JP6694682B2 - ナノ粒子活性物質組成物におけるフレーク状凝集の軽減 - Google Patents
ナノ粒子活性物質組成物におけるフレーク状凝集の軽減 Download PDFInfo
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- JP6694682B2 JP6694682B2 JP2015185009A JP2015185009A JP6694682B2 JP 6694682 B2 JP6694682 B2 JP 6694682B2 JP 2015185009 A JP2015185009 A JP 2015185009A JP 2015185009 A JP2015185009 A JP 2015185009A JP 6694682 B2 JP6694682 B2 JP 6694682B2
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- chloride
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- 239000000203 mixture Substances 0.000 title claims description 297
- 239000013543 active substance Substances 0.000 title claims description 195
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- 239000002245 particle Substances 0.000 claims description 232
- 238000000034 method Methods 0.000 claims description 113
- 239000003381 stabilizer Substances 0.000 claims description 98
- -1 sorbitan ester Chemical class 0.000 claims description 60
- 239000002105 nanoparticle Substances 0.000 claims description 55
- 239000006185 dispersion Substances 0.000 claims description 40
- 239000000126 substance Substances 0.000 claims description 38
- 238000004220 aggregation Methods 0.000 claims description 33
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 27
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 27
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 26
- 239000003795 chemical substances by application Substances 0.000 claims description 24
- 150000001875 compounds Chemical class 0.000 claims description 21
- 230000004931 aggregating effect Effects 0.000 claims description 19
- 125000002091 cationic group Chemical group 0.000 claims description 18
- 239000007788 liquid Substances 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 16
- 229920000642 polymer Polymers 0.000 claims description 15
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 14
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 14
- 239000003638 chemical reducing agent Substances 0.000 claims description 14
- 239000000872 buffer Substances 0.000 claims description 13
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 13
- 229920001577 copolymer Polymers 0.000 claims description 12
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 11
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 11
- 229930195729 fatty acid Natural products 0.000 claims description 11
- 239000000194 fatty acid Substances 0.000 claims description 11
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 10
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 244000060011 Cocos nucifera Species 0.000 claims description 9
- 235000013162 Cocos nucifera Nutrition 0.000 claims description 9
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 9
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 claims description 9
- 125000000129 anionic group Chemical group 0.000 claims description 9
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 9
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 9
- 229920001223 polyethylene glycol Polymers 0.000 claims description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 8
- 229920001400 block copolymer Polymers 0.000 claims description 8
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 8
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 8
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 8
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 8
- 150000003904 phospholipids Chemical class 0.000 claims description 8
- 229920001983 poloxamer Polymers 0.000 claims description 8
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 8
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 7
- 239000002202 Polyethylene glycol Substances 0.000 claims description 7
- 229920002678 cellulose Polymers 0.000 claims description 7
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 6
- 235000010980 cellulose Nutrition 0.000 claims description 6
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical group OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 6
- 239000007972 injectable composition Substances 0.000 claims description 6
- 239000012064 sodium phosphate buffer Substances 0.000 claims description 6
- AISMNBXOJRHCIA-UHFFFAOYSA-N trimethylazanium;bromide Chemical compound Br.CN(C)C AISMNBXOJRHCIA-UHFFFAOYSA-N 0.000 claims description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 5
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 5
- 239000001913 cellulose Substances 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- 235000011187 glycerol Nutrition 0.000 claims description 5
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 claims description 5
- 108010010803 Gelatin Proteins 0.000 claims description 4
- 229920003115 HPC-SL Polymers 0.000 claims description 4
- 235000010443 alginic acid Nutrition 0.000 claims description 4
- 229920000615 alginic acid Polymers 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 238000000149 argon plasma sintering Methods 0.000 claims description 4
- JBIROUFYLSSYDX-UHFFFAOYSA-M benzododecinium chloride Chemical compound [Cl-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 JBIROUFYLSSYDX-UHFFFAOYSA-M 0.000 claims description 4
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 4
- 239000008116 calcium stearate Substances 0.000 claims description 4
- 235000013539 calcium stearate Nutrition 0.000 claims description 4
- 239000004359 castor oil Substances 0.000 claims description 4
- 235000019438 castor oil Nutrition 0.000 claims description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 4
- 239000004927 clay Substances 0.000 claims description 4
- DDXLVDQZPFLQMZ-UHFFFAOYSA-M dodecyl(trimethyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCC[N+](C)(C)C DDXLVDQZPFLQMZ-UHFFFAOYSA-M 0.000 claims description 4
- 239000008273 gelatin Substances 0.000 claims description 4
- 229920000159 gelatin Polymers 0.000 claims description 4
- 235000019322 gelatine Nutrition 0.000 claims description 4
- 235000011852 gelatine desserts Nutrition 0.000 claims description 4
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 4
- 229960003511 macrogol Drugs 0.000 claims description 4
- HICYUNOFRYFIMG-UHFFFAOYSA-N n,n-dimethyl-1-naphthalen-1-ylmethanamine;hydrochloride Chemical compound [Cl-].C1=CC=C2C(C[NH+](C)C)=CC=CC2=C1 HICYUNOFRYFIMG-UHFFFAOYSA-N 0.000 claims description 4
- 239000008057 potassium phosphate buffer Substances 0.000 claims description 4
- 239000007974 sodium acetate buffer Substances 0.000 claims description 4
- YJHSJERLYWNLQL-UHFFFAOYSA-N 2-hydroxyethyl(dimethyl)azanium;chloride Chemical compound Cl.CN(C)CCO YJHSJERLYWNLQL-UHFFFAOYSA-N 0.000 claims description 3
- 229920002307 Dextran Polymers 0.000 claims description 3
- SHBUUTHKGIVMJT-UHFFFAOYSA-N Hydroxystearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OO SHBUUTHKGIVMJT-UHFFFAOYSA-N 0.000 claims description 3
- 102000016943 Muramidase Human genes 0.000 claims description 3
- 108010014251 Muramidase Proteins 0.000 claims description 3
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 3
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 3
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 235000021355 Stearic acid Nutrition 0.000 claims description 3
- 239000008351 acetate buffer Substances 0.000 claims description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
- 235000019270 ammonium chloride Nutrition 0.000 claims description 3
- 229960001927 cetylpyridinium chloride Drugs 0.000 claims description 3
- YMKDRGPMQRFJGP-UHFFFAOYSA-M cetylpyridinium chloride Chemical group [Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 YMKDRGPMQRFJGP-UHFFFAOYSA-M 0.000 claims description 3
- 239000007979 citrate buffer Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 claims description 3
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 claims description 3
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 claims description 3
- 229940072106 hydroxystearate Drugs 0.000 claims description 3
- 239000004325 lysozyme Substances 0.000 claims description 3
- 235000010335 lysozyme Nutrition 0.000 claims description 3
- 229960000274 lysozyme Drugs 0.000 claims description 3
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 claims description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- 235000021317 phosphate Nutrition 0.000 claims description 3
- 239000008363 phosphate buffer Substances 0.000 claims description 3
- 229920001987 poloxamine Polymers 0.000 claims description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 3
- 150000003856 quaternary ammonium compounds Chemical class 0.000 claims description 3
- 239000008117 stearic acid Substances 0.000 claims description 3
- JVAZJLFFSJARQM-RMPHRYRLSA-N (2r,3r,4s,5s,6r)-2-hexoxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound CCCCCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O JVAZJLFFSJARQM-RMPHRYRLSA-N 0.000 claims description 2
- QAQSNXHKHKONNS-UHFFFAOYSA-N 1-ethyl-2-hydroxy-4-methyl-6-oxopyridine-3-carboxamide Chemical compound CCN1C(O)=C(C(N)=O)C(C)=CC1=O QAQSNXHKHKONNS-UHFFFAOYSA-N 0.000 claims description 2
- DBRHJJQHHSOXCQ-UHFFFAOYSA-N 2,2-dihydroxyethyl(methyl)azanium;chloride Chemical compound [Cl-].C[NH2+]CC(O)O DBRHJJQHHSOXCQ-UHFFFAOYSA-N 0.000 claims description 2
- MPNXSZJPSVBLHP-UHFFFAOYSA-N 2-chloro-n-phenylpyridine-3-carboxamide Chemical compound ClC1=NC=CC=C1C(=O)NC1=CC=CC=C1 MPNXSZJPSVBLHP-UHFFFAOYSA-N 0.000 claims description 2
- 241000416162 Astragalus gummifer Species 0.000 claims description 2
- CXRFDZFCGOPDTD-UHFFFAOYSA-M Cetrimide Chemical compound [Br-].CCCCCCCCCCCCCC[N+](C)(C)C CXRFDZFCGOPDTD-UHFFFAOYSA-M 0.000 claims description 2
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims description 2
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 claims description 2
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- JVAZJLFFSJARQM-UHFFFAOYSA-N O-n-hexyl beta-D-glucopyranoside Natural products CCCCCCOC1OC(CO)C(O)C(O)C1O JVAZJLFFSJARQM-UHFFFAOYSA-N 0.000 claims description 2
- 239000004721 Polyphenylene oxide Substances 0.000 claims description 2
- 229920001615 Tragacanth Polymers 0.000 claims description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 2
- NJSSICCENMLTKO-HRCBOCMUSA-N [(1r,2s,4r,5r)-3-hydroxy-4-(4-methylphenyl)sulfonyloxy-6,8-dioxabicyclo[3.2.1]octan-2-yl] 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)O[C@H]1C(O)[C@@H](OS(=O)(=O)C=2C=CC(C)=CC=2)[C@@H]2OC[C@H]1O2 NJSSICCENMLTKO-HRCBOCMUSA-N 0.000 claims description 2
- FOLJTMYCYXSPFQ-CJKAUBRRSA-N [(2r,3s,4s,5r,6r)-6-[(2s,3s,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)-2-(octadecanoyloxymethyl)oxolan-2-yl]oxy-3,4,5-trihydroxyoxan-2-yl]methyl octadecanoate Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](COC(=O)CCCCCCCCCCCCCCCCC)O[C@@H]1O[C@@]1(COC(=O)CCCCCCCCCCCCCCCCC)[C@@H](O)[C@H](O)[C@@H](CO)O1 FOLJTMYCYXSPFQ-CJKAUBRRSA-N 0.000 claims description 2
- 150000003926 acrylamides Chemical group 0.000 claims description 2
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 2
- 150000005215 alkyl ethers Chemical class 0.000 claims description 2
- 125000005211 alkyl trimethyl ammonium group Chemical group 0.000 claims description 2
- UUZYBYIOAZTMGC-UHFFFAOYSA-M benzyl(trimethyl)azanium;bromide Chemical compound [Br-].C[N+](C)(C)CC1=CC=CC=C1 UUZYBYIOAZTMGC-UHFFFAOYSA-M 0.000 claims description 2
- WMLFGKCFDKMAKB-UHFFFAOYSA-M benzyl-diethyl-tetradecylazanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCC[N+](CC)(CC)CC1=CC=CC=C1 WMLFGKCFDKMAKB-UHFFFAOYSA-M 0.000 claims description 2
- 229920001222 biopolymer Polymers 0.000 claims description 2
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- 239000005018 casein Substances 0.000 claims description 2
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 claims description 2
- 235000021240 caseins Nutrition 0.000 claims description 2
- 229940082500 cetostearyl alcohol Drugs 0.000 claims description 2
- 235000012000 cholesterol Nutrition 0.000 claims description 2
- 229960001231 choline Drugs 0.000 claims description 2
- WOQQAWHSKSSAGF-WXFJLFHKSA-N decyl beta-D-maltopyranoside Chemical compound O[C@@H]1[C@@H](O)[C@H](OCCCCCCCCCC)O[C@H](CO)[C@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 WOQQAWHSKSSAGF-WXFJLFHKSA-N 0.000 claims description 2
- JDRSMPFHFNXQRB-IBEHDNSVSA-N decyl glucoside Chemical compound CCCCCCCCCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O JDRSMPFHFNXQRB-IBEHDNSVSA-N 0.000 claims description 2
- CDJGWBCMWHSUHR-UHFFFAOYSA-M decyl(triethyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCC[N+](CC)(CC)CC CDJGWBCMWHSUHR-UHFFFAOYSA-M 0.000 claims description 2
- RLGGVUPWOJOQHP-UHFFFAOYSA-M decyl-(2-hydroxyethyl)-dimethylazanium;chloride Chemical compound [Cl-].CCCCCCCCCC[N+](C)(C)CCO RLGGVUPWOJOQHP-UHFFFAOYSA-M 0.000 claims description 2
- PLMFYJJFUUUCRZ-UHFFFAOYSA-M decyltrimethylammonium bromide Chemical compound [Br-].CCCCCCCCCC[N+](C)(C)C PLMFYJJFUUUCRZ-UHFFFAOYSA-M 0.000 claims description 2
- 229960004670 didecyldimethylammonium chloride Drugs 0.000 claims description 2
- GQOKIYDTHHZSCJ-UHFFFAOYSA-M dimethyl-bis(prop-2-enyl)azanium;chloride Chemical compound [Cl-].C=CC[N+](C)(C)CC=C GQOKIYDTHHZSCJ-UHFFFAOYSA-M 0.000 claims description 2
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 claims description 2
- NLEBIOOXCVAHBD-QKMCSOCLSA-N dodecyl beta-D-maltoside Chemical compound O[C@@H]1[C@@H](O)[C@H](OCCCCCCCCCCCC)O[C@H](CO)[C@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 NLEBIOOXCVAHBD-QKMCSOCLSA-N 0.000 claims description 2
- VVNBOKHXEBSBQJ-UHFFFAOYSA-M dodecyl(triethyl)azanium;bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](CC)(CC)CC VVNBOKHXEBSBQJ-UHFFFAOYSA-M 0.000 claims description 2
- XJWSAJYUBXQQDR-UHFFFAOYSA-M dodecyltrimethylammonium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)C XJWSAJYUBXQQDR-UHFFFAOYSA-M 0.000 claims description 2
- PBRIXADXGMHVMW-UHFFFAOYSA-N formaldehyde;4-(2,4,4-trimethylpentan-2-yl)phenol Chemical compound O=C.CC(C)(C)CC(C)(C)C1=CC=C(O)C=C1 PBRIXADXGMHVMW-UHFFFAOYSA-N 0.000 claims description 2
- NIDYWHLDTIVRJT-UJPOAAIJSA-N heptyl-β-d-glucopyranoside Chemical compound CCCCCCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O NIDYWHLDTIVRJT-UJPOAAIJSA-N 0.000 claims description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 2
- 229940071826 hydroxyethyl cellulose Drugs 0.000 claims description 2
- PYIDGJJWBIBVIA-UYTYNIKBSA-N lauryl glucoside Chemical compound CCCCCCCCCCCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O PYIDGJJWBIBVIA-UYTYNIKBSA-N 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- 235000010981 methylcellulose Nutrition 0.000 claims description 2
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- JVAZJLFFSJARQM-YBXAARCKSA-N n-Hexyl-beta-D-glucopyranoside Natural products CCCCCCO[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JVAZJLFFSJARQM-YBXAARCKSA-N 0.000 claims description 2
- UMWKZHPREXJQGR-XOSAIJSUSA-N n-methyl-n-[(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl]decanamide Chemical compound CCCCCCCCCC(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO UMWKZHPREXJQGR-XOSAIJSUSA-N 0.000 claims description 2
- VHYYJWLKCODCNM-OIMNJJJWSA-N n-methyl-n-[(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl]heptanamide Chemical compound CCCCCCC(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO VHYYJWLKCODCNM-OIMNJJJWSA-N 0.000 claims description 2
- GCRLIVCNZWDCDE-SJXGUFTOSA-N n-methyl-n-[(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl]nonanamide Chemical compound CCCCCCCCC(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO GCRLIVCNZWDCDE-SJXGUFTOSA-N 0.000 claims description 2
- SBWGZAXBCCNRTM-CTHBEMJXSA-N n-methyl-n-[(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl]octanamide Chemical compound CCCCCCCC(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO SBWGZAXBCCNRTM-CTHBEMJXSA-N 0.000 claims description 2
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Description
米国特許第5,145,684号(「‘684特許」)に最初に記載されたナノ粒子活性物質組成物は、表面上に非架橋表面安定剤が吸着または会合した難溶性治療用または診断用物質を含む粒子である。
「高分子表面安定剤とジオクチルナトリウムスルホスクシナートとの相乗的組合せ体を含むナノ粒子分散体(Nanoparticulate Dispersions Comprising a Synergistic Combination of a Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate)」に関する米国特許第6,592,903号;「衛生的湿式磨砕のための装置(Apparatus for sanitary wet milling)」に関する米国特許第6,582,285号;「無定形シクロスポリンを含むナノ粒子組成物(Nanoparticulate Compositions Comprising Amorphous Cyclosporine)」に関する米国特許第6,656,504号;「物質の磨砕のための系および方法(System and Method for Milling Materials)」に関する米国特許第6,742,734号;「小規模ミルおよびその方法(Small Scale Mill and Method Thereof)」に関する米国特許第6,745,962号;「ナノ粒子薬の液滴エアゾール剤(Liquid droplet aerosols of nanoparticulate drugs)」に関する米国特許第6,811,767号;「即時放出特性と制御放出特性との組合せを含有する組成物(Compositions having a combination of immediate release and controlled release characteristics)」に関する米国特許第6,908,626号;「表面安定剤としてのビニルピロリドンと酢酸ビニルとのコポリマーを含むナノ粒子組成物(Nanoparticulate compositions comprising copolymers of vinyl pyrrolidone and vinyl acetate as surface stabilizers)」に関する米国特許第6,969,529号;および「物質の磨砕のための系および方法(System and Method for Milling Materials)」に関する米国特許第6,976,647号;「小規模ミルの使用方法(Method of Using a Small Scale Mill)」に関する米国特許第6,991,191号;「ナノ粒子メゲストロール製剤(Nanoparticulate Megestrol Formulation)」に関する米国特許第7,101,576号;「ナノ粒子活性物質組成物の微粒子の剤形のin vivo有効性を評価するためのin vitro法(In vitro methods for evaluating the in vivo effectiveness of dosage forms of microparticulate of nanoparticulate active agent compositions)」に関する米国特許第7,198,795号;「表面安定剤としてのビニルピロリドンと酢酸ビニルとのコポリマーを含むナノ粒子薬物組成物の製造方法(Methods of making nanoparticulate drug compositions comprising copolymers of vinyl pyrrolidone and vinyl acetate as surface stabilizers)」に関する米国特許第7,244,451号;「ナノ粒子フィブラート製剤(Nanoparticulate Fibrate Formulations)」に関する米国特許第7,276,249号;「カチオン性表面安定剤を含有する生物接着性ナノ粒子組成物(Bioadhesive nanoparticulate compositions having cationic surface stabilizers)」に関する米国特許第7,288,267号;「ナノ粒子フェノフィブラート組成物を使用する治療方法(Methods of treatment using nanoparticulate fenofibrate compositions)」に関する米国特許第7,320,802号;および「ナノ粒子トピラマート製剤(Nanoparticulate topiramate formulations)」に関する米国特許第7,390,505号(それらの全てを明示的に参照により本明細書に組み入れることとする)。
「ナノ粒子ビカルタミド製剤(Nanoparticulate bicalutamide formulations)」に関する米国特許公開第20060159767号:「ナノ粒子タクロリムス製剤(Nanoparticulate tacrolimus formulations)」に関する米国特許公開第20060159766号:「ナノ粒子ベンゾチオフェン製剤(Nanoparticulate benzothiophene formulations)」に関する米国特許公開第20060159628号:「注射可能なナノ粒子オランザピン製剤(Injectable nanoparticulate olanzapine formulations)」に関する米国特許公開第20060154918号:「トピラマート医薬組成物(Topiramate pharmaceutical composition)」に関する米国特許公開第20060121112号:「制御放出性ナノ粒子組成物(Controlled Release Nanoparticulate Compositions)」に関する米国特許公開第20020012675 A1号:「物質を磨砕するための組成物および方法(Compositions and method for milling materials)」に関する米国特許公開第20040195413 A1号:「マイクログラム量のナノ粒子候補化合物の磨砕(Milling microgram quantities of nanoparticulate candidate compounds)」に関する米国特許公開第20040173696 A1号:「制御放出性ナノ粒子組成物(Controlled Release Nanoparticulate Compositions)」に関する2002年1月31日付け公開の米国特許公開第20020012675 A1号:「ナノ粒子フィブラート製剤(Nanoparticulate Fibrate Formulations)」に関する米国特許公開第20050276974号:「表面安定剤としてのペプチドを含有するナノ粒子組成物(Nanoparticulate compositions having a peptide as a surface stabilizer)」に関する米国特許公開第20050238725号:「ナノ粒子メゲストロール製剤(Nanoparticulate megestrol formulations)」に関する米国特許公開第20050233001号:「抗体を含む組成物およびナノ粒子活性物質の運搬を標的化するためのその使用方法(Compositions comprising antibodies and methods of using the same for targeting nanoparticulate active agent delivery)」に関する米国特許公開第20050147664号:「新規メタキサロン組成物(Novel metaxalone compositions)」に関する米国特許公開第20050063913号:「シルデナフィル遊離塩基の新規組成物(Novel compositions of sildenafil free base)」に関する米国特許公開第20050042177号:「ゲル安定化ナノ粒子活性物質組成物(Gel stabilized nanoparticulate active agent compositions)」に関する米国特許公開第20050031691号:「新規グリピジド組成物(Novel glipizide compositions)」に関する米国特許公開第20050019412号:「新規グリセオフルビン組成物(Novel griseofulvin compositions)」に関する米国特許公開第20050004049号:「ナノ粒子トピラマート製剤(Nanoparticulate topiramate formulations)」に関する米国特許公開第20040258758号:「安定ナノ粒子活性物質の液体投与組成物(Liquid dosage compositions of stable nanoparticulate active agents)」に関する米国特許公開第20040258757号:「ナノ粒子メロキシカム製剤(Nanoparticulate meloxicam formulations)」に関する米国特許公開第20040229038号:「新規フルチカゾン製剤(Novel fluticasone formulations)」に関する米国特許公開第20040208833号:「物質を磨砕するための組成物および方法(Compositions and method for milling materials)」に関する米国特許公開第20040195413号:「プルランを含む固体剤形(Solid dosage forms comprising pullulan)」に関する米国特許公開第20040156895号:「新規ニメスリド組成物(Novel nimesulide compositions)」に関する米国特許公開第20040156872号:「新規トリアムシノロン組成物(Novel triamcinolone compositions)」に関する米国特許公開第20040141925号:「新規ニフェジピン組成物(Novel nifedipine compositions)」に関する米国特許公開第20040115134号:「低粘度液体剤形(Low viscosity liquid dosage forms)」に関する米国特許公開第20040105889号:「固体ナノ粒子活性物質のガンマ照射(Gamma irradiation of solid nanoparticulate active agents)」に関する米国特許公開第20040105778号:「新規ベンゾイルペルオキシド組成物(Novel benzoyl peroxide compositions)」に関する米国特許公開第20040101566号:「ナノ粒子ベクロメタゾンジプロピオナート組成物(Nanoparticulate beclomethasone dipropionate compositions)」に関する米国特許公開第20040057905号
:「血管新生インヒビターのナノ粒子組成物(Nanoparticulate compositions of angiogenesis inhibitors)」に関する米国特許公開第20040033267号:「ナノ粒子ステロール製剤および新規ステロールの組合せ(Nanoparticulate sterol formulations and novel sterol combinations)」に関する米国特許公開第20040033202号:「ナノ粒子ナイスタチン製剤(Nanoparticulate nystatin formulations)」に関する米国特許公開第20040018242号:「薬物運搬系および方法(Drug delivery systems and methods)」に関する米国特許公開第20040015134号:「ナノ粒子ポリコサノール製剤および新規ポリコサノールの組合せ(Nanoparticulate polycosanol formulations & novel polycosanol combinations)」に関する米国特許公開第20030232796号:「低下した脆砕性を有する急速溶解剤形(Fast dissolving dosage forms having reduced friability)」に関する米国特許公開第20030215502号:「表面安定剤としてのリゾチームを含有するナノ粒子組成物(Nanoparticulate compositions having lysozyme as a surface stabilizer)」に関する米国特許公開第20030185869号:「マイトジェン活性化タンパク質(MAP)キナーゼインヒビターのナノ粒子組成物(Nanoparticulate compositions of mitogen-activated protein (MAP) kinase inhibitors)」に関する米国特許公開第20030181411号:「(Compositions having a combination of immediate release and controlled release characteristics)」に関する米国特許公開第20030137067号:「表面安定剤としてのビニルピロリドンと酢酸ビニルとのコポリマーを含むナノ粒子組成物(Nanoparticulate compositions comprising copolymers of vinyl pyrrolidone and vinyl acetate as surface stabilizers)」に関する米国特許公開第20030108616号:「ナノ粒子インスリン(Nanoparticulate insulin)」に関する米国特許公開第20030095928号:「小規模ミルまたはミクロフルイディクスを使用するハイスループットスクリーニングのための方法(Method for high through put screening using a small scale mill or microfluidics)」に関する米国特許公開第20030087308号:「薬物運搬系および方法(Drug delivery systems & methods)」に関する米国特許公開第20030023203号:「物質を磨砕するための系および方法(System and method for milling materials)」に関する米国特許公開第20020179758号:および「衛生的湿式磨砕のための装置(Apparatus for sanitary wet milling)」に関する米国特許公開第20010053664号はナノ粒子活性物質組成物を記載しており、それらを明示的に参照により本明細書に組み入れることとする。
いずれの粒子組成物も静脈内(I.V.)または筋肉内(I.M.)投与に関してFDAにより承認されるためには、該組成物は、米国薬局方(United States Pharmacopeia)のGeneral Chapter 788(「USP<788>」)に記載されている基準を満たさなければならないことが当業者に公知である。特に、米国では、いずれの粒子物質注射溶液も、USP<788>の粒子のサイズおよび数の要件を満たさなければならない。すなわち、USP<788>に記載されている承認された「光暗化(Light Obscuration)」試験(「方法1」として公知)では、(i)10μmを超えるサイズの粒子が粒子組成物中に6,000個以下、および(ii)25μmを超えるサイズの粒子が600個以下しか存在しないことが必要である。顕微鏡試験である「方法2」においては、粒子組成物は(i)粒子組成物中に、10μmを超えるサイズの粒子を3,000個以下、および(ii)25μmを超えるサイズの粒子を300個以下しか含有してはならない。理論上想定される大きな粒子は、互いに塊化した個々の粒子の凝集物の存在を表す。ナノ粒子製剤は、おそらくコロイド界面現象により引き起こされるフレーク状凝集物(「FLA」)を形成する固有傾向を有する、と理論上想定される。凝集物の形態はその全体的形状において極めて二次元のものであるため、「FLA」は、おそらく、気-液境界において形成されるのであろう。そのような凝集物は、一般には、光学顕微鏡検査および走査電子顕微鏡技術を用いて観察されているが、光散乱に基づく粒子分粒技術を用いては検出されていない。
本発明は、本明細書においては、以下および本出願の全体に記載されている幾つかの定義を用いて説明される。
本発明の組成物は、ナノ粒子活性物質、該活性物質の表面に吸着または会合する少なくとも1つの表面安定剤、および少なくとも1つのフレーク状凝集軽減剤を含む。また、該組成物は1以上の第2のフレーク状凝集軽減剤を含みうる。本発明において有用な表面安定剤は該ナノ粒子活性物質の表面に物理的に付着または会合するが、該活性物質またはそれ自体と化学的に反応しない。該表面安定剤の個々の分子は分子間架橋を実質的に引き起こさない。
本発明のナノ粒子は少なくとも1つの活性物質、治療用物質または診断用物質(「薬物」と総称される)を含む。治療用物質は、例えばタンパク質、ペプチドおよびヌクレオチドのような生物学的物質を含む医薬物質、または例えば造影剤(X線造影剤を含む)のような診断用物質でありうる。
該活性物質は、例えば以下のものを含む種々の公知クラスの薬物から選択されうる:栄養薬効物質、COX-2インヒビター、レチノイド、抗癌物質、NSAID、タンパク質、ペプチド、ヌクレオチド、抗肥満薬、栄養薬効物質、栄養補助食品(食品サプリメント)、カロテノイド、コルチコステロイド、エラスターゼインヒビター、抗菌物質、腫瘍学療法、鎮吐薬、鎮痛薬、心血管剤、抗炎症剤、駆虫剤、抗不整脈剤、抗生物質(ペニシリンを含む)、抗凝固薬、抗うつ薬、抗糖尿病薬、抗てんかん薬、抗ヒスタミン薬、抗高血圧剤、抗ムスカリン剤、抗マイコバクテリア剤、抗腫瘍剤、免疫抑制剤、抗甲状腺剤、抗ウイルス剤、抗不安薬、鎮静薬(睡眠薬および神経遮断薬)、収斂剤、β-アドレナリン受容体遮断剤、血液製剤および同効薬、心臓変力剤、造影剤、コルチコステロイド、咳抑制剤(去痰および粘液溶解薬)、診断剤、診断用イメージング剤、利尿薬、ドーパミン作動薬(抗パーキンソン剤)、止血、免疫学的物質、脂質調節剤、筋弛緩薬、副交感神経刺激薬、副甲状腺カルシトニンおよびビスホスホナート、プロスタグランジン、放射性医薬品、性ホルモン(ステロイドを含む)、抗アレルギー剤、興奮薬および食欲減退物質、交感神経作用薬、甲状腺剤、血管拡張薬およびキサンチン。
有用な抗癌物質は、好ましくは、アルキル化剤、代謝拮抗物質、天然物、ホルモンおよびアンタゴニスト、ならびに放射性増感剤のような雑多な物質から選択される。
鎮痛性物質はNSAIDまたはCOX-2インヒビターでありうる。
本発明の組成物は1以上の表面安定剤を含む。本発明の表面安定剤は、好ましくは、該活性物質粒子の表面上に吸着され、または該活性物質粒子の表面と会合する。本発明において特に有用な表面安定剤は該活性物質粒子またはそれ自体と化学的に反応しない。好ましくは、該補助的表面安定剤の個々の分子は分子間架橋を実質的に引き起こさない。
(i)R1-R4のいずれもがCH3ではない;
(ii)R1-R4の1つがCH3である;
(iii)R1-R4の3つがCH3である;
(iv)R1-R4の全てがCH3である;
(v)R1-R4の2つがCH3であり、R1-R4の1つがC6H5CH2であり、R1-R4の1つが、7個以下の炭素原子のアルキル鎖である;
(vi)R1-R4の2つがCH3であり、R1-R4の1つがC6H5CH2であり、R1-R4の1つが、19個以上の炭素原子のアルキル鎖である;
(vii)R1-R4の2つがCH3であり、R1-R4の1つが基C6H5(CH2)n(ここで、n>1である)である;
(viii)R1-R4の2つがCH3であり、R1-R4の1つがC6H5CH2であり、R1-R4の1つが少なくとも1つのヘテロ原子を含む;
(ix)R1-R4の2つがCH3であり、R1-R4の1つがC6H5CH2であり、R1-R4の1つが少なくとも1つのハロゲンを含む;
(x)R1-R4の2つがCH3であり、R1-R4の1つがC6H5CH2であり、R1-R4の1つが少なくとも1つの環状断片を含む;
(xi)R1-R4の2つがCH3であり、R1-R4の1つがフェニル環である;または
(xii)R1-R4の2つがCH3であり、R1-R4の2つが純粋に脂肪族の断片である。
本発明は、ナノ粒子活性物質組成物に糖を加えることにより又はナノ粒子活性物質のpHレベルを塩基性条件へと増加させることによりフレーク状凝集の軽減が達成されうるという驚くべき知見に関する。
本発明の医薬組成物は、1以上の結合剤、充填剤、滑沢剤、懸濁化剤、甘味剤、香味剤、保存剤、バッファー、湿潤剤、崩壊剤、起泡剤および他の賦形剤をも含みうる。そのような賦形剤は当技術分野で公知である。
本発明の組成物は、約2000nm(すなわち、2ミクロン)未満の有効平均粒径を有するナノ粒子活性物質粒子を含有する。本発明の他の実施形態においては、該活性物質粒子は、光散乱法、顕微鏡検査または他の適当な方法による測定で、約1900 nm未満、約1800 nm未満、約1700 nm未満、約1600 nm未満、約1500 nm未満、約1400 nm未満、約1300 nm未満、約1200 nm未満、約1100 nm未満、約1000 nm未満、約990 nm未満、約980 nm未満、約970 nm未満、約960 nm未満、約950 nm未満、約940 nm未満、約930 nm未満、約920 nm未満、約910 nm未満、約900 nm未満、約890 nm未満、約880 nm未満、約870 nm未満、約860 nm未満、約850 nm未満、約840 nm未満、約830 nm未満、約820 nm未満、約810 nm未満、約800 nm未満、約790 nm未満、約780 nm未満、約770 nm未満、約760 nm未満、約750 nm未満、約740 nm未満、約730 nm未満、約720 nm未満、約710 nm未満、約700 nm未満、約690 nm未満、約680 nm未満、約670 nm未満、約660 nm未満、約650 nm未満、約640 nm未満、約630 nm未満、約620 nm未満、約610 nm未満、約600 nm未満、約590 nm未満、約580 nm未満、約570 nm未満、約560 nm未満、約550 nm未満、約540 nm未満、約530 nm未満、約520 nm未満、約510 nm未満、約500 nm未満、約490 nm未満、約480 nm未満、約470 nm未満、約460 nm未満、約450 nm未満、約440 nm未満、約430 nm未満、約420 nm未満、約410 nm未満、約400 nm未満、約390 nm未満、約380 nm未満、約370 nm未満、約360 nm未満、約350 nm未満、約340 nm未満、約330 nm未満、約320 nm未満、約310 nm未満、約300 nm未満、約290 nm未満、約280 nm未満、約270 nm未満、約260 nm未満、約250 nm未満、約240 nm未満、約230 nm未満、約220 nm未満、約210 nm未満、約200 nm未満、約190 nm未満、約180 nm未満、約170 nm未満、約160 nm未満、約150 nm未満、約140 nm未満、約130 nm未満、約120 nm未満、約110 nm未満、約100未満、約75 nm、または約50 nm未満のサイズを有する。
粒子組成物の代表的サンプリングの1以上は、商業的に入手可能な分粒および計数装置を使用してUSP法に従いアッセイされうる。これらの商業的に入手可能な粒子計数装置は、サンプル粒子の注射溶液がUSP<788>粒径要件に適合していることを確認するために設計されたものである。
以下の説明文は、注射剤用の粒子薬品を製造するためのUSP<788>指針から採用されたものであり、その第788章の全体を参照により本明細書に組み入れることとする。
粒子のサイズとサイズに応じた粒子数との自動的決定を可能にする遮光の原理に基づく適当な装置を使用する。粒子非含有水に関する定義が、Reagents, Indicators and Solutionの節のReagent Specificationsに記載されている。
該試験は、好ましくは層流キャビネットにおいて、粒状物を限定する条件下で行われる。
該容器をゆっくりと連続的に20回反転させることにより、該サンプルの内容物を混合する。必要に応じて、密封栓を注意深く取り外す。容器開口部の外部表面を、粒子非含有水の噴射を用いて清浄化し、該内容物が汚染されないように該栓を取り外す。適当な手段(例えば、2分間の放置または音波処理)により気泡を排除する。
100mlを超える呼称容量を有する容器内に供給された調製物に関して、試験1.Aの基準を適用する。
適当な双眼顕微鏡、粒状物を保持するためのフィルター装置、および検査のための膜フィルターを使用する。
該試験は、好ましくは層流キャビネットにおいて、粒状物を限定する条件下で行われる。
本発明は、承認粒子薬品を得るためのUSP<788>に記載されている特定の装置または方法に限定されない。例えば、USP<788>の「顕微鏡検査」の種々の態様、例えば、フィルターの細孔のサイズ、照明の源および方向、顕微鏡で粒子を可視化するのを補助するために使用されるカラーフィルターのタイプ、ならびに希釈により溶液の粘度を減少させうる種々の方法は様々なものとなりうることが、当業者に公知である。例えば、該フィルターは、約5μmのサイズ、約4μmのサイズ、約3μmのサイズ、約2μmのサイズまたは約1μmのサイズのフィルター孔径を有しうることが、当業者に公知である。1つの実施形態においては、該フィルター孔径は約1〜5μmのサイズである。同様に、観察するサンプルを載せる顕微鏡プラットフォームは顕微鏡装置の上または下から照明されうることが公知である。1つの実施形態においては、照明源は上からである。同様に、照明の源および方向に応じて、サンプルを可視化するために使用されるカラーフィルターを変更することが可能であることが、当業者に公知である。したがって、この目的のために暗色、黒色、灰色または白色のフィルターが利用可能であることが、当業者に公知である。1つの実施形態においては、該フィルターは白色である。したがって、1つの実施形態においては、本発明は、白色フィルターを使用して上から照明される5μmの細孔サイズを有するフィルターを使用することにより、USP<788>サイズ閾値要件に適合した粒子薬品を得ることを想定している。もう1つの実施形態においては、USP<788>法において粘度を減少させるための溶液の希釈方法は当業者に公知である。
活性物質、表面安定剤およびフレーク状凝集軽減剤の相対量は広範に変動しうる。個々の成分の最適量は、例えば、選択された個々の活性物質および表面安定剤、該表面安定剤の水溶液の親水性親油性比(HLB)、融点および表面張力などに左右されうる。
少なくとも1つの表面安定剤と少なくとも1つのフレーク状凝集軽減剤とを含む本発明のナノ粒子活性物質組成物は、例えば、磨砕または粉砕(限定的なものではないが湿式磨砕を含む)、均質化、沈殿、凍結、鋳型エマルション技術、超臨界流体技術、ナノエレクトロスプレー技術またはそれらの任意の組合せを用いて製造されうる。ナノ粒子活性物質組成物の典型的な製造方法は'684特許に記載されている。ナノ粒子活性物質組成物の製造方法は以下のものにも記載されている:「医薬物質の粉砕方法(Method of Grinding Pharmaceutical Substances)」に関する米国特許第5,518,187号;「医薬物質の連続的粉砕方法(Continuous Method of Grinding Pharmaceutical Substances)」に関する米国特許第5,718,388号;「医薬物質の粉砕方法(Method of Grinding Pharmaceutical Substances)」に関する米国特許第5,862,999号;「結晶成長修飾剤でのナノ粒子医薬物質の共微小沈殿(Co-Microprecipitation of Nanoparticulate Pharmaceutical Agents with Crystal Growth Modifiers)」に関する米国特許第5,665,331号;「結晶成長修飾剤でのナノ粒子医薬物質の共微小沈殿(Co-Microprecipitation of Nanoparticulate Pharmaceutical Agents with Crystal Growth Modifiers)」に関する米国特許第5,662,883号;「ナノ粒子医薬物質の微小沈殿(Microprecipitation of Nanoparticulate Pharmaceutical Agents)」に関する米国特許第5,560,932号;「ナノ粒子を含有するX線造影組成物の製造方法(Process of Preparing X-Ray Contrast Compositions Containing Nanoparticles)」に関する米国特許第5,543,133号;「安定薬物ナノ粒子の製造方法(Method of Preparing Stable Drug Nanoparticles)」に関する米国特許第5,534,270号;「ナノ粒子を含有する治療用組成物の製造方法(Process of Preparing Therapeutic Compositions Containing Nanoparticles)」に関する米国特許第5,510,118号;および「凝集を軽減する荷電リン脂質を含有するナノ粒子組成物の製造方法(Method of Preparing Nanoparticle Compositions Containing Charged Phospholipids to Reduce Aggregation)」に関する米国特許第5,470,583号(これらの全てを明示的に参照により本明細書に組み入れることとする)。
ナノ粒子コロイド性分散液を得るための活性物質の磨砕は、該活性物質が難溶性である液体分散媒に活性物質粒子を分散させ、ついで粉砕媒体の存在下で機械的手段を適用して、該活性物質の粒径を所望の有効平均粒径まで減少させることを含む。該分散媒は、例えば水、サフラワー油、エタノール、t-ブタノール、グリセリン、ポリエチレングリコール(PEG)、ヘキサンまたはグリコールでありうる。水が、好ましい分散媒である。
所望のナノ粒子活性物質組成物を形成させるためのもう1つの方法は微小沈殿(microprecipitation)によるものである。これは、微量毒性溶媒または可溶化重金属不純物を伴わないで、1以上の表面安定剤および1以上のコロイド安定性増強界面活性剤の存在下で難溶性活性物質の安定ナノ粒子活性物質分散液を製造する方法である。そのような方法は、例えば、(1)該難溶性活性物質を適当な溶媒に溶解し、(2)少なくとも1つの表面安定剤および場合によっては1以上のフレーク状凝集軽減剤を含む溶液に工程(1)からの調製物を加えて透明溶液を得、(3)適当な非溶媒を使用して工程(2)からの調製物を沈殿させることを含む。該方法の後、形成した塩が存在する場合には、通常の手段による該分散液の透析またはダイアフィルトレーションおよび濃縮により該塩を除去することが可能である。
活性物質ナノ粒子活性物質組成物を製造する典型的な均質化方法は「ナノ粒子を含有する治療用組成物の製造方法(Process of Preparing Therapeutic Compositions Containing Nanoparticles)」に関する米国特許第5,510,118号に記載されている。
所望のナノ粒子活性物質組成物を形成させるためのもう1つの方法は液体中への噴霧凍結(SFL)によるものである。この技術は、1以上の表面安定剤と共に活性物質の有機または有機水性溶液を含む。1以上のフレーク状凝集軽減剤は粒子サイズ減少の前、途中または後で加えられうる。該組成物は低温液体、例えば液体窒素中に注入される。活性物質溶液の滴は、結晶化および粒子成長を最小にするのに十分な速度で凍結して、ナノ構造化活性物質粒子を生成する。溶媒系およびプロセス条件の選択に応じて、該ナノ粒子活性物質粒子は種々の粒子形態を有しうる。単離工程においては、該活性物質粒子のアグロメレーションまたは熟成を回避する条件下で該窒素および溶媒を除去する。
所望のナノ粒子活性物質組成物を形成させるもう1つの方法は鋳型エマルションによるものである。鋳型エマルションは、制御された粒径分布および迅速な溶解性能を有するナノ構造化活性物質粒子を生成する。該方法は、水中油型エマルションを調製し、ついで活性物質および1以上の表面安定剤を含む非水性溶液で膨潤させることを含む。1以上のフレーク状凝集軽減剤は粒径減少の前、途中または後のいずれかで加えられうる。該活性物質の粒径分布は、該活性物質のローディングの前のエマルション滴のサイズの直接的な結果であり、これは、このプロセスにおいて制御され最適化されうる特性である。さらに、溶媒および安定剤の選択された使用により、オストワルド熟成を伴わずに又はそれが抑制されて、エマルション安定性が達成される。ついで該溶媒および水を除去し、安定化ナノ構造化活性物質粒子を回収する。プロセス条件の適当な制御により、種々の活性物質粒子形態が得られうる。
ナノ粒子活性物質組成物は、超臨界流体を使用する方法においても製造されうる。そのような方法においては、該活性物質を、少なくとも1つの表面安定剤をも含有しうる溶液またはビヒクルに溶解する。1以上のフレーク状凝集軽減剤は粒径減少の前、途中または後のいずれかで加えられうる。ついで該溶液および超臨界流体を粒子形成容器内に同時導入する。表面安定剤が該容器内に予め加えられていない場合には、それを該粒子形成容器に加えることが可能である。該ビヒクルの分散および抽出が超臨界流体の作用により実質的に同時に生じるように、温度および圧力を制御する。超臨界流体として有用であると記載されている化学物質には、二酸化炭素、一酸化二窒素、六フッ化硫黄、キセノン、エチレン、クロロトリフルオロメタン、エタンおよびトリフルオロメタンが含まれる。
エレクトロスプレーイオン化においては、非常に小さな荷電した通常は金属の毛管を通って液体が押出される。この液体は、大量の溶媒に溶解された所望の活性物質を含有し、該溶媒は、通常、該活性物質(例えば、アナライト)より遥かに揮発性である。しばしば、揮発性酸、塩基またはバッファーもこの溶液に加えられる。該アナライトは溶解状態のプロトン化形態のイオンまたはアニオンとして存在する。同じ電荷は反発するため、該液体は該毛管から押出され、直径約10μmの小さな滴のエアゾールまたは霧状物を形成する。エアゾール滴のこの噴射は、少なくとも部分的には、テイラー・コーン(Taylor cone)の形成およびこのコーンの先端からの噴射を含む過程により生じる。該液体の噴霧を補助し該小滴中の中性溶媒の蒸発を補助するために、窒素ガスのような中性担体ガスが使用されることもある。該小滴が蒸発し、空気中に懸濁されるにつれて、該荷電アナライト分子は互いに、より接近する。同様に荷電した分子が互いに接近するにつれて該滴は不安定になり、該滴は再び破壊される。これはクーロン分裂と称される。なぜなら、それを駆動するのは荷電アナライト分子間の反発性クーロン力だからである。該アナライトが溶媒を失って孤立イオンになるまで、この過程が反復される。
本発明のナノ粒子活性物質組成物は、経口、直腸、眼内、非経口(静脈内、筋肉内または皮下)、槽内、肺、膣内、腹腔内、局所(散剤、軟膏剤または点滴剤)投与または頬側もしくは鼻腔内スプレー(これらに限定されるものではない)を含むいずれかの通常の手段によりヒトおよび動物に投与されうる。
本実施例の目的は、USP<788>標準を満たす、注射に適したナノ粒子メロキシカム(meloxicam)分散液を製造すること、および該分散液の安定性を試験することであった。
本実施例の目的は、粒状物および粒径の安定性に関してナノ粒子メロキシカム製剤をスクリーニングすることであった。
本実施例の目的は、メロキシカム粒子のサイズおよび粒状物に関して、マンニトールを含むナノ粒子メロキシカム製剤の安定性を試験することであった。
本実施例の目的は、粒状物およびメロキシカム粒径の安定性に関して、スクロースおよび/またはマンニトールを含むナノ粒子メロキシカム製剤をスクリーニングすることであった。
本実施例の目的は、滅菌濾過法に対するナノ粒子メロキシカム製剤の適合性、ひいては非経口的使用に対する適合性を示すことであった。
本実施例の目的は、メロキシカム粒径および粒状物に関して、種々のpHレベルを有するメロキシカム製剤の安定性を評価することであった。
Claims (19)
- (a)2000nm未満の平均粒径を有する活性物質であって、これは活性物質粒子の少なくとも50重量%が、光散乱法による測定で2000nm未満の粒径を有することを意味し、結晶相、無定形相、半結晶相およびそれらの混合物からなる群から選択される相である、前記活性物質、
(b)該活性物質の表面上に吸着される少なくとも1つの表面安定剤、および
(c)フレーク状凝集軽減剤
を含むナノ粒子注射可能組成物であって、
前記フレーク状凝集軽減剤が、リン酸バッファー、酢酸バッファー、クエン酸バッファー、リン酸ナトリウムバッファー、リン酸カリウムバッファーおよび酢酸ナトリウムバッファーからなる群から選択されるバッファーであり、7を超えるpHを有する、前記組成物。 - 該活性物質が、約1900 nm未満、約1800 nm未満、約1700 nm未満、約1600 nm未満、約1500 nm未満、約1400 nm未満、約1300 nm未満、約1200 nm未満、約1100 nm未満、約1000 nm未満、約900 nm未満、約800 nm未満、約700 nm未満、約600 nm未満、約500 nm未満、約400 nm未満、約300 nm未満、約250 nm未満、約200 nm未満、約150 nm未満、約100 nm未満、約75 nmおよび約50 nm未満からなる群から選択される平均粒径を有する、請求項1に記載の組成物。
- 該組成物が、10μmより大きなサイズを有する活性物質粒子を6,000個以下含有し、25μmより大きなサイズを有する活性物質粒子を600個以下含有する、請求項1または2に記載の組成物。
- 該組成物が、10μmより大きなサイズを有する活性物質粒子を3,000個以下含有し、25μmより大きなサイズを有する活性物質粒子を300個以下含有する、請求項1〜3のいずれか1項に記載の組成物。
- 該組成物が、25μmより大きな約1000個未満の活性物質粒子、25μmより大きな約900個未満の活性物質粒子、25μmより大きな約800個未満の活性物質粒子、25μmより大きな約700個未満の活性物質粒子、25μmより大きな約600個未満の活性物質粒子、25μmより大きな約500個未満の活性物質粒子、25μmより大きな約400個未満の活性物質粒子、25μmより大きな約300個未満の活性物質粒子、25μmより大きな約250個未満の活性物質粒子、25μmより大きな約200個未満の活性物質粒子、25μmより大きな約150個未満の活性物質粒子、25μmより大きな約100個未満の活性物質粒子、または25μmより大きな約50個未満の活性物質粒子を含有する、請求項1〜4のいずれか1項に記載の組成物。
- 該組成物が、10μmより大きな約10000個未満の活性物質粒子、10μmより大きな約9000個未満の活性物質粒子、10μmより大きな約8000個未満の活性物質粒子、10μmより大きな約7000個未満の活性物質粒子、10μmより大きな約6000個未満の活性物質粒子、10μmより大きな約5000個未満の活性物質粒子、10μmより大きな約4000個未満の活性物質粒子、10μmより大きな約3000個未満の活性物質粒子、10μmより大きな約2000個未満の活性物質粒子、または10μmより大きな約1000個未満の活性物質粒子を含有する、請求項1〜5のいずれか1項に記載の組成物。
- 該表面安定剤が、アニオン性表面安定剤、カチオン性表面安定剤、両性イオン性表面安定剤およびイオン性表面安定剤からなる群から選択される、請求項1〜6のいずれか1項に記載の組成物。
- 該表面安定剤が、セチルピリジニウムクロリド、ゼラチン、カゼイン、ホスファチド、デキストラン、グリセロール、アラビアゴム、コレステロール、トラガント、ステアリン酸、ベンザルコニウムクロリド、ステアリン酸カルシウム、グリセロールモノステアラート、セトステアリルアルコール、セトマクロゴール乳化ワックス、ソルビタンエステル、ポリオキシエチレンアルキルエーテル、ポリオキシエチレンヒマシ油誘導体、ポリオキシエチレンソルビタン脂肪酸エステル、ポリエチレングリコール、ドデシルトリメチルアンモニウムブロミド、ポリオキシエチレンステアラート、コロイド性二酸化ケイ素、ホスファート、ドデシル硫酸ナトリウム、カルボキシメチルセルロースカルシウム、ヒドロキシプロピルセルロース、ヒプロメロース、カルボキシメチルセルロースナトリウム、メチルセルロース、ヒドロキシエチルセルロース、ヒプロメロースフタラート、非結晶セルロース、マグネシウムアルミニウムシリカート、トリエタノールアミン、ポリビニルアルコール、ポリビニルピロリドン、エチレンオキシドおよびホルムアルデヒドとの4-(1,1,3,3-テトラメチルブチル)-フェノールポリマー、ポロキサマー; ポロキサミン、荷電リン脂質、ジオクチルスルホスクシナート、ナトリウムスルホコハク酸のジアルキルエステル、ラウリル硫酸ナトリウム、アルキルアリールポリエーテルスルホナート、スクロースステアラートとスクロースジステアラートとの混合物、p-イソノニルフェノキシポリ-(グリシドール)、デカノイル-N-メチルグルカミド; N-デシルβ-D-グルコピラノシド; n-デシルβ-D-マルトピラノシド; n-ドデシルβ-D-グルコピラノシド; n-ドデシルβ-D-マルトシド; ヘプタノイル-N-メチルグルカミド; n-ヘプチル-β-D-グルコピラノシド; n-ヘプチルβ-D-チオグルコシド; n-ヘキシルβ-D-グルコピラノシド; ノナノイル-N-メチルグルカミド; N-ノイルβ-D-グルコピラノシド; オクタノイル-N-メチルグルカミド; n-オクチル-β-D-グルコピラノシド; オクチルβ-D-チオグルコピラノシド; リゾチーム、PEG-リン脂質、PEG-コレステロール、PEG-コレステロール誘導体、PEG-ビタミンA、酢酸ビニルとビニルピロリドンとのランダムコポリマー、カチオン性ポリマー、カチオン性生体高分子、カチオン性多糖、カチオン性セルロース、カチオン性アルギナート、カチオン性非ポリマー化合物、カチオン性リン脂質、カチオン性脂質、ポリメチルメタクリラートトリメチルアンモニウムブロミド、スルホニウム化合物、ポリビニルピロリドン-2-ジメチルアミノエチルメタクリラートジメチルスルファート、ヘキサデシルトリメチルアンモニウムブロミド、ホスホニウム化合物、第四級アンモニウム化合物、ベンジル-ジ(2-クロロエチル)エチルアンモニウムブロミド、ココナッツトリメチルアンモニウムクロリド、ココナッツトリメチルアンモニウムブロミド、ココナッツメチルジヒドロキシエチルアンモニウムクロリド、ココナッツメチルジヒドロキシエチルアンモニウムブロミド、デシルトリエチルアンモニウムクロリド、デシルジメチルヒドロキシエチルアンモニウムクロリド、デシルジメチルヒドロキシエチルアンモニウムクロリドブロミド、C12-15ジメチルヒドロキシエチルアンモニウムクロリド、C12-15ジメチルヒドロキシエチルアンモニウムクロリドブロミド、ココナッツジメチルヒドロキシエチルアンモニウムクロリド、ココナッツジメチルヒドロキシエチルアンモニウムブロミド、ミリスチルトリメチルアンモニウムメチルスルファート、ラウリルジメチルベンジルアンモニウムクロリド、ラウリルジメチルベンジルアンモニウムブロミド、ラウリルジメチル(エテノキシ)4アンモニウムクロリド、ラウリルジメチル(エテノキシ)4アンモニウムブロミド、N-アルキル(C12-18)ジメチルベンジルアンモニウムクロリド、N-アルキル(C14-18)ジメチル-ベンジルアンモニウムクロリド、N-テトラデシリドメチルベンジルアンモニウムクロリド一水和物、ジメチルジデシルアンモニウムクロリド、N-アルキルおよび(C12-14)ジメチル 1-ナフチルメチルアンモニウムクロリド、トリメチルアンモニウムハライド、アルキル-トリメチルアンモニウム塩、ジアルキル-ジメチルアンモニウム塩、ラウリルトリメチルアンモニウムクロリド、エトキシ化アルキルアミドアルキルジアルキルアンモニウム塩、エトキシル化トリアルキルアンモニウム塩、ジアルキルベンゼンジアルキルアンモニウムクロリド、N-ジデシルジメチルアンモニウムクロリド、N-テトラデシルジメチルベンジルアンモニウム,クロリド一水和物、N-アルキル(C12-14)ジメチル 1-ナフチルメチルアンモニウムクロリド、ドデシルジメチルベンジルアンモニウムクロリド、ジアルキルベンゼンアルキルアンモニウムクロリド、ラウリルトリメチルアンモニウムクロリド、アルキルベンジルメチルアンモニウムクロリド、アルキルベンジルジメチルアンモニウムブロミド、C12トリメチルアンモニウムブロミド、C15トリメチルアンモニウムブロミド、C17トリメチルアンモニウムブロミド、ドデシルベンジルトリエチルアンモニウムクロリド、ポリ-ジアリルジメチルアンモニウムクロリド(DADMAC)、ジメチルアンモニウムクロリド、アルキルジメチルアンモニウムハロゲニド、トリセチルメチルアンモニウムクロリド、デシルトリメチルアンモニウムブロミド、ドデシルトリエチルアンモニウムブロミド、テトラデシルトリメチルアンモニウムブロミド、メチルトリオクチルアンモニウムクロリド、POLYQUAT 10(商標)、テトラブチルアンモニウムブロミド、ベンジルトリメチルアンモニウムブロミド、コリンエステル、ベンザルコニウムクロリド、ステアラルコニウムクロリド化合物、セチルピリジニウムブロミド、セチルピリジニウムクロリド、第四級化ポリオキシエチルアルキルアミンのハロゲン化物塩、MIRAPOL(商標)、ALKAQUAT(商標)、アルキルピリジニウム塩; アミン、アミン塩、アミンオキシド、イミドアゾリニウム塩、プロトン化第四級アクリルアミド、メチル化第四級ポリマーならびにカチオン性グアーからなる群から選択される、請求項1〜7のいずれか1項に記載の組成物。
- 該表面安定剤が、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース等級HPC-SL、ポリビニルピロリドン、エチレンオキシドおよびプロピレンオキシドに基づくブロックコポリマー、ポロキサマー、ビニルピロリドンと酢酸ビニルとのコポリマー、ジステアリルパルミタートグリセリル、ポリオキシエチレンソルビタン脂肪酸エステル、マクロゴール15ヒドロキシステアラート、チロキサポル(商標)およびクレモフォール(登録商標)からなる群から選択される、請求項1〜7のいずれか1項に記載の組成物。
- 8を超える、または9を超えるpHを有する、請求項1〜9のいずれか一項に記載の組成物。
- 1以上の製薬上許容される賦形剤、担体またはそれらの組合せを更に含む、請求項1〜10のいずれか1項に記載の組成物。
- 1より多いフレーク状凝集軽減剤を更に含む、請求項1〜11のいずれか1項に記載の組成物。
- 1より多い活性物質を更に含む、請求項1〜12のいずれか1項に記載の組成物。
- (a)活性物質と少なくとも1つの表面安定剤とのナノ粒子分散液を調製し、ここで、該分散液が、約2000 nm未満の有効平均粒径を有するナノ粒子活性物質を含み、これは活性物質粒子の少なくとも50重量%が、光散乱法による測定で2000nm未満の粒径を有することを意味し、かつ前記分散液が、少なくとも1つの表面安定剤と、該活性物質が難溶性である液体とをさらに含み、
(b)工程(a)の分散液にフレーク状凝集軽減剤を加えることを含み、フレーク状凝集軽減剤が、7を超えるpHを有する組成物を与えるバッファーであり、該バッファーが、リン酸バッファー、酢酸バッファー、クエン酸バッファー、リン酸ナトリウムバッファー、リン酸カリウムバッファーおよび酢酸ナトリウムバッファーからなる群から選択される、ナノ粒子組成物におけるフレーク状凝集を軽減する方法であって、
工程(a)及び工程(b)が、同時に又は連続的に行われ、前記活性物質が、結晶相、無定形相、半結晶相およびそれらの混合物からなる群から選択される相である、
方法。 - 該表面安定剤が、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース等級HPC-SL、ポリビニルピロリドン、エチレンオキシドおよびプロピレンオキシドに基づくブロックコポリマー、ポロキサマー、ビニルピロリドンと酢酸ビニルとのコポリマー、ジステアリルパルミタートグリセリル、ポリオキシエチレンソルビタン脂肪酸エステル、マクロゴール15ヒドロキシステアラート、チロキサポル(商標)およびクレモフォール(登録商標)からなる群から選択される、請求項14に記載の方法。
- 該組成物が、8を超える、または9を超えるpHを有する、請求項14又は15に記載の方法。
- 該組成物が、1以上の製薬上許容される賦形剤、担体またはそれらの組合せを更に含む、請求項14〜16のいずれか1項に記載の方法。
- 該組成物が、1より多いフレーク状凝集軽減剤を更に含む、請求項14〜17のいずれか1項に記載の方法。
- 該組成物が、1より多い活性物質を更に含む、請求項14〜18のいずれか1項に記載の方法。
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US11717481B2 (en) | 2023-08-08 |
US20180250229A1 (en) | 2018-09-06 |
JP2012528171A (ja) | 2012-11-12 |
EP2435027A2 (en) | 2012-04-04 |
JP2018138567A (ja) | 2018-09-06 |
EP3167875A1 (en) | 2017-05-17 |
AU2010254180A1 (en) | 2012-01-19 |
US20100316725A1 (en) | 2010-12-16 |
JP6072539B2 (ja) | 2017-02-01 |
US20220211626A1 (en) | 2022-07-07 |
US20160228554A1 (en) | 2016-08-11 |
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US9974747B2 (en) | 2018-05-22 |
JP2022126786A (ja) | 2022-08-30 |
CA2763456A1 (en) | 2010-12-02 |
US9345665B2 (en) | 2016-05-24 |
ES2609415T3 (es) | 2017-04-20 |
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