HRP960365A2 - New medicaments and the use thereof - Google Patents
New medicaments and the use thereof Download PDFInfo
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- HRP960365A2 HRP960365A2 HR19528145.4A HRP960365A HRP960365A2 HR P960365 A2 HRP960365 A2 HR P960365A2 HR P960365 A HRP960365 A HR P960365A HR P960365 A2 HRP960365 A2 HR P960365A2
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- Croatia
- Prior art keywords
- inhalation
- ethanol
- hydroxy
- mimetic
- fact
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- 239000003814 drug Substances 0.000 title claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 239000013543 active substance Substances 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 5
- 125000006309 butyl amino group Chemical group 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 210000002345 respiratory system Anatomy 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 150000003431 steroids Chemical class 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 claims description 2
- RTLJQOLVPIGICL-UHFFFAOYSA-N 4-[2-(tert-butylamino)-1-hydroxyethyl]-2-(methylsulfonylmethyl)phenol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CS(C)(=O)=O)=C1 RTLJQOLVPIGICL-UHFFFAOYSA-N 0.000 claims description 2
- LSLYOANBFKQKPT-DIFFPNOSSA-N 5-[(1r)-1-hydroxy-2-[[(2r)-1-(4-hydroxyphenyl)propan-2-yl]amino]ethyl]benzene-1,3-diol Chemical compound C([C@@H](C)NC[C@H](O)C=1C=C(O)C=C(O)C=1)C1=CC=C(O)C=C1 LSLYOANBFKQKPT-DIFFPNOSSA-N 0.000 claims description 2
- KUVIULQEHSCUHY-XYWKZLDCSA-N Beclometasone 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)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O KUVIULQEHSCUHY-XYWKZLDCSA-N 0.000 claims description 2
- 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 2
- BQTXJHAJMDGOFI-NJLPOHDGSA-N Dexamethasone 21-(4-Pyridinecarboxylate) Chemical compound O=C([C@]1(O)[C@@]2(C)C[C@H](O)[C@]3(F)[C@@]4(C)C=CC(=O)C=C4CC[C@H]3[C@@H]2C[C@H]1C)COC(=O)C1=CC=NC=C1 BQTXJHAJMDGOFI-NJLPOHDGSA-N 0.000 claims description 2
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 2
- VQDBNKDJNJQRDG-UHFFFAOYSA-N Pirbuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=N1 VQDBNKDJNJQRDG-UHFFFAOYSA-N 0.000 claims description 2
- GIIZNNXWQWCKIB-UHFFFAOYSA-N Serevent Chemical compound C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCCCC=2C=CC=CC=2)=C1 GIIZNNXWQWCKIB-UHFFFAOYSA-N 0.000 claims description 2
- WKHOPHIMYDJVSA-UHFFFAOYSA-N [3-[2-(tert-butylamino)-1-hydroxyethyl]-5-(2-methylpropanoyloxy)phenyl] 2-methylpropanoate Chemical compound CC(C)C(=O)OC1=CC(OC(=O)C(C)C)=CC(C(O)CNC(C)(C)C)=C1 WKHOPHIMYDJVSA-UHFFFAOYSA-N 0.000 claims description 2
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- 239000000043 antiallergic agent Substances 0.000 claims description 2
- 229960003060 bambuterol Drugs 0.000 claims description 2
- ANZXOIAKUNOVQU-UHFFFAOYSA-N bambuterol Chemical compound CN(C)C(=O)OC1=CC(OC(=O)N(C)C)=CC(C(O)CNC(C)(C)C)=C1 ANZXOIAKUNOVQU-UHFFFAOYSA-N 0.000 claims description 2
- 229960004495 beclometasone Drugs 0.000 claims description 2
- 229960004620 bitolterol Drugs 0.000 claims description 2
- FZGVEKPRDOIXJY-UHFFFAOYSA-N bitolterol Chemical compound C1=CC(C)=CC=C1C(=O)OC1=CC=C(C(O)CNC(C)(C)C)C=C1OC(=O)C1=CC=C(C)C=C1 FZGVEKPRDOIXJY-UHFFFAOYSA-N 0.000 claims description 2
- 229960004436 budesonide Drugs 0.000 claims description 2
- 229960001386 carbuterol Drugs 0.000 claims description 2
- KEMXXQOFIRIICG-UHFFFAOYSA-N carbuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(NC(N)=O)=C1 KEMXXQOFIRIICG-UHFFFAOYSA-N 0.000 claims description 2
- 229960001117 clenbuterol Drugs 0.000 claims description 2
- STJMRWALKKWQGH-UHFFFAOYSA-N clenbuterol Chemical compound CC(C)(C)NCC(O)C1=CC(Cl)=C(N)C(Cl)=C1 STJMRWALKKWQGH-UHFFFAOYSA-N 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- 229960001022 fenoterol Drugs 0.000 claims description 2
- 229960000676 flunisolide Drugs 0.000 claims description 2
- 229960002848 formoterol Drugs 0.000 claims description 2
- BPZSYCZIITTYBL-UHFFFAOYSA-N formoterol Chemical compound C1=CC(OC)=CC=C1CC(C)NCC(O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-UHFFFAOYSA-N 0.000 claims description 2
- 229960000708 hexoprenaline Drugs 0.000 claims description 2
- OXLZNBCNGJWPRV-UHFFFAOYSA-N hexoprenaline Chemical compound C=1C=C(O)C(O)=CC=1C(O)CNCCCCCCNCC(O)C1=CC=C(O)C(O)=C1 OXLZNBCNGJWPRV-UHFFFAOYSA-N 0.000 claims description 2
- 229950002451 ibuterol Drugs 0.000 claims description 2
- RQTOOFIXOKYGAN-UHFFFAOYSA-N nedocromil Chemical compound CCN1C(C(O)=O)=CC(=O)C2=C1C(CCC)=C1OC(C(O)=O)=CC(=O)C1=C2 RQTOOFIXOKYGAN-UHFFFAOYSA-N 0.000 claims description 2
- 229960004398 nedocromil Drugs 0.000 claims description 2
- 229960005414 pirbuterol Drugs 0.000 claims description 2
- 229960002288 procaterol Drugs 0.000 claims description 2
- FKNXQNWAXFXVNW-BLLLJJGKSA-N procaterol Chemical compound N1C(=O)C=CC2=C1C(O)=CC=C2[C@@H](O)[C@@H](NC(C)C)CC FKNXQNWAXFXVNW-BLLLJJGKSA-N 0.000 claims description 2
- 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 2
- 229960002720 reproterol Drugs 0.000 claims description 2
- WVLAAKXASPCBGT-UHFFFAOYSA-N reproterol Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2N=CN1CCCNCC(O)C1=CC(O)=CC(O)=C1 WVLAAKXASPCBGT-UHFFFAOYSA-N 0.000 claims description 2
- 229960002052 salbutamol Drugs 0.000 claims description 2
- 229960004017 salmeterol Drugs 0.000 claims description 2
- 229950007862 sulfonterol Drugs 0.000 claims description 2
- 229960000195 terbutaline Drugs 0.000 claims description 2
- 208000018569 Respiratory Tract disease Diseases 0.000 claims 1
- 239000013566 allergen Substances 0.000 claims 1
- 230000003266 anti-allergic effect Effects 0.000 claims 1
- 201000010099 disease Diseases 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
- 229960004756 ethanol Drugs 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 239000000443 aerosol Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 229960001361 ipratropium bromide Drugs 0.000 description 4
- KEWHKYJURDBRMN-ZEODDXGYSA-M ipratropium bromide hydrate Chemical compound O.[Br-].O([C@H]1C[C@H]2CC[C@@H](C1)[N@@+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 KEWHKYJURDBRMN-ZEODDXGYSA-M 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000003380 propellant Substances 0.000 description 3
- 230000001629 suppression Effects 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- 208000009079 Bronchial Spasm Diseases 0.000 description 2
- 208000014181 Bronchial disease Diseases 0.000 description 2
- 206010006482 Bronchospasm Diseases 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000001078 anti-cholinergic effect Effects 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 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 description 1
- KOTMQCNDGLTIHR-UHFFFAOYSA-N 4-[2-[[4-(benzimidazol-1-yl)-2-methylbutan-2-yl]amino]-1-hydroxyethyl]-3-fluorophenol Chemical compound C1=NC2=CC=CC=C2N1CCC(C)(C)NCC(O)C1=CC=C(O)C=C1F KOTMQCNDGLTIHR-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 239000004147 Sorbitan trioleate Substances 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- LPCWKMYWISGVSK-UHFFFAOYSA-N bicyclo[3.2.1]octane Chemical compound C1C2CCC1CCC2 LPCWKMYWISGVSK-UHFFFAOYSA-N 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 230000000572 bronchospasmolytic effect Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
- C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
-
- 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
- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
-
- 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
Description
Izum se odnosi na inhalacijsku upotrebu soli (endo,syn)-(-)-3-(3-hidroksi-1-okso-2-fenilpropoksi) -8-metil-8-(1-metiletil)-8-azoniabiciklo[3.2.1]oktana kao bronhospazmolitika s jakim i posebno dugotrajnim djelovanjem te upotrebu soli kod proizvodnje astmatika.
Racemat gore navedenog spoja (kao bromid) u prodaji je pod oznakom Ipratropium bromid kao aktivna tvar u antikolinergnim lijekovima.
Kako je sada iznenađujuće nađeno, omjeri učinkovitosti racemata, lijevo zakrećućeg i desno zakrećućeg enantiomera jasno su različiti i pokazuju važne posebnosti koje značajno odstupaju od normalnog slučaja. Eutomer (tj. enantiomer sa željenom, odnosno ciljanim aktivnošću) je L-(-)-enatiomer. Proučavanjem vezanja receptora na CHO-HM receptorima moglo se je pronaći da L-(-)-enantiomeri u usporedbi s racematom imaju okruglo dvostruko viši afinitet. Taj omjer odgovara čestim opažanjima kod usporedbe djelovanja enatiomera i racemata.
U ovom slučaju iznenađujuće je, međutim, da je kod primjene inhalacijom na (narkotiziranom) psu usporedbom eutomera s racematom u masenom omjeru 1:2 primijećena ne samo viša jačina učinka, već je također opaženo i značajno produljeno trajanje učinkovitosti.
Na slici 1 prikazano je postotno suzbijanje bronhospazme ovisno o vrmenu. Pri tome crtkana linija (krivulja B) predstavlja tijek za (endo, syn)-(-)-3-(3-hidroksi-1-okso-2-fenilpropoksi)-8-metil-8-(1-metiletil)-8-azonia biciklo [3.2.1] oktan, a puna linija (krivulja A) predstavlja tijek za odgovarajući racemat, pri čemu je bio upotrijebljen hidrobromid. Bilo je dato 5 pg čistog L-(-)-enantiomera i odgovarajućih 10 μg racemata. Pokus je bio proveden na 5 pokusnih životinja s čistim L-enantiomerima (BIIH 150 BR), dok je racemat bio apliciran kod sedam pokusnih životinja.
Iz slike 1 može se zaključiti da je suzbijanje bronhospazme na psu inducirane s acetilkolinom davanjem aerosola Ipratropium bromida (krivulja A) nakon otprilike 10 minuta doseglo maksimum od pribl. 55% i nakon 60 minuta gotovo je opet dosegnuta polazna razina. S istom količinom eutomera (krivulja B) , jer je on prisutan u racematu, nakon otprilike 10 minuta postiže se 60%-tno suzbijanje, koje je tek nakon 180 minuta doseglo polaznu razinu. Mjerenjem vremena poluvrijednosti za eutomer BIIH 150 BR utvrđeno je pribl. četiri puta dulje trajanje učinkovitosti.
Za proizvodnju eutomera kombiniranom primjenom visokotlačne tekućinske kromatografije i prekristalizacije iz racemata se dobije eutomer u vrlo čistom obliku. Kao weutomer" u smislu predloženog izuma označavaju se također i jako obogaćeni proizvodi (preko pribl. 90%), ponajprije sa iznad 95, naročito preko 97% L-(-)-enatiomera. Anion odgovara istom onom u dotičnom polaznom spoju. Po želji, također se može se izvršiti izmjena.
Pomoću slijedećeg primjera pobliže će se objasniti proizvodnja L-(-)- i D-(+)-enantiomera.
18 grama ipratropij bromida rastavi se pomoću visokotlačne tekućinske kromatografije preko kiralne OD-kolone (250x20 mm) s mobilnom fazom sastavljenom od 600 dijelova heksana, 250 dijelova metanola, 150 dijelova etanola i 1 dijela zasićene alkoholne otopine NaBr (v:v:v:v, brzina protoka 6 ml/min, valna dužina 254 nm; osjetljivost 0,5 A.U.F.S; rješenje zadatka 1 g ipratropij bromida/5 ml etanola + 5 ml mobilne faze 4-2,5 konc. octene kiseline).
Ponovljenim kromatografiranjem i prekristalizacijom iz etanola dobije se L-(-)-enantiomer, bijeli kristali, talište 239-40°C (raspad), specifično zakretanja [a]20D = -24,06°C (c = 1,014; H2O), čistoća enantiomera 97,4% (HPLC) i D-(+)-enantiomer, bijeli kristali, talište 238-39°C (raspad), specifično zakretanja [a]20D = +24,26°C (c = 1,018; H2O), čistoća enantiomera 98,9% (HPLC). Elementarna analiza i spektri jasno potvrđuju te spojeve.
L-(-)-eutomer u obliku različitih soli prikladan je, sukladno svojoj naravi kao antikolinergik, npr. za liječenje kroničnog opstrukcijskog bronhitisa i astme inhalacijskom primjenom, pri čemu su sporedni efekti maksimalno isključeni.
Za aplikaciju pomiješa se aktivnu tvar s poznatim pomoćnim tvarima i/ili nosačima u upotrebljive galenske pripravke, npr. inhalacijske otopine, suspenzije u ukapljenim potisnim plinovima, u pripravke koji sadrže liposome, odnosno proliposome, praške za inhalaciju (po potrebi u kapsulama) za aplikaciju u uobičajenim inhalacijskim napravama.
Primjeri formulacija (podaci u masenim postocima):
1. Odmjerni aerosol
aktivna tvar prema izumu 0,005
sorbitantrioleat 0,1
monofluortriklormetan i
difluordiklormetan, 2:2 do 100
Suspenziju se stavi u uobičajenu posudu za aerosol s ventilom za doziranje. Kod posluživanja oslobađa se primjerice 50 ul suspenzije. Po želji, može se dozirati i više aktivne tvari (npr. 0,02 mas. %).
Umjesto potisnog plina koji sadrži klor također se mogu koristiti i alternativni potisni plinovi kao TG 134a (1,1,1,2-tetrafluoretan) i/ili TG 227 (1,1,1,2,3,3,3-heptafluorpropan).
2. Prah za inhalaciju
Mikronizirani prah aktivne tvari (veličina čestica 0,5 do 7 μm) pomiješa se s mikroniziranom laktozom i po potrebi s dodacima puni u kapsule od tvrde želatine. U svaku kapsulu stavlja se primjerice 0,01 mg aktivne tvari i 5 mg laktoze. Prah se može inhalirati iz uobičajenih inhalacijskih aparata, npr. prema DE-A 3345772.
3. Inhalacijske otopine
Također se mogu koristiti vodene otopine aktivne tvari, pri čemu se za stvaranje aerosola može koristiti primjerice aparat prema WO91/14468. Po jednom prskanju aplicira se npr. 0,005 mg aktivne tvari.
Upotrebljiva aktivna tvar prema izumu može se korisno upotrijebiti također i u kombinaciji s drugim aktivnim tvarima za terapiju dišnih puteva. Posebno se mogu spomenuti β2-mimetici, koji se kod pojedinačne primjene upotrebljavaju u kombinaciji s 50-100% doze.
Navode se:
Bambuterol
Bitolterol
Carbuterol
Clenbuterol
Fenoterol
Formoterol
Hexoprenalin
Ibuterol
Pirbuterol
Procaterol
Reproterol
Salbutamol
Salmeterol
Sulfonterol
Terbutalin
Tolubuterol
1-(2-fluor-4-hidroksifenil)-2-[4-(1-benzimidazolil) -2-metil-2-butilamino] etanol,
eritro-5’-hidroksi-8’-(1-hidroksi-2-izopropilamino-butil)-2H-1,4-benzoksazin-3-(4H)-on,
1-(4-amino-3-klor-5-trifluormetilfenil)-2-terc.butil-amino)etanol,
1-(4-etoksikarbonilamino-3-cijan-5-fluorfenil)-2-(terc.butilamino)etanol.
Kao daljnji partneri za kombinacije prikladni su stereoidi koji se mogu primijeniti inhalacijski, kao Budesonid, Beclometason (odnosno 17,21-dipropionat), Dexametazon-21-izonikotinat, Flunisolid i antialergici kao dinatrij krornoglikat, Nedocromil, Epinastin. Kod tih partera za kombinacije također se mogu dati jednake ili manje doze nego kod njihove samostalne primjene.
Claims (8)
1. Sol (endo, syn)-(-)-3-(3-hidroksi-1-okso-2-fenil-propoksi)-8-metil-8-(1-metiletil)-8-azoniabiciklo[3.2 .1]-oktana, naznačena time, da je čistoća enatiomera od 90 do 100, ponajprije 95 do 100%.
2. Sol prema zahtjevu 1, naznačena time, da kao anion sadrži Br-, Cl- ili CH3CO3-.
3. Pripravci lijekova za inhalaciju, naznačeni time, da sadrže spoj prema zahtjevu 1 ili 2, po potrebi uz uobičaje pomoćne i/ili noseće tvari i/ili druge aktivne tvari.
4. Pripravci lijekova za inhalaciju prema zahtjevu 3, naznačeni time, da pored spoja prema zahtjevu 1 ili 2 sadrže učinkovitu dozu jednog β2-mimetika, jednog inhalacijski primjenljivog stereoida ili jednog inhalacijski primjenljivog alergika.
5. Pripravci lijekova za inhalaciju prema zahtjevu 4, naznačeni time, da kao β2-mimetik sadrže
Bambuterol
Bitolterol
Carbuterol
Clenbuterol
Fenoterol
Formoterol
Hexoprenalin
Ibuterol
Pirbuterol
Procaterol
Reproterol
Salbutamol
Salmeterol
Sulfonterol
Terbutalin
Tolubuterol
1-(2-fluor-4-hidroksifenil)-2-[4-(1-benziraidazolil)-2-metil-2-butilamino]etanol,
eritro-5'-hidroksi-8'-(1-hidroksi-2-izopropilamino-butil)-2H-1,4-benzoksazin-3-(4H)-on,
1-(4-amino-3-klor-5-trifluormetilfenil)-2-terc.butil-amino)etanol,
1-(4-etoksikarbonilamino-3-cijan-5-fluorfenil)-2-(terc.butilamino)etanol,
kao stereoid upotrebljava se Budesonid, Beclometason (odnosno 17,21-dipropionat), Dexamethazon-21-izonikotinat, Flunisolid i kao antialergik dinatrijkromoglikat, Nedokromil i Epinastin.
6. Upotreba spojeva prema zahtjevima 1 ili 2, naznačena time, da se oni, po potrebi u kombinaciji s drugim aktivnim tvarima za terapiju dišnih puteva inhalacijom, koriste za proizvodnju lijekova za liječenje bolesti dišnih puteva.
7. Upotreba prema zahtjevu 6, naznačena time, da kao partner za kombinaciju služi β2-mimetik stereoid ili antialergik.
8. Inhalacijska primjena učinkovite doze aktivne tvari prema zahtjevu l ili 2, odnosno kombinacije te aktivne tvari s drugim aktivnim tvarima koje služe za terapiju dišnih puteva, naznačena time, da služe za liječenje bolesti dišnih puteva.
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|---|---|---|---|
| DE19528145A DE19528145A1 (de) | 1995-08-01 | 1995-08-01 | Neue Arzneimittel und ihre Verwendung |
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| HRP960365B1 HRP960365B1 (en) | 2002-04-30 |
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| US (1) | US6299861B1 (hr) |
| EP (1) | EP0843676B1 (hr) |
| JP (1) | JPH11510150A (hr) |
| KR (1) | KR100445016B1 (hr) |
| CN (1) | CN1120841C (hr) |
| AR (1) | AR004179A1 (hr) |
| AT (1) | ATE208390T1 (hr) |
| AU (1) | AU6739796A (hr) |
| BG (1) | BG63780B1 (hr) |
| BR (1) | BR9609951A (hr) |
| CA (1) | CA2226934C (hr) |
| CO (1) | CO4750836A1 (hr) |
| CZ (1) | CZ291998B6 (hr) |
| DE (2) | DE19528145A1 (hr) |
| DK (1) | DK0843676T3 (hr) |
| EE (1) | EE04614B1 (hr) |
| ES (1) | ES2167592T3 (hr) |
| HK (2) | HK1013597A1 (hr) |
| HR (1) | HRP960365B1 (hr) |
| HU (1) | HU228056B1 (hr) |
| IL (1) | IL118986A (hr) |
| MX (1) | MX9800864A (hr) |
| MY (1) | MY115201A (hr) |
| NO (1) | NO317561B1 (hr) |
| NZ (1) | NZ315645A (hr) |
| PL (1) | PL183789B1 (hr) |
| PT (1) | PT843676E (hr) |
| RO (1) | RO120260B1 (hr) |
| RU (1) | RU2171258C2 (hr) |
| SI (1) | SI0843676T1 (hr) |
| SK (1) | SK283260B6 (hr) |
| TR (1) | TR199800121T1 (hr) |
| TW (1) | TW449597B (hr) |
| UA (1) | UA55391C2 (hr) |
| WO (1) | WO1997005136A1 (hr) |
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| DE19921693A1 (de) * | 1999-05-12 | 2000-11-16 | Boehringer Ingelheim Pharma | Neuartige Arzneimittelkompositionen auf der Basis von anticholinergisch wirksamen Verbindungen und ß-Mimetika |
| US20100197719A1 (en) * | 1999-05-12 | 2010-08-05 | Boehringer Ingelheim Pharma Kg | Medicament compositions containing anticholinergically-effective compounds and betamimetics |
| ES2165768B1 (es) | 1999-07-14 | 2003-04-01 | Almirall Prodesfarma Sa | Nuevos derivados de quinuclidina y composiciones farmaceuticas que los contienen. |
| US6858593B2 (en) | 2000-08-05 | 2005-02-22 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative compositions |
| US6787532B2 (en) | 2000-08-05 | 2004-09-07 | Smithkline Beecham Corporation | Formulation containing anti-inflammatory androstane derivatives |
| GB0019172D0 (en) | 2000-08-05 | 2000-09-27 | Glaxo Group Ltd | Novel compounds |
| US6777400B2 (en) | 2000-08-05 | 2004-08-17 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative compositions |
| US6750210B2 (en) | 2000-08-05 | 2004-06-15 | Smithkline Beecham Corporation | Formulation containing novel anti-inflammatory androstane derivative |
| US6777399B2 (en) | 2000-08-05 | 2004-08-17 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative compositions |
| US6759398B2 (en) | 2000-08-05 | 2004-07-06 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative |
| US6858596B2 (en) | 2000-08-05 | 2005-02-22 | Smithkline Beecham Corporation | Formulation containing anti-inflammatory androstane derivative |
| US7776315B2 (en) * | 2000-10-31 | 2010-08-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pharmaceutical compositions based on anticholinergics and additional active ingredients |
| US20020151541A1 (en) * | 2000-10-31 | 2002-10-17 | Michel Pairet | Pharmaceutical compositions containing tiotropium salts and antihistamines and their use |
| US20100310477A1 (en) * | 2000-11-28 | 2010-12-09 | Boehringer Ingelheim Pharma Gmbh & Co. Kg. | Pharmaceutical compositions based on anticholingerics and additional active ingredients |
| UA77656C2 (en) | 2001-04-07 | 2007-01-15 | Glaxo Group Ltd | S-fluoromethyl ester of 6-alpha, 9-alpha-difluoro-17-alpha-[(2-furanylcarbonyl)oxy]-11-beta-hydroxy-16- alpha-methyl-3-oxoandrosta-1,4-dien-17-beta-carbothioacid as anti-inflammatory agent |
| US6455028B1 (en) * | 2001-04-23 | 2002-09-24 | Pharmascience | Ipratropium formulation for pulmonary inhalation |
| AU2002303425A1 (en) * | 2001-04-24 | 2002-11-05 | Epigenesis Pharmaceuticals, Inc. | Composition, formulations and kit for treatment of respiratory and lung disease with non-glucocorticoid steroids and/or ubiquinone and a bronchodilating agent |
| US20030018019A1 (en) * | 2001-06-23 | 2003-01-23 | Boehringer Ingelheim Pharma Kg | Pharmaceutical compositions based on anticholinergics, corticosteroids and betamimetics |
| JP2003221335A (ja) | 2001-10-26 | 2003-08-05 | Dey Lp | 慢性閉塞性肺疾患の症状を緩和するためのアルブテロールおよびイプラトロピウム吸入溶液、システム、キットおよび方法 |
| US20030203930A1 (en) * | 2001-10-26 | 2003-10-30 | Imtiaz Chaudry | Albuterol and ipratropium inhalation solution, system, kit and method for relieving symptoms of chronic obstructive pulmonary disease |
| US20030140920A1 (en) * | 2001-10-26 | 2003-07-31 | Dey L.P. | Albuterol inhalation soultion, system, kit and method for relieving symptoms of pediatric asthma |
| US6702997B2 (en) | 2001-10-26 | 2004-03-09 | Dey, L.P. | Albuterol inhalation solution, system, kit and method for relieving symptoms of pediatric asthma |
| US20030191151A1 (en) * | 2001-10-26 | 2003-10-09 | Imtiaz Chaudry | Albuterol and ipratropium inhalation solution, system, kit and method for relieving symptoms of chronic obstructive pulmonary disease |
| GB0202635D0 (en) * | 2002-02-05 | 2002-03-20 | Glaxo Wellcome Mfg Pte Ltd | Formulation containing novel anti-inflammatory androstane derivative |
| GB2389530B (en) | 2002-06-14 | 2007-01-10 | Cipla Ltd | Pharmaceutical compositions |
| US20050043343A1 (en) * | 2003-07-28 | 2005-02-24 | Boehringer Ingelheim International Gmbh | Medicaments for inhalation comprising an anticholinergic and a PDE IV inhibitor |
| US20050026948A1 (en) * | 2003-07-29 | 2005-02-03 | Boehringer Ingelheim International Gmbh | Medicaments for inhalation comprising an anticholinergic and a betamimetic |
| US20050038004A1 (en) * | 2003-07-31 | 2005-02-17 | Robinson Cynthia B. | Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with an anticholinergic bronchodilator for treatment of asthma or chronic obstructive pulmonary disease |
| US20090317476A1 (en) * | 2003-07-31 | 2009-12-24 | Robinson Cynthia B | Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a leukotriene receptor antagonist for treatment of asthma or chronic obstructive pulmonary disease |
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| PE20060826A1 (es) * | 2004-12-06 | 2006-10-08 | Smithkline Beecham Corp | Derivado oleofinico de 8-azoniabiciclo[3.2.1]octano y combinacion farmaceutica que lo comprende |
| JP2008538758A (ja) * | 2005-04-23 | 2008-11-06 | 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 | 抗コリン作用薬に加えてベータ受容体刺激薬及びステロイドを含有する吸入用の医薬組成物 |
| US20060239935A1 (en) * | 2005-04-23 | 2006-10-26 | Boehringer Ingelheim International Gmbh | Compositions for inhalation |
| EP2100599A1 (en) | 2008-03-13 | 2009-09-16 | Laboratorios Almirall, S.A. | Inhalation composition containing aclidinium for treatment of asthma and chronic obstructive pulmonary disease |
| EP2100598A1 (en) | 2008-03-13 | 2009-09-16 | Laboratorios Almirall, S.A. | Inhalation composition containing aclidinium for treatment of asthma and chronic obstructive pulmonary disease |
| EP2510928A1 (en) | 2011-04-15 | 2012-10-17 | Almirall, S.A. | Aclidinium for use in improving the quality of sleep in respiratory patients |
| TW201311649A (zh) * | 2011-09-05 | 2013-03-16 | Everlight Chem Ind Corp | 用於太陽能電池電解液之化合物及其製法、含有該化合物之電解液及太陽能電池 |
| CN111751454B (zh) * | 2019-03-29 | 2023-12-08 | 天津药业研究院股份有限公司 | 一种异丙托溴铵中间体i的含量和有关物质的检测方法 |
| CN110361494B (zh) * | 2019-06-26 | 2023-08-15 | 四川普锐特药业有限公司 | 异丙托溴铵气雾剂中杂质g的检测方法 |
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| US3505337A (en) * | 1967-12-22 | 1970-04-07 | Boehringer Sohn Ingelheim | N - hydrocarbyl-substituted noratropinium,haloalkylates and o-acyl derivatives thereof |
| DE2903957A1 (de) * | 1979-02-02 | 1980-08-07 | Boehringer Sohn Ingelheim | Mittel zur behandlung der nasalen hypersekretion |
| US5225183A (en) * | 1988-12-06 | 1993-07-06 | Riker Laboratories, Inc. | Medicinal aerosol formulations |
| DE4140861C2 (de) * | 1991-12-11 | 2003-12-11 | Boehringer Ingelheim Kg | Verfahren zur Gewinnung von quartären Tropasäurealkaloiden |
| WO1994013263A1 (en) * | 1992-12-09 | 1994-06-23 | Jager Paul D | Stabilized medicinal aerosol solution formulations |
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