CN102525722A - Intelligent compound gestodene vaginal ring preparation with memory effect and application of intelligent compound gestodene vaginal ring preparation - Google Patents
Intelligent compound gestodene vaginal ring preparation with memory effect and application of intelligent compound gestodene vaginal ring preparation Download PDFInfo
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- CN102525722A CN102525722A CN2010106131179A CN201010613117A CN102525722A CN 102525722 A CN102525722 A CN 102525722A CN 2010106131179 A CN2010106131179 A CN 2010106131179A CN 201010613117 A CN201010613117 A CN 201010613117A CN 102525722 A CN102525722 A CN 102525722A
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Abstract
The invention relates to a contraceptive, in particular to an intelligent compound gestodene vaginal ring preparation with a memory effect. A vaginal ring consists of a controlled release membrane, a gestodene/ethinyloestradiol-containing carrier and a shape memory material, and can slowly release a contraceptive at constant speed within 21 days. By implementing the preparation, the remarkable contraception effect can be achieved, the inconvenience caused by the oral administration of the contraceptive is avoided, and the appliance of the administration is improved.
Description
Technical field
Patent of the present invention belongs to the new drug-supplying system of intravaginal field, promptly relates to the intelligent progestational compound dienone with SME and the preparation and the application thereof of ethinylestradiol pessary.
Background technology
Continuous expansion along with China and world population scale; Actively take safety, effectively avoid conception and control birth measure with control the population size, improve the quality of the population and the physique of the entire people extremely urgent, " safe and effective avoiding conception and controling birth " research has become one of healthy reproduction field " ten challenge " greatly.
Adopt synthetic steroid hormone as the history in existing 60 years of contraceptive.The initial main oral tablet that uses, because of need are regularly taken every day, Chang Yinwei misses and vomiting etc. the and influence contraceptive effect of oral contraceptive, causes unexpected pregnant.In order to overcome above-mentioned shortcoming, people begin to develop novel forms such as injection, subdermal implants and pessary.The drug anesthesia of injection administrable is tired, and there are pain and subcutaneous irritative symptoms in the part, and subdermal implants needs underwent operative to carry out heeling-in, and the psychology and the beauty treatment acceptance of user are all relatively poor.Contraceptive vaginal ring (CVR) is a kind of novel contraceptive medical instrument that last century, early seventies grew up; Be that contraceptive steroid is placed in the carrier of non-activity; Medicine is through the disperse in body of its micropore; Through the contraceptive of constant release minimum effective dose, transvaginal absorbs, and reaches the purpose of long-term contraception.Its advantage is: whole body blood drug level is kept reduced levels, and drug side effect is lighter, no liver first-pass effect; Pessary places intravaginal release for a long time; Avoid oral contraceptive to need the inconvenience of administration every day, and can insert easily as required or take out, avoided the deficiency of subdermal implants.
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 carries out the research and development of 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.
The gestodene is the strongest a kind of steroidal class contraceptive of activity of generally acknowledging up to now; Its secretion and endometrial growth to follicular development, pituitary gonadotropic hormone all has the obvious suppression effect; Only need extremely low dosage just can reach the effect that continues to suppress ovulation; And it does not have androgenic activity, helps to keep the balance of women self hormone, with the safety that obtains near ideal and comfortable.Gestodene's marketed drugs preparation is gestodene and ethinylestradiol compound oral tablet at present, and clinical data shows that the oral back of progestational compound dienone sheet blood drug level is unstable, and gastrointestinal side effects such as multiple vomiting have influenced its curative effect and acceptance.Therefore, the researcher attempts it is prepared into Atrigel both at home and abroad, is intended to improve the compliance of taking medicine.96109379.X, the patent reported about progestational compound dienone transdermal patch of 200810018880.x, 200480041321.0 and 89108149.6; 96112746.5 be research about progestational compound dienone subdermal implantation preparation, the patent of 200610135105.3,200810182857.4 report progestational compound dienone microspheres.Up to now, do not see the patent report of progestational compound dienone pessary.
Summary of the invention
The invention discloses a kind of have memory effect intelligent progestational compound dienone medicine for vaginal ring and application thereof.This pessary has intelligent memory effect, softness, slip-off preventing; Can in 21 days, keep the constant release of medicine, have long-acting, thereby well improve the compliance that uses the crowd; Guarantee contraceptive effect, further bring into play the advantage of gestodene's compound preparation.
Summary of the invention:
1, implementation method:
One, in proportion crude drug is handled after, mixing with drug carrier material, process the pastille carrier material;
Two, adopt the coextrusion mode, pastille carrier material and release-controlled film material are extruded jointly, process the bimetallic tube of hollow, as shown in Figure 1;
Three, bimetallic tube is cut into certain-length, insert memory material;
Four, welding fabrication is carried out at the bimetallic tube two ends that will contain memory material, and is as shown in Figure 2.
2, description of drawings:
Fig. 1 is hollow two-layer pipe figure
Wherein 1 is release-controlled film, and 2 for containing drug carrier, and 3 is hollow pipe.
Fig. 2 is the pessary structure chart
Wherein 1 is release-controlled film, and 2 for containing drug carrier, and 4 is shape-memory material.
Fig. 3 is the external stripping curve of GEST-EE compound recipe pessary comparative example
Fig. 4 is the external stripping curve of GEST-EE compound recipe pessary
Fig. 5 is GEST-EE compound recipe pessary blood drug level-time graph
3, specific embodiment
The comparative example
Take by weighing 1kg silicone rubber and 3.04g gestodene and 1.17g ethinylestradiol mix homogeneously, obtain the silicone rubber material of pastille, put into extruder; Blank silicone rubber is put into another extruder, and coextrusion becomes bimetallic tube, baking, and the outer wall thickness 200 μ m of the long tube that obtains, the pipe overall diameter is 5mm, the pipe interior diameter is 0.15mm.It is the 150mm segment that the bimetallic tube of extruding is cut into length, and the Ti-Ni memory alloy wire is penetrated wherein, with bimetallic tube two ends welding fabrication, promptly gets the compound recipe pessary that contains gestodene and ethinylestradiol.
Take by weighing 3.04g gestodene and 9.12g PVP, solvent method is prepared into solid dispersion, with itself and 1kg silicone rubber and 1.17g ethinylestradiol mix homogeneously, obtains the silicone rubber material of pastille, puts into extruder; Blank silicone rubber is put into another extruder, and coextrusion becomes bimetallic tube, baking, and the outer wall thickness 200 μ m of the long tube that obtains, the pipe overall diameter is 5mm, the pipe interior diameter is 0.15mm.It is the 150mm segment that the bimetallic tube of extruding is cut into length, and the Ti-Ni memory alloy wire is penetrated wherein, with bimetallic tube two ends welding fabrication, promptly gets the compound recipe pessary that contains gestodene and ethinylestradiol.
Take by weighing 3.72g gestodene and 1.43g ethinylestradiol and 22.32g PEG6000, the fusion method method is prepared into solid dispersion, with itself and 1kg EVA mix homogeneously, obtains the EVA raw material of pastille, and above-mentioned raw materials is put into extruder; Blank EVA is put into an other extruder, adopt the method for coextrusion to process bimetallic tube, outer tube layer wall thickness 120 μ m; External diameter of pipe is 4mm; Bore is 0.1mm, and it is the 157mm segment that the bimetallic tube of extruding is cut into length, and the Ti-Ni memory alloy wire is penetrated wherein; With the two ends welding fabrication, both must contain the compound recipe pessary of gestodene and ethinylestradiol.
External release test
Instrument: 1, HPLC Waters 2695vp
2, intelligent dissolution test appearance ZRS-8G
Process:
1, getting on the stirring paddle that one of nylon filament is fixed on underproof ring digestion instrument, is dissolution medium with the distilled water, and volume is 150ml, and design temperature is 37 ℃, and rotating speed is 50 rev/mins, the external stripping of per 24 hours sampling detection of drugs, METHOD FOR CONTINUOUS DETERMINATION 21 days.
2, standard substance gestodene and ethinylestradiol are available from Zizhu Pharmaceutical Co., Ltd., Beijing.
3, with C18 250mm analytical column (enlightening horse)
Setting the HPLC testing conditions is: the gestodene detects wavelength 239nm, and ethinylestradiol detects wavelength 205nm, sensitivity 0.1AUFS, and mobile phase is acetonitrile: water=50: 50, flow velocity are 1.0ml/min, sample size is 20 μ l.The external stripping curve of comparative example's product is as shown in Figure 3, and its external release amount reached since the 3rd day steadily, gestodene's release amount: 15-17 μ g/ days; The release amount of ethinylestradiol: 4-5 μ g/ days.
21 days external stripping curve of the embodiment of the invention 1 product is as shown in Figure 4, reaches stable since the 4th day external release amount, gestodene's release amount: 50-65 μ g/ days; The release amount of ethinylestradiol: 11-15 μ g/ days.The crude drug extracorporeal releasing quantity of medicine after treatment obviously increases.
Rat body giving drugs into nose is for dynamic test test method as a result: 16 adult female rats are divided into 2 groups at random; Be respectively pastille compound recipe pessary group (embodiment 1 product; Place after 21 days and take out) and oral Minulet sheet matched group; 0.5h before administration; 0.5h, 2h, 4h, 8h, 24h, 2d, 3d, 4d, 5d, 6d, 7d, 9d, 11d, 13d, 15d, 17d, 19d and 21d get blood examination and survey blood drug level after the administration, and drug-time curve is as shown in Figure 5, and pastille compound recipe pessary can be kept relative stable blood concentration in administration in 21 days.
Pharmacodynamic result in the rat body
Test method: 30 adult female rats are divided into 3 groups at random, are respectively blank group, oral administration group (oral Minulet sheet, gestodene 6mg/kg; Ethinylestradiol 1.5mg/kg) pastille compound recipe pessary group (embodiment 1 product); Rat mates after different disposal, serves as conceived first day vaginal suppository to occur, and the cervical vertebra dislocation method is put to death female Mus after 14 days; Cut open the inspection rat uterus, observe rat.The result is as shown in the table
Vagina administration is to the contraceptive efficacy of rat
Can find out from result of the test; Oral administration group and compound recipe pessary administration group contraceptive effect are all good; Compare with matched group and all to have significant difference; And no significance is poor between oral administration group and the pessary administration group, and prompting pessary administration group has tangible contraceptive effect, and its drug effect is suitable with the oral administration group.
Claims (8)
1. a compound recipe pessary that contains gestodene and ethinylestradiol is made up of release-controlled film, pastille skeleton and shape-memory material, it is characterized in that pastille skeleton part by following component and proportion than forming:
1 part of medicine
Medical high polymer controlled-release material 100-500 part
Medicine dispersible carrier 0.1-100 part
Surfactant 0.1-100 part
Its Chinese medicine by gestodene and ethinylestradiol with weight ratio 10: 1-1: 1 forms.
2. the described gestodene's compound recipe of claim 1 pessary is characterized in that realizing sustained-release and controlled release with the bimetallic tube mode that the macromolecule controlled-release material of pastille skeleton and control drug release is processed.
3. claim 1 or 2 described progestational compound dienone pessaries is characterized in that the release-controlled film material is medical high polymer controlled-release material silicone rubber or ethylene-vinyl acetate copolymer.
4. claim 1 or 2 described progestational compound dienone pessaries is characterized in that the medical high polymer controlled-release material of selecting for use can be silicone rubber or ethylene-vinyl acetate copolymer.
5. claim 1 or 2 described progestational compound dienone pessaries is characterized in that the medicine dispersible carrier of selecting for use can be 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.
6. claim 1 or 2 described progestational compound dienone pessaries is characterized in that the surfactant of selecting for use can be 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.
7. claim 1 or 2 described progestational compound dienone pessaries is characterized in that said shape-memory material is a memorial alloy.
8. claim 1 or the 2 described progestational compound dienone pessaries application in the preparation contraceptive.
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| CN2010106131179A CN102525722A (en) | 2010-12-30 | 2010-12-30 | Intelligent compound gestodene vaginal ring preparation with memory effect and application of intelligent compound gestodene vaginal ring preparation |
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| CN2010106131179A CN102525722A (en) | 2010-12-30 | 2010-12-30 | Intelligent compound gestodene vaginal ring preparation with memory effect and application of intelligent compound gestodene vaginal ring preparation |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1549703A (en) * | 2001-08-31 | 2004-11-24 | �����ι�˾ | Drug delivery system |
| CN101983041A (en) * | 2008-04-02 | 2011-03-02 | 拜耳先灵药品股份有限公司 | An intrauterine system |
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- 2010-12-30 CN CN2010106131179A patent/CN102525722A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1549703A (en) * | 2001-08-31 | 2004-11-24 | �����ι�˾ | Drug delivery system |
| CN101983041A (en) * | 2008-04-02 | 2011-03-02 | 拜耳先灵药品股份有限公司 | An intrauterine system |
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Application publication date: 20120704 |