CN103751099B - Bifonazole vaginal expansion plug and preparation method thereof and detection method - Google Patents
Bifonazole vaginal expansion plug and preparation method thereof and detection method Download PDFInfo
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Abstract
The present invention relates to a kind of bifonazole vaginal expansion plug and preparation method thereof and detection method, this expansible plug comprises bifonazole and substrate formed pastille substrate and expandable carrier; Pastille Medium Culture adds Polyethylene Glycol 32 glyceryl monolaurate, chitin, potassium sorbate, xylitan monostearate and capric monoglyceride, it is high that the bifonazole vaginal expansion plug made has stability, dispersion of medicine, zest is little, bioavailability is high, evident in efficacy beneficial effect of Denging; And the bifonazole vaginal expansion plug provided have employed six leading technologies of original creation, can prevent medicinal liquid from outflowing, prevent superinfection.
Description
Technical field
The invention belongs to vaginal suppository field, particularly a kind of bifonazole vaginal expansion plug and preparation method thereof and detection method.
Background technology
Bifonazole, chemistry (±)-1-(α-biphenyl-4-base benzyl by name)-1H-imidazoles, its structural formula is as follows:
Bifonazole is the micro-yellow crystalline powder of off-white color fat; Odorless, bitter in the mouth; Easily molten in chloroform, slightly molten in methanol or dehydrated alcohol, almost insoluble in water.
Bifonazole is imidazoles antifungal agent, its antibacterial substrate is the synthesis of double inhibition fungal cell membrane ergosterol, act on except P450-14a demethyl except the same with other imidazoleses, also act on methylol bran propylhomoserin CoA-reductase, there is broad-spectrum antifungal effect, have inhibitory action to the pathomycete of 90%; Traditional Chinese medicines electricity in existing ointment, gel, suppository etc. 2010 editions; Bifonazole is made local topical dosage form, pointed to therapentic part, the concentration of topical remedy can be improved; But due to the bad control of dosage of ointment and gel, so the application of suppository is more extensive by contrast.Bifonazole suppository is used for the treatment of vulvovaginal candidiasis; Such as, (Wang Huizhen, the Cui Yimin such as Wang Huizhen, Lu Yunlan. the preparation of bifonazole bolt and observation of curative effect [J], Journal of Chinese Hospital Pharmacy, 1996,16 (6): 278) disclose a kind of suppository be made up of bifonazole 1g and mixed fatty glycerides 99g; This suppository is yielding, easily becomes sour, and therefore character is unstable; (the Zhang Xiurong such as Zhang Xiurong, wangdan, Yang Hui etc. control preparation and the quality standard research [J] of type of effervescent suppository in bifonazole, China Dispensary, 2010,21 (17): 1587-1589) disclose a kind of hollow type of effervescent suppository be made up of bifonazole, semi-synthetic fatty acid glyceride, citric acid and sodium bicarbonate, this suppository mesostroma and active component separately, play the effect increasing stability; And the sphere of action of this suppository is wide, but due to the poorly water-soluble of bifonazole, and then have impact on the bioavailability of this suppository, affect the performance of suppository curative effect; In addition, common bifonazole 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 bifonazole bolt, giving full play to curative effect, the invention provides a kind of bifonazole vaginal expansion plug and preparation method thereof; Additionally provide a kind of science detection method that can control above-mentioned bifonazole vaginal expansion plug product quality simultaneously.
The concrete technical scheme of the present invention is as follows:
The invention provides a kind of bifonazole vaginal expansion plug, this expansible plug comprises the bifonazole that weight portion is 5-30 part, the expandable expandable carrier of weight portion to be the substrate of 75-215 part and weight portion be 60-400 part, bifonazole and substrate formed pastille substrate are coated in expandable carrier surface, and the swell value of 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 or glyceride;
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;
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,
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, substrate of the present invention is the mixture of Acrawax and water-soluble base, and the ratio of weight and number of Acrawax and water-soluble base is 1:15.5-20.5
Preferably, Acrawax is mixed fatty glycerides, and water-soluble base is Macrogol 4000, and the ratio of weight and number of mixed fatty glycerides and Macrogol 4000 is 1:17.The mixing of Acrawax and water-soluble base can improve melting of expansible plug and become the time limit, can reduce the zest of water-soluble base to vagina simultaneously.
In order to improve dissolution and the bioavailability of bifonazole vaginal expansion plug, pastille substrate of the present invention also comprises Polyethylene Glycol 32 glyceryl monolaurate that weight portion is 7-20 part.
In order to improve the stability of expansible plug, the present invention also comprises at pastille Medium Culture the chitin that weight portion is 2-6 part.
In order to provide the stability of expansible plug further, prevent becoming sour and being out of shape of expansible plug, pastille substrate of the present invention also comprises the potassium sorbate that chitin that weight portion is 0.5-2 part and weight portion are 0.5-2 part.
Further improvement, pastille substrate of the present invention also comprises the xylitan monostearate that weight portion is 3-7.5 part.Wherein xylitan monostearate plays the effect of dispersant, can promote disperseing equably in expansible plug of bifonazole, makes expansible plug play curative effect more fully.
Further improvement, pastille substrate of the present invention also comprises the capric monoglyceride that weight portion is 1-5 part.Capric monoglyceride plays the effect of moisturizing, improves the compliance of patient.
Further improvement, the parts by weight of each composition of expansible plug of the present invention are preferably:
Bifonazole vaginal expansion plug bioavailability provided by the invention is high, stable in properties, and little to the zest of vagina, safe and reliable.
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, is designed to the shape such as duckbill, spherical, oval, avette, bullet shaped, torpedo, cylindrical, conical or clavate.
The expandable carrier rear end of bifonazole 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 bifonazole 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 bifonazole 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 bifonazole 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, obtained fused mass;
B. bifonazole is mixed homogeneously with Polyethylene Glycol 32 glyceryl monolaurate and potassium sorbate, obtained first mixture;
C. xylitan monostearate being added ratio of weight and number is in the dehydrated alcohol of 1:1, stirs, and adds the first mixture that step b is obtained, continues to stir 30min, spraying dry, obtained second mixture;
D. the second mixture is mixed homogeneously with capric monoglyceride, obtained 3rd mixture;
E. the 3rd mixture is added in the obtained fused mass of step a, add chitin under stirring, mix homogeneously, obtained pastille substrate;
2) preparation of expansible plug: pastille substrate poured in bolt mould, inserts expandable carrier, cooling and shaping, obtained suppository.
The preparation method of bifonazole 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 bifonazole 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 bifonazole 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 bifonazole 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 bifonazole 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 bifonazole 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 bifonazole vaginal expansion plug, take weight M;
H. the expandable carrier scraped in the described bifonazole 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 bifonazole 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 bifonazole 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 bifonazole 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 bifonazole 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 bifonazole 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 bifonazole 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 bifonazole 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 bifonazole 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 bifonazole 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 bifonazole 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 bifonazole 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 bifonazole 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 as follows:
Get bifonazole vaginal expansion plug 10, accurately weighed, put in evaporating dish, put in water-bath and be heated to fusing, cooling, do not stop to stir, make mix homogeneously; Precision takes in right amount (being about equivalent to bifonazole 50mg), put in tool plug conical flask, add chloroform 30ml and make dissolving, add water 15ml and dilute sulfuric acid 5ml, add dimethyl yellow-solvent blue 19 mixing indicator solution 0.6ml again, with the titration of sulfenyl sodium succinate dioctyl ester test solution, during to nearly terminal, powerful jolting, continues to be titrated to chloroform layer and becomes cervinus from green; Separately get bifonazole reference substance and be about 50mg, accurately weighed, be measured in the same method; Consume the ratio calculation of sulfenyl sodium succinate dioctyl ester test solution volume according to the two, to obtain final product.
It is high that bifonazole vaginal expansion plug provided by the present invention has bioavailability, stability height waits beneficial effect, and this bifonazole vaginal expansion plug have employed six leading technologies of original creation, expandable carrier in described bifonazole 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 bifonazole vaginal expansion plug fully contact with vaginal walls, and prevent medicinal liquid from outflowing, also there is effect that cleaning vagina prevents superinfection, add Polyethylene Glycol 32 glyceryl monolaurate at pastille Medium Culture and play the absorption promoting bifonazole, improve the stability of expansible plug, chitin and potassium sorbate play the effect of stabilizing agent, improve the stability of expansible plug, xylitan monostearate and capric monoglyceride play the effect of dispersant and wetting agent, it is high that the mixing of above adjuvant makes the bifonazole vaginal expansion plug made have stability, dispersion of medicine, zest is little, and bioavailability is high, evident in efficacy beneficial effect of Denging.
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. mixed fatty glycerides and Macrogol 4000 are placed in water-bath heating and melting, obtained fused mass;
B. bifonazole is added the fused mass mix homogeneously that step a is obtained, 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 3.4g.
Embodiment 2
Preparation method:
1) preparation of pastille substrate:
A. semi-synthetic fatty acid glyceride and polyoxyethylene monostearate are placed in water-bath heating and melting, obtained fused mass;
B. bifonazole is mixed homogeneously with Polyethylene Glycol 32 glyceryl monolaurate, obtained first mixture;
C. the first mixture is added in the obtained 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 3.0g.
Embodiment 3
Preparation method: by the obtained 100 pieces of duckbill suppositorys of the method for embodiment 2, every piece of heavily about 2.9g.
Embodiment 4
Preparation method:
1) preparation of pastille substrate:
A. semi-synthetic cocos nucifera oil ester and propylene glycol stearate are placed in water-bath heating and melting, obtained fused mass;
B. bifonazole is mixed homogeneously with Polyethylene Glycol 32 glyceryl monolaurate and potassium sorbate, obtained first mixture;
C. the first mixture is added in the obtained fused mass of step a, add chitin under stirring, 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 cylindrical suppositorys, every piece of heavily about 4.1g.
Embodiment 5
Preparation method: by the obtained 100 pieces of bullet shaped suppositorys of the method for embodiment 4, every piece of heavily about 1.9g.
Embodiment 6
Preparation method:
1) preparation of pastille substrate:
A. cocoa butter is placed in water-bath heating and melting, obtained fused mass;
B. bifonazole is mixed homogeneously with Polyethylene Glycol 32 glyceryl monolaurate and potassium sorbate, obtained first mixture;
C. xylitan monostearate being added ratio of weight and number is in the dehydrated alcohol of 1:1, stirs, and adds the first mixture that step b is obtained, continues to stir 30min, spraying dry, obtained second mixture;
D. the second mixture is added in the obtained fused mass of step a, add chitin under stirring, 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 torpedo suppositorys, every piece of heavily about 5.0g.
Embodiment 7
Preparation method: make 100 pieces of clavate suppositorys by the method for embodiment 6, every piece of heavily about 4.6g.
Embodiment 8
Preparation method:
1) preparation of pastille substrate:
A. mixed fatty glycerides and Macrogol 4000 are placed in water-bath heating and melting, obtained fused mass;
B. bifonazole is mixed homogeneously with Polyethylene Glycol 32 glyceryl monolaurate and potassium sorbate, obtained first mixture;
C. xylitan monostearate being added ratio of weight and number is in the dehydrated alcohol of 1:1, stirs, and adds the first mixture that step b is obtained, continues to stir 30min, spraying dry, obtained second mixture;
D. the second mixture is mixed homogeneously with capric monoglyceride, obtained 3rd mixture;
E. the 3rd mixture is added in the obtained fused mass of step a, add chitin under stirring, 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 3.6g.
Embodiment 9
Preparation method: make 100 oval suppositorys by the method for embodiment 8, every piece of heavily about 2.7g.
Embodiment 10
Preparation method: make 100 spherical suppositorys by the method for embodiment 8, every piece of heavily about 3.1g.
The disclosed hollow type of effervescent suppository such as the Zhang Xiurong recorded in comparative examples 11(background technology)
Preparation method: be prepared into 100 pieces of duckbill suppositorys, every piece of heavily about 1.82g by disclosed methods such as Zhang Xiurong.
Test example 1
The bifonazole vaginal expansion plug that embodiment of the present invention 1-10 provides and the bifonazole hollow type of effervescent suppository of comparative examples 11, the outward appearance of each sample, containing bifonazole amount (labelled amount %), melt become the time limit, single related substance the testing result of amount in table 1;
The testing result of the expansible plug of table 1 embodiment 1-10 and the hollow type of effervescent suppository indices of embodiment 11
| Embodiment | Character | Labelled amount (%) | Melt and become the time limit (min) | Single related substance (%) |
| 1 | Micro-yellow, smooth surface | 92.37 | 21.3 | 0.38 |
| 2 | Micro-yellow, smooth surface | 95.68 | 22.1 | 0.35 |
| 3 | Micro-yellow, smooth surface | 99.74 | 23.5 | 0.37 |
| 4 | Micro-yellow, smooth surface | 103.59 | 22.4 | 0.28 |
| 5 | Micro-yellow, smooth surface | 98.02 | 26.5 | 0.21 |
| 6 | Micro-yellow, smooth surface | 97.95 | 21.1 | 0.23 |
| 7 | Micro-yellow, smooth surface | 98.64 | 26.5 | 0.28 |
| 8 | Micro-yellow, smooth surface | 99.15 | 20.6 | 0.19 |
| 9 | Micro-yellow, smooth surface | 102.93 | 24.8 | 0.24 |
| 10 | Micro-yellow, smooth surface | 100.16 | 21.6 | 0.31 |
| 11 | Micro-yellow, smooth surface | 95.78 | 24.8 | 0.38 |
Test example 2 stability test
1. accelerated test
The bifonazole vaginal expansion plug of Example 8, be divided into 3 batches, be numbered sample 1, sample 2 and sample 3 respectively, the bifonazole hollow type of effervescent suppository product in contrast of Example 11, 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 the character of expansible plug, containing bifonazole amount (labelled amount %), melt the amount becoming time limit and single related substance, result of the test is in table 2;
Three batch samples of table 2 embodiment 8 and the accelerated test result of reference substance
Bifonazole 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 described expansible plug, the amount containing bifonazole, melts the amount becoming time limit and single related substance obvious change does not all occur; And the bifonazole hollow type of effervescent suppository of embodiment 11 is placed after 6 months under high humidity, suppository turns yellow, and speckle appears in surface, and fracture phenomena occurs, and the content of bifonazole significantly declines, and melts change duration, the amount of single related substance significantly increases; Show that bifonazole vaginal expansion plug of the present invention stability compared with bifonazole hollow type of effervescent suppository significantly improves.
2. long term test
The bifonazole vaginal expansion plug of Example 8, be divided into 3 batches, be numbered sample 1 respectively, sample 2 and sample 3, the bifonazole hollow type of effervescent suppository product in contrast of Example 11, by sample and reference substance all at temperature 25 DEG C ± 2 DEG C, relative humidity is place 24 months under the condition of 60% ± 10%, sampling in every 3 months once, respectively at 0 month, 3 months, 6 months, 9 months, 12 months, 18 months, sampling in 24 months, detect the character of expansible plug, containing the amount (labelled amount %) of bifonazole, melt the amount becoming time limit and single related substance, 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
Bifonazole vaginal expansion plug provided by the invention as can be seen from the table, under the environment of constant temperature high humidity, places after 24 months, the color of described expansible plug, the amount containing bifonazole, melts the amount becoming time limit and single related substance obvious change does not all occur; And after the bifonazole hollow type of effervescent suppository of embodiment 11 places 9 months, suppository darkens, and speckle appears in surface, places after 12 months, there is fracture phenomena in suppository surface; And the content of bifonazole significantly declines in bifonazole suppository, melt and become time limit significant prolongation, the amount of single related substance significantly increases; Show that bifonazole vaginal expansion plug of the present invention stability compared with bifonazole hollow type of effervescent suppository significantly improves; And the holding time is long.
Test example 3 swell value measures
Method one
Get bifonazole 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 bifonazole vaginal expansion plug of embodiment 1-10 according to above-mentioned swell value assay method is as shown in table 4;
The swell value of table 4 embodiment 1-10 bifonazole vaginal expansion plug
| Embodiment | Average diameter (mm) before expanding | Average diameter (mm) after expanding | Swell value (doubly) | Result |
| Embodiment 1 | 12.23 | 22.49 | 1.84 | Qualified |
| Embodiment 2 | 12.05 | 20.37 | 1.69 | Qualified |
| Embodiment 3 | 12.17 | 21.98 | 1.81 | Qualified |
| Embodiment 4 | 12.17 | 22.56 | 1.85 | Qualified |
| Embodiment 5 | 12.09 | 19.74 | 1.63 | Qualified |
| Embodiment 6 | 11.98 | 21.03 | 1.75 | Qualified |
| Embodiment 7 | 11.86 | 18.88 | 1.59 | Qualified |
| Embodiment 8 | 12.13 | 22.61 | 1.86 | Qualified |
| Embodiment 9 | 11.79 | 20.25 | 1.72 | Qualified |
| Embodiment 10 | 12.26 | 23.11 | 1.88 | Qualified |
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 bifonazole 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 bifonazole vaginal expansion plug of embodiment 1-10, the equal conformance with standard of its weight differential.
The therapeutic effect of test example 5 pairs of vulvovaginal candidiasiss
Stochastic choice vulvovaginal candidiasis patient 50 example, the age 21-55 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 27 example and matched group 23 example, treatment group gives the bifonazole vaginal expansion plug of embodiment 8, once a day, within 7 days, is a course for the treatment of simultaneously; Matched group gives common bifonazole 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 exfoliative cyte, 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 and exfoliative cyte quantity obviously reduce, and the mucosa under tissue slice is more complete, and mucosa recovers normal, diagnosable effective; Vaginal mucosa is congested, red and swollen phenomenon takes a turn for the better to some extent, white bean dregs sample secretions reduces, vaginal smear examination Candida albicans and exfoliative cyte quantity decrease, mucosa under tissue slice has slight defect, the visible telangiectasis of submucous tissue, a small amount of neutrophil infiltration is had 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 5;
Table 5 liang group compares vulvovaginal candidiasis therapeutic effect
The bifonazole vaginal expansion plug of the embodiment of the present invention has good therapeutic effect to vulvovaginal candidiasis as can be seen from the table, effective percentage reaches 96.3%, compare with matched group and there is diversity (P<0.05), and do not occur toxic and side effects in process of the test.
Test example 6 mucomembranous pungency test
6.1 test objective
Observe the irritant reaction situation that bifonazole vaginal expansion plug produces rabbit vagina mucosa;
6.2 test material
Test medicine: the bifonazole vaginal expansion plug described in embodiment 8; Contrast medicine: common bifonazole bolt;
Experimental animal: rabbit 10, body weight 2.0-2.5kg, male and female half and half;
Rearing conditions: each cage 1 rabbit, temperature: 25 DEG C ± 2 DEG C, humidity 50% ± 2%, illumination 12h, free diet, observes 3 days no abnormality seens;
6.3 test method
Rabbit is divided into 2 groups at random, often organizes 5, be bifonazole vaginal expansion plug group and bifonazole bolt group, respectively bifonazole vaginal expansion plug and bifonazole bolt be placed in respectively the vagina depths of rabbit; Administration every day 1 time, successive administration 7 days; After last administration 24h, observe the mucosa situation of change of 12 rabbit, and histopathologic examination is carried out to vaginal mucosa;
6.4 result of the tests and conclusion
Test shows, bifonazole vaginal expansion plug of the present invention does not affect, on the impact of vaginal mucosa no abnormality seen the hair of rabbit, feed and defecation; The phenomenons such as the perusal of each group of rabbit vagina mucosa has no congested, red and swollen, damaged and rotten to the corn, histopathologic examination's result shows rabbit mucosal tissue structural integrity, has no hemorrhage, the phenomenon such as inflammation and necrosis; And the phenomenons such as congested, red and swollen, histopathologic examination's mucosa structural integrity appear in the rabbit perusal of bifonazole bolt group administration, but there is the phenomenons such as rotten to the corn, the results are shown in Table 6;
Table 6 bifonazole vaginal expansion plug and bifonazole bolt are to rabbit vagina mucomembranous pungency test result
Conclusion: bifonazole vaginal expansion plug of the present invention is little to rabbit vagina mucous membrane irritation.
Claims (10)
1. a bifonazole vaginal expansion plug, it is characterized in that, described expansible plug comprises the bifonazole that weight portion is 5-30 part, the expandable expandable carrier of weight portion to be the substrate of 75-215 part and weight portion be 60-400 part, described bifonazole 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 is the mixture of Acrawax and water-soluble base, described Acrawax is mixed fatty glycerides, described water-soluble base is Macrogol 4000, and the ratio of weight and number of described mixed fatty glycerides and Macrogol 4000 is 1:17.
2. bifonazole vaginal expansion plug as claimed in claim 1, it is characterized in that, described pastille substrate also comprises Polyethylene Glycol 32 glyceryl monolaurate that weight portion is 7-20 part.
3. bifonazole vaginal expansion plug as claimed in claim 2, is characterized in that, described pastille substrate also comprises the potassium sorbate that chitin that weight portion is 0.5-2 part and weight portion are 0.5-2 part.
4. bifonazole vaginal expansion plug as claimed in claim 3, it is characterized in that, described pastille substrate also comprises the xylitan monostearate that weight portion is 3-7.5 part.
5. bifonazole vaginal expansion plug as claimed in claim 4, it is characterized in that, described pastille substrate also comprises the capric monoglyceride that weight portion is 1-5 part.
6. bifonazole vaginal expansion plug as claimed in claim 5, it is characterized in that, the parts by weight of each composition of described expansible plug are:
7. the bifonazole vaginal expansion plug as described in as arbitrary in claim 1-6, 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.
8. the preparation method of bifonazole vaginal expansion plug as claimed in claim 5, 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, obtained fused mass;
B. bifonazole is mixed homogeneously with Polyethylene Glycol 32 glyceryl monolaurate and potassium sorbate, obtained first mixture;
C. xylitan monostearate being added ratio of weight and number is in the dehydrated alcohol of 1:1, stirs, and adds the first mixture that step b is obtained, continues to stir 30min, spraying dry, obtained second mixture;
D. the second mixture is mixed homogeneously with capric monoglyceride, obtained 3rd mixture;
E. the 3rd mixture is added in the obtained fused mass of step a, add chitin under stirring, mix homogeneously, obtained pastille substrate;
2) preparation of expansible plug: pastille substrate poured in bolt mould, inserts expandable carrier, cooling and shaping, obtained suppository.
9. the detection method of the bifonazole vaginal expansion plug as described in as arbitrary in claim 1-7, 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 bifonazole 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 bifonazole 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 bifonazole 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 bifonazole 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 bifonazole vaginal expansion plug, take weight M;
H. the expandable carrier scraped in the described bifonazole 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)。
10. the detection method of bifonazole vaginal expansion plug as claimed in claim 9, 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 bifonazole 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 bifonazole 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 bifonazole 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 bifonazole 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 bifonazole 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.
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Effective date of registration: 20211117 Address after: 150040 office building 7, Bohai Third Road, haping road concentration area, Harbin Economic Development Zone, Harbin, Heilongjiang Province Patentee after: Harbin Tianmei Pharmaceutical Co.,Ltd. Address before: 150069, No. three, No. 7, Bohai, Harbin, Heilongjiang, China Patentee before: HARBIN OT PHARMACEUTICALS Co.,Ltd. Patentee before: Qiu Mingshi |
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Denomination of invention: Diphenylbenzazole vaginal dilation suppository and its preparation and detection method Effective date of registration: 20230908 Granted publication date: 20160224 Pledgee: China Merchants Bank Co.,Ltd. Harbin Branch Pledgor: Harbin Tianmei Pharmaceutical Co.,Ltd. Registration number: Y2023230000075 |