WO2022231532A1 - 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
- WO2022231532A1 WO2022231532A1 PCT/TR2021/050409 TR2021050409W WO2022231532A1 WO 2022231532 A1 WO2022231532 A1 WO 2022231532A1 TR 2021050409 W TR2021050409 W TR 2021050409W WO 2022231532 A1 WO2022231532 A1 WO 2022231532A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- process according
- sorbitan
- rotational speed
- polyoxyethylene
- tank
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 51
- 230000008569 process Effects 0.000 title claims abstract description 47
- 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 13
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 19
- 239000000203 mixture Substances 0.000 claims description 51
- 239000013543 active substance Substances 0.000 claims description 28
- 238000002156 mixing Methods 0.000 claims description 20
- 239000006172 buffering agent Substances 0.000 claims description 19
- 239000007951 isotonicity adjuster Substances 0.000 claims description 16
- -1 polyoxyethylene Polymers 0.000 claims description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 13
- 239000002270 dispersing agent Substances 0.000 claims description 13
- 239000000375 suspending agent Substances 0.000 claims description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 235000002639 sodium chloride Nutrition 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 10
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 10
- 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
- 239000008215 water for injection Substances 0.000 claims description 9
- 229960002714 fluticasone Drugs 0.000 claims description 8
- 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
- 239000003862 glucocorticoid Substances 0.000 claims description 8
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 8
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 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
- 229960000289 fluticasone propionate Drugs 0.000 claims description 6
- 238000000265 homogenisation Methods 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
- 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 5
- 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
- 229940061607 dibasic sodium phosphate Drugs 0.000 claims description 4
- 235000010445 lecithin Nutrition 0.000 claims description 4
- 239000000787 lecithin Substances 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
- 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
- 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
- 238000009736 wetting Methods 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
- 229920001400 block copolymer Polymers 0.000 claims description 2
- 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
- 229940093471 ethyl oleate Drugs 0.000 claims description 2
- 229940068939 glyceryl monolaurate Drugs 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 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
- 125000006353 oxyethylene group Chemical group 0.000 claims description 2
- 229940068918 polyethylene glycol 400 Drugs 0.000 claims description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 2
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 claims description 2
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 claims description 2
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 claims description 2
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 claims description 2
- 229940101027 polysorbate 40 Drugs 0.000 claims description 2
- 229940113124 polysorbate 60 Drugs 0.000 claims description 2
- 229940068968 polysorbate 80 Drugs 0.000 claims description 2
- 239000001103 potassium chloride Substances 0.000 claims description 2
- 235000011164 potassium chloride Nutrition 0.000 claims description 2
- 235000011071 sorbitan monopalmitate Nutrition 0.000 claims description 2
- 239000001570 sorbitan monopalmitate Substances 0.000 claims description 2
- 229940031953 sorbitan monopalmitate Drugs 0.000 claims description 2
- 239000001587 sorbitan monostearate Substances 0.000 claims description 2
- 235000011076 sorbitan monostearate Nutrition 0.000 claims description 2
- 229940035048 sorbitan monostearate Drugs 0.000 claims description 2
- 235000019337 sorbitan trioleate Nutrition 0.000 claims description 2
- 229960000391 sorbitan trioleate Drugs 0.000 claims description 2
- 239000001589 sorbitan tristearate Substances 0.000 claims description 2
- 235000011078 sorbitan tristearate Nutrition 0.000 claims description 2
- 229960004129 sorbitan tristearate Drugs 0.000 claims description 2
- 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
- 229940072958 tetrahydrofurfuryl oleate Drugs 0.000 claims description 2
- 208000006673 asthma Diseases 0.000 abstract description 8
- 208000023504 respiratory system disease Diseases 0.000 abstract description 8
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 abstract description 6
- 230000000414 obstructive effect Effects 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 239000006260 foam Substances 0.000 description 6
- 210000004072 lung Anatomy 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- 238000009472 formulation Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 2
- 229940110339 Long-acting muscarinic antagonist Drugs 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000007979 citrate buffer Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000010419 fine particle Substances 0.000 description 2
- 229960001469 fluticasone furoate Drugs 0.000 description 2
- XTULMSXFIHGYFS-VLSRWLAYSA-N fluticasone furoate Chemical group O([C@]1([C@@]2(C)C[C@H](O)[C@]3(F)[C@@]4(C)C=CC(=O)C=C4[C@@H](F)C[C@H]3[C@@H]2C[C@H]1C)C(=O)SCF)C(=O)C1=CC=CO1 XTULMSXFIHGYFS-VLSRWLAYSA-N 0.000 description 2
- 230000036512 infertility Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 229940125389 long-acting beta agonist Drugs 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 210000002345 respiratory system Anatomy 0.000 description 2
- 229940127211 short-acting beta 2 agonist Drugs 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- JFUAWXPBHXKZGA-IBGZPJMESA-N 4-fluoro-2-[(4r)-5,5,5-trifluoro-4-hydroxy-2-methyl-4-(1h-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-yl]phenol Chemical class C([C@@](O)(CC=1NC2=CN=CC=C2C=1)C(F)(F)F)C(C)(C)C1=CC(F)=CC=C1O JFUAWXPBHXKZGA-IBGZPJMESA-N 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 102100038199 Desmoplakin Human genes 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 208000011623 Obstructive Lung disease Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical group CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001139 anti-pruritic effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- 230000008450 motivation Effects 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 235000011067 sorbitan monolaureate Nutrition 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Classifications
-
- 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
-
- 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
-
- 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 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.
- 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.
- LAMA long acting muscarinic antagonists
- LABA long acting beta agonists
- SABA short acting beta-2 agonists
- glucocorti costeroids 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.
- 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.
- EP1494647B1 relates to a process for the preparation of aqueous suspensions of drug particles, to be administered by inhalation, which produces homogenous dispersions of particles characterized by optimal size and size distribution. Also mentioned in the patent document that the active ingredient is homogenized, again under vacuum, using the turbine system and operating at a speed of between 750 and 4000 rpm, preferably between 1000 and 3600 rpm and even more preferably between 1600 and 3000 rpm for 5-60 minutes preferably for 20-40 minutes.
- the main object of the present invention is to provide a production method for preparing sterilized pharmaceutical glucocorticosteroid compositions for inhalation which eliminates all aforesaid 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 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 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 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 to be used in pharmaceutical formulations for inhalation by nebulization which saves time and provides one-pot manufacturing accordingly.
- Another object of the present invention is to provide a process for the preparation of sterilized suspensions to be used in pharmaceutical formulations for inhalation by nebulization in which the active agent(s) and excipients are added in separately and respectively and are mixed at different rotational speeds.
- Another object of the present invention is to obtain sterilized suspensions provided by the above-mentioned process comprising glucocorticosteroids.
- a further object of the present invention is to obtain sterilized suspensions 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 sterilization.
- 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 by optimizing the process steps involving device, active agent and excipients.
- 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 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: i. filling a tank which has homogenizer with water for injection and wetting the walls of the tank with water for injection. ii. adding the pre-weighed isotonic agent and at least two buffering agents to the water in the tank which has homogenizer, respectively, and mixing at first rotational speed. iii. adding the pre-weighed at least two dispersing or suspending agents to the mixture in the tank which has homogenizer and mixing at a second rotational speed iv. adding the active agent to the mixture in the tank which has homogenizer and mixing at a second rotational speed v.
- mixing, homogenization and autoclaving are carried out in one tank.
- the water for injection in the step numbered (i) is heated to 40- 60° C, more preferably 45-55° C, more preferably 50° C.
- 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.
- said 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.
- said 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.
- said buffering agents is selected from the group comprising citric acid, sodium citrate, phosphoric acid, monosodium phosphate, dibasic sodium phosphate and mixtures thereof.
- said buffering agents in the step numbered (ii) are monosodium phosphate dihydrate and dibasic sodium phosphate anhydrous.
- Another important factor is the preparation of a suitable dissolution medium by including the dispersing or suspending agents in the process before the active agents to help dissolve the active agents that is insoluble in water.
- said 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) and polysorbate 80 (polyoxyethylene (20) sorbitan monooleate) sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate and 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, te
- said dispersing or suspending agents in the step numbered (iii) are sorbitan monolaurate and polysorbate 20.
- the active agent is selected glucocorticosteroid or pharmaceutically acceptable salt thereof.
- said 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.
- said glucocorticosteroids is fluticasone.
- said fluticasone salt is fluticasone furoate.
- the rotational speed at which the mixing process takes place is also critical. If a homogeneous mixing cannot be achieved at low rotational speed; the determined mixture uniformity results cannot be achieved. On the other hand, at high rotational speed, the mixture foams and the active agents attach to the foam and collect at the top of the mixture. Thus, the uniformity of mixing will not be achieved again. If the mixture cannot be homogeneous, a suitable product with desired therapeutic properties cannot be produced.
- the steps of adding isotonic agents, buffering agents, dispersing or suspending agents and active agents used in the process to the process and the mixing speed applied are of great importance in order to ensure homogenization and prevent losses in the process.
- the isotonic agent and buffering agents must be mixed at first rotational speed in step numbered (ii).
- said first rotational speed in the step numbered (ii) is 18000- 33600 rpm, preferably 19000-30000 rpm, more preferably 20000-25000 rpm.
- the high rotational speed causes the product to foam. Since the active agents adhere to the foam, the problem of loss of active agents and blend uniformity is observed in the prepared suspension. On the other hand, mixing the active agents at a very low rotational speed causes the problem of blend uniformity. It is therefore a fundamental subject of the present invention to add the mixing speed at different speeds specific to the active agents/isotonic agents/buffering agents/dispersing or suspending agents.
- said second rotational speed in the step numbered (iii) and (iv) is 8800-18000 rpm, preferably 8800-15000 rpm, more preferably 8800-13000 rpm.
- the effect of the final mixing time in the step numbered (iv) on the blend uniformity is great. If the final 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 final 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. In this case, the desired quality target profile cannot be achieved since the active agents targeted to reach the lungs cannot reach the lungs properly.
- the duration of the step number (iv) is 1-15 minutes, preferably 2-13 minutes, more preferably 3-10 minutes.
- said process reduces processing times and gives rise to suspensions with a homogenous, thus producing compositions with a high level of physical stability and therapeutic efficacy.
- autoclaving in the step numbered (v) is at 121 °C for about 15-30 minutes.
- the pharmaceutical compositions subjected to the invention are prepared by these steps: i. filling the tank which has homogenizer with water for injection and wetting the walls of the tank with water for injection ii. adding the pre-weighed sodium chloride, monosodium phosphate dihydrate and dibasic sodium phosphate to the water in the tank which has homogenizer, respectively, and mixing at 18000-33600 rpm, preferably 19000-30000 rpm, more preferably 20000-25000 rpm iii.
- 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 furoate.
- 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;
- 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.
Abstract
The invention relates to a process for the preparation of a sterilized suspension 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 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.
Priority Claims and Related Applications
This application claims the benefit of PCT application Nos. PCT/TR2021/050408, all filed April 29, 2021 , the entire content of which is incorporated by reference herein in its entirety.
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 save 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.
The patent application numbered EP3299013A1 relates to improvements in or relating to pharmaceutical compositions comprising a fluticasone ester. In particular, the invention relates to novel formulations of use in the administration of fluticasone propionate by inhalation.
The patent application numbered EP1494647B1 relates to a process for the preparation of aqueous suspensions of drug particles, to be administered by inhalation, which produces homogenous dispersions of particles characterized by optimal size and size distribution. Also mentioned in the patent document that the active ingredient is homogenized, again under vacuum, using the turbine system and operating at a speed of between 750 and 4000 rpm, preferably between 1000 and 3600 rpm and even more preferably between 1600 and 3000 rpm for 5-60 minutes preferably for 20-40 minutes.
As seen above, there are several processes for producing sterile pharmaceutical formulations for inhalation. However, the stages of adding the excipients and active agents used in the process and the rotation speed applied are of great importance in terms of ensuring homogenization, completing the process in a short time and preventing losses in the process. For example, the high rotational speed causes the product to foam. Since the active agents adhere to the foam, the problem of loss of active agents occurs and poor blend uniformity is observed in the prepared suspension. On the other hand, mixing the active agents at a very low rotational speed causes the problem of blend uniformity.
The steps of adding excipients and active agents used in the process to the process and the rotational speed applied are of great importance in order to ensure homogenization and prevent losses in the process.
On the other hand, these inventions do not include any mention of motivation that excipients or active agents of different properties should be added in a certain order and mixed in the process at different rotational speeds.
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 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 aforesaid 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 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 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 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 to be used in pharmaceutical formulations for inhalation by nebulization which saves time and provides one-pot manufacturing accordingly.
Another object of the present invention is to provide a process for the preparation of sterilized suspensions to be used in pharmaceutical formulations for inhalation by nebulization in which the active agent(s) and excipients are added in separately and respectively and are mixed at different rotational speeds.
Another object of the present invention is to obtain sterilized suspensions provided by the above-mentioned process comprising glucocorticosteroids.
A further object of the present invention is to obtain sterilized suspensions 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 sterilization.
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 by optimizing the process steps involving device, active agent and excipients.
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.
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: i. filling a tank which has homogenizer with water for injection and wetting the walls of the tank with water for injection. ii. adding the pre-weighed isotonic agent and at least two buffering agents to the water in the tank which has homogenizer, respectively, and mixing at first rotational speed. iii. adding the pre-weighed at least two dispersing or suspending agents to the mixture in the tank which has homogenizer and mixing at a second rotational speed iv. adding the active agent to the mixture in the tank which has homogenizer and mixing at a second rotational speed v. autoclaving the product in the tank which has homogenizer vi. filling the autoclaved product into nebul vials
wherein said first rotational speed in the step numbered (ii) is 18000-33600 rpm and said second rotational speed in the step numbered (iii) and (iv) is 8800-18000rpm.
According to one embodiment, mixing, homogenization and autoclaving are carried out in one tank.
According to one embodiment, the water for injection in the step numbered (i) is heated to 40- 60° C, more preferably 45-55° C, more preferably 50° C.
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, said 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, said 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, said 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, said buffering agents in the step numbered (ii) are monosodium phosphate dihydrate and dibasic sodium phosphate anhydrous.
Another important factor is the preparation of a suitable dissolution medium by including the dispersing or suspending agents in the process before the active agents to help dissolve the active agents that is insoluble in water.
According to the one embodiment, said 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) and polysorbate 80 (polyoxyethylene (20) sorbitan monooleate) sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate and 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, said dispersing or suspending agents in the step numbered (iii) are sorbitan monolaurate and polysorbate 20.
According to the preferred embodiment, the active agent is selected glucocorticosteroid or pharmaceutically acceptable salt thereof.
In a preferred embodiment of the invention, said 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, said glucocorticosteroids is fluticasone. According to this preferred embodiment, said fluticasone salt is fluticasone furoate.
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 in the present process, the blend uniformity cannot be achieved.
In the invention, the rotational speed at which the mixing process takes place is also critical. If a homogeneous mixing cannot be achieved at low rotational speed; the determined mixture uniformity results cannot be achieved. On the other hand, at high rotational speed, the mixture foams and the active agents attach to the foam and collect at the top of the mixture. Thus, the uniformity of mixing will not be achieved again. If the mixture cannot be homogeneous, a suitable product with desired therapeutic properties cannot be produced.
The steps of adding isotonic agents, buffering agents, dispersing or suspending agents and active agents used in the process to the process and the mixing speed applied are of great importance in order to ensure homogenization and prevent losses in the process.
According to the invention, the isotonic agent and buffering agents must be mixed at first rotational speed in step numbered (ii).
According to one embodiment, said first rotational speed in the step numbered (ii) is 18000- 33600 rpm, preferably 19000-30000 rpm, more preferably 20000-25000 rpm.
During the addition of dispersing or suspending agents and active agents, the high rotational speed causes the product to foam. Since the active agents adhere to the foam, the problem of loss of active agents and blend uniformity is observed in the prepared suspension. On the other hand, mixing the active agents at a very low rotational speed causes the problem of blend uniformity. It is therefore a fundamental subject of the present invention to add the mixing speed at different speeds specific to the active agents/isotonic agents/buffering agents/dispersing or suspending agents.
According to one embodiment, said second rotational speed in the step numbered (iii) and (iv) is 8800-18000 rpm, preferably 8800-15000 rpm, more preferably 8800-13000 rpm.
The effect of the final mixing time in the step numbered (iv) on the blend uniformity is great. If the final 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 final 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. In this case, 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, the duration of the step number (iv) is 1-15 minutes, preferably 2-13 minutes, more preferably 3-10 minutes.
According to one embodiment, said process reduces processing times and gives rise to suspensions with a homogenous, thus producing compositions with a high level of physical stability and therapeutic efficacy.
In an embodiment, autoclaving in the step numbered (v) is at 121 °C for about 15-30 minutes.
According to one embodiment, the pharmaceutical compositions subjected to the invention are prepared by these steps: i. filling the tank which has homogenizer with water for injection and wetting the walls of the tank with water for injection ii. adding the pre-weighed sodium chloride, monosodium phosphate dihydrate and dibasic sodium phosphate to the water in the tank which has homogenizer, respectively, and mixing at 18000-33600 rpm, preferably 19000-30000 rpm, more preferably 20000-25000 rpm iii. adding the pre-weighed polysorbate 20 (Tween 20) and sorbitan monolaurate (Span 20) to the mixture in the tank which has homogenizer and mixing at 8800-18000 rpm, preferably 8800-15000 rpm, more preferably 8800-13000 rpm iv. adding the active agent to the mixture in the tank which has homogenizer and mixing at 8800-18000 rpm, preferably 8800-15000 rpm, more preferably 8800-13000 rpm v. autoclaving the product in the tank which has homogenizer vi. filling the autoclaved product into nebul vials wherein said first rotational speed in the step numbered (ii) is 18000-33600 rpm and said second rotational speed in the step numbered (iii) and (iv) is 8800-18000 rpm.
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 furoate.
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: i. filling a tank which has homogenizer with water for injection and wetting the walls of the tank with water for injection. ii. adding the pre-weighed isotonic agent and at least two buffering agents to the water in the tank which has homogenizer, respectively, and mixing at first rotational speed. iii. adding the pre-weighed at least two dispersing or suspending agents to the mixture in the tank which has homogenizer and mixing at a second rotational speed iv. adding the active agent to the mixture in the tank which has homogenizer and mixing at a second rotational speed v. autoclaving the product in the tank which has homogenizer vi. filling the autoclaved product into nebul vials wherein said first rotational speed in the step numbered (ii) is 18000-33600 rpm and said second rotational speed in the step numbered (iii) and (iv) is 8800-18000rpm.
2. A process according to claim 1, wherein said water for injection in the step numbered
(1) is heated to 40-60° C, more preferably 45-55° C, more preferably 50° C.
3. A process according to claim 1 , wherein said first rotational speed in the step numbered (ii) is preferably 19000-30000 rpm, more preferably 20000-25000 rpm.
4. A process according to claim 1, wherein said second rotational speed in the step numbered (iii) and (iv) preferably is 8800-15000 rpm, more preferably 8800-13000 rpm.
5. A process according to claim 1, wherein said 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) and polysorbate 80 (polyoxyethylene (20) sorbitan monooleate) sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate and 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.
6. A process according to claim 5, wherein said dispersing or suspending agents are polysorbate 20 and sorbitan monolaurate.
7. A process according to claim 1 , wherein said 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.
8. A process according to claim 7, wherein said the isotonic agent is sodium chloride.
9. A process according to claim 1, wherein buffering agents is selected from the group comprising citric acid, sodium citrate, phosphoric acid, monosodium phosphate, dibasic sodium phosphate and mixtures thereof.
10. A process according to claim 9, wherein buffering agents are monosodium phosphate dihydrate and dibasic sodium phosphate anhydrous.
11. A process according to claim 1, 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.
12. A process according to claim 11, wherein the glucocorticosteroid is fluticasone propionate.
13. A process according to claim 1, duration of the step number (iv) is 1-15 minutes, preferably 2-13 minutes, more preferably 3-10 minutes.
14. A process according to claim 1, mixing, homogenisation and autoclaving are carried out in one tank.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/TR2021/050409 WO2022231532A1 (en) | 2021-04-29 | 2021-04-29 | Process for the preparation of sterilized suspensions for the inhalation by nebulization |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/TR2021/050409 WO2022231532A1 (en) | 2021-04-29 | 2021-04-29 | Process for the preparation of sterilized suspensions for the inhalation by nebulization |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2022231532A1 true WO2022231532A1 (en) | 2022-11-03 |
Family
ID=83848704
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/TR2021/050409 WO2022231532A1 (en) | 2021-04-29 | 2021-04-29 | Process for the preparation of sterilized suspensions for the inhalation by nebulization |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2022231532A1 (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004004739A1 (en) * | 2002-07-02 | 2004-01-15 | Altana Pharma Ag | Ciclesonide-containing sterile aqueous suspension |
| EP1574222A1 (en) * | 2004-03-12 | 2005-09-14 | Cipla Ltd. | Sterilization process |
| EP1683514A1 (en) * | 2005-01-20 | 2006-07-26 | Eratech S.r.l. | Concentrated suspensions of drugs and their use to produce suspensions for inhalatory administration |
| CN108175763A (en) * | 2017-12-19 | 2018-06-19 | 亿腾医药（苏州）有限公司 | A kind of preparation method of budesonide sterile raw material and its sucking suspension |
-
2021
- 2021-04-29 WO PCT/TR2021/050409 patent/WO2022231532A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004004739A1 (en) * | 2002-07-02 | 2004-01-15 | Altana Pharma Ag | Ciclesonide-containing sterile aqueous suspension |
| EP1574222A1 (en) * | 2004-03-12 | 2005-09-14 | Cipla Ltd. | Sterilization process |
| EP1683514A1 (en) * | 2005-01-20 | 2006-07-26 | Eratech S.r.l. | Concentrated suspensions of drugs and their use to produce suspensions for inhalatory administration |
| CN108175763A (en) * | 2017-12-19 | 2018-06-19 | 亿腾医药（苏州）有限公司 | A kind of preparation method of budesonide sterile raw material and its sucking suspension |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2327450C2 (en) | Pharmaceutical products and compositions containig specific anticholinergic agents, antagonists of beta-2 and corticosteroids | |
| AU710821B2 (en) | Fluticasone propionate formulations | |
| JP3480736B2 (en) | Use of mometasone furoate for the treatment of airway channels and lung disease | |
| US20070293460A1 (en) | Delivery of a combination therapy for asthma and chronic obstructive pulmonary disease | |
| JP2009502997A (en) | Pharmaceutical formulation comprising a long acting beta2-agonist for spray administration | |
| US20060292083A1 (en) | Inhalation compositions with high drug ratios | |
| JP5001657B2 (en) | Aqueous suspension of ciclesonide for nebulization | |
| US20120067343A1 (en) | Aerosol Composition for Administering Drugs | |
| US20070098644A1 (en) | Delivery of a combination therapy for asthma and chronic obstructive pulmonary disease | |
| CN115998680A (en) | Inhalation solution pharmaceutical composition and preparation method thereof | |
| US20040258626A1 (en) | Inhalation compositions | |
| RU2611665C2 (en) | Improved composition of corticosteroid suspension for inhalation | |
| WO2022231532A1 (en) | Process for the preparation of sterilized suspensions for the inhalation by nebulization | |
| KR20140042898A (en) | Method for preparing metered dose sprayed inhaler for treating respiratory disease | |
| TR2023013883T2 (en) | METHOD OF PREPARING STERILIZED SUSPENSIONS FOR INHALATION BY NEBULIZATION | |
| WO2022231533A1 (en) | Process for the preparation of sterilized suspensions for the inhalation by nebulization | |
| TR2023013885T2 (en) | METHOD OF PREPARING STERILIZED SUSPENSIONS FOR INHALATION BY NEBULIZATION | |
| WO2022231531A1 (en) | Process for the preparation of sterilized suspensions for the inhalation by nebulization | |
| WO2022098321A1 (en) | Process for the preparation of sterilised suspensions for the administration by inhalation | |
| TR2023005107T2 (en) | METHOD FOR PREPARING STERILIZED SUSPENSIONS FOR USE BY INHALATION | |
| WO2024051683A1 (en) | Pharmaceutical composition for inhalation for preventing or treating respiratory disease | |
| WO2024025486A1 (en) | A process for the preparation of suspensions for inhalation by nebulization | |
| CN117064869A (en) | Capsule type inhalation powder spray and preparation method thereof | |
| CN115137713A (en) | Amphotericin B atomization inhalation preparation and preparation method thereof | |
| CN115463117A (en) | Budesonide salbutamol compound aerosol inhalation suspension with high delivery efficiency and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 21939505 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 21939505 Country of ref document: EP Kind code of ref document: A1 |