CN104906585A - Oxiracetam high-capacity injection composition and preparing method thereof - Google Patents
Oxiracetam high-capacity injection composition and preparing method thereof Download PDFInfo
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- CN104906585A CN104906585A CN201510267823.5A CN201510267823A CN104906585A CN 104906585 A CN104906585 A CN 104906585A CN 201510267823 A CN201510267823 A CN 201510267823A CN 104906585 A CN104906585 A CN 104906585A
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Abstract
The invention provides an oxiracetam high-capacity injection composition and a preparing method thereof. An oxiracetam high-capacity injection comprises oxiracetam as an active ingredient, sodium chloride or glucose as an isoosmotic adjusting agent, tartaric acid or malic acid as a pH modifier, and water for injection. The oxiracetam high-capacity injection has the advantages of being simple in prescription, high in stability, low in untoward effect, suitable for industrial production and the like.
Description
Technical field
The present invention relates to technical field of medicine, be specifically related to a kind of oxiracetam high-capacity injection composition and method of making the same.
Background technology
Venous transfusion is the main path of clinical treatment and first aid using medicine and supply nutrition, and medication infusion phlebitis is one of common clinically drug-induced disease.Generally believe at present, phlebitis forms one of venothrombotic risk factor.The pH value of blood of human body is 7.35-7.45, and the pH scope that human body can tolerate transfusion is 4-9.Transfusion pH lower than 4 or higher than 9 time, can cause pain and phlebitic generation, and the phlebitic order of severity is directly related with the pH of transfusion, pH value is lower, and phlebitis is more serious.Japan Otsuka Pharmaceutical Co., Ltd. Kuwahara etc. adopts rabbit to test, result show instillation pH value lower than 4.5 transfusion cause phlebitic incidence rate up to 100%, along with the continuous rising of transfusion pH value, the degree of phlebitic incidence rate and inflammation constantly declines, pH rise to 6.5 and more than, substantially there is not phlebitis.(Chinese medical forward position, 2009,4 (22): 13)
Oxiracetam (Oxiracetam) is pyrrolidinone compounds brain metabolism improving medicine, can be used for the memory ability and the learning capacity that improve alzheimer disease and memory disorder patient, develops listing in 1987 first by Italian ISF company.The chemistry of oxiracetam is called Esomeprazole, and molecular formula is C6H10N2O3, and structural formula is as follows:
Oxiracetam there is hydroxyl and carbonyl is positioned at pyrrole ring homonymy and heteropleural two kinds of situations, and the oxiracetam of these two kinds of space conformations is difficult to separately.Hydroxyl and carbonyl easily form intramolecular hydrogen bond when being positioned at the homonymy of pyrrole ring, and then cause oxiracetam dissolubility to reduce, and crystallize out, particularly more easily occurs in high temperature area.Containing amido link in oxiracetam molecule, it is unstable in aqueous, and under sterilising conditions, be easily hydrolyzed into the acid of impurity oxiracetam, in long storage periods, impurity also increases.
Prior art has some to study in the related substance controlling oxiracetam injection, but still there are some problems.Such as, oxiracetam injection related substance prepared by CN103505408A is higher, and pH value is about 3.7; The Oxiracetam sodium chloride injection that CN102512378B utilizes citric acid to prepare, although related substance controls better, the pH value of injection only can reach about 3.5.Being in human body can outside tolerable pH range, and phlebitic probability occurs after infusion to be increased greatly.And for example, although CN101732251 have employed complicated liposome technology, its related substances of its oxiracetam injection prepared is still more than 0.2%.
Therefore, how while effectively controlling oxiracetam injection its related substances, keep the pH value of injection in the scope that human body can tolerate, remain and need those skilled in the art to put forth effort the technical problem solved.
Summary of the invention
In years of researches work, we are surprised to find that, can the related substance of oxiracetam high-capacity injection be controlled in very low level by selecting specific pH adjusting agent (tartaric acid or malic acid), the pH value range of injection is also within the scope that human body can tolerate, and the preparation technology of oxiracetam high-capacity injection of the present invention is simple, with low cost, be very applicable to suitability for industrialized production.Accordingly, we complete the present invention.
Particularly, the invention provides a kind of oxiracetam high-capacity injection, it is composed as follows:
Wherein, described isoosmotic adjusting agent is sodium chloride or glucose, and pH adjusting agent is wherein selected from tartaric acid or malic acid.Wherein, the preferred sodium chloride of isoosmotic adjusting agent, the preferred 0.1-2.25g of consumption; The preferred tartaric acid of pH adjusting agent.
As the preferred technical solution of the present invention, wherein said pH is preferably adjusted to 4.5-5.5.
More specifically, the invention provides following oxiracetam high-capacity injection:
(1) an oxiracetam high-capacity injection, it is composed as follows:
(2) an oxiracetam high-capacity injection, it is composed as follows:
(3) an oxiracetam high-capacity injection, it is composed as follows:
(4) an oxiracetam high-capacity injection, it is composed as follows:
(5) an oxiracetam high-capacity injection, it is composed as follows:
In addition, present invention also offers the preparation method of described oxiracetam high-capacity injection, comprising: get supplementary material, add 80% water for injection to dissolve, regulate pH to be 4.0-6.0 by pH adjusting agent, add 0.01-0.1% active carbon, stirring and adsorbing 30 minutes, filtering decarbonization, adds water to full dose, detects, qualified rear use 0.22 μm of filter membrane fine straining, subpackage, 121 DEG C of sterilizings 15 minutes, to obtain final product.
The using dosage of the described oxiracetam high-capacity injection that the present invention relates to can be determined according to the judgement of clinician.
Design based on scientific and rational prescription, the related substance of oxiracetam high-capacity injection prepared by the present invention can control in extremely low level (0.03%-0.06%), and its pH value (4.0-6.0) is also applicable to infusion in human body very much simultaneously.In addition, the preparation technology of oxiracetam injection of the present invention is simple, with low cost, is very applicable to suitability for industrialized production.Therefore, compared with prior art, the present invention achieves outstanding substantive distinguishing features and significant technological progress.
Detailed description of the invention
Detailed description of the invention is only and further explains and describes the present invention, should not be interpreted as any limitation of the invention.
In embodiment, supplementary material used is commercial.
Embodiment 1 oxiracetam high-capacity injection of the present invention
Prescription:
Preparation method:
Get the supplementary material of recipe quantity, add 80% water for injection and dissolve, regulate pH to be 4.0-6.0 by pH adjusting agent, add 0.01-0.1% active carbon, stirring and adsorbing 30 minutes, filtering decarbonization, adds water to full dose, detects, qualified rear use 0.22 μm of filter membrane fine straining, subpackage, 121 DEG C of sterilizings 15 minutes, to obtain final product.
Embodiment 2 oxiracetam high-capacity injection of the present invention
Prescription:
Preparation method:
Get the supplementary material of recipe quantity, add 80% water for injection and dissolve, regulate pH to be 4.0-6.0 by pH adjusting agent, add 0.01-0.1% active carbon, stirring and adsorbing 30 minutes, filtering decarbonization, adds water to full dose, detects, qualified rear use 0.22 μm of filter membrane fine straining, subpackage, 121 DEG C of sterilizings 15 minutes, to obtain final product.
Embodiment 3 oxiracetam high-capacity injection of the present invention
Prescription:
Preparation method:
Get the supplementary material of recipe quantity, add 80% water for injection and dissolve, regulate pH to be 4.0-6.0 by pH adjusting agent, add 0.01-0.1% active carbon, stirring and adsorbing 30 minutes, filtering decarbonization, adds water to full dose, detects, qualified rear use 0.22 μm of filter membrane fine straining, subpackage, 121 DEG C of sterilizings 15 minutes, to obtain final product.
Embodiment 4 oxiracetam high-capacity injection of the present invention
Prescription:
Preparation method:
Get the supplementary material of recipe quantity, add 80% water for injection and dissolve, regulate pH to be 4.0-6.0 by pH adjusting agent, add 0.01-0.1% active carbon, stirring and adsorbing 30 minutes, filtering decarbonization, adds water to full dose, detects, qualified rear use 0.22 μm of filter membrane fine straining, subpackage, 121 DEG C of sterilizings 15 minutes, to obtain final product.
Embodiment 5 oxiracetam high-capacity injection of the present invention
Prescription:
Preparation method:
Get the supplementary material of recipe quantity, add 80% water for injection and dissolve, regulate pH to be 4.0-6.0 by pH adjusting agent, add 0.01-0.1% active carbon, stirring and adsorbing 30 minutes, filtering decarbonization, adds water to full dose, detects, qualified rear use 0.22 μm of filter membrane fine straining, subpackage, 121 DEG C of sterilizings 15 minutes, to obtain final product.
Reference examples 1 Oxiracetam sodium chloride injection (CN103505408A embodiment 1)
Prescription (description the 0028th section):
Preparation method (description 0029-0038 section):
(1) take formula ratio citric acid and sodium citrate, be dissolved in the water for injection of 80% formula ratio;
(2) take formula ratio oxiracetam and sodium chloride, be dissolved in above-mentioned solution;
(3) formula full dose is injected water to;
(4) solution 0.5% activated carbon adsorption 30 minutes;
(5) solution 0.45 μm and 0.22 μm of filter membrane filters successively;
(6) fill filtrate is in infusion bottle, jumps a queue, rolls lid;
(7) sample is in 121 × 15min moist heat sterilization;
(8) lamp inspection;
(9) packaging gets product.
Reference examples 2 Oxiracetam sodium chloride injection (CN102512378B embodiment 1)
Prescription (description 0052-0058 section):
Preparation method:
See patent (description the 0059th section):
In clean area, first by the citric acid of recipe quantity, sodium chloride adds in appropriate water for injection, stirring and dissolving, add the oxiracetam of recipe quantity again, be stirred to and dissolve completely, adjust ph is to 3.0-4.0, the active carbon getting the 0.1%-0.5% (W/V) accounting for solution total amount adds appropriate water for injection and stirs evenly, benefit injects water to bright (estimation should be " full dose ") entirely, agitation cycle more than 15 minutes, first coarse filtration takes off charcoal, by microporous filter membrane (such as 0.22 μm of filter membrane) fine straining, after microporous filter membrane fine straining, fine straining liquid can be got and carry out content, pH value, endotoxin, the projects such as visible foreign matters detect, qualified rear inflated with nitrogen, embedding, more than 121 DEG C pressure sterilizings 15 minutes, lamp inspection, obtain.
The quality of experimental example oxiracetam high-capacity injection and stability study
According to Chinese Pharmacopoeia version in 2010 two annex Ⅹ Ⅸ C crude drug and pharmaceutical preparation stability test guideline, carry out high temperature (60 DEG C ± 2 DEG C) and illumination (4500 ± 500LX) study on the stability, detect the quality of oxiracetam injection that embodiment 1-6 and reference examples 1-2 obtains, determination of related substances chromatographic condition: be filler with the octadecylsilane chemically bonded silica of embedded polar group; With 0.02mol/L tartaric acid solution for mobile phase; Flow velocity is 0.5ml/min, and determined wavelength is 210nm.Result is as follows:
The oxiracetam injection that embodiment 1-6 and reference examples 1-2 is obtained carries out accelerated test 6 months (40 DEG C ± 2 DEG C, RH75% ± 5%), and testing result is as follows:
Visible, the related substance of the oxiracetam injection that embodiment of the present invention 1-5 obtains stably can remain on the pole low-level of 0.03%-0.06%, and the related substance of reference examples 1 is then up to 0.15%-0.32%.On the other hand, the pH value of the oxiracetam injection that embodiment of the present invention 1-5 obtains also stably maintains between 4.8-5.5, compared with the pH3.5-3.7 of prior art reference examples 1-2, is more applicable to infusion in human body, reduces drug risk.
Claims (9)
1. an oxiracetam high-capacity injection, it is composed as follows:
。
2. oxiracetam high-capacity injection according to claim 1, wherein said isoosmotic adjusting agent is sodium chloride or glucose, and pH adjusting agent is tartaric acid or malic acid.
3. oxiracetam high-capacity injection according to claim 1, wherein said pH regulator is to 4.5-5.5.
4. oxiracetam high-capacity injection according to claim 1, it is composed as follows:
5. oxiracetam high-capacity injection according to claim 1, it is composed as follows:
6. oxiracetam high-capacity injection according to claim 1, it is composed as follows:
7. oxiracetam high-capacity injection according to claim 1, it is composed as follows:
8. oxiracetam high-capacity injection according to claim 1, it is composed as follows:
9. the preparation method of the arbitrary described oxiracetam high-capacity injection of claim 1-7, comprising: get supplementary material, adds 80% water for injection and dissolves, pH is regulated to be 4.0-6.0 by pH adjusting agent, add 0.01-0.1% active carbon, stirring and adsorbing 30 minutes, filtering decarbonization, add water to full dose, detect, qualified rear use 0.22 μm of filter membrane fine straining, subpackage, 121 DEG C of sterilizings 15 minutes, to obtain final product.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105412007A (en) * | 2015-12-15 | 2016-03-23 | 河北仁合益康药业有限公司 | Levetiracetam-sodium chloride injection compound and preparation method thereof |
| CN105434339A (en) * | 2015-12-15 | 2016-03-30 | 河北仁合益康药业有限公司 | Levetiracetam-sodium chloride injection composition and preparation method thereof |
| CN105477012A (en) * | 2015-12-15 | 2016-04-13 | 河北仁合益康药业有限公司 | Levetiracetam sodium chloride injection composition and preparation method thereof |
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| CN1424034A (en) * | 2002-12-03 | 2003-06-18 | 诸葛华明 | Preparing method of oxiracetam injection and products thereof |
| CN102512378A (en) * | 2011-12-09 | 2012-06-27 | 天津市汉康医药生物技术有限公司 | Stable and safe oxiracetam pharmaceutical composition for injection |
| CN102512363A (en) * | 2011-12-23 | 2012-06-27 | 重庆药友制药有限责任公司 | Oxiracetam injection and preparation method thereof |
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2015
- 2015-05-23 CN CN201510267823.5A patent/CN104906585A/en active Pending
Patent Citations (3)
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| CN1424034A (en) * | 2002-12-03 | 2003-06-18 | 诸葛华明 | Preparing method of oxiracetam injection and products thereof |
| CN102512378A (en) * | 2011-12-09 | 2012-06-27 | 天津市汉康医药生物技术有限公司 | Stable and safe oxiracetam pharmaceutical composition for injection |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105412007A (en) * | 2015-12-15 | 2016-03-23 | 河北仁合益康药业有限公司 | Levetiracetam-sodium chloride injection compound and preparation method thereof |
| CN105434339A (en) * | 2015-12-15 | 2016-03-30 | 河北仁合益康药业有限公司 | Levetiracetam-sodium chloride injection composition and preparation method thereof |
| CN105477012A (en) * | 2015-12-15 | 2016-04-13 | 河北仁合益康药业有限公司 | Levetiracetam sodium chloride injection composition and preparation method thereof |
| CN105412007B (en) * | 2015-12-15 | 2018-05-25 | 河北仁合益康药业有限公司 | A kind of Levetiracetam sodium chloride injection composition and preparation method thereof |
| CN105477012B (en) * | 2015-12-15 | 2018-08-17 | 河北仁合益康药业有限公司 | A kind of Levetiracetam sodium chloride injection composition and preparation method thereof |
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Address after: 051500 Haixing Road, Zhaoxian County Industrial Park, Shijiazhuang, Hebei Applicant after: HEBEI RENHE YIKANG PHARMACEUTICAL CO., LTD. Address before: 053411 Hengshui City, Hebei, Wuyi County, Qing Liang store town Applicant before: HEBEI RENHE YIKANG PHARMACEUTICAL CO., LTD. |
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