CN1839800A - Vinorelbine Bitartrate lipsome freeze-drying powder injection and its preparation method - Google Patents
Vinorelbine Bitartrate lipsome freeze-drying powder injection and its preparation method Download PDFInfo
- Publication number
- CN1839800A CN1839800A CN 200610001318 CN200610001318A CN1839800A CN 1839800 A CN1839800 A CN 1839800A CN 200610001318 CN200610001318 CN 200610001318 CN 200610001318 A CN200610001318 A CN 200610001318A CN 1839800 A CN1839800 A CN 1839800A
- Authority
- CN
- China
- Prior art keywords
- liposome
- preparation
- organic solvent
- vitamin
- injection
- Prior art date
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- Granted
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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 238000002347 injection Methods 0.000 title claims abstract description 19
- 239000007924 injection Substances 0.000 title claims abstract description 19
- 239000000843 powder Substances 0.000 title claims abstract description 8
- 238000004108 freeze drying Methods 0.000 title claims description 8
- CILBMBUYJCWATM-HGBQGYOLSA-N vinorelbine D-tartrate Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O.OC(=O)[C@@H](O)[C@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-HGBQGYOLSA-N 0.000 title abstract description 6
- 239000002502 liposome Substances 0.000 claims abstract description 57
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims abstract description 38
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims abstract description 38
- 229930003427 Vitamin E Natural products 0.000 claims abstract description 19
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims abstract description 19
- 235000019165 vitamin E Nutrition 0.000 claims abstract description 19
- 229940046009 vitamin E Drugs 0.000 claims abstract description 19
- 239000011709 vitamin E Substances 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 12
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 8
- -1 phosphatide Chemical compound 0.000 claims abstract description 5
- UAXNMTICKQUESH-DDDIARMZSA-N ac1l4f25 Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC2C3=CC=CC=C3NC22)CC(CC)=C[C@@H]1C[C@]2(C(=O)OC)C1=CC(C23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC UAXNMTICKQUESH-DDDIARMZSA-N 0.000 claims description 35
- 239000003814 drug Substances 0.000 claims description 35
- 239000003960 organic solvent Substances 0.000 claims description 31
- 239000012528 membrane Substances 0.000 claims description 29
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 21
- 235000012000 cholesterol Nutrition 0.000 claims description 18
- 239000008363 phosphate buffer Substances 0.000 claims description 17
- 210000000481 breast Anatomy 0.000 claims description 14
- 230000006837 decompression Effects 0.000 claims description 14
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- 229940079593 drug Drugs 0.000 claims description 13
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- 238000001914 filtration Methods 0.000 claims description 12
- 150000003904 phospholipids Chemical class 0.000 claims description 12
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 9
- 229930195725 Mannitol Natural products 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 9
- 239000000594 mannitol Substances 0.000 claims description 9
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- 238000004090 dissolution Methods 0.000 claims description 8
- 150000002632 lipids Chemical class 0.000 claims description 8
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 7
- 230000001804 emulsifying effect Effects 0.000 claims description 7
- 239000008347 soybean phospholipid Substances 0.000 claims description 7
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 6
- 108010001394 Disaccharidases Proteins 0.000 claims description 6
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 6
- 150000004676 glycans Chemical class 0.000 claims description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 6
- 150000002772 monosaccharides Chemical class 0.000 claims description 6
- 229920001282 polysaccharide Polymers 0.000 claims description 6
- 239000005017 polysaccharide Substances 0.000 claims description 6
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 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 claims description 5
- 239000007853 buffer solution Substances 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 238000011275 oncology therapy Methods 0.000 claims description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 4
- 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 claims description 4
- 239000008103 glucose Substances 0.000 claims description 4
- 239000003978 infusion fluid Substances 0.000 claims description 4
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 3
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 3
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 3
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- 229930006000 Sucrose Natural products 0.000 claims description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 3
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 3
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 3
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 3
- 230000002421 anti-septic effect Effects 0.000 claims description 3
- 239000003963 antioxidant agent Substances 0.000 claims description 3
- 230000003078 antioxidant effect Effects 0.000 claims description 3
- 235000006708 antioxidants Nutrition 0.000 claims description 3
- 239000004202 carbamide Substances 0.000 claims description 3
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 239000000787 lecithin Substances 0.000 claims description 3
- 229940067606 lecithin Drugs 0.000 claims description 3
- 235000010445 lecithin Nutrition 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 239000001103 potassium chloride Substances 0.000 claims description 3
- 235000011164 potassium chloride Nutrition 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 239000005720 sucrose Substances 0.000 claims description 3
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 2
- 150000008065 acid anhydrides Chemical class 0.000 claims 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims 2
- 235000010265 sodium sulphite Nutrition 0.000 claims 2
- ZIIUUSVHCHPIQD-UHFFFAOYSA-N 2,4,6-trimethyl-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide Chemical compound CC1=CC(C)=CC(C)=C1S(=O)(=O)NC1=CC=CC(C(F)(F)F)=C1 ZIIUUSVHCHPIQD-UHFFFAOYSA-N 0.000 claims 1
- 239000005711 Benzoic acid Substances 0.000 claims 1
- QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 claims 1
- 102000015439 Phospholipases Human genes 0.000 claims 1
- 108010064785 Phospholipases Proteins 0.000 claims 1
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- 239000007979 citrate buffer Substances 0.000 claims 1
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- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims 1
- 125000001033 ether group Chemical group 0.000 claims 1
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 claims 1
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- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims 1
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- Medicinal Preparation (AREA)
Abstract
The invention relates to an antineoplastic vinorelbine bitartrate liposome, its freeze-dried powder injection and preparing process, wherein the preparation comprises liposome of vinorelbine bitartrate and pharmaceutically acceptable carrying agent, the liposome of vinorelbine bitartrate contains the following constituents: vinorelbine bitartrate, phosphatide, cholesterin and vitamin E, their weight ratio being 1 : 1-100 : 1-15 : 0.01-0.05.
Description
Technical field:
The present invention relates to a kind of Liposomal formulation of antitumor drug Vinorelbine monotartrate.
Background technology:
Vinorelbine monotartrate (Vinorelbine Bitartrate common name vinorelbine), it is a kind of semisynthetic vinca alkaloids, its mechanism of action and vincaleucoblastine (VLB) and vincristine (VCR) are basic identical, main by the microtubule formation in the retardance cell mitogen process, make cell division stop at mitosis metaphase, be cell cycle specific agents.The same with other vinblastine, vinorelbine also can suppress the circulation of aminoacid front and back and the metabolism of glutathion; Rely on the Ca of calmodulin
SweetThe activity of-ATP enzyme; The biological oxidation of cell and nucleic acid and greasy biosynthesis.Clinical nonsmall-cell lung cancer, metastatic breast cancer, advanced ovarian cancer, the malignant lymphoma etc. of being mainly used in.But after this medicine intravenous injection, it is big that toxic and side effects compares, and common is bone marrow depression, gastrointestinal toxicity and alopecia etc., and in addition, weakness of the lower extremities can appear in long-term prescription.These toxic and side effects make the clinical practice of vinorelbine be subjected to very big restriction.Urgent need is sought a kind of effective method, can be under the situation that does not increase drug dose, and the half-life of prolong drug, the antitumous effect of raising medicine, the toxic and side effects of minimizing medicine strengthens the clinical practice of medicine.
Liposome is a kind of targeted drug carrier, belongs to a kind of novel form of targeting drug delivery system.It can be engulfed medicine and activate the autoimmune function of body by the huge system of biting, and the interior distribution of the body that changes encapsulated medicine, drug main will be put aside in histoorgans such as liver, spleen, lung and bone marrow, thereby improve the therapeutic index of medicine, reduce the toxicity of the therapeutic dose and the reduction medicine of medicine.
The mid-80, some companies that specialize in the liposome exploitation set up in succession, have carried out the research with liposomal encapsulated anticarcinogen, have the liposome dosage form of many cancer therapy drugs to go on the market in succession in recent years.Liposome will obtain more and more general application as the carrier of antitumor drug.
Summary of the invention:
The present invention has invented a kind of new Vinorelbine monotartrate liposomal pharmaceutical preparation according to the characteristic of liposome vectors properties of materials and Vinorelbine monotartrate product itself.
Vinorelbine monotartrate Liposomal formulation of the present invention is a kind of freeze-dried powder injection, the present invention has found through screening and can make the liposome Chinese medicine continue to discharge, improve blood drug level, prolong drug circulation time in blood, improve bioavailability of medicament, can reduce simultaneously the toxic and side effects of medicine again, strengthen the effective pharmaceutical formulation of compliance of patients.
Vinorelbine monotartrate Liposomal formulation of the present invention is made up of the liposome and the medicine acceptable carrier of cancer therapy drug Vinorelbine monotartrate.The liposome of wherein said cancer therapy drug Vinorelbine monotartrate contains following composition: Vinorelbine monotartrate, phospholipid, cholesterol, vitamin E, the weight ratio between them are 1 part: 5-100 part: 1-15 part: 0.01-0.05 part.
Its preferably ratio be: 1 part of vinorelbine, phosphatidase 13 0-70 part, cholesterol 5-15 part, the plain E0.02-0.04 part of dimension dirt.
Most preferably Vinorelbine monotartrate is 1 part, 0 part of phosphatidase 16,10 parts in cholesterol, 0.03 part of vitamin E.
Wherein said phospholipid is soybean phospholipid, lecithin or and synthetic phospholipid.
Above medicine material all can have been bought from the market.
The liposome that above liposome prescription is made and make the combination of the necessary medicine acceptable carrier of preparation of the present invention, make Vinorelbine monotartrate Liposomal formulation of the present invention, described medicine acceptable carrier is a useful in preparing drug formulations, and the needed conventional carrier of freeze-dried powder injection particularly is as the pH value regulator, buffer system, frozen-dried supporting agent, antioxidant, antiseptic, solvent for injection etc., the addition of these carriers also are conventional.
But the present invention also provides the method for the suitability for industrialized production of Vinorelbine monotartrate Liposomal formulation of the present invention.
Vinorelbine monotartrate Liposomal formulation of the present invention can adopt following method preparation:
Method one:
1) get 1 part of Vinorelbine monotartrate, phosphatidase 15-100 part by weight, vitamin E 0.01-0.05 part with cholesterol 1-15 part, is dissolved in the organic solvent mix homogeneously;
2) with lipid soln on membrane evaporator, organic solvent is removed in decompression;
3) dispose the phosphate buffer of PH6-8 by writing out a prescription;
4) with adding organic solvent dissolution in the adipose membrane that forms, add phosphate buffer again, mixing, emulsifying continues on membrane evaporator, and organic solvent is removed in decompression; Get liposome turbid liquor;
The gained liposome turbid liquor is carried out the high pressure breast spare, reduce particle diameter promptly, an amount of lyophilizing holder is dissolved in the liposome aseptic filtration;
5) be up to the standards, bottling, capping, lyophilizing gets product.
Method two:
1) get 1 part of Vinorelbine monotartrate, phosphatidase 15-100 part by weight, vitamin E 0.01-0.05 part with cholesterol 1-15 part, is dissolved in the organic solvent mix homogeneously;
2) dispose the phosphate buffer of PH6-8 by writing out a prescription;
3) with step 1) solution and step 2) solution is mixed, emulsifying, organic solvent is removed in decompression on membrane evaporator; Get liposome turbid liquor;
4) the gained liposome turbid liquor is carried out the high pressure breast and spare, reduce particle diameter.The lyophilizing holder of an amount of recipe quantity is dissolved in the liposome aseptic filtration.
5) be up to the standards, bottling, capping, lyophilizing gets product.
Preferred manufacturing procedure is as follows:
Method one:
1) get 1 part of Vinorelbine monotartrate, phosphatidase 13 0-70 part by weight, vitamin E 0.02-0.04 part and cholesterol 5-15 part are dissolved in the organic solvent mix homogeneously;
2) with above-mentioned lipid soln on membrane evaporator, organic solvent is removed in decompression;
3) dispose the phosphate buffer of PH6-8 by writing out a prescription;
4) with adding organic solvent dissolution in the adipose membrane that forms, add phosphate buffer again, mixing, emulsifying continues on membrane evaporator, and organic solvent is removed in decompression; Get liposome turbid liquor;
5) the gained liposome turbid liquor is carried out the high pressure breast and spare, reduce particle diameter promptly.The lyophilizing holder of an amount of recipe quantity is dissolved in the liposome aseptic filtration;
6) be up to the standards, bottling, capping, lyophilizing gets product.
Method two:
1) get 1 part of Vinorelbine monotartrate, phosphatidase 13 0-70 part by weight, vitamin E 0.02-0.04 part and cholesterol 5-15 part are dissolved in the organic solvent mix homogeneously;
2) dispose the phosphate buffer of PH6-8 by writing out a prescription;
3) solution 1 is mixed with solution 2, emulsifying, organic solvent is removed in decompression on membrane evaporator; Get liposome turbid liquor;
4) it is even the gained liposome turbid liquor to be carried out high pressure breast, reduces particle diameter, and the lyophilizing holder of an amount of recipe quantity is dissolved in the liposome aseptic filtration.
5) be up to the standards, bottling, capping, lyophilizing gets product.
In the described preparation method, when disposing the phosphate buffer of PH6-8, can add the pH value regulator and regulate pH value, described pH value regulator is selected from sodium hydroxide, potassium chloride, sodium chloride, phosphate, carbonate, citrate, nicotiamide, Benzoylamide, urea, thiourea, ethylenediamine, diethylamine, ethanolamine, diethanolamine, triethanolamine and triethylamine etc.
In the described preparation method, the organic solvent of step 1) is selected from EC.
In the described preparation method, described frozen-dried supporting agent is selected from dextran, monosaccharide, disaccharidase and polysaccharide; Wherein monosaccharide is mannitol, glucose, and disaccharidase is lactose, sucrose, and polysaccharide is a trehalose.
The lyophilized injectable powder of Vinorelbine monotartrate liposome of the present invention, when mixing use with the injection infusion solutions with proper proportion, its envelop rate is 60～90%, particle diameter is 40nm～1 μ m.Described proper proportion refers to dilute with the injection infusion solutions pharmaceutically to be suitable for ratio.Described injection infusion solutions is selected from: glucose injection, sodium chloride injection, dextran injection, several amino acids and vitamin Mixtard etc.
In the liposome of the present invention, contain the 1-10mg Vinorelbine monotartrate in every ml liposome turbid liquor.
Liposome of the present invention can be used prior art for preparing such as rotary evaporation method, reverse phase evaporation, multi-emulsion method and PH gradient method.
Vinorelbine monotartrate liposome of the present invention is carried out acute toxicity test, and the common vinorelbine preparation of rat intravenous injection LD50 is 11.2mg/kg, 95% confidence limit 10.32-12.24mg/kg; Injection vinorelbine liposome LD50 is 21.38mg/kg, 95% confidence limit 20.25-22.41mg/kg.Improved 0.91 times with common vinorelbine comparison LD50.Gastrointestinal tract and neural toxicity are obviously alleviated.
Vinorelbine monotartrate Liposomal formulation, particularly the present invention of the present invention are preferably filled a prescription, the Vinorelbine monotartrate content height in its unit volume, and the envelop rate height, good stability has stable drug loading again.The liposome Chinese medicine continues to discharge, and has significantly improved blood drug level, the circulation time of prolong drug in blood.The obvious toxic and side effects that reduces medicine of Vinorelbine monotartrate liposome freeze-dried powder injection of the present invention has improved the curative effect of medicine, has strengthened the clinical usability of medicine.
The specific embodiment:
Further specify the present invention by the following examples, but not as limitation of the present invention.
Embodiment 1
Taking by weighing 600mg soybean phospholipid (purity＞76% phosphatidylcholine) and 100mg cholesterol is dissolved in the ether, mix homogeneously, this solution is placed the ground round-bottomed flask, in under the condition of 100rpm and decompression, boiling off organic solvent with Rotary Evaporators in the 30-32 ℃ of water bath with thermostatic control, make filmogen such as phospholipid form an even lipid membrane at drag; In above-mentioned adipose membrane, add the 30ml ether dissolution, the 10mg vinorelbine is added in 5ml (2-10ml) the PH7.4 phosphate buffer in addition, in again it being joined in the above-mentioned adipose membrane solution, rotate the removal organic solvent at 32 ℃ with Rotary Evaporators, become the milky liposome turbid liquor until the hydration of lipoid thin film, ice bath dot matrix ultrasonic (ultrasonic cell disruptor) reduces particle diameter promptly.With vitamin E 0.3mg, 300mg mannitol is dissolved in the liposome, and (membrane filter aperture 0.2 μ m) will finally disperse thing to be divided in the cillin bottle lyophilization then after the aseptic filtration.
Vinorelbine Liposomal formulation of the present invention is the injection dried frozen aquatic products, constant product quality, and stability experiment carries out under 25 ± 2 ℃, and the result shows, and stable during 25 ± 2 ℃ of this product, every index is all in the scope of quality standard regulation; Low temperature keeps sample and investigates 1 year, and every index is all stable, and stability experiment research prompting this product is stored as under cryogenic conditions.
Embodiment 2
Taking by weighing 600mg lecithin (purity＞93% phosphatidylcholine) and 100mg cholesterol is dissolved in the 30ml ether; Again vinorelbine is dissolved in the buffer of 10mlPH7.4, above-mentioned two liquid is mixed carry out emulsifying, rotate the removal organic solvent at 32 ℃ with Rotary Evaporators then, become the milky liposome turbid liquor until mixed liquor.Ice bath dot matrix ultrasonic (supersonic cell crusher) reduces particle diameter promptly.With vitamin E 0.3mg, 300mg mannitol is dissolved in the liposome, and (membrane filter aperture 0.2 μ m) will finally disperse thing to be divided in the cillin bottle lyophilization then after the aseptic filtration.
Vinorelbine Liposomal formulation of the present invention is the injection dried frozen aquatic products, constant product quality, and stability experiment carries out under 25 ± 2 ℃, and the result shows, and stable during 25 ± 2 ℃ of this product, every index is all in the scope of quality standard regulation; Low temperature keeps sample and investigates 1 year, and every index is all stable, and stability experiment research prompting this product is stored as under cryogenic conditions.
Embodiment 3
Taking by weighing 5mg Vinorelbine monotartrate, 300mg soybean phospholipid (purity＞76% phosphatidylcholine) and 30mg cholesterol is dissolved in the ether, mix homogeneously, this solution is placed the ground round-bottomed flask, in under the condition of 100rpm and decompression, boiling off organic solvent with Rotary Evaporators in the 30-32 ℃ of water bath with thermostatic control, make filmogen such as phospholipid form an even lipid membrane at drag; Add the 30ml ether dissolution in above-mentioned adipose membrane, other adds 5ml (2-10ml) PH7.4 phosphate buffer, and the ultrasonic one-tenth breast of water-bath is removed organic solvent at 30 ℃ with Rotary Evaporators, and until becoming the milky liposome turbid liquor, the high pressure breast is even to reduce particle diameter promptly.With vitamin E 0.3mg, 500mg mannitol is dissolved in the liposome, and (membrane filter aperture 0.2 μ m) will finally disperse thing to be divided in the cillin bottle lyophilization then after the aseptic filtration.
Embodiment 4
Taking by weighing 1mg Vinorelbine monotartrate, 100mg soybean phospholipid (purity＞76% phosphatidylcholine) and 15mg cholesterol is dissolved in the ether, mix homogeneously, this solution is placed the ground round-bottomed flask, in under the condition of 100rpm and decompression, boiling off organic solvent with Rotary Evaporators in the 30-32 ℃ of water bath with thermostatic control, make filmogen such as phospholipid form an even lipid membrane at drag; Add the 30ml ether dissolution in above-mentioned adipose membrane, other adds 5ml (2-10ml) PH7.4 phosphate buffer, and the ultrasonic one-tenth breast of water-bath is removed organic solvent at 30 ℃ with Rotary Evaporators, and until becoming the milky liposome turbid liquor, the high pressure breast is even to reduce particle diameter promptly.With vitamin E 0.3mg, 500mg mannitol is dissolved in the liposome, and (membrane filter aperture 0.2 μ m) will finally disperse thing to be divided in the cillin bottle lyophilization then after the aseptic filtration.
Embodiment 5
Taking by weighing 1mg Vinorelbine monotartrate, 5mg soybean phospholipid (purity＞76% phosphatidylcholine) and 1mg cholesterol is dissolved in the ether, mix homogeneously, this solution is placed the ground round-bottomed flask, in under the condition of 100rpm and decompression, boiling off organic solvent with Rotary Evaporators in the 30-32 ℃ of water bath with thermostatic control, make filmogen such as phospholipid form an even lipid membrane at drag; Add the 30ml ether dissolution in above-mentioned adipose membrane, other adds 5ml (2-10ml) PH7.4 phosphate buffer, and the ultrasonic one-tenth breast of water-bath is removed organic solvent at 30 ℃ with Rotary Evaporators, and until becoming the milky liposome turbid liquor, the high pressure breast is even to reduce particle diameter promptly.With vitamin E 0.01mg, 500mg mannitol is dissolved in the liposome, and (membrane filter aperture 0.2 μ m) will finally disperse thing to be divided in the cillin bottle lyophilization then after the aseptic filtration.
Embodiment 6
Taking by weighing 1mg Vinorelbine monotartrate, 100mg soybean phospholipid (purity＞76% phosphatidylcholine) and 15mg cholesterol is dissolved in the ether, mix homogeneously, this solution is placed the ground round-bottomed flask, in under the condition of 100rpm and decompression, boiling off organic solvent with Rotary Evaporators in the 30-32 ℃ of water bath with thermostatic control, make filmogen such as phospholipid form an even lipid membrane at drag; Add the 30ml ether dissolution in above-mentioned adipose membrane, other adds 5ml (2-10ml) PH7.4 phosphate buffer, and the ultrasonic one-tenth breast of water-bath is removed organic solvent at 30 ℃ with Rotary Evaporators, and until becoming the milky liposome turbid liquor, the high pressure breast is even to reduce particle diameter promptly.With vitamin E 0.05mg, 500mg mannitol is dissolved in the liposome, and (membrane filter aperture 0.2 μ m) will finally disperse thing to be divided in the cillin bottle lyophilization then after the aseptic filtration.
Claims (10)
1. liposome freeze-drying powder injection preparation, it is characterized in that: liposome and medicine acceptable carrier by the cancer therapy drug Vinorelbine monotartrate are formed.
2. the preparation of claim 1, it is characterized in that: the liposome of described cancer therapy drug Vinorelbine monotartrate contains Vinorelbine monotartrate, phospholipid, cholesterol, vitamin E, and their weight ratio is 1: 5-100: 1-15: 0.01-0.05.
3. the preparation of claim 2, it is characterized in that: described liposome contains 1 part of Vinorelbine monotartrate, phosphatidase 13 0-70 part, cholesterol 5-15 part, vitamin E 0.02-0.04 part.
4. the preparation of claim 3, it is characterized in that: described liposome contains 1 part of Vinorelbine monotartrate, 0 part of phosphatidase 16,10 parts in cholesterol, 0.03 part of vitamin E.
5. the preparation of claim 4, it is characterized in that: described phospholipid is selected from soybean phospholipid, lecithin and synthetic phospholipid.
6. the preparation of claim 1, it is characterized in that: described medicine acceptable carrier is selected from pH value regulator, buffer system, frozen-dried supporting agent, antioxidant, antiseptic, solvent for injection.
7. the preparation of claim 6, it is characterized in that: described pH value regulator is selected from: sodium hydroxide, potassium chloride, sodium chloride, phosphate, carbonate, citrate, nicotiamide, Benzoylamide, urea, thiourea, ethylenediamine, diethylamine, ethanolamine, diethanolamine, triethanolamine and triethylamine; Buffer system is selected from: phosphatebuffer buffer system, citrate buffer system, carbonate buffer system system; Frozen-dried supporting agent is selected from: dextrorotation acid anhydride sugar, monosaccharide, disaccharidase and polysaccharide, and wherein monosaccharide is mannitol, glucose, and disaccharidase is lactose, sucrose, and polysaccharide is a trehalose; Antioxidant is selected from: vitamin E, vitamin-e ester, sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate; Antiseptic is selected from: methyl parahydroxybenzoate, ethylparaben, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate, benzoic acid, sodium benzoate, sorbic acid; Solvent for injection is selected from: water for injection, injection normal saline, glucose for injection solution.
8. the preparation of claim 1 is characterized in that: the addition of frozen-dried supporting agent, the calculating of by phospholipase weight ratio, 1 part of phospholipid adds 0.2-4 part frozen-dried supporting agent, described preparation is when mixing use with the injection infusion solutions with proper proportion, its envelop rate is 60～90%, and particle diameter is 40nm-1 μ m.
9. the preparation method of the preparation of claim 1 is characterized in that: through following step preparation method one:
1) get 1 part of Vinorelbine monotartrate, phosphatidase 15-100 part by weight, vitamin E 0.01-0.05 part with cholesterol 1-15 part, is dissolved in the organic solvent mix homogeneously;
2) with lipid soln on membrane evaporator, organic solvent is removed in decompression;
3) dispose the phosphate buffer of PH6-8 by writing out a prescription;
4) with adding organic solvent dissolution in the adipose membrane that forms, add phosphate buffer again, mixing, emulsifying continues on membrane evaporator, and organic solvent is removed in decompression; Get liposome turbid liquor;
The gained liposome turbid liquor is carried out the high pressure breast spare, reduce particle diameter promptly, an amount of lyophilizing holder is dissolved in the liposome aseptic filtration;
5) be up to the standards, bottling, capping, lyophilizing gets product;
Method two:
1) get 1 part of Vinorelbine monotartrate, phosphatidase 15-100 part by weight, vitamin E 0.01-0.05 part with cholesterol 1-15 part, is dissolved in the organic solvent mix homogeneously;
2) dispose the phosphate buffer of PH6-8 by writing out a prescription;
3) with step 1) solution and step 2) solution is mixed, emulsifying, organic solvent is removed in decompression on membrane evaporator; Get liposome turbid liquor;
4) it is even the gained liposome turbid liquor to be carried out high pressure breast, reduces particle diameter, the lyophilizing holder of an amount of recipe quantity is dissolved in the liposome, and aseptic filtration,
5) be up to the standards, bottling, capping, lyophilizing gets product.
10. the preparation method of claim 9, it is characterized in that: the phosphate buffer of described configuration PH6-8, can add sodium hydroxide, potassium chloride, sodium chloride, phosphate, carbonate, citrate, nicotiamide, Benzoylamide, urea, thiourea, ethylenediamine, diethylamine, ethanolamine, diethanolamine, triethanolamine or triethylamine as the pH value regulator, described organic solvent is ether or chloroform; Described lyophilizing holder is selected from dextrorotation acid anhydride sugar, monosaccharide, disaccharidase and polysaccharide, and wherein monosaccharide is mannitol, glucose, and disaccharidase is lactose, sucrose, and polysaccharide is a trehalose.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101129374B (en) * | 2007-06-26 | 2010-09-08 | 齐鲁制药有限公司 | Vinflunine pharmaceutical composition and method of producing the same and application of the same |
| CN101933904B (en) * | 2009-07-01 | 2011-11-16 | 齐鲁制药有限公司 | Vinorelbine long circulation liposome preparation and preparation method thereof |
| US9700511B2 (en) | 2013-03-15 | 2017-07-11 | Tlc Biopharmaceuticals, Inc. | Controlled drug release liposome composition |
| US10220095B2 (en) | 2013-03-15 | 2019-03-05 | Taiwan Liposome Company, Ltd | Controlled drug release liposome compositions and methods thereof |
| CN115645358A (en) * | 2022-09-09 | 2023-01-31 | 江苏豪森药业集团有限公司 | Vinorelbine tartrate injection preparation and preparation method thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7311924B2 (en) * | 1999-04-01 | 2007-12-25 | Hana Biosciences, Inc. | Compositions and methods for treating cancer |
| ES2186484B1 (en) * | 2000-10-10 | 2004-07-01 | Lipotec, S.A. | LIPOSOMES ENCAPSULATING ANTI-CANCER DRUGS AND USE OF THEM IN THE TREATMENT OF EVIL TUMORS. |
-
2006
- 2006-01-19 CN CNB2006100013187A patent/CN100438855C/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101129374B (en) * | 2007-06-26 | 2010-09-08 | 齐鲁制药有限公司 | Vinflunine pharmaceutical composition and method of producing the same and application of the same |
| CN101933904B (en) * | 2009-07-01 | 2011-11-16 | 齐鲁制药有限公司 | Vinorelbine long circulation liposome preparation and preparation method thereof |
| US9700511B2 (en) | 2013-03-15 | 2017-07-11 | Tlc Biopharmaceuticals, Inc. | Controlled drug release liposome composition |
| US10220095B2 (en) | 2013-03-15 | 2019-03-05 | Taiwan Liposome Company, Ltd | Controlled drug release liposome compositions and methods thereof |
| US11147881B2 (en) | 2013-03-15 | 2021-10-19 | Taiwan Liposome Company, Ltd. | Controlled drug release liposome compositions and methods thereof |
| CN115645358A (en) * | 2022-09-09 | 2023-01-31 | 江苏豪森药业集团有限公司 | Vinorelbine tartrate injection preparation and preparation method thereof |
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| CN100438855C (en) | 2008-12-03 |
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