CN100571685C - The preparation technology of a kind of ropivacaine and officinal salt lyophilized injectable powder thereof - Google Patents
The preparation technology of a kind of ropivacaine and officinal salt lyophilized injectable powder thereof Download PDFInfo
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- CN100571685C CN100571685C CNB2007100130274A CN200710013027A CN100571685C CN 100571685 C CN100571685 C CN 100571685C CN B2007100130274 A CNB2007100130274 A CN B2007100130274A CN 200710013027 A CN200710013027 A CN 200710013027A CN 100571685 C CN100571685 C CN 100571685C
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Abstract
The invention belongs to medical technical field, particularly, relate generally to the preparation technology of a kind of ropivacaine and officinal salt lyophilized injectable powder thereof.The invention provides the preparation technology of a kind of ropivacaine and officinal salt lyophilized injectable powder thereof, particularly this product freeze-drying preparation technology.Ropivacaine of the present invention and pharmaceutical salts freeze-dried powder preparation technology lyophilization stage thereof comprise: (1) pre-freeze stage; (2) the pre-freeze constant temperature stage; (3) the drying bu sublimation stage; (4) gradient increased temperature drying stage again.The ropivacaine and the officinal salt lyophilized injectable powder thereof of preparation technology's preparation of the present invention obviously hang down and have reduced the product percent defective, have improved product stability, have the product yield height, and constant product quality waits the significance advantage by force.
Description
The invention belongs to medical technical field, particularly, the present invention relates generally to the preparation technology of a kind of ropivacaine and officinal salt thereof, particularly this product freeze-drying preparation technology.
Ropivacaine is a New-type long-acting local anesthetic, is mainly used in surgical operation anesthesia, epidural anesthesia, postoperative the dispel 72 hours parts or the regional anesthesia of pain and birth process clinically.Ropivacaine be one of main medicine of inhibiting pain in parturition pharmaceutical research new development (Xiao Hui etc. the clinical observation of inhibiting pain in parturition. Guangdong medical science 2000; 21 (5): 357-358.), it is similar to the physicochemical property of bupivacaine, all belongs to piperazine ketone xylidine class.This medicine does not have obvious influence to the uterus placental blood flow, and the ropivacaine of low concentration can block the sensory nerve transmission effectively and very little to the nervus motorius influence, and sensation is separated with the motion retardance with making, and this medicine is applicable to postoperative analgesia and obstetrical analgesia.In the infra document, ropivacaine raw material and officinal salt thereof and freeze-dried powder preparation method have been related to, CN 1660094A, CN 1517337A, CN 1121388C, CN 1626081A, CN1074918C.
Owing to have optical isomer in the ropivacaine structure, enantiomer takes place and makes the transition in this product easily under aqueous solution state, influence product quality, and it is prepared into water-free lyophilized injectable powder is one of method that addresses this problem.The general technology of preparation freeze-dried powder is that product active ingredient and necessary adjuvant are dissolved in the entry earlier, in a small amount of of then the solution branch being packed into the container, puts into freezer dryer and carries out lyophilization.The greatest factor of decision product quality also is the product lyophilization stage.In the prior art, having mentioned the ropivacaine officinal salt is prepared into injectable powder and will be dissolved in the water through finished product, carry out lyophilization then, and provided a kind of freeze drying process (CN 1626081A), but the final step in this freeze drying process is drying process again, this technology is directly to be raised to 20 ℃ by cryogenic product, technological design is good inadequately, and it is unsatisfactory through injection ropivacaine product appearance type shape and other pharmacy indexs of this preparation technology's preparation, even can not reach the requirement of Chinese Pharmacopoeia, the quality and the yield rate of product have been influenced, waste product is more in this prepared product, cause the wasting of resources, product cost increases, and not quite is fit to commercial production.Existing document (CN 1660094A) has also been mentioned a kind of method for preparing ropivacaine and officinal salt powder pin thereof, this method is to adopt the continuous spray drying method of vacuum, this preparation method is compared with freeze-drying, has preparation technology's more complicated, and equipment drops into the high deficiency of funds.
The problem that the present invention is based on above-mentioned technology existence proposes, and a kind of freeze drying process for preparing in ropivacaine and the officinal salt freeze-dried powder technology thereof is provided.Have the product appearance shapeliness by the ropivacaine of this lyophilization preparation and the freeze-dried powder of pharmaceutical salts thereof, meet Chinese Pharmacopoeia freeze-dried powder product regulation, finished product rate height, advantages such as constant product quality.
Ropivacaine of the present invention and pharmaceutical salts freeze-dried powder preparation technology thereof adopt common process that ropivacaine and pharmaceutical salts thereof and necessary adjuvant are mixed with aqueous solution, and this aqueous solution is put into freezer dryer, carry out the lyophilization stage then.
In the following description, as not specifying the semi-finished product A above-mentioned ropivacaine for preparing of representative and pharmaceutical salts and necessary adjuvant aqueous solution.
Ropivacaine of the present invention and pharmaceutical salts freeze-dried powder preparation technology lyophilization stage thereof comprise: (1) pre-freeze stage; (2) the pre-freeze constant temperature stage; (3) the drying bu sublimation stage; (4) gradient increased temperature drying stage again.Concrete steps are as follows:
1. pre-freeze stage: branch is installed semi-finished product A put into freezer dryer, and make semi-finished product A arrive the pre-freeze temperature between 2～3 hours, the pre-freeze temperature is between-35 ℃～-45 ℃.
2. pre-freeze constant temperature stage: semi-finished product A kept this pre-freeze temperature-time 1～2 hour after arriving the pre-freeze temperature.
3. drying bu sublimation stage: reduce freezer dryer freeze drying box vacuum to less than 0.1mmHg, the temperature that promotes semi-finished product A rises between-20 ℃～-25 ℃, and the distillation sublimation drying was at 10～12 hours.
4. gradient increased temperature drying stage again: keep freezer dryer freeze drying box vacuum less than 0.1mmHg, progressively promote semi-finished product A temperature, remain on-10 ℃ respectively ,-5 ℃, 10 ℃, 15 ℃ and 25 ℃, each temperature spot maintenance freeze-day with constant temperature 3～5 hours.Promptly get ropivacaine and pharmaceutical salts freeze-dried powder thereof.
In order to verify preparation technology's of the present invention advantage, we compare the ropivacaine of this prepared and the product of pharmaceutical salts freeze-dried powder and prior art for preparing thereof, and the present technique preparing product has been carried out study on the stability test and zoology toxicological test.
Method and supplementary material proportioning according to embodiment 1 prepare ropivacaine and pharmaceutical salts freeze-dried powder thereof, get product I, adopt prior art for preparing ropivacaine and pharmaceutical salts freeze-dried powder thereof simultaneously, get contrast product II.
Take by weighing mannitol 84.5g, join 1900ml water for injection, stirring makes molten entirely, adds s-ropivacaine mesylate 84.5g then, and gradation progressively adds, and the limit edged stirs.Add the back and continue heating (80 ℃) stirring 20 minutes, make molten entirely.The control liquid PH value is 5, adds water for injection to 2000ml.With 0.1% (W/V) active carbon, 50 ℃ adsorbed 15 minutes down, and decarburization is filtered; Gained filtrate is with 0.22 μ m filtering with microporous membrane, get clear and bright solution, be semi-finished product A, check semi-finished product content, and semi-finished product are packed in the 10ml cillin bottle, put into freezer dryer, start freezer dryer, carry out lyophilization, step is as follows: products temperature is dropped to-45 ℃, kept 2 hours.Vacuum in the freezer dryer drying baker is reduced to below the 0.1mmHg, keeps this vacuum, promote product temperature to-20 ℃, sublimation drying 12 hours.Promote product temperature to 20 ℃ then, dry 12 hours again, contrast product II.
Get the product I and the contrast product II of the inventive method preparation, carry out following test, observe outward appearance, content and the temperature of product.To contain the method for measurement as follows for s-ropivacaine mesylate in the product: adopt high performance liquid chromatography, (two appendix VD of Chinese Pharmacopoeia version in 2005)
Chromatographic condition: with octadecylsilane chemically bonded silica is filler; With acetonitrile-phosphate buffer (get sodium dihydrogen phosphate 1.5g, triethylamine 1.5ml adds water to 500ml, transfers pH to 3.5 with phosphoric acid) (25: 75) is mobile phase; The detection wavelength is 215nm.Number of theoretical plate calculates by s-ropivacaine mesylate should be not less than 2000.
The algoscopy precision takes by weighing product I and product I I is an amount of, adds mobile phase respectively and makes the solution that contains s-ropivacaine mesylate 35 μ g among every 1ml approximately, and precision is measured 20 μ l, and this does not inject chromatograph of liquid, the record chromatogram; It is an amount of that other gets the s-ropivacaine mesylate reference substance, measures with method, presses external standard method with calculated by peak area, promptly.
Simultaneously, get semi-finished product A, add mobile phase and make the solution that contains s-ropivacaine mesylate 35 μ g among every 1ml approximately, adopt said method to measure s-ropivacaine mesylate content among the semi-finished product A.
The sundry item assay method requires to measure according to Chinese Pharmacopoeia version appendix in 2005.
Get every series-produced product I and contrast product II, observe face shaping, record substandard product quantity, the result is as follows:
The product number of rejects and percent defective (with every batch of 1000 bottles of calculating)
| Defective reason | Atrophy (bottle) | Layering (bottle) | Caking (bottle) | Percent defective |
| Product I | 1 | 2 | 3 | 0.6％ |
| Contrast product II | 72 | 28 | 12 | 11.2％ |
With the product I of preparation method preparation of the present invention, add injection water 50ml dissolving, place under the room temperature, inject chromatograph of liquid respectively at 0,1,2,3,5,6 hour accurate 20 μ l of absorption, measure content, the result is as follows.
Preparing product redissolution effect of the present invention and content
| Semi-finished product A | 0 hour | 4 hours | 8 hours | 16 hours | 24 hours | |
| Outward appearance | - | Melt achromatism and clarity rapidly | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity |
| Content (%) | 103.68 | 103.29 | 103.31 | 103.17 | 103.22 | 103.15 |
With the product I of preparation technology's preparation of the present invention, place the climatic chamber of 25 ℃ of RH60%, detect related item respectively at sampling in 0,3,6,9,12,18,24 month, the result is as follows.
Preparation technology's preparing product study on the stability result of the present invention
| Time (moon) | Character | Clarity | The clarity of solution | Acidity (pH value) | Content (%) |
| 0 | The white loose block | Up to specification | Up to specification | 5.09 | 100.66 |
| 3 | The white loose block | Up to specification | Up to specification | 5.07 | 100.50 |
| 6 | The white loose block | Up to specification | Up to specification | 5.04 | 100.56 |
| 9 | The white loose block | Up to specification | Up to specification | 5.02 | 100.41 |
| 12 | The white loose block | Up to specification | Up to specification | 4.93 | 100.26 |
| 18 | The white loose block | Up to specification | Up to specification | 4.88 | 100.19 |
| 24 | The white loose block | Up to specification | Up to specification | 4.82 | 100.03 |
Above result of the test shows, compares with prior art, by the ropivacaine and the officinal salt lyophilized injectable powder thereof of prepared of the present invention, the obviously low product percent defective that reduced, improved product stability, had the product yield height, constant product quality waits the significance advantage by force.
In order to understand better and to implement the present invention, the embodiment of the invention is explained, but the present invention never only limits to this.
Embodiment 1
Take by weighing mannitol 84.5g, join 1900ml water for injection, stirring makes molten entirely, adds s-ropivacaine mesylate 84.5g then, and gradation progressively adds, and the limit edged stirs.Add the back and continue heating (80 ℃) stirring 20 minutes, make molten entirely.The control liquid PH value is 5, adds water for injection to 2000ml.With 0.1% (W/V) active carbon, 50 ℃ adsorbed 15 minutes down, and decarburization is filtered; Gained filtrate is with 0.22 μ m filtering with microporous membrane, clear and bright solution, be semi-finished product A, semi-finished product A is packed in the 10ml cillin bottle, put into freezer dryer, start freezer dryer, carry out lyophilization, step is as follows:
(1) the pre-freeze stage: branch is installed semi-finished product A put into freezer dryer, and make semi-finished product A arrive the pre-freeze temperature at 2 hours, the pre-freeze temperature is at-40 ℃.
(2) the pre-freeze constant temperature stage: semi-finished product A kept this pre-freeze temperature-time 1.5 hours after arriving the pre-freeze temperature.
(3) the drying bu sublimation stage: reduce freezer dryer freeze drying box vacuum extremely less than 0.1mmHg, the temperature that promotes semi-finished product A rises to-25 ℃, distillation sublimation drying 12 hours.
(4) gradient increased temperature drying stage again: keep freezer dryer freeze drying box vacuum less than 0.1mmHg, progressively promote semi-finished product A temperature, remain on-10 ℃ respectively ,-5 ℃, 10 ℃, 15 ℃ and 25 ℃, each temperature spot maintenance freeze-day with constant temperature 3 hours.Promptly get the s-ropivacaine mesylate freeze-dried powder.
Embodiment 2
Take by weighing mannitol 70g, join 1900ml water for injection, stirring makes molten entirely, adds Ropivacaine HCL 70g then, and gradation progressively adds, and the limit edged stirs.Add the back and continue heating (80 ℃) stirring 20 minutes, make molten entirely.The control liquid PH value is 5, adds water for injection to 2000ml.With 0.1% (W/V) active carbon, 50 ℃ adsorbed 15 minutes down, and decarburization is filtered; Gained filtrate is with 0.22 μ m filtering with microporous membrane, clear and bright solution, be semi-finished product A, semi-finished product A is packed in the 10ml cillin bottle, put into freezer dryer, start freezer dryer, carry out lyophilization, step is as follows:
(1) the pre-freeze stage: branch is installed semi-finished product A put into freezer dryer, and make semi-finished product A arrive the pre-freeze temperature at 3 hours, the pre-freeze temperature is at-35 ℃.
(2) the pre-freeze constant temperature stage: semi-finished product A kept this pre-freeze temperature-time 1 hour after arriving the pre-freeze temperature.
(3) the drying bu sublimation stage: reduce freezer dryer freeze drying box vacuum extremely less than 0.1mmHg, the temperature that promotes semi-finished product A rises to-20 ℃, distillation sublimation drying 10 hours.
(4) gradient increased temperature drying stage again: keep freezer dryer freeze drying box vacuum less than 0.1mmHg, progressively promote semi-finished product A temperature, remain on-10 ℃ respectively ,-5 ℃, 10 ℃, 15 ℃ and 25 ℃, each temperature spot maintenance freeze-day with constant temperature 5 hours.Promptly get the Ropivacaine HCL freeze-dried powder.
Embodiment 3
Other steps make semi-finished product A with embodiment 1, and semi-finished product A is packed in the 10ml cillin bottle, put into freezer dryer, start freezer dryer, carry out lyophilization, and step is as follows:
(1) the pre-freeze stage: branch is installed semi-finished product A put into freezer dryer, and make semi-finished product A arrive the pre-freeze temperature at 2 hours, the pre-freeze temperature is at-45 ℃.
(2) the pre-freeze constant temperature stage: semi-finished product A kept this pre-freeze temperature-time 2 hours after arriving the pre-freeze temperature.
(3) the drying bu sublimation stage: reduce freezer dryer freeze drying box vacuum extremely less than 0.1mmHg, the temperature that promotes semi-finished product A rises to-22 ℃, distillation sublimation drying 11 hours.
(4) gradient increased temperature drying stage again: keep freezer dryer freeze drying box vacuum less than 0.1mmHg, progressively promote semi-finished product A temperature, remain on-10 ℃ respectively ,-5 ℃, 10 ℃, 15 ℃ and 25 ℃, each temperature spot maintenance freeze-day with constant temperature 4 hours.Promptly get the s-ropivacaine mesylate freeze-dried powder.
Claims (4)
1. injection Ropivacaine mesylate or hydrochlorate freeze drying process of preparing same, it is characterized in that comprising the pre-freeze stage, the pre-freeze constant temperature stage, drying bu sublimation stage and gradient increased temperature be drying stage again, wherein gradient increased temperature again drying stage to be product keeping vacuum to the environment less than 0.1mmHg, progressively heat up, remain on-10 ℃ ,-5 ℃, 10 ℃, 15 ℃ and 25 ℃, each temperature spot kept freeze-day with constant temperature 3～5 hours.
2. injection Ropivacaine mesylate according to claim 1 or hydrochlorate freeze drying process of preparing same is characterized in that the pre-freeze stage for arrived the pre-freeze temperature between 3～5 hours, and the pre-freeze temperature is between-35 ℃～-45 ℃.
3. injection Ropivacaine mesylate according to claim 1 or hydrochlorate freeze drying process of preparing same is characterized in that the pre-freeze constant temperature stage, keep the pre-freeze temperature-time 1～2 hour.
4. injection Ropivacaine mesylate according to claim 1 or hydrochlorate freeze drying process of preparing same, it is characterized in that the drying bu sublimation stage keeps the vacuum of freeze drying box less than 0.1mmHg, temperature rises between-20 ℃～-25 ℃, and sublimation drying was at 10～12 hours.
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| CN102038651B (en) * | 2010-12-25 | 2013-04-03 | 山东新时代药业有限公司 | Ropivacaine mesylate freeze-dried powder injection |
| CN106038496A (en) * | 2016-07-12 | 2016-10-26 | 山西普德药业有限公司 | Ropivacaine mesylate freeze-dried powder injection for injection and preparation method thereof |
| CN110151707B (en) * | 2019-05-20 | 2020-08-14 | 天津乾丰瑞科技有限公司 | Ropivacaine mesylate pharmaceutical composition and preparation method thereof |
| CN115006711A (en) * | 2022-06-23 | 2022-09-06 | 广东瑞程医学科技有限公司 | Microneedle loaded with active self-regeneration factor and preparation method and application thereof |
| CN116211811A (en) * | 2023-01-10 | 2023-06-06 | 成都天台山制药股份有限公司 | Tramadol hydrochloride freeze-dried powder and preparation method thereof |
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Non-Patent Citations (2)
| Title |
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| "冷冻干燥技术及其在中药研究中的应用". 闫家福等.中国实验方剂学杂志，第vol 12卷第no 12期. 2006 |
| "冷冻干燥技术及其在中药研究中的应用". 闫家福等.中国实验方剂学杂志，第vol 12卷第no 12期. 2006 * |
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