CN101088492A - Stable supersaturated gemcitabine hydrochloride solution and its prepn process - Google Patents
Stable supersaturated gemcitabine hydrochloride solution and its prepn process Download PDFInfo
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- CN101088492A CN101088492A CNA2006100446751A CN200610044675A CN101088492A CN 101088492 A CN101088492 A CN 101088492A CN A2006100446751 A CNA2006100446751 A CN A2006100446751A CN 200610044675 A CN200610044675 A CN 200610044675A CN 101088492 A CN101088492 A CN 101088492A
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- gemcitabine hydrochloride
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The present invention discloses stable supersaturated gemcitabine hydrochloride solution and its preparation process. Gemcitabine hydrochloride in certain amount is heated in pH 4-8 condition for being dissolved completely to obtain supersaturated gemcitabine hydrochloride solution of 45 g/l concentration, higher than the saturation concentration at 23 deg.c, and the supersaturated gemcitabine hydrochloride solution is packed in single dosage container while the solution is still hot. The supersaturated gemcitabine hydrochloride solution may be maintained at room temperature without separating out, and filling nitrogen and/or adding antioxidant can further raise the chemical stability. It may be used in preparing gemcitabine hydrochloride preparation for intravenous injection.
Description
Technical field
The present invention relates to supersaturated solution of a kind of medicine and preparation method thereof, be specifically related to supersaturated solution that contains gemcitabine hydrochloride and preparation method thereof.
Background technology
Gemcitabine, English name Gemcitabine, the 2 '-deoxidation-2 ' by name of its chemistry, 2 '-difluoro adenosine (β-isomer), molecular formula is C
9H
11F
2N
3O
4, molecular weight is 299.66.
Gemcitabine is the antitumor drug that U.S. Lilly drugmaker produces, and drugs approved by FDA in 1996 is as a line medicine for the treatment of cancer of pancreas, and approval in 1998 is as treatment non-small cell lung cancer drug.China was in the approval of import in 1999, and homemade imitation products ratifies to carry out clinical trial on June 15th, 2000.
The gemcitabine of producing both at home and abroad is gemcitabine hydrochloride lyophilized powder injection at present.Its reason is the Jixitabing hydrochloride solution type injection agent instability, can not store the long period.It is reported that gemcitabine hydrochloride is placed under 40 ℃ of conditions in the 0.1N hydrochloric acid solution decomposed to 86% in 4 weeks, decomposed to 72% under the alkali condition of 0.1N sodium hydroxide.
The ejection preparation of medicine has solution-type and dry powder doses, and unsettled medicine adopts dry powder doses, and medicine can be preserved the long period.Dry powder doses and aqueous solution compare: 1) complex process, production cost height; 2) need to inject the solution dissolving, use inconvenience, increased the chance of polluting; 3) gemcitabine hydrochloride aqueous solution pH2.5～3.0, the room temperature shelf-stability is relatively poor; 4) gemcitabine hydrochloride is in pH＞4 o'clock, and dissolubility reduces, and only is when being lower than 23 ℃ can not satisfy the requirement of preparation higher concentration injection by 15g/L (g/L is meant that the solution of every liter of volume contains the quality of gemcitabine, and is as follows).Therefore, the stability that solves Jixitabing hydrochloride solution has been arranged artificially and improved its dissolubility in pH＞4 environment, carried out a large amount of research.
CN00133414X has announced Jixitabin solution preparation, its to the effect that: the solvent of gemcitabine alkali and dissolving gemcitabine alkali.Production technology: with dissolvings such as gemcitabine alkali water, ethanol, propylene glycol.
CN1650883A has announced Jixitabing hydrochloride solution type injection agent, and this injection contains alkaline matter or salt of weak acid as stabilizing agent.The document is made raw material with gemcitabine hydrochloride, with the water for injection dissolving, adds stabilizing agent, isotonic agent, transfers the solution pH value 3.6～7.5, obtains stable injection of solution agent, and its stability meets the requirements.Gemcitabine hydrochloride is mixed with injection of solution agent and gemcitabine alkali is mixed with the injection of solution agent relatively, do not need to change the gemcitabine hydrochloride crude drug into the gemcitabine base, simplify production technology and reduce cost.The document is thought and has been solved Jixitabing hydrochloride solution injection problem of unstable under the meta-alkalescence condition of generally acknowledging both at home and abroad.
WO2005014010 has announced a kind of gemcitabine hydrochloride Pharmaceutical composition that contains cyclodextrin as solubilizing agent.The dissolubility of said composition gemcitabine hydrochloride under the condition of pH4～9 can reach 40g/L, and it is stable that room temperature is placed 2 years.
When preparing injection according to CN1650883A, under 23 ℃, pH4～7 conditions, the dissolubility of gemcitabine hydrochloride is 15g/L only, is difficult for the injection of preparation high concentration, and the solution that makes placed 10 days under 60 ℃ of conditions, and degradation product obviously increases.Though can make the dissolubility of gemcitabine hydrochloride reach 40g/L according to WO2005014010, need to add cyclodextrin as solubilizing agent; A large amount of cyclodextrin that studies have shown that have certain nephrotoxicity, so avoid using cyclodextrin in the preparation as far as possible.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of gemcitabine hydrochloride supersaturated solution and preparation method thereof is provided.
Gemcitabine hydrochloride supersaturated solution of the present invention, it is characterized in that under the condition of pH4～8, make quantitative gemcitabine hydrochloride be dissolved in solvent fully by heating, obtain concentration for surpassing the gemcitabine hydrochloride supersaturated solution of the saturated concentration of gemcitabine hydrochloride in the time of 23 ℃ (concentration in gemcitabine, as follows) to 45g/L.
Above-mentioned gemcitabine hydrochloride supersaturated solution needs the filtered while hot degerming, presses the direct fill of individual packaging dosage before the cooling to final seal of vessel; The no hydrochloric acid gemcitabine solid in product cooling back that obtains is separated out.According to the literature, under 23 ℃, pH4～8 conditions, the dissolubility of gemcitabine hydrochloride only is 15g/L.Gemcitabine hydrochloride supersaturated solution characteristics of the present invention are that concentration surpasses 15g/L in the time of 23 ℃, can reach 45g/L.
Preferably, the concentration of gemcitabine hydrochloride supersaturated solution is 20～40g/L.
Preferably, above-mentioned solvent is the isotonic aqueous solution of water or biocompatibility.PH value is preferred 5～7, most preferably pH6.
Preferably, above-mentioned gemcitabine hydrochloride dissolving heating-up temperature is 30～90 ℃, more preferably 45～80 ℃.
Preferably, charge into nitrogen in the gemcitabine hydrochloride supersaturated solution and/or add antioxidant, can further suppress the degraded of gemcitabine hydrochloride, wherein antioxidant is selected from pharmaceutically acceptable material.
Above-mentioned antioxidant is selected from but is not limited to: sulphite, ascorbic acid and derivant, thioated thing, amino acids, phenols, amine or chelating agen.Wherein sulfites is selected from: sodium sulfite, sodium sulfite, sodium metabisulfite or sodium thiosulfate; Ascorbic acid derivates is selected from ascorbic acid or the different bad hematic acid of D-; The thioated thing is selected from one or more in thioglycerol, 2 mercapto ethanol, 5-sulfo--D-glucose or the TGA; Amino acids is selected from one or more in L-cysteine or its salt, L-methionine, L-arginine, the L-tryptophan; Amine is selected from the pyridoxamine hydrochlorate; Chelating agen is selected from disodiumedetate or calcio-disodium edetate.
The dosage of above-mentioned antioxidant is 0.01%～0.5%W/V, mass volume ratio.
The preparation method of gemcitabine hydrochloride supersaturated solution of the present invention, be in pH4～8,30～90 ℃ of heating-up temperatures, the isotonic aqueous solution of quantitative gemcitabine hydrochloride is fully water-soluble or biocompatibility, form supersaturated solution, the concentration of gemcitabine is 15～45g/L, the filtered while hot degerming is pressed the direct fill of individual packaging dosage to final seal of vessel before the cooling.So just can not separate out crystallization.
For further improving the stability of gemcitabine hydrochloride supersaturated solution, can when packing final container into, charge into nitrogen and/or add antioxidant.The selection of antioxidant and consumption are as previously mentioned.
Above-mentioned solution temperature should not be too high, if temperature reaches 100 ℃, temperature retention time surpasses 5 hours, and degradation material increases obviously.The pH of solution also can not be too high, and when pH is transferred to more than 8,100 ℃ of temperature retention times surpass 4 hours, and degradation material also is significantly increased.
Well-known to those skilled in the art, for better controlling the pH of solution, can add buffer agent, as: carbonate, phosphate, lactate, acetate, citrate, maleate etc.The pH scope should not surpass 8, is not less than 4.Preferred pH5～7, most preferably pH value is 6.Buffer agent can be used alone or be used in combination.
In addition, well-known to those skilled in the art, can add isotonic agent in the solution, as sodium chloride, glucose, mannitol, contain potassium, calcium, the magnesium solution of physiological tolerance amount.Isotonic agent can be used alone or be used in combination.
Gemcitabine hydrochloride supersaturated solution provided by the invention has characteristics stable, high concentration, the pharmaceutical preparation that can be used for preparing intravenously administrable.
The stability study one of gemcitabine hydrochloride supersaturated solution is the physical stability (crystallize situation) of observing supersaturated solution, the one, and adopt high performance liquid chromatograph to measure content and its degradation material of gemcitabine hydrochloride.
In the stability test, content and determination of related substances method are: high performance liquid chromatograph is measured the content of gemcitabine.The Waters chromatograph, the C18 post is measured wavelength 268nm, mobile phase: ammonium acetate buffer-methanol=90: 10.
Below be injection stability test data of the present invention, in order to beneficial effect of the present invention to be described.
Table 1 prepares the contrast of sample physical stability with gemcitabine hydrochloride supersaturated solution of the present invention and prior art for preparing
| Gemcitabine hydrochloride concentration (23 ℃) | CN00133414 | CN1650883A | WO2005014010 (adding cyclodextrin) | Gemcitabine hydrochloride supersaturated solution of the present invention |
| 10g/L | Do not separate out crystal | Do not separate out crystal | Do not separate out crystal | Do not separate out crystal |
| 15g/L | Do not separate out crystal | Do not separate out crystal | Do not separate out crystal | Do not separate out crystal |
| 16g/L | Separated out in 10 days | Separated out in 10 days | Do not separate out crystal | Do not separate out crystal |
| 20g/L | Crystal was separated out in 2 days | Crystal was separated out in 2 days | Do not separate out crystal | Do not separate out crystal |
| 40g/L | Separate out crystal in the 2h | Separate out crystal in the 2h | Do not separate out crystal | Do not separate out crystal |
| 45g/L | Separate out crystal rapidly | Separate out crystal rapidly | Do not separate out crystal | Do not separate out crystal |
Table 2 contrasts with gemcitabine hydrochloride supersaturated solution of the present invention and prior art for preparing sample chemical stability
About 2.7, the 100 ℃ of 2h degraded of gemcitabine hydrochloride aqueous solution pH is more than 20%, and chemical stability is relatively poor; Describe as patent CN1650883AH and patent WO2005014010, between pH4～8, the chemical stability of gemcitabine hydrochloride aqueous solution is better, 100 ℃ of 2h degradeds about 3%, but, about 23 ℃, pH 4～8 o'clock, the dissolubility the highest 15g/L of gemcitabine hydrochloride in water, the requirement that does not reach preparation high concentration injection.And gemcitabine hydrochloride supersaturated solution of the present invention amazing be that concentration can reach 45g/L, and room temperature is down long-term places no solid and separate out.When being heated to Jixitabing hydrochloride solution more than at least 30 ℃, under the condition of pH4～8, can make the supersaturated solution of gemcitabine concentration 15～45g/L, this solution aseptic filtration direct packaging while hot seals in the final container of individual packaging dosage, the supersaturated solution that obtains can not separated out the gemcitabine hydrochloride solid, when adding antioxidant, its chemical stability is much better than the gemcitabine hydrochloride injection according to the CN1650883A preparation.
The present invention makes gemcitabine hydrochloride certain density, stable supersaturated solution first, adds the stability that antioxidant can further increase solution.This supersaturated solution can be used for preparing the solution type injection agent of gemcitabine hydrochloride.This supersaturated solution contains antioxidant as stabilizing agent, and the method for employing heating for dissolving is prepared into the supersaturated solution of hydrochloric gemcitabine.This supersaturated solution can prepare the pharmaceutical preparation of intravenous route administration.
The specific embodiment
Further specify the present invention by the following examples, these examples should be as restriction of the present invention.
Embodiment 1: get gemcitabine hydrochloride 227.7mg (containing gemcitabine 200mg), dissolve with 6ml water for injection, add 0.09g sodium chloride, add the 0.5N sodium hydroxide again, regulating pH is 4.5, above-mentioned solution is heated to 30～40 ℃, makes the crystallization dissolving of separating out complete, is settled to 10ml with water for injection.Aseptic filtration while hot then, be sub-packed in the ampoule of 10ml, every 10ml seals.
Embodiment 2: get gemcitabine hydrochloride 341.6mg (containing gemcitabine 300mg), dissolve with 6ml water for injection, add 0.09g sodium chloride, add the 0.5N sodium hydroxide again, regulating pH is 6.0, above-mentioned solution is heated to 50～60 ℃, makes the crystallization dissolving of separating out complete, is settled to 10ml with water for injection.Aseptic filtration while hot then, be sub-packed in the ampoule, inflated with nitrogen seals.
Embodiment 3: get gemcitabine hydrochloride 455mg (containing gemcitabine 400mg), with the dissolving of 6ml water for injection, add 0.09g sodium chloride, add the 0.5N sodium hydroxide again, regulating pH is 5.5, and above-mentioned solution is heated to 60～80 ℃, make the crystallization dissolving of separating out complete, be diluted to 10ml with water for injection.Aseptic filtration while hot then, be sub-packed in the ampoule of 5ml, every 5ml, inflated with nitrogen seals.
Embodiment 4: get gemcitabine hydrochloride 512mg (containing gemcitabine 450mg), dissolve with 6ml water for injection, add 10mg L-arginine and 0.09g sodium chloride, add the 0.5N sodium hydroxide then, regulating pH is 8.0, above-mentioned solution is heated to 45～50 ℃, makes the crystallization dissolving of separating out complete, is settled to 10ml with water for injection.Aseptic filtration while hot then, be sub-packed in the ampoule, seal.
Embodiment 5: get gemcitabine hydrochloride 455mg (containing gemcitabine 400mg), use the 6ml physiological saline solution, add 10mg L-arginine, add the 0.5N sodium hydroxide then, regulating pH is 6.0, above-mentioned solution is heated to 45～50 ℃, makes the crystallization dissolving of separating out complete, is settled to 10ml with normal saline.Aseptic filtration while hot then, be sub-packed in the cillin bottle of 5ml, every 5ml, inflated with nitrogen seals.
Embodiment 6: get gemcitabine hydrochloride 455mg (containing gemcitabine 400mg), dissolve with 6ml water for injection, add 15mg sodium sulfite and 0.09g sodium chloride, add the 0.5N sodium hydroxide again, regulating pH is 7.0, above-mentioned solution is heated to 45～50 ℃, makes the crystallization dissolving of separating out complete, is settled to 10ml with water for injection.Aseptic filtration while hot then, be sub-packed in the ampoule, inflated with nitrogen seals.
Embodiment 7: get gemcitabine hydrochloride 455mg (containing gemcitabine 400mg), dissolve with 6ml water for injection, add 5mg TGA and 0.09g sodium chloride, add the 0.5N sodium hydroxide then, regulating pH is 6.0, above-mentioned solution is heated to 45～50 ℃, makes the crystallization dissolving of separating out complete, is settled to 10ml with water for injection.Aseptic filtration while hot then, be sub-packed in the cillin bottle of 10ml, every 5ml seals.
Embodiment 8: get gemcitabine hydrochloride 455mg (containing gemcitabine 400mg), use the 6ml physiological saline solution, add 5mg L-arginine, 20mg L-methionine and 0.09g sodium chloride, add the 0.5N sodium hydroxide then, regulating pH is 4.5, and normal saline is settled to 10ml.Above-mentioned solution is heated to 80～90 ℃, makes the crystallization dissolving of separating out fully, aseptic filtration while hot then, is sub-packed in the ampoule, seals.
Embodiment 9: get gemcitabine hydrochloride 455mg (containing gemcitabine 400mg), disodiumedetate 0.9mg, with 50～60 ℃ of 6ml physiological saline solutions, add the 10mgL-arginine, add 1N sodium hydroxide 0.7ml then, regulating pH is 7.0, is settled to 10ml with 50～60 ℃ of normal saline.Aseptic filtration while hot then, be sub-packed in the ampoule, seal.
Embodiment 10: get gemcitabine hydrochloride 512mg (containing gemcitabine 450mg), dissolve with 6ml phosphate buffer (PH6.0), add 20mg ascorbic acid and 0.09g sodium chloride, add the 0.5N sodium hydroxide, regulating pH is 5.0, above-mentioned solution is heated to 45～50 ℃, makes the crystallization dissolving of separating out complete, is settled to 10ml with phosphate buffer.Aseptic filtration while hot then, be sub-packed in the ampoule, inflated with nitrogen seals.
Embodiment 11: get gemcitabine hydrochloride 455mg (containing gemcitabine 400mg), dissolve with 6ml phosphate buffer (PH6.0), add 50mg hydrochloric acid pyridoxamine and 0.09g sodium chloride, add the 0.5N sodium hydroxide again, regulating pH is 6.0, above-mentioned solution is heated to 45～50 ℃, makes the crystallization dissolving of separating out complete, is settled to 10ml with phosphate buffer.Aseptic filtration while hot then, be sub-packed in the ampoule, seal.
The product of above embodiment preparation all can be used as the medicinal application of intravenously administrable.
The stability test result of table 3 gemcitabine hydrochloride supersaturated solution
| The sampling test content | Stability under the different tests condition | ||
| Physical stability | Chemical stability (gemcitabine content %) | ||
| 2～8 ℃ 3 months | 0 day | 40 ℃ 3 months | |
| Embodiment 1 | No crystal is separated out | 99.8％ | 96.5％ |
| Embodiment 2 | No crystal is separated out | 100.5％ | 97.9％ |
| Embodiment 3 | No crystal is separated out | 100.3％ | 97.6％ |
| Embodiment 4 | No crystal is separated out | 99.7％ | 96.2％ |
| Embodiment 5 | No crystal is separated out | 99.9％ | 99.3％ |
| Embodiment 6 | No crystal is separated out | 100.7％ | 98.7％ |
| Embodiment 7 | No crystal is separated out | 100.2％ | 99.5％ |
| Embodiment 8 | No crystal is separated out | 100.6％ | 99.3％ |
| Embodiment 9 | No crystal is separated out | 99.8％ | 98.3％ |
| Embodiment 10 | No crystal is separated out | 100.4％ | 99.2％ |
| Embodiment 11 | No crystal is separated out | 99.6％ | 99.0％ |
Claims (11)
1. gemcitabine hydrochloride supersaturated solution, it is characterized in that under the condition of pH4～8, make quantitative gemcitabine hydrochloride be dissolved in solvent fully by heating, obtain concentration for surpassing the gemcitabine hydrochloride supersaturated solution of the saturated concentration of gemcitabine hydrochloride in the time of 23 ℃ to 45g/L.
2. the gemcitabine hydrochloride supersaturated solution described in claim 1 is characterized in that, described supersaturation concentration is 20～40g/L.
3. the gemcitabine hydrochloride supersaturated solution described in claim 1 is characterized in that, described solvent is the isotonic aqueous solution of water or biocompatibility.
4. the gemcitabine hydrochloride supersaturated solution described in claim 1 is characterized in that, described pH value 5～7, preferred pH 6.
5. the gemcitabine hydrochloride supersaturated solution described in claim 1 is characterized in that, described heating-up temperature is 30～90 ℃, preferred 45～80 ℃.
6. the gemcitabine hydrochloride supersaturated solution described in claim 1 is characterized in that, charges into nitrogen in the described gemcitabine hydrochloride supersaturated solution and/or adds antioxidant.
7. the gemcitabine hydrochloride supersaturated solution described in claim 6 is characterized in that, described antioxidant is selected from sulphite, ascorbic acid and derivant, thioated thing, amino acids, phenols, amine or chelating agen.
8. the gemcitabine hydrochloride supersaturated solution described in claim 7 is characterized in that, described sulphite is selected from: sodium sulfite, sodium sulfite, sodium metabisulfite or sodium thiosulfate; Described ascorbic acid derivates is selected from ascorbic acid or the different bad hematic acid of D-; Described thioated thing is selected from one or more in thioglycerol, 2 mercapto ethanol, 5-sulfo--D-glucose, the TGA.
9. the gemcitabine hydrochloride supersaturated solution described in claim 7 is characterized in that, described amino acids is selected from one or more in L-cysteine or its salt, L-methionine, L-arginine, the L-tryptophan; Described amine is selected from the pyridoxamine hydrochlorate; Described chelating agen is selected from disodiumedetate or calcio-disodium edetate.
10. the preparation method of a gemcitabine hydrochloride supersaturated solution, in pH4～8, heating-up temperature is under 30～90 ℃ of conditions, the isotonic aqueous solution of quantitative gemcitabine hydrochloride is fully water-soluble or biocompatibility, form supersaturated solution, the concentration of gemcitabine is 15～45g/L, the filtered while hot degerming is pressed the direct fill of individual packaging dosage to final seal of vessel before the cooling.
11. the application of each described gemcitabine hydrochloride supersaturated solution of claim 1～9 is used to prepare the preparation of intravenous route administration.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110383062.1A CN102406603B (en) | 2006-06-12 | 2006-06-12 | Supersaturated solution that gemcitabine hydrochloride is stable and preparation method thereof |
| CN2006100446751A CN101088492B (en) | 2006-06-12 | 2006-06-12 | Stable supersaturated gemcitabine hydrochloride solution and its preparation process |
| PCT/CN2007/001604 WO2007143895A1 (en) | 2006-06-12 | 2007-05-17 | Supersaturated solution of gemcitabine hydrochloride and prepraration method thereof |
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|---|---|---|---|
| CN2006100446751A CN101088492B (en) | 2006-06-12 | 2006-06-12 | Stable supersaturated gemcitabine hydrochloride solution and its preparation process |
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| CN201110383062.1A Division CN102406603B (en) | 2006-06-12 | 2006-06-12 | Supersaturated solution that gemcitabine hydrochloride is stable and preparation method thereof |
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| CN101088492B CN101088492B (en) | 2012-02-22 |
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| CN2006100446751A Active CN101088492B (en) | 2006-06-12 | 2006-06-12 | Stable supersaturated gemcitabine hydrochloride solution and its preparation process |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102614137A (en) * | 2012-05-02 | 2012-08-01 | 南京臣功制药股份有限公司 | Gemcitabine hydrochloride freeze-dried powder injection and preparation method thereof |
| 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 |
| CN109077995A (en) * | 2012-04-27 | 2018-12-25 | 太阳医药工业有限公司 | I.e. pourable Jixitabin solution |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2459170A2 (en) | 2009-07-31 | 2012-06-06 | Astron Research Limited | A stable composition of ready-to-use gemcitabine injection |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1156587A (en) * | 1996-12-13 | 1997-08-13 | 孙旭光 | Non-crystal mannitol injection and preparing process thereof |
| CN1181829C (en) * | 2000-11-03 | 2004-12-29 | 中国人民解放军军事医学科学院附属医院 | Jixitabin solution preparation |
| WO2005014010A1 (en) * | 2003-07-24 | 2005-02-17 | Eli Lilly And Company | Pharmaceutical composition comprising gemcitabine and cyclodextrines |
| US20060089328A1 (en) * | 2004-10-22 | 2006-04-27 | Edgar Schridde | Ready-to-use gemcitabine solutions |
| US20060089329A1 (en) * | 2004-10-22 | 2006-04-27 | Edgar Schridde | Ready-to-use gemcitabine solution concentrates |
| 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 |
-
2006
- 2006-06-12 CN CN201110383062.1A patent/CN102406603B/en active Active
- 2006-06-12 CN CN2006100446751A patent/CN101088492B/en active Active
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- 2007-05-17 WO PCT/CN2007/001604 patent/WO2007143895A1/en active Application Filing
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109077995A (en) * | 2012-04-27 | 2018-12-25 | 太阳医药工业有限公司 | I.e. pourable Jixitabin solution |
| CN102614137A (en) * | 2012-05-02 | 2012-08-01 | 南京臣功制药股份有限公司 | Gemcitabine hydrochloride freeze-dried powder injection and preparation method thereof |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101088492B (en) | 2012-02-22 |
| WO2007143895A1 (en) | 2007-12-21 |
| CN102406603A (en) | 2012-04-11 |
| CN102406603B (en) | 2015-12-16 |
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