CN1181829C - Jixitabin solution preparation - Google Patents
Jixitabin solution preparation Download PDFInfo
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- CN1181829C CN1181829C CNB00133414XA CN00133414A CN1181829C CN 1181829 C CN1181829 C CN 1181829C CN B00133414X A CNB00133414X A CN B00133414XA CN 00133414 A CN00133414 A CN 00133414A CN 1181829 C CN1181829 C CN 1181829C
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- gemcitabine
- injection
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- water
- alkali
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Abstract
The present invention discloses a pharmaceutical solution of Gemcitabine, which is composed of Gemcitabine alkali with medicine effective dose and pharmacologically acceptable solvent for injection.
Description
The present invention relates to a kind of pharmaceutical solutions of antitumor drug gemcitabine.
Gemcitabine (Gemcitabine), chemistry is by name 2 '-deoxidation-2 ', 2 '-difluoro cytidine, the β type; Molecular formula is C
9H
11F
2N
3O
4, molecular weight is 263.16, is a kind of effective antitumour medicine, the preparation of listing is the lyophilization injectable powder of its hydrochlorate at present.Gemcitabine hydrochloride is unstable in aqueous solution, and gemcitabine hydrochloride around placing under the 40 degree conditions, decomposes to 86% in the 0.1N hydrochloric acid solution according to research reports; Under the alkali condition of 0.1N sodium hydroxide, only remain 72% around under 40 degree conditions, placing.Therefore require gemcitabine hydrochloride lyophilized formulations dissolving back in 24 hours, must use clinically.Because it is acid that its hydrochlorate preparation is in aqueous solution, pH is about 2.0, so freeze dried powder must add the pH regulator agent and just can meet injection in the requirement more than 4.Even gemcitabine hydrochloride preparation pH value scope like this, in the market is still about 2.7～3.3.
In the medicine almost the injection more than 95% be the aqueous solution dosage form.Have only unsettled medicine just to adopt freeze dried powder, freeze dried powder and aqueous solution relatively have following shortcoming: 1. production cost height; 2. complex process, working condition requires high; 3. use inconvenience, need to inject solution and dissolve again, increased the chance of polluting.
We are by discovering in a large number, use the gemcitabine base and make raw material, with gemcitabine base water, ethanol, propylene glycol, glycerol, etc. dissolving alone or in combination, also can add PVP (polyvinylpyrrolidone), can obtain stable Jixitabin solution preparation, its stability and curative effect are identical with freeze dried powder.Gemcitabine hydrochloride is a prodrug, enter the interior back of body under neutrallty condition, gemcitabine separates with hydrochloric acid, gemcitabine (being base) is activated gemcitabine nucleoside diphosphate (dFdCDP) or nucleoside triphosphate (dFdCTP) by the nucleoside kinase metabolism in cell, is produced the cytotoxicity of gemcitabine by these two active component combineds effect.Therefore the curative effect of gemcitabine hydrochloride and gemcitabine base is identical.
Jixitabin solution preparation of the present invention is realized in the following manner:
Raw material: the gemcitabine base,
Production technology: gemcitabine alkali water, ethanol, propylene glycol, glycerol are dissolved as solvent separately or with their combinations, in case of necessity can be to wherein adding an amount of PVP or mannitol.
The buffer system that is suitable for injection of the present invention is that those keep any buffer system of the PH scope of aqueous solution preparation at 4.5-9, comprise material and combinations thereof such as phosphoric acid, citric acid, sodium dihydrogen phosphate, sodium hydrogen phosphate, acetate, Ascorbate, lactate, carbonate, Tris, preferably citric acid and sodium hydrogen phosphate buffer system.PH scope after these two kinds of composition combinations is consistent with human internal environment's pH value, can avoid the zest to human body as far as possible, can not cause uncomfortable reaction after the injection, and this system composition has complexation of metal ions and prevents autooxidation simultaneously.
Injection of the present invention can also add any be suitable for using in the injection stabilizing agent, isotonic agent, antiseptic, cosolvent etc.The stabilizing agent that can select is as hetastarch, polyvinylpyrrolidone, carboxymethyl cellulose, hydroxyethyl-cellulose, ethyl oleate, sorbitol, triglyceride, dextrin etc.Isotonic agent can be a sodium chloride, calcium chloride, potassium chloride, sodium iodide, potassium iodide etc.Antiseptic can be benzyl alcohol, phenethanol, quaternary ammonium salt, methaform, sorbic acid, methyl butex etc., cosolvent can be nonionic surfactant such as polyoxyethylene 20 sorbitan monooleate, glycerol, sorbitol, mannitol, propylene glycol, glucose, etc., other can be used and also can add the useful adjuvant of injection of the present invention.
Gemcitabine injection of the present invention and gemcitabine hydrochloride lyophilized powder injection compare the effect of KB cell killing:
Concentration (ng/ml) and clone's number (± SD)
50 25 12.5 6.25 1.25 0
Gemcitabine injection 18 ± 3 120 ± 5 209 ± 6 312 ± 12 410 ± 13 489 ± 16
Gemcitabine hydrochloride freeze-dried powder 16 ± 2 129 ± 3 211 ± 7 301 ± 9 423 ± 11 476 ± 12
Jixitabin solution preparation and gemcitabine hydrochloride lyophilized powder injection stability compare:
Time (moon) and medicament contg (%)
0 1 2 3
Gemcitabine injection 100.0 99.8 100.1 99.6
Gemcitabine hydrochloride lyophilized powder injection 100.0 100.8 99.2 99.7
Change gemcitabine hydrochloride lyophilized powder injection into solution, indicate in the research aspect this stability of drug and the dissolubility to have obtained breakthrough.
The present invention is described by the following examples, and these embodiment should be as the restriction to content of the present invention.
Embodiment 1: get gemcitabine alkali 200mg, with a little distilled water for injection dissolving, dose distilled water for injection again to 8ml, divide in the peace bottle of the 1ml that packs into, make the intravenous fluid that concentration is the 25mg/ml/ bottle.
Embodiment 2: get gemcitabine alkali 200mg, with a little distilled water for injection dissolving, dose distilled water for injection again to 16ml, divide in the peace bottle of the 1ml that packs into, make the intravenous fluid that concentration is the 12.5mg/ml/ bottle.
Embodiment 3: get gemcitabine alkali 200mg, with a little distilled water for injection dissolving, dose distilled water for injection again to 32ml, divide in the peace bottle of the 1ml that packs into, make the intravenous fluid that concentration is the 6.25mg/ml/ bottle.
Embodiment 4: gemcitabine alkali 200mg, make the intravenous fluid that concentration is 150mg/ml with the glycerol dissolving.
Embodiment 5: gemcitabine alkali 200mg, make the intravenous fluid that concentration is 75mg/ml with the glycerol dissolving.
Embodiment 6: gemcitabine alkali 200mg, make the intravenous fluid that concentration is 50mg/ml with the glycerol dissolving.
Embodiment 7: gemcitabine alkali 200mg, make the intravenous fluid that concentration is 100mg/ml with the propylene glycol dissolving.
Embodiment 8: gemcitabine alkali 200mg, make the intravenous fluid that concentration is 50mg/ml with the propylene glycol dissolving.
Embodiment 9: gemcitabine alkali 200mg, make the intravenous fluid that concentration is 40mg/ml with dissolve with ethanol.
Embodiment 10: gemcitabine alkali 200mg, make the intravenous fluid that concentration is 20mg/ml with dissolve with ethanol.
Embodiment 11: gemcitabine alkali 200mg, water: glycerol=dissolving in 99: 1 makes the intravenous fluid that concentration is the 25mg/ml/ bottle.
Embodiment 12: gemcitabine alkali 200mg, water: glycerol=dissolving in 1: 99 makes the intravenous fluid that concentration is the 25mg/ml/ bottle.
Embodiment 13: gemcitabine alkali 200mg, water: glycerol=dissolving in 50: 50 makes the intravenous fluid that concentration is the 25mg/ml/ bottle.
Embodiment 14: gemcitabine alkali 200mg, water: the intravenous fluid that concentration is the 25mg/ml/ bottle is made in propylene glycol=dissolving in 99: 1.
Embodiment 15: gemcitabine alkali 200mg, water: propylene glycol=dissolving in 1: 99 makes the intravenous fluid that concentration is the 25mg/ml/ bottle.
Embodiment 16: gemcitabine alkali 200mg, water: the intravenous fluid that concentration is the 25mg/ml/ bottle is made in propylene glycol=dissolving in 50: 50.
Embodiment 17: gemcitabine alkali 200mg, water: the intravenous fluid that concentration is the 25mg/ml/ bottle is made in ethanol=dissolving in 99: 1.
Embodiment 18: gemcitabine alkali 200mg, water: the intravenous fluid that concentration is the 25mg/ml/ bottle is made in ethanol=dissolving in 1: 99.
Embodiment 19: gemcitabine alkali 200mg, water: the intravenous fluid that concentration is the 25mg/ml/ bottle is made in ethanol=dissolving in 50: 50.
Embodiment 20: gemcitabine alkali 200mg, water: PVP=100: the intravenous fluid that concentration is the 25mg/ml/ bottle is made in 1 dissolving.
Embodiment 21: gemcitabine alkali 200mg, water: the intravenous fluid that concentration is the 25mg/ml/ bottle is made in mannitol=dissolving in 100: 1.
Embodiment 22: gemcitabine alkali 200mg, use phosphate buffered solution: mannitol: benzyl alcohol :=100: 1: 1: the intravenous fluid that concentration is the 25mg/ml/ bottle is made in dissolving.
Claims (8)
1. Jixitabin solution type injection, it consists of: the gemcitabine alkali of physiology effective dose, water, ethanol, propylene glycol, glycerol are made solvent and the available medicine acceptable auxiliary of preparation solution type injection agent separately or with their combinations.
2. the injection of claim 1, wherein solvent is a water.
3. the injection of claim 1, wherein solvent is an ethanol.
4. the injection of claim 1, wherein solvent is a propylene glycol.
5. the injection of claim 1, wherein solvent is a glycerol.
6. the injection of claim 1, wherein solvent is the mixed solvent of water and propylene glycol.
7. the injection of claim 1, wherein solvent is water and ethanol mixed solvent.
8. the injection of claim 1, wherein solvent is the mixed solvent of water and glycerol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB00133414XA CN1181829C (en) | 2000-11-03 | 2000-11-03 | Jixitabin solution preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB00133414XA CN1181829C (en) | 2000-11-03 | 2000-11-03 | Jixitabin solution preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1352944A CN1352944A (en) | 2002-06-12 |
| CN1181829C true CN1181829C (en) | 2004-12-29 |
Family
ID=4595704
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB00133414XA Expired - Fee Related CN1181829C (en) | 2000-11-03 | 2000-11-03 | Jixitabin solution preparation |
Country Status (1)
| Country | Link |
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| CN (1) | CN1181829C (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10323278A1 (en) | 2003-05-21 | 2004-12-16 | Stada Arzneimittel Ag | Ready-to-use gemcitabine solution concentrates |
| DE10323279A1 (en) | 2003-05-21 | 2004-12-16 | Stada Arzneimittel Ag | Ready-to-use gemcitabine solutions |
| CN1302782C (en) * | 2005-01-17 | 2007-03-07 | 北京京卫燕康药物研究所有限公司 | Jixitabing hydrochloride solution type injection agent |
| CN101088492B (en) * | 2006-06-12 | 2012-02-22 | 齐鲁制药(海南)有限公司 | Stable supersaturated gemcitabine hydrochloride solution and its preparation process |
| US20120129799A1 (en) * | 2009-07-31 | 2012-05-24 | Astron Research Limited | stable composition of ready-to-use gemcitabine injection |
| CN101606947B (en) * | 2009-08-06 | 2011-03-30 | 山东罗欣药业股份有限公司 | Gemcitabine hydrochloride composition and preparation method thereof |
| CN113577019A (en) * | 2012-04-27 | 2021-11-02 | 太阳医药工业有限公司 | Ready-to-fill gemcitabine solutions |
| CN102764241B (en) * | 2012-06-19 | 2013-07-03 | 哈药集团生物工程有限公司 | Freeze-dried pharmaceutical composition containing gemcitabine hydrochloride |
| 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 |
| TWI674097B (en) * | 2014-06-25 | 2019-10-11 | 英商努卡那公眾有限公司 | Formulations of phosphate derivatives |
| CN108440625A (en) * | 2018-04-18 | 2018-08-24 | 日照市普达医药科技有限公司 | A kind of Difluoronucleosides class antimetabolite anticarcinogen destroying cellular replication |
-
2000
- 2000-11-03 CN CNB00133414XA patent/CN1181829C/en not_active Expired - Fee Related
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| Publication number | Publication date |
|---|---|
| CN1352944A (en) | 2002-06-12 |
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