CN103083260A - Gemcitabine hydrochloride for injection as well as preparation method thereof - Google Patents
Gemcitabine hydrochloride for injection as well as preparation method thereof Download PDFInfo
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- CN103083260A CN103083260A CN2013100483479A CN201310048347A CN103083260A CN 103083260 A CN103083260 A CN 103083260A CN 2013100483479 A CN2013100483479 A CN 2013100483479A CN 201310048347 A CN201310048347 A CN 201310048347A CN 103083260 A CN103083260 A CN 103083260A
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Abstract
The invention discloses gemcitabine hydrochloride for injection. The gemcitabine hydrochloride for injection is frozen and dried by an emulsion prepared from components in parts by weight as follows: 1 part of gemcitabine hydrochloride, 10-15 parts of polylactic acid-hydroxyacetic acid and 1-2 parts of gelatin. According to the invention, gemcitabine hydrochloride dissolved in an oil phase is wrapped in PLGA [Poly(Lactic-co-Glycolicacid)] to avoid degradation in the presence of water, so that the product quality is improved and the stability is enhanced. When the product is redissolved, microballoon particles are uniformly distributed, the drug carrying capacity reaches over 65% and the encapsulation efficiency reaches over 87%, and the drug is continuously and stably released.
Description
Technical field
The invention belongs to the pharmaceutical preparations technology field, in particular to a kind of hydrochloride for injection gemcitabine and preparation method thereof.
Background technology
Gemcitabine hydrochloride (Gemcitabine hydrochloride) is the synthetic a kind of Difluoronucleosides series antineoplastic medicament that destroys cellular replication of nineteen eighty-three U.S. Eli Lilly company.But metabolism is the triphosphoric acid compound in cell, stops DNA synthetic.Nineteen ninety-five is in Sweden, Holland, Finland and South Africa listing, be approved for treatment cancer of pancreas and nonsmall-cell lung cancer, the tumour medicine Advisory Board of existing FDA has recommended this product to be used for late period and Metastatic Nsclc, cancer of pancreas, bladder cancer, breast carcinoma and other entity tumors.Gemcitabine is one of the most effective first-line drug for the treatment of nonsmall-cell lung cancer, it is also the goldstandard for the treatment of at present advanced pancreatic cancer, the advantages such as it has mechanism of action uniqueness, wide, the high remission rate of antitumor spectra, extend life cycle and toxic reaction is low, with other chemotherapeutics without crossing drug resistant and toxic reaction without characteristics such as stacks.Particularly it can effectively extend patient's life, improves quality of life of patients.
The chemical name of gemcitabine hydrochloride is (+) 2 ˊ-deoxidation-2 ˊ, and 2 ˊ-difluocytosine hydrochlorate is white crystalline powder, dissolve in water, and slightly soluble in methanol, almost insoluble in ethanol, chloroform and acetone.Find through Destructive Test Study, gemcitabine hydrochloride all has in various degree destruction at illumination, acid, alkali, high temperature and oxidizing condition, and is the most obvious with the Oxidative demage degraded, is secondly that high irenine destroys, and it is less that illumination and acid destroy degraded.In order to improve the stability of gemcitabine hydrochloride in injection, the general solution of prior art is to avoid the degraded of effective ingredient by screening suitable additives and consumption.CN101564381A discloses a kind of hydrochloride for injection gemcitabine, formed by gemcitabine hydrochloride, mannitol and sodium acetate, wherein gemcitabine hydrochloride and mannitol weight proportion are 1: 0.5～5, and gemcitabine hydrochloride and sodium acetate weight proportion are 1: 0.01～0.1.Its preparation method is: get mannitol and sodium acetate, be dissolved in water for injection, then add gemcitabine hydrochloride, stirring and dissolving is transferred between pH to 2.7～3.3, and standardize solution is through the filtering with microporous membrane of 0.22 μ m, fill, sabot, lyophilizing, tamponade, outlet, use the aluminium-plastic combined cover tying, packing after quality inspection is qualified, and get final product.Yet in said preparation, the consumption of adjuvant is too large, causes the content of active component relatively low, minimumly can to 16.5%, significantly reduce the curative effect of unit formulation.CN101606947A discloses a kind of gemcitabine hydrochloride composition, by 57 parts of gemcitabine hydrochlorides, 20～50 parts, mannitol, sodium acetate forms in right amount, and the freeze drying process that adopts is for to be down to-42～-38 ℃ with the freeze drying box temperature, put into the good medicine of fill, insulation 3h, open vacuum pump, in drying baker, vacuum is 3～9Pa, slowly be warming up to-22～-18 ℃, programming rate is 0.3 ℃/min, insulation 2h, and then be warming up to 0 ℃ with 0.5 ℃/min, insulation 15h, the drying baker temperature is warming up to 8～12 ℃ with 1 ℃/min speed, insulation 3～5h, be warming up to 34～36 ℃ with 2 ℃/min speed again, insulation 10h, and get final product.The need of production of this lyophilized injectable powder as raw material, has limited the large-scale production of said preparation according to the specific synthetic gemcitabine hydrochloride that reaches the process for refining preparation.CN102144981A discloses a kind of gemcitabine hydrochloride lyophilized powder injection and preparation method thereof.This injectable powder comprises gemcitabine hydrochloride 20-30 part, mannitol 5-9 part, sodium acetate 3-10 part, lactose 5-9 part.Its lyophilization divides pre-freeze stage, primary drying stage and 3 stages of redrying stage.Although it is simple that this lyophilized injectable powder has a process route, freeze-drying time is short, easy to operate advantage, yet owing to having increased lactose as additives, easily introduce aborning the anaphylactogen that residual protein and assorted sugar wait related substance to bring, the safety of preparation can not get ensureing.
Summary of the invention
In view of the deficiencies in the prior art, in order to improve the stability of gemcitabine hydrochloride, drug effect in the while extension body, the misery of the frequent medication of minimizing patient, hydrochloride for injection gemcitabine that the object of the present invention is to provide a kind of steady quality, slowly discharges and preparation method thereof.
In order to realize purpose of the present invention, the inventor studies by lot of experiments, has finally obtained following technical scheme:
A kind of hydrochloride for injection gemcitabine is mixed with the emulsion lyophilizing by the component that comprises following weight portion and forms:
1 part of gemcitabine hydrochloride
10～50 parts of poly lactic-co-glycolic acids
1～2 part, gelatin.
Purpose of the present invention can also realize like this:
Above-mentioned hydrochloride for injection gemcitabine preferably, is mixed with the emulsion lyophilizing by the component that comprises following weight portion and forms:
1 part of gemcitabine hydrochloride
20～30 parts of poly lactic-co-glycolic acids
1.5～1.8 parts, gelatin.
Above-mentioned hydrochloride for injection gemcitabine further preferably, is mixed with the emulsion lyophilizing by the component that comprises following weight portion and forms:
1 part of gemcitabine hydrochloride
23～25 parts of poly lactic-co-glycolic acids
1.6～1.7 parts, gelatin.
The molecular weight of described poly lactic-co-glycolic acid is 6000～20000.
In described poly lactic-co-glycolic acid, the ratio of lactide and Acetic acid, hydroxy-, bimol. cyclic ester is 75/25.
Second purpose of the present invention is to provide a kind of preparation method of above-mentioned hydrochloride for injection gemcitabine, comprises the steps:
(1) gemcitabine hydrochloride and the gelatin with recipe quantity is dissolved in water for injection, and dissolving and mixing are as interior water;
(2) poly lactic-co-glycolic acid with recipe quantity is dissolved in dichloromethane as oil phase;
(3) get in the water for injection that polyvinyl alcohol is dissolved in 75～85 ℃, the mass concentration that makes polyvinyl alcohol is 0.9%～1.05%, as outer water;
(4) the interior water that step (1) is obtained slowly splashes in the oil phase that step (2) obtains, 15000～20000r/min vibrates at a high speed emulsifying approximately after 3～5min, be cooled to 10 ℃, as colostrum, and join the outer aqueous phase that step (3) obtains, 15000～20000r/min approximately 3～5min of emulsifying that vibrates at a high speed, 3000～6000r/min keeps 3-5h to fling to dichloromethane, 10000～15000r/min high speed centrifugation, remove polyvinyl alcohol after adopting water for injection to wash 3～7 times, packing, lyophilization and get final product.
The hydrochloride for injection gemcitabine of the present invention's preparation is the medicine carrying microballoons that contains gemcitabine hydrochloride after redissolving, the term here " medicine carrying microballoons " refers to that medicine disperses or is attracted in macromolecule, polymeric matrix and the microparticulate system that forms, pharmaceutical pack can be rolled in biodegradable carrier material, medicine is along with the corrosion of carrier material discharges gradually, can make vivo medicine concentration keep for a long time certain level, play the effect of long-acting slow-release, reduce the medication number of times, increase patient compliance.The gemcitabine hydrochloride freeze-dried powder of the present invention's preparation is after redissolving, and the microspherulite diameter size distribution is even, and drug loading reaches on 65%, and envelop rate is all more than 87%, and drug release continues and stablizes.The present invention also tests by vitro release and shows, in the burst size of beginning in 1 hour lower than 30%, sustainable 16 days of the release in vitro time of microsphere, can keep for a long time effective blood drug concentration, solve the problems such as the blood concentration fluctuation that conventional formulation brings, administration number of times be frequent, improved patient's quality of life.
Hydrochloride for injection gemcitabine technology of preparing provided by the invention after being dissolved in gemcitabine hydrochloride in oil phase, is wrapped in PLGA, has avoided it to meet the water degraded, has improved product quality, has increased its stability.Be embodied in: product is in the accelerated test process of 6 months, and medicine carrying microballoons particle diameter, envelop rate, carrying drug ratio, water content and its related substances change not obvious.
The specific embodiment
Form by the following examples, the hydrochloride for injection gemcitabine that the present invention relates to and preparation method thereof is described in further detail, but this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example, all technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Embodiment 1
1kg gemcitabine hydrochloride, 1.6kg gelatin are dissolved in 25L water, and dissolving and mixing are as interior water (W1 phase); 25kg poly lactic-co-glycolic acid (in poly lactic-co-glycolic acid, the ratio of lactide and Acetic acid, hydroxy-, bimol. cyclic ester is 75/25, molecular weight 6000) is dissolved in the 180L dichloromethane as oil phase (O phase); The 22kg polyvinyl alcohol is dissolved in the water for injection of 80 ℃, the mass body volume concentrations that makes polyvinyl alcohol is 1.0%(w/v), as outer water (W2 phase); With W1 slowly splash into mutually O mutually in, 18000r/min vibrates at a high speed emulsifying approximately after 4min, is cooled to 10 ℃, as colostrum, and join W2 mutually in, the 15000r/min approximately 5min of emulsifying that vibrates at a high speed, 5000r/min keep 3-5h to fling to dichloromethane, the 10000r/min high speed centrifugation, adopt the water for injection washing to remove polyvinyl alcohol 3-5 time, packing is partly jumped a queue, the sample inlet, carry out lyophilization as follows:
(1) product is put into freeze dryer after, first freeze dryer flaggy temperature is down to 0 ℃ and keeps 10～30min, then be down to-35 ℃～-45 ℃ and keep 2h;
(2) control the interior vacuum of freeze drying box at 10～20Pa, the flaggy temperature is warming up to 0 ℃ with 6 ℃/h of constant rate of speed, and keeps 2h;
(3) control the interior vacuum of freeze drying box at 5～10Pa, the flaggy temperature is warming up to 30 ℃ with 8 ℃/h of constant rate of speed, and keeps 4h.
Embodiment 2
1kg gemcitabine hydrochloride, 1.8kg gelatin are dissolved in 30L water, and dissolving and mixing are as interior water (W1 phase); 30kg poly lactic-co-glycolic acid (in poly lactic-co-glycolic acid, the ratio of lactide and Acetic acid, hydroxy-, bimol. cyclic ester is 75/25, molecular weight 6000) is dissolved in the 200L dichloromethane as oil phase (O phase); The 25kg polyvinyl alcohol is dissolved in the water for injection of 80 ℃, the mass body volume concentrations that makes polyvinyl alcohol is 0.98%(w/v), as outer water (W2 phase); With W1 slowly splash into mutually O mutually in, 15000r/min vibrates at a high speed emulsifying approximately after 5min, is cooled to 10 ℃, as colostrum, and join W2 mutually in, the 15000r/min approximately 5min of emulsifying that vibrates at a high speed, 5000r/min keep 3-5h to fling to dichloromethane, the 15000r/min high speed centrifugation, adopt the water for injection washing to remove polyvinyl alcohol 4-7 time, packing is partly jumped a queue, the sample inlet carries out lyophilization by the step of embodiment 1.
Embodiment 3
1kg gemcitabine hydrochloride, 1kg gelatin are dissolved in 20L water, and dissolving and mixing are as interior water (W1 phase); 15kg poly lactic-co-glycolic acid (in poly lactic-co-glycolic acid, the ratio of lactide and Acetic acid, hydroxy-, bimol. cyclic ester is 75/25, molecular weight 6000) is dissolved in the 100L dichloromethane as oil phase (O phase); The 16kg polyvinyl alcohol is dissolved in the water for injection of 80 ℃, the mass body volume concentrations that makes polyvinyl alcohol is 1.05%(w/v), as outer water (W2 phase); With W1 slowly splash into mutually O mutually in, 15000r/min vibrates at a high speed emulsifying approximately after 5min, is cooled to 10 ℃, as colostrum, and join W2 mutually in, the 20000r/min approximately 3min of emulsifying that vibrates at a high speed, 4000r/min keep 3-5h to fling to dichloromethane, the 10000r/min high speed centrifugation, adopt the water for injection washing to remove polyvinyl alcohol 3-5 time, packing is partly jumped a queue, the sample inlet carries out lyophilization by the step of embodiment 1.
The factors influencing test of embodiment 5 hydrochloride for injection gemcitabines
Get the gemcitabine hydrochloride lyophilized powder injection of embodiment of the present invention 1-3 preparation, under the condition of Packing Sound, put under 40 ℃ ± 2 ℃, the accelerated test condition of 75% ± 5%RH and placed 6 months, respectively at sampling at the 1st, 2,3,6 the end of month (available 0.9% sodium chloride injection dissolving), investigate the variation of medicine carrying microballoons particle diameter, envelop rate, carrying drug ratio, moisture, the related substance aspect of product, the results are shown in Table 1.
The accelerated test result of table 1 hydrochloride for injection gemcitabine
By the accelerated test result of table 1 as can be known, the gemcitabine hydrochloride freeze-dried powder of the present invention's preparation is after redissolving, and the microspherulite diameter size distribution is even, and drug loading reaches on 65%, and envelop rate is all more than 87%; In addition, sample is in the accelerated test process of 6 months, and medicine carrying microballoons particle diameter, envelop rate, carrying drug ratio, water content and its related substances change not obvious.In addition, the present invention also tests by vitro release and shows, in the burst size of beginning in 1 hour lower than 30%, sustainable 16 days of the release in vitro time of microsphere.
Claims (6)
1. hydrochloride for injection gemcitabine is characterized in that: be mixed with the emulsion lyophilizing by the component that comprises following weight portion and form:
1 part of gemcitabine hydrochloride
10～50 parts of poly lactic-co-glycolic acids
1～2 part, gelatin.
2. hydrochloride for injection gemcitabine according to claim 1 is characterized in that: be mixed with the emulsion lyophilizing by the component that comprises following weight portion and form:
1 part of gemcitabine hydrochloride
20～30 parts of poly lactic-co-glycolic acids
1.5～1.8 parts, gelatin.
3. hydrochloride for injection gemcitabine according to claim 2 is characterized in that: be mixed with the emulsion lyophilizing by the component that comprises following weight portion and form:
1 part of gemcitabine hydrochloride
23～25 parts of poly lactic-co-glycolic acids
1.6～1.7 parts, gelatin.
4. according to claim 1-3 described hydrochloride for injection gemcitabines of any one, it is characterized in that: the molecular weight of described poly lactic-co-glycolic acid is 6000～20000.
5. hydrochloride for injection gemcitabine according to claim 4, it is characterized in that: in described poly lactic-co-glycolic acid, the ratio of lactide and Acetic acid, hydroxy-, bimol. cyclic ester is 75/25.
6. the preparation method of the described hydrochloride for injection gemcitabine of any one, is characterized in that comprising the steps:
(1) decitabine and the gelatin with recipe quantity is dissolved in water for injection, and dissolving and mixing are as interior water;
(2) poly lactic-co-glycolic acid with recipe quantity is dissolved in dichloromethane as oil phase;
(3) get in the water for injection that polyvinyl alcohol is dissolved in 75～85 ℃, the concentration that makes polyvinyl alcohol is 0.9%～1.05%(w/v), as outer water;
(4) the interior water that step (1) is obtained slowly splashes in the oil phase that step (2) obtains, 15000～20000r/min vibrates at a high speed emulsifying approximately after 3～5min, be cooled to 10 ℃, as colostrum, and join the outer aqueous phase that step (3) obtains, 15000～20000r/min approximately 3～5min of emulsifying that vibrates at a high speed, 3000～6000r/min keeps 3-5h to fling to dichloromethane, 10000～15000r/min high speed centrifugation, adopt the water for injection washing to remove packing after polyvinyl alcohol for 3～7 times, lyophilization and get final product.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103864871A (en) * | 2014-03-10 | 2014-06-18 | 洪军 | Gemcitabine hydrochloride compound |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102641281A (en) * | 2011-02-19 | 2012-08-22 | 山东新时代药业有限公司 | Monosialotetrahexosyl ganglioside sodium for injection and preparation method thereof |
| CN103006587A (en) * | 2013-01-14 | 2013-04-03 | 山东新时代药业有限公司 | Decitabine for injection and preparation method thereof |
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- 2013-02-05 CN CN2013100483479A patent/CN103083260A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102641281A (en) * | 2011-02-19 | 2012-08-22 | 山东新时代药业有限公司 | Monosialotetrahexosyl ganglioside sodium for injection and preparation method thereof |
| CN103006587A (en) * | 2013-01-14 | 2013-04-03 | 山东新时代药业有限公司 | Decitabine for injection and preparation method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103864871A (en) * | 2014-03-10 | 2014-06-18 | 洪军 | Gemcitabine hydrochloride compound |
| CN103864871B (en) * | 2014-03-10 | 2016-03-02 | 洪军 | A kind of gemcitabine hydrochloride compound |
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Application publication date: 20130508 |