CN102144963B - Citicoline sodium glucose injecta and preparation process thereof - Google Patents
Citicoline sodium glucose injecta and preparation process thereof Download PDFInfo
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- CN102144963B CN102144963B CN2010101066239A CN201010106623A CN102144963B CN 102144963 B CN102144963 B CN 102144963B CN 2010101066239 A CN2010101066239 A CN 2010101066239A CN 201010106623 A CN201010106623 A CN 201010106623A CN 102144963 B CN102144963 B CN 102144963B
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Abstract
The invention discloses a citicoline sodium glucose injecta and a preparation process thereof. The citicoline sodium glucose injecta mainly contains the active ingredients: citicoline sodium, isotonic agent glucose, a stabilizer, a pH regulator and water for injection, wherein the stabilizer is selected from one or two of malic acid, sale compounds thereof and sulfite compounds; the pH regulator is one or more of sodium hydroxide, hydrochloric acid, malic acid and apple sodium; the weight ratio of the active ingredients of the Citicoline sodium to the isotonic agent glucose is 1:(20-100), the weight ratio of the active ingredients of the citicoline sodium to the stabilizer is 1:(0.02-2), and the stabilizer is added to solve the problem of unstable heating and excessive related substances of the injecta in the production and storage process and improve the quality stability and the safe validation of medicaments.
Description
Technical field
The present invention relates to Western medicine medicine and preparation technology thereof, particularly relate to citicoline sodium glucose injection and preparation technology thereof.
Background technology
The chemical name of citicoline sodium glucose injection principal agent is: single sodium salt of choline cytidine diphosphate ester.
This product is nucleoside derivates, citicoline can strengthen reticular formation of brain stem, especially with consciousness closely-related up network structure activation system function; Increase pyramidal system's function, improve paralysis motorica; Improve large cerebral circulation, by reducing large Brain blood obstruction, increase large cerebral blood flow and promote the brain matter metabolism, to promoting brain function to recover and promotion is revived etc. and to be had certain effect.
This product is in production and storage, and quality investigation index related substance raises, and has recorded citicoline sodium glucose injection in 2010 editions Chinese Pharmacopoeias having promulgated, and related substance is stipulated comparatively strictly.And there is the problem that heat stability is relatively poor and related substance exceeds standard in existing citicoline sodium glucose injection.
Summary of the invention
The purpose of this invention is to provide the better citicoline sodium glucose injection of a kind of stability.
The object of the present invention is achieved like this: a kind of citicoline sodium glucose injection, mainly formed by active component C14H25N4NaO11P2 and isotonic agent glucose and water for injection, and also have stabilizing agent and pH adjusting agent;
Stabilizing agent is selected from one or both of malic acid and salt compounds and sulphite compounds;
PH adjusting agent is one or more of sodium hydroxide, hydrochloric acid, malic acid and natrium malicum;
The weight ratio of described active component C14H25N4NaO11P2 and isotonic agent glucose is 1: 20～100, and the weight ratio of active component C14H25N4NaO11P2 and stabilizing agent is 1: 0.02～2.
The aforementioned stable agent is malic acid and sodium sulfite, perhaps natrium malicum and sodium sulfite, perhaps malic acid and sodium pyrosulfite, perhaps natrium malicum and sodium sulfite.
Another purpose of the present invention provides the preparation technology of above-mentioned citicoline sodium glucose injection.
Another purpose of the present invention is achieved in that a kind of preparation technology of citicoline sodium glucose injection, mainly may further comprise the steps:
A, add an amount of water for injection in dense preparing tank, heating drops into glucose and the stabilizing agent of recipe quantity, and stirring and dissolving adds the injection active carbon of recipe quantity, boils 15 minutes, and solution is through the decarburization of titanium rod filter, and filtrate pumps in the dilute preparing tank;
B, the C14H25N4NaO11P2 that drops into recipe quantity in dilute preparing tank and an amount of pH adjusting agent add to the full amount of water for injection, and stir;
C, detect in medicinal liquid content and the pH value control scope 5.7～6.3 qualified after, medicinal liquid through the titanium rod filter, 0.22 μ m microporous filter membrane fine straining is to the visible foreign matters passed examination, fill upper butyl rubber plug, is sent sterilization after adding a cover, roll lid in glass infusion bottle;
D, sample be through 115 ℃, 30 minutes or 121 ℃, 8 minutes (best sterilising conditions) pressure sterilizings, offers for sale lamp inspection, product inspection and get final product after being cooled to below 60 ℃.
For the not good enough problem of existing citicoline sodium glucose injection stability, we study in great detail prescription and the production method thereof of this kind, have proposed new prescription and the preparation technology thereof of this kind under the prerequisite that guarantees drug safety and effectiveness.By the stability study to three batches of production samples, show sample is placed related substance after 3 months and is improved a lot than the stability of original prescription technique sample as a result.
Citicoline sodium glucose injection of the present invention has following advantage:
(1) citicoline sodium glucose injection, by adding stabilizing agent, solve citicoline sodium glucose injection and in production and storage, be subjected to thermally labile, the problem that related substance exceeds standard, improve the quality stability of citicoline sodium glucose injection and the safety and effectiveness of medicine, be conducive to the long-time preservation of medicine.2010 editions Chinese Pharmacopoeias have recorded this product, but most manufacturer adopts routine prescription technique can not produce qualified products, get this product optimization prescription by our institute, can provide high-quality reliable product for market, and better application prospect is arranged.
(2) citicoline among the present invention can strengthen reticular formation of brain stem, especially with consciousness closely-related up network structure activation system function; Increase pyramidal system's function, improve paralysis motorica; Improve large cerebral circulation, by reducing large Brain blood obstruction, increase large cerebral blood flow and promote the brain matter metabolism, to promoting brain function to recover and promotion is revived etc. and to be had certain effect.This product clinic is applied.
Citicoline sodium glucose injection preparation technology of the present invention is simple, easy to operate, is particularly suitable for large-scale industrial production.
The specific embodiment
Citicoline sodium glucose injection of the present invention mainly is comprised of C14H25N4NaO11P2 and the pharmaceutical carriers such as isotonic agent, stabilizing agent and pH adjusting agent as active component.This stabilizing agent is one or both of malic acid and its esters, sulphite compounds (comprising sodium sulfite, sodium sulfite, sodium pyrosulfite etc.), and the weight ratio of active component C14H25N4NaO11P2 and aforementioned stable agent respectively is: 1: 0.02～2.
Above-mentioned C14H25N4NaO11P2, isotonic agent, the stabilizing agent ratio in intravenous fluid is: C14H25N4NaO11P2 0.25g～0.5g, stabilizing agent adopt malic acid and sodium sulfite, malic acid 0.005g～1g wherein, sodium sulfite 0.005g～1g.
Above-mentioned pH value regulator is one or several of sodium hydroxide, hydrochloric acid, malic acid (natrium malicum).
Above-mentioned isotonic agent is: glucose
The acid of aforementioned stable agent preferably apple and sodium sulfite, isotonic agent select glucose, the preferred sodium hydroxide of pH adjusting agent.
Above-mentioned C14H25N4NaO11P2, glucose, malic acid and sodium sulfite (stabilizing agent preferred ingredient) are than being: contain C14H25N4NaO11P2 0.25g～0.5g, malic acid 0.005g～1g, sodium sulfite 0.005g～1g in every bottle of intravenous fluid, glucose is 5g～25g.
Embodiment 1:
Preparation prescription:
Principal agent: C14H25N4NaO11P2 2.5g
Isotonic agent: glucose 50g
Stabilizing agent: malic acid 0.5g
Sodium sulfite 0.5g
PH adjusting agent 10% sodium hydroxide is an amount of
Water for injection adds to 1000ml
Preparation technology:
(1), in dense preparing tank, add an amount of water for injection, heating drops into glucose, malic acid, the sodium sulfite of recipe quantity, stirring and dissolving adds the injection active carbon of recipe quantity, boils 15 minutes, solution takes off charcoal through titanium rod filter, filtrate pumps in the dilute preparing tank.
(2), in dilute preparing tank, drop into the C14H25N4NaO11P2 of recipe quantity and 10% an amount of sodium hydroxide solution, add to the full amount of water for injection, stir.
(3), detect medicinal liquid content and pH value (middle control scope 5.7～6.3) qualified after, medicinal liquid through titanium rod filter ,≤0.22 μ m microporous filter membrane fine straining is to the visible foreign matters passed examination, fill upper butyl rubber plug, is sent sterilization after adding a cover, roll lid in glass infusion bottle.
(4), sample is through 115 ℃ of 30min or 121 ℃ of 8min pressure sterilizings, offer for sale after being cooled to below 60 ℃.Lamp inspection, product inspection and get final product.
Embodiment 2:
Preparation prescription:
Principal agent: C14H25N4NaO11P2 2.5g
Isotonic agent: glucose 50g
Stabilizing agent: natrium malicum 0.5g
Sodium sulfite 0.5g
PH adjusting agent 10% sodium hydroxide is an amount of
Water for injection adds to 1000ml
Press the technique preparation of embodiment 1.
Embodiment 3:
Preparation prescription:
Principal agent: C14H25N4NaO11P2 2.5g
Isotonic agent: glucose 50g
Stabilizing agent: malic acid 0.5g
Sodium pyrosulfite 0.5g
PH adjusting agent 10% sodium hydroxide is an amount of
Water for injection adds to 1000ml
Press the technique preparation of embodiment 1.
Embodiment 4:
Preparation prescription:
Principal agent: C14H25N4NaO11P2 2.5g
Isotonic agent: glucose 50g
Stabilizing agent: natrium malicum 0.5g
Sodium sulfite 0.5g
PH adjusting agent 10% hydrochloric acid is an amount of
Water for injection adds to 1000ml
The citicoline sodium glucose injection indices that above-described embodiment makes is as follows by two controls of 2010 editions Chinese Pharmacopoeias:
1, character: colourless or almost colourless clear liquid;
2, pH value: 4.5～6.5 (primary standard is 3.5～5.5);
3, visible foreign matters: qualified;
4, sterility test: qualified;
5, particulate matter: qualified;
6, content: qualified;
7, related substance: single impurity must not cross 0.5%, and other impurity peaks must not be crossed 0.7% (primary standard must not be defined as 1.0%).
The stability test of citicoline sodium glucose injection
According to the citicoline sodium glucose injection quality standard this product has been carried out accelerated test and the test that keeps sample for a long time:
1, sample source:
Treating excess syndrome is executed 1 citicoline sodium glucose injection three batch sample A091001, A091002, A091003 as the stability test sample, provide simultaneously the study on the stability data by original prescription explained hereafter sample (lot number: B091001, B091002, B091003), to make comparisons.
2, mainly investigate project:
Character, pH value, visible foreign matters, content and related substance etc., and in 0 month and test end month aseptic and pyrogen of investigation.
3 methods of inspection:
According to " two citicoline sodium glucose injections of Chinese pharmacopoeia version in 2010 (containing exposure draft and formal version) quality standard check.
4 accelerated tests:
Experimental condition method: get test specimen by commercially available back, placing temperature is 40 ℃ ± 2 ℃ water isolation type electro-heating standing-temperature cultivator, in 1st month, 2 months, 3 months, 6 samplings at the end of month of duration of test once, detect by the main investigation project of stability, result of the test sees Table 1.
5 long term tests:
Experimental condition method: the test sample of getting three lot numbers, press commercially available back, place temperature be 25 ℃ ± 2 ℃, the water isolation type electro-heating standing-temperature cultivator, in duration of test sampling in 0th month, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months once, detect by the main investigation project of stability, result of the test sees Table 2.
Table 1 citicoline sodium glucose injection accelerated test result
Table 2 citicoline sodium glucose injection long-term test results
Result of the test as can be known from show: sample (black matrix part in the table) quality by the preparation of revision formulation and technology meets 2010 editions pharmacopeia regulations and better stable, and 3 months samples of accelerated test are investigated qualified, can reach 2 years so infer its effect duration.By the sample quality of original prescription technique preparation meet the proper mass standard code but its related substances reaches the limitation the upper limit, other total impurities amount does not meet 2010 editions pharmacopeia regulations, accelerate and long term test as a result related substance rising in 3 months more, less stable.
Investigate through above accelerated test and long term test, the result proves that citicoline sodium glucose injection proportion of composing of the present invention and preparation technology are practical, and end product quality is stable, has obvious stability advantage.
Claims (2)
1. citicoline sodium glucose injection is characterized in that: described injection composed as follows:
C14H25N4NaO11P2,2.5g; Glucose, 50g; Malic acid, 0.5g; Sodium sulfite, 0.5g; 10% sodium hydroxide is regulated pH to 5.7～6.3; Water for injection adds to 1000ml.
2. preparation technology according to the citicoline sodium glucose injection of claim 1 may further comprise the steps:
A, add an amount of water for injection in dense preparing tank, heating drops into glucose and the stabilizing agent of recipe quantity, and stirring and dissolving adds the injection active carbon of recipe quantity, boils 15 minutes, and solution is through the decarburization of titanium rod filter, and filtrate pumps in the dilute preparing tank;
B, the C14H25N4NaO11P2 that drops into recipe quantity in dilute preparing tank and an amount of pH adjusting agent add to the full amount of water for injection, and stir;
C, detect in medicinal liquid content and the pH value control scope 5.7～6.3 qualified after, medicinal liquid through the titanium rod filter, 0.22 μ m microporous filter membrane fine straining is to the visible foreign matters passed examination, fill upper butyl rubber plug, is sent sterilization after adding a cover, roll lid in glass infusion bottle;
D, sample be through 115 ℃, 30 minutes or 121 ℃, 8 minutes pressure sterilizings, offers for sale lamp inspection, product inspection and get final product after being cooled to below 60 ℃.
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| CN2010101066239A CN102144963B (en) | 2010-02-05 | 2010-02-05 | Citicoline sodium glucose injecta and preparation process thereof |
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| CN102144963B true CN102144963B (en) | 2013-04-10 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103239392B (en) * | 2012-02-09 | 2015-01-07 | 四川科伦药物研究有限公司 | Ornidazole injection preparation and preparation method |
| CN103006550A (en) * | 2012-12-11 | 2013-04-03 | 哈药集团三精制药股份有限公司 | Citicoline sodium injection and preparation method thereof |
| CN104027304B (en) * | 2014-06-04 | 2015-05-27 | 回音必集团(江西)东亚制药有限公司 | Citicoline sodium glucose injection |
| CN107468705A (en) * | 2017-09-01 | 2017-12-15 | 济南康和医药科技有限公司 | A kind of compound electrolyte glucose injection and preparation method thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1395935A (en) * | 2002-08-23 | 2003-02-12 | 李大鹏 | Citicoline sodium injection for intravenous injection and its preparing process |
| CN1559613A (en) * | 2004-03-10 | 2005-01-05 | 杨喜鸿 | Medicinal invert sugar injection |
| CN1803126A (en) * | 2006-01-24 | 2006-07-19 | 贵阳云岩西创药物科技开发有限公司 | Compound nicholin formulation and its preparation method and uses |
| CN101032487A (en) * | 2006-03-07 | 2007-09-12 | 苑立超 | Levofloxacin mesylate transfusion and the preparing method |
| CN101361739A (en) * | 2007-08-09 | 2009-02-11 | 太景生物科技股份有限公司 | Anti-bacteria agent for parenteral administration |
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- 2010-02-05 CN CN2010101066239A patent/CN102144963B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1395935A (en) * | 2002-08-23 | 2003-02-12 | 李大鹏 | Citicoline sodium injection for intravenous injection and its preparing process |
| CN1559613A (en) * | 2004-03-10 | 2005-01-05 | 杨喜鸿 | Medicinal invert sugar injection |
| CN1803126A (en) * | 2006-01-24 | 2006-07-19 | 贵阳云岩西创药物科技开发有限公司 | Compound nicholin formulation and its preparation method and uses |
| CN101032487A (en) * | 2006-03-07 | 2007-09-12 | 苑立超 | Levofloxacin mesylate transfusion and the preparing method |
| CN101361739A (en) * | 2007-08-09 | 2009-02-11 | 太景生物科技股份有限公司 | Anti-bacteria agent for parenteral administration |
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Address after: 611138 Sichuan science and Technology Development Zone, Wenjiang District, Chengdu City, Xinhua Road, the central section of the two paragraph Patentee after: SICHUAN KELUN DRUG RESEARCH INSTITUTE CO., LTD. Address before: Jinli Street West Qingyang District of Chengdu City, Sichuan province Jinjiang 610072 South Garden era No. 107 No. 3 18 floor Patentee before: Kelun Pharmaceutical Research Co., Ltd. |
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Effective date of registration: 20160714 Address after: 414100 eco industrial park, Yueyang County, Yueyang, Hunan, Hunan Patentee after: Hunan Kelun Pharmaceutical Co., Ltd. Address before: 611138 Sichuan science and Technology Development Zone, Wenjiang District, Chengdu City, Xinhua Road, the central section of the two paragraph Patentee before: SICHUAN KELUN DRUG RESEARCH INSTITUTE CO., LTD. |