CN103655491A - Irinotecan hydrochloride pharmaceutical composition and preparation method thereof - Google Patents
Irinotecan hydrochloride pharmaceutical composition and preparation method thereof Download PDFInfo
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Abstract
The invention discloses irinotecan hydrochloride pharmaceutical composition and a preparation method thereof. The composition contains irinotecan hydrochloride and mannitol. The preparation method comprises the following steps: 1), preparation is performed: ambroxol hydrochloride and mannitol are placed into a preparation tank in a weight ratio of 1:(1-20), water for injection is added, and the mixture is stirred until complete dissolution and uniform mixing are achieved; 2), sterile filtration, subpackaging and half stoppering are performed; and 3), vacuum freeze drying is performed to obtain a product. The composition and the preparation method have the advantages that the formula is simple, the technology is advanced, the quality is uniform and stable, moisture drying is thorough, and the redissolution performance is better.
Description
Technical field
The invention belongs to medical technology preparation field, be specifically related to a kind of irinotecan hydrochloride composition and method of making the same of injection.
Background technology
Irinotecan hydrochloride irinotecan is the semi-synthetic derivant of camptothecine.Camptothecine can be combined with topoisomerase I specifically, and the latter induces reversibility single-strand break, thereby DNA double chain structure is untwisted; Irinotecan and active metabolite SN-38 thereof can be combined with topoisomerase I-DNA complex, thereby stop connecting again of fracture strand.Existing research prompting, the cytotoxicity of irinotecan is owing in DNA building-up process, and replicative enzyme and topoisomerase I-DNA mono-irinotecan (or SN-38) three complex interact, thereby cause DNA double chain interruption.Mammalian cell can not be repaired this DNA double chain interruption effectively.Be applicable to the treatment for the Metastatic Colorectal Cancer of being grown up, the patient for through containing the failure of 5-Fu chemotherapy, can be used as second line treatment.
Irinotecan hydrochloride essential information is as follows:
English name: Irinotecan hydrochloride
No. CAS: 100286-90-6
Chemical name: (+)-(4S)-4,11-diethyl-4-hydroxyl-9-(4-sends pyridine base to send pyridine) carbonyl-1H-pyrans 3,4:6,7 indolizines 1,2b quinoline-3,14-(4H, 12H)-dione hydrochloride
Chemical structural formula:
Molecular formula: C33H38N4O6HCl
Molecular weight: 623.15
Irinotecan hydrochloride poor stability, the dosage forms that adopt freeze-dried powder during clinical use more, irinotecan itself is poorly soluble, therefore clinical preparation is used its hydrochlorate as active component more, and well-known, hydrochloric acid is volatile acid, highly volatile, under vacuum condition, the speed of volatilization is faster.Adopt traditional freeze-dry process, because part HCl in irinotecan hydrochloride is pumped under high vacuum condition, cause irinotecan hydrochloride salify not thorough, part irinotecan exists with the form of base, during clinical use, can not dissolve completely, occur visible foreign matters, particulate matter and the underproof phenomenon of clarity, these phenomenons all show, in the hydrochloride for injection irinotecan that adopts traditional freeze-dry process to prepare, may have more molecule.In these granules, diameter can block blood flow when by pulmonary capillary at 5～20 microns and above granule, thereby cause as even worried in pulmonary infarction complication dead, exogenous granule also can form phlebitis in injection site, also may cause that vein blood vessel blocks and patient's injury simultaneously, have larger clinical safety hidden danger.In the urgent need to a kind of hydrochloric acid of avoiding, volatilize, improve the technical scheme of irinotecan hydrochloride lyophilized injectable powder redissolution performance.
Summary of the invention
The object of the invention is to provide for above weak point the irinotecan hydrochloride composition and method of making the same of injection, this poor stability of irinotecan hydrochloride is needed to lyophilizing, highly volatile HCl dissociate the medicine of indissoluble base again simultaneously, the present invention can significantly reduce even to eliminate the phenomenon that HCl is pumped under high vacuum environment, and the safety of preparation redissolution performance and clinical application is more guaranteed.
The present inventor finds by research experiment, by the dry link of the trunk of vacuum lyophilization is carried out to suitable control stage by stage, without significant prolongation freeze-drying time, can effectively control the volatilization of HCl, obtains the lyophilized formulations of redissolution function admirable.
First, Speed Reduction products temperature with 10～15 ℃/h, as 40 ℃ of products temperature Di Yu –, be incubated and within 60 minutes, make irinotecan hydrochloride medicinal liquid fully charge, by this process, can, so that irinotecan hydrochloride medicinal liquid is frozen into framework jail, there is larger distillation duct simultaneously, what make that moisture can be unobstructed is pumped, the situation that while having reduced distillation, HCl is pulled away with steam.
Secondly, at intensification sublimation stage, Sheng for the first time 20 ℃ of Wen Zhi –, maintenance vacuum is 5～10Pa, continues 3 hours, Shengs for the second time 10 ℃ of Wen Zhi –, maintenance vacuum is 10～15Pa, continues 3 hours, Shengs for the third time 5 ℃ of Wen Zhi –, maintenance vacuum is 15～20Pa, continues 3 hours, is warming up to 5 ℃ the 4th time, maintenance vacuum is 20～30Pa, continue 3 hours, by corresponding especially temperature and vacuum degree control, make HCl also not have obvious volatilization after temperature raises.
Again, due to process above, substantially to have completed trunk dry, in goods, water content seldom, most of HCl is connected with very firm chemical bond with irinotecan, and the risk of HCl volatilization is extremely low, so be warming up to 20 ℃ the 5th time, do not control vacuum, continue 3 hours, completed in the short period of time dry to residual moisture, make the freeze-drying time can significant prolongation.
Finally, the final drying temperature of goods is 25 ℃, continues 6 hours, tamponade, outlet, uses aluminium-plastic combined cover tying, packing after quality inspection is qualified, obtain, in this process, only have the adsorbed water of minute quantity to exist, HCl can volatilize hardly, higher baking temperature can guarantee that product dried is more thorough, thereby has better stability.
By said method, can significantly reduce even to eliminate the phenomenon that HCl is pumped under high vacuum environment, the safety of preparation redissolution performance and clinical application is more guaranteed.
The irinotecan hydrochloride compositions of injection provided by the invention, specific as follows:
An irinotecan hydrochloride compositions for injection, contains irinotecan hydrochloride and lactose, is prepared as follows:
(1) preparation:
Irinotecan hydrochloride, lactose are put in Agitation Tank for 1:1～20 by weight proportion, injected water, stir and make it to dissolve completely and mix homogeneously;
(2) aseptic filtration, subpackage:
By irinotecan hydrochloride solution obtained above through filtering with microporous membrane to sterilizing room, be sub-packed in cillin bottle, partly jump a queue;
(3) vacuum lyophilization:
A, pre-freeze: the irinotecan hydrochloride medicinal liquid installing for above-mentioned minute is put in freeze dryer, with the Speed Reduction products temperature of 10～15 ℃/h, when products temperature is low in 40 ℃ of –, be incubated and within 60 minutes, make irinotecan hydrochloride medicinal liquid fully charge;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, and keep 55 ℃ of rear cabinet condenser temperature Wei – 45～–;
C, dry: open vacuum pump and in every valve, start the sublimation drying that heats up,
Sheng for the first time 20 ℃ of Wen Zhi –, maintenance vacuum is 5～10Pa, continues 3 hours,
Sheng for the second time 10 ℃ of Wen Zhi –, maintenance vacuum is 10～15Pa, continues 3 hours,
Sheng for the third time 5 ℃ of Wen Zhi –, maintenance vacuum is 15～20Pa, continues 3 hours,
Be warming up to 5 ℃ the 4th time, maintenance vacuum is 20～30Pa, continues 3 hours,
Be warming up to 20 ℃ the 5th time, do not control vacuum, continue 3 hours,
Final drying temperature is 25 ℃, continues 6 hours.
(4) tamponade, outlet.
(5) use aluminium-plastic combined cover tying, obtain.
A kind of preparation method of irinotecan hydrochloride compositions of injection is:
(1) preparation:
Irinotecan hydrochloride, lactose are put in Agitation Tank for 1:1～20 by weight proportion, injected water, stir and make it to dissolve completely and mix homogeneously;
(2) aseptic filtration, subpackage:
By irinotecan hydrochloride solution obtained above through filtering with microporous membrane to sterilizing room, be sub-packed in cillin bottle, partly jump a queue;
(3) vacuum lyophilization:
A, pre-freeze: the irinotecan hydrochloride medicinal liquid installing for above-mentioned minute is put in freeze dryer, with the Speed Reduction products temperature of 10～15 ℃/h, when products temperature is low in 40 ℃ of –, be incubated and within 60 minutes, make irinotecan hydrochloride medicinal liquid fully charge;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, and keep 55 ℃ of rear cabinet condenser temperature Wei – 45～–;
C, dry: open vacuum pump and in every valve, start the sublimation drying that heats up,
Sheng for the first time 20 ℃ of Wen Zhi –, maintenance vacuum is 5～10Pa, continues 3 hours,
Sheng for the second time 10 ℃ of Wen Zhi –, maintenance vacuum is 10～15Pa, continues 3 hours,
Sheng for the third time 5 ℃ of Wen Zhi –, maintenance vacuum is 15～20Pa, continues 3 hours,
Be warming up to 5 ℃ the 4th time, maintenance vacuum is 20～30Pa, continues 3 hours,
Be warming up to 20 ℃ the 5th time, do not control vacuum, continue 3 hours,
Final drying temperature is 25 ℃, continues 6 hours.
(4) tamponade, outlet.
(5) use aluminium-plastic combined cover tying, obtain.
Only hydrochloric irinotecan, lactose in the product of lyophilizing, in finished product, in component and raw material, ratio does not have substantial variation.
The irinotecan hydrochloride composition and method of making the same of injection of the present invention, this poor stability of irinotecan hydrochloride is needed to lyophilizing, highly volatile HCl dissociate the medicine of indissoluble base again simultaneously, can significantly reduce even to eliminate the phenomenon that HCl is pumped under high vacuum environment, the safety of preparation redissolution performance and clinical application is more guaranteed.The present invention has improved the redissolution performance of the irinotecan hydrochloride compositions of injection greatly, the irinotecan hydrochloride composition quality stable homogeneous of the injection of preparation, content is evenly accurate, and moisture drying is thorough, and the stability in transportation and storage process is better.Preparation technology of the present invention is simple, facilitates feasiblely, reproducible, and production cost is lower, is easy to realize industrialized great production, thereby can produce considerable economic and social benefit.
The specific embodiment
Below will describe irinotecan hydrochloride medicines compositions of the present invention in detail.Enumerate embodiment below, the present invention is described in more detail, but these concrete examples are not intended to limit the present invention.
Embodiment 1
Irinotecan hydrochloride medicines compositions described in every 1000 bottles, its formula consists of:
Irinotecan hydrochloride 40g
Lactose 400g
Purified water is added to 50kg
Preparation technology:
(1) preparation: irinotecan hydrochloride, lactose are put in Agitation Tank for 1:1～20 by weight proportion, injected water, stir and make it to dissolve completely and mix homogeneously;
(2) aseptic filtration, subpackage: by irinotecan hydrochloride solution obtained above through filtering with microporous membrane to sterilizing room, be sub-packed in cillin bottle, partly jump a queue;
(3) vacuum lyophilization:
A, pre-freeze: the irinotecan hydrochloride medicinal liquid installing for above-mentioned minute is put in freeze dryer, with the Speed Reduction products temperature of 10～15 ℃/h, when products temperature is low in 40 ℃ of –, be incubated and within 60 minutes, make irinotecan hydrochloride medicinal liquid fully charge;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, and keep 55 ℃ of rear cabinet condenser temperature Wei – 45～–;
C, dry: open vacuum pump and in every valve, start the sublimation drying that heats up,
Sheng for the first time 20 ℃ of Wen Zhi –, maintenance vacuum is 5～10Pa, continues 3 hours,
Sheng for the second time 10 ℃ of Wen Zhi –, maintenance vacuum is 10～15Pa, continues 3 hours,
Sheng for the third time 5 ℃ of Wen Zhi –, maintenance vacuum is 15～20Pa, continues 3 hours,
Be warming up to 5 ℃ the 4th time, maintenance vacuum is 20～30Pa, continues 3 hours,
Be warming up to 20 ℃ the 5th time, do not control vacuum, continue 3 hours,
Final drying temperature is 25 ℃, continues 6 hours.
(4) tamponade, outlet.
(5) use aluminium-plastic combined cover tying, obtain.
Embodiment 2
Irinotecan hydrochloride medicines compositions described in every 1000 bottles, its formula consists of:
Irinotecan hydrochloride 20g
Lactose 300g
Purified water is added to 50kg
Preparation technology: with embodiment 1.
Embodiment 3
Irinotecan hydrochloride medicines compositions described in every 1000 bottles, its formula consists of:
Irinotecan hydrochloride 40g
Lactose 200g
Purified water is added to 50kg
Preparation technology: with embodiment 1.
Comparative example 1
Irinotecan hydrochloride 40g
Lactose 400g
Purified water is added to 50kg
Preparation technology:
(1) preparation: irinotecan hydrochloride, lactose are put in Agitation Tank for 1:1～20 by weight proportion, injected water, stir and make it to dissolve completely and mix homogeneously;
(2) aseptic filtration, subpackage: by irinotecan hydrochloride solution obtained above through filtering with microporous membrane to sterilizing room, be sub-packed in cillin bottle, partly jump a queue;
(3) vacuum lyophilization:
A, pre-freeze: the irinotecan hydrochloride medicinal liquid installing for above-mentioned minute is put in freeze dryer, with the Speed Reduction products temperature of 10～15 ℃/h, when products temperature is low in 40 ℃ of –, be incubated and within 60 minutes, make irinotecan hydrochloride medicinal liquid fully charge;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, and keep 55 ℃ of rear cabinet condenser temperature Wei – 45～–;
C, dry: open vacuum pump and in every valve, start the sublimation drying that heats up, final drying temperature is 25 ℃, continues 6 hours.
(4) tamponade, outlet.
(5) use aluminium-plastic combined cover tying, obtain.
Comparative example 2
Irinotecan hydrochloride 20g
Lactose 300g
Purified water is added to 50kg
Preparation technology: with comparative example 1.
Test example 1
By embodiment 1～3 and comparative example 1～2, respectively prepare respectively the irinotecan hydrochloride compositions of injection, then check respectively solubility, visible foreign matters, clarity and particulate matter, it the results are shown in Table 1:
The irinotecan hydrochloride medicines compositions check result of table 1 injection
As can be seen from Table 1, technical scheme of the present invention (embodiment 1～3) compares with prior art (comparative example 1～2), the redissolution performance that has significantly improved irinotecan hydrochloride compositions has clear superiority on the quality control level of visible foreign matters, clarity and particulate matter.
Claims (2)
1. an irinotecan hydrochloride compositions for injection, is characterized in that containing irinotecan hydrochloride and lactose, as follows preparation:
(1) preparation:
Irinotecan hydrochloride, lactose are put in Agitation Tank for 1:1～20 by weight proportion, added ethanol, water for injection, stir and make it to dissolve completely and mix homogeneously;
(2) aseptic filtration, subpackage:
By irinotecan hydrochloride solution obtained above through filtering with microporous membrane to sterilizing room, be sub-packed in cillin bottle, partly jump a queue;
(3) vacuum lyophilization:
A, pre-freeze: the irinotecan hydrochloride medicinal liquid installing for above-mentioned minute is put in freeze dryer, with the Speed Reduction products temperature of 10～15 ℃/h, when products temperature is low in 40 ℃ of –, be incubated and within 60 minutes, make irinotecan hydrochloride medicinal liquid fully charge;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, and keep 55 ℃ of rear cabinet condenser temperature Wei – 45～–;
C, dry: open vacuum pump and in every valve, start the sublimation drying that heats up,
Sheng for the first time 20 ℃ of Wen Zhi –, maintenance vacuum is 5～10Pa, continues 3 hours,
Sheng for the second time 10 ℃ of Wen Zhi –, maintenance vacuum is 10～15Pa, continues 3 hours,
Sheng for the third time 5 ℃ of Wen Zhi –, maintenance vacuum is 15～20Pa, continues 3 hours,
Be warming up to 5 ℃ the 4th time, maintenance vacuum is 20～30Pa, continues 3 hours,
Be warming up to 20 ℃ the 5th time, do not control vacuum, continue 3 hours,
Final drying temperature is 25 ℃, continues 6 hours.
(4) tamponade, outlet.
(5) use aluminium-plastic combined cover tying, obtain.
2. a preparation method for the irinotecan hydrochloride compositions of injection claimed in claim 1, is characterized in that preparation method is:
(1) preparation:
Irinotecan hydrochloride, lactose are put in Agitation Tank for 1:1～20 by weight proportion, injected water, stir and make it to dissolve completely and mix homogeneously;
(2) aseptic filtration, subpackage:
By irinotecan hydrochloride solution obtained above through filtering with microporous membrane to sterilizing room, be sub-packed in cillin bottle, partly jump a queue;
(3) vacuum lyophilization:
A, pre-freeze: the irinotecan hydrochloride medicinal liquid installing for above-mentioned minute is put in freeze dryer, with the Speed Reduction products temperature of 10～15 ℃/h, when products temperature is low in 40 ℃ of –, be incubated and within 60 minutes, make irinotecan hydrochloride medicinal liquid fully charge;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, and keep 55 ℃ of rear cabinet condenser temperature Wei – 45～–;
C, dry: open vacuum pump and in every valve, start the sublimation drying that heats up,
Sheng for the first time 20 ℃ of Wen Zhi –, maintenance vacuum is 5～10Pa, continues 3 hours,
Sheng for the second time 10 ℃ of Wen Zhi –, maintenance vacuum is 10～15Pa, continues 3 hours,
Sheng for the third time 5 ℃ of Wen Zhi –, maintenance vacuum is 15～20Pa, continues 3 hours,
Be warming up to 5 ℃ the 4th time, maintenance vacuum is 20～30Pa, continues 3 hours,
Be warming up to 20 ℃ the 5th time, do not control vacuum, continue 3 hours,
Final drying temperature is 25 ℃, continues 6 hours.
(4) tamponade, outlet.
(5) use aluminium-plastic combined cover tying, obtain.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102058548A (en) * | 2010-12-30 | 2011-05-18 | 江苏奥赛康药业有限公司 | Ambroxol hydrochloride composition for injection and preparation method thereof |
| CN102091045A (en) * | 2010-12-30 | 2011-06-15 | 江苏奥赛康药业有限公司 | Hydrochloride diltiazem composition for injection and preparation method thereof |
| CN102125550A (en) * | 2010-12-30 | 2011-07-20 | 江苏奥赛康药业有限公司 | Ondansetron hydrochloride composition for injection and preparation method thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102058548A (en) * | 2010-12-30 | 2011-05-18 | 江苏奥赛康药业有限公司 | Ambroxol hydrochloride composition for injection and preparation method thereof |
| CN102091045A (en) * | 2010-12-30 | 2011-06-15 | 江苏奥赛康药业有限公司 | Hydrochloride diltiazem composition for injection and preparation method thereof |
| CN102125550A (en) * | 2010-12-30 | 2011-07-20 | 江苏奥赛康药业有限公司 | Ondansetron hydrochloride composition for injection and preparation method thereof |
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Application publication date: 20140326 |