CN101732319B - Landiolol hydrochloride active ingredient-containing medicinal composition for injection and preparation method thereof - Google Patents
Landiolol hydrochloride active ingredient-containing medicinal composition for injection and preparation method thereof Download PDFInfo
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- CN101732319B CN101732319B CN2008101533510A CN200810153351A CN101732319B CN 101732319 B CN101732319 B CN 101732319B CN 2008101533510 A CN2008101533510 A CN 2008101533510A CN 200810153351 A CN200810153351 A CN 200810153351A CN 101732319 B CN101732319 B CN 101732319B
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Abstract
The invention discloses a landiolol hydrochloride active ingredient-containing medicinal composition for injection. A landiolol hydrochloride freeze-dried preparation for injection has good medicinal stability, and is very convenient for clinical use and transportation. The preparation is special for emergency treatment of tachycardia arrhythmia (atrial fibrillation, atrial flutter and nodal tachycardia) during clinical surgeries. The invention provides a preparation method.
Description
Technical field
The present invention relates to technical field of medicine, relate in particular to medicinal composition for injections that contains landiolol hydrochloride active ingredient and preparation method thereof.
Background technology
Cardiovascular disease is the maximum killer of human health, is to cause in the dead disease first in China.In largest ACC (AHA) when holding annual meeting in 2003; Young professor J of U.S. Cleveland CF CWR university mentions: the U.S. has 3,000 ten thousand patients to make non-cardiac surgery every year; Wherein about 3,000,000 people have coronary heart disease or cardiovascular risk factors, like hypertension, diabetes.Heart infarction takes place in 1～4 day and reaches 3%～17%, wherein 40%～70% death in the operation back.
A series of in recent years clinical trials show, use the generation that beta-blocker can obviously reduce the non-cardiac surgery cardiovascular event, and this has obtained domestic and international experts and scholars' approval.In the up-to-date guide of ACC/AHA of promulgation in 2002, point out: high-risk patient is implemented non-cardiac surgery generally should use the beta receptor retardance; Special recommendation is used to accompany arrhythmia, Symptomatic coronary heart disease, untreated hypertension or dangerous with other main coronary heart disease, like patients such as diabetes.During operation,, discharge superfluous catecholamine, the heartbeat number is increased, be prone to cause the tachycardia arrhythmia because endotracheal intubation and tube drawing, incision skin and operation technique etc. cause sympathetic activation to the various stimulations of health.Particularly with ischemic heart disease and hypertensive patient,, thereby cause ischemia such as coronary artery only because the load that increase will strengthen heart is counted in heartbeat.Therefore, when anesthesia surgery, particularly patient have ischemic heart desease or hypertensive patient to carry out anesthesia surgery, there is very big risk.The a tree name bibliographical information, even in the country of medical facilities such as America and Europe and advanced technology, the incidence rate of above-mentioned accident can reach more than 7%.Because the arrhythmia that causes during anesthesia surgery is the emergency of unexpected the jeopardized patient life of a speciogenesis, require this sick first aid medicine of treatment should have convenient drug administration, rapid-action, characteristics that the half-life is short.Esmolol is first ultrashort effect of using clinically, second filial generation β1-Shou Ti blocker optionally.Hydrochloride landiolol then is on the esmolol basis, to carry out architecture advances and the noval chemical compound that obtains.
Hydrochloride landiolol (Landiolol hydrochloride); Chemical name is that benzenpropanoic acid [(4S)-2 for 4-[(2S)-2-hydroxyl-3-[[2-[(4-morpholine carbonyl) amino] ethyl] amino] propoxyl group]; 2-dimethyl-1,3-dioxolanes-4-yl] methyl ester hydrochloride, molecular formula is C
25H
39N
3O
8HCl, molecular weight are 546.05, and character is a white crystalline powder, and very easily water-soluble and methanol is soluble in ethanol (99.5%).Its structural formula is:
(hydrochloride landiolol; Landiolol hydrochloride) develops by the little wild pharmaceutical industries company of Japan (Ono); On July 5th, 2002 is by Japanese health ministry approval listing; Commodity are called ONOACT, specification 50mg, the tachycardia arrhythmia (auricular fibrillation, atrial flutter and sinus tachycardia) when being used to treat operation.No matter be that Landiolol all has more advantage than esmolol from curative effect or safety, can be used as the regeneration product of esmolol.But the domestic hydrochloride for injection Landiolol of not producing does not as yet have import hydrochloride for injection Landiolol yet.
Because stimulations such as anesthesia procedure, operation invasion and attack discharge catecholamine in sympathetic nerve, the tachycardia arrhythmia causes happening suddenly during operation.There is the high-risk patient of myocardial ischaemias such as ischemic disease, hypertension myocardial oxygen consumption when the tachycardia arrhythmia to increase before the art, possibly causes ischemic heart disease or cardiac insufficiency, must make emergent management this.Treated the tachycardia arrhythmia in the past and use calcium antagonist, beta-blocker, but asking as the time spent of these medicines is longer, modulability is poor, therefore worries very much cardiac function in use and excessively reduces and the Insufficient generation of severe cardiac.And have β 1 effect at the injection beta-blocker of clinical use so far, the effect of pair beta 2 receptor is also arranged simultaneously, worry bronchoconstriction takes place and cause that respiratory function worsens, peripheral vessel shrinks and causes that circulatory disturbance waits until side effect.For this reason, β 1 blocker that the clinical expectation developmental function time is short, selectivity is strong.
Hydrochloride landiolol is that a kind of novel modulability good action time is ultrashort and have β 1 blocker of high selectivity; Mainly the receptor that is present in heart is had an effect; From the heart rate increase effect that SNE and the free norepinephrine of adrenal medulla and epinephrine cause, express its arrhythmia effect through antagonism.Have: the 1. pharmacological actions such as effect of β1Shou Ti selectivity SV when 2. 4. 3. the persistence of β retardation reduce tachycardia to ARR effect.
This medicament can hydrolysis in people's liver and blood plasma, metabolism rapidly.The hepatic metabolism clearance rate receives the liver blood current control, accounts for the half the of systemic clearance.In addition, metabolic half life is 4.1 minutes in the blood plasma of in vitro, and the metabolism contribution rate in the blood plasma is also very big.
Landiolol in JIUYUE, 2002, is compared with esmolol hydrochloride first in Japan's listing in Japan, and these article onset times is fast, and effect is by force the esmolol hydrochloride succedaneum, is to move the arrhythmia choice drug of overrunning for preventing in the operation process in Japan.
Summary of the invention
The technical problem that the present invention will solve is to provide a kind of method for preparing that contains the medicinal composition for injections of landiolol hydrochloride active ingredient.
The invention provides a kind of water can rapid dissolved hydrochloride for injection Landiolol lyophilized formulations.
Hydrochloride for injection Landiolol lyophilized formulations of the present invention is made up of every bottle of content the composition of following weight proportion:
Hydrochloride landiolol 10-100%
Adjuvant 0-90%
The content of active ingredient hydrochloric acid Landiolol is in the prescription of lyophilized formulations of the present invention: every bottle is 10mg, 25mg, 50mg, 100mg or 200mg.
Adjuvant in the prescription of lyophilized formulations of the present invention is characterized in that described adjuvant is excipient and pH regulator agent.
Excipient is in the prescription of lyophilized formulations according to the invention: the mixture of one or more in lactose, mannitol, dextran, glucose, gelatin hydrolysate, sorbitol, aminoacid, sodium chloride, calcium chloride, sucrose, polyvidone, sodiocitrate or the sodium ascorbyl phosphate.
The pH regulator agent is in the prescription of lyophilized formulations according to the invention: hydrochloric acid, sulphuric acid, acetic acid, lactic acid, methanesulfonic acid, phosphoric acid, citric acid, boric acid, tartaric acid, malic acid, aminoacid, sodium carbonate, sodium citrate, the mixture of one or more in sodium dihydrogen phosphate, sodium hydrogen phosphate, sodium bicarbonate or the sodium hydroxide.
Another object of the present invention has provided the method for preparing of hydrochloride for injection Landiolol lyophilized formulations:
A) form:
1. hydrochloride landiolol 10-100%
2. adjuvant 0-90%
B) get water for injection 0.5-8ml, regulate pH value with the pH value regulator, active medicine hydrochloride landiolol and excipient are added, stirring is all dissolved active medicine and excipient, can be heated to 30-70 ℃;
C) solution that will the number of preparation adds active carbon by the amount of every bottle of 0.1-10mg, stirring and adsorbing 10-30 minute, removes by filter active carbon;
D) add to the configuration amount 1-10ml of regulation with water for injection; The pH value 5.5-6.5 of reuse pH value regulator regulator solution; With 0.2-0.65 μ m filtering with microporous membrane, filtrating is sub-packed in the low Pyrex control injection bottle of 2-25ml after the assay was approved, every bottle of packing solution 1-10ml;
The low Pyrex control injection bottle that branch is installed solution is put in the vacuum freezing drying oven, carries out vacuum lyophilization by cryodesiccated method, 18-55 hour drying time.
G) cryodesiccated method step is following:
Quick-freezing is cooled to-20---and 50 ℃, to keep 1-6 hour, evacuation slowly is warming up to 35-40 ℃ under vacuum state, takes out after reducing to room temperature,, add a cover butyl rubber plug, roll the envelope aluminium lid, get product.
The advantage of preparation of the present invention is: pharmaceutical preparation is stable, and dissolubility is good in water, is convenient to preserve, transport, carry and clinical practice, and is clinical safe in utilization effective.
The specific embodiment
Below in conjunction with embodiment the present invention is done further explain, but should understand the non-scope that only limits to these embodiment of scope of the present invention.
Embodiment 1
Prescription 1: every bottle of hydrochloric Landiolol 25mg of lyophilized formulations
Method for preparing: get water for injection 600ml, regulate the about 4.0-6.0 of pH value, active medicine hydrochloride landiolol and lactose are added, stir and make whole dissolvings, be heated to 50-60 ℃ approximately with 1mol/L hydrochloric acid solution or 1mol/L sodium hydroxide solution; Add active carbon, stirring and adsorbing 10-30 minute, remove by filter active carbon; Add to the configuration amount 1000ml of regulation with water for injection; The pH value 5.5-6.5 of reuse 1mol/L hydrochloric acid solution or 1mol/L sodium hydroxide solution regulator solution; With 0.2-0.65 μ m filtering with microporous membrane; Filtrating is sub-packed in the low Pyrex control injection bottle of 2-25ml after the assay was approved, every bottle of packing solution 2ml; The low Pyrex control injection bottle that branch is installed solution is put in the vacuum freezing drying oven, carries out vacuum lyophilization by cryodesiccated method, and quick-freezing is cooled to-20---and 50 ℃; Kept 1-6 hour, evacuation slowly is warming up to 35-40 ℃ under vacuum state; Take out after reducing to room temperature, add a cover butyl rubber plug, roll the envelope aluminium lid; Get product 18-55 hour drying time.
The product inspection result:
Character: white loose block and powder
Differentiate:
1. these article have absorption maximum in the wavelength of 274 ± 2nm and 223 ± 2nm
2. in the chromatogram that under the assay item, writes down, the retention time of need testing solution main peak should be consistent with the retention time of reference substance solution main peak.
Acidity: 5.9
Content: 98.5%
Other index is all up to specification.
Embodiment 2
Prescription 2: every bottle of hydrochloric Landiolol 50mg of lyophilized formulations
Method for preparing: get water for injection 1500ml, regulate the about 4.0-6.0 of pH value, active medicine hydrochloride landiolol and dextran are added, stir and make whole dissolvings, be heated to 40-60 ℃ approximately with 3mol/L sodium dihydrogen phosphate or 3mol/L sodium dihydrogen phosphate; Add active carbon, stirring and adsorbing 10-30 minute, remove by filter active carbon; Add to the configuration amount 2000ml of regulation with water for injection; The pH value 5.5-6.5 of reuse 3mol/L sodium dihydrogen phosphate or 3mol/L sodium dihydrogen phosphate regulator solution; With 0.2-0.65 μ m filtering with microporous membrane; Filtrating is sub-packed in the low Pyrex control injection bottle of 2-25ml after the assay was approved, every bottle of packing solution 2ml; The low Pyrex control injection bottle that branch is installed solution is put in the vacuum freezing drying oven, carries out vacuum lyophilization by cryodesiccated method, and quick-freezing is cooled to-20---and 50 ℃; Kept 1-6 hour, evacuation slowly is warming up to 35-40 ℃ under vacuum state; Take out after reducing to room temperature, add a cover butyl rubber plug, roll the envelope aluminium lid; Get product 18-55 hour drying time.
The product inspection result:
Character: white loose block and powder
Differentiate:
3. these article have absorption maximum in the wavelength of 274 ± 2nm and 223 ± 2nm
4. in the chromatogram that under the assay item, writes down, the retention time of need testing solution main peak should be consistent with the retention time of reference substance solution main peak.
Acidity: 5.8
Content: 99.5%
Other index is all up to specification.
Embodiment 3
Prescription 3: every bottle of hydrochloric Landiolol 100mg of lyophilized formulations
Method for preparing: get water for injection 3000ml, regulate the about 4.0-6.0 of pH value, active medicine hydrochloride landiolol and mannitol are added, stir and make whole dissolvings, be heated to 40-60 ℃ approximately with 4% citric acid soln or 10% liquor sodii citratis; Add active carbon, stirring and adsorbing 10-30 minute, remove by filter active carbon; Add to the configuration amount 3000ml of regulation with water for injection; The pH value 5.5-6.5 of reuse 4% citric acid soln or 10% liquor sodii citratis regulator solution; With 0.2-0.65 μ m filtering with microporous membrane; Filtrating is sub-packed in the low Pyrex control injection bottle of 2-25ml after the assay was approved, every bottle of packing solution 4ml; The low Pyrex control injection bottle that branch is installed solution is put in the vacuum freezing drying oven, carries out vacuum lyophilization by cryodesiccated method, and quick-freezing is cooled to-20---and 50 ℃; Kept 1-6 hour, evacuation slowly is warming up to 35-40 ℃ under vacuum state; Take out after reducing to room temperature, add a cover butyl rubber plug, roll the envelope aluminium lid; Get product 18-55 hour drying time.
The product inspection result:
Character: white loose block and powder
Differentiate:
5. these article have absorption maximum in the wavelength of 274 ± 2nm and 223 ± 2nm
6. in the chromatogram that under the assay item, writes down, the retention time of need testing solution main peak should be consistent with the retention time of reference substance solution main peak.
Acidity: 6.0
Content: 101.5%
Other index is all up to specification.
Claims (1)
1. medicinal composition for injections that contains landiolol hydrochloride active ingredient is characterized in that per 1000 bottles are processed by following composition:
Hydrochloride landiolol 50g
Dextran 10 0g
3mol/L sodium dihydrogen phosphate or 3mol/L disodium phosphate soln are an amount of
Water for injection adds to 2L
Process 1000 bottles
Realize through following steps:
1) get water for injection 1500ml, regulate pH value 4.0-6.0 with the 3mol/L sodium dihydrogen phosphate, active medicine hydrochloride landiolol and dextran are added, stirring is all dissolved active medicine and excipient, is heated to 40-60 ℃;
2) solution for preparing is added active carbon, stirring and adsorbing 10-30 minute, remove by filter active carbon;
3) water for injection is added to 2000ml; The pH value 5.5-6.5 of reuse 3mol/L disodium phosphate soln; With 0.2-0.65 μ m filtering with microporous membrane, filtrating is sub-packed in the low Pyrex control injection bottle of 7ml after the assay was approved, every bottle of packing solution 2ml;
4) the low Pyrex control injection bottle that branch is installed solution is put in the vacuum freezing drying oven, carries out vacuum lyophilization by cryodesiccated method, 18-55 hour drying time;
5) cryodesiccated method step is following: quick-freezing is cooled to-20--50 ℃, keeps 1-6 hour, and evacuation slowly is warming up to 35-40 ℃ under vacuum state, takes out after reducing to room temperature, adds a cover butyl rubber plug, rolls the envelope aluminium lid, gets product.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008101533510A CN101732319B (en) | 2008-11-26 | 2008-11-26 | Landiolol hydrochloride active ingredient-containing medicinal composition for injection and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008101533510A CN101732319B (en) | 2008-11-26 | 2008-11-26 | Landiolol hydrochloride active ingredient-containing medicinal composition for injection and preparation method thereof |
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| Publication Number | Publication Date |
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| CN101732319A CN101732319A (en) | 2010-06-16 |
| CN101732319B true CN101732319B (en) | 2012-11-07 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102475706A (en) * | 2010-11-28 | 2012-05-30 | 天津市汉康医药生物技术有限公司 | Landiolol hydrochloride medicine composition for injection and preparation method thereof |
| EP2796139A1 (en) | 2013-04-26 | 2014-10-29 | AOP Orphan Pharmaceuticals AG | Use of landiolol hydrochloride in the long-term treatment of tachyarrhythmias |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1827109A (en) * | 2006-04-14 | 2006-09-06 | 北京润德康医药技术有限公司 | Lyophilized injection powder using Lanluodier and its salt as active ingredients and preparing technique therefor |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1827109A (en) * | 2006-04-14 | 2006-09-06 | 北京润德康医药技术有限公司 | Lyophilized injection powder using Lanluodier and its salt as active ingredients and preparing technique therefor |
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