CN111511349B - 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
- CN111511349B CN111511349B CN201880082678.5A CN201880082678A CN111511349B CN 111511349 B CN111511349 B CN 111511349B CN 201880082678 A CN201880082678 A CN 201880082678A CN 111511349 B CN111511349 B CN 111511349B
- Authority
- CN
- China
- Prior art keywords
- irinotecan
- sorbitan
- polyoxylglyceride
- oral administration
- pharmaceutically acceptable
- 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.)
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- 229960004768 irinotecan Drugs 0.000 title claims abstract description 69
- 150000003839 salts Chemical class 0.000 title claims abstract description 26
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 22
- 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 70
- 239000000203 mixture Substances 0.000 claims description 26
- -1 sorbitan ester Chemical class 0.000 claims description 24
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 18
- 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 group CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 claims description 10
- RZRNAYUHWVFMIP-HXUWFJFHSA-N glycerol monolinoleate Natural products CCCCCCCCC=CCCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-HXUWFJFHSA-N 0.000 claims description 10
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical group 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
- 229940068886 polyethylene glycol 300 Drugs 0.000 claims description 5
- 229920002507 Poloxamer 124 Polymers 0.000 claims description 4
- 229940093448 poloxamer 124 Drugs 0.000 claims description 4
- GURKHSYORGJETM-WAQYZQTGSA-N irinotecan hydrochloride (anhydrous) Chemical compound Cl.C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 GURKHSYORGJETM-WAQYZQTGSA-N 0.000 claims 4
- 229960000779 irinotecan hydrochloride Drugs 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 12
- 238000002347 injection Methods 0.000 abstract description 5
- 239000007924 injection Substances 0.000 abstract description 5
- 238000010521 absorption reaction Methods 0.000 abstract description 4
- 238000001727 in vivo Methods 0.000 abstract description 3
- 238000009472 formulation Methods 0.000 description 21
- 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 12
- 239000000243 solution Substances 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
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-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
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- 238000001514 detection method Methods 0.000 description 5
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- 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 description 4
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 4
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- 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 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 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 description 3
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- 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
- 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 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 description 3
- 239000004147 Sorbitan trioleate Substances 0.000 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 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 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 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 description 3
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- 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 3
- 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 3
- 230000007774 longterm Effects 0.000 description 3
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- 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 3
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- 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 description 3
- 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 description 2
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 description 2
- 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
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- 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
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 238000000034 method Methods 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
- 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
- 238000001556 precipitation Methods 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
- 239000000600 sorbitol Substances 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
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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Inorganic Chemistry (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a pharmaceutical composition comprising irinotecan or a pharmaceutically acceptable salt thereof, and a preparation of the pharmaceutical composition can effectively orally administer irinotecan, and can increase the administration convenience of irinotecan compared with the existing injection administration, thereby providing high in vivo absorption rate.
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 is characterized by comprising irinotecan or a pharmaceutically acceptable salt thereof as an active ingredient and polyethylene glycol, polyoxylglyceride, an acylglycerol complex and sorbitan ester.
Background
Irinotecan (irinotecan) can be synthesized from 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 '-bipiperidine ] -1' -carboxylic acid ester having the structure according to formula 1.
Chemical formula 1:
irinotecan is a topoisomerase I inhibitor, which 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 of metastatic rectal cancer or colon cancer, etc.
Irinotecan shows excellent antitumor activity against a wide variety of tumor models for experiments, and in particular, lung cancer, pancreatic cancer, non-hodgkin lymphoma, cervical cancer, head and neck cancer, brain tumor, ovarian cancer, and the like are being studied (WO 2001/30351).
Irinotecan is a prodrug that is metabolized by carboxylesterase in the liver to the active metabolite SN-38.SN-38 is 100-1000-fold more potent than irinotecan. Irinotecan and its active metabolite SN-38 bind to the topoisomerase I-DNA complex and prevent deoxyribonucleic acid untangling.
SN-38 has the chemical name "7-Ethyl-10-hydroxycamptothecin", and has the structure of formula II below.
Formula II:
currently irinotecan is only administered intravenously as an aqueous solution, once a week or once every three weeks, for 30 to 90 minutes. Currently, aqueous solutions of hydrochloride trihydrate as irinotecan for intravenous administration of (CPT-11) are under the trade nameAre commercially available.
The route of administration of such commercially available irinotecan formulations is intravenous injection administration, and has a disadvantage in that it requires long-term access to hospitals. Today, solid oral dosage forms such as tablet dosage forms can provide great convenience to patients who need to repeatedly visit a clinic or hospital for a long period of time to receive intravenous chemotherapy administration. 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 constrained by hospital syringes. In addition, from the viewpoints of pharmacology and economy, when the administration is performed at home, the medical administration cost can be greatly reduced.
Therefore, a solution for improving convenience of administration and reducing cost of intravenous administration has been developed by developing an oral preparation that a patient can self-administer at home, but there is no successful oral preparation at present.
The efficacy of irinotecan is dose-and schedule-dependent, and long-term low-dose administration of irinotecan is known to be more effective and less toxic than short-term high-dose administration. An effective long-term administration method of irinotecan is oral administration, when the metabolic proportion of total SN-38 relative to total irinotecan is higher than when administered intravenously.
However, irinotecan has been reported to have a bioavailability as low as 9% when orally administered, and has a disadvantage that it is difficult to formulate irinotecan into an orally administered drug as a poorly soluble drug (EP 2328557).
In order to solve these problems, the present inventors have attempted to develop a preparation for oral administration comprising irinotecan as an active ingredient, and after orally administering the preparation for oral administration of the present invention to ICR mice, the in vivo absorption condition and the like were confirmed by analyzing the blood concentration of SN-38, which is an active metabolite of irinotecan, and the present invention has been completed.
Disclosure of Invention
Technical problem
The present invention provides a formulation for oral administration comprising irinotecan or a pharmaceutically acceptable salt thereof. Specifically, formulations for oral administration are provided by comprising irinotecan or a pharmaceutically acceptable salt thereof as an active ingredient, and by a pharmaceutical composition comprising polyethylene glycol, polyoxyglycerols, acylglycerol complexes, and sorbitan esters.
The present invention provides a preparation for oral administration which solves the problems of poorly soluble irinotecan and contains 100% of irinotecan, and which improves convenience of administration and biological absorptivity.
Technical proposal
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 stabilizer, a cosolvent, an excipient, an emulsifier and the like.
The irinotecan or a pharmaceutically acceptable salt thereof of the present invention may be the hydrochloride salt of irinotecan, but is not limited thereto.
Also, irinotecan or a pharmaceutically acceptable salt thereof may be a solvate thereof, including a hydrate such as a monohydrate, a dihydrate, a trihydrate, and the like.
The present invention relates to a pharmaceutical composition for oral administration, characterized by comprising irinotecan or a pharmaceutically acceptable salt thereof as an active ingredient, and polyethylene glycol, polyoxyglycerate, 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 poloxamer, polyoxylglyceride, acylglycerol complex and sorbitan ester.
The poloxamer is a compound of the following chemical formula III.
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 (caprylocaproyl polyoxylglyceride), lauroyl polyoxylglyceride (lauroyl polyoxylglyceride), linoleoyl polyoxylglyceride (linoleoyl 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. As the commercial products, capmul GMO, monols 90-O18, peceol, etc. can be used.
The acylglycerol complex refers to a complex such as monoacylglycerol, diacylglycerol, or triacylglycerol.
The sorbitan ester may be, but is not limited to, sorbitan monostearate (sorbitan monostearate), sorbitan diisostearate (Sorbitan diisostearate), sorbitan sesquistearate (sorbitan sesquistearate), sorbitan sesquistearate (sorbitan sesquiisostearate), sorbitan tristearate (sorbitan tristearate), sorbitan triisostearate (sorbitan triisostearate), sorbitan monooleate (sorbitan monooleate), sorbitan dioleate (sorbitan dioleate), sorbitan sesquioleate (sorbitan sesquioleate), sorbitan trioleate (sorbitan trioleate), sorbitan monolaurate (sorbitan monolaurate), or sorbitan monopalmitate (sorbitan monopalmitate).
Specifically, the invention relates to a pharmaceutical composition for oral administration, which comprises 0.1 to 10 weight percent of irinotecan or pharmaceutically acceptable salt thereof, 5 to 40 weight percent of polyethylene glycol, 40 to 80 weight percent of polyoxyglyceride, 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 less than or equal to 100 weight percent.
And, the present 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 poloxamer, 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.
ADVANTAGEOUS EFFECTS OF INVENTION
The present invention provides a formulation for oral administration comprising 100% irinotecan by solving the problem of poor solubility of irinotecan.
Also, the above-mentioned preparation for oral administration has an advantage in that irinotecan, which can be used only as an injection, is used as an oral preparation by improving the bioavailability of irinotecan, thereby improving the convenience of administration for patients and reducing the costs due to administration of the injection.
Drawings
FIG. 1 is a graph showing pharmacokinetic parameters for 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 polyethylene glycol, polyoxylglyceride, an acylglycerol complex and sorbitan ester.
The present invention also provides a pharmaceutical composition for oral administration, comprising irinotecan or a pharmaceutically acceptable salt thereof as an active ingredient, and poloxamer, polyoxylglyceride, an acylglycerol complex and sorbitan ester.
The term "pharmaceutically acceptable salt" refers to salts commonly used in the pharmaceutical field, such as, but not limited to, hydrochloride, hydrobromide, hydroiodide, hydrogen fluoride, sulfate, sulfonate, citrate, camphorite, 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, diethylamino, dimethylamino, and tris (hydroxymethyl) aminomethane.
Preferably, irinotecan, or a pharmaceutically acceptable salt thereof, of the present invention can be the hydrochloride salt of irinotecan.
Also, irinotecan or a pharmaceutically acceptable salt thereof may be a solvate thereof, including a hydrate such as a monohydrate, a dihydrate, a 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 one or more selected from the group consisting 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, or triacylglycerol.
The sorbitan ester may be one or more selected from the group consisting of sorbitan monostearate, sorbitan diisostearate, sorbitan sesquistearate, sorbitol 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 ingredient, 5 to 40 weight percent of polyethylene glycol, 40 to 80 weight percent of polyoxyglyceride, 5 to 50 weight percent of acylglycerol complex and 5 to 30 weight percent of sorbitan ester, wherein the sum of the ingredients is less than or equal to 100 weight percent.
The invention also provides a pharmaceutical composition for oral administration, which comprises 0.1 to 10 weight percent of active ingredient, 5 to 40 weight percent of poloxamer, 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 sum of the ingredients is less than or equal to 100 weight percent.
In particular, the 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.
In particular, the 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 compositions for oral administration described above are useful in the treatment of cancer, and are not limited to, the treatment of a variety of different types of cancer, including lung cancer, stomach cancer, pancreatic cancer, non-hodgkin's lymphoma, cervical cancer, head and neck cancer, brain tumor, ovarian cancer, and the like. In one embodiment, the formulations for oral administration described above are useful for treating colon or rectal cancer.
The composition of the present invention may be formulated into pills, capsules, tablets (including single-layer tablets, bilayer tablets, core tablets, etc.), granules, etc., but is not limited thereto.
The formulations for oral administration described above may be administered to mammals, including humans, having any indication of irinotecan or a pharmaceutically acceptable salt thereof.
The above-described preparation for oral administration of the present invention may be prepared according to any preparation method for solid preparation for oral administration known in the art, specifically, granules, pills, capsules or tablets.
The present invention will be further specifically described by way of examples. However, these examples are for illustrative purposes only to aid in understanding the present invention, and the scope of the present invention is not limited to the following examples.
Example 1 and example 2
Preparation of formulations for oral administration comprising irinotecan
Pharmaceutical formulations for oral administration comprising irinotecan were prepared according to the ingredients and contents of table 1 below.
After irinotecan was completely dissolved in ethanol, polyoxylglyceride (LABRASOL), polyethylene glycol (polyethylene glycol 300), sorbitan ester (span 80), glycerol monooleate (maisine CC) was added, and then the formulation of example 1 was prepared by concentration under reduced pressure at 40 ℃. The formulation of example 1 was confirmed to have a clear oily solution dosage form.
Also, after irinotecan was completely dissolved in ethanol, polyoxylglyceride (LABRASOL), poloxamer (kollisolv P124), sorbitan ester (span 80), glycerol monooleate (maisine CC) was added, and then the formulation of example 2 was prepared by concentrating under reduced pressure at 40 ℃. The formulation of example 2 was confirmed to have a clear oily solution formulation.
TABLE 1
Test example 1
Irinotecan content determination
The irinotecan content of the formulations prepared in example 1 and example 2 was determined.
Taking a certain amount of irinotecan standard substance, preparing standard solution by using acetonitrile and methanol mixed solution, taking a certain amount of dosage form, and preparing detection solution by using acetonitrile and methanol mixed solution. The prepared test solution and standard solution were analyzed by High Performance Liquid Chromatography (HPLC) under the following conditions.
The analysis result value is calculated by the following content calculation formula.
1) Irinotecan content (%) =a T /A S *C S /C T *P
2)A T : area of irinotecan Kang Feng of the detection solution
3)A S : area of irinotecan Kang Feng of standard solution
4)C S : irinotecan concentration of standard solution (mg/ml)
5)C T : irinotecan concentration of detection solution (mg/ml)
6) P: purity of standard
HPLC: shimadzu LC-20AD (Shimadzu LC-20 AD)
The detecting instrument comprises: ultraviolet ray detector (ultraviolet detector)
Detection wavelength: 255nm
Column: 4.6mm X250 mm,5 μm, C18
Column temperature: 40 DEG C
Injection amount: 15 μl
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 formulations for oral administration containing 100% irinotecan as the main drug could be formulated.
Test example 2
Biological absorption rate evaluation
The formulations of example 1 and example 2 were orally administered to ICR mice (6 week old, female) using a gastric sonde (gastric sonde) at a dose of 70 mg/kg.
After administration, blood was collected from mice by orbital collection at 0min, 30 min, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, and centrifuged at 6000xg at 4 ℃ for 20min to obtain a supernatant and a plasma sample.
To the obtained plasma sample, 100. Mu.L of potassium phosphate (0.1M, pH 4.2) was added, and the blood concentration of SN-38 as an active metabolite of irinotecan was analyzed using a high performance liquid chromatography-fluorescence detector (HPLC-FLD detector).
The in vivo absorption of the dosage forms prepared in example 1 and example 2 was confirmed by high performance liquid chromatography under the following conditions.
High performance liquid chromatography: agilent 1260 (Agilen 1260)
The detecting instrument comprises: fluorescent detector (Fluorescence detector)
Detection wavelength: 228 (excitation) -543 (emission) nm 20min (228 (excitation) -543 (emission) nm for 20 min) (SN-38)
Column: 4.6mm X250 mm,5 μm, C18
Column temperature: 30 DEG C
Injection amount: 30 μl
The pharmacokinetic parameters for SN-38 as an active metabolite are shown in Table 2 below, and the blood concentration of SN-38 as a function of time is shown in FIG. 1.
TABLE 2
As shown in table 2 above, it can be seen that Tmax is rapidly absorbed at 1 hour and has high bioavailability in the formulation of example 1.
Test example 3
Additive ratio confirmation test
The results of the irinotecan content and bioabsorption rate evaluation tests of test examples 1 and 2 were repeatedly performed according to the proportion of the additive, showing excellent results, and the proportion of the additive is shown in table 3.
TABLE 3 Table 3
Comparative examples 1 to 5
Formulations comprising irinotecan were prepared according to the ingredients and amounts of table 4 below.
After irinotecan was completely dissolved in ethanol, one excipient selected from the group consisting of polyoxyl glyceride (Labrasol), polyethylene glycol (polyethylene glycol 300), sorbitan ester (span 80), glycerol monooleate (main CC), poloxamer (kollisolv P124) was added, and then the formulations of comparative examples 1 to 5 were prepared by concentration under reduced pressure at 40 ℃. The formulations of comparative examples 1 to 5 all produced precipitates in the form of opaque solutions.
TABLE 4 Table 4
Finally, it was found that the compositions of comparative examples 1 to 5 were difficult to prepare due to problems such as precipitation.
Claims (3)
1. A pharmaceutical composition for oral administration, characterized by comprising irinotecan or a pharmaceutically acceptable salt thereof as an active ingredient and polyethylene glycol, polyoxylglyceride, an acylglycerol complex and sorbitan ester,
wherein the composition comprises 0.1-10 wt% of active ingredient, 5-40 wt% of polyethylene glycol, 40-80 wt% of polyoxyglyceride, 5-50 wt% of acylglycerol complex and 5-30 wt% of sorbitan ester, the sum of the components is less than or equal to 100 wt%,
wherein the polyethylene glycol is polyethylene glycol 300,
wherein the polyoxylglyceride is caprylocaproyl polyoxylglyceride,
wherein the acylglycerol complex is glycerol monooleate,
wherein the sorbitan ester is sorbitan monooleate.
2. A pharmaceutical composition for oral administration, which comprises irinotecan or a pharmaceutically acceptable salt thereof as an active ingredient and comprises poloxamer, polyoxylglyceride, an acylglycerol complex and sorbitan ester,
wherein the composition comprises 0.1-10 wt% of active ingredient, 5-40 wt% of poloxamer, 40-80 wt% of polyoxylglyceride, 5-50 wt% of acylglycerol complex and 5-30 wt% of sorbitan ester, the sum of all components is less than or equal to 100 wt%,
wherein the poloxamer is poloxamer 124,
wherein the polyoxylglyceride is caprylocaproyl polyoxylglyceride,
wherein the acylglycerol complex is glycerol monooleate,
wherein the sorbitan ester is sorbitan monooleate.
3. The pharmaceutical composition for oral administration according to claim 1 or 2, wherein the pharmaceutically acceptable salt of irinotecan is irinotecan hydrochloride.
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 |
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| CN111511349A CN111511349A (en) | 2020-08-07 |
| CN111511349B true CN111511349B (en) | 2024-01-23 |
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Country Status (3)
| Country | Link |
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| KR (1) | KR102066402B1 (en) |
| CN (1) | CN111511349B (en) |
| WO (1) | WO2019124789A1 (en) |
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| KR102185475B1 (en) * | 2019-06-20 | 2020-12-02 | 대화제약 주식회사 | Pharmaceutical compositions for oral administration comprising irinotecan free base |
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| Publication number | Publication date |
|---|---|
| KR20190076585A (en) | 2019-07-02 |
| KR102066402B1 (en) | 2020-01-15 |
| CN111511349A (en) | 2020-08-07 |
| WO2019124789A1 (en) | 2019-06-27 |
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