CN102351857B - Tropiseiron hydrochloride compound - Google Patents
Tropiseiron hydrochloride compound Download PDFInfo
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- CN102351857B CN102351857B CN 201110242323 CN201110242323A CN102351857B CN 102351857 B CN102351857 B CN 102351857B CN 201110242323 CN201110242323 CN 201110242323 CN 201110242323 A CN201110242323 A CN 201110242323A CN 102351857 B CN102351857 B CN 102351857B
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- tropisetron
- tropiseiron
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to a tropiseiron hydrochloride compound and a preparation method thereof. The invention also relates to application of an injection containing the tropiseiron hydrochloride compound in preparation of drugs for treating nausea and vomit.
Description
Technical field
The invention belongs to medical technical field, be specifically related to Tropiseiron hydrochloride compound and preparation method thereof, the invention still further relates to the medicine that uses this crystal manufacturing treatment nausea and vomiting.
Background technology
At present, chemotherapy and radiation remains antineoplastic Main Means, but because it can cause nausea, vomit, often causes patient's treatment effectively not carry out.The mechanism that chemotherapy and radiation causes nausea, vomits is because radiotherapy, Chemotherapy in GI mucosal tissue, make the class pheochromocyte of stomach and intestine discharge Dopamine HCL and serotonin (5-HT), these neurotransmitters and 5-HT
3Receptors bind acts on vomiting center by neural reflex and causes nausea, vomits.Therefore 5-HT is nauseant important chemical mediator, its basic structure is indole ring.Studies show that tropisetron and 5-HT
3The avidity of acceptor is the strongest, can the utmost point effectively competes the 5-HT of periphery and maincenter
3Acceptor, thus the neural reflex of blocking-up vomiting has and can optionally block 5-HT
3The effect of acceptor.Single dose administration, lasting medicine, reusable in each radiotherapy, chemotherapy treatment without tolerance, there is no the extrapyramidal symptoms.Adopt recommended dose, can be used safely in old age, liver, renal insufficiency patient and children more than two years old.Tropisetron has injection and two kinds of formulations of capsule, oral almost completely absorption (〉 95%), the blood medicine peaking time is 3 hours.Absolute bioavailability depends on dosage, when dosage is 5 mg, is the 6O% left and right.It eliminates the transformation period oral is 8.6-41.9 hour, and quiet notes are 7.3-30.3 hour.Discharge through urine or bile, metabolite through the ratio of urine and excrement discharge be 5:1 therefore, administration every day 1 time can be kept curative effect for 24 hours.Chemotherapy the 1st day, half an hour before the chemotherapeutics infusion, vein 5 mg that slowly instil, just can well control nauseating, vomit.The few side effects of tropisetron only has individually one to cross headache or constipation, fatigue and gastrointestinal dysfunction, and these symptoms do not affect the continuation of medicine and use.
Tropisetron hydrochloride (tropisetron hydrochloride) is an antiemetic new drug, is the indolecarboxylic acid derivative, and structural formula is as follows:
The Tropisetron hydrochloride structural formula
Tropisetron hydrochloride is developed by Novartis Co.,Ltd, and commodity were called Navoban (trepisetron), were a kind of highly selective serotonin 3 (5 one HT in Holland's listing in 1992
3) receptor antagonist, be applicable to prevent and treat the nausea and vomiting that children and adult's cancer chemotherapy, radiotherapy and operation cause afterwards, now in the listing of global dozens of country.With similar drugs relatively, it is little that this product has a determined curative effect, better tolerance, side reaction, and the advantage such as easy to use.Tropisetron hydrochloride is used widely in big-and-middle-sized hospital.
Tropisetron hydrochloride has multiple preparation method, and because preparation method especially process for purification is different, purity is also different.
In research process, repeat the method for document, the Tropisetron hydrochloride impurity number that obtains is more, and total impurities is higher, and the Tropisetron hydrochloride that makes moisture absorption weightening finish under high humidity is obvious.The Tropisetron hydrochloride that the present invention obtains has advantages of: purity is high, and maximum contaminant is less than 1 ‰; Good stability is even the moisture absorption weightening finish is also not obvious under high humidity.
Summary of the invention
One object of the present invention discloses a kind of Tropiseiron hydrochloride compound.
Another object of the present invention discloses the preparation method of Tropiseiron hydrochloride compound.
Another purpose of the present invention discloses the pharmaceutical composition that comprises Tropiseiron hydrochloride compound.
The invention also discloses the application of Tropisetron hydrochloride crystal in making treatment nausea and vomiting medicine.
Now in conjunction with purpose of the present invention, content of the present invention is specifically described.
The invention provides a kind of Tropisetron hydrochloride (shown in the formula I) compound,
This Tropisetron hydrochloride crystal adopts D/Max-2500.9161 type x-ray diffractometer to measure, condition determination: Cu Ka target, tube voltage 40KV, tube current 100mA.X-ray powder diffraction charateristic avsorption band (2 θ) and D value are as follows,
| The |
2 θ (degree) | Spacing (d) | I/ |
| 1 | 19.140 | 4.6332 | 100 |
| 2 | 23.220 | 3.8275 | 2 |
| 3 | 28.120 | 3.1707 | 8 |
| 4 | 29.100 | 3.0661 | 11 |
| 5 | 32.200 | 2.7776 | 16 |
| 6 | 33.960 | 2.6376 | 79 |
| 7 | 38.720 | 2.3236 | 45 |
| 8 | 40.880 | 2.2057 | 1 |
| 9 | 47.400 | 1.9164 | 1 |
| 10 | 48.120 | 1.8894 | 2 |
| 11 | 48.860 | 1.8625 | 11 |
| 12 | 49.520 | 1.8392 | 1 |
See Fig. 1.
[0012]?
In the present invention, the mensuration of 2 θ values is used light source, and precision is ± 0.2 °, represents that therefore above-mentioned value of getting has allowed certain reasonably limit of error, and its limit of error is ± 0.2 °.
Fusing point test: measure fusing point according to Pharmacopoeia of People's Republic of China (2010 editions, two ones) appendix VI C first method, the fusing point that records is 280.1 ℃-281.1 ℃.
Another object of the present invention discloses the preparation method of Tropisetron hydrochloride crystal, by with Tropisetron hydrochloride in acetone-heated in water solution dissolving, naturally cool to room temperature, then be incubated for some time and obtain.
It is characterized in that comprising the following steps: that Tropisetron hydrochloride adds in the mixed solution of 6-9 times of (weight or measurement (WM) ratio) acetone-water=9-6:1-4, be heated to 60 ℃-65 ℃, be incubated 30 minutes, filtered while hot, naturally cool to room temperature, then be incubated 1-3 hour, crystallization, filter, drying obtains the above-mentioned Tropisetron hydrochloride crystal of high purity.
The method good reproducibility is amplified to pilot scale, and content and crystal formation all can fine reproductions.
Tropisetron hydrochloride used, synthetic according to the method that document US4789673 (1988) provides, the chemical structure of synthetic Tropisetron hydrochloride is correct through nuclear magnetic resonance spectrum, ultimate analysis proof chemical structure.
Another purpose of the present invention provides the composition that comprises the Tropisetron hydrochloride that Tropisetron hydrochloride crystal and one or more pharmaceutically acceptable carriers form.
Pharmaceutical composition of the present invention is prepared as follows: Application standard and conventional technology; crystal of the present invention acceptable liquid vehicle on technology of pharmaceutics is combined, and makes it at random on technology of pharmaceutics acceptable auxiliary and vehicle and be combined and be prepared into particulate or microballoon.Said composition is for the preparation of injection.
The amount of the active ingredient that contains in pharmaceutical composition and unit dosage form (crystal of the present invention) can specifically be applied according to patient's the state of an illness, the situation of diagnosis, the amount of compound used or concentration are regulated in a wider scope, and the weight range of active compound is 1%～30%(weight of composition).
The present invention also provides the application of Tropisetron hydrochloride crystal in making treatment nausea and vomiting medicine.
Through mouse test, the crystal that the Tropisetron hydrochloride crystal that the present invention obtains and document US4789673 (1988) obtain (fusing point: 283 ℃-285 ℃) toxicity is suitable; Through the test of animal (pigeon) antiemetic, the crystal that the Tropisetron hydrochloride crystal that the present invention obtains and document US4789673 (1988) obtain (fusing point: 283 ℃-285 ℃) equivalence.
Stability test
The contriver is studied the chemical stability of crystal formation of the present invention, and the investigation condition is high temperature (60 ℃ ± 2 ℃), (4500Lx ± 500lx), (92.5%, RH) investigate index is outward appearance to high humidity to strong illumination, content and related substance.
Result: under high light, high temperature, super-humid conditions from 0-10 days, outward appearance, related substance, content do not change, and illustrates that chemical stability is good, manufacturing and the standing storage of suitable pharmaceutical preparation.
At 40 ℃, under different relative humidity (RH) conditions (75%, 92.5%), the mensuration of moisture in the Tropisetron hydrochloride crystal that document US4789673 (1988) obtains:
Result: at 40 ℃, under different relative humidity (RH) conditions (75%, 92.5%), the Tropisetron hydrochloride crystal that document US4789673 (1988) obtains has the moisture absorption weightening finish.
Figure of description:
Fig. 1, the X-ray diffractogram of Tropiseiron hydrochloride compound;
Fig. 2, the IR figure of Tropiseiron hydrochloride compound;
Embodiment:
The present invention is described further below in conjunction with embodiment, makes this area professional and technical personnel better understand the present invention.Embodiment is only indicative, means that never it limits the scope of the invention by any way.
Tropisetron hydrochloride (tropisetron hydrochloride) used in the present invention is synthetic according to the method that document US4789673 (1988) provides, crude product is made with extra care 1 time with dehydrated alcohol or 95% ethanol, get white crystals, fusing point: 283 ℃-285 ℃, purity 99.56% (HPLC normalization method); Make with extra care 1 time with dehydrated alcohol or 95% ethanol, get white crystals, although fusing point is still 283 ℃-285 ℃, purity is increased to 99.92% (HPLC normalization method).Its chemical structure is through nuclear magnetic resonance spectrum, ultimate analysis conclusive evidence.
Wherein results of elemental analyses is as follows:
Measured value (calculated value), C:63.64 (63.55), H:6.60 (6.63), N:8.73 (8.81),
Cl:11.05(11.11)；
The proof chemical structure is correct.
The moisture that records with the karl Fischer method is 0.28%.
In the 1000ml reaction flask of stirring, thermometer, condenser is housed, add acetone-water (8:2) mixed solution of 80 gram Tropisetron hydrochlorides (1 highly finished product) and 560ml, start stirring, be heated to 60 ℃-65 ℃, treat all molten clearly, be incubated 30 minutes, filtered while hot.Filtrate naturally cools to room temperature, then is incubated 2 hours, and crystallization filters, and drying namely gets high-purity hydrochloric acid tropisetron crystal, fusing point: 280.1 ℃-281.1 ℃, and purity 99.96% (HPLC normalization method), dissolvent residual detects and meets the requirements.
Results of elemental analyses:
Measured value (calculated value), C:63.64 (63.57), H:6.60 (6.62), N:8.73 (8.72),
Cl:11.05(11.01)；
The X-ray diffractogram of this crystallization is seen Fig. 1.Instrument model and condition determination: Rigaku D/max 2500 type diffractometers; CuKa 40Kv 100mA; 2 θ sweep limit: 0-50
°
The infrared spectrogram of this crystallization is seen Fig. 2, uses the KBr compressing tablet during mensuration.
Application standard, routine techniques preparation contain the injection liquid of Tropiseiron hydrochloride compound of the present invention, specification:
5mg/5ml/ props up.
Claims (6)
1. lead to the Tropiseiron hydrochloride compound of formula I,
（Ⅰ）
It is characterized in that: in measuring as the characteristic X-ray powder with the CuKa ray, its collection of illustrative plates as shown in Figure 1.
2. the preparation method of the described Tropiseiron hydrochloride compound of claim 1, by with Tropisetron hydrochloride in acetone-heated in water solution dissolving, naturally cool to room temperature, then be incubated for some time and obtain.
3. according to claim 2 method, it is characterized in that comprising the following steps: that Tropisetron hydrochloride adds in the mixed solution of 6-9 times of acetone-water=9-6:1-4, be heated to 60 ℃-65 ℃, be incubated 30 minutes, filtered while hot naturally cools to room temperature, be incubated again 1-3 hour, crystallization filters, and drying obtains.
4. one kind contains the composition that the described Tropiseiron hydrochloride compound of claim 1 and one or more pharmaceutically acceptable carriers form.
5. composition claimed in claim 4, is characterized in that said composition is for the preparation of injection.
6. the application of the described Tropisetron hydrochloride of claim 1 in making treatment nausea and vomiting medicine.
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| CN 201110242323 CN102351857B (en) | 2011-08-23 | 2011-08-23 | Tropiseiron hydrochloride compound |
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| CN 201110242323 CN102351857B (en) | 2011-08-23 | 2011-08-23 | Tropiseiron hydrochloride compound |
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| CN102351857B true CN102351857B (en) | 2013-06-12 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104844591A (en) * | 2014-02-17 | 2015-08-19 | 中国医学科学院药物研究所 | Tropisetron hydrochloride crystal form II substance, preparation method, composition and uses thereof |
| CN104844592A (en) * | 2014-02-17 | 2015-08-19 | 中国医学科学院药物研究所 | Tropisetron hydrochloride crystal form III substance, preparation method, composition and uses thereof |
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| CN102367252A (en) * | 2011-11-03 | 2012-03-07 | 天津市汉康医药生物技术有限公司 | Tropisetron hydrochloride compound |
| CN103073542B (en) * | 2013-01-25 | 2015-06-10 | 回音必集团抚州制药有限公司 | Preparation method and application of tropisetron citrate crystal form II |
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| CN105055416A (en) * | 2015-08-10 | 2015-11-18 | 青岛蓝盛洋医药生物科技有限责任公司 | Postoperative antemetic tropisetron hydrochloride composition freeze-dried powder injection |
| CN104997779A (en) * | 2015-08-18 | 2015-10-28 | 青岛蓝盛洋医药生物科技有限责任公司 | Medicine tropisetron hydrochloride composition for treating nausea and vomiting caused by chemotherapy |
| CN105012302A (en) * | 2015-09-01 | 2015-11-04 | 青岛蓝盛洋医药生物科技有限责任公司 | Tropisetron hydrochloride composition for vomit-stopping medicine |
| CN105168212A (en) * | 2015-09-11 | 2015-12-23 | 青岛蓝盛洋医药生物科技有限责任公司 | Medicine tropisetron hydrochloride composition for treating nausea and emesis |
| CN105078916A (en) * | 2015-09-15 | 2015-11-25 | 青岛华之草医药科技有限公司 | Vomit-stopping drug tropisetron hydrochloride composition tablet |
| CN105125518A (en) * | 2015-09-16 | 2015-12-09 | 青岛华之草医药科技有限公司 | Medicinal tropisetron hydrochloride composition capsule for treating nausea and vomiting |
| CN105193737A (en) * | 2015-09-21 | 2015-12-30 | 青岛华之草医药科技有限公司 | Medicinal tropisetron hydrochloride composition dry suspension for treating nausea and emesis |
| CN105106212A (en) * | 2015-09-22 | 2015-12-02 | 青岛华之草医药科技有限公司 | Vomit-stopping drug, namely, tropisetron hydrochloride composition tablets |
| CN105147685A (en) * | 2015-09-29 | 2015-12-16 | 青岛华之草医药科技有限公司 | Tropisetron hydrochloride composition granules serving as postoperative vomit-stopping medicine |
| CN111773129A (en) * | 2020-07-08 | 2020-10-16 | 中国医学科学院整形外科医院 | Application of tropisetron in preparation of daily chemical or medicine for improving skin |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4789673A (en) * | 1982-07-13 | 1988-12-06 | Peter Donatsch | Heterocyclic carboxylic acid amides and esters |
| CN101033225A (en) * | 2007-04-02 | 2007-09-12 | 北京成宇化工有限公司 | Process of preparing troipisetron |
| CN101787021A (en) * | 2010-03-05 | 2010-07-28 | 王明 | High-purified tropisetron hydrochloride compound |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20010112673A (en) * | 2000-06-09 | 2001-12-21 | 김환기 | Preparation of Tropisetron HCl |
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2011
- 2011-08-23 CN CN 201110242323 patent/CN102351857B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4789673A (en) * | 1982-07-13 | 1988-12-06 | Peter Donatsch | Heterocyclic carboxylic acid amides and esters |
| CN101033225A (en) * | 2007-04-02 | 2007-09-12 | 北京成宇化工有限公司 | Process of preparing troipisetron |
| CN101787021A (en) * | 2010-03-05 | 2010-07-28 | 王明 | High-purified tropisetron hydrochloride compound |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104844591A (en) * | 2014-02-17 | 2015-08-19 | 中国医学科学院药物研究所 | Tropisetron hydrochloride crystal form II substance, preparation method, composition and uses thereof |
| CN104844592A (en) * | 2014-02-17 | 2015-08-19 | 中国医学科学院药物研究所 | Tropisetron hydrochloride crystal form III substance, preparation method, composition and uses thereof |
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| CN102351857A (en) | 2012-02-15 |
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