CN117750944A - Vinorelbine tartrate liposome and raw material composition, preparation method and application thereof - Google Patents
Vinorelbine tartrate liposome and raw material composition, preparation method and application thereof Download PDFInfo
- Publication number
- CN117750944A CN117750944A CN202280053356.4A CN202280053356A CN117750944A CN 117750944 A CN117750944 A CN 117750944A CN 202280053356 A CN202280053356 A CN 202280053356A CN 117750944 A CN117750944 A CN 117750944A
- Authority
- CN
- China
- Prior art keywords
- liposome
- parts
- salt
- sucrose octasulfate
- ammonium sulfate
- 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.)
- Pending
Links
- 239000002502 liposome Substances 0.000 title claims abstract description 183
- 229960002166 vinorelbine tartrate Drugs 0.000 title claims abstract description 60
- GBABOYUKABKIAF-IWWDSPBFSA-N vinorelbinetartrate Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)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 GBABOYUKABKIAF-IWWDSPBFSA-N 0.000 title claims abstract description 60
- 239000000203 mixture Substances 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 239000002994 raw material Substances 0.000 title claims abstract description 24
- 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 56
- 239000012528 membrane Substances 0.000 claims abstract description 48
- 150000003839 salts Chemical class 0.000 claims abstract description 39
- 150000003904 phospholipids Chemical class 0.000 claims abstract description 34
- 239000000463 material Substances 0.000 claims abstract description 30
- 235000012000 cholesterol Nutrition 0.000 claims abstract description 28
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical class 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 GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 claims abstract 13
- 239000003814 drug Substances 0.000 claims description 91
- 229940079593 drug Drugs 0.000 claims description 73
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 50
- 239000000243 solution Substances 0.000 claims description 45
- WEPNHBQBLCNOBB-FZJVNAOYSA-N sucrose octasulfate Chemical compound OS(=O)(=O)O[C@@H]1[C@H](OS(O)(=O)=O)[C@H](COS(=O)(=O)O)O[C@]1(COS(O)(=O)=O)O[C@@H]1[C@H](OS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@@H](COS(O)(=O)=O)O1 WEPNHBQBLCNOBB-FZJVNAOYSA-N 0.000 claims description 34
- 229930006000 Sucrose Natural products 0.000 claims description 30
- 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 30
- 239000005720 sucrose Substances 0.000 claims description 30
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 28
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 28
- -1 polyethylene Polymers 0.000 claims description 27
- 239000007864 aqueous solution Substances 0.000 claims description 24
- 239000012071 phase Substances 0.000 claims description 24
- 206010028980 Neoplasm Diseases 0.000 claims description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 238000011068 loading method Methods 0.000 claims description 19
- 238000002347 injection Methods 0.000 claims description 16
- 239000007924 injection Substances 0.000 claims description 16
- 238000000108 ultra-filtration Methods 0.000 claims description 14
- 239000008346 aqueous phase Substances 0.000 claims description 13
- 229960002066 vinorelbine Drugs 0.000 claims description 12
- 239000000644 isotonic solution Substances 0.000 claims description 11
- 238000002156 mixing Methods 0.000 claims description 10
- 230000002401 inhibitory effect Effects 0.000 claims description 9
- 239000011780 sodium chloride Substances 0.000 claims description 9
- 229920002505 N-(Carbonyl-Methoxypolyethylene Glycol 2000)-1,2-Distearoyl-Sn-Glycero-3-Phosphoethanolamine Polymers 0.000 claims description 8
- 229910052700 potassium Inorganic materials 0.000 claims description 8
- SRLOHQKOADWDBV-NRONOFSHSA-M sodium;[(2r)-2,3-di(octadecanoyloxy)propyl] 2-(2-methoxyethoxycarbonylamino)ethyl phosphate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCCNC(=O)OCCOC)OC(=O)CCCCCCCCCCCCCCCCC SRLOHQKOADWDBV-NRONOFSHSA-M 0.000 claims description 8
- 239000004698 Polyethylene Substances 0.000 claims description 7
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 7
- 229910052783 alkali metal Inorganic materials 0.000 claims description 7
- 230000004087 circulation Effects 0.000 claims description 7
- 210000003022 colostrum Anatomy 0.000 claims description 7
- 235000021277 colostrum Nutrition 0.000 claims description 7
- 229920000573 polyethylene Polymers 0.000 claims description 7
- 239000011591 potassium Substances 0.000 claims description 7
- 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 6
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 6
- 238000001125 extrusion Methods 0.000 claims description 6
- 150000002632 lipids Chemical class 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 230000005907 cancer growth Effects 0.000 claims description 5
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 5
- 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 claims description 5
- 239000002671 adjuvant Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 3
- 238000011534 incubation Methods 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- DBLXOVFQHHSKRC-UHFFFAOYSA-N ethanesulfonic acid;2-piperazin-1-ylethanol Chemical compound CCS(O)(=O)=O.OCCN1CCNCC1 DBLXOVFQHHSKRC-UHFFFAOYSA-N 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000008347 soybean phospholipid Substances 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims 1
- 230000010261 cell growth Effects 0.000 claims 1
- 238000005538 encapsulation Methods 0.000 description 34
- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound 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 GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 23
- 230000000694 effects Effects 0.000 description 18
- 238000000338 in vitro Methods 0.000 description 18
- 241000699670 Mus sp. Species 0.000 description 11
- 206010059516 Skin toxicity Diseases 0.000 description 10
- 231100000438 skin toxicity Toxicity 0.000 description 10
- 231100000331 toxic Toxicity 0.000 description 10
- 230000002588 toxic effect Effects 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- 239000002245 particle Substances 0.000 description 7
- 230000037396 body weight Effects 0.000 description 6
- 210000001185 bone marrow Anatomy 0.000 description 6
- XISWAUUBQBEDFB-QRDGSJRXSA-F octapotassium;[(2r,3r,4s,5r,6r)-2-[(2s,3s,4r,5r)-3,4-disulfonatooxy-2,5-bis(sulfonatooxymethyl)oxolan-2-yl]oxy-3,5-disulfonatooxy-6-(sulfonatooxymethyl)oxan-4-yl] sulfate Chemical compound [K+].[K+].[K+].[K+].[K+].[K+].[K+].[K+].[O-]S(=O)(=O)O[C@H]1[C@H](OS([O-])(=O)=O)[C@@H](COS(=O)(=O)[O-])O[C@@]1(COS([O-])(=O)=O)O[C@@H]1[C@H](OS([O-])(=O)=O)[C@@H](OS([O-])(=O)=O)[C@H](OS([O-])(=O)=O)[C@@H](COS([O-])(=O)=O)O1 XISWAUUBQBEDFB-QRDGSJRXSA-F 0.000 description 6
- 230000001629 suppression Effects 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 238000004364 calculation method Methods 0.000 description 5
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- 241000894007 species Species 0.000 description 5
- 102000001554 Hemoglobins Human genes 0.000 description 4
- 108010054147 Hemoglobins Proteins 0.000 description 4
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 4
- 238000012377 drug delivery Methods 0.000 description 4
- 230000000857 drug effect Effects 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 229960002885 histidine Drugs 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-N 0.000 description 3
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 3
- 101001105486 Homo sapiens Proteasome subunit alpha type-7 Proteins 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
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- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 208000031648 Body Weight Changes Diseases 0.000 description 2
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- 102000029749 Microtubule Human genes 0.000 description 2
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- JLPULHDHAOZNQI-JLOPVYAASA-N [(2r)-3-hexadecanoyloxy-2-[(9e,12e)-octadeca-9,12-dienoyl]oxypropyl] 2-(trimethylazaniumyl)ethyl phosphate Chemical class CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC JLPULHDHAOZNQI-JLOPVYAASA-N 0.000 description 2
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- 239000012266 salt solution Substances 0.000 description 2
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- 238000010998 test method Methods 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
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- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- NZAQRZWBQUIBSF-UHFFFAOYSA-N 4-(4-sulfobutoxy)butane-1-sulfonic acid Chemical compound OS(=O)(=O)CCCCOCCCCS(O)(=O)=O NZAQRZWBQUIBSF-UHFFFAOYSA-N 0.000 description 1
- 238000011729 BALB/c nude mouse Methods 0.000 description 1
- 206010065553 Bone marrow failure Diseases 0.000 description 1
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- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 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
- 208000002375 Hand-Foot Syndrome Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- 239000011543 agarose gel Substances 0.000 description 1
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- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
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- 229910052791 calcium Inorganic materials 0.000 description 1
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- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
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- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
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- 210000000865 mononuclear phagocyte system Anatomy 0.000 description 1
- 230000003039 myelosuppressive effect Effects 0.000 description 1
- 229940086322 navelbine Drugs 0.000 description 1
- LQOAWDYRUPQHRM-QRDGSJRXSA-N octaazanium;[(2r,3r,4s,5r,6r)-2-[(2s,3s,4r,5r)-3,4-disulfonatooxy-2,5-bis(sulfonatooxymethyl)oxolan-2-yl]oxy-3,5-disulfonatooxy-6-(sulfonatooxymethyl)oxan-4-yl] sulfate Chemical compound [NH4+].[NH4+].[NH4+].[NH4+].[NH4+].[NH4+].[NH4+].[NH4+].[O-]S(=O)(=O)O[C@H]1[C@H](OS([O-])(=O)=O)[C@@H](COS(=O)(=O)[O-])O[C@@]1(COS([O-])(=O)=O)O[C@@H]1[C@H](OS([O-])(=O)=O)[C@@H](OS([O-])(=O)=O)[C@H](OS([O-])(=O)=O)[C@@H](COS([O-])(=O)=O)O1 LQOAWDYRUPQHRM-QRDGSJRXSA-N 0.000 description 1
- CPRSOZZDECJZKH-QRDGSJRXSA-F octasodium;[(2r,3r,4s,5r,6r)-2-[(2s,3s,4r,5r)-3,4-disulfonatooxy-2,5-bis(sulfonatooxymethyl)oxolan-2-yl]oxy-3,5-disulfonatooxy-6-(sulfonatooxymethyl)oxan-4-yl] sulfate Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[O-]S(=O)(=O)O[C@H]1[C@H](OS([O-])(=O)=O)[C@@H](COS(=O)(=O)[O-])O[C@@]1(COS([O-])(=O)=O)O[C@@H]1[C@H](OS([O-])(=O)=O)[C@@H](OS([O-])(=O)=O)[C@H](OS([O-])(=O)=O)[C@@H](COS([O-])(=O)=O)O1 CPRSOZZDECJZKH-QRDGSJRXSA-F 0.000 description 1
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- 230000002035 prolonged effect Effects 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate 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-PYGJLNRPSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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Abstract
Vinorelbine tartrate liposome and raw material composition, preparation method and application thereof. The liposome raw material composition comprises 1-8.3 parts of vinorelbine salt, 2-12 parts of phospholipid, 0.1-0.8 part of long-circulating membrane material, 0.7-4.0 parts of cholesterol and drug-carrying salt. The liposome has good pharmaceutics characteristics and good application prospect.
Description
The present application claims priority to China patent application 2021111625656 with application date 2021/9/30 and priority to China patent application 2022111852813 with application date 2022/9/27. The present application refers to the entirety of the above-mentioned chinese patent application.
The invention relates to a vinorelbine tartrate liposome and a raw material composition, a preparation method and application thereof.
Vinorelbine is a semisynthetic derivative of the semisynthetic growth-spring alkali, is sold in the form of tartrate, belongs to a cell cycle specific drug, mainly acts on the later stage of DNA synthesis of tumor cells, prevents microtubulin from polymerizing to form microtubules, induces the depolymerization of the microtubules, and stops mitosis proliferation of the tumor cells at the middle stage of mitosis, thereby achieving the purpose of resisting tumors. The current commercial product is vinorelbine tartrate injection (trade name: navelbine Norveyor) developed by the French Pierflower pharmaceutical company (Pierre Fabre Medicament Production) in 1989, and the indication obtained in batch is non-small cell lung cancer, and the indication obtained in batch and transferred breast cancer in 1991 is still FDA for first-line administration of non-small cell lung cancer. Vinorelbine tartrate injection (trade name: gano) of Haossen pharmaceutical industry in China is marketed in 1998, and the product belongs to a new 2002 variety, and freeze-dried powder FDA in 2012 is approved to be marketed. In addition, the soft capsules of vinorelbine tartrate developed by the company of the French Pierfab pharmaceutical are also commercially available. However, the injection in the commercial products is easy to cause phlebitis, bone marrow suppression and other side effects in clinic use, and the oral preparation has low bioavailability.
The liposome is used as a drug carrier of a mature nano drug delivery system and is recognized by researchers and enterprises, and the liposome has the main characteristics of protecting encapsulated drugs, increasing the stability of the drugs, reducing vascular irritation in clinical use, changing the distribution behavior of the drugs in vivo, and carrying and encapsulating the drugs to passively or actively target focus positions, thereby improving the effective utilization rate of the drugs, reducing the damage to normal tissues and enhancing the curative effect of the clinical drugs.
In view of the characteristics of liposomes as drug delivery systems and the clinical disadvantages of vinorelbine tartrate formulations, different enterprises design different prescriptions and drug delivery modes to develop vinorelbine liposomes. The vinorelbine tartrate liposome developed by Qilu [ CN101933904] is unstable in preparation system, and is required to be split into three independent units of blank liposome, sodium phosphate solution and vinorelbine tartrate, and the three split units are mixed and heated appropriately before clinical use, so that intravenous injection can be carried out, and great inconvenience is brought to clinical use. The vinorelbine tartrate liposome developed by Taiwan micro-liposome company [ US6465008B2] adopts mixed salt of ammonium sulfate and dextran sodium sulfate for carrying medicine, and the prepared vinorelbine tartrate liposome has longer half life of more than 30h and has certain skin toxicity (about 20%). Whereas the vinorelbine tartrate liposome developed by the stone medicine group [ EP2494960A1] adopts sulfobutyl ether cyclodextrin for carrying medicine, the prepared vinorelbine tartrate liposome has the advantages of short half-life in vivo of about 5.4 hours and medicine carrying encapsulation rate of lower than 80 percent.
Therefore, in order to solve the above problems, a suitable drug-carrying salt and a production process must be found to prepare the vinorelbine tartrate liposome meeting the requirements of clinical application and industrial production.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects of poor stability, inconvenient use, short half-life period, high skin toxicity and the like of the vinorelbine tartrate liposome in the prior art, and therefore, the invention provides the vinorelbine tartrate liposome, and the raw material composition, the preparation method and the application thereof. The liposome has the advantages of good stability, proper drug release rate, small toxic and side effects, low skin toxicity, good pharmacokinetics and convenient use, and the preparation process is simple and is suitable for industrial production.
The invention solves the technical problems through the following technical proposal.
The first aspect of the present invention provides a liposome raw material composition, which comprises, by weight, 1-8.3 parts of vinorelbine salt, 2-12 parts of phospholipid, 0.1-0.8 part of long-circulating membrane material, 0.7-4.0 parts of cholesterol and drug-carrying salt;
the drug-carrying salt is an aqueous solution of sucrose octasulfate-ammonium sulfate, the concentration of the sucrose octasulfate in the sucrose octasulfate-ammonium sulfate is 1-75mM, and the concentration of the ammonium sulfate in the sucrose octasulfate-ammonium sulfate is 100-500mM.
In the present invention, the vinorelbine salt is preferably vinorelbine tartrate.
In the present invention, the fraction of the vinorelbine salt is preferably 2 to 3 parts, for example 2.77 parts.
In the present invention, the number of parts of the phospholipid is preferably 2 to 3 parts, for example, 2.8 parts.
In the present invention, the phospholipid may be a liposome-forming conventional phospholipid, and may be one or more of soybean phospholipid, hydrogenated Soybean Phospholipid (HSPC), di-hard phosphatidylcholine (DSPC), di-palmitoyl phosphatidylcholine (DPPC), di-myristoyl phosphatidylcholine (DMPC) and di-oleoyl phosphatidylcholine (DOPC), such as hydrogenated soybean phospholipid and/or di-hard phosphatidylcholine.
In the present invention, the part of the long-circulating film material is preferably 0.1 to 0.5 part, for example, 0.34 part.
In the present invention, the long-circulating membrane material may be a conventional long-circulating membrane material in liposome, preferably polyethylene glycol-derivatized phospholipid, preferably polyethylene glycol-dipalmitoyl phosphatidylethanolamine (mPEG-DPPE) and/or polyethylene glycol-distearoyl phosphatidylethanolamine (mPEG-DSPE), such as mPEG2000-DSPE. The polyethylene glycol of said polyethylene glycol-dipalmitoyl phosphatidylethanolamine and the polyethylene glycol of said polyethylene glycol-distearoyl phosphatidylethanolamine preferably have a molecular weight of 500-5000Da, for example 2000.
In the present invention, the cholesterol is preferably 0.7 to 2.5 parts.
In the present invention, the liposome raw material composition preferably contains, in parts by weight, 1.4 to 8.3 parts (e.g., 2.77 parts or 5.53 parts) of vinorelbine salt, 7.59 parts of phospholipid, 0.15 to 0.49 parts of long circulating membrane material, and 2.53 parts of cholesterol.
Wherein, the part of the vinorelbine salt is preferably 1.4-2.8 parts.
Wherein, the liposome raw material composition more preferably comprises any one of the following raw materials in the group 1-5 by weight:
group 1:2.77 parts of vinorelbine salt, 7.59 parts of phospholipid, 0.49 part of long circulation membrane material and 2.53 parts of cholesterol;
group 2:1.38 parts of vinorelbine salt, 7.59 parts of phospholipid, 0.49 parts of long-circulating membrane material and 2.53 parts of cholesterol;
group 3:5.53 parts of vinorelbine salt, 7.59 parts of phospholipid, 0.49 part of long circulation membrane material and 2.53 parts of cholesterol.
Group 4:8.31 parts of vinorelbine salt, 7.59 parts of phospholipid, 0.49 part of long-circulating membrane material and 2.53 parts of cholesterol;
group 5:2.77 parts of vinorelbine salt, 7.59 parts of phospholipid, 0.15 part of long circulation membrane material and 2.53 parts of cholesterol.
In the present invention, the concentration of ammonium sulfate in the sucrose octasulfate-ammonium sulfate is preferably 200 to 400, for example 300mM.
In the present invention, the sucrose octasulfate salt in the sucrose octasulfate salt-ammonium sulfate is preferably one or more of sucrose octasulfate alkali metal salt, sucrose octasulfate alkaline earth metal salt, sucrose octasulfate ammonium salt and sucrose octasulfate organic amine salt, for example, sucrose octasulfate alkali metal salt (for example, sucrose octasulfate potassium or sucrose octasulfate sodium).
Wherein, the alkali metal salt of sucrose octasulfate is preferably one or more of lithium sucrose octasulfate, sodium sucrose octasulfate and potassium sucrose octasulfate, such as potassium sucrose octasulfate.
Wherein, the sucrose octasulfate alkaline earth metal salt is preferably sucrose octasulfate calcium and/or sucrose octasulfate magnesium.
Wherein, the organic amine salt of sucrose octasulfate is preferably one or more of trimethylamine sucrose octasulfate, diethylamine sucrose octasulfate and triethylamine sucrose octasulfate.
In the present invention, the aqueous solution of sucrose octasulfate salt-ammonium sulfate is an aqueous solution of 1.5 to 30mM of sucrose octasulfate alkali metal salt and 200 to 400mM of ammonium sulfate (i.e., the concentration of sucrose octasulfate potassium in the aqueous solution of sucrose octasulfate salt-ammonium sulfate is 1.5 to 30mM, and the concentration of ammonium sulfate is preferably 300 mM), for example, an aqueous solution of 15mM of sucrose octasulfate potassium and 300mM of ammonium sulfate.
In the present invention, the raw material composition of the liposome may further comprise other raw materials, such as an ultrafiltration medium, which may be a 9.0% (W/W) sucrose solution as an ultrafiltration medium, according to conventional requirements in the art in preparing liposomes.
The invention also provides a preparation method of the liposome, which is prepared from the raw material composition and comprises the following steps: carrying out drug loading by adopting an ammonium sulfate gradient method to obtain the liposome.
In the present invention, the conditions and operations for carrying the drug may be those conventional in the art, and the present invention preferably uses the following conditions:
wherein the temperature of the medicine carrying is preferably 42-52 ℃.
Wherein, the time for carrying the medicine is preferably 5-30min.
Wherein, the drug-carrying can also comprise a cooling step, for example, the obtained liposome is rapidly cooled to below 20 ℃ in an ice-water bath with the temperature of 0-5 ℃.
In the invention, the drug loading is preferably carried out by carrying out drug loading on vinorelbine salt and blank liposome to obtain the liposome;
the blank liposome comprises a liposome membrane and an inner water phase in the liposome membrane;
the liposome membrane comprises the following components in parts by weight: 2-12 parts of phospholipid, 0.7-4.0 parts of cholesterol and 0.1-0.8 part of long-circulating membrane material;
the inner water phase is a sucrose octasulfate-ammonium sulfate aqueous solution, the concentration of the sucrose octasulfate is 1-75mM, and the concentration of the ammonium sulfate is 100-500mM.
The blank liposome is more preferably prepared by the following method; the preparation method of the blank lipid comprises the following steps:
step 1: mixing the phospholipid, the cholesterol, the long-circulating membrane material and the ethanol to obtain an oil phase solution;
step 2: injecting the oil phase solution obtained in the step 1 into the aqueous solution of sucrose octasulfate-ammonium sulfate by adopting an ethanol injection method to obtain a liposome colostrum solution;
step 3: the liposome colostrum solution obtained in the step 2 is extruded to obtain a mixture;
step 4: and (3) carrying out ultrafiltration on the mixture obtained in the step (3) by taking the isotonic solution as a medium to obtain blank liposome.
In step 1, the temperature of the mixing may be 55-70 ℃.
In step 2, the incubation temperature in the ethanol injection method can be 55-65 ℃.
In step 3, the temperature in the extrusion process may be 55-65 ℃.
In step 3, the extruded pore size in the extrusion method may be 100nm and 80nm in sequence.
In step 4, the isotonic solution is preferably an aqueous sodium chloride solution and/or an aqueous sucrose solution, for example, an aqueous solution (W/W) of 0.9% (W/W) sodium chloride and 9.0% sucrose.
In the present invention, the drug-loaded method may further comprise an ultrafiltration step, for example, ultrafiltration using a 9.0% (W/W) sucrose solution as an ultrafiltration medium.
In a third aspect, the present invention provides a liposome prepared from the above liposome raw material composition.
In the present invention, the liposome is preferably prepared according to the above-mentioned liposome preparation method.
In the present invention, the liposome is preferably used for inhibiting the growth of cancer cells.
In a fourth aspect, the invention provides a liposome comprising a liposome membrane and an aqueous phase within the liposome membrane; the aqueous phase in the liposome membrane comprises 1 to 8.3 parts by weight of a drug entity, wherein the drug entity contains sucrose octasulfate anions, sulfate anions and vinorelbine cations;
the liposome membrane comprises the following components in parts by weight: 2-12 parts of phospholipid, 0.7-4 parts of cholesterol and 0.1-0.8 part of long-circulating membrane material.
In the invention, the parts of the drug entity are preferably 2-3 parts.
In the present invention, the pharmaceutical entity is preferably obtained by the following method: carrying out drug loading on vinorelbine salt by an ammonium sulfate gradient method in the presence of a sucrose octasulfate-ammonium sulfate aqueous solution to obtain a drug entity; the vinorelbine salt (including species and parts) and the aqueous solution of sucrose octasulfate-ammonium sulfate (including species and concentrations) are as described above.
Wherein, the conditions and operation of the medicine carrying can be the same as the above.
In the present invention, the phospholipid (including the type and the part of the phospholipid), the part of the cholesterol and the long-circulating membrane material (including the type and the part of the long-circulating membrane material) can be the same as described above.
In the present invention, the aqueous phase in the liposome membrane may further include water.
In the invention, the liposome can also comprise an external water phase of the liposome membrane, wherein the external water phase of the liposome membrane is an isotonic solution. The isotonic solution is preferably an aqueous sodium chloride solution and/or an aqueous sucrose solution, for example, an aqueous solution (W/W) of 0.9% (W/W) sodium chloride and 9.0% sucrose.
In the present invention, the liposome is preferably used for inhibiting the growth of cancer cells.
In a fifth aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned liposome and an adjuvant, wherein the adjuvant is the above-mentioned isotonic solution and/or pharmaceutically acceptable buffer.
In the pharmaceutical composition, the concentration of the pharmaceutically acceptable buffer is preferably 0.01-1mM, and the pH is preferably 5.5-8.0.
In the pharmaceutical composition, the pharmaceutically acceptable buffer is preferably one or more of 4-hydroxyethylpiperazine ethane sulfonic acid (HEPES), histidine solution, and phosphate solution, for example, histidine buffer (e.g., ph=6.5, in an amount prescribed).
The invention also provides application of the substance A in preparing a medicament for inhibiting the growth of cancer cells; the substance A is the liposome, the liposome obtained by the preparation method of the liposome or the pharmaceutical composition.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: the liposome has the advantages of high encapsulation efficiency, good stability, high drug activity, proper drug release rate, small toxic and side effects, good pharmacokinetics and convenient use, and the preparation process is simple and is suitable for industrial production.
FIG. 1 is a graph showing the effect of different drug-loaded salt species on in vitro release of formulations.
FIG. 2 is a graph of the effect of drug-to-lipid ratio on in vitro release of formulations.
FIG. 3 is a graph comparing the body weight change of mice dosed with vinorelbine tartrate liposomes of different loading salts at a dose of 7.5mg/kg.
FIG. 4 is a graph comparing the change in body weight of mice dosed with vinorelbine tartrate liposomes at a dose of 10.0mg/kg.
FIG. 5 is a graph comparing skin toxicity scores of vinorelbine tartrate liposomes administered at 7.5mg/kg of drug delivery.
FIG. 6 is a graph comparing skin toxicity scores of vinorelbine tartrate liposomes administered at a dose of 10.0mg/kg.
FIG. 7 is a graph comparing the plasma levels of vinorelbine tartrate liposomes administered at 7.5mg/kg in rats.
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
The method for measuring the encapsulation efficiency comprises the following steps: 100ul of liposome is measured, the liposome and the free drug part are separated by using Sepharose CL-4B agarose gel, 6ml of 0.9% NaCl solution is added to elute the liposome part, 7ml of 0.9% NaCl solution is added to elute the free drug part, the content of the free drug and the content of the liposome part are respectively measured by using a liquid chromatography, and the encapsulation efficiency is calculated according to the formula of encapsulation efficiency = liposome part/(liposome part + free drug part) ×100%.
The in vitro release method comprises the following steps: the release rates were measured by mixing 1.6ml of the sample with 2.4ml of the release solution as release solution from 0.005M ammonium chloride/0.3M glucose/0.01M L-histidine, transferring the mixture into a dialysis bag, incubating the dialysis bag in a constant temperature water bath shaker at 37℃and 90rpm, and sampling at 1.0h, 2.0h, 3.0h, and 4.5h, respectively. The in vitro release rate was calculated as%in vitro release rate=initial encapsulation rate% -encapsulation rate after release test.
Example 1 drug-loaded salt binding experiments
Preparing a 60mg/ml vinorelbine tartrate aqueous solution and drug-carrying salt solutions with different concentrations according to the volume ratio of 1:2, after fully stirring and mixing, centrifuging to obtain a supernatant, detecting the content of the vinorelbine tartrate, and calculating the combination efficiency of the vinorelbine tartrate and the drug-carrying salt. The data are shown in table 1 below:
the sedimentation percentage calculation formula: percent precipitation = 100% -C 1 /C 2 Wherein C 1 API concentration of supernatant after centrifugation, C 2 Is the theoretical concentration of the API in the above mixed solution, i.e., 20mg/ml.
TABLE 1 precipitation binding assays of vinorelbine tartrate at different drug-loaded salt solution concentrations
Results:
ammonium sulfate does not form a precipitate with vinorelbine tartrate, indicating that ammonium sulfate is not suitable as a drug-carrying salt alone. Sucrose octasulfate metal salts (e.g., li, na, K, ca, mg or Al salts) form stable precipitates with vinorelbine tartrate, but are not capable of providing an effective ammonium gradient to the aqueous phase within and outside of the liposome nor alone as drug-carrying salts.
The ammonium sulfate and the sucrose octasulfate potassium are mixed, the ammonium sulfate is utilized to provide an ammonium gradient, the sucrose octasulfate potassium is combined with the drug, the effective drug loading can be realized, meanwhile, the concentration of the ammonium sulfate and the sucrose octasulfate potassium is changed, and the combination ratio of the drug-carrying salt and the vinorelbine tartrate (API) can be adjusted.
Example 2
(1) Preparing an oil phase: hydrogenated soybean phosphatidylcholine, cholesterol, PEGylated phosphatidylethanolamine (mPEG 2000-DSPE) and absolute ethanol were mixed and dissolved at 55-70℃according to the formulation of Table 2 below to obtain an oil phase solution.
(2) Preparing an aqueous phase: according to the formula, mixing and dissolving ammonium sulfate, sucrose octasulfate potassium salt and water at 55-65 ℃ to obtain an aqueous phase solution with the concentration of ammonium sulfate of 300mM and the concentration of sucrose octasulfate potassium salt of 15 mM.
(3) And (3) injecting the oil phase solution obtained in the step (1) into the water phase solution obtained in the step (2), and completing incubation at 55-65 ℃ to obtain a liposome colostrum solution.
(4) Extruding the liposome colostrum solution obtained in the step (3) through a 100nm and 80nm polycarbonate film at 55-65 ℃ to obtain the proper particle size. The liposome solution was ultrafiltered using 0.9% (W/W) sodium chloride solution and 9.0% (W/W) sucrose solution as ultrafiltration medium to remove ammonium sulfate and potassium sucrose octasulfate in the liposome external water phase and ethanol in the water phase, thereby constructing an internal and external liposome water phase salt gradient to obtain a blank liposome solution.
(5) And (3) mixing the blank liposome solution obtained in the step (4) with the completely dissolved vinorelbine tartrate solution, incubating at 42-52 ℃ for 5-30min, and rapidly cooling the hot mixed solution to below 20 ℃ in an ice-water bath at 0-5 ℃ to finish drug loading.
(6) The drug loaded liposome sample from step (5) was subjected to a second ultrafiltration using sucrose solution 9.0% (W/W), free drug was removed and prescribed amount of histidine buffer (ph=6.5) was added for sizing.
TABLE 2
Reference liposome 1
1) Preparing an aqueous phase: sucrose octasulfate triethylamine and water were mixed and dissolved at 55-65℃to obtain a sucrose octasulfate triethylamine (SOSTEA) aqueous solution having a concentration of 75 mM.
The other steps are identical to those described above.
Reference liposome 2
1) Preparing an aqueous phase: mixing and dissolving ammonium sulfate, dextran sulfate sodium and water at 55-65 ℃ to obtain an aqueous phase solution with the concentration of ammonium sulfate of 300mM and the concentration of dextran sulfate sodium (DS) of 3 mM.
The other steps are identical to the steps described above.
Reference liposome 3
1) Preparing an aqueous phase: ammonium sulfate was dissolved by mixing with water at 55-65℃to give an aqueous solution having a concentration of 300mM.
The other steps are identical to the steps described above.
The liposomes of example 2 and reference liposomes 1-3 were subjected to encapsulation efficiency and in vitro release testing, the results of which are shown in Table 3 below and FIG. 1.
Table 3: influence of different drug-carrying salt types on encapsulation efficiency and in-vitro release of preparation
Results and discussion:
the drug-loaded salt is vinorelbine liposome (reference liposome 1) with 3mM DS/300mM AS, the encapsulation rate after drug loading is less than 90%, and the lower encapsulation rate can influence the safety and effectiveness of the preparation.
The vinorelbine liposome (reference liposome 2) with 75mM SOSTEA as the drug-carrying salt has too slow drug release rate, which causes the drug wrapped by the liposome to accumulate in normal tissues in a large amount, and has serious toxic and side effects on human bodies.
The vinorelbine liposome (reference liposome 3) with the drug-loaded salt of 300mM AS has too high drug release rate, which leads to massive drug release in the blood circulation process, insufficient exposure of the drug at the tumor part and unexpected efficacy.
The vinorelbine liposome with 15mM SOSK/300mM AS AS carrier salt (example 2) has high encapsulation efficiency and proper drug release rate, which enables the optimal anticancer efficacy to be balanced with minimal toxic and side effects.
Examples 3 to 4
1) Preparing an aqueous phase: 8 mM sucrose octasulfate potassium salt/300 mM ammonium sulfate aqueous solution, 30mM, respectively, were prepared at 55-65deg.C.
Other procedures were consistent with example 2 to obtain liposomes of examples 3 and 4.
The liposomes of examples 3 and 4 were subjected to encapsulation efficiency and in vitro release tests, the results of which are shown in Table 4 below.
Table 4: influence of different drug-carrying salt concentrations on encapsulation efficiency and in-vitro release of preparation
Results and discussion:
the vinorelbine liposome with different drug-carrying salt concentrations has higher encapsulation rate (more than or equal to 90 percent), and the drug-releasing behavior of the preparation can be regulated and controlled by changing the concentration of the drug-carrying salt SOSK.
Example 5
Blank liposomes of different particle sizes were prepared by combining and extruding the liposome colostrum solution obtained in step (3) of example 2 at 55-65deg.C.
Other procedures were consistent with example 2 to obtain liposomes of different particle sizes.
Liposomes of different particle sizes were subjected to encapsulation efficiency and in vitro release testing, the results of which are shown in table 5 below.
Table 5: influence of liposomes of different particle sizes on encapsulation efficiency of preparation and in vitro release
Results:
different extrusion times and membrane combinations are adopted to prepare the vinorelbine tartrate liposome with different particle sizes. The particle size of the vinorelbine tartrate liposome is changed within the range of 90-135nm, and the vinorelbine tartrate liposome has higher encapsulation efficiency (more than or equal to 90 percent) and proper in-vitro release rate.
Examples 6 to 8
1) The blank liposome solution obtained in step (4) of example 2 was mixed with 6.93mg (ratio of lipid to drug 1.40:7.59 27.7mg (ratio of lipid to drug 5.54:7.59 41.58mg (ratio of drug to lipid is 8.31:7.59 Incubating the vinorelbine tartrate solution at 55-65deg.C for 20-40min, and rapidly cooling the hot mixed solution to below 20deg.C in ice-water bath at 0-5deg.C to complete drug loading.
Other steps were identical to example 2, and liposomes with different ratios were obtained.
Liposomes of different ratios (example 2, example 6, example 7, example 8) were subjected to encapsulation efficiency and in vitro release tests, the results of which are shown in Table 6 below and FIG. 2.
Table 6: drug-lipid ratio to encapsulation efficiency and in vitro release effect
Remarks: "post-drug encapsulation efficiency" refers to the encapsulation efficiency measured for the sample after drug loading is complete. And carrying out secondary ultrafiltration on the sample after the medicine loading is finished to remove free medicine. The "product encapsulation efficiency" refers to the sample encapsulation efficiency obtained after secondary ultrafiltration and weight fixing.
Results and discussion:
with the increase of the drug-to-lipid ratio, the encapsulation efficiency after drug loading is reduced, and the in-vitro release is in an ascending trend. The drug release behavior of the preparation can be regulated and controlled by changing the drug-to-lipid ratio, but the drug-to-lipid ratio is too high, SOS is insufficient to lock all drugs, and the encapsulation efficiency of the preparation is reduced. The ratio of medicine to fat is adjusted to 2.77:7.59 (i.e., example 2), the formulation has a high encapsulation efficiency and a suitable drug release rate.
Example 9
1) Preparing an oil phase: according to the formula, phosphatidylcholine Distearate (DSPC), cholesterol and pezited phosphatidylethanolamine are mixed and dissolved with absolute ethyl alcohol at 55-70 ℃ to obtain oil phase solution.
Other steps were consistent with example 2.
Liposomes of different phospholipid species were subjected to encapsulation efficiency and in vitro release assays, the results of which are shown in the following table.
TABLE 7 influence of phospholipid species on encapsulation efficiency of formulations and in vitro Release
Results and discussion:
as can be seen from the above data and example 2: the vinorelbine tartrate liposome prepared by adopting different phospholipids (HSPC and DSPC) has the encapsulation rate of more than or equal to 90% after drug loading and has no obvious difference in vitro release. This suggests that both HSPC, DSPC are alternative.
Examples 10 to 11
1) Preparing an oil phase: hydrogenated soybean phosphatidylcholine, cholesterol, and various amounts of 0.74mg (i.e., 0.15 parts), 12.25mg (i.e., 2.45 parts), and PEGylated phosphatidylethanolamine (mPEG 2000-DSPE) were mixed with absolute ethanol according to the formulation and dissolved at 55-70℃to obtain an oil phase solution.
Other procedures were consistent with example 2 to obtain liposomes of different mPEG2000-DSPE.
Liposomes of different ratios were subjected to encapsulation efficiency and in vitro release testing, the results of which are shown in Table 8 below.
Table 8: effect of mPEG2000-DSPE content on formulation encapsulation efficiency, in vitro release
Results and discussion:
the increase of the feeding amount of mPEG2000-DSPE can reduce the encapsulation rate and the in-vitro release rate after drug loading, but if the liposome is not added or the adding amount is too small, the liposome cannot escape the reticuloendothelial system for phagocytosis, so that the in-vivo circulation time is prolonged, and the tumor targeting is enhanced. According to the experimental results, a suitable amount of mPEG2000-DSPE is 0.49 parts.
Example 12: comparative study of toxic side effects and myelosuppressive effects of different drug-loaded salt vinorelbine liposomes
1. Investigation of toxic side effects
Female BALB/c nude mice are adopted to carry out the comparison study of toxic and side effects on vinorelbine liposome of different drug-carrying salts, and the experimental design is shown in the following table 8:
TABLE 9
Observations were made during the study for the items in table 10 below:
table 10
Wherein the skin toxicity scoring criteria are as follows in table 11:
TABLE 11
The weight change results are shown in table 12 and fig. 3 and 4.
Table 12
At the doses of 7.5mg/kg, 10mg/kg, the maximum average body weight of the mice of reference liposome 1 varied by more than 15%, and a number of mice were euthanized during the experiment. Example 2 (prescription made), reference liposome 2, reference liposome 3 all had less than 15% of maximum body weight change. After stopping the administration, the body weight of each group of mice was slowly restored, and all the body weights of the mice were restored to normal level on day 20 of the administration.
The skin toxicity results are shown in table 13 and figures 5 and 6.
TABLE 13
At the doses of 7.5mg/kg and 10mg/kg, example 2 showed significantly less skin toxicity than the reference liposomes 1 and 2. There was no statistically significant difference between the skin toxicity scores of example 2 and reference liposome 3 at the 7.5mg/kg dose, and the skin toxicity score of reference liposome 3 at the 10mg/kg dose was slightly better than that of example 2.
2. Research of bone marrow suppression
The blood routine results after 96h of the last 1 dose are shown in Table 14:
TABLE 14
From blood routine results, it can be seen that bone marrow suppression has dose dependency, and the bone marrow suppression degree of all prescribed doses of 10mg/kg is higher than 7.5mg/kg.
At the doses of 7.5mg/kg and 10mg/kg, the reference liposome 1 mice showed a significant decrease in red blood cell, hemoglobin, and platelet counts, and SOSTEA as a drug-loaded salt caused severe myelosuppression.
At the dose of 7.5mg/kg, the three drug-loaded salts of example 2, reference liposome 2 and reference liposome 3 were equivalent to the suppression of mouse bone marrow, and the counts of red blood cells, hemoglobin and platelets were reduced to some extent.
At the dose of 10mg/kg, the reference liposome 2 red blood cell, hemoglobin and platelet count were significantly reduced, and the bone marrow suppression degree was greater than that of example 2 (self-made prescription) and reference liposome 3.
Routine results for first dosing to day 20 table 15:
table 15:
on day 20 post-administration, platelet counts of example 2, reference liposome 3 quickly recovered to normal levels, with signs of slow recovery of erythrocytes and hemoglobin. The reference liposome 1 platelet count quickly returned to normal levels, but red blood cells did not develop any recovery progress.
The conclusions are shown in Table 16:
table 16
Example 13: pharmacokinetic experiment contrast study
The PK comparison study is carried out on the vinorelbine liposome with different drug-carrying salts by adopting rats, and the experimental design is as follows:
1. the basic information of animal PK experiments with vinorelbine tartrate is shown in Table 17
TABLE 17
2. The information collected for the animal PK experimental samples of vinorelbine tartrate is shown in table 18:
TABLE 18
3. The results of the test blood sample of the animal PK test for vinorelbine tartrate are shown in table 19 and fig. 7:
TABLE 19
Results and discussion: the vinorelbine tartrate injection enters the body of the rat and is rapidly eliminated; the different drug-carrying salts of vinorelbine tartrate have slow drug release behavior in vivo.
The drug is released too quickly in the blood circulation process, so that the exposure of the drug at the tumor part is insufficient, and the drug effect cannot reach the expected effect; the drug release is too slow, and a large amount of drug accumulates in normal tissues such as skin, so that serious toxic and side effects such as hand-foot syndrome can be generated, and the PK result shows that the reference liposome 1 is released too slow and the reference liposome 3 is released too fast, and the liposome (example 2) has a proper drug release rate, so that the preparation requirement of the ideal vinorelbine tartrate liposome can be met.
Example 13: comparison of potency of self-made vinorelbine tartrate liposome and vinorelbine tartrate injection against colonic cancer cell HT-29 mice
The test method comprises the following steps: every 1×10 7 Each cell was resuspended in 100ul of medium containing 50% matrigel and inoculated into the right armpit of the mouse. When the tumor volume average reaches about 139mm 3 When (calculation formula of tumor volume: v=0.5a×b) 2 A and b represent tumor length and width, respectively), and Q3D 4 intravenous administration was performed by group at a single dose of 7.5mg/kg by random grouping through Excel according to tumor size and body weight.
Animals are normally raised after administration, the anti-tumor effect of the tested drugs is dynamically observed by using a method for measuring tumor diameters, and the calculation formula of tumor volume is V=0.5a×b 2 Wherein a and b represent the length and width of the tumor, respectively, and the experimental results were analyzed using GraphPad Prism 5.
Results of the pharmacodynamic test: the results of comparing the efficacy of the self-made vinorelbine tartrate liposome and the vinorelbine tartrate injection against the colon cancer cell HT-29 mice are shown in Table 19
TABLE 19
Conclusion: as shown by the results of the drug effect tests, compared with a blank group, the vinorelbine tartrate liposome and the vinorelbine tartrate injection have the tumor inhibiting effect. The vinorelbine tartrate liposome has stronger inhibition on HT-29 tumor growth than the vinorelbine tartrate injection.
Example 14: comparison of potency of self-made vinorelbine tartrate liposome and vinorelbine tartrate injection against fibrosarcoma cell HT-1080 mice
The test method comprises the following steps: every 5×10 6 Each cell was resuspended in 100ul of medium containing 50% matrigel and inoculated into the right armpit of the mouse. When the tumor volume average reached about 144mm 3 When (calculation formula of tumor volume: v=0.5a×b) 2 A and b represent tumor length and width, respectively), and Q4D x 2 intravenous administration was performed by group, with a single dose of 10.0mg/kg, by random grouping through Excel according to tumor size and body weight.
Animals are normally raised after administration, the anti-tumor effect of the tested drugs is dynamically observed by using a method for measuring tumor diameters, and the calculation formula of tumor volume is V=0.5a×b 2 Wherein a and b represent the length and width of the tumor, respectively, and the experimental results were analyzed using GraphPad Prism 5.
Results of the pharmacodynamic test: the results of comparing the efficacy of the self-made vinorelbine tartrate liposome and the vinorelbine tartrate injection against fibrosarcoma HT-1080 mice are shown in Table 20.
Table 20
Conclusion: as shown by the results of the drug effect tests, compared with a blank group, the vinorelbine tartrate liposome and the vinorelbine tartrate injection have the tumor inhibiting effect. The vinorelbine tartrate liposome has stronger inhibition on HT-1080 tumor growth than the vinorelbine tartrate injection.
It is known in the art that an ideal vinorelbine tartrate liposome should possess several characteristics: 1) Higher drug loading efficiency; 2) A suitable in vivo half-life to achieve a balance between optimal tumor inhibiting effect and minimal toxic side effects; 3) The storage process is relatively stable, and no medicine leakage occurs; 4) The preparation process is simple and is suitable for industrial production.
The inventor of the present invention has conducted extensive research on drug-carrying salts and preparation processes, and finally the liposome of the present invention has the advantages of high encapsulation efficiency, good stability, small toxic and side effects, superior drug effect and convenient clinical use.
Claims (13)
- The liposome raw material composition is characterized by comprising, by weight, 1-8.3 parts of vinorelbine salt, 2-12 parts of phospholipid, 0.1-0.8 part of long-circulating membrane material, 0.7-4.0 parts of cholesterol and drug-carrying salt;the drug-carrying salt is an aqueous solution of sucrose octasulfate-ammonium sulfate, the concentration of the sucrose octasulfate in the sucrose octasulfate-ammonium sulfate is 1-75mM, and the concentration of the ammonium sulfate in the sucrose octasulfate-ammonium sulfate is 100-500mM.
- The liposome raw material composition of claim 1, wherein the liposome raw material composition satisfies one or more of the following conditions:(1) The vinorelbine salt is vinorelbine tartrate, for example, 2.77 parts;(2) The parts of the phospholipid are 2-3 parts, such as 2.8 parts;(3) The phospholipid is one or more of soybean phospholipid, hydrogenated soybean phospholipid, di-hard phosphatidylcholine, di-palmitoyl phosphatidylcholine, di-myristoyl phosphatidylcholine and di-oleoyl phosphatidylcholine, such as hydrogenated soybean phospholipid and/or di-hard phosphatidylcholine;(4) The parts of the long-circulation film material are 0.1-0.5 part, such as 0.34 part;(5) The long-circulation membrane material is polyethylene glycol-derived phospholipid, preferably polyethylene glycol-dipalmitoyl phosphatidylethanolamine and/or polyethylene glycol-distearoyl phosphatidylethanolamine, such as mPEG2000-DSPE;(6) The cholesterol is 0.7-2.5 parts;(7) The concentration of sucrose octasulfate in the sucrose octasulfate-ammonium sulfate is 1-50mM, such as 30mM;(8) The concentration of ammonium sulfate in the sucrose octasulfate-ammonium sulfate is 200-400, such as 300mM;(9) The sucrose octasulfate salt in the sucrose octasulfate salt-ammonium sulfate is one or more of sucrose octasulfate alkali metal salt, sucrose octasulfate alkaline earth metal salt, sucrose octasulfate ammonium and sucrose octasulfate organic amine salt, such as sucrose octasulfate alkali metal salt.
- Liposome raw material composition according to claim 2, characterized in that the aqueous solution of sucrose octasulfate-ammonium sulfate is an aqueous solution of 1.5-30mM sucrose octasulfate alkali metal salt and 200-400mM ammonium sulfate, such as an aqueous solution of 15mM sucrose octasulfate potassium and 300mM ammonium sulfate;and/or, the liposome raw material composition comprises, by weight, 1.4-8.3 parts of vinorelbine salt, 7.59 parts of phospholipid, 0.15-0.49 parts of long-circulating membrane material and 2.53 parts of cholesterol; the parts of the vinorelbine salt are preferably 1.4-2.8 parts.
- A liposome raw material composition according to claim 3, wherein the liposome raw material composition comprises any one of the following raw materials 1 to 5 in parts by weight:group 1:2.77 parts of vinorelbine salt, 7.59 parts of phospholipid, 0.49 part of long circulation membrane material and 2.53 parts of cholesterol;group 2:1.38 parts of vinorelbine salt, 7.59 parts of phospholipid, 0.49 parts of long-circulating membrane material and 2.53 parts of cholesterol;group 3:5.53 parts of vinorelbine salt, 7.59 parts of phospholipid, 0.49 part of long-circulating membrane material and 2.53 parts of cholesterol;group 4:8.31 parts of vinorelbine salt, 7.59 parts of phospholipid, 0.49 part of long-circulating membrane material and 2.53 parts of cholesterol;group 5:2.77 parts of vinorelbine salt, 7.59 parts of phospholipid, 0.15 part of long circulation membrane material and 2.53 parts of cholesterol.
- A method for preparing liposomes, characterized in that it is prepared using a liposome raw material composition according to any one of claims 1 to 4, comprising the steps of: carrying out drug loading by adopting an ammonium sulfate gradient method to obtain the liposome.
- The method for producing a liposome according to claim 5,(1) The temperature of the medicine carrying is 42-52 ℃;(2) The medicine carrying time is 5-30min;(3) After the medicine is loaded, the method further comprises an ultrafiltration step, for example, ultrafiltration is carried out by adopting 9.0% sucrose solution as an ultrafiltration medium;(4) The drug loading is to carry out drug loading on vinorelbine salt and blank liposome to obtain the liposome;the blank liposome comprises a liposome membrane and an inner water phase in the liposome membrane;the liposome membrane comprises the following components in parts by weight: 2-12 parts of phospholipid, 0.7-4.0 parts of cholesterol and 0.1-0.8 part of long-circulating membrane material;the inner water phase is a sucrose octasulfate-ammonium sulfate aqueous solution, the concentration of the sucrose octasulfate is 1-75mM, and the concentration of the ammonium sulfate is 100-500mM;preferably by the following method; the preparation method of the blank lipid comprises the following steps:step 1: mixing the phospholipid, the cholesterol, the long-circulating membrane material and the ethanol to obtain an oil phase solution;step 2: injecting the oil phase solution obtained in the step 1 into the aqueous solution of sucrose octasulfate-ammonium sulfate by adopting an ethanol injection method to obtain a liposome colostrum solution;step 3: the liposome colostrum solution obtained in the step 2 is extruded to obtain a mixture;step 4: and (3) carrying out ultrafiltration on the mixture obtained in the step (3) by taking the isotonic solution as a medium to obtain blank liposome.
- The method of claim 6, wherein in step 1 of (1) the method of preparing a blank lipid, the temperature of the mixing is 55-70 ℃;(2) In the step 2, the incubation temperature in the ethanol injection method is 55-65 ℃;(3) In the step 3, the temperature in the extrusion method is 55-65 ℃;(4) In the step 3, the aperture of extrusion in the extrusion method is sequentially 100nm and 80nm;(5) In step 4, the isotonic solution is aqueous sodium chloride and/or aqueous sucrose, for example, 0.9% sodium chloride and 9.0% sucrose.
- A liposome prepared from the liposome raw material composition of any one of claims 1 to 4.
- The liposome according to claim 8, wherein the liposome is prepared according to the preparation method of the liposome according to any one of claims 5 to 8;and/or, the liposomes are useful for inhibiting cancer cell growth.
- A liposome comprising a liposome membrane and an aqueous phase within the liposome membrane; the aqueous phase in the liposome membrane comprises 1 to 8.3 parts by weight of a drug entity, wherein the drug entity contains sucrose octasulfate anions, sulfate anions and vinorelbine cations;the liposome membrane comprises the following components in parts by weight: 2-12 parts of phospholipid, 0.7-4 parts of cholesterol and 0.1-0.8 part of long-circulating membrane material.
- The liposome of claim 10, wherein the liposome satisfies one or more of the following conditions:(1) The parts of the drug entities are 2-3 parts;(2) The pharmaceutical entity is obtained by the following method: carrying out drug loading on vinorelbine salt by an ammonium sulfate gradient method in the presence of a sucrose octasulfate-ammonium sulfate aqueous solution to obtain a drug entity; the aqueous solution of vinorelbine salt and sucrose octasulfate salt-ammonium sulfate as claimed in any one of claims 1-4; the conditions and operation of the medicine carrying are as defined in claim 6 or 7;(3) The phospholipid, the part of the cholesterol and the long circulation membrane material are all as defined in any one of claims 1 to 4;(4) The water phase in the liposome membrane also comprises water;(5) The liposome also comprises an external water phase of the liposome membrane, wherein the external water phase of the liposome membrane is an isotonic solution; the isotonic solution is preferably an aqueous sodium chloride solution and/or an aqueous sucrose solution, for example an aqueous solution of 0.9% sodium chloride and 9.0% sucrose;(6) The liposome is used for inhibiting the growth of cancer cells.
- A pharmaceutical composition comprising a liposome according to any one of claims 8-11 and an adjuvant, said adjuvant being an isotonic solution and/or a pharmaceutically acceptable buffer, said isotonic solution being according to claim 7;the concentration of the pharmaceutically acceptable buffer is preferably 0.01-1mM, and the pH is preferably 5.5-8.0;the pharmaceutically acceptable buffer is preferably one or more of 4-hydroxyethyl piperazine ethane sulfonic acid, histidine solution and phosphate solution, for example histidine buffer.
- Use of substance a in the manufacture of a medicament for inhibiting the growth of cancer cells; substance a is a liposome according to any one of claims 8-11 or a pharmaceutical composition according to claim 12.
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| CN202211185281 | 2022-09-27 | ||
| PCT/CN2022/123371 WO2023051799A1 (en) | 2021-09-30 | 2022-09-30 | Vinorelbine tartrate liposome, and raw material composition thereof, preparation method therefor, and application thereof |
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| WO2003018018A2 (en) * | 2001-08-24 | 2003-03-06 | Neopharm, Inc. | Vinorelbine compositions and methods of use |
| KR101376895B1 (en) * | 2004-05-03 | 2014-03-25 | 헤르메스 바이오사이언스, 인코포레이티드 | Liposomes useful for drug delivery |
| SG11201507110WA (en) * | 2013-03-15 | 2015-10-29 | Taiwan Liposome Co Ltd | Engineering a control drug release profile via liposome composition in both aqueous andnon-aqueous compartments |
| US20180110771A1 (en) * | 2016-10-21 | 2018-04-26 | Ipsen Biopharm Ltd. | Liposomal Irinotecan Preparations |
| CN109364025A (en) * | 2017-11-17 | 2019-02-22 | 和龙 | Liposome composition, preparation method and its application |
| US20220211621A1 (en) * | 2019-04-25 | 2022-07-07 | Tlc Biopharmaceuticals, Inc. | Liposomal sustained-release compositions containing a therapeutic drug and use thereof |
| CN111035616B (en) * | 2019-12-30 | 2022-03-22 | 上海景峰制药有限公司 | Gemcitabine liposome and preparation method and application thereof |
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