention is connected with bracing wire, the stype after expansion, is drawn by tractive expandable carrier rear end
Line, the absorption virus being killed on expandable carrier, toxin, the dead bark that comes off pull out external the most in the lump, change dressings just etc. every time
The most thoroughly cleaning in doing to vagina, fundamentally prevention of inflammation recurs again, and this expansible plug i.e. belongs to " treatment cleaning integration
Dosage form ".
Meeting, in order to reach the terconazole (triaconazole) vaginal expansion plug of the present invention, the effect that water can expand rapidly, described expandable carrier absorbs water
After, the maximum water absorption of every is not less than 1.5 milliliters.Suitable water absorption, it is ensured that suitable swell value, too low or too high
Water absorption, all can cause bad impact.When water absorption is too low, it is impossible to ensure that the terconazole (triaconazole) vaginal expansion plug of the present invention is met
Feature that water breakthrough i.e. expands and make expansion insufficient；When water absorption is too high, absorption ingredient that expandable carrier can be too much and limit
Make its diffusion.Therefore, water absorption is too low or too high, is not the most the desired expandable carrier of the present invention.
Another aspect of the present invention provides terconazole (triaconazole) vaginal expansion plug, and described method comprises the steps:
1) preparation of pastille substrate:
A. substrate is placed in water-bath and adds heat fusing, prepare fused mass；
B. take hexamethylenamine and add the water of 2-7 times amount, be fully ground to the water quantities pastel less than 5%, grind lower addition
Terconazole (triaconazole), mix homogeneously, prepare the first mixture；
C. the first mixture is mixed homogeneously with emulsifying agent, prepare the second mixture；
D. by the fused mass of the second mixture of step c Yu a step, mix homogeneously, prepare pastille substrate；
2) pastille substrate is poured in bolt mould, insert expandable carrier, cooling and shaping, make pastille substrate bolt core；
3) preparation of pastille mucous membrane agent:
Terconazole (triaconazole) is mixed homogeneously with mucous membrane agent, prepares pastille mucous membrane agent；
4) by the pastille mucous membrane agent in step 3) with discontinuous Sprayable spray attachment in step 2) in prepare pastille base
On matter bolt core, substrate bolt core is formed one layer of pastille mucous layer, prepares described terconazole (triaconazole) vaginal expansion plug.
The preparation method of terconazole (triaconazole) vaginal expansion plug of the present invention have employed " the integrally formed skill of the disposable fill of stype
Art ".
Another aspect of the present invention additionally provides the detection method of described terconazole (triaconazole) vaginal expansion plug, and described detection method includes
Swell value assay method, weight differential detection method, assay etc..
Wherein said swell value assay method includes:
If a. the radial direction along described terconazole (triaconazole) vaginal expansion plug end face is chosen a little or does, measure described expandable carrier
Initial length H；
After the most described saturated water suction of terconazole (triaconazole) vaginal expansion plug, measure after in a walks, expandable carrier expands at selected location
Length h；
When c. calculating described swell value, calculate according to I formula；
(I)
Wherein, p represent axial swell value, h represent expansion after length, H represent initial length；Or, swell value mensuration side
Method is as follows:
A. axially choose at one or some positions along described terconazole (triaconazole) vaginal expansion plug, measure at the beginning of described expandable carrier
Beginning diameter R；
After the most described saturated water suction of terconazole (triaconazole) vaginal expansion plug, measure after in a walks, expandable carrier expands at selected location
Diameter r；
When c. calculating described swell value, calculate by II formula；
(II)
Wherein, P represents that swell value radially, r represent that expanded diameter, R represent initial diameter；Described weight differential measures
Method includes:
A. take described terconazole (triaconazole) vaginal expansion plug, weigh weight M；
B. take the expandable carrier in the described terconazole (triaconazole) vaginal expansion plug scraping pastille substrate and pastille mucous layer, be dried,
Weigh weight m, according to pastille substrate and gross weight X of pastille mucous layer as described in formula III calculating:
X=M-m
(III).
Further, in the detection method of described terconazole (triaconazole) vaginal expansion plug, after carrying out melting the detection of change time limit, then carry out as
At least one detection method lower:
1) swell value assay method is as follows:
If a. the first radial direction along described terconazole (triaconazole) vaginal expansion plug end face is chosen a little or does, measure described expandable carrier
Initial length H after, then roll different angles measure several times, average Hi；
After the most described terconazole (triaconazole) vaginal expansion plug carries out melting the detection of change time limit, mensuration expands at selected location in a walks and carries
Length h after volume expansion；Roll different angles again to measure several times, seek average length hi after expansion；
When c. calculating described swell value, calculate according to I formula；
(I)
Wherein, pi represent axial swell value, hi represent expansion after average length, Hi represent average initial length；
Or, swell value assay method is as follows:
A. first axially choose at one or some positions an angle along described terconazole (triaconazole) vaginal expansion plug, measure described
After the initial diameter R of expandable carrier, then rolling different angles measurement several times, average Ri；
After the most described terconazole (triaconazole) vaginal expansion plug carries out melting the detection of change time limit, mensuration expands at selected location in a walks and carries
Diameter r after volume expansion；Roll different angles again to measure several times, seek average diameter ri after expansion；
When c. calculating described swell value, calculate by II formula；
(II)
Wherein, Pi represent swell value radially, ri represent expansion after average diameter, Ri represent average initial diameter；
2) weight differential assay method:
A. take described terconazole (triaconazole) vaginal expansion plug, weigh weight M；
B. scrape pastille substrate and pastille mucous layer, expandable carrier is placed in 20-90 DEG C of organic solvent, take out, in 50-
150 DEG C of dry 1-10h, weigh weight m, according to pastille substrate and gross weight X of pastille mucous layer as described in III formula calculating
X=M-m(III)
Wherein, one or more during described organic solvent includes ethanol, methanol or isopropanol.
Further, in the detection method of described terconazole (triaconazole) vaginal expansion plug, described expandable carrier is cotton sliver, described inspection
Survey includes at least one method following:
1) swell value assay method:
Take described terconazole (triaconazole) vaginal expansion plug 3, survey its afterbody cotton sliver diameter with slide gauge, roll about 90 ° and survey one again
Secondary, survey twice for every, obtain every 2 meansigma methodss Ri measured；It is used for melting after the change time limit measures and terminate by above-mentioned 3 bolts, vertical
I.e. take out residue cotton sliver, treat that water is disconnected and drip, be the gentliest placed on glass plate, measure two ends and the centre of each cotton sliver with slide gauge
Three positions, measure three positions after rolling about 90 ° again, and each cotton sliver obtains six data altogether, obtains 6 meansigma methodss of mensuration
Ri, calculates 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:
Taking described terconazole (triaconazole) vaginal expansion plug 10, accurately weighed weight, gently scrapes pastille substrate and pastille mucosa respectively
Layer (cotton sliver must not be lost), cotton sliver is placed in the 200-400ml ethanol of 50-80 DEG C (if substrate has been used glycerin gelatine, will
Cotton sliver is placed in repeated washing twice in the water of 60 DEG C), it is preferable that cotton sliver is placed in the 300ml ethanol of 60-70 DEG C, and
80khz frequency ultrasound cleans 5 minutes, makes the stromatolysis of cotton sliver surface residual remove, and takes out cotton sliver and firmly extracts, then uses filter paper
Inhaling 3 times, be dried 2 hours in 105 DEG C, take out, after room temperature is placed 1 hour, accurately weighed cotton sliver weight, obtains every pastille respectively
The gross weight of substrate and pastille mucous layer is with relative to the average pastille substrate of total grain number and pastille mucous layer gross weight and right
The two compares, and more than 2, and must not must not have 1 overrun 1 times beyond average total weight ± 10%.
The assay method of the swell value of terconazole (triaconazole) vaginal expansion plug provided by the present invention uses multi-angle repetitive measurement side
Method, improves the accuracy of measurement, adds the operability of mensuration, and method is easier to judge；Performing state-promulgated pharmacopoeia annex
During the standard detection terconazole (triaconazole) of the present invention vaginal expansion plug of weight differential, pastille substrate and pastille mucous layer need to be scraped
Coming, the scraping degree grasped due to operator is different, causes every scraping degree difference relatively big, so the present invention uses solvent
Dissolving the substrate on expansible plug surface, through verification experimental verification, when the substrate using hot ethanol to clean expansible plug surface, result is more managed
Thinking, repeatability is higher, and described weight differential assay method is more convenient stable.
Terconazole (triaconazole) vaginal expansion plug provided by the present invention has the beneficial effects such as stability height, good effect, and this spy
Health azoles vaginal expansion plug have employed six leading technologies of original creation, adding of the described expandable carrier in terconazole (triaconazole) vaginal expansion plug
Enter to apply " the disposable fill of stype is integrally formed " technology of original creation, " control of the inner core coefficient of expansion " technology, " human engineering
Bolt type " technology, " treatment cleaning integration " dosage form, " administration of intravaginal sticking type " technology, " design of lateral leakage protection key " six skills
Art, this expandable carrier can make the pastille mucous layer of terconazole (triaconazole) vaginal expansion plug be fully contacted with vaginal walls, and prevent medicinal liquid
Outflow；Also there is cleaning vagina and prevent effect of superinfection；Selected emulsifying agent and hexamethylenamine, improve terconazole (triaconazole)
Dissolubility, improves its bioavailability；The pastille mucous layer that described mucous membrane agent and terconazole (triaconazole) are mixed to prepare just can adsorb
On vagina skin, promote the absorption of skin, improve the bioavailability of medicine further.
Accompanying drawing explanation
Fig. 1 is the structural representation of the terconazole (triaconazole) vaginal expansion plug of the present invention, and 1 is pastille mucous layer, and 2 is pastille substrate, 3
For expandable carrier, 4 is bracing wire；
Fig. 2 and Fig. 3 swell value assay method schematic diagram.
Detailed description of the invention
Embodiment 1
Preparation method:
1) preparation of pastille substrate:
A. Oleum Linderae, lanonol are placed in water-bath and add heat fusing, prepare fused mass；
B. by the fused mass of terconazole (triaconazole) Yu a step, mix homogeneously, prepare pastille substrate；
2) pastille substrate is poured in bolt mould, insertion cotton sliver, cooling and shaping, prepared 100 pieces of cylindrical suppositorys, every piece
2.7g。
Embodiment 2
Preparation method:
1) preparation of pastille substrate:
A. Oleum Linderae, lanonol are placed in water-bath and add heat fusing, prepare fused mass；
B. take hexamethylenamine and add the water of 2 times amount, be fully ground to water quantities less than 5% pastel, add spy under grinding
Health azoles, mix homogeneously, prepare mixture；
C. by the fused mass of the mixture of b step Yu a step, mix homogeneously, prepare pastille substrate；
2) pastille substrate is poured in bolt mould, insert cotton sliver, cooling and shaping, prepare 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 water-bath and add heat fusing, prepare fused mass；
B. take hexamethylenamine and add the water of 4 times amount, be fully ground to water quantities less than 5% pastel, add spy under grinding
Health azoles, mix homogeneously, prepare the first mixture；
C. the first mixture is mixed homogeneously with casein, prepare the second mixture；
D. by the fused mass of the second mixture of step c Yu a step, mix homogeneously, prepare pastille substrate；
2) pastille substrate is poured in bolt mould, insertion elastic fiber, cooling and shaping, prepared 100 pieces of avette suppositorys, every piece
2.3g。
Embodiment 4
Preparation method: making 100 pieces of conical suppositorys by embodiment 3 method, every piece weighs about 4.7g.
Embodiment 5
Preparation method:
1) preparation of pastille substrate:
A. lauric acid three ester, glycerin gelatine are placed in water-bath and add heat fusing, prepare fused mass；
B. take hexamethylenamine and add the water of 7 times amount, be fully ground to water quantities less than 5% pastel, add spy under grinding
Health azoles, mix homogeneously, prepare the first mixture；
C. the first mixture is mixed homogeneously with moon sodium silicate, prepare the second mixture；
D. by the fused mass of the second mixture of step c Yu a step, mix homogeneously, prepare pastille substrate；
2) pastille substrate is poured in bolt mould, insert cotton sliver, cooling and shaping, make 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, prepares pastille mucous membrane agent；
4) by the pastille mucous membrane agent in step 3) with discontinuous Sprayable spray attachment in step 2) in prepare pastille base
On matter bolt core, forming one layer of pastille mucous layer, prepare 100 pieces of bullet shaped suppositorys on substrate bolt core, every piece weighs about 4.6g.
Embodiment 6
Preparation method: making 100 pieces of torpedo suppositorys by embodiment 5 method, every piece weighs about 4.8g.
Embodiment 7
Preparation method: making 100 pieces of spherical suppositorys by embodiment 5 method, every piece weighs about 3g.
Embodiment 8
Preparation method: making 100 pieces of avette suppositorys by embodiment 5 method, every piece weighs about 4g.
Test example 1 stability test
1. accelerated test
Terconazole (triaconazole) vaginal expansion plug described in Example 2-8 and commercially available terconazole (triaconazole) vaginal suppository, all at constant temperature 25 DEG C ± 2
At DEG C, relative humidity be 65% ± 5% constant humidity under the conditions of place 6 months, testing 1 month period, 2 months, 3 months, 6 months
End is separately sampled once, by the regulation in Chinese Pharmacopoeia, and the character of detection expansible plug, the labelled amount (%) containing terconazole (triaconazole), when melting change
Limit, the accelerated test of the terconazole (triaconazole) vaginal expansion plug described in embodiment 2-5 the results are shown in Table 1, and the terconazole (triaconazole) described in embodiment 6-8 is cloudy
The accelerated test of road expansible plug and terconazole (triaconazole) suppository the results are shown in Table 2.
The accelerated test result of terconazole (triaconazole) vaginal expansion plug described in table 1 embodiment 2-5
Terconazole (triaconazole) vaginal expansion plug described in table 2 embodiment 6-8 and the accelerated test result of terconazole (triaconazole) vaginal suppository
Terconazole (triaconazole) vaginal expansion plug described in embodiment of the present invention 2-8 as can be seen from the table, in the environment of constant temperature high humidity,
After placing 6 months, the color of described expansible plug does not changes, described expansible plug smooth surface, speckle does not occur, ruptures
Phenomenon, in described expansible plug, the labelled amount of terconazole (triaconazole) does not occurs significantly to change, melt change the time limit do not occur significantly to extend yet；
And after terconazole (triaconazole) vaginal suppository is placed 1 month under high humidity, suppository surface just becomes coarse, after placing 6 months, suppository occurs broken
Splitting, color becomes more and more deeper；And the content of described terconazole (triaconazole) is remarkably decreased, melt change the time limit significantly extend；Show the present invention
Described terconazole (triaconazole) vaginal expansion plug stability compared with terconazole (triaconazole) vaginal suppository significantly improves.
2. long term test
Terconazole (triaconazole) vaginal expansion plug described in Example 2-8 and commercially available terconazole (triaconazole) vaginal suppository, in temperature 25 DEG C ± 2 DEG C
Under, relative humidity is to place under conditions of 60% ± 10% 36 months, sampling in every 3 months once, respectively at 0 month, 3 months, 6
Month, 9 months, sampling in 12 months, character, the labelled amount (%) containing terconazole (triaconazole) of detection expansible plug and melt and become the time limit, 12 months with
After, still need to continue to investigate index of correlation, sampled respectively at 18 months, 24 months, 36 months and detect, and testing result and 0
The moon compares, and the long-term test results of the terconazole (triaconazole) vaginal expansion plug described in embodiment 2-6 is shown in Table 3, and embodiment 7-8 and terconazole (triaconazole) are cloudy
The long-term test results of road bolt is shown in Table 4.
The long-term test results of terconazole (triaconazole) vaginal expansion plug described in table 3 embodiment 2-6
Terconazole (triaconazole) vaginal expansion plug and the long-term test results of terconazole (triaconazole) vaginal suppository described in table 4 embodiment 7-8
Terconazole (triaconazole) vaginal expansion plug described in embodiment of the present invention 2-8 as can be seen from the table, the long term test of 36 months
In, the color of described expansible plug does not changes, described suppository smooth surface, and phenomenon speckle do not occur, rupturing is described swollen
In swollen bolt, the labelled amount of terconazole (triaconazole) does not occurs significantly to change, melt change the time limit do not occur significantly to extend yet；And terconazole (triaconazole) is cloudy
After road bolt is placed 3 months, suppository surface just becomes coarse, and after placing 36 months, suppository ruptures, and color becomes increasingly
Deeply；And the content of described terconazole (triaconazole) is remarkably decreased, melt change the time limit significantly extend；Show that terconazole (triaconazole) vagina of the present invention is swollen
Swollen bolt stability compared with terconazole (triaconazole) vaginal suppository significantly improves.
Test example 2 swell value determination test
Method one
Take described terconazole (triaconazole) vaginal expansion plug 3, survey its afterbody cotton sliver diameter with slide gauge, roll about 90 ° and survey one again
Secondary, survey twice for every, obtain every 2 meansigma methodss Ri measured；It is used for melting after the change time limit measures and terminate by above-mentioned 3 bolts, vertical
I.e. take out residue cotton sliver, treat that water is disconnected and drip, be the gentliest placed on glass plate, measure two ends and the centre of each cotton sliver with slide gauge
Three positions, measure three positions after rolling about 90 ° again, and each cotton sliver obtains six data altogether, obtains 6 meansigma methodss of mensuration
Ri, calculates the swell value Pi of every, and the swell value of three bolts is all higher than 1.5.
The swell value such as table 5 of terconazole (triaconazole) vaginal expansion plug described in embodiment 1-8 is measured according to above-mentioned swell value assay method
Shown in.
The swell value of table 5 embodiment 1-8 terconazole (triaconazole) vaginal expansion plug
| Embodiment | Average diameter (mm) before expanding | Average diameter (mm) after expansion | Swell value (again) | 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 vaginal expansion plug:
1) swell value assay method:
A. the first radial direction along described vaginal expansion plug end face chooses tri-points of C1, C2, C3, measures described swollen with slide gauge
After initial length H1, H2, H3 of swollen carrier, then roll 90 ° of measurements, the radial direction along described vaginal expansion plug end face choose C1, C4,
After tri-some slide gaugies of C5 measure initial length H4, H5, H6 of described expandable carrier, ask H1, H2, H3, H4, H5 and H6
Meansigma methods Hi；
After the most described vaginal expansion plug carries out melting the detection of change time limit, with slide gauge measure C1 selected in a walks, C2,
Length h1, h2, h3 after tri-position expandable carrier expansions of C3；Roll 90 ° again, measure in a walks selected with slide gauge
Length h4, h5, h6 after tri-position expandable carrier expansions of C1, C4, C5, seek the average length of h1, h2, h3, h4, h5 and h6,
It is average length hi after expansion；
When c. calculating described swell value, calculate according to I formula；
(I)
Wherein, pi represent axial swell value, hi represent expansion after average length, Hi represent average initial length；
Or, swell value assay method:
D. first axially choose tri-points of A1, A2 and A3 an angle along described vaginal expansion plug, survey with slide gauge
After initial diameter R1, R2 and R3 of fixed described expandable carrier, then roll 90 °, axially choose B1, B2 along described vaginal expansion plug
With tri-points of B3, with slide gauge measure described expandable carrier initial diameter R4, R5 and R6 after, ask R1, R2, R3, R4, R5 and
Meansigma methods Ri of six initial diameters of R6；
After the most described vaginal expansion plug carries out melting the detection of change time limit, measure A1, A2 and A3 position selected in d walks swollen
Swollen carrier expanded diameter is respectively r1, r2 and r3,；Roll 90 ° again and measure B1, B2 and B3 position expansion selected in d step
Carrier expanded diameter is respectively r4, r5 and r6, seeks the meansigma methods of r1, r2, r3, r4, r5 and r6, obtains average diameter after expansion
ri；
When f. calculating described swell value, calculate by II formula；
(II)
Wherein, Pi represent swell value radially, ri represent expansion after average diameter, Ri represent flat
All initial diameters.
Test example 3 weight differential determination test
Taking described terconazole (triaconazole) vaginal expansion plug 10, accurately weighed weight, gently scrapes pastille substrate and pastille mucosa respectively
Layer (must not lose cotton sliver), is placed in cotton sliver in the 200-400ml ethanol of 50-80 DEG C, it is preferable that cotton sliver is placed in 60-70 DEG C
300ml ethanol in, and clean 5 minutes at 80khz frequency ultrasound, make the stromatolysis of cotton sliver surface residual remove, take out cotton
Bar is firmly extracted, then inhales 3 times with filter paper, is dried 2 hours in 105 DEG C, takes out, after room temperature is placed 1 hour, and accurately weighed cotton respectively
Bar weight, obtains the pastille substrate of the gross weight of every pastille substrate and pastille mucous layer and average relative to total grain number and contains
Medicine mucous layer gross weight, and compare the two, more than 2, and must not must not have 1 beyond average total weight ± 10%
Overrun 1 times.
Repeating aforesaid operations, detection terconazole (triaconazole) vaginal expansion plug described in embodiment 1-8, its weight differential all meets mark
Accurate.
Test example 4 clinical trial
One, research method
(1) research approach is with reference to relevant " the department of obstetrics and gynecology reproductive tract of Ministry of Health of the People's Republic of China's new drug clinical guidance principle
The clinical verification of inflammation local application " content and formulate.
(2) diagnostic criteria
1, vulvovaginal candidiasis symptom: pruritus vulvae, having more white bean dregs sample leucorrhea is the main disease of this disease
Shape, 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, inside nympha and vaginal mucosa with white
Membranoid substance, the visible red and swollen or rotten to the corn face of vaginal mucosa and shallow table ulcer after erasing, leucorrhea is white, grumeleuse shape and bean dregs sample, slightly
Band stink；
3, lab testing: smear detects, and looks for pseudohypha under microscope, and positive rate is up to 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: use the terconazole (triaconazole) vaginal expansion plug described in the embodiment of the present invention 7 to treat, every day one, 7 days
It it is a course for the treatment of.
2, matched group: using the treatment of terconazole (triaconazole) vaginal suppository, every day one, 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: include pudendum and vaginal secretions inspection；
(3) lab testing: include 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 substantially alleviates, gynecologial examination and lab testing are clearly better；
3, effective: symptom has alleviated, 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 vulvovaginal candidiasis compares and is shown in Table 6；
The therapeutic effect of vulvovaginal candidiasis is compared by 6 liang of groups of table
| Group | Case load | Disease is 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 comparitive study treatment groups are better than matched group.
Three, conclusion
Terconazole (triaconazole) vaginal expansion plug reaches 96.7% to the effective percentage of vulvovaginal candidiasis, and curative effect is better than matched group；?
During verifying its curative effect, do not find toxic and side effects, safe and reliable, evident in efficacy.
Claims (10)
1. a terconazole (triaconazole) vaginal expansion plug, it is characterised in that described expansible plug includes terconazole (triaconazole), substrate and expandable expansion
Carrier；Described terconazole (triaconazole) and substrate formed pastille substrate are coated in expandable carrier surface, and described expandable carrier is in saturated water suction
After swell value more than 1.1, the parts by weight of each composition of described expansible plug are:
Terconazole (triaconazole) 2-20
Substrate 70-250
Expandable carrier 80-350
Described substrate includes Acrawax, natural acid ester, lipoidis substrate, water-soluble base, gel-type vehicle, hydrogenation
One or more in oil, glyceride, distillate oil or colloidal compound；
Described Acrawax includes that mixed fatty glycerides, propylene glycol stearate, fixed oil, semi-synthetic fatty acid are sweet
One or more in grease, semi-synthetic cocos nucifera oil ester, semi-synthetic Petiolus Trachycarpi grease or semi-synthetic Fructus Litseae ester；
Described natural acid ester includes the one or many in oleum sapii, Oleum Linderae, Fructus Foeniculi fat, methyl oleate or cocoa butter
Kind；
Described lipoidis substrate includes lanoline or lanonol；
Described water-soluble base includes PEG400, polyethylene glycol 1500, Macrogol 4000, polyethylene glycol 6000, glycerol
One or more in gelatin, polysorbate60, polysorbate65, polyoxyethylene monostearate or poloxamer；
Described gel-type vehicle includes in sodium carboxymethyl cellulose, hypromellose, carbomer, alginic acid or sodium alginate
Plant or multiple；
Described hydrogenated oil and fat includes one or more in hydrogenated vegetable oil, hydrogenated groundnut, castor oil hydrogenated or cotmar；
Described glyceride includes tripalmitin, glycerol tristearate, glycerol behenic acid ester or lauric acid three ester
In one or more；
Described distillate oil includes fractionating palm oil or fractionated coconut oil；
Described colloidal compound includes one or more in arabic gum, gelatin or pectin；
Described pastille substrate also includes the hexamethylenamine that weight portion is 5-30 part.
2. terconazole (triaconazole) vaginal expansion plug as claimed in claim 1, it is characterised in that described pastille substrate also includes that weight portion is
The emulsifying agent of 5-20 part, described emulsifying agent be casein, moon sodium silicate, chitose, emulsifing wax, pectin, pine glue in one or
Multiple.
3. terconazole (triaconazole) vaginal expansion plug as claimed in claim 2, it is characterised in that be accompanied by a layer outside described pastille substrate
Pastille mucous layer, described pastille mucous layer includes the terconazole (triaconazole) that weight portion is 2-5 part and the mucous membrane agent that weight portion is 5-20 part, institute
State mucous membrane agent and include one or more in acetyl tributyl citrate, acetyltriethyl citrate.
4. terconazole (triaconazole) vaginal expansion plug as claimed in claim 3, it is characterised in that described pastille mucous layer is discontinuous
Shape is distributed.
5. the terconazole (triaconazole) vaginal expansion plug as described in claim 1-4 is arbitrary, it is characterised in that described expandable carrier is in saturated suction
Swell value after water is more than 1.5, and described swell value is swell value radially；Described expandable carrier is cotton sliver；Described pastille substrate
Being coated in Semi surrounding type at the front end 1/5-4/5 of described expandable carrier, the rear end of described expandable carrier is connected with bracing wire；Described swollen
After the water suction of swollen carrier, the maximum water absorption of every is not less than 1.5 milliliters.
6. the preparation method of terconazole (triaconazole) vaginal expansion plug as claimed in claim 3, it is characterised in that described method includes as follows
Step:
1) preparation of pastille substrate:
A. substrate is placed in water-bath and adds heat fusing, prepare fused mass；
B. take hexamethylenamine add 2-7 times amount water, be fully ground to water quantities less than 5% pastel, add spy under grinding
Health azoles, mix homogeneously, prepare the first mixture；
C. the first mixture mixture is mixed homogeneously with emulsifying agent, prepare the second mixture；
D. by the fused mass of the second mixture of step c Yu a step, mix homogeneously, prepare pastille substrate；
2) pastille substrate is poured in bolt mould, insert expandable carrier, cooling and shaping, make pastille substrate bolt core；
3) preparation of pastille mucous membrane agent:
Terconazole (triaconazole) is mixed homogeneously with mucous membrane agent, prepares pastille mucous membrane agent；
4) by step 3) in pastille mucous membrane agent with discontinuous Sprayable spray attachment in step 2) in prepare pastille substrate bolt
On core, substrate bolt core is formed one layer of pastille mucous layer, prepares described terconazole (triaconazole) vaginal expansion plug.
7. the detection method of the terconazole (triaconazole) vaginal expansion plug as described in any one of claim 1-3, it is characterised in that described detection
Method includes at least one method following:
1) swell value assay method is as follows:
If a. the radial direction along described terconazole (triaconazole) vaginal expansion plug end face is chosen a little or does, measure the initial of described expandable carrier
Length H；
After the most described saturated water suction of terconazole (triaconazole) vaginal expansion plug, measure length after expandable carrier expands at selected location in a walks
h；
When c. calculating described swell value, calculate according to I formula；
Wherein, p represent axial swell value, h represent expansion after length, H represent initial length；
Or, swell value assay method is as follows:
A. axially choose at one or some positions along described terconazole (triaconazole) vaginal expansion plug, measure the initial straight of described expandable carrier
Footpath R；
After the most described saturated water suction of terconazole (triaconazole) vaginal expansion plug, measure in a walks expandable carrier expanded diameter at selected location
r；
When c. calculating described swell value, calculate by II formula；
Wherein, P represents that swell value radially, r represent that expanded diameter, R represent initial diameter；
2) weight differential assay method:
A. take described terconazole (triaconazole) vaginal expansion plug, weigh weight M；
B. take the expandable carrier in the described terconazole (triaconazole) vaginal expansion plug scraping pastille substrate and pastille mucous layer, be dried, weigh
Weight m, according to pastille substrate and gross weight X of pastille mucous layer as described in formula III calculating:
X=M-m
(Ⅲ)。
8. the detection method of terconazole (triaconazole) vaginal expansion plug as claimed in claim 7, it is characterised in that carry out melting the detection of change time limit
After, then carry out at least one detection method following:
1) swell value assay method is as follows:
If a. the first radial direction along described terconazole (triaconazole) vaginal expansion plug end face is chosen a little or does, measure at the beginning of described expandable carrier
After beginning length H, then rolling different angles measurement several times, average Hi；
After the most described terconazole (triaconazole) vaginal expansion plug carries out melting the detection of change time limit, measure in a walks expandable carrier at selected location swollen
Swollen rear length h；Roll different angles again to measure several times, seek average length hi after expansion；
When c. calculating described swell value, calculate according to I formula；
Wherein, pi represent axial swell value, hi represent expansion after average length, Hi represent average initial length；
Or, swell value assay method is as follows:
A. first axially choose at one or some positions an angle along described terconazole (triaconazole) vaginal expansion plug, measure described expansion
After the initial diameter R of carrier, then rolling different angles measurement several times, average Ri；
After the most described terconazole (triaconazole) vaginal expansion plug carries out melting the detection of change time limit, measure in a walks expandable carrier at selected location swollen
Swollen rear diameter r；Roll different angles again to measure several times, seek average diameter ri after expansion；
When c. calculating described swell value, calculate by II formula；
Wherein, Pi represent swell value radially, ri represent expansion after average diameter, Ri represent average initial diameter；
2) weight differential assay method:
A. take described terconazole (triaconazole) vaginal expansion plug, weigh weight M；
B. scrape pastille substrate and pastille mucous layer, expandable carrier is placed in 20-90 DEG C of organic solvent, take out, in 50-150
DEG C dry 1-10h, weighs weight m, according to pastille substrate and gross weight X of pastille mucous layer as described in calculating such as III formula
X=M-m (III)
Wherein, one or more during described organic solvent includes ethanol, methanol or isopropanol.
9. the detection method of terconazole (triaconazole) vaginal expansion plug as claimed in claim 8, it is characterised in that
Described expandable carrier is cotton sliver, and described detection includes at least one method following:
1) swell value assay method:
Take described terconazole (triaconazole) vaginal expansion plug 3, survey its afterbody cotton sliver diameter with slide gauge, roll 90 ° and survey again once, every
Survey twice, obtain every 2 meansigma methodss Ri measured；It is used for above-mentioned 3 bolts melting after the change time limit measures and terminate, takes out surplus immediately
Remaining cotton sliver, treats that water is disconnected and drips, be the gentliest placed on glass plate, measures the two ends of each cotton sliver and middle three portions with slide gauge
Position, measures three positions after rolling 90 ° again, and each cotton sliver obtains six data altogether, obtains 6 meansigma methodss r of mensurationi, calculate
The swell value P of everyi；
2) weight differential assay method:
Taking described terconazole (triaconazole) vaginal expansion plug 10, accurately weighed weight, gently scrapes pastille substrate and pastille mucous layer respectively, should
Gently the process of scraping must not lose cotton sliver, is placed in by cotton sliver in the 200-400ml ethanol of 50-80 DEG C, and cleans at 80khz frequency ultrasound
5 minutes, make the stromatolysis of cotton sliver surface residual remove, take out cotton sliver and firmly extract, then inhale 3 times with filter paper, be dried in 105 DEG C
2 hours, taking out, after room temperature is placed 1 hour, accurately weighed cotton sliver weight, obtains every pastille substrate and pastille mucous layer respectively
Gross weight with relative to the average pastille substrate of total grain number and pastille mucous layer gross weight, and the two is compared.
10. the detection method of terconazole (triaconazole) vaginal expansion plug as claimed in claim 9, it is characterised in that described weight differential is surveyed
Determine in method, cotton sliver is placed in the 300ml ethanol of 60-70 DEG C.
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| Application Number | Priority Date | Filing Date | Title |
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|---|---|---|---|
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103181889A (en) * | 2012-11-29 | 2013-07-03 | 哈尔滨欧替药业有限公司 | Expandable vaginal suppository |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103181889A (en) * | 2012-11-29 | 2013-07-03 | 哈尔滨欧替药业有限公司 | Expandable vaginal suppository |
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Effective date of registration: 20211117 Address after: 150040 office building 7, Bohai Third Road, haping road concentration area, Harbin Economic Development Zone, Harbin, Heilongjiang Province Patentee after: Harbin Tianmei Pharmaceutical Co.,Ltd. Address before: 150069, No. three, No. 7, Bohai, Harbin, Heilongjiang, China Patentee before: HARBIN OT PHARMACEUTICALS Co.,Ltd. Patentee before: Qiu Mingshi |
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Denomination of invention: Teconazole vaginal dilation suppository and its preparation and detection method Effective date of registration: 20230908 Granted publication date: 20161005 Pledgee: China Merchants Bank Co.,Ltd. Harbin Branch Pledgor: Harbin Tianmei Pharmaceutical Co.,Ltd. Registration number: Y2023230000075 |