CN110337292A - 医药品 - Google Patents
医药品 Download PDFInfo
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- CN110337292A CN110337292A CN201880014470.XA CN201880014470A CN110337292A CN 110337292 A CN110337292 A CN 110337292A CN 201880014470 A CN201880014470 A CN 201880014470A CN 110337292 A CN110337292 A CN 110337292A
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- 239000003814 drug Substances 0.000 title description 14
- 239000000203 mixture Substances 0.000 claims abstract description 76
- 150000001875 compounds Chemical class 0.000 claims abstract description 73
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 70
- 150000003839 salts Chemical class 0.000 claims abstract description 63
- 239000012453 solvate Substances 0.000 claims abstract description 49
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract description 38
- 229920001225 polyester resin Polymers 0.000 claims abstract description 24
- 229920005672 polyolefin resin Polymers 0.000 claims abstract description 22
- 125000001424 substituent group Chemical group 0.000 claims abstract description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 8
- -1 polyethylene terephthalate Polymers 0.000 claims description 89
- 238000000034 method Methods 0.000 claims description 32
- 229920000139 polyethylene terephthalate Polymers 0.000 claims description 16
- 239000005020 polyethylene terephthalate Substances 0.000 claims description 15
- 229920005989 resin Polymers 0.000 claims description 15
- 239000011347 resin Substances 0.000 claims description 15
- 239000004743 Polypropylene Substances 0.000 claims description 12
- 229920001155 polypropylene Polymers 0.000 claims description 12
- 239000004698 Polyethylene Substances 0.000 claims description 11
- 229920000573 polyethylene Polymers 0.000 claims description 10
- 150000002148 esters Chemical class 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 abstract description 29
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 abstract description 18
- 239000000126 substance Substances 0.000 abstract description 15
- 238000002360 preparation method Methods 0.000 abstract description 4
- 238000006243 chemical reaction Methods 0.000 abstract description 3
- 238000005516 engineering process Methods 0.000 abstract description 3
- 235000002639 sodium chloride Nutrition 0.000 description 65
- 238000004519 manufacturing process Methods 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 14
- 239000003889 eye drop Substances 0.000 description 14
- 229940012356 eye drops Drugs 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 229920001684 low density polyethylene Polymers 0.000 description 13
- 239000004702 low-density polyethylene Substances 0.000 description 13
- 239000008213 purified water Substances 0.000 description 13
- 208000010412 Glaucoma Diseases 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 229960000686 benzalkonium chloride Drugs 0.000 description 11
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 11
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 11
- 239000004327 boric acid Substances 0.000 description 11
- 235000010338 boric acid Nutrition 0.000 description 11
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 11
- 229920001903 high density polyethylene Polymers 0.000 description 11
- 239000004700 high-density polyethylene Substances 0.000 description 11
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 10
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 10
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 10
- VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical compound C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 9
- 239000006096 absorbing agent Substances 0.000 description 9
- KKEYFWRCBNTPAC-UHFFFAOYSA-N benzene-dicarboxylic acid Natural products OC(=O)C1=CC=C(C(O)=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-N 0.000 description 9
- 235000019441 ethanol Nutrition 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- 229920001577 copolymer Polymers 0.000 description 8
- 239000007788 liquid Substances 0.000 description 7
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 7
- 235000019799 monosodium phosphate Nutrition 0.000 description 7
- 230000000144 pharmacologic effect Effects 0.000 description 7
- 229920000728 polyester Polymers 0.000 description 7
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- FMRHJJZUHUTGKE-UHFFFAOYSA-N Ethylhexyl salicylate Chemical compound CCCCC(CC)COC(=O)C1=CC=CC=C1O FMRHJJZUHUTGKE-UHFFFAOYSA-N 0.000 description 6
- OURRXQUGYQRVML-AREMUKBSSA-N [4-[(2s)-3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl]phenyl]methyl 2,4-dimethylbenzoate Chemical compound CC1=CC(C)=CC=C1C(=O)OCC1=CC=C([C@@H](CN)C(=O)NC=2C=C3C=CN=CC3=CC=2)C=C1 OURRXQUGYQRVML-AREMUKBSSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 230000009471 action Effects 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 229920000642 polymer Polymers 0.000 description 6
- 238000004321 preservation Methods 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 235000011121 sodium hydroxide Nutrition 0.000 description 6
- 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 5
- 206010030043 Ocular hypertension Diseases 0.000 description 5
- 208000030533 eye disease Diseases 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 238000006116 polymerization reaction Methods 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- MKPLKVHSHYCHOC-AHTXBMBWSA-N travoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)COC1=CC=CC(C(F)(F)F)=C1 MKPLKVHSHYCHOC-AHTXBMBWSA-N 0.000 description 5
- 229960002368 travoprost Drugs 0.000 description 5
- FWKQNCXZGNBPFD-UHFFFAOYSA-N Guaiazulene Chemical compound CC(C)C1=CC=C(C)C2=CC=C(C)C2=C1 FWKQNCXZGNBPFD-UHFFFAOYSA-N 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 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
- 239000000654 additive Substances 0.000 description 4
- 230000000996 additive effect Effects 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 239000012964 benzotriazole Substances 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 235000011187 glycerol Nutrition 0.000 description 4
- 229960005150 glycerol Drugs 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- GGXICVAJURFBLW-CEYXHVGTSA-N latanoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1 GGXICVAJURFBLW-CEYXHVGTSA-N 0.000 description 4
- 229960001160 latanoprost Drugs 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 4
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- VDYRZXYYQMMFJW-UHFFFAOYSA-N 2-(dimethylamino)-n-(1-oxo-2h-isoquinolin-6-yl)-2-thiophen-3-ylacetamide Chemical compound C=1C=C2C(O)=NC=CC2=CC=1NC(=O)C(N(C)C)C=1C=CSC=1 VDYRZXYYQMMFJW-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- 229920002675 Polyoxyl Polymers 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- AQOKCDNYWBIDND-FTOWTWDKSA-N bimatoprost Chemical compound CCNC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)CCC1=CC=CC=C1 AQOKCDNYWBIDND-FTOWTWDKSA-N 0.000 description 3
- 229960002470 bimatoprost Drugs 0.000 description 3
- FQUNFJULCYSSOP-UHFFFAOYSA-N bisoctrizole Chemical compound N1=C2C=CC=CC2=NN1C1=CC(C(C)(C)CC(C)(C)C)=CC(CC=2C(=C(C=C(C=2)C(C)(C)CC(C)(C)C)N2N=C3C=CC=CC3=N2)O)=C1O FQUNFJULCYSSOP-UHFFFAOYSA-N 0.000 description 3
- 229910021538 borax Inorganic materials 0.000 description 3
- 229910052801 chlorine Inorganic materials 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
- 201000010099 disease Diseases 0.000 description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 229960003511 macrogol Drugs 0.000 description 3
- QUAMTGJKVDWJEQ-UHFFFAOYSA-N octabenzone Chemical compound OC1=CC(OCCCCCCCC)=CC=C1C(=O)C1=CC=CC=C1 QUAMTGJKVDWJEQ-UHFFFAOYSA-N 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- 125000002971 oxazolyl group Chemical group 0.000 description 3
- 229920000098 polyolefin Polymers 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 102000000568 rho-Associated Kinases Human genes 0.000 description 3
- 108010041788 rho-Associated Kinases Proteins 0.000 description 3
- 239000004328 sodium tetraborate Substances 0.000 description 3
- 235000010339 sodium tetraborate Nutrition 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- QCHFTSOMWOSFHM-WPRPVWTQSA-N (+)-Pilocarpine Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 description 2
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 2
- REPVLJRCJUVQFA-UHFFFAOYSA-N (-)-isopinocampheol Natural products C1C(O)C(C)C2C(C)(C)C1C2 REPVLJRCJUVQFA-UHFFFAOYSA-N 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 2
- WMFHUUKYIUOHRA-UHFFFAOYSA-N (3-phenoxyphenyl)methanamine;hydrochloride Chemical compound Cl.NCC1=CC=CC(OC=2C=CC=CC=2)=C1 WMFHUUKYIUOHRA-UHFFFAOYSA-N 0.000 description 2
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 description 2
- VUHMIPWBDMGTNL-MHCZMQLOSA-N 1,2-dimethoxy-4-[(e)-prop-1-enyl]benzene;1,2,4-trimethoxy-5-[(e)-prop-1-enyl]benzene Chemical compound COC1=CC=C(\C=C\C)C=C1OC.COC1=CC(OC)=C(\C=C\C)C=C1OC VUHMIPWBDMGTNL-MHCZMQLOSA-N 0.000 description 2
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- ICKWICRCANNIBI-UHFFFAOYSA-N 2,4-di-tert-butylphenol Chemical class CC(C)(C)C1=CC=C(O)C(C(C)(C)C)=C1 ICKWICRCANNIBI-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- WSSJONWNBBTCMG-UHFFFAOYSA-N 2-hydroxybenzoic acid (3,3,5-trimethylcyclohexyl) ester Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C1=CC=CC=C1O WSSJONWNBBTCMG-UHFFFAOYSA-N 0.000 description 2
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- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
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- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
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- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
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- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
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- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 238000000149 argon plasma sintering Methods 0.000 description 2
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Abstract
本发明确立一种将异喹啉-6-氨基衍生物稳定地制剂化成眼科用药剂等的技术。该医药制剂通过将含有下述通式(1)(式中,R1和R2分别独立地表示氢原子或C1~C4烷基,R3表示氢原子或羟基,A表示-CH(R4)-或-CH2-CH(R4)-(其中,R4表示可以具有取代基的C6~C10芳基或可以具有取代基的5~10元的杂芳基),式(1)还包含其互变异构体。)所示的化合物或其盐或者它们的溶剂合物的水性组合物收纳在聚酯系树脂制容器或聚烯烃系树脂制容器中而得到:
Description
技术领域
本发明涉及医药制剂等。
背景技术
迄今为止,已知几种异喹啉-6-氨基衍生物在高眼压症或青光眼等眼睛疾病的预防或治疗中是有用的。
具体而言,例如报导了以下的结构式:
所示的化合物(化学名:{4-[(2S)-3-氨基-1-(异喹啉-6-基氨基)-1-氧代丙烷-2-基]苯基}甲基2,4-二甲基苯甲酸酯([4-[(2S)-3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl]phenyl]methyl 2,4-dimethylbenzoate)、国际通用名:netarsudil。其中,以下在本说明书中,有时标记为“奈他地尔”。),其也作为AR-13324已知,具有Rho激酶抑制作用、去甲肾上腺素转运体抑制作用等药理作用,在高眼压症或青光眼等眼睛疾病的预防或治疗中是有用的(例如专利文献1、非专利文献1、2)。
另外,同样地报导了以下的结构式:
所示的化合物(化学名:外消旋(2R)-2-(二甲基氨基)-N-(1-氧代-1,2-二氢异喹啉-6-基)-2-(噻吩-3-基)乙酰胺(rac-(2R)-2-(dimethylamino)-N-(1-oxo-1,2-dihydroisoquinolin-6-yl)-2-(thiophen-3-yl)acetamide)、国际通用名:verosudil。其中,以下在本说明书中,有时标记为“维罗舒地尔”。),其也作为AR-12286已知,具有Rho激酶抑制作用,在高眼压症等眼睛疾病的预防或治疗中是有用的(例如专利文献2、非专利文献1、3)。
因此,确立将这些异喹啉-6-氨基衍生物稳定地制剂化成例如眼科用药剂等的技术是非常有用的。
而在专利文献3中记载了在150mL塑料容器中调制了含有奈他地尔或维罗舒地尔的组合物。但是,在该文献中,各组合物的调制是为了用于药理试验而完成的,关于组合物中的奈他地尔或维罗舒地尔的稳定性,没有任何记载,另外,关于该容器是何种材质和特性,也没有任何记载。
现有技术文献
专利文献
专利文献1:日本特表2012-525386号公报
专利文献2:WO2009/091898号小册子
专利文献3:日本特表2016-515520号公报
非专利文献
非专利文献1:Bacharach J.et al.,Ophthalmology 122(2)302-7(2015)
非专利文献2:Sturdivant JM.et al.,Bioorg Med Chem Lett.26(10)2475-80(2016)
非专利文献3:Williams RD.et al.,Am.J.Ophthalmol.152(5)834-41(2011)
发明内容
发明解决的技术问题
本发明要解决的技术问题在于:确立一种将奈他地尔或维罗舒地尔等异喹啉-6-氨基衍生物稳定地制剂化成眼科用药剂等的技术。用于解决技术问题的技术手段
眼科用药剂等通常是含有水的组合物(水性组合物)。其中,本发明的发明人调制了含有奈他地尔等异喹啉-6-氨基衍生物的水性组合物,将其收纳在容器中,确认了其保存性。然后意外地发现了,在高温下长期保存时,异喹啉-6-氨基衍生物的含量降低。
因此,为了改善异喹啉-6-氨基衍生物在水性组合物中对热的稳定性,本发明的发明人进行了进一步深入研究。然后发现,将含有异喹啉-6-氨基衍生物的水性组合物收纳在聚酯系树脂制容器或聚烯烃系树脂制容器这样的特定容器中时,高温保存时的含量降低被抑制,成为热稳定性得到改善的医药制剂,从而完成了本发明。
即,本发明提供一种医药制剂,其通过将含有下述通式(1)所示的化合物或其盐或者它们的溶剂合物的水性组合物收纳在聚酯系树脂制容器或聚烯烃系树脂制容器而得到,
(式中,R1和R2分别独立地表示氢原子或C1~C4烷基,
R3表示氢原子或羟基,
A表示-CH(R4)-或-CH2-CH(R4)-(其中,R4表示可以具有取代基的C6~C10芳基或可以具有取代基的5~10元的杂芳基。),
式(1)还包含其互变异构体。)。
发明效果
根据本发明,能够改善奈他地尔所代表的异喹啉-6-氨基衍生物在水性组合物中的稳定性。
具体实施方式
在本说明书中,“通式(1)所示的化合物或其盐或者它们的溶剂合物”除了包含通式(1)所示化合物自身,还包含其盐或溶剂合物。
(式中,R1和R2分别独立地表示氢原子或C1~C4烷基,
R3表示氢原子或羟基,
A表示-CH(R4)-或-CH2-CH(R4)-(其中,R4表示可以具有取代基的C6~C10芳基或可以具有取代基的5~10元的杂芳基。),
式(1)还包含其互变异构体。)
其中,作为通式(1)所示的化合物的盐,只要是药学上可接受的盐即可,没有特别限定,具体而言,例如可以列举盐酸盐、硫酸盐、硝酸盐、氢氟酸盐、氢溴酸盐等无机酸盐;乙酸盐、酒石酸盐、乳酸盐、柠檬酸盐、富马酸盐、马来酸盐、琥珀酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、甲苯磺酸盐、萘磺酸盐、樟脑磺酸盐等有机酸盐等,优选为盐酸盐、甲磺酸盐。
另外,作为通式(1)所示的化合物或其盐的溶剂合物,可以列举水合物和醇合物等。
进一步而言,通式(1)所示的化合物的化学结构中存在不对称碳原子时,可以存在各种立体异构体,作为通式(1)所示的化合物,其立体构型没有特别限定,可以为单一的立体异构体,也可以为各种立体异构体的任意比例的混合物。
其中,在本说明书中,各种式子所示的化合物在其化学结构中具有不对称碳原子时,只要没有特别指定立体构型,这样的式子就包含各种立体异构体单独和它们的任意比例的全部混合物。因此,没有特别指定立体构型的式子所示的化合物可以为单一的立体异构体,还可以为各种立体异构体的任意比例的混合物。
另外,通式(1)除了包含通式(1)直接表示的化合物自身以外,还包含其互变异构体。具体而言,例如在R3为羟基的下述通式(1a)的情况下,可以生成其互变异构体(通式(1b)),“通式(1)所示的化合物”除了包含下述通式(1a)所示的化合物以外,还包含通式(1b)所示的化合物。
在本说明书中,“C1~C4烷基”是指直链状、支链状或环状的碳原子数1~4的烷基。作为“C1~C4烷基”,具体而言,例如可以列举甲基、乙基、正丙基、异丙基、环丙基、正丁基、叔丁基、异丁基等,优选甲基。
在本说明书中,“C6~C10芳基”是指碳原子数6~10的芳基。作为“C6~C10芳基”,具体而言例如可以列举苯基、萘基等,优选苯基。
在本说明书中,“5~10元的杂芳基”是指含有1~4个选自氧原子、硫原子和氮原子中的杂原子作为环构成原子的5~10元的单环式、多环式或缩合环式的芳香族杂环基。作为“5~10元的杂芳基”,具体而言,例如可以列举呋喃基、噻吩基、吡咯基、噁唑基、异噁唑基、噻唑基、异噻唑基、咪唑基、吡唑基、噁二唑基、噻二唑基、三唑基、四唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并呋喃基、异苯并呋喃基、苯并噻吩基、吲哚基、异吲哚基、吲唑基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并噁二唑基、苯并噻二唑基、苯并三唑基、喹啉基、异喹啉基、噌啉基、喹唑啉基、喹喔啉基、酞嗪基、萘啶基、嘌呤基、喋啶基、呋喃并吡啶基、噻吩并吡啶基、吡咯并吡啶基、噁唑并吡啶基、噻唑并吡啶基、咪唑并吡啶基等,优选噻吩基。
在本说明书中,作为“可以具有取代基的C6~C10芳基”、“可以具有取代基的5~10元的杂芳基”中的“取代基”,具体而言,例如可以列举卤原子、-CH2-OC(=O)-R5(其中,作为R5,是指可以具有1~3个C1~C4烷基作为取代基的C6~C10芳基(例如2,4-二甲基苯基)。),优选氯原子、2,4-二甲基苯基羧甲基。
在本说明书中,作为“可以具有取代基的C6~C10芳基”,优选4-氯苯基、4-(2,4-二甲基苯基羧甲基)苯基。
在本说明书中,作为“可以具有取代基的5~10元的杂芳基”,优选3-噻吩基。
R3为羟基时,R3的取代位置只要在异喹啉环上,就没有限定,优选异喹啉环的1位。
在本说明书中,作为“通式(1)所示的化合物或其盐或者它们的溶剂合物”,优选下述式(2):
所示的化合物或其盐或者它们的溶剂合物,更优选下述式(3):
所示的化合物(奈他地尔)(化学名:{4-[(2S)-3-氨基-1-(异喹啉-6-基氨基)-1-氧代丙烷-2-基]苯基}甲基2,4-二甲基苯甲酸酯([4-[(2S)-3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl]phenyl]methyl 2,4-dimethylbenzoate)、国际通用名:netarsudil)或其盐或者它们的溶剂合物,特别优选下述式(4):
所示的上述式(3)所示化合物的2甲磺酸盐(化学名:{4-[(2S)-3-氨基-1-(异喹啉-6-基氨基)-1-氧代丙烷-2-基]苯基}甲基2,4-二甲基苯甲酸酯2甲磺酸盐([4-[(2S)-3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl]phenyl]methyl 2,4-dimethyl benzoate dimethanesulfonate)。其中,以下在本说明书中,有时特别标记为“奈他地尔2甲磺酸盐”。)。
另外,作为其他的方式,作为“通式(1)所示的化合物或其盐或者它们的溶剂合物”,优选下述式(5)或(5'):
所示的化合物或它们的盐或者它们的溶剂合物,更优选下述式(6):
所示的化合物(维罗舒地尔)(化学名:外消旋(2R)-2-(二甲基氨基)-N-(1-氧代-1,2-二氢异喹啉-6-基)-2-(噻吩-3-基)乙酰胺(rac-(2R)-2-(dimethylamino)-N-(1-oxo-1,2-dihydroisoquinolin-6-yl)-2-(thiophen-3-yl)acetamide)、国际通用名:verosudil。)、其互变异构体或它们的盐或者它们的溶剂合物,特别优选下述式(7):
所示的上述式(6)所示化合物的1盐酸盐(化学名:外消旋(2R)-2-(二甲基氨基)-N-(1-氧代-1,2-二氢异喹啉-6-基)-2-(噻吩-3-基)乙酰胺1盐酸盐(rac-(2R)-2-(dimethylamino)-N-(1-oxo-1,2-dihydroisoquinolin-6-yl)-2-(thiophen-3-yl)acetamide monohydrochloride)。其中,以下在本说明书中,有时特别标记为“维罗舒地尔1盐酸盐”。)。
进一步而言,作为其他的方式,作为“通式(1)所示的化合物或其盐或者它们的溶剂合物”,优选下述式(8):
所示的化合物(3-氨基-2-(4-氯苯基)-N-(异喹啉-6-基)丙酰胺)或其盐或者它们的溶剂合物。
通式(1)所示的化合物或其盐或者它们的溶剂合物是公知的,可以利用公知的方法进行制造。具体而言,例如可以参考专利文献1~3所记载的方法或非专利文献2记载的方法进行制造。其中,这些文献的内容作为参照而被引入本说明书中。
另外,通式(1)所示的化合物或其盐或者它们的溶剂合物已经被市售,可以使用这些市售品。作为市售品,具体而言,例如可以列举Medchemexpress公司制造或ChemsceneLLS公司制造的奈他地尔2甲磺酸盐(式(4)所示的化合物)、Shanghai biopharmaleader公司制造的奈他地尔的1盐酸盐(式(3)所示化合物的1盐酸盐)、MedKoo biosciences公司制造的维罗舒地尔(式(6)所示化合物的游离体)等。
水性组合物中的通式(1)所示的化合物或其盐或者它们的溶剂合物的含量没有特别限定,可以根据适用疾病和患者的性别、年龄、症状等适当研究而确定,从获得优异的药理作用的观点考虑,相对于水性组合物全部容量,将通式(1)所示的化合物换算成游离体时,优选含有0.0001~5w/v%,更优选含有0.001~3w/v%,进一步优选含有0.005~2w/v%,特别优选含有0.01~1w/v%。
特别是在作为通式(1)所示的化合物使用奈他地尔时,从获得优异的药理作用的观点考虑,相对于水性组合物全部容量,将奈他地尔换算成游离体时,优选含有0.0001~1w/v%,更优选含有0.001~0.5w/v%,进一步优选含有0.005~0.1w/v%,特别优选含有0.01~0.04w/v%。
另外,在作为通式(1)所示的化合物使用维罗舒地尔时,从获得优异的药理作用的观点考虑,相对于水性组合物全部容量,将维罗舒地尔换算成游离体时,优选含有0.01~3.5w/v%,更优选含有0.1~2.5w/v%,进一步优选含有0.2~1.5w/v%,特别优选含有0.3~0.8w/v%。
进一步而言,在作为通式(1)所示的化合物使用式(8)所示的化合物时,从获得优异的药理作用的观点考虑,相对于水性组合物全部容量,将式(8)所示的化合物换算成游离体时,优选含有0.0001~3w/v%,更优选含有0.001~2w/v%,进一步优选含有0.005~1w/v%,特别优选含有0.01~0.5w/v%。
在本说明书中,“水性组合物”是指至少含有水的组合物,作为其性状,只要能够收纳在后述的容器中,就没有特别限定,例如可以列举液状(溶液或悬浮液)、半固体状(软膏)。其中,作为组合物中的水,例如可以使用精制水、注射用水、灭菌精制水等。
水性组合物所含的水的含量没有特别限定,优选为5质量%以上,更优选为20质量%以上,进一步优选为50质量%以上,更进一步优选为90质量%以上,特别优选为90~99.99质量%。
除了上述的化合物以外,根据剂型,水性组合物还可以含有医药品或医药品部外品等中所利用的添加物。作为这样的添加物,例如可以列举无机盐类、等渗压剂、螯合剂、稳定剂、pH调节剂、防腐剂、抗氧化剂、增稠剂、表面活性剂、增溶剂、悬浮剂、清凉剂、分散剂、保存剂、油性基剂、乳剂性基剂、水溶性基剂等。
作为这样的添加物,具体而言,例如可以例示抗坏血酸、天冬氨酸钾、亚硫酸氢钠、藻酸、苯甲酸钠、苯甲酸苄酯、ε-氨基己酸、茴香油、乙醇、乙烯-乙酸乙烯酯共聚物、乙二胺四乙酸钠、乙二胺四乙酸四钠、氯化钾、氯化钙水合物、氯化钠、氯化镁、盐酸、盐酸烷基二氨基乙基甘氨酸液、羧基乙烯基聚合物、干燥亚硫酸钠、干燥碳酸钠、d-樟脑、dl-樟脑、木糖醇、柠檬酸水合物、柠檬酸钠水合物、甘油、葡糖酸、L-谷氨酸、L-谷氨酸钠、肌酸酐、氯己定葡糖酸盐液、氯丁醇、结晶磷酸二氢钠、香叶醇、软骨素硫酸钠、乙酸、乙酸钾、乙酸钠水合物、氧化钛、结冷胶、二丁基羟基甲苯、溴化钾、苯度溴铵(Benzododecinium bromide)、酒石酸、氢氧化钠、硬脂酸聚烃氧酯45、精制羊毛脂、D-山梨糖醇、山梨糖醇液、山梨酸、山梨酸钾、牛磺酸、碳酸氢钠、碳酸钠水合物、硫代硫酸钠水合物、硫柳汞、四丁酚醛、脱氢乙酸钠、氨丁三醇、浓甘油、浓缩混合生育酚、白色凡士林、薄荷水、薄荷油、浓苯扎氯铵液50、对羟基苯甲酸乙酯、对羟基苯甲酸丁酯、对羟基苯甲酸丙酯、对羟基苯甲酸甲酯、透明质酸钠、人血清白蛋白、羟乙基纤维素、羟丙基纤维素、羟丙甲纤维素、冰醋酸、焦亚硫酸钠、苯乙醇、葡萄糖、丙二醇、香柠檬油、苯扎氯铵、苯扎氯铵液、苄醇、苄索氯铵、苄索氯铵液、硼砂、硼酸或其盐(例如硼酸、硼酸铵、硼砂)、聚维酮、聚氧乙烯(200)聚氧亚丙基二醇(70)、聚苯乙烯磺酸钠、聚山梨酸酯80、聚氧乙烯硬化蓖麻油60、聚乙烯醇(部分皂化物)、d-冰片、聚乙二醇4000、聚乙二醇6000、D-甘露糖醇、柠檬酸酐、无水磷酸一氢钠、无水磷酸二氢钠、甲磺酸、甲基纤维素、l-薄荷醇、单乙醇胺、单硬脂酸铝、单硬脂酸聚乙二醇酯、桉油、碘化钾、硫酸、硫酸羟喹啉、液体石蜡、龙脑、磷酸、磷酸氢钠水合物、磷酸二氢钾、磷酸二氢钠、磷酸二氢钠一水合物、苹果酸、凡士林等。
作为添加物,例如优选氯化钾、氯化钙水合物、氯化钠、氯化镁、甘油、乙酸、乙酸钾、乙酸钠水合物、酒石酸、氢氧化钠、碳酸氢钠、碳酸钠水合物、浓甘油、羟乙基纤维素、羟丙基纤维素、羟丙甲纤维素、硼砂、硼酸或其盐、聚维酮、聚山梨酸酯80、聚氧乙烯硬化蓖麻油、单硬脂酸聚乙二醇酯、聚乙烯醇(部分皂化物)、聚乙二醇4000、聚乙二醇6000、柠檬酸酐、无水磷酸一氢钠、无水磷酸二氢钠、甲基纤维素、单乙醇胺、磷酸、磷酸氢钠水合物、磷酸二氢钾、磷酸二氢钠、磷酸二氢钠一水合物、透明质酸钠、葡萄糖、l-薄荷醇等。
另外,除了上述的化合物以外,根据适用疾病等,水性组合物还可以含有其他的药效成分。作为这样的药效成分,例如可以列举:包含布那唑嗪盐酸盐等布那唑嗪或其盐或者它们的溶剂合物的α1受体阻断剂;包含溴莫尼定酒石酸盐等溴莫尼定或其盐或者它们的溶剂合物、阿可乐定或其盐或者它们的溶剂合物的α2受体激动剂;包含卡替洛尔盐酸盐等卡替洛尔或其盐或者它们的溶剂合物、尼普洛尔或其盐或者它们的溶剂合物、噻吗洛尔马来酸盐等噻吗洛尔或其盐或者它们的溶剂合物、倍他洛尔盐酸盐等倍他洛尔或其盐或者它们的溶剂合物、左布诺洛尔盐酸盐等左布诺洛尔或其盐或者它们的溶剂合物、苯呋洛尔或其盐或者它们的溶剂合物、美替洛尔或其盐或者它们的溶剂合物的β阻断剂;包含多佐胺盐酸盐等多佐胺或其盐或者它们的溶剂合物、布林佐胺或其盐或者它们的溶剂合物、乙酰唑胺或其盐或者它们的溶剂合物、双氯非那胺或其盐或者它们的溶剂合物、醋甲唑胺或其盐或者它们的溶剂合物的碳酸酐酶抑制剂;包含异丙基乌诺前列酮或其盐或者它们的溶剂合物、他氟前列素或其盐或者它们的溶剂合物、曲伏前列素或其盐或者它们的溶剂合物、比马前列素或其盐或者它们的溶剂合物、拉坦前列素或其盐或者它们的溶剂合物、氯前列醇或其盐或者它们的溶剂合物、氟前列醇或其盐或者它们的溶剂合物的前列腺素或其衍生物(例如前列腺素F2α衍生物);包含利舒地尔或其盐或者它们的溶剂合物、Y-39983、H-1129的Rho激酶抑制剂;包含地匹福林盐酸盐等地匹福林或其盐或者它们的溶剂合物、肾上腺素、肾上腺素硼酸盐、肾上腺素盐酸盐等肾上腺素或其盐或者它们的溶剂合物的拟交感神经药;包含溴地斯的明或其盐或者它们的溶剂合物、匹鲁卡品、匹鲁卡品盐酸盐、匹鲁卡品硝酸盐等匹鲁卡品或其盐或者它们的溶剂合物、卡巴胆碱或其盐或者它们的溶剂合物的拟副交感神经药;包含洛美利嗪盐酸盐等洛美利嗪或其盐或者它们的溶剂合物的钙拮抗剂;包含地美卡林或其盐或者它们的溶剂合物、二乙氧膦酰硫胆碱或其盐或者它们的溶剂合物、毒扁豆碱或其盐或者它们的溶剂合物的胆碱酯酶抑制剂等,可以配合它们的1种或2种以上。
作为其他的药效成分,优选β阻断剂,优选噻吗洛尔。
其中,水性组合物也可以不含上述前列腺素或其衍生物。例如,作为一个方式的水性组合物,优选以下的<A-1>~<A-10>以外的组合物。
<A-1>含有(外消旋)-2-(二甲基氨基)-N-(1-羟基异喹啉-6-基)-2-(噻吩-3-基)乙酰胺盐酸盐、曲伏前列素、硼酸、D-甘露糖醇、苯扎氯铵、硬脂酸聚烃氧酯40、聚乙二醇400、EDTA和精制水的组合物。
<A-2>含有(外消旋)-2-(二甲基氨基)-N-(1-羟基异喹啉-6-基)-2-(噻吩-3-基)乙酰胺盐酸盐、曲伏前列素、硼酸、D-甘露糖醇、苯扎氯铵、克列莫佛(Cremophor)RH40、聚乙二醇400、EDTA和精制水的组合物。
<A-3>含有(外消旋)-2-(二甲基氨基)-N-(1-羟基异喹啉-6-基)-2-(噻吩-3-基)乙酰胺盐酸盐、曲伏前列素、硼酸、D-甘露糖醇、硬脂酸聚烃氧酯40、聚乙二醇400、EDTA和精制水的组合物。
<A-4>含有(外消旋)-2-(二甲基氨基)-N-(1-羟基异喹啉-6-基)-2-(噻吩-3-基)乙酰胺盐酸盐、拉坦前列素、磷酸二氢钠、磷酸氢二钠、苯扎氯铵、氯化钠、EDTA和精制水的组合物。
<A-5>含有(外消旋)-2-(二甲基氨基)-N-(1-羟基异喹啉-6-基)-2-(噻吩-3-基)乙酰胺盐酸盐、拉坦前列素、硼酸、D-甘露糖醇、苯扎氯铵、EDTA和精制水的组合物。
<A-6>含有(外消旋)-2-(二甲基氨基)-N-(1-羟基异喹啉-6-基)-2-(噻吩-3-基)乙酰胺盐酸盐、比马前列素、磷酸二氢钠、磷酸氢二钠、苯扎氯铵、氯化钠、EDTA和精制水的组合物。
<A-7>含有(外消旋)-2-(二甲基氨基)-N-(1-羟基异喹啉-6-基)-2-(噻吩-3-基)乙酰胺盐酸盐、比马前列素、磷酸二氢钠、磷酸氢二钠、苯扎氯铵、氯化钠、EDTA和精制水的组合物。
<A-8>含有(外消旋)-2-(二甲基氨基)-N-(1-羟基异喹啉-6-基)-2-(噻吩-3-基)乙酰胺盐酸盐、比马前列素、硼酸、D-甘露糖醇和精制水的组合物。
<A-9>含有2,4-二甲基苯甲酸(S)-4-(3-氨基-1-(异喹啉-6-基氨基)-1-氧代丙烷-2-基)苄酯、曲伏前列素、硼酸、D-甘露糖醇、苯扎氯铵、硬脂酸聚烃氧酯40、聚乙二醇400、EDTA和精制水的组合物。
<A-10>含有2,4-二甲基苯甲酸(S)-4-(3-氨基-1-(异喹啉-6-基氨基)-1-氧代丙烷-2-基)苄酯、拉坦前列素、硼酸、D-甘露糖醇、苯扎氯铵、硬脂酸聚烃氧酯40、聚乙二醇400、EDTA和精制水的组合物。
水性组合物的pH(25℃)没有特别限定,优选为3~9,更优选为3.5~8,进一步优选为4~7,特别优选为5~6。另外,相对于生理盐水的渗透压比没有特别限定,优选为0.6~3,特别优选为0.6~2。
本发明的医药制剂使用聚酯系树脂制容器或聚烯烃系树脂制容器。
在本说明书中,“容器”是指直接收纳上述水性组合物的包装体。容器是包括第十七次修正日本药典通则定义的“密闭容器”、“气密容器”、“密封容器”的任意容器在内的概念。
关于该容器的形态,只要能够收纳上述水性组合物,就没有特别限定,可以根据剂型、医药制剂的用途等适当选择、设定。作为这样的容器的形态,具体而言,例如可以列举注射剂用容器、吸入剂用容器、喷雾剂用容器、瓶状容器、管状容器、滴眼剂用容器、滴鼻剂用容器、滴耳剂用容器、袋状容器等。
作为容器,从有利地利用通式(1)所示的化合物所具有的药理作用的观点考虑,优选为滴眼剂用容器。
在本说明书中,“聚酯系树脂制容器”是指容器中至少与水性组合物接触的部分为“聚酯系树脂制”的容器。因此,例如在与水性组合物接触的内层设置聚酯系树脂的层、在其外侧使其他材质的树脂等叠层等而形成的容器也属于“聚酯系树脂制容器”。其中,构成聚酯系树脂的二羧酸、二元醇没有特别限定,作为二羧酸,例如可以列举邻苯二甲酸、对苯二甲酸、2,6-萘二羧酸等;作为二元醇,例如可以列举乙二醇、1,3-丙二醇、1,4-丁二醇、1,4-环己烷二甲醇、双酚等。另外,可以为单一种类的聚酯单元的聚合物,也可以为多种的聚酯单元的聚合物。另外,为多种的聚酯单元的聚合物时,其聚合方式没有特别限定,可以为无规聚合,也可以为嵌段聚合。另外,其有规立构性(tacticity)没有特别限定。
作为这样的聚酯系树脂,具体而言,例如可以列举聚亚烷基对苯二甲酸酯(例如聚对苯二甲酸乙二醇酯、聚对苯二甲酸丁二醇酯等)、聚亚烷基萘二甲酸酯(例如聚萘二甲酸乙二醇酯、聚萘二甲酸丁二醇酯等)、聚亚环烷基对苯二甲酸酯(例如聚(1,4-亚环己基二亚甲基对苯二甲酸酯)等)、聚芳酯(例如由双酚和苯二甲酸构成的树脂等)等均聚聚酯、含有这些均聚聚酯单元作为主要成分的共聚聚酯以及上述均聚聚酯的共聚物等,可以使用它们中的1种或者组合使用它们中的2种以上。作为聚酯系树脂,从抑制通式(1)所示的化合物在高温保存时含量降低的观点考虑,优选聚对苯二甲酸乙二醇酯。
另外,在本说明书中,“聚酯系树脂制”是指其材质的至少一部分含有聚酯系树脂,例如,聚酯系树脂和其他树脂的2种以上的树脂的混合物(聚合物合金)也包含在“聚酯系树脂制”内。
在本说明书中,“聚烯烃系树脂制容器”是指容器中至少与水性组合物接触的部分为“聚烯烃系树脂制”的容器。因此,例如在与水性组合物接触的内层设置聚烯烃系树脂的层、在其外侧使其他材质的树脂等叠层等而成的容器也相当于“聚烯烃系树脂制容器”。其中,聚烯烃系树脂没有特别限定,可以为单一种类的单体的聚合物(均聚物),也可以为多种单体的共聚物(copolymer)。另外,为共聚物时,其聚合方式没有特别限定,可以为无规聚合,也可以为嵌段聚合。另外,其有规立构性(tacticity)没有特别限定。
作为这样的聚烯烃系树脂,具体而言,例如可以列举聚乙烯(更详细而言,例如低密度聚乙烯(包含直链状低密度聚乙烯)、高密度聚乙烯、中密度聚乙烯等)、聚丙烯、环状聚烯烃、聚(4-甲基戊烯)、聚四氟乙烯、乙烯-丙烯共聚物、乙烯-α-烯烃共聚物、乙烯-丙烯酸共聚物、乙烯-甲基丙烯酸共聚物、乙烯-乙酸乙烯酯共聚物、乙烯-丙烯酸乙酯共聚物等,可以使用它们中的1种或者组合使用它们中的2种以上。作为聚烯烃系树脂,从抑制通式(1)所示的化合物在高温保存时含量降低的观点考虑,优选聚乙烯、聚丙烯、环状聚烯烃,更优选低密度聚乙烯、中密度聚乙烯、高密度聚乙烯、聚丙烯,特别优选低密度聚乙烯、高密度聚乙烯、聚丙烯。
其中,在本说明书中,“聚烯烃系树脂制”是指其材质的至少一部分含有聚烯烃系树脂,例如,聚烯烃系树脂和其他的树脂的2种以上的树脂的混合物(聚合物合金)也包含在“聚烯烃系树脂制”内。
还优选向容器中掺入紫外线吸收剂或紫外线散射剂等阻碍紫外线透过的物质。由此,通式(1)所示的化合物对光的稳定性得到改善。具体而言,例如,作为紫外线散射剂,可以列举氧化钛;氧化锌等。另外,作为紫外线吸收剂,可以列举:2-(2H-苯并三唑-2-基)-对甲酚(例如Tinuvin P、BASF公司)、2-(2H-苯并三唑-2-基)-4,6-双(1-甲基-1-苯基乙基)苯酚(例如Tinuvin 234、BASF公司)、2-(3,5-二叔丁基-2-羟基苯基)苯并三唑(例如Tinuvin320、BASF公司)、2-[5-氯(2H)-苯并三唑-2-基]-4-甲基-6-(叔丁基)苯酚(例如Tinuvin 326、BASF公司)、2-(3,5-二叔丁基-2-羟基苯基)-5-氯苯并三唑(例如Tinuvin327、BASF公司)、2-(2H-苯并三唑-2-基)-4,6-二叔戊基苯酚(例如Tinuvin PA328、BASF公司)、2-(2H-苯并三唑-2-基)-4-(1,1,3,3-四甲基丁基)苯酚(例如Tinuvin 329、BASF公司)、2,2'-亚甲基双[6-(2H-苯并三唑-2-基)-4-(1,1,3,3-四甲基丁基)苯酚(例如Tinuvin 360、BASF公司)、甲基3-(3-(2H-苯并三唑-2-基)-5-叔丁基-4-羟基苯基)丙酸酯与聚乙二醇300的反应产物(例如Tinuvin 213、BASF公司)、2-(2H-苯并三唑-2-基)-6-十二烷基-4-甲基苯酚(例如Tinuvin 571、BASF公司)、2-(2'-羟基-3',5'-二叔戊基苯基)苯并三唑、2-[2'-羟基-3'-(3”,4”,5”,6”-四氢邻苯二甲酰亚胺甲基)-5'-甲基苯基]苯并三唑、2,2'-亚甲基双[4-(1,1,3,3-四甲基丁基)-6-(2H-苯并三唑-2-基)苯酚]等苯并三唑系紫外线吸收剂;2,2-双{[2-氰基-3,3-二苯基丙烯酰氧基]甲基}丙烷-1,3-二基=双(2-氰基-3,3-二苯基丙烯酸酯)(例如Uvinul 3030FF、BASF公司)、2-氰基-3,3-二苯基丙烯酸乙酯(例如Uvinul 3035、BASF公司)、2-氰基-3,3-二苯基丙烯酸2-乙基己酯(例如Uvinul 3039、BASF公司)等的氰基丙烯酸酯系紫外线吸收剂;2-(4,6-二苯基-1,3,5-三嗪-2-基)-5-[(己基)氧]-苯酚(例如Tinuvin 1577ED、BASF公司)等三嗪系紫外线吸收剂;辛苯酮(例如Chimassorb 81、BASF公司)、2,2'-二羟基-4,4'-二甲氧基二苯甲酮(例如Uvinul 3049、BASF公司)、2,2'-4,4'-四氢二苯甲酮(例如Uvinul3050、BASF公司)、羟甲氧苯酮、羟基甲氧基二苯甲酮磺酸、羟基甲氧基二苯甲酮磺酸钠、二羟基二甲氧基二苯甲酮、二羟基二甲氧基二苯甲酮二磺酸钠、二羟基二苯甲酮、四羟基二苯甲酮等二苯甲酮系紫外线吸收剂;二异丙基肉桂酸甲酯、西诺沙酯、二对甲氧基肉桂酸单-2-乙基己酸甘油酯、对甲氧基肉桂酸异丙酯-肉桂酸二异丙酯混合物、对甲氧基肉桂酸2-乙基己酯、肉桂酸苄酯等肉桂酸系紫外线吸收剂;对氨基苯甲酸、对氨基苯甲酸乙酯、对氨基苯甲酸甘油酯、对二甲基氨基苯甲酸戊酯、对二甲基氨基苯甲酸2-乙基己酯、4-[N,N-二(2-羟基丙基)氨基]苯甲酸乙酯等苯甲酸酯系紫外线吸收剂;水杨酸乙二醇酯、水杨酸辛酯、水杨酸二丙二醇酯、水杨酸苯酯、水杨酸高孟酯(Homomenthyl Salicylate)、水杨酸甲酯等水杨酸系紫外线吸收剂;愈创蓝油烃(Guaiazulene);二甲氧基亚苄基二氧代四氢咪唑丙酸2-乙基己酯;2,4,6-三[4-(2-乙基己基氧基羰基)苯胺基]1,3,5-三嗪;对羟基苯甲醚;4-叔丁基-4'-甲氧基二苯甲酰甲烷;苯基苯并咪唑磺酸;2-(4-二乙基氨基-2-羟基苯甲酰基)-苯甲酸己酯等。
其中,容器中掺入阻碍紫外线透过的物质时,其配合比例根据该物质的种类等而不同,例如在容器中可以为0.001~50质量%、优选为0.002~25质量%、特别优选为0.01~10质量%左右。
容器优选能够用肉眼辨识(能够观察)其内部。若能够辨识内部,则会产生能够在医药制剂的制造工序中检査有无异物混入等、医药制剂的使用者能够确认内容物(水性组合物)的剩余量等优点。其中,可辨识性至少在容器表面的一部分被确保即可(例如,即使滴眼剂用容器的侧面因收缩膜等而无法透视,若能够辨识底面,也称为能够辨识。)。在容器表面的一部分能够辨识内部时,由此能够确认容器内的水性组合物。
水性组合物向容器中的收纳方法没有特别限定,可以根据容器的形态等利用通常方法进行填充等。
医药制剂或水性组合物例如可以按照第十七次修正日本药典制剂总则等所记载的公知的方法制成各种剂型。作为剂型,例如可以列举注射剂、吸入液剂、滴眼剂、眼软膏剂、滴耳剂、滴鼻液剂、灌肠剂、外用液剂、喷雾剂、软膏剂、凝胶剂、经口液剂、糖浆剂等。作为剂型,从有利地利用通式(1)所示的化合物所具有的药理作用的观点考虑,优选眼睛疾病用剂、具体为滴眼剂、眼软膏剂,特别优选滴眼剂。
医药制剂的适用疾病没有特别限定,可以根据通式(1)所示的化合物所具有的药理作用等适当选择。
具体而言,例如基于通式(1)所示的化合物所具有的Rho激酶抑制作用、去甲肾上腺素转运体抑制作用和眼压降低作用,可以作为高眼压症或青光眼的预防或治疗剂而利用。其中,作为青光眼,更详细而言,例如可以列举原发性开角型青光眼、正常眼压青光眼、分泌过多性青光眼、急性闭角型青光眼、慢性闭角型青光眼、虹膜高褶综合征(plateauiris syndrome)、混合型青光眼、类固醇性青光眼、囊膜性青光眼、色素性青光眼、淀粉样蛋白青光眼、新生血管性青光眼、恶性青光眼等。
其中,在将水性组合物或医药制剂用作眼睛疾病(优选选自高眼压症和青光眼中的疾病)的预防或治疗剂时,例如可以1日1~3次左右适量给药。
本说明书不受这些任何限定,例如公开以下的方式的实施方式。
[1]一种医药制剂,其通过将含有下述通式(1)所示的化合物或其盐或者它们的溶剂合物的水性组合物收纳在聚酯系树脂制容器或聚烯烃系树脂制容器中而得到。
(式中,R1和R2分别独立地表示氢原子或C1~C4烷基,
R3表示氢原子或羟基,
A表示-CH(R4)-或-CH2-CH(R4)-(其中,R4表示可以具有取代基的C6~C10芳基或可以具有取代基的5~10元的杂芳基。),
式(1)还包含其互变异构体。)
[2]如[1]所述的医药制剂,其中,上述通式(1)所示的化合物为下述式(2)、(5)、(5')或(8)所示的化合物:
[3]如[1]所述的医药制剂,其中,上述通式(1)所示的化合物为下述式(3)或(6)所示的化合物:
[4]如[1]所述的医药制剂,其中,上述通式(1)所示的化合物为下述式(4)或(7)所示的化合物:
[5]如[1]~[4]中任一项所述的医药制剂,其中,上述聚酯系树脂为聚对苯二甲酸乙二醇酯。
[6]如[1]~[5]中任一项所述的医药制剂,其中,上述聚烯烃系树脂为聚乙烯或聚丙烯。
[7]如[1]~[6]中任一项所述的医药制剂,其中,上述容器为滴眼剂用容器。
[8]一种提高上述通式(1)所示的化合物或其盐或者它们的溶剂合物在水性组合物中的热稳定性的方法,其包括将含有上述通式(1)所示的化合物或其盐或者它们的溶剂合物的水性组合物收纳在聚酯系树脂制容器或聚烯烃系树脂制容器中的工序(其中,“提高热稳定性的方法”是指高温下保存时抑制含量降低的方法。并且,例如,与将同一水性组合物收纳在玻璃制的容器中的情况相比,若高温(例如80℃)下保存一定时间(例如1周)后含量降低被抑制,则称为“提高了热稳定性”。)。
[9]如[8]所述的方法,其中,上述通式(1)所示的化合物为上述式(2)、(5)、(5')或(8)所示的化合物。
[10]如[8]所述的方法,其中,上述通式(1)所示的化合物为上述式(3)或(6)所示的化合物。
[11]如[8]所述的方法,其中,上述通式(1)所示的化合物为上述式(4)或(7)所示的化合物。
[12]如[8]~[11]中任一项所述的方法,其中,上述聚酯系树脂为聚对苯二甲酸乙二醇酯。
[13]如[8]~[12]中任一项所述的方法,其中,上述聚烯烃系树脂为聚乙烯或聚丙烯。
[14]如[8]~[13]中任一项所述的方法,其中,上述容器为滴眼剂用容器。
实施例
接着,列举实施例对本发明进一步进行说明,但是本发明不受这些任何限定。
另外,在以下的试验例中,关于利用HPLC的奈他地尔的测定,使用ODS柱作为柱,使用0.01摩尔/L磷酸缓冲液和乙腈作为流动相,使用紫外吸光光度计(波长:254nm)作为检测器。
[试验例1]热稳定性试验
通过确认在高温条件下保存一定时间后奈他地尔的含量是否降低,评价奈他地尔在水性组合物中对热的稳定性。
即,在按照通常方法调制表1所示配方的水性组合物后,装入聚对苯二甲酸乙二醇酯(PET)制、低密度聚乙烯(LDPE)制、高密度聚乙烯(HDPE)制或聚丙烯(PP)制的容器中,分别制成实施例1~4的医药制剂。另外,还将相同的水性组合物装入玻璃制的容器中,制成比较例的医药制剂。
将所得到的各医药制剂在80℃保存1周。为了确认保存后的奈他地尔的含量是否降低,测定各医药制剂的保存前后的水性组合物中的奈他地尔的浓度。使用HPLC,测定水性组合物中的峰面积相对于浓度已知的奈他地尔溶液的峰面积的比率,由此算出水性组合物中的奈他地尔的浓度。
然后,利用所得到的水性组合物中的奈他地尔的浓度,按照以下的式子评价奈他地尔的残存率(%)。
残存率(%)={(保存后的水性组合物中的奈他地尔的浓度)/(保存前的水性组合物中的奈他地尔的浓度)}×100
将结果示于表2。
[表1]
成分 | 分量(每100mL) |
奈他地尔2甲磺酸盐 | 0.02848g(以游离体计为0.02g) |
硼酸 | 0.05g |
氢氧化钠 | 适量(pH5.0) |
精制水 | 余量 |
[表2]
如表2记载的结果所示,将含有奈他地尔的水性组合物收纳在聚对苯二甲酸乙二醇酯(PET)制的容器(实施例1)、聚乙烯(LDPE、HDPE)制的容器(实施例2、3)、聚丙烯(PP)制的容器(实施例4)中时,与收纳在玻璃制的容器(比较例)的情况相比较,在高温条件下保存时的含量降低相对地被抑制了。
特别是收纳在聚对苯二甲酸乙二醇酯(PET)制或聚乙烯(LDPE、HDPE)制的容器中时,含量降低的抑制程度显著。
根据以上的试验例1的结果明确了,通过将含有奈他地尔所代表的上述通式(1)所示的化合物或其盐或者它们的溶剂合物的水性组合物收纳在聚对苯二甲酸乙二醇酯所代表的聚酯系树脂制容器或者聚乙烯、聚丙烯所代表的聚烯烃系树脂制容器中,高温条件下保存时,也可以将含量降低相对地抑制得较低,保存稳定性优异。
[试验例2]吸附试验
为了研究奈他地尔是否向聚酯系树脂制容器吸附,使聚酯系树脂制的切片与含有奈他地尔的水性组合物共存,保存一定时间后,确认水性组合物中的奈他地尔的含量是否降低。
即,按照通常方法调制表3所示的水性组合物后,将其中的5mL收纳在玻璃容器中,然后,将3片聚对苯二甲酸乙二醇酯(PET)制的树脂切片(分别为1cm×2cm的大小)浸渍在水性组合物中,得到例1的医药制剂。另外,除了不浸渍聚对苯二甲酸乙二醇酯制的树脂切片以外,与例1同样操作,得到例2的医药制剂。
将所得到的各医药制剂在60℃保存1周。为了确认保存后的奈他地尔的含量是否降低,利用与试验例1相同的方法,评价奈他地尔的残存率(%)。
将结果示于表3。
[表3]
如表3记载的结果所示,根据例1和例2的对比,即使使聚对苯二甲酸乙二醇酯制的树脂切片与含有奈他地尔的水性组合物共存,也没有看到含量降低。
根据以上的试验结果明确了,即使将含有奈他地尔所代表的通式(1)所示的化合物或其盐或者它们的溶剂合物的水性组合物收纳在聚对苯二甲酸乙二醇酯所代表的聚酯系树脂制容器中,也看不到高温条件下因吸附等导致的含量降低,聚酯系树脂制容器适于收纳水性组合物。
[制造例1~36]
按照通常方法调制含有表4~表12所记载的成分和分量(每100mL水性组合物的量(g))的水性组合物,将其收纳在聚对苯二甲酸乙二醇酯制的滴眼剂用容器,能够制造制造例1~36的医药制剂。
[表4]
[表5]
[表6]
[表7]
[表8]
[表9]
[表10]
[表11]
[表12]
[制造例37~72]
在制造例1~36中,使用高密度聚乙烯制的滴眼剂用容器代替聚对苯二甲酸乙二醇酯制的滴眼剂用容器,能够制造制造例37~72的医药制剂。
[制造例73~108]
在制造例1~36中,使用聚丙烯制的滴眼剂用容器代替聚对苯二甲酸乙二醇酯制的滴眼剂用容器,能够制造制造例73~108的医药制剂。
[制造例109~144]
在制造例1~36中,使用低密度聚乙烯制的滴眼剂用容器代替聚对苯二甲酸乙二醇酯制的滴眼剂用容器,能够制造制造例109~144的医药制剂。
[制造例145~288]
作为制造例145~288的医药制剂,可以在制造例1~144中,使用以游离体计为0.5g的维罗舒地尔1盐酸盐代替奈他地尔2甲磺酸盐,按照通常方法制造。
[制造例289~432]
作为制造例289~432的医药制剂,可以在制造例1~144中,使用以游离体计为0.7g的维罗舒地尔1盐酸盐代替奈他地尔2甲磺酸盐,按照通常方法制造。
[制造例433~576]
作为制造例433~576的医药制剂,可以在制造例1~144中,使用0.02g的式(8)所示的化合物代替奈他地尔2甲磺酸盐,按照通常方法制造。
产业上的可利用性
利用本发明,能够提供稳定性优异的医药制剂,能够适合利用于医药品行业等中。
Claims (10)
1.一种医药制剂,其特征在于:
其是通过将含有下述通式(1)所示的化合物或其盐或者它们的溶剂合物的水性组合物收纳在聚酯系树脂制容器或聚烯烃系树脂制容器而得到的,
式中,R1和R2分别独立地表示氢原子或C1~C4烷基,
R3表示氢原子或羟基,
A表示-CH(R4)-或-CH2-CH(R4)-,其中,R4表示可以具有取代基的C6~C10芳基或可以具有取代基的5~10元的杂芳基,
式(1)还包含其互变异构体。
2.如权利要求1所述的医药制剂,其特征在于:
所述通式(1)所示的化合物为下述式(2)、(5)、(5')或(8)所示的化合物:
3.如权利要求1所述的医药制剂,其特征在于:
所述通式(1)所示的化合物为下述式(3)所示的化合物:
4.如权利要求1~3中任一项所述的医药制剂,其特征在于:
所述聚酯系树脂为聚对苯二甲酸乙二醇酯。
5.如权利要求1~3中任一项所述的医药制剂,其特征在于:
所述聚烯烃系树脂为聚乙烯或聚丙烯。
6.一种提高下述通式(1)所述的化合物或其盐或者它们的溶剂合物在水性组合物中的热稳定性的方法,其特征在于,包括:
将含有所述通式(1)所示的化合物或其盐或者它们的溶剂合物的水性组合物收纳在聚酯系树脂制容器或聚烯烃系树脂制容器的工序,
式中,R1和R2分别独立地表示氢原子或C1~C4烷基,
R3表示氢原子或羟基,
A表示-CH(R4)-或-CH2-CH(R4)-,其中,R4表示可以具有取代基的C6~C10芳基或可以具有取代基的5~10元的杂芳基,
式(1)还包含其互变异构体。
7.如权利要求6所述的方法,其特征在于:
所述通式(1)所示的化合物为下述式(2)、(5)、(5')或(8)所示的化合物:
8.如权利要求6所述的方法,其特征在于:
所述通式(1)所示的化合物为下述式(3)所示的化合物:
9.如权利要求6~8中任一项所述的方法,其特征在于:
所述聚酯系树脂为聚对苯二甲酸乙二醇酯。
10.如权利要求6~8中任一项所述的方法,其特征在于:
所述聚烯烃系树脂为聚乙烯或聚丙烯。
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