CN102600001A - Slow-release mifepristone vaginal ring preparation and application thereof - Google Patents
Slow-release mifepristone vaginal ring preparation and application thereof Download PDFInfo
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- CN102600001A CN102600001A CN201110021243XA CN201110021243A CN102600001A CN 102600001 A CN102600001 A CN 102600001A CN 201110021243X A CN201110021243X A CN 201110021243XA CN 201110021243 A CN201110021243 A CN 201110021243A CN 102600001 A CN102600001 A CN 102600001A
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Abstract
The invention relates to a preparation method for two types of slow-release mifepristone vaginal ring preparations. The first type of slow-release mifepristone vaginal ring preparation includes from 1.0 to 4.5 wt% of mifepristone, from 1.5 to 13.5 wt% of drug scattered carrier, from 0.05 to 20 wt% of surfactant and from 62 to 97.45wt% of medical high polymer release control materials. The second type of slow-release mifepristone vaginal ring preparation includes from 1.0 to 4.5 wt% of mifepristone, from 1.5 to 13.5 wt% of drug scattered carrier, from 0.05 to 20 wt% of surfactant, from 62 to 97.45wt% of medical high polymer release control materials, and a thin release control membrane covered on the outside of each slow-release mifepristone vaginal ring preparation. Due to the preparation method, a slow-release mifepristone vaginal ring can slowly release the mifepristone within seven days, a first pass effect and gastrointestinal reaction of mifepristone orally taken drug are avoided, bioavailability of the drug and pharmacy compliance of a patient are improved.
Description
Technical field
The present invention relates to novel contraceptive medical instrument field, particularly load the slow release medicine for vaginal ring and the application thereof of mifepristone medicine.
Background technology
Along with the develop rapidly of society, the safe and effective measure that avoids conception and control birth is actively taked in the continuous expansion of world population scale, with control the population size, improve the quality of the population and the physique of the entire people extremely urgent.And the quickening of rhythm of life, and the competition that is growing more intense makes people's pressure increase, especially working woman, gynaecopathia is comed one after another, like hysteromyoma etc.This shows that love the healthy of women can not be ignored.
Mifepristone (Mifepristone) at first by French Roussel-Uclaf company the eighties in last century research and development produce; Have very strong gestation and Antiglucocorticoid effect; But several no progestogen, androgen and estrogen-like effects; And progesterone receptor had the falling tone effect, be a kind of competitive progesterone receptor antagonist of acceptor levels.The mifepristone oral absorption is rapid, eliminates slowlyer, is two Room open models, and tangible first pass effect is arranged.The oral bioavailability of mifepristone is 30%-56% the people, is 39% rat, is 30% rabbit, is 15% monkey.Rat and people's bioavailability is comparatively approaching, this shows that the oral bioavailability of mifepristone is lower.
Mifepristone at first as the medicinal application of termination of early pregnancy in clinical, its effectiveness and safety are confirmed.In addition, also a large amount of research has been carried out in other clinical practices of mifepristone both at home and abroad, comprised conventional contraception, treatment women's hysteromyoma and endometriosis etc., all obtained certain achievement.The exemplary application low dose mifepristone administration is used for contraception and treatment clinically in recent years, and side reaction is less.
Mifepristone is oral to need takes every day, and Chang Yinwei misses and vomiting etc. causes unexpected gestation or treatment failure, has influenced the effect of oral contraception and treatment.In order to overcome above-mentioned shortcoming, Recent study about the vagina administration preparation of mifepristone, common have tablet, membrane, gel, suppository, a contraceptive vaginal ring etc.Contraceptive vaginal ring (VCR) can provide a kind of lasting, low dose of release mode, has slow controlled release mechanism, and whole body blood drug level is steady, and drug side effect is lighter, no liver first-pass effect, and put and get conveniently, pin or subdermal implants are superior to practising contraception.
Calendar year 2001, Dutch Ou Jianong company has released nuvaring (containing etonogestrel and ethinylestradiol) pessary, obtains good market effect in countries such as America and Europe and Africa.The domestic megestrol silicone rubber contraceptive vaginal ring that began one's study from 1972 is developed levonorgestrel pessary and estrogen and progestogen pessary etc. later on successively.But so far, domesticly do not see that also the pessary of listing product is arranged.
At present, the medicine of pessary institute slow release all is to be main with steroid hormone, and has brought more significant exogenous slow releasing pharmaceutical to the secretion of human body endogenous gonadal hormone and the interference and the influence of adjusting thus, has restricted the acceptability of pessary contraceptive method.The researcher attempts mifepristone is prepared into Atrigel both at home and abroad, is intended to improve the compliance of taking medicine.02136837.6 disclose the patent of mifepristone semi-solid skeleton preparation preparation; 200610042252.6 reported the preparation of gel and membrane in the relevant vagina administration mifepristone preparation; 200510027902.5,03116893.0,02111977.5,01112712.0 etc. mention mifepristone be prepared into pessary; But all do not see being described in detail of mifepristone medicine for vaginal ring; 01268469.4 disclose a kind of pessary of slow release mifepristone, its summary of the invention is not narrated concrete technology, and does not have embodiment.This research group with mifepristone with find that medicine not have release basically after polymer manufacture becomes pessary; After passing through lot of test then; After finding unexpectedly mifepristone is prepared into solid dispersion; Ring formation again, burst size increases greatly, and in the regular hour, presents slow release or release characteristics.
Summary of the invention
The invention provides a kind of lasting, release mode slowly, i.e. mifepristone pessary.The preparation of mifepristone pessary sees processes for details:
1, mifepristone is molecularity and is dispersed in the dispersant, and by character such as the special solid of dispersion, ring-type, ions, the attaching space of mifepristone and release medium is increased greatly, thereby increased the stripping quantity of mifepristone.
2, after mifepristone dispersion and macromolecular material mechanical mixture,, therefore add an amount of single or blended surfactant because the backlash characteristics of macromolecular material itself has influenced the quick stripping of mifepristone.Because surfactant is met thermal expansion in the preparation processing process, in macromolecular material, form mechanicalness gap structure and passage, make medicine be easy to stripping; Because the solubilization of surfactant when increasing the medicine stripping, has also improved medicine bioavailability in vivo.
Medicine for vaginal ring of the present invention comprises pastille part and the release-controlled film that is coated on the pastille part.The consisting of of pastille part (content, weight %) wherein:
Form content (weight %)
Medicine 1.0～4.5
Medicine dispersible carrier 1.5～13.5
Surfactant 0.05～20
Medical high polymer controlled-release material 62～97.45
The described release-controlled film thickness that is coated on the pastille part is 0.02～1mm.
Wherein said medical high polymer controlled-release material is selected from Dow corning silastic-382 medical grade silicone rubber; Dow corning Q7 medical grade silicone rubber series; Dow corning is implanted level MDX series, Dow corning Class VI silicone rubber, or the medical grade silicone rubber of other respective series.
Wherein said release-controlled film is selected from Dow corning silastic-382 medical grade silicone rubber; Dow corning Q7 medical grade silicone rubber series; Dow corning is implanted level MDX series, Dow corning Class VI silicone rubber, or the medical grade silicone rubber of other respective series.
Described surfactant is selected from one or more surfactant mixtures in span 20-80, brejs 52-76, OP emulsifying agent, PEG400-20000, PVP, pluronic-124, pluronic-188, sodium lauryl sulphate, myristyl sodium sulfonate, dodecyl sodium sulfate and the triethanolamine for the physiology goes up acceptable surfactant.
Described medicine dispersible carrier is that the physiology goes up the acceptable drug dispersible carrier, is selected from one or more the mixture in glycerin, propylene glycol, PEG400-20000, succinic acid, cholic acid, deoxycholic acid, hexadecanol, octadecanol, β type cyclodextrin, γ type cyclodextrin, PVP, HPMC, methylcellulose, ethyl cellulose, the hydroxypropyl cellulose.Selected medicine dispersible carrier is the material that is different from surfactant.
Pessary ring external diameter of the present invention can be set in 45mm～55mm scope, and cross-sectional diameter can be set in 4mm～6mm scope.
Preparation technology of the present invention adopts the molded vulcanization moulding process in the technical field, specifically may further comprise the steps:
(1), by aforementioned ratio crude drug is handled, with the mixing 5-20min of drug carrier material;
(2), the silicone rubber tube that cuts into a straight shape after mixing, hot-press vulcanization molding in the mould, curing temperature:
110 ℃～150 ℃, cure time: 5-20min;
(3), coat the release-controlled film of one deck 0.02-1mm on the product that obtains in (2) again.
The invention provides a kind of pastille matrix type pessary, and the double-tube type of processing with pastille skeleton and medical high polymer controlled-release material realizes slow release, and slow releasing pharmaceutical is the mifepristone of gestation receptor class, is used for the pessary of conventional contraception.Can in 7 days, slowly discharge contraceptive, and produce tangible contraceptive effect, avoid the first pass effect and the gastrointestinal reaction of oral contraceptive, improve bioavailability and the compliance of taking medicine.
Description of drawings
Fig. 1 does not add the release profiles of the mifepristone A type pessary of any adjuvant.
Fig. 2 is the release profiles of mifepristone A type pessary of the present invention.
Fig. 3 is the release profiles of mifepristone Type B pessary of the present invention.
Specific embodiment
Medicine: 30mg
Silicone rubber: 2.97g
With mifepristone crude drug and mixing silicon rubber, obtain the silicone rubber of pastille, cut into the silicone rubber tube of a straight shape, put into mould, hot-press vulcanization on the vulcanizing press obtains mifepristone A type pessary.
Medicine: 30mg
PVP：60mg
Silicone rubber: 2.91g
With PVP is disperse medium, adopts solvent method to prepare the mifepristone solid dispersion, with itself and silicone rubber mix homogeneously; Obtain the silicone rubber of pastille, cut into the silicone rubber tube of a straight shape, put into mould; Hot-press vulcanization on the vulcanizing press obtains mifepristone A type pessary; Silicone rubber is pressed into the thin skin of 0.05mm thickness, is coated to the falope of above-mentioned preparation, the hot-press vulcanization molding promptly gets mifepristone Type B pessary.
Medicine: 30mg
PEG6000：60mg
Dodecyl sodium sulfate: 4mg
Silicone rubber: 2.906g
Taking by weighing an amount of mifepristone, is disperse medium with PEG 6000, adopts solvent method to prepare solid dispersion; Add an amount of dodecyl sodium sulfate,, obtain the silicone rubber of pastille itself and a certain amount of silicone rubber mix homogeneously; Cut into the silicone rubber tube of a straight shape; Put into mould, hot-press vulcanization on the vulcanizing press obtains mifepristone A type pessary; Silicone rubber is pressed into the thin skin of 0.05mm thickness, is coated to the falope of above-mentioned preparation, the hot-press vulcanization molding promptly gets mifepristone Type B pessary.
Medicine: 50mg
PVP：100mg
Dodecyl sodium sulfate: 4mg
Silicone rubber: 4.846g
With PVP is disperse medium, adopts solvent method to prepare the mifepristone solid dispersion, adds an amount of dodecyl sodium sulfate; With itself and a certain amount of silicone rubber mix homogeneously; Obtain the silicone rubber of pastille, cut into the silicone rubber tube of a straight shape, put into mould; Hot-press vulcanization on the vulcanizing press obtains the mifepristone A type pessary of larger sectional area; Silicone rubber is pressed into the thin skin of 0.05mm thickness, is coated to the falope of above-mentioned preparation, the hot-press vulcanization molding promptly gets mifepristone Type B pessary.
Embodiment of the invention 1-3 product is compared with comparative example's product, and it is very fast that mifepristone A type pessary begins drug release rate, and release amount higher (8-10mg) tends to be steady (2-6mg) since second day release amount, has the slow release characteristics; Mifepristone Type B pessary drug release rate is (2-6mg) comparatively steadily, meets the dynamic (dynamical) rule of zero-order release.This shows, the mifepristone crude drug after treatment, the burst size of medicine obviously increases; Increase the cross-sectional area of pessary, the burst size of mifepristone also obviously increases; The release of medicine is more steady behind the peplos.
Preliminary pharmacodynamic result in the rat body
Test method: 30 adult female rats are divided into 3 groups at random; Be respectively blank group, oral administration group (oral mifepristone sheet, 1mg//day), mifepristone pessary group (embodiment 1 product), rat mates after different disposal; Vaginal suppository to occur is conceived first day; The cervical vertebra dislocation method is put to death female Mus after 14 days, cuts open the inspection rat uterus, observes the rat situation of becoming pregnant.The result is as shown in the table:
Table 1 vagina administration is to the contraceptive efficacy of rat
Can find out from result of the test; Pessary administration group and oral administration group contraceptive effect are all good; Compare with matched group and all to have significant difference; And there was no significant difference between pessary administration group and the oral administration group, prompting pessary administration group has tangible contraceptive effect, and its drug effect is suitable with the oral administration group.
Claims (9)
1. the pessary of two kinds of slow release RU486, a kind of is matrix type pessary (A type); Another kind comprises pastille part and the release-controlled film (Type B) that is coated on the pastille part.It is characterized in that consisting of of described pastille part:
Form content (weight %)
Medicine 1.0～4.5
Surfactant 0.05～20
Medicine dispersible carrier 1.5～13.5
Medical high polymer controlled-release material 62～97.45
The difference of the two is whether to contain the release-controlled film that is coated on the pastille part, and described release-controlled film thickness is 0.02～1mm.
2. the pessary of slow release RU486 according to claim 1; It is characterized in that wherein said medical high polymer controlled-release material is selected from Dow corning silastic-382 medical grade silicone rubber; Dow corning Q7 medical grade silicone rubber series; Dow corning Class VI silicone rubber, Dow corning are implanted level MDX series, or the medical grade silicone rubber of other respective series.
3. the pessary of slow release RU486 according to claim 1; It is characterized in that wherein said release-controlled film is selected from Dow corning silastic-382 medical grade silicone rubber; Dow corning Q7 medical grade silicone rubber series; Dow corning Class VI silicone rubber, Dow corning are implanted level MDX series, or the medical grade silicone rubber of other respective series.
4. the pessary of a kind of slow release RU486 according to claim 1; It is characterized in that wherein said surfactant for the physiology goes up acceptable surfactant, is selected from one or more surfactant mixtures in span 20-80, brejs 52-76, OP emulsifying agent, PEG400-20000, PVP, pluronic-124, pluronic-188, sodium lauryl sulphate, myristyl sodium sulfonate, dodecyl sodium sulfate and the triethanolamine.
5. the pessary of slow release RU486 according to claim 1; It is characterized in that wherein said medicine dispersible carrier is that the physiology goes up the acceptable drug dispersible carrier, be selected from one or more the mixture in glycerin, propylene glycol, PEG400-20000, succinic acid, cholic acid, deoxycholic acid, hexadecanol, octadecanol, β type cyclodextrin, γ type cyclodextrin, PVP, HPMC, methylcellulose, ethyl cellulose, the hydroxypropyl cellulose.Selected medicine dispersible carrier is the material that is different from surfactant.
6. the pessary of slow release RU486 according to claim 1 is characterized in that the pessary ring external diameter of this slow release RU486 can be set in 45mm～55mm scope, cross-sectional diameter can be set in 4mm～6mm scope.
7. the pessary of slow release RU486 according to claim 1, the peplos that it is characterized in that processing with pastille skeleton and medical high polymer controlled-release material realize sustained-release and controlled release.
8. the pessary of slow release RU486 according to claim 1 is characterized in that the medicine of the pessary institute slow release of this slow release RU486 is the RU486 of gestation receptor class.
9. the application of the pessary of slow release RU486 according to claim 1 aspect female contraception (conventional contraception) and treatment (endometriosis, adenomyoma etc.).
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| Application Number | Priority Date | Filing Date | Title |
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| CN201110021243XA CN102600001A (en) | 2011-01-19 | 2011-01-19 | Slow-release mifepristone vaginal ring preparation and application thereof |
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| CN201110021243XA CN102600001A (en) | 2011-01-19 | 2011-01-19 | Slow-release mifepristone vaginal ring preparation and application thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014087106A1 (en) * | 2012-12-06 | 2014-06-12 | Laboratoire Hra-Pharma | Solid dispersion of a selective modulator of the progesterone receptor |
| CN106267234A (en) * | 2015-06-26 | 2017-01-04 | 上海市计划生育科学研究所 | Pessary containing non-nucleoside reverse transcriptase inhibitor and preparation method thereof |
| CN106456838A (en) * | 2014-04-01 | 2017-02-22 | 保利医学公司 | Contraceptive and related device |
| CN108175930A (en) * | 2018-01-22 | 2018-06-19 | 中国人民解放军军事科学院军事医学研究院 | A kind of vagina administration apparatus of 3D printing |
| CN109248139A (en) * | 2017-07-14 | 2019-01-22 | 国家卫生计生委科学技术研究所 | The preparation method and application of Levonorgestrel Compourd pesseulum |
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| CN1382500A (en) * | 2001-04-25 | 2002-12-04 | 上海市计划生育科学研究所 | Medicine for vaginal ring and its application |
| CN2525971Y (en) * | 2001-11-13 | 2002-12-18 | 程定超 | Pessary of slow-released mifepristone |
| CN1463762A (en) * | 2002-06-07 | 2003-12-31 | 上海市计划生育科学研究所 | Novel pessary and method for preparing same |
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2011
- 2011-01-19 CN CN201110021243XA patent/CN102600001A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1382500A (en) * | 2001-04-25 | 2002-12-04 | 上海市计划生育科学研究所 | Medicine for vaginal ring and its application |
| CN2525971Y (en) * | 2001-11-13 | 2002-12-18 | 程定超 | Pessary of slow-released mifepristone |
| CN1463762A (en) * | 2002-06-07 | 2003-12-31 | 上海市计划生育科学研究所 | Novel pessary and method for preparing same |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014087106A1 (en) * | 2012-12-06 | 2014-06-12 | Laboratoire Hra-Pharma | Solid dispersion of a selective modulator of the progesterone receptor |
| FR2999081A1 (en) * | 2012-12-06 | 2014-06-13 | Hra Pharma Lab | SOLID DISPERSION OF A SELECTIVE PROGESTERONE RECEPTOR MODULATOR |
| CN105120899A (en) * | 2012-12-06 | 2015-12-02 | Hra医药实验室 | Solid dispersion of a selective modulator of the progesterone receptor |
| JP2016506390A (en) * | 2012-12-06 | 2016-03-03 | ラボラトワール・アシュエールア−ファルマＬａｂｏｒａｔｏｉｒｅ Ｈｒａ−Ｐｈａｒｍａ | Solid dispersions of selective progesterone receptor modulators |
| EA029701B1 (en) * | 2012-12-06 | 2018-05-31 | Лаборатуар Хра-Фарма | Solid dispersion of a selective modulator of the progesterone receptor, method for preparing same and composition based thereon |
| CN105120899B (en) * | 2012-12-06 | 2018-07-24 | Hra医药实验室 | The solid dispersions of selective progestogen receptor regulator |
| CN106456838A (en) * | 2014-04-01 | 2017-02-22 | 保利医学公司 | Contraceptive and related device |
| CN106456838B (en) * | 2014-04-01 | 2020-12-29 | 保利医学公司 | Contraceptive device and related device |
| CN106267234A (en) * | 2015-06-26 | 2017-01-04 | 上海市计划生育科学研究所 | Pessary containing non-nucleoside reverse transcriptase inhibitor and preparation method thereof |
| CN106267234B (en) * | 2015-06-26 | 2020-04-10 | 上海市计划生育科学研究所 | Vaginal ring containing non-nucleoside reverse transcriptase inhibitor and preparation method thereof |
| CN109248139A (en) * | 2017-07-14 | 2019-01-22 | 国家卫生计生委科学技术研究所 | The preparation method and application of Levonorgestrel Compourd pesseulum |
| CN108175930A (en) * | 2018-01-22 | 2018-06-19 | 中国人民解放军军事科学院军事医学研究院 | A kind of vagina administration apparatus of 3D printing |
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Application publication date: 20120725 |