CN103655489A - Epirubicin hydrochloride pharmaceutical composition and preparation method thereof - Google Patents
Epirubicin hydrochloride pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN103655489A CN103655489A CN201310701283.8A CN201310701283A CN103655489A CN 103655489 A CN103655489 A CN 103655489A CN 201310701283 A CN201310701283 A CN 201310701283A CN 103655489 A CN103655489 A CN 103655489A
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Abstract
The invention discloses epirubicin hydrochloride pharmaceutical composition and a preparation method thereof. The composition contains epirubicin 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 to be completely dissolved and uniformly mixed; 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 is dried thoroughly, and the redissolution performance is better.
Description
Technical field
The invention belongs to medical technology preparation field, be specifically related to a kind of epirubicin hydrochloride composition and method of making the same of injection.
Background technology
Epirubicin hydrochloride is a cell cycle nonspecific agent (CCNSA), and its Main Function position is nucleus.The mechanism of action of this product can be combined with DNA relevant with it.The cell of In vitro culture adds this product to penetrate rapidly in born of the same parents, enters nucleus and is combined with DNA, thereby suppress synthesizing and mitosis of nucleic acid.Confirmed that epirubicin has the effect of the anti-experimental character tumor of wide spectrum, also has inhibitory action to topoisomerase.Curative effect equates with amycin or is slightly high, and toxicity especially cardiac toxicity lower than amycin.Be applicable to treat malignant lymphoma, breast carcinoma, pulmonary carcinoma, soft tissue sarcoma, esophageal carcinoma, gastric cancer, hepatocarcinoma, cancer of pancreas, melanoma, colorectal carcinoma, ovarian cancer, multiple myeloma, leukemia, intravesical administration contributes to the treatment of superficial bladder cancer, cancer in situ and prevents the postoperative recurrence of its transurethral resection.
Epirubicin hydrochloride essential information is as follows:
English name: Epirubicin Hydrochloride
No. CAS: 163451-81-8
Chemical name: (8S, 10S)-10-[(3 '-amino-2 ', 3 ', 6 '-tri-deoxidations-α-L-arabopyranose base) oxo]-6; 8,11-trihydroxy-8-(glycolyl)-1-methoxyl group-7,8; 9,10-tetrahydrochysene aphthacene-5,12-dione hydrochloride
Chemical structural formula:
Molecular formula: C27H29NO11HCl
Molecular weight: 579.99
Epirubicin hydrochloride poor stability, the dosage forms that adopt freeze-dried powder during clinical use more, epirubicin 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 epirubicin hydrochloride is pumped under high vacuum condition, cause epirubicin hydrochloride salify not thorough, part epirubicin 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 epirubicin 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 epirubicin hydrochloride lyophilized injectable powder redissolution performance.
Summary of the invention
The object of the invention is to provide for above weak point the epirubicin hydrochloride composition and method of making the same of injection, this poor stability of epirubicin 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 epirubicin hydrochloride medicinal liquid fully charge, by this process, can, so that epirubicin 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 epirubicin, 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 epirubicin hydrochloride compositions of injection provided by the invention, specific as follows:
An epirubicin hydrochloride compositions for injection, contains epirubicin hydrochloride and lactose, is prepared as follows:
(1) preparation:
Epirubicin 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 epirubicin 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 epirubicin 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 epirubicin 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 epirubicin hydrochloride compositions of injection is:
(1) preparation:
Epirubicin 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 epirubicin 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 epirubicin 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 epirubicin 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 epirubicin, lactose in the product of lyophilizing, in finished product, in component and raw material, ratio does not have substantial variation.
The epirubicin hydrochloride composition and method of making the same of injection of the present invention, this poor stability of epirubicin 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 epirubicin hydrochloride compositions of injection greatly, the epirubicin 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 epirubicin hydrochloride pharmaceutical composition 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
Epirubicin hydrochloride pharmaceutical composition described in every 1000 bottles, its formula consists of:
Epirubicin hydrochloride 100g
Lactose 500g
Purified water is added to 50kg
Preparation technology:
(1) preparation: epirubicin 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 epirubicin 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 epirubicin 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 epirubicin 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
Epirubicin hydrochloride pharmaceutical composition described in every 1000 bottles, its formula consists of:
Epirubicin hydrochloride 50g
Lactose 500g
Purified water is added to 50kg
Preparation technology: with embodiment 1.
Embodiment 3
Epirubicin hydrochloride pharmaceutical composition described in every 1000 bottles, its formula consists of:
Epirubicin hydrochloride 50g
Lactose 300g
Purified water is added to 50kg
Preparation technology: with embodiment 1.
Comparative example 1
Epirubicin hydrochloride 100g
Lactose 500g
Purified water is added to 50kg
Preparation technology:
(1) preparation: epirubicin 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 epirubicin 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 epirubicin 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 epirubicin 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 ℃,
Continue 6 hours.
(4) tamponade, outlet.
(5) use aluminium-plastic combined cover tying, obtain.
Comparative example 2
Epirubicin hydrochloride 50g
Lactose 500g
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 epirubicin hydrochloride compositions of injection, then check respectively solubility, visible foreign matters, clarity and particulate matter, it the results are shown in Table 1:
The epirubicin hydrochloride pharmaceutical composition 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 epirubicin hydrochloride compositions has clear superiority on the quality control level of visible foreign matters, clarity and particulate matter.
Claims (2)
1. an epirubicin hydrochloride compositions for injection, is characterized in that containing epirubicin hydrochloride and lactose, as follows preparation:
(1) preparation:
Epirubicin 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 epirubicin 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 epirubicin 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 epirubicin 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 epirubicin hydrochloride compositions of injection claimed in claim 1, is characterized in that preparation method is:
(1) preparation:
Epirubicin 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 epirubicin 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 epirubicin 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 epirubicin 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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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111265480A (en) * | 2018-12-04 | 2020-06-12 | 石药集团中奇制药技术（石家庄）有限公司 | Epirubicin liposome and preparation method thereof |
| CN113679679A (en) * | 2021-09-10 | 2021-11-23 | 四川汇宇制药股份有限公司 | Preparation method of epirubicin hydrochloride for injection |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101683342A (en) * | 2008-09-22 | 2010-03-31 | 广东肇庆星湖生物科技股份有限公司 | Methylphenidatefrozen dry powder preparation for injection and preparation process thereof |
| CN102614118A (en) * | 2012-03-15 | 2012-08-01 | 北京协和药厂 | Preparation method for epirubicin hydrochloride preparation for injection and preparation |
-
2013
- 2013-12-18 CN CN201310701283.8A patent/CN103655489A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101683342A (en) * | 2008-09-22 | 2010-03-31 | 广东肇庆星湖生物科技股份有限公司 | Methylphenidatefrozen dry powder preparation for injection and preparation process thereof |
| CN102614118A (en) * | 2012-03-15 | 2012-08-01 | 北京协和药厂 | Preparation method for epirubicin hydrochloride preparation for injection and preparation |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111265480A (en) * | 2018-12-04 | 2020-06-12 | 石药集团中奇制药技术（石家庄）有限公司 | Epirubicin liposome and preparation method thereof |
| CN111265480B (en) * | 2018-12-04 | 2022-10-21 | 石药集团中奇制药技术（石家庄）有限公司 | Epirubicin liposome and preparation method thereof |
| CN113679679A (en) * | 2021-09-10 | 2021-11-23 | 四川汇宇制药股份有限公司 | Preparation method of epirubicin hydrochloride for injection |
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Application publication date: 20140326 |