WO2000069415A2 - Melt granulation - Google Patents
Melt granulation Download PDFInfo
- Publication number
- WO2000069415A2 WO2000069415A2 PCT/SI2000/000013 SI0000013W WO0069415A2 WO 2000069415 A2 WO2000069415 A2 WO 2000069415A2 SI 0000013 W SI0000013 W SI 0000013W WO 0069415 A2 WO0069415 A2 WO 0069415A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutical formulation
- formulation according
- clarithromycin
- prepared
- granulate
- Prior art date
Links
- 238000007909 melt granulation Methods 0.000 title claims abstract description 8
- 238000000576 coating method Methods 0.000 claims abstract description 16
- 239000011248 coating agent Substances 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 12
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 claims description 31
- 229960002626 clarithromycin Drugs 0.000 claims description 31
- 239000008194 pharmaceutical composition Substances 0.000 claims description 23
- 238000002360 preparation method Methods 0.000 claims description 17
- 239000008187 granular material Substances 0.000 claims description 14
- 239000000725 suspension Substances 0.000 claims description 14
- 229920000642 polymer Polymers 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- 239000000654 additive Substances 0.000 claims description 6
- 150000002632 lipids Chemical class 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 235000000346 sugar Nutrition 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 4
- 210000002784 stomach Anatomy 0.000 claims description 4
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 150000002191 fatty alcohols Chemical class 0.000 claims description 3
- 235000003599 food sweetener Nutrition 0.000 claims description 3
- 239000003765 sweetening agent Substances 0.000 claims description 3
- 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 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 235000013681 dietary sucrose Nutrition 0.000 claims description 2
- 229920003145 methacrylic acid copolymer Polymers 0.000 claims description 2
- 229920005862 polyol Polymers 0.000 claims description 2
- 150000003077 polyols Chemical class 0.000 claims description 2
- 229960004793 sucrose Drugs 0.000 claims description 2
- 208000035143 Bacterial infection Diseases 0.000 claims 1
- 230000000996 additive effect Effects 0.000 claims 1
- 208000022362 bacterial infectious disease Diseases 0.000 claims 1
- 238000000048 melt cooling Methods 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 238000011282 treatment Methods 0.000 claims 1
- 239000008203 oral pharmaceutical composition Substances 0.000 abstract description 9
- 235000019658 bitter taste Nutrition 0.000 abstract description 6
- 230000000873 masking effect Effects 0.000 abstract description 4
- 235000019640 taste Nutrition 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000003814 drug Substances 0.000 description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 239000003120 macrolide antibiotic agent Substances 0.000 description 8
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 229940041033 macrolides Drugs 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- GLDOVTGHNKAZLK-UHFFFAOYSA-N n-octadecyl alcohol Natural products CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 6
- 239000002245 particle Substances 0.000 description 5
- 239000008188 pellet Substances 0.000 description 5
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 4
- 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 4
- 229940100692 oral suspension Drugs 0.000 description 4
- 108010011485 Aspartame Proteins 0.000 description 3
- 229920003148 Eudragit® E polymer Polymers 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000000605 aspartame Substances 0.000 description 3
- 235000010357 aspartame Nutrition 0.000 description 3
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 3
- 229960003438 aspartame Drugs 0.000 description 3
- NEDGUIRITORSKL-UHFFFAOYSA-N butyl 2-methylprop-2-enoate;2-(dimethylamino)ethyl 2-methylprop-2-enoate;methyl 2-methylprop-2-enoate Chemical compound COC(=O)C(C)=C.CCCCOC(=O)C(C)=C.CN(C)CCOC(=O)C(C)=C NEDGUIRITORSKL-UHFFFAOYSA-N 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 229960003276 erythromycin Drugs 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- MIDXCONKKJTLDX-UHFFFAOYSA-N 3,5-dimethylcyclopentane-1,2-dione Chemical compound CC1CC(C)C(=O)C1=O MIDXCONKKJTLDX-UHFFFAOYSA-N 0.000 description 2
- XPCTZQVDEJYUGT-UHFFFAOYSA-N 3-hydroxy-2-methyl-4-pyrone Chemical compound CC=1OC=CC(=O)C=1O XPCTZQVDEJYUGT-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- 229910002012 Aerosil® Inorganic materials 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 235000013736 caramel Nutrition 0.000 description 2
- 229960001631 carbomer Drugs 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004040 coloring Methods 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000845 maltitol Substances 0.000 description 2
- 235000010449 maltitol Nutrition 0.000 description 2
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 2
- 229940035436 maltitol Drugs 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 2
- 239000004172 quinoline yellow Substances 0.000 description 2
- IZMJMCDDWKSTTK-UHFFFAOYSA-N quinoline yellow Chemical compound C1=CC=CC2=NC(C3C(C4=CC=CC=C4C3=O)=O)=CC=C21 IZMJMCDDWKSTTK-UHFFFAOYSA-N 0.000 description 2
- 229940051201 quinoline yellow Drugs 0.000 description 2
- 235000012752 quinoline yellow Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 229960002920 sorbitol Drugs 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 239000004408 titanium dioxide Substances 0.000 description 2
- 239000001069 triethyl citrate Substances 0.000 description 2
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 2
- 235000013769 triethyl citrate Nutrition 0.000 description 2
- 239000008371 vanilla flavor Substances 0.000 description 2
- 239000000811 xylitol Substances 0.000 description 2
- 235000010447 xylitol Nutrition 0.000 description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 2
- 229960002675 xylitol Drugs 0.000 description 2
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical class O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-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
- 239000005995 Aluminium silicate Substances 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 208000019505 Deglutition disease Diseases 0.000 description 1
- PYGXAGIECVVIOZ-UHFFFAOYSA-N Dibutyl decanedioate Chemical compound CCCCOC(=O)CCCCCCCCC(=O)OCCCC PYGXAGIECVVIOZ-UHFFFAOYSA-N 0.000 description 1
- 206010013911 Dysgeusia Diseases 0.000 description 1
- 239000004150 EU approved colour Substances 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 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
- 229920003138 Eudragit® L 30 D-55 Polymers 0.000 description 1
- 229920003136 Eudragit® L polymer Polymers 0.000 description 1
- 229920003137 Eudragit® S polymer Polymers 0.000 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 229920002907 Guar gum 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
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- HYMLWHLQFGRFIY-UHFFFAOYSA-N Maltol Natural products CC1OC=CC(=O)C1=O HYMLWHLQFGRFIY-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- GWFGDXZQZYMSMJ-UHFFFAOYSA-N Octadecansaeure-heptadecylester Natural products CCCCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCCCC GWFGDXZQZYMSMJ-UHFFFAOYSA-N 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 244000299461 Theobroma cacao Species 0.000 description 1
- 235000005764 Theobroma cacao ssp. cacao Nutrition 0.000 description 1
- 235000005767 Theobroma cacao ssp. sphaerocarpum Nutrition 0.000 description 1
- 244000290333 Vanilla fragrans Species 0.000 description 1
- 235000009499 Vanilla fragrans Nutrition 0.000 description 1
- 235000012036 Vanilla tahitensis Nutrition 0.000 description 1
- -1 acetal diethylaminoacetate Chemical class 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- PZZYQPZGQPZBDN-UHFFFAOYSA-N aluminium silicate Chemical compound O=[Al]O[Si](=O)O[Al]=O PZZYQPZGQPZBDN-UHFFFAOYSA-N 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 229910000323 aluminium silicate Inorganic materials 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- 235000001046 cacaotero Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 229940082500 cetostearyl alcohol Drugs 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000008369 fruit flavor Substances 0.000 description 1
- 229920001002 functional polymer Polymers 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 150000002596 lactones Chemical group 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229940091250 magnesium supplement Drugs 0.000 description 1
- 229940043353 maltol Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- NKBWPOSQERPBFI-UHFFFAOYSA-N octadecyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCCCC NKBWPOSQERPBFI-UHFFFAOYSA-N 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 239000006069 physical mixture Substances 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
Definitions
- the present invention belongs to the field of pharmaceutical technology and discloses melt granulation.
- the present invention discloses a simple one-step process for coating clarithromycin or derivatives thereof by means of melt granulation in order to effectively cover their bitterness, as well as a new, patient- friendly oral pharmaceutical formulation suitable also for diabetics, which at the same time also enables variations in the rate and site of the release of the active component.
- Clarithromycin is a slightly basic, practically water-insoluble, acid-sensitive macrolide antibiotic with a very bitter taste that remains in the mouth for several hours after taking a therapeutical dose.
- the commercially available oral suspension with clarithromycin contains a considerable amount of sugar (which does not eliminate the bitter aftertaste), but it still has a relatively unpleasant taste. Moreover, the technology of the preparation thereof is a multistep one and hence expensive.
- the present invention arises from the need to prepare an oral suspension with clarithromycin or derivatives thereof, which will be tasty, effective and obtainable by means of a one-step process.
- Clarithromycin is a semi-synthetic antibiotic obtained by methylation of erythromycin in the lactone position C6. The synthesis is described in US 4,331,803 and US 4,672,109. It is active against gram-positive bacteria and, due to the broad spectrum of antimicrobial activity, it is used clinically. On the market it is available in the form of coated tablets, suspensions and prolonged-release tablets.
- JP 85/163823 discloses an oral medicament with clarithromycin, citric acid increasing the abso ⁇ tion of antibiotic in the alimentary tract, disintegrants, excipients and lubricants.
- EP 0277042 discloses an oral pharmaceutical formulation (also with macrolides) with an improved taste and having a coating of particular polymers (especially polyvinyl acetal diethylaminoacetate - AEA), soluble in gastric juice and with a mean particle diameter under 60 ⁇ m.
- US 4,808,411 discloses a pharmaceutical formulation with erythromycin or its derivatives and a carbomer, possibly in the form of ion-complex particles coated with a polymer, which can be suspended in a liquid carrier.
- JP 01-308,223 discloses the preparation of film-coated microgranules of a sustained- release medicament containing AEA and water in addition to clarithromycin.
- EP 0302370 and WO 90/08537 disclose improved oral pharmaceutical formulations (oil solution, suspension, emulsion) of erythromycin and derivatives to be filled into soft gelatine capsules with N-methyl-pyrrolidone.
- EP-B-0420992 discloses a process for the production of an oral pharmaceutical formulation (also with macrolides) with a masked taste, which comprises spraying a medicament suspension into a cold water solution of AEA.
- JP 02-279,622 discloses oral medicaments with AEA, prepared by a fine granulation of a medicament (clarithromycin) dispersed in a melted oil base (cacao butter), followed by suspending the fine particles in a water solution of AEA and spray-drying the suspension.
- AEA a fine granulation of a medicament (clarithromycin) dispersed in a melted oil base (cacao butter), followed by suspending the fine particles in a water solution of AEA and spray-drying the suspension.
- US 5,017,383 discloses a method for the production of a finely coated pharmaceutical formulation, which comprises mixing frozen particles of a liquid medium with a medicament (also with macrolides) and a coating in the form of a fine powder adhering onto the surface of the particles.
- JP 05-255,075 discloses melt granulation of macrolides, wherein the coating consists of polymers soluble in stomach (particularly Eudragit E), which are dispersed in compounds with a low melting point.
- the final granulation is performed by spraying.
- the final preparation of a dry syrup is accomplished by mixing granules with sugar and hydroxypropyl methyl cellulose (HPMC).
- US 5,599,556 and US 5,609,909 disclose the masking of the taste of encapsulated clarithromycin particles with prolamine coatings prior to the preparation of a suspension.
- WO 96/34628 discloses an oral pharmaceutical formulation (also with macrolides) for masking the taste (particularly a dry syrup), which contains a medicament with an unpleasant taste, a higher polymer soluble in stomach (particularly AEA and Eudragit E) and a monoglyceride with a low melting point (particularly glyceryl monostearate) in the stable crystal form ⁇ (transformed from the metastable form ⁇ by additional shaking at increased temperature), and a method of masking the taste.
- WO 97/16174 discloses a process of water granulation of a macrolide antibiotic with a carbomer (acrylic polymer).
- US 5,705,190 discloses a controlled-release solid oral pharmaceutical formulation (also of clarithromycin) containing a medicament weakly soluble in water, a water- soluble alginate salt, a complex salt of alginic acid with a metal cation and an organic carboxylic acid facilitating the dissolution of the medicament.
- US 5,707,646 discloses a pharmaceutical formulation (also with macrolides) for oral use (particularly a dry syrup) containing a medicament with an unpleasant taste, a functional polymer (particularly AEA or/and Eudragit E) in a substance with a melting point of 40-120 °C, a sugar alcohol (e.g. sorbitol) and a basic oxide (particularly MgO).
- a pharmaceutical formulation also with macrolides
- a dry syrup containing a medicament with an unpleasant taste
- a functional polymer particularly AEA or/and Eudragit E
- a sugar alcohol e.g. sorbitol
- a basic oxide particularly MgO
- WO 98/46239 discloses a delayed-release pharmaceutical formulation containing an erythromycin derivative and a hydrophilic water-soluble polymer, which in oral use has an improved taste profile and fewer gastrointestinal side effects in comparison with the common form.
- the preparation technology includes, inter alia, wet granulation, drying, sieving and milling processes.
- the aim of the present invention is a new oral pharmaceutical formulation with clarithromycin or derivatives thereof.
- clarithromycin which may be present alone or in a homogeneuos mixture with conventional adjuvants, with a lipid film- forming substance having a low melting point (below 100 °C).
- the granulate was prepared in the melt in a mixer-granulator, thus in one step and in one vessel without the use of any solvents. From the granulate various conventional final pharmaceutical formulations such as suspensions in concentrations of 125 mg/5 ml and 250 mg/5 ml, tablets or capsules can be prepared.
- the base for coating can be clarithromycin itself or its mixture with excipients such as lactose, calcium carbonate, sodium hydrogen phosphate, NaCl, citric acid, PEG or stomach-insoluble polymers such as Eudragit L or S (1:1 or 1 :2 copolymer of methacrylic acid and MMA), microcrystalline cellulose etc.
- excipients such as lactose, calcium carbonate, sodium hydrogen phosphate, NaCl, citric acid, PEG or stomach-insoluble polymers such as Eudragit L or S (1:1 or 1 :2 copolymer of methacrylic acid and MMA), microcrystalline cellulose etc.
- the weight ratio between clarithromycin and these excipients amounts from 5: 1 to 1 : 1.2
- lipid film-forming substance almost insoluble in water there can be used a higher fatty alcohol, preferably stearyl, cetostearyl or cetyl alcohol or a suitable acid such as stearic acid or a physical mixture or an ester of several such components e.g. stearyl stearate.
- a higher fatty alcohol preferably stearyl, cetostearyl or cetyl alcohol or a suitable acid such as stearic acid or a physical mixture or an ester of several such components e.g. stearyl stearate.
- the weight ratio between clarithromycin and these excipients amounts from 2: 1 to 1 :2.
- the melt granulation is performed in such a way that a mixture of clarithromycin (possibly with addition of adjuvants) and of the lipid for coating is heated in a granulator under mixing to the melting point of the lipid component and then the obtained granulate is slowly cooled.
- viscosity enhancers and stabilizers such as xanthan gum, guar gum, silica gel, magnesium aluminium silicate etc.
- sugar or sweetening agents such as aspartame, sodium saccharinate or erythritol, caramel, vanilla or fruit flavours and colouring agents can also be added.
- all the cited additives for the preparation of suspensions cannot cover the bitterness of clarithromycin by themselves.
- the pharmaceutical formulation of the present invention can be improved by using polyols instead of sugar, which makes it also suitable for diabetics.
- polyols instead of sugar
- e.g. xylitol and mannitol and their combinations with maltitol, maltol and sorbitol can be used.
- the present pharmaceutical formulation represents the only oral suspension with clarithromycin, which is not based on sugar (saccharose).
- Fatty alcohols such as stearyl alcohol possess, in proportion to their concentration, a delaying effect on the release of the active component from the pharmaceutical formulation. This property can be used for controlling the clarithromycin release rate and an oral suspension with delayed action can be prepared.
- a gastroresistant layer onto the granulate base from the melt, the site of clarithromycin release in the alimentary tract can be affected.
- Polymers forming a gastroresistant coating such as shellac, cellulose acetate phthalate, HPMC phthalate, ethylcellulose latex, polymethacrylates etc. can be used therefor.
- the preparation of the granulate was identical to that of Examples 1 or 2. Additionally, a gastroresistant coating was applied; for 200 mg of pellet cores the following dispersion was prepared:
- the preparation of the granulate was identical to the one of Examples 1 or 2. Additionally, a gastroresistant coating was applied; for 500 mg of pellet cores the following water dispersion was prepared: Eudragit L 30 D-55 48.612 mg triethyl citrate 0.893 mg talc 0.495 mg water 332.143 mg
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Communicable Diseases (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Liquid Deposition Of Substances Of Which Semiconductor Devices Are Composed (AREA)
- Glanulating (AREA)
- Crystals, And After-Treatments Of Crystals (AREA)
Abstract
The present invention discloses a simple one-step process of coating by means of melt granulation for effective masking of bitterness, and a new, patient-friendly oral pharmaceutical formulation suitable also for diabetics, which at the same time also enables variations in the rate and site of the release of the active component.
Description
MELT GRANULATION
Technical Field
International Patent Classification: A 61 J 3/02, C 07 G 11/00
The present invention belongs to the field of pharmaceutical technology and discloses melt granulation.
More specifically, the present invention discloses a simple one-step process for coating clarithromycin or derivatives thereof by means of melt granulation in order to effectively cover their bitterness, as well as a new, patient- friendly oral pharmaceutical formulation suitable also for diabetics, which at the same time also enables variations in the rate and site of the release of the active component.
Technical Problem
Clarithromycin is a slightly basic, practically water-insoluble, acid-sensitive macrolide antibiotic with a very bitter taste that remains in the mouth for several hours after taking a therapeutical dose.
Since some groups of patients (children, the elderly, patients with swallowing disorders) cannot take solid medical preparations (tablets, capsules) and the same groups are also very sensitive to the (un)acceptable taste of a medical preparation, there existed a need to find an effective technological solution to cover or mask the bitter taste of clarithromycin or its derivatives, i.e. a need to prepare a suspension for oral use, which will be both patient-friendly and therapeutically effective.
The commercially available oral suspension with clarithromycin contains a considerable amount of sugar (which does not eliminate the bitter aftertaste), but it
still has a relatively unpleasant taste. Moreover, the technology of the preparation thereof is a multistep one and hence expensive.
Thus, the present invention arises from the need to prepare an oral suspension with clarithromycin or derivatives thereof, which will be tasty, effective and obtainable by means of a one-step process.
Prior Art
Clarithromycin is a semi-synthetic antibiotic obtained by methylation of erythromycin in the lactone position C6. The synthesis is described in US 4,331,803 and US 4,672,109. It is active against gram-positive bacteria and, due to the broad spectrum of antimicrobial activity, it is used clinically. On the market it is available in the form of coated tablets, suspensions and prolonged-release tablets.
Different oral pharmaceutical formulations with clarithromycin are also described in the following patents:
JP 85/163823 discloses an oral medicament with clarithromycin, citric acid increasing the absoφtion of antibiotic in the alimentary tract, disintegrants, excipients and lubricants.
EP 0277042 discloses an oral pharmaceutical formulation (also with macrolides) with an improved taste and having a coating of particular polymers (especially polyvinyl acetal diethylaminoacetate - AEA), soluble in gastric juice and with a mean particle diameter under 60 μm.
US 4,808,411 discloses a pharmaceutical formulation with erythromycin or its derivatives and a carbomer, possibly in the form of ion-complex particles coated with a polymer, which can be suspended in a liquid carrier.
JP 01-308,223 discloses the preparation of film-coated microgranules of a sustained- release medicament containing AEA and water in addition to clarithromycin.
EP 0302370 and WO 90/08537 disclose improved oral pharmaceutical formulations (oil solution, suspension, emulsion) of erythromycin and derivatives to be filled into soft gelatine capsules with N-methyl-pyrrolidone.
EP-B-0420992 discloses a process for the production of an oral pharmaceutical formulation (also with macrolides) with a masked taste, which comprises spraying a medicament suspension into a cold water solution of AEA.
JP 02-279,622 discloses oral medicaments with AEA, prepared by a fine granulation of a medicament (clarithromycin) dispersed in a melted oil base (cacao butter), followed by suspending the fine particles in a water solution of AEA and spray-drying the suspension.
US 5,017,383 discloses a method for the production of a finely coated pharmaceutical formulation, which comprises mixing frozen particles of a liquid medium with a medicament (also with macrolides) and a coating in the form of a fine powder adhering onto the surface of the particles.
JP 05-255,075 discloses melt granulation of macrolides, wherein the coating consists of polymers soluble in stomach (particularly Eudragit E), which are dispersed in compounds with a low melting point. The final granulation is performed by spraying. The final preparation of a dry syrup is accomplished by mixing granules with sugar and hydroxypropyl methyl cellulose (HPMC).
US 5,599,556 and US 5,609,909 disclose the masking of the taste of encapsulated clarithromycin particles with prolamine coatings prior to the preparation of a suspension.
WO 96/34628 discloses an oral pharmaceutical formulation (also with macrolides) for masking the taste (particularly a dry syrup), which contains a medicament with an unpleasant taste, a higher polymer soluble in stomach (particularly AEA and Eudragit E) and a monoglyceride with a low melting point (particularly glyceryl monostearate) in the stable crystal form β (transformed from the metastable form α by additional shaking at increased temperature), and a method of masking the taste.
WO 97/16174 discloses a process of water granulation of a macrolide antibiotic with a carbomer (acrylic polymer).
US 5,705,190 discloses a controlled-release solid oral pharmaceutical formulation (also of clarithromycin) containing a medicament weakly soluble in water, a water- soluble alginate salt, a complex salt of alginic acid with a metal cation and an organic carboxylic acid facilitating the dissolution of the medicament.
US 5,707,646 discloses a pharmaceutical formulation (also with macrolides) for oral use (particularly a dry syrup) containing a medicament with an unpleasant taste, a functional polymer (particularly AEA or/and Eudragit E) in a substance with a melting point of 40-120 °C, a sugar alcohol (e.g. sorbitol) and a basic oxide (particularly MgO).
WO 98/46239 discloses a delayed-release pharmaceutical formulation containing an erythromycin derivative and a hydrophilic water-soluble polymer, which in oral use has an improved taste profile and fewer gastrointestinal side effects in comparison with the common form. The preparation technology includes, inter alia, wet granulation, drying, sieving and milling processes.
Thus, numerous publications exist in the patent and other literature in that field disclosing the composition and preparation of various pharmaceutical formulations with clarithromycin. However, we have not found any literature source disclosing such a simple process for the preparation of a clarithromycin suspension having such a
simple composition, a good smell and taste as well as a possibility of upgrading for diabetics. Additionally, it also enables the controlling of the rate and the site of the release of the active component.
Technical Solution
The aim of the present invention is a new oral pharmaceutical formulation with clarithromycin or derivatives thereof. Surprisingly, the bitter taste of clarithromycin has been very successfully masked by coating clarithromycin, which may be present alone or in a homogeneuos mixture with conventional adjuvants, with a lipid film- forming substance having a low melting point (below 100 °C). The granulate was prepared in the melt in a mixer-granulator, thus in one step and in one vessel without the use of any solvents. From the granulate various conventional final pharmaceutical formulations such as suspensions in concentrations of 125 mg/5 ml and 250 mg/5 ml, tablets or capsules can be prepared.
The base for coating can be clarithromycin itself or its mixture with excipients such as lactose, calcium carbonate, sodium hydrogen phosphate, NaCl, citric acid, PEG or stomach-insoluble polymers such as Eudragit L or S (1:1 or 1 :2 copolymer of methacrylic acid and MMA), microcrystalline cellulose etc. The weight ratio between clarithromycin and these excipients amounts from 5: 1 to 1 : 1.2
As the lipid film-forming substance almost insoluble in water there can be used a higher fatty alcohol, preferably stearyl, cetostearyl or cetyl alcohol or a suitable acid such as stearic acid or a physical mixture or an ester of several such components e.g. stearyl stearate. The weight ratio between clarithromycin and these excipients amounts from 2: 1 to 1 :2.
The melt granulation is performed in such a way that a mixture of clarithromycin (possibly with addition of adjuvants) and of the lipid for coating is heated in a granulator under mixing to the melting point of the lipid component and then the
obtained granulate is slowly cooled. For the final preparation of the granulate for suspensions there are also added viscosity enhancers and stabilizers such as xanthan gum, guar gum, silica gel, magnesium aluminium silicate etc. For a better taste, smell and appearance, sugar or sweetening agents such as aspartame, sodium saccharinate or erythritol, caramel, vanilla or fruit flavours and colouring agents can also be added. However, all the cited additives for the preparation of suspensions cannot cover the bitterness of clarithromycin by themselves.
The pharmaceutical formulation of the present invention can be improved by using polyols instead of sugar, which makes it also suitable for diabetics. For this purpose e.g. xylitol and mannitol and their combinations with maltitol, maltol and sorbitol can be used. Thus, the present pharmaceutical formulation represents the only oral suspension with clarithromycin, which is not based on sugar (saccharose).
Fatty alcohols such as stearyl alcohol possess, in proportion to their concentration, a delaying effect on the release of the active component from the pharmaceutical formulation. This property can be used for controlling the clarithromycin release rate and an oral suspension with delayed action can be prepared.
Additionally or optionally, by applying a gastroresistant layer onto the granulate base from the melt, the site of clarithromycin release in the alimentary tract can be affected. Polymers forming a gastroresistant coating such as shellac, cellulose acetate phthalate, HPMC phthalate, ethylcellulose latex, polymethacrylates etc. can be used therefor.
The present invention is illustrated but in no way limited by the following Examples:
Example 1
In a mixer-granulator 2 kg of clarithromycin and 2 kg of stearyl alcohol were homogeneously mixed. During mixing it was heated to the melting point and a
chopper was switched on. Then it was cooled under constant mixing. Spherical granules/pellets were formed. Dry additives were added thereto.
Dry additives per vial or per 5.00 g of clarithromycin-stearyl granulate (pellets):
Na2HP04 1.000 g
NaCl 1.000 g aspartame 0.100 g aerosil 0.400 g vanilla flavour 0.070 g ammonium glycirhizinate 0.140 g xylitol 60.690 g methyl hydroxybenzoate 0.260 g titanium dioxide 0.050 g quinoline yellow colouring agent 0.010 g
total dry matter per vial 69.000 g water added 55.000 g suspension volume obtained 100.000 ml suspension content 125 mg clarithromycin /5 ml
Example 2
The process was identical to that of Example 1, only that 1.25 kg of clarithromycin, 1.25 kg of stearic acid and 1.5 kg of NaH2P04 were homogeneously mixed.
Dry additives per vial or per 7.2 g of clarithromycin-coated granulate (pellets):
NaCl 1.000 g aspartame 0.100 g aerosil 0.400 g
caramel flavour 0.070 g erytritol 0.140 g maltitol 60.690 g methyl hydroxybenzoate 0.260 g titanium dioxide 0.050 g quinoline yellow colouring agent 0.010 g citric acid 0.010 g
Example 3
The preparation of the granulate was identical to that of Examples 1 or 2. Additionally, a gastroresistant coating was applied; for 200 mg of pellet cores the following dispersion was prepared:
HPMC phthalate 55 48.612 mg dibutyl sebacate 0.893 mg talc 0.495 mg ethanol 332.143 mg acetone 332.143 mg
If a gastroresistant coating was applied, the amount of the sweetening agent was reduced for 50 mg; otherwise the preparation of the final suspension was identical to the one of Example 1.
Example 4
The preparation of the granulate was identical to the one of Examples 1 or 2. Additionally, a gastroresistant coating was applied; for 500 mg of pellet cores the following water dispersion was prepared:
Eudragit L 30 D-55 48.612 mg triethyl citrate 0.893 mg talc 0.495 mg water 332.143 mg
The preparation of the water dispersion: triethyl citrate, talc and the antifoaming agent were dispersed in water and homogenized. Immediately before use, it was added under stirring into the Eudragit dispersion and filtered.
Claims
1. Pharmaceutical formulation in the form of a granulate for oral use, characterized in that it contains clarithromycin or its derivatives coated with a lipid substance.
2. Pharmaceutical formulation according to claim 1, characterized in that clarithromycin or its derivative is admixed with other pharmaceutically acceptable additives.
3. Pharmaceutical formulation according to claim 2, characterized in that the pharmaceutically acceptable additive is a polymer insoluble in stomach.
4. Pharmaceutical formulation according to claim 3, characterized in that the polymer insoluble in stomach is a copolymer of methacrylic acid and methyl methacrylate.
5. Pharmaceutical formulation according to claim 1, characterized in that the lipid substance is a higher fatty alcohol or a suitable acid or a mixture thereof.
6. Pharmaceutical formulation according to claim 1, characterized in that it is, by the addition of other pharmaceutically acceptable substances, prepared in the form of tablets or capsules.
7. Pharmaceutical formulation according to claim 1, characterized in that it is, by the addition of other pharmaceutically acceptable substances, prepared in the form of a suspension.
8. Pharmaceutical formulation according to claim 7, characterized in that it is prepared without sugar (saccharose).
9. Pharmaceutical formulation according to claim 7, characterized in that polyols are added as sweetening agents.
10. Pharmaceutical formulation according to any of claims 1 to 6, characterized in that, additionally, a gastroresistant coating is applied.
11. A process for the preparation of a pharmaceutical formulation according to claim 1, characterized in that it comprises a homogeneous mixing of a coating mixture, melt granulation, cooling and an addition of other excipients for the formation of a granulate.
12. A process for the preparation of a pharmaceutical formulation according to claim 11, characterized in that it is completed by applying a gastroresistant coating.
13. Pharmaceutical formulation in granulate form for oral use, characterized in that it is prepared according to the process of claim 11.
14. Pharmaceutical formulation according to claim 1 useful for the treatment and prophylaxis of bacterial infections.
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SK1664-2001A SK16642001A3 (en) | 1999-05-19 | 2000-05-18 | Pharmaceutical formulation in granular form |
| EP00931886A EP1183013A2 (en) | 1999-05-19 | 2000-05-18 | Melt granulation |
| AU49697/00A AU4969700A (en) | 1999-05-19 | 2000-05-18 | Melt granulation |
| EEP200100607A EE200100607A (en) | 1999-05-19 | 2000-05-18 | Pharmaceutical composition in granular form and a process for its preparation |
| PL00351654A PL351654A1 (en) | 1999-05-19 | 2000-05-18 | Melt granulation |
| HR20010932A HRP20010932A2 (en) | 1999-05-19 | 2001-12-18 | Melt granulation |
| BG106236A BG106236A (en) | 1999-05-19 | 2001-12-19 | Melt granulation |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SIP-9900119 | 1999-05-19 | ||
| SI9900119A SI20244A (en) | 1999-05-19 | 1999-05-19 | Melt granulation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2000069415A2 true WO2000069415A2 (en) | 2000-11-23 |
| WO2000069415A3 WO2000069415A3 (en) | 2001-04-26 |
Family
ID=20432471
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/SI2000/000013 WO2000069415A2 (en) | 1999-05-19 | 2000-05-18 | Melt granulation |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP1183013A2 (en) |
| AU (1) | AU4969700A (en) |
| BG (1) | BG106236A (en) |
| CZ (1) | CZ20014133A3 (en) |
| EE (1) | EE200100607A (en) |
| HR (1) | HRP20010932A2 (en) |
| HU (1) | HUP0201233A3 (en) |
| PL (1) | PL351654A1 (en) |
| RU (1) | RU2001134166A (en) |
| SI (1) | SI20244A (en) |
| SK (1) | SK16642001A3 (en) |
| WO (1) | WO2000069415A2 (en) |
| YU (1) | YU82001A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001072284A1 (en) * | 2000-03-28 | 2001-10-04 | Biochemie Gesellschaft M.B.H. | Granulated particles with masked taste |
| EP1333807A2 (en) * | 2000-10-13 | 2003-08-13 | Advancis Pharmaceuticals | Extended release erythromycin derivatives |
| EP1484056A1 (en) * | 2002-02-21 | 2004-12-08 | Otsuka Pharmaceutical Co., Ltd. | Sustained release preparations and process for producing the same |
| US7943585B2 (en) | 2003-12-22 | 2011-05-17 | Sandoz, Inc. | Extended release antibiotic composition |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991019486A1 (en) * | 1990-06-14 | 1991-12-26 | Kalmo Enterprises, Inc. | Stable aqueous drug suspensions |
| WO1993017667A1 (en) * | 1992-03-12 | 1993-09-16 | Taisho Pharmaceutical Co., Ltd. | Composition for oral preparations |
| WO1994012157A1 (en) * | 1992-11-30 | 1994-06-09 | Kv Pharmaceutical Company | Tastemasked pharmaceutical materials |
| WO2000061119A2 (en) * | 1999-04-09 | 2000-10-19 | Pharmaplus S.R.L. | A process for the microencapsulation of medicaments |
-
1999
- 1999-05-19 SI SI9900119A patent/SI20244A/en not_active IP Right Cessation
-
2000
- 2000-05-18 SK SK1664-2001A patent/SK16642001A3/en unknown
- 2000-05-18 WO PCT/SI2000/000013 patent/WO2000069415A2/en not_active Application Discontinuation
- 2000-05-18 EE EEP200100607A patent/EE200100607A/en unknown
- 2000-05-18 RU RU2001134166/14A patent/RU2001134166A/en not_active Application Discontinuation
- 2000-05-18 AU AU49697/00A patent/AU4969700A/en not_active Abandoned
- 2000-05-18 YU YU82001A patent/YU82001A/en unknown
- 2000-05-18 CZ CZ20014133A patent/CZ20014133A3/en unknown
- 2000-05-18 PL PL00351654A patent/PL351654A1/en not_active Application Discontinuation
- 2000-05-18 EP EP00931886A patent/EP1183013A2/en not_active Withdrawn
- 2000-05-18 HU HU0201233A patent/HUP0201233A3/en unknown
-
2001
- 2001-12-18 HR HR20010932A patent/HRP20010932A2/en not_active Application Discontinuation
- 2001-12-19 BG BG106236A patent/BG106236A/en unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991019486A1 (en) * | 1990-06-14 | 1991-12-26 | Kalmo Enterprises, Inc. | Stable aqueous drug suspensions |
| WO1993017667A1 (en) * | 1992-03-12 | 1993-09-16 | Taisho Pharmaceutical Co., Ltd. | Composition for oral preparations |
| WO1994012157A1 (en) * | 1992-11-30 | 1994-06-09 | Kv Pharmaceutical Company | Tastemasked pharmaceutical materials |
| WO2000061119A2 (en) * | 1999-04-09 | 2000-10-19 | Pharmaplus S.R.L. | A process for the microencapsulation of medicaments |
Non-Patent Citations (2)
| Title |
|---|
| S. EL-SHANAWANY: "Sustained release of nitrofurantoin frominert wax matrixes" JOURNAL OF CONTROLLED RELEASE, vol. 26, no. 1, 1 July 1993 (1993-07-01), pages 11-19, XP000377735 Amsterdam (NL) * |
| S. ZGOULLI ET AL.: "Microencapsulation of erythromycin and clarithromycin using a spray-drying technique" JOURNAL OF MICROENCAPSULATION, vol. 16, no. 5, September 1999 (1999-09), pages 565-571, XP000834849 London (GB) * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001072284A1 (en) * | 2000-03-28 | 2001-10-04 | Biochemie Gesellschaft M.B.H. | Granulated particles with masked taste |
| EP1333807A2 (en) * | 2000-10-13 | 2003-08-13 | Advancis Pharmaceuticals | Extended release erythromycin derivatives |
| EP1333807A4 (en) * | 2000-10-13 | 2005-06-29 | Advancis Pharmaceuticals | Extended release erythromycin derivatives |
| EP1484056A1 (en) * | 2002-02-21 | 2004-12-08 | Otsuka Pharmaceutical Co., Ltd. | Sustained release preparations and process for producing the same |
| EP1484056A4 (en) * | 2002-02-21 | 2009-06-10 | Otsuka Pharma Co Ltd | Sustained release preparations and process for producing the same |
| US7927628B2 (en) | 2002-02-21 | 2011-04-19 | Otsuka Pharmaceutical Co., Ltd. | Sustained release preparations and process for producing the same |
| US7943585B2 (en) | 2003-12-22 | 2011-05-17 | Sandoz, Inc. | Extended release antibiotic composition |
Also Published As
| Publication number | Publication date |
|---|---|
| HUP0201233A2 (en) | 2002-08-28 |
| CZ20014133A3 (en) | 2002-03-13 |
| HRP20010932A2 (en) | 2003-04-30 |
| EE200100607A (en) | 2003-02-17 |
| BG106236A (en) | 2002-08-30 |
| HUP0201233A3 (en) | 2003-10-28 |
| PL351654A1 (en) | 2003-05-19 |
| YU82001A (en) | 2004-07-15 |
| WO2000069415A3 (en) | 2001-04-26 |
| SI20244A (en) | 2000-12-31 |
| RU2001134166A (en) | 2003-08-27 |
| EP1183013A2 (en) | 2002-03-06 |
| SK16642001A3 (en) | 2002-05-09 |
| AU4969700A (en) | 2000-12-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP3470198B2 (en) | Composition for oral administration | |
| RU2403015C2 (en) | Gastroresistant pharmaceutical compositions containing rifaximin | |
| JP4346817B2 (en) | Oral preparation | |
| US5707646A (en) | Taste masking pharmaceutical composition | |
| EP2258351B1 (en) | Granules containing lansoprazole in large amount | |
| US20070148235A1 (en) | Pharmaceutical composition | |
| EP1194153B1 (en) | Taste masked pharmaceutical liquid formulations | |
| JP4740740B2 (en) | Drug-containing particles and solid preparation containing the particles | |
| US8147874B2 (en) | Coated pellets | |
| RU2241460C2 (en) | Cefuroxime axetyl-containing pharmaceutical composition with masked bitter taste | |
| EP1267840B1 (en) | Granulated particles with masked taste | |
| JP2000103730A (en) | Medicine composition having improved feeling of administration | |
| CZ20014379A3 (en) | Composition for masking taste and process for preparing thereof | |
| JP2973751B2 (en) | Method for producing flavored oral composition | |
| EP1183013A2 (en) | Melt granulation | |
| US20210077451A1 (en) | A stable oral pharmaceutical composition of ferric citrate | |
| WO2004096175A2 (en) | Taste masked microcapsules and processes for their preparation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WWE | Wipo information: entry into national phase |
Ref document number: P-820/01 Country of ref document: YU |
|
| AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
| AK | Designated states |
Kind code of ref document: A3 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A3 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 16642001 Country of ref document: SK |
|
| WWE | Wipo information: entry into national phase |
Ref document number: PV2001-4133 Country of ref document: CZ |
|
| WWE | Wipo information: entry into national phase |
Ref document number: P20010932A Country of ref document: HR Ref document number: 2000931886 Country of ref document: EP |
|
| ENP | Entry into the national phase |
Ref document number: 2000 106236 Country of ref document: BG Kind code of ref document: A |
|
| WWP | Wipo information: published in national office |
Ref document number: 2000931886 Country of ref document: EP |
|
| WWP | Wipo information: published in national office |
Ref document number: PV2001-4133 Country of ref document: CZ |
|
| REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
| NENP | Non-entry into the national phase |
Ref country code: JP |
|
| WWW | Wipo information: withdrawn in national office |
Ref document number: 2000931886 Country of ref document: EP |