CN102178646B - Stable Tegafur injection and preparation method thereof - Google Patents
Stable Tegafur injection and preparation method thereof Download PDFInfo
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- CN102178646B CN102178646B CN201110104472.8A CN201110104472A CN102178646B CN 102178646 B CN102178646 B CN 102178646B CN 201110104472 A CN201110104472 A CN 201110104472A CN 102178646 B CN102178646 B CN 102178646B
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Abstract
The invention discloses stable Tegafur injection and a preparation method thereof. The stable Tegafur injection is prepared mainly by the following steps of: mixing Tegafur and water for injection; adjusting the pH value to be 10.5 to 12.0 by using sodium hydroxide solution and/or acidic solution; adding an antioxidant and a pH value buffering agent and introducing nitrogen to perform protection; and performing high-temperature sterilization to prepare the injection. By the method, the Tegafur injection can be more stable; high-temperature sterilization can be performed; relative substances are greatly reduced compared with those in the prior art; particularly, the problems that the pH value is reduced, the color of the solution is changed to yellow, visible foreign matters are detected to be unqualified and relative substances are detected to be unqualified in the high-temperature sterilization and storage process of the Tegafur injection adopting the products in the prior art are solved; and the stable Tegafur injection can guarantee that the products meet the rule of the medicament quality standard and contributes to clinic administration and popularization.
Description
Technical field
The invention belongs to medical technical field, particularly, relate to a kind of stable tegafur injection and preparation method thereof.
Background technology
Ftorafur is the derivant of fluorouracil, is converted to fluorouracil and brings into play its anti-tumor activity in vivo through liver activation, is clinically mainly used in treating digestive tract tumor, as gastric cancer, rectal cancer, cancer of pancreas, hepatocarcinoma, also can be used for breast carcinoma.The preparation formulation of current domestic listing mainly contains injection and oral formulations, and the bioavailability of this product oral formulations is poorer than injection, and clinical practice tegafur injection is more more.
In the tegafur injection quality standard that Chinese Pharmacopoeia version in 2010 is recorded, the pH value scope of regulation injection is 9.5～10.5, and the thin layer chromatography that the detection method of related substance in tegafur injection quality standard is recorded by Chinese Pharmacopoeia version in 2005 has been modified as the higher high performance liquid chromatography of accuracy in detection, the limit of fluorouracil in related substance is ordered≤1.0%.The existing production technology of domestic tegafur injection is generally that ftorafur raw material sodium hydroxide solution is dissolved and regulates the pH value of injection is 9.5～10.5, subpackage with after through 100 ℃ of pressure sterilizings 30 minutes, to obtain final product.Due to ftorafur dissolubility extreme difference, poor stability in aqueous solution, cause this product in production high temperature sterilize, transportation and storage process, easily to occur following problem: first, under long-term storage and winter low temperature condition, easily separate out the precipitate such as tiny white point, white piece, solution muddiness, cause the visible foreign matters check item of product defective.The second, pH declines fast, causes pH value check item defective.The 3rd, after high temperature sterilize the inspection of product related substance be above standard regulation 1.0%, solution colour flavescence, cause product related substance and colour of solution project defective.
For these reasons, the tegafur injection quality standard check that adopts tegafur injection that prior art is produced to record according to Chinese Pharmacopoeia version in 2010, may occur that the multiple inspection indexs such as visible foreign matters, pH value, solution colour, related substance are against regulation.Affect production and the clinical practice of tegafur injection, made troubles to clinical application and popularization.
Domestic published patent of invention (CN101897633A) " a kind of stable tegafur injection and preparation method thereof " solution of the above problems is, in prescription, add carbonate, regulating the pH value of injection with sodium hydroxide or hydrochloric acid solution is 10.0, use activated carbon adsorption related substance, after product fill without high temperature sterilize.The defect that this scheme exists be the tegafur injection produced in the time of the process without high temperature sterilize, although can solve, pH value declines and the problem of crystallize, once product through high temperature sterilize, there will be related substance inspection defective.As injection products, increased the risk of injection polluted bacteria without high temperature sterilize, cause clinical practice risk higher.In addition, the related substance of tegafur injection is mainly degraded and is produced because of principal agent in high temperature sterilize and put procedure, adopts activated carbon adsorption cannot solve the product problem that related substance increases in high temperature sterilize and put procedure in solution preparation process.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of stable tegafur injection and preparation method thereof.Find by creative work, this tegafur injection is more stable, the content of related substance fluorouracil reduces greatly compared with prior art, solves tegafur injection and adopts prior art products carrying out occurring in high temperature sterilize and storage process that pH value declines, solution colour flavescence, visible foreign matters inspection are defective, related substance checks underproof problem.
The present invention addresses the above problem adopted technical scheme: a kind of stable tegafur injection, mainly to be made by ftorafur and water for injection, and the pH value of described tegafur injection is 10.5～12.0.
The constituent of described tegafur injection also comprises antioxidant, and the concentration of described antioxidant is 1mg～10g/100ml.
Described antioxidant is at least one in Cys, sodium sulfite, aminoacid and VC cetylate.
The constituent of described tegafur injection also comprises pH value buffer agent, and the concentration of described pH value buffer agent is 1mg～10g/100ml.
Described pH value buffer agent is at least one in phosphate, citrate, acetate, carbonate, tartrate and lactate.
Described osmotic pressure regulator is at least one in glucose, sodium chloride, xylitol, mannitol, fructose.
As preferably, the constituent of a kind of stable tegafur injection of the present invention can also comprise osmotic pressure regulator, and the concentration of described osmotic pressure regulator is 0.5g～10g/100ml.
Described osmotic pressure regulator is at least one in glucose, sodium chloride, xylitol, mannitol, fructose.Sodium chloride consumption is preferably 0.9g/100ml; Glucose, xylitol, mannitol, fructose consumption are all preferably 5g/100ml～10g/100ml.
In technique scheme, " described osmotic pressure regulator is at least one in glucose, sodium chloride, xylitol, mannitol, fructose " refers to that described osmotic pressure regulator can be at least one in glucose, sodium chloride, xylitol, mannitol, fructose, can be also wherein several combination arbitrarily.
A preparation method for stable tegafur injection, comprises the steps:
(1) take ftorafur 1g～100g, antioxidant 10mg～50g, pH value buffer agent 10mg～50g;
(2) acid solution and/or sodium hydroxide are mixed with respectively the solution of any concentration, for subsequent use;
(3) get 40 ℃ of following water for injection 500ml, order adds antioxidant, pH value buffer agent, ftorafur successively, stir, with acid solution and/or sodium hydroxide solution adjusting pH value to 10.5～12.0 of step (2) preparation, supply 40 ℃ of following waters for injection to 1000ml;
(4) step (3) gained solution, adds active carbon, and addition is calculated according to 0.005g～0.5g/100ml, stirs 10～60 minutes, filters decarburization;
(5) by the extremely clarification of step (4) gained injection fine straining, inflated with nitrogen protection, fill, high temperature sterilize, to obtain final product.
In such scheme step (2), described acid solution and/or sodium hydroxide refer to that what add can be any in acid solution, sodium hydroxide, can be also that acid solution, sodium hydroxide are with arbitrary proportion proportioning; In step (2), add if the one in acid solution and sodium hydroxide, prepare in advance a kind of solution for standby of any concentration; If what add is two kinds of acid solution, sodium hydroxide, be mixed with respectively the solution for standby of any concentration.Described acid solution is the one in phosphoric acid, hydrochloric acid, lactate, acetic acid, citric acid, tartaric acid and acidic amino acid.
Described high temperature sterilize method is the one in following method: 10～45 minutes, 121 ℃ pressure sterilizings of 10～45 minutes, 115 ℃ pressure sterilizings of 100 ℃ of pressure sterilizings 8～15 minutes.
In sum, the invention has the beneficial effects as follows: the present invention makes tegafur injection more stable, and the content of related substance fluorouracil reduces greatly compared with prior art, having solved satisfactorily tegafur injection adopts prior art products carrying out occurring in high temperature sterilize and storage process that pH value declines, solution colour flavescence, visible foreign matters inspection are defective, related substance checks underproof problem, can guarantee that product meets the regulation of drug standard, is convenient to clinical application and popularization.
The present invention, by creative work, discloses a kind of stable tegafur injection and preparation method thereof.Research is found by experiment, pH value in the tegafur injection quality standard that Chinese Pharmacopoeia version in 2010 is recorded by 9.5～10.5 revisions to higher pH value 10.5～12.0 o'clock, in the prescription of this injection, add antioxidant, pH value buffer agent and inflated with nitrogen protection, can make tegafur injection more stable, can carry out high temperature sterilize, related substance reduces greatly compared with prior art, particularly having solved tegafur injection adopts prior art products carrying out occurring in high temperature sterilize and storage process that pH value declines, solution colour flavescence, visible foreign matters checks defective, related substance checks underproof problem.
The specific embodiment
Below in conjunction with embodiment, this technological invention is described in further detail, but the embodiment of this technological invention is not limited to this.
embodiment 1
A kind of stable tegafur injection and preparation method thereof, comprises the steps: that (1) takes ftorafur 1g～100g, antioxidant 10mg～50g, pH value buffer agent 10mg～50g; (2) acid solution and/or sodium hydroxide are mixed with respectively the solution of any concentration, for subsequent use; (3) get 40 ℃ of following water for injection 500ml, order adds antioxidant, pH value buffer agent, ftorafur successively, stir, it is 10.5～12.0 that the acid solution of preparing by step (2) and/or sodium hydroxide solution regulate pH value, supplies 40 ℃ of following waters for injection to 1000ml; (4) step (3) gained solution, adds active carbon, and described activated carbon dosage is 0.005g～0.5g/100ml, stirs 10～60 minutes, filters decarburization; (5) by the extremely clarification of step (4) gained injection fine straining, inflated with nitrogen protection, fill, high temperature sterilize, to obtain final product.
Composition and the content thereof of the concrete each component of the present embodiment are as follows:
Ftorafur 40.0g
Sodium sulfite 5.0g
Sodium lactate 10.0g
Lactic acid and/or sodium hydrate regulator solution pH value.
Lactic acid and/or sodium hydroxide are mixed with respectively 10%～20% solution, for subsequent use; Get 40 ℃ of following water for injection 500ml, order adds sodium sulfite, sodium lactate, ftorafur successively, stirs, and regulating pH value with the lactic acid solution of above-mentioned preparation and/or sodium hydroxide solution is 10.5～12.0, supplies 40 ℃ of waters for injection below to 1000ml; Gained solution, adds active carbon, and described activated carbon dosage is 0.1g/100ml, stirs 30 minutes, filters decarburization; Gained injection fine straining is to clarification, inflated with nitrogen protection, and fill, 121 ℃ of pressure sterilizings 8 minutes, to obtain final product.
embodiment 2
Composition and the content thereof of the concrete each component of the present embodiment are as follows:
Ftorafur 40.0g
Cys 2.0g
Sodium citrate 5.0g
Citric acid and/or sodium hydrate regulator solution pH value.
Citric acid and/or sodium hydroxide are mixed with respectively 10%～20% solution, for subsequent use; Get 40 ℃ of following water for injection 500ml, order adds Cys, sodium citrate, ftorafur successively, stir, regulating pH value with the citric acid solution of above-mentioned preparation and/or sodium hydroxide solution is 10.5～12.0, supplies 40 ℃ of waters for injection below to 1000ml; Gained solution, adds active carbon, and described activated carbon dosage is 0.1g/100ml, stirs 30 minutes, filters decarburization; Gained injection fine straining is to clarification, inflated with nitrogen protection, and fill, 115 ℃ of pressure sterilizings 30 minutes, to obtain final product.
embodiment 3
Composition and the content thereof of the concrete each component of the present embodiment are as follows:
Ftorafur 40.0g
Cys 5.0g
Sodium carbonate 20.0g
Hydrochloric acid and/or sodium hydrate regulator solution pH value.
Hydrochloric acid and/or sodium hydroxide are mixed with respectively 10%～20% solution, for subsequent use; Get 40 ℃ of following water for injection 500ml, order adds Cys, sodium carbonate, ftorafur successively, stirs, and regulating pH value with the hydrochloric acid solution of above-mentioned preparation and/or sodium hydroxide solution is 10.5～12.0, supplies 40 ℃ of waters for injection below to 1000ml; Gained solution, adds active carbon, and described activated carbon dosage is 0.1g/100ml, stirs 30 minutes, filters decarburization; Gained injection fine straining is to clarification, inflated with nitrogen protection, and fill, 100 ℃ of pressure sterilizings 30 minutes, to obtain final product.
When the present invention specifically implements, antioxidant can be the one in Cys, sodium sulfite, aminoacid and VC cetylate, and its consumption is the arbitrary value in 1mg～10g/100ml, as 1mg/100ml, 5g/100ml, 10g/100ml.Ftorafur concentration can be the arbitrary value in 0.1g～10g/100ml, for example 0.1g/100ml, 5g/100ml and 10g/100ml.PH value buffer agent can be the one in phosphate, citrate, acetate, carbonate, tartrate and lactate, and its concentration can be the arbitrary value in 1mg～10g/100ml, for example 1mg/100ml, 5g/100ml and 10g/100ml.
embodiment 4
The comparative test of tegafur injection stability
Utilize the stability of the prepared tegafur injection of this technological invention fine, can make tegafur injection quality more stable, can carry out high temperature sterilize, related substance reduces greatly compared with prior art, has particularly solved tegafur injection and has adopted prior art products carrying out occurring that pH value, solution colour, visible foreign matters, related substance check underproof problem in high temperature sterilize and storage process.With prior art and utilize the prepared tegafur injection of this technological invention respectively according to the related request of two appendix XI X C pharmaceutical preparation stability test guidelines of Chinese Pharmacopoeia version in 2010, contrast has been investigated at 25 ℃ and has been placed 24 months, place 6 months for 40 ℃, 0～5 ℃ of low temperature place 10 days and different temperatures high temperature sterilize after the stability of medicine, result is utilized the prepared tegafur injection of this technological invention constant product quality under above-mentioned experimental condition, every detection index all meets the regulation of this product quality standard, obviously be better than the existing production technology of tegafur injection.
The pharmacological results shows: utilize the prepared stable tegafur injection of this technological invention without hemolytic, without anaphylaxis, nonirritant, meet the requirement of drug administration by injection.
Known according to the above results, the tegafur injection of this technological invention can make tegafur injection more stable, can carry out high temperature sterilize, related substance reduces greatly compared with prior art, particularly having solved tegafur injection adopts prior art products carrying out occurring in high temperature sterilize and storage process that pH value declines, solution colour flavescence, visible foreign matters inspection are defective, related substance checks underproof problem, can guarantee that the visible foreign matters inspection of product meets the regulation of drug standard, is convenient to clinical application and popularization.
As mentioned above, just can realize preferably this technological invention.
Claims (1)
1. a preparation method for stable tegafur injection, is characterized in that, described tegafur injection is made up of ftorafur, antioxidant, pH value buffer agent and water for injection, and described antioxidant is Cys, and pH value buffer agent is sodium carbonate; The preparation method of tegafur injection comprises the steps: to take ftorafur 40.0g, Cys 5.0g, sodium carbonate 20.0g; Hydrochloric acid and/or sodium hydroxide are mixed with respectively 10%～20% solution, for subsequent use; Get 40 ℃ of following water for injection 500ml, order adds Cys, sodium carbonate, ftorafur successively, stirs, and regulating pH value with the hydrochloric acid solution of above-mentioned preparation and/or sodium hydroxide solution is 10.5～12.0, supplies 40 ℃ of waters for injection below to 1000ml; Gained solution, adds active carbon, and described activated carbon dosage is 0.1g/100ml, stirs 30 minutes, filters decarburization; Gained injection fine straining is to clarification, inflated with nitrogen protection, and fill, 100 ℃ of pressure sterilizings 30 minutes, to obtain final product.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1526395A (en) * | 2003-08-20 | 2004-09-08 | 山东华鲁制药有限公司 | Tegafur-sodium chloride injection and its prepn |
| CN101897663A (en) * | 2009-05-31 | 2010-12-01 | 哈药集团生物工程有限公司 | Stable tegafur injection formula and preparation process thereof |
| CN102100667A (en) * | 2011-02-16 | 2011-06-22 | 山东华鲁制药有限公司 | Method for stabilizing tegafur in aqueous solution |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1526395A (en) * | 2003-08-20 | 2004-09-08 | 山东华鲁制药有限公司 | Tegafur-sodium chloride injection and its prepn |
| CN101897663A (en) * | 2009-05-31 | 2010-12-01 | 哈药集团生物工程有限公司 | Stable tegafur injection formula and preparation process thereof |
| CN102100667A (en) * | 2011-02-16 | 2011-06-22 | 山东华鲁制药有限公司 | Method for stabilizing tegafur in aqueous solution |
Non-Patent Citations (1)
| Title |
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| 毕殿洲.注射剂.《药剂学》.2003,(第四版),92、241-253. * |
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Denomination of invention: Stable Tegafur injection and preparation method thereof Effective date of registration: 20141120 Granted publication date: 20140604 Pledgee: China Huarong Asset Management Limited by Share Ltd Sichuan branch Pledgor: Sichuan Sunnyhope Pharmaceutical Co., Ltd. Registration number: 2014510000035 |
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Date of cancellation: 20180209 Granted publication date: 20140604 Pledgee: China Huarong Asset Management Limited by Share Ltd Sichuan branch Pledgor: Sichuan Sunnyhope Pharmaceutical Co., Ltd. Registration number: 2014510000035 |