CN103845295A - Palonosetron preparation for injection and preparation method thereof - Google Patents
Palonosetron preparation for injection and preparation method thereof Download PDFInfo
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- CN103845295A CN103845295A CN201210520541.8A CN201210520541A CN103845295A CN 103845295 A CN103845295 A CN 103845295A CN 201210520541 A CN201210520541 A CN 201210520541A CN 103845295 A CN103845295 A CN 103845295A
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- palonosetron
- injection
- mannitol
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to palonosetron hydrochloride freeze-dried powder injection. The invention also relates to preparation of the freeze-dried powder injection. By adding beta-cyclodextrin or hydroxypropyl beta-cyclodextrin and mannitol, the palonosetron preparation has the characteristics of being smooth in surface, delicate, uniform, free of cracks, breakage and adhesion to a bottle, white in color, shaped like a loose piece, good in formation, also good in dissolubility, quite easy to dissolve, clear and transparent in solution and stable in product quality.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of lyophilized formulations of PalonosetronHydrochloride, the nausea and vomiting that it can be used for anti-tumor chemotherapeutic to cause.
Background technology
Along with the raising of chemotherapy status in oncotherapy and the application of more and more new chemotherapeutics, people are also more deep to the understanding of chemotherapy adverse effect.The untoward reaction of chemotherapy can be temporarily or the Long-term Effect patient's quality of life, the dosage of possible limit treatment and the course for the treatment of, serious also entail dangers to life of situation.What chemotherapy caused feels sick, vomits is the untoward reaction that cancer patient is the most frightened, controls deficiency can produce a series of relevant complication to feeling sick, vomitting.Serious feel sick, vomiting can make patient forbidding to later chemotherapy, even occurs being reluctant or abandons the thought of further chemotherapy, makes chemotherapy hard to carry on.Nauseating, the vomiting that chemotherapy causes can be divided into acute reaction, retardance reaction and expection property and react three classes.
The nausea and vomiting of property chemotherapy induction refers to previously in treatment, occur unmanageable patient in advance, before new round treatment cycle starts, nausea and vomiting occurs, and this reaction can appear in approximately 25% patients undergoing chemotherapy.The nausea and vomiting of this type of chemotherapy induction and tumor type and the chemotherapy regimen that is about to carry out have nothing to do, the main cause that psychentonia causes this type of vomiting to occur often.The patient of nausea and vomiting once occurred in previous treatment cycle, and the probability that property chemotherapy induction nausea and vomiting in advance occurs is very high.And once the nausea and vomiting of property chemotherapy induction occurs in advance, existing antiemetic is substantially invalid, therefore, patient is carried out to behavior adjusting and the systematic desensitization, is this type of patient's better treatment means.In addition,, for preventing property nausea and vomiting in advance, effectively control vomiting in chemotherapy, to alleviate patients ' psychological shade most important.
Nauseating, vomiting that chemotherapeutics causes mainly cause digestive tract Mongolia membrane damage to start by these medicines, and especially ileum is eaten the damage of film.All membrane damage causes enteric epithelium to have a liking for inscription cell release 5-HT, irritates and imports vagal 5-HT into
3receptor, the reaction thereby excited vomiting center causes vomiting, or be passed to vomiting center by excited chemoreceptor and cause vomiting.5-HT
35-HT and 5-HT that receptor antagonist mainly discharges by blocking competitively digestive tract Mongolia film
3receptors bind, thus the effect of resisting emesis there is.
5-HT
3receptor antagonist, since 1986, has had nearly 10 kinds of medicines such as ondansetron, granisetron, tropisetron to drop into clinical research and use.5-HT
3receptor antagonist may be by acting on the 5-HT on vagus nerve
3receptor and by acting on the 5-HT in central nervous system (AP) and nucleus solitarius (NTS)
3receptor, suppresses both excitements, and blocking-up, to the afferent impulse of vomiting center, has suppressed vomiting.Utilize all 5-HT of studies confirm that of radioligand
3receptor antagonist all optionally with 5-HT
3receptor combines, and ondansetron, granisetron, tropisetron are directly and 5-HT
3receptor combines, and and 5-HT
1, 5-HT
2, dopamine D 1, D2 receptor, M-ChR and histamine H
1receptor is all without combination.Thereby its side effect incidence rate is low, almost without extrapyramidal system.There are some researches show tropisetron and 5-HT
4receptor has weak adhesion.At present, to various 5-HT
3the clinical experimental study that receptor antagonist carries out has confirmed their relative safety and effectiveness in DDP treatment.This type of clinical drug is used for preventing of acute CINV.
PalonosetronHydrochloride (Palonosetron Hydrochloride) chemistry 2-[(S by name) the pungent a heatable brick bed-3-yl of-1-azabicyclo [2,2,2]]-2,3,3a (S), 4,5,6-, six hydrogen-IH-benzisoquinoline-1-keto hydrochloride.Chemical constitution is:
Molecular formula: C
19h
24n
2oHCl
Molecular weight: 332.87
PalonosetronHydrochloride is the 5-HT that Helsinn Hea1thcare company of Switzerland develops
3receptor antagonist, in JIUYUE, 2003 is at the U.S.'s its injection (aqueous injection) that goes on the market, and trade name is Aloxi
tM, the vomiting reaction while being mainly used in clinically treating cancer chemotherapy, radiotherapy.PalonosetronHydrochloride is a kind of 5-HT of potent, high selectivity
3receptor antagonist, is characterized in 5-HT
3receptor affinity is high, blocking effect is strong, and toxic and side effects is little, and biology declines the phase long (approximately 40h) in vivo, to vomitting than existing other 5-HT period of delay
3receptor antagonist is effective, be a kind of safe, effective, act on lasting antiemetic.
According to the literature, PalonosetronHydrochloride is unstable in aqueous solution, places for a long time, and the hydrolysis of part hydrochlorate separates, and produces insoluble visible foreign matters, affects drug quality, lessens the curative effect, and makes lyophilized preparation so suitable.But the lyophilized formulations dissolubility made from conventional method is general, injecting needs to rock a few minutes after water and could dissolve completely, the convenience that impact is used, and the slightly turbid light of solution, and the safety that impact is used, nor convenient.
The raw material of cyclodextrin inclusion is cyclodextrin, is starch is used by the Bacillus alcalophilus separating in soil, cultivates the alkali starch enzyme hydrolysis that obtains and obtains.Common are α, β, tri-kinds of cyclodextrin of γ, formed by 6,7,8 glucose glycan molecules respectively.Cyclodextrin is the novel material that comprises of current video and medicine.The dissolubility that cyclodextrin inclusion can increase medicine maybe can increase the stability of medicine; Make the property brought into play liquid, solid or oily liquids powdered; Reduce zest and the toxic and side effects of medicine; Cover the biological utilisation of bitterness and raising medicine etc.At present medicinal α, beta cyclodextrin are comparatively conventional, and from increasing drug solubility, α cyclodextrin material is excellent, and packet content beta cyclodextrin is more advantageous.
Summary of the invention
The object of the present invention is to provide a kind of injection palonosetron preparation, preparation main active is: PalonosetronHydrochloride, beta-schardinger dextrin-or HP-β-CD, mannitol, wherein in 0.25mg palonosetron, beta-schardinger dextrin-or HP-β-CD consumption are 0.1～20mg, and the consumption of mannitol is 0.25～25mg.
Preparation main active is in 0.5mg palonosetron, and beta-schardinger dextrin-or HP-β-CD consumption are 0.2～50mg, and the consumption of mannitol is 0.5mg～50mg.
Another object of the present invention has been to provide the preparation method of above-mentioned hydrochloride for injection palonosetron preparation, realize by following steps: first by PalonosetronHydrochloride and beta-schardinger dextrin-or HP-β-CD dissolving, add again mannitol to dissolve, with citric acid-sodium hydrogen phosphate buffer (pH4.0) tune pH, the quick pre-freeze of medicinal liquid after subpackage, then carry out lyophilizing.
In the preparation method of hydrochloride for injection palonosetron of the present invention, first freeze drying box is cooled to-40 DEG C～-50 DEG C, then put into sample, make its quick freezing, time is 100 minutes～150 minutes, and sublimation temperature is-40 DEG C～-10 DEG C, and the time is 15～25 hours, baking temperature is-10 DEG C～30 DEG C, and the time is 5～15 hours.
Hydrochloride for injection palonosetron provided by the present invention, surfacing, fine and smooth homogeneous, not dry and cracked, not damaged, sticky bottle, is the loose block of white, and redissolves well, very easily dissolves solution clear, constant product quality.
The present invention comprises by cyclodextrin and derivant thereof the sample that excipient lyophilizing makes in addition again by PalonosetronHydrochloride, and formability is good, and solubility is good, and product quality is more stable.This product has overcome employing dextran, glucose and lactose as skeleton agent, carry out finding that the surface effect of lyophilized formulations is undesirable after lyophilizing preparation, and solubility is bad, and solution has the weak point of turbid light.
Detailed description of the invention
The present invention is described further in conjunction with specific embodiments.
Embodiment 1
PalonosetronHydrochloride lyophilized formulations described in every 1000 bottles, its formula consists of:
PalonosetronHydrochloride 0.25g
Beta-schardinger dextrin-10g
Mannitol 20g
Water for injection 1L
Preparation technology: 1, take PalonosetronHydrochloride and beta-schardinger dextrin-, add 80% water for injection to stir and make its dissolving, then add mannitol, stir completely and dissolve, with citric acid-disodium hydrogen phosphate buffer (pH4.0) adjust pH 4.0～6.0, benefit adds to the full amount of water for injection, and adds cumulative volume 0.05～0.1%(g/ml) carbon stirring and adsorbing 20 minutes for pin, filter decarburization.
2, with the microporous filter membrane fine straining of 0.22 μ m.
3, the inspection of semifinished product.
4, fill, presses half plug.
5, lyophilizing: first freeze drying box is cooled to-40 DEG C～-50 DEG C, then puts into sample, make its quick freezing, time is 100 minutes～150 minutes, and sublimation temperature is-40 DEG C～-10 DEG C, and the time is 15～25 DEG C hours, baking temperature is-10 DEG C～30 DEG C, and the time is 5～15 hours.
Embodiment 2
PalonosetronHydrochloride lyophilized formulations described in every 1000 bottles, its formula consists of:
PalonosetronHydrochloride 0.25g
HP-β-CD 15g
Mannitol 18g
Water for injection 1L
Preparation technology: 1, take PalonosetronHydrochloride and HP-β-CD, add 80% water for injection to stir and make its dissolving, then add mannitol, stir completely and dissolve, with citric acid-disodium hydrogen phosphate buffer (pH4.0) adjust pH 4.0～6.0, benefit adds to the full amount of water for injection, and adds cumulative volume 0.05～0.1%(g/ml) carbon stirring and adsorbing 20 minutes for pin, filter decarburization.
2, with the microporous filter membrane fine straining of 0.22 μ m.
3, the inspection of semifinished product.
4, fill, presses half plug.
5, lyophilizing: first freeze drying box is cooled to-40 DEG C～-50 DEG C, then puts into sample, make its quick freezing, time is 100 minutes～150 minutes, and sublimation temperature is-40 DEG C～-10 DEG C, and the time is 15～25 DEG C hours, baking temperature is-10 DEG C～30 DEG C, and the time is 5～15 hours.
Embodiment 3
PalonosetronHydrochloride lyophilized formulations described in every 1000 bottles, its formula consists of:
PalonosetronHydrochloride 0.5g
Beta-schardinger dextrin-20g
Mannitol 25g
Water for injection 2L
Preparation technology: 1, take PalonosetronHydrochloride and beta-schardinger dextrin-, add 80% water for injection to stir and make its dissolving, then add mannitol, stir completely and dissolve, with citric acid-disodium hydrogen phosphate buffer (pH4.0) adjust pH 4.0～6.0, benefit adds to the full amount of water for injection, and adds cumulative volume 0.05～0.1%(g/ml) carbon stirring and adsorbing 20 minutes for pin, filter decarburization.
2, with the microporous filter membrane fine straining of 0.22 μ m.
3, the inspection of semifinished product.
4, fill, presses half plug.
5, lyophilizing: first freeze drying box is cooled to-40 DEG C～-50 DEG C, then puts into sample, make its quick freezing, time is 100 minutes～150 minutes, and sublimation temperature is-40 DEG C～-10 DEG C, and the time is 15～25 DEG C hours, baking temperature is-10 DEG C～30 DEG C, and the time is 5～15 hours.
Embodiment 4
PalonosetronHydrochloride lyophilized formulations described in every 1000 bottles, its formula consists of:
PalonosetronHydrochloride 0.5g
HP-β-CD 30g
Mannitol 35g
Water for injection 2L
Preparation technology: 1, take PalonosetronHydrochloride and HP-β-CD, add 80% water for injection to stir and make its dissolving, then add mannitol, stir completely and dissolve, with citric acid-disodium hydrogen phosphate buffer (pH4.0) adjust pH 4.0～6.0, benefit adds to the full amount of water for injection, and adds cumulative volume 0.05～0.1%(g/ml) carbon stirring and adsorbing 20 minutes for pin, filter decarburization.
2, with the microporous filter membrane fine straining of 0.22 μ m.
3, the inspection of semifinished product.
4, fill, presses half plug.
5, lyophilizing: first freeze drying box is cooled to-40 DEG C～-50 DEG C, then puts into sample, make its quick freezing, time is 100 minutes～150 minutes, and sublimation temperature is-40 DEG C～-10 DEG C, and the time is 15～25 DEG C hours, baking temperature is-10 DEG C～30 DEG C, and the time is 5～15 hours.
Embodiment 5
The PalonosetronHydrochloride lyophilized injectable powder stability contrast test that prepared embodiment of the present invention 1 PalonosetronHydrochloride freeze-dried powder and other conventional methods are made, taking character color and luster, content as investigating index, carry out observation and the mensuration of 12 months by a definite date, the results are shown in Table 1.
Table 1
[0021] embodiment 6
Get the PalonosetronHydrochloride powder pin that PalonosetronHydrochloride freeze-dried powder prepared by embodiment 1 prepared with other conventional method and add water for injection under identical condition, injectable powder prepared by acetonideexample 1 dissolves at once, and the injectable powder that conventional method makes need rock more than 30 seconds and could dissolve.
[0022] embodiment 7
Choose freeze-dried powder prepared by PalonosetronHydrochloride freeze-dried powder that above embodiment 1-4 makes and other conventional methods, under 60 DEG C of high temperature, illumination 4500Lx condition, place respectively and within 10 days, carry out influence factor and test investigation; Under 40 DEG C of high temperature, relative humidity 75% ± 5% condition 6 months, carry out accelerated test investigation; Under 25 DEG C of high temperature, relative humidity 60% ± 10% condition 18 months, carry out long term test investigation, detect the variation of every quality index, data result is referring to table 2-table 4.
Table 2 influence factor result
Table 3 accelerated test result
Table 4 long-term test results
[0023] conclusion: can be found out by above data result, the PalonosetronHydrochloride freeze-dried powder influence factor 10 days for preparing by embodiment 1-4, accelerate June and long-term 18 months after every quality index without significant change, good stability.
Claims (3)
1. a hydrochloride for injection palonosetron preparation, formed by following component: PalonosetronHydrochloride, beta-schardinger dextrin-or HP-β-CD, mannitol, in 0.25mg palonosetron, beta-schardinger dextrin-or HP-β-CD consumption are 0.1～20mg, the consumption of mannitol is 0.25～25mg, described preparation is realized by following steps: first by hydrochloric acid Paro Nuo Siqiong and beta-schardinger dextrin-or HP-β-CD dissolving, add again mannitol to dissolve, with citric acid-sodium hydrogen phosphate buffer tune pH3.0～6.0, the quick pre-freeze of medicinal liquid after subpackage, carry out again lyophilizing.
2. hydrochloride for injection palonosetron preparation according to claim 1, is characterized in that: preparation forms in 0.5mg palonosetron, and beta-schardinger dextrin-or HP-β-CD consumption are 0.2～50mg, and the consumption of mannitol is 0.5～50mg.
3. hydrochloride for injection palonosetron preparation according to claim 1, it is characterized in that: described preparation method is first freeze drying box temperature drop to be low to moderate to-40 DEG C～-50 DEG C, then put into sample, make its quick freezing, time is 100 minutes～150 minutes, and sublimation temperature is-40 DEG C～-10 DEG C, and the time is 15～25 hours, baking temperature is-10 DEG C～30 DEG C, and the time is 5～15 hours.
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| CN201210520541.8A CN103845295A (en) | 2012-12-07 | 2012-12-07 | Palonosetron preparation for injection and preparation method thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016175586A3 (en) * | 2015-04-29 | 2016-12-22 | 주식회사 삼양바이오팜 | Pharmaceutical package |
| JP2019031465A (en) * | 2017-08-09 | 2019-02-28 | ナガセ医薬品株式会社 | Pharmaceutical composition |
| JP2019038758A (en) * | 2017-08-23 | 2019-03-14 | 武田テバファーマ株式会社 | Pharmaceutical composition containing palonosetron or pharmaceutically acceptable salt thereof |
| US11433021B2 (en) * | 2018-01-12 | 2022-09-06 | Orion Corporation | Palonosetron for the treatment or prevention of nausea and vomiting |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101130080A (en) * | 2007-07-24 | 2008-02-27 | 山东大学 | Gelling agent for controlling and releasing 5-HT* acceptor antagon and method of preparing the same |
| CN101444508A (en) * | 2008-12-29 | 2009-06-03 | 海南瑞基药物研究有限公司 | Tropisetron preparation for injection and preparation method thereof |
-
2012
- 2012-12-07 CN CN201210520541.8A patent/CN103845295A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101130080A (en) * | 2007-07-24 | 2008-02-27 | 山东大学 | Gelling agent for controlling and releasing 5-HT* acceptor antagon and method of preparing the same |
| CN101444508A (en) * | 2008-12-29 | 2009-06-03 | 海南瑞基药物研究有限公司 | Tropisetron preparation for injection and preparation method thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016175586A3 (en) * | 2015-04-29 | 2016-12-22 | 주식회사 삼양바이오팜 | Pharmaceutical package |
| JP2019031465A (en) * | 2017-08-09 | 2019-02-28 | ナガセ医薬品株式会社 | Pharmaceutical composition |
| JP2019038758A (en) * | 2017-08-23 | 2019-03-14 | 武田テバファーマ株式会社 | Pharmaceutical composition containing palonosetron or pharmaceutically acceptable salt thereof |
| US11433021B2 (en) * | 2018-01-12 | 2022-09-06 | Orion Corporation | Palonosetron for the treatment or prevention of nausea and vomiting |
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Application publication date: 20140611 |