CN102552126B - High-safety ropivacaine hydrochloride injection and preparation method thereof - Google Patents
High-safety ropivacaine hydrochloride injection and preparation method thereof Download PDFInfo
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- CN102552126B CN102552126B CN 201210019757 CN201210019757A CN102552126B CN 102552126 B CN102552126 B CN 102552126B CN 201210019757 CN201210019757 CN 201210019757 CN 201210019757 A CN201210019757 A CN 201210019757A CN 102552126 B CN102552126 B CN 102552126B
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Abstract
The invention relates to a high-safety ropivacaine hydrochloride injection and a preparation method of the high-safety ropivacaine hydrochloride injection. The formula of the high-safety ropivacaine hydrochloride injection comprises 20-200g of ropivacaine hydrochloride, 70-100g of sodium chloride, appropriate amount of sodium hydroxide or hydrochloric acid and 10000ml of water for injection. The formula is prepared into 1000 injections, and the pH value of the injection is 4.0-6.0. The injection has good stability, high drug content and safe and reliable effect.
Description
Technical field
The present invention relates to medical technical field.Particularly relate to a kind of high security Ropivacaine HCL injection and preparation method thereof.
Background technology
Ropivacaine is a kind of novel long-acting local anesthetics of amide derivatives, is applicable to surgical operation anesthesia, epidural anesthesia, postoperative or labor pains.Because ropivacaine is lower to the toxicity of heart, less to the influence of uterus PBF, be local anesthetic by the FDA approval therefore in 2000, be used for surgical operation, postoperative pain and 72 hours local anesthesia of birth process.Clinical practice shows that ropivacaine is lighter to puerpera's nervus motorius retardance, and the spontaneous labor rate is high, and neonate is to the better tolerance of ropivacaine.Therefore, ropivacaine is a kind of safe and effective local anaesthetics in the present clinical practice, has higher using value.
When ropivacaine was used as local anaesthetics, the injection with its salt form provided usually.But present Ropivacaine HCL injection has the shortcoming of poor stability.For solving the problem of ropivacaine injection poor stability; To be 200310117329,200410077510,200710013027 patent application carry out lyophilization with the salt form of ropivacaine to application number; Processed the ropivacaine salt freeze-dried powder-injection, in the hope of improving the bin stability of ropivacaine.
It is worth noting; Though above-mentioned patent application has been removed the water that can influence ropivacaine stability through Freeze Drying Technique, also introduced new problem simultaneously, for example clarity is defective when redissolution maybe new impurity possibly occur for lyophilized injectable powder; Need to add a large amount of drying protectants; And freezing dry process is complicated, and cost is high, because of the extra redissolution step application inconvenience of needs etc.
Therefore, injection remains a kind of very important form of medication of ropivacaine salt, and has further research to influence the factor of ropivacaine stability, with the demand of the storage stability that solves ropivacaine.
Summary of the invention
The purpose of this invention is to provide a kind of good stability, high security Ropivacaine HCL injection that medicament contg is high and preparation method thereof.
The present invention realizes through following embodiment.
Ropivacaine HCL 20-200g,
Sodium chloride 70-100g,
Sodium hydroxide or hydrochloric acid an amount of and
Water for injection adds to 10000ml;
Said prescription is made into 1000 injection, and the pH value of injection is 4.0-6.0.
Preferably, the prescription of said injection is formed as follows:
Ropivacaine HCL 20-100g,
Sodium chloride 71-86g,
Sodium hydroxide or hydrochloric acid an amount of and
Water for injection adds to 10000ml;
Said prescription is made into 1000 injection, and the pH value of injection is 4.0-6.0.
The method for preparing of above-mentioned Ropivacaine HCL injection comprises the steps:
(1), with Ropivacaine HCL and sodium chloride stirring and dissolving in the water for injection of full dose 1/3-4/5 volume, add an amount of sodium hydroxide or hydrochloric acid, pH value is transferred to 4.0-6.0;
(2), under 30-70 ℃ of heat-retaining condition, coarse filtration was carried out in medicinal liquid circulating filtration absorption in the plate filter that contains the 0.01-0.5% active carbon in 10-60 minute, survey intermediate products content and pH value, qualified after, with 0.22 μ m filtering with microporous membrane;
(3), the filtrating that obtains in the step (2) is added to full dose with water for injection, left standstill 0.5-2 hour;
(4), filtrate after standing is canned in the container of high-temperature resistance plastice material, the sealing, 110-125 ℃ steam sterilization 8-30 minute, promptly get the Ropivacaine HCL injection.
The present invention sets out according to the safety that the Ropivacaine HCL injection uses; The method of a kind of high security Ropivacaine HCL of a kind of the present invention of packing injection is provided; Be specially: earlier that the Ropivacaine HCL injection for preparing is canned in the container of high-temperature resistance plastice material; Sealing, under 110-125 ℃ of temperature steam sterilization 8-30 minute then.
The applicant finds in the research and development of product and development unexpectedly; When preparation Ropivacaine HCL injection; The consumption of active carbon, adsorption process and the canned liquid process that leaves standstill before canned; Not only can influence the content of injection Chinese medicine, and the stability of injection is had very big influence.Mainly show as following several respects:
1. working concentration is the active carbon of 0.01-0.5%; Bacterial endotoxin and impurity in the ability active adsorption injection have guaranteed the physical stability and the biological stability of injection in the storage process, simultaneously; Can make the medicament contg in the injection reach 99.99%, improve the curative effect of unit dosage forms;
2. earlier active carbon is joined in the feed liquid usually in the prior art; Decolouring removes by filter activated carbon through filter then ", promptly active carbon and filter separate; can cause the absorption of bacterial endotoxin and impurity incomplete; thus influence the stability of injection, and the present invention is adsorbed feed liquid simultaneously and is filtered, thus adsorption effect is better;
3. normally directly fill of heat absorption back of prior art; Can cause the injection after canned to have crystal to separate out like this, be unfavorable for the stable of product quality, and the present invention adopt the fill again after static 0.5-2 hour before fill of fill liquid; Supplementary material is fully dissolved, guarantee after sterilization, can not separate out;
4. prior art is sterilized earlier usually and is afterwards packed; And adopting high-temperature resistance plastice material container to carry out independent packaging earlier, the present invention sterilizes again; Guarantee that the inside and outside of infusion pump package material all is aseptic; Reduce injection germ contamination probability in use, this is in particularly important to the very high subarachnoid anesthesia of aseptic requirement.
Do further explanation below in conjunction with preferred embodiment of the present invention, these embodiment are interpreted as can not limiting practical range of the present invention, and its modification and equivalent way all covered in protection scope of the present invention.
Embodiment 1:
Prescription:
Ropivacaine HCL 50g,
Sodium chloride 80g,
Sodium hydroxide or hydrochloric acid an amount of and
Water for injection adds to 10000ml;
Said prescription is made into 1000 injection, and the pH value of injection is 5.0;
Method for preparing is: Ropivacaine HCL and sodium chloride stirring and dissolving in the water for injection of full dose 1/3 volume, are added an amount of sodium hydroxide or hydrochloric acid, pH value is transferred to 5.0; Under 48 ℃ of heat-retaining conditions, coarse filtration was carried out in medicinal liquid circulating filtration absorption in the plate filter that contains 0.01% active carbon in 10 minutes, survey intermediate products content and pH value, qualified after, with 0.22 μ m filtering with microporous membrane; The filtrating that obtains is added to full dose with water for injection, left standstill 0.5 hour after stirring 10min, canned then in the container of high-temperature resistance plastice material, sealing, 110 ℃ of steam sterilizations 8 minutes promptly get the Ropivacaine HCL injection.
Embodiment 2:
Prescription:
Ropivacaine HCL 75g,
Sodium chloride 75g,
Sodium hydroxide or hydrochloric acid an amount of and
Water for injection adds to 10000ml;
Said prescription is made into 1000 injection, and the pH value of injection is 5.0;
Method for preparing is: Ropivacaine HCL and sodium chloride stirring and dissolving in the water for injection of full dose 4/5 volume, are added an amount of sodium hydroxide or hydrochloric acid, pH value is transferred to 5.0; Under 50 ℃ of heat-retaining conditions, coarse filtration was carried out in medicinal liquid circulating filtration absorption in the plate filter that contains 0.5% active carbon in 60 minutes, survey intermediate products content and pH value, qualified after, with 0.22 μ m filtering with microporous membrane; The filtrating that obtains is added to full dose with water for injection, left standstill 2 hours after stirring 10min, canned then in the container of high-temperature resistance plastice material, sealing, 125 ℃ of steam sterilizations 30 minutes promptly get the Ropivacaine HCL injection.
Test Example 1: amount of activated is to the influence of medicine and impurity content
Test method: adopt the medicinal charcoal of different amounts to handle the Ropivacaine HCL injection of embodiment 2 prescriptions respectively, and the medicine and the impurity content of the injection after handling with high effective liquid chromatography for measuring.The chromatographic condition of colleges and universities' liquid chromatography is: Agilent C18 (150mm * 4.6mm, 5 μ m); Mobile phase is acetonitrile-phosphate buffer (50: 50); The detection wavelength is 240nm; Flow velocity is 1.0ml/min.Experimental result is seen table 1.
Table 1, different medicinal charcoal consumption are to the influence of medicine and impurity content
The result shows that the consumption of medicinal charcoal is big more, and medicine and impurity are adsorbed manyly more, but medicament contg also descends simultaneously, and when the medicinal charcoal consumption was 0.025%, the medicament contg in the injection was higher, and impurity is less.
Test Example 2: absorbing process is to the influence of injection stability
Test method: the Ropivacaine HCL injection that adopts different adsorption PROCESS FOR TREATMENT embodiment 2 prescriptions respectively; Wherein the circulating filtration method absorption of the present invention of sample 4 usefulness is 60 minutes; The common active carbon adsorption of sample 5 usefulness was handled 60 minutes, and the consumption of active carbon is 0.5%, and temperature is 50 ℃; Then, the sample after handling is placed 37 ℃ and room temperature respectively, and in the sampling of different time point, with the medicament contg of high effective liquid chromatography for measuring injection.The chromatographic condition of colleges and universities' liquid chromatography is with Test Example 1.Experimental result is seen table 2.
Table 2, different absorbing process are handled the stability study (n=3) of back injection
The result shows; Sample 4 with circulating filtration method adsorption treatment of the present invention is more stable in hot test and long term test; This possibly be because some impurity in the injection has harmful effect to the stability of Ropivacaine HCL injection; Because circulating filtration method energy of adsorption more effectively adsorbs impurity, therefore removed and caused the unsettled influence factor of Ropivacaine HCL injection.
Test Example 3: leave standstill influence before canned to stability
Test method: the injection stock solution of comparing embodiment 2 formulation has carried out leaving standstill before canned and the long-time stability that leave standstill respectively, and wherein sample 6 left standstill before canned 1 hour, and sample 7 is directly canned.Experimental result is seen table 3.
Table 3, leave standstill influence (room temperature) before canned to long-time stability
| n | 0 month | 2 months | 6 months | |
| Sample 6 | 3 | 100.0±0.0 | 99.99±0.1 | 99.97±0.0 |
| Sample 7 | 3 | 100.0±0.0 | 99.98±0.0 | 99.91±0.2 |
The result shows, injection leaves standstill sample 6 long-time stability at room temperature of processing before canned better.
Test Example 4: outer package microbiological contamination test
Test method: with the injection stock solution (n=10) of embodiment 2 formulation respectively before independent packaging with independent packaging after 121 ℃ of steam sterilizations 8 minutes, and room temperature places, respectively at 0,6 with measured the microbiological contamination rate of two kinds of samples in 12 months.Experimental result is seen table 4.
The microbiological contamination rate (n=15) of table 4, different sterilization method samples
| 0 month | 6 months | 12 months | |
| Sterilization before the independent packaging | 0 | 0 | 13％ |
| Sterilize after the independent packaging | 0 | 0 | 0 |
The result shows, compares with sterilization before the independent packaging, and sterilization can effectively be controlled germ contamination after independent packaging, and it is inside and outside by the probability of germ contamination to have reduced the infusion pump package material.
Claims (2)
1. a high security Ropivacaine HCL injection is characterized in that, the prescription of said injection is formed as follows:
Ropivacaine HCL 50g,
Sodium chloride 80g,
Sodium hydroxide or hydrochloric acid an amount of and
Water for injection adds to 10000ml;
Said prescription is made into 1000 injection, and the pH value of injection is 5.0;
Method for preparing is: Ropivacaine HCL and sodium chloride stirring and dissolving in the water for injection of full dose 1/3 volume, are added an amount of sodium hydroxide or hydrochloric acid, pH value is transferred to 5.0; Under 48 ℃ of heat-retaining conditions, coarse filtration was carried out in medicinal liquid circulating filtration absorption in the plate filter that contains 0.01% active carbon in 10 minutes, survey intermediate products content and pH value, qualified after, with 0.22 μ m filtering with microporous membrane; The filtrating that obtains is added to full dose with water for injection, left standstill 0.5 hour after stirring 10min, canned then in the container of high-temperature resistance plastice material, sealing, 110 ℃ of steam sterilizations 8 minutes promptly get the Ropivacaine HCL injection.
2. high security Ropivacaine HCL injection is characterized in that the prescription of said injection is formed as follows:
Ropivacaine HCL 75g,
Sodium chloride 75g,
Sodium hydroxide or hydrochloric acid an amount of and
Water for injection adds to 10000ml;
Said prescription is made into 1000 injection, and the pH value of injection is 5.0;
Method for preparing is: Ropivacaine HCL and sodium chloride stirring and dissolving in the water for injection of full dose 4/5 volume, are added an amount of sodium hydroxide or hydrochloric acid, pH value is transferred to 5.0; Under 50 ℃ of heat-retaining conditions, coarse filtration was carried out in medicinal liquid circulating filtration absorption in the plate filter that contains 0.5% active carbon in 60 minutes, survey intermediate products content and pH value, qualified after, with 0.22 μ m filtering with microporous membrane; The filtrating that obtains is added to full dose with water for injection, left standstill 2 hours after stirring 10min, canned then in the container of high-temperature resistance plastice material, sealing, 125 ℃ of steam sterilizations 30 minutes promptly get the Ropivacaine HCL injection.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102697708A (en) * | 2012-04-17 | 2012-10-03 | 上海禾丰制药有限公司 | Ropivacaine hydrochloride injection and preparation process thereof |
| CN102670489B (en) * | 2012-05-10 | 2013-10-02 | 华仁药业（日照）有限公司 | Ropivacaine hydrochloride sodium chloride injection and preparation method thereof |
| CN103690479B (en) * | 2013-12-04 | 2016-01-20 | 广东嘉博制药有限公司 | A kind of Glycopyrronium bromide injection and preparation method thereof |
| CN104208020B (en) * | 2014-09-05 | 2016-08-24 | 河北一品制药有限公司 | A kind of Ropivacaine HCL injection and preparation method thereof |
| US11224593B2 (en) | 2015-07-13 | 2022-01-18 | Neon Laboratories Limited | Hyperbaric injection solution of ropivacaine hydrochloride and process for preparation thereof |
| WO2017017693A1 (en) | 2015-07-24 | 2017-02-02 | Neon Laboratories Limited | Stabilized injectable emulsion of propofol and ketamine |
| CN106177970B (en) * | 2016-07-12 | 2019-09-17 | 扬子江药业集团有限公司 | Ropivacaine injection preparation and its preparation method and application |
| CN109568259A (en) * | 2018-12-31 | 2019-04-05 | 辰欣药业股份有限公司 | A kind of liquid drugs injection and preparation method thereof containing s-ropivacaine mesylate |
| CN114504552A (en) * | 2021-11-02 | 2022-05-17 | 浙江仙琚萃泽医药科技有限公司 | Method for preparing ropivacaine suspension injection and powder preparation and ropivacaine suspension injection and powder preparation obtained thereby |
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| CN1626081A (en) * | 2003-12-10 | 2005-06-15 | 北京博尔达生物技术开发有限公司 | Ropivacaine freeze-dried powder and injection preparation in use for injection and preparation method |
| CN101658490A (en) * | 2008-08-25 | 2010-03-03 | 西安博森生物制药有限责任公司 | Preparation method of ropivacaine mesylate injection packed by soda-lime glass bottle |
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Address after: 511517 bio tech city, hi tech Zone, Guangdong, Qingyuan Patentee after: GUANGDONG JIABO PHARMACEUTICAL CO., LTD. Address before: 511517 bio pharmaceutical City, Qingyuan hi tech Industrial Development Zone, Guangdong Patentee before: Qingyuan Jiabo Pharmaceutical Co., Ltd. |
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Inventor after: Wu Chuanbin Inventor after: Xie Chunyan Inventor after: Yue Feng Inventor after: Zeng Shaoqun Inventor after: Cai Wenjian Inventor after: Tong Weiguo Inventor after: Liang Chengbiao Inventor after: Peng Chuangye Inventor after: Li Qing Inventor after: Wu Yanhua Inventor before: Yue Feng Inventor before: Liang Chengbiao Inventor before: Zeng Shaoqun Inventor before: Tong Weiguo Inventor before: Cai Wenjian |
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Application publication date: 20120711 Assignee: Pei Sheng medical science and Technology (Guangzhou) Co., Ltd. Assignor: GUANGDONG JIABO PHARMACEUTICAL CO., LTD. Contract record no.: 2018440000074 Denomination of invention: High-safety ropivacaine hydrochloride injection and preparation method thereof Granted publication date: 20121219 License type: Common License Record date: 20180605 Application publication date: 20120711 Assignee: Qingyuan Bo Jian Pharmaceutical Co., Ltd. Assignor: GUANGDONG JIABO PHARMACEUTICAL CO., LTD. Contract record no.: 2018440000075 Denomination of invention: High-safety ropivacaine hydrochloride injection and preparation method thereof Granted publication date: 20121219 License type: Common License Record date: 20180605 |
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