CN1823775A - Stable palonosetron injection liquid and its preparation method - Google Patents
Stable palonosetron injection liquid and its preparation method Download PDFInfo
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- CN1823775A CN1823775A CN 200510057449 CN200510057449A CN1823775A CN 1823775 A CN1823775 A CN 1823775A CN 200510057449 CN200510057449 CN 200510057449 CN 200510057449 A CN200510057449 A CN 200510057449A CN 1823775 A CN1823775 A CN 1823775A
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- injection
- palonosetron
- citrate buffer
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Abstract
A high-stability injection of Paluonosiqiong is prepared from Paluonosiqiong or its medicinal salt, and the additive for injection chosen from citrate buffer solution, xylitol, sorbitol and sodium chloride. It has low cost.
Description
Technical field:
The present invention relates to a kind of stable medicine intravenous fluid, be specifically related to a kind of palonosetron or its officinal salt, and be the intravenous fluid that adjuvant, especially palonosetron Hcl become effective ingredient with xylitol or sorbitol or sodium chloride.
Background technology:
Palonosetron Hcl (Palonosetron Hydrochloride) chemical structural formula is:
Chemical name is 2-[(S)-1-azabicyclo [2,2,2] octane-3-yl]-2,3,3a (S), 4,5,6-six hydrogen-1H-benzisoquinoline-1-keto hydrochloride.
Palonosetron Hcl is white or off-white color crystalline powder, odorless, tasteless.In water, dissolve, be insoluble in ethanol.
The palonosetron Hcl injection is colourless or almost colourless clear and bright solution.
Palonosetron Hcl is 5-hydroxy tryptamine 3 receptor antagonists that Switzerland Helsinn Healthcare company develops, and in JIUYUE, 2003 is gone on the market in the U.S., and (aqueous injection, specification: the 0.25mg palonosetron/5ml), trade name is Aloxi to its injection
TM, the vomiting reaction when being mainly used in treatment cancer chemotherapy, radiotherapy clinically.Palonosetron Hcl is a kind of 5-hydroxy tryptamine 3 receptor antagonists of potent, high selectivity, be characterized in strong to 5-hydroxy tryptamine 3 receptor affinity height, blocking effect, toxic and side effects is little, biology declines the phase long (approximately 40h) in vivo, more effective to period of delay vomiting than existing other 5-hydroxy tryptamine 3 receptor antagonists, be a kind of safe, effective, act on persistent antiemetic.
U.S. Pat 5202333 (the applying date: 1991.5.22) in embodiment 13, disclose an oral administration solution prescription of palonosetron Hcl, an injection prescription and a tablet formulation.In disclosed this injection prescription, palonosetron Hcl concentration is 10-100mg/ml, has adopted the dextran monohydrate, adjuvants such as citric acid monohydrate compound and sodium hydroxide, the pH value of this prescription is 3.7, but poor stability, the pharmaceutical control and administration requirement that does not reach various countries 1-2 shelf stable for periods.
The world patent WO2004067005 of Switzerland Helsinn Healthcare company application (open day: 2004.8.12) disclose a kind of stable palonosetron Hcl pharmaceutical solutions of chemotherapy antiemetic that is used for, wherein the palonosetron Hcl concentration range is 0.01mg/ml～5.0mg/ml, preferred 0.05mg/ml, the pH scope is 4.00～6.00, and adjuvant is citric acid, trisodium citrate, EDTA, mannitol etc.This prescription is considered to quite stable for the prescription of listing injection, and its shelf stable for periods can reach more than the 1-2.The result of study that PCT applies for a patent the embodiment 3 of WO2004067005 thinks and transfers isoosmotic palonosetron Hcl solution stable inadequately with sodium chloride do not have mannitol good.
We are unexpected the discovery in wideer pH value scope (PH3.00～7.00) in the injection process of development palonosetron, is that the palonosetron Hcl injection of adjuvant has identical stability with external commercially available injection of palonosetron sample (containing mannitol and EDTA) with citric acid, trisodium citrate (or citrate buffer), xylitol or sorbitol or sodium chloride.And we do not have hemolytic, blood vessel irritation and anaphylaxis by the pharmacological testing proof according to this prepared injection of filling a prescription.The adjuvant that adopts in the injection formula of the present invention is citric acid, trisodium citrate (or citrate buffer), xylitol (or sorbitol or sodium chloride), and mannitol and EDTA, citric acid, trisodium citrate, wherein the price comparison costliness of adjuvant mannitol and EDTA have been used in the prescription of external product.Therefore, injection prescription of the present invention is compared with the injection that goes on the market, does not adopt EDTA, and has adopted comparatively cheap adjuvant, thereby has reduced production cost significantly, has improved injection stability simultaneously, and the production technology simple possible is easy to suitability for industrialized production.
Summary of the invention:
The invention provides a kind of stable injection that contains palonosetron or officinal salt, the concentration of palonosetron is 0.01mg/ml～9mg/ml in this injection, preferred 0.05mg/ml.
The officinal salt of the said palonosetron of the present invention is inorganic acid salt example hydrochloric acid salt, phosphate, sulfate and other acylate, and being preferably hydrochlorate is palonosetron Hcl,
The pharmaceutic adjuvant that injection of palonosetron of the present invention adopted (injection additives) comprises xylitol, sorbitol, sodium chloride and citrate buffer.Sodium chloride described here, xylitol, sorbitol can be used as isoosmotic adjusting agent and stabilizing agent, wherein the concentration range of sodium chloride is 5mg/ml～20mg/ml, preferred 9～11mg/ml, the concentration range of xylitol and sorbitol is 40mg/ml～100mg/ml, preferred 50mg/ml～60mg/ml.
The concentration range of above-mentioned said citrate buffer is 1mg/ml～10mg/ml, preferred 2mg/ml～5mg/ml (in sodium citrate and citric acid weight sum).Citrate buffer can make by citric acid and sodium hydroxide reaction; Also can make by sodium citrate and hydrochloric acid reaction; Can also get by the citric acid and the sodium citrate mixing of constant weight proportioning, wherein, the weight ratio scope of citric acid and sodium citrate is 1: 10 to 10: 1, preferred 1: 1.5 to 1.5: 1, by densitometer, the concentration range of the two all can be 0.5mg/ml～5mg/ml, preferred 1mg/ml～1.5mg/ml.The conventional preparation method preparation of the available buffer of the preparation of citrate buffer.
The said citrate buffer of the present invention can be used as the pH value regulator, also can be used as stabilizing agent.
Injection pH scope of the present invention is 3.00～7.00.
Another object of the present invention provides the preparation method of stable palonosetron Hcl injection: in this preparation method is that palonosetron Hcl is mixed with the buffer as xylitol or Pyrusussuriensis or sodium chloride and PH regulator lemon hydrochlorate (sodium salt) of injection additives of depyrogenation (injection pharmaceutic adjuvant), available in case of necessity hydrochloric acid (preferred dilute hydrochloric acid) or sodium hydroxide solution are regulated pH to 3.00～7.00, smart worry, embedding, sterilize finished product.
The palonosetron Hcl injection, by palonosetron Hcl and the injection additive preparing of depyrogenation become solution, smart worry, embedding, sterilization make finished product, the gained injection is that 5ml contains palonosetron 0.25mg.
Preparation method is: take by weighing recipe quantity injection additives such as xylitol or sorbitol or sodium chloride respectively, PH regulator citrate buffer such as citric acid and trisodium citrate, dissolve with proper amount of water for injection, add an amount of needle-use activated carbon, the heated and stirred depyrogenation, filtering decarbonization obtains fine straining liquid, then cool to room temperature, add palonosetron Hcl again, dissolving, available in case of necessity hydrochloric acid (preferred dilute hydrochloric acid) or sodium hydroxide solution are regulated pH to 3.00～7.00, add the injection water to amount of preparation, gained solution mixed cellulose ester microporous membrane fine straining, embedding, sterilization gets product.
Formulating:
1. the solution pH value is regulated
Preparation contains the solution of palonosetron 0.25mg/1ml and injection additives, adopting xylitol or sorbitol or sodium chloride is additives, make the injection pH value keep stable with citric acid and trisodium citrate as the injection buffer agent, regulating pH value respectively with 0.1M HCL before the standardize solution is 3.00,3.70,4.50,5.5,7.0, add water to the scale standardize solution, fine straining, embedding, sterilization gets product.The injection liquid samples of prepared different pH value is carried out stability test, and the result shows that the injection of palonosetron of pH3.00～7.00 all can keep physicochemical property stable under high temperature (40 ℃, 60 ℃), high humidity (75%RH, 92%RH), illumination condition.
2. the solution osmotic pressure is regulated
Because injection of palonosetron generally is an intravenously administrable, therefore need to regulate injection to equating with plasma osmotic pressure, injection of the present invention adopts xylitol or sorbitol or the sodium chloride osmotic pressure regulator as injection of palonosetron, sample carries out stability test, related substance does not have significant change, proves that injection of palonosetron of the present invention keeps stable under high temperature (60 ℃) condition.
3. needle-use activated carbon depyrogenation
By evidence, needle-use activated carbon has strong adsorption to palonosetron, and the content that causes adding palonosetron in the solution behind the charcoal descends significantly, because contained principal agent specification is very little in this product, every injection only contains palonosetron 0.25mg.Therefore, can be by controling environment and test tool and adjuvant (injection additives) used the active carbon depyrogenation, to guarantee the finished product apyrogeneity.Then need use earlier the active carbon depyrogenation for adjuvant solution, and then mix with palonosetron and to be mixed with finished product.
4. sterilizing methods
Injection liquid samples of the present invention adopted 100 ℃ of flowing steam sterilizations 30 minutes, and the gained finished product is qualified through the inspection of pharmacology health examination bacterium, and related substance is not seen significant change.
Embodiment
Further illustrate the present invention by the following examples, but be not limited to scope of embodiments.
Embodiment 1
Palonosetron Hcl injection prescription (prescription) sees Table 1
Table 1 palonosetron Hcl injection prescription list
| The prescription composition | 1 | 2 | 3 | 4 (commercially available prescriptions) |
| Palonosetron Hcl xylitol sorbierite sodium chloride sweet mellow wine EDTA citric acid natrium citricum pH value water for injection adds to | 0.28mg 250mg - - 6.4mg 5mg 3.73 5ml | 0.28mg - 250mg - 6.4mg 5mg 3.75 5ml | 0.28mg - - 45mg 6.4mg 5mg 3.75 5ml | 0.28mg 207mg 2.5mg 7.8mg 18mg 5.10 5ml |
Preparation technology:
Amount by prescription 1 takes by weighing xylitol, citric acid, trisodium citrate, add an amount of water for injection dissolving, add an amount of needle-use activated carbon, heated and stirred, filtering decarbonization, in the fine straining liquid of cool to room temperature, add the palonosetron Hcl 0.28mg (being equivalent to base 0.25mg) that accurately takes by weighing, stir evenly dissolving, regulate about pH to 3.7, add water to amount of preparation 5ml with 0.1M HCL, be that palonosetron concentration is 0.25mg/5ml, use the mixed cellulose ester microporous membrane filtration sterilization, every the smart worry of ampoule packing 5ml liquid, sealing by fusing, 100 ℃ of sterilizations of flowing steam 30 minutes get product.
By the preparation manipulation method of above-mentioned prescription 1 injection finished product, make the palonosetron Hcl injection finished product of prescription 2, prescription 3 respectively.
By the preparation manipulation method of above-mentioned prescription 1 injection finished product, make the injection finished product of prescription 4 (for commercially available palonosetron Hcl injection prescription), and be reference example.
Embodiment 2
Stability test
Palonosetron Hcl injection liquid samples (prescription 1,2,3) and external commercially available injection prescription sample (prescription 4) that embodiment 1 is made place 60 ℃ of influence factor's baking ovens, placed 10 days, observe relatively them in 0 day, the 5th day and the 10th day outward appearance, the variation of impurity level, investigate the heat stability of preparation.With its related substance of high effective liquid chromatography for measuring the 0th day, the 5th day and the 10th day.The result shows, compares with external commercially available prod, and placement is after 5 days and 10 days down in 60 ℃ for the injection liquid samples that embodiment 1 makes, and its outward appearance, impurity level have no significant change, and show its better heat stability.Concrete data see Table 2.
The related substance (%) of table 20 day, 5 days and influence factor's test in 10 days
| The prescription number | 1 | 2 | 3 | 4 (commercially available prescriptions) |
| 0 day 5 days 10 days | 0.3 0.3 0.4 | 0.3 0.6 0.8 | 0.1 0.3 0.3 | 0.1 0.3 0.4 |
Conclusion: the sample that adopts prepared injection liquid samples of the present invention and external commercially available prod to write out a prescription carries out stability test under the same conditions, the result shows that palonosetron Hcl injection heat stability of the present invention is consistent with external listing prescription sample, injection impurity has no significant change, so, palonosetron Hcl injection of the present invention has good stable, and the stable storing phase can remain on more than 2 years.
Claims (10)
1, a kind of stable injection of palonosetron contains palonosetron or its officinal salt and injection additives, it is characterized in that: the injection additives comprise (a) citrate buffer and (b) xylitol or sorbitol or sodium chloride.
2, palonosetron officinal salt according to claim 1 is a hydrochlorate.
3, injection of palonosetron according to claim 1, the concentration range that it is characterized in that palonosetron is 0.01mg/ml～9mg/ml.
4, injection of palonosetron according to claim 3, wherein the concentration of palonosetron is preferably 0.05mg/ml.
5, injection of palonosetron according to claim 1 is characterized in that the pH scope is 3.00～7.00.
6, according to the described arbitrary injection of palonosetron of claim 1～5, it is characterized in that: its injection additives are xylitol and citrate buffer.
7, according to the described arbitrary injection of palonosetron of claim 1～5, it is characterized in that: its injection additives are sorbitol and citrate buffer.
8, according to the described arbitrary injection of palonosetron of claim 1～5, it is characterized in that: its injection additives are sodium chloride and citrate buffer.
9, according to the described arbitrary injection of palonosetron of claim 6～9, the concentration range of its said citrate buffer is 1mg/ml～10mg/ml.
10, a kind of method for preparing injection of palonosetron according to claim 1 is characterized in that this method comprises following process:
A) take by weighing xylitol or sorbitol or sodium chloride, add citrate buffer, with an amount of water for injection dissolving; Then
B) add proper amount of active carbon, the heating depyrogenation, filtering decarbonization obtains filtrate;
C) treat the filtrate cool to room temperature in step, add palonosetron Hcl, dissolving again, regulate pH to 3.00～7.00 with hydrochloric acid or sodium hydroxide in case of necessity, add the injection water to amount of preparation; Then
D) gained solution mixed cellulose ester microporous membrane fine straining must be considered liquid, and embedding is in ampoule bottle, and flowing steam sterilization 30 minutes obtains palonosetron Hcl injection finished product.
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| CNB2005100574492A CN100367962C (en) | 2005-12-19 | 2005-12-19 | Stable palonosetron injection liquid and its preparation method |
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| CNB2005100574492A CN100367962C (en) | 2005-12-19 | 2005-12-19 | Stable palonosetron injection liquid and its preparation method |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100455286C (en) * | 2006-11-21 | 2009-01-28 | 深圳海创医药科技发展有限公司 | Injection of palonosetron and preparation process thereof |
| US20100048607A1 (en) * | 2008-08-25 | 2010-02-25 | Chandrashekhar Kocherlakota | Formulations comprising palonosetron |
| JP2019031465A (en) * | 2017-08-09 | 2019-02-28 | ナガセ医薬品株式会社 | Pharmaceutical composition |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100336508C (en) * | 2005-02-23 | 2007-09-12 | 重庆医药工业研究院有限责任公司 | Stable palonosetron injection |
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2005
- 2005-12-19 CN CNB2005100574492A patent/CN100367962C/en active Active
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100455286C (en) * | 2006-11-21 | 2009-01-28 | 深圳海创医药科技发展有限公司 | Injection of palonosetron and preparation process thereof |
| US20100048607A1 (en) * | 2008-08-25 | 2010-02-25 | Chandrashekhar Kocherlakota | Formulations comprising palonosetron |
| JP2019031465A (en) * | 2017-08-09 | 2019-02-28 | ナガセ医薬品株式会社 | Pharmaceutical composition |
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| CN100367962C (en) | 2008-02-13 |
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