CN100490794C - Lomustine liposome freeze-drying powder injection and its preparation method - Google Patents
Lomustine liposome freeze-drying powder injection and its preparation method Download PDFInfo
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- CN100490794C CN100490794C CNB2006100013191A CN200610001319A CN100490794C CN 100490794 C CN100490794 C CN 100490794C CN B2006100013191 A CNB2006100013191 A CN B2006100013191A CN 200610001319 A CN200610001319 A CN 200610001319A CN 100490794 C CN100490794 C CN 100490794C
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- lomustine
- liposome
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- 239000002502 liposome Substances 0.000 title claims abstract description 59
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 title claims abstract description 48
- 229960002247 lomustine Drugs 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 239000000843 powder Substances 0.000 title claims abstract description 8
- 238000002347 injection Methods 0.000 title claims description 12
- 239000007924 injection Substances 0.000 title claims description 12
- 238000004108 freeze drying Methods 0.000 title claims description 8
- 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 34
- 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 34
- 229930003427 Vitamin E Natural products 0.000 claims abstract description 17
- 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 17
- 235000019165 vitamin E Nutrition 0.000 claims abstract description 17
- 229940046009 vitamin E Drugs 0.000 claims abstract description 17
- 239000011709 vitamin E Substances 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims description 30
- 235000012000 cholesterol Nutrition 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 14
- 229940079593 drug Drugs 0.000 claims description 13
- 150000003904 phospholipids Chemical class 0.000 claims description 12
- 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 8
- 239000008347 soybean phospholipid Substances 0.000 claims description 8
- 238000011275 oncology therapy Methods 0.000 claims description 4
- 238000009472 formulation Methods 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 2
- 229940107161 cholesterol Drugs 0.000 claims description 2
- 239000000787 lecithin Substances 0.000 claims description 2
- 229940067606 lecithin Drugs 0.000 claims description 2
- 235000010445 lecithin Nutrition 0.000 claims description 2
- 229940067631 phospholipid Drugs 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 10
- -1 phosphatide Chemical compound 0.000 abstract description 4
- 239000003937 drug carrier Substances 0.000 abstract description 2
- HVYWMOMLDIMFJA-UHFFFAOYSA-N 3-cholesterol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 HVYWMOMLDIMFJA-UHFFFAOYSA-N 0.000 abstract 1
- 230000001093 anti-cancer Effects 0.000 abstract 1
- 230000000118 anti-neoplastic effect Effects 0.000 abstract 1
- 239000000470 constituent Substances 0.000 abstract 1
- 239000012528 membrane Substances 0.000 description 26
- 239000003960 organic solvent Substances 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- 210000000481 breast Anatomy 0.000 description 15
- 239000008363 phosphate buffer Substances 0.000 description 13
- 230000006837 decompression Effects 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
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- 150000002632 lipids Chemical class 0.000 description 8
- 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 description 7
- 229930195725 Mannitol Natural products 0.000 description 7
- 238000004090 dissolution Methods 0.000 description 7
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- 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 6
- 238000009835 boiling Methods 0.000 description 6
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
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- 231100000331 toxic Toxicity 0.000 description 5
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- 206010028980 Neoplasm Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
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- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- 108010001394 Disaccharidases Proteins 0.000 description 2
- 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 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 230000021235 carbamoylation Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- ILYCWAKSDCYMBB-OPCMSESCSA-N dihydrotachysterol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1/C[C@@H](O)CC[C@@H]1C ILYCWAKSDCYMBB-OPCMSESCSA-N 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 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 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 150000002772 monosaccharides Chemical class 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 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 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 1
- 206010065553 Bone marrow failure Diseases 0.000 description 1
- 206010051779 Bone marrow toxicity Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 230000010337 G2 phase Effects 0.000 description 1
- 206010059024 Gastrointestinal toxicity Diseases 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 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 description 1
- 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 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 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 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000003005 anticarcinogenic agent Substances 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 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
- 231100000366 bone marrow toxicity Toxicity 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
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- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940093181 glucose injection Drugs 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 108010021522 pork drug combination 30:70 pork; isophane insulin insulin Proteins 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
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- 208000011581 secondary neoplasm Diseases 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
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- 239000005720 sucrose Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
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- Medicinal Preparation (AREA)
Abstract
The invention relates to an antineoplastic Lomustine liposome, its freeze-dried powder njection and preparing process, wherein the preparation comprises liposome of Lomustine and pharmaceutically acceptable carrier, the liposome of the anti-cancer Lomustine contains the following constituents: Lomustine, phosphatide, cholesterin and vitamin E, their weight ratio being 1 : 2-100 : 1-15 : 0.01-0.05.
Description
Technical field:
The present invention relates to a kind of Liposomal formulation of antitumor drug lomustine.
Background technology:
Lomustine (Lomustine, lomustine) is a kind of alkylating agent class antineoplastic agent, as cell cycle nonspecific agent (CCNSA), to being in G2-S border, or the early stage cell of S is the most responsive, also there is inhibitory action the G2 phase, advance people's human body after, its molecule is fractured into two parts from carbamyl amine key: one is the chlorethamin part, with chlorinolysis from, form the ethylene carbonium ion, performance hydrocarbonylation effect causes the DNA chain interruption, RNA and protein receptor are to hydrocarbonylation, and these are main relevant with anti-tumor effect; Another partly becomes isocyanates for carbamyl. or be converted into ammonia formic acid again, with the effect of performance carbamylation, main and protein is particularly with wherein reactions such as lysine terminal amino group.It is believed that this is main relevant with the bone marrow toxicity effect, the carbamylation effect also can destroy some pherons, makes DNA be subjected to be difficult to repair after the hydrocarbonylation destruction, helps antitumaous effect.Clinical treatment brain primary tumor and secondary tumors, Hodgkin and other lymphoma, the melanoma etc. of being mainly used in; Should can be used for solid tumor or share in gastric cancer and rectal cancer with fluorouracil; Share treatment pulmonary carcinoma with methotrexate, cyclophosphamide.But behind this drug administration, it is big that toxic and side effects compares, and common is gastrointestinal toxicity and liver function injury etc., and in addition, bone marrow depression can appear in long-term prescription, and cumulative bad is arranged.These toxic and side effects make the clinical practice of lomustine 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.Medicine with liposome after, can targeting in tumor locus, thereby improve the therapeutic index of medicine, can also reduce the therapeutic dose of medicine simultaneously, reduce systemic adverse reactions, improve drug safety.
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 lomustine liposomes pharmaceutical preparation according to the characteristic of liposome vectors properties of materials and lomustine product itself.
Lomustine liposomes preparation 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.
Lomustine liposomes preparation of the present invention is made up of the liposome and the medicine acceptable carrier of cancer therapy drug lomustine.The liposome of wherein said cancer therapy drug lomustine contains following composition: lomustine, phospholipid, cholesterol, vitamin E, the weight ratio between them are 1 part: 2-100 part: 1-15 part: 0.01-0.05 part.
Preferred weight ratio is: 1 part of lomustine, phosphatidase 13 0-70 part, cholesterol 5-15 part, vitamin E 0.02-0.04 part.
Most preferably lomustine is 1 part, 0 part of phosphatidase 16,6 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 lomustine liposomes preparation of the present invention, described medicine acceptable carrier is a useful in preparing drug formulations, particularly the needed conventional carrier of freeze-dried powder injection, as the pH value regulator, buffer system, frozen-dried supporting agent, cosolvent, antioxidant, antiseptic, solvent for injection etc., the addition of these carriers also is conventional.
But the present invention also provides the method for the suitability for industrialized production of lomustine liposomes preparation of the present invention.
Lomustine liposomes preparation of the present invention can adopt following method preparation:
Method one:
1) get 1 part of lomustine, phosphatidase 12-100 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 lomustine, phosphatidase 12-100 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 lomustine, 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 lomustine, 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 lomustine liposomes of the present invention, when mixing use with the injection infusion solutions with proper proportion, its envelop rate is 60～90%, particle diameter is 20nm-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 0.1-10mg lomustine 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.
Lomustine liposomes of the present invention is carried out acute toxicity test, and the common lomustine preparation of rat intravenous injection LD50 is 11.2mg/kg, 95% confidence limit 10.32-12.24mg/kg; It is 21.38mg/kg that the present invention injects lomustine liposomes LD50,95% confidence limit 20.25-22.41mg/kg.Improved 0.91 times with common lomustine comparison LD50.Gastrointestinal tract and neural toxicity are obviously alleviated.
Lomustine liposomes preparation, particularly the present invention of the present invention are preferably filled a prescription, the lomustine 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 lomustine liposomes 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 10mg lomustine, 600mg soybean phospholipid (purity〉76% phosphatidylcholine) and 60mg 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.
Lomustine liposomes preparation 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 10mg lomustine, 600mg soybean phospholipid (purity〉93% phosphatidylcholine) and 60mg 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 5ml (2-10ml) PH7.4 phosphate buffer in above-mentioned adipose membrane, go rotation at 30 ℃ with Rotary Evaporators, become the milky liposome turbid liquor until the hydration of lipoid thin film, 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.
Lomustine liposomes preparation 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 lomustine, 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 lomustine, 100mg 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 0.3mg, 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 lomustine, 2mg soybean phospholipid (purity〉76% phosphatidylcholine) and 10mg 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 lomustine, 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 (3)
1. liposome freeze-drying powder injection preparation, it is characterized in that: liposome and medicine acceptable carrier by the cancer therapy drug lomustine are formed, described Liposomal formulation comprises lomustine, phospholipid, cholesterol, vitamin E, its weight proportion is: 1 part of lomustine, phosphatidase 13 0-70 part, cholesterol 5-15 part, vitamin E 0.02-0.04 part.
2. the preparation of claim 1, it is characterized in that: described Liposomal formulation contains 1 part of lomustine, 0 part of phosphatidase 16,6 parts in cholesterol, 0.03 part of vitamin E.
3. the preparation of claim 1, it is characterized in that: described phospholipid is selected from soybean phospholipid, lecithin and synthetic phospholipid.
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