EP1492498A2 - Hfa-suspensionsformulierungen eines anhydrats - Google Patents

Hfa-suspensionsformulierungen eines anhydrats

Info

Publication number: EP1492498A2
Authority: EP; European Patent Office
Prior art keywords: hfa; acid; contain; suspensions; tiotropium
Prior art date: 2002-03-28
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Withdrawn

Application number

EP03717219A

Other languages

German (de)

English (en)

French (fr)

Inventor

Christel Schmelzer

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Boehringer Ingelheim Pharma GmbH and Co KG

Boehringer Ingelheim Pharmaceuticals Inc

Original Assignee

Boehringer Ingelheim Pharma GmbH and Co KG

Boehringer Ingelheim Pharmaceuticals Inc

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2002-03-28

Filing date

2003-03-20

Publication date

2005-01-05

2003-03-20 Application filed by Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim Pharma GmbH and Co KG

2005-01-05 Publication of EP1492498A2 publication Critical patent/EP1492498A2/de

Status Withdrawn legal-status Critical Current

Links

239000000725 suspension Substances 0.000 title claims abstract description 47
239000000203 mixture Substances 0.000 title claims abstract description 17
238000009472 formulation Methods 0.000 title abstract description 9
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 abstract description 27
239000003380 propellant Substances 0.000 claims abstract description 24
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 27
229960000257 tiotropium bromide Drugs 0.000 claims description 27
229940110309 tiotropium Drugs 0.000 claims description 26
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
239000007789 gas Substances 0.000 claims description 20
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
239000004094 surface-active agent Substances 0.000 claims description 13
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
239000004480 active ingredient Substances 0.000 claims description 9
OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 9
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
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-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
239000003814 drug 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
CRSOQBOWXPBRES-UHFFFAOYSA-N neopentane Chemical compound CC(C)(C)C CRSOQBOWXPBRES-UHFFFAOYSA-N 0.000 claims description 6
239000002671 adjuvant Substances 0.000 claims description 5
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
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
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
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 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
238000004519 manufacturing process Methods 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
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
108010011485 Aspartame Proteins 0.000 claims description 3
239000004255 Butylated hydroxyanisole Substances 0.000 claims description 3
239000004322 Butylated hydroxytoluene Substances 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
239000011786 L-ascorbyl-6-palmitate Substances 0.000 claims description 3
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 claims description 3
229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
235000010385 ascorbyl palmitate Nutrition 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
235000019282 butylated hydroxyanisole Nutrition 0.000 claims description 3
CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 claims description 3
229940043253 butylated hydroxyanisole Drugs 0.000 claims description 3
235000010354 butylated hydroxytoluene Nutrition 0.000 claims description 3
229940095259 butylated hydroxytoluene Drugs 0.000 claims description 3
239000000470 constituent 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
235000013355 food flavoring agent Nutrition 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
239000001294 propane Substances 0.000 claims description 3
230000001225 therapeutic effect Effects 0.000 claims description 3
239000011732 tocopherol Substances 0.000 claims description 3
229930003799 tocopherol Natural products 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
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
PHYFQTYBJUILEZ-UHFFFAOYSA-N Trioleoylglycerol Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCCCCCCCC)COC(=O)CCCCCCCC=CCCCCCCCC PHYFQTYBJUILEZ-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
NFCRBQADEGXVDL-UHFFFAOYSA-M cetylpyridinium chloride monohydrate Chemical compound O.[Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 NFCRBQADEGXVDL-UHFFFAOYSA-M 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
125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 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
208000023504 respiratory system disease Diseases 0.000 claims description 2
229940037001 sodium edetate Drugs 0.000 claims description 2
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 description 2
229940117972 triolein Drugs 0.000 claims description 2
HDIFHQMREAYYJW-XGXNLDPDSA-N Glyceryl Ricinoleate Chemical class CCCCCC[C@@H](O)C\C=C/CCCCCCCC(=O)OCC(O)CO HDIFHQMREAYYJW-XGXNLDPDSA-N 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 9
239000013078 crystal Substances 0.000 description 7
238000012986 modification Methods 0.000 description 6
230000004048 modification Effects 0.000 description 6
239000002245 particle Substances 0.000 description 6
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 4
239000013543 active substance Substances 0.000 description 3
239000000443 aerosol Substances 0.000 description 3
238000002425 crystallisation Methods 0.000 description 3
230000008025 crystallization Effects 0.000 description 3
238000000113 differential scanning calorimetry Methods 0.000 description 3
238000001035 drying Methods 0.000 description 3
-1 hydroxydi-2-thienylacetyl Chemical group 0.000 description 3
150000004682 monohydrates Chemical class 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
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
235000001050 hortel pimenta Nutrition 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
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 description 1
QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
241000723346 Cinnamomum camphora Species 0.000 description 1
244000223760 Cinnamomum zeylanicum 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
239000004593 Epoxy Substances 0.000 description 1
238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
238000004566 IR spectroscopy Methods 0.000 description 1
240000009023 Myrrhis odorata Species 0.000 description 1
235000007265 Myrrhis odorata Nutrition 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
YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
230000001078 anti-cholinergic effect Effects 0.000 description 1
238000013459 approach Methods 0.000 description 1
229960000846 camphor Drugs 0.000 description 1
229930008380 camphor Natural products 0.000 description 1
238000006243 chemical reaction Methods 0.000 description 1
235000017803 cinnamon Nutrition 0.000 description 1
238000001816 cooling Methods 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
230000007717 exclusion Effects 0.000 description 1
238000011049 filling Methods 0.000 description 1
238000010438 heat treatment Methods 0.000 description 1
238000009776 industrial production Methods 0.000 description 1
238000002329 infrared spectrum Methods 0.000 description 1
238000011835 investigation 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
VTTKBFMNVGIDQJ-UHFFFAOYSA-N nonane;hydrobromide Chemical compound Br.CCCCCCCCC VTTKBFMNVGIDQJ-UHFFFAOYSA-N 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
238000002360 preparation method Methods 0.000 description 1
238000000746 purification 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
238000002922 simulated annealing Methods 0.000 description 1
239000002002 slurry Substances 0.000 description 1
239000002904 solvent Substances 0.000 description 1
238000001694 spray drying Methods 0.000 description 1
238000003756 stirring Methods 0.000 description 1
230000005469 synchrotron radiation Effects 0.000 description 1
ZZIZZTHXZRDOFM-XFULWGLBSA-N tamsulosin hydrochloride Chemical compound [H+].[Cl-].CCOC1=CC=CC=C1OCCN[C@H](C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 ZZIZZTHXZRDOFM-XFULWGLBSA-N 0.000 description 1
238000012360 testing method Methods 0.000 description 1
239000000341 volatile oil Substances 0.000 description 1
238000012982 x-ray structure analysis Methods 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

Definitions

the invention relates to propellant gas preparations for metered dose aerosols with suspension formulations of the crystalline anhydrate of (1c., 2ß, 4ß, 5 ⁇ , 7ß) -7- [(hydroxydi-2-thienylacetyl) oxy] -9,9-dimethyl-3-oxa-9- azoniatricyclo [3.3.1.0 2 ' 4 ] nonane bromide.
Patent application EP 418 716 A1 known and has the following chemical
Tiotropium bromide is preferably administered by inhalation.
the object of the present invention is to provide HFA metered dose aerosols containing tiotropium bromide as the only active substance in suspended form.
the present invention relates to suspensions of this crystalline tiotropium bromide anhydrate in the propellant gases HFA 227 and / or HFA 134a, optionally in a mixture with one or more further propellant gases, preferably selected from the group consisting of propane, butane, pentane, dimethyl ether, CHCIF 2 , CH 2 F 2) CF 3 CH 3 , isobutane, isopentane and neopentane.
crystalline tiotropium bromide anhydrate in the context of the present invention, this should be regarded as a reference to the anhydrous, crystalline modification of the tiotropium bromide which can be obtained by drying the crystalline tiotropium bromide monohydrate.
this crystal modification is optionally also referred to as crystalline tiotropium bromide in anhydrous form.
suspensions are preferred according to the invention which contain only HFA 227, a mixture of HFA 227 and HFA 134a or only HFA 134a as the propellant gas. If a mixture of the 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 can be used are freely variable.
one or more further propellants are selected in the suspension formulations according to the invention, selected from the group consisting of propane, butane, pentane, dimethyl ether, CHCIF 2 , CH 2 F 2 , CF 3 CH 3 , isobutane, If isopentane and neopentane are used, the proportion of this further propellant gas component is preferably below 50%, preferably below 40%, particularly preferably below 30%.
the suspensions according to the invention preferably contain between 0.001 to 0.8% tiotropium. Suspensions which contain 0.08 to 0.5%, particularly preferably 0.2 to 0.4% tiotropium are preferred according to the invention.
Tiotropium is the free ammonium cation.
the propellant gas suspensions according to the invention are characterized in that they contain tiotropium in the form of the crystalline tiotropium bromide anhydrate which is outstandingly suitable for this application. Accordingly, the present invention preferably relates to suspensions containing 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%, particularly preferably 0.24 to 0.48%, crystalline tiotropium bromide anhydrate.
the percentages given in the context of the present invention are always mass percentages. If mass fractions for tiotropium are expressed in mass percentages, the corresponding values for the crystalline tiotropium bromide anhydrate preferably used in the context of the present invention can be obtained by multiplying by the conversion factor 1, 2036.
suspension formulation may also be used instead of the term suspension. Both terms are to be regarded as equivalent within the scope of the present invention.
the inhalation aerosols or suspension formulations containing propellant gas according to the invention may also contain further constituents such as surface-active agents (surfactants, surfactants), adjuvants, antioxidants or flavoring agents.
surface-active agents surfactants, surfactants, adjuvants, antioxidants or flavoring agents.
the surface-active agents (surfactants, surfactants) optionally contained in the suspensions according to the invention are preferably selected from the group consisting of polysorbate 20, polysorbate 80, Myvacet 9-45, Myvacet 9-08, isopropyl myristate, oleic acid, propylene glycol, polyethylene glycol, Brij, ethyl oleate, Glyceryl trioleate glyceryl monolaurate, glyceryl monooleate, glyceryl monosterate, glyceryl monoricinoleate, cetyl alcohol, steryl alcohol, cetyl pyridinum chloride, block polymers, natural oil, ethanol and isopropanol.
polysorbate 20, polysorbate 80, Myvacet 9-45, Myvacet 9-08 or isopropyl myristate are preferably used.
Myvacet 9-45 or isopropyl myristate are particularly preferably used.
surface-active agents are present in the suspensions according to the invention, these are preferably used in a proportion of 0.0005-1%, particularly preferably 0.005-0.5%.
the adjuvants optionally contained in the suspensions according to the invention are preferably selected from the group consisting of alanine, albumin, ascorbic acid, aspartame, betaine, cysteine, phosphoric acid, nitric acid, hydrochloric acid, sulfuric acid and citric acid.
Ascorbic acid, phosphoric acid, hydrochloric acid or citric acid are particularly preferably used, particularly preferably hydrochloric acid or citric acid. If adjuvants are present in the suspensions according to the invention, these are preferably used in a proportion of 0.0001-1.0%, preferably 0.0005-0.1%, particularly preferably 0.001-0.01%, a proportion of 0.001 -0.005% according to the invention is of particular importance.
the antioxidants optionally present in the suspensions according to the invention are preferably selected from the group consisting of ascorbic acid, citric acid, sodium edetate, editic acid tocopherols, butylated hydroxytoluene, butylated hydroxyanisole and ascorbyl palmitate, with tocopherols, butylated hydroxytoluene, butylated hydroxyanisole or ascorbyl palmitate being used with preference.
the flavoring agents optionally contained in the suspensions according to the invention are preferably selected from the group consisting of peppermint, sacharin, dentomint, aspartame and essential oils (for example cinnamon, anise, menthol, camphor), with peppermint or Dentomint® being particularly preferred.
Process obtained in finely divided form.
the active substance After micronization, the active substance preferably has an average particle size of 0.5 to 10 ⁇ m, preferably 1 to 6 ⁇ m, particularly preferably 1.5 to 5 ⁇ m. At least 50%, preferably at least 60%, particularly preferably at least 70% of the active ingredient particles preferably have a particle size which lies within the size ranges mentioned above. Particularly preferred at least 80%, most preferably at least 90% of the active ingredient particles with their particle size are in the ranges mentioned above.
suspensions can also be prepared which, in addition to the propellant gases mentioned, only contain the active ingredient and no further additives. Accordingly, a further aspect of the present invention is aimed at suspensions which only contain the active ingredient without further additives.
the suspensions according to the invention can be prepared by methods known in the art.
the constituents of the formulation are mixed with the propellant gas (s) (if appropriate at low temperatures) and filled into suitable containers.
pMDIs pressurized metered dose inhalers
a further aspect of the present invention relates to medicaments in the form of suspensions as described above in connection with one or more inhalers suitable for the administration of these suspensions.
the present invention relates to inhalers, characterized in that they contain suspensions containing propellant gas according to the invention described above.
the present invention further relates to containers (cartridges) which can be used with a suitable valve in a suitable inhaler and which contain one of the above-mentioned suspensions containing propellant gas according to the invention. Suitable containers (cartridges) and methods for filling these cartridges with the suspensions containing propellant gas according to the invention are known from the prior art.
the present invention further relates to the use of the suspensions according to the invention for the manufacture of a medicament which can be administered by inhalation or nasal administration, preferably for the manufacture of a medicament for the inhalative or nasal treatment of diseases in which anticholinergics can have a therapeutic benefit.
the present invention particularly preferably further relates to the use of the suspensions according to the invention for producing a medicament for inhalation treatment of respiratory diseases, preferably asthma or COPD.
the tiotropium bromide obtainable according to EP 418 716 A1 can be used to prepare the crystalline tiotropium bromide monohydrate. This is then implemented as described below.
the crystalline tiotropium bromide monohydrate obtainable according to the procedure described above was subjected to an investigation by means of DSC (differential scanning calorimetry).
the DSC diagram has two characteristic signals. The first, relatively broad, endothermic signal between 50-120 ° C is due to the dehydration of the tiotropium bomide monohydrate to the anhydrous form. The second, relatively sharp, endothermic maximum at 230 ⁇ 5 ° C is attributable to the melting of the substance.
This data was obtained using a Mettler DSC 821 and evaluated using the Mettler software package STAR. The data were collected at a heating rate of 10 K / min.
the crystalline tiotropium bromide monohydrate was characterized by means of IR spectroscopy. The data were collected using a Nicolet FTIR spectrometer and evaluated with the Nicolet software package OMNIC, version 3.1. The measurement was carried out with 2.5 ⁇ mol tiotropium bromide monohydrate in 300 mg KBr.
AFC7R-4 circular diffractometer Rasterku
the structure solution and refinement of the crystal structure was carried out using direct methods (program SHELXS86) and FMLQ refinement (program TeXsan).
the crystalline tiotropium bromide monohydrate obtained as described above is dried by careful drying at 80-100 ° C. under reduced pressure, preferably in a high vacuum for a period of at least 30
the anhydrous form can also be produced by storing it over dried silica gel at room temperature for a period of at least 24 hours.
the crystalline tiotropium bromide anhydrate obtainable by the above process is micronized according to processes known per se in the prior art with the exclusion of moisture in order to provide the active ingredient in the form of the average particle size which corresponds to the specifications according to the invention.

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EP03717219A 2002-03-28 2003-03-20 Hfa-suspensionsformulierungen eines anhydrats Withdrawn EP1492498A2 (de)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
DE10214264A DE10214264A1 (de)	2002-03-28	2002-03-28	HFA-Suspensionsformulierungen eines Anhydrats
DE10214264		2002-03-28
PCT/EP2003/002899 WO2003082244A2 (de)	2002-03-28	2003-03-20	Hfa-suspensionsformulierungen eines anhydrats

Publications (1)

Publication Number	Publication Date
EP1492498A2 true EP1492498A2 (de)	2005-01-05

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Application Number	Title	Priority Date	Filing Date
EP03717219A Withdrawn EP1492498A2 (de)	2002-03-28	2003-03-20	Hfa-suspensionsformulierungen eines anhydrats

Country Status (21)

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EP (1)	EP1492498A2 (sr)
JP (1)	JP5147158B2 (sr)
KR (1)	KR101005717B1 (sr)
CN (1)	CN1642525A (sr)
AU (1)	AU2003221509B2 (sr)
BR (1)	BR0308709A (sr)
CA (1)	CA2479638C (sr)
DE (1)	DE10214264A1 (sr)
EA (1)	EA008610B1 (sr)
EC (1)	ECSP045322A (sr)
HR (1)	HRP20040890A2 (sr)
IL (1)	IL163696A0 (sr)
ME (1)	ME00246B (sr)
MX (1)	MXPA04009338A (sr)
NO (1)	NO20044004L (sr)
NZ (1)	NZ536030A (sr)
PL (1)	PL371295A1 (sr)
RS (1)	RS52481B (sr)
UA (1)	UA79776C2 (sr)
WO (1)	WO2003082244A2 (sr)
ZA (1)	ZA200405637B (sr)

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JP2008540367A (ja) *	2005-05-02	2008-11-20	ベーリンガーインゲルハイムインターナショナルゲゼルシャフトミットベシュレンクテルハフツング	新規結晶性臭化チオトロピウム
WO2006117299A2 (en) *	2005-05-02	2006-11-09	Boehringer Ingelheim International Gmbh	Novel crystalline forms of tiotropium bromide
US8815258B2 (en)	2009-05-29	2014-08-26	Pearl Therapeutics, Inc.	Compositions, methods and systems for respiratory delivery of two or more active agents
AU2015201037C1 (en) *	2009-05-29	2017-07-27	Pearl Therapeutics, Inc.	Respiratory delivery of active agents
PL3111927T3 (pl)	2009-05-29	2020-06-29	Pearl Therapeutics, Inc.	Kompozycje do wziewnego podawania środków aktywnych oraz związane z nimi sposoby i systemy
SG11201507286QA (en)	2013-03-15	2015-10-29	Pearl Therapeutics Inc	Methods and systems for conditioning of particulate crystalline materials
CN114712337A (zh) *	2016-09-19	2022-07-08	墨西哥氟石股份公司	药物组合物

Family Cites Families (9)

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Publication number	Priority date	Publication date	Assignee	Title
DE3931041C2 (de) *	1989-09-16	2000-04-06	Boehringer Ingelheim Kg	Ester von Thienylcarbonsäuren mit Aminoalkoholen, ihre Quaternierungsprodukte, Verfahren zu ihrer Herstellung und diese enthaltende Arzneimittel
JP4672143B2 (ja) *	1998-08-04	2011-04-20	ヤゴテックアーゲー	医薬用エーロゾル製剤
GB0009583D0 (en) *	2000-04-18	2000-06-07	Glaxo Group Ltd	Respiratory 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
GB0009606D0 (en) *	2000-04-18	2000-06-07	Glaxo Group Ltd	Therapeutic combinations
JP2004512379A (ja) *	2000-10-31	2004-04-22	ベーリンガー　インゲルハイム　ファルマ　ゲゼルシャフト　ミット　ベシュレンクテル　ハフツング　ウント　コンパニー　コマンディトゲゼルシャフト	新規医薬組成物
DE10113366A1 (de) *	2001-03-20	2002-09-26	Boehringer Ingelheim Pharma	Neue Arzneimittelkompositionen auf der Basis von Anticholinergika und Endothelinantagonisten
DE10111058A1 (de) *	2001-03-08	2002-09-12	Boehringer Ingelheim Pharma	Neue Arzneimittelkompositionen auf der Basis von Anticholinergika und NK¶1¶-Rezeptor-Antagonisten

2002
- 2002-03-28 DE DE10214264A patent/DE10214264A1/de not_active Withdrawn
2003
- 2003-03-20 EP EP03717219A patent/EP1492498A2/de not_active Withdrawn
- 2003-03-20 CN CNA038072475A patent/CN1642525A/zh active Pending
- 2003-03-20 IL IL16369603A patent/IL163696A0/xx unknown
- 2003-03-20 EA EA200401159A patent/EA008610B1/ru unknown
- 2003-03-20 WO PCT/EP2003/002899 patent/WO2003082244A2/de not_active Ceased
- 2003-03-20 HR HR20040890A patent/HRP20040890A2/hr not_active Application Discontinuation
- 2003-03-20 JP JP2003579782A patent/JP5147158B2/ja not_active Expired - Lifetime
- 2003-03-20 UA UA20041008758A patent/UA79776C2/uk unknown
- 2003-03-20 ME MEP-2008-473A patent/ME00246B/me unknown
- 2003-03-20 CA CA2479638A patent/CA2479638C/en not_active Expired - Fee Related
- 2003-03-20 BR BR0308709-3A patent/BR0308709A/pt not_active Application Discontinuation
- 2003-03-20 NZ NZ536030A patent/NZ536030A/en not_active IP Right Cessation
- 2003-03-20 MX MXPA04009338A patent/MXPA04009338A/es active IP Right Grant
- 2003-03-20 RS YU86004A patent/RS52481B/sr unknown
- 2003-03-20 PL PL03371295A patent/PL371295A1/xx not_active Application Discontinuation
- 2003-03-20 KR KR1020047015174A patent/KR101005717B1/ko not_active Expired - Lifetime
- 2003-03-20 AU AU2003221509A patent/AU2003221509B2/en not_active Expired
2004
- 2004-07-15 ZA ZA2004/05637A patent/ZA200405637B/en unknown
- 2004-09-23 NO NO20044004A patent/NO20044004L/no not_active Application Discontinuation
- 2004-09-28 EC EC2004005322A patent/ECSP045322A/es unknown

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO03082244A2 *

Also Published As

Publication number	Publication date
UA79776C2 (en)	2007-07-25
WO2003082244A2 (de)	2003-10-09
MXPA04009338A (es)	2005-01-25
DE10214264A1 (de)	2003-10-16
AU2003221509A1 (en)	2003-10-13
NZ536030A (en)	2006-07-28
CN1642525A (zh)	2005-07-20
ME00246B (me)	2011-05-10
BR0308709A (pt)	2005-01-04
NO20044004L (no)	2004-10-05
EA008610B1 (ru)	2007-06-29
WO2003082244A3 (de)	2004-02-05
CA2479638A1 (en)	2003-10-09
ECSP045322A (es)	2005-01-28
CA2479638C (en)	2011-01-04
YU86004A (sh)	2006-08-17
HRP20040890A2 (en)	2005-06-30
IL163696A0 (en)	2005-12-18
PL371295A1 (en)	2005-06-13
MEP47308A (en)	2011-02-10
AU2003221509B2 (en)	2008-01-24
JP2005527550A (ja)	2005-09-15
KR101005717B1 (ko)	2011-01-05
ZA200405637B (en)	2005-07-27
JP5147158B2 (ja)	2013-02-20
EA200401159A1 (ru)	2005-04-28
RS52481B (sr)	2013-02-28
KR20040098022A (ko)	2004-11-18

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Publication	Publication Date	Title
EP1809243B1 (de)	2012-07-18	Aerosolsuspensionsformulierungen mit tg 227 ea als treibmittel
EP1326862B1 (de)	2004-09-15	Kristallines monohydrat von tiotropiumbromid, verfahren zu dessen herstellung und dessen verwendung zur herstellung eines arzneimittels
WO1997005136A1 (de)	1997-02-13	Ein enantiomer von ipratropiumbromid mit verlängerter wirkungsdauer
EP1682542B1 (de)	2009-12-30	Neues kristallines anhydrat mit anticholinerger wirksamkeit
US20080044361A1 (en)	2008-02-21	HFA Suspension Formulations Containing an Anticholinergic
EP1695701B1 (de)	2015-01-07	HFA-Suspensionsformulierungen enthaltend ein Anticholinergikum
EP2083007A1 (de)	2009-07-29	Tiotropiumsalze, Verfahren zu deren Herstellung sowie diese enthaltende Arzneimittelformulierungen
EP1492498A2 (de)	2005-01-05	Hfa-suspensionsformulierungen eines anhydrats
US7244415B2 (en)	2007-07-17	HFA suspension formulations of an anhydrate
DE102004032322A1 (de)	2006-02-09	Aerosolsuspensionsformulierungen mit TG 227 ea als Teibmittel
DE10209243A1 (de)	2003-09-18	Neue Arzneimittelkombination zur Inhalation
DE10145438A1 (de)	2003-04-03	Neue Arzneimittel zur Inhalation