CN103735493B - Fibrauretin vaginal expansion plug and preparation method thereof and detection method - Google Patents
Fibrauretin vaginal expansion plug and preparation method thereof and detection method Download PDFInfo
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- CN103735493B CN103735493B CN201310750981.7A CN201310750981A CN103735493B CN 103735493 B CN103735493 B CN 103735493B CN 201310750981 A CN201310750981 A CN 201310750981A CN 103735493 B CN103735493 B CN 103735493B
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Abstract
The present invention relates to a kind of fibrauretin vaginal expansion plug and preparation method thereof and detection method, this expansible plug comprises micronized fibrauretin and substrate formed pastille substrate and expandable carrier; Pastille Medium Culture also comprises xylitol acid anhydride glyceryl monostearate, POLY-karaya, sorbitan monolaurate, myristyl alcohol and spherical sucrose; Fibrauretin vaginal expansion plug stability of the present invention is high, evident in efficacy, not yielding, not easily become sour; And the fibrauretin vaginal expansion plug provided have employed six leading technologies of original creation, has and prevents medicinal liquid from outflowing, rapid-action, prevent the beneficial effects such as superinfection.
Description
Technical field
The invention belongs to vaginal suppository field, particularly a kind of fibrauretin vaginal expansion plug and preparation method thereof and detection method.
Background technology
Fibrauretin is extract the alkaloid obtained in the stem of menispermaceae plant Caulis Fibraureae FibraurearecisaPierre., 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 the hot water, slightly molten in water.
Existing fibrauretin preparation comprises fibrauretin tablet, capsule and suppository, because suppository overcomes the gastrointestinal side effect of Tablet and Capsula, so fibrauretin bolt is widely used; New drug standard the 64th of becoming a full member has included fibrauretin bolt, clinically for vulvovaginal candidiasis; It is made up of fibrauretin and water-soluble base, but water-soluble base has zest to vagina; And the dissolution velocity of fibrauretin in water is comparatively slow, easily there is caking in course of dissolution, then dissolve difficulty, cause that the bioavailability of suppository is low, targeting is poor, the drug effect of fibrauretin can not be given full play to; And the suppository made is rotten, distortion, have a strong impact on the absorption of medicine, cause transport and store all inconvenient; And common fibrauretin bolt also exists not easy to clean, easy pollution clothes; Active component and human contact face little, cause absorb insufficient, do not play the technical problems such as the optimum curative effect of prescription.
Summary of the invention
In order to solve the problems of the technologies described above, improve the stability of fibrauretin bolt, giving full play to the curative effect of fibrauretin bolt, the invention provides a kind of fibrauretin vaginal expansion plug and preparation method thereof; Additionally provide a kind of science detection method that can control above-mentioned fibrauretin vaginal expansion plug product quality simultaneously.
The concrete technical scheme of the present invention is as follows:
The invention provides a kind of fibrauretin vaginal expansion plug, this expansible plug comprises the fibrauretin that weight portion is 1-15 part, the expandable expandable carrier of weight portion to be the substrate of 65-200 part and weight portion be 80-400 part, described fibrauretin and substrate formed pastille substrate are coated in expandable carrier surface, and the swell value of described expandable 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 comprise 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 one or more;
Natural acid ester comprise in oleum sapii, Oleum Linderae, Fructus Foeniculi fat, Ke Kemu fat or cocoa butter one or more;
Lipoidis substrate comprises lanoline or lanonol;
Water-soluble base comprise in PEG400, polyethylene glycol 1500, Macrogol 4000, polyethylene glycol 6000, glycerin gelatine, polysorbate60, polysorbate65, polyethylene oxide condensate Idropostal, polyoxyethylene monostearate or poloxamer one or more;
Hydrogenated oil and fat comprise in hydrogenated vegetable oil, hydrogenated groundnut, castor oil hydrogenated or cotmar one or more;
Glyceride comprises AdepsSolidus, MassaEstarinumA, MassaEstarinumAS, MassaEstarinumB, MassaEstarinumC, MassaEstarinumD, MassaEstarinumE, MassaEstarinumI, MassaEstarinumT, MassaMf13, SuppositoryBaseW, SuppositoryBaseAB, SuppositoryBaseA, SuppositoryBaseB, SuppositoryBaseBC, SuppositoryBaseBD, SuppositoryBaseBBC, SuppositoryBaseE, SuppositoryBaseBCF, SuppositoryBaseC, SuppositoryBaseD, SuppositoryBase299, WecobeeW, WecobeeK, WecobeeS, WecobeeM, WecobeeES, Massuppol, Massuppol15, SuppocireOSI, SuppocireOSIxSuppocireA, SuppocireB, SuppocireC, SuppocireD, SuppocireDM, SuppocireH, SuppocireL, TegesterTriglycerideBases-9, TegesterTriglycerideBases-MA, one or more in TegesterTriglycerideBases-57,
Distillate oil comprises fractionating palm 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 in " industrial pharmacy theory and practice " book (L. La Heman, H.A. profit Berman, J.L. card Buddhist nun is uncommon. 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 by adding expandable carrier to realize in suppository.Ordinary suppository is due to the relation of gravity, no matter user is standing, under sitting posture or formula position of lying, always there is vagina or lessly can not to touch pastille substrate, after expandable carrier expands, pastille substrate can contact with vaginal walls in 360 °, abundant administration, administration enlarged areas 6 times, medicine directly attaches to lesions position, makes the position that originally cannot contact medicine also effectively can be attached 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, thus avoid superinfection, make its no longer recurrent exerbation.In addition, the introducing of expandable carrier applies " lateral leakage protection key " design concept, because the expansion of expandable 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 expandable carrier after saturated water suction can be made to be greater than 1.1.
Further improvement, in order to reduce the zest of water-soluble base to vagina, the preferred Acrawax of substrate of the present invention; Preferably, this Acrawax is 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 is 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 vaginal expansion plug, fibrauretin is carried out micronization by the present invention, wherein the particle diameter d of fibrauretin
0.9for 12-22.5 μm.As the particle diameter d of fibrauretin
0.9for 10-25 μm 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 improvement, it is the xylitol acid anhydride glyceryl monostearate of 5-20 part and the POLY-karaya of 0.5-3 part that pastille substrate of the present invention also comprises weight portion.Wherein, xylitol acid anhydride glyceryl monostearate and POLY-karaya by micronized fibrauretin parcel in the mixture, can enable fibrauretin disperse better, prevent the cohesion of composition in fibrauretin vaginal expansion plug, improve the stability of expansible plug.
Further improvement, the pastille substrate of expansible plug also comprises the sorbitan monolaurate that weight portion is 4-8 part.Sorbitan monolaurate can be used as antiseptic.
In order to improve the fusing point of substrate, make it not easily become sour, pastille substrate of the present invention also comprises the myristyl alcohol that weight portion is 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 the spherical sucrose that weight portion is 1.5-3.7 part.
Further improvement, the parts by weight of each composition of expansible plug of the present invention are preferably:
Preferably, the swell value of expandable carrier of the present invention after saturated water suction is greater than 1.5, and swell value is radial swell value; Expandable carrier includes but not limited to cotton sliver, also can comprise other sterilizable materials that can expand, as non-woven fabrics, elastic fiber etc.
Pastille substrate of the present invention is the 1/5-4/5 place, front end that Semi surrounding type is coated in expandable carrier, according to " human engineering suppository " shape, be designed to the shape such as duckbill, oval, spherical, avette, bullet shaped, torpedo, cylindrical, conical or clavate.
The expandable carrier rear end of fibrauretin vaginal expansion plug of the present invention is connected with bracing wire, suppository after expansion, by the rear end bracing wire of tractive expandable carrier, be adsorbed on the virus be killed on expandable carrier, toxin, the dead bark that comes off also pull out external in the lump, change dressings at every turn and just equal to do to vagina once thoroughly to clean, fundamentally prevention of inflammation recurs again, and namely this expansible plug belongs to " the integrated dosage form for the treatment of cleaning ".
In order to reach fibrauretin vaginal expansion plug of the present invention meet water can the effect of undergoes rapid expansion, after expandable carrier water suction, the maximum water absorption of every is not less than 1.5 milliliters; Suitable water absorption, can ensure the swell value be suitable for, too low or too high water absorption, all can cause bad impact.When water absorption is too low, can not ensure that fibrauretin vaginal expansion plug of the present invention is met feature that namely water expand and makes expansion insufficient; When water absorption is too high, the absorption ingredient that expandable carrier can be too much and limit its diffusion; Therefore, water absorption is too low or too high, is not the expandable carrier desired by the present invention.
The present invention provides the preparation method of fibrauretin vaginal expansion plug on the other hand, and the method comprises the steps:
1) preparation of pastille substrate:
A. substrate is placed in water-bath heating and melting, adds myristyl alcohol under stirring, mix homogeneously, obtained fused mass;
B. fibrauretin comminution by gas stream is carried out micronization processes 2 times, pulverizing pressure is 7bar, obtained particle diameter d
0.9for the fibrauretin of 12-22.5 μm;
C. the fibrauretin of step b is mixed homogeneously with xylitol acid anhydride glyceryl monostearate and POLY-karaya, continue under stirring to add sorbitan monolaurate and spherical sucrose, mix homogeneously, obtained mixture;
D. the mixture of step c is added in the fused mass of step a, mix homogeneously, obtained pastille substrate;
2) preparation of expansible plug: pour in bolt mould by the pastille substrate of steps d, insert expandable carrier, cooling and shaping, makes suppository.
The preparation method of fibrauretin vaginal expansion plug of the present invention have employed " the integrally formed technology of the disposable fill of stype ".
The present invention additionally provides the detection method of fibrauretin vaginal expansion 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. the radial direction along described fibrauretin vaginal expansion plug end face is chosen a bit or some points, measures the initial length H of described expandable carrier;
B., after the saturated water suction of described fibrauretin vaginal expansion plug, expandable carrier expansion rear length h in selected location place in a step is determined at;
When c. calculating described swell value, calculate according to I formula;
Wherein, p represent axial swell value, h represent expand after length, H represent initial length;
Or described swell value assay method is as follows:
D. the axis along described fibrauretin vaginal expansion plug chooses a place or some positions, measures the initial diameter R of described expandable carrier;
E., after the saturated water suction of described fibrauretin vaginal expansion plug, selected location place expandable carrier expanded diameter r in d step is determined at;
When f. calculating described swell value, calculate by II formula;
Wherein, P represents the swell value of radial direction, r represents expanded diameter, R represents initial diameter;
Described weight differential assay method comprises:
G. get described fibrauretin vaginal expansion plug, take weight M;
H. the expandable carrier scraped in the described fibrauretin vaginal expansion plug of pastille substrate is got, dry, take weight m, the weight X according to pastille substrate as described in formula III calculating:
X＝M-m
(Ⅲ)。
Further, in the detection method of fibrauretin vaginal expansion plug of the present invention, after carrying out melting the detection of change time limit, then carry out following at least one detection method:
1) swell value assay method is as follows:
A. first choose a bit or some points along the radial direction of described fibrauretin vaginal expansion plug end face, after measuring the initial length H of described expandable carrier, then different angles of rolling measure several times, and average Hi;
B., after described fibrauretin vaginal expansion plug carries out melting the detection of change time limit, expandable carrier expansion rear length h in selected location place in a step is determined at; Different angles of rolling again measure several times, ask average length hi after expanding;
When c. calculating described swell value, calculate according to I formula;
Wherein, pi represent axial swell value, hi represent expand after average length, Hi represent average initial length;
Or described swell value assay method is as follows:
D. first choose a place or some positions an angle along the axis of described fibrauretin vaginal expansion plug, after measuring the initial diameter R of described expandable carrier, then different angles of rolling measure several times, and average Ri;
E., after described fibrauretin vaginal expansion plug carries out melting the detection of change time limit, selected location place expandable carrier expanded diameter r in d step is determined at; Different angles of rolling again measure several times, ask average diameter ri after expanding;
When f. calculating described swell value, calculate by II formula;
Wherein, Pi represents the swell value of radial direction, ri represents the rear average diameter that expands, Ri represents average initial diameter.
Wherein said melt become time limit assay method (existing Chinese Pharmacopoeia two annex) comprising: get described fibrauretin vaginal expansion plug 3, after room temperature places 1 hour, be placed on respectively on lower floor's plectane of 3 metal rack, load in respective sleeve pipe, and fixing with hook.Unless otherwise specified, be dipped vertically into respectively by said apparatus in the container filling 37.0 ± 0.5 DEG C of water being no less than 4L, its upper end position at 90mm place, underwater, should fill a rot, overturn this device in the solution once every 10 minutes in container.Above numerical range should not be construed as limitation of the present invention, and the technical scheme not in above-mentioned numerical range is also in protection scope of the present invention.
2) weight differential assay method:
G. get described fibrauretin vaginal expansion plug, take weight M;
H. scrape pastille substrate, expandable carrier is placed in 20-90 DEG C of organic solvent, take out, in 50-150 DEG C of dry 1-10h, take weight m, according to the weight X of pastille substrate as described in III formula calculating
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 vaginal expansion plug of the present invention, expandable carrier is cotton sliver, and detection method comprises following at least one method:
1) swell value assay method:
Get fibrauretin vaginal expansion plug 3, survey its afterbody cotton sliver diameter with slide gauge, roll about 90 ° and survey once again, survey twice for every, obtain every 2 meansigma methods Ri measured; Above-mentioned 3 bolts are used for melt and become after the time limit measures and terminate, take out residue cotton sliver immediately, treat that water is disconnected to drip, all gently be placed on glass plate, the two ends of each cotton sliver and middle three positions are measured with slide gauge, roll after about 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 fibrauretin vaginal expansion plug 10, accurately weighed weight respectively, gently scrape pastille substrate (cotton sliver must not be lost), cotton sliver is placed in the 200-400ml ethanol of 50-80 DEG C, preferably, cotton sliver is placed in the 300ml ethanol of 60-70 DEG C, and clean 5 minutes at 80khz frequency ultrasound, the stromatolysis of cotton sliver surface residual is removed, take out cotton sliver firmly to extract, 3 times are inhaled again with filter paper, in 105 DEG C of dryings 2 hours, take out, after room temperature places 1 hour, accurately weighed cotton sliver weight respectively, obtain every pastille matrix weight and average pastille matrix weight, every pastille matrix weight compares with average pastille matrix weight, what exceed average pastille matrix weight ± 10% must not more than 2, and 1 overrun 1 times must not be had.
The assay method of the swell value of fibrauretin vaginal expansion plug provided by the present invention adopts multi-angle repetitive measurement method, improves the accuracy of measurement, adds the operability of mensuration, and method is easier to judge; When the standard detection performing state-promulgated pharmacopoeia annex weight differential fibrauretin vaginal expansion plug of the present invention, substrate need be scraped off, the scraping degree grasped due to operator is different, cause every scraping degree difference comparatively large, so the present invention adopts the substrate on dissolution with solvents expansible plug surface, through verification experimental verification, when adopting the substrate on hot ethanol cleaning 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 annex V D high effective liquid chromatography for measuring, and assay method is as follows:
Get fibrauretin vaginal expansion plug 10, 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, trinitrophenol test solution 30ml is slowly added immediately under constantly stirring, hold over night, filter with the incipient fusion crucible of weighed weight, the precipitation saturated aqueous solution washing of trinitrophenol fibrauretin, the 15ml gradation that adds water again is washed, and be dried to constant weight at 105 DEG C, accurately weighed, be multiplied with 0.7612, obtain in test sample containing C
21h
22o
4hCl3H
2the weight of O.
Fibrauretin vaginal expansion plug provided by the present invention has stability height and waits beneficial effect, and this fibrauretin vaginal expansion plug have employed six leading technologies of original creation, expandable carrier in described fibrauretin vaginal expansion plug add " the disposable fill of stype the is integrally formed " technology applying original creation, " control of the inner core coefficient of expansion " technology, " human engineering bolt type " technology, " the clean integration for the treatment of " dosage form, " administration of intravaginal sticking type " technology, " design of lateral leakage protection key " six technology, this expandable carrier can make the pastille substrate of fibrauretin vaginal expansion plug fully contact with vaginal walls, and prevent medicinal liquid from outflowing, also there is effect that cleaning vagina prevents superinfection, after fibrauretin is made micronization by the present invention, improve the bioavailability of fibrauretin vaginal expansion plug, fibrauretin after micronization is wrapped in xylitol acid anhydride glyceryl monostearate and POLY-karaya, the dispersion of fibrauretin can be beneficial to, be more conducive to the performance of fibrauretin vaginal expansion plug curative effect, sorbitan monolaurate, myristyl alcohol, spherical sucrose is added at pastille Medium Culture, not only increase the stability of fibrauretin vaginal expansion plug, and this expansible plug is not yielding, not easily becomes sour, stores and convenient transportation.
Accompanying drawing explanation
The schematic diagram of Fig. 1 and Fig. 2 swell value assay method.
Detailed description of the invention
Embodiment 1
Preparation method:
1) preparation of pastille substrate:
A. fixed oil and semi-synthetic Petiolus Trachycarpi grease are placed in water-bath heating and melting, obtained fused mass;
B. fibrauretin comminution by gas stream is carried out micronization processes 2 times, pulverizing pressure is 7bar, obtained particle diameter d
0.9it is the fibrauretin of 12 μm;
C. the fibrauretin of step b is added in the fused mass of step a, mix homogeneously, obtained pastille substrate;
2) preparation of expansible plug: pastille substrate poured in bolt mould, insert 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 water-bath heating and melting, obtained fused mass;
B. fibrauretin comminution by gas stream is carried out micronization processes 2 times, pulverizing pressure is 7bar, obtained particle diameter d
0.9it is the fibrauretin of 12 μm;
C. the fibrauretin of step b is mixed homogeneously with xylitol acid anhydride glyceryl monostearate and POLY-karaya, obtained mixture;
D. the mixture of step c is added in the fused mass of step a, mix homogeneously, obtained pastille substrate;
2) preparation of expansible plug: pastille substrate poured in bolt mould, insert 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 of heavily about 5.0g.
Embodiment 4
Preparation method:
1) preparation of pastille substrate:
A. fixed oil and semi-synthetic Petiolus Trachycarpi grease are placed in water-bath heating and melting, obtained fused mass;
B. fibrauretin comminution by gas stream is carried out micronization processes 2 times, pulverizing pressure is 7bar, obtained particle diameter d
0.9it is the fibrauretin of 15 μm;
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, obtained mixture;
D. the mixture of step c is added in the fused mass of step a, mix homogeneously, obtained pastille substrate;
2) preparation of expansible plug: pastille substrate poured in bolt mould, insert 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 water-bath heating and melting, add myristyl alcohol under stirring, mix homogeneously, obtained fused mass;
B. fibrauretin comminution by gas stream is carried out micronization processes 2 times, pulverizing pressure is 7bar, obtained particle diameter d
0.9it is the fibrauretin of 20 μm;
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, obtained mixture;
D. the mixture of step c is added in the fused mass of step a, mix homogeneously, obtained pastille substrate;
2) preparation of expansible plug: pastille substrate poured in bolt mould, insert cotton sliver, cooling and shaping, makes 100 pieces of duckbill suppositorys, every piece of heavily about 3.9g.
Embodiment 7
Preparation method: make 100 pieces of oval suppositorys, every piece of heavily about 4.3g by embodiment 6.
Embodiment 8
Preparation method:
1) preparation of pastille substrate:
A. fixed oil and semi-synthetic Petiolus Trachycarpi grease are placed in water-bath heating and melting, add myristyl alcohol under stirring, mix homogeneously, obtained fused mass;
B. fibrauretin comminution by gas stream is carried out micronization processes 2 times, pulverizing pressure is 7bar, obtained particle diameter d
0.9it is the fibrauretin of 15 μm;
C. the fibrauretin of step b is mixed homogeneously with xylitol acid anhydride glyceryl monostearate and POLY-karaya, continue under stirring to add sorbitan monolaurate and spherical sucrose, mix homogeneously, obtained mixture;
D. the mixture of step c is added in the fused mass of step a, mix homogeneously, obtained pastille substrate;
2) preparation of expansible plug: pastille substrate poured in bolt mould, insert 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 of heavily about 3.6g.
Test example 1
The outward appearance of the fibrauretin vaginal expansion plug that embodiment of the present invention 1-9 provides, containing fibrauretin amount (labelled amount %), melt become the time limit testing result in table 1;
The testing result of the fibrauretin vaginal expansion plug indices of table 1 embodiment 1-9
Test example 2 stability test
1. accelerated test
The fibrauretin vaginal expansion plug of Example 8, be divided into 3 batches, be numbered sample 1, sample 2 and sample 3 respectively, get commercially available fibrauretin bolt product in contrast, by sample and reference substance all at 25 DEG C ± 2 DEG C, relative humidity is place 6 months under the condition of 65% ± 5%, sample respectively once 1 month, 2 months, 3 months, 6 the end of month at duration of test, by the regulation in Chinese Pharmacopoeia, detect expansible plug character, containing fibrauretin amount (labelled amount %), melt 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 vaginal expansion plug provided by the present invention as can be seen from the table, under the environment of constant temperature high humidity, places after 6 months, the color of expansible plug, the amount containing fibrauretin, melt become the time limit all there is not obvious change; And commercially available fibrauretin suppository is placed after 6 months under high humidity, the jaundice of suppository surface, and there is speckle, some suppository breaks, and the content of fibrauretin significantly declines, and melts change duration; Show that fibrauretin vaginal expansion plug of the present invention stability compared with fibrauretin suppository significantly improves.
2. long term test
The fibrauretin vaginal expansion plug of Example 8, be divided into 3 batches, be numbered sample 1 respectively, sample 2 and sample 3, get commercially available fibrauretin bolt product in contrast, by sample and reference substance all at temperature 25 DEG C ± 2 DEG C, relative humidity is place 36 months under the condition of 60% ± 10%, sampling in every 3 months once, respectively at 0 month, 3 months, 6 months, 9 months, sampling in 12 months, detect the character of expansible plug, containing the amount (labelled amount %) of 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 compared with 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 vaginal expansion plug provided by the invention as can be seen from the table, under the environment of constant temperature high humidity, places after 36 months, the color of described expansible plug, the amount containing fibrauretin, melt become the time limit all there is not obvious change; And after commercially available fibrauretin suppository places 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 vaginal expansion plug of the present invention stability compared with fibrauretin suppository significantly improves; And the holding time is long.
Test example 3 swell value measures
Method one
Get fibrauretin vaginal expansion plug 3, survey its afterbody cotton sliver diameter with slide gauge, roll about 90 ° and survey once again, survey twice for every, obtain every 2 meansigma methods Ri measured; Above-mentioned 3 bolts are used for melt and become after the time limit measures and terminate, take out residue cotton sliver immediately, treat that water is disconnected to drip, all gently be placed on glass plate, the two ends of each cotton sliver and middle three positions are measured with slide gauge, roll after about 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.
The swell value measuring the fibrauretin vaginal expansion plug of embodiment 1-9 according to above-mentioned swell value assay method is as shown in table 4;
The swell value of table 4 embodiment 1-9 fibrauretin vaginal expansion plug
Method two
As depicted in figs. 1 and 2:
1) swell value assay method:
A. first C1, C2, C3 tri-points are chosen along the radial direction of described vaginal expansion plug end face, measure initial length H1, H2, H3 of described expandable carrier with slide gauge after, roll again 90 ° and measure, choose after C1, C4, C5 tri-some slide gaugies measure initial length H4, H5, H6 of described expandable carrier along the radial direction of described vaginal expansion plug end face, ask the meansigma methods Hi of H1, H2, H3, H4, H5 and H6;
B., after described vaginal expansion plug carries out melting the detection of change time limit, C1, C2, C3 selected in a step tri-rear length h1 of position expandable carrier expansion, h2, h3 is determined at slide gauge; Roll 90 ° again, be determined at C1, C4, C5 selected in a step tri-rear length h4 of position expandable carrier expansion, h5, h6 with slide gauge, ask the average length of h1, h2, h3, h4, h5 and h6, be average length hi after expanding;
When c. calculating described swell value, calculate according to I formula;
Wherein, pi represent axial swell value, hi represent expand after average length, Hi represent average initial length;
Or, swell value assay method:
D. first A1, A2 and A3 tri-points are chosen an angle along the axis of described vaginal expansion plug, measure initial diameter R1, R2 and R3 of described expandable carrier with slide gauge after, roll 90 ° again, axis along described vaginal expansion plug chooses B1, B2 and B3 tri-points, measure initial diameter R4, R5 and R6 of described expandable carrier with slide gauge after, ask the meansigma methods Ri of R1, R2, R3, R4, R5 and R6 six initial diameters;
E., after described vaginal expansion plug carries out melting the detection of change time limit, be determined at selected A1, A2 and A3 position expandable carrier expanded diameter in d step and be respectively r1, r2 and r3; B1, B2 and B3 position expandable carrier expanded diameter measured selected by d step that rolls again 90 ° is respectively r4, r5 and r6, asks the meansigma methods of r1, r2, r3, r4, r5 and r6, average diameter ri after must expanding;
When f. calculating described swell value, calculate by II formula;
Wherein, Pi represents the swell value of radial direction, ri represents the rear average diameter that expands, Ri represents average initial diameter.
Test example 4 weight differential determination test
Get fibrauretin vaginal expansion plug 10, accurately weighed weight respectively, gently scrape pastille substrate (cotton sliver must not be lost), cotton sliver is placed in the 300ml ethanol of 60-70 DEG C, if (substrate comprises glycerin gelatine, cotton sliver is placed in the 300ml water of 60-70 DEG C), and clean 5 minutes at 80khz frequency ultrasound, the stromatolysis of cotton sliver surface residual is removed, take out cotton sliver firmly to extract, 3 times are inhaled again with filter paper, in 105 DEG C of dryings 2 hours, take out, after room temperature places 1 hour, accurately weighed cotton sliver weight respectively, obtain every pastille matrix weight and average pastille matrix weight, every pastille matrix weight compares with average pastille matrix weight, what exceed average pastille matrix weight ± 10% must not more than 2, and 1 overrun 1 times must not be had.
Repeat aforesaid operations, detect the fibrauretin vaginal expansion plug of embodiment 1-9, the equal conformance with standard of its weight differential.
Test example 5
The fibrauretin vaginal expansion plug (tested group) of Example 8 and commercially available fibrauretin (matched group), with purified water 500ml for dissolution medium, temperature 37 DEG C, rotating speed 100r/min, respectively at 2,4,6,10,15,20,30,45,60 minutes right place sampling 5ml, 45 μm of filtering with microporous membranes, measure stripping quantity, calculate relative accumulation stripping percentage rate; Experimental result is in table 5;
The result of table 5 liang group cumulative defaultlogic (%)
Show that the cumulative leaching rate of fibrauretin vaginal expansion plug of the present invention is obviously better than fibrauretin bolt.
The therapeutic effect of test example 6 pairs of vulvovaginal candidiasis
Stochastic choice vulvovaginal candidiasis patient 50 example, the age 25-55 year between; Get rid of gestation and age of sucking patient; Patient main suit has pruritus vulvae, burn feeling, white bean dregs sample leucorrhea, with urgent micturition, dysurea, then can make a definite diagnosis further with vaginal secretions plate coating checking; 50 routine vulvovaginal candidiasis patients are divided into treatment group 33 example and matched group 17 example, treatment group gives the fibrauretin vaginal expansion 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 mucosa recovers normal, diagnosable effective; 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 slight defect, the visible telangiectasis of submucous tissue, has a small amount of neutrophil infiltration in tissue, effectively diagnosable; Symptom is without any change, and diagnosable is invalid; After 4 courses for the treatment of of successive administration, the therapeutic effect for the treatment of group and matched group is in table 6;
Table 6 liang group compares vulvovaginal candidiasis therapeutic effect
Fibrauretin vaginal expansion plug as can be seen from the table described in the embodiment of the present invention has good therapeutic effect to vulvovaginal candidiasis, and effective percentage reaches 96.0%, compares have diversity (P<0.05) with matched group.
Test example 7 fibrauretin vaginal expansion plug is to the irritation test of rabbit vagina mucosa
Get rabbit 10, be divided into 2 groups at random, often organize 5, be divided into tested group and matched group; The described tested group of fibrauretin vaginal expansion plug giving embodiment 8, every day 1 time, successive administration 7 days, matched group gives fibrauretin bolt, every day 1 time, successive administration 7 days; The daily general signs of fore-and-aft observing rabbit, comprise appetite, hair color, with or without abnormal secretion thing etc.; During administration, each group is showed no obvious abnormalities phenomenon; Last administration 24h takes out vagina tissue, for fibrauretin vaginal expansion plug group, and perusal smooth mucosal, without phenomenons such as hyperemia, edema, hemorrhage, ulcer and erosions, pathological examination mucosa structural integrity, without ulcer, inflammation and erosion formation; For fibrauretin bolt group, perusal mucosa is more coarse, has hyperemia, edema, phenomenon, pathological examination mucosa structural integrity, but has ulcer and rotten to the corn formation; Show that fibrauretin vaginal expansion plug of the present invention is to mucosa nonirritant.
Claims (14)
1. a fibrauretin vaginal expansion plug, it is characterized in that, described expansible plug comprises the fibrauretin that weight portion is 1-15 part, the expandable expandable carrier of weight portion to be the substrate of 65-200 part and weight portion be 80-400 part, described fibrauretin and substrate formed pastille substrate are coated in expandable carrier surface, and the swell value of described expandable carrier after saturated water suction is greater than 1.1;
Described substrate be selected from Acrawax, natural acid ester or water-soluble base one or more;
Described Acrawax be selected from 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 one or more;
Described natural acid ester be selected from oleum sapii, Oleum Linderae, Fructus Foeniculi fat, Ke Kemu fat or cocoa butter one or more;
Described water-soluble base be selected from PEG400, polyethylene glycol 1500, Macrogol 4000, polyethylene glycol 6000, glycerin gelatine, polysorbate60, polysorbate65, polyoxyethylene monostearate or poloxamer one or more;
It is the xylitol acid anhydride glyceryl monostearate of 5-20 part and the POLY-karaya of 0.5-3 part that described pastille substrate also comprises weight portion.
2. fibrauretin vaginal expansion plug as claimed in claim 1, it is characterized in that, described substrate is Acrawax; 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.
3. fibrauretin vaginal expansion plug as claimed in claim 1, it is characterized in that, the ratio of weight and number of described fixed oil and semi-synthetic Petiolus Trachycarpi grease is 10:1.
4. fibrauretin vaginal expansion plug as claimed in claim 1, is characterized in that, the particle diameter d of described fibrauretin
0.9for 12-22.5 μm.
5. fibrauretin vaginal expansion plug as claimed in claim 1, it is characterized in that, described pastille substrate also comprises the sorbitan monolaurate that weight portion is 4-8 part.
6. fibrauretin vaginal expansion plug as claimed in claim 5, it is characterized in that, described pastille substrate also comprises the myristyl alcohol that weight portion is 1.5-3.7 part.
7. fibrauretin vaginal expansion plug as claimed in claim 6, it is characterized in that, described pastille substrate also comprises the spherical sucrose that weight portion is 1.5-3.7 part.
8. fibrauretin vaginal expansion plug as claimed in claim 7, it is characterized in that, the parts by weight of each composition of described expansible plug are:
9. the fibrauretin vaginal expansion plug as described in as arbitrary in claim 1-8, it is characterized in that, the swell value of described expandable carrier after saturated water suction is greater than 1.5, and described swell value is radial swell value; Described expandable carrier is cotton sliver; Described pastille substrate is the 1/5-4/5 place, front end that Semi surrounding type is coated in described expandable carrier, and the rear end of described expandable carrier is connected with bracing wire; After described expandable carrier water suction, the maximum water absorption of every is not less than 1.5 milliliters.
10. the preparation method of fibrauretin vaginal expansion plug as claimed in claim 7, it is characterized in that, described method comprises the steps:
1) preparation of pastille substrate:
A. substrate is placed in water-bath heating and melting, adds myristyl alcohol under stirring, mix homogeneously, obtained fused mass;
B. fibrauretin comminution by gas stream is carried out micronization processes 2 times, pulverizing pressure is 7bar, obtained particle diameter d
0.9for the fibrauretin of 12-22.5 μm;
C. the fibrauretin of step b is mixed homogeneously with xylitol acid anhydride glyceryl monostearate and POLY-karaya, continue under stirring to add sorbitan monolaurate and spherical sucrose, mix homogeneously, obtained mixture;
D. the mixture of step c is added in the fused mass of step a, mix homogeneously, obtained pastille substrate;
2) preparation of expansible plug: pour in bolt mould by the pastille substrate of steps d, insert expandable carrier, cooling and shaping, makes suppository.
11. as arbitrary in claim 1-8 as described in the detection method of fibrauretin vaginal expansion plug, it is characterized in that, described detection method comprises following at least one method:
1) swell value assay method is as follows:
A. the radial direction along described fibrauretin vaginal expansion plug end face is chosen a bit or some points, measures the initial length H of described expandable carrier;
B., after the saturated water suction of described fibrauretin vaginal expansion plug, expandable carrier expansion rear length h in selected location place in a step is determined at;
When c. calculating described swell value, calculate according to I formula;
Wherein, p represent axial swell value, h represent expand after length, H represent initial length;
Or swell value assay method is as follows:
D. the axis along described fibrauretin vaginal expansion plug chooses a place or some positions, measures the initial diameter R of described expandable carrier;
E., after the saturated water suction of described fibrauretin vaginal expansion plug, selected location place expandable carrier expanded diameter r in d step is determined at;
When f. calculating described swell value, calculate by II formula;
Wherein, P represents the swell value of radial direction, r represents expanded diameter, R represents initial diameter;
2) weight differential assay method:
G. get described fibrauretin vaginal expansion plug, take weight M;
H. the expandable carrier scraped in the described fibrauretin vaginal expansion plug of pastille substrate is got, dry, take weight m, the weight X according to pastille substrate as described in formula III calculating:
X＝M-m
(Ⅲ)。
The detection method of 12. fibrauretin vaginal expansion plug as claimed in claim 11, is characterized in that, after carrying out melting the detection of change time limit, then carries out following at least one detection method:
1) swell value assay method is as follows:
A. first choose a bit or some points along the radial direction of described fibrauretin vaginal expansion plug end face, after measuring the initial length H of described expandable carrier, then different angles of rolling measure several times, and average Hi;
B., after described fibrauretin vaginal expansion plug carries out melting the detection of change time limit, expandable carrier expansion rear length h in selected location place in a step is determined at; Different angles of rolling again measure several times, ask average length hi after expanding;
When c. calculating described swell value, calculate according to I formula;
Wherein, pi represent axial swell value, hi represent expand after average length, Hi represent average initial length;
Or swell value assay method is as follows:
D. first choose a place or some positions an angle along the axis of described fibrauretin vaginal expansion plug, after measuring the initial diameter R of described expandable carrier, then different angles of rolling measure several times, and average Ri;
E., after described fibrauretin vaginal expansion plug carries out melting the detection of change time limit, selected location place expandable carrier expanded diameter r in d step is determined at; Different angles of rolling again measure several times, ask average diameter ri after expanding;
When f. calculating described swell value, calculate by II formula;
Wherein, Pi represents the swell value of radial direction, ri represents the rear average diameter that expands, Ri represents average initial diameter;
2) weight differential assay method:
G. get described fibrauretin vaginal expansion plug, take weight M;
H. scrape pastille substrate, expandable carrier is placed in 20-90 DEG C of organic solvent, take out, in 50-150 DEG C of dry 1-10h, take weight m, according to the weight X of pastille substrate as described in III formula calculating
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 vaginal expansion plug as claimed in claim 12, it is characterized in that, described expandable carrier is cotton sliver, and described detection method comprises following at least one method:
1) swell value assay method:
Get described fibrauretin vaginal expansion plug 3, survey its afterbody cotton sliver diameter with slide gauge, roll 90 ° and survey again once, survey twice for every, obtain every 2 meansigma methods Ri measured; Above-mentioned 3 bolts are used for melt and become after the time limit measures and terminate, take out residue cotton sliver immediately, treat that water is disconnected to drip, all gently be placed on glass plate, the two ends of each cotton sliver and middle three positions are measured with slide gauge, roll after 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 described fibrauretin vaginal expansion plug 10, accurately weighed weight respectively, gently scrape pastille substrate, cotton sliver must not be lost, cotton sliver is placed in the 200-400ml ethanol of 50-80 DEG C, and clean 5 minutes at 80kHz frequency ultrasound, the stromatolysis of cotton sliver surface residual is removed, take out cotton sliver firmly to extract, 3 times are inhaled again with filter paper, in 105 DEG C of dryings 2 hours, take out, after room temperature places 1 hour, accurately weighed cotton sliver weight respectively, obtain every pastille matrix weight and average pastille matrix weight, every pastille matrix weight compares with average pastille matrix weight, what exceed average pastille matrix weight ± 10% must not more than 2, and 1 overrun 1 times must not be had.
The detection method of 14. fibrauretin vaginal expansion plug as claimed in claim 13, is characterized in that, cotton sliver is placed in the 300ml ethanol of 60-70 DEG C.
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| 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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| 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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Effective date of registration: 20211115 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. 7, Bohai Third Road, Pingfang Industrial Zone, economic and Technological Development Zone, Harbin, Heilongjiang Province Patentee before: HARBIN OT PHARMACEUTICALS Co.,Ltd. Patentee before: Qiu Mingshi |
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Denomination of invention: Huangtensu vaginal dilation suppository and its preparation and detection method Effective date of registration: 20230908 Granted publication date: 20160309 Pledgee: China Merchants Bank Co.,Ltd. Harbin Branch Pledgor: Harbin Tianmei Pharmaceutical Co.,Ltd. Registration number: Y2023230000075 |