CN105142671B - 卡巴他赛和磺基丁基醚β-环糊精的组合物 - Google Patents
卡巴他赛和磺基丁基醚β-环糊精的组合物 Download PDFInfo
- Publication number
- CN105142671B CN105142671B CN201380073396.6A CN201380073396A CN105142671B CN 105142671 B CN105142671 B CN 105142671B CN 201380073396 A CN201380073396 A CN 201380073396A CN 105142671 B CN105142671 B CN 105142671B
- Authority
- CN
- China
- Prior art keywords
- composition
- cabazitaxel
- solution
- cyclodextrin
- sbecd
- 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.)
- Active
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 46
- BMQGVNUXMIRLCK-OAGWZNDDSA-N cabazitaxel Chemical group O([C@H]1[C@@H]2[C@]3(OC(C)=O)CO[C@@H]3C[C@@H]([C@]2(C(=O)[C@H](OC)C2=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=3C=CC=CC=3)C[C@]1(O)C2(C)C)C)OC)C(=O)C1=CC=CC=C1 BMQGVNUXMIRLCK-OAGWZNDDSA-N 0.000 title claims abstract description 33
- 229960001573 cabazitaxel Drugs 0.000 title claims abstract description 33
- 229940097346 sulfobutylether-beta-cyclodextrin Drugs 0.000 title claims abstract description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 29
- 235000019441 ethanol Nutrition 0.000 claims abstract description 19
- 239000004094 surface-active agent Substances 0.000 claims abstract description 6
- 239000007864 aqueous solution Substances 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 3
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- 239000012736 aqueous medium Substances 0.000 abstract description 2
- 238000011287 therapeutic dose Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 30
- VNDHXHMRJVTMTK-WZVRVNPQSA-H hexasodium 4-[[(1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36R,37R,38R,39R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R)-36,37,38,39,40,41,42,43,44,45,46,47,48,49-tetradecahydroxy-10-(hydroxymethyl)-15,20,25,30,35-pentakis(4-sulfonatobutoxymethyl)-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan-5-yl]methoxy]butane-1-sulfonate Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].OC[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@H](O[C@@H]3COCCCCS([O-])(=O)=O)O[C@H]3[C@H](O)[C@@H](O)[C@H](O[C@@H]3COCCCCS([O-])(=O)=O)O[C@H]3[C@H](O)[C@@H](O)[C@H](O[C@@H]3COCCCCS([O-])(=O)=O)O[C@H]3[C@H](O)[C@@H](O)[C@H](O[C@@H]3COCCCCS([O-])(=O)=O)O[C@H]3[C@H](O)[C@@H](O)[C@H](O[C@@H]3COCCCCS([O-])(=O)=O)O[C@H]3[C@H](O)[C@@H](O)[C@H](O[C@@H]3COCCCCS([O-])(=O)=O)O[C@H]1[C@H](O)[C@H]2O VNDHXHMRJVTMTK-WZVRVNPQSA-H 0.000 description 20
- 238000002360 preparation method Methods 0.000 description 10
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 7
- 206010028980 Neoplasm Diseases 0.000 description 7
- 229960003668 docetaxel Drugs 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 229920000858 Cyclodextrin Polymers 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 4
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 4
- 229920000053 polysorbate 80 Polymers 0.000 description 4
- 229940068968 polysorbate 80 Drugs 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 206010041067 Small cell lung cancer Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 210000001015 abdomen Anatomy 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 108010082117 matrigel Proteins 0.000 description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000001116 FEMA 4028 Substances 0.000 description 2
- 208000032612 Glial tumor Diseases 0.000 description 2
- 206010018338 Glioma Diseases 0.000 description 2
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 2
- 230000001387 anti-histamine Effects 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- 229960004853 betadex Drugs 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000006143 cell culture medium Substances 0.000 description 2
- 239000003246 corticosteroid Substances 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000000630 rising effect Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 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 2
- 208000000587 small cell lung carcinoma Diseases 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- -1 sulfobutyl Chemical group 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- 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
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical group C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 235000016408 Podocarpus macrophyllus Nutrition 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 241000220324 Pyrus Species 0.000 description 1
- 238000011579 SCID mouse model Methods 0.000 description 1
- 244000162450 Taxus cuspidata Species 0.000 description 1
- 235000009065 Taxus cuspidata Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- 201000001531 bladder carcinoma Diseases 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000037058 blood plasma level Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 208000010749 gastric carcinoma Diseases 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 235000021017 pears Nutrition 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000013223 sprague-dawley female rat Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 208000010570 urinary bladder carcinoma Diseases 0.000 description 1
Classifications
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种组合物，所述组合物包含：(a)卡巴他赛(cabazitaxel)和(b)磺基丁基醚β‑环糊精。这种组合物在水性介质中展现出出乎意料的所需的稳定性，允许在不使用乙醇或表面活性剂的情况下施用治疗剂量的药物。
Description
发明领域
本发明涉及一种组合物，所述组合物包含：(a)卡巴他赛(cabazitaxel)和(b)磺基丁基醚β-环糊精。这种组合物在水性介质中展现出出乎意料的所需的稳定性，因此允许在不需要乙醇和表面活性剂的情况下施用治疗剂量的药物。
发明背景
卡巴他赛，(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(乙酰氧基)-15-{[(2R,3S)-3-{[(叔丁氧基)羰基]氨基}-2-羟基-3-苯基丙酰基]氧基}-1-羟基-9,12-二甲氧基-10,14,17,17-四甲基-11-氧代-6-氧杂四环[11.3.1.03,10.04,7]十七碳-13-烯-2-基苯甲酸酯，是微管抑制剂，其正在被研究用于多种癌症治疗，包括头颈癌、非小细胞肺癌(non-small celllung cancer,NSCLC)、小细胞肺癌(small cell lung cancer,SCLC)、神经胶质瘤(glioma)、膀胱癌、胃和食道癌、乳腺癌以及卵巢癌。已经具体设计卡巴他赛以克服与紫杉醇(paclitaxel)和多西他赛(docetaxel)以及与许多其他抗癌药物相关的多重耐药性(MDR)。
由于其在水中的低溶解度，卡巴他赛的商用制剂采用聚山梨醇酯80(表面活性剂)作为增溶剂并且采用乙醇作为稀释剂。由于这种表面活性剂和乙醇的存在，这种制剂需要给病人以抗组胺药(antihistamine)、皮质类固醇(corticosteroid)和H2拮抗剂事先用药。这种制剂在向病人中输注前还需要两步制备过程。在第一步中，必须将含有卡巴他赛和赋形剂的小药瓶与含有乙醇的另一个小药瓶混合；在第二步中，然后将该混合溶液用盐水或5％葡萄糖稀释。根据其标签，在室温下，剂量给药溶液必须八小时内使用，或者如果冷藏的话，在24小时内使用。两个时间限制包括大约1小时的输注时间。
因此，将会合乎需要的是拥有这样的卡巴他赛制剂：其展现出增加的稳定性；其不需要表面活性剂和/或乙醇的存在；并且其可以以更简单和方便的过程制备。
尽管现有技术已经提出了有关化合物的制剂，如具有取代的环糊精的多西他赛，这种制剂仍然含有乙醇。因此，例如，Young等人(美国专利8,481,511)公开了比例为1:10-150的多西他赛(docetaxel)与羟丙基-β-环糊精或磺基丁基-β-环糊精的包合配合物。该配合物如下制备：通过搅拌将溶解在乙醇中的多西他赛加入至环糊精的水溶液中，直到多西他赛完全溶解；将所述溶液在0.2-04μm微孔膜中过滤，然后通过减压移除乙醇以获得液体形式的包合配合物；或者通过减压移除乙醇，接着移除水，然后干燥以获得固体形式的包合配合物。Young等人强调了其最终组合物中降低的乙醇浓度的益处，指出“低的残留乙醇水平为提高多西他赛稳定性和降低刺激和其他副作用提供了有利的保证”。因此，出乎意料的是，可以使用磺基丁基醚β环糊精制备改进的卡巴他赛制剂，所述制剂不含有任何残留的乙醇。
发明描述
本发明涉及一种组合物，所述组合物包含：(a)卡巴他赛和(b)磺基丁基醚β-环糊精(“SBECD”)。
通常，卡巴他赛与SBECD的重量比在1:30至1:1000之间；优选地，该比例在1:90至1:200之间。在一个特别优选的实施方案中，本发明的组合物包含重量比为大约1:133的卡巴他赛和SBECD。
这种组合物还可以任选地包含加入以提高其药物性能的额外组分。尤其是，可以将酸、碱、和/或盐加入至组合物中以调节组合物的pH和渗涨度(tonicity)。特别优选的是，使用HCl、NaOH、柠檬酸和NaCl调节组合物的pH和渗涨度。
在某些实施方案中，组合物是适于通过静脉内注射或输注施用的无菌液体水溶液并且包含0.5％至70％之间的SBECD，优选1％至40％之间的SBECD，并且更优选2％至20％之间的SBECD。
在其它实施方案中，本发明的组合物是无菌固体冻干物形式，或者是包含2％至70％之间、优选20％至60％之间的SBECD的水溶液形式；所述两种形式均适于储存。
本发明的组合物可以通过将卡巴他赛与SBECD的水溶液混合而制备。通常在室温下将这种组合物混合，尽管可以采用更高或更低的温度。之后通常将混合物过滤并储存。如果需要的话，可以将过滤的溶液冷冻干燥用于储存。
实施例：
实施例1.SBECD水溶液中的卡巴他赛溶解度
将过量的卡巴他赛与SBECD水溶液在23℃混合16小时。将所得到的悬浮液通过0.22μm滤器过滤，并且通过HPLC分析澄清的滤液溶液。卡巴他赛在溶液中的浓度在以下表中给出。
表.在23℃下在SBECD水溶液中卡巴他赛的平衡溶解度
实施例2.SBECD水溶液中卡巴他赛溶液的稳定性
通过先后将SBECD溶解在水中并且将卡巴他赛溶解在所得到的溶液中，接着通过0.22μm滤器过滤，制备在20％SBECD水溶液中的含有2.02mg/mL卡巴他赛的溶液。随后用水将部分溶液稀释以分别形成包含1％、2.6％和5％SBECD的三种溶液。将溶液在温度23℃下温育并且在选定的时间点使用HPLC分析。结果在以下表中给出。所有溶液都是稳定的。
表.在使用不同稀释度的具有SBECD的水性组合物中的卡巴他赛浓度
实施例3.20％SBECD水溶液中的卡巴他赛溶液的制备
将2180mg的SBECD溶解在8707mg的蒸馏水中。将16.4mg卡巴他赛加入至该溶液中并且混合直到完全溶解。将溶液通过0.22μm滤器过滤。
实施例4.卡巴他赛和SBECD的冻干组合物的制备
使用干冰将实施例3的溶液快速冷冻。将冷冻的材料冷冻干燥。
实施例5.卡巴他赛组合物在等渗NaCl溶液中的恢复(reconstruction)。
将9.80mL的0.9％NaCl水溶液加至200mg的实施例3的冻干组合物中。将混合物轻轻地混合以制备澄清溶液，所述溶液包含0.15mg/mL卡巴他赛在2％SBECD中的溶液以及0.9％NaCl。
实施例6.药物代谢动力学
雌性Sprague-Dawley大鼠，每组8只动物，接受1小时实施例3的溶液或者等同于卡巴他赛的商用组合物的包含卡巴他赛、聚山梨醇酯80、乙醇和水的溶液的静脉内(i.v.)输注。两种组合物都以剂量8mg/kg施用。在输注开始之后0.5、1、1.08、1.25、1.5、2、3、和4小时收集血液样品；在取样期间从每只动物获取三个样品。使用HPLC测定每个样品中的卡巴他赛的血浆水平。结果在以下表中给出。
结果表明，实施例3的溶液和等同于卡巴他赛的商用组合物的溶液提供相等的对卡巴他赛的暴露(exposure)。
实施例7.在3LL模型中的功效
用鼠3LL细胞(200,000个)静脉内接种C57BL/6小鼠，并且在接种后第1、4和7天用10mg/kg的实施例3的溶液或者等同于卡巴他赛的商用组合物的包含卡巴他赛、聚山梨醇酯80、乙醇和水的溶液的静脉内注射进行治疗。在对照组中使用盐水注射。记录小鼠体重以评价对治疗的耐受性。没有记录到死亡。在第18天时将动物处死并且对肺中的转移进行计数。结果在以下表中给出。
实施例8.在MDA-MB 231模型中的功效
将在含有30％基质胶(Matrigel)的细胞培养基中的MDA-MB-231细胞(每个部位500,000个细胞)皮下接种在裸Balb/c小鼠的肋腹(在中肋腹中)的2侧。在第16天后，当肿瘤达到0.5-0.8cm时，将动物随机分为三组并且在第1、4和7天用盐水(对照)治疗，或者用7.5mg/kg的实施例3的溶液或等同于卡巴他赛的商用组合物的包含卡巴他赛、聚山梨醇酯80、乙醇和水的溶液治疗。在研究期间记录肿瘤尺寸和体重，并且在研究结束时移出肿瘤并称重。结果在以下表中给出。
实施例9.在DU-145模型中的功效
将在含有50％基质胶的细胞培养基中的人前列腺癌(prostate carcinoma)DU-145细胞(每个部位2,000,000个细胞)皮下接种在SCID小鼠的中肋腹的2侧。在第21天后(当肿瘤达到0.5-0.8cm时)将动物随机分为三组并且在此之后第1、4和7天用盐水(对照)治疗，或者用7.5mg/kg的实施例3的溶液或等同于卡巴他赛的商用组合物的包含卡巴他赛、聚山梨醇酯80、乙醇和水的溶液治疗。记录肿瘤尺寸和体重。结果在以下表中给出。
Claims (5)
1.一种水性组合物，所述组合物包含：(a)卡巴他赛和(b)磺基丁基醚β-环糊精，其中所述组合物不含任何乙醇。
2.根据权利要求1所述的组合物，其中所述组合物为水溶液形式，包含以重量计1％至40％之间的磺基丁基醚β-环糊精。
3.根据权利要求2所述的组合物，其中所述组合物为水溶液形式，包含以重量计2％至20％之间的磺基丁基醚β-环糊精。
4.根据权利要求1所述的组合物，其中所述组合物为由权利要求1的组合物形成的固体冻干物形式。
5.根据权利要求1所述的组合物，其中所述组合物不含任何表面活性剂。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201261848172P | 2012-12-24 | 2012-12-24 | |
| US61/848,172 | 2012-12-24 | ||
| PCT/IB2013/003255 WO2014122498A2 (en) | 2012-12-24 | 2013-12-23 | Cabazitaxel composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105142671A CN105142671A (zh) | 2015-12-09 |
| CN105142671B true CN105142671B (zh) | 2018-09-14 |
Family
ID=51300216
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201380073396.6A Active CN105142671B (zh) | 2012-12-24 | 2013-12-23 | 卡巴他赛和磺基丁基醚β-环糊精的组合物 |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US9919053B2 (zh) |
| EP (1) | EP2934593B1 (zh) |
| JP (1) | JP6498610B2 (zh) |
| KR (1) | KR102161866B1 (zh) |
| CN (1) | CN105142671B (zh) |
| AU (1) | AU2013377404B2 (zh) |
| BR (1) | BR112015015202B8 (zh) |
| CA (1) | CA2900508C (zh) |
| DK (1) | DK2934593T3 (zh) |
| ES (1) | ES2771423T3 (zh) |
| HU (1) | HUE048505T2 (zh) |
| MX (1) | MX371067B (zh) |
| PL (1) | PL2934593T3 (zh) |
| PT (1) | PT2934593T (zh) |
| RU (1) | RU2678772C2 (zh) |
| WO (1) | WO2014122498A2 (zh) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018109731A1 (en) * | 2016-12-16 | 2018-06-21 | Orbicular Pharmaceutical Technologies Private Limited | Pharmaceutical compositions of taxane and its derivatives |
| CN113559277B (zh) * | 2018-01-11 | 2023-11-17 | 比卡生物科技（广州）有限公司 | 一种注射用卡巴他赛组合物及其制备方法 |
| JP7274785B2 (ja) * | 2018-07-25 | 2023-05-17 | ビカ バイオテクノロジー （グアンジョウ） カンパニー リミテッド | 注射用ドセタキセル組成物およびそのための調製法 |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050233945A1 (en) * | 2003-07-18 | 2005-10-20 | Larry Brown | Methods for fabrication, uses and compositions of small spherical particles of insulin prepared by controlled phase separation |
| EP1443969A2 (en) * | 2001-10-18 | 2004-08-11 | Decode Genetics EHF | Non-inclusion cyclodextrin complexes |
| JP2005022989A (ja) * | 2003-06-30 | 2005-01-27 | Otsuka Pharmaceut Factory Inc | 可溶化または分散化された難溶性化合物を含む組成物 |
| AU2004285032A1 (en) * | 2003-10-31 | 2005-05-12 | The University Of Kansas | Sulfoalkyl ether-alkyl ether cyclodextrin derivatives |
| CN100486645C (zh) * | 2006-09-12 | 2009-05-13 | 南京师范大学 | 含有环糊精紫杉醇包合物的药物组合物及其制备方法 |
| CN100411688C (zh) * | 2006-09-12 | 2008-08-20 | 南京师范大学 | 含有环糊精/多烯紫杉醇包合物的药物组合物及其制备方法 |
| KR101502533B1 (ko) * | 2007-11-22 | 2015-03-13 | 에스케이케미칼주식회사 | 우수한 안정성을 갖는 택산 유도체 함유 주사제용동결건조 조성물 및 이의 제조방법 |
| US20120065255A1 (en) * | 2009-10-19 | 2012-03-15 | Nagesh Palepu | Cabazitaxel formulations and methods of preparing thereof |
| US20120058971A1 (en) * | 2009-11-23 | 2012-03-08 | Cerulean Pharma Inc. | Cyclodextrin-based polymers for therapeutic delivery |
| WO2013024495A1 (en) * | 2011-08-18 | 2013-02-21 | Dr. Reddys Laboratories Limited | Pharmaceutical formulations of cabazitaxel |
-
2013
- 2013-12-23 ES ES13874815T patent/ES2771423T3/es active Active
- 2013-12-23 WO PCT/IB2013/003255 patent/WO2014122498A2/en active Application Filing
- 2013-12-23 CA CA2900508A patent/CA2900508C/en active Active
- 2013-12-23 MX MX2015008225A patent/MX371067B/es active IP Right Grant
- 2013-12-23 CN CN201380073396.6A patent/CN105142671B/zh active Active
- 2013-12-23 PL PL13874815T patent/PL2934593T3/pl unknown
- 2013-12-23 PT PT138748157T patent/PT2934593T/pt unknown
- 2013-12-23 KR KR1020157020157A patent/KR102161866B1/ko active IP Right Grant
- 2013-12-23 DK DK13874815.7T patent/DK2934593T3/da active
- 2013-12-23 BR BR112015015202A patent/BR112015015202B8/pt active IP Right Grant
- 2013-12-23 HU HUE13874815A patent/HUE048505T2/hu unknown
- 2013-12-23 AU AU2013377404A patent/AU2013377404B2/en active Active
- 2013-12-23 EP EP13874815.7A patent/EP2934593B1/en active Active
- 2013-12-23 US US14/655,214 patent/US9919053B2/en active Active
- 2013-12-23 RU RU2015130495A patent/RU2678772C2/ru not_active Application Discontinuation
- 2013-12-23 JP JP2015550161A patent/JP6498610B2/ja active Active
Also Published As
| Publication number | Publication date |
|---|---|
| KR20150127035A (ko) | 2015-11-16 |
| RU2015130495A (ru) | 2017-01-27 |
| US9919053B2 (en) | 2018-03-20 |
| WO2014122498A3 (en) | 2014-12-04 |
| PT2934593T (pt) | 2020-03-09 |
| US20150328321A1 (en) | 2015-11-19 |
| CA2900508C (en) | 2021-04-13 |
| RU2678772C2 (ru) | 2019-02-01 |
| ES2771423T3 (es) | 2020-07-06 |
| HUE048505T2 (hu) | 2020-07-28 |
| JP2016508138A (ja) | 2016-03-17 |
| JP6498610B2 (ja) | 2019-04-10 |
| MX2015008225A (es) | 2016-07-20 |
| CA2900508A1 (en) | 2014-08-14 |
| WO2014122498A2 (en) | 2014-08-14 |
| CN105142671A (zh) | 2015-12-09 |
| MX371067B (es) | 2020-01-15 |
| AU2013377404B2 (en) | 2018-08-23 |
| EP2934593A4 (en) | 2016-08-10 |
| PL2934593T3 (pl) | 2020-05-18 |
| EP2934593A2 (en) | 2015-10-28 |
| DK2934593T3 (da) | 2020-02-17 |
| AU2013377404A2 (en) | 2015-08-27 |
| KR102161866B1 (ko) | 2020-10-05 |
| BR112015015202B1 (pt) | 2021-12-21 |
| EP2934593B1 (en) | 2020-02-05 |
| BR112015015202A2 (pt) | 2017-07-11 |
| AU2013377404A1 (en) | 2015-07-30 |
| BR112015015202B8 (pt) | 2022-02-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5587198B2 (ja) | タキサン誘導体を含有する、安定性が改良された凍結乾燥医薬組成物、及びその製法 | |
| AU2015283343A1 (en) | Purified therapeutic nanoparticles and preparation methods thereof | |
| DK2525796T3 (en) | An aqueous solution comprising 3-quinuclidinoner for the treatment of hyperproliferative disease, autoimmune disease and heart disease | |
| CN104042567A (zh) | 一种蛇葡萄素纳米胶束及其应用 | |
| CN105142671B (zh) | 卡巴他赛和磺基丁基醚β-环糊精的组合物 | |
| TWI593430B (zh) | 含紫杉烷系活性成分液體組成物、其製造方法及液體製劑 | |
| RU2398578C2 (ru) | Фармацевтическая композиция, содержащая производное таксана, которая предназначена для приготовления инфузионного раствора, способ его приготовления и использование | |
| CN108066774A (zh) | 一种注射用卡巴他赛组合物及其制备方法 | |
| CN108697726A (zh) | 液态药物制剂 | |
| CN107137349B (zh) | 一种藤黄酸纳米混悬剂及其制备方法 | |
| CN104414963A (zh) | 一种含左西孟旦的药物组合物 | |
| CN101513400A (zh) | 蛇葡萄素碱性氨基酸助溶体系及其抗肿瘤活性研究 | |
| CZ2005796A3 (cs) | Farmaceutická kompozice obsahující derivát taxanuse zlepsenou terapeutickou úcinností | |
| CN102210868A (zh) | 四氢嘧啶及其衍生物在制备口服吸收促进剂中的应用 | |
| TW201215412A (en) | Stable pharmaceutical composition | |
| CN106619541A (zh) | 艾沙康唑鎓硫酸盐冻干粉针剂及制备方法 | |
| CN108066335B (zh) | 一种含有紫杉醇或其类似物的药物组合物及其制备方法 | |
| CN101129374B (zh) | 长春氟宁药物组合物及其制备方法与应用 | |
| CN104703626B (zh) | 用于治疗癌症的基于碘油的抗肿瘤乳剂 | |
| CN105125532A (zh) | 一种治疗癌症的药物奥沙利铂组合物 | |
| WO2003099288A1 (fr) | Composition medicinale | |
| TW471972B (en) | Taxane composition and method | |
| CN105055324A (zh) | 一种铂类抗癌药物奥沙利铂组合物 | |
| RU2428175C2 (ru) | Способ получения парентерального фармацевтического раствора | |
| CN105250317A (zh) | 一种抗肿瘤药物奥沙利铂组合物 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20171121 Address after: Quebec Applicant after: Softto Kimmel pharmaceutical company Address before: Quebec Applicant before: SUPRATEK PHARMA INC. |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant |