CN103211772B - Etoposide lyophilized powder for injection - Google Patents
Etoposide lyophilized powder for injection Download PDFInfo
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- CN103211772B CN103211772B CN201310092539.XA CN201310092539A CN103211772B CN 103211772 B CN103211772 B CN 103211772B CN 201310092539 A CN201310092539 A CN 201310092539A CN 103211772 B CN103211772 B CN 103211772B
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- CN
- China
- Prior art keywords
- etoposide
- injection
- lyophilized powder
- freeze
- dry powder
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Links
- 229960005420 etoposide Drugs 0.000 title claims abstract description 34
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 title claims abstract description 34
- 238000002347 injection Methods 0.000 title abstract description 5
- 239000007924 injection Substances 0.000 title abstract description 5
- 239000008176 lyophilized powder Substances 0.000 title abstract 4
- 239000000843 powder Substances 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 239000008215 water for injection Substances 0.000 claims description 10
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 claims description 7
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 7
- 239000004475 Arginine Substances 0.000 claims description 7
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 7
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 7
- 229920002307 Dextran Polymers 0.000 claims description 7
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 7
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 7
- 229960001305 cysteine hydrochloride Drugs 0.000 claims description 7
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 claims description 7
- 239000008101 lactose Substances 0.000 claims description 7
- 239000000600 sorbitol Substances 0.000 claims description 7
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 6
- 229960003589 arginine hydrochloride Drugs 0.000 claims description 5
- 239000003963 antioxidant agent Substances 0.000 abstract description 8
- 230000003078 antioxidant effect Effects 0.000 abstract description 8
- 239000000546 pharmaceutical excipient Substances 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 3
- 230000007547 defect Effects 0.000 abstract description 2
- 239000012535 impurity Substances 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000012216 screening Methods 0.000 abstract description 2
- 239000002738 chelating agent Substances 0.000 abstract 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 235000006708 antioxidants Nutrition 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002671 adjuvant Substances 0.000 description 4
- 239000013618 particulate matter Substances 0.000 description 4
- 239000013558 reference substance Substances 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 229960003121 arginine Drugs 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- 238000005261 decarburization Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 210000004907 gland Anatomy 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000005374 membrane filtration Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- -1 chelating agen Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 229960002086 dextran Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940083697 etoposide 50 mg Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 235000003969 glutathione Nutrition 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical class COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 1
- 239000003600 podophyllotoxin derivative Substances 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention relates to an etoposide lyophilized powder for injection. The powder can overcome the defects of etoposide, improve the bioavailability of etoposide, is convenient to use, can be absorbed fast, and can come into play rapidly. By screening the prescription of the etoposide lyophilized powder for injection, the invention finds that the combined use of a specific excipient with an antioxidant and a chelating agent at the same time can generate a finished product of etoposide lyophilized powder for injection with the advantages of high stability, fewer impurities, little side effect, high safety, convenient storage and use, low production cost, and the like.
Description
Technical field
The application relates to a kind of etoposide freeze-dry powder.
Background technology
Etoposide (etoposide) is a semi-synthetic podophyllotoxin derivative, has broad-spectrum anti-tumor activity, clinical acute leukemia, carcinoma of testis and the small cell lung cancer of being used for the treatment of.But the absolute bioavailability of etoposide oral formulations only has 25%～75%.The poorly water-soluble of etoposide and to be decomposed into non-activity product in acid medium be the main cause that causes its oral formulations bioavailability low.
Summary of the invention
The application's object is to provide a kind of novel etoposide freeze-dry powder, can overcome the defect of above-mentioned etoposide, improves etoposide bioavailability, easy to use, absorbs soon, plays a role rapidly.
The present invention is by the screening to etoposide freeze-dry powder prescription, find to use specific excipient, and use antioxidant and chelating agen simultaneously, the stability of the etoposide freeze-dry powder preparation for injection finished product obtaining is high, impurity is few, and side effect is little, and safety is higher, there is the advantages such as convenience stores and uses, and production cost is low.
Etoposide freeze-dry powder of the present invention, comprises active constituents of medicine etoposide, excipient, antioxidant, chelating agen, pH adjusting agent.
Wherein said excipient is one or more of mannitol, sorbitol, dextran, glucose, lactose; Antioxidant is one or more of arginine, cysteine hydrochloride or glutathion; Chelating agen is disodiumedetate; PH regulator is hydrochloric acid, citric acid, sodium hydroxide or sodium bicarbonate.
Applicant is surprised to find that, use the compositions of sorbitol, dextran and lactose as excipient, and three's part by weight is 1:3:1; And antioxidant is selected the compositions of arginine and cysteine hydrochloride, and the two part by weight is 1:4; And use chelating agen disodiumedetate simultaneously.The etoposide freeze-dry powder agent stability preparing is high, and its related substances is low.
Technical solution of the present invention is (weight content):
PH adjusting agent regulates pH to 5.0-6.5
Preparation method:
The etoposide, excipient, antioxidant and the chelating agen that take respectively recipe quantity, add in water for injection, is fully stirred to dissolve, and adds active carbon, absorption, and decarburization is filtered.Regulate pH value to 5.0-6.5.With after 0.22 μ m membrane filtration, fill is to cleaning in the cillin bottle of drying and sterilizing, and every fills 3mL, and half gland is opened freeze dryer, is cooled to-40 DEG C, and lyophilizing, rolls lid, checks packaging.
Preferably, technical solution of the present invention is:
Etoposide 80g
Compositions (three's part by weight the is 1:3:1) 200g of sorbitol, dextran and lactose
Compositions (the two part by weight the is 1:4) 5g of arginine and cysteine hydrochloride
Disodiumedetate 10g
Hydrochloric acid solution (0.1mol/l) regulates pH to 6.5 in right amount
Water for injection adds to 1000ml
Embodiment 1:
Etoposide 80g
Compositions (three's part by weight the is 1:3:1) 200g of sorbitol, dextran and lactose
Compositions (the two part by weight the is 1:4) 5g of arginine and cysteine hydrochloride
Disodiumedetate 10g
Hydrochloric acid solution (0.1mol/l) regulates pH to 6.5 in right amount
Water for injection adds to 1000ml
Preparation method:
The etoposide, sorbitol, dextran, lactose, arginine, cysteine hydrochloride and the disodiumedetate that take respectively recipe quantity, add in water for injection, is fully stirred to dissolve, and adds active carbon, absorption, and decarburization is filtered.Hydrochloric acid solution regulates pH value to 6.5.With after 0.22 μ m membrane filtration, fill is to cleaning in the cillin bottle of drying and sterilizing, and every fills 3mL, and half gland is opened freeze dryer, is cooled to-40 DEG C, and lyophilizing, rolls lid, checks packaging.
Embodiment 2
Etoposide 90g
Compositions (three's part by weight the is 1:3:1) 300g of sorbitol, dextran and lactose
Compositions (the two part by weight the is 1:4) 5g of arginine and cysteine hydrochloride
Disodiumedetate 5g
Citric acid (0.1mol/l) regulates pH to 5.5 in right amount
Water for injection adds to 1000ml
Preparation method is with embodiment 1
Embodiment 3
Citric acid (0.1mol/l) regulates pH to 6.0 in right amount
Water for injection adds to 1000ml
Preparation method is with embodiment 1
Embodiment 4
Sodium bicarbonate (0.1mol/l) regulates pH to 6.5 in right amount
Water for injection adds to 1000ml
Preparation method is with embodiment 1
Embodiment 5
Citric acid (0.1mol/l) regulates pH to 5.5 in right amount
Water for injection adds to 1000ml
Preparation method is with embodiment 1
Embodiment 6
Sodium hydroxide (0.1mol/l) regulates pH to 6.0 in right amount
Water for injection adds to 1000ml
Preparation method is with embodiment 1
Stability controlled trial
Embodiment 1-6 and reference substance (CN101422439A etoposide freeze-dry powder), bottled, under (40 ± 2 DEG C), relative humidity (75 ± 5) % condition, place 6 months, monitoring humidity, in 1,2,3,6 sampling at the end of month, etoposide in freeze-dried powder is carried out to Detection of Stability, to investigate preparation accelerated stability.Equally, sample bottle is loaded under (25 ± 2 DEG C), relative humidity (60 ± 10) % condition and places 24 months, and monitoring humidity, in 0,3,6,9,12,24 sampling at the end of month, etoposide in freeze-dried powder is carried out to Detection of Stability, to investigate preparation long-time stability.The results are shown in Table 1. and table 2.
Reference substance prescription:
Etoposide 50mg
Mannitol 150mg
Sodium bicarbonate is appropriate
Table 1 accelerated test result
Table 2 experiment steady in a long-term
Table 1 and table 2 result of the test show etoposide freeze-dry powder of the present invention with respect to prior art aspect preparation stability, have advantages of outstanding; And selecting specific adjuvant is that the etoposide freeze-dry powder (embodiment 3-6) that the etoposide freeze-dry powder (embodiment 1,2) of excipient and antioxidant is prepared with respect to other adjuvants has unforeseeable stabilizing effect.
Redissolve and test
Particulate matter assay method after redissolving: by embodiment 1-6 and each 4 0.9% sodium chloride solutions that are dissolved in 250ml of reference substance, measure the particulate matter of solution after redissolving.The results are shown in Table 3.
Table 3
Table 3 data show that the embodiment of the present invention is obviously few with respect to the rear particulate matter of reference substance redissolution.Particularly having selected specific adjuvant is that after etoposide freeze-dry powder (embodiment 3-6) that the etoposide freeze-dry powder (embodiment 1,2) of excipient and antioxidant is prepared with respect to other adjuvants redissolves particulate matter is still less.
Claims (1)
1. an etoposide freeze-dry powder, is characterized in that, is made up of following component:
Water for injection adds to 1000ml
The part by weight of described sorbitol, dextran and lactose is 1:3:1; The part by weight of described arginine and cysteine hydrochloride is 1:4.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310092539.XA CN103211772B (en) | 2013-03-21 | 2013-03-21 | Etoposide lyophilized powder for injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310092539.XA CN103211772B (en) | 2013-03-21 | 2013-03-21 | Etoposide lyophilized powder for injection |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103211772A CN103211772A (en) | 2013-07-24 |
| CN103211772B true CN103211772B (en) | 2014-07-23 |
Family
ID=48810165
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310092539.XA Active CN103211772B (en) | 2013-03-21 | 2013-03-21 | Etoposide lyophilized powder for injection |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103211772B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1795870A (en) * | 2004-12-20 | 2006-07-05 | 云南创立生物医药集团股份有限公司 | Medication composition of containing |
| CN101010315A (en) * | 2004-04-30 | 2007-08-01 | 拜耳制药公司 | Substituted pyrazolyl urea derivatives useful in the treatment of cancer |
| CN101422439A (en) * | 2008-11-14 | 2009-05-06 | 李铁军 | Etoposide freeze-dry powder preparation for injection and preparation method thereof |
-
2013
- 2013-03-21 CN CN201310092539.XA patent/CN103211772B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101010315A (en) * | 2004-04-30 | 2007-08-01 | 拜耳制药公司 | Substituted pyrazolyl urea derivatives useful in the treatment of cancer |
| CN1795870A (en) * | 2004-12-20 | 2006-07-05 | 云南创立生物医药集团股份有限公司 | Medication composition of containing |
| CN101422439A (en) * | 2008-11-14 | 2009-05-06 | 李铁军 | Etoposide freeze-dry powder preparation for injection and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103211772A (en) | 2013-07-24 |
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Address after: 266103 Qingdao economic and Technological Development Zone, unity Road, No. 3601, Shandong Applicant after: Qingdao Zhengda Haier Pharmaceutical Co.,Ltd. Address before: 266103 Haier Road, Shandong, Qingdao, No. 1 Applicant before: Qingdao Zhengda Haier Pharmaceutical Co.,Ltd. |
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Address after: 266103 3601 Tuen Jie Road, Qingdao economic and Technological Development Zone, Shandong Patentee after: CP PHARMACEUTICAL (QINGDAO) Co.,Ltd. Address before: 266103 3601 Tuen Jie Road, Qingdao economic and Technological Development Zone, Shandong Patentee before: Qingdao Zhengda Haier Pharmaceutical Co.,Ltd. |
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Address after: No.3601 Tuanjie Road, Qingdao Economic and Technological Development Zone, Shandong Province 266426 Patentee after: Qingdao Guoxin Pharmaceutical Co.,Ltd. Country or region after: China Address before: No. 3601 Tuanjie Road, Qingdao Economic and Technological Development Zone, Shandong Province Patentee before: CP PHARMACEUTICAL (QINGDAO) Co.,Ltd. Country or region before: China |