US20110301177A1 - Capsule pharmaceutical dosage form comprising a suspension formulation of an indolinone derivative - Google Patents
Capsule pharmaceutical dosage form comprising a suspension formulation of an indolinone derivative Download PDFInfo
- Publication number
- US20110301177A1 US20110301177A1 US12/995,869 US99586909A US2011301177A1 US 20110301177 A1 US20110301177 A1 US 20110301177A1 US 99586909 A US99586909 A US 99586909A US 2011301177 A1 US2011301177 A1 US 2011301177A1
- Authority
- US
- United States
- Prior art keywords
- capsule
- formulation
- methyl
- active substance
- formulation according
- 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.)
- Abandoned
Links
- 239000002775 capsule Substances 0.000 title claims abstract description 111
- 239000000203 mixture Substances 0.000 title claims abstract description 98
- 238000009472 formulation Methods 0.000 title claims abstract description 91
- 239000000725 suspension Substances 0.000 title claims abstract description 47
- 239000002552 dosage form Substances 0.000 title abstract description 12
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical class C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 title 1
- 239000013543 active substance Substances 0.000 claims abstract description 52
- MMMVNAGRWOJNMW-FJBFXRHMSA-N nintedanib esylate Chemical compound CCS(O)(=O)=O.O=C1NC2=CC(C(=O)OC)=CC=C2\C1=C(C=1C=CC=CC=1)\NC(C=C1)=CC=C1N(C)C(=O)CN1CCN(C)CC1 MMMVNAGRWOJNMW-FJBFXRHMSA-N 0.000 claims abstract description 22
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 36
- 150000002632 lipids Chemical group 0.000 claims description 33
- 239000000787 lecithin Substances 0.000 claims description 28
- 235000010445 lecithin Nutrition 0.000 claims description 28
- 229940067606 lecithin Drugs 0.000 claims description 28
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical group CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 27
- 239000007903 gelatin capsule Substances 0.000 claims description 27
- 229920000159 gelatin Polymers 0.000 claims description 21
- 235000019322 gelatine Nutrition 0.000 claims description 21
- 150000003626 triacylglycerols Chemical class 0.000 claims description 20
- 108010010803 Gelatin Proteins 0.000 claims description 17
- 239000008273 gelatin Substances 0.000 claims description 17
- 235000011852 gelatine desserts Nutrition 0.000 claims description 17
- 229940116364 hard fat Drugs 0.000 claims description 17
- 201000010099 disease Diseases 0.000 claims description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 14
- 239000002562 thickening agent Substances 0.000 claims description 14
- 239000007963 capsule composition Substances 0.000 claims description 13
- 229940057917 medium chain triglycerides Drugs 0.000 claims description 13
- 238000004806 packaging method and process Methods 0.000 claims description 13
- 229920002675 Polyoxyl Polymers 0.000 claims description 11
- 239000004411 aluminium Substances 0.000 claims description 11
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 11
- 229910052782 aluminium Inorganic materials 0.000 claims description 11
- 239000004359 castor oil Substances 0.000 claims description 11
- 235000019438 castor oil Nutrition 0.000 claims description 11
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 125000005456 glyceride group Chemical group 0.000 claims description 9
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 8
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 8
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 8
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 8
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 8
- 239000007966 viscous suspension Substances 0.000 claims description 8
- 239000003925 fat Substances 0.000 claims description 7
- 229920003023 plastic Polymers 0.000 claims description 7
- 239000004033 plastic Substances 0.000 claims description 7
- 230000003176 fibrotic effect Effects 0.000 claims description 6
- 230000001900 immune effect Effects 0.000 claims description 6
- 208000026278 immune system disease Diseases 0.000 claims description 6
- 230000000771 oncological effect Effects 0.000 claims description 6
- 230000001575 pathological effect Effects 0.000 claims description 6
- 229920001223 polyethylene glycol Polymers 0.000 claims description 6
- 229940068917 polyethylene glycols Drugs 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 claims description 6
- BHIZVZJETFVJMJ-UHFFFAOYSA-N 2-hydroxypropyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCC(C)O BHIZVZJETFVJMJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 239000003921 oil Substances 0.000 claims description 5
- 235000019198 oils Nutrition 0.000 claims description 5
- 229940026235 propylene glycol monolaurate Drugs 0.000 claims description 5
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 4
- OVYMWJFNQQOJBU-UHFFFAOYSA-N 1-octanoyloxypropan-2-yl octanoate Chemical compound CCCCCCCC(=O)OCC(C)OC(=O)CCCCCCC OVYMWJFNQQOJBU-UHFFFAOYSA-N 0.000 claims description 4
- NFIHXTUNNGIYRF-UHFFFAOYSA-N 2-decanoyloxypropyl decanoate Chemical compound CCCCCCCCCC(=O)OCC(C)OC(=O)CCCCCCCCC NFIHXTUNNGIYRF-UHFFFAOYSA-N 0.000 claims description 4
- GHHURQMJLARIDK-UHFFFAOYSA-N 2-hydroxypropyl octanoate Chemical compound CCCCCCCC(=O)OCC(C)O GHHURQMJLARIDK-UHFFFAOYSA-N 0.000 claims description 4
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 4
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 4
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 claims description 4
- 241001465754 Metazoa Species 0.000 claims description 4
- 239000005642 Oleic acid Substances 0.000 claims description 4
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000004373 Pullulan Substances 0.000 claims description 4
- 229920001218 Pullulan Polymers 0.000 claims description 4
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 claims description 4
- 239000002285 corn oil Substances 0.000 claims description 4
- 235000005687 corn oil Nutrition 0.000 claims description 4
- 229940099371 diacetylated monoglycerides Drugs 0.000 claims description 4
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 claims description 4
- 229940093471 ethyl oleate Drugs 0.000 claims description 4
- 239000011521 glass Substances 0.000 claims description 4
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 4
- 229940049918 linoleate Drugs 0.000 claims description 4
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 4
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 4
- 235000019423 pullulan Nutrition 0.000 claims description 4
- WECGLUPZRHILCT-HZJYTTRNSA-N rac-1-monolinoleoylglycerol Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(=O)OCC(O)CO WECGLUPZRHILCT-HZJYTTRNSA-N 0.000 claims description 4
- 239000001587 sorbitan monostearate Substances 0.000 claims description 4
- 235000011076 sorbitan monostearate Nutrition 0.000 claims description 4
- 229940035048 sorbitan monostearate Drugs 0.000 claims description 4
- 235000012424 soybean oil Nutrition 0.000 claims description 4
- 239000003549 soybean oil Substances 0.000 claims description 4
- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 4
- 239000008158 vegetable oil Substances 0.000 claims description 4
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 3
- 230000037396 body weight Effects 0.000 claims description 3
- 239000001087 glyceryl triacetate Substances 0.000 claims description 3
- 235000013773 glyceryl triacetate Nutrition 0.000 claims description 3
- 229940072106 hydroxystearate Drugs 0.000 claims description 3
- 229940066675 ricinoleate Drugs 0.000 claims description 3
- 229960002622 triacetin Drugs 0.000 claims description 3
- 239000001069 triethyl citrate Substances 0.000 claims description 3
- 235000013769 triethyl citrate Nutrition 0.000 claims description 3
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims description 3
- SHBUUTHKGIVMJT-UHFFFAOYSA-N Hydroxystearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OO SHBUUTHKGIVMJT-UHFFFAOYSA-N 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- WBHHMMIMDMUBKC-QJWNTBNXSA-M ricinoleate Chemical compound CCCCCC[C@@H](O)C\C=C/CCCCCCCC([O-])=O WBHHMMIMDMUBKC-QJWNTBNXSA-M 0.000 claims description 2
- 238000007789 sealing Methods 0.000 claims description 2
- OYHQOLUKZRVURQ-HZJYTTRNSA-M 9-cis,12-cis-Octadecadienoate Chemical group CCCCC\C=C/C\C=C/CCCCCCCC([O-])=O OYHQOLUKZRVURQ-HZJYTTRNSA-M 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 239000005022 packaging material Substances 0.000 abstract description 7
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 20
- 239000003086 colorant Substances 0.000 description 17
- 239000004615 ingredient Substances 0.000 description 15
- 239000000126 substance Substances 0.000 description 15
- 239000003814 drug Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 229940079593 drug Drugs 0.000 description 11
- 238000004090 dissolution Methods 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 6
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 6
- 238000009736 wetting Methods 0.000 description 6
- 239000000969 carrier Substances 0.000 description 5
- 238000005538 encapsulation Methods 0.000 description 5
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical class CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 5
- 238000011049 filling Methods 0.000 description 5
- 239000012458 free base Substances 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 239000004014 plasticizer Substances 0.000 description 5
- 239000004800 polyvinyl chloride Substances 0.000 description 5
- 229920000915 polyvinyl chloride Polymers 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000004094 surface-active agent Substances 0.000 description 5
- 239000001828 Gelatine Substances 0.000 description 4
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 4
- 239000008186 active pharmaceutical agent Substances 0.000 description 4
- 229940088679 drug related substance Drugs 0.000 description 4
- 229920002690 Polyoxyl 40 HydrogenatedCastorOil Polymers 0.000 description 3
- 229920001328 Polyvinylidene chloride Polymers 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 3
- 235000013871 bee wax Nutrition 0.000 description 3
- 239000012166 beeswax Substances 0.000 description 3
- 229940092738 beeswax Drugs 0.000 description 3
- 239000008119 colloidal silica Substances 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 3
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 3
- 239000012052 hydrophilic carrier Substances 0.000 description 3
- 239000012669 liquid formulation Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000005033 polyvinylidene chloride Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- 239000010936 titanium Substances 0.000 description 3
- 229910052719 titanium Inorganic materials 0.000 description 3
- 229920004439 Aclar® Polymers 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000013103 analytical ultracentrifugation Methods 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 239000013065 commercial product Substances 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 238000009506 drug dissolution testing Methods 0.000 description 2
- 230000001804 emulsifying effect Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000011888 foil Substances 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- 239000012051 hydrophobic carrier Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 229960003511 macrogol Drugs 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- TZBAVQKIEKDGFH-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound [Cl-].C1=CC=C2SC(C(=O)NCC[NH+](CC)CC)=CC2=C1 TZBAVQKIEKDGFH-UHFFFAOYSA-N 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 150000003839 salts Chemical group 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 239000004408 titanium dioxide 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 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 239000003833 bile salt Substances 0.000 description 1
- 229940093761 bile salts Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 229960001777 castor oil Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- PWEOPMBMTXREGV-UHFFFAOYSA-N decanoic acid;octanoic acid;propane-1,2-diol Chemical compound CC(O)CO.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCCCC(O)=O.CCCCCCCCCC(O)=O PWEOPMBMTXREGV-UHFFFAOYSA-N 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 229920002457 flexible plastic Polymers 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 229920001903 high density polyethylene Polymers 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000004700 high-density polyethylene Substances 0.000 description 1
- 239000012943 hotmelt Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000007641 inkjet printing Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 125000000400 lauroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002669 linoleoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000007645 offset printing Methods 0.000 description 1
- 125000002811 oleoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- -1 polyethylene Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229940068886 polyethylene glycol 300 Drugs 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 229940057838 polyethylene glycol 4000 Drugs 0.000 description 1
- 229940057847 polyethylene glycol 600 Drugs 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000007639 printing Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Images
Classifications
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4816—Wall or shell material
- A61K9/4825—Proteins, e.g. gelatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
- A61J1/03—Containers specially adapted for medical or pharmaceutical purposes for pills or tablets
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4816—Wall or shell material
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5052—Proteins, e.g. albumin
- A61K9/5057—Gelatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to a suspension formulation containing the active substance 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate, to a capsule pharmaceutical dosage form containing said suspension formulation, to a to process for preparing said suspension formulation, to a process for preparing said capsule comprising said suspension formulation and to the packaging material for the finished capsule.
- Some pharmacologically active substances may have biopharmaceutical and/or physicochemical properties which make them difficult to formulate into common administration forms. Such substances may be conveniently administered in liquid form either in a lipophilic or hydrophilic carrier system, either as a solution or a suspension, either mixed with a single carrier excipient or mixed with a complex carrier medium made up of several components. Encapsulation of such liquid formulations in soft gelatin capsules potentially offers a very convenient way of administering such pharmacologically active substances.
- GI gastrointestinal
- bile salts behave as biological detergents that, when mixed with phospholipids, form thermodynamically stable mixed micelles. In many instances the choice of formulation will be limited by solvent capacity, and in others the drug will not be sufficiently soluble in any lipid formulations.
- the carrier medium may be designed to spontaneously form an emulsion or microemulsion in the stomach thereby facilitating absorption of the pharmacologically active substance.
- These systems are commonly known as self (micro-)emulsifying drug delivery systems (SEDDS or SMEDDS). They have to be accurately prepared and even slight variations in the composition cannot be tolerated without irreversibly upsetting the system, and destroying its beneficial properties.
- the active substance may precipitate out as a consequence of a change in the solubilizing properties of the capsule formulation. This precipitation process may be irreversible and lead to an under-dosing of the patient.
- the emulsifying properties of the capsule formulation may also be changed, and, upon administration, an emulsion may not be formed in the stomach. As a consequence, the pharmacologically active substance may not be correctly or reproducibly absorbed.
- suspensions do represent thermodynamic instable multiphase systems, various characteristics have to be taken into account during development of these systems.
- the physical stability of the suspension formulation has to be ensured from the perspective of particle growth as well as from the perspective of re-crystallization in a potential polymorphic form which may have a different solubility or from the perspective of sedimentation associated by caking of the sediment. These factors may influence the liberation of the active substance from the dosage form and hence alter the extent of patient's exposure during the shelf-life of the product. Hence no solubility of the active substance in a single carrier excipient or in the carrier system would be the prerequisite for a physically stable system.
- Lipophilic excipients are commonly employed as moisture barrier systems to protect chemically instable substances.
- different types of fats or waxes may be applied on solid dosage forms or on their manufacturing intermediates to prevent migration of ambient water vapour or oxygen and to improve the chemical stability of the active substance.
- Hot-melt inclusions of the drug into lipophilic binders may as well prevent contact with moisture.
- solid hydrophobic systems poorly disintegrate, drug release in these systems is delayed, in contrast to drug release in low viscous liquid lipid formulations. This delayed drug release is reflected by the specific plasma profiles of the active substance of a modified drug delivery system (Ritschel W. et al., Die Tablette, 2002, 2nd ed., ECV, Aulendorf, p. 267f).
- viscosity of liquid systems is a crucial parameter and has to be carefully adjusted to ensure adequate drug release.
- lipophilic or ‘lipid’ formulations are a diverse group of formulations which have a wide range of properties. These result from the blending of up to five classes of excipients, ranging from pure triglyceride oils, through mixed glycerides, lipophilic surfactants, hydrophilic surfactants and water-soluble cosolvents.
- the performance of a formulation may be assessed by measuring its relative bioavailability, i.e. comparing its bioavailability with the bioavailability of an aqueous solution of the active substance. If the systems show a comparable bioavailability, not with respect to the dissolution rate but with respect to the drug permeability, pre-systemic or systemic metabolization of the active substance will determine the systemic exposure. Thus, (lipid) suspensions may also show satisfactory exposure of the patient due to the adequate solubility of the active substance within physiological conditions.
- 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate is an innovative substance having valuable pharmacological properties, especially for the treatment of oncological diseases, immunologic diseases or pathological conditions involving an immunologic component, or fibrotic diseases.
- This substance is described as base in WO 01/27081, as monoethanesulfonate salt form in WO 2004/013099, for its use in the treatment of immunologic diseases or pathological conditions involving an immunologic component in WO 2004/017948, for its use in the treatment of oncological diseases in WO 2004/096224, for its use in the treatment of fibrotic diseases in WO 2006/067165, and as other salt forms in WO 2007/141283.
- the aim of the present invention is to obtain for the above drug substance an oral pharmaceutical dosage form which meets adequate chemical stability as well as bioavailability requirements for the desired dosage range tailored to treatment, and a packaging material suitable for the product.
- Such specific pharmaceutical dosage form is not known from the prior art for this drug substance.
- a first object of the present invention is a formulation of the active substance 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate which comprises a suspension of the active substance.
- a further object of the present invention is the above formulation in which the suspension of the active substance is a viscous suspension of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate comprising a carrier, a thickener and optionally a glidant/solubilizing agent.
- a further object of the present invention is the above formulation in which the carrier is selected from glycerol, acetylated monoglycerides, corn oil glycerides, caprylic-capric triglycerides, medium chain triglycerides, medium chain partial glycerides, caprylic/capric/linoleic triglycerides, caprylic/capric/succinic triglycerides, propylene glycol dicaprylate/dicaprate, ethyl oleate, glycerol mono/dioleate, glycerol monolinolate, macrogolglycerol caprylocaprate, macrogolglycerol linoleate, oleic acid, liquid or semisolid low/intermediate viscous polyethylene glycols (e.g.
- the carrier is a lipid (lipophilic) carrier.
- the carrier is selected from the following lipid (lipophilic) carriers: acetylated monoglycerides, corn oil glycerides, medium chain triglycerides, medium chain partial glycerides, caprylic-capric triglycerides, caprylic/capric/linoleic triglycerides, caprylic/capric/succinic triglycerides, propylene glycol dicaprylate/dicaprate, ethyl oleate, glycerol mono/dioleate, glycerol monolinolate, macrogolglycerol caprylocaprate, macrogolglycerol linoleate, oleic acid, polyoxyl castor oil, polyoxyl hydrogenated castor oil, propylene glycol monocaprylate, propylene glycol monolaurate, refined animal derived oil, refined soybean oil, refined vegetable oil, sorbitan monostearate, or mixture
- a further object of the present invention is the above formulation in which the thickener is selected from semisolid highly viscous or solid polyethyleneglycols (e.g. polyethylene 1000 to 20000), preferably polyethyleneglycols 1000 to 6000, preferably polyethyleneglycol 4000, or oleogel forming excipients, such as Colloidal Silica or Bentonit, or lipophilic or amphiphilic excipients of high viscosity, such as bees wax, glycerol monostearate, hydrogenated vegetable oil, partially hydrogenated vegetable oil or hard fats.
- semisolid highly viscous or solid polyethyleneglycols e.g. polyethylene 1000 to 20000
- polyethyleneglycols 1000 to 6000 preferably polyethyleneglycol 4000
- oleogel forming excipients such as Colloidal Silica or Bentonit
- lipophilic or amphiphilic excipients of high viscosity such as bees wax, glycerol monostearate, hydrogen
- the thickener is selected from oleogel forming excipients, such as Colloidal Silica or Bentonit, or lipophilic or amphiphilic excipients of high viscosity, such as bees wax, glycerol monostearate, hydrogenated vegetable oil, partially hydrogenated vegetable oil or hard fats.
- oleogel forming excipients such as Colloidal Silica or Bentonit
- lipophilic or amphiphilic excipients of high viscosity such as bees wax, glycerol monostearate, hydrogenated vegetable oil, partially hydrogenated vegetable oil or hard fats.
- the formulation further comprises a glidant/solubilizing agent.
- a further object of the present invention is the above formulation in which the glidant/solubilizing agent is selected from lecithin.
- a further object of the present invention is the above formulation comprising a viscous suspension of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate in medium chain triglycerides, hard fat and lecithin.
- a further object of the present invention is the above formulation which further comprises one or more macrogolglycerols and/or solubilizing agents like lauroyl macrogolglycerides, linoleoyl macrogolglycerides, macrogolglycerol caprylocaprate, macrogolglycerol linolate, oleoyl macrogolglycerides, polyoxyl castor oil, polyoxyl hydrogenated castor oil, polysorbate and propylene glycol monolaurate.
- macrogolglycerols and/or solubilizing agents like lauroyl macrogolglycerides, linoleoyl macrogolglycerides, macrogolglycerol caprylocaprate, macrogolglycerol linolate, oleoyl macrogolglycerides, polyoxyl castor oil, polyoxyl hydrogenated castor oil, polysorbate and propylene glycol monolaurate.
- a further object of the present invention is the above formulation, wherein the macrogolglycerols are selected from macrogolglycerol hydroxystearate or macrogolglycerol ricinoleate.
- a further object of the present invention is a capsule comprising a capsule shell and a capsule formulation, characterized in that the capsule formulation comprises the above formulation.
- a further object of the present invention is the above capsule, characterised in that the capsule is a soft gelatin capsule.
- a further object of the present invention is the above capsule, characterised in that the capsule shell comprises glycerol as plasticizing agent.
- a further object of the present invention is a capsule comprising a capsule shell and a capsule formulation, characterized in that the capsule formulation comprises the above formulation and in that the capsule is a hard gelatin or a hydroxypropylmethylcellulose (HPMC) capsule, a polyvinyl alcohol polymer capsule or a pullulan capsule, optionally with a sealing or banding.
- HPMC hydroxypropylmethylcellulose
- a further object of the present invention is the above defined formulation or the above defined capsule for use as medicament.
- a further object of the present invention is the above defined formulation or the above defined capsule for use as pharmaceutical composition with an antiproliferative activity.
- a further object of the present invention is the above defined formulation or the above defined capsule for the treatment of a disease or condition selected from oncological diseases, immunologic diseases or pathological conditions involving an immunologic component, and fibrotic diseases.
- a further object of the present invention is the use of the above defined formulation or the above defined capsule for the preparation of a medicament for the treatment of a disease or condition selected from oncological diseases, immunologic diseases or pathological conditions involving an immunologic component, and fibrotic diseases.
- a further object of the present invention is a process for the treatment and/or prevention of a disease or condition selected from oncological diseases, immunologic diseases or pathological conditions involving an immunologic component, and fibrotic diseases, characterised in that an effective amount of the above defined formulation or the above defined capsule is administered orally to a patient once or several times daily.
- a further object of the present invention is the above defined formulation or the above defined capsule for use in a dosage range of from 0.1 mg to 20 mg of active substance/kg body weight, preferably 0.5 mg to 4 mg active substance/kg body weight.
- a further object of the present invention is a glass container or flexible/hard plastic container suitable for the packaging of capsules, containing one or more of the above defined capsules.
- a further object of the present invention is an aluminium pouch or double poly bag suitable for the packaging of capsules, containing one or more of the above defined capsules.
- a further object of the present invention is a plastic (e.g. PVC, PVDC or Aclar®) blister suitable for the packaging of capsules, containing one or more of the above defined capsules, optionally with an over-packaging of an aluminium pouch.
- a plastic e.g. PVC, PVDC or Aclar®
- a further object of the present invention is an aluminium blister suitable for the packaging of capsules, containing one or more of the above defined capsules.
- FIG. 1- Mass gain by moisture sorption (Dm in %) under different relative humidity conditions (r.H. in %) for a soft gelatin capsule (A) and for a lipid suspension formulation (B).
- a soft gelatin capsule including a liquid formulation comprising a viscous suspension of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate in medium chain triglycerides, hard fat and lecithin, meets the adequate bioavailability requirements for the desired dosage range tailored to treatment with the drug substance 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate.
- This liquid formulation consists of a lipid suspension of the active substance.
- the dosage form is divided into three different compartments, namely (a) a hydrophilic capsule shell and (b) the hydrophobic carrier system in which (c) the slightly hygroscopic powder of active substance is suspended. Due to ambient moisture the content of water may vary within these different compartments. It will migrate by diffusion until an equilibrium state is reached. The water content may affect different properties of the drug product, such as the chemical stability of the active substance (predominantly via hydrolysis) or the elasticity of the capsule shell.
- the water uptake in the present system is primarily in the capsule shell. This can be shown by water vapour sorption experiments (shown in FIG.
- soft gelatin capsules have a capsule shell made of gelatin, one or more plasticizing agents, in particular glycerol, optionally further auxiliary materials, such as dyes, colorant pigments, flavouring agents, sugar, oligosaccharides or polysaccharides, and a capsule formulation (or capsule filling) containing a solvent, adjuvants and one or more pharmacologically active substances.
- plasticizing agents in particular glycerol
- auxiliary materials such as dyes, colorant pigments, flavouring agents, sugar, oligosaccharides or polysaccharides
- a capsule formulation or capsule filling
- the present invention relates to a lipid suspension formulation of the active substance 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate.
- the lipid suspension formulation of the active substance 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate comprises a viscous suspension of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate in a lipid carrier, a thickener and a glidant/solubilizing agent.
- the amount of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate is comprised within the range of 1 to 90 weight % of the lipid suspension formulation, preferably within 10 and 50%.
- the active substance must be either completely insoluble or dissolved in the carrier.
- a solubility screening of lipophilic hydrophilic and amphiphilic excipients and mixtures revealed various potential carriers for formulating the lipid suspension in accordance with the present invention.
- the choice of these lipid carriers for the lipid suspension in accordance with the present invention represents a further object of the present invention.
- suitable carriers or carrier components for the active substance 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate are acetylated monoglycerides, corn oil glycerides, ethyl oleate, glycerol mono/dioleate, glycerol monolinolate, macrogolglycerol caprylocaprate, macrogolglycerol linoleate, medium chain partial glycerides, medium chain triglycerides, caprylic-capric triglycerides, caprylic/capric/linoleic triglycerides, caprylic/capric/succinic triglycerides, propylene glycol dicaprylate/dica
- Stability issues such as hydrolytic degradation of the active substance may also be caused by hydrophilic carrier components. Therefore, carrier systems based on hydrophilic polyethylene glycols will generally show inferior stability than more hydrophobic carriers such as lipid carriers.
- the most preferred lipid carrier is medium chain triglycerides. It is comprised within the range of 1 to 90 weight % of the lipid suspension formulation, preferably within 10 and 70%.
- Suitable medium chain triglycerides may be the commercial product Miglyol 812®, Miglyol 810®, Miglyol 818®, Miglyol 829® or Miglyol 840®.
- a thickener adjusts the viscosity of the suspension. It stabilizes the suspension system, ensures optimal processing and guarantees an adequate capsule quality, especially as far as content uniformity or dissolution behaviour are concerned.
- suitable thickeners to be used in the present invention are oleogel forming excipients, such as Colloidal Silica or Bentonit, or lipophilic or amphiphilic excipients of high viscosity, such as bees wax, glycerol monostearate, hydrogenated vegetable oil, partially hydrogenated vegetable oil or hard fats.
- the most preferred thickener is hard fat. It is preferably comprised within the range of 1 to 30 weight % of the suspension formulation, most preferably within 10 and 30 weight %.
- the most suitable hard fats have a melting range of 30° C. to 44° C., most preferably a melting range of 33° C. to 40° C.
- Suitable commercially available products are Gelucire® 33/01, Witepsol° W35 or Softisan® 378.
- the determination of the most suitable melting range for hard fats can be performed as shown in FIG. 3 , by measurement of the effect of the melting range of the hard fat on the in-vitro dissolution behaviour over time.
- Lecithin is a common excipient for carrier-systems in soft gelatin capsules. It is used as a glidant of the highly concentrated suspension during encapsulation, prevents blocking of ducts and pumps and ensures high mass uniformity of the encapsulated formulation. Furthermore Lecithin acts as a surfactant, which may improve distribution of the formulation-droplets during in-vitro dissolution testing as well as in-vivo for drug resorption. Furthermore it may also improve wetting of the active substance crystals. Suitable lecithin may be the commercial product Topcithin®.
- the amount of lecithin is comprised within the range of 0.1 to 10 weight % of the lipid suspension formulation, most preferably within 0.25 and 2.5%.
- the present invention relates to a lipid suspension formulation of the active substance 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate, comprising a viscous suspension of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate in medium chain triglycerides, hard fat, lecithin and one or more macrogolglycerols, such as for example macrogolglycerol-hydroxystearate (traded for example under the name Eumulgin® HRE to 40 PH)
- the amount of macrogolglycerol(s) is comprised within the range of 0.1 to 50 weight % of the lipid suspension formulation, most preferably within 0.3 and 10%.
- lipid (lipophilic) suspension formulations comprising a viscous suspension of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate in medium chain triglycerides, hard fat and lecithin are preferred.
- FIG. 4 shows the results of a comparison of the absolute bioavailability (BA in %) tested in the rat over 24 hours for the aqueous solution (S) versus different carrier systems (P1, P2 and P3) of the active substance in accordance with the present invention. The experiment is described in the following.
- Formulation P1 P2 P3 Ingredients [%]* Active Substance 43.48 42.19 31.75 Triglycerides, 37.83 41.77 — Medium-Chain Hard fat 18.26 12.66 — Cremophor RH40 — 2.95 — Lecithin 0.43 0.42 — Glycerol 85% — — 3.17 Purified Water — — 4.76 Macrogol 600 — — 58.10 Macrogol 4000 — — 2.22 *slight deviations of the quantities towards 100 percent may be caused by rounding errors
- the semi-solid suspensions are filled in hard gelatin capsules (Capsugel, no. to Y0303490). Each capsule contains approximately 15 to 20 mg of the formulation.
- the capsules are applied to the rats with a special device similar to gavage. For comparison an aqueous solution containing 0.5% Natrosol 250 FIX is applied via gavage. For calculation of the absolute bioavailability an additional group of rats is dosed intravenously with the compound dissolved in 5% glucose solution (aqueous solution (S)). 5 male Han Wistar rats (strain: CrlGlxBrlHan:WI) are used per group.
- Blood sampling times are 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h post dose and plasma is analysed by a validated HPLC/MS/MS method. From the plasma level time curves areas under the curve (AUC) are calculated by linear trapezoidal rule. Dose normalised AUCs of the oral formulation are divided by dose normalised AUCs of the intravenous formulation for the calculation of the absolute bioavailability. As can be seen from the results of the experiment shown in FIG.
- the bioavailability is similar for the aqueous solution (S: 11%) and the different carrier systems of active substance (P1: 14%, P2: 10% and P3: 10%), however the inter-individual variation (standard deviation of bioavailability) is smaller for the aqueous solution (S) and the carrier system (P1) when compared to the carrier systems (P2) and (P3) (2.8 and 4.1 versus 7.4 and 7.1), indicating a practically complete relative bioavailability for the tested formulations (P1, P2 and P3) versus the solution (S) but a higher variation in the carrier systems (P2) and (P3).
- the present invention further relates to a capsule pharmaceutical dosage form consisting of a capsule shell and a capsule formulation (or capsule filling), characterized in that the capsule formulation (or capsule filling) comprises the lipid suspension formulation as to hereinbefore described.
- the capsule pharmaceutical dosage form may be a soft gelatine capsule, a hard gelatine capsule, or an hydroxypropylmethylcellulose (HPMC) capsule or a polyvinyl alcohol polymer capsule or a pullulan capsule.
- the filled in capsule may further be sealed or banded.
- HPMC hydroxypropylmethylcellulose
- the capsule is a soft gelatin capsule consisting of a capsule shell comprising gelatin, one or more plasticizing agents and optionally further auxiliary materials, and a capsule formulation (or capsule filling), characterized in that the capsule formulation (or capsule filling) comprises the lipid suspension formulation as hereinbefore described.
- the capsule pharmaceutical dosage form according to the invention may be stored in suitable glass containers or in flexible/hard plastic containers, preferably non-PVC materials based, or in plastic (e.g. PVC, PVDC or Aclar®) blisters optionally with an over-packaging of aluminium (aluminium pouch), or in aluminium blisters consisting of e.g a bottom foil of PA/Al/PVC and an aluminium lidding foil, the later providing the highest water protection.
- the containers may be designed so as to provide particular protection for the capsule pharmaceutical dosage form according to the invention, and especially the soft gelatin capsules, e.g. to protect them from light, oxygen or water.
- Flexible plastic containers may contain additional protection, e.g. in the form of an additional aluminium packaging.
- the capsule pharmaceutical dosage form according to the invention may be prepared by conventional methods of producing capsules known from the literature.
- the soft gelatin capsule according to the invention may be prepared by conventional methods of producing soft gelatin capsules known from the literature, such as for example the “rotary die procedure”, described for example in Swarbrick, Boylann, Encyclopedia of pharmaceutical technology, Marcel Dekker, 1990, Vol. 2, pp 269 ff or in Lachmann et al., “The Theory and Practice of Industrial Pharmacy”, 2nd Edition, pages 404-419, 1976, or other procedures, such as those described for example in Emerson R. F. et al., to “Soft gelatin capsule update”, Drug Dev. Ind. Pharm., Vol. 12, No. 8-9, pp. 1133-44, 1986.
- the lipid suspension formulation may be prepared by conventional methods of producing formulations known from the literature, i.e. by mixing the ingredients at a pre-determined temperature in a pre-determined order in order to obtain a homogenized suspension.
- the lipid suspension formulation may be prepared in accordance with the procedure described in Example 10, which is also an object of the present invention
- Lipid suspension formulation of the active substance, finished soft gelatin capsules containing same and packaging materials for the packaging of finished soft gelatin capsules according to the invention are illustrated by the Examples and Figures that follow.
- the Examples serve purely as an illustration and are not to be construed in a limiting capacity.
- the active substance in all the Examples is 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate.
- Formulation A B Ingredients [%]* Active Substance 43.48 43.48 43.48 Triglycerides, 28.70 37.83 38.045 Medium-Chain Hard fat 27.39 18.26 18.26 Lecithin 0.43 0.43 0.215 *slight deviations of the quantities towards 100 percent may be caused by rounding errors
- Packaging materials for the packaging of the soft gelatin capsules of above examples 4 to 8 may be glass containers, flexible/hard plastic containers or PVC/PVDC blisters, optionally within an aluminium pouch, or alu/alu blisters.
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Transplantation (AREA)
- Oncology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP08157748.8 | 2008-06-06 | ||
EP08157748 | 2008-06-06 | ||
PCT/EP2009/056878 WO2009147212A1 (en) | 2008-06-06 | 2009-06-04 | Capsule pharmaceutical dosage form comprising a suspension formulation of an indolinone derivative |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2009/056878 A-371-Of-International WO2009147212A1 (en) | 2008-06-06 | 2009-06-04 | Capsule pharmaceutical dosage form comprising a suspension formulation of an indolinone derivative |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/015,186 Continuation US20140004187A1 (en) | 2008-06-06 | 2013-08-30 | Capsule pharmaceutical dosage form comprising a suspension formulation of an indolinone derivative |
Publications (1)
Publication Number | Publication Date |
---|---|
US20110301177A1 true US20110301177A1 (en) | 2011-12-08 |
Family
ID=40911908
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/995,869 Abandoned US20110301177A1 (en) | 2008-06-06 | 2009-06-04 | Capsule pharmaceutical dosage form comprising a suspension formulation of an indolinone derivative |
US14/015,186 Abandoned US20140004187A1 (en) | 2008-06-06 | 2013-08-30 | Capsule pharmaceutical dosage form comprising a suspension formulation of an indolinone derivative |
US14/877,132 Abandoned US20160022672A1 (en) | 2008-06-06 | 2015-10-07 | Capsule pharmaceutical dosage form comprising a suspension formulation of an indolinone derivative |
US15/204,277 Active 2029-06-07 US9907756B2 (en) | 2008-06-06 | 2016-07-07 | Capsule pharmaceutical dosage form comprising a suspension formulation of an indolinone derivative |
Family Applications After (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/015,186 Abandoned US20140004187A1 (en) | 2008-06-06 | 2013-08-30 | Capsule pharmaceutical dosage form comprising a suspension formulation of an indolinone derivative |
US14/877,132 Abandoned US20160022672A1 (en) | 2008-06-06 | 2015-10-07 | Capsule pharmaceutical dosage form comprising a suspension formulation of an indolinone derivative |
US15/204,277 Active 2029-06-07 US9907756B2 (en) | 2008-06-06 | 2016-07-07 | Capsule pharmaceutical dosage form comprising a suspension formulation of an indolinone derivative |
Country Status (35)
Country | Link |
---|---|
US (4) | US20110301177A1 (pl) |
EP (1) | EP2299987B1 (pl) |
JP (2) | JP5661031B2 (pl) |
KR (2) | KR101725469B1 (pl) |
CN (2) | CN105193720B (pl) |
AR (1) | AR072059A1 (pl) |
AU (1) | AU2009254548B2 (pl) |
BR (1) | BRPI0913434B8 (pl) |
CA (1) | CA2726267C (pl) |
CL (1) | CL2010001279A1 (pl) |
CO (1) | CO6280467A2 (pl) |
CY (1) | CY1120533T1 (pl) |
DK (1) | DK2299987T3 (pl) |
EA (1) | EA029996B1 (pl) |
EC (1) | ECSP10010660A (pl) |
ES (1) | ES2669469T3 (pl) |
HR (1) | HRP20180709T1 (pl) |
HU (1) | HUE039187T2 (pl) |
IL (1) | IL208954A (pl) |
LT (1) | LT2299987T (pl) |
MA (1) | MA32385B1 (pl) |
MX (2) | MX2010013203A (pl) |
MY (1) | MY158930A (pl) |
NO (1) | NO2299987T3 (pl) |
NZ (1) | NZ603162A (pl) |
PE (1) | PE20100254A1 (pl) |
PL (1) | PL2299987T3 (pl) |
PT (1) | PT2299987T (pl) |
RS (1) | RS57142B1 (pl) |
SI (1) | SI2299987T1 (pl) |
TW (1) | TW201002691A (pl) |
UA (1) | UA104590C2 (pl) |
UY (1) | UY31879A (pl) |
WO (1) | WO2009147212A1 (pl) |
ZA (1) | ZA201007636B (pl) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20150209360A1 (en) * | 2014-01-30 | 2015-07-30 | Orbz, Llc | Oral caffeine delivery composition |
US10105323B2 (en) | 2008-06-06 | 2018-10-23 | Boehringer Ingelheim International Gmbh | Pharmaceutical dosage form for immediate release of an indolinone derivative |
US10561630B2 (en) * | 2016-10-25 | 2020-02-18 | Glykon Technologies Group, Llc | Hydroxycitric acid compounds and capsule liquid delivery |
US20210346302A1 (en) * | 2018-10-15 | 2021-11-11 | Cipla Limited | Pharmaceutical Formulation |
US20230158018A1 (en) * | 2018-09-13 | 2023-05-25 | Ftf Pharma Private Limited | Non-aqueous chemotherapeutic suspensions for oral dosage |
Families Citing this family (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EA029996B1 (ru) | 2008-06-06 | 2018-06-29 | Бёрингер Ингельхайм Интернациональ Гмбх | Капсулярная лекарственная форма, содержащая суспензионную композицию производного индолинона |
UA107560C2 (uk) * | 2008-06-06 | 2015-01-26 | Фармацевтична лікарська форма для негайного вивільнення похідної індолінону | |
JO3659B1 (ar) * | 2010-06-02 | 2020-08-27 | Astellas Deutschland Gmbh | أشكال جرعات بينداموستين عن طريق الفم وإستخداماته العلاجية |
NZ603872A (en) * | 2010-06-02 | 2014-07-25 | Astellas Deutschland Gmbh | Oral dosage forms of bendamustine |
GB201020032D0 (en) * | 2010-11-25 | 2011-01-12 | Sigmoid Pharma Ltd | Composition |
WO2014049099A1 (en) | 2012-09-28 | 2014-04-03 | Boehringer Ingelheim International Gmbh | Pharmaceutical combinations comprising dual angiopoietin-2 / dll4 binders and anti-vegf-r agents |
US20140350022A1 (en) | 2013-05-10 | 2014-11-27 | Boehringer Ingelheim International Gmbh | Efficacious treatment of NSCLC and predictive clinical marker of the responsiveness of a tumour to a treatment |
AU2014296032A1 (en) | 2013-07-31 | 2016-03-17 | Windward Pharma, Inc. | Aerosol tyrosine kinase inhibitor compounds and uses thereof |
CN114504562A (zh) * | 2015-03-13 | 2022-05-17 | 江苏豪森药业集团有限公司 | 含有吲哚满酮衍生物混悬液的胶囊制剂及其制备方法 |
CN107019697A (zh) * | 2016-02-02 | 2017-08-08 | 瑞阳(苏州)生物科技有限公司 | 预防或治疗纤维化疾病的药物组合物及其应用 |
CN108066343A (zh) * | 2016-11-08 | 2018-05-25 | 瑞阳(苏州)生物科技有限公司 | 一种预防或治疗肾纤维化疾病的药物 |
WO2018108669A1 (en) | 2016-12-12 | 2018-06-21 | Boehringer Ingelheim International Gmbh | Nintedanib for use in methods for the treatment of interstitial lung diseases by coadministration with olodaterol |
CN110573161A (zh) | 2017-03-28 | 2019-12-13 | 勃林格殷格翰国际有限公司 | 用于治疗肌营养不良的方法的尼达尼布 |
CN107184549B (zh) * | 2017-04-11 | 2020-11-20 | 江苏大学 | 一种尼达尼布自微乳制剂和其制成的软胶囊及制备方法 |
AU2018357775B2 (en) | 2017-10-23 | 2024-02-15 | Boehringer Ingelheim International Gmbh | New combination of active agents for the treatment of progressive fibrosing interstitial lung diseases (PF-ILD) |
WO2019106692A1 (en) * | 2017-11-29 | 2019-06-06 | Sun Pharmaceutical Industries Limited | Oral suspension of nintedanib esylate |
EP4328230A3 (en) | 2018-03-07 | 2024-04-24 | Pliant Therapeutics, Inc. | Amino acid compounds and methods of use |
TWI770624B (zh) | 2018-06-15 | 2022-07-11 | 漢達生技醫藥股份有限公司 | 尼洛替尼十二烷基硫酸鹽在製備用於治療慢性骨髓性白血病之劑型的用途 |
CN112386580B (zh) * | 2019-08-13 | 2022-07-08 | 齐鲁制药有限公司 | 具有改善的溶出度和稳定性的尼达尼布药物制剂、制备方法及其应用 |
KR20220109439A (ko) | 2019-12-04 | 2022-08-04 | 이도르시아 파마슈티컬스 리미티드 | 섬유증 질환의 치료에서 사용하기 위한 아제티딘 lpa1 수용체 길항제와 피르페니돈 및/또는 닌테다닙의 조합 |
US20230135671A1 (en) | 2020-04-01 | 2023-05-04 | Boehringer Ingelheim International Gmbh | Use of biomarkers in the treatment of fibrotic conditions |
EP4098246A1 (en) | 2021-05-31 | 2022-12-07 | Lotus Pharmaceutical Co., Ltd. | Formulation of nintedanib |
WO2023064943A1 (en) * | 2021-10-14 | 2023-04-20 | Pliant Therapeutics, Inc. | Integrin inhibitors and uses thereof in combination with other agents |
CN114404382B (zh) * | 2022-01-24 | 2023-05-12 | 南京康川济医药科技有限公司 | 乙磺酸尼达尼布软胶囊及其制备方法 |
WO2023161668A1 (en) | 2022-02-28 | 2023-08-31 | Nuformix Technologies Limited | Compositions and methods for treatment of idiopathic pulmonary fibrosis |
WO2024037982A1 (en) | 2022-08-16 | 2024-02-22 | Boehringer Ingelheim International Gmbh | Pharmaceutical formulations of nintedanib for intraocular use |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5817323A (en) * | 1993-06-28 | 1998-10-06 | R.P. Scherer Corporation | Soft gelatin capsule shell compositions |
US20060293260A1 (en) * | 2005-05-24 | 2006-12-28 | Wyeth | Useful high load concentrate compositions for control of ecto-and endo-parasites |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2870062A (en) | 1956-04-27 | 1959-01-20 | Scherer Corp R P | Gelatin composition for capsules |
GB8305693D0 (en) | 1983-03-02 | 1983-04-07 | Scherer Ltd R P | Pharmaceutical compositions |
EP0169398B1 (de) | 1984-07-24 | 1990-08-29 | R.P. Scherer GmbH | Oxytetracyclin-HC1-Weichgelatinekapseln und Verfahren zu ihrer Herstellung |
DE19603402A1 (de) | 1995-02-24 | 1996-08-29 | Basf Ag | Weichgelatinekapseln |
US6762180B1 (en) | 1999-10-13 | 2004-07-13 | Boehringer Ingelheim Pharma Kg | Substituted indolines which inhibit receptor tyrosine kinases |
JP2004531537A (ja) * | 2001-05-01 | 2004-10-14 | ファイザー・プロダクツ・インク | 一様な薬剤分布と効力を有する低用量製薬組成物の製造方法 |
DE10233500A1 (de) * | 2002-07-24 | 2004-02-19 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 3-Z-[1-(4-(N-((4-Methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylen]-6-methoxycarbonyl-2-indolinon-Monoethansulfonat und dessen Verwendung als Arzneimittel |
US20050043233A1 (en) | 2003-04-29 | 2005-02-24 | Boehringer Ingelheim International Gmbh | Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells or angiogenesis |
US20060058311A1 (en) * | 2004-08-14 | 2006-03-16 | Boehringer Ingelheim International Gmbh | Combinations for the treatment of diseases involving cell proliferation |
PE20060777A1 (es) * | 2004-12-24 | 2006-10-06 | Boehringer Ingelheim Int | Derivados de indolinona para el tratamiento o la prevencion de enfermedades fibroticas |
PT1948180E (pt) * | 2005-11-11 | 2013-05-10 | Boehringer Ingelheim Int | Tratamento de combinação de cancro compreendendo inibidores de egfr/her2 |
UA107560C2 (uk) | 2008-06-06 | 2015-01-26 | Фармацевтична лікарська форма для негайного вивільнення похідної індолінону | |
EA029996B1 (ru) | 2008-06-06 | 2018-06-29 | Бёрингер Ингельхайм Интернациональ Гмбх | Капсулярная лекарственная форма, содержащая суспензионную композицию производного индолинона |
JP5993573B2 (ja) | 2008-06-06 | 2016-09-14 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 医薬組み合わせ |
EP2387401A1 (en) | 2009-01-14 | 2011-11-23 | Boehringer Ingelheim International GmbH | Method for treating colorectal cancer |
US8802384B2 (en) | 2009-03-12 | 2014-08-12 | Boehringer Ingelheim International Gmbh | Method or system using biomarkers for the monitoring of a treatment |
US20120142703A1 (en) | 2009-05-14 | 2012-06-07 | Boehringer Ingelheim International Gmbh | New combination therapy in treatment of oncological and fibrotic diseases |
-
2009
- 2009-06-04 EA EA201001856A patent/EA029996B1/ru not_active IP Right Cessation
- 2009-06-04 PT PT97575930T patent/PT2299987T/pt unknown
- 2009-06-04 UA UAA201100098A patent/UA104590C2/ru unknown
- 2009-06-04 SI SI200931833T patent/SI2299987T1/en unknown
- 2009-06-04 MX MX2010013203A patent/MX2010013203A/es active IP Right Grant
- 2009-06-04 JP JP2011512128A patent/JP5661031B2/ja active Active
- 2009-06-04 US US12/995,869 patent/US20110301177A1/en not_active Abandoned
- 2009-06-04 CN CN201510660732.8A patent/CN105193720B/zh not_active Ceased
- 2009-06-04 LT LTEP09757593.0T patent/LT2299987T/lt unknown
- 2009-06-04 HU HUE09757593A patent/HUE039187T2/hu unknown
- 2009-06-04 NZ NZ60316209A patent/NZ603162A/en unknown
- 2009-06-04 NO NO09757593A patent/NO2299987T3/no unknown
- 2009-06-04 KR KR1020107027317A patent/KR101725469B1/ko active IP Right Grant
- 2009-06-04 KR KR1020177004310A patent/KR20170020557A/ko not_active Application Discontinuation
- 2009-06-04 AU AU2009254548A patent/AU2009254548B2/en active Active
- 2009-06-04 WO PCT/EP2009/056878 patent/WO2009147212A1/en active Application Filing
- 2009-06-04 CA CA2726267A patent/CA2726267C/en active Active
- 2009-06-04 PE PE2009000782A patent/PE20100254A1/es not_active Application Discontinuation
- 2009-06-04 MY MYPI2010005645A patent/MY158930A/en unknown
- 2009-06-04 CN CN200980121067.8A patent/CN102056598B/zh not_active Ceased
- 2009-06-04 DK DK09757593.0T patent/DK2299987T3/en active
- 2009-06-04 EP EP09757593.0A patent/EP2299987B1/en active Active
- 2009-06-04 RS RS20180491A patent/RS57142B1/sr unknown
- 2009-06-04 BR BRPI0913434A patent/BRPI0913434B8/pt active IP Right Grant
- 2009-06-04 ES ES09757593.0T patent/ES2669469T3/es active Active
- 2009-06-04 PL PL09757593T patent/PL2299987T3/pl unknown
- 2009-06-04 MX MX2014006908A patent/MX359229B/es unknown
- 2009-06-05 TW TW098118825A patent/TW201002691A/zh unknown
- 2009-06-05 AR ARP090102039A patent/AR072059A1/es unknown
- 2009-06-08 UY UY0001031879A patent/UY31879A/es not_active Application Discontinuation
-
2010
- 2010-10-26 ZA ZA2010/07636A patent/ZA201007636B/en unknown
- 2010-10-26 IL IL208954A patent/IL208954A/en active IP Right Grant
- 2010-11-22 CL CL2010001279A patent/CL2010001279A1/es unknown
- 2010-12-03 CO CO10152519A patent/CO6280467A2/es not_active Application Discontinuation
- 2010-12-03 EC EC2010010660A patent/ECSP10010660A/es unknown
- 2010-12-06 MA MA33402A patent/MA32385B1/fr unknown
-
2013
- 2013-08-30 US US14/015,186 patent/US20140004187A1/en not_active Abandoned
-
2014
- 2014-08-11 JP JP2014163667A patent/JP5905542B2/ja active Active
-
2015
- 2015-10-07 US US14/877,132 patent/US20160022672A1/en not_active Abandoned
-
2016
- 2016-07-07 US US15/204,277 patent/US9907756B2/en active Active
-
2018
- 2018-05-07 HR HRP20180709TT patent/HRP20180709T1/hr unknown
- 2018-05-15 CY CY20181100499T patent/CY1120533T1/el unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5817323A (en) * | 1993-06-28 | 1998-10-06 | R.P. Scherer Corporation | Soft gelatin capsule shell compositions |
US20060293260A1 (en) * | 2005-05-24 | 2006-12-28 | Wyeth | Useful high load concentrate compositions for control of ecto-and endo-parasites |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10105323B2 (en) | 2008-06-06 | 2018-10-23 | Boehringer Ingelheim International Gmbh | Pharmaceutical dosage form for immediate release of an indolinone derivative |
US20150209360A1 (en) * | 2014-01-30 | 2015-07-30 | Orbz, Llc | Oral caffeine delivery composition |
US10561630B2 (en) * | 2016-10-25 | 2020-02-18 | Glykon Technologies Group, Llc | Hydroxycitric acid compounds and capsule liquid delivery |
US20230158018A1 (en) * | 2018-09-13 | 2023-05-25 | Ftf Pharma Private Limited | Non-aqueous chemotherapeutic suspensions for oral dosage |
US20210346302A1 (en) * | 2018-10-15 | 2021-11-11 | Cipla Limited | Pharmaceutical Formulation |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9907756B2 (en) | Capsule pharmaceutical dosage form comprising a suspension formulation of an indolinone derivative | |
US20140163040A1 (en) | Pharmaceutical dosage form for immediate release of an indolinone derivative | |
US10105323B2 (en) | Pharmaceutical dosage form for immediate release of an indolinone derivative | |
AU2015227503B2 (en) | Capsule pharmaceutical dosage form comprising a suspension formulation of an indolinone derivative | |
AU2015210331A1 (en) | Pharmaceutical dosage form for immediate release of an indolinone derivative |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: BOEHRINGER INGELHEIM INTERNATIONAL GMBH, GERMANY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MESSERSCHMID, ROMAN;BINDER, RUDOLF;BOCK, THOMAS;AND OTHERS;SIGNING DATES FROM 20110215 TO 20110307;REEL/FRAME:026284/0339 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |