CN111511349A - Pharmaceutical composition for oral administration comprising irinotecan or a pharmaceutically acceptable salt thereof - Google Patents
Pharmaceutical composition for oral administration comprising irinotecan or a pharmaceutically acceptable salt thereof Download PDFInfo
- Publication number
- CN111511349A CN111511349A CN201880082678.5A CN201880082678A CN111511349A CN 111511349 A CN111511349 A CN 111511349A CN 201880082678 A CN201880082678 A CN 201880082678A CN 111511349 A CN111511349 A CN 111511349A
- Authority
- CN
- China
- Prior art keywords
- sorbitan
- irinotecan
- oral administration
- pharmaceutical composition
- weight percent
- 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.)
- Granted
Links
- 229960004768 irinotecan Drugs 0.000 title claims abstract description 70
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 30
- 150000003839 salts Chemical class 0.000 title claims abstract description 28
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound 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 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 title abstract description 69
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 20
- -1 sorbitan ester Chemical class 0.000 claims description 17
- 239000002202 Polyethylene glycol Substances 0.000 claims description 14
- 239000004480 active ingredient Substances 0.000 claims description 14
- 229920001983 poloxamer Polymers 0.000 claims description 14
- 229960000502 poloxamer Drugs 0.000 claims description 14
- 229920001223 polyethylene glycol Polymers 0.000 claims description 14
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 claims description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 9
- RZRNAYUHWVFMIP-HXUWFJFHSA-N glycerol monolinoleate Natural products CCCCCCCCC=CCCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-HXUWFJFHSA-N 0.000 claims description 9
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 claims description 7
- 239000001593 sorbitan monooleate Substances 0.000 claims description 7
- 235000011069 sorbitan monooleate Nutrition 0.000 claims description 7
- 229940035049 sorbitan monooleate Drugs 0.000 claims description 7
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 claims description 6
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 6
- 229920002507 Poloxamer 124 Polymers 0.000 claims description 5
- 239000004615 ingredient Substances 0.000 claims description 5
- 229940093448 poloxamer 124 Drugs 0.000 claims description 5
- 229940068886 polyethylene glycol 300 Drugs 0.000 claims description 5
- 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 claims description 4
- 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 claims description 4
- 125000003696 stearoyl 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])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- CUNWUEBNSZSNRX-RKGWDQTMSA-N (2r,3r,4r,5s)-hexane-1,2,3,4,5,6-hexol;(z)-octadec-9-enoic acid Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O CUNWUEBNSZSNRX-RKGWDQTMSA-N 0.000 claims description 3
- PAFJZWHXMSQJKV-UQZRNVAESA-N (3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol;octadecanoic acid Chemical compound OC[C@@H](O)C1OC[C@H](O)[C@H]1O.OC[C@@H](O)C1OC[C@H](O)[C@H]1O.OC[C@@H](O)C1OC[C@H](O)[C@H]1O.CCCCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O PAFJZWHXMSQJKV-UQZRNVAESA-N 0.000 claims description 3
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 claims description 3
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 claims description 3
- ONJPCDHZCFGTSI-NJYHNNHUSA-N CC(C)CCCCCCCCCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCCCCCCCCCC(C)C)[C@H]1OC[C@H](O)[C@H]1O Chemical compound CC(C)CCCCCCCCCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCCCCCCCCCC(C)C)[C@H]1OC[C@H](O)[C@H]1O ONJPCDHZCFGTSI-NJYHNNHUSA-N 0.000 claims description 3
- 229920002511 Poloxamer 237 Polymers 0.000 claims description 3
- 229920002517 Poloxamer 338 Polymers 0.000 claims description 3
- IYFATESGLOUGBX-YVNJGZBMSA-N Sorbitan monopalmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O IYFATESGLOUGBX-YVNJGZBMSA-N 0.000 claims description 3
- 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 3
- 239000004147 Sorbitan trioleate Substances 0.000 claims description 3
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 claims description 3
- AQKOHYMKBUOXEB-RYNSOKOISA-N [(2R)-2-[(2R,3R,4S)-4-hydroxy-3-(16-methylheptadecanoyloxy)oxolan-2-yl]-2-(16-methylheptadecanoyloxy)ethyl] 16-methylheptadecanoate Chemical compound CC(C)CCCCCCCCCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCCCCCCCCCC(C)C)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCCCCCCCCCC(C)C AQKOHYMKBUOXEB-RYNSOKOISA-N 0.000 claims description 3
- IJCWFDPJFXGQBN-RYNSOKOISA-N [(2R)-2-[(2R,3R,4S)-4-hydroxy-3-octadecanoyloxyoxolan-2-yl]-2-octadecanoyloxyethyl] octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCCCCCCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCCCCCCCCCCCC IJCWFDPJFXGQBN-RYNSOKOISA-N 0.000 claims description 3
- TTZKGYULRVDFJJ-GIVMLJSASA-N [(2r)-2-[(2s,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-[(z)-octadec-9-enoyl]oxyethyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1O TTZKGYULRVDFJJ-GIVMLJSASA-N 0.000 claims description 3
- 229920001993 poloxamer 188 Polymers 0.000 claims description 3
- 229940044519 poloxamer 188 Drugs 0.000 claims description 3
- 229920001992 poloxamer 407 Polymers 0.000 claims description 3
- 229940044476 poloxamer 407 Drugs 0.000 claims description 3
- 229940068918 polyethylene glycol 400 Drugs 0.000 claims description 3
- 229940057847 polyethylene glycol 600 Drugs 0.000 claims description 3
- 229940094543 polyethylene glycol 900 Drugs 0.000 claims description 3
- 229940035044 sorbitan monolaurate Drugs 0.000 claims description 3
- 239000001570 sorbitan monopalmitate Substances 0.000 claims description 3
- 235000011071 sorbitan monopalmitate Nutrition 0.000 claims description 3
- 229940031953 sorbitan monopalmitate Drugs 0.000 claims description 3
- 239000001587 sorbitan monostearate Substances 0.000 claims description 3
- 235000011076 sorbitan monostearate Nutrition 0.000 claims description 3
- 229940035048 sorbitan monostearate Drugs 0.000 claims description 3
- 229960005078 sorbitan sesquioleate Drugs 0.000 claims description 3
- 235000019337 sorbitan trioleate Nutrition 0.000 claims description 3
- 229960000391 sorbitan trioleate Drugs 0.000 claims description 3
- 239000001589 sorbitan tristearate Substances 0.000 claims description 3
- 235000011078 sorbitan tristearate Nutrition 0.000 claims description 3
- 229960004129 sorbitan tristearate Drugs 0.000 claims description 3
- 239000000263 2,3-dihydroxypropyl (Z)-octadec-9-enoate Substances 0.000 claims description 2
- RZRNAYUHWVFMIP-GDCKJWNLSA-N 3-oleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-GDCKJWNLSA-N 0.000 claims description 2
- 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 claims description 2
- RZRNAYUHWVFMIP-UHFFFAOYSA-N monoelaidin Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims 6
- 229960000779 irinotecan hydrochloride Drugs 0.000 claims 1
- 238000002347 injection Methods 0.000 abstract description 5
- 239000007924 injection Substances 0.000 abstract description 5
- 238000001727 in vivo Methods 0.000 abstract description 3
- 230000009885 systemic effect Effects 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 27
- 238000009472 formulation Methods 0.000 description 23
- FJHBVJOVLFPMQE-QFIPXVFZSA-N 7-Ethyl-10-Hydroxy-Camptothecin Chemical compound C1=C(O)C=C2C(CC)=C(CN3C(C4=C([C@@](C(=O)OC4)(O)CC)C=C33)=O)C3=NC2=C1 FJHBVJOVLFPMQE-QFIPXVFZSA-N 0.000 description 13
- WSWCOQWTEOXDQX-MQQKCMAXSA-M (E,E)-sorbate Chemical compound C\C=C\C=C\C([O-])=O WSWCOQWTEOXDQX-MQQKCMAXSA-M 0.000 description 11
- 229940075554 sorbate Drugs 0.000 description 11
- 239000000126 substance Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- 239000012086 standard solution Substances 0.000 description 4
- 102000053602 DNA Human genes 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- 208000015634 Rectal Neoplasms Diseases 0.000 description 3
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 239000002207 metabolite Substances 0.000 description 3
- 206010038038 rectal cancer Diseases 0.000 description 3
- 201000001275 rectum cancer Diseases 0.000 description 3
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 2
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 101710183280 Topoisomerase Proteins 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229940127093 camptothecin Drugs 0.000 description 2
- 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 description 2
- 239000002775 capsule Substances 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 150000001982 diacylglycerols Chemical class 0.000 description 2
- 150000004683 dihydrates Chemical class 0.000 description 2
- 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 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 201000010536 head and neck cancer Diseases 0.000 description 2
- 208000014829 head and neck neoplasm Diseases 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 125000005645 linoleyl group Chemical group 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 150000002759 monoacylglycerols Chemical class 0.000 description 2
- 150000004682 monohydrates Chemical class 0.000 description 2
- 239000006186 oral dosage form Substances 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 150000004684 trihydrates Chemical class 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 102000004308 Carboxylic Ester Hydrolases Human genes 0.000 description 1
- 108090000863 Carboxylic Ester Hydrolases Proteins 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010055114 Colon cancer metastatic Diseases 0.000 description 1
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229920002556 Polyethylene Glycol 300 Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940114081 cinnamate Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- RVPUETSFKVWTTO-UHFFFAOYSA-N methylaminomethanesulfonic acid Chemical compound CNCS(O)(=O)=O RVPUETSFKVWTTO-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-M naphthalene-1-sulfonate Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-M 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- GHBFNMLVSPCDGN-UHFFFAOYSA-N rac-1-monooctanoylglycerol Chemical compound CCCCCCCC(=O)OCC(O)CO GHBFNMLVSPCDGN-UHFFFAOYSA-N 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- CUGZEDSDRBMZMY-UHFFFAOYSA-N trihydrate;hydrochloride Chemical compound O.O.O.Cl CUGZEDSDRBMZMY-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- 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
- A61K47/08—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
- 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
-
- 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
Abstract
The present invention relates to a pharmaceutical composition comprising irinotecan or a pharmaceutically acceptable salt thereof, which can be formulated to effectively administer irinotecan orally and can increase the ease of administration of irinotecan compared with the conventional administration by injection, thereby providing a high in vivo systemic yield.
Description
Technical Field
The present invention relates to a pharmaceutical composition for oral administration comprising irinotecan or a pharmaceutically acceptable salt thereof. Specifically, the present invention relates to a pharmaceutical composition for oral administration, which comprises irinotecan or a pharmaceutically acceptable salt thereof as an active ingredient, and comprises polyethylene glycol, polyoxylglycerides, acylglycerol complex and sorbitan ester.
Background
Irinotecan (irinotecan) can be synthesized from camptothecin (camptothecin) and is an anticancer chemotherapeutic agent mainly applied to metastatic colon cancer or rectal cancer. Irinotecan has the chemical name (S) -4, 11-diethyl-3, 4, 12, 14-tetrahydro-4-hydroxy-3, 14-dioxo-1H-pyrano [3', 4': 6, 7] -indolizino [1, 2-b ] quinolin-9-yl- [1, 4 'bispiperidine ] -1' -carboxylic acid ester having the structure of the following chemical formula 1.
Chemical formula 1:
irinotecan is a topoisomerase I inhibitor that inhibits the action of topoisomerase that plays a role in the replication, gene recombination and transcription of deoxyribonucleic acid (DNA), and is used in cancer treatment or the like for metastatic rectal cancer or colon cancer.
Irinotecan exhibits excellent antitumor activity against a wide variety of tumor models for experiments, and specifically, lung cancer, pancreatic cancer, non-hodgkin's lymphoma, cervical cancer, head and neck cancer, brain tumor, ovarian cancer and the like are being studied (WO 2001/30351).
Irinotecan is a prodrug (produgs) that is metabolized by carboxylesterases in the liver to the active metabolite SN-38. SN-38 is 100-fold to 1000-fold more potent than irinotecan. Irinotecan and its active metabolite SN-38 bind to the topoisomerase I-DNA complex and prevent deoxyribonucleic acid unwinding.
SN-38 has the chemical name "7-Ethyl-10-hydroxycamptothecin" (7-Ethyl-10-hydroxy-camptothecin), and has the structure of the following chemical formula II.
Chemical formula II:
currently, irinotecan is administered intravenously only as an aqueous solution, once a week or once every three weeks for 30 minutes to 90 minutes. Currently, aqueous solutions for intravenous administration (CPT-11) as the hydrochloride trihydrate of irinotecan are available under the trade name
It is commercially available.
The route of administration of this commercially available irinotecan preparation is an intravenous injection administration mode, and has a disadvantage that it requires a long-term visit to a hospital. Today, solid oral dosage forms such as tablet dosage forms can provide great convenience to patients who need to visit a clinic or hospital repeatedly for a long period of time to receive intravenous chemotherapy. The development of oral dosage forms significantly improves the quality of life of patients who need to undergo multiple treatment cycles by preventing the patients from being confined to hospital syringes. In addition, from the pharmacological and economic viewpoints, the medical management cost can be greatly reduced when the drug can be administered by a patient at home.
Therefore, there has been no successful oral preparation at present, although a proposal for improving the convenience of administration and reducing the cost of intravenous administration has been developed by developing an oral preparation which can be self-administered by a patient at home.
The efficacy of irinotecan is dose-and schedule-dependent, and long-term low-dose administration of irinotecan is known to be more efficacious and less toxic than short-term high-dose administration. An effective long-term administration method of irinotecan is oral administration, and when it is administered orally, the metabolic ratio of total SN-38 relative to total irinotecan is higher than that when it is administered intravenously.
However, irinotecan is reported to have a bioavailability as low as 9% when orally administered, and has a disadvantage that it is difficult to formulate it for oral administration as a poorly soluble drug (EP 2328557).
In order to solve these problems, the present inventors attempted to develop a formulation for oral administration comprising irinotecan as an active ingredient, and after orally administering the formulation for oral administration of the present invention to ICR mice, confirmed the in vivo absorption and the like by analyzing the blood concentration of SN-38, which is an active metabolite of irinotecan, and completed the present invention.
Disclosure of Invention
Technical problem
The present invention provides a formulation for oral administration comprising irinotecan or a pharmaceutically acceptable salt thereof. Specifically, a formulation for oral administration is provided by containing irinotecan or a pharmaceutically acceptable salt thereof as an active ingredient, and by a pharmaceutical composition containing polyethylene glycol, polyoxylglyceride, acylglycerol complex and sorbitan ester.
The present invention provides a preparation for oral administration that solves the problem of poorly soluble irinotecan and contains 100% of irinotecan and improves the ease of administration and the bioavailability.
Technical scheme
The invention relates to a pharmaceutical composition, which comprises irinotecan or pharmaceutically acceptable salt thereof as an active ingredient and further comprises additives such as a stabilizing agent, a cosolvent, an excipient, an emulsifier and the like.
Irinotecan of the present invention or a pharmaceutically acceptable salt thereof may be a hydrochloride salt of irinotecan, but is not limited thereto.
And, irinotecan or its pharmaceutically acceptable salt may be a solvate thereof, and the solvate includes hydrates such as monohydrate, dihydrate, trihydrate and the like.
The present invention relates to a pharmaceutical composition for oral administration, which comprises irinotecan or a pharmaceutically acceptable salt thereof as an active ingredient, and comprises polyethylene glycol, a polyoxylglyceride, an acylglycerol complex and sorbitan ester.
The polyethylene glycol may be polyethylene glycol (PEG)300, polyethylene glycol 400, polyethylene glycol 600, or polyethylene glycol 900, but is not limited thereto.
Also, the present invention relates to a pharmaceutical composition for oral administration comprising irinotecan or a pharmaceutically acceptable salt thereof as an active ingredient, and comprising poloxamer, polyoxylglycerides, acylglycerol complexes and sorbitan esters.
The poloxamer is a compound of the following chemical formula III.
Chemical formula III:
the poloxamer may be poloxamer 124 (a-11, b-21), poloxamer 188 (a-70, b-30), poloxamer 217 (a-52, b-35), poloxamer 237 (a-62, b-39), poloxamer 228 (a-97, b-39) poloxamer 338 (a-128, b-54) or poloxamer 407 (a-98, b-67), but is not limited thereto.
The polyoxylglyceride may be caprylocaproyl polyoxylglyceride (caproyl polyoxylglyceride), lauroyl polyoxylglyceride (lauroyl polyoxylglyceride), linoleyl polyoxylglyceride (linoleyl polyoxylglyceride), oleoyl polyoxylglyceride (oleoyl polyoxylglyceride) or stearoyl polyoxylglyceride (stearoyl polyoxylglyceride), but is not limited thereto.
The acylglycerol complex may be glycerol monooleate, glycerol behenate, glycerol stearate or glycerol palmitostearate, but is not limited thereto. Commercially available products such as Capmul GMO, monomuls 90-O18, peceol, and the like can be used.
The acylglycerol complex refers to a complex such as monoacylglycerol, diacylglycerol, triacylglycerol, or the like.
The Sorbitan ester may be, but is not limited to, Sorbitan monostearate (sorbate), Sorbitan diisostearate (sorbate), Sorbitan sesquistearate (sorbate), Sorbitan tristearate (sorbate), Sorbitan triisostearate (sorbate), Sorbitan monooleate (sorbate monooleate), Sorbitan dioleate (sorbate), Sorbitan sesquioleate (sorbate), Sorbitan trioleate (sorbate), or Sorbitan monolaurate (sorbate), Sorbitan monopalmitate (sorbate).
Specifically, the invention relates to a pharmaceutical composition for oral administration, which comprises 0.1 to 10 weight percent of irinotecan or a pharmaceutically acceptable salt thereof, 5 to 40 weight percent of polyethylene glycol, 40 to 80 weight percent of polyoxylglycerides, 5 to 50 weight percent of acylglycerol complex and 5 to 30 weight percent of sorbitan ester, wherein the total weight of the components is less than or equal to 100 weight percent.
Also, the present invention relates to a pharmaceutical composition for oral administration, which comprises 0.1 to 10 weight percent of irinotecan or its pharmaceutically acceptable salt, 5 to 40 weight percent of poloxamer, 40 to 80 weight percent of polyoxylglycerides, 5 to 50 weight percent of acylglycerol complex, and 5 to 30 weight percent of sorbitan ester, wherein the total of the above components is 100 weight percent or less.
ADVANTAGEOUS EFFECTS OF INVENTION
The present invention provides a formulation for oral administration containing 100% irinotecan by solving the problem of poor solubility of irinotecan.
Also, the above-mentioned formulation for oral administration has advantages in that irinotecan, which can be used only as an injection, can be used as an oral formulation by improving the bioavailability of irinotecan, thereby improving the convenience of administration to patients and reducing the cost incurred by administration of injections.
Drawings
Figure 1 is a graph showing pharmacokinetic parameters relating to SN-38 as an active metabolite of irinotecan.
Detailed Description
The present invention provides a pharmaceutical composition for oral administration, comprising irinotecan or a pharmaceutically acceptable salt thereof as an active ingredient, and comprising polyethylene glycol, polyoxylglycerides, acylglycerol complexes and sorbitan esters.
Also, the present invention provides a pharmaceutical composition for oral administration comprising irinotecan or a pharmaceutically acceptable salt thereof as an active ingredient, and comprising poloxamer, polyoxylglycerides, acylglycerol complexes and sorbitan esters.
The term "pharmaceutically acceptable salt" as used above means salts commonly used in the pharmaceutical field, such as, but not limited to, hydrochloride, hydrobromide, hydroiodide, hydrogen fluoride, sulfate, sulfonate, citrate, camphorate, maleate, acetate, lactate, nicotinate, nitrate, succinate, phosphate, malonate, malate, salicylate, phenylacetate, stearate, formate, fumarate, urea, sodium, potassium, calcium, magnesium, zinc, lithium, cinnamate, methylamino, methanesulfonate, picrate, p-toluenesulfonate, naphthalenesulfonate, tartrate, triethylamino, dimethylamino, and tris (hydroxymethyl) aminomethane.
Preferably, irinotecan of the present invention or a pharmaceutically acceptable salt thereof may be the hydrochloride salt of irinotecan.
And, irinotecan or its pharmaceutically acceptable salt may be a solvate thereof, and the solvate includes hydrates such as monohydrate, dihydrate, trihydrate and the like.
The polyethylene glycol may be one or more selected from the group consisting of polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, and polyethylene glycol 900, but is not limited thereto.
The poloxamer may be selected from one or more of poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338 and poloxamer 407, but is not limited thereto.
The polyoxylglyceride may be one or more selected from the group consisting of caprylocaproyl polyoxylglyceride, lauroyl polyoxylglyceride, linoleoyl polyoxylglyceride, oleoyl polyoxylglyceride, and stearoyl polyoxylglyceride, but is not limited thereto.
The acylglycerol complex may be one or more selected from the group consisting of glycerol monooleate, glycerol behenate, glycerol stearate and glycerol palmitostearate, but is not limited thereto.
The acylglycerol complex refers to a complex such as monoacylglycerol, diacylglycerol, triacylglycerol, or the like.
The sorbitan ester may be one or more selected from the group consisting of sorbitan monostearate, sorbitan diisostearate, sorbitan sesquistearate, sorbitan sesquiisostearate, sorbitan tristearate, sorbitan triisostearate, sorbitan monooleate, sorbitan dioleate, sorbitan sesquioleate, sorbitan trioleate, sorbitan monolaurate and sorbitan monopalmitate, but is not limited thereto.
The invention provides a pharmaceutical composition for oral administration, which comprises 0.1 to 10 weight percent of active ingredients, 5 to 40 weight percent of polyethylene glycol, 40 to 80 weight percent of polyoxylglyceride, 5 to 50 weight percent of acylglycerol complex and 5 to 30 weight percent of sorbitan ester, wherein the total weight of the ingredients is less than or equal to 100 weight percent.
Also, the present invention provides a pharmaceutical composition for oral administration, which comprises 0.1 to 10% by weight of an active ingredient, 5 to 40% by weight of poloxamer, 40 to 80% by weight of polyoxylglycerides, 5 to 50% by weight of acylglycerol complex and 5 to 30% by weight of sorbitan ester, and the total of the above ingredients is 100% by weight or less.
Specifically, the present invention provides a pharmaceutical composition for oral administration comprising irinotecan or a pharmaceutically acceptable salt thereof, polyethylene glycol 300, caprylocaproyl polyoxylglyceride, glycerol monooleate, and sorbitan monooleate.
Specifically, the present invention provides a pharmaceutical composition for oral administration comprising irinotecan or a pharmaceutically acceptable salt thereof, poloxamer 124, caprylocaproyl polyoxylglyceride, glycerol monooleate, and sorbitan monooleate.
The above composition for oral administration can be used for the treatment of cancer, but not limited to, various types of cancer, including lung cancer, stomach cancer, pancreatic cancer, non-hodgkin's lymphoma, cervical cancer, head and neck cancer, brain tumor, ovarian cancer, etc. In one embodiment, the above formulation for oral administration can be used for treating colon cancer or rectal cancer.
The composition of the present invention may be formulated into pills, capsules, tablets (including single-layer tablets, double-layer tablets, inner-core tablets, etc.), granules, etc., but is not limited thereto.
The above formulations for oral administration may be administered to mammals, including humans, for any indication of irinotecan or a pharmaceutically acceptable salt thereof.
The above-mentioned formulation for oral administration of the present invention may be prepared according to any method for preparing a solid preparation for oral administration known in the art, specifically, granules, pills, capsules or tablets.
The present invention will be described in more detail with reference to examples. However, these examples are only for illustrative purposes to facilitate understanding of the present invention, and the scope of the present invention is not limited to the following examples.
Examples 1 and 2
Preparation of a formulation for oral administration comprising irinotecan
Pharmaceutical formulations for oral administration containing irinotecan were prepared according to the ingredients and contents of table 1 below.
Irinotecan was completely dissolved in ethanol, and then polyoxylglyceride (L ABRASO L), polyethylene glycol (polyethylene glycol 300), sorbitan ester (span 80), and glycerol monooleate (maisine CC) were added thereto, followed by concentration under reduced pressure at 40 ℃ to prepare the formulation of example 1.
After irinotecan was completely dissolved in ethanol, polyoxylglyceride (L ABRASO L), poloxamer (kollisolv P124), sorbitan ester (span 80), and glycerol monooleate (maisine CC) were added, and then the mixture was concentrated under reduced pressure at 40 ℃.
TABLE 1
Test example 1
Measurement of irinotecan content
The formulations prepared in example 1 and example 2 were measured for irinotecan content.
A certain amount of irinotecan standard substance is taken, a mixed solution of acetonitrile and methanol is used for preparing a standard solution, a certain amount of dosage form is taken, a mixed solution of acetonitrile and methanol is used for preparing a detection solution, and the prepared detection solution and the standard solution are analyzed by using high performance liquid chromatography (HP L C) under the following conditions.
The analysis result value was calculated by the following content calculation formula.
1) Content (%) of irinotecan ═ aT/AS*CS/CT*P
2)AT: irinotecan peak area of detection solution
3)AS: irinotecan peak area of standard solution
4)CS: irinotecan concentration (mg/ml) of standard solution
5)CT: the irinotecan concentration (mg/ml) of the test solution was examined
6) P: purity of the standard
HP L C Shimadzu L C-20AD (Shimadzu L C-20AD)
A detector: ultraviolet ray detector (ultraviolet detector)
Detection wavelength: 255nm
Column 4.6mm × 250mm, 5 μm, C18
Column temperature: 40 deg.C
Injection amount: 15 μ l
From the above analysis results, it was confirmed that the irinotecan content in the formulations of example 1 and example 2 was 99.8% and 100.2%, respectively. Finally, when the components of the formulations of example 1 and example 2 were used, it can be seen that the formulation can be formulated as a formulation for oral administration containing 100% of irinotecan as a main drug.
Test example 2
Evaluation of biological absorption Rate
The formulations of example 1 and example 2 were orally administered to ICR mice (6 weeks old, female) using a gastric Sonde (gastroprobe) at a dose of 70 mg/kg.
After administration, mouse blood was collected by orbital bleeding at 0min, 30 min, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, centrifuged at 6000Xg at 4 ℃ for 20min, and the supernatant was taken and plasma samples were obtained.
To the obtained plasma sample, 100 μ L of potassium phosphate (0.1M, pH 4.2) was added, and the blood concentration of SN-38, which is an active metabolite of irinotecan, was analyzed using a high performance liquid chromatography-fluorescence detector (HP L C-F L D detector).
The in vivo absorption of the formulations prepared in examples 1 and 2 was confirmed by high performance liquid chromatography under the following conditions.
High performance liquid chromatography: agilent 1260(Agilen 1260)
A detector: fluorescence detector (Fluorescence detector)
Detection wavelength: 228(excitation) -543(emission) nm 20min (228(excitation) -543(emission) nmfor 20min) (SN-38)
Column 4.6mm × 250mm, 5 μm, C18
Column temperature: 30 deg.C
Injection amount: 30 μ l
Pharmacokinetic parameters relating to SN-38 as an active metabolite are shown in the following Table 2, and the blood concentration of SN-38 according to time is shown in FIG. 1.
TABLE 2
As shown in the above table 2, it can be seen that Tmax was rapidly absorbed in 1 hour in the formulation of example 1, and had high bioavailability.
Test example 3
Additive ratio confirmation test
The results of the irinotecan content and bioabsorption rate evaluation tests of test example 1 and test example 2 were repeated according to the additive ratio, and excellent results were shown, and the additive ratio is shown in table 3.
TABLE 3
Comparative examples 1 to 5
Formulations containing irinotecan were prepared according to the ingredients and levels of table 4 below.
Irinotecan was completely dissolved in ethanol, and then one excipient selected from polyoxylglyceride (L abrasol), polyethylene glycol (300), sorbitan ester (span 80), glyceryl monooleate (maisine CC), and poloxamer (kollisolv P124) was added thereto, followed by concentration under reduced pressure at 40 ℃ to prepare the formulations of comparative examples 1 to 5, the formulations of comparative examples 1 to 5 all precipitated and were in the form of an opaque solution.
TABLE 4
Finally, it was found that the compositions of comparative examples 1 to 5 were difficult to formulate due to problems such as formation of precipitates.
Claims (12)
1. A pharmaceutical composition for oral administration comprising irinotecan or a pharmaceutically acceptable salt thereof as an active ingredient, and comprising polyethylene glycol, polyoxylglycerides, acylglycerol complexes and sorbitan esters.
2. The pharmaceutical composition for oral administration is characterized by comprising irinotecan or a pharmaceutically acceptable salt thereof as an active ingredient, and further comprising poloxamer, polyoxylglycerides, acylglycerol complexes and sorbitan esters.
3. The pharmaceutical composition for oral administration according to claim 1, wherein the polyethylene glycol is one or more selected from the group consisting of polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600 and polyethylene glycol 900.
4. The pharmaceutical composition for oral administration according to claim 2, wherein the poloxamer is selected from one or more of the group consisting of poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338 and poloxamer 407.
5. The pharmaceutical composition for oral administration according to claim 1 or 2, wherein the polyoxylglyceride is one or more selected from the group consisting of caprylocaproyl polyoxylglyceride, lauroyl polyoxylglyceride, linoleoyl polyoxylglyceride, oleoyl polyoxylglyceride and stearoyl polyoxylglyceride.
6. The pharmaceutical composition for oral administration according to claim 1 or 2, wherein the acylglycerol complex is one or more selected from the group consisting of glycerol monooleate, glycerol behenate, glycerol stearate and glycerol palmitostearate.
7. The pharmaceutical composition for oral administration according to claim 1 or 2, wherein the sorbitan ester is one or more selected from the group consisting of sorbitan monostearate, sorbitan diisostearate, sorbitan sesquistearate, sorbitan tristearate, sorbitan triisostearate, sorbitan monooleate, sorbitan dioleate, sorbitan sesquioleate, sorbitan trioleate, sorbitan monolaurate and sorbitan monopalmitate.
8. The pharmaceutical composition for oral administration according to claim 1 or 2, wherein the pharmaceutically acceptable salt of irinotecan is irinotecan hydrochloride.
9. The pharmaceutical composition for oral administration according to claim 1, comprising 0.1 to 10 weight percent of the active ingredient, 5 to 40 weight percent of polyethylene glycol, 40 to 80 weight percent of polyoxylglyceride, 5 to 50 weight percent of acylglycerol complex and 5 to 30 weight percent of sorbitan ester, and the sum of the above components is 100 weight percent or less.
10. The pharmaceutical composition for oral administration according to claim 2, comprising 0.1 to 10 weight percent of the active ingredient, 5 to 40 weight percent of the poloxamer, 40 to 80 weight percent of the polyoxylglyceride, 5 to 50 weight percent of the acylglycerol complex and 5 to 30 weight percent of the sorbitan ester, the sum of the above ingredients being equal to or less than 100 weight percent.
11. The pharmaceutical composition for oral administration of claim 1, comprising irinotecan or its pharmaceutically acceptable salt, polyethylene glycol 300, caprylocaproyl polyoxylglyceride, glycerol monooleate, and sorbitan monooleate.
12. The pharmaceutical composition for oral administration of claim 2, comprising irinotecan or its pharmaceutically acceptable salt, poloxamer 124, caprylocaproyl polyoxylglyceride, glyceryl monooleate, and sorbitan monooleate.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020170178501A KR102066402B1 (en) | 2017-12-22 | 2017-12-22 | Pharmaceutical composition for oral administration comprising irinotecan or its pharmaceutically acceptable salt |
| KR10-2017-0178501 | 2017-12-22 | ||
| PCT/KR2018/014747 WO2019124789A1 (en) | 2017-12-22 | 2018-11-27 | Pharmaceutical composition containing irinotecan or pharmaceutically acceptable salt thereof for oral administration |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111511349A true CN111511349A (en) | 2020-08-07 |
| CN111511349B CN111511349B (en) | 2024-01-23 |
Family
ID=66994891
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201880082678.5A Active CN111511349B (en) | 2017-12-22 | 2018-11-27 | Pharmaceutical composition for oral administration comprising irinotecan or a pharmaceutically acceptable salt thereof |
Country Status (3)
| Country | Link |
|---|---|
| KR (1) | KR102066402B1 (en) |
| CN (1) | CN111511349B (en) |
| WO (1) | WO2019124789A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR102185475B1 (en) * | 2019-06-20 | 2020-12-02 | 대화제약 주식회사 | Pharmaceutical compositions for oral administration comprising irinotecan free base |
Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1327387A (en) * | 1999-08-10 | 2001-12-19 | 法玛西雅厄普约翰公司 | Pharmaceutical formulations in hydroxypropylmenthyl cellulose capsules |
| CN1382050A (en) * | 1999-10-22 | 2002-11-27 | 法玛西雅意大利公司 | Oral formulations for anti-tumor compounds |
| CN1642958A (en) * | 2002-03-01 | 2005-07-20 | 法玛西雅意大利公司 | Crystalline polymorphic form of irinotecan hydrochloride |
| JP2005255643A (en) * | 2004-03-15 | 2005-09-22 | Masato Kusunoki | Anti-tumor effect-reinforcing method and anti-tumor effect-reinforcing agent |
| US20050208146A1 (en) * | 2003-10-30 | 2005-09-22 | Pfizer Inc | Novel dosage and administration method for oral camptosar |
| CN1960729A (en) * | 2004-06-01 | 2007-05-09 | 泰尔茂株式会社 | Irinotecan preparation |
| US20070299099A1 (en) * | 2004-10-01 | 2007-12-27 | Kabushiki Kaisha Yakult Honsha | Acid Addition Salt of Irinotecan |
| WO2015054390A1 (en) * | 2013-10-08 | 2015-04-16 | Promedior, Inc. | Methods for treating fibrotic cancers |
| WO2016064970A1 (en) * | 2014-10-22 | 2016-04-28 | The Board Of Regents Of The University Of Texas System | Small-molecule inhibitors targeting discoidin domain receptor 1 and uses thereof |
| US20160303102A1 (en) * | 2013-12-05 | 2016-10-20 | Alrise Biosystems Gmbh | Process for the production of drug formulations for oral administration |
| CN106103451A (en) * | 2014-01-17 | 2016-11-09 | 昂科拉制药有限公司 | For treating the solid oral dosage form of the irinotecan of cancer |
| CN107949375A (en) * | 2015-06-30 | 2018-04-20 | 韩美药品株式会社 | Oral solid formulation containing Irinotecan and preparation method thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1620099A1 (en) * | 2003-04-28 | 2006-02-01 | Pharmacia & Upjohn Company LLC | Use of irinotecan for treatment of resistant breast cancer |
| US8637569B2 (en) * | 2009-10-22 | 2014-01-28 | Api Genesis, Llc | Methods of increasing solubility of poorly soluble compounds and methods of making and using formulations of such compounds |
-
2017
- 2017-12-22 KR KR1020170178501A patent/KR102066402B1/en active IP Right Grant
-
2018
- 2018-11-27 CN CN201880082678.5A patent/CN111511349B/en active Active
- 2018-11-27 WO PCT/KR2018/014747 patent/WO2019124789A1/en active Application Filing
Patent Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1327387A (en) * | 1999-08-10 | 2001-12-19 | 法玛西雅厄普约翰公司 | Pharmaceutical formulations in hydroxypropylmenthyl cellulose capsules |
| CN1382050A (en) * | 1999-10-22 | 2002-11-27 | 法玛西雅意大利公司 | Oral formulations for anti-tumor compounds |
| CN1642958A (en) * | 2002-03-01 | 2005-07-20 | 法玛西雅意大利公司 | Crystalline polymorphic form of irinotecan hydrochloride |
| US20050208146A1 (en) * | 2003-10-30 | 2005-09-22 | Pfizer Inc | Novel dosage and administration method for oral camptosar |
| JP2005255643A (en) * | 2004-03-15 | 2005-09-22 | Masato Kusunoki | Anti-tumor effect-reinforcing method and anti-tumor effect-reinforcing agent |
| CN1960729A (en) * | 2004-06-01 | 2007-05-09 | 泰尔茂株式会社 | Irinotecan preparation |
| US20070299099A1 (en) * | 2004-10-01 | 2007-12-27 | Kabushiki Kaisha Yakult Honsha | Acid Addition Salt of Irinotecan |
| WO2015054390A1 (en) * | 2013-10-08 | 2015-04-16 | Promedior, Inc. | Methods for treating fibrotic cancers |
| US20160303102A1 (en) * | 2013-12-05 | 2016-10-20 | Alrise Biosystems Gmbh | Process for the production of drug formulations for oral administration |
| CN106103451A (en) * | 2014-01-17 | 2016-11-09 | 昂科拉制药有限公司 | For treating the solid oral dosage form of the irinotecan of cancer |
| WO2016064970A1 (en) * | 2014-10-22 | 2016-04-28 | The Board Of Regents Of The University Of Texas System | Small-molecule inhibitors targeting discoidin domain receptor 1 and uses thereof |
| CN107949375A (en) * | 2015-06-30 | 2018-04-20 | 韩美药品株式会社 | Oral solid formulation containing Irinotecan and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| LALIT MOHAN NEGI，ETAL: "Nano scale self-emulsifying oil based carrier system for improved oral bioavailability of camptothecin derivative by P-Glycoprotein modulation", 《COLLOIDS SURF B BIOINTERFACES》 * |
| LALIT MOHAN NEGI，ETAL: "Nano scale self-emulsifying oil based carrier system for improved oral bioavailability of camptothecin derivative by P-Glycoprotein modulation", 《COLLOIDS SURF B BIOINTERFACES》, 15 June 2013 (2013-06-15) * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111511349B (en) | 2024-01-23 |
| KR102066402B1 (en) | 2020-01-15 |
| KR20190076585A (en) | 2019-07-02 |
| WO2019124789A1 (en) | 2019-06-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4311369B2 (en) | Stable pharmaceutical composition containing 4,5-epoxymorphinan derivative | |
| US9216175B2 (en) | Sublingual buprenorphine spray | |
| EP2168579B1 (en) | Oral preparation comprising specific organic acid, and method for improvement in dissolution property and chemical stability of oral preparation | |
| EP2310363B1 (en) | Anticancer oral formulation | |
| AU2005291807B2 (en) | Liposomes with improved drug retention for treatment of cancer | |
| JP2005002123A5 (en) | ||
| BRPI0611162A2 (en) | (r) -n-methylnaltrexone, process for its synthesis and pharmaceutical use | |
| KR20210106946A (en) | Solid formulation for for oral administration containing irinotecan and a process for the preparation thereof | |
| US9839611B2 (en) | Sublingual buprenorphine spray | |
| CN111511349B (en) | Pharmaceutical composition for oral administration comprising irinotecan or a pharmaceutically acceptable salt thereof | |
| EP3995134A1 (en) | Micromolecule pi4kiiialpha inhibitor composition, preparation method therefor and use thereof | |
| CN112654626A (en) | Compound and use thereof | |
| CN114796105B (en) | Stable AST-3424 injection preparation and preparation method thereof | |
| KR102185475B1 (en) | Pharmaceutical compositions for oral administration comprising irinotecan free base | |
| WO2019050974A1 (en) | Analgesic formulation for control of pain in dogs | |
| US9867818B2 (en) | Sublingual buprenorphine spray | |
| EP1685137B1 (en) | Particle-forming compositions containing fused pyrrolocarbazoles | |
| US10266499B2 (en) | Imidazole derivatives as prodrugs of diclofenac | |
| CN104470361A (en) | Bioavailability of oral methylnaltrexone increases with a phosphatidylcholine-based formulation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |