CN103520088B - Nystatin expandable vaginal expansible plug and preparation method thereof and detection method - Google Patents
Nystatin expandable vaginal expansible plug and preparation method thereof and detection method Download PDFInfo
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Abstract
The present invention relates to a kind of nystatin expandable vaginal expansible plug and preparation method thereof and detection method, described expansible plug comprises nysfungin and substrate formed pastille substrate and expandable carrier; Described nysfungin and beta-schardinger dextrin-form clathrate, improve dissolubility and the stability of nysfungin; It is moist to reduce the adding of calcium glycerophosphate in pastille substrate drawing of nysfungin, increases the stability of suppository; Specific sclerosing agent is also comprised in the pastille substrate of further described suppository; And nystatin expandable vaginal expansible plug provided by the present invention have employed seven leading technologies of original creation, and have and prevent medicinal liquid from outflowing, stability is high, curative effect is lasting, prevents the beneficial effects such as superinfection.
Description
Technical field
The invention belongs to vaginal suppository field, particularly a kind of nystatin expandable vaginal expansible plug and preparation method thereof and detection method.
Background technology
Nysfungin is polyene antifungal antibiotic, and it is yellow or brownish-yellow powder, have draw moist, all unstable to light, air, soda acid, soluble,very slightly in water; Be mainly used in vulvovaginal candidiasis clinically.The formulation development of nysfungin is always very undesirable, have impact on the application of nysfungin, and listing preparation mainly comprises tablet and suppository at present; After vagina filled in by tablet, nysfungin can not stripping, is difficult to play a role; So current being most widely used of suppository, accept by extensive patients.
Nysfungin suppository records in " chemical drugs provincial standard rising national standard " the 5th, is mainly used in vulvovaginal candidiasis; Also a kind of suppository made for active component and semi-synthetic fatty acid glyceride with nystatin and menthol is disclosed in CN101254201; Prior art is also few to the research of nysfungin suppository, simultaneously because nysfungin nature is unstable, after making suppository, and poor stability; And common nysfungin suppository also 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, increase the stability of nysfungin, give full play to curative effect, the present invention have studied a kind of nystatin expandable vaginal expansible plug and preparation method thereof; Additionally provide a kind of science detection method that can control above-mentioned nystatin expandable vaginal expansible plug product quality simultaneously.
The concrete technical scheme of the present invention is as follows:
The invention provides a kind of nystatin expandable vaginal expansible plug, described expansible plug comprises nysfungin, substrate and expandable expandable carrier, described nysfungin 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; The parts by weight of each composition of described expansible plug are:
Nysfungin 4-20
Substrate 80-200
Expandable carrier 50-400
Described substrate comprise in Acrawax, natural acid ester, lipoidis substrate, water-soluble base, gel-type vehicle, hydrogenated oil and fat, glyceride, distillate oil, stearate or colloidal compound one or more;
Described 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;
Described natural acid ester comprise in oleum sapii, Oleum Linderae, Fructus Foeniculi fat, Ke Kemu fat or cocoa butter one or more;
Described lipoidis substrate comprises lanoline or lanonol;
Described 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;
Described gel-type vehicle comprise in sodium carboxymethyl cellulose, hypromellose, carbomer, alginic acid or sodium alginate one or more;
Described hydrogenated oil and fat comprise in hydrogenated vegetable oil, hydrogenated groundnut, castor oil hydrogenated or cotmar one or more;
Described glyceride comprises Adeps Solidus, Massa Estarinum A, MassaEstarinum AS, Massa Estarinum B, Massa Estarinum C, MassaEstarinum D, Massa Estarinum E, Massa Estarinum I, Massa EstarinumT, Massa Mf13, Suppository Base W, Suppository Base AB, SuppositoryBase A, Suppository Base B, Suppository Base BC, Suppository BaseBD, Suppository Base BBC, Suppository Base E, Suppository BaseBCF, Suppository Base C, Suppository Base D, Suppository Base299, Wecobee W, Wecobee K, Wecobee S, Wecobee M, Wecobee ES, Massuppol, Massuppol15, Suppocire OSI, Suppocire OSIx SuppocireA, Suppocire B, Suppocire C, Suppocire D, Suppocire DM, SuppocireH, Suppocire L, Tegester Triglyceride Bases-9, TegesterTriglyceride Bases-MA, Tegester Triglyceride Bases-57, tripalmitin, glycerol tristearate, one or more in Gan You behenic acid ester or lauric acid three ester,
Described distillate oil comprises fractionating palm oil or fractionated coconut oil;
Described stearate comprise in xylitan monostearate, stearic acid palm glycerides, polyethylene glycol mono stearate, ethylene glycol monostearate or glyceryl monostearate one or more;
Described colloidal compound comprise in arabic gum, gelatin or pectin one or more.
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).
Wherein every must not tire of 1mg is less than 4500 nysfungin units.
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 described 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, the parts by weight of each composition of described expansible plug are:
Nysfungin 5-15
Substrate 100-180
Expandable carrier 80-250
Described substrate is the mixture of gel-type vehicle and distillate oil, and the ratio of weight and number of described gel-type vehicle and distillate oil is 2-5:1.Because the dissolubility of nysfungin is bad, after making suppository with fat-soluble substrate, affect it in intravaginal release, affect the bioavailability of suppository, the present invention draws by experiment, select the mixture of gel-type vehicle and distillate oil that active component can be made to have good release, the fusing point of described mixed-matrix improves simultaneously, can further improve the stability of suppository.
Further, described gel-type vehicle is hypromellose, and described distillate oil is fractionating palm oil, and the parts by weight of each composition of described expansible plug are:
Preferably, pastille substrate of the present invention also comprises the beta-schardinger dextrin-that weight portion is 6-30 part, described beta-schardinger dextrin-and nysfungin form clathrate, described beta-schardinger dextrin-comprise in glucose group-beta-cyclodextrin, hydroxyethyl-β-cyclodextrin or HP-β-CD one or more; Described beta-schardinger dextrin-by nysfungin enclose in its circulus, can improve the dissolubility of nysfungin, and then improves the bioavailability of nysfungin suppository, also can improve the stability of nysfungin simultaneously.
Further preferably, the pastille substrate of nystatin expandable vaginal expansible plug of the present invention also comprises the calcium glycerophosphate that weight portion is 5-20 part, it is moist that described calcium glycerophosphate can reduce drawing of nysfungin, increases the stability of nysfungin in suppository, thus improve the stability of suppository; Improve the mobility of each composition simultaneously, be convenient to the molding of suppository.
Further preferred, pastille substrate of the present invention also comprises the sclerosing agent that weight portion is 0.5-3 part, described sclerosing agent comprise in behenic acid, hexadecanol or microwax one or more, described sclerosing agent can improve the molding of suppository; Selected specific sclerosing agent also has further prolong drug to vagina action time, and make " prolonged drug layering release ", within one day, be administered once, drug effect reaches 24 hours, raising patient compliance.
The swell value of expandable carrier of the present invention after saturated water suction is greater than 1.5, and described swell value is radial swell value; Described 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 described expandable carrier, according to " human engineering suppository " shape, is designed to the shape such as duckbill, spherical, avette, bullet shaped, torpedo, cylindrical, conical or clavate.
The rear end of the expandable carrier of nystatin expandable vaginal expansible plug of the present invention is connected with bracing wire, stype 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 nystatin expandable vaginal expansible plug of the present invention meet water can the effect of undergoes rapid expansion, after described 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 nysfungin 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 nystatin expandable vaginal expansible plug on the other hand, and described method comprises the steps:
1) preparation of pastille substrate:
A. substrate is placed in water-bath heating and melting, obtained fused mass;
B. get the water that beta-schardinger dextrin-adds 2-5 times amount, be fully ground to the pastel that water quantities is less than 5%, add nysfungin under grinding, mix homogeneously, lyophilization, obtained clathrate;
C. clathrate is mixed homogeneously with calcium glycerophosphate and sclerosing agent, obtained mixture;
D. by the fused mass of the mixture of step c and a step, mix homogeneously, obtained pastille substrate;
2) pour in bolt mould by pastille substrate, insert expandable carrier, cooling and shaping, makes suppository.
The preparation method of nystatin expandable vaginal expansible 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 described nystatin expandable vaginal expansible plug on the other hand, and described detection method comprises swell value assay method, weight differential detection method, assay etc.
Wherein said swell value assay method comprises:
A. the radial direction along described nystatin expandable vaginal expansible 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 nystatin expandable vaginal expansible 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:
A. the axis along described nystatin expandable vaginal expansible plug chooses a place or some positions, measures the initial diameter R of described expandable carrier;
B., after the saturated water suction of described nystatin expandable vaginal expansible plug, selected location place expandable carrier expanded diameter r in a step is determined at;
When c. 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:
A. get described nystatin expandable vaginal expansible plug, take weight M;
B. the expandable carrier scraped in the described nystatin expandable vaginal expansible 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 described nystatin expandable vaginal expansible plug, 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 nystatin expandable vaginal expansible 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 nystatin expandable vaginal expansible 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:
A. first choose a place or some positions an angle along the axis of described nystatin expandable vaginal expansible plug, after measuring the initial diameter R of described expandable carrier, then different angles of rolling measure several times, and average Ri;
B., after described nystatin expandable vaginal expansible plug carries out melting the detection of change time limit, selected location place expandable carrier expanded diameter r in a step is determined at; Different angles of rolling again measure several times, ask average diameter ri after expanding;
When c. 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 nystatin expandable vaginal expansible 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 with hook fix.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:
A. get described nystatin expandable vaginal expansible plug, take weight M;
B. 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 comprises one or more in ethanol, methanol or isopropyl alcohol.
Further, in the detection method of described nystatin expandable vaginal expansible plug, described expandable carrier is cotton sliver, and described detection method comprises following at least one method:
1) swell value assay method:
Get described nystatin expandable vaginal expansible 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, measure the two ends of each cotton sliver and middle three positions with slide gauge, roll after about 90 ° and measure three positions again, each cotton sliver obtains six data altogether, obtain 6 meansigma methods ri of mensuration, calculate the swell value Pi of every, the swell value of three bolts all should be greater than 1.5.
2) weight differential assay method:
Get described nystatin expandable vaginal expansible 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 nystatin expandable vaginal expansible 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 nystatin expandable vaginal expansible 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 described weight differential assay method is more convenient stable.
Described content assaying method measures according to Chinese Pharmacopoeia version in 2010 two annex XI A antibiotic-microbial assays.
Get described nystatin expandable vaginal expansible plug 5, accurately weighed, cut into pieces, mixing, precision takes in right amount (being about equivalent to nysfungin 50,000 unit), put in 50ml measuring bottle, add dimethyl formamide ultrasonic dissolution, and be diluted to scale, shake up, make the solution about containing nysfungin 1000 unit in every 1ml, put in ice bath and make matrix set, filter immediately, getting subsequent filtrate puts to room temperature, as need testing solution, it is appropriate that another precision takes nysfungin standard substance, add dimethyl formamide to dissolve and the standard solution being diluted to 1000 units in every 1ml, precision measures need testing solution and standard solution uses phosphate buffer (pH6.0) (to get dipotassium hydrogen phosphate 20g and potassium dihydrogen phosphate 80g in right amount respectively, be dissolved in water to 1000ml) be diluted to the solution containing 14 units and 28 units in every 1ml, test organism is made with cereuisiae fermentum (9763), measure according to antibiotic-microbial assays, monolayer bacterium layer 8 ~ 12ml is added in two dish, cultivate 18 ~ 24 hours for 29 ~ 31 DEG C.
It is high that nystatin expandable vaginal expansible plug provided by the present invention has stability, the beneficial effects such as good effect, and this nystatin expandable vaginal expansible plug have employed seven leading technologies of original creation, expandable carrier in described nystatin expandable vaginal expansible 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 nystatin expandable vaginal expansible plug fully contact with vaginal walls, and prevent medicinal liquid from outflowing, also there is effect that cleaning vagina prevents superinfection, selected substrate can ensure that nysfungin has good release characteristics, can improve the stability of suppository simultaneously, also comprise beta-schardinger dextrin-in described pastille substrate, described beta-schardinger dextrin-by nysfungin enclose in its circulus, can improve dissolubility and the stability of nysfungin, it is moist to reduce the adding of calcium glycerophosphate in described pastille substrate drawing of nysfungin, improves the stability of nysfungin, selected specific sclerosing agent also has the effect of further prolong drug to vagina extended durations of action, and make " prolonged drug layering release ", within one day, be administered once, drug effect reaches 24 hours, improves patient compliance.
Accompanying drawing explanation
The vitro release result of the test of nystatin expandable vaginal expansible plug described in Fig. 1 embodiment 7-9;
Fig. 2 and Fig. 3 swell value assay method schematic diagram.
Detailed description of the invention
Embodiment 1
Preparation method:
1) preparation of pastille substrate:
A. hypromellose and fractionating palm oil are placed in water-bath heating and melting, obtained fused mass;
B. by the fused mass of nysfungin and a step, mix homogeneously, obtained pastille substrate;
2) pour in bolt mould by pastille substrate, 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 Petiolus Trachycarpi grease and propylene glycol stearate are placed in water-bath heating and melting, obtained fused mass;
B. get the water that HP-β-CD adds 3 times amount, be fully ground to the pastel that water quantities is less than 5%, add nysfungin under grinding, mix homogeneously, lyophilization, obtained clathrate;
C. by the fused mass of the clathrate of b step and a step, mix homogeneously, obtained pastille substrate;
2) pour in bolt mould by pastille substrate, insert cotton sliver, cooling and shaping, makes 100 pieces of cylindrical suppositorys, every piece of heavily about 5.0g.
Embodiment 3
Preparation method: make 100 pieces of clavate suppositorys by embodiment 2 method, every piece of heavily about 1.9g.
Embodiment 4
Preparation method: make 100 pieces of spherical suppositorys by embodiment 2 method, every piece of heavily about 2.3g.
Embodiment 5
Preparation method:
1) preparation of pastille substrate:
A. carbomer, alginic acid and fractionated coconut oil are placed in water-bath heating and melting, obtained fused mass;
B. get the water that HP-β-CD adds 5 times amount, be fully ground to the pastel that water quantities is less than 5%, add nysfungin under grinding, mix homogeneously, lyophilization, obtained clathrate;
C. by clathrate and calcium glycerophosphate mix homogeneously, obtained mixture;
D. by the fused mass of the mixture of step c and a step, mix homogeneously, obtained pastille substrate;
2) pour in bolt mould by pastille substrate, insert cotton sliver, cooling and shaping, makes 100 pieces of avette suppositorys, every piece of heavily about 2.1g.
Embodiment 6
Preparation method: make 100 pieces of bullet shaped suppositorys by embodiment 5 method, every piece of heavily about 4.7g.
Embodiment 7
Preparation method:
1) preparation of pastille substrate:
A. hypromellose and fractionating palm oil are placed in water-bath heating and melting, obtained fused mass,
B. get the water that glucose group-beta-cyclodextrin and hydroxyethyl-β-cyclodextrin add 3 times amount, be fully ground to the pastel that water quantities is less than 5%, add nysfungin under grinding, mix homogeneously, lyophilization, obtained clathrate;
C. by nysfungin with calcium glycerophosphate with behenic acid is mixed homogeneously, obtained mixture;
D. by the fused mass of the mixture of step c and a step, mix homogeneously, obtained pastille substrate;
2) pour in bolt mould by pastille substrate, insert cotton sliver, cooling and shaping, makes 100 pieces of spherical suppositorys, every piece of heavily about 3.6g.
Embodiment 8
Preparation method: make 100 pieces of duckbill suppositorys by embodiment 7 method, every piece of heavily about 3.7g.
Embodiment 9
Preparation method: make 100 pieces of torpedo suppositorys by embodiment 7 method, every piece of heavily about 4.1g.
Test example 1 stability test
1. accelerated test
The nysfungin suppository that nystatin expandable vaginal expansible plug described in Example 2-9 and chemical drugs provincial standard rising national standard (the 5th) are recorded, all at constant temperature 30 DEG C ± 2 DEG C, relative humidity is place 6 months under the constant humidity condition of 65% ± 5%, duration of test 1 month, 2 months, 3 months, 6 the end of month sample once respectively, by the regulation in Chinese Pharmacopoeia, detect the character of expansible plug, containing the labelled amount (%) of nysfungin, melt and become the time limit, the accelerated test of the nystatin expandable vaginal expansible plug described in embodiment 2-5 the results are shown in Table 1, nystatin expandable vaginal expansible plug described in embodiment 6-9 and the accelerated test of nysfungin suppository the results are shown in Table 2.
The accelerated test result of nystatin expandable vaginal expansible plug described in table 1 embodiment 2-5
The accelerated test result of nystatin expandable vaginal expansible plug and nysfungin suppository described in table 2 embodiment 6-9
Nystatin expandable vaginal expansible plug as can be seen from the table described in embodiment of the present invention 2-9, under the environment of constant temperature high humidity, place after 6 months, the color of described expansible plug does not change, described expansible plug smooth surface, the phenomenon of do not occur speckle, breaking, in described expansible plug there is not obvious change in the labelled amount of nysfungin, melt become the time limit do not occur significantly to extend yet; And nysfungin suppository is placed after 1 month under high humidity, suppository surface just becomes coarse, and place after 6 months, suppository breaks, and color becomes more and more darker; And the content of described nysfungin significantly declines, melt and become time limit significant prolongation; Show that nystatin expandable vaginal expansible plug of the present invention stability compared with nysfungin suppository significantly improves.
2. long term test
The nysfungin suppository that nystatin expandable vaginal expansible plug described in Example 2-9 and chemical drugs provincial standard rising national standard (the 5th) are recorded, 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 nysfungin labelled amount (%) and melt 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, the long-term test results of the nystatin expandable vaginal expansible plug described in embodiment 2-3 is in table 3, the long-term test results of the nystatin expandable vaginal expansible plug described in embodiment 4-7 is in table 4, the long-term test results of embodiment 8-9 and nysfungin suppository is in table 5.
The long-term test results of nystatin expandable vaginal expansible plug described in table 3 embodiment 2-3
The long-term test results of nystatin expandable vaginal expansible plug described in table 4 embodiment 4-7
The long-term test results of nystatin expandable vaginal expansible plug and nysfungin suppository described in table 5 embodiment 8-9
Nystatin expandable vaginal expansible plug as can be seen from the table described in embodiment of the present invention 2-9, in the long term test of 36 months, the color of described expansible plug does not change, described suppository smooth surface, the phenomenon of do not occur speckle, breaking, in described expansible plug there is not obvious change in the labelled amount of nysfungin, melt become the time limit do not occur significantly to extend yet; And after nysfungin suppository places 3 months, suppository surface just becomes coarse, places after 36 months, and suppository breaks, and color becomes more and more darker; And the content of described nysfungin significantly declines, melt and become time limit significant prolongation; Show that nystatin expandable vaginal expansible plug of the present invention stability compared with nysfungin suppository significantly improves.
Test example 2 vitro release determination test
The vitro release of suppository detects: with reference to 2010 editions " Chinese Pharmacopoeia " annex XIXD vitro release testing inspection.
Get the nystatin expandable vaginal expansible plug described in above embodiment 7-9 respectively, put in medicament dissolution instrument, sample respectively in 1h, 2h, 4h, 6h, 12h, 16h, 24h, stripping percentage rate is detected by high performance liquid chromatography, and calculating the cumulative release percentage rate of medicine, the drug release profiles of the drug release process of described expansible plug is shown in Fig. 1.
As can be seen from the figure nystatin expandable vaginal expansible plug medicine slow releasing in 24h described in embodiment 7-9; Illustrate that sclerosing agent can extend the action time of expansion suppository to vagina, extend curative effect.Test example 3 swell value determination test
Method one
Get described nystatin expandable vaginal expansible 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, measure the two ends of each cotton sliver and middle three positions with slide gauge, roll after about 90 ° and measure three positions again, each cotton sliver obtains six data altogether, obtain 6 meansigma methods ri of mensuration, calculate the swell value Pi of every, the swell value of three bolts is all greater than 1.5.
The swell value measuring nystatin expandable vaginal expansible plug described in embodiment 1-9 according to above-mentioned swell value assay method is as shown in table 6.
The swell value of table 6 embodiment 1-9 nystatin expandable vaginal expansible plug
| Embodiment | Average diameter (mm) before expanding | Average diameter (mm) after expanding | Swell value (doubly) | Result |
| Embodiment 1 | 12.09 | 21.28 | 1.76 | Qualified |
| Embodiment 2 | 11.94 | 20.07 | 1.68 | Qualified |
| Embodiment 3 | 12.31 | 19.97 | 1.62 | Qualified |
| Embodiment 4 | 12.28 | 22.51 | 1.83 | Qualified |
| Embodiment 5 | 12.13 | 22.45 | 1.85 | Qualified |
| Embodiment 6 | 12.01 | 22.36 | 1.86 | Qualified |
| Embodiment 7 | 12.15 | 20.85 | 1.72 | Qualified |
| Embodiment 8 | 12.22 | 22.68 | 1.86 | Qualified |
| Embodiment 9 | 12.34 | 23.41 | 1.90 | Qualified |
Method two
As shown in Figures 2 and 3, the detection method of vaginal expansion plug:
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 described nystatin expandable vaginal expansible 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, 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 nystatin expandable vaginal expansible plug described in embodiment 1-9, the equal conformance with standard of its weight differential.
Test example 5 clinical trial
One, research method
(1) research approach is formulated about " clinical verification of department of obstetrics and gynecology urogenital tract infection local application " content with reference to Ministry of Health of the People's Republic of China's new drug clinical guidance principle.
(2) diagnostic criteria
1, vulvovaginal candidiasis symptom: pruritus vulvae, has more white bean dregs sample leucorrhea to be the cardinal symptom of this disease, can with pudendum burn feeling, urgent micturition, dysurea and sexual anhedonia;
2, gynecologial examination: swelling of external genitals, epidermis can strip off, and can have scratch, inside nympha and vaginal mucosa with white membranoid substance, the red and swollen or rotten to the corn face of visible vaginal mucosa and shallow table ulcer after erasing, leucorrhea be white, grumeleuse shape and bean dregs sample, slightly stink;
3, lab testing: smear detects, and look for pseudohypha under microscope, positive rate can reach 60%.
(3) case standard is tested
Include case history standard in: in 21-50 year, meet the married woman of bacteriodiagnosis.
(4) Therapeutic Method
1, treatment group: use the nystatin expandable vaginal expansible plug described in the embodiment of the present invention 6 to treat, every day one 7 days is a course for the treatment of.
2, matched group: use nysfungin suppository treatment, every day one 7 days is a course for the treatment of.
(5) observation item
Therapeutic is observed
(1) symptom: vaginitis symptom, the amount of secretions, color, abnormal smells from the patient;
(2) gynecologial examination: comprise pudendum and vaginal secretions inspection;
(3) lab testing: under comprising mirror, plate coating checking.
(6) curative effect determinate standard
1, fully recover: transference cure, gynecologial examination and lab testing normal;
2, effective: symptom obviously alleviates, gynecologial examination and lab testing are clearly better;
3, effective: symptom alleviates to some extent, gynecologial examination and lab testing take a turn for the better;
4, invalid: unchanged before and after treatment.
Two, therapeutic outcome
(1) two group is compared in table 7 to the therapeutic effect of vulvovaginal candidiasis;
The therapeutic effect of table 7 liang group to vulvovaginal candidiasis compares
| Group | Case load | Disease more | Effective | Effectively | Invalid | Effective percentage (%) |
| Treatment group | 34 | 27 | 2 | 4 | 1 | 97.1 |
| Matched group | 20 | 11 | 2 | 2 | 5 | 75.0 |
Two groups of comparitive study treatment groups are better than matched group.
Three, conclusion
The effective percentage of nystatin expandable vaginal expansible plug to vulvovaginal candidiasis reaches 97.1%, and curative effect is better than matched group; In its curative effect process of checking, do not find toxic and side effects, safe and reliable, evident in efficacy.
Claims (9)
1. a nystatin expandable vaginal expansible plug, is characterized in that, described expansible plug comprises nysfungin, substrate and expandable expandable carrier; Described nysfungin 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, and the parts by weight of each composition of described expansible plug are:
Nysfungin 4-20
Substrate 80-200
Expandable carrier 50-400
Described substrate be selected from Acrawax, natural acid ester, lipoidis substrate, water-soluble base, gel-type vehicle, hydrogenated oil and fat, glyceride, distillate oil or colloidal compound 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 lipoidis substrate is selected from lanoline or lanonol;
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;
Described gel-type vehicle be selected from sodium carboxymethyl cellulose, hypromellose, carbomer, alginic acid or sodium alginate one or more;
Described hydrogenated oil and fat be selected from hydrogenated groundnut, castor oil hydrogenated or cotmar one or more;
Described glyceride be selected from tripalmitin, glycerol tristearate, Gan You behenic acid ester or lauric acid three ester one or more;
Described distillate oil is selected from fractionating palm oil or fractionated coconut oil;
Described colloidal compound be selected from arabic gum, gelatin or pectin one or more;
Described pastille substrate also comprises the beta-schardinger dextrin-that weight portion is 6-30 part, described beta-schardinger dextrin-and nysfungin form clathrate, described beta-schardinger dextrin-be selected from glucose group-beta-cyclodextrin, hydroxyethyl-β-cyclodextrin or HP-β-CD one or more;
Described pastille substrate also comprises the calcium glycerophosphate that weight portion is 5-20 part;
Described pastille substrate also comprises the sclerosing agent that weight portion is 0.5-3 part, described sclerosing agent be selected from behenic acid, hexadecanol or microwax one or more.
2. nystatin expandable vaginal expansible plug as claimed in claim 1, it is characterized in that, the parts by weight of each composition of described expansible plug are:
Described substrate is the mixture of gel-type vehicle and distillate oil, and the ratio of weight and number of described gel-type vehicle and distillate oil is 2-5:1.
3. nystatin expandable vaginal expansible plug as claimed in claim 2, it is characterized in that, described gel-type vehicle is hypromellose, and described distillate oil is fractionating palm oil, and the parts by weight of each composition of described expansible plug are:
4. the nystatin expandable vaginal expansible plug as described in as arbitrary in claim 1-3, 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.
5. the preparation method of nystatin expandable vaginal expansible plug as claimed in claim 1, 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. get the water that beta-schardinger dextrin-adds 2-5 times amount, be fully ground to the pastel that water quantities is less than 5%, add nysfungin under grinding, mix homogeneously, lyophilization, obtained clathrate;
C. clathrate is mixed homogeneously with calcium glycerophosphate and sclerosing agent, obtained mixture;
D. by the fused mass of the mixture of step c and a step, mix homogeneously, obtained pastille substrate;
2) pour in bolt mould by pastille substrate, insert expandable carrier, cooling and shaping, makes suppository.
6. the detection method of the nystatin expandable vaginal expansible plug as described in as arbitrary in claim 1-3, 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 nystatin expandable vaginal expansible 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 nystatin expandable vaginal expansible 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:
A. the axis along described nystatin expandable vaginal expansible plug chooses a place or some positions, measures the initial diameter R of described expandable carrier;
B., after the saturated water suction of described nystatin expandable vaginal expansible plug, selected location place expandable carrier expanded diameter r in a step is determined at;
When c. 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:
A. get described nystatin expandable vaginal expansible plug, take weight M;
B. the expandable carrier scraped in the described nystatin expandable vaginal expansible 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)。
7. the detection method of nystatin expandable vaginal expansible plug as claimed in claim 6, 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 nystatin expandable vaginal expansible 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 nystatin expandable vaginal expansible 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:
A. first choose a place or some positions an angle along the axis of described nystatin expandable vaginal expansible plug, after measuring the initial diameter R of described expandable carrier, then different angles of rolling measure several times, and average Ri;
B., after described nystatin expandable vaginal expansible plug carries out melting the detection of change time limit, selected location place expandable carrier expanded diameter r in a step is determined at; Different angles of rolling again measure several times, ask average diameter ri after expanding;
When c. 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:
A. get described nystatin expandable vaginal expansible plug, take weight M;
B. 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.
8. the detection method of nystatin expandable vaginal expansible plug as claimed in claim 7, it is characterized in that, described expandable carrier is cotton sliver, and described detection comprises following at least one method:
1) swell value assay method:
Get described nystatin expandable vaginal expansible 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 nystatin expandable vaginal expansible 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.
9. the detection method of nystatin expandable vaginal expansible plug as claimed in claim 8, 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 |
| CN103284996A (en) * | 2013-06-03 | 2013-09-11 | 哈尔滨欧替药业有限公司 | Vagina swelling metronidazole clotrimazole suppository and preparation method and detection method thereof |
| CN103301098A (en) * | 2013-06-21 | 2013-09-18 | 哈尔滨欧替药业有限公司 | Compound chlorhexidine vaginal expansion suppository as well as preparation method and detection method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
| CN103284996A (en) * | 2013-06-03 | 2013-09-11 | 哈尔滨欧替药业有限公司 | Vagina swelling metronidazole clotrimazole suppository and preparation method and detection method thereof |
| CN103301098A (en) * | 2013-06-21 | 2013-09-18 | 哈尔滨欧替药业有限公司 | Compound chlorhexidine vaginal expansion suppository as well as preparation method and detection method thereof |
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