TW200538457A - Aqueous solutions comprising camptothecin - Google Patents
Aqueous solutions comprising camptothecin Download PDFInfo
- Publication number
- TW200538457A TW200538457A TW094104227A TW94104227A TW200538457A TW 200538457 A TW200538457 A TW 200538457A TW 094104227 A TW094104227 A TW 094104227A TW 94104227 A TW94104227 A TW 94104227A TW 200538457 A TW200538457 A TW 200538457A
- Authority
- TW
- Taiwan
- Prior art keywords
- aqueous solution
- camptothecin
- sodium
- preparation
- cpt
- Prior art date
Links
- 239000007864 aqueous solution Substances 0.000 title claims abstract description 68
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 title claims description 42
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 title claims description 41
- 229940127093 camptothecin Drugs 0.000 title claims description 41
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 title claims description 41
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 90
- 238000002360 preparation method Methods 0.000 claims abstract description 51
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims abstract description 22
- 239000001632 sodium acetate Substances 0.000 claims abstract description 22
- 235000017281 sodium acetate Nutrition 0.000 claims abstract description 22
- 235000011054 acetic acid Nutrition 0.000 claims description 29
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 26
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 21
- 229920000858 Cyclodextrin Polymers 0.000 claims description 18
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 16
- 235000010323 ascorbic acid Nutrition 0.000 claims description 13
- 239000011668 ascorbic acid Substances 0.000 claims description 13
- 229960005070 ascorbic acid Drugs 0.000 claims description 13
- 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 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 9
- 235000010378 sodium ascorbate Nutrition 0.000 claims description 9
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims description 9
- 229960005055 sodium ascorbate Drugs 0.000 claims description 9
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 claims description 9
- 238000002347 injection Methods 0.000 claims description 8
- 239000007924 injection Substances 0.000 claims description 8
- 235000010265 sodium sulphite Nutrition 0.000 claims description 8
- -1 sodium fluorenyl acetate Chemical compound 0.000 claims description 5
- 239000004615 ingredient Substances 0.000 claims description 4
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 claims description 4
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 4
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 3
- RWPGFSMJFRPDDP-UHFFFAOYSA-L potassium metabisulfite Chemical compound [K+].[K+].[O-]S(=O)S([O-])(=O)=O RWPGFSMJFRPDDP-UHFFFAOYSA-L 0.000 claims description 3
- 235000010263 potassium metabisulphite Nutrition 0.000 claims description 3
- 235000010352 sodium erythorbate Nutrition 0.000 claims description 3
- 239000004320 sodium erythorbate Substances 0.000 claims description 3
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 3
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 3
- RBWSWDPRDBEWCR-RKJRWTFHSA-N sodium;(2r)-2-[(2r)-3,4-dihydroxy-5-oxo-2h-furan-2-yl]-2-hydroxyethanolate Chemical compound [Na+].[O-]C[C@@H](O)[C@H]1OC(=O)C(O)=C1O RBWSWDPRDBEWCR-RKJRWTFHSA-N 0.000 claims description 3
- 230000000259 anti-tumor effect Effects 0.000 claims description 2
- 229940043349 potassium metabisulfite Drugs 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- GURKHSYORGJETM-WAQYZQTGSA-N irinotecan hydrochloride (anhydrous) Chemical compound Cl.C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 GURKHSYORGJETM-WAQYZQTGSA-N 0.000 description 39
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 10
- 229960000779 irinotecan hydrochloride Drugs 0.000 description 8
- 235000011121 sodium hydroxide Nutrition 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000013078 crystal Substances 0.000 description 7
- 239000008215 water for injection Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 239000006228 supernatant Substances 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 238000009210 therapy by ultrasound Methods 0.000 description 4
- 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 3
- 239000002253 acid Substances 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 239000000872 buffer 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
- 238000009472 formulation Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 229930185472 acuminatum Natural products 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 239000003405 delayed action preparation Substances 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 150000003839 salts Chemical group 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- FBDOJYYTMIHHDH-OZBJMMHXSA-N (19S)-19-ethyl-19-hydroxy-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-2,4,6,8,10,14,20-heptaen-18-one Chemical compound CC[C@@]1(O)C(=O)OCC2=CN3Cc4cc5ccccc5nc4C3C=C12 FBDOJYYTMIHHDH-OZBJMMHXSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- KLFJSYOEEYWQMR-NRFANRHFSA-N 10-methoxycamptothecin Chemical compound C1=C(OC)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 KLFJSYOEEYWQMR-NRFANRHFSA-N 0.000 description 1
- IHPYMWDTONKSCO-UHFFFAOYSA-N 2,2'-piperazine-1,4-diylbisethanesulfonic acid Chemical compound OS(=O)(=O)CCN1CCN(CCS(O)(=O)=O)CC1 IHPYMWDTONKSCO-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 241000759909 Camptotheca Species 0.000 description 1
- 241000759905 Camptotheca acuminata Species 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 101150073133 Cpt1a gene Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- 229930182843 D-Lactic acid Natural products 0.000 description 1
- JVTAAEKCZFNVCJ-UWTATZPHSA-N D-lactic acid Chemical compound C[C@@H](O)C(O)=O JVTAAEKCZFNVCJ-UWTATZPHSA-N 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 101000610640 Homo sapiens U4/U6 small nuclear ribonucleoprotein Prp3 Proteins 0.000 description 1
- 240000005979 Hordeum vulgare Species 0.000 description 1
- 235000007340 Hordeum vulgare Nutrition 0.000 description 1
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 239000007990 PIPES buffer Substances 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 101001110823 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-A Proteins 0.000 description 1
- 101000712176 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-B Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 102100040374 U4/U6 small nuclear ribonucleoprotein Prp3 Human genes 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000013011 aqueous formulation Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 201000009613 breast lymphoma Diseases 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-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)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 GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 1
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- GNBVPFITFYNRCN-UHFFFAOYSA-M sodium thioglycolate Chemical compound [Na+].[O-]C(=O)CS GNBVPFITFYNRCN-UHFFFAOYSA-M 0.000 description 1
- 229940046307 sodium thioglycolate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229940035024 thioglycerol Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 206010046766 uterine cancer 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides 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
- A61K31/395—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
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
- A61K47/02—Inorganic compounds
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
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200538457 九、發明說明： 【發明所屬之技術領域】 本發明係關於一種喜樹鹼類之溶解性優良且穩定之水溶 液製劑者。 【先前技術】 喜樹鹼（camptothecin，CPT)係中國原產之喜樹 (camptotheca acuminata)之果實或根等中所含有之生物 鹼，又，喜樹鹼之半合成衍生物即7-乙基哌啶基哌啶基 • 羰氧基喜樹鹼（cpt-1丨）（專利文獻1)係維持喜樹鹼較高之抗 腫瘤活性並且作為毒性得以減輕之化合物而特別重要之物 質。該7-乙基-10-哌啶基哌啶基羰氧基喜樹鹼於生物體内得 以代謝’成為作為半合成衍生物之乙基·ι〇_經基喜樹驗 (SN-3 8)(專利文獻2)，從而得以表現活性。 7-乙基-10-哌啶基哌啶基羰氧基喜樹鹼等喜樹鹼類主要 藉由靜脈注射對患者投藥。因此，目前7-乙基-1〇-哌啶基旅 唆基幾氧基吾樹驗等喜樹驗類作為藉由山梨糖醇等施以等 _ 張化之製劑而上市並流通使用。眾所周知，關於該製劑化 迄今為止已實行有各種試驗，例如使喜樹鹼衍生物包含於 膠原與2-羥乙基•甲基丙烯酸酯之共聚體中之緩釋型製劑 (專利文獻3)，或者使喜樹鹼或其衍生物包含於含有聚乳酸_ 乙醇酸共聚體之載體中之緩釋型製劑（專利文獻4)。 然而’喜樹鹼類對水之溶解度較低，故必須以加熱之方 式調製水溶液製劑，為使製程簡化，業者希望開發無需加 熱即可製造含有喜樹鹼類之水溶液製劑。 99586.doc 200538457 專利文獻1:日本專利特公平3-4077號公報 專利文獻2 :日本專利特公昭62-47193號公報 專利文獻3:日本專利特開平7-277981號公報 專利文獻4:日本專利特開平1〇-17472號公報 【發明内容】 [發明所欲解決之問題] 本發明之目的在於提供一種於製造時無需加熱且喜樹鹼 類處於穩定溶解狀態之含有喜樹鹼類之水溶液製劑。 本發明者等鑒於上述課題實行銳意研究之結果，發現若 於含有喜樹鹼類之水溶液製劑中添加醋酸及醋酸鈉，進而 調整為特定之pH值範圍内，則喜樹鹼類水溶液中之溶解性 將會增大，故可以高於先前之濃度溶解喜樹鹼類，由此得 到穩定的含有喜樹鹼類之水溶液製劑，從而完成本發明^ 即，本發明係提供一種含有喜樹鹼類之水溶液製劑者， 其特徵在於··其含有下列成分（A)及（B): (A) 喜樹鹼類， (B) 醋酸及醋酸鈉， PH值為2〜5。 [發明之效果] 於本發明之水溶液製财，於製造時無需加熱即可高濃 度溶解喜樹驗類。 【實施方式】 —本發明之水溶液製劑中所使用之成分(A)喜樹鹼類係水 溶液製劑之有效成分’例如可列舉如1〇_Μ基喜樹驗、u· 99586.doc 200538457 經基喜樹驗、9·甲氧基喜樹鹼U氧基喜樹驗、u_甲氧 基吾樹驗等天㈣源者，又，亦可列舉，將天然之喜樹驗 專作為原料並加以化學修飾而得到之7_乙基魯㈣基旅 咬基幾氧基喜樹驗（以下亦稱為CPT_U)等化合物。作為喜樹 鹼類較好是CPT-11。 成分（B)中之醋酸鈉亦可以 劑之方式生成。於該情形 、碳酸鈉、碳酸氫鈉等， 本發明之水溶液製劑中所使用 於水溶液製劑中添加醋酸及鹼性 下，作為鹼性劑可列舉氫氧化鈉
較好是氫氧化納。X ’於水溶液製劑中，亦可藉由與其他 化合物之鹽交換形成醋酸鈉。 於本發明之水溶液製劑中，成分（B)醋酸及醋酸鈉換算成 醋酸’則較好是含有〇·1〜1〇重量0/〇。 對於本發明之水溶液製劑中之喜樹鹼類100 mg,就提高 喜樹鹼類之對水溶液性劑之溶解性方面而言，醋酸及醋酸 鈉若以醋酸換算量計算，較好是含有10〜2000 mg，更好是 含有1〇〜1〇〇〇1^，特別好的是含有20〜5〇()11^。 本發明之水溶液製劑中，若進而添加⑴環糊精、（ii)抗壞 血酸及抗壞血酸鈉、（iii)丙二醇或（iv)選自亞硫酸氫鈉、亞 硫I鈉、焦亞硫酸卸、異抗壞金酸納、酼基乙酸納、焦亞 硫酸鈉及α _硫代甘油所組成之群組中i種以上之化合物作 為成分（C)，則喜樹鹼類之溶解性將進一步提高因而較為理 想0 成分（C)之⑴環糊精係6〜12個葡萄糖分子藉由α 4,4葡 糖苷鍵結合連成環狀之非還原性麥牙募糖，並可列舉α •環 99586.doc 200538457 糊精、万-環糊精、r 環糊精及此等之衍生物。作為環糊精 之衍生物，可列舉麥芽糖基環糊精、葡糖基環糊精、二甲 基裒糊精、羥丙基環糊精等。作為環糊精，較好是点-環糊 精、r _環糊精、羥丙基石-環糊精等。 於本發明之水溶液製劑中，就喜樹鹼類之溶解性方面而 曰，較好是含有1〜2〇重量。/❶之環糊精、特別好的是含有i 5 〜14重量％之環糊精。 對於本發明之水溶液製劑中之喜樹鹼類100 mg，就提高 _ 喜樹鹼類對水溶液性劑溶解性方面而言，較好是含有3〇〜 1000 mg環糊精、特別好的是含有9〇〜7〇〇 糊精。 又，於使用環糊精之情形時，就喜樹鹼類之溶解性方面 而ό，成分（B)醋酸及醋酸鈉之含有量以醋酸換算量計算， 杈好是0·1〜5.0重量％，更好是〇·3〜3 〇重量％，特別好是〇 5 〜2·0重量％。 本發明之水溶液製劑中，若添加（ii)抗壞血酸及抗壞血酸 鈉作為成分（C)，則可獲得喜樹鹼類之溶解性進一步提高之 水溶液製劑，因而較為理想。 抗壞血酸鈉可以於水溶液製劑中添加鹼性劑至抗壞血酸 之方式得以生成。於此情形時，作為鹼性劑，可列舉氫氧 化納、碳酸鈉、碳酸氫鈉等，而較好是氫氧化鈉。又，於 水溶液製劑中，藉由與其他化合物之鹽交換亦可形成抗壞 血酸鈉。 於本發明之水溶液製劑中，抗壞血酸及抗壞血酸鈉換算 為抗壞血酸，較好是含有5〜20重量％，特別好是含有6〜15 99586.doc -9- 200538457 重量％。 於使用抗壞血酸及抗壞血酸鈉之情形時，就喜樹鹼類之 洛解性方面而言，成分（B)醋酸及醋酸鈉之含有量以醋酸換 算$計算，更好是含有0·5〜8重量％，特別好是含有0.7〜ό 重量％。 又’就吾樹驗類之溶解性方面而言，醋酸、抗壞血酸及 此等之鈉鹽以換算成各自酸之含有量之合計量計算，則較 好疋含有0·1〜20重量％，更好是含有〇·3〜15重量％，特別 好是含有0.4〜14重量0/〇。 對於本發明之水溶液製劑中之喜樹鹼類1〇〇 就提高 喜樹驗類對水溶液性劑中之溶解性方面而言，醋酸、抗壞 血酸及此等之鈉鹽以換算成各自酸之含有量之合計量計 算，則較好是含有500〜200〇11^，特別好是含有8〇〇〜15〇〇 mg。 於使用（111)丙二醇作為成分（C)之情形時，較好是於本發 明之水溶液製劑中含有40〜70重量％，特別好是含有5〇〜6〇 重量％。 又，對於本發明之水溶液製劑中之喜樹鹼類1〇〇 mg，就 提高喜樹鹼類對水溶液性劑中之溶解性方面而言，較好是 含有1〜4 g丙二醇，特別好是含有2〜3 §丙二醇。 於使用丙二醇之情形時，就喜樹鹼類之溶解性方面而 言，成分（B)醋酸及醋酸鈉之含有量以醋酸換算量計算，則 更好是含有〇·5〜8重量％，特別好是含有〇·7〜6重量％。、 於本發明之水溶液製劑中，若添加（iv)選自亞硫酸氮納、 99586.doc -10- 200538457 亞硫酸鈉、焦亞硫酸鉀、異抗壞血酸鈉、巯基乙酸鈉、焦 亞硫酸納及α -硫代甘油所組成之群組中一種以上之化合物 作為成分（C)，則可獲得喜樹鹼類之溶解性進一步提高之水 溶液製劑因而較為理想。 對於本發明之水溶液製劑中之喜樹鹼類1〇〇 mg ,就喜掛: 驗類之溶解性方面而言，較好是含有1〜300 mg成分（C)之選 自（iv)之化合物，特別好是含有10〜2〇〇 mg。 本發明之水溶液製劑之pH值，就喜樹鹼類之溶解性方面 而言，於室溫（25。〇下為2〜5，然而更好是2·5〜4·8。pH值 之調整較好是使用醋酸、鹽酸、硫酸等之酸，氫氧化納、 碳酸鈉、碳酸氫鈉等含有鈉之鹼之方式實行。 本發明之水溶液製劑由於作為有效成分之喜樹驗類具肩 優良之惡性腫瘤治療效果，所以可用作抗腫瘤性製劑。作 為治療對象惡性腫瘤，可列舉肺癌、子宮癌、印巢癌、s 癌、結腸·直腸癌、乳癌、淋巴癌、騰臟癌等。 又，作為本發明之水溶液製劑之劑型，較好是注射用製 劑、特別好的是靜脈内投與用製劑。於將其作為該注射用 製劑時，除上述成分以外亦可使用以注射用蒸餾水，葡萄 糖、甘露糖、乳糠為代表之糖類，以食鹽等為代表之無機 鹽類，HEPES、PIPES等有機胺，其他通常注射劑中所錢 之穩定劑、賦形劑、緩衝劑等成分。於注射用製劑中，較 好是含有1〜50 mg/mL喜樹鹼類，特別好是含有⑺〜⑽ mg/mL喜樹鹼類。 [實施例] 99586.doc -11 - 200538457 下面列舉實施例進一步詳細說明本發明，本發明ϋ #限 定於任意此等者。 (實施例1) 於添加醋酸並調整pH值之表1中所揭示之水溶液10 mL中 添加250〜500 mg之CPT-11，並以10分鐘超聲波處理之方式 將CPT-11分散入水中，使其溶解，其後於室溫下攪拌所需 要之天數。其次，將溶液取樣，以3000 r/min離心分離30分 鐘，將上清液以0.45 μπι過濾器過濾。準確量取所濾取之1 mL • 上清液，以90%甲醇水溶液混合為50 mL。按下述條件，通 過HPLC測定處於溶解狀態之CPT-11之量。 HPLC條件： 管柱：Symmetry Shield RP18(3.5 /z m、4.6x50 mm)
管柱溫度：50°C 流速：2.0 mL/min 移動相：使A液為50 mmol/L甲酸緩衝液（ρΗ5·5)/乙腈/甲 醇 = 850/100/50、使B液為50mmol/L甲酸緩衝液（pH5·5)/乙 ^ 腈/甲醇=750/250/50，將B液以15分鐘實行0〜100%之線性 梯度，於其後5分鐘内以100% A液實行平衡化。
注入量：10 pL 檢測波長：254 nm 測定於室溫下攪拌1日及2日後各水溶液中CPT-11溶解量 之結果表示於表1。再者，結果以每1 mL水溶液中之CPT-11 溶解量（CPT-11 mg/mL)表示。 99586.doc •12· 200538457 [表i] 水溶液5 mL中之成分添加量(mg) 水溶液 pH*1 攪拌曰數 醋酸鈉 環糊精種類 1曰 2曰 1 100 - 4.0 28.07 27.87 本 2 100 β 92.5 4.0 29.46 29.13 發 3 100 7 336 4.0 31.66 31.52 明 4 100 7 672 4.0 30.89 32.09 5 100 羥丙基冷 308 4.0 31.12 31.18 比 1 乳酸 250 4.0 19.03 較 2 蘋果酸 250 4.0 - 18.89 例 3 檸檬酸 250 4.0 - 20.06 * 1:已實行添加醋酸並調整pH值之處理
本發明之含有喜樹鹼類之水溶液製劑均為CPT-11之溶解 性優良者。又，此等水溶液製劑於室溫（25°C )下即使未經避 光而靜置3日亦未發生變色、且並未析出結晶。進而，即使 振動亦未確認出CPT-11之結晶析出。 (實施例2) 於表2中揭示之10 mL水溶液中添加250〜500 mg之 CPT-11，施行10分鐘超聲波處理使CPT-11分散入水中並溶 解，其後於室溫下攪拌所需要之天數。繼而，將溶液取樣， 以3000 r/min離心分離30分鐘，從而將上清液以0·45 μπι過 濾器過濾。準確量取所濾取之上清液1 mL，以90°/。甲醇水 溶液混合50 mL。以與實施例1相同條件，通過HPLC測定處 於溶解狀態之CPT-11之量。 測定於室溫下攪拌一日及兩日後各水溶液中之CPT-11溶 99586.doc -13 - 200538457 解量之結果表示於表2。再者，結果以每1 mL水溶液之溶解 CPT-11 量（CPT-11 mg/mL)表示。 [表2] 編號 水溶液5mL中之成分添加量(mg) 水溶液 pH 攪拌曰數 醋酸 醋酸鈉 抗壞血酸 NaOH 1曰 2曰 本 發 明 6 200 20 700 2.8 44.54 44.61 7 200 20 500 2.9 38.70 38.45 8 200 50 700 3.2 43.64 44.07 9 200 100 700 3.6 45.87 47.24 10 200 20 700 15 3.1 43.45 43.56 11 200 20 700 20 3.2 41.97 41.79 12 200 20 700 50 3.7 42.41 42.50 13 200 20 700 100 4.2 38.16 39.11 比 較 例 4 250 4.0*2 - 20.91 * 2:已實行添加氫氧化鈉並調整pH值之處理 本發明之編號第6至第13例之含有喜樹鹼類之水溶液製 劑均為CPT-11之溶解性優良者。又，此等水溶液製劑於室 溫（25°C)下即使未經避光而靜置3日亦未產生變色，且並未 析出結晶。進而，即使振動亦未確認出CPT-11之結晶析出。 而另一方面，單獨添加抗壞血酸時則CPT-11之溶解性不充 分。 (實施例3) 於表3中揭示之使用醋酸將pH值調整為4.0之水溶液10 mL中添加250〜500 mg之CPT-11，實行10分鐘超聲波處理 從而使CPT-11分散入水中並溶解，其後於室溫下攪拌所需 99586.doc -14- 200538457 要之天數。繼而，將溶液取樣，以3000 r/min離心分離30 分鐘，將上清液以0.45 // m過濾器過濾。準確量取所濾、取 之上清液1 mL，以90%甲醇水溶液混合50 mL。以與實施例 1相同之條件，測定處於溶解狀態之CPT-11量。 於室溫下攪拌1日及2日後，測定各水溶液中之CPT-11之 溶解量之結果表示於表3。再者，結果以每1 mL水溶液之溶 解 CPT-11 量（CPT-11 mg/mL)表示。
[表3] 編號 水溶液5mL中之成分添加量(mg) 水溶液 pH*2 攪拌曰數 醋酸鈉 添加劑 1曰 2曰 14 30 亞硫酸氫鈉 200 4.0 25.38 25.30 15 30 亞硫酸鈉 100 4.0 27.93 27.82 本 16 30 酼基乙酸鈉 50 4.0 22.15 22.38 發 17 30 焦亞硫酸鉀 200 4.0 25.70 25.79 明 18 30 焦亞硫酸鈉 50 4.0 21.80 21.97 19 30 α-硫代甘油 50 4.0 19.63 20.32 20 30 異抗壞血酸鈉 50 4.0 21.99 21.69 * 3 :已實行添加醋酸並調整pH值之處理 本發明之編號第14至第20例之含有喜樹鹼類之水溶液製 劑均為CPT-11之溶解性優良者。又，此等水溶液製劑於室 溫（25°C)下即使未經避光而靜置3日亦未產生變色，且並未 析出結晶。進而，即使振動亦未確認出CPT-11之結晶析出。 (實施例4) 於含有醋酸鈉100 mg、醋酸20 mg、亞硫酸納60 mg及丙 二醇3000 mg之pH值為4·0之10 mL水溶液中添加250〜500 99586.doc -15- 200538457 mg之CPT-ll，並實施10分鐘超聲波處理從而使CPT-11分散 入水中並溶解，其後以與實施例1同樣之方式，測定每1 mL 水溶液之溶解CPT-11量（CPT-11 mg/mL)。第一日為32.26 mg/mL，第二日為3 1.20 mg/mL。作為比較，於除去醋酸納、 醋酸及亞硫酸鈉之溶液中，第一天之溶解量為18.46 mg/mL，第二天溶解量為18.12 mg/mL。 (實施例5) 藉由以下製法，獲得下述例1至例7之注射劑。 P 於預先添加各添加劑並使之溶解之溶液3.5 mL中添加鹽 酸Irinotecan(CPT-ll)100 mg，充分擾拌使之溶解。於此溶 液中添加含有各添加劑之溶液，使其為5 mL。 (例1) 鹽酸 Irinotecan 醋酸鈉 醋酸 注射用水 總量 pH值 (例2) 鹽酸 Irinotecan 醋酸鈉 醋酸 泠壞糊精 注射用水 總量 pH值 99586.doc
100 mg 50 mg 120 mg 5 mL 4.0
100 mg 100 mg 3 80 mg 92.5 mg 5 mL 4.0 -16- 200538457 (例3) 鹽酸 Irinotecan 100 mg 醋酸 380 mg 氫氧化納 46 mg γ環糊精 672 mg 注射用水 總量 5 mL pH值 4.0 (例4) 鹽酸 Irinotecan 100 mg 抗壞血酸 700 mg 醋酸鈉 100 mg 醋酸 200 mg 注射用水 總量 5 mL pH值 3.6 (例5) 鹽酸 Irinotecan 100 mg 醋酸鈉 20 mg 抗壞血酸鈉 700 mg 醋酸 200 mg 注射用水 總量 5 mL pH值 4.5 (例6) 鹽酸 Irinotecan 100 mg 抗壞血酸鈉 20 mg -17-
99586.doc 200538457 氫氧化鈉 100 mg 醋酸 20 mg 注射用水 總量 5 mL pH值 4.5 (例7) 鹽酸 Irinotecan 100 mg 醋酸鈉 30 mg 醋酸 100 mg 亞硫酸鈉 100 mg 注射用水 總量 5 mL pH值 4.0 例1至例7之含有喜樹鹼類之水溶液製劑（注射劑）均為微 黃色澄清透明之水溶液，且並未確認出鹽酸Irinotecan之結 晶析出。
99586.doc 18-
Claims (1)
- 200538457 十、申請專利範圍： 1 · 一種含有喜樹鹼類之水溶液製劑，其特徵在於：其含有 以下成分（A)及（B): (A) 喜樹鹼類 (B) 醋酸及醋酸鈉 且pH值為2〜5。 2.如請求項1之含有喜樹鹼類之水溶液製劑，其中進而含有 成分（C): (C) (i)環糊精； (ii) 抗壞血酸及抗壞血酸鈉； (iii) 丙二醇； 或（iv)選自亞硫酸氫鈉、亞硫酸鈉、焦亞硫酸鉀、異抗 壞金酸鈉、酼基乙酸鈉、焦亞硫酸鈉及α -硫代甘油所組 成之群組之一種以上之化合物。 3·如請求項1或2之含有喜樹鹼類之水溶液製劑，其中喜樹 鹼類係7_乙基-10-哌啶基哌啶基羰氧基喜樹鹼。 4·如請求項1或2之含有喜樹鹼類之水溶液製劑，其中水溶 液製劑係抗腫瘤性製劑。 5·如請求項1或2之含有喜樹鹼類之水溶液製劑，其係注射 用製劑。 99586.doc 200538457 七、指定代表囷： (一) 本案指定代表圖為：（無） (二) 本代表圖之元件符號簡單說明： 八、本案若有化學式時，請揭示最能顯示發明特徵的化學式： (無）99586.doc
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| CA (1) | CA2556254A1 (zh) |
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| US20110177161A1 (en) * | 2007-05-24 | 2011-07-21 | Dr. Reddy's Laboratories Limited | Pharmaceutical compositions of [5(s)-(2'-hydroxyethoxy)-20(s)-camptothecin |
| WO2009126950A2 (en) * | 2008-04-11 | 2009-10-15 | Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College | Diterpene glycosides as natural solubilizers |
| EP2445535A4 (en) | 2009-06-24 | 2014-12-17 | Univ Louisiana State | TERPENIC GLYCOSIDES AND THEIR COMBINATIONS AS SOLUBILIZATION AGENTS |
| US10098813B2 (en) | 2014-09-03 | 2018-10-16 | Sun Pharmaceutical Industries Limited | Perfusion dosage form |
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| JPS6019790A (ja) * | 1983-07-14 | 1985-01-31 | Yakult Honsha Co Ltd | 新規なカンプトテシン誘導体 |
| US5447936A (en) * | 1993-12-22 | 1995-09-05 | Bionumerik Pharmaceuticals, Inc. | Lactone stable formulation of 10-hydroxy 7-ethyl camptothecin and methods for uses thereof |
| JP4094710B2 (ja) * | 1997-11-06 | 2008-06-04 | 株式会社ヤクルト本社 | 新規なカンプトテシン誘導体 |
| HUP0103314A3 (en) * | 1998-08-05 | 2002-07-29 | Aventis Pharma Sa | Use of camptothecin derivatives, with reduced gastrointestinal toxicity |
| US6383471B1 (en) * | 1999-04-06 | 2002-05-07 | Lipocine, Inc. | Compositions and methods for improved delivery of ionizable hydrophobic therapeutic agents |
| WO2001066123A2 (en) * | 2000-03-09 | 2001-09-13 | Yale University | Composition consisting of phy906 and chemotherapeutic agents |
| US6653319B1 (en) * | 2001-08-10 | 2003-11-25 | University Of Kentucky Research Foundation | Pharmaceutical formulation for poorly water soluble camptothecin analogues |
| TW200306314A (en) * | 2002-04-16 | 2003-11-16 | Tanabe Seiyaku Co | Liquid preparation comprising camptothecin derivative and pharmaceutical composition producible by lyophilizing the preparation |
| US20060030578A1 (en) * | 2002-08-20 | 2006-02-09 | Neopharm, Inc. | Pharmaceutically active lipid based formulation of irinotecan |
| JP4245384B2 (ja) | 2003-03-18 | 2009-03-25 | 株式会社ヤクルト本社 | カンプトテシン類含有医薬組成物 |
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2005
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| DE602005024923D1 (de) | 2011-01-05 |
| ATE489094T1 (de) | 2010-12-15 |
| WO2005077370A1 (ja) | 2005-08-25 |
| JP4451850B2 (ja) | 2010-04-14 |
| EP1714653A4 (en) | 2008-05-21 |
| EP1714653B1 (en) | 2010-11-24 |
| CA2556254A1 (en) | 2005-08-25 |
| WO2005077370A8 (ja) | 2006-01-05 |
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