WO2022231531A1 - Process for the preparation of sterilized suspensions for the inhalation by nebulization - Google Patents
Process for the preparation of sterilized suspensions for the inhalation by nebulization Download PDFInfo
- Publication number
- WO2022231531A1 WO2022231531A1 PCT/TR2021/050408 TR2021050408W WO2022231531A1 WO 2022231531 A1 WO2022231531 A1 WO 2022231531A1 TR 2021050408 W TR2021050408 W TR 2021050408W WO 2022231531 A1 WO2022231531 A1 WO 2022231531A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- process according
- mixture
- rotational speed
- proceeding
- sorbitan
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 70
- 239000000725 suspension Substances 0.000 title claims abstract description 28
- 238000002663 nebulization Methods 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 230000001954 sterilising effect Effects 0.000 claims abstract description 47
- 238000004659 sterilization and disinfection Methods 0.000 claims abstract description 47
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 18
- 239000000203 mixture Substances 0.000 claims description 86
- 238000002156 mixing Methods 0.000 claims description 30
- 239000006172 buffering agent Substances 0.000 claims description 18
- 239000007951 isotonicity adjuster Substances 0.000 claims description 15
- -1 polyoxyethylene Polymers 0.000 claims description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 239000002270 dispersing agent Substances 0.000 claims description 12
- 235000002639 sodium chloride Nutrition 0.000 claims description 12
- 239000000375 suspending agent Substances 0.000 claims description 12
- 239000003862 glucocorticoid Substances 0.000 claims description 11
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000008215 water for injection Substances 0.000 claims description 9
- MGNNYOODZCAHBA-GQKYHHCASA-N fluticasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(O)[C@@]2(C)C[C@@H]1O MGNNYOODZCAHBA-GQKYHHCASA-N 0.000 claims description 8
- 229960002714 fluticasone Drugs 0.000 claims description 7
- 229960000289 fluticasone propionate Drugs 0.000 claims description 7
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 7
- 229940068977 polysorbate 20 Drugs 0.000 claims description 7
- 239000011780 sodium chloride Substances 0.000 claims description 7
- 229940035044 sorbitan monolaurate Drugs 0.000 claims description 7
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 6
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 6
- WMWTYOKRWGGJOA-CENSZEJFSA-N fluticasone propionate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(OC(=O)CC)[C@@]2(C)C[C@@H]1O WMWTYOKRWGGJOA-CENSZEJFSA-N 0.000 claims description 6
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 claims description 6
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 6
- 229920000053 polysorbate 80 Polymers 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 5
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 4
- 229920001219 Polysorbate 40 Polymers 0.000 claims description 4
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 4
- 239000000787 lecithin Substances 0.000 claims description 4
- 235000010445 lecithin Nutrition 0.000 claims description 4
- 229940067606 lecithin Drugs 0.000 claims description 4
- ARIWANIATODDMH-UHFFFAOYSA-N rac-1-monolauroylglycerol Chemical compound CCCCCCCCCCCC(=O)OCC(O)CO ARIWANIATODDMH-UHFFFAOYSA-N 0.000 claims description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 4
- VBJGJHBYWREJQD-UHFFFAOYSA-M sodium;dihydrogen phosphate;dihydrate Chemical compound O.O.[Na+].OP(O)([O-])=O VBJGJHBYWREJQD-UHFFFAOYSA-M 0.000 claims description 4
- 239000001593 sorbitan monooleate Substances 0.000 claims description 4
- 235000011069 sorbitan monooleate Nutrition 0.000 claims description 4
- 229940035049 sorbitan monooleate Drugs 0.000 claims description 4
- NBMKJKDGKREAPL-CXSFZGCWSA-N (8s,9r,10s,11s,13s,14s,16r,17r)-9-chloro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-3-one Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O NBMKJKDGKREAPL-CXSFZGCWSA-N 0.000 claims description 3
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 claims description 3
- ZESRJSPZRDMNHY-YFWFAHHUSA-N 11-deoxycorticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 ZESRJSPZRDMNHY-YFWFAHHUSA-N 0.000 claims description 3
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 claims description 3
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 claims description 3
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 claims description 3
- LUKZNWIVRBCLON-GXOBDPJESA-N Ciclesonide Chemical compound C1([C@H]2O[C@@]3([C@H](O2)C[C@@H]2[C@@]3(C[C@H](O)[C@@H]3[C@@]4(C)C=CC(=O)C=C4CC[C@H]32)C)C(=O)COC(=O)C(C)C)CCCCC1 LUKZNWIVRBCLON-GXOBDPJESA-N 0.000 claims description 3
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 claims description 3
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 claims description 3
- POPFMWWJOGLOIF-XWCQMRHXSA-N Flurandrenolide Chemical compound C1([C@@H](F)C2)=CC(=O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O POPFMWWJOGLOIF-XWCQMRHXSA-N 0.000 claims description 3
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 claims description 3
- MKPDWECBUAZOHP-AFYJWTTESA-N Paramethasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]2(C)C[C@@H]1O MKPDWECBUAZOHP-AFYJWTTESA-N 0.000 claims description 3
- LWZFANDGMFTDAV-BURFUSLBSA-N [(2r)-2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O LWZFANDGMFTDAV-BURFUSLBSA-N 0.000 claims description 3
- 229960002478 aldosterone Drugs 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 229960004436 budesonide Drugs 0.000 claims description 3
- 229960003728 ciclesonide Drugs 0.000 claims description 3
- 229960004544 cortisone Drugs 0.000 claims description 3
- WBGKWQHBNHJJPZ-LECWWXJVSA-N desonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O WBGKWQHBNHJJPZ-LECWWXJVSA-N 0.000 claims description 3
- 229960003662 desonide Drugs 0.000 claims description 3
- 229960002593 desoximetasone Drugs 0.000 claims description 3
- VWVSBHGCDBMOOT-IIEHVVJPSA-N desoximetasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@H](C(=O)CO)[C@@]1(C)C[C@@H]2O VWVSBHGCDBMOOT-IIEHVVJPSA-N 0.000 claims description 3
- 229960003654 desoxycortone Drugs 0.000 claims description 3
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 claims description 3
- 229940061607 dibasic sodium phosphate Drugs 0.000 claims description 3
- 238000005429 filling process Methods 0.000 claims description 3
- 229960004511 fludroxycortide Drugs 0.000 claims description 3
- 229960003469 flumetasone Drugs 0.000 claims description 3
- WXURHACBFYSXBI-GQKYHHCASA-N flumethasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]2(C)C[C@@H]1O WXURHACBFYSXBI-GQKYHHCASA-N 0.000 claims description 3
- 229960000676 flunisolide Drugs 0.000 claims description 3
- GAKMQHDJQHZUTJ-ULHLPKEOSA-N fluocortolone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(=O)CO)[C@@]2(C)C[C@@H]1O GAKMQHDJQHZUTJ-ULHLPKEOSA-N 0.000 claims description 3
- 229960000890 hydrocortisone Drugs 0.000 claims description 3
- 229960001810 meprednisone Drugs 0.000 claims description 3
- PIDANAQULIKBQS-RNUIGHNZSA-N meprednisone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)CC2=O PIDANAQULIKBQS-RNUIGHNZSA-N 0.000 claims description 3
- 229960004584 methylprednisolone Drugs 0.000 claims description 3
- 229960001664 mometasone Drugs 0.000 claims description 3
- QLIIKPVHVRXHRI-CXSFZGCWSA-N mometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CCl)(O)[C@@]1(C)C[C@@H]2O QLIIKPVHVRXHRI-CXSFZGCWSA-N 0.000 claims description 3
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 3
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 3
- 229960002858 paramethasone Drugs 0.000 claims description 3
- 229960005205 prednisolone Drugs 0.000 claims description 3
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 claims description 3
- 229960004618 prednisone Drugs 0.000 claims description 3
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 claims description 3
- MIXMJCQRHVAJIO-TZHJZOAOSA-N qk4dys664x Chemical compound O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O MIXMJCQRHVAJIO-TZHJZOAOSA-N 0.000 claims description 3
- 239000001509 sodium citrate Substances 0.000 claims description 3
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 3
- 239000001488 sodium phosphate Substances 0.000 claims description 3
- 235000011067 sorbitan monolaureate Nutrition 0.000 claims description 3
- 239000000263 2,3-dihydroxypropyl (Z)-octadec-9-enoate Substances 0.000 claims description 2
- HJRDNARELSKHEF-CLFAGFIQSA-N 2-[2-[(z)-octadec-9-enoyl]oxyethoxy]ethyl (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCCOCCOC(=O)CCCCCCC\C=C/CCCCCCCC HJRDNARELSKHEF-CLFAGFIQSA-N 0.000 claims description 2
- RZRNAYUHWVFMIP-GDCKJWNLSA-N 3-oleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-GDCKJWNLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical group CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 claims description 2
- IYFATESGLOUGBX-YVNJGZBMSA-N Sorbitan monopalmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O IYFATESGLOUGBX-YVNJGZBMSA-N 0.000 claims description 2
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 claims description 2
- 239000004147 Sorbitan trioleate Substances 0.000 claims description 2
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 claims description 2
- IJCWFDPJFXGQBN-RYNSOKOISA-N [(2R)-2-[(2R,3R,4S)-4-hydroxy-3-octadecanoyloxyoxolan-2-yl]-2-octadecanoyloxyethyl] octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCCCCCCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCCCCCCCCCCCC IJCWFDPJFXGQBN-RYNSOKOISA-N 0.000 claims description 2
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- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 claims description 2
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- RZRNAYUHWVFMIP-UHFFFAOYSA-N monoelaidin Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-UHFFFAOYSA-N 0.000 claims description 2
- 125000001117 oleyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- GIPDEPRRXIBGNF-KTKRTIGZSA-N oxolan-2-ylmethyl (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC1CCCO1 GIPDEPRRXIBGNF-KTKRTIGZSA-N 0.000 claims description 2
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- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
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- 208000006673 asthma Diseases 0.000 abstract description 8
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
Definitions
- the invention relates to a process for the preparation of sterilized suspensions by gamma sterilization to be used in pharmaceutical formulations for inhalation by nebulization which is used in the treatment of chronic obstructive pulmonary disease (COPD), asthma and other obstructive respiratory diseases.
- COPD chronic obstructive pulmonary disease
- Obstructive lung disease is a significant public health problem. Asthma, chronic obstructive pulmonary disease (COPD) and other obstructive airway diseases are highly prevalent chronic diseases in the general population. These obstructive airway illnesses are manifested with chronic inflammation affecting the whole respiratory tract. Obstruction is usually intermittent and reversible in asthma but is progressive and irreversible in COPD.
- COPD chronic obstructive pulmonary disease
- nebulizers One alternative of MDI or DPI is the development of nebulizers in which aqueous solutions of pharmacologically-active substances are sprayed under high pressure so as to produce a mist of inhalable particles.
- Drugs combine pharmacologic activity with pharmaceutical properties. Desirable performance characteristics expected from them are physical and chemical stability, ease of processing, accurate and reproducible delivery to the target organ, and availability at the site of action.
- compositions for inhalation used in the treatment of obstructive respiratory diseases can comprise various active agents such as long acting muscarinic antagonists (LAMA), long acting beta agonists (LABA), short acting beta-2 agonists (SABA) and glucocorti costeroids.
- LAMA long acting muscarinic antagonists
- LABA long acting beta agonists
- SABA short acting beta-2 agonists
- Glucocorticosteroids are a class of drug that lowers inflammation in the body. Inhaled glucocorticosteroids reduce inflammation in the airways that carry air to the lungs (bronchial tubes) and reduce the mucus made by the bronchial tubes which makes easier to breathe.
- glucocorticosteroids such as ciclesonide, budesonide, fluticasone, aldosterone, beklometazone, betametazone, chloprednol, cortisone, cortivasole, deoxycortone, desonide, desoxymetasone, dexametasone, difluorocortolone, fluchlorolone, flumetasone, flunisolide, fluquinolone, fluquinonide, flurocortisone, fluorocortolone, flurometolone, flurandrenolone, halcynonide, hydrocortisone, icometasone, meprednisone, methylprednisolone, mometasone, paramethasone, prednisolone, prednisone, tixocortole, triamcynol
- Fluticasone is the most commonly used glucocorticosteroid for inhalation.
- Fluticasone Propionate is the propionate salt form of fluticasone, a synthetic trifluorinated glucocorticoid receptor agonist with antiallergic, anti-inflammatory and antipruritic effects.
- Fluticasone propionate sold under the brand name Flixotide, is a steroid medication.
- Sterilization is necessary for the complete destruction or removal of all microorganisms that could contaminate pharmaceuticals or other materials and thereby constitute a health hazard.
- the efficacy of any sterilization process will depend on the nature of the product, the extent and type of any contamination, and the conditions under which the final product has been prepared. The requirements for Good Manufacturing Practice should be observed throughout all stages of manufacture and sterilization. (The International Pharmacopoeia - Ninth Edition, 2019 5.8 Methods of sterilization) There are two types of sterilization can be used to manufacture sterile pharmaceutical formulations for inhalation: chemical and physical. Chemical sterilization, for the most part, has been based on exposure to toxic compounds, for example, formaldehyde, ethylene oxide.
- ethylene oxide has been found to leave residual amounts of ethylene oxide in the drug preparation. Ethylene oxide leaves a toxic residue, flammable explosive, carcinogenic, and has been found that the residual levels are often above the pharmaceutically acceptable limits as set by most regulatory agencies.
- Pyhsical methods include a sun-light method, heat methods (dry heat which includes red heat, flaming, incineration, hot air oven, infra-red and moist heat which includes below 100oC, at 100oC, above 100oC), vibration methods, filtration methods and radiation methods.
- Radiation sterilization with high energy gamma rays or accelerated electrons has proven to be a useful method for the industrial sterilization of heat-sensitive products.
- Gamma sterilization has the ability to destroy microorganisms with an insignificant increase in temperature of irradiated materials, thus preserving their properties, safe and secure. There is no residue or radioactivity left in the products, easy to control.
- the continuous nature of the process allows the products to be processed mechanically and fully automatically, thus virtually eliminating the human factor in the process. It does not harm the environment and can be applied to different kinds of materials.
- the patent application numbered US20100255102 relates to methods for sterilization of dispersions of one or more nanoparticulate active agents which is less than 1 micron via gamma irradiation, and compositions comprising such sterilized dispersions.
- portions of the dispersion have been filled into glass vials which were then capped.
- the vials have been subjected to varying doses of g radiation (0, 15, 25, and 40 kGy).
- the undesirable odor and impurity problems are observed at a very high beam dose of sterilization (for example, 25, and 40 kGy).
- the effective average particle size of one or more nanoparticulate active agents is preferably less than about 2 microns.
- the main object of the present invention is to provide a production method for preparing sterilized pharmaceutical glucocorticosteroid compositions for inhalation which eliminates all of their problems and brings additional advantages to the relevant prior art.
- Another object of the present invention is to provide a process for the preparation of sterilized suspensions by gamma sterilization to be used in pharmaceutical formulations for inhalation by nebulization for use in the prevention, treatment, or in the alleviation of the symptoms of respiratory diseases, particularly asthma and chronic obstructive pulmonary disease.
- Another object of the present invention is to provide a process for the preparation of sterilized suspensions by gamma sterilization to be used in pharmaceutical formulations for inhalation by nebulization with increased stability, enhanced fine particle dose (FPD), fine particle fraction (FPF), delivery rate and total active agent values.
- FPD fine particle dose
- FPF fine particle fraction
- Another object of the present invention is to provide a process for the preparation of sterilized suspensions by gamma sterilization to be used in pharmaceutical formulations for inhalation by nebulization with enhanced uniformity and homogeneity.
- Another object of the present invention is to provide a process for the preparation of sterilized suspensions by gamma sterilization to be used in pharmaceutical formulations for inhalation by nebulization in which the active agent(s) and excipients are added in separately and respectively.
- Another object of the present invention is to obtain sterilized suspensions by gamma sterilization provided by the above-mentioned process comprising glucocorticosteroids.
- a further object of the present invention is to obtain sterilized suspensions by gamma sterilization comprising a glucocorticosteroid.
- Another object of the present invention is to obtain inhalation compositions comprising fluticasone or a pharmaceutically acceptable salt thereof.
- Another object of the present invention is to obtain sterilized suspension compositions comprising glucocorticosteroids, isotonic agents, buffering agents, dispersing or suspending agents.
- Another object of the present invention is to produce a much lower level of total impurities than the prior art sterilizations.
- Another object of the invention is to show how changes made in the process steps of the drug formulation improve the process in order to ensure effective delivery of the active substance.
- the two mixtures should be prepared in different mixing vessels.
- the mentioned mixtures are named as Mixture 1 and Mixture 2.
- Mixture 1 and Mixture 2 These mixtures have different process steps.
- the active and excipients used in the process steps in a certain order in the process steps and using certain mixing speeds in certain steps are important in terms of increased stability, enhanced fine particle dose (FPD), fine particle fraction (FPF), delivery rate and total active agent values.
- FPD enhanced fine particle dose
- FPF fine particle fraction
- delivery rate total active agent values.
- BFS Bit fill seal
- LDPE pellets are placed in the machine, ampoules are formed with heat and air in the filling machine. And the ampoules are sealed with heat and air without leaving the filling machine. After this stage, sterilization is necessary for the complete destruction or removal of all microorganisms that could contaminate obtained mixture and thereby constitute a health hazard.
- the inventors have been observed physical and chemical degradations when they applied the various sterilization types specified in the state of the art to this process.
- Gamma sterilization can be applied fully automatically and it is a form of sterilization that is far from the effect of human factors.
- One of the most important aspects of the invention is the use of gamma sterilization, among the sterilization types mentioned in the state of the art.
- the inventors have surprisingly been found that the problems of chemical and physical degradation of the product have been solved when they applied gamma sterilization.
- the problems of chemical and physical degradation of the product have been solved with gamma sterilization.
- the beam dose which is used in gamma sterilization is also very important for the applicability of the invention.
- the inventors have been encountered odor and impurity problems when they applied a high beam dose of sterilization (for example, 45 KGY, 40 KGY, 35 KGY, 30 KGY, 25 KGY)
- the inventors have been surprisingly found that have not been encountered odor and impurity problems when they have applied the beam dose of sterilization which is 3-20 KGY, preferably 3-15 KGY, more preferably 6-12 KGY.
- the beam dose of gamma sterilization is 6 - 12 KGY.
- the present invention relates to a process for the preparation of sterilized suspensions to be used in pharmaceutical formulations for inhalation by nebulization, which comprises the following steps: a- obtaining Mixture 1 by:
- the heating step is performed in the step numbered a) (i), (ii) and b) (i), (ii).
- the temperature of the mixture in the step numbered a) (i), (ii) and b) (i), (ii) is 45°C-55°C.
- the first rotational speed is 200-2000 rpm, preferably 300-1800 rpm, more preferably 400-1500 rpm.
- Another important factor is the preparation of a suitable dispersing medium by including the dispersing or suspending agents in the process before the active agents to help disperse the active agents that is insoluble in water.
- the dispersing or suspending agent is selected from the group comprising polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), polysorbate 80 (polyoxyethylene (20) sorbitan monooleate), sorbitan monolaurate (span 20), sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, sorbitan monooleate, sorbitan trioleate (SpanR85), sorbitan mono-oleate, polyoxyethylene (20) sorbitan monooleate, natural lecithin, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, block copolymers of oxyethylene and oxypropylene, synthetic lecithin, diethylene glycol dioleate,
- the cooling step is performed in the step numbered a) (iii) and b) (iii) of the process.
- the temperature of the mixture in the step numbered a) (iii) and b) (iii) is 30°C-40°C.
- the active agent is selected glucocorticosteroid or pharmaceutically acceptable salt thereof.
- the glucocorticosteroid is selected from the group comprising ciclesonide, budesonide, fluticasone, aldosterone, beklometazone, betametazone, chloprednol, cortisone, cortivasole, deoxycortone, desonide, desoxymetasone, dexametasone, difluorocortolone, fluchlorolone, flumetasone, flunisolide, fluquinolone, fluquinonide, flurocortisone, fluorocortolone, flurometolone, flurandrenolone, halcynonide, hydrocortisone, icometasone, meprednisone, methylprednisolone, mometasone, paramethasone, prednisolone, prednisone, tixocortole, triamcynolondane or mixtures thereof.
- the glucocorticosteroids is fluticasone.
- the fluticasone salt is fluticasone furoate.
- the second rotational speed is 3000-15000 rpm, preferably 3000-13000 rpm, more preferably 3000-10000 rpm.
- the liquid pharmaceutical composition typically comprises isotonic agents.
- the isotonic agents may be any pharmaceutically acceptable isotonic agents. Suspensions will desirably be isotonic.
- the formulations which are used present process may be adjusted to desired isotonicity by the addition of suitable isotonic agents.
- the isotonic agent in the step numbered (ii) is selected from the group comprising mannitol, sodium chloride, potassium chloride and sodium bromide or a pharmaceutically acceptable salt thereof.
- the isotonic agents in the step numbered (ii) is sodium chloride.
- the liquid pharmaceutical composition comprises one or more buffering agents.
- the buffering agents are pharmaceutically acceptable buffering agents.
- the buffering agents may be any buffering agents suitable for use in a liquid pharmaceutical composition suitable for inhalation.
- One or more buffering agents are typically selected from citrate or phosphate buffers.
- Citrate buffers is selected from the group comprising citric acid, sodium citrate and mixtures thereof.
- Phosphate buffers is selected from the group comprising phosphoric acid, monosodium phosphate, dibasic sodium phosphate and mixtures thereof.
- the pharmaceutical composition comprises at least two buffering agents in the present invention.
- the buffering agents is selected from the group comprising citric acid, sodium citrate, phosphoric acid, monosodium phosphate, dibasic sodium phosphate and mixtures thereof.
- the buffering agents in the step numbered (ii) are monosodium phosphate dihydrate and dibasic sodium phosphate anhydrous.
- the applied process steps have a direct effect on the blend uniformity, which is one of the first chemical indicators of the product's quality profile. It has been observed that if the above steps are not followed and are applied high beam dose of the sterilization in the present process, the blend uniformity cannot be achieved.
- the steps of adding isotonic agents, buffering agents, dispersing or suspending agents, temperatures of certain step numbered and active agents used in the process, the mixing speed applied are and the beam dose of sterilization of great importance in order to ensure homogenization and prevent losses in the process.
- duration of the step numbered a) (ii) and b) (ii) is 1-20 minutes, preferably 2-15 minutes, more preferably 3-13 minutes.
- duration of the step numbered a) (iv) is 100-140 minutes, preferably 105-135 minutes, more preferably 110-130 minutes.
- duration of the step numbered a) (iii), (v) and b) (iii) is 45-75 minutes, preferably 50-70 minutes, more preferably 55-65 minutes.
- the filtration process in the step numbered b) (iv) is carried out by filtering through 0.45 micron + 0.2 micron pore diameter membrane filter.
- compositions subjected to the invention are prepared by these steps: a- obtaining Mixture 1 by:
- the invention also defines sterilized suspension compositions obtained by the process subjected to the invention.
- a sterilized suspension composition comprises a glucocorticosteroid or pharmaceutically acceptable salt thereof.
- a sterilized suspension composition comprises fluticasone propionate.
- a sterilized suspension composition comprising glucocorticosteroids, isotonic agents, buffering agents, dispersing or suspending agents.
- the amount of polysorbate 20 is between 0-1.0 % by weight of the total composition.
- the amount of sorbitan monolaurate is between 0-0.3 % by weight of the total composition.
- the amount of monosodium phosphate dihydrate is between 0- 2 % by weight of the total composition.
- the amount of dibasic sodium phosphate anhydrous is between 0-1 % by weight of the total composition.
- the amount of sodium chloride is between 0-0.9 % by weight of the total composition.
- the concentration of active agents in the pharmaceutical composition is 1 mg/1 ml_, 0.25 mg/1 ml_, 2 mg/2 ml_ and 0.5 mg/2 ml_.
- the process for sterilized suspension composition for nebulization subjected to the invention comprises; - fluticasone propionate,
- the below-given formulations can be used process for preparing a sterilized suspension composition subjected to the invention.
- These examples are not limiting the scope of the present invention and should be considered under the light of the foregoing detailed disclosure.
- Example 2 According to a preferred embodiment, a sterilized suspension composition subjected to the invention is used in the treatment of the respiratory diseases selected from asthma and chronic obstructive pulmonary disease and other obstructive respiratory diseases.
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Abstract
The invention relates to a process for the preparation of a sterilized suspension by gamma sterilization to be used in pharmaceutical formulations for inhalation by nebulization which is used in the treatment of chronic obstructive pulmonary disease (COPD), asthma and other obstructive respiratory diseases.
Description
PROCESS FOR THE PREPARATION OF STERILIZED SUSPENSIONS FOR THE
INHALATION BY NEBULIZATION
Field of Invention
The invention relates to a process for the preparation of sterilized suspensions by gamma sterilization to be used in pharmaceutical formulations for inhalation by nebulization which is used in the treatment of chronic obstructive pulmonary disease (COPD), asthma and other obstructive respiratory diseases.
The background of the invention
Obstructive lung disease is a significant public health problem. Asthma, chronic obstructive pulmonary disease (COPD) and other obstructive airway diseases are highly prevalent chronic diseases in the general population. These obstructive airway illnesses are manifested with chronic inflammation affecting the whole respiratory tract. Obstruction is usually intermittent and reversible in asthma but is progressive and irreversible in COPD.
People who are suffering from these airway diseases may be treated with medications such as corticosteroids, which are administered via metered-dose inhalers or dry powder inhalers. However, certain patient populations, e.g., neurologically impaired, elderly, or pediatric asthmatics, may lack the breath coordination needed for metered-dose inhalers or lack the lung capacity needed to use DPIs. Thus, these asthma patients require the administration of therapy via nebulizers. One alternative of MDI or DPI is the development of nebulizers in which aqueous solutions of pharmacologically-active substances are sprayed under high pressure so as to produce a mist of inhalable particles.
Drugs combine pharmacologic activity with pharmaceutical properties. Desirable performance characteristics expected from them are physical and chemical stability, ease of processing, accurate and reproducible delivery to the target organ, and availability at the site of action.
Pharmaceutical compositions for inhalation used in the treatment of obstructive respiratory diseases can comprise various active agents such as long acting muscarinic antagonists (LAMA), long acting beta agonists (LABA), short acting beta-2 agonists (SABA) and glucocorti costeroids.
Glucocorticosteroids are a class of drug that lowers inflammation in the body. Inhaled glucocorticosteroids reduce inflammation in the airways that carry air to the lungs (bronchial tubes) and reduce the mucus made by the bronchial tubes which makes easier to breathe.
Among the various types of drug which are administered by inhalation for the treatment of the pulmonary diseases, glucocorticosteroids, such as ciclesonide, budesonide, fluticasone, aldosterone, beklometazone, betametazone, chloprednol, cortisone, cortivasole, deoxycortone, desonide, desoxymetasone, dexametasone, difluorocortolone, fluchlorolone, flumetasone, flunisolide, fluquinolone, fluquinonide, flurocortisone, fluorocortolone, flurometolone, flurandrenolone, halcynonide, hydrocortisone, icometasone, meprednisone, methylprednisolone, mometasone, paramethasone, prednisolone, prednisone, tixocortole, triamcynolondane or mixtures thereof. They are generally administered in suspension, in an aqueous phase that usually also contains one or more pharmaceutically acceptable excipients, such as dispersing and/or suspending agents, isotonic and/or buffering agents, or in a propellant.
Fluticasone is the most commonly used glucocorticosteroid for inhalation. Fluticasone Propionate is the propionate salt form of fluticasone, a synthetic trifluorinated glucocorticoid receptor agonist with antiallergic, anti-inflammatory and antipruritic effects. Fluticasone propionate, sold under the brand name Flixotide, is a steroid medication.
In order to ensure an effective and safe penetration into the low respiratory tract of the patient, i.e. bronchioli and alveoli, one of the most important parameters that must be met by pharmaceutical formulations for inhalation is sterility. This requirement is becoming more and more mandatory as confirmed by the FDA final rule "Sterility Requirement for Aqueous-Based Drug Products for Oral Inhalation" published in the Federal Register of May 26, 2000 (65 FR 34082) governing the quality and safety of pharmaceutical products for a number of reasons, including the fact that the lungs are a particularly vulnerable organ of the human body, and many patients who use inhaled drugs have general health problems.
Sterilization is necessary for the complete destruction or removal of all microorganisms that could contaminate pharmaceuticals or other materials and thereby constitute a health hazard. The efficacy of any sterilization process will depend on the nature of the product, the extent and type of any contamination, and the conditions under which the final product has been prepared. The requirements for Good Manufacturing Practice should be observed throughout all stages of manufacture and sterilization. (The International Pharmacopoeia - Ninth Edition, 2019 5.8 Methods of sterilization)
There are two types of sterilization can be used to manufacture sterile pharmaceutical formulations for inhalation: chemical and physical. Chemical sterilization, for the most part, has been based on exposure to toxic compounds, for example, formaldehyde, ethylene oxide. However, when used to sterilize glucocorticosteroids, ethylene oxide has been found to leave residual amounts of ethylene oxide in the drug preparation. Ethylene oxide leaves a toxic residue, flammable explosive, carcinogenic, and has been found that the residual levels are often above the pharmaceutically acceptable limits as set by most regulatory agencies.
Pyhsical methods include a sun-light method, heat methods (dry heat which includes red heat, flaming, incineration, hot air oven, infra-red and moist heat which includes below 100oC, at 100oC, above 100oC), vibration methods, filtration methods and radiation methods.
As a result of moist heat sterilization of the inhaler nebulization suspension products (by autoclaving) the suspension is exposed to high temperature. Corticosteroids are affected by high temperatures. This causes crystal growth and clumping in the suspension. It may cause adverse changes in some chemical and physical tests of the suspension. As an example of these changes, due to the inhomogeneity of the mixture, a dose below 5 microns reaching the lungs could not be fully reached and the therapeutic effect could not be provided. On the other hand, controlling steam sterilization (autoclave sterilization) depends on factors such as temperature, vacuum, pressure, vacuum, packaging and humidity.
Irradiation based sterilization is known and has been recommended for glucocorticosteroids (see Ilium and Moeller in Arch. Pharm. Chemi. Sci. , Ed. 2, 1974, pp. 167-174).
Sterilization by b or g-irradiation is also known. Indeed, Ilium and Moeller in Arch. Pharm. Chemi. Sci., Ed. 2,1974, pp. 167-174 recommend the use of irradiation to sterilize glucocorticosteroids.
Radiation sterilization with high energy gamma rays or accelerated electrons has proven to be a useful method for the industrial sterilization of heat-sensitive products. Gamma sterilization has the ability to destroy microorganisms with an insignificant increase in temperature of irradiated materials, thus preserving their properties, safe and secure. There is no residue or radioactivity left in the products, easy to control. The continuous nature of the process allows the products to be processed mechanically and fully automatically, thus virtually eliminating the human factor in the process. It does not harm the environment and can be applied to different kinds of materials.
The patent application numbered US20100255102 relates to methods for sterilization of dispersions of one or more nanoparticulate active agents which is less than 1 micron via gamma irradiation, and compositions comprising such sterilized dispersions. In this patent document, portions of the dispersion have been filled into glass vials which were then capped. The vials have been subjected to varying doses of g radiation (0, 15, 25, and 40 kGy). However, the undesirable odor and impurity problems are observed at a very high beam dose of sterilization (for example, 25, and 40 kGy). This patent document also mentioned that the effective average particle size of one or more nanoparticulate active agents is preferably less than about 2 microns. Small particles between 0.1 and 0.5 micron are retained by the alveoli; most are exhaled. However, there is no mention that is mentioned for the application of gamma sterilization to pharmaceuticals containing the active ingredients with a mean particle size greater than 2 microns.
As seen above, there are various processes for producing sterile pharmaceutical formulations for inhalation. The active and excipients used in the process steps in a certain order in the process steps and using certain mixing speeds in certain steps, the time and temperature of the process steps are important in terms of increased stability, enhanced fine particle dose, fine particle fraction, delivery rate and total active agent values.
The steps of adding active agents and excipients used in the process to the process, the rotational speeds, beam dose of sterilization applied are of great importance in order to ensure homogenization and prevent losses in the process.
Considering the state of art, it can be seen that the prior art has not put enough emphasis on alternative solutions for this problem. Thus, there is still a need for innovative processes that will solve the homogenization problem, and which will provide a standardized method for the fast, robust and reproducible production of stable homogeneous suspension inhalation compositions with enhanced FPF, delivery rate and total active ingredient values.
Objects and Brief Description of the Invention
The main object of the present invention is to provide a production method for preparing sterilized pharmaceutical glucocorticosteroid compositions for inhalation which eliminates all of their problems and brings additional advantages to the relevant prior art.
Another object of the present invention is to provide a process for the preparation of sterilized suspensions by gamma sterilization to be used in pharmaceutical formulations for inhalation
by nebulization for use in the prevention, treatment, or in the alleviation of the symptoms of respiratory diseases, particularly asthma and chronic obstructive pulmonary disease.
Another object of the present invention is to provide a process for the preparation of sterilized suspensions by gamma sterilization to be used in pharmaceutical formulations for inhalation by nebulization with increased stability, enhanced fine particle dose (FPD), fine particle fraction (FPF), delivery rate and total active agent values.
Another object of the present invention is to provide a process for the preparation of sterilized suspensions by gamma sterilization to be used in pharmaceutical formulations for inhalation by nebulization with enhanced uniformity and homogeneity.
Another object of the present invention is to provide a process for the preparation of sterilized suspensions by gamma sterilization to be used in pharmaceutical formulations for inhalation by nebulization in which the active agent(s) and excipients are added in separately and respectively.
Another object of the present invention is to obtain sterilized suspensions by gamma sterilization provided by the above-mentioned process comprising glucocorticosteroids.
A further object of the present invention is to obtain sterilized suspensions by gamma sterilization comprising a glucocorticosteroid.
Another object of the present invention is to obtain inhalation compositions comprising fluticasone or a pharmaceutically acceptable salt thereof.
Another object of the present invention is to obtain sterilized suspension compositions comprising glucocorticosteroids, isotonic agents, buffering agents, dispersing or suspending agents.
Another object of the present invention is to produce a much lower level of total impurities than the prior art sterilizations.
Another object of the present invention is to describe a process for forming suspension and solution-type inhaler formulations to be delivered to the patient via nebulization.
Another object of the present invention is to access of inhaler formulations to the lungs is achieved.
Another object of the invention is to show how changes made in the process steps of the drug formulation improve the process in order to ensure effective delivery of the active substance.
Detailed description of the invention
In accordance with the objects outlined above, detailed features of the present invention are given herein.
In order to implement the invention, firstly, the two mixtures should be prepared in different mixing vessels. The mentioned mixtures are named as Mixture 1 and Mixture 2. These mixtures have different process steps. The active and excipients used in the process steps in a certain order in the process steps and using certain mixing speeds in certain steps are important in terms of increased stability, enhanced fine particle dose (FPD), fine particle fraction (FPF), delivery rate and total active agent values.
Accordingly, the obtaining of Mixture 1 is by the following steps:
(i) mixing the water for injection at a first rotational speed
(ii) adding respectively at least one dispersing or suspending agent and mixing the mixture at a first rotational speed
(iii) cooling the mixture obtained at a first rotational speed
(iv) adding glucocorticosteroid and mixing the mixture at a first rotational speed
(v) homogenizing the mixture in the homogenizer at a second rotational speed
Accordingly, the obtaining of Mixture 2 is by the following steps:
(i) mixing the water for injection at a first rotational speed in the tank
(ii) adding respectively isotonic agent, and at least two buffering agents, and mixing the mixture at a first rotational speed
(iii) cooling the mixture obtained at a first rotational speed
(iv) performing the filtration process
These two mixtures are mixed and filled to the nebul vials. BFS (Blow fill seal) technology is used for filling in the present invention. In this technology, LDPE pellets are placed in the machine, ampoules are formed with heat and air in the filling machine. And the ampoules are sealed with heat and air without leaving the filling machine. After this stage, sterilization is necessary for the complete destruction or removal of all microorganisms that could contaminate obtained mixture and thereby constitute a health hazard.
The inventors have been observed physical and chemical degradations when they applied the various sterilization types specified in the state of the art to this process. Gamma sterilization can be applied fully automatically and it is a form of sterilization that is far from the effect of human factors. One of the most important aspects of the invention is the use of gamma sterilization, among the sterilization types mentioned in the state of the art. On the other hand, the inventors have surprisingly been found that the problems of chemical and physical degradation of the product have been solved when they applied gamma sterilization. The problems of chemical and physical degradation of the product have been solved with gamma sterilization.
In addition, the beam dose which is used in gamma sterilization is also very important for the applicability of the invention. The inventors have been encountered odor and impurity problems when they applied a high beam dose of sterilization (for example, 45 KGY, 40 KGY, 35 KGY, 30 KGY, 25 KGY) However, the inventors have been surprisingly found that have not been encountered odor and impurity problems when they have applied the beam dose of sterilization which is 3-20 KGY, preferably 3-15 KGY, more preferably 6-12 KGY.
According to one embodiment, the beam dose of gamma sterilization is 6 - 12 KGY.
The present invention relates to a process for the preparation of sterilized suspensions to be used in pharmaceutical formulations for inhalation by nebulization, which comprises the following steps: a- obtaining Mixture 1 by:
(i) mixing the water for injection at the first rotational speed
(ii) adding respectively at least one dispersing or suspending agent and mixing the mixture at the first rotational speed
(iii) cooling the mixture obtained at the first rotational speed
(iv) adding glucocorticosteroid and mixing the mixture at the first rotational speed
(v) homogenizing the mixture in the homogenizer at the second rotational speed b- obtaining Mixture 2 by:
(i) mixing the water for injection at the first rotational speed in the tank
(ii) adding respectively isotonic agent, and at least two buffering agents, and mixing the mixture at the first rotational speed
(iii) cooling the mixture obtained at the first rotational speed
(iv) performing the filtration process c- mixing the Mixture 1 and Mixture 2 at the first rotational speed d- performing Gamma sterilization process after the filling process to vials wherein the beam dose of gamma sterilization is 3-20 KGY, preferably 3-15 KGY, more preferably 6-12 KGY.
The heating step is performed in the step numbered a) (i), (ii) and b) (i), (ii). According to one embodiment, the temperature of the mixture in the step numbered a) (i), (ii) and b) (i), (ii) is 45°C-55°C.
According to one embodiment, the first rotational speed is 200-2000 rpm, preferably 300-1800 rpm, more preferably 400-1500 rpm.
Another important factor is the preparation of a suitable dispersing medium by including the dispersing or suspending agents in the process before the active agents to help disperse the active agents that is insoluble in water.
According to the one embodiment, the dispersing or suspending agent is selected from the group comprising polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), polysorbate 80 (polyoxyethylene (20) sorbitan monooleate), sorbitan monolaurate (span 20), sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, sorbitan monooleate, sorbitan trioleate (SpanR85), sorbitan mono-oleate, polyoxyethylene (20) sorbitan monooleate, natural lecithin, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, block copolymers of oxyethylene and oxypropylene, synthetic lecithin, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, glyceryl mono-oleate, polyethylene glycol 400 and glyceryl monolaurate or mixtures thereof..
According to the preferred embodiment, the dispersing or suspending agents in the step numbered (iii) are sorbitan monolaurate and polysorbate 20.
The cooling step is performed in the step numbered a) (iii) and b) (iii) of the process. According to the preferred embodiment, the temperature of the mixture in the step numbered a) (iii) and b) (iii) is 30°C-40°C.
According to the preferred embodiment, the active agent is selected glucocorticosteroid or pharmaceutically acceptable salt thereof.
In a preferred embodiment of the invention, the glucocorticosteroid is selected from the group comprising ciclesonide, budesonide, fluticasone, aldosterone, beklometazone, betametazone, chloprednol, cortisone, cortivasole, deoxycortone, desonide, desoxymetasone, dexametasone, difluorocortolone, fluchlorolone, flumetasone, flunisolide, fluquinolone, fluquinonide, flurocortisone, fluorocortolone, flurometolone, flurandrenolone, halcynonide, hydrocortisone, icometasone, meprednisone, methylprednisolone, mometasone, paramethasone, prednisolone, prednisone, tixocortole, triamcynolondane or mixtures thereof.
According to the preferred embodiment, the glucocorticosteroids is fluticasone. According to this preferred embodiment, the fluticasone salt is fluticasone furoate.
According to the preferred embodiment, the second rotational speed is 3000-15000 rpm, preferably 3000-13000 rpm, more preferably 3000-10000 rpm.
The liquid pharmaceutical composition typically comprises isotonic agents. The isotonic agents may be any pharmaceutically acceptable isotonic agents. Suspensions will desirably be isotonic. The formulations which are used present process may be adjusted to desired isotonicity by the addition of suitable isotonic agents.
According to a preferred embodiment, the isotonic agent in the step numbered (ii) is selected from the group comprising mannitol, sodium chloride, potassium chloride and sodium bromide or a pharmaceutically acceptable salt thereof.
According to the preferred embodiment, the isotonic agents in the step numbered (ii) is sodium chloride.
Typically, the liquid pharmaceutical composition comprises one or more buffering agents. The buffering agents are pharmaceutically acceptable buffering agents. The buffering agents may be any buffering agents suitable for use in a liquid pharmaceutical composition suitable for inhalation. One or more buffering agents are typically selected from citrate or phosphate buffers. Citrate buffers is selected from the group comprising citric acid, sodium citrate and mixtures thereof. Phosphate buffers is selected from the group comprising phosphoric acid, monosodium phosphate, dibasic sodium phosphate and mixtures thereof.
According to one embodiment, the pharmaceutical composition comprises at least two buffering agents in the present invention.
According to one embodiment, the buffering agents is selected from the group comprising citric acid, sodium citrate, phosphoric acid, monosodium phosphate, dibasic sodium phosphate and mixtures thereof.
According to the preferred embodiment, the buffering agents in the step numbered (ii) are monosodium phosphate dihydrate and dibasic sodium phosphate anhydrous.
The applied process steps have a direct effect on the blend uniformity, which is one of the first chemical indicators of the product's quality profile. It has been observed that if the above steps are not followed and are applied high beam dose of the sterilization in the present process, the blend uniformity cannot be achieved.
The steps of adding isotonic agents, buffering agents, dispersing or suspending agents, temperatures of certain step numbered and active agents used in the process, the mixing speed applied are and the beam dose of sterilization of great importance in order to ensure homogenization and prevent losses in the process.
The effect of the applied mixing time in the steps of the process on the blend uniformity is great. If the mixture is mixed for a short time, a homogeneous mixing cannot be achieved and the determined blend uniformity results cannot be achieved. On the other hand, if the mixture is mixed for a long time; due to the action of the homogenizer, the active agents can be broken and damaged and the particle size can be reduced. Therefore, the applied mixing time applied in the process steps is important for obtaining the desired results. If the times mentioned in certain process steps are not applied, the desired quality target profile cannot be achieved since the active agents targeted to reach the lungs cannot reach the lungs properly.
According to one embodiment, duration of the step numbered a) (ii) and b) (ii) is 1-20 minutes, preferably 2-15 minutes, more preferably 3-13 minutes.
According to one embodiment, duration of the step numbered a) (iv) is 100-140 minutes, preferably 105-135 minutes, more preferably 110-130 minutes.
According to one embodiment, duration of the step numbered a) (iii), (v) and b) (iii) is 45-75 minutes, preferably 50-70 minutes, more preferably 55-65 minutes.
According to one embodiment, the filtration process in the step numbered b) (iv) is carried out by filtering through 0.45 micron + 0.2 micron pore diameter membrane filter.
According to one embodiment, the pharmaceutical compositions subjected to the invention are prepared by these steps: a- obtaining Mixture 1 by:
(i) mixing the water for injection in a glass beaker at a rotational speed-1
(ii) adding respectively polysorbate 20 (twen 20) and sorbitan monolaurate (span 20) and mixing the mixture at 200-2000 rpm, preferably 300-1800 rpm, more preferably 400-1500 rpm
(iii) cooling the mixture obtained at 200-2000 rpm, preferably 300-1800 rpm, more preferably 400-1500 rpm
(iv) adding fluticasone propionate and mixing the mixture at 200-2000 rpm, preferably 300- 1800 rpm, more preferably 400-1500 rpm
(v) performing the homogenization process of the mixture at 3000-15000 rpm, preferably 3000- 13000 rpm, more preferably 3000-10000 rpm b- obtaining Mixture 2 by:
(i) mixing the water for injection at at 200-2000 rpm, preferably 300-1800 rpm, more preferably 400-1500 rpm in the tank
(ii) adding respectively sodium chloride, monosodium phosphate dihydrate and anhydrous dibasic sodium phosphate, and mixing the mixture at 200-2000 rpm, preferably 300-1800 rpm, more preferably 400-1500 rpm
(iii) cooling the mixture obtained at 200-2000 rpm, preferably 300-1800 rpm, more preferably 400-1500 rpm
(iv) performing the filtration process c- mixing the Mixture 1 and Mixture 2 at 200-2000 rpm, preferably 300-1800 rpm, more preferably 400-1500 rpm d- performing Gamma sterilization process after the filling process to vials
wherein the beam dose of gamma sterilization is 3-20 KGY, preferably 3-15 KGY, more preferably 6-12 KGY.
The invention also defines sterilized suspension compositions obtained by the process subjected to the invention.
According to the preferred embodiment, a sterilized suspension composition comprises a glucocorticosteroid or pharmaceutically acceptable salt thereof.
According to the preferred embodiment, a sterilized suspension composition comprises fluticasone propionate.
According to the preferred embodiment, a sterilized suspension composition comprising glucocorticosteroids, isotonic agents, buffering agents, dispersing or suspending agents.
According to one embodiment, the amount of polysorbate 20 is between 0-1.0 % by weight of the total composition.
According to one embodiment, the amount of sorbitan monolaurate is between 0-0.3 % by weight of the total composition.
According to one embodiment, the amount of monosodium phosphate dihydrate is between 0- 2 % by weight of the total composition.
According to one embodiment, the amount of dibasic sodium phosphate anhydrous is between 0-1 % by weight of the total composition.
According to one embodiment, the amount of sodium chloride is between 0-0.9 % by weight of the total composition.
According to one embodiment, the concentration of active agents in the pharmaceutical composition is 1 mg/1 ml_, 0.25 mg/1 ml_, 2 mg/2 ml_ and 0.5 mg/2 ml_.
According to one preferred embodiment, the process for sterilized suspension composition for nebulization subjected to the invention comprises;
- fluticasone propionate,
- polysorbate 20,
- sorbitan monolaurate,
- monosodium phosphate dihydrate, - dibasic sodium phosphate anhydrous,
- sodium chloride,
- water for injection.
According to all these embodiments, the below-given formulations can be used process for preparing a sterilized suspension composition subjected to the invention. These examples are not limiting the scope of the present invention and should be considered under the light of the foregoing detailed disclosure.
Example 1 :
Example 2:
According to a preferred embodiment, a sterilized suspension composition subjected to the invention is used in the treatment of the respiratory diseases selected from asthma and chronic obstructive pulmonary disease and other obstructive respiratory diseases.
Claims
1. A process for the preparation of a sterilized suspension to be used in pharmaceutical formulations for inhalation by nebulization, which comprises the following steps: a- obtaining Mixture 1 by:
(i) mixing the water for injection at a first rotational speed
(ii) adding respectively at least two dispersing or suspending agent and mixing the mixture at a first rotational speed
(iii) cooling the mixture obtained at a first rotational speed
(iv) adding glucocorticosteroid and mixing the mixture at a first rotational speed
(v) homogenizing the mixture in the homogenizer at a second rotational speed b- obtaining Mixture 2 by:
(i) mixing the water for injection at a first rotational speed in the tank
(ii) adding respectively isotonic agent, and at least two buffering agents, and mixing the mixture at a first rotational speed
(iii) cooling the mixture obtained at a first rotational speed
(iv) performing the filtration process c- mixing the Mixture 1 and Mixture 2 at first rotational speed d- performing Gamma sterilization process after the filling process to vials wherein the beam dose of gamma sterilization is 3-20 KGY, preferably 3-15 KGY, more preferably 6-12 KGY.
2. A process according to claim 1 , wherein the dispersing or suspending agent is selected from the group comprising polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), polysorbate 80 (polyoxyethylene (20) sorbitan monooleate), sorbitan monolaurate (span 20), sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, sorbitan monooleate, sorbitan trioleate (SpanR85), sorbitan mono-oleate, polyoxyethylene (20) sorbitan monooleate, natural lecithin, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, block copolymers of oxyethylene and oxypropylene, synthetic lecithin, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, glyceryl mono-oleate, polyethylene glycol 400 and glyceryl monolaurate or mixtures thereof.
3. A process according to claim 2, wherein the dispersing or suspending agents are respectively polysorbate 20 and sorbitan monolaurate.
4. A process according to any one of the proceeding claims, wherein the first rotational speed is 200-2000 rpm, preferably 300-1800 rpm, more preferably 400-1500 rpm.
5. A process according to any one of the proceeding claims, wherein the glucocorticosteroid is selected from the group comprising ciclesonide, budesonide, fluticasone, aldosterone, beklometazone, betametazone, chloprednol, cortisone, cortivasole, deoxycortone, desonide, desoxymetasone, dexametasone, difluorocortolone, fluchlorolone, flumetasone, flunisolide, fluquinolone, fluquinonide, flurocortisone, fluorocortolone, flurometolone, flurandrenolone, halcynonide, hydrocortisone, icometasone, meprednisone, methylprednisolone, mometasone, paramethasone, prednisolone, prednisone, tixocortole, triamcynolondane or mixtures thereof.
6. A process according to claim 5, wherein the glucocorticosteroid is fluticasone propionate.
7. A process according to any one of the proceeding claims, wherein the second rotational speed is 3000-15000 rpm, preferably 3000-13000 rpm, more preferably 3000-10000 rpm.
8. A process according to any one of the proceeding claims, wherein the isotonic agent is selected from the group comprising mannitol, sodium chloride, potassium chloride and sodium bromide or a pharmaceutically acceptable salt thereof.
9. A process according to claim 8, wherein the isotonic agent is sodium chloride.
10. A process according to any one of the proceeding claims, wherein buffering agents is selected from the group comprising citric acid, sodium citrate, phosphoric acid, monosodium phosphate, dibasic sodium phosphate and mixtures thereof.
11. A process according to claim 10, wherein buffering agents are monosodium phosphate dihydrate and dibasic sodium phosphate anhydrous.
12. A process according to any one of the proceeding claims, wherein the filtration process in the step numbered b) (iv) is carried out by filtering through 0.45 micron + 0.2 micron pore diameter PES capsule membrane filter.
13. A process according to any one of the proceeding claims, wherein the temperature of the mixture in the step numbered a) (i), (ii) and b) (i), (ii) is 45°C-55°C.
14. A process according to any one of the proceeding claims, wherein the temperature of the mixture in the step numbered a) (iii) and b) (iii) is 30°C-40°C.
15. A process according to any one of the proceeding claims, wherein duration of the step numbered a) (ii) and b) (ii) is 1-20 minutes, preferably 2-15 minutes, more preferably 3-13 minutes.
16. A process according to any one of the proceeding claims, wherein duration of the step numbered a) (iv) is 100-140 minutes, preferably 105-135 minutes, more preferably 11Q- 130 minutes.
17. A process according to any one of the proceeding claims, wherein duration of the step numbered a) (iii), (v) and b) (iii) is 45-75 minutes, preferably 50-70 minutes, more preferably 55-65 minutes.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050175546A1 (en) * | 2002-04-17 | 2005-08-11 | Barbara Sambuco | Process for preparation of a sterile suspension of corticosteroid particles for the administration by inhalation |
| US20090252801A1 (en) * | 2005-11-29 | 2009-10-08 | Farmbios S.P.A. | Process for the Preparation of Micronised Sterile Steroids |
| CN103505412A (en) * | 2012-06-26 | 2014-01-15 | 上海臣邦医药科技有限公司 | Method for preparing fluticasone propionate suspension for inhalation |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050175546A1 (en) * | 2002-04-17 | 2005-08-11 | Barbara Sambuco | Process for preparation of a sterile suspension of corticosteroid particles for the administration by inhalation |
| US20090252801A1 (en) * | 2005-11-29 | 2009-10-08 | Farmbios S.P.A. | Process for the Preparation of Micronised Sterile Steroids |
| CN103505412A (en) * | 2012-06-26 | 2014-01-15 | 上海臣邦医药科技有限公司 | Method for preparing fluticasone propionate suspension for inhalation |
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