CN102512688A - Nilestriol-beta-cyclodextrin inclusion compound and preparation method thereof - Google Patents
Nilestriol-beta-cyclodextrin inclusion compound and preparation method thereof Download PDFInfo
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- CN102512688A CN102512688A CN2011104527354A CN201110452735A CN102512688A CN 102512688 A CN102512688 A CN 102512688A CN 2011104527354 A CN2011104527354 A CN 2011104527354A CN 201110452735 A CN201110452735 A CN 201110452735A CN 102512688 A CN102512688 A CN 102512688A
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- nilestriol
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- schardinger dextrin
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Abstract
The invention discloses a nilestriol-beta-cyclodextrin inclusion compound and a preparation method thereof. The nilestriol-beta-cyclodextrin inclusion compound is prepared from nilestriol and beta-cyclodextrin at a mole ratio of 1 to 1. Drug auxiliary materials are added into the nilestriol-beta-cyclodextrin inclusion compound, so that the nilestriol-beta-cyclodextrin inclusion compound is prepared into an oral solid preparation through a proper preparation process. According to the preparation method disclosed by the invention, the solubility of the nilestriol in water is improved, and the nilestriol-beta-cyclodextrin inclusion compound is good for being absorbed and functioned.
Description
Technical field
The invention belongs to the pharmaceutical technology field, be specifically related to cyclodextrin clathrate and the preparation and the method for preparing of nilestriol.
Background technology
Nilestriol (Nilestriol) is the derivant of estriol, is the estriol durative action preparation.Estriol is the metabolite of estradiol, and its pharmacological action is similar with estradiol, but biological activity is low, thus to endometrial proliferative effect also a little less than, be applicable to the controversies in hormone replacement in the elderly of perimenopausal women; Increased lipotropy after go up introducing the ring amyl ether because of its 3, helped intestinal absorption and be stored in the fatty tissue, slowly discharged later on and play long-acting; Introduce acetenyls and strengthen estrogen activity for its 17.Clinically be used for menopause or the climacteric syndrome that estrogen deficiency causes,, perspire like hectic fever, headache, dizzy, fatigue, irritated irritability, nervousness, xerosis vulae, senile vaginitis etc.Have the people that it has been carried out the research of others in recent years, like radioprotective, prevent and treat osteoporosis, the influence and the gynecological of blood fat is won birth control apparatus etc., nilestriol can reduce the bone conversion, increases the bone amount.
The absorption of medicine is mainly carried out under dissolved state, and the insoluble drug dissolving is slower, and the absorption of medicine can only slowly be carried out gradually, because intravital metabolism causes medicine peak value blood drug level to reduce, curative effect descends.According to " 2010 editions records of Chinese pharmacopoeia, nilestriol is water-soluble hardly, and traditional nilestriol oral formulations is directly to process with the nilestriol crude drug, because its water-fast characteristic has influenced the absorption of oral formulations, influences clinical result of use simultaneously; Be badly in need of improving the water miscible preparation of nilestriol at present clinically,, reduce toxic and side effects to improve curative effect.
Summary of the invention
Primary and foremost purpose of the present invention is to improve the shortcoming and defect of nilestriol solubility problem of the prior art, thereby a kind of Benexate Hydrochloride of water-soluble nilestriol is provided.
Second purpose of the present invention is to provide the method for preparing of the Benexate Hydrochloride of above-mentioned nilestriol.
The 3rd purpose of the present invention is to provide the Benexate Hydrochloride of above-mentioned nilestriol to add the preparation that adjuvant is processed.
The 4th purpose of the present invention is to provide the method for preparing of the Benexate Hydrochloride preparation of above-mentioned nilestriol.
Nilestriol-Benexate Hydrochloride of the present invention comprises nilestriol and beta-schardinger dextrin-.
According to a preferred embodiment of the invention, the mol ratio of said nilestriol and beta-schardinger dextrin-is 1: 1.
The method for preparing of nilestriol-Benexate Hydrochloride of the present invention may further comprise the steps:
A) nilestriol is dissolved in the organic solvent, simultaneously, beta-schardinger dextrin-is dissolved in the water;
B) above-mentioned nilestriol solution and beta-schardinger dextrin-solution are mixed, stir;
C) drying;
D) acetone rinsing, drying under reduced pressure.
According to a preferred embodiment of the invention, said organic solvent is chloroform, dichloromethane, acetone, methanol, ethanol or above-mentioned any several kinds mixed solvent, preferred acetone.Further, said steps A) in, said nilestriol be through ultrasonic dissolution in organic solvent, said beta-schardinger dextrin-be through ultrasonic or stirring and dissolving in water.Said step B) in, the time of said stirring is 0.5～24 hour, preferred 4 hours.Said step C) is lyophilization or spray drying.
Nilestriol of the present invention-Benexate Hydrochloride preparation comprises described nilestriol-Benexate Hydrochloride and adjuvant.
According to a preferred embodiment of the invention, said adjuvant comprises any two or more adjuvant in starch, lactose, sucrose, mannitol, citric acid, sodium bicarbonate, polyvinyl pyrrolidone, hydroxypropyl emthylcellulose, cross-linking sodium carboxymethyl cellulose, magnesium stearate, the micropowder silica gel.
According to a preferred embodiment of the invention, said preparation is an oral solid formulation.
According to a preferred embodiment of the invention, said oral solid formulation comprises ordinary tablet, dispersible tablet, chewable tablet, effervescent tablet, capsule.
The present invention has following beneficial effect:
1, select beta-schardinger dextrin-as the enclose material; Utilize its clathration; The nilestriol enclose is processed clathrate; Make nilestriol become water soluble (20 ℃ of dissolubility in water are greater than 500mg), improved the dissolubility of nilestriol in water by water-soluble (20 ℃ of dissolubility in water are less than 10mg) hardly.
2, solved the drawback that the absorption that causes because of nilestriol is water insoluble in traditional oral formulations is slow, affect the treatment.After oral drugs are taken, through processes such as disintegrate, dispersion, medicine dissolution, absorptions, after medicine only is transformed into solution state, could be by gastrointestinal absorption.The oral formulations that nilestriol cyclodextrin clathrate of the present invention is processed has increased the water solublity of medicine, makes it take back dissolving formation solution rapidly, is more conducive to the absorption of medicine; Simultaneously,, reduced the influence of metabolism, improved the curative effect of medicine, reduced toxic and side effects, increased the adaptability of patient, for the patient provides better choice to medicine to peak value blood drug level owing to accelerated the speed of drug release, absorption.
The present invention has solved the water solublity problem of nilestriol emphatically, makes nilestriol by the water-soluble water soluble that becomes hardly, adopts this technological preparation; Oral back medicine dissolves absorption rapidly; It is minimum that drug metabolism influence in the absorption process is dropped to, and improved medicine peak value blood drug level, improved curative effect; For clinical practice provides curative effect more excellent medicine, have a good application prospect.
The specific embodiment
Below, the present invention is explained further details through specific embodiment.Should be understood that following examples only are used to the present invention is described but not are used to limit scope of the present invention.
The preparation of embodiment 1, nilestriol-Benexate Hydrochloride
The method for preparing of the nilestriol-Benexate Hydrochloride of present embodiment is following:
Take by weighing nilestriol 3.8g, add 28ml acetone, ultrasonic 20 minutes, make nilestriol be dissolved in the acetone fully; Other takes by weighing beta-schardinger dextrin-11.35g, adds 55 ℃ 255ml purified water, and constant temperature stirs, and beta-schardinger dextrin-is dissolved in the purified water fully.Then, make the beta-schardinger dextrin-aqueous solution remain on 55 ℃, mixing speed and be not less than under 2500 rev/mins the condition, slowly add the acetone soln of nilestriol, after both all mix, keeps former having ready conditions to continue stirring 4 hours.Mixture is cooled to room temperature, and-5 ℃ of lyophilizations obtain white powder.This white powder washes with 30ml acetone at twice, and drying under reduced pressure 2 hours finally obtains nilestriol-Benexate Hydrochloride.
Above-mentioned clathrate is dissolved in 20 ℃ processes saturated solution in the pure water, the concentration of nilestriol is 5.3mg/ml in this solution, and promptly the dissolubility in water is 530mg 20 ℃ the time.
The preparation of embodiment 2, nilestriol-Benexate Hydrochloride
The method for preparing of the nilestriol-Benexate Hydrochloride of present embodiment is following:
Take by weighing nilestriol 3.8g, add 30ml acetone, made nilestriol be dissolved in the acetone fully in ultrasonic 20 minutes; Other takes by weighing beta-schardinger dextrin-11.35g, adds 25～30 ℃ 300ml purified water, and the ultrasonic beta-schardinger dextrin-that makes is dissolved in the purified water fully.Then, make the beta-schardinger dextrin-aqueous solution remain on 25～30 ℃, mixing speed and be not less than under 2500 rev/mins the condition, slowly add the acetone soln of nilestriol; After both all mix; Keep former having ready conditions to continue to stir 4 hours, spray drying obtains white powder.This white powder washes with 30ml acetone at twice, and drying under reduced pressure 2 hours finally obtains nilestriol-Benexate Hydrochloride.
Above-mentioned clathrate is dissolved in 20 ℃ processes saturated solution in the pure water, the concentration of nilestriol is 5.3mg/ml in this solution, and promptly the dissolubility in water is 530mg 20 ℃ the time.
The preparation of embodiment 3, nilestriol-Benexate Hydrochloride preparation
The method for preparing of the nilestriol of present embodiment-Benexate Hydrochloride preparation is following:
Nilestriol-the Benexate Hydrochloride that obtains in embodiment 1 or 2 is got 4g pulverize, cross 100 mesh sieves, comprise that with other adjuvant amylum pregelatinisatum 80g, cross-linking sodium carboxymethyl cellulose 8g, magnesium stearate 0.8g mix then, direct compression gets dispersible tablet.
The preparation of embodiment 4, nilestriol-Benexate Hydrochloride preparation
The method for preparing of the nilestriol of present embodiment-Benexate Hydrochloride preparation is following:
Nilestriol-the Benexate Hydrochloride that obtains in embodiment 1 or 2 is got 4g pulverize, cross 100 mesh sieves, comprise that with other adjuvant starch 20g and lactose 60g mix then.24 orders are granulated after in said mixture, adding 2% hydroxypropyl emthylcellulose 20ml, and 24 order granulate after 65 ℃ of dryings add cross-linking sodium carboxymethyl cellulose 5g and magnesium stearate 0.8g then again, mix, and tabletting gets ordinary tablet.
The preparation of embodiment 5, nilestriol-Benexate Hydrochloride preparation
The method for preparing of the nilestriol of present embodiment-Benexate Hydrochloride preparation is following:
Nilestriol-the Benexate Hydrochloride that obtains in embodiment 1 or 2 is got 4g pulverize, cross 100 mesh sieves, other adjuvant comprises that mannitol 45g and lactose 45g pulverize simultaneously, crosses 100 mesh sieves, then above-mentioned nilestriol-Benexate Hydrochloride and adjuvant is mixed.24 orders are granulated after in said mixture, adding 4% hydroxypropyl emthylcellulose 22ml, and 24 order granulate after 65 ℃ of dryings add magnesium stearate 1g then again, mix, and tabletting gets chewable tablet.
The preparation of embodiment 6, nilestriol-Benexate Hydrochloride preparation
The method for preparing of the nilestriol of present embodiment-Benexate Hydrochloride preparation is following:
Nilestriol-the Benexate Hydrochloride that obtains in embodiment 1 or 2 is got 4g to be pulverized; Cross 100 mesh sieves; Other adjuvant comprises that lactose 35g, starch 20g, citric acid 18g and sodium bicarbonate 22g pulverize simultaneously; Cross 100 mesh sieves, then above-mentioned nilestriol-Benexate Hydrochloride and adjuvant are mixed.In said mixture, add 2% polyvinyl pyrrolidone 18g, through fluidized bed granulation, add magnesium stearate 0.6g then, mix, tabletting gets effervescent tablet.
The present invention utilizes the clathration of beta-schardinger dextrin-, and the nilestriol enclose that is insoluble in water is gone into beta-schardinger dextrin-, through detecting the water-soluble that has improved nilestriol well, makes nilestriol dissolubility in the water in the time of 20 ℃ improve more than 50 times.Because the raising of drug solubility adopts this technological preparation to help absorption by human body, increase curative effect.
Should be pointed out that the present invention has only carried out concrete introduction to certain preferred embodiment, protection scope of the present invention includes, but are not limited to cited numerical range and preferred version.Any modification and variation that meets aim of the present invention all allows.
Claims (12)
1. a nilestriol-Benexate Hydrochloride is characterized in that, said clathrate comprises nilestriol and beta-schardinger dextrin-.
2. clathrate as claimed in claim 1 is characterized in that, the mol ratio of said nilestriol and beta-schardinger dextrin-is 1: 1.
3. the method for preparing of the clathrate described in claim 1 or 2 is characterized in that may further comprise the steps:
A) nilestriol is dissolved in the organic solvent, simultaneously, beta-schardinger dextrin-is dissolved in the water;
B) above-mentioned nilestriol solution and beta-schardinger dextrin-solution are mixed, stir;
C) drying;
D) acetone rinsing, drying under reduced pressure.
4. method for preparing as claimed in claim 3 is characterized in that, said organic solvent is chloroform, dichloromethane, acetone, methanol, ethanol or above any several kinds mixed solvent.
5. method for preparing as claimed in claim 3 is characterized in that, said steps A) in, said nilestriol be through ultrasonic dissolution in organic solvent.
6. method for preparing as claimed in claim 3 is characterized in that, said steps A) in, said beta-schardinger dextrin-be through ultrasonic or stirring and dissolving in water.
7. method for preparing as claimed in claim 3 is characterized in that, said step B) in, the time of said stirring is 0.5～24 hour.
8. method for preparing as claimed in claim 3 is characterized in that, said step C) be lyophilization or spray drying.
9. nilestriol-Benexate Hydrochloride preparation is characterized in that said preparation comprises nilestriol-Benexate Hydrochloride as claimed in claim 1 and adjuvant.
10. preparation as claimed in claim 9; It is characterized in that said adjuvant comprises any two or more adjuvant in starch, lactose, sucrose, mannitol, citric acid, sodium bicarbonate, polyvinyl pyrrolidone, hydroxypropyl emthylcellulose, cross-linking sodium carboxymethyl cellulose, magnesium stearate, the micropowder silica gel.
11. preparation as claimed in claim 9 is characterized in that, said preparation is an oral solid formulation.
12. preparation as claimed in claim 11 is characterized in that, said oral solid formulation comprises ordinary tablet, dispersible tablet, chewable tablet, effervescent tablet, capsule.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2011104527354A CN102512688A (en) | 2011-12-29 | 2011-12-29 | Nilestriol-beta-cyclodextrin inclusion compound and preparation method thereof |
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| CN2011104527354A CN102512688A (en) | 2011-12-29 | 2011-12-29 | Nilestriol-beta-cyclodextrin inclusion compound and preparation method thereof |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1482921A (en) * | 2000-12-20 | 2004-03-17 | ���ֹɷݹ�˾ | Compositions of estrogen-cyclodextrin complexes |
| CN101116666A (en) * | 2000-12-20 | 2008-02-06 | 舍林股份公司 | Compositions of estrogen-cyclodextrin complexes |
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- 2011-12-29 CN CN2011104527354A patent/CN102512688A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1482921A (en) * | 2000-12-20 | 2004-03-17 | ���ֹɷݹ�˾ | Compositions of estrogen-cyclodextrin complexes |
| CN101116666A (en) * | 2000-12-20 | 2008-02-06 | 舍林股份公司 | Compositions of estrogen-cyclodextrin complexes |
Non-Patent Citations (1)
| Title |
|---|
| 关洪亮等: "尼尔雌醇的荧光光谱法研究和应用", 《分析试验室》, vol. 25, no. 1, 31 January 2006 (2006-01-31), pages 20 - 22 * |
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Application publication date: 20120627 |