HRP980406A2 - Thermodynamically stable modification of 1-(4-carbazolyloxy-3-/2-(2-methoxyphenoxy)ethylamino/-2-propanole, process for its preparation and pharmaceutical compositions containing it - Google Patents
Thermodynamically stable modification of 1-(4-carbazolyloxy-3-/2-(2-methoxyphenoxy)ethylamino/-2-propanole, process for its preparation and pharmaceutical compositions containing itInfo
- Publication number
- HRP980406A2 HRP980406A2 HR97112491.2A HRP980406A HRP980406A2 HR P980406 A2 HRP980406 A2 HR P980406A2 HR P980406 A HRP980406 A HR P980406A HR P980406 A2 HRP980406 A2 HR P980406A2
- Authority
- HR
- Croatia
- Prior art keywords
- carbazolyloxy
- methoxyphenoxy
- ethylamino
- modification
- preparation
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 13
- 230000004048 modification Effects 0.000 title claims description 10
- 238000012986 modification Methods 0.000 title claims description 10
- 238000002360 preparation method Methods 0.000 title claims description 6
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 title 1
- OGHNVEJMJSYVRP-UHFFFAOYSA-N carvedilol Chemical compound COC1=CC=CC=C1OCCNCC(O)COC1=CC=CC2=C1C1=CC=CC=C1N2 OGHNVEJMJSYVRP-UHFFFAOYSA-N 0.000 claims description 19
- 229960004195 carvedilol Drugs 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000002844 melting Methods 0.000 claims description 12
- 230000008018 melting Effects 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 5
- 238000002329 infrared spectrum Methods 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 208000019622 heart disease Diseases 0.000 claims description 3
- 238000002441 X-ray diffraction Methods 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 230000005855 radiation Effects 0.000 claims 1
- 239000011541 reaction mixture Substances 0.000 claims 1
- 239000002775 capsule Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 238000001069 Raman spectroscopy Methods 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000203 mixture 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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000000113 differential scanning calorimetry Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 108010010803 Gelatin Chemical class 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 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
- 241000124008 Mammalia Species 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 238000001237 Raman spectrum Methods 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000008273 gelatin Chemical class 0.000 description 2
- 229920000159 gelatin Chemical class 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 235000019271 petrolatum Nutrition 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- LSPHULWDVZXLIL-UHFFFAOYSA-N Camphoric acid Natural products CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical compound CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- -1 gums Polymers 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002076 thermal analysis method Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Description
Predloženi izum odnosi se na novu termodinamički postojanu modifikaciju (±) 1-(4-karbazoliloksi)-3-[2-(2-metoksi fenoksi)etilamino]-2-propanola (karvedilola), njene farmacetuski prihvatljive soli ili njene optički aktivne oblike, postupke za njenu proizvodnju i na farmaceutske sastave koji ju sadrže.
Karvedilol, s talištem pri 114-115oC, je spoj s odličnim farmakološkim svojstvima (Merck Index 11. Ed. No. 1882), poznat je kao aktivna tvar u liječenju kardijalnih bolesti. Pripravljanje i njegova upotreba u medicini opisani su u EP-B-0 004 920.
Karvediol ima kiralno središte i kao takav postoji u obliku pojedinačnih stereoizomera ili u racemičnom obliku. Oboje, racemat i stereoizomeri mogu se dobiti u skladu s postupkom dobro poznatim u struci (EP-B-0127099).
Sada je otkriveno da se, ovisno o metodi pripravljanja, karvedilol može izolirati u dvije različite modifikacije koje se razlikuju svojim infra-crvenim Ramanovim i spektrom difrakcije X-zraka na prahu, i njihovim talištem. Dva polimorfna oblika su monotropna i zbog toga se označavaju kao oblik I i oblik II. Poželjno je proizvesti terapeutsko sredstvo koje jedinstvenog i definiranog sastava koje ima visoku postojanost pri skladištenju.
Predloženim izumom dat je termodinamički postojan kristaliničan oblik karvedilola uglavnom bez drugih fizičkih oblika koji ima talište pri pribl. 123-126ºC, i infra-crveni spektar s oštrim pikom pri 3451 cm-1, koji se ovdje u nastavku navodi kao oblik I.
Izumom je također dat postupak za proizvodnju tog uglavnom čistog oblika I. U drugoj izvedbi izuma data je farmaceutska formulacija koja kao aktivan sastojak sadrži uglavnom čisti oblik I karvedilola.
Konačno, predloženim izumom data je metoda upotrebe novog uglavnom čistog oblika za prevenciju i/ili liječenje cirkulacijskih i kardijalnih bolesti.
Tamo gdje se u ovom opisu navode oblik I ili oblik II uglavnom bez drugih fizičkih oblika, misli se ponajprije da je u toj modifikaciji prisutno najmanje 90 mas. % oblika I ili oblika II.
Oblik II je modifikacija karvedilola proizvedena i očišćenja u skladu s EP-B-0 004 920.
Sada je iznenađujuće pronađeno da se nova termodinamički postojana modifikacija karvedilola (oblik I) s višim talištem dobije kad se postupak pripravljanja malo promijeni.
Talište svakog oblika, I, odnosno II, ovisi o stupnju njegove čistoće, i pronađeno da oblik I ima talište pri pribl. 123-126ºC, a oblik II pri 114-115ºC.
Otkriveno je nadalje da je oblik I termodinamički postojan oblik, što je njegova prednost. Zbog toga se tom termodinamički postojanom obliku daje prednost kod pripravljanja farmaceutskih formulacija.
Smatra se da spojevi obuhvaćaju i njihove farmaceutski prihvatljive soli i metodu predloženog izuma. Pojam “farmaceutski prihvatljivih soli” odnosi se na soli uglavnom čistog oblika I koje su bitno netoksične za živi organizam. Za pretvorbu karvedilola u njegovu farmakološki prihvatljivu sol, on reagira ponajprije u organskom otapalu s ekvivalentnom količinom anorganske ili organske kiseline, na primjer solne kiseline, bromovodične kiseline, fosforne kiseline, octene kiseline, limunske kiseline maleinske kiseline ili benzojeve kiseline. Smatra se da svaki posebni anion koji tvori dio bilo koje soli ovog izuma nije kritičan ako je sol kao takova farmakološki prihvatljiva i ako anionska jedinica ne doprinosi neželjenoj kvaliteti.
Za rastavljanje racemata, može se upotrijebiti, na primjer, vinsku kiselinu, jabučnu kiselinu, kamfornu kiselinu ili kamforsulfonsku kiselinu.
U skladu s drugim aspektom izuma dat je farmaceutski sastav koji sadrži oblik I uglavnom bez drugih fizičkih oblika i farmaceutski prihvatljiv nosač ili pomoćno sredstvo.
Spojevi predloženog izuma mogu se dati na bilo koji prikladan način, ponajprije u obliku farmaceutskog sastava prilagođenog takovom načinu davanja i dozom učinkovitom za namijenjeno liječenje. Stručnjaci su već utvrdili terapeutski učinkovite doze spojeva predloženog izuma potrebne za prevenciju ili sprečavanje progresije bolesnog stanja.
S tim u skladu izumom je dat razred novih farmaceutskih sastava koji sadrže oblik I karvedilola prema predloženom izumu zajedno s jednim ili više netoksičnih farmaceutski prihvatljivih nosača i/ili pomoćnih sredstava (koja se ovdje zajedno navode kao “noseći materijali”) i, po želji, druge aktivne sastojke. Spojevi i sastavi mogu se dati, na primjer, oralno, intravaskularno, intraperitonealno, subkutano, intramuskularno ili površinski.
Za sve načine davanja farmaceutski sastav može biti u obliku, na primjer, tablete, kapsule, kreme, pomasti, gela, losiona, suspenzije ili tekućine. Farmaceutski sastav se radi ponajprije u obliku jediničnog doziranje koje sadrži određenu količinu aktivnog sastojka. Primjeri takovih jediničnih doza jesu tablete ili kapsule. Prikladna dnevna doza za sisavca može se široko mijenjati ovisno o uvjetima pacijenta i o drugim faktorima. Međutim, prikladna može biti doza od pribl. 0,01 do 100 mg/kg tjelesne težine, posebno od pribl. 0,05 do 3 mg/kg tjelesne težine, odnosno od 0,01-10 mg/cm2 kože. Aktivan sastojak se također može dati injekcijom.
Režim doziranja za liječenje bolesnog stanja sa spojevima i/ili sastavima ovog izuma bira se u skladu s raznim faktorima koji uključuju tip, starost, težinu, spol i medicinsko stanje pacijenta i u skladu s ozbiljnošću bolesti, pa se stoga može široko mijenjati.
Za terapeutske svrhe spojevi izuma se obično kombiniraju s jednim ili više pomoćnih sredstava prikladnih za traženi način davanja. Ako se daje per os, spoj se može pomiješati s laktozom, saharozom, škrobnim prahom, celuloznim esterom alkanskih kiselina, celuloznim alkil esterom, talkom, stearinskom kiselinom, magnezijevim stearatom, magnezijevim oksidom, natrijevim i kalcijevim solima fosforne i sumporne kiseline, želatinom, akacijom, natrijevim alginatom, polivinil-pirolidonom i/ili polivinil alkoholom, i tako se tabletira ili kapsulira za prikladno davanje. Alternativno, spoj se može otopiti u vodi, polietilen glikolu, propilen glikolu, etanolu, kukuruznom ulju, ulju od sjemenki pamuka, sezamovom ulju, benzil alkoholu, natrijevom kloridi i/ili raznim puferima. Prikladni dodaci za upotrebu u obliku pomasti, krema ili gelova jesu, na primjer, parafin, vazelin, prirodni vosak, škrob, celuloza ili polietilen glikol. Dobri su i drugi dodaci i načini davanja koji su općenito poznati u struci.
Odgovarajuća doziranja u svakom datom slučaju ovise naravno i o naravi i ozbiljnosti stanja koje se liječi, načinu davanja i vrsti dotičnog sisavca, uključiv njegovu veličinu i svaku individualnu idiosinkraziju.
Tipični nosači, razređivači i pomoćna sredstva uključuju, na primjer, vodu, laktozu, želatinski škrob, magnezijev stearat, talk, biljna ulja, gume, polialkilen glikole, petrolej žele, itd. Farmaceutski sastavi se mogu preraditi u kruti oblik, kao što su granule, puderi ili čepići, ili u tekuće oblike kao što su otopine, suspenzije ili emulzije. Farmaceutskim sastavima se mogu dodati uobičajene farmaceutske pomoćne tvari kao što su konzervansi, stabilizatori, sredstva za kvašenje, emulgatori, puferi itd.
Kao što je navedeno, data doza i režim liječenja ovisit će, na primjer, o bolesti, njenoj težini, o pacijentu kojeg se liječi i o njegovoj reakciji na liječenje i stoga se može široko mijenjati.
Karakterizacija oblika I i II karvedilola
Termomikroskopija
Termalna analiza je izvršena s Koflerovim grijaćim postoljem (Reichert, Beč) montiranim na mikroskop Olympus BH-2 opremljen s video opremom ili s mikroskopom Thermovat® s Koflerovim grijaćim postoljem (Reichert, Beč); obadva mikroskopa imaju mogućnost polarizacije i digitalni termometar.
Oblik II sastoji se od heterogenih kristala romboidnog do heksagonalnog izgleda i lamelarnog oblika veličine do 120 μm, koji se tale pri pribl. 114-115oC, dok se oblik I sastoji od zrna, odnosno prizmi veličine 40 μm, koje se tale pri pribl. 123-126oC.
Diferencijalna pretražna kalorimetrija (DSC)
DCS je provedena s DSC-7 (Perkin-Elmer, Norwalk, Ct., SAD) opremljenim s rashladnim sistemom CCA-7, s perforiranim aluminijskim kapsulama za uzorke (25 μl), pri čemu se u svaku kapsulu može odvagnuti 1,5 mg (vaga UM 3 s ultra mikro ljestvicom, Mettler, CH-Greifensee, Švicarska). Dušik 4,0 kao protočni plin (20 ml min-1). Zapisivanje DSC signala potpomognuto računalom. Baždarenje temperature za CCa krivulje s talištem za vodu i kofein anhidrat (talište 236,2oC), svaka tvar u tijesno zatvorenoj kapsuli uzorka. Baždarenje ordinata (DSC signal) s toplinom taljenja indija 99,999% (Perkin-Elmer, Norwalk, Ct., SAD).
Izmjerena tališta u skladu su s talištima koja su određenim termomikroskopski. Mjerenjem topline taljenja (oblik I: ΔHf 48,2 kJ/molu; oblik II: ΔHf 51,0 kJ/molu) može se ocijeniti da je kristalizat, koji se sastoji od oblika I, onečišćen s približno 2 do 3 % oblika II, što se također može vidjeti termomikroskopski.
FT-IR, FT Ramanova spektroskopija i difraktometrija X-zraka
FT-IR spektroskopija provedena je s Brukerovim IFS 25 FT-IR spektrometrom. Za izradu KBr tableta, smrvljen je u prah približno 1 mg uzorka s 270 mg KBr. Spektri su očitani transmisijski u rasponu od 4000 do 600 cm-1. Rezolucija: 2 cm-1 (50 interferograma).
FT Ramanova spektroskopija provedena je s Brukerovim RFS 100 FT Ramanovim spektrometrom opremljenim s diodno pumpanim Nd:YAG laserom (1064 nm) i detektorom visoke osjetljivosti hlađenim s tekućim dušikom. Praškasti uzorci su isprešani u malim aluminijskim posudicama, spektri su zabilježeni pri početnoj snazi od 200 mW, rezolucija 4 cm-1 (50 interferograma).
Difraktometrija X-zraka na prahu provedena je sa Siemensovim difraktometrom D-5000, sa X-zrakama, Diffrac/AT s θ/θ goniometrom, CuKα-zrakama, monokromatizacija s nikalnim filtrom, rotacija uzorka tijekom mjerenja, scintilacijski brojač, kutno područje 2o do 40o (2θ), stupnjevi po 0,01o (2θ), vrijeme mjerenja 2 sek.
IR spektri obaju modifikacija pokazuju velike razlike u području oscilacije valencije (oblik I 3451 cm-1; oblik II 3345 cm-1) (slike 1 i 2), koje su uzrokovane s različitim vodikovim mostovima. To odgovara Ramanovim spektrima koji se razlikuju samo malo. Najveća razlika u Ramanovom spektru je pri približno 2942 i približno 755 cm-1 (slike 3 i 4). Sliku difrakcije X zraka na prahu za oblik I karakteriziraju pikovi pri 2θ = 9,5, 10,8, 12,0, 14,6, 19,6, 21,5 i 22,3 (slika 5) dok karakteristični pikovi oblika II nastaju pri 2θ = 5,9, 14,9, 17,6, 18,5 i 24,4 (slika 6).
Postupak za pripravljanje oblika I karvedilola
Primjer 1
Sirov karvedilol je proizveden u skladu s postupkom opisanim u EP-B-0 004 920, u metanolu. Sirov karvedilol (računato na osnovi 300 g suhog karvedilola), 15 g CXA-ugljena i 2800 ml metanola grije se 15 minuta pod refluksom u trogrloj tikvici. Vruću otopinu se profiltrira i ispere s 300 ml vrućeg metanola i grije se ponovno pod refluksom. Zatim se otopinu ohladi za pola sata na 30ºC, miješa se između 3 i 22 sata i polako se ohladi na 0oC kroz 3 1/2 sata. Nakon miješanja otopine još dva sata pri 0ºC proizvod se izolira, ispere se tri puta sa 40 ml metanola i suši se 24 sata pod vakuumom pri 60ºC. Dobiveno je 203-255 g čistog oblika I koji je karakteriziran kako je ranije opisano.
Oblik II može se dobiti dodatnom prekristalizacijom u izopropanolu.
Primjer 2
A 1:1 mješavinu oblika I i oblika II suspendira se u izopropanolu i miješa se s magnetskom mješalicom 18 sati u dobro začepljenoj staklenoj posudi. Za to vrijeme temperatura se brzo povisi i spusti između 10 i 25oC. Zatim se uzorak profiltrira kroz lijevak s mikro staklenim filtrom (G3), osuši i izvadi. IR spektar tog uzorka odgovarao je obliku I. DSC krivulje nisu imale vršnu vrijednost pri 114-115ºC, stoga je to bio čisti oblik I.
Ovaj opis i primjeri trebaju se smatrati ilustrativnim i oni ne ograničavaju predloženi izum i u granicama duha i svrhe izuma stručnjak može zamisliti i druge izvedbe.
Claims (7)
1. Modifikacija (±) 1-(4-karbazoliloksi)-3-[2-(2-metoksifenoksi)etilamino]-2-propanola koja ima slijedeći oblik difrakcije X-zraka dobiven sa CuKα zračenjem pri 2θ = 9,5, 10,8, 12,0, 14,5, 19,6, 21,5, 22,3, i infracrveni spektar koji ima oštre vršne vrijednosti pri 3451 cm-1, naznačena time, da ima talište pri pribl. 123-126ºC.
2. Farmakološki prihvatljive soli ili optički aktivni oblici spoja, naznačenog time, da je u skladu sa zahtjevom 1.
3. Postupak za pripravlajnje i izolaciju uglavnom čistog oblika spoja, naznačenog time, da je u skladu sa zahtjevom 1.
4. Postupak prema zahtjevu 3, naznačen time, da se promijenjeni postupak provodi od 3 do 22 sata u metanolu pri temperaturi između 25 i 35ºC.
5. Postupak prema zahtjevu 4, naznačen time, da se modifikacija karvedilola s višim talištem dobije pri 0ºC iz promijenjene reakcijske smjese.
6. Farmaceutski sastav, naznačen time, da sadrži uglavnom čisti oblik postojane modifikacije 1-(4-karb-azoliloksi)-3-[2-(2-metoksifenoksi)etilamino]-2-propanola kao aktivnog sastojka prema zahtjevu 1 zajedno s jednim ili više farmaceutski prihvatljivih nosača ili pomoćnih tvari.
7. Upotreba farmaceutskog sastava prema zahtjevu 5, naznačena time, da se on koristi za profilaksu ili za liječenje kardijalnih bolesti.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP97112491A EP0893440A1 (en) | 1997-07-22 | 1997-07-22 | Thermodynamically stable modification of 1-(4-carbazolyloxy)-3-[2-(2-methoxyphenoxy)ethylamino]-2-propanole, process for its preparation and pharmaceutical compositions containing it |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP980406A2 true HRP980406A2 (en) | 1999-04-30 |
Family
ID=8227094
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HR97112491.2A HRP980406A2 (en) | 1997-07-22 | 1998-07-22 | Thermodynamically stable modification of 1-(4-carbazolyloxy-3-/2-(2-methoxyphenoxy)ethylamino/-2-propanole, process for its preparation and pharmaceutical compositions containing it |
Country Status (32)
| Country | Link |
|---|---|
| EP (2) | EP0893440A1 (hr) |
| JP (1) | JP2001510824A (hr) |
| KR (1) | KR100336229B1 (hr) |
| CN (1) | CN1125047C (hr) |
| AR (1) | AR015133A1 (hr) |
| AT (1) | ATE236123T1 (hr) |
| AU (1) | AU740453B2 (hr) |
| BR (1) | BR9810776A (hr) |
| CA (1) | CA2296637C (hr) |
| CZ (1) | CZ296947B6 (hr) |
| DE (1) | DE69812964T2 (hr) |
| DK (1) | DK1000027T3 (hr) |
| ES (1) | ES2195366T3 (hr) |
| HK (1) | HK1029339A1 (hr) |
| HR (1) | HRP980406A2 (hr) |
| HU (1) | HUP0003198A3 (hr) |
| IL (1) | IL133677A (hr) |
| MA (1) | MA26523A1 (hr) |
| MY (1) | MY117734A (hr) |
| NO (1) | NO313588B1 (hr) |
| NZ (1) | NZ502136A (hr) |
| PE (1) | PE96999A1 (hr) |
| PL (1) | PL191602B1 (hr) |
| PT (1) | PT1000027E (hr) |
| RU (1) | RU2202542C2 (hr) |
| SI (1) | SI1000027T1 (hr) |
| TR (1) | TR200000148T2 (hr) |
| TW (1) | TW505631B (hr) |
| UY (1) | UY25108A1 (hr) |
| WO (1) | WO1999005105A1 (hr) |
| YU (1) | YU2200A (hr) |
| ZA (1) | ZA986475B (hr) |
Families Citing this family (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2402336C (en) * | 2000-04-03 | 2008-03-11 | F. Hoffmann-La Roche Ag | Concentrated solutions of carvedilol |
| EP1655285A1 (en) * | 2000-06-28 | 2006-05-10 | Teva Pharmaceutical Industries Ltd. | Method for preparation of a crystalline form of carvedilol (form II) |
| KR20080064908A (ko) * | 2000-06-28 | 2008-07-09 | 테바 파마슈티컬 인더스트리즈 리미티드 | 카르베딜올 |
| DE60212130D1 (en) * | 2001-07-13 | 2006-07-20 | Smithkline Beecham Corp | Carvedilolpolymorph |
| ES2298401T3 (es) | 2001-09-21 | 2008-05-16 | Egalet A/S | Dispersiones solidas de liberacion controlada de carvedilol. |
| CN1308307C (zh) * | 2001-09-28 | 2007-04-04 | 弗·哈夫曼-拉罗切有限公司 | 假多晶型的卡维地洛 |
| WO2003059807A2 (en) | 2002-01-15 | 2003-07-24 | Teva Pharmaceutical Industries Ltd. | Crystalline solids of carvedilol and processes for their preparation |
| AU2003231283A1 (en) * | 2002-04-30 | 2003-11-17 | Sb Pharmco Puerto Rico Inc. | Carvedilol monocitrate monohydrate |
| US20050261355A1 (en) | 2002-06-27 | 2005-11-24 | Sb Pharmco Puerto Rico Inc., | Carvedilol hydobromide |
| US7268156B2 (en) * | 2002-06-27 | 2007-09-11 | Sb Pharmco Puerto Rico Inc. | Carvedilol phosphate salts and/or solvates thereof, corresponding compositions and/or methods of treatment |
| US20040151772A1 (en) | 2002-11-08 | 2004-08-05 | Egalet A/S | Controlled release carvedilol compositions |
| ATE495732T1 (de) | 2003-03-26 | 2011-02-15 | Egalet As | Morphin-system mit kontrollierter freisetzung |
| WO2004094378A1 (en) * | 2003-04-21 | 2004-11-04 | Matrix Laboratories Ltd | Process for the preparation of carvedilol form-ii |
| SI21616A (sl) * | 2003-09-02 | 2005-04-30 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Nove kristalne oblike karvedilola |
| US7750036B2 (en) | 2003-11-25 | 2010-07-06 | Sb Pharmco Puerto Rico Inc. | Carvedilol salts, corresponding compositions, methods of delivery and/or treatment |
| EP1838670B1 (en) * | 2004-12-09 | 2009-10-14 | ZaCh System S.p.A. | Process for the preparation of carvedilol and its enantiomers |
| WO2006135757A1 (en) * | 2005-06-09 | 2006-12-21 | Teva Pharmaceutical Industries Ltd. | Crystalline forms of carvedilol and processes for their preparation |
| WO2008002683A2 (en) | 2006-06-28 | 2008-01-03 | Teva Pharmaceutical Industries Ltd. | Polymorphous forms of carvedilol phosphate |
| US20080249317A1 (en) * | 2007-04-04 | 2008-10-09 | Apotex Inc. | Novel amorphous form of carvedilol phosphate and processes for the preparation thereof |
| WO2008148798A2 (en) | 2007-06-04 | 2008-12-11 | Egalet A/S | Controlled release pharmaceutical compositions for prolonged effect |
| CA2751667C (en) | 2009-02-06 | 2016-12-13 | Egalet Ltd. | Immediate release composition resistant to abuse by intake of alcohol |
| AU2010265213B2 (en) | 2009-06-24 | 2012-08-23 | Egalet Ltd. | Controlled release formulations |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2815926A1 (de) * | 1978-04-13 | 1979-10-18 | Boehringer Mannheim Gmbh | Neue carbazolyl-(4)-oxy-propanolamin-derivate, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel |
| DE3319027A1 (de) * | 1983-05-26 | 1984-11-29 | Boehringer Mannheim Gmbh, 6800 Mannheim | Verfahren zur herstellung von optisch aktiven carbazol-derivaten, neue r- und s-carbazol-derivate, sowie arzneimittel, die diese verbindungen enthalten |
-
1997
- 1997-07-22 EP EP97112491A patent/EP0893440A1/en not_active Withdrawn
-
1998
- 1998-07-15 MY MYPI98003245A patent/MY117734A/en unknown
- 1998-07-15 PE PE1998000626A patent/PE96999A1/es not_active Application Discontinuation
- 1998-07-18 JP JP2000504104A patent/JP2001510824A/ja active Pending
- 1998-07-18 CZ CZ20000221A patent/CZ296947B6/cs not_active IP Right Cessation
- 1998-07-18 BR BR9810776-3A patent/BR9810776A/pt not_active Application Discontinuation
- 1998-07-18 WO PCT/EP1998/004475 patent/WO1999005105A1/en active IP Right Grant
- 1998-07-18 KR KR1020007000667A patent/KR100336229B1/ko not_active IP Right Cessation
- 1998-07-18 AT AT98937576T patent/ATE236123T1/de not_active IP Right Cessation
- 1998-07-18 DE DE69812964T patent/DE69812964T2/de not_active Expired - Fee Related
- 1998-07-18 YU YU2200A patent/YU2200A/sh unknown
- 1998-07-18 PT PT98937576T patent/PT1000027E/pt unknown
- 1998-07-18 NZ NZ502136A patent/NZ502136A/en unknown
- 1998-07-18 CN CN98807436A patent/CN1125047C/zh not_active Expired - Fee Related
- 1998-07-18 CA CA002296637A patent/CA2296637C/en not_active Expired - Fee Related
- 1998-07-18 EP EP98937576A patent/EP1000027B1/en not_active Expired - Lifetime
- 1998-07-18 ES ES98937576T patent/ES2195366T3/es not_active Expired - Lifetime
- 1998-07-18 AU AU86319/98A patent/AU740453B2/en not_active Ceased
- 1998-07-18 PL PL338432A patent/PL191602B1/pl unknown
- 1998-07-18 DK DK98937576T patent/DK1000027T3/da active
- 1998-07-18 TW TW087111738A patent/TW505631B/zh not_active IP Right Cessation
- 1998-07-18 RU RU2000103033/04A patent/RU2202542C2/ru not_active IP Right Cessation
- 1998-07-18 TR TR2000/00148T patent/TR200000148T2/xx unknown
- 1998-07-18 HU HU0003198A patent/HUP0003198A3/hu unknown
- 1998-07-18 SI SI9830442T patent/SI1000027T1/xx unknown
- 1998-07-18 IL IL13367798A patent/IL133677A/en not_active IP Right Cessation
- 1998-07-20 MA MA25178A patent/MA26523A1/fr unknown
- 1998-07-21 AR ARP980103547A patent/AR015133A1/es unknown
- 1998-07-21 ZA ZA9806475A patent/ZA986475B/xx unknown
- 1998-07-22 UY UY25108A patent/UY25108A1/es not_active IP Right Cessation
- 1998-07-22 HR HR97112491.2A patent/HRP980406A2/hr not_active Application Discontinuation
-
2000
- 2000-01-21 NO NO20000301A patent/NO313588B1/no unknown
-
2001
- 2001-01-02 HK HK01100012A patent/HK1029339A1/xx not_active IP Right Cessation
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| HRP980406A2 (en) | Thermodynamically stable modification of 1-(4-carbazolyloxy-3-/2-(2-methoxyphenoxy)ethylamino/-2-propanole, process for its preparation and pharmaceutical compositions containing it | |
| US6730326B2 (en) | Thermodynamically stable modification of 1-(4-carbazolyl-oxy-3[2-(2-methoxyphenoxy)-ethylamino]-2-propanol process for its preparation and pharmaceutical compositions containing it | |
| CA2305803C (en) | Crystalline antifungal polymorph | |
| HU196775B (en) | Process for production of morfologically unique new modifications of famotidin and medical compositions containing such substances | |
| AU2002255017B2 (en) | Polymorph of 4-[2-[4-[1-(2-ethoxyethyl)-1H-benzimidazole-2-yl]-1-piperidinyl]ethyl]-alpha, alpha-dimethyl-benzeneacetic acid | |
| KR100425656B1 (ko) | 약제의결정변체 | |
| ZA200500372B (en) | Novel salt and polymorphs of desloratadine hemifumarate | |
| JPS61197577A (ja) | １−置換−６−フルオロ−７−（ピロ−ル−１−イル）−１，４−ジヒドロ−４−オキソキノリン−３−カルボン酸誘導体およびその製造法 | |
| JPS6219577A (ja) | 新規なベンジルピペラジン誘導体および該化合物を有効成分とする医薬組成物 | |
| US4438142A (en) | Pharmaceutical combination | |
| MXPA00000507A (en) | Thermodynamically stable modification of 1-(4-carbazolyloxy)-3- [2-(2-methoxyphenoxy)ethylamino]-2- propanole, process for its preparation and pharmaceutical compositions containing it | |
| EP0771798A1 (en) | Novel polymorphs of lesopitron dichlorohydrate and its hydrated forms, preparation methods and compositions containing them | |
| MXPA06002732A (es) | Compuesto de indol que contiene sulfonamida cristalina y proceso para su preparacion. | |
| PL205568B1 (pl) | Polimorf 1 bilastyny, sposoby jego wytwarzania, preparaty farmaceutyczne go zawierające oraz jego zastosowanie |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A1OB | Publication of a patent application | ||
| PNAN | Change of the applicant name, address/residence |
Owner name: ROCHE DIAGNOSTICS GMBH, DE |
|
| AIPI | Request for the grant of a patent on the basis of a substantive examination of a patent application | ||
| ODBI | Application refused |