AU2016385282B2 - Pharmaceutical composition comprising nebivolol with improved dissolution rate - Google Patents
Pharmaceutical composition comprising nebivolol with improved dissolution rate Download PDFInfo
- Publication number
- AU2016385282B2 AU2016385282B2 AU2016385282A AU2016385282A AU2016385282B2 AU 2016385282 B2 AU2016385282 B2 AU 2016385282B2 AU 2016385282 A AU2016385282 A AU 2016385282A AU 2016385282 A AU2016385282 A AU 2016385282A AU 2016385282 B2 AU2016385282 B2 AU 2016385282B2
- Authority
- AU
- Australia
- Prior art keywords
- nebivolol
- pharmaceutical composition
- pharmaceutically acceptable
- dissolution rate
- solid oral
- Prior art date
- 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.)
- Active
Links
- KOHIRBRYDXPAMZ-YHBROIRLSA-N (S,R,R,R)-nebivolol Chemical compound C1CC2=CC(F)=CC=C2O[C@H]1[C@H](O)CNC[C@@H](O)[C@H]1OC2=CC=C(F)C=C2CC1 KOHIRBRYDXPAMZ-YHBROIRLSA-N 0.000 title claims abstract description 76
- 229960000619 nebivolol Drugs 0.000 title claims abstract description 76
- 238000004090 dissolution Methods 0.000 title abstract description 50
- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 27
- 230000003113 alkalizing effect Effects 0.000 claims abstract description 33
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 33
- 239000000654 additive Substances 0.000 claims abstract description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 239000004480 active ingredient Substances 0.000 claims abstract description 16
- 230000000996 additive effect Effects 0.000 claims abstract description 14
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 12
- LALFOYNTGMUKGG-BGRFNVSISA-L rosuvastatin calcium Chemical compound [Ca+2].CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O.CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O LALFOYNTGMUKGG-BGRFNVSISA-L 0.000 claims abstract description 7
- 229960004796 rosuvastatin calcium Drugs 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims description 47
- 238000000034 method Methods 0.000 claims description 23
- 239000001095 magnesium carbonate Substances 0.000 claims description 16
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 16
- 239000007787 solid Substances 0.000 claims description 15
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 claims description 14
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 14
- 239000000395 magnesium oxide Substances 0.000 claims description 13
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims description 13
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims description 12
- 239000008203 oral pharmaceutical composition Substances 0.000 claims description 12
- 229960000672 rosuvastatin Drugs 0.000 claims description 11
- JWEXHQAEWHKGCW-VCVZPGOSSA-N (S,R,R,R)-nebivolol hydrochloride Chemical compound [Cl-].C1CC2=CC(F)=CC=C2O[C@H]1[C@H](O)C[NH2+]C[C@@H](O)[C@H]1OC2=CC=C(F)C=C2CC1 JWEXHQAEWHKGCW-VCVZPGOSSA-N 0.000 claims description 9
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 claims description 8
- 229940068174 nebivolol hydrochloride Drugs 0.000 claims description 7
- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 claims description 6
- 206010019280 Heart failures Diseases 0.000 claims description 5
- 206010020772 Hypertension Diseases 0.000 claims description 5
- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 claims description 3
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims description 3
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 claims description 3
- 239000002083 C09CA01 - Losartan Substances 0.000 claims description 3
- 239000002080 C09CA02 - Eprosartan Substances 0.000 claims description 3
- 239000004072 C09CA03 - Valsartan Substances 0.000 claims description 3
- 239000002053 C09CA06 - Candesartan Substances 0.000 claims description 3
- 239000005537 C09CA07 - Telmisartan Substances 0.000 claims description 3
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 3
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 claims description 3
- 108010061435 Enalapril Proteins 0.000 claims description 3
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 claims description 3
- 239000005480 Olmesartan Substances 0.000 claims description 3
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 claims description 3
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 claims description 3
- 229960000528 amlodipine Drugs 0.000 claims description 3
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 claims description 3
- 229960005370 atorvastatin Drugs 0.000 claims description 3
- 229960000932 candesartan Drugs 0.000 claims description 3
- SGZAIDDFHDDFJU-UHFFFAOYSA-N candesartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SGZAIDDFHDDFJU-UHFFFAOYSA-N 0.000 claims description 3
- 229960000873 enalapril Drugs 0.000 claims description 3
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 claims description 3
- 229960004563 eprosartan Drugs 0.000 claims description 3
- OROAFUQRIXKEMV-LDADJPATSA-N eprosartan Chemical compound C=1C=C(C(O)=O)C=CC=1CN1C(CCCC)=NC=C1\C=C(C(O)=O)/CC1=CC=CS1 OROAFUQRIXKEMV-LDADJPATSA-N 0.000 claims description 3
- 229960003765 fluvastatin Drugs 0.000 claims description 3
- 229960002003 hydrochlorothiazide Drugs 0.000 claims description 3
- 229960004294 lercanidipine Drugs 0.000 claims description 3
- ZDXUKAKRHYTAKV-UHFFFAOYSA-N lercanidipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)(C)CN(C)CCC(C=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZDXUKAKRHYTAKV-UHFFFAOYSA-N 0.000 claims description 3
- 229960004773 losartan Drugs 0.000 claims description 3
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 claims description 3
- 229960004844 lovastatin Drugs 0.000 claims description 3
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 claims description 3
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 claims description 3
- VKQFCGNPDRICFG-UHFFFAOYSA-N methyl 2-methylpropyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)C)C1C1=CC=CC=C1[N+]([O-])=O VKQFCGNPDRICFG-UHFFFAOYSA-N 0.000 claims description 3
- 229960000227 nisoldipine Drugs 0.000 claims description 3
- 229960005117 olmesartan Drugs 0.000 claims description 3
- VTRAEEWXHOVJFV-UHFFFAOYSA-N olmesartan Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 VTRAEEWXHOVJFV-UHFFFAOYSA-N 0.000 claims description 3
- 229960002965 pravastatin Drugs 0.000 claims description 3
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 claims description 3
- 229960003401 ramipril Drugs 0.000 claims description 3
- HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 claims description 3
- 229960002855 simvastatin Drugs 0.000 claims description 3
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 claims description 3
- 229960005187 telmisartan Drugs 0.000 claims description 3
- 229960004699 valsartan Drugs 0.000 claims description 3
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 abstract description 21
- 230000008859 change Effects 0.000 abstract description 7
- 230000007423 decrease Effects 0.000 abstract description 7
- 239000000080 wetting agent Substances 0.000 abstract description 7
- 239000002131 composite material Substances 0.000 abstract description 6
- 230000001225 therapeutic effect Effects 0.000 abstract description 4
- 230000009471 action Effects 0.000 abstract description 3
- 230000002265 prevention Effects 0.000 abstract 1
- 239000003826 tablet Substances 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 239000008187 granular material Substances 0.000 description 18
- 230000000052 comparative effect Effects 0.000 description 16
- 239000000314 lubricant Substances 0.000 description 12
- 238000005550 wet granulation Methods 0.000 description 11
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 10
- 235000019359 magnesium stearate Nutrition 0.000 description 10
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 9
- 229940016286 microcrystalline cellulose Drugs 0.000 description 9
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 9
- 239000008108 microcrystalline cellulose Substances 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 8
- 229920000053 polysorbate 80 Polymers 0.000 description 8
- 230000008569 process Effects 0.000 description 7
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 229920003109 sodium starch glycolate Polymers 0.000 description 5
- 239000008109 sodium starch glycolate Substances 0.000 description 5
- 229940079832 sodium starch glycolate Drugs 0.000 description 5
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.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 WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 4
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 4
- 229920002785 Croscarmellose sodium Polymers 0.000 description 4
- 239000002876 beta blocker Substances 0.000 description 4
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 238000007922 dissolution test Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 229920003125 hypromellose 2910 Polymers 0.000 description 4
- 229940031672 hypromellose 2910 Drugs 0.000 description 4
- 229960001021 lactose monohydrate Drugs 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010048554 Endothelial dysfunction Diseases 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229940097320 beta blocking agent Drugs 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 230000008694 endothelial dysfunction Effects 0.000 description 3
- -1 etc. Polymers 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- 0 CCC(*)C(CC1)Oc(cc2)c1cc2F Chemical compound CCC(*)C(CC1)Oc(cc2)c1cc2F 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 208000011775 arteriosclerosis disease Diseases 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 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 description 2
- 239000002775 capsule Substances 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 2
- 239000013065 commercial product Substances 0.000 description 2
- 230000003511 endothelial effect Effects 0.000 description 2
- 210000003989 endothelium vascular Anatomy 0.000 description 2
- 239000007941 film coated tablet Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- LODHFNUFVRVKTH-ZHACJKMWSA-N 2-hydroxy-n'-[(e)-3-phenylprop-2-enoyl]benzohydrazide Chemical compound OC1=CC=CC=C1C(=O)NNC(=O)\C=C\C1=CC=CC=C1 LODHFNUFVRVKTH-ZHACJKMWSA-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
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- WRFYIYOXJWKONR-UHFFFAOYSA-N 4-bromo-2-methoxyaniline Chemical compound COC1=CC(Br)=CC=C1N WRFYIYOXJWKONR-UHFFFAOYSA-N 0.000 description 1
- KBIWNQVZKHSHTI-UHFFFAOYSA-N 4-n,4-n-dimethylbenzene-1,4-diamine;oxalic acid Chemical compound OC(=O)C(O)=O.CN(C)C1=CC=C(N)C=C1 KBIWNQVZKHSHTI-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
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 208000020446 Cardiac disease Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 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 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- IJGTUZLIPFSEJO-WCCKRBBISA-N O=[N].OC(=O)[C@@H](N)CCCNC(N)=N Chemical compound O=[N].OC(=O)[C@@H](N)CCCNC(N)=N IJGTUZLIPFSEJO-WCCKRBBISA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Natural products OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920002319 Poly(methyl acrylate) Polymers 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Natural products OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229920001531 copovidone Polymers 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 201000006517 essential tremor Diseases 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- FETSQPAGYOVAQU-UHFFFAOYSA-N glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 description 1
- 229940046813 glyceryl palmitostearate Drugs 0.000 description 1
- 229960004275 glycolic acid Drugs 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940057948 magnesium stearate Drugs 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
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 229910017604 nitric acid 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
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical class [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229960005137 succinic acid Drugs 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000012085 test solution Substances 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
- 230000024883 vasodilation Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- 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
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cardiology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Heart & Thoracic Surgery (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention relates to a pharmaceutical composition having an improved dissolution rate of nebivolol. A pharmaceutical composition, containing nebivolol or a pharmaceutically acceptable salt thereof, an alkalizing agent, and a pharmaceutically acceptable additive, for prevention or treatment of cardiovascular diseases, does not cause a decrease in the dissolution rate of nebivolol and can significantly improve the dissolution rate, not only at low pH, such as pH 1.2, but also at a relatively high pH of 5 to 7, so that an improved therapeutic effect can be expected. In addition, the pharmaceutical composition can reduce the preparation cost since the micronization of nebivolol or the addition of a wetting agent is not required, and can minimize the occurrence of a deviation of bioavailability due to pre- or post-meal intake since there is little deviation of the dissolution rate due to the pH change, thereby maintaining a constant pharmaceutical action, and thus, the pharmaceutical composition is very useful in the preparation of a composite preparation containing a nebivolol preparation, or another active ingredient, such as rosuvastatin calcium.
Description
PHARMACEUTICAL COMPOSITION COMPRISING NEBIVOLOL
WITH IMPROVED DISSOLUTION RATE
Technical Field
The present invention relates to a pharmaceutical composition having an improved dissolution rate of nebivolol and a method for preparing the same. More specifically, the present invention relates to a pharmaceutical composition with an improved dissolution rate, comprising nebivolol or a pharmaceutically acceptable salt thereof as an active ingredient, an alkalizing agent and a pharmaceutically acceptable additive.
Background Art
A beta-blocker is used for the treatment of hypertension, angina pectoris, myocardial infarction, cardiac disorders, migraine or essential tremor, etc.
Nebivolol, a beta-blocker, which is a 2,2’-iminobisethanol derivative represented by the fol lowing Formula 1, has a centrosymmetric structure with four chiral centers.
Nebivolol, a mixture of D- and L-form enantiomers, is a β-receptor blocking agent, which is highly selective for β I-adrenergic receptor, and has a vasodilation activity related to an effect on endothelial nitrogen oxide, which makes nebivolol
2016385282 29 Aug 2019 different from other conventional β-blockers. It is believed that nebivolol increases the concentration of nitrogen oxide via L-arginine-nitrogen oxide pathway in vascular endothelium, and it is found that nebivolol improves endothelial dysfunction and vascular elasticity. Furthermore, it is known that nebivolol has an antioxidant effect which is beneficial to vascular endothelial functionality, and therefore, nebivolol is used as an effective antihypertensive agent having a beneficial effect on vascular endothelium and cardiovascular system. It is also found that nebivolol is effective on cardiovascular disorders such as hypertension, congestive heart failure, arteriosclerosis and endothelial dysfunction, etc.
Generally, a pharmaceutical composition is provided as a solid formulation suitable for oral administration, i.e., tablets, etc., in consideration of convenient use, in which case bioavailability is significantly required. A critical factor affecting bioavailability is a dissolution process in vivo, which may be determined by a dissolution rate via a dissolution test in a laboratory. In this regard, nebivolol has a problem of a very low dissolution rate at a relatively high pH.
In order to solve the problem of nebivolol, KR Patent No. 0361636 discloses a method of micronizing nebivolol. However, micronized nebivolol still has a problem of a low dissolution rate, and also has a great deviation of bioavailability under fasting or fed condition. EP Patent No. 0145067 discloses a method of improving a dissolution rate of nebivolol by adding a wetting agent to micronized nebivolol. KR Patent No. 896266 discloses a nebivolol hydrochloride form with improved dissolution rate without using a wetting agent, and KR Patent Publication No. 2011-0130872 discloses a pharmaceutical composition using crystalline form nebivolol with starch in order to improve a dissolution rate of nebivolol.
In the conventional methods, however, nebivolol should be milled and sieved to be micronized, which is very inconvenient and uneconomical due to increased process time and cost. Addition of a wetting agent also contributes to rise of manufacturing cost. In addition, a great deviation of bioavailability under fasting or fed condition
2016385282 29 Aug 2019 could decrease therapeutic effect.
Furthermore, in the conventional methods, only the dissolution rate of nebivolol at pH 1.2 to 4.0 was confirmed, and the dissolution rate in water was not verified. According to the preliminary experiment performed previously to the present invention, it was confirmed that all the nebivolol preparations showed a low dissolution rate of 70% or less when tested in water. When the preparations with decreased dissolution rate of drug are administered, oral absorption and bioavailability of drug may decrease, which may lead to decreased efficacy of drug in a human body. Accordingly, there has been a compelling need for development of a nebivolol preparation ensuring a satisfactory dissolution rate without a deviation in vivo.
Under the circumstance, the present inventors have intensively studied for preparing a nebivolol preparation with a stable and enhanced dissolution rate without a deviation at the pH change in vivo and found that an alkalizing agent added to a pharmaceutical composition comprising nebivolol results in a significant enhancement of a dissolution rate even at pH 5 to 7 or in water as well as at a low pH to complete the present invention.
Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present disclosure as it existed before the priority date of each of the appended claims.
Disclosure of Invention
Throughout this specification the word comprise, or variations such as comprises or comprising, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.
An aim of at least a preferred embodiment of the present invention is to provide a pharmaceutical composition with an improved dissolution rate of nebivolol and a
2016385282 29 Aug 2019 method for preparing the same.
Summary
Disclosed herein is a pharmaceutical composition for preventing or treating cardiovascular diseases, comprising nebivolol or a pharmaceutically acceptable salt thereof, an alkalizing agent and a pharmaceutically acceptable additive and a method of preparation.
In an embodiment, the pharmaceutically acceptable salt of nebivolol is preferably a nebivolol hydrochloride, and may be comprised in an amount of 0.2 to 10 parts by weight based on 100 parts by weight of the composition.
The alkalizing agent is preferable to show a pH of 8 to 12 when suspended or dissolved in water, and may be selected from the group consisting of magnesium oxide, magnesium carbonate and magnesium aluminum silicate. Furthermore, the alkalizing agent may be comprised in an amount of 0.02 to 10 parts by weight based on 100 parts by weight of the composition.
In accordance with one aspect of the present invention, there is provided a solid oral pharmaceutical composition for preventing or treating cardiovascular diseases, comprising nebivolol or a pharmaceutically acceptable salt thereof, an alkalizing agent, and a pharmaceutically acceptable additive, wherein the alkalizing agent is at least one selected from the group consisting of magnesium oxide, magnesium carbonate and magnesium aluminum silicate.
In another embodiment, the pharmaceutical composition may further comprise an additional active ingredient for preventing or treating cardiovascular diseases. The additional active ingredient may be at least one selected from the group consisting of hydrochlorothiazide, ramipril, enalapril, lercanidipine, nisoldipine, amlodipine, losartan, eprosartan, candesartan, telmisartan, valsartan, olmesartan, rosuvastatin, atorvastatin, pravastatin, fluvastatin, lovastatin, simvastatin and pharmaceutically acceptable salts thereof, and rosuvastatin calcium is preferred.
2016385282 29 Aug 2019
In accordance with another aspect of the present invention, there is provided a method for preparing a solid oral pharmaceutical composition, which comprises the steps of:
a) mixing nebivolol or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive to form a mixture; and
b) formulating the mixture, wherein an alkalizing agent is added in step a) or b) and is at least one selected from the group consisting of magnesium oxide, magnesium carbonate and magnesium aluminum silicate.
Advantageous Effects of Invention
The pharmaceutical composition of the present invention does not cause a decrease in the dissolution rate of nebivolol and can significantly improve the dissolution rate, not only at a low pH, such as pH 1.2, but also at a relatively high pH of 5 to 7, so that an improved therapeutic effect can be expected. Furthermore, the pharmaceutical composition may reduce the manufacturing cost since the micronization of nebivolol or the addition of a wetting agent is not required, and can minimize the occurrence of a deviation of bioavailability under fasting or fed condition since there is little deviation of dissolution rate due to the pH change, thereby maintaining a constant pharmacological action, and therefore, the pharmaceutical composition is very useful in the preparation of a nebivolol preparation or a composite preparation containing an additional active ingredient, such as rosuvastatin calcium.
Brief Description of Drawings
Fig. 1 is a graph showing a dissolution rate of nebivolol in water over time for the preparations of Examples 1 to 6 and Comparative Examples 1 to 3, measured according to paddle method.
Detailed Description
Hereinafter, the present invention will be further explained.
Nebivolol, an active ingredient, of the pharmaceutical composition according to the present invention, which is represented by the following Formula 1, is a highly selective β I-blocker and known to be efficacious in the control of hypertension.
In the composition according to the present invention, nebivolol may be used as various forms such as a free base or a pharmaceutically acceptable salt thereof, as long as an equivalent pharmacological activity of nebivolol is maintained.
As for the pharmaceutically acceptable salt, since nebivolol is basic, it may be treated with acid to be converted into a pharmaceutically acceptable acid addition salt thereof. Examples of a suitable acid include an inorganic acid such as a hydrohalogenic acid (e.g., hydrochloric acid, hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid, etc.; or an organic acid such as acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, ethanedioic acid, propanedioic acid, butanedioic acid, (Z)-2-butenedioic acid, (E)-2-butenedioic acid, 2hydroxybutanedioic acid, 2,3-dihydroxybutanedioic acid, 2-hydroxy-1,2,3propanetricarboxylic acid, methanesullbnic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxybenzoic acid. 4-amino2-hydroxybenzoic acid, etc. According to the present invention, a preferred acid addition salt is hydrochloride.
The amount of nebivolol or a pharmaceutically acceptable salt thereof in the pharmaceutical composition may be adjusted in an acceptable range if needed, and preferably, 0.2 to 10 parts by weight, more preferably, 1 to 4 parts by weight based on 100 parts by weight of the composition. According to an embodiment of the present
2016385282 29 Aug 2019 invention, the amount of nebivolol is 1.5 to 3.6 parts by weight, as nebivolol hydrochloride form, based on 100 parts by weight of the composition.
The pharmaceutical composition according to the present invention is characterized in that an alkalizing agent is comprised in the composition in order to solve the problem that the dissolution rate of nebivolol or a pharmaceutically acceptable salt thereof decreases at pH 5.0 to 7.0, e.g., in water, thereby resulting in reduced absorption and bioavailability. It is generally known that since nebivolol is weak base, its solubility and dissolution rate would reduce with the increase of pH. Surprisingly, the present inventors found that the dissolution rate of nebivolol significantly increased with the addition of an alkalizing agent, which would be quite unexpected by those skilled in the art and confirmed for the first time by the present inventors.
In a preferred embodiment of the present invention, the alkalizing agent showing a pH of 8 to 12 when suspended or dissolved in water may be selected. For example, magnesium oxide, magnesium carbonate or magnesium aluminum silicate is preferred. According to the present invention, an excellent dissolution rate of nebivolol may be obtained at a low pH such as pH 1.2 as well as at pH 5 to 7, e.g., in water, by the addition of an alkalizing agent to nebivolol or a pharmaceutically acceptable salt thereof, thereby maintaining a high dissolution rate of drug even with the pH change when administered to a living body. Therefore, the problem of a low dissolution rate of nebivolol and the consequential sudden change in dissolution rate in vivo may be settled.
In the composition of the present invention, the amount of alkalizing agent is preferably 0.02 to 10 parts by weight, more preferably, 0.04 to 4 parts by weight based on 100 parts by weight of the composition. If the amount of alkalizing agent is less than 0.02 parts by weight based on 100 parts by weight of the composition, the effect on improvement of dissolution rate may be week, whereas an excessive amount over 10 parts by weight based on 100 parts by weight of the composition may lead to a decreased dissolution rate of nebivolol. In the Examples of the present invention,
2016385282 29 Aug 2019 compositions containing nebivolol with each of magnesium carbonate, magnesium oxide and magnesium aluminum silicate as an alkalizing agent (Examples 1 to 5) and composite preparations of nebivolol and rosuvastatin containing an alkalizing agent (Examples 6 to 9) were compared with a preparation similar to commercial product containing no alkalizing agent (Comparative Example 1) and preparations of Comparative Examples 2 and 3, and it was confirmed that the compositions of Examples showed significantly high dissolution rates of nebivolol in water.
The pharmaceutical composition according to the present invention further comprises a pharmaceutically acceptable additive, in addition to an active ingredient and an alkalizing agent, within a range having no influence on the effect of the present invention. Specifically, the pharmaceutically acceptable additive may be at least one selected from the group consisting of a filler, a binder, a disintegrant, a glidant and a lubricant.
Examples of the filler which may be used in the present composition include cellulose derivatives such as microcrystalline cellulose, low-substituted hydroxypropyl cellulose, methyl cellulose, etc., starches such as potato starch, corn starch, etc., lactose, fructose, etc.
Examples of the binder include polyvinyl pyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, methyl cellulose, poloxamer, polyethylene oxide, polymethylacrylate, natural gums, synthetic gums, copovidone, gelatin, etc.
Examples of the disintegrant include sodium starch glycolate, sodium carboxymethyl cellulose, croscarmellose sodium, low-substituted hydroxypropyl cellulose, pre-gelatinized starch, crospovidone, etc.
Examples of the glidant include colloidal silicon dioxide, magnesium aluminum metasilicate, etc.
Examples of the lubricant include magnesium stearate, stearic acid, sodium stearyl fumarate, glyceryl palmitostearate, etc.
2016385282 29 Aug 2019
In a preferred embodiment, the pharmaceutical composition of the present invention may comprise, as pharmaceutically acceptable additives, 40 to 95 parts by weight of a filler, 1 to 10 parts by weight of a binder, 1 to 10 parts by weight of a disintegrant, 0.1 to 2 parts by weight of a glidant, 0.1 to 2 parts by weight of a lubricant based on 100 parts by weight of the composition.
The type of administration for the pharmaceutical composition with improved dissolution rate according to the present invention is not specifically limited, and may be any one suitable for various administration route such as oral, parenteral (i.e., intramuscular, subcutaneous, intravenous, etc.). Oral administration is especially preferred for the present composition. Examples of formulations for oral administration include tablets, capsules, granules, troches, emulsions, suspensions, etc. Preferably, the present composition may be provided as a solid formulation for oral administration such as tablets or capsules in consideration of convenient use. The composition according to the present invention may be effectively used since it has no decrease in the dissolution rate regardless of the administered formulations and also has little deviation of dissolution rate due to the pH change in vivo.
The composition according to the present invention uses an alkalizing agent such as magnesium carbonate, magnesium oxide and magnesium aluminum silicate, and therefore, without going through a complicated and high-priced process such as micronization of nebivolol or addition of a wetting agent, it may ensure an excellent dissolution rate of 80% or higher within 15 minutes after starting dissolution with no decrease of dissolution rate in water, as confirmed in Experimental Example. Accordingly, the composition according to the present invention may reduce the manufacturing cost since the micronization of nebivolol or the addition of a wetting agent is not required, and may minimize the occurrence of a deviation of bioavailability under fasting or fed condition since there is little deviation of the dissolution rate due to the pH change, thereby ensuring a constant pharmacological action and an improved therapeutic effect.
2016385282 29 Aug 2019
The pharmaceutical composition of the present invention may be prepared according to a conventional manufacturing process of a solid oral dosage form, for example, direct compression, wet granulation, dry granulation, etc. Preferred method for preparing a pharmaceutical composition according to the present invention comprises the steps of: a) mixing nebivolol or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive to form a mixture; and b) formulating the mixture, wherein an alkalizing agent is added in step a) or b).
Preferably, the mixing step may comprise the step of mixing an active ingredient comprising an effective amount of nebivolol or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive to form a mixture and compressing the mixture to form granules. More preferably, granules may be prepared by a wet granulation method.
Preferably, the formulating step may comprise the step of mixing the granules prepared from the mixture with the remains of a pharmaceutically acceptable additive and compressing into tablets. In the manufacturing method according to the present invention, an alkalizing agent may be mixed with an active ingredient and an additive to be granulated in the mixing step, or post-mixed with granules prepared in the mixing step and the remains of a pharmaceutically acceptable additive in the formulating step.
In a further embodiment, the manufacturing method may further comprise the step of coating the formulated pharmaceutical composition by a conventional method.
The pharmaceutical composition of the present invention may further comprise an additional active ingredient for preventing or treating cardiovascular diseases such as hypertension, congestive heart failure, arteriosclerosis, metabolic disorder, endothelial dysfunction, etc. in addition to nebivolol or a pharmaceutically acceptable salt thereof. Examples of the additional active ingredient for preventing or treating cardiovascular diseases include, but not limited to, hydrochlorothiazide, ramipril, enalapril, lercanidipine, nisoldipine, amlodipine, losartan, eprosartan, candesartan, telmisartan, valsartan, olmesartan, rosuvastatin, atorvastatin, pravastatin, fluvastatin, lovastatin,
2016385282 29 Aug 2019 simvastatin or pharmaceutically acceptable salts thereof. In a preferred embodiment, the further active ingredient is rosuvastatin or a pharmaceutically acceptable salt thereof, more preferably, rosuvastatin calcium.
Mode for the Invention
Hereinafter, the present invention is explained in detail by Examples. The following Examples are intended to further illustrate the present invention without limiting its scope.
Examples 1 to 3
In accordance with the composition as described in Table 1, nebivolol hydrochloride was mixed with additives, and purified water with Tween 80 dissolved therein was added thereto. The mixture was used to prepare granules according to a wet granulation method. Subsequently, magnesium oxide, magnesium carbonate or magnesium aluminum silicate, as an alkalizing agent, and the remains of additives were post-mixed with the granules, and colloidal silicon dioxide and magnesium stearate, as a lubricant, were added thereto. The resultant was compressed into tablets (239.2 mg/tablet) using a tablet press (STP Machinery Co., Ltd., ZP198 Model) with a round punch having a diameter of 8.6 mm.
Table 1 below shows the amount of component per tablet.
[Table 1]
| Components | Process | Example 1 | Example 2 | Example 3 | |||
| mg/Tab | % | mg/Tab | % | mg/Tab | % | ||
| Nebivolol HCI | Wet granulation | 5.45 | 2.3 | 5.45 | 2.3 | 5.45 | 2.3 |
| Lactose monohydrate | 168.99 | 70.6 | 170.49 | 71.3 | 170.89 | 71.4 | |
| Microcrystalline cellulose | 46.00 | 19.2 | 46.00 | 19.2 | 46.00 | 19.2 | |
| Hypromellose 2910 | 4.60 | 1.9 | 4.60 | 1.9 | 4.60 | 1.9 | |
| Tween 80 | 0.46 | 0.2 | 0.46 | 0.2 | 0.46 | 0.2 | |
| Butylated hydroxyanisole | - | - | - | ||||
| Microcrystalline cellulose | Post-mixing | - | - | - | |||
| Sodium starch glycolate | 10.00 | 4.2 | 10.00 | 4.2 | 10.00 | 4.2 |
2016385282 29 Aug 2019
| Croscarmellose Na | - | - | - | ||||
| Magnesium oxide | 2.0 | 0.8 | 0.50 | 0.2 | 0.10 | 0.04 | |
| Magnesium aluminum silicate | - | - | - | ||||
| Magnesium carbonate | - | - | - | ||||
| Rosuvastatin Ca | - | - | - | ||||
| Colloidal silicon dioxide | Lubricant mixing | 0.50 | 0.2 | 0.50 | 0.2 | 0.50 | 0.2 |
| Magnesium stearate | 1.20 | 0.5 | 1.20 | 0.5 | 1.20 | 0.5 | |
| Ethanol | |||||||
| Water | 35.00 | 35.00 | 35.00 | ||||
| Opadry 03B28796 | |||||||
| Subtotal for wet granules | 225.50 | 227.00 | 227.40 | ||||
| Total | 239.20 | 100.0 | 239.20 | 100.0 | 239.20 | 100.0 |
Examples 4 and 5
In accordance with the composition as described in Table 2, nebivolol hydrochloride was mixed with additives, and purified water was added thereto. The mixture was used to prepare granules according to a wet granulation method. Subsequently, magnesium oxide, magnesium carbonate or magnesium aluminum silicate, as an alkalizing agent, and the remains of additives were post-mixed with the granules, and colloidal silicon dioxide and magnesium stearate, as a lubricant, were added thereto. The resultant was compressed into tablets (350.0 mg/tablet) using a tablet press (STP Machinery Co., Ltd., ZP198 Model) with a round punch having a diameter of 10 mm.
Examples 6 and 7
In accordance with the composition as described in Table 2, nebivolol hydrochloride was mixed with additives, and a mixture of purified water and ethanol with BHA and Tween 80 dissolved therein was added thereto. The mixture was used to prepare granules according to a wet granulation method. Subsequently, rosuvastatin calcium, magnesium aluminum silicate, as an alkalizing agent, and the remains of additives were post-mixed with the granules, and colloidal silicon dioxide and magnesium stearate, as a lubricant, were added thereto. The resultant was compressed into tablets (350.0 mg/tablet: Example 6; 147.0 mg/tablet: Example 7) using a tablet press (STP Machinery Co., Ltd., ZP198 Model) with a round punch having a diameter of 10 mm or 7.5 mm.
The tablets thus obtained were coated by spray coating with Opadry 03B28796 (Colorcon, Inc.) dissolved in 80% ethanol and water to produce film-coated tablets.
2016385282 29 Aug 2019
Table 2 below shows the amount of component per tablet.
[Table 2]
| Components | Process | Example 4 | Example 5 | Example 6 | Example 7 | ||||
| mg/Tab | % | mg/Tab | % | mg/Tab | % | mg/Tab | % | ||
| Nebivolol HC1 | Wet granulation | 5.45 | 1.6 | 5.45 | 1.6 | 5.45 | 1.5 | 5.45 | 3.6 |
| Lactose monohydrate | 185.35 | 53.0 | 189.35 | 54.1 | 162.32 | 44.8 | 68.33 | 45.0 | |
| Microcrystalline cellulose | 80.00 | 22.9 | 80.00 | 22.9 | 80.00 | 22.1 | 33.70 | 22.2 | |
| Hypromellose 2910 | 12.00 | 3.4 | 12.00 | 3.4 | 12.00 | 3.3 | 5.00 | 3.3 | |
| Tween 80 | 0.20 | 0.06 | 0.10 | 0.07 | |||||
| Butylated hydroxyanisole | - | - | 0.03 | 0.0 | 0.02 | 0.0 | |||
| Microcrystalline cellulose | Postmixing | 40.00 | 11.4 | 40.00 | 11.4 | 42.00 | 11.6 | 17.70 | 11.6 |
| Sodium starch glycolate | 15.00 | 4.3 | - | 15.00 | 4.1 | 6.30 | 4.1 | ||
| Croscarmellose Na | 15.00 | 4.3 | |||||||
| Magnesium oxide | - | - | - | ||||||
| Magnesium aluminum silicate | 7.00 | 2.0 | 7.00 | 1.9 | 3.00 | 2.0 | |||
| Magnesium carbonate | - | 3.00 | 0.9 | - | - | ||||
| Rosuvastatin Ca | - | - | 20.80 | 5.7 | 5.20 | 3.4 | |||
| Colloidal silicon dioxide | Lubricant mixing | 1.70 | 0.5 | 1.70 | 0.5 | 1.70 | 0.5 | 0.70 | 0.5 |
| Magnesium stearate | 3.50 | 1.0 | 3.50 | 1.0 | 3.50 | 1.0 | 1.50 | 1.0 | |
| Ethanol | 3.00 | 2.00 | |||||||
| Water | 45.00 | 45.00 | 41.00 | 18.00 | |||||
| Opadry 03B28796 | 12.0 | 3.3 | 5.0 | 3.3 | |||||
| Subtotal for wet granules | 282.80 | 286.80 | 260.00 | 112.60 | |||||
| Total | 350.00 | 100.0 | 350.00 | 100.0 | 362.0 | 100.0 | 152.0 | 100.0 |
2016385282 29 Aug 2019
Examples 8 and 9
In accordance with the composition as described in Table 3, nebivolol hydrochloride was mixed with additives, and a mixture of purified water and ethanol with Tween 80 dissolved therein was added thereto. The mixture was used to prepare granules according to a wet granulation method. Subsequently, rosuvastatin calcium, magnesium carbonate, as an alkalizing agent, and the remains of additives were postmixed with the granules, and colloidal silicon dioxide and magnesium stearate, as a lubricant, were added thereto. The resultant was compressed into tablets (350.0 mg/tablet) using a tablet press (STP Machinery Co., Ltd., ZP198 Model) with a round punch having a diameter of 10 mm.
The tablets thus obtained were coated by spray coating with Opadry 03F680010 (Colorcon, Inc.) dissolved in 80% ethanol to produce film-coated tablets.
[Table 3]
| Components | Process | Example 8 | Example 9 | ||
| mg/Tab | % | mg/Tab | % | ||
| Nebivolol HCI | Wet granulation | 5.45 | 1.5 | 5.45 | 1.5 |
| Lactose monohydrate | 162.35 | 44.8 | 162.35 | 44.8 | |
| Microcrystalline cellulose | 80.00 | 22.1 | 80.00 | 22.1 | |
| Hypromellose 2910 | 12.00 | 3.3 | 12.00 | 3.3 | |
| Tween 80 | 0.20 | 0.06 | 0.20 | 0.06 | |
| Microcrystalline cellulose | Post-mixing | 48.00 | 13.3 | 63.60 | 17.6 |
| Sodium starch glycolate | 15.00 | 4.1 | 15.00 | 4.1 | |
| Magnesium carbonate | 1.00 | 0.3 | 1.00 | 0.3 | |
| Rosuvastatin Ca | 20.80 | 5.7 | 5.20 | 1.4 | |
| Colloidal silicon dioxide | Lubricant mixing | 1.70 | 0.5 | 1.70 | 0.5 |
| Magnesium stearate | 3.50 | 1.0 | 3.50 | 1.0 | |
| Opadry 03F680010 | 12.00 | 3.3 | 12.00 | 3.3 | |
| Total | 362.00 | 100.0 | 362.00 | 100.0 |
Comparative Examples 1 to 3
In accordance with the composition as described in Table 4, nebivolol hydrochloride was mixed with additives, and purified water with Tween 80 dissolved therein (Comparative Examples 1 and 2) or purified water (Comparative Example 3)
2016385282 29 Aug 2019 was added thereto. The mixture was used to prepare granules according to a wet granulation method. Subsequently, the remains of additives were post-mixed with the granules, and colloidal silicon dioxide and magnesium stearate, as a lubricant, were added thereto. The resultant was compressed into tablets (239.2 mg/tablet: Comparative Example 1 similar to a commercial product; 350.0 mg/tablet: Comparative Examples 2 and 3) using a tablet press (STP Machinery Co., Ltd., ZP198 Model) with a round punch having a diameter of 8.6 mm or 10.0 mm.
[Table 4]
| Components | Process | Comparative Example 1 | Comparative Example 2 | Comparative Example 3 | |||
| mg/Tab | % | mg/Tab | % | mg/Tab | % | ||
| Nebivolol HC1 | Wet granulation | 5.45 | 2.3 | 5.45 | 1.6 | 5.45 | 1.6 |
| Lactose monohydrate | 141.75 | 59.3 | 191.89 | 54.8 | 192.35 | 55.0 | |
| Microcrystalline cellulose | 46.00 | 19.2 | 80.00 | 22.9 | 120.00 | 34.03 | |
| Hypromellose 2910 | 4.60 | 1.9 | 12.00 | 3.4 | 12.00 | 3.4 | |
| Tween 80 | 0.46 | 0.2 | 0.46 | 0.1 | - | ||
| Butylated hydroxyanisole | - | - | - | ||||
| Microcrystalline cellulose | Post-mixing | 23.00 | 9.6 | 40.00 | 11.4 | - | |
| Sodium starch glycolate | - | 15.00 | 4.3 | - | |||
| Croscarmellose Na | 16.10 | 6.7 | - | 15.00 | 4.3 | ||
| Magnesium oxide | - | - | - | ||||
| Magnesium aluminum silicate | - | - | - | ||||
| Magnesium carbonate | - | - | - | ||||
| Rosuvastatin Ca | - | - | - | ||||
| Colloidal silicon dioxide | Lubricant mixing | 0.69 | 0.3 | 1.70 | 0.5 | 1.70 | 0.5 |
| Magnesium stearate | 1.15 | 0.5 | 3.50 | 1.0 | 3.50 | 1.0 | |
| Ethanol | |||||||
| Water | 35.00 | 35.00 | 35.00 | ||||
| Opadry 03B28796 | |||||||
| Subtotal for wet granules | 198.26 | 289.80 | 329.80 | ||||
| Total | 239.20 | 100.0 | 350.00 | 100.0 | 350.00 | 100.0 |
Experimental Example: Dissolution test in water
Tablets prepared in Examples 1 to 6, 8 and 9 and Comparative Examples 1 to 3 were subjected to a drug dissolution test to determine the dissolution rate of nebivolol.
Dissolution test was performed at 50 rpm according to paddle method using water as a dissolution medium. 5 mL of each test solution taken at 5, 10, 15, 30, 45, 90 and 120 minutes after starting the test was filtered through a membrane filter and analyzed using HPLC under the following condition to calculate dissolution rate against the standard solution. Table 5 and Fig. 1 show the results.
- Analytical conditions of HPLC Detector: UV 225 nm
Column: Xbridge Cl8, 4.6 x 150 mm, 5 pm
Mobile phase: buffer/methanol (40/60) (Buffer: 3.4 g of tetrabutyl ammonium hydrogen sulfate dissolved in IL of water)
2016385282 29 Aug 2019
Flow rate: 1.0 mL/min
Injection volume: 20 μL [Table 5]
| Samples | 0 | 5 | 10 | 15 | 30 | 45 | 60 | 90 | 120 |
| Example 1 | 0.0 | 68.4 | 85.9 | 87.1 | 90.7 | 91.1 | 91.5 | 91.7 | 92.4 |
| Example 2 | 0.0 | 64.7 | 78.7 | 86.0 | 87.2 | 88.7 | 90.0 | 91.5 | 93.3 |
| Example 3 | 0.0 | 68.1 | 75.8 | 84.2 | 84.8 | 85.4 | 86.0 | 86.6 | 87.1 |
| Example 4 | 0.0 | 71.8 | 83.7 | 85.8 | 92.3 | 92.6 | 93.0 | 93.3 | 93.7 |
| Example 5 | 0.0 | 74.2 | 81.9 | 84.4 | 87.8 | 88.4 | 90.0 | 91.8 | 93.0 |
| Example 6 | 0.0 | 80.6 | 91.3 | 93.0 | 95.6 | 96.9 | 97.6 | 98.0 | 98.3 |
| Example 8 | 0.0 | 68.3 | 88.8 | 91.9 | 93.8 | - | - | - | - |
| Example 9 | 0.0 | 68.0 | 78.8 | 83.5 | 87.8 | - | - | - | - |
| Comparative Example 1 | 0.0 | 0.0 | 1.9 | 2.4 | 4.9 | 7.4 | 10.2 | 13.7 | 15.7 |
| Comparative Example 2 | 0.0 | 56.6 | 57.0 | 55.4 | 55.5 | 55.9 | 54.7 | 54.6 | 54.54 |
| Comparative Example 3 | 0.0 | 53.1 | 50.7 | 44.1 | 34.1 | 26.8 | 21.5 | 13.2 | 11.5 |
As confirmed in Table 5 and Fig. 1, all of the nebivolol preparations and the composite preparations comprising nebivolol and rosuvastatin according to the present invention showed excellent dissolution rates of 83% to 93% within 15 minutes after starting the test, while the tablets of Comparative Examples 1 to 3 prepared without adding alkalizing agents showed very low dissolution rates even at 2 hours after starting
2016385282 29 Aug 2019 the test.
Furthermore, it was confirmed that the composite preparations of nebivolol and rosuvastatin using magnesium carbonate as an alkalizing agent (Examples 8 and 9) as well as those using magnesium aluminum silicate (Examples 6 and 7) showed dissolution rates of 80% or higher at 15 minutes after starting the test.
The above results demonstrates that nebivolol preparations as well as composite preparations comprising nebivolol and an additional active ingredient for preventing or treating cardiovascular diseases may have the effect of improving dissolution rate of nebivolol in water of relatively high pH, regardless of the type of alkalizing agent.
Claims (10)
- CLAIMS:1. A solid oral pharmaceutical composition, comprising nebivolol or a pharmaceutically acceptable salt thereof, an alkalizing agent, and a pharmaceutically acceptable additive, wherein the alkalizing agent is at least one selected from the group consisting of magnesium oxide, magnesium carbonate and magnesium aluminum silicate.
- 2. The solid oral pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt of nebivolol is a nebivolol hydrochloride.
- 3. The solid oral pharmaceutical composition of claim 1 or 2, wherein the nebivolol or a pharmaceutically acceptable salt thereof is included in an amount of 0.2 to 10 parts by weight based on 100 parts by weight of the composition.
- 4. The solid oral pharmaceutical composition of any one of claims 1-3, wherein the alkalizing agent is included in an amount of 0.02 to 10 parts by weight based on 100 parts by weight of the composition.
- 5. The solid oral pharmaceutical composition of any one of claims 1 to 4, further comprising an additional active ingredient for preventing or treating cardiovascular diseases.
- 6. The solid oral pharmaceutical composition of claim 5, wherein the active ingredient for preventing or treating cardiovascular diseases is at least one selected from the group consisting of hydrochlorothiazide, ramipril, enalapril, lercanidipine, nisoldipine, amlodipine, losartan, eprosartan, candesartan, telmisartan, valsartan, olmesartan, rosuvastatin, atorvastatin, pravastatin, fluvastatin, lovastatin, simvastatin and pharmaceutically acceptable salts thereof.
- 7. The solid oral pharmaceutical composition of claim 6, wherein the active ingredient for preventing or treating cardiovascular diseases is rosuvastatin calcium.
- 8. The solid oral pharmaceutical composition of any one of claims 1-7, when used to prevent or treat cardiovascular diseases selected from the group consisting of hypertension and heart failure.
- 9. The solid oral pharmaceutical composition of claim 8, wherein the heart failure is congestive heart failure.2016385282 01 Nov 2019
- 10. A method for preparing the solid oral pharmaceutical composition of any one of claims 1-7, which comprises the steps of:a) mixing nebivolol or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive to form a mixture; andb) formulating the mixture, wherein an alkalizing agent is added in step a) or b) and is at least one selected from the group consisting of magnesium oxide, magnesium carbonate and magnesium aluminum silicate
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR20160002626 | 2016-01-08 | ||
| KR10-2016-0002626 | 2016-01-08 | ||
| KR10-2016-0171842 | 2016-12-15 | ||
| KR1020160171842A KR102203229B1 (en) | 2016-01-08 | 2016-12-15 | Pharmaceutical composition with improved dissolution rate comprising nebivolol |
| PCT/KR2016/014771 WO2017119629A1 (en) | 2016-01-08 | 2016-12-16 | Pharmaceutical composition comprising nebivolol with improved dissolution rate |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| AU2016385282A1 AU2016385282A1 (en) | 2018-08-23 |
| AU2016385282A2 AU2016385282A2 (en) | 2018-10-11 |
| AU2016385282B2 true AU2016385282B2 (en) | 2019-11-21 |
Family
ID=59430720
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2016385282A Active AU2016385282B2 (en) | 2016-01-08 | 2016-12-16 | Pharmaceutical composition comprising nebivolol with improved dissolution rate |
Country Status (6)
| Country | Link |
|---|---|
| KR (1) | KR102203229B1 (en) |
| CN (1) | CN108463250B (en) |
| AU (1) | AU2016385282B2 (en) |
| CA (1) | CA3010857C (en) |
| MX (1) | MX2018008443A (en) |
| MY (1) | MY201954A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024055984A1 (en) * | 2022-09-14 | 2024-03-21 | 上海云晟研新生物科技有限公司 | Nebivolol and amlodipine composition, preparation method therefor, and use thereof |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20070062507A (en) * | 2004-07-30 | 2007-06-15 | 토렌트 파마슈티칼스 리미티드 | Nebivolol and its pharmaceutically acceptable salts, process for preparation and pharmaceutical compositions of nebivolol |
| KR20080016527A (en) * | 2005-01-31 | 2008-02-21 | 밀란 래보러토리즈, 인크. | Pharmaceutical composition comprising hydroxylated nebivolol |
| KR20080025699A (en) * | 2005-05-31 | 2008-03-21 | 밀란 래보러토리즈, 인크. | Compositions comprising nebivolol |
| CN101361720A (en) * | 2008-10-08 | 2009-02-11 | 刘全胜 | Nebivolol hydrochloric acid orally disintegrating tablet and preparation method thereof |
| WO2010068789A1 (en) * | 2008-12-10 | 2010-06-17 | Transcept Pharmaceuticals, Inc. | Polyethylene glycol-coated sodium carbonate as a pharmaceutical excipient and compositions produced from the same |
| WO2011028016A2 (en) * | 2009-09-04 | 2011-03-10 | 한올바이오파마주식회사 | Pharmaceutical preparation comprising beta-adrenergic blockers and angiotensin ii receptor blockers |
| US20110250272A1 (en) * | 2007-08-31 | 2011-10-13 | Galenix Innovations | Solid, orodispersible and/or dispersible composition, without an excipient of known effect and its process of preparation |
| KR20110117758A (en) * | 2010-04-22 | 2011-10-28 | 한올바이오파마주식회사 | Pharmaceutical formulation comprising beta adrenoceptor-blockers and hmg-coa reductase inhibitors |
| KR20110130872A (en) * | 2010-05-28 | 2011-12-06 | 현대약품 주식회사 | Pharmaceutical composition comprising crystalline nebivolol hydrochloride and method for manufacturing the same |
| US20140057954A1 (en) * | 2012-08-22 | 2014-02-27 | Forest Laboratories Holdings Ltd. | Chemical composition |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101022791B (en) * | 2004-06-04 | 2011-11-16 | 麦兰实验室公司 | Compositions comprising nebivolol |
| CN100508971C (en) * | 2007-03-30 | 2009-07-08 | 北京福瑞康正医药技术研究所 | Medicine composition possessing vasodilation and beta1 receptor blocking effects |
| GB201003766D0 (en) * | 2010-03-05 | 2010-04-21 | Univ Strathclyde | Pulsatile drug release |
| CN102304103A (en) * | 2011-06-03 | 2012-01-04 | 郑州泰基鸿诺药物科技有限公司 | Fenofibrate acid salt, preparation method, pharmaceutical composition and application |
| CN103860492A (en) * | 2012-12-18 | 2014-06-18 | 重庆福安药业集团庆余堂制药有限公司 | Nebivolol hydrochloride oral solid drug composition and preparation method thereof |
| CN104688708B (en) * | 2013-12-06 | 2017-06-23 | 北京万生药业有限责任公司 | A kind of preparation method of Atorvastatin calcium preparation |
| CN103655454A (en) * | 2013-12-27 | 2014-03-26 | 辽宁亿灵科创生物医药科技有限公司 | Lansoprazole drug composition |
| CN103816124B (en) * | 2014-03-19 | 2016-08-17 | 国药集团致君（深圳）制药有限公司 | A kind of esomeprazole pastille pellet composition and preparation method thereof |
-
2016
- 2016-12-15 KR KR1020160171842A patent/KR102203229B1/en active IP Right Grant
- 2016-12-16 CA CA3010857A patent/CA3010857C/en active Active
- 2016-12-16 MY MYPI2018702352A patent/MY201954A/en unknown
- 2016-12-16 MX MX2018008443A patent/MX2018008443A/en unknown
- 2016-12-16 CN CN201680078111.1A patent/CN108463250B/en active Active
- 2016-12-16 AU AU2016385282A patent/AU2016385282B2/en active Active
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20070062507A (en) * | 2004-07-30 | 2007-06-15 | 토렌트 파마슈티칼스 리미티드 | Nebivolol and its pharmaceutically acceptable salts, process for preparation and pharmaceutical compositions of nebivolol |
| KR20080016527A (en) * | 2005-01-31 | 2008-02-21 | 밀란 래보러토리즈, 인크. | Pharmaceutical composition comprising hydroxylated nebivolol |
| KR20080025699A (en) * | 2005-05-31 | 2008-03-21 | 밀란 래보러토리즈, 인크. | Compositions comprising nebivolol |
| US20110250272A1 (en) * | 2007-08-31 | 2011-10-13 | Galenix Innovations | Solid, orodispersible and/or dispersible composition, without an excipient of known effect and its process of preparation |
| CN101361720A (en) * | 2008-10-08 | 2009-02-11 | 刘全胜 | Nebivolol hydrochloric acid orally disintegrating tablet and preparation method thereof |
| WO2010068789A1 (en) * | 2008-12-10 | 2010-06-17 | Transcept Pharmaceuticals, Inc. | Polyethylene glycol-coated sodium carbonate as a pharmaceutical excipient and compositions produced from the same |
| WO2011028016A2 (en) * | 2009-09-04 | 2011-03-10 | 한올바이오파마주식회사 | Pharmaceutical preparation comprising beta-adrenergic blockers and angiotensin ii receptor blockers |
| KR20110117758A (en) * | 2010-04-22 | 2011-10-28 | 한올바이오파마주식회사 | Pharmaceutical formulation comprising beta adrenoceptor-blockers and hmg-coa reductase inhibitors |
| KR20110130872A (en) * | 2010-05-28 | 2011-12-06 | 현대약품 주식회사 | Pharmaceutical composition comprising crystalline nebivolol hydrochloride and method for manufacturing the same |
| US20140057954A1 (en) * | 2012-08-22 | 2014-02-27 | Forest Laboratories Holdings Ltd. | Chemical composition |
Non-Patent Citations (2)
| Title |
|---|
| Pradeepthi et al, "Formulation and evaluation of gastro retentive floating tablets of nebivolol", International Journal of Inventions in Pharmaceutical Sciences (2014), Vol. 2, No. 5, pages 857-864 * |
| Swapna et al, "FORMULATION AND EVALUATION OF IMMEDIATE RELEASE TABLETS OF NEBIVOLOL HYDROCHLORIDE", World Journal of Pharmacy and Pharmaceutical Sciences (2015), Vol. 4, No. 1, Pages 687-698 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108463250B (en) | 2021-07-30 |
| AU2016385282A2 (en) | 2018-10-11 |
| CA3010857A1 (en) | 2017-07-13 |
| AU2016385282A1 (en) | 2018-08-23 |
| KR20170083484A (en) | 2017-07-18 |
| KR102203229B1 (en) | 2021-01-14 |
| MX2018008443A (en) | 2019-05-30 |
| CA3010857C (en) | 2020-09-15 |
| CN108463250A (en) | 2018-08-28 |
| MY201954A (en) | 2024-03-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2391348B1 (en) | Solid pharmaceutical composition comprising amlodipine and losartan with improved stability | |
| AU2007328630B2 (en) | Pharmaceutical composition comprising amlodipine and losartan | |
| EP2568972B1 (en) | Pharmaceutical formulation in the form of bilayered tablets comprising hmg-coa reductase inhibitor and irbesartan | |
| JP6895779B2 (en) | Azilsartan-containing solid pharmaceutical composition | |
| US20020107236A1 (en) | Methods of treating sexual dysfunction associated with hypertension | |
| AU2007297333A1 (en) | Solid dosage form of olmesartan medoxomil and amlodipine | |
| EP1978956A1 (en) | Complex formulation comprising amlodipine camsylate and simvastatin and method for preparation thereof | |
| KR20150138104A (en) | Pharmaceutical preperation containing Bepotastine and Glyceryl Behenate | |
| AU2016385282B2 (en) | Pharmaceutical composition comprising nebivolol with improved dissolution rate | |
| KR101171375B1 (en) | Oral solid dosage form comprising poorly soluble drugs | |
| TWI681773B (en) | Solid pharmaceutical composition comprising amlodipine and losartan | |
| EA028969B1 (en) | Method for the prevention and/or treatment of cardiovascular diseases | |
| AU2013346397B2 (en) | A pharmaceutical composition containing an ace inhibitor and a calcium channel blocker | |
| KR101920996B1 (en) | A Complex Formulation Comprising HMG-CoA Reductase Inhibitor and Calcium Channel Blocker | |
| JP5113476B2 (en) | Temocapril hydrochloride tablets with excellent storage stability | |
| JP7101464B2 (en) | A method for improving the quality of azilsartan or a salt thereof and amlodipine or a salt-containing tablet thereof, and azilsartan or a salt thereof and amlodipine or a salt-containing tablet thereof and a method for producing the same. | |
| US20030180354A1 (en) | Amlodipine maleate formulations | |
| EP3360542A1 (en) | Tablet forms of vilazodone hydrochloride | |
| EP4302755A1 (en) | Palbociclib formulation containing an amino acid | |
| WO2018163199A1 (en) | "sustained release compositions of ranolazine" | |
| JP2010516712A (en) | Pharmaceutical composition comprising nebivolol or a nebivolol analogue | |
| JP2021116284A (en) | Ezetimibe and atorvastatin-containing pharmaceutical composition | |
| WO2017119629A1 (en) | Pharmaceutical composition comprising nebivolol with improved dissolution rate | |
| KR20150078215A (en) | Pharmaceutical combination comprising eprosartan and amrodipine, and method of preparing the same | |
| EP3342400A1 (en) | A pharmaceutical composition comprising valsartan and chlorthalidone |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| DA3 | Amendments made section 104 |
Free format text: THE NATURE OF THE AMENDMENT IS AS SHOWN IN THE STATEMENT FILED 29 AUG 2018 |
|
| FGA | Letters patent sealed or granted (standard patent) |