CN102949337B - Gemcitabine hydrochloride injection and preparation method thereof - Google Patents
Gemcitabine hydrochloride injection and preparation method thereof Download PDFInfo
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- CN102949337B CN102949337B CN201210438346.0A CN201210438346A CN102949337B CN 102949337 B CN102949337 B CN 102949337B CN 201210438346 A CN201210438346 A CN 201210438346A CN 102949337 B CN102949337 B CN 102949337B
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Abstract
The invention relates to gemcitabine hydrochloride injection and a preparation method of the gemcitabine hydrochloride injection. Specifically, 1ml of gemcitabine hydrochloride injection comprises the following components of 30-70mg of gemcitabine hydrochloride, 1-5mg of NaCl, 10-50mg of hydroxypropyl-beta-cyclodextrin and 1-10mg of pH (Potential of Hydrogen) regulator. The gemcitabine hydrochloride injection provided by the invention is better in stability, simple in preparation and convenient in use, and can reduce the pollution ways of drugs.
Description
Technical field
The present invention relates to ejection preparation of a kind of antitumor drug and preparation method thereof, relate in particular to gemcitabine hydrochloride injection and preparation method thereof.
Background technology
Gemcitabine, English name is Gemcitabine, chemistry 2 '-deoxidation-2 ' by name, 2 '-bis-fluorine adenosines (β-isomer), molecular formula is C
9h
11f
2n
3o
4, molecular weight is 263.1.Its preparation is gemcitabine hydrochloride, and molecular formula is C
9h
11f
2n
3o
4hCl, molecular weight is 299.66.Gemcitabine hydrochloride be a kind of white to pale solid, soluble in water, be slightly soluble in methanol, be insoluble to ethanol and polar organic solvent.Structural formula is as follows:
Gemcitabine is a kind of antitumor drug that U.S. Lilly company produces, the first-line drug through U.S. FDA approval conduct treatment cancer of pancreas in 1996, and approval in 1998 is as treatment nonsmall-cell lung cancer medicine.China was in the approval of import in 1999.
FDA ratifies two kinds of dosage forms: freeze-dried powder and injection.Gemcitabine hydrochloride is in the market lyophilized injectable powder, and its reason is that gemcitabine hydrochloride injection is unstable, can not long-term storage.But compare with pharmaceutical solutions, freeze dried powder has complex process, and production cost is high, need to inject solution and dissolve, use inconvenience and increased the defects such as chance of drug contamination.
Patent application CN1181829C also provides a kind of injection of gemcitabine hydrochloride, and it makes the aqueous solution of water, ethanol, propylene glycol or mannitol as solvent, but the gemcitabine hydrochloride poor stability that this application makes is difficult for preserving.It is reported, gemcitabine hydrochloride is placed and is decomposed to 86% in 4 weeks in 0.1N hydrochloric acid solution under 40 ℃ of conditions, under the alkali condition of 0.1N sodium hydroxide, decomposes to 72%.Therefore, require clinically must within 24 hours, use after the dissolving of gemcitabine hydrochloride lyophilized formulations.
Therefore, need a kind of good stability of exploitation on market badly, preparation technology is simple, gemcitabine hydrochloride injection easy to use.
Summary of the invention
The present invention is intended to solve the problems of the technologies described above, provide a kind of stability better, prepare gemcitabine hydrochloride injection simple and easy to use, in every milliliter of injection, contain the gemcitabine hydrochloride of 30-70mg, the HP-β-CD of the NaCl of 1-5mg, 10-50mg and the pH adjusting agent of 1-10mg.Optional, injection of the present invention can also comprise the conventional adjuvant of other injection.
Preferably, the gemcitabine hydrochloride that contains 50-60mg in every milliliter of injection, the NaCl of 3-5mg, the pH adjusting agent of the HP-β-CD of 25-30mg and 3-8mg.
Preferably, in described injection, the weight ratio of gemcitabine hydrochloride and HP-β-CD is 2:1.
Preferably, described pH adjusting agent is selected from one or both in sodium hydrogen phosphate or potassium metabisulfite.
The present invention also aims to provide a kind of method of preparing described gemcitabine hydrochloride injection, comprise the steps:
-gemcitabine hydrochloride is dissolved with solvent for injection;
-add sodium chloride and HP-β-CD, heating for dissolving;
-add pH adjusting agent, and to make pH value be 4-7;
-use water for injection standardize solution, filter bottling.
Wherein, the solvent for injection that dissolves gemcitabine hydrochloride in described preparation method can be water for injection, ethanol, propylene glycol or glycerol, preferably water for injection or ethanol, more preferably 30% alcoholic solution.
Through research, inventor is surprised to find, and uses preparation prescription of the present invention can make gemcitabine hydrochloride injection keep extraordinary stability.Gemcitabine hydrochloride freeze-dried powder complicated with respect to using, that opportunities for contamination is many, has higher clinical value.At relative humidity, be 75% ± 5%, ambient temperature is under the condition of 40 ℃, sample of the present invention can at least be deposited more than 6 months, and this defect that need use within 24 hours after preparation with respect to freeze-dried powder has obtained very big progress, and has facilitated medical personnel's use.Meanwhile, because preparation of the present invention is injection, therefore do not need to prepare link, reduced the contaminated approach of medicine.
The specific embodiment
To further illustrate the present invention by specific embodiment below, but within this does not represent that the present invention is only defined in the express ranges of specific embodiment.
Embodiment 1:(1000 bottle)
Press recipe quantity, gemcitabine hydrochloride is joined in 30% alcoholic solution of 1000ml, dissolve and stir, then add sodium chloride and HP-β-CD, heating for dissolving, adds sodium dihydrogen phosphate by pH regulator to 6, uses water for injection standardize solution.Solution is delivered in sterilizing room, through 0.22 μ m filtering with microporous membrane, to clarification, by the loading amount of every bottle of 6ml, be filled in the cillin bottle of 25ml, beyond the Great Wall butyl rubber bung.
Embodiment 2:(1000 bottle)
Press recipe quantity, gemcitabine hydrochloride is joined in the water for injection of 1000ml, dissolve and stir, then add sodium chloride and HP-β-CD, heating for dissolving, adds sodium dihydrogen phosphate by pH regulator to 6, uses water for injection standardize solution.Solution is delivered in sterilizing room, through 0.22 μ m filtering with microporous membrane, to clarification, by the loading amount of every bottle of 6ml, be filled in the cillin bottle of 25ml, beyond the Great Wall butyl rubber bung.
Embodiment 3:(1000 bottle)
Press recipe quantity, gemcitabine hydrochloride is joined in 30% alcoholic solution of 1000ml, dissolve and stir, then add sodium chloride and HP-β-CD, heating for dissolving, adds sodium dihydrogen phosphate by pH regulator to 6, uses water for injection standardize solution.Solution is delivered in sterilizing room, through 0.22 μ m filtering with microporous membrane, to clarification, by the loading amount of every bottle of 6ml, be filled in the cillin bottle of 25ml, beyond the Great Wall butyl rubber bung.
Embodiment 4:(1000 bottle)
Press recipe quantity, gemcitabine hydrochloride is joined in 30% alcoholic solution of 1000ml, dissolve and stir, then add sodium chloride and HP-β-CD, heating for dissolving, adds sodium dihydrogen phosphate by pH regulator to 6, uses water for injection standardize solution.Solution is delivered in sterilizing room, through 0.22 μ m filtering with microporous membrane, to clarification, by the loading amount of every bottle of 6ml, be filled in the cillin bottle of 25ml, beyond the Great Wall butyl rubber bung.
Embodiment 5:(1000 bottle)
Press recipe quantity, gemcitabine hydrochloride is joined in 30% alcoholic solution of 1000ml, dissolve and stir, then add sodium chloride and HP-β-CD, heating for dissolving, adds potassium metabisulfite by pH regulator to 6, uses water for injection standardize solution.Solution is delivered in sterilizing room, through 0.22 μ m filtering with microporous membrane, to clarification, by the loading amount of every bottle of 6ml, be filled in the cillin bottle of 25ml, beyond the Great Wall butyl rubber bung.
Embodiment 6:(1000 bottle)
Press recipe quantity, gemcitabine hydrochloride is joined in 30% alcoholic solution of 1000ml, dissolve and stir, then add sodium chloride and HP-β-CD, heating for dissolving, adds sodium bicarbonate by pH regulator to 6, uses water for injection standardize solution.Solution is delivered in sterilizing room, through 0.22 μ m filtering with microporous membrane, to clarification, by the loading amount of every bottle of 6ml, be filled in the cillin bottle of 25ml, beyond the Great Wall butyl rubber bung.
For further proof effect of the present invention, the inventor has carried out stability of drug products experiment, has measured under different condition the content of gemcitabine hydrochloride in each embodiment sample.
Assay method: high performance liquid chromatography
Experimental apparatus: Waters chromatograph, C18 pillar
Measure wavelength: 275nm
Mobile phase: methanol: water=90:10
Flow velocity: 1ml/min
Experimental example 1
As can be seen here, the prescription sample stability of embodiment 1 is fine, can compared with under exacting terms, deposit longer time, the stability of embodiment 3, embodiment 4, embodiment 5 also shows well, the stability data of embodiment 6 is relatively poor.
Claims (3)
1. a gemcitabine hydrochloride injection, it is characterized in that, in every milliliter of injection, contain the gemcitabine hydrochloride of 30-70mg, the HP-β-CD of the NaCl of 1-5mg, 10-50mg and the pH adjusting agent of 1-10mg, described pH adjusting agent is selected from sodium hydrogen phosphate, described injection regulates pH to 6 by pH adjusting agent before standardize solution, in described injection, the weight ratio of gemcitabine hydrochloride and HP-β-CD is 2:1, and described injection needs gemcitabine hydrochloride to join in 30% alcoholic solution and dissolve in the preparation.
2. gemcitabine hydrochloride injection as claimed in claim 1, is characterized in that, contains the gemcitabine hydrochloride of 50-60mg, the HP-β-CD of the NaCl of 3-5mg, 25-30mg and the pH adjusting agent of 3-8mg in every milliliter of injection.
3. a method of preparing the gemcitabine hydrochloride injection as described in any one in claim 1-2, comprises the steps:
-by 30% dissolve with ethanol solution for gemcitabine hydrochloride;
-add sodium chloride and HP-β-CD, heating for dissolving;
-add pH adjusting agent, and to make pH value be 6;
-use water for injection standardize solution, filter bottling.
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| CN201210438346.0A CN102949337B (en) | 2012-11-05 | 2012-11-05 | Gemcitabine hydrochloride injection and preparation method thereof |
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| CN201210438346.0A CN102949337B (en) | 2012-11-05 | 2012-11-05 | Gemcitabine hydrochloride injection and preparation method thereof |
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| CN102949337B true CN102949337B (en) | 2014-03-19 |
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| CN103585168A (en) * | 2013-11-27 | 2014-02-19 | 哈尔滨誉衡药业股份有限公司 | Medicine composition containing gemcitabine hydrochloride |
| CN104027303A (en) * | 2014-04-25 | 2014-09-10 | 北京依诺泰药物化学技术有限公司 | Aqueous gemcitabine hydrochloride solution injection and preparation method |
| CN106727363B (en) * | 2015-11-19 | 2021-01-05 | 济南高合医疗科技有限公司 | Pharmaceutical compositions of lyophilized forms of nucleoside phosphoramidate prodrugs |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1650883A (en) * | 2005-01-17 | 2005-08-10 | 黄家章 | Jixitabing hydrochloride solution type injection agent |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1650883A (en) * | 2005-01-17 | 2005-08-10 | 黄家章 | Jixitabing hydrochloride solution type injection agent |
Non-Patent Citations (1)
| Title |
|---|
| Brewster ME等.环糊精在注射剂中应用的前景.《国外医药－合成药、生化药、制药分册》.1990,第11卷(第6期),第360－362页. * |
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Address after: 222069 Jiangsu city in Lianyungang Province, the economic and Technological Development Zone, Road No. 9 Patentee after: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Address before: 222069 Jiangsu city in Lianyungang Province, the economic and Technological Development Zone, Road No. 9 Patentee before: Jiangsu best Pharmaceutical Co.,Ltd. Address after: 222069 Jiangsu city in Lianyungang Province, the economic and Technological Development Zone, Road No. 9 Patentee after: Jiangsu best Pharmaceutical Co.,Ltd. Address before: 222069 Jiangsu city in Lianyungang Province, the economic and Technological Development Zone, Road No. 9 Patentee before: JIANGSU HANSOH PHARMACEUTICAL Co.,Ltd. |