JP5292288B2 - Tmc278の水性懸濁液 - Google Patents
Tmc278の水性懸濁液 Download PDFInfo
- Publication number
- JP5292288B2 JP5292288B2 JP2009515890A JP2009515890A JP5292288B2 JP 5292288 B2 JP5292288 B2 JP 5292288B2 JP 2009515890 A JP2009515890 A JP 2009515890A JP 2009515890 A JP2009515890 A JP 2009515890A JP 5292288 B2 JP5292288 B2 JP 5292288B2
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- JP
- Japan
- Prior art keywords
- amino
- composition
- cyanoethenyl
- benzonitrile
- pyrimidinyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- YIBOMRUWOWDFLG-ONEGZZNKSA-N rilpivirine Chemical compound CC1=CC(\C=C\C#N)=CC(C)=C1NC1=CC=NC(NC=2C=CC(=CC=2)C#N)=N1 YIBOMRUWOWDFLG-ONEGZZNKSA-N 0.000 title abstract description 119
- 239000007900 aqueous suspension Substances 0.000 title description 5
- 208000031886 HIV Infections Diseases 0.000 claims abstract description 52
- 208000037357 HIV infectious disease Diseases 0.000 claims abstract description 52
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims abstract description 52
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 43
- 239000002105 nanoparticle Substances 0.000 claims abstract description 26
- 239000011859 microparticle Substances 0.000 claims abstract description 23
- 238000010254 subcutaneous injection Methods 0.000 claims abstract description 23
- 239000007929 subcutaneous injection Substances 0.000 claims abstract description 23
- 238000010255 intramuscular injection Methods 0.000 claims abstract description 22
- 239000007927 intramuscular injection Substances 0.000 claims abstract description 22
- 239000000203 mixture Substances 0.000 claims description 90
- 230000036470 plasma concentration Effects 0.000 claims description 74
- 239000002245 particle Substances 0.000 claims description 44
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 42
- 239000003814 drug Substances 0.000 claims description 42
- 230000002265 prevention Effects 0.000 claims description 39
- -1 2-Cyanoethenyl Chemical group 0.000 claims description 33
- 239000003607 modifier Substances 0.000 claims description 29
- 229940079593 drug Drugs 0.000 claims description 28
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 22
- YIBOMRUWOWDFLG-UHFFFAOYSA-N 4-[[4-[4-(2-cyanoethenyl)-2,6-dimethylanilino]pyrimidin-2-yl]amino]benzonitrile Chemical compound CC1=CC(C=CC#N)=CC(C)=C1NC1=CC=NC(NC=2C=CC(=CC=2)C#N)=N1 YIBOMRUWOWDFLG-UHFFFAOYSA-N 0.000 claims description 14
- 208000015181 infectious disease Diseases 0.000 claims description 13
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- 239000004480 active ingredient Substances 0.000 claims description 10
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- 238000004519 manufacturing process Methods 0.000 claims description 8
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 239000003755 preservative agent Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 5
- 239000000194 fatty acid Substances 0.000 claims description 5
- 229930195729 fatty acid Natural products 0.000 claims description 5
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 4
- 239000008365 aqueous carrier Substances 0.000 claims description 4
- 229920001223 polyethylene glycol Polymers 0.000 claims description 4
- 229920000136 polysorbate Polymers 0.000 claims description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 4
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical group C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 229930003427 Vitamin E Natural products 0.000 claims description 3
- 239000006172 buffering agent Substances 0.000 claims description 3
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 3
- 230000002335 preservative effect Effects 0.000 claims description 3
- 235000019165 vitamin E Nutrition 0.000 claims description 3
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- 239000008215 water for injection Substances 0.000 claims description 3
- 229960000502 poloxamer Drugs 0.000 claims 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 125000000714 pyrimidinyl group Chemical group 0.000 claims 1
- 239000012929 tonicity agent Substances 0.000 claims 1
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- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 abstract description 5
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- 230000005540 biological transmission Effects 0.000 description 10
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000002585 base Substances 0.000 description 9
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- 239000007951 isotonicity adjuster Substances 0.000 description 8
- 208000030507 AIDS Diseases 0.000 description 7
- 241000282472 Canis lupus familiaris Species 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 241000700605 Viruses Species 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
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- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
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- 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 5
- 229940122313 Nucleoside reverse transcriptase inhibitor Drugs 0.000 description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 5
- 239000006185 dispersion Substances 0.000 description 5
- 238000012545 processing Methods 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- 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 4
- CPLXHLVBOLITMK-UHFFFAOYSA-N Magnesium oxide Chemical compound [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 238000007918 intramuscular administration Methods 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 235000015424 sodium Nutrition 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 3
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 3
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 3
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
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- 239000006070 nanosuspension Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 230000000750 progressive effect Effects 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- 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 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- CFKMVGJGLGKFKI-UHFFFAOYSA-N 4-chloro-m-cresol Chemical compound CC1=CC(O)=CC=C1Cl CFKMVGJGLGKFKI-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- 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 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 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 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
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- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
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- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
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- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
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- 230000002401 inhibitory effect Effects 0.000 description 2
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- 239000000395 magnesium oxide Substances 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
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- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 2
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- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 2
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- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
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- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
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- RBNPOMFGQQGHHO-UHFFFAOYSA-N -2,3-Dihydroxypropanoic acid Natural products OCC(O)C(O)=O RBNPOMFGQQGHHO-UHFFFAOYSA-N 0.000 description 1
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 1
- IQXJCCZJOIKIAD-UHFFFAOYSA-N 1-(2-methoxyethoxy)hexadecane Chemical compound CCCCCCCCCCCCCCCCOCCOC IQXJCCZJOIKIAD-UHFFFAOYSA-N 0.000 description 1
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 1
- 229940078693 1-myristylpicolinium Drugs 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-N 0.000 description 1
- LODHFNUFVRVKTH-ZHACJKMWSA-N 2-hydroxy-n'-[(e)-3-phenylprop-2-enoyl]benzohydrazide Chemical compound OC1=CC=CC=C1C(=O)NNC(=O)\C=C\C1=CC=CC=C1 LODHFNUFVRVKTH-ZHACJKMWSA-N 0.000 description 1
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 238000010951 particle size reduction Methods 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- XEBWQGVWTUSTLN-UHFFFAOYSA-M phenylmercury acetate Chemical compound CC(=O)O[Hg]C1=CC=CC=C1 XEBWQGVWTUSTLN-UHFFFAOYSA-M 0.000 description 1
- 229920001987 poloxamine Polymers 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 229940113116 polyethylene glycol 1000 Drugs 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229960002814 rilpivirine Drugs 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 238000002398 sedimentation field-flow fractionation Methods 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 230000005582 sexual transmission Effects 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 238000005549 size reduction Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- FHHPUSMSKHSNKW-SMOYURAASA-M sodium deoxycholate Chemical compound [Na+].C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 FHHPUSMSKHSNKW-SMOYURAASA-M 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229940074404 sodium succinate Drugs 0.000 description 1
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 229940001482 sodium sulfite Drugs 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- JAJWGJBVLPIOOH-IZYKLYLVSA-M sodium taurocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 JAJWGJBVLPIOOH-IZYKLYLVSA-M 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- YNJORDSKPXMABC-UHFFFAOYSA-M sodium;2-hydroxypropane-2-sulfonate Chemical compound [Na+].CC(C)(O)S([O-])(=O)=O YNJORDSKPXMABC-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 229940035024 thioglycerol Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000014599 transmission of virus Effects 0.000 description 1
- 238000011295 triple combination therapy Methods 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229920001664 tyloxapol Polymers 0.000 description 1
- MDYZKJNTKZIUSK-UHFFFAOYSA-N tyloxapol Chemical compound O=C.C1CO1.CC(C)(C)CC(C)(C)C1=CC=C(O)C=C1 MDYZKJNTKZIUSK-UHFFFAOYSA-N 0.000 description 1
- 229960004224 tyloxapol Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 description 1
- GFQYVLUOOAAOGM-UHFFFAOYSA-N zirconium(iv) silicate Chemical compound [Zr+4].[O-][Si]([O-])([O-])[O-] GFQYVLUOOAAOGM-UHFFFAOYSA-N 0.000 description 1
Classifications
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- A61K9/10—Dispersions; Emulsions
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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-
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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Description
本発明は、水性の製薬学的に許容され得る担体中に懸濁されたNNRTI化合物TMC278のマイクロ−もしくはナノ粒子を含んでなる、筋肉内又は皮下注入を介する投与のための製薬学的組成物ならびにHIV感染の処置及び予防におけるそのような製薬学的組成物の使用に関する。
後天性免疫不全症候群(AIDS)の原因として知られるヒト免疫不全ウイルス(HIV)感染の処置は、大きな医学的挑戦であり続けている。HIVは免疫学的圧力を逃れることができ、多様な細胞型及び成長条件に適応することができ、且つ現在利用できる薬剤治療に対する耐性を発現することができる。現在利用できる薬剤治療にはヌクレオシド逆転写酵素阻害剤(NRTIs)、非−ヌクレオシド逆転写酵素阻害剤(NNRTIs)、ヌクレオチド逆転写酵素阻害剤(NtRTIs)、HIV−プロテアーゼ阻害剤(PIs)及びもっと最近の融合阻害剤が含まれる。
、且つ運ぶ必要性のような多くの理由のために望ましくない。高い薬剤負荷量は、患者が彼らの投薬量全部を摂取せず、それにより処方される投薬管理に従い損なう危険を増加させる。これは処置の有効性を低下させると共に、ウイルス耐性の発現にも導く。高い薬剤負荷量と関連する問題は、患者が多数の異なる抗−HIV薬を摂取しなければならない抗−HIV治療において顕著である。
得る血漿レベルを生ずる。この場合も、必要な投与の回数は減少し、それはやはり薬剤負荷量及び感染の危険にある人の薬剤コンプライアンスの点で有利である。
本発明は筋肉内又は皮下注入による投与のための製薬学的組成物であって:
(a)表面に吸着した表面改質剤を有するマイクロ−もしくはナノ粒子の形態におけるTMC278、その塩、立体異性体又は立体異性体混合物;及び
(b)中にTMC278活性成分が懸濁されている製薬学的に許容され得る水性担体
を含んでなるマイクロ−もしくはナノ粒子の懸濁液の形態におけるTMC278、その塩、立体異性体又は立体異性体混合物の治療的に有効な量を含んでなる製薬学的組成物に関する。
3ヵ月毎に1回投与されるかもしくは投与されることになる本明細書で規定される使用又は方法に関する。
本発明で用いられる化合物は、化合物TMC278(R278474又はリルピビリン(rilpivirine)とも呼ばれる)あるいは4−[[4−[[4−(2−シアノエテニル)−2,6−ジメチルフェニル]アミノ]−2−ピリミジニル]アミノ]ベンゾニトリルである。
し得る。例えばμl当たり約50、100、200個か又はそれより多くの細胞でのCD4カウントの増加も、抗−HIV処置の有効性の指標である。CD4カウントは特にμl当たり約200個の細胞より高いか又はμl当たり約350個の細胞より高いレベルまで増加するべきである。ウイルス負荷又はCD4カウントあるいは両方を用いてHIV感染の程度を診断することができる。
定される最低血漿レベルに可能な限り近いレベルに保つことが望ましいかも知れない。これは、投与の頻度及び/又は各投与で投与されるTMC278の量を減少させることを可能にするであろう。それは望ましくない副作用を避けることも可能にし、それは感染する危険にある健康な人々であり、従って副作用を耐える傾向が比較的低い、標的とされる集団群のほとんどにおける投薬形態物の受容性に寄与するであろう。予防の場合には、TMC278の血漿レベルを比較的低いレベルに保つことができる。1つの態様は、TMC278の最低血漿レベルが本明細書で規定される通りであり、最高血漿レベルが、やはり本明細書で規定されるRT阻害剤を治療的に作用させる最低血漿レベルに大体等しい、上記又は下記で規定されるHIV感染の予防のための使用又は方法に関する。
ない。
(1)表面に吸着した表面改質剤を有するマイクロ−もしくはナノ粒子の形態におけるTMC278又はその立体異性体もしくは立体異性体混合物;及び
(2)中に活性成分が懸濁されている製薬学的に許容され得る水性担体
より成る粒子の懸濁液の形態におけるTMC278又はその立体異性体もしくは立体異性体混合物の治療的に有効な量を含んでなる製薬学的組成物に関する。
anti−solvent)」)におけるような超臨界流体の使用により、あるいはそのような方法の組み合わせにより調製することができる。1つの態様において、TMC278を液体分散媒中に分散させ、磨砕媒体の存在下で機械的手段を適用し、TMC278の粒度を約50μmより小さい、特に約1,000nmより小さい平均有効粒度まで減じる段階を含んでなる方法を用いる。表面改質剤の存在下で粒子の寸法を減じることができる。
(a)超微粉砕された形態でTMC278を得;
(b)超微粉砕されたTMC278を液体媒体に加えて予備混合物/予備分散系を形成
し;そして
(c)予備混合物を磨砕媒体の存在下で機械的手段に供して、平均有効粒度を減じる
ことを含んでなる。
analysis)により決定される約100μmより小さいのが好ましい。超微粉砕されたTMC278の平均有効粒度が約100μmより大きい場合、TMC278化合物の粒子の寸法を100μmより小さく減じるのが好ましい。
(a)3%〜50%(w/v)又は10%〜40%(w/v)又は10%〜30%(w/
v)のTMC278;
(b)0.5%〜10%又は0.5%〜2%(w/v)の湿潤剤;
(c)0%〜10%又は0%〜5%又は0%〜2%又は0%〜1%の1種もしくはそれよ
り多い緩衝剤;
(d)0%〜10%又は0%〜6%(w/v)の等張化剤、
(e)0%〜2%(w/v)の防腐剤;及び
(f)100%とするのに十分な注入用水
を含んでなることができる。
(i) HIV阻害剤の組み合わせを用いる該患者の処置;及び続く
(ii)本発明に従うTMC278又はその製薬学的に許容され得る酸−付加塩の抗−ウ
イルス的に有効な量を含んでなる製薬学的組成物の断続的投与
を含んでなり、ここで組成物は少なくとも1週間の時間間隔で投与される。
250mlのガラスビン及び磨砕媒体として用いられるZrO2ビーズをオートクレーブ中で滅菌した。5グラムの薬剤物質を、60mlの注射用水中の1.25gのPluronic F108の溶液と一緒に250mlのガラスビン中に入れた。500μmの平均粒度を有する300グラムのZrO2−ビーズを加えた。ビンをローラーミル上に置いた。懸濁液を100rpmで72時間超微粉砕した。磨砕プロセスの最後に、濃厚ナノ懸濁液をシリンジで取り出し、バイアル中に充填した。得られる調製物は、以下の表中の調製物1である。HPLC/UVにより、濃度の決定を行った。25mg/mlのTMC278の最終的濃度まで希釈を行なった。得られる懸濁液を光から保護した。
EPGをTweenTM 80中で可溶化した。
本研究は、ナノ化されたTMC278又はそのHCl−塩の注入可能な調製物が長時間の間、安定な血漿レベルを生ずることを示す。この研究は、雄のビーグル犬において、ナ
ノ懸濁液(前実施例の調製物1)を5mg/kgで1回、筋肉内(IM)又は皮下注入した後のTMC278塩基及び塩酸塩の血漿速度論を比較する。
Claims (43)
- 筋肉内又は皮下注入による投与のための製薬学的組成物であって:
(a)表面に吸着した表面改質剤を有するマイクロ−もしくはナノ粒子の形態における4−[[4−[[4−(2−シアノエテニル)−2,6−ジメチルフェニル]アミノ]−2−ピリミジニル]アミノ]ベンゾニトリル、その塩、立体異性体又は立体異性体混合物;及び
(b)4−[[4−[[4−(2−シアノエテニル)−2,6−ジメチルフェニル]アミノ]−2−ピリミジニル]アミノ]ベンゾニトリル活性成分が懸濁されている製薬学的に許容され得る水性担体
を含んでなるマイクロ−もしくはナノ粒子の懸濁液の形態における、HIV感染の長期処置のため、又はHIVに感染する危険性のある患者におけるHIV感染の長期予防のために治療的に有効な量の4−[[4−[[4−(2−シアノエテニル)−2,6−ジメチルフェニル]アミノ]−2−ピリミジニル]アミノ]ベンゾニトリル、その塩、立体異性体又は立体異性体混合物を含んでなる製薬学的組成物。 - 4−[[4−[[4−(2−シアノエテニル)−2,6−ジメチルフェニル]アミノ]−2−ピリミジニル]アミノ]ベンゾニトリルが塩基形態で存在する請求項1に記載の組成物。
- 4−[[4−[[4−(2−シアノエテニル)−2,6−ジメチルフェニル]アミノ]−2−ピリミジニル]アミノ]ベンゾニトリルが塩基形態のE−異性体として存在する請求項2に記載の組成物。
- 表面改質剤がポロキサマー、α−トコフェリルポリエチレングリコールスクシネート、ポリオキシエチレンソルビタン脂肪酸エステル及び負に帯電したリン脂質の塩の群から選ばれる請求項1〜3のいずれかに記載の組成物。
- 表面改質剤がPluronicTM F108、ビタミンE TGPS、TweenTM 80及びLipoidTM EPGから選ばれる請求項1〜3のいずれかに記載の組成物。
- 表面改質剤がポロキサマーである請求項1〜4のいずれかに記載の組成物。
- 表面改質剤がPluronic TM F108である請求項6に記載の組成物。
- 4−[[4−[[4−(2−シアノエテニル)−2,6−ジメチルフェニル]アミノ]−2−ピリミジニル]アミノ]ベンゾニトリル対表面改質剤の相対量(w/w)が1:1〜約10:1の範囲内である請求項1〜7のいずれかに記載の組成物。
- 4−[[4−[[4−(2−シアノエテニル)−2,6−ジメチルフェニル]アミノ]−2−ピリミジニル]アミノ]ベンゾニトリルマイクロ−もしくはナノ粒子の平均有効粒度が約50μmより小さい請求項1〜8のいずれかに記載の組成物。
- 4−[[4−[[4−(2−シアノエテニル)−2,6−ジメチルフェニル]アミノ]−2−ピリミジニル]アミノ]ベンゾニトリル、その塩、立体異性体又は立体異性体混合物をナノ粒子形態で含んでなる請求項1〜8のいずれかに記載の組成物。
- 4−[[4−[[4−(2−シアノエテニル)−2,6−ジメチルフェニル]アミノ]−2−ピリミジニル]アミノ]ベンゾニトリルマイクロ−もしくはナノ粒子の平均有効粒度が約200nmより小さい請求項1〜8のいずれかに記載の組成物。
- 4−[[4−[[4−(2−シアノエテニル)−2,6−ジメチルフェニル]アミノ]−2−ピリミジニル]アミノ]ベンゾニトリルマイクロ−もしくはナノ粒子の平均有効粒度が約130nmである請求項1〜8のいずれかに記載の組成物。
- 4−[[4−[[4−(2−シアノエテニル)−2,6−ジメチルフェニル]アミノ]−2−ピリミジニル]アミノ]ベンゾニトリルマイクロ−もしくはナノ粒子の平均有効粒度が約50nm〜約1000nmの範囲内である請求項1〜8のいずれかに記載の組成物。
- 4−[[4−[[4−(2−シアノエテニル)−2,6−ジメチルフェニル]アミノ]−2−ピリミジニル]アミノ]ベンゾニトリルマイクロ−もしくはナノ粒子の平均有効粒度が約50nm〜約400nmの範囲内である請求項1〜8のいずれかに記載の組成物。
- 4−[[4−[[4−(2−シアノエテニル)−2,6−ジメチルフェニル]アミノ]−2−ピリミジニル]アミノ]ベンゾニトリルマイクロ−もしくはナノ粒子の平均有効粒度が約150nm〜約220nmの範囲内である請求項1〜8のいずれかに記載の組成物。
- 感染する危険性のある患者におけるHIV感染の長期予防のために治療的に有効な量を含んでなる請求項1〜15に記載の組成物。
- 治療的に有効な量が0.5mg/日〜約50mg/日の範囲である4−[[4−[[4−(2−シアノエテニル)−2,6−ジメチルフェニル]アミノ]−2−ピリミジニル]アミノ]ベンゾニトリルの投薬量に基いて計算される請求項16に記載の組成物。
- 治療的に有効な量が約1mg/日〜約10mg/日の範囲である4−[[4−[[4−(2−シアノエテニル)−2,6−ジメチルフェニル]アミノ]−2−ピリミジニル]アミノ]ベンゾニトリルの投薬量に基いて計算される請求項17に記載の組成物。
- 治療的に有効な量が約10mg/日〜約25mg/日の範囲である4−[[4−[[4−(2−シアノエテニル)−2,6−ジメチルフェニル]アミノ]−2−ピリミジニル]アミノ]ベンゾニトリルの投薬量に基いて計算される請求項16に記載の組成物。
- 治療的に有効な量が約15mg〜約1,500mgの1ヶ月の投薬量の4−[[4−[[4−(2−シアノエテニル)−2,6−ジメチルフェニル]アミノ]−2−ピリミジニル]アミノ]ベンゾニトリルに相当する請求項16に記載の組成物。
- 治療的に有効な量が約30mg〜約300mgの1ヶ月の投薬量の4−[[4−[[4−(2−シアノエテニル)−2,6−ジメチルフェニル]アミノ]−2−ピリミジニル]アミノ]ベンゾニトリルに相当する請求項20に記載の組成物。
- 治療的に有効な量が約60mg〜約150mgの1ヶ月の投薬量の4−[[4−[[4−(2−シアノエテニル)−2,6−ジメチルフェニル]アミノ]−2−ピリミジニル]アミノ]ベンゾニトリルに相当する請求項21に記載の組成物。
- HIV感染の長期処置のために治療的に有効な量を含んでなる請求項1〜15のいずれかに記載の組成物。
- 治療的に有効な量が約5mg/日〜約50mg/日の範囲である4−[[4−[[4−(2−シアノエテニル)−2,6−ジメチルフェニル]アミノ]−2−ピリミジニル]アミノ]ベンゾニトリルの投薬量に基いて計算される請求項23に記載の組成物。
- 治療的に有効な量が約10mg/日〜約25mg/日の範囲である4−[[4−[[4−(2−シアノエテニル)−2,6−ジメチルフェニル]アミノ]−2−ピリミジニル]アミノ]ベンゾニトリルの投薬量に基いて計算される約10mg/日〜約25mg/日の範囲である請求項24に記載の組成物。
- 組成物の合計体積に基づく重量により:
(a)3%〜50%又は10%〜40%又は10%〜30%の4−[[4−[[4−(2
−シアノエテニル)−2,6−ジメチルフェニル]アミノ]−2−ピリミジニル]
アミノ]ベンゾニトリル;
(b)0.5%〜10%又は0.5%〜2%の表面改質剤;
(c)0%〜10%又は0%〜5%又は0%〜2%又は0%〜1%の1種もしくはそれよ
り多い緩衝剤;
(d)0%〜10%又は0%〜6%の等張化剤、
(e)0%〜2%の防腐剤;及び
(f)100%とするのに十分な量の注入用水
を含んでなる請求項1〜3にいずれかに記載の組成物。 - 組成物が1週間〜2年の時間間隔で断続的に筋肉内又は皮下注入により投与するためのものである請求項1〜19及び23〜25のいずれかに記載の組成物。
- 組成物が1ヶ月〜1年の時間間隔で断続的に筋肉内又は皮下注入により投与するためのものである請求項27に記載の組成物。
- 組成物が1週間〜1ヶ月の範囲内又は1ヶ月〜3ヶ月の範囲内又は3ヶ月〜6ヶ月の範囲内又は6ヶ月〜12ヶ月の範囲内又は12ヶ月〜24ヶ月の範囲内である時間間隔で断続的に筋肉内又は皮下注入により投与するためのものである請求項27に記載の組成物。
- 組成物が2週間毎に1回又は1ヶ月毎に1回又は3ヶ月毎に1回断続的に筋肉内又は皮下注入により投与するためのものである請求項27に記載の組成物。
- 組成物が1ヶ月毎に1回断続的に筋肉内又は皮下注入により投与するためのものである請求項30に記載の組成物。
- 組成物が3ヶ月毎に1回断続的に筋肉内又は皮下注入により投与するためのものである請求項30に記載の組成物。
- 組成物が2ヶ月毎に1回断続的に筋肉内又は皮下注入により投与するためのものである請求項29に記載の組成物。
- HIV感染の長期処置のため、又はHIVに感染する危険性のある患者におけるHIV感染の長期予防のため薬剤の製造のための請求項1〜26のいずれかに記載の製薬学的組成物の使用。
- 薬剤が1週間〜2年の時間間隔で断続的に筋肉内又は皮下注入により投与される請求項34に記載の使用。
- 薬剤が1ヶ月〜1年の時間間隔で断続的に筋肉内又は皮下注入により投与される請求項34に記載の使用。
- 薬剤が1週間〜1ヶ月の範囲内又は1ヶ月〜3ヶ月の範囲内又は3ヶ月〜6ヶ月の範囲内又は6ヶ月〜12ヶ月の範囲内又は12ヶ月〜24ヶ月の範囲内である時間間隔で断続的に筋肉内又は皮下注入により投与される請求項34に記載の使用。
- 薬剤が2週間毎に1回又は1ヶ月毎に1回又は3ヶ月毎に1回断続的に筋肉内又は皮下注入により投与される請求項34に記載の使用。
- 薬剤が1ヶ月毎に1回断続的に筋肉内又は皮下注入により投与される請求項38に記載の使用。
- 薬剤が3ヶ月毎に1回断続的に筋肉内又は皮下注入により投与される請求項38に記載の使用。
- 薬剤が2ヶ月毎に1回断続的に筋肉内又は皮下注入により投与される請求項37に記載の使用。
- 組成物中の4−[[4−[[4−(2−シアノエテニル)−2,6−ジメチルフェニル]アミノ]−2−ピリミジニル]アミノ]ベンゾニトリルの有効量が、4−[[4−[[4−(2−シアノエテニル)−2,6−ジメチルフェニル]アミノ]−2−ピリミジニル]アミノ]ベンゾニトリルの血液血漿濃度が長時間の間20ng/ml〜90ng/mlの範囲のレベルに維持されるように選択される請求項34に記載の使用。
- (a)超微粉砕された形態で4−[[4−[[4−(2−シアノエテニル)−2,6−ジ
メチルフェニル]アミノ]−2−ピリミジニル]アミノ]ベンゾニトリルを得;
(b)超微粉砕された4−[[4−[[4−(2−シアノエテニル)−2,6−ジメチル
フェニル]アミノ]−2−ピリミジニル]アミノ]ベンゾニトリルを液体媒体に加
えて予備混合物/予備分散系を形成せしめ;そして
(c)予備混合物を磨砕媒体の存在下で機械的手段に供して、平均有効粒度を減じる
ことを含んでなる請求項1〜33のいずれかに記載の製薬学的組成物の調製方法。
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