JP2022032754A - Ionic liquid having p-boronophenylalanine as component - Google Patents
Ionic liquid having p-boronophenylalanine as component Download PDFInfo
- Publication number
- JP2022032754A JP2022032754A JP2020136911A JP2020136911A JP2022032754A JP 2022032754 A JP2022032754 A JP 2022032754A JP 2020136911 A JP2020136911 A JP 2020136911A JP 2020136911 A JP2020136911 A JP 2020136911A JP 2022032754 A JP2022032754 A JP 2022032754A
- Authority
- JP
- Japan
- Prior art keywords
- boronophenylalanine
- ionic liquid
- pharmaceutical composition
- liquid
- meglumine
- 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
- NFIVJOSXJDORSP-QMMMGPOBSA-N (2s)-2-amino-3-(4-boronophenyl)propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(B(O)O)C=C1 NFIVJOSXJDORSP-QMMMGPOBSA-N 0.000 title claims abstract description 95
- 239000002608 ionic liquid Substances 0.000 title claims abstract description 48
- 239000007788 liquid Substances 0.000 claims abstract description 45
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 30
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 5
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 36
- 229960003194 meglumine Drugs 0.000 claims description 30
- 239000004480 active ingredient Substances 0.000 claims description 12
- 150000001768 cations Chemical class 0.000 claims description 8
- 206010028980 Neoplasm Diseases 0.000 claims description 7
- 238000001959 radiotherapy Methods 0.000 claims description 7
- 239000003623 enhancer Substances 0.000 claims description 6
- 150000001450 anions Chemical class 0.000 claims description 5
- 238000002059 diagnostic imaging Methods 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 3
- 238000000034 method Methods 0.000 description 22
- 239000000203 mixture Substances 0.000 description 15
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 229910052796 boron Inorganic materials 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- -1 D-form Chemical compound 0.000 description 7
- 239000000654 additive Substances 0.000 description 7
- 235000002639 sodium chloride Nutrition 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 229930091371 Fructose Natural products 0.000 description 5
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 5
- 239000005715 Fructose Substances 0.000 description 5
- 230000000996 additive effect Effects 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 4
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 4
- 239000000470 constituent Substances 0.000 description 4
- 235000011187 glycerol Nutrition 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
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- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 4
- 239000003002 pH adjusting agent Substances 0.000 description 4
- 239000002504 physiological saline solution Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 239000004359 castor oil Substances 0.000 description 3
- 235000019438 castor oil Nutrition 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
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- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
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- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- 239000012901 Milli-Q water Substances 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 2
- 235000010724 Wisteria floribunda Nutrition 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229960004926 chlorobutanol Drugs 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 235000001727 glucose Nutrition 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
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- 229910017053 inorganic salt Inorganic materials 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 2
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 2
- 229960002216 methylparaben Drugs 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229940127557 pharmaceutical product Drugs 0.000 description 2
- 229960003742 phenol Drugs 0.000 description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 239000001103 potassium chloride Substances 0.000 description 2
- 235000011164 potassium chloride Nutrition 0.000 description 2
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 2
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 2
- 229960003415 propylparaben Drugs 0.000 description 2
- 235000010413 sodium alginate Nutrition 0.000 description 2
- 239000000661 sodium alginate Substances 0.000 description 2
- 229940005550 sodium alginate Drugs 0.000 description 2
- 229910001415 sodium ion Inorganic materials 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- COKATDACLNKLCL-QMMMGPOBSA-N (2s)-2-[borono(fluoro)amino]-3-phenylpropanoic acid Chemical compound OB(O)N(F)[C@H](C(O)=O)CC1=CC=CC=C1 COKATDACLNKLCL-QMMMGPOBSA-N 0.000 description 1
- CRVYPNHLIAWRNV-UHFFFAOYSA-N 2,4,6-triiodobenzoic acid Chemical group OC(=O)C1=C(I)C=C(I)C=C1I CRVYPNHLIAWRNV-UHFFFAOYSA-N 0.000 description 1
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 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
- RAXXELZNTBOGNW-UHFFFAOYSA-O Imidazolium Chemical compound C1=C[NH+]=CN1 RAXXELZNTBOGNW-UHFFFAOYSA-O 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-O Pyrazolium Chemical compound C1=CN[NH+]=C1 WTKZEGDFNFYCGP-UHFFFAOYSA-O 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-O Pyrrolidinium ion Chemical compound C1CC[NH2+]C1 RWRDLPDLKQPQOW-UHFFFAOYSA-O 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- ABBQHOQBGMUPJH-UHFFFAOYSA-M Sodium salicylate Chemical compound [Na+].OC1=CC=CC=C1C([O-])=O ABBQHOQBGMUPJH-UHFFFAOYSA-M 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
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- 239000003125 aqueous solvent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
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- 201000011510 cancer Diseases 0.000 description 1
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
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- 239000001307 helium Substances 0.000 description 1
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
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- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
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- RWSOTUBLDIXVET-UHFFFAOYSA-O sulfonium Chemical compound [SH3+] RWSOTUBLDIXVET-UHFFFAOYSA-O 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
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- 210000001519 tissue Anatomy 0.000 description 1
- 239000012929 tonicity agent Substances 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nuclear Medicine (AREA)
Abstract
Description
特許法第３０条第２項適用申請有り １．刊行物名：第１６回日本中性子捕捉療法学会学術大会プログラム・抄録集 発行日 ：２０１９年８月１５日 ２．研究集会名：第１６回日本中性子捕捉療法学会学術大会 開催日 ：２０１９年９月７日 開催場所：京都大学キャンパス宇治おうばくプラザThere is an application for application of Article 30,
本発明は、イオン液体とp－ボロノフェニルアラニンを含む放射線治療に用いる増強剤、p－ボロノフェニルアラニンの体内分布をＰＥＴで画像化するための標識化剤、高濃度のp－ボロノフェニルアラニンを溶解した医薬品原料に関する。 The present invention comprises an ionic liquid and a enhancer used for radiotherapy containing p-boronophenylalanine, a labeling agent for imaging the distribution of p-boronophenylalanine in the body with PET, and a high concentration of p-boronophenylalanine. Regarding dissolved pharmaceutical raw materials.
癌のホウ素中性子捕捉療法（以下「ＢＮＣＴ」ともいう。）は、あらかじめ腫瘍組織に取り込ませた１０Ｂ核と生体にほぼ影響を及ばさない熱中性子線の捕捉反応によって生じるα粒子および７Ｌｉ粒子によって腫瘍細胞を障害する放射線療法である。ＢＮＣＴに用いる薬剤としてｐ－ボロノフェニルアラニンが知られており、既に臨床でも用いられている。 Boron neutron capture therapy of cancer (hereinafter also referred to as "BNCT") is an alpha particle and 7 Li particle generated by the capture reaction of 10B nuclei previously incorporated into tumor tissue and thermal neutrons that have almost no effect on the living body. It is a radiation therapy that damages tumor cells. P-boronophenylalanine is known as a drug used for BNCT and has already been used clinically.
しかしながら、p－ボロノフェニルアラニンは、生理的ｐＨでの溶解性が極めて乏しく、実用上の大きな問題となっている。このため、p－ボロノフェニルアラニンの溶解を促進させるために、p－ボロノフェニルアラニンのフルクトース錯体を形成させる方法（特許文献１）、ｐ－ボロノフェニルアラニンにアルカリ溶液中で、単糖またはポリオールを添加し、イオン交換樹脂により無機塩を除去する方法（特許文献２）、ソルビトールを添加する方法（特許文献３）、メグルミンを溶解剤として用いる方法（特許文献４）が知られている。 However, p-boronophenylalanine has extremely poor solubility at physiological pH, which poses a major practical problem. Therefore, in order to promote the dissolution of p-boronophenylalanine, a method for forming a fructose complex of p-boronophenylalanine (Patent Document 1), a monosaccharide or a polyol is added to p-boronophenylalanine in an alkaline solution. A method of adding and removing an inorganic salt with an ion exchange resin (Patent Document 2), a method of adding sorbitol (Patent Document 3), and a method of using meglumin as a solubilizer (Patent Document 4) are known.
しかしながら、特許文献１記載の方法はp－ボロノフェニルアラニンフルクトース錯体の水溶性は不十分であり、例えば体重６０ｋｇの患者用にp－ボロノフェニルアラニンの３０ｇ相当量を室温でフルクトースとの錯体水溶液として調製すると、溶液量は少なくとも１．２Ｌ程度と、極めて大きな液量を必要とし実用上問題がある。また、フルクトース錯体法と比較して、特許文献３記載のソルビトール法では溶解度はあまり向上せず、特許文献２記載のポリオールを添加し、イオン交換樹脂により無機塩を除去する方法もフルクトース錯体法の４倍程度しか溶解度が向上していない。また、特許文献２の方法は操作が煩雑であり実用に適しておらず、特許文献１の方法は細胞毒性の点で問題があった。更に、特許文献４に記載されている方法により得られるp－ボロノフェニルアラニンの濃度の具体例は１０．４％程度であり（特許文献４、表３）実用上十分とは言えなかった。
However, the method described in
２０００年以降、イオン液体は触媒、電気化学等の分野で用いられるようになり、製剤分野では経皮吸収促進等の目的で用いられている（非特許文献１）。また、難溶性薬物の溶解法として、メグルミン、脂肪酸、エタノールの混合物を用いた難溶性薬物の溶解方法が知られている（特許文献５）。 Since 2000, ionic liquids have been used in fields such as catalysts and electrochemicals, and have been used in the pharmaceutical field for the purpose of promoting percutaneous absorption (Non-Patent Document 1). Further, as a method for dissolving a poorly soluble drug, a method for dissolving a poorly soluble drug using a mixture of meglumine, fatty acid and ethanol is known (Patent Document 5).
しかしながら、ホウ素製剤の有効成分をイオン液体の構成成分とする手法は、全く知られていない。 However, no method is known in which the active ingredient of the boron preparation is used as a constituent component of the ionic liquid.
本発明は、ＢＮＣＴ療法に好適な高濃度のｐ－ボロノフェニルアラニンを含有する液状組成物を提供することを目的とする。 An object of the present invention is to provide a liquid composition containing a high concentration of p-boronophenylalanine suitable for BNCT therapy.
本発明は、
〔１〕ｐ－ボロノフェニルアラニンからなるイオン液体、
〔２〕〔１〕記載のイオン液体において、アニオンがｐ－ボロノフェニルアラニンであり、カチオンがメグルミンであることを特徴とするイオン液体、
〔３〕〔１〕または〔２〕記載のイオン液体を含むことを特徴とする液状医薬組成物、
〔４〕メグルミンのｐ－ボロノフェニルアラニンに対する割合が、モル比で１以下であることを特徴とする〔３〕記載の液状医薬組成物、
〔５〕ｐ－ボロノフェニルアラニンを１５～５０％含むことを特徴とする〔３〕または〔４〕記載の液状医薬組成物、
〔６〕ｐ－ボロノフェニルアラニンを３０～４５％含むことを特徴とする〔３〕または〔４〕記載の液状医薬組成物、
〔７〕〔３〕から〔６〕のいずれかひとつに記載の液状医薬組成物を有効成分として含むことを特徴とする腫瘍の放射線治療に用いる増強剤、
〔８〕放射線治療が、中性子捕捉療法であることを特徴とする〔７〕記載の増強剤および、
〔９〕ＰＥＴによる画像診断に用いることを特徴とする〔３〕から〔６〕のいずれかひとつ記載の液状医薬組成物に関する。
The present invention
[1] An ionic liquid composed of p-boronophenylalanine,
[2] In the ionic liquid according to [1], the ionic liquid characterized in that the anion is p-boronophenylalanine and the cation is meglumine.
[3] A liquid pharmaceutical composition comprising the ionic liquid according to [1] or [2].
[4] The liquid pharmaceutical composition according to [3], wherein the ratio of meglumine to p-boronophenylalanine is 1 or less in terms of molar ratio.
[5] The liquid pharmaceutical composition according to [3] or [4], which contains 15 to 50% of p-boronophenylalanine.
[6] The liquid pharmaceutical composition according to [3] or [4], which contains 30 to 45% of p-boronophenylalanine.
[7] An enhancer used for radiotherapy of a tumor, which comprises the liquid pharmaceutical composition according to any one of [3] to [6] as an active ingredient.
[8] The enhancer according to [7], wherein the radiotherapy is a neutron capture therapy.
[9] The present invention relates to the liquid pharmaceutical composition according to any one of [3] to [6], which is used for diagnostic imaging by PET.
本発明におけるｐ－ボロノフェニルアラニンからなるイオン液体とは、ｐ－ボロノフェニルアラニンが単独または他のカチオンと共にイオン液体を構成している液体を示す。 The ionic liquid composed of p-boronophenylalanine in the present invention refers to a liquid in which p-boronophenylalanine alone or together with other cations constitutes an ionic liquid.
本発明に使用するｐ－ボロノフェニルアラニンは、フェニルアラニンをホウ素(10Ｂ)で標識したボロノフェニルアラニン(略称：ＢＰＡ)（化１）であればどのようなものでも良い。 The p-boronophenylalanine used in the present invention may be any boronophenylalanine (abbreviation: BPA) (formation 1) in which phenylalanine is labeled with boron ( 10 B).
また、イオン液体を構成し得るアニオン基またはカチオン基が保持される構造を維持するものであればボロノフェニルアラニンの誘導体も含まれる。ボロノフェニルアラニンの誘導体としては、p－ボロノフェニルアラニンの体内分布をＰＥＴで画像化するために、p－ボロノフェニルアラニンを放射性核種18Ｆで標識した化合物フルオロボロノフェニルアラニン(ＦＰ－ボロノフェニルアラニン)等が含まれる。
ｐ－ボロノフェニルアラニンの光学異性体としては、Ｌ－体，Ｄ－体，Ｌ－体およびＤ－体のジアステレオマーのどのようなものでも良いが、とりわけＬ－体が好ましい。
In addition, a derivative of boronophenylalanine is also included as long as it maintains a structure in which an anionic group or a cationic group that can constitute an ionic liquid is retained. As a derivative of boronophenylalanine, a compound fluoroboronophenylalanine (FP-boronophenylalanine) in which p-boronophenylalanine is labeled with a radionuclide 18F in order to image the distribution of p-boronophenylalanine in the body by PET. Etc. are included.
The optical isomer of p-boronophenylalanine may be any of L-form, D-form, L-form and D-form diastereomers, but L-form is particularly preferable.
メグルミンとは、以下の構造を持つソルビトールから誘導されたアミノ糖であり、可溶化剤、溶解補助剤等として日本薬局方に収載された医薬品添加物である。配合薬の賦形剤としても用いられるが、２，４，６－トリヨード安息香酸部分を有する有機ヨウ素造影剤を中和し溶解させる溶解剤として用いられている。 Meglumine is an amino sugar derived from sorbitol having the following structure, and is a pharmaceutical additive listed in the Japanese Pharmacopoeia as a solubilizer, a solubilizing agent, and the like. It is also used as an excipient for combination drugs, but it is also used as a solubilizer that neutralizes and dissolves an organoiodine contrast agent having a 2,4,6-triiodobenzoic acid moiety.
本発明におけるイオン液体とは、幅広い温度範囲で液体として存在する塩であり、イオンのみからなる液体を示す。イオン液体のカチオンとしては、アンモニウム、イミダゾリウム、コリン、スルホニウム、ピラゾリウム、ピリジニウム、ピロリジニウム、ホスホニウムが挙げられ、そのカチオンに組み合わされるアニオンとしては、ＣＯＯ－、ＣＨ３ＣＯＯ－，ＣＦ３ＣＯＯ－，ＮＯ３ －，Ｂｒ－，Ｃｌ－等が挙げられ、これは例えばp－ボロノフェニルアラニンの中に内在する官能基であっても良い。p－ボロノフェニルアラニン単独でイオン液体を構成する場合は、p－ボロノフェニルアラニン分子内のアンモニア基がカチオンとして作用するとともにカルボキシ基がアニオンとして作用する。 The ionic liquid in the present invention is a salt that exists as a liquid in a wide temperature range, and indicates a liquid consisting only of ions. Examples of the cation of the ionic liquid include ammonium, imidazolium, choline, sulfonium, pyrazolium, pyridinium, pyrrolidinium, and phosphonium, and examples of anions combined with the cation include COO − , CH 3 COO − , CF 3 COO − , NO. Examples thereof include 3- , Br-, Cl- , etc., which may be, for example, a functional group contained in p - boronophenylalanine. When p-boronophenylalanine alone constitutes an ionic liquid, the ammonia group in the p-boronophenylalanine molecule acts as a cation and the carboxy group acts as an anion.
メグルミン等カチオンをp－ボロノフェニルアラニンと混合して用いる場合は、p－ボロノフェニルアラニンはアニオンとしてイオン液体の構成に関与する。p－ボロノフェニルアラニンと混合してイオン液体を構成するカチオンとしては、メグルミンの他にコリン・アルギニン・ヒスチジン等が挙げられる。 When a cation such as meglumine is mixed with p-boronophenylalanine, p-boronophenylalanine is involved in the composition of the ionic liquid as an anion. Examples of the cation mixed with p-boronophenylalanine to form an ionic liquid include choline, arginine, histidine and the like in addition to meglumine.
本発明における液状医薬組成物とはｐ－ボロノフェニルアラニンから構成されるイオン液体を含む液体状組成物であって、ｐ－ボロノフェニルアラニンを有効成分とする液状医薬組成物を示す。ｐ－ボロノフェニルアラニンを有効成分とする液状医薬組成物とは、ｐ－ボロノフェニルアラニンの腫瘍細胞への集積性を利用し、ホウ素(10Ｂ)と熱中性子との核反応で生じる高ＬＥＴ放射線のα粒子(ヘリウムイオン)を用いて癌細胞のみを破壊する効果を主薬効とする液体状の医薬組成物を示す。 The liquid pharmaceutical composition in the present invention is a liquid composition containing an ionic liquid composed of p-boronophenylalanine, and shows a liquid pharmaceutical composition containing p-boronophenylalanine as an active ingredient. A liquid pharmaceutical composition containing p-boronophenylalanine as an active ingredient is a high-LET radiation generated by a nuclear reaction between boron ( 10 B) and thermal neutrons by utilizing the accumulation of p-boronophenylalanine in tumor cells. The present invention shows a liquid pharmaceutical composition having the effect of destroying only cancer cells by using α particles (helium ion) of the above.
液状医薬組成物中のｐ－ボロノフェニルアラニンの濃度は、液状組成物中のｖ／ｗ濃度として、１５～５０％、好ましくは２０～５０％、更に好ましくは３０～５０％、とりわけ好ましくは３０～４５％である。当該濃度をｐｐｍとして換算すると７２００ｐｐｍ～２４０００ｐｐｍ、好ましくは９６００ｐｐｍ～２４０００ｐｐｍ、更に好ましくは１４０００ｐｐｍ～２１０００ｐｐｍ、とりわけ好ましくは１６０００ｐｐｍ～２１０００ｐｐｍである。
本発明のメグルミンのｐ－ボロノフェニルアラニンに対する割合は、モル比で１以下、好ましくは１～０．７、とりわけ好ましくは０．８未満であって０．７以上である。
The concentration of p-boronophenylalanine in the liquid pharmaceutical composition is 15 to 50%, preferably 20 to 50%, more preferably 30 to 50%, and particularly preferably 30 as the v / w concentration in the liquid composition. It is ~ 45%. When the concentration is converted into ppm, it is 7200 ppm to 24000 ppm, preferably 9600 ppm to 24000 ppm, more preferably 14000 ppm to 21000 ppm, and particularly preferably 16000 ppm to 21000 ppm.
The ratio of meglumine to p-boronophenylalanine of the present invention is 1 or less, preferably 1 to 0.7, and particularly preferably less than 0.8 and 0.7 or more in terms of molar ratio.
本発明の液状組成物のｐＨは、生体への投与を考慮して、中性付近のｐＨであることが好ましい。より具体的には、６．５から７．５の範囲であり、特に好ましくは７．４付近である。ｐＨの調節には必要に応じて、当該技術分野で用いられる適当なｐＨ調整剤（塩酸、炭酸水素ナトリウムなど）、緩衝剤などを使用してもよい。 The pH of the liquid composition of the present invention is preferably near neutral in consideration of administration to a living body. More specifically, it is in the range of 6.5 to 7.5, and particularly preferably around 7.4. If necessary, an appropriate pH adjuster (hydrochloric acid, sodium hydrogencarbonate, etc.), a buffer, or the like used in the art may be used for adjusting the pH.
本発明の液状組成物の浸透圧比は特に限定されないが、生理食塩水対比で、１から２までの範囲内にあることが好ましい。より好ましくは、１．１から１．４の範囲である。この範囲にある場合には、注射剤の場合、痛みの軽減や投与時間の短縮が可能になる。 The osmotic pressure ratio of the liquid composition of the present invention is not particularly limited, but it is preferably in the range of 1 to 2 in comparison with physiological saline. More preferably, it is in the range of 1.1 to 1.4. Within this range, injectables can reduce pain and shorten administration time.
本発明の液状組成物中には、その生体内外での安定性を高めるため、必要により生体に含まれるナトリウム、マグネシウム等各種金属イオンが含まれていてもよい。ナトリウムイオンの場合その濃度は、細胞内液と細胞外液の電解質バランスが大きく崩れないように体液のナトリウムイオン濃度範囲に近い数値範囲であることが好ましい。 The liquid composition of the present invention may contain various metal ions such as sodium and magnesium contained in the living body, if necessary, in order to enhance the stability in and out of the living body. In the case of sodium ion, the concentration is preferably in a numerical range close to the sodium ion concentration range of the body fluid so that the electrolyte balance between the intracellular fluid and the extracellular fluid is not significantly disturbed.
本発明の液状組成物には、必要に応じて、リン酸緩衝液、トリス塩酸緩衝液、酢酸緩衝液、炭酸緩衝液、クエン酸緩衝液等の緩衝剤を加えてもよい。これらの緩衝剤は、製剤の安定化や刺激性の低下に有用な場合がある。 If necessary, a buffering agent such as a phosphate buffer solution, a Tris hydrochloric acid buffer solution, an acetate buffer solution, a carbonic acid buffer solution, or a citric acid buffer solution may be added to the liquid composition of the present invention. These buffers may be useful for stabilizing the formulation and reducing irritation.
さらに本発明の組成物には、液体製剤の添加物として医薬品医療機器等法で許容される添加物を、必要に応じて含有させることができる。そのような添加物として、通常、液体、特に水性の組成物に用いられる添加剤、例えば、塩化ベンザルコニウム、ソルビン酸カリウム、塩酸クロロヘキシジン等の保存剤、エデト酸Na等の安定化剤、ヒドロキシエチルセルロース、ヒドロキシプロピルメチルセルロース等の増粘剤、塩化ナトリウム、塩化カリウム、グリセリン、ショ糖、ブドウ糖等の等張化剤、ポリソルベート８０、ポリオキシエチレン硬化ヒマシ油等の界面活性剤、塩化ナトリウム、塩化カリウム、グリセリン等の等張剤、塩酸、水酸化ナトリウム等のｐＨ調整剤が挙げられる。
Further, the composition of the present invention may contain, if necessary, an additive permitted by the Pharmaceuticals and Medical Devices Act as an additive for a liquid preparation. Such additives are usually additives used in liquids, especially aqueous compositions, such as preservatives such as benzalkonium chloride, potassium sorbate, chlorohexidine hydrochloride, stabilizers such as sodium edetate, hydroxy. Thickeners such as ethyl cellulose and hydroxypropylmethyl cellulose, tonicity agents such as sodium chloride, potassium chloride, glycerin, sucrose and glucose, surfactants such as
本発明の液状組成物がＢＮＣＴに用いられる医薬品である場合、ｐ－ボロノフェニルアラニンを有効成分とし、イオン液体を含むことを特徴とする液状医薬組成物の投与方法は、腫瘍の近傍にｐ－ボロノフェニルアラニンを送達させる方法であればどのような物でも良いが、好ましくは静脈投与、腹腔内投与、経皮投与を用いる。また、本発明の液状組成物がＰＥＴに用いられる診断用医薬品である場合、投与方法として静脈投与が用いられる。 When the liquid composition of the present invention is a pharmaceutical product used for BNCT, a method for administering the liquid pharmaceutical composition, which comprises p-boronophenylalanine as an active ingredient and an ionic liquid, is a p-in the vicinity of a tumor. Any method for delivering boronophenylalanine may be used, but intravenous administration, intraperitoneal administration, and transdermal administration are preferably used. When the liquid composition of the present invention is a diagnostic drug used for PET, intravenous administration is used as the administration method.
静脈投与、腹腔内投与等体内に直接注入する投与方法の場合は、ｐ－ボロノフェニルアラニンからなるイオン液体を含むことを特徴とする液状医薬組成物に対して、必要により例えば、ポリソルベート８０，ポリオキシエチレン硬化ヒマシ油６０，ポリエチレングリコール，カルボキシメチルセルロース，アルギン酸ナトリウム等分散剤、メチルパラベン，プロピルパラベン，ベンジルアルコール，クロロブタノール，フェノール等の保存剤、例えば、塩化ナトリウム，グリセリン，Ｄ－マンニトール、グルコース等の等張化剤を加え、例えば、注射用蒸留水，生理的食塩水，リンゲル液等の水溶剤で希釈化し、ｐ－ボロノフェニルアラニンを有効成分とし、イオン液体を含むことを特徴とする静脈投与、腹腔内投与に用いる液状医薬組成物を製造する。
In the case of an administration method such as intravenous administration or intraperitoneal administration, which comprises a liquid pharmaceutical composition comprising an ionic liquid consisting of p-boronophenylalanine, for example,
また、経皮投与により腫瘍の近傍にｐ－ボロノフェニルアラニンを送達する場合は、必要により例えば、ポリソルベート８０，ポリオキシエチレン硬化ヒマシ油６０，ポリエチレングリコール，カルボキシメチルセルロース，アルギン酸ナトリウム等分散剤、メチルパラベン，プロピルパラベン，ベンジルアルコール，クロロブタノール，フェノール等の保存剤、例えば、塩化ナトリウム，グリセリン，Ｄ－マンニトール、グルコース等の等張化剤を加え、例えば、オリーブ油，ゴマ油，綿実油，トウモロコシ油等の植物油、プロピレングリコール等の油性溶剤に溶解、懸濁あるいは乳化することにより、経皮投与に用いるｐ－ボロノフェニルアラニンを有効成分とし、イオン液体を含むことを特徴とする液状医薬組成物を製造する。
When p-boronophenylalanine is delivered to the vicinity of the tumor by transdermal administration, for example,
なお、上記医薬品組成物の製造工程においては、所望により例えば、サリチル酸ナトリウム，酢酸ナトリウム等の溶解補助剤、例えば、ヒト血清アルブミン等の安定剤、例えば、ベンジルアルコール等の無痛化剤等の添加物、更に医薬品医療機器等法において認められているものであれば必要に応じて抗酸化剤、着色剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤、無痛化剤、防腐剤、ゲル化剤を用いても良い。 In the manufacturing process of the above-mentioned pharmaceutical composition, if desired, for example, an additive such as a solubilizing agent such as sodium salicylate and sodium acetate, for example, a stabilizer such as human serum albumin, and an additive such as a painkiller such as benzyl alcohol. Furthermore, if it is permitted by the Pharmaceuticals and Medical Devices Act, antioxidants, colorants, lysis aids, suspending agents, tonicity agents, buffers, pain-relieving agents, preservatives, etc. , A gelling agent may be used.
また、ｐ－ボロノフェニルアラニンを有効成分とし、イオン液体を含むことを特徴とする液状医薬組成物は、必要により治療の際に例えば、注射用蒸留水，生理的食塩水，リンゲル液等の水溶剤または医薬品用のローション、クリームで希釈しても良い。 In addition, a liquid pharmaceutical composition containing p-boronophenylalanine as an active ingredient and containing an ionic liquid can be used as a water solvent such as distilled water for injection, physiological saline, Ringer's solution, etc. at the time of treatment, if necessary. Alternatively, it may be diluted with a medicinal lotion or cream.
本発明のｐ－ボロノフェニルアラニンを有効成分とし、イオン液体を含むことを特徴とする液状医薬組成物は、以下の製造方法で製造することができる。 The liquid pharmaceutical composition characterized by containing p-boronophenylalanine of the present invention as an active ingredient and containing an ionic liquid can be produced by the following production method.
１．ｐ－ボロノフェニルアラニンを有効成分とし、メグルミンおよびイオン液体を含むことを特徴とする液状医薬組成物の製造法
室温において、ｐ－ボロノフェニルアラニンに対して、モル比で２以下、好ましくは１以下、とりわけ好ましくは０．２以上０．８未満であるメグルミンを純水に溶解させ濃度を０.００２ｍｏｌ/Ｌ～０.０２ｍｏｌ/Ｌとする。これに対してｐ－ボロノフェニルアラニンを前記のようにメグルミンに対して規定した量で加え、更に純水を溶解する。ｐ－ボロノフェニルアラニンの終濃度は、１５～５０ｖ／ｗ％，好ましくは２０～５０ｖ／ｗ％、更に好ましくは３０～５０ｖ／ｗ％、とりわけ好ましくは３５～４５ｖ／ｗ％に調整する。必要により、前記医薬品製剤添加物を加え、ｐ－ボロノフェニルアラニンを有効成分とし、イオン液体を含むことを特徴とする液状医薬組成物を製造する。
本発明に使用するｐ－ボロノフェニルアラニンは、フェニルアラニンをホウ素(10Ｂ)で標識したボロノフェニルアラニンであればどのようなものでも良く、市販品を用いても良い。
また、ｐ－ボロノフェニルアラニンを合成する場合は、特開平１１－２５５７７３号、特開２０００－２１２１８５号、米国特許５１５７１４９号記載の公知の方法を参考にして合成しても良い。
ｐ－ボロノフェニルアラニンの光学異性体としては、Ｌ－体，Ｄ－体，Ｌ－体およびＤ－体のジアステレオマーのどのようなものでも良いが、とりわけＬ－体が好ましい。
添加する純水としては、例えば市販のＭｉＬＬｉ－Ｑ Ｗａｔｅｒ（商品名）市販の純水を用いても良い。
1. 1. A method for producing a liquid pharmaceutical composition containing p-boronophenylalanine as an active ingredient and containing meglumin and an ionic liquid. At room temperature, the molar ratio to p-boronophenylalanine is 2 or less, preferably 1 or less. Particularly preferably, meglumine having a concentration of 0.2 or more and less than 0.8 is dissolved in pure water to adjust the concentration to 0.002 mol / L to 0.02 mol / L. On the other hand, p-boronophenylalanine is added in an amount specified for meglumine as described above, and pure water is further dissolved. The final concentration of p-boronophenylalanine is adjusted to 15 to 50 v / w%, preferably 20 to 50 v / w%, more preferably 30 to 50 v / w%, and particularly preferably 35 to 45 v / w%. If necessary, the pharmaceutical product additive is added to produce a liquid pharmaceutical composition characterized by containing p-boronophenylalanine as an active ingredient and an ionic liquid.
The p-boronophenylalanine used in the present invention may be any boronophenylalanine in which phenylalanine is labeled with boron ( 10 B), and a commercially available product may be used.
Further, when synthesizing p-boronophenylalanine, it may be synthesized by referring to known methods described in JP-A-11-255773, JP-A-2000-212185, and US Pat. No. 5,157,149.
The optical isomer of p-boronophenylalanine may be any of L-form, D-form, L-form and D-form diastereomers, but L-form is particularly preferable.
As the pure water to be added, for example, commercially available MiLLi-Q Water (trade name) commercially available pure water may be used.
２．ｐ－ボロノフェニルアラニンを構成成分とするイオン液体を用いた液状医薬組成の処方例
処方例１
p－ボロノフェニルアラニンとメグルミンから構成されるイオン液体６５．４５mＬにＴｗｅｅｎ８０（界面活性剤、富士フィルム和光純薬株式会社製）１６．３６ｍｌ、エタノール６５．４５ｍｌを加え、ｐＨ調整剤としての塩酸を適量加えながら、リン酸生理食塩水緩衝液（ｐＨ７．４）を加え全量を６５４ｍＬに調整した。
上記医薬液体組成物を治療または画像診断に用いる場合は、その使用前に生理食塩水等により希釈し、医薬品医療機器等法の基準に適合する用量、濃度に調整した後、p－ボロノフェニルアラニンとメグルミンから構成されるイオン液体を含む液状医薬組成物として使用することができる。
2. 2. Prescription example of a liquid pharmaceutical composition using an ionic liquid containing p-boronophenylalanine as a constituent. Prescription example 1
To 65.45 mL of an ionic liquid composed of p-boronophenylalanine and meglumin, add 16.36 ml of Tween80 (surfactant, manufactured by Fuji Film Wako Pure Chemical Industries, Ltd.) and 65.45 ml of ethanol, and add hydrochloric acid as a pH adjuster. Phosphate saline buffer (pH 7.4) was added while adding an appropriate amount to adjust the total volume to 654 mL.
When the above-mentioned pharmaceutical liquid composition is used for treatment or diagnostic imaging, it is diluted with physiological saline or the like before use, adjusted to a dose and concentration conforming to the standards of the Pharmaceuticals and Medical Devices Act, and then p-boronophenylalanine. It can be used as a liquid pharmaceutical composition containing an ionic liquid composed of and meglumin.
処方例２
p－ボロノフェニルアラニンとメグルミンから構成されるイオン液体１００μＬにｐＨ調整剤としての塩酸１０μＬを加えながら、リン酸生理食塩水緩衝液（ｐＨ７．４）８９０μＬを加え全量を１ｍＬに調整し、p－ボロノフェニルアラニンとメグルミンから構成されるイオン液体を含む液状医薬組成物を製造した。
Prescription example 2
While adding 10 μL of hydrochloric acid as a pH adjuster to 100 μL of an ionic liquid composed of p-boronophenylalanine and meglumin, 890 μL of phosphate saline buffer (pH 7.4) was added to adjust the total volume to 1 mL, and p- A liquid pharmaceutical composition containing an ionic liquid composed of boronophenylalanine and meglumin was produced.
実施例１
１－１．p－ボロノフェニルアラニンとメグルミンから構成されるイオン液体の製造
メグルミン（富士フィルム和光純薬株式会社製）のＦＴ－ＩＲを測定し、図１に示した。また、Ｐ－ボロノフェニルアラニン（インターファーマプラハ社製）のＦＴ－ＩＲを測定し、図２に示した。
前記メグルミン２３４．３ｍｇ（０．００１２ｍｏｌ）を超純水（商品名：，ＭｉＬＬｉ－ＱＷａｔｅｒ、メルクミリポア社製）４０ｍｌに溶解させた。これに前記ｐ－ボロノフェニルアラニン２４９．６ｍｇ（２０８ｇ／ｍｏｌ，０．００１２ｍｏｌ）を加え、更に超純粋１００ｍｌを加え、溶解させた。
前記メグルミン、p－ボロノフェニルアラニン混合溶液を、スターラーで撹拌しながら２週間反応させた。
エバポレーターで、水分を除去しp－ボロノフェニルアラニンに対して、モル比１：１のメグルミンから構成されるイオン液体を製造した。
得られたp－ボロノフェニルアラニンとメグルミンから構成されるイオン液体の１Ｈ－ＮＭＲおよびＦＴ－ＩＲを測定し、各々図３および図４に示した。
１ＨＮＭＲの測定結果は文献〔Ａａｔｈｉｒａ，ｅｔ ａｌ．，（アアシラ他）、Ｊｏｕｒｎａｌ ｏｆ ｉｎｄｕｓｔｒｉａｌ ａｎｄ Ｅｎｇｉｎｅｅｒｉｎｇ Ｃｈｅｍｉｓｔｒｙ（ジャーナル オブ インダストリアル アンド エンジニアリング ケミストリー）、Ｖｏｌｕｍｅ ６４（６４巻）、２５Ａｕｇｕｓｔ ２０１８（２０１８年８月２５日）Ｐａｇｅｓ４２０－４２９（４２０～４２９頁）〕を参考にして特定した。ＦＴ－ＩＲでは特有のピークを確認したため、p－ボロノフェニルアラニンとメグルミンモル比（１：１）のイオン液体の生成が確認された。
Example 1
1-1. Production of ionic liquid composed of p-boronophenylalanine and meglumine The FT-IR of meglumine (manufactured by Fuji Film Wako Pure Chemical Industries, Ltd.) was measured and shown in FIG. In addition, the FT-IR of P-boronophenylalanine (manufactured by Interpharma Prague) was measured and shown in FIG.
The meglumine 234.3 mg (0.0012 mol) was dissolved in 40 ml of ultrapure water (trade name :, MiLLi-QWater, manufactured by Merck Millipore). To this, 249.6 mg (208 g / mol, 0.0012 mol) of the above p-boronophenylalanine was added, and 100 ml of ultrapure was further added and dissolved.
The mixed solution of meglumine and p-boronophenylalanine was reacted for 2 weeks with stirring with a stirrer.
An ionic liquid composed of meglumine having a molar ratio of 1: 1 with respect to p-boronophenylalanine was produced by removing water with an evaporator.
1 H-NMR and FT-IR of the obtained ionic liquid composed of p-boronophenylalanine and meglumine were measured and shown in FIGS. 3 and 4, respectively.
1 The measurement results of HNMR are described in the literature [Athira, et al. , (Aashira et al.), Journal of industrial and Engineering Chemistry, Volume 64 (Volume 64), 25August 2018 (August 25, 2018) Pages 420-429 (420-420) And specified. Since a peculiar peak was confirmed in FT-IR, the formation of an ionic liquid having a p-boronophenylalanine to meglumine molar ratio (1: 1) was confirmed.
１－２．p－ボロノフェニルアラニンとメグルミンから構成されるイオン液体中のp－ボロノフェニルアラニンの濃度およびホウ素濃度の測定
p－ボロノフェニルアラニンとメグルミンから構成されるイオン液体１０μＬに超純粋（商品名：ＭｉＬＬｉ－Ｑ Ｗａｔｅｒ、メルクミリポア社製）１００mＬを加えサンプル溶液を作成した。ＩＣＰ－ＯＥＳ分析によりホウ素濃度を測定した。
1-2. Measurement of p-boronophenylalanine concentration and boron concentration in an ionic liquid composed of p-boronophenylalanine and meglumine
A sample solution was prepared by adding 100 mL of ultrapure (trade name: MiLLi-Q Water, manufactured by Merck Millipore) to 10 μL of an ionic liquid composed of p-boronophenylalanine and meglumine. Boron concentration was measured by ICP-OES analysis.
得られたホウ素濃度から原液のホウ素濃度を算出したところ２２１１７ｐｐｍであった。またＢＰＡ濃度を測定したところ４２．８Ｗ／Ｖ％であった。これは、特許文献４に記載されているＰ－ボロノフェニルアラニン製剤中のＰ－ボロノフェニルアラニンの最高濃度、１０．４％よりも、遥かに高い値であり予期せぬ効果であった。
本件発明によりＰ－ボロノフェニルアラニン高濃度製剤の提供が可能になった。
When the boron concentration of the stock solution was calculated from the obtained boron concentration, it was 22117 ppm. The BPA concentration was measured and found to be 42.8 W / V%. This was an unexpected effect because it was much higher than the maximum concentration of P-boronophenylalanine of 10.4% in the P-boronophenylalanine preparation described in
The present invention makes it possible to provide a high-concentration P-boronophenylalanine preparation.
実施例２
使用するメグルミンの量を２３４．３ｍｇ（０．００１２ｍｏｌ）から１６４．０ｍｇ（０．０００８４ｍｏｌ）に代える以外は実施例１と同様の方法により、Ｐ－ボロノフェニルアラニンに対してモル比０．７のメグルミンから構成されるイオン液体を製造した。
得られたＰ－ボロノフェニルアラニンとメグルミン（１：０．７）から構成されるイオン液体の１Ｈ－ＮＭＲおよびＦＴ－ＩＲを測定し、各々図５および図６に示した。
１Ｈ－ＮＭＲの測定結果は文献〔Ａａｔｈｉｒａ，ｅｔ ａｌ．，（アアシラ他）、Ｊｏｕｒｎａｌ ｏｆ ｉｎｄｕｓｔｒｉａｌ ａｎｄ Ｅｎｇｉｎｅｅｒｉｎｇ Ｃｈｅｍｉｓｔｒｙ（ジャーナル オブ インダストリアル アンド エンジニアリング ケミストリー）、Ｖｏｌｕｍｅ ６４（６４巻）、２５Ａｕｇｕｓｔ ２０１８（２０１８年８月２５日）Ｐａｇｅｓ４２０－４２９（４２０～４２９頁）〕を参考にして特定した。ＦＴ－ＩＲでは特有のピークを確認したため、Ｐ－ボロノフェニルアラニンとメグルミンモル比（１：０．７）の場合においてもイオン液体の生成が確認された。
Example 2
By the same method as in Example 1 except that the amount of meglumine used was changed from 234.3 mg (0.0012 mol) to 164.0 mg (0.00084 mol), the molar ratio to P-boronophenylalanine was 0.7. An ionic liquid composed of meglumine was produced.
1 H-NMR and FT-IR of the obtained ionic liquid composed of P-boronophenylalanine and meglumine (1: 0.7) were measured and shown in FIGS. 5 and 6, respectively.
1 The measurement results of 1 H-NMR are described in the literature [Athira, et al. , (Aashira et al.), Journal of industrial and Engineering Chemistry, Volume 64 (Volume 64), 25August 2018 (August 25, 2018) Pages 420-429 (420-420) And specified. Since a peculiar peak was confirmed in FT-IR, the formation of an ionic liquid was confirmed even in the case of P-boronophenylalanine and meglumine molar ratio (1: 0.7).
本発明により、高濃度ｐ－ボロノフェニルアラニンを内包し、かつ安全な腫瘍の放射線治療に用いる増強剤およびＰＥＴに用いる診断用医薬品が提供される。 INDUSTRIAL APPLICABILITY The present invention provides an enhancer containing a high concentration of p-boronophenylalanine and used for radiation therapy of a safe tumor, and a diagnostic drug used for PET.
Ｍｅｇ ：メグルミン
１０ＢＰＡ ：Ｐ－ボロノフェニルアラニン
ＩＬ ：イオン液体
Meg: Meglumine
10 BPA: P-boronophenylalanine IL: ionic liquid
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