CN103735493A - Palmatine vaginal swelling bolt as well as preparation method and detection method thereof - Google Patents
Palmatine vaginal swelling bolt as well as preparation method and detection method thereof Download PDFInfo
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- CN103735493A CN103735493A CN201310750981.7A CN201310750981A CN103735493A CN 103735493 A CN103735493 A CN 103735493A CN 201310750981 A CN201310750981 A CN 201310750981A CN 103735493 A CN103735493 A CN 103735493A
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Abstract
The invention relates to a palmatine vaginal swelling bolt as well as a preparation method and a detection method thereof. The swelling bolt comprises a medicated substrate formed by micronized palmatine and a substrate, and an expansion carrier, wherein the medicated substrate also comprises xylitol anhydride glycerol monostearate, karaya gum, sorbitol lauric acid ester, myristyl alcohol and spherical saccharose. The palmatine vaginal swelling bolt disclosed by the invention is high in stability, significant in curative effect, not easy to deform, and free of rancidity, and the provided palmatine vaginal swelling bolt adopts six original leading technologies, and has the beneficial effects that the soup is prevented from flowing out, the palmatine vaginal swelling bolt is quick to take effect, secondary infection is prevented and the like.
Description
Technical field
The invention belongs to vaginal suppository field, particularly a kind of fibrauretin vagina expansible plug and preparation method thereof and detection method.
Background technology
Fibrauretin is in the stem of menispermaceae plant Caulis Fibraureae Fibraurea recisa Pierre., to extract the alkaloid obtaining, and main component is hydrochloric acid palmatine, has effects for removing toxic heat, for gynecological inflammation, bacillary dysentery, enteritis, respiratory tract and urinary tract infection, surgical infection, eye conjunctivitis etc.; The odorless of fibrauretin own, bitter in the mouth, easily molten in hot water, slightly molten in water.
Existing fibrauretin preparation comprises fibrauretin tablet, capsule and suppository, because suppository has overcome the gastrointestinal side effect of Tablet and Capsula, so fibrauretin bolt is widely used; New drug the 64th of the standard of becoming a full member included fibrauretin bolt, clinically for vulvovaginal candidiasis; It is made by fibrauretin and water-soluble base, but water-soluble base has zest to vagina; And the dissolution velocity of fibrauretin in water is slower, in course of dissolution, be prone to caking, then dissolving is difficult, causes the bioavailability of suppository low, targeting is poor, can not give full play to the drug effect of fibrauretin; And the suppository of making is rotten, distortion, have a strong impact on the absorption of medicine, cause transportation and store all inconvenient; And common fibrauretin bolt also exists not easy to clean, easy pollution clothes; Active component and people's contact level are little, cause absorbing insufficient, do not bring into play the technical problems such as optimum curative effect of prescription.
Summary of the invention
In order to solve the problems of the technologies described above, improve the stability of fibrauretin bolt, give full play to the curative effect of fibrauretin bolt, the invention provides a kind of fibrauretin vagina expansible plug and preparation method thereof; A kind of science detection method that can control above-mentioned fibrauretin 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 fibrauretin vagina expansible plug, this expansible plug comprises that weight portion is the fibrauretin of 1-15 part, weight portion is the substrate of 65-200 part and the expandable expansion carrier that weight portion is 80-400 part, described fibrauretin 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;
Wherein, substrate comprises one or more in Acrawax, natural acid ester, lipoidis substrate, water-soluble base, hydrogenated oil and fat, glyceride or distillate oil;
Acrawax comprises one or more in mixed fatty glycerides, propylene glycol stearate, fixed oil, semi-synthetic fatty acid glyceride, semi-synthetic cocos nucifera oil ester, Witepsol, semi-synthetic Petiolus Trachycarpi grease or semi-synthetic Fructus Litseae ester;
Natural acid ester comprises one or more in oleum sapii, Oleum Linderae, Fructus Foeniculi fat, Ke Kemu fat or cocoa butter;
Lipoidis substrate comprises lanoline or lanonol;
Water-soluble base comprises one or more in PEG400, polyethylene glycol 1500, Macrogol 4000, polyethylene glycol 6000, glycerin gelatine, polysorbate60, polysorbate65, polyoxyethylene condensation substance Idropostal, polyoxyethylene monostearate or poloxamer;
Hydrogenated oil and fat comprises one or more in hydrogenated vegetable oil, hydrogenated groundnut, castor oil hydrogenated or cotmar;
Glyceride comprises Adeps Solidus, Massa Estarinum A, Massa Estarinum AS, Massa Estarinum B, Massa Estarinum C, Massa Estarinum D, Massa Estarinum E, Massa Estarinum I, Massa Estarinum T, Massa Mf13, Suppository Base W, Suppository Base AB, Suppository Base A, Suppository Base B, Suppository Base BC, Suppository Base BD, Suppository Base BBC, Suppository Base E, Suppository Base BCF, Suppository Base C, Suppository Base D, Suppository Base299, Wecobee W, Wecobee K, Wecobee S, Wecobee M, Wecobee ES, Massuppol, Massuppol15, Suppocire OSI, Suppocire OSIx Suppocire A, Suppocire B, Suppocire C, Suppocire D, Suppocire DM, Suppocire H, Suppocire L, Tegester Triglyceride Bases-9, Tegester Triglyceride Bases-MA, one or more in Tegester Triglyceride Bases-57,
Distillate oil comprises fractional distillation Petiolus Trachycarpi oil or fractionated coconut oil;
Preferably, substrate comprises one or more in Acrawax, natural acid ester or water-soluble base.
The substrate of English name of the present invention is included (L. La Heman in < < industrial pharmacy theory and practice > > book, H.A. sharp Berman, J.L. block Buddhist nun uncommon. industrial pharmacy theory and practice, Chemical Industry Press, second edition: 215-217).
The present invention has adopted original creation " intravaginal sticking type medicine-feeding technology ", and this technology by adding expansion carrier to realize in suppository.Ordinary suppository is due to the relation of gravity, no matter user be standing, sitting posture or lie under formula position, always have vagina can not or the less pastille substrate that touches, after expansion carrier expands, pastille substrate can be 360 ° and contact with vaginal walls, fully administration, 6 times of administration enlarged areas, medicine directly attaches to lesions position, makes the position that originally cannot contact medicine also can obtain effectively attaching treatment; And due to the buffer action that stype plays in the middle of vagina, make no longer to contact with each other between wound surface, thereby avoid superinfection, it is shown effect no longer repeatedly.In addition, " anti-side leakage key " design concept has been applied in the introducing of expansion carrier, because the expansion of expansion carrier tail end (non-pastille substrate) can be close to vaginal wall, and then prevent the outflow of medicine and substrate, reduce the pollution of medicated clothing and keep the valid density of medicine; And by " inner core coefficient of expansion control technology ", the swell value of carrier after saturated water suction that can make to expand is greater than 1.1.
Further improve, in order to reduce the zest of water-soluble base to vagina, matrix optimization Acrawax of the present invention; Preferably, this Acrawax is that the mixture cures oil of fixed oil and semi-synthetic Petiolus Trachycarpi grease and the ratio of weight and number of semi-synthetic Petiolus Trachycarpi grease are 8.5-13.5:1; Further preferably, the ratio of weight and number of fixed oil and semi-synthetic Petiolus Trachycarpi grease is 10:1.
In order to improve the bioavailability of fibrauretin vagina expansible plug, the present invention carries out micronization by fibrauretin, wherein the particle diameter d of fibrauretin
0.9for 12-22.5 μ m.Particle diameter d when fibrauretin
0.9for 10-25 μ m is more conducive to the stripping of fibrauretin, excessive or too small particle size range is all unfavorable for the stripping of fibrauretin, can not improve very much the bioavailability of expansible plug.
Further improve, pastille substrate of the present invention also comprises that weight portion is the xylitol acid anhydride glyceryl monostearate of 5-20 part and the POLY-karaya of 0.5-3 part.Wherein, xylitol acid anhydride glyceryl monostearate and POLY-karaya can be wrapped in micronized fibrauretin in mixture, can make fibrauretin disperse better, prevent the cohesion of composition in fibrauretin vagina expansible plug, improve the stability of expansible plug.
Further improve, the pastille substrate of expansible plug also comprises that weight portion is the sorbitan monolaurate of 4-8 part.Sorbitan monolaurate can be used as antiseptic.
In order to improve the fusing point of substrate, make it be difficult for becoming sour, pastille substrate of the present invention also comprises that weight portion is the myristyl alcohol of 1.5-3.7 part.
In order to increase the denseness of each composition in expansible plug, pastille substrate of the present invention also comprises that weight portion is the spherical sucrose of 1.5-3.7 part.
Further improve, the parts by weight of each composition of expansible plug of the present invention are preferably:
Preferably, the swell value of expansion carrier of the present invention after saturated water suction is greater than 1.5, and swell value is swell value radially; Expansion carrier includes but not limited to cotton sliver, also can comprise the sterilizable material that other can expand, as non-woven fabrics, elastic fiber etc.
Pastille substrate of the present invention is the front end 1/5-4/5 place that Semi surrounding type is coated in expansion carrier, according to " human engineering suppository " shape, be designed to the shapes such as duckbill, oval, spherical, avette, bullet shaped, torpedo, cylindrical, taper shape or clavate.
The expansion carrier rear end of fibrauretin vagina expansible plug of the present invention is connected with bracing wire, suppository after expansion, by the rear end bracing wire of tractive expansion carrier, the dead bark that be adsorbed on the virus being killed on expansion carrier, toxin, comes off is also pulled out external in the lump, change dressings at every turn and just equal to do once thoroughly clean to vagina, fundamentally prevention of inflammation recurs again, and this expansible plug belongs to " integrated dosage form is cleaned in treatment ".
In order to reach fibrauretin vagina expansible plug of the present invention, meet the effect that water can expand rapidly, after the water suction of expansion carrier, the maximum water absorption of every is not less than 1.5 milliliters; Suitable water absorption, can guarantee suitable swell value, and too low or too high water absorption all can cause bad impact.When water absorption is too low, can not guarantee that fibrauretin vagina expansible plug of the present invention meets the feature that water expand and make to expand insufficient; When water absorption is too high, expansion carrier is understood too much absorption ingredient and is limited its diffusion; Therefore, water absorption is too low or too high, is not the desired expansion carrier of the present invention.
The present invention provides the preparation method of fibrauretin vagina expansible plug on the other hand, and the method comprises the steps:
1) preparation of pastille substrate:
A. substrate is placed in to water-bath heating and melting, under stirring, adds myristyl alcohol, mix homogeneously, makes fused mass;
B. fibrauretin is carried out to micronization processes 2 times with comminution by gas stream, pulverizing pressure is 7bar, makes particle diameter d
0.9fibrauretin for 12-22.5 μ m;
C. the fibrauretin of step b is mixed homogeneously with xylitol acid anhydride glyceryl monostearate and POLY-karaya, continue to add sorbitan monolaurate and spherical sucrose under stirring, mix homogeneously, makes mixture;
D. the mixture of step c is added in the fused mass of step a, mix homogeneously, makes pastille substrate;
2) preparation of expansible plug: the pastille substrate of steps d is poured in bolt mould, inserted expansion carrier, cooling and shaping, makes suppository.
The preparation method of fibrauretin 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 fibrauretin vagina expansible plug on the other hand, and this detection method comprises swell value assay method, weight differential detection method, assay etc.
Wherein swell value assay method comprises:
A. along radially the choosing a bit or some points of described fibrauretin vagina expansible plug end face, measure the initial length H of described expansion carrier;
B. after the saturated water suction of described fibrauretin vagina expansible plug, be determined at the rear length h of selected location place's expansion carrier expansion in a step;
While c. calculating described swell value, according to I formula, calculate;
（I）
Wherein, p represent axial swell value, h represent to expand after length, H represent initial length;
Or described swell value assay method is as follows:
D. along described fibrauretin vagina expansible plug axially choose a place or some positions, measure the initial diameter R of described expansion carrier;
E. after the saturated water suction of described fibrauretin vagina expansible plug, be determined at the rear diameter r of selected location place's expansion carrier expansion in d step;
While f. calculating described swell value, by II formula, calculate;
（II）
Wherein, P represent swell value, r radially represent to expand after diameter, R represent initial diameter;
Described weight differential assay method comprises:
G. get described fibrauretin vagina expansible plug, take weight M;
H. get the expansion carrier in the described fibrauretin vagina expansible plug that scrapes pastille substrate, dry, take weight m, according to the weight X of pastille substrate as described in calculating as III formula:
X=M-m
（Ⅲ）。
Further, in the detection method of fibrauretin vagina expansible plug of the present invention, melt and become after time limit detection, then carry out following at least one detection method:
1) swell value assay method is as follows:
A. first along radially the choosing a bit or some points of described fibrauretin 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 fibrauretin vagina expansible plug melts after the detection of change time limit, is determined at the rear length h of selected location place's expansion carrier expansion in a step; The different angles of rolling are again measured several times, ask the rear average length hi that expands;
While c. calculating described swell value, according to I formula, calculate;
（I）
Wherein, pi represent axial swell value, hi represent to expand after average length, Hi represent average initial length;
Or described swell value assay method is as follows:
D. first an angle along described fibrauretin vagina expansible plug axially choose a place or some positions, measure after the initial diameter R of described expansion carrier, then the different angles of rolling measure several times, Ri averages;
E. described fibrauretin vagina expansible plug melts after the detection of change time limit, is determined at the rear diameter r of selected location place's expansion carrier expansion in d step; The different angles of rolling are again measured several times, ask the rear average diameter ri that expands;
While f. calculating described swell value, by II formula, calculate;
（II）
Wherein, Pi represent swell value, ri radially represent to expand after average diameter, Ri represent to put down
Equal initial diameter.
The wherein said change time limit assay method (two appendix of existing Chinese Pharmacopoeia) that melts comprising: gets 3 of described fibrauretin vagina expansible plugs, in room temperature, places after 1 hour, be placed on respectively on lower floor's plectane of 3 metal rack, pack in sleeve pipe separately, and fixing with hook.Unless otherwise specified, said apparatus is dipped vertically into respectively in the container that fills 37.0 ± 0.5 ℃ of water that are no less than 4L, its upper end position should fill a rot at 90mm place, underwater in container, every 10 minutes, overturn this device once in solution.Above numerical range should not be construed as limitation of the present invention, and the technical scheme in above-mentioned numerical range is not in protection scope of the present invention yet.
2) weight differential assay method:
G. get described fibrauretin vagina expansible plug, take weight M;
H. scrape pastille substrate, expansion carrier is placed in to 20-90 ℃ of organic solvent, take out, in 50-150 ℃ of dry 1-10h, take weight m, according to the weight X of pastille substrate as described in the calculating of III formula
X=M-m（Ⅲ）
Wherein, described organic solvent is selected from one or more in ethanol, methanol or isopropyl alcohol.
Further, in the detection method of fibrauretin vagina expansible plug of the present invention, expansion carrier is cotton sliver, and detection method comprises following at least one method:
1) swell value assay method:
Get 3 of fibrauretin vagina expansible plugs, with slide gauge, survey its afterbody cotton sliver diameter, roll approximately 90 ° and survey once again, survey twice for every, obtain 2 meansigma methods Ri of every mensuration; Above-mentioned 3 bolts are used for melting and become after the time limit measures and finish, take out immediately residue cotton sliver, treat disconnected of water, all gently be placed on glass plate, with slide gauge, measure two ends and middle three positions of each cotton sliver, roll after approximately 90 ° and measure three positions again, each cotton sliver obtains six data altogether, obtains 6 meansigma methods r of mensuration
i, calculate the swell value P of every
i, the swell value of three bolts all should be greater than 1.5.
2) weight differential assay method:
Get 10 of fibrauretin vagina expansible plugs, the accurately weighed weight of difference, gently scrape pastille substrate (must not lose cotton sliver), cotton sliver is placed in to the 200-400ml ethanol of 50-80 ℃, preferably, cotton sliver is placed in to the 300ml ethanol of 60-70 ℃, and 80khz frequency ultrasonic cleaning 5 minutes, the remaining stromatolysis in cotton sliver surface is removed, taking out cotton sliver firmly extracts, with filter paper, inhale 3 times again, in 105 ℃, be dried 2 hours, take out, room temperature was placed after 1 hour, the accurately weighed cotton sliver weight of difference, obtain every pastille substrate weight and average pastille substrate weight, every pastille substrate weight and average pastille substrate weight ratio are, what exceed average pastille substrate weight ± 10% must not be more than 2, and must not there is 1 times of 1 overrun.
The assay method of the swell value of fibrauretin vagina expansible plug provided by the present invention adopts repeatedly measuring method of multi-angle, has improved the accuracy of measuring, and has increased the operability of measuring, and method is easier to judgement; When carrying out the standard detection fibrauretin vagina of the present invention expansible plug of state-promulgated pharmacopoeia appendix weight differential, substrate need be scraped off, the scraping degree of grasping due to operator is different, cause every scraping degree difference larger, so the present invention adopts the substrate on dissolution with solvents expansible plug surface, through verification experimental verification, when adopting hot ethanol to clean the substrate on expansible plug surface, result is better, and repeatability is higher, and weight differential assay method is more convenient stable.
Content assaying method is according to Chinese Pharmacopoeia appendix V D high effective liquid chromatography for measuring, and assay method is as follows:
Get 10 of fibrauretin vagina expansible plugs, put in beaker, heating water 150ml and 0.1mol/L sodium hydroxide solution 15ml, be stirred to dissolve, let cool, in dislocation 250ml measuring bottle, be diluted with water to scale, shake up, filter, precision measures subsequent filtrate 100ml, add 0.1mol/L hydrochloric acid solution 10ml, under constantly stirring, slowly add immediately trinitrophenol test solution 30ml, standing over night, with the incipient fusion crucible of weighed weight, filter, the saturated aqueous solution washing of trinitrophenol fibrauretin for precipitation, add again water 15ml gradation washing, and be dried to constant weight at 105 ℃, accurately weighed, with 0.7612 multiply each other, obtain and in test sample, contain C
21h
22o
4hCl3H
2the weight of O.
Fibrauretin vagina expansible plug provided by the present invention has the high beneficial effect that waits of stability, and this fibrauretin vagina expansible plug has adopted six leading technologies of original creation, expansion carrier in described fibrauretin vagina expansible plug add " the disposable fill of stype is integrally formed " technology of having applied original creation, " control of the inner core coefficient of expansion " technology, " human engineering bolt type " technology, " treatment is clean integrated " dosage form, " administration of intravaginal sticking type " technology, " anti-side leakage key design " six technology, this expansion carrier can make the pastille substrate of fibrauretin vagina expansible plug fully contact with vaginal walls, and prevent medicinal liquid outflow, also there is the effect that cleaning vagina prevents superinfection, the present invention makes fibrauretin after micronization, improved the bioavailability of fibrauretin vagina expansible plug, fibrauretin after micronization is wrapped in xylitol acid anhydride glyceryl monostearate and POLY-karaya, can be beneficial to the dispersion of fibrauretin, be more conducive to the performance of fibrauretin vagina expansible plug curative effect, in pastille substrate, add sorbitan monolaurate, myristyl alcohol, spherical sucrose, not only improved the stability of fibrauretin vagina expansible plug, and this expansible plug is not yielding, is difficult for becoming sour, storage and convenient transportation.
Accompanying drawing explanation
The schematic diagram of Fig. 1 and Fig. 2 swell value assay method.
The specific embodiment
Embodiment 1
Preparation method:
1) preparation of pastille substrate:
A. fixed oil and semi-synthetic Petiolus Trachycarpi grease are placed in to water-bath heating and melting, make fused mass;
B. fibrauretin is carried out to micronization processes 2 times with comminution by gas stream, pulverizing pressure is 7bar, makes particle diameter d
0.9it is the fibrauretin of 12 μ m;
C. the fibrauretin of step b is added in the fused mass of step a, mix homogeneously, makes pastille substrate;
2) preparation of expansible plug: pastille substrate is poured in bolt mould, inserted cotton sliver, cooling and shaping, makes 100 pieces of bullet shaped suppositorys, every piece of heavily about 3.2g.
Embodiment 2
Preparation method:
1) preparation of pastille substrate:
A. semi-synthetic fatty acid glyceride and semi-synthetic Fructus Litseae ester are placed in to water-bath heating and melting, make fused mass;
B. fibrauretin is carried out to micronization processes 2 times with comminution by gas stream, pulverizing pressure is 7bar, makes particle diameter d
0.9it is the fibrauretin of 12 μ m;
C. the fibrauretin of step b is mixed homogeneously with xylitol acid anhydride glyceryl monostearate and POLY-karaya, make mixture;
D. the mixture of step c is added in the fused mass of step a, mix homogeneously, makes pastille substrate;
2) preparation of expansible plug: pastille substrate is poured in bolt mould, inserted cotton sliver, cooling and shaping, makes 100 pieces of avette suppositorys, every piece of heavily about 2.2g.
Embodiment 3
Preparation method: make 100 pieces of torpedo suppositorys by the method for embodiment 2, every piece heavily approximately 5.0
g.
Embodiment 4
Preparation method:
1) preparation of pastille substrate:
A. fixed oil and semi-synthetic Petiolus Trachycarpi grease are placed in to water-bath heating and melting, make fused mass;
B. fibrauretin is carried out to micronization processes 2 times with comminution by gas stream, pulverizing pressure is 7bar, makes particle diameter d
0.9it is the fibrauretin of 15 μ m;
C. the fibrauretin of step b is mixed homogeneously with xylitol acid anhydride glyceryl monostearate and POLY-karaya, continue to add sorbitan monolaurate under stirring, mix homogeneously, makes mixture;
D. the mixture of step c is added in the fused mass of step a, mix homogeneously, makes pastille substrate;
2) preparation of expansible plug: pastille substrate is poured in bolt mould, inserted cotton sliver, cooling and shaping, makes 100 pieces of clavate suppositorys, every piece of heavily about 1.5g.
Embodiment 5
Preparation method: make 100 pieces of cylindrical suppositorys by the method for embodiment 4, every piece of heavily about 2.7g.
Embodiment 6
Preparation method:
1) preparation of pastille substrate:
A. Ke Kemu fat and Oleum Linderae are placed in to water-bath heating and melting, under stirring, add myristyl alcohol, mix homogeneously, makes fused mass;
B. fibrauretin is carried out to micronization processes 2 times with comminution by gas stream, pulverizing pressure is 7bar, makes particle diameter d
0.9it is the fibrauretin of 20 μ m;
C. the fibrauretin of step b is mixed homogeneously with xylitol acid anhydride glyceryl monostearate and POLY-karaya, continue to add sorbitan monolaurate under stirring, mix homogeneously, makes mixture;
D. the mixture of step c is added in the fused mass of step a, mix homogeneously, makes pastille substrate;
2) preparation of expansible plug: pastille substrate is poured in bolt mould, inserted cotton sliver, cooling and shaping, makes 100 pieces of duckbill suppositorys, every piece of heavily about 3.9g.
Embodiment 7
Preparation method: by the 100 pieces of oval suppositorys of making of embodiment 6, every piece heavily approximately 4.3
g.
Embodiment 8
Preparation method:
1) preparation of pastille substrate:
A. fixed oil and semi-synthetic Petiolus Trachycarpi grease are placed in to water-bath heating and melting, under stirring, add myristyl alcohol, mix homogeneously, makes fused mass;
B. fibrauretin is carried out to micronization processes 2 times with comminution by gas stream, pulverizing pressure is 7bar, makes particle diameter d
0.9it is the fibrauretin of 15 μ m;
C. the fibrauretin of step b is mixed homogeneously with xylitol acid anhydride glyceryl monostearate and POLY-karaya, continue to add sorbitan monolaurate and spherical sucrose under stirring, mix homogeneously, makes mixture;
D. the mixture of step c is added in the fused mass of step a, mix homogeneously, makes pastille substrate;
2) preparation of expansible plug: pastille substrate is poured in bolt mould, inserted cotton sliver, cooling and shaping, makes 100 pieces of conical suppositorys, every piece of heavily about 3.3g.
Embodiment 9
Preparation method: make 100 pieces of spherical suppositorys by the method for embodiment 8, every piece heavily approximately 3.6
g.
Test example 1
The outward appearance of the fibrauretin vagina expansible plug that embodiment of the present invention 1-9 provides, containing the amount (labelled amount %) of fibrauretin, melt become the time limit testing result in Table 1;
The testing result of the fibrauretin vagina expansible plug indices of table 1 embodiment 1-9
| Embodiment | Character | Labelled amount (%) | Melt and become the time limit (min) |
| 1 | Yellow, smooth surface | 93.43 | 24.3 |
| 2 | Yellow, smooth surface | 96.87 | 22.6 |
| 3 | Yellow, smooth surface | 98.66 | 23.1 |
| 4 | Yellow, smooth surface | 100.25 | 21.8 |
| 5 | Yellow, smooth surface | 102.34 | 25.9 |
| 6 | Yellow, smooth surface | 98.86 | 21.6 |
| 7 | Yellow, smooth surface | 99.23 | 20.7 |
| 8 | Yellow, smooth surface | 99.95 | 19.8 |
| 9 | Yellow, smooth surface | 100.03 | 21.4 |
Test example 2 stability tests
1. accelerated test
Get the fibrauretin vagina expansible plug of embodiment 8, be divided into 3 batches, be numbered respectively sample 1, sample 2 and sample 3, get commercially available fibrauretin bolt product in contrast, sample and reference substance all at 25 ℃ ± 2 ℃, are placed 6 months under the condition that relative humidity is 65% ± 5%, at duration of test, sample respectively once 1 month, 2 months, 3 months, 6 the end of month, press the regulation in Chinese Pharmacopoeia, detect the character of expansible plug, containing the amount (labelled amount %) of fibrauretin, melt and become the time limit, result of the test is in Table 2;
Three batch samples of table 2 embodiment 8 and the accelerated test result of reference substance
Fibrauretin vagina expansible plug provided by the present invention, under the environment of constant temperature high humidity, places after 6 months as can be seen from the table, the color of expansible plug, the amount that contains fibrauretin, melts and becomes the time limit and all do not occur significantly to change; And commercially available fibrauretin suppository is placed after 6 months under high humidity, suppository surface jaundice, and occur speckle, some suppository breaks, and the content of fibrauretin significantly declines, and melts change duration; Show that fibrauretin vagina expansible plug of the present invention compares stability with fibrauretin suppository and significantly improve.
2. long term test
Get the fibrauretin vagina expansible plug of embodiment 8, be divided into 3 batches, be numbered respectively sample 1, sample 2 and sample 3, get commercially available fibrauretin bolt product in contrast, by sample and reference substance all at 25 ℃ ± 2 ℃ of temperature, relative humidity is to place 36 months under 60% ± 10% condition, sampling in every 3 months once, respectively at 0 month, 3 months, 6 months, 9 months, sampling in 12 months, detect the character of expansible plug, amount (labelled amount %) containing fibrauretin, 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, result of the test is in Table 3,
Three batch samples of table 3 embodiment 8 and the long-term test results of reference substance
Fibrauretin vagina expansible plug provided by the invention, under the environment of constant temperature high humidity, places after 36 months as can be seen from the table, the color of described expansible plug, the amount that contains fibrauretin, melts and becomes the time limit and all do not occur significantly to change; And commercially available fibrauretin suppository was placed after 9 months, suppository darkens, and places after 12 months, and speckle appears in suppository surface, and fracture phenomena occurs; And the content of fibrauretin significantly declines in fibrauretin suppository, melt and become time limit significant prolongation; Show that fibrauretin vagina expansible plug of the present invention compares stability with fibrauretin suppository and significantly improve; And the holding time is long.
Test example 3 swell values are measured
Method one
Get 3 of fibrauretin vagina expansible plugs, with slide gauge, survey its afterbody cotton sliver diameter, roll approximately 90 ° and survey once again, survey twice for every, obtain 2 meansigma methods Ri of every mensuration; Above-mentioned 3 bolts are used for melting and become after the time limit measures and finish, take out immediately residue cotton sliver, treat disconnected of water, all gently be placed on glass plate, with slide gauge, measure two ends and middle three positions of each cotton sliver, roll after approximately 90 ° and measure three positions again, each cotton sliver obtains six data altogether, obtains 6 meansigma methods r of mensuration
i, calculate the swell value P of every
i, the swell value of three bolts is all greater than 1.5.
As shown in table 4 according to the swell value of the fibrauretin vagina expansible plug of above-mentioned swell value assay method mensuration embodiment 1-9;
The swell value of table 4 embodiment 1-9 fibrauretin vagina expansible plug
| Embodiment | Average diameter (mm) before expanding | Average diameter (mm) after expanding | Swell value (doubly) | Result |
| Embodiment 1 | 12.18 | 22.03 | 1.81 | Qualified |
| Embodiment 2 | 11.74 | 20.15 | 1.72 | Qualified |
| Embodiment 3 | 11.89 | 22.44 | 1.89 | Qualified |
| Embodiment 4 | 12.25 | 22.95 | 1.87 | Qualified |
| Embodiment 5 | 11.98 | 19.37 | 1.62 | Qualified |
| Embodiment 6 | 12.09 | 21.41 | 1.77 | Qualified |
| Embodiment 7 | 11.83 | 20.86 | 1.76 | Qualified |
| Embodiment 8 | 12.11 | 21.69 | 1.79 | Qualified |
| Embodiment 9 | 12.28 | 22.74 | 1.85 | Qualified |
Method two
As shown in Figures 2 and 3:
1) swell value assay method:
A. first along described vagina expansible plug end face, radially choose C1, C2, tri-points of C3, with slide gauge, measure after initial length H1, H2, the H3 of described expansion carrier, the 90 ° of measurements of rolling again, radially choose C1, C4, tri-points of C5 along described vagina expansible plug end face are measured after initial length H4, H5, the H6 of described expansion carrier with slide gauge, ask the meansigma methods Hi of H1, H2, H3, H4, H5 and H6;
B. described vagina expansible plug melts after the detection of change time limit, with slide gauge, is determined at selected C1, C2 in a step, C3 tri-expansions of position expansion carriers rear length h1, h2, h3; Roll again 90 °, with slide gauge, be determined at selected C1, C4 in a step, C5 tri-expansions of position expansion carriers rear length h4, h5, h6, ask the average length of h1, h2, h3, h4, h5 and h6, be the rear average length hi that expands;
While c. calculating described swell value, according to I formula, calculate;
（I）
Wherein, pi represent axial swell value, hi represent to expand after average length, Hi represent average initial length;
Or, swell value assay method:
D. first an angle, along described vagina expansible plug, axially choose A1, A2 and tri-points of A3, with slide gauge, measure after initial diameter R1, the R2 and R3 of described expansion carrier, roll again 90 °, along described vagina expansible plug, axially choose B1, B2 and tri-points of B3, with slide gauge, measure after initial diameter R4, the R5 and R6 of described expansion carrier, ask the meansigma methods Ri of R1, R2, R3, R4, R5 and six initial diameters of R6;
E. described vagina expansible plug melts and becomes after the time limit detects, and after being determined in d step selected A1, A2 and A3 position expansion carrier and expanding, diameter is respectively r1, r2 and r3; Roll again 90 ° measure in d step selected B1, B2 and B3 position expansion carrier and expand after diameter be respectively r4, r5 and r6, ask the meansigma methods of r1, r2, r3, r4, r5 and r6, average diameter ri afterwards must expand;
While f. calculating described swell value, by II formula, calculate;
（II）
Wherein, Pi represent swell value, ri radially represent to expand after average diameter, Ri represent average initial diameter.
Test example 4 weight differential determination tests
Get 10 of fibrauretin vagina expansible plugs, the accurately weighed weight of difference, gently scrape pastille substrate (must not lose cotton sliver), cotton sliver is placed in to the 300ml ethanol of 60-70 ℃, if (substrate comprises glycerin gelatine, cotton sliver is placed in to the 300ml water of 60-70 ℃), and 80khz frequency ultrasonic cleaning 5 minutes, the remaining stromatolysis in cotton sliver surface is removed, taking out cotton sliver firmly extracts, with filter paper, inhale 3 times again, in 105 ℃, be dried 2 hours, take out, room temperature was placed after 1 hour, the accurately weighed cotton sliver weight of difference, obtain every pastille substrate weight and average pastille substrate weight, every pastille substrate weight and average pastille substrate weight ratio are, what exceed average pastille substrate weight ± 10% must not be more than 2, and must not there is 1 times of 1 overrun.
Repeat aforesaid operations, detect the fibrauretin vagina expansible plug of embodiment 1-9, the equal conformance with standard of its weight differential.
Test example 5
Get the fibrauretin vagina expansible plug (tested group) of embodiment 8 and commercially available fibrauretin (matched group), take purified water 500ml as dissolution medium, 37 ℃ of temperature, rotating speed 100r/min, respectively at 2,4,6,10,15,20,30,45,60 minutes timing spot sampling 5ml, 45 μ m filtering with microporous membranes, measure stripping quantity, calculate accumulation stripping percentage rate relatively; Experimental result is in Table 5;
The result of table 5 liang group accumulation stripping percentage rate (%)
The cumulative leaching rate that shows fibrauretin vagina expansible plug of the present invention is obviously better than fibrauretin bolt.
The therapeutic effect of 6 pairs of vulvovaginal candidiasis of test example
Random vulvovaginal candidiasis patient 50 examples of selecting, the age is between 25-55 year; Get rid of gestation and age of sucking patient; Patient main suit has pruritus vulvae, burn feeling, white bean dregs sample leucorrhea, can be with urgent micturition, dysurea, more further make a definite diagnosis with vaginal secretions plate coating checking; 50 routine vulvovaginal candidiasis patients are divided into treatment group 33 example and matched group 17 examples, treatment group gives the fibrauretin vagina expansible plug of embodiment 8, once a day, within 7 days, is a course for the treatment of simultaneously; Matched group gives fibrauretin bolt, once a day, within 7 days, is a course for the treatment of.
On inspection, vaginal mucosa is without congested, red and swollen, smooth surface, and without white bean dregs sample secretions, vagina picture checks without Candida albicans, and tissue slice is shown in that mucosa is complete, and mucosal tissue is normal, diagnosable recovery from illness; Vaginal mucosa is congested, red and swollen phenomenon is clearly better, and white bean dregs sample secretions obviously reduces, and vaginal smear examination Candida albicans quantity obviously reduces, and it is normal, diagnosable effective that mucosa recovers; Vaginal mucosa is congested, red and swollen phenomenon takes a turn for the better to some extent, and white bean dregs sample secretions reduces, and vaginal smear examination Candida albicans decreases, mucosa under tissue slice has slightly damaged, the visible telangiectasis of submucous tissue, has a small amount of neutrophil infiltration in tissue, diagnosable effective; Symptom is without any variation, and diagnosable is invalid; Successive administration is after 4 courses for the treatment of, and the therapeutic effect for the treatment of group and matched group is in Table 6;
Table 6 liang group is to the comparison of vulvovaginal candidiasis therapeutic effect
Fibrauretin vagina expansible plug described in the embodiment of the present invention has good therapeutic effect to vulvovaginal candidiasis as can be seen from the table, and effective percentage reaches 96.0%, relatively has diversity (P<0.05) with matched group.
The irritation test of test example 7 fibrauretin vagina expansible plugs to rabbit vagina mucosa
Get 10 of rabbit, be divided at random 2 groups, 5 every group, be divided into tested group and matched group; Described tested group of fibrauretin vagina expansible plug that gives embodiment 8, every day 1 time, successive administration 7 days, matched group gives fibrauretin bolt, every day 1 time, successive administration 7 days; The general signs of administration every day fore-and-aft observing rabbit, comprises appetite, hair color, has or not abnormal secretion thing etc.; During administration, each group is showed no obvious abnormalities phenomenon; Last administration 24h takes out vagina tissue, for fibrauretin vagina expansible plug group, and perusal smooth mucosal, without hyperemia, edema, hemorrhage, ulcer and the phenomenon such as rotten to the corn, pathological examination mucosa structural integrity, without ulcer, inflammation and rotten to the corn formation; For fibrauretin bolt group, perusal mucosa is more coarse, has hyperemia, edema, phenomenon, pathological examination mucosa structural integrity, but have ulcer and rotten to the corn formation; Show that fibrauretin vagina expansible plug of the present invention is to mucosa nonirritant.
Claims (13)
1. a fibrauretin vagina expansible plug, it is characterized in that, described expansible plug comprises that weight portion is the fibrauretin of 1-15 part, weight portion is the substrate of 65-200 part and the expandable expansion carrier that weight portion is 80-400 part, described fibrauretin and substrate formed pastille substrate are coated in expansion carrier surface, and the swell value of described expansion carrier after saturated water suction is greater than 1.1;
Described substrate comprises one or more in Acrawax, natural acid ester or water-soluble base;
Described Acrawax comprises one or more in mixed fatty glycerides, propylene glycol stearate, fixed oil, semi-synthetic fatty acid glyceride, semi-synthetic cocos nucifera oil ester, semi-synthetic Petiolus Trachycarpi grease or semi-synthetic Fructus Litseae ester;
Described natural acid ester comprises one or more in oleum sapii, Oleum Linderae, Fructus Foeniculi fat, Ke Kemu fat or cocoa butter;
Described water-soluble base comprises one or more in PEG400, polyethylene glycol 1500, Macrogol 4000, polyethylene glycol 6000, glycerin gelatine, polysorbate60, polysorbate65, polyoxyethylene monostearate or poloxamer.
2. fibrauretin vagina expansible plug as claimed in claim 1, is characterized in that, described substrate is Acrawax; Preferably, described Acrawax is the mixture of fixed oil and semi-synthetic Petiolus Trachycarpi grease, and the ratio of weight and number of described fixed oil and semi-synthetic Petiolus Trachycarpi grease is 8.5-13.5:1; Preferably, the ratio of weight and number of described fixed oil and semi-synthetic Petiolus Trachycarpi grease is 10:1.
3. fibrauretin vagina expansible plug as claimed in claim 1, is characterized in that, the particle diameter d of described fibrauretin
0.9for 12-22.5 μ m.
4. fibrauretin vagina expansible plug as claimed in claim 1, is characterized in that, described pastille substrate also comprises that weight portion is the xylitol acid anhydride glyceryl monostearate of 5-20 part and the POLY-karaya of 0.5-3 part.
5. fibrauretin vagina expansible plug as claimed in claim 4, is characterized in that, described pastille substrate also comprises that weight portion is the sorbitan monolaurate of 4-8 part.
6. fibrauretin vagina expansible plug as claimed in claim 5, is characterized in that, described pastille substrate also comprises that weight portion is the myristyl alcohol of 1.5-3.7 part.
7. fibrauretin vagina expansible plug as claimed in claim 6, is characterized in that, described pastille substrate also comprises that weight portion is the spherical sucrose of 1.5-3.7 part.
8. fibrauretin vagina expansible plug as claimed in claim 7, is characterized in that, the parts by weight of described each composition of expansible plug are:
9. the fibrauretin vagina expansible plug as described in as arbitrary in claim 1-8, is characterized in that, the swell value of described expansion carrier after saturated water suction is greater than 1.5, and described swell value is swell value radially; Described expansion carrier is cotton sliver; Described pastille substrate is the front end 1/5-4/5 place that Semi surrounding type is coated in described expansion carrier, and the rear end of described expansion carrier is connected with bracing wire; After described expansion carrier water suction, the maximum water absorption of every is not less than 1.5 milliliters.
10. the preparation method of fibrauretin vagina expansible plug as claimed in claim 7, 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, under stirring, adds myristyl alcohol, mix homogeneously, makes fused mass;
B. fibrauretin is carried out to micronization processes 2 times with comminution by gas stream, pulverizing pressure is 7bar, makes particle diameter d
0.9fibrauretin for 12-22.5 μ m;
C. the fibrauretin of step b is mixed homogeneously with xylitol acid anhydride glyceryl monostearate and POLY-karaya, continue to add sorbitan monolaurate and spherical sucrose under stirring, mix homogeneously, makes mixture;
D. the mixture of step c is added in the fused mass of step a, mix homogeneously, makes pastille substrate;
2) preparation of expansible plug: the pastille substrate of steps d is poured in bolt mould, inserted expansion carrier, cooling and shaping, makes suppository.
11. as the detection method of the fibrauretin vagina expansible plug of claim 1-8 or 10 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 fibrauretin vagina expansible plug end face, measure the initial length H of described expansion carrier;
B. after the saturated water suction of described fibrauretin vagina expansible plug, be determined at the rear length h of selected location place's expansion carrier expansion in a step;
While c. calculating described swell value, according to I formula, calculate;
（I）
Wherein, p represent axial swell value, h represent to expand after length, H represent initial length;
Or swell value assay method is as follows:
D. along described fibrauretin vagina expansible plug axially choose a place or some positions, measure the initial diameter R of described expansion carrier;
E. after the saturated water suction of described fibrauretin vagina expansible plug, be determined at the rear diameter r of selected location place's expansion carrier expansion in d step;
While f. calculating described swell value, by II formula, calculate;
（II）
Wherein, P represent swell value, r radially represent to expand after diameter, R represent initial diameter;
2) weight differential assay method:
G. get described fibrauretin vagina expansible plug, take weight M;
H. get the expansion carrier in the described fibrauretin vagina expansible plug that scrapes pastille substrate, dry, take weight m, according to the weight X of pastille substrate as described in calculating as III formula:
X=M-m
（Ⅲ）。
The detection method of 12. fibrauretin vagina expansible plugs as claimed in claim 11, 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 fibrauretin 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 fibrauretin vagina expansible plug melts after the detection of change time limit, is determined at the rear length h of selected location place's expansion carrier expansion in a step; The different angles of rolling are again measured several times, ask the rear average length hi that expands;
While c. calculating described swell value, according to I formula, calculate;
（I）
Wherein, pi represent axial swell value, hi represent to expand after average length, Hi represent average initial length;
Or swell value assay method is as follows:
D. first an angle along described fibrauretin vagina expansible plug axially choose a place or some positions, measure after the initial diameter R of described expansion carrier, then the different angles of rolling measure several times, Ri averages;
E. described fibrauretin vagina expansible plug melts after the detection of change time limit, is determined at the rear diameter r of selected location place's expansion carrier expansion in d step; The different angles of rolling are again measured several times, ask the rear average diameter ri that expands;
While f. calculating described swell value, by II formula, calculate;
（II）
Wherein, Pi represent swell value, ri radially represent to expand after average diameter, Ri represent to put down
Equal initial diameter;
2) weight differential assay method:
G. get described fibrauretin vagina expansible plug, take weight M;
H. scrape pastille substrate, expansion carrier is placed in to 20-90 ℃ of organic solvent, take out, in 50-150 ℃ of dry 1-10h, take weight m, according to the weight X of pastille substrate as described in the calculating of III formula
X=M-m（Ⅲ）
Wherein, described organic solvent is selected from one or more in ethanol, methanol or isopropyl alcohol.
The detection method of 13. fibrauretin vagina expansible plugs as claimed in claim 12, is characterized in that, described expansion carrier is cotton sliver, and described detection method comprises following at least one method:
1) swell value assay method:
Get 3 of described fibrauretin vagina expansible plugs, with slide gauge, survey its afterbody cotton sliver diameter, roll approximately 90 ° and survey once again, survey twice for every, obtain 2 meansigma methods Ri of every mensuration; Above-mentioned 3 bolts are used for melting and become after the time limit measures and finish, take out immediately residue cotton sliver, treat disconnected of water, all gently be placed on glass plate, with slide gauge, measure two ends and middle three positions of each cotton sliver, roll after approximately 90 ° and measure three positions again, each cotton sliver obtains six data altogether, obtains 6 meansigma methods r of mensuration
i, calculate the swell value P of every
i, the swell value of three bolts all should be greater than 1.5;
2) weight differential assay method:
Get 10 of described fibrauretin vagina expansible plugs, the accurately weighed weight of difference, gently scrape pastille substrate (must not lose cotton sliver), cotton sliver is placed in to the 200-400ml ethanol of 50-80 ℃, preferably, cotton sliver is placed in to the 300ml ethanol of 60-70 ℃, and 80khz frequency ultrasonic cleaning 5 minutes, the remaining stromatolysis in cotton sliver surface is removed, taking out cotton sliver firmly extracts, with filter paper, inhale 3 times again, in 105 ℃, be dried 2 hours, take out, room temperature was placed after 1 hour, the accurately weighed cotton sliver weight of difference, obtain every pastille substrate weight and average pastille substrate weight, every pastille substrate weight and average pastille substrate weight ratio are, what exceed average pastille substrate weight ± 10% must not be more than 2, and must not there is 1 times of 1 overrun.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104971145A (en) * | 2015-06-30 | 2015-10-14 | 哈尔滨欧替药业有限公司 | Zangfukang vaginal expansive suppository as well as preparation method and detection method thereof |
Citations (2)
| 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 |
| CN103284941A (en) * | 2013-05-17 | 2013-09-11 | 哈尔滨欧替药业有限公司 | Expansion suppository of clotrimazole or salt thereof, preparation method and detection method |
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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 |
| CN103284941A (en) * | 2013-05-17 | 2013-09-11 | 哈尔滨欧替药业有限公司 | Expansion suppository of clotrimazole or salt thereof, preparation method and detection method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104971145A (en) * | 2015-06-30 | 2015-10-14 | 哈尔滨欧替药业有限公司 | Zangfukang vaginal expansive suppository as well as preparation method and detection method thereof |
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