ZA200405637B - Hfa-suspension formulation of an anhydrate - Google Patents
Hfa-suspension formulation of an anhydrate Download PDFInfo
- Publication number
- ZA200405637B ZA200405637B ZA2004/05637A ZA200405637A ZA200405637B ZA 200405637 B ZA200405637 B ZA 200405637B ZA 2004/05637 A ZA2004/05637 A ZA 2004/05637A ZA 200405637 A ZA200405637 A ZA 200405637A ZA 200405637 B ZA200405637 B ZA 200405637B
- Authority
- ZA
- South Africa
- Prior art keywords
- hfa
- acid
- contain
- suspensions
- tiotropium
- Prior art date
Links
- 239000000725 suspension Substances 0.000 title claims description 46
- 239000000203 mixture Substances 0.000 title claims description 16
- 238000009472 formulation Methods 0.000 title description 9
- LERNTVKEWCAPOY-VOGVJGKGSA-N C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 Chemical compound C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 LERNTVKEWCAPOY-VOGVJGKGSA-N 0.000 claims description 26
- 229940110309 tiotropium Drugs 0.000 claims description 26
- LERNTVKEWCAPOY-DZZGSBJMSA-N tiotropium Chemical compound O([C@H]1C[C@@H]2[N+]([C@H](C1)[C@@H]1[C@H]2O1)(C)C)C(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 LERNTVKEWCAPOY-DZZGSBJMSA-N 0.000 claims description 26
- 229960000257 tiotropium bromide Drugs 0.000 claims description 26
- 239000007789 gas Substances 0.000 claims description 23
- 239000003380 propellant Substances 0.000 claims description 23
- YFMFNYKEUDLDTL-UHFFFAOYSA-N 1,1,1,2,3,3,3-heptafluoropropane Chemical compound FC(F)(F)C(F)C(F)(F)F YFMFNYKEUDLDTL-UHFFFAOYSA-N 0.000 claims description 22
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 18
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 claims description 16
- 239000013543 active substance Substances 0.000 claims description 11
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 10
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 9
- 239000004094 surface-active agent Substances 0.000 claims description 9
- -1 Brij Chemical compound 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims description 6
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-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
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- 239000002671 adjuvant Substances 0.000 claims description 6
- NNPPMTNAJDCUHE-UHFFFAOYSA-N isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 claims description 6
- QWTDNUCVQCZILF-UHFFFAOYSA-N isopentane Chemical compound CCC(C)C QWTDNUCVQCZILF-UHFFFAOYSA-N 0.000 claims description 6
- 229940074928 isopropyl myristate Drugs 0.000 claims description 6
- CRSOQBOWXPBRES-UHFFFAOYSA-N neopentane Chemical compound CC(C)(C)C CRSOQBOWXPBRES-UHFFFAOYSA-N 0.000 claims description 6
- 235000010323 ascorbic acid Nutrition 0.000 claims description 5
- 239000011668 ascorbic acid Substances 0.000 claims description 5
- 229960005070 ascorbic acid Drugs 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 239000004615 ingredient Substances 0.000 claims description 5
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 4
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 4
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 239000005642 Oleic acid Substances 0.000 claims description 4
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 4
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 4
- 239000003963 antioxidant agent Substances 0.000 claims description 4
- 235000006708 antioxidants Nutrition 0.000 claims description 4
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 claims description 4
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 4
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 4
- 229960002969 oleic acid Drugs 0.000 claims description 4
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 4
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 4
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 4
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 4
- 229940068977 polysorbate 20 Drugs 0.000 claims description 4
- 229920000053 polysorbate 80 Polymers 0.000 claims description 4
- 229940068968 polysorbate 80 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
- MRBKEAMVRSLQPH-UHFFFAOYSA-N 3-tert-butyl-4-hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1 MRBKEAMVRSLQPH-UHFFFAOYSA-N 0.000 claims description 3
- 108010011485 Aspartame Proteins 0.000 claims description 3
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 3
- 235000010357 aspartame Nutrition 0.000 claims description 3
- 239000000605 aspartame Substances 0.000 claims description 3
- 229960003438 aspartame Drugs 0.000 claims description 3
- 208000006673 asthma Diseases 0.000 claims description 3
- 239000001273 butane Substances 0.000 claims description 3
- AFABGHUZZDYHJO-UHFFFAOYSA-N dimethyl butane Natural products CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 239000000796 flavoring agent Substances 0.000 claims description 3
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 claims description 3
- 239000001282 iso-butane Substances 0.000 claims description 3
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 239000001294 propane Substances 0.000 claims description 3
- 230000001225 therapeutic effect Effects 0.000 claims description 3
- 229930003799 tocopherol Natural products 0.000 claims description 3
- 239000011732 tocopherol Substances 0.000 claims description 3
- 235000019149 tocopherols Nutrition 0.000 claims description 3
- QUEDXNHFTDJVIY-UHFFFAOYSA-N γ-tocopherol Chemical class OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-UHFFFAOYSA-N 0.000 claims description 3
- 239000000263 2,3-dihydroxypropyl (Z)-octadec-9-enoate Substances 0.000 claims description 2
- HDIFHQMREAYYJW-FMIVXFBMSA-N 2,3-dihydroxypropyl (e)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C\CCCCCCCC(=O)OCC(O)CO HDIFHQMREAYYJW-FMIVXFBMSA-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
- 102000009027 Albumins Human genes 0.000 claims description 2
- 108010088751 Albumins Proteins 0.000 claims description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N Betaine Natural products C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 claims description 2
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 2
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 claims description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical compound C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 235000004279 alanine Nutrition 0.000 claims description 2
- 229940065524 anticholinergics inhalants for obstructive airway diseases Drugs 0.000 claims description 2
- 229960003237 betaine Drugs 0.000 claims description 2
- 229960000541 cetyl alcohol Drugs 0.000 claims description 2
- 229960001927 cetylpyridinium chloride Drugs 0.000 claims description 2
- 239000000812 cholinergic antagonist Substances 0.000 claims description 2
- 229960004106 citric acid Drugs 0.000 claims description 2
- 235000018417 cysteine Nutrition 0.000 claims description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 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
- RZRNAYUHWVFMIP-UHFFFAOYSA-N monoelaidin Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 239000003921 oil Substances 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 229920000642 polymer Polymers 0.000 claims description 2
- 229960004063 propylene glycol Drugs 0.000 claims description 2
- 235000013772 propylene glycol Nutrition 0.000 claims description 2
- 230000000241 respiratory effect Effects 0.000 claims description 2
- 229940037001 sodium edetate Drugs 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 235000011149 sulphuric acid Nutrition 0.000 claims description 2
- PHYFQTYBJUILEZ-UHFFFAOYSA-N Trioleoylglycerol Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCCCCCCCC)COC(=O)CCCCCCCC=CCCCCCCCC PHYFQTYBJUILEZ-UHFFFAOYSA-N 0.000 claims 1
- YMKDRGPMQRFJGP-UHFFFAOYSA-M cetylpyridinium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 YMKDRGPMQRFJGP-UHFFFAOYSA-M 0.000 claims 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 claims 1
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 claims 1
- 229940117972 triolein Drugs 0.000 claims 1
- 238000000034 method Methods 0.000 description 12
- MQLXPRBEAHBZTK-SEINRUQRSA-M tiotropium bromide hydrate Chemical compound O.[Br-].C[N+]1(C)[C@H]2C[C@@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 MQLXPRBEAHBZTK-SEINRUQRSA-M 0.000 description 10
- 230000010355 oscillation Effects 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 239000013078 crystal Substances 0.000 description 6
- 230000004048 modification Effects 0.000 description 6
- 238000012986 modification Methods 0.000 description 6
- 239000002245 particle Substances 0.000 description 6
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 238000000113 differential scanning calorimetry Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 2
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 2
- 244000246386 Mentha pulegium Species 0.000 description 2
- 235000016257 Mentha pulegium Nutrition 0.000 description 2
- 235000004357 Mentha x piperita Nutrition 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 235000010385 ascorbyl palmitate Nutrition 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 235000001050 hortel pimenta Nutrition 0.000 description 2
- 150000004682 monohydrates Chemical class 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 241000723347 Cinnamomum Species 0.000 description 1
- 241000723346 Cinnamomum camphora Species 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 240000004760 Pimpinella anisum Species 0.000 description 1
- 235000012550 Pimpinella anisum Nutrition 0.000 description 1
- 238000003991 Rietveld refinement Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000000137 annealing Methods 0.000 description 1
- 230000001078 anti-cholinergic effect Effects 0.000 description 1
- 229960000846 camphor Drugs 0.000 description 1
- 229930008380 camphor Natural products 0.000 description 1
- NFCRBQADEGXVDL-UHFFFAOYSA-M cetylpyridinium chloride monohydrate Chemical compound O.[Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 NFCRBQADEGXVDL-UHFFFAOYSA-M 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 235000017803 cinnamon Nutrition 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 230000005469 synchrotron radiation Effects 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
Classifications
-
- 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
- A61K9/10—Dispersions; Emulsions
-
- 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
- A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pulmonology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dispersion Chemistry (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Otolaryngology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Description
. ~ 80282pct.210 . : - HFA suspension formulations of an anhydrate
The invention relates to propellant gas preparations for metered-dose aerosols with suspension formulations of the crystalline anhydrate of (10,2B,4B,5a,7B)-7- [(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9- azoniatricyclo[3.3.1.0%“|nonane-bromide.
The compound ( 1a,2,4p,5a,7p)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3- oxa-9-azoniatricyclo[3.3.1.02*Jnonane-bromide, is known from European Patent
Application EP 418 716 A1 and has the following chemical structure: + Me
Me—y’ 0) H _ 0 Br
S 0)
Yan 7S — U) 75 The compound has valuable pharmacological properties and is known by the name tiotropium bromide (BA679). Tiotropium bromide is a highly effective anticholinergic and can therefore provide therapeutic benefit in the treatment of asthma or COPD (chronic obstructive pulmonary disease).
Tiotropium bromide is preferably administered by inhalation.
The aim of the present invention is to prepare HFA-metered-dose aerosols containing tiotropium bromide as the sole active ingredient in suspended form.
It has been found that, depending on the choice of conditions which can be used when purifying the crude product obtained after industrial manufacture, tiotropium bromide occurs in various crystalline modifications.
It has been found that these different modifications can be deliberately produced by selecting the salvents used for the crystallisation as well as by a suitable choice of
Co 2 the process conditions used in the crystallisation process. One of these crystalline modifications is the crystalline monohydrate of tiotropium bromide.
It has now surprisingly been found that starting from this crystalline monohydrate of tiotropium bromide which is not yet known in the art it is possible to obtain an anhydrous crystal modification of tiotropium bromide (tiotropium anhydrate) which is exceptionally suitable for the preparation of suspensions in the propellant gases HFA 227 and/or HFA 134a for administration by inhalation. 170 Accordingly, the present invention relates to suspensions of this crystalline tiotropium bromide anhydrate in the propellant gases HFA 227 and/or HFA 134a, optionally in admixture with one or more other propellant gases, preferably selected from the group consisting of propane, butane, pentane, dimethylether, CHCIF,, CH,F,,
CF,CH, isobutane, isopentane and neopentane.
Where reference is made within the scope of the present invention to crystalline tiotropium bromide anhydrate this should be taken as a reference to the anhydrous crystalline modification of tiotropium bromide which can be obtained by drying the crystalline tiotropium bromide monohydrate. This crystal modification is also optionally known within the scope of the present invention as crystalline tiotropium bromide in anhydrous form.
Preferred suspensions according to the invention are those which contain as propellant gas HFA 227 on its own, a mixture of HFA 227 and HFA 134a or HFA 134a on its own.
If a mixture of propellant gases HFA 227 and HFA 134a is used in the suspension formulations according to the invention, the weight ratios in which these two propellant gas components are used may be freely selected.
If in the suspension formulations according to the invention one or more other propellant gases are used in addition to the propellant gases HFA 227 and/or HFA 134a , selected from the group consisting of propane, butane, pentane, dimethylether, CHCIF,, CH,F,, CF,CH, isobutane, isopentane and neopentane, the proportion of this other propellant gas component is preferably less than 50 %, preferably less than 40%, more preferably less than 30%.
The suspensions according to the invention preferably contain between 0.001 and 0.8% tiotropium. Suspensions which contain 0.08 to 0.5%, more preferably 0.2 to 0.4% tiotropium are preferred according to the invention.
By tiotropium is meant the free ammonium cation. The propellant gas suspensions according to the invention are characterised in that they contain tiotropium in the form of the crystalline tiotropium bromide anhydrate which is exceptionally suitable for this application. Accordingly, the present invention preferably relates to suspensions which contain between 0.0012 and 96% crystalline tiotropium bromide anhydrate. Of particular interest according to the invention are suspensions which contain 0.096 to 0.6%, more preferably 0.24 to 0.48% crystalline tiotropium bromide anhydrate.
The percentages specified within the scope of the present invention are always percent by mass. If parts by mass of tiotropium are given in percent by mass, the corresponding values for the crystalline tiotropium bromide anhydrate which is preferably used within the scope of the present invention may be obtained by multiplying by a conversion factor of 1.2036.
In some cases within the scope of the present invention the term suspension formulation may be used instead of the term suspension. The two terms are to be regarded as interchangeable within the scope of the present invention.
The propellant-containing inhalation aerosols or suspension formulations according to the invention may also contain other ingredients such as surface-active agents (surfactants), adjuvants, antioxidants or flavourings.
The surface-active agents (surfactants) which may be contained in the suspensions according to the invention are preferably selected from among Polysorbate 20,
Polysorbate 80, Myvacet 9-45, Myvacet 9-08, isopropylmyristate, oleic acid, propyleneglycol, polyethyleneglycol, Brij, ethyloleate, glyceryl tricleate, glyceryl monolaurate, glyceryl monooleate, glyceryl monosterate, glyceryl monoricinoleate, cetylalcohol, sterylalcohol, cetylpyridinium chloride, block polymers, natural oil, ethanol and isopropanol. Of the abovementioned suspension adjuvants Polysorbate 20, Polysorbate 80, Myvacet 9-45, Myvacet 9-08 or isopropylmyristate are preferably used. Myvacet 9-45 or isopropylmyristate are particularly preferred.
Where the suspensions according to the invention contain surfactants, these are preferably present in an amount of 0.0005 - 1 %, more preferably 0.005 - 0.5 %.
The adjuvants optionally contained in the suspensions according to the invention are preferably selected from among alanine, albumin, ascorbic acid, aspartame, betaine, cysteine, phosphoric acid, nitric acid, hydrochloric acid, sulphuric acid and citric acid.
Co 4
Of these, ascorbic acid, phosphoric acid, hydrochloric acid or citric acid are preferred, while hydrochloric acid or citric acid is more preferable.
Where the suspensions according to the invention contain adjuvants, these are preferably present in an amount of 0.0001-1.0 %, preferably 0.0005-0.1 %, more preferably 0.001-0.01 %, while an amount of from 0.001-0.005 % is particularly preferred according to the invention.
The antioxidants optionally contained in the suspensions according to the invention are preferably selected from among ascorbic acid, citric acid, sodium edetate, editic acid, tocopherols, butylhydroxytoluene, butylhydroxyanisol and ascorbyl palmitate, of which tocopherols, butylhydroxytoluene, butylhydroxyanisol and ascorbyl palmitate are preferred.
The flavourings which may be contained in the suspensions according to the invention are preferably selected from among peppermint, saccharine, Dentomint®, aspartame and ethereal oils (e.g. cinnamon, aniseed, menthol, camphor), of which peppermint or Dentomint® is particularly preferred.
For administration by inhalation it is necessary to prepare the active substance in finely divided form. The crystalline tiotropium bromide anhydrate which may be obtained as detailed in the experimental section is either ground (micronised or obtained in finely divided form by other technical methods known in principle in the art (such as precipitation and spray drying). Methods of micronising active substances are known in the art. Preferably, after micronisation, the active substance has an average particle size of 0.5 to 10 um, preferably 1 to 6 ym, more preferably 1.5 to 5 um. Preferably, at least 50%, more preferably at least 60%, most preferably at least 70% of the particles of active substance have a particle size which is within the ranges specified above. More preferably, at least 80%, most preferably atleast 90% of the particles of active substance have a particle size within the ranges specified above.
Surprisingly, it has been found that it is also possible to prepare suspensions which contain, apart from the abovementioned propellant gases, only the active substance and no other additives. Accordingly, in another aspect, the present invention relates to suspensions which contain only the active substance and no other additives.
. oo 5
The suspensions according to the invention may be prepared by methods known in "the art. For this the ingredients of the formulation are mixed with the propellant gas or gases (optionally at low temperatures) and transferred into suitable containers.
The propellant gas-containing suspensions according to the invention mentioned above may be administered using inhalers known in the art (pMDls = pressurised metered dose inhalers). Accordingly, in another aspect, the present invention relates to pharmaceutical compositions in the form of suspensions as hereinbefore described combined with one or more inhalers suitable for administering these suspensions. In addition, the present invention relates to inhalers which are characterised in that they contain the propellant gas-containing suspensions described above according to the invention. The present invention also relates to containers (cartridges) which are fitted with a suitable valve and can be used in a suitable inhaler and which contain one of the above-mentioned propellant gas- containing suspensions according to the invention. Suitable containers (cartridges) and methods of filling these cartridges with the propellant gas-containing suspensions according to the invention are known from the prior art.
In view of the pharmaceutical activity of tiotropium the present invention further relates to the use of the suspensions according to the invention for preparing a drug for administration by inhalation or by nasal route, preferably for preparing a drug for the treatment by inhalation or by nasal route of diseases in which anticholinergics may provide a therapeutic benefit.
Most preferably, the invention further relates to the use of the suspensions according to the invention for preparing a pharmaceutical composition for the treatment by inhalation of respiratory complaints, preferably asthma or COPD.
The Examples that follow serve to illustrate the present invention more fully by way of example, without restricting it to their content.
Starting materials
Crystalline tiotropium bromide monohydrate:
The tiotropium obtained according to EP 418 716 A1may be used to prepare the crystalline tiotropium bromide monohydrate. This is then reacted as described below. 15.0 kg of tiotropium bromide are added to 25.7 kg of water in a suitable reaction vessel. The mixture is heated to 80-90°C and stirred at constant temperature until a clear solution is formed. Activated charcoal (0.8 kg), moistened with water, is to 6 , suspended in 4.4 kg of water, this mixture is added to the solution containing tiotropium bromide and rinsed with 4.3 kg of water. The mixture thus obtained is stirred for at least 15 min. at 80-90°C and then filtered through a heated filter into an apparatus which has been preheated to an outer temperature of 70°C. The filter is rinsed with 8.6 kg of water. The contents of the apparatus are cooled to a temperature of 20-25°C at a rate of 3-5°C every 20 minutes. Using cold water the apparatus is cooled further to 10-15°C and crystallisation is completed by stirring for at least another hour. The crystals are isolated using a suction filter drier, the crystal slurry isolated is washed with 9 L of cold water (10-15°C) and cold acetone (10- 15°C). The crystals obtained are dried at 25°C for 2 hours in a nitrogen current.
Yield: 13.4 kg of tiotropium bromide monohydrate (86 % of theory).
The tiotropium bromide monohydrate obtainable using the method described above was investigated by DSC (Differential Scanning Calorimetry). The DSC diagram shows two characteristic signals. The first, relatively broad, endothermic signal between 50-120°C can be attributed to the dehydration of the tiotropium bromide monohydrate into the anhydrous form. The second, relatively sharp, endothermic peak at 230 + 5°C can be put down to the melting of the substance. This data was obtained using a Mettler DSC 821 and evaluated using the Mettler STAR software package. The data was recorded at a heating rate of 10 K/min.
The crystalline tiotropium bromide monohydrate was characterised by IR spectroscopy. The data was obtained using a Nicolet FTIR spectrometer and evaluated with the Nicolet OMNIC software package, version 3.1. The measurement was carried out with 2.5 pmol of tiotropium bromide monohydrate in 300 mg of KBr.
The following Table shows some of the essential bands of the IR spectrum.
Wave number (cm™) Attribution Type of oscillation 3570, 3410 O-H elongated oscillation 3105 Aryl C-H elongated oscillation 1730 Cc=0 elongated oscillation 1260 Epoxide C-O elongated oscillation 1035 Ester C-OC elongated oscillation 720 Thiophene cyclic oscillation
Co 7
The monocrystal X-ray structural analysis carried out showed that the crystalline tiotropium bromide hydrate obtainable by the above process has a simple monoclinic cell with the following dimensions: a=18.0774A b=11.97114, c=9.9321 &, 8 = 102.691°, V = 2096.96 AZ.
These data were obtained using an AFC7R 4-circuit diffractometer (Rigaku) using monochromatic copper K, radiation. The structural resolution and refinement of the crystal structure were obtained by direct methods (SHELXS86 Program) and FMLQ- refinement (TeXsan Program).
Crystalline tiotropium bromide anhydrate:
The anhydrous form is produced from the crystalline tiotropium bromide monohydrate obtained as described above by careful drying at 80 —100 °C under reduced pressure, preferably under high vacuum over a period of at least 30 minutes. Alternatively to the drying step at 80 — 100 °C in vacuo the anhydrous form may also be prepared by storing over dried silica gel at ambient temperature over a period of at least 24 hours.
The crystalline structure of the anhydrous tiotropium bromide was determined from high-resolution X-ray powder data (synchrotron radiation) by a real space mixture using a so-called "simulating annealing” process. A final Rietveld analysis was carried out to refine the structural parameters. These investigations showed that the crystalline tiotropium bromide anhydrate which is used in the suspensions according to the invention is characterised by the elementary cell a =10.4336(2)A, b =11.3297(3)A, c=17.6332(4) A and a = 90°,
B =105.158(2)° and y = 90° (cell volume =2011.89(8) A3).
To prepare the suspensions according to the invention the crystalline tiotropium bromide anhydrate obtainable by the above process is micronised by methods known in the art, with the exclusion of moisture, to prepare the active substance in the form of the average particle size which corresponds to the specifications according to the invention.
. oo 8
Examples of formulations
Suspensions containing other ingredients in addition to active substance and propellant gas: a) 0.02 % Tiotropium* 0.20 % Polysorbate 20 99.78 % HFA 227 b) 0.02 % Tiotropium* 1.00 % Isopropylmyristate 98.98 % HFA 227
Cc) 0.02 % Tiotropium* 0.3 % Myvacet 9-45 99.68 % HFA 227 d) 0.04 % Tiotropium* 1.00 % Myvacet 9-08 98.96 % HFA 227 e) 0.04 % Tiotropium* 0.04 % Polysorbate 80 99.92 % HFA 227 f) 0.04 % Tiotropium* 0.005 % Oleic acid 99.955 % HFA 227 a) 0.02 % Tiotropium* 0.1 % Myvacet 945 60.00 % HFA 227 39.88 % HFA 134a h) 0.02 % Tiotropium* 0.30 % Isopropylmyristate 20.00 % HFA 227 79.68 % HFA 134a i) 0.02 % Tiotropium* 0.01 % Oleic acid 60.00 % HFA 227 39.97 % HFA 134a *used in the form of the tiotropium bromide anhydrate (conversion factor 1.2036)
Co o
Suspensions containing only active substance and propellant gas: 1) 0.02 % Tiotropium* 99.98 % HFA 227
K) 0.02 % Tiotropium* 99.98 % HFA 134a 1) 0.04 % Tiotropium* 99.96 % HFA 227 m) 0.04 % Tiotropium* 99.96 % HFA 134a n) 0.02 % Tiotropium* 20.00 % HFA 227 79.98 % HFA 134a 0) 0.02 % Tiotropium* 60.00 % HFA 227 39.98 % HFA 134a p) 0.04 % Tiotropium* 40.00 % HFA 227 59.96 % HFA 134a q) 0.04 % Tiotropium* 80.00 % HFA 227 19.96 % HFA 134a * used in the form of the tiotropium bromide anhydrate (conversion factor 1.2036)
Claims (9)
- ’ vo. 10 } Patent Claims 1) Suspensions of crystalline tiotropium bromide anhydrate in the propellant gases HFA 227 and/or HFA 134a, optionally in admixture with one or more other propellant gases selected from the group consisting of propane, butane, pentane, dimethylether, CHCIF,, CH,F,, CF,CH, isobutane, isopentane and neopentane.
- 2) Suspensions according to claim 1, characterised in that they contain between0.001 and 0.8% tiotropium.
- 3) Suspensions according to claim 1 or 2, characterised in that they contain as other ingredients surface-active agents (surfactants), adjuvants, antioxidants and/or flavourings.
- 4) Suspensions according to claim 3, characterised in that they contain as surface- active agents (surfactants) one or more compounds selected from the group consisting of Polysorbate 20, Polysorbate 80, Myvacet 9-45, Myvacet 9-08, isopropylmyristate, oleic acid, propyleneglycol, polyethyleneglycol, Brij, ethyl oleate, glyceryl trioleate, glyceryl monolaurate, glyceryl monooleate, glyceryl monosterate, glyceryl monoricinoleate, cetylalcohol, sterylalcohol, cetylpyridinium chloride, block polymers, natural oil, ethanol and isopropanol .
- 5) Suspensions according to claim 3, characterised in that they contain as adjuvants one or more compounds selected from the group consisting of alanine, albumin, ascorbic acid, aspartame, betaine, cysteine, phosphoric acid, nitric acid, hydrochloric acid, sulphuric acid and citric acid.
- 6) Suspensions according to claim 3, characterised in that they contain as antioxidants one or more compounds selected from the group consisting of ascorbic acid, citric acid, sodium edetate, editic acid, tocopherols, butylhydroxytoluene, butylhydroxyanisol and ascorby! palmitate.
- 7) Suspensions according to claim 1 or 2, characterised in that they contain no other ingredients apart from the active substance and the propellant gas or gases.
- 8) Use of a suspension according to one of claims 1 to 7 for preparing a pharmaceutical composition, preferably for preparing a pharmaceutical. Co » : composition for the treatment by inhalation or nasal route of diseases in which anticholinergics may confer a therapeutic benefit.
- 9) Use according to claim 8, characterised in that the diseases are respiratory complaints, preferably asthma or COPD.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10214264A DE10214264A1 (en) | 2002-03-28 | 2002-03-28 | HFA suspension formulations of an anhydrate |
PCT/EP2003/002899 WO2003082244A2 (en) | 2002-03-28 | 2003-03-20 | Hfa-suspension formulation of an anhydrate |
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ZA200405637B true ZA200405637B (en) | 2005-07-27 |
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ZA2004/05637A ZA200405637B (en) | 2002-03-28 | 2004-07-15 | Hfa-suspension formulation of an anhydrate |
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EP (1) | EP1492498A2 (en) |
JP (1) | JP5147158B2 (en) |
KR (1) | KR101005717B1 (en) |
CN (1) | CN1642525A (en) |
AU (1) | AU2003221509B2 (en) |
BR (1) | BR0308709A (en) |
CA (1) | CA2479638C (en) |
DE (1) | DE10214264A1 (en) |
EA (1) | EA008610B1 (en) |
EC (1) | ECSP045322A (en) |
HR (1) | HRP20040890A2 (en) |
IL (1) | IL163696A0 (en) |
ME (1) | ME00246B (en) |
MX (1) | MXPA04009338A (en) |
NO (1) | NO20044004L (en) |
NZ (1) | NZ536030A (en) |
PL (1) | PL371295A1 (en) |
RS (1) | RS52481B (en) |
UA (1) | UA79776C2 (en) |
WO (1) | WO2003082244A2 (en) |
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AU2006243239A1 (en) * | 2005-05-02 | 2006-11-09 | Boehringer Ingelheim International Gmbh | Crystalline forms of tiotropium bromide |
WO2006117299A2 (en) * | 2005-05-02 | 2006-11-09 | Boehringer Ingelheim International Gmbh | Novel crystalline forms of tiotropium bromide |
AU2015201037C1 (en) * | 2009-05-29 | 2017-07-27 | Pearl Therapeutics, Inc. | Respiratory delivery of active agents |
PL3106149T3 (en) * | 2009-05-29 | 2020-06-01 | Pearl Therapeutics, Inc. | Compositions for pulmonary delivery of long-acting muscarinic antagonists and long-acting beta-2 adrenergic receptor agonists and associated methods and systems |
US8815258B2 (en) | 2009-05-29 | 2014-08-26 | Pearl Therapeutics, Inc. | Compositions, methods and systems for respiratory delivery of two or more active agents |
ES2712988T5 (en) | 2013-03-15 | 2022-10-21 | Pearl Therapeutics Inc | Methods and systems for conditioning particulate crystalline materials |
WO2018051132A1 (en) * | 2016-09-19 | 2018-03-22 | Mexichem Fluor S.A. De C.V. | Pharmaceutical composition |
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DE3931041C2 (en) * | 1989-09-16 | 2000-04-06 | Boehringer Ingelheim Kg | Esters of thienyl carboxylic acids with amino alcohols, their quaternization products, processes for their preparation and medicaments containing them |
WO2000007567A1 (en) * | 1998-08-04 | 2000-02-17 | Jago Research Ag | Medicinal aerosol formulations |
GB0009605D0 (en) * | 2000-04-18 | 2000-06-07 | Glaxo Group Ltd | Medicaments |
GB0009592D0 (en) * | 2000-04-18 | 2000-06-07 | Glaxo Group Ltd | Respiratory combinations |
GB0009583D0 (en) * | 2000-04-18 | 2000-06-07 | Glaxo Group Ltd | Respiratory formulations |
GB0009606D0 (en) * | 2000-04-18 | 2000-06-07 | Glaxo Group Ltd | Therapeutic combinations |
EP1341538B1 (en) * | 2000-10-31 | 2009-12-23 | Boehringer Ingelheim Pharma GmbH & Co.KG | Medicament compositions with salts of tiotropium and epinastin for the therapy of respiratory diseases |
DE10111058A1 (en) * | 2001-03-08 | 2002-09-12 | Boehringer Ingelheim Pharma | New drug compositions based on anticholinergics and NK¶1¶ receptor antagonists |
DE10113366A1 (en) * | 2001-03-20 | 2002-09-26 | Boehringer Ingelheim Pharma | Medicament for treating inflammatory or obstructive respiratory diseases, e.g. asthma or chronic obstructive pulmonary disease, containing synergistic combination of anticholinergic agent and endothelin antagonist |
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2002
- 2002-03-28 DE DE10214264A patent/DE10214264A1/en not_active Withdrawn
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2003
- 2003-03-20 PL PL03371295A patent/PL371295A1/en not_active Application Discontinuation
- 2003-03-20 BR BR0308709-3A patent/BR0308709A/en active Pending
- 2003-03-20 AU AU2003221509A patent/AU2003221509B2/en not_active Expired
- 2003-03-20 UA UA20041008758A patent/UA79776C2/en unknown
- 2003-03-20 KR KR1020047015174A patent/KR101005717B1/en active IP Right Grant
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- 2003-03-20 CA CA2479638A patent/CA2479638C/en not_active Expired - Fee Related
- 2003-03-20 WO PCT/EP2003/002899 patent/WO2003082244A2/en active Application Filing
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- 2003-03-20 IL IL16369603A patent/IL163696A0/en unknown
- 2003-03-20 CN CNA038072475A patent/CN1642525A/en active Pending
- 2003-03-20 MX MXPA04009338A patent/MXPA04009338A/en active IP Right Grant
- 2003-03-20 EP EP03717219A patent/EP1492498A2/en not_active Withdrawn
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KR101005717B1 (en) | 2011-01-05 |
AU2003221509A1 (en) | 2003-10-13 |
RS52481B (en) | 2013-02-28 |
EA008610B1 (en) | 2007-06-29 |
NO20044004L (en) | 2004-10-05 |
CN1642525A (en) | 2005-07-20 |
EA200401159A1 (en) | 2005-04-28 |
MXPA04009338A (en) | 2005-01-25 |
IL163696A0 (en) | 2005-12-18 |
UA79776C2 (en) | 2007-07-25 |
NZ536030A (en) | 2006-07-28 |
CA2479638A1 (en) | 2003-10-09 |
EP1492498A2 (en) | 2005-01-05 |
KR20040098022A (en) | 2004-11-18 |
MEP47308A (en) | 2011-02-10 |
ME00246B (en) | 2011-05-10 |
WO2003082244A3 (en) | 2004-02-05 |
HRP20040890A2 (en) | 2005-06-30 |
WO2003082244A2 (en) | 2003-10-09 |
JP5147158B2 (en) | 2013-02-20 |
DE10214264A1 (en) | 2003-10-16 |
ECSP045322A (en) | 2005-01-28 |
JP2005527550A (en) | 2005-09-15 |
BR0308709A (en) | 2005-01-04 |
AU2003221509B2 (en) | 2008-01-24 |
CA2479638C (en) | 2011-01-04 |
YU86004A (en) | 2006-08-17 |
PL371295A1 (en) | 2005-06-13 |
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