CN104971050A - Freeze-dried powder injection of tropisetron hydrochloride composition serving as vomit-stopping drug and preparation method of freeze-dried powder injection - Google Patents
Freeze-dried powder injection of tropisetron hydrochloride composition serving as vomit-stopping drug and preparation method of freeze-dried powder injection Download PDFInfo
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- CN104971050A CN104971050A CN201510470610.2A CN201510470610A CN104971050A CN 104971050 A CN104971050 A CN 104971050A CN 201510470610 A CN201510470610 A CN 201510470610A CN 104971050 A CN104971050 A CN 104971050A
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Abstract
The invention relates to a freeze-dried powder injection of a tropisetron hydrochloride composition serving as a vomit-stopping drug and a preparation method of the freeze-dried powder injection, belonging to the technical field of medicines. The composition comprises tropisetron hydrochloride and an excipient, wherein the excipient is trehalose, and the tropisetron hydrochloride is a compound in a novel crystal form; an x-ray powder diffraction diagram obtained through Cu-K alpha ray measurement is as shown in the figure 1; the tropisetron hydrochloride is different from the tropisetron hydrochloride reported by the prior art. Experiments prove that the compound in the novel crystal form is high in purity, good in flowability and stability, low in impurity content, low in moisture absorption possibility as well as safe and reliable in clinical application; and the freeze-dried powder injection prepared from the compound in the novel crystal form is good in stability after being matched with a solvent, extremely low in insoluble particle content and very suitable for clinical application.
Description
Technical field
The invention belongs to medical art, relate to the agent of a kind of antiemetic Navoban (Soz) composite freeze-dried powder.
Background technology
Navoban (Soz) is selectivity peripheral neurons and central nervous system's 5-hydroxytryptamine receptor antagonist, can selectively block vomiting reflex maincenter, the excitement of peripheral neurons presynaptic 5-seretonine receptor 5, act on 5-seretonine receptor 5 of the vagal activity importing nervus centralis area postrema into, can the nausea and vomiting that caused by chemotherapy of Prevention and Curation, do not cause extrapyramidal system untoward reaction.
In prior art, for the crystal formation of Navoban (Soz), had many research, but the hygroscopicity of impurity content, stability and crystal formation is still undesirable, brings difficulty also to while have impact on self stability the preparation of preparation.
The present invention is through a large amount of experimental studies, and obtained a kind of Navoban (Soz) crystalline compounds being different from prior art, the purity of this Tropiseiron hydrochloride compound is high, good fluidity, good stability, not easily moisture absorption, impurity content is low, preparation for preparation brings conveniently, and clinical practice is safe and reliable, utilizes the lyophilized injectable powder that this crystal compound is obtained, good stability, good with solvent compatibility rear stability, particulate matter content is extremely low, is very suitable for clinical practice.
Summary of the invention
Goal of the invention of the present invention is to provide the agent of a kind of antiemetic Navoban (Soz) composite freeze-dried powder.
In order to complete object of the present invention, the technical scheme of employing is:
The present invention relates to the agent of a kind of antiemetic Navoban (Soz) composite freeze-dried powder, comprise Navoban (Soz) and excipient, described Navoban (Soz) is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.
As preferably, with parts by weight, described compositions is made up of the Navoban (Soz) of 1-3 weight portion, the excipient of 15-21 weight portion.
As preferably, with parts by weight, described compositions is made up of the Navoban (Soz) of 3 weight portions, the excipient of 18 weight portions.
As preferably, the preparation method of described compositions comprises the following steps:
Get Tropiseiron hydrochloride compound of the present invention, use water for injection stirring and dissolving, add the excipient of recipe quantity, adjust ph, be then stirred to pH constant after, mend inject water to 100 times that liquor capacity is Navoban (Soz) weight, then active carbon coarse filtration is used, successively through 1.0 μm, 0.45 μm, the microporous filter membrane aseptic filtration of 0.22 μm, filter into sterilizing room, measure pH and content qualified after, fill, pressure half plug, put into the freeze drying box being cooled to-40 DEG C, frozen drying, tamponade outlet, rolls lid.
As preferably, described excipient is trehalose.
As preferably, described lyophilization is:
Pre-freeze: by point medicinal liquid installed in-40 DEG C of insulation lyophilizing 5 hours;
Distillation: medicinal liquid good for pre-freeze is carried out evacuation ,-20 DEG C are incubated lyophilizing 18 hours;
Dry: the sample after distillation being terminated is warming up to 30 DEG C, heat preservation and dryness 3 hours.
As preferably, described adjustment pH is 6.0-8.0.
The preparation method of the Navoban (Soz) crystal in the present composition comprises the following steps:
(1) ground by Navoban (Soz) crude product, cross 60 mesh sieves, then joining volume is in the deionized water of 6 times of Navoban (Soz) weight, and 130 revs/min are stirred 10 minutes;
Add the ethanol that volume is 4 times of Navoban (Soz) weight under (2) 90 revs/min of stirrings, be warming up to 30 DEG C simultaneously;
(3) after solution adds, leave standstill 3 hours, the volume dripping 0 DEG C under 150 revs/min of conditions stirred is 8 times of ether of Navoban (Soz) weight, the mixed solution of chloroform, and the volume ratio of ether, chloroform is at the uniform velocity dropwise in 2:3,2h;
(4) be cooled to-5 DEG C after being added dropwise to complete, continue to stir 2h under the stir speed (S.S.) of 110 revs/min, leave standstill 1h crystallize out, filter, washing, vacuum drying obtains Navoban (Soz) crystal.
Below technical scheme of the present invention is made further explanation:
The present invention is by the precise controlling to crystallization condition, and prepared a kind of Navoban (Soz) novel crystal forms unlike the prior art, the X-ray powder diffraction pattern of this Navoban (Soz) crystal unlike the prior art.Simultaneously due to the ins and outs of this crystal formation, find through test, this crystal compound purity is high, good fluidity, good stability, impurity content is low, not easily moisture absorption, clinical practice is safe and reliable, utilize the lyophilized injectable powder that this crystal compound is obtained, good stability, good with solvent compatibility rear stability, particulate matter content is extremely low, is very suitable for clinical practice.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction that the Navoban (Soz) crystal of the embodiment of the present invention 1 preparation uses the measurement of Cu-K alpha ray to obtain.
Detailed description of the invention
Below by specific embodiment, summary of the invention of the present invention is described in further detail, but does not therefore limit content of the present invention.
embodiment 1:the preparation of Navoban (Soz) crystal
(1) ground by Navoban (Soz) crude product, cross 60 mesh sieves, then joining volume is in the deionized water of 6 times of Navoban (Soz) weight, and 130 revs/min are stirred 10 minutes;
Add the ethanol that volume is 4 times of Navoban (Soz) weight under (2) 90 revs/min of stirrings, be warming up to 30 DEG C simultaneously;
(3) after solution adds, leave standstill 3 hours, the volume dripping 0 DEG C under 150 revs/min of conditions stirred is 8 times of ether of Navoban (Soz) weight, the mixed solution of chloroform, and the volume ratio of ether, chloroform is at the uniform velocity dropwise in 2:3,2h;
(4) be cooled to-5 DEG C after being added dropwise to complete, continue to stir 2h under the stir speed (S.S.) of 110 revs/min, leave standstill 1h crystallize out, filter, washing, vacuum drying obtains Navoban (Soz) crystal.
The X-ray powder diffraction pattern that the Navoban (Soz) crystal prepared uses the measurement of Cu-K alpha ray to obtain as shown in Figure 1.
embodiment 2:the preparation of Navoban (Soz) lyophilized injectable powder:
Prescription: with parts by weight, the Navoban (Soz) crystal-form compound 3 parts that embodiment 1 is obtained, trehalose 15 parts.
Get Tropiseiron hydrochloride compound of the present invention, use water for injection stirring and dissolving, add the trehalose of recipe quantity, adjust ph is 6.0-8.0, be then stirred to pH constant after, mend inject water to 100 times that liquor capacity is Navoban (Soz) weight, then active carbon coarse filtration is used, successively through 1.0 μm, 0.45 μm, the microporous filter membrane aseptic filtration of 0.22 μm, filter into sterilizing room, measure pH and content qualified after, fill, pressure half plug, put into the freeze drying box being cooled to-40 DEG C, frozen drying, tamponade outlet, rolls lid.
Described lyophilization is:
Pre-freeze: by point medicinal liquid installed in-40 DEG C of insulation lyophilizing 5 hours;
Distillation: medicinal liquid good for pre-freeze is carried out evacuation ,-20 DEG C are incubated lyophilizing 18 hours;
Dry: the sample after distillation being terminated is warming up to 30 DEG C, heat preservation and dryness 3 hours.
embodiment 3:the preparation of Navoban (Soz) lyophilized injectable powder:
Prescription: with parts by weight, the Navoban (Soz) crystal-form compound 3 parts that embodiment 1 is obtained, trehalose 18 parts.
Get Tropiseiron hydrochloride compound of the present invention, use water for injection stirring and dissolving, add the trehalose of recipe quantity, adjust ph is 6.0-8.0, be then stirred to pH constant after, mend inject water to 100 times that liquor capacity is Navoban (Soz) weight, then active carbon coarse filtration is used, successively through 1.0 μm, 0.45 μm, the microporous filter membrane aseptic filtration of 0.22 μm, filter into sterilizing room, measure pH and content qualified after, fill, pressure half plug, put into the freeze drying box being cooled to-40 DEG C, frozen drying, tamponade outlet, rolls lid.
Described lyophilization is:
Pre-freeze: by point medicinal liquid installed in-40 DEG C of insulation lyophilizing 5 hours;
Distillation: medicinal liquid good for pre-freeze is carried out evacuation ,-20 DEG C are incubated lyophilizing 18 hours;
Dry: the sample after distillation being terminated is warming up to 30 DEG C, heat preservation and dryness 3 hours.
embodiment 4:the preparation of Navoban (Soz) lyophilized injectable powder:
Prescription: with parts by weight, the Navoban (Soz) crystal-form compound 3 parts that embodiment 1 is obtained, trehalose 21 parts.
Get Tropiseiron hydrochloride compound of the present invention, use water for injection stirring and dissolving, add the trehalose of recipe quantity, adjust ph is 6.0-8.0, be then stirred to pH constant after, mend inject water to 100 times that liquor capacity is Navoban (Soz) weight, then active carbon coarse filtration is used, successively through 1.0 μm, 0.45 μm, the microporous filter membrane aseptic filtration of 0.22 μm, filter into sterilizing room, measure pH and content qualified after, fill, pressure half plug, put into the freeze drying box being cooled to-40 DEG C, frozen drying, tamponade outlet, rolls lid.
Described lyophilization is:
Pre-freeze: by point medicinal liquid installed in-40 DEG C of insulation lyophilizing 5 hours;
Distillation: medicinal liquid good for pre-freeze is carried out evacuation ,-20 DEG C are incubated lyophilizing 18 hours;
Dry: the sample after distillation being terminated is warming up to 30 DEG C, heat preservation and dryness 3 hours.
experimental example 1: fluidity test
The mobility of this experimental example to the Navoban (Soz) crystal that the embodiment of the present invention 1 obtains detects.
Method: according to the embodiment of the present invention 1 method continuous production 6 batches of Navoban (Soz)s (batch: 1,2,3,4,5 and 6), sample from 6 batches of obtained Navoban (Soz)s respectively, adopt fixed funnel method, funnel is placed in the suitable height on graph paper, Navoban (Soz) crystal is freely flowed down from bell mouth, until the cone top formed contacts with bell mouth, measure hypotenuse and the horizontal angle (θ angle of repose) of Navoban (Soz) accumulation horizon.The results are shown in Table 1:
The fluidity test result of table 1 Navoban (Soz)
From the interpretation of table 1, the mobility of Navoban (Soz) crystal of the present invention is fine.
experimental example 2: influence factor tests
1, hot test
The Navoban (Soz) crystalline compounds that Example 1 prepares, simulation listing packaging, puts in sealing clean container, place 10 days at 40 ± 2 DEG C of temperature, in the 5th day and sampling in the 10th day, detect by stability high spot reviews project, result of the test compared with 0 day.
2, high humility test
The Navoban (Soz) crystalline compounds that Example 1 prepares, simulation listing packaging, put in sealing clean container, place 10 days under the condition of 25 ± 2 DEG C of relative humiditys 90% ± 5%, in the 5th day and sampling in the 10th day, detect by stability high spot reviews project, result of the test compared with 0 day.
3, strong illumination test
The Navoban (Soz) crystalline compounds that Example 1 prepares, simulation listing packaging, puts in sealing clean container, being placed in illumination is place 10 days under the condition of 4500lx, in the 5th day and sampling in the 10th day, detect by stability high spot reviews project, result compared with 0 day.The results are shown in Table 2
Table 2 influence factor result of the test
Result shows: the Navoban (Soz) crystalline compounds that the present invention prepares, and its stability is good, and under high temperature, high humidity, high light conditions, equal retention is stablized.
experimental example 3: Acceleration study
The Navoban (Soz) crystalline compounds that Example 1 prepares 3 batches and marketable material, simulation listing packaging, put in sealing clean container, in 40 DEG C ± 2 DEG C, place 6 months under relative humidity 70% ± 5% condition, at duration of test respectively at 1,2,3,6 sampling at the end of month once, each stability high spot reviews project is tested.The results are shown in Table 3.
Table 3 accelerated test result
Result shows: the Navoban (Soz) crystalline compounds that the present invention prepares, known through accelerated test result, its good stability, and total assorted content is low.
experimental example 4: wettability test
1 instrument
PL203 electronic balance, LRH-250-S constant temperature and humidity incubator, HH-400SD testing chamber for medicine stability;
2 methods
Get the glass desicator (for ensureing that saline solution is saturated, excessive salt should be had bottom exsiccator to exist) that bottom fills salt supersaturated solution, the built-in weighing botle of exsiccator, places 48h to constant humidity in calorstat.The Navoban (Soz) crystalline compounds that Example 1 prepares and each 2g of marketable material, put in weighing botle, accurately weighed, bottle cap is opened, put into exsiccator top, put in 25 DEG C of constant temperature and humidity incubators or 20 DEG C of stability test casees by different temperatures requirement and preserve, operation repetitive 3 parts, weigh respectively at different time, calculate the hydroscopicity of different time.
Computing formula:
result is as table 4:
Table 4 hygroscopicity test results
According to above-mentioned experiment, the hygroscopicity of Navoban (Soz) crystalline compounds prepared by the present invention is low, good stability.
Claims (8)
1. an antiemetic Navoban (Soz) composite freeze-dried powder agent, comprises Navoban (Soz) and excipient, it is characterized in that: described Navoban (Soz) is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.
2. antiemetic Navoban (Soz) composite freeze-dried powder according to claim 1 agent, is characterized in that: with parts by weight, is made up of the Navoban (Soz) of 1-3 weight portion, the excipient of 15-21 weight portion.
3. antiemetic Navoban (Soz) composite freeze-dried powder according to claim 2 agent, is characterized in that: with parts by weight, is made up of the Navoban (Soz) of 3 weight portions, the excipient of 18 weight portions.
4., according to the arbitrary described antiemetic Navoban (Soz) composite freeze-dried powder agent of claim 1-3, it is characterized in that, described excipient is trehalose.
5. prepare a method for the arbitrary described antiemetic Navoban (Soz) composite freeze-dried powder agent of claim 1-3, it is characterized in that comprising the following steps:
Get Tropiseiron hydrochloride compound of the present invention, use water for injection stirring and dissolving, add the excipient of recipe quantity, adjust ph, be then stirred to pH constant after, mend inject water to 100 times that liquor capacity is Navoban (Soz) weight, then active carbon coarse filtration is used, successively through 1.0 μm, 0.45 μm, the microporous filter membrane aseptic filtration of 0.22 μm, filter into sterilizing room, measure pH and content qualified after, fill, pressure half plug, put into the freeze drying box being cooled to-40 DEG C, frozen drying, tamponade outlet, rolls lid.
6. the preparation method of antiemetic Navoban (Soz) composite freeze-dried powder according to claim 5 agent, it is characterized in that, described lyophilization is:
Pre-freeze: by point medicinal liquid installed in-40 DEG C of insulation lyophilizing 5 hours;
Distillation: medicinal liquid good for pre-freeze is carried out evacuation ,-20 DEG C are incubated lyophilizing 18 hours;
Dry: the sample after distillation being terminated is warming up to 30 DEG C, heat preservation and dryness 3 hours.
7. the preparation method of antiemetic Navoban (Soz) composite freeze-dried powder according to claim 5 agent, is characterized in that: described adjustment pH is 6.0-8.0.
8. antiemetic Navoban (Soz) composite freeze-dried powder according to claim 1 agent, it is characterized in that, the preparation method of the crystal of described Navoban (Soz) comprises the following steps:
(1) ground by Navoban (Soz) crude product, cross 60 mesh sieves, then joining volume is in the deionized water of 6 times of Navoban (Soz) weight, and 130 revs/min are stirred 10 minutes;
Add the ethanol that volume is 4 times of Navoban (Soz) weight under (2) 90 revs/min of stirrings, be warming up to 30 DEG C simultaneously;
(3) after solution adds, leave standstill 3 hours, the volume dripping 0 DEG C under 150 revs/min of conditions stirred is 8 times of ether of Navoban (Soz) weight, the mixed solution of chloroform, and the volume ratio of ether, chloroform is at the uniform velocity dropwise in 2:3,2h;
(4) be cooled to-5 DEG C after being added dropwise to complete, continue to stir 2h under the stir speed (S.S.) of 110 revs/min, leave standstill 1h crystallize out, filter, washing, vacuum drying obtains Navoban (Soz) crystal.
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|---|---|---|---|
| CN201510470610.2A CN104971050A (en) | 2015-08-05 | 2015-08-05 | Freeze-dried powder injection of tropisetron hydrochloride composition serving as vomit-stopping drug and preparation method of freeze-dried powder injection |
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| CN201510470610.2A CN104971050A (en) | 2015-08-05 | 2015-08-05 | Freeze-dried powder injection of tropisetron hydrochloride composition serving as vomit-stopping drug and preparation method of freeze-dried powder injection |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000048581A2 (en) * | 1999-02-18 | 2000-08-24 | Novartis Ag | Use of 5-ht3 receptor antagonists for treating musculoeskeletal diseases |
| WO2001062257A2 (en) * | 2000-02-22 | 2001-08-30 | Sepracor Inc. | Bupropion metabolites and methods of their synthesis and use |
| CN101838266A (en) * | 2009-02-17 | 2010-09-22 | 回音必集团抚州制药有限公司 | Citric acid tropisetron raw material medicine and preparation technology of raw material medicine and injection liquid |
| CN103073542A (en) * | 2013-01-25 | 2013-05-01 | 回音必集团抚州制药有限公司 | Preparation method and application of tropisetron citrate crystal form II |
| CN103360386A (en) * | 2013-07-18 | 2013-10-23 | 珠海金鸿药业股份有限公司 | Tropisetron hydrochloride compound, its preparation method, and pharmaceutical composition containing the same |
-
2015
- 2015-08-05 CN CN201510470610.2A patent/CN104971050A/en not_active Withdrawn
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000048581A2 (en) * | 1999-02-18 | 2000-08-24 | Novartis Ag | Use of 5-ht3 receptor antagonists for treating musculoeskeletal diseases |
| WO2001062257A2 (en) * | 2000-02-22 | 2001-08-30 | Sepracor Inc. | Bupropion metabolites and methods of their synthesis and use |
| CN101838266A (en) * | 2009-02-17 | 2010-09-22 | 回音必集团抚州制药有限公司 | Citric acid tropisetron raw material medicine and preparation technology of raw material medicine and injection liquid |
| CN103073542A (en) * | 2013-01-25 | 2013-05-01 | 回音必集团抚州制药有限公司 | Preparation method and application of tropisetron citrate crystal form II |
| CN103360386A (en) * | 2013-07-18 | 2013-10-23 | 珠海金鸿药业股份有限公司 | Tropisetron hydrochloride compound, its preparation method, and pharmaceutical composition containing the same |
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Application publication date: 20151014 |