GB2406517A - Controlled release micropellets of tetracyclines - Google Patents
Controlled release micropellets of tetracyclines Download PDFInfo
- Publication number
- GB2406517A GB2406517A GB0421759A GB0421759A GB2406517A GB 2406517 A GB2406517 A GB 2406517A GB 0421759 A GB0421759 A GB 0421759A GB 0421759 A GB0421759 A GB 0421759A GB 2406517 A GB2406517 A GB 2406517A
- Authority
- GB
- United Kingdom
- Prior art keywords
- pharmaceutical composition
- tetracycline
- cellulose
- composition according
- pellets
- 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.)
- Granted
Links
- 239000004098 Tetracycline Substances 0.000 title claims abstract description 65
- 235000019364 tetracycline Nutrition 0.000 title claims abstract description 63
- 150000003522 tetracyclines Chemical class 0.000 title claims abstract description 34
- 238000013270 controlled release Methods 0.000 title claims abstract description 11
- 229940040944 tetracyclines Drugs 0.000 title description 3
- 229960002180 tetracycline Drugs 0.000 claims abstract description 62
- 229930101283 tetracycline Natural products 0.000 claims abstract description 61
- 239000008188 pellet Substances 0.000 claims abstract description 50
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims abstract description 31
- 239000002775 capsule Substances 0.000 claims abstract description 30
- 229960004023 minocycline Drugs 0.000 claims abstract description 27
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 26
- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 claims abstract description 24
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 21
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 20
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 claims abstract description 15
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims abstract description 15
- 150000002148 esters Chemical class 0.000 claims abstract description 12
- 239000001993 wax Substances 0.000 claims abstract description 8
- 239000003925 fat Substances 0.000 claims abstract description 7
- 229920005862 polyol Polymers 0.000 claims abstract description 7
- 150000003077 polyols Chemical class 0.000 claims abstract description 7
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 6
- 239000000194 fatty acid Substances 0.000 claims abstract description 6
- 229930195729 fatty acid Natural products 0.000 claims abstract description 6
- 150000004665 fatty acids Chemical class 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 41
- -1 tetracycline compound Chemical class 0.000 claims description 36
- 229920000642 polymer Polymers 0.000 claims description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- 239000000203 mixture Substances 0.000 claims description 28
- WTJXVDPDEQKTCV-UHFFFAOYSA-N 4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;hydron;chloride Chemical compound Cl.C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2C1CC1C(N(C)C)C(=O)C(C(N)=O)=C(O)C1(O)C2=O WTJXVDPDEQKTCV-UHFFFAOYSA-N 0.000 claims description 19
- 229960002421 minocycline hydrochloride Drugs 0.000 claims description 19
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 16
- 229940079593 drug Drugs 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 16
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 16
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 16
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 15
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 13
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 13
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 13
- 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 claims description 13
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 231100000252 nontoxic Toxicity 0.000 claims description 10
- 230000003000 nontoxic effect Effects 0.000 claims description 10
- 239000001856 Ethyl cellulose Substances 0.000 claims description 9
- 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 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- 229920001249 ethyl cellulose Polymers 0.000 claims description 9
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 8
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 6
- 229940069328 povidone Drugs 0.000 claims description 6
- 229920000623 Cellulose acetate phthalate Polymers 0.000 claims description 5
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 5
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 5
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 5
- OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-N 0.000 claims description 5
- 229940081734 cellulose acetate phthalate Drugs 0.000 claims description 5
- 229920000159 gelatin Polymers 0.000 claims description 5
- 235000019322 gelatine Nutrition 0.000 claims description 5
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 5
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 5
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 5
- 229920000609 methyl cellulose Polymers 0.000 claims description 5
- 239000001923 methylcellulose Substances 0.000 claims description 5
- 235000010981 methylcellulose Nutrition 0.000 claims description 5
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 5
- 150000003626 triacylglycerols Chemical class 0.000 claims description 5
- WTJXVDPDEQKTCV-VQAITOIOSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;hydrochloride Chemical compound Cl.C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O WTJXVDPDEQKTCV-VQAITOIOSA-N 0.000 claims description 4
- 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 claims description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 4
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 claims description 4
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 claims description 4
- 229920003145 methacrylic acid copolymer Polymers 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 239000011928 denatured alcohol Substances 0.000 claims description 3
- 210000002966 serum Anatomy 0.000 claims description 3
- 239000001828 Gelatine Substances 0.000 claims description 2
- 150000004671 saturated fatty acids Chemical class 0.000 claims description 2
- 239000000454 talc Substances 0.000 claims description 2
- 229910052623 talc Inorganic materials 0.000 claims description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 claims 1
- 239000002552 dosage form Substances 0.000 abstract description 6
- 229920002678 cellulose Polymers 0.000 abstract description 4
- 239000001913 cellulose Substances 0.000 abstract description 4
- 125000005456 glyceride group Chemical group 0.000 abstract 1
- 229920000058 polyacrylate Polymers 0.000 abstract 1
- 238000004090 dissolution Methods 0.000 description 9
- 239000008187 granular material Substances 0.000 description 9
- 238000000576 coating method Methods 0.000 description 8
- 229960004667 ethyl cellulose Drugs 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000012738 dissolution medium Substances 0.000 description 6
- 210000002784 stomach Anatomy 0.000 description 6
- 239000002585 base Substances 0.000 description 5
- 238000002835 absorbance Methods 0.000 description 4
- 239000011248 coating agent Substances 0.000 description 4
- 238000001125 extrusion Methods 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 3
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 3
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 210000004051 gastric juice Anatomy 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 239000003979 granulating agent Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- AZXUDNJDZHNFIH-REXXEDAASA-N (4s,4as,5ar,12ar)-2-carbamoyl-4-(dimethylazaniumyl)-10,11,12a-trihydroxy-9-(methylamino)-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracen-1-olate Chemical compound CN(C)[C@@H]1C(=O)C(C(N)=O)=C(O)[C@@]2(O)C(=O)C3=C(O)C4=C(O)C(NC)=CC=C4C[C@H]3C[C@H]21 AZXUDNJDZHNFIH-REXXEDAASA-N 0.000 description 2
- UCOXGFBGSLDEPZ-ADMKQJKVSA-N (4s,4as,5ar,12ar)-4-(dimethylamino)-1,10,11,12a-tetrahydroxy-7-(methylamino)-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound CN(C)[C@@H]1C(=O)C(C(N)=O)=C(O)[C@@]2(O)C(=O)C3=C(O)C(C(O)=CC=C4NC)=C4C[C@H]3C[C@H]21 UCOXGFBGSLDEPZ-ADMKQJKVSA-N 0.000 description 2
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 2
- 229920003081 Povidone K 30 Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- JCSGAUKCDAVARS-UHFFFAOYSA-N demethyltetracycline Natural products CN(C1C(=C(C(C2(C(=C3C(C4=C(C=CC=C4C(C3CC12)O)O)=O)O)O)=O)C(=O)N)O)C JCSGAUKCDAVARS-UHFFFAOYSA-N 0.000 description 2
- 239000003599 detergent Substances 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 239000004014 plasticizer Substances 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical class OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 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
- RMVMLZHPWMTQGK-SOUFLCLCSA-N (4s,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1([C@H]2O)=CC=CC(O)=C1C(O)=C1[C@@H]2C[C@H]2[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]2(O)C1=O RMVMLZHPWMTQGK-SOUFLCLCSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- PYGXAGIECVVIOZ-UHFFFAOYSA-N Dibutyl decanedioate Chemical compound CCCCOC(=O)CCCCCCCCC(=O)OCCCC PYGXAGIECVVIOZ-UHFFFAOYSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- 101001081590 Homo sapiens DNA-binding protein inhibitor ID-1 Proteins 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- GTTSNKDQDACYLV-UHFFFAOYSA-N Trihydroxybutane Chemical compound CCCC(O)(O)O GTTSNKDQDACYLV-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- BAPJBEWLBFYGME-UHFFFAOYSA-N acrylic acid methyl ester Natural products COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- CDQSJQSWAWPGKG-UHFFFAOYSA-N butane-1,1-diol Chemical compound CCCC(O)O CDQSJQSWAWPGKG-UHFFFAOYSA-N 0.000 description 1
- BMRWNKZVCUKKSR-UHFFFAOYSA-N butane-1,2-diol Chemical compound CCC(O)CO BMRWNKZVCUKKSR-UHFFFAOYSA-N 0.000 description 1
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000008199 coating composition Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003778 fat substitute Substances 0.000 description 1
- 235000013341 fat substitute Nutrition 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229910021485 fumed silica Inorganic materials 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 102000049143 human ID1 Human genes 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000013629 media batch Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000007896 modified release capsule Substances 0.000 description 1
- 230000007935 neutral effect Effects 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
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008014 pharmaceutical binder Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- YPFDHNVEDLHUCE-UHFFFAOYSA-N propane-1,3-diol Chemical compound OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 238000005563 spheronization Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 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
- A61K9/14—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
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- 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
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Inorganic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention concerns a controlled release dosage form comprising (I) a tetracycline, (II) an excipient selected from waxes, fats or glycerides or other esters of fatty acids with polyols and (III) a cellulose or acrylate polymer or polyvinyl - pyrrolidone; (II) is present in a range of 8.35% of (I) and (III) is present in the range of 20 - 100% of (I). Preferred is a capsule containing pellets of minocycline, glycerol monostearate, cellulose and polyvinyl pyrrolidone.
Description
24065 1 7
TETRACYCLINE CONTROLLED RELEASE PHARMACEUTICAL
COMPOSITION
FIELD OF THE INVENTION
This invention is concerned with a pharmaceutical composition for the controlled release of antibacterial agents comprising tetracycline compounds. More specifically, it is concerned with pellets comprising a 1() tetracycline compound blended with an excipient, the pellets being formulated to control the rate of release of the tetracycline in the human stomach and human intestine upon oral administration, in order to achieve an optimal blood level. When the pellets are filled into capsules or compressed into tablets, and the like, there are provided controlled release dosage forms of tetracycline compounds.
BACKGROUND OF THE INVENTION 2()
Tetracycline compounds are widely used in therapy primarily for their antimicrobial effect. A preferred family of such agents comprises the 7or 9-alkylamino-6- deoxy-6-demethyl-tetracyclines, including the non-toxic 2s acid-addition salts thereof.
In Bechgaard, U.S. 4,606,909, the placement of a sparingly soluble active substance, such as tetracycline, in an oral controlled release dosage form is disclosed.
So The sparingly soluble active substance must be used with a dispersionenhancing substance, such as an anionic detergent to promote solubility in intestinal fluids. The composition is formed into small spheres and enteric coated to eliminate any release of drug in the stomach.
is The coated spheres are tabletted or loaded into capsules.
The requirement to use a dispersion-enhancing substance, especially an anionic detergent, is a negative factor.
In EP 310 814 B1, spheronized spheres containing minocycline HCl are made by mixing minocycline with s microcrystalline cellulose followed by spheronization, and are thereby stated to be adapted to retard the rate of release of the tetracycline compound in the human stomach and to promote rapid release of said tetracycline compound in the human intestine upon administration.
l0 However, in order to achieve the desired dissolution profile, the teaching is that coating of the pellets is necessary.
SUMMARY OF THE INVENTION
A need still exists for an improved controlled release tetracycline containing composition, especially one without coatings such as film coatings, and especially capsules which confers controlled release even though the capsule only contains one type of pellet. The above objective has been met by the present invention in a way not suggested in the foregoing prior art. The composition of the present invention is formulated to control release on oral administration. Preferably, it will have a 2s prolonged release of the tetracycline compound compared to a traditional formulation.
This is accomplished by preparing a composition, e.g. in the form of pellets, containing the tetracycline with at least one excipient and at least one polymer giving the composition the unexpected and advantageous properties.
According to the present invention there is provided a pharmaceutical composition which comprises as (I) a tetracycline compound or a non-toxic acid addition salt thereof; (II) at least one pharmaceutically acceptable excipient selected from the group consisting of waxes; fats; esters of fatty acids with polyols; monoglycerides; diglycerides; and triglycerides said excipient (or excipients) being present in an amount of 8-35\ of the amount of the tetracycline (w/w); and (III) at least one polymer selected from the group consisting of: microcrystalline cellulose; polyvinylpyrrolidone; hydroxypropylmethyl cellulose; methylcellulose; ethylcellulose; hydroxyethyl cellulose) hydroxypropyl cellulose; hydroxypropyl methylcellulose phthalate; cellulose acetate phthalate; hydroxypropyl methylcellulose succinate; a polymer or copolymer of (meth)acrylic acid or an ester thereof; and sodium carboxymethylcellulose, said polymer (or polymers) being present in an amount of 20100 of the amount of the tetracycline (w/w). 2('
Also provided is a pharmaceutical composition in the form of a plurality of pellets and a capsule filled with a plurality of said pellets as well as a process for the preparation of the composition. 2s
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a pharmaceutical composition which comprises a tetracycline compound or a non-toxic acid addition salt thereof and at least one pharmaceutically acceptable excipient selected from the group consisting of waxes; fats; esters of fatty acids with polyols; monoglycerides; diglycerides; triglycerides; and mixtures thereof, said excipient (or 3s excipients belonging to said group) being present in an amount of 8- 35\ of the amount of the tetracycline (w/w).
The excipient has preferably a melting temperature above 25 C, and more preferably above 40 C, such as above 50 C, above 60 C or above 70 C. An excipient of this kind can found in the group comprising mono, di or trimesters of S glycerol with a saturated fatty acid having more than 10 carbon atoms, more preferably 16 or more, e.g. 18 C atoms. It is presently preferred to use an ester of glycerol with stearic acid, such as glycerol monostearate. 1()
The pharmaceutical composition according to the invention further comprises a polymer selected from the group consisting of: microcrystalline cellulose; polyvinylpyrrolidone; hydroxypropylmethyl cellulose; methylcellulose; ethylcellulose; hydroxyethyl cellulose; hydroxypropyl cellulose; hydroxypropyl methylcellulose phthalate; cellulose acetate phthalate; hydroxypropyl methylcellulose succinate; a polymer or copolymer of (meth)acrylic acid or an ester thereof; sodium carboxymethyl-cellulose, or a mixture thereof.
Examples on preferred embodiments of the pharmaceutical composition is a composition which comprises a tetracycline compound or a non-toxic acid addition salt 2s thereof and, measured relative to the weight of tetracycline (such as minocycline) (w/w), 8-35 of an excipient as defined in claim 1 and 20- 100\ of polymers, a pharmaceutical composition which comprises minocycline hydrochloride and, measured relative to the weight of So minocycline (w/w), 8-35 glycerol monostearate and 20- polymers, and a pharmaceutical composition which comprises minocycline hydrochloride and, measured relative to the weight of minocycline (w/w), 10-30\ glycerol monostearate, 20-60 microcrystalline cellulose and 3-15\ polyvinyl pyrrolidone. It should be understood that if a dosage form comprises 100 mg tetracycline compound, it should further comprise e.g. 10-30 mg glycerol monostearate, 20-60 mg microcrystalline cellulose and 3- 15 mg polyvinyl pyrrolidone. It is presently preferred that the composition comprises, relative to the weight of the tetracycline (w/w), 10-30\ (such as 12-28%, 14-25\, or 16-20), of the above excipient(s), 20-80\ (such as 25-70\, 30-60\ or 35-551) of the polymer or mixtures of polymers. Especially, it is preferred that the composition comprises 20-60\ (such as 30-50t or 35-45) cellulose (eg. microcrystalline) and 3 lo 14 (such as 412\, 5-10\ or 6-9) polyvinylpyrrolidone.
A preferred pharmaceutical composition therefore comprises 55-65twt minocycline hydrochloride, 9-12 twt glycerol monostearate, 22-27 twt microcrystalline cellulose, and 3-6 twt povidone.
In an interesting embodiment, the form of the pharmaceutical composition is a pellet having a size in the range of 0,1 to 4,0 mm, such as in the range 0,5 to 3 mm, in the range 1,0 to 2,5 mm and in the range 1,5 to 2,1 mm. A range from 1,7 to 2,0 mm is preferred.
The size of the pellet can vary depending of the release rate desired. It is presently preferred that 30-50t, preferably 35-45\ of said tetracycline compound is released from said pellets in 20 minutes when suspended in water having a pH of 7,2 at ambient temperature (37 C) at a drug concentration of about 100 mg of drug/900 ml of water, and that 60- 85%, preferably 65-80 of said l() tetracycline compound is released from said pellets in 60 minutes when suspended in water having a pH of 7,2 at ambient temperature (37 C) at a drug concentration of about 100 mg of drug/900 ml of water.
The invention also relates to a capsule, such as a hard gelatine capsule, which contains a plurality of the pellets as defined above, especially a controlled release pharmaceutical composition in oral dosage unit form comprising a gelatins capsule filled solely with pellets having an average diameter of from about 0.1 to about 3.5 millimeters, each pellet being similar in composition and s comprising an effective antibacterial amount of a 7-or 9- alkylamino-6-deoxy-6-demethyl-tetracycline or a non-toxic acid addition salt thereof, a pharmaceutically acceptable excipient as defined above, and a polymer, such as a polymer defined above. 1()
A presently preferred embodiment is a capsule filled with a number of spherical pellets comprising minocycline, glycerol monostearate, polyvinyl pyrrolidone (such as povidone) and microcrystalline cellulose, the pellets having an average size from 1,0 to 2,5 mm.
A capsule of the invention may have the following dissolution profile in water, 37 C: In 20 minutes: Between 24 and 35\, such as 27-32, is dissolved In 50 minutes: Between 47 and 62\, such as 51-57t, is dissolved In 180 minutes: More than 80\ is dissolved An other embodiment relates to a capsule which comprises pellets comprising a tetracycline compound or a non-toxic acid addition salt thereof and at least one pharmaceutically acceptable excipient selected from the group consisting of waxes; fats; esters of fatty acids 0 with polyols; monoglycerides; diglycerides; triglycerides; and mixtures thereof, said capsule when containing 100 mg of minocycline (base equivalent) has the following pharmacokinetic data in fasted state: AUC (ng.h/ml) in the range of 10000-35000, preferably in the range 15000- 27000, and more preferably in the range 18000-25000, and most preferably in the range 19000 23000. Cmax (ng/ml) should be in the range 700-2800, preferably in the range 1000-2000, more preferably in the range 1200-1800, and presently most preferred in the range 1400-1600. Tmax (h) shound be in the range 1, 0 to 2,0, more preferably in the range 1,2 to 1,8, and most S preferably in the range 1,4 to 1,6.
The invention also relates to a pharmaceutical composition, e.g. capsule or dosage form as defined above, which reaches a peak concentration (Cmax) in serum JO of the tetracycline released in no more than 4 hours, such as from 1 to 2 hours or from 1,25 to 1,75 hours, after administration in fasted state. Preferably, minocycline is administered, eg. as the hydrochloride.
The Cmax is calculated when a 100 mg single dose, calculated as minocycline base is administered.
The invention further relates to a pharmaceutical composition, e.g. capsule or dosage form as defined above, which has a Cmax in the range 1000-2000 ng/ml (such as in the range 1300-1700 or 1400-1600) and/or an AUC (extrapolated to infinity) in the range 15000-27000 ng x in/ml (such as in the range 19000-24000 or 20000 23000) when 100 mg of the tetracycline (equivalent to the base) is administered in fasted state. Preferably, the tetracycline is minocycline, and presently most preferred minocycline hydrochloride.
A further embodiment relates to a method for producing the composition and pellets of the invention, said method comprising a combination of the following steps: - The tetracycline drug is mixed with the excipient as defined above (eg. glycerol monostearate), preferably whilst being heated in order to facilitate mixing, eg. to more than 50, more than 55, or more than 60 C. x
The temperature may be allowed to drop, eg to below or below 40 C, preferably under mixing.
- The optionally cooled granulate, preferably milled, is blended with one or more polymers. If polyvinyl pyrrolidone is added, a solution (eg. dissolved in IMS/water, such as in a 50-60\ v/v solution) is preferably used.
1U - If needed, an additional volume of IMS/water is added until the granule is sufficiently wet for extrusion. The wet granule is extruded using an extruder fitted with a suitable screen, and spheronized using a spheroniser at sufficient speed, The process is continued until the extrudate has rounded to form spheroids of the desired size. The pellets are dried, screened and blended with purified talc.
It has been surprisingly found that when a combination of water and IMS is used as the granulating agent, the process for the manufacture of the pharmaceutical composition proceeds without degradation of the tetracycline and without poor extrusion. When water 2s alone is used as the granulating agent, the active degrades. When IMS is used alone as the granulating agent, it evaporates rapidly and extrusion is poor.
DEFINITIONS 3()
The term "Tetracycline" should be understood broadly and relates to tetracycline compounds in general. The term comprises members of the tetracycline family comprising substituted 7- and/or 9-amino tetracyclines. Typical compounds are, for example, 7-methylamino-6-deoxy-6-demethyltetracycline, 7-ethylamino-6-deoxy-6-demethyltetracycline, 7-isopropylamino-6-deoxy-6-demethyltetracycline, 9-methylamino-6-deoxy-6-demethyltetracycline, 9-ethylamino-6-deoxy-6-demethyltetracycline, 9-isopropylamino-6-deoxy-6-demethyltetracycline, s 7,9-di(ethylamino)-6deoxy-6-demethyltetracycline, 7-dimethylamino-6-deoxy-6-demethyltetracycline, 9-dimethylamino-6-deoxy-6-demethyltetracycline, 7-methylamino-6-deoxytetracyline, 9-ethylamino-6-deoxytetracyline, 1(, 7,9-di(methylamino-6-deoxytetracycline, 7-diethylamino-6-deoxytetracyline, 9-diethylamino-6-deoxytetracyline, 7,9-di(methylethylamino)-6-deoxytetracycline, 7-methylamino-9-ethylamino-6-deoxytetracycline, and 9 -methylamino-5-hydroxy-6-deoxytetracycline.
Preferred members of this family comprise tetracycline compounds selected from (a) 7-dimethylamino-6-deoxy-6-demethyl-tetracycline; (b) 7-methylamino-6-deoxy-6-dimethyl-tetracycline; 2() (c) 9-methylamino-6-deoxy-6-demethyl-tetracycline; (d) 7-ethylamino-6-deoxy-6--demethyl-tetracycline; (e) 7-isopropylamino-6-deoxy-6 demethyl-tetracycline; (f) a non-toxic acid addition salt of (a) - (e), inclusive or (g) a mixture of any of the foregoing.
An interesting tetracycline compound is 7-dimethylamino 6-deoxy-6-demethyltetracycline (minocycline) and its non toxic acid addition salts, e.g., hydrochloric, sulfonic, trichloroacetic acid salts, and the like, especially preferably the hydrochloric acid addition salts.
The tetracycline compounds and methods for their preparation are disclosed in the prior art and are know 3s to the skilled artisan. For best results, the controlled release composition of this invention in dosage unit form may, for example, contain from 25 to 200 mg, and more preferably 50 and 100 mg, of the tetracycline compound, for example, minocycline hydrochloride.
The term "pellet" comprises rounded; oblong; spherical; ellipsoid; beadshaped; rod-shaped and cylindrical particles having for example an average size of 0,1 to 4,0 mm. The pellet can be obtained by granulation, spheronisation, by spraying a core seed with the core JO element formulation in a fluidized bed coaler, using a centrifugal granulator or spheronizer, by applying tetracycline and excipient onto Spheres (such as sugar spheres, European Pharmacopoeia, 4th edition p 1973), etc. The term "spheres" in relation to the pellet is well known in the pharmaceutical art, and means spherical granules having a average diameter of approximately 0.1 to 3.5 millimeters, preferably from 0.5 to 2,5 mm. The spheres can have a average diameter of at least 0,5: 0,8; 1,0; 1,3; 1,5; or even at least 1,7 mm, and an average diameter of at most 3,0 mm, 2,8; 2,6; 2,4; 2,2; 2,0; 1,7; or even at most 1,5 mm. Ranges can be produced by freely combining a lower average diameter with an upper average diameter, eg. pellets having an average diameter falling within the range 1,7 to 2,0 mm is an embodiment of the present invention.
The term "wax" comprises natural and artificial waxes.
The term "fat'' comprises natural and artificial fats. 3'
The term "polyol" comprises molecules having a carbon backbone and at least two hydroxy groups, such as propylenglycol, ethylenglycol, butanetriol, butanediol (including 2,3- or 1,2- butylenglycol, and 1,4 butandiol), 1,3-propandiol, glycerol and derivatives thereof.
It is also among the features of the invention to provide oral dosage units by forming the pellets to tablets.
In some features of the invention, especially when the drug is coated on the pellet, the pellets can include a layer of a polymer substantially uniformly coating each of said pellets, such as a polymer being slowly erodable in the human stomach and rapidly erodable in the human ID small intestine upon oral administration.
In both instances (i.e. coated or uncoated pellets), a water-soluble tetracycline compound, i.e., one which requires less than 500 parts by volume of water to lS dissolve 1 part by weight of the tetracycline compound at ambient temperature is preferred. Moreover, using either uncoated pellets or coated pellets, it is presently preferred that 65-80% of the tetracycline compound will be released from spherical pellets within one hour, and that it will be substantially completely released, i. e., more than 85 percent released, in no more than about 120 minutes when suspended in deionized water (pH about 7,2) at body temperatures e.g., 37 C, at a drug concentration of about 100 mg/900 ml w/v. In the film coated version, 2s ultra thin coatings are preferred for this reason.
Ultrathin means, for purposes of this disclosure, that the weight of the film will be from 2 to less than about 10, preferably from about 2 to about 5 percent by weight based on the weight of the film coated pellets. 3(,
The film forming polymer, if used, can vary widely in type, and amount, which correlates to film thickness. It is important, however, that any film forming polymer either be somewhat erodable in gastric juice and/or used as in ultrathin layer or layers to permit release of a minor proportion of the tetracycline compound in the stomach, the importance of which has been set forth above.
Although from 2 to less than about 10 weight percent of film content based on the weight of the film coated spheres is suitable for most readily gastric juice erodable polymers, it is preferred to use 2 to 5 percent of any film because thin layers of all polymers, even those of somewhat higher resistances to acidic gastric juices, will permit release of the required small amounts of tetracycline compound in the stomach.
Illustrative but not limiting film forming polymers are lO cellulose and acrylic acid based polymers. Particularly to be mentioned are methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, hydroxypropyl methylcellulose succinate, polymers and copolymers of (meth)acrylic acid and (meth) acrylic acid methyl ester and mixtures of any of the foregoing. The coatings can include conventional additives, such as plasticizers, pigments, colorants, etc. The plasticizers can include mineral oil, high boiling esters, vegetable oils and the like. Commercial coating compositions found to be useful include Eudragit a product of Rohm Pharma, Weiterstadt, Germany and Surelease@, a product of Colorcon, Inc., West Point, PA. The former comprises an anionic polymerizate of methacrylic acid and methyl methacrylate. The latter comprises an aqueous dispersion of ethyl cellulose, dibutyl sebacate, oleic acid, fumed silica, and ammonium hydroxide.
3() Preferred as coating materials are ethyl-cellulose and hydroxypropyl methylcellulose, and the commercial coatings exemplified herein.
A suitable form of ethylcellulose is one having a viscosity in the range of 5 to 100 cps at 20 C (U.S. National Formulary XIII)(content of ethoxy groups 44 to 51 by weight), and more particularly a viscosity of 50 cps at 20 C (content of ethoxy groups 48 to 49\ by weight). A suitable form of hydroxypropyl methylcellulose is one having a viscosity in the range 3 to 100 cps at 20 C. (U.S. National Formulary XIII), and more s particularly a viscosity of 6 cps at 20 C.
The spheres containing tetracycline compound thereon or therein can, if desired, be coated with an aqueous or organic solvent solution of the desired film forming polymer, using fluid bed technology or pan-coating, and the like, but preferably fluid beds are used.
It is preferred however if the pellets of the invention are uncoated.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. l is a graphical representation of the release of minocycline hydrochloride from uncoated spheres in accordance with this invention in acid, pH l,2, with EP paddle apparatus at 50 rpm. The graphically represented data appears below the figure.
Fig. 2 is a graphical representation of the release of minocycline hydrochloride from uncoated spheres in accordance with this invention in deionized water, pH 7,2 with EP paddle apparatus at 50 rpm. The graphically represented data appears below the figure.
Fig. 3 is a graphical representation of the release of So minocycline hydrochloride from encapsulated uncoated spheres in accordance with this invention in various media. The underlying data is found in example 6.
EXAMPLE 1
Determination of the Dissolution of tetracycline capsules, exemplified by Minocycline MR Capsules, by W Us Reagents Minocycline Hydrochloride Characterised reference standard Water RO, deionised or distilled 1() Dissolution Medium Water Dissolution Conditions Manual and Automated Apparatus: EP paddle apparatus (paddles/round bottom vessels) Paddle speed: 50rpm Cell pathlength: 0.5cm Wavelength: 348nm Run time: 3 hours Sampling volume: lOml Filters: 20p polyethylene 2s Automated Pump setting 3.9ml/min Standard Preparation 3() 1. Transfer approximately 60mg of Minocycline Hydrochloride characterized reference standard, accurately weighed, to a lOOml volumetric flask.
2. Dissolve in and dilute to volume with dissolution medium (Solution A).
is 3. Dilute lOml of Solution A to 50ml with dissolution medium. Mix well.
Procedure (Manual and Automated) 1. Transfer one capsule held in a three pronged capsule weight (sinker) into each of 6 dissolution vessels containing 900ml of degassed dissolution medium at 37 C + 0.5 C and proceed according to the stated conditions.
2. Measure the absorbance of the standard solution using dissolution medium as the reference solvent.
3. Measure the absorbance of the sample solution at 5 I() minute intervals between initial and 1 hour and at minute intervals between 1 and 3 hours using dissolution medium as the reference solvent Calculation Is i) Manual Minocycline dissolved = WsUd x P x Aspl x 9 Astd x 1.08 x 5 ii) Icalis dissolution software Input standard concentration with respect to minocycline: Minocycline concentration (mg/L) = Wstd x 2 1.08 Where: Aspl = sample absorbance WsUd = Minocycline HCl standard weight (mg) Astd = standard absorbance P = potency of reference standard, expressed as a decimal 3()
EXAMPLE 2
Manufacturing of pellets comprising minocycline, povidone, glycerol monostearate and talc. 3s
Minocycline hydrochloride: 60088 g; Glycerol monostearate 40-55: 10360 g; 1(, Microcrystalline cellulose 101: 23828 g; Povidone K-30: 4662 g; Purified talc: 518 g; Purified water; Industrial methylated spirit 74 OP (IMS).
1.The minocycline HCl is placed into a suitable mixer.
The glycerol monostearate is screened through an appropriate mesh and added to the mixer.
JO 2.The powder bed is heated whilst mixing.
3.When the powder bed temperature has reached 65 degrees C the powder bed is cooled whilst mixing.
4.Mixing is stopped when the bed temperature has dropped to below 40 degrees C. 5.The cooled granulate is milled.
6.The milled granule is placed in a suitable mixer and blended with microcrystalline cellulose.
7.A solution of povidone dissolved in IMS/water 56 v/v is prepared.
8.The povidone solution is used to granule the blend from step 6 with an additional volume of IMS/water being added until the granule is sufficiently wet for extrusion.
9.A sample of the wet granule is extruded using an extruder fitted with a suitable screen.
10. Spheronizing the sample using a spheroniser at sufficient speed, The process is continued until the extrudate has rounded to form spheroids of the desired size.
3(' 11. The pellets are dried.
12. The dried pellets are screened.
13. The pellet fraction and the purified talc are placed in a suiLbale mixer and blended.
14. The pellets are encapsulated.
EXAMPLE 3
Composition of a capsule of the invention Pellet: Minocycline hydrochloride 116mg; Glycerol monostearate 20mg; Microcrystalline cellulose 46mg; Povidone K-30 9mg; lo Purified water ND; Industrial methylated spirit 74 OP BP ND.
Hard gelatin capsule: Gelatin 80-84% Water 14.5 Colours up to 100
EXAMPLE 4
The dissolution rate of the capsules made according to example 2 is measured according to the procedure in
example 1.
The dissolution in water at neutral pH (7,2) and at a temperature of 37 degrees C is found as follows: In 20 minutes: Between 24 and 35t is dissolved In 50 minutes: Between 47 and 62t is dissolved In 180 minutes: More than 80t is dissolved 3()
EXAMPLE 5
Single dosis experiment.
Pharmacokinetic Variables For Minocycline Modifed Release Capsules in the fasted state.
Minocycline was assayed using a validated high performance liquid chromatographic method and the analytical work performed in accordance with good s laboratory practice guidelines. The following pharmacokinetic variables were measured: maximum concentration (Cmax), time to maximum concentration (Tmax), area under the curve to the last data point and extrapolated to infinity (AUC0-t and AUC0-)' apparent lt, terminal half-life (tl/2), ratio of Cmax and AUC0-. All analyses were performed using BIOPRO (v3.2). The results are shown below: Minocycline Variable Unit Mean Cmax ng/ml 1492 Tmax h 1.5 AUCo - t ng.h/ml 20288 DUCT ng.h/ml 21798 Tl/2 h 13.8 Cmax/AUCo-= l/h 0.07 Is Pharmacokinetic Variables for Minocycline Modified Release Capsules in the fed state Minocycline Variable Unit Mean Cmax ng/ml 1266 Tmax 4 AUCo - t ng.h/ml 20531 DUCT ng. h/ml 22399 Tl/2 h 14.5 Cmax/AUCo-= l/h 0.06 In the experiments, a capsule of the invention (example 3) was used, comprising Minocycline hydrochloride in an amount equivalent to 100 mg Minocycline base
EXAMPLE 6
Dissolution in various media Batch CT0563 is Minocycline hydrochloride MR capsules.
Method details - Paddles, round bottom vessels, 50rpm, 900ml, 348nm.
Dissolution |Time 1 CT0563 O.1M Cll'55] _ _. CT0563CT0563 (mine) HCl pH3 pH5 pH8 water
O O O O O
4 1 1 1 2 2 31 12 13 12 12 47 20 22 20 19 57 27 28 27 26 64 32 34 32 31 69 37 39 36 35 73 41 43 40 39 77 44 47 44 43 79 47 50 47 46 82 50 53 50 48 83 53 56 52 51 84 55 58 55 53 87 61 64 61 59 87 66 69 66 64 87 70 73 70 68 88 74 77 74 72 88 76 79 77 75 88 79 81 80 77 88 81 83 82 79 88 82 85 84 81 In the experiments, a capsule of the invention was used, comprising Minocycline hydrochloride in an amount equivalent to loo mg Minocycline base.
Remarks: The above-mentioned patents and publications are incorporated herein by reference.
Many variations will suggest themselves to those skilled in this art in light of the foregoing detailed description. For example, instead of 7-dimethyl-6-deoxy- 6-demethyltetracycline hydrochloride, the free base, the sulfuric acid and the trichloroacetic acid addition salts can be used. Instead of 7-dimethyl--6-deoxy-6- demethyltetracycline hydrochloride, the hydrochlorides of the following compounds can be used: 7-methylamino-6deoxy-6-demethyltetracycline; 9-methyl-amino-6-deoxy-6 2(' demethyltetracycline; 7-ethylamino-6-deoxy-6- demethyltetracycline; and 7-isopropylamino-6--deoxy-6- demethyltetracycline. As a film former, ethylcellulose can be used alone. The pellets can be filled into either hard gelatin or soft gelatin capsules in conventional capsule-filling machines, to provide 50 and lOO milligrams of minocycline hydrochloride content in each capsule. The pellets can also be mixed with conventional pharmaceutical binders and/or excipients and compressed into tablets. All such obvious variations are within the full-intended scope of the appended claims.
Claims (28)
1. A pharmaceutical composition which comprises (I) a tetracycline compound or a non-toxic acid addition salt thereof; (II) at least one pharmaceutically acceptable excipient selected from the group consisting of waxes; fats; esters 1() of fatty acids with polyols; monoglycerides; diglycerides; and triglycerides said excipient (or excipients) being present in an amount of 8-35\ of the amount of the tetracycline (w/w); and (III) at least one polymer selected from the group consisting of: microcrystalline cellulose; polyvinylpyrrolidone; hydroxypropylmethyl cellulose; methylcellulose; ethylcellulose; hydroxyethyl cellulose; hydroxypropyl cellulose; hydroxypropyl methylcellulose phthalate; cellulose acetate phthalate; hydroxypropyl methylcellulose succinate; a polymer or copolymer of (meth)acrylic acid or an ester thereof; and sodium carboxymethyl- cellulose, said polymer (or polymers) being present in an amount of 20- 100% of the amount of the tetracycline (w/w).
2. A pharmaceutical composition according to claim l in which said excipient is a mono, di or trimester of glycerol with a saturated fatty acid having more than lo carbon atoms.
3. A pharmaceutical composition according to claim 2 wherein said excipient is glycerol monostearate.
4. A pharmaceutical composition according to claim 3 comprising 16 to 20 glycerol monostearate relative to the amount of the tetracycline (w/w). /
5. A pharmaceutical composition according to any one of claims 1 to 4 wherein said polymer is microcrystalline cellulose.
6. A pharmaceutical composition according to claim 5 comprising 35 to 45t microcrystalline cellulose relative to the amount of the tetracycline (w/w).
lO
7. A pharmaceutical composition as claimed in claim 1 to 6 further comprising polyvinyl pyrrolidone.
8. A pharmaceutical composition according to claim 7 comprising 6 to 9 polyvinyl pyrrolidone relative to the IS amount of the tetracycline (w/w).
9. A pharmaceutical composition as claimed in any one of claims 1 to 8 wherein the tetracycline compound or salt thereof is minocycline or a salt thereof. 2()
10. A pharmaceutical composition as claimed in claim 9 wherein the tetracycline compound or salt thereof is minocycline hydrochloride.
2s
11. A pharmaceutical composition as claimed in claim 10 which comprises minocycline hydrochloride and, measured relative to the weight of minocycline HCl (w/w), 10-30 glycerol monostearate, 20-60 microcrystalline cellulose and 3-15\ polyvinyl pyrrolidone.
12. A pharmaceutical composition according to any of the preceding claims, wherein said composition is formulated as a plurality of pellets having a size in the range of 0.1 to 4.0 mm.
13. A pharmaceutical composition according to any of the preceding claims, wherein said composition is formulated as a plurality of pellets having a size in the range 0.5 to 2 mm.
14. A pharmaceutical composition according to claim 12 s or 13 wherein 3050\ of said tetracycline compound is released from said pellets in 20 minutes when suspended in water having a pH of 7,2 at ambient temperature (37 C) at a drug concentration of about 100 mg of drug/900 ml of water. 1()
15. A pharmaceutical composition according to claim 14 wherein 35-45\ of said tetracycline compound is released from said pellets in 20 minutes when suspended in water having a pH of 7,2 at ambient temperature (37 C) at a As drug concentration of about 100 mg of drug/900 ml of water.
16. A pharmaceutical composition according to claim 12 or 13 wherein 60-85\ of said tetracycline compound is released from said pellets in 60 minutes when suspended in water having a pH of 7,2 at ambient temperature (37 C) at a drug concentration of about 100 mg of drug/900 ml of water.
17. A pharmaceutical composition according to claim 16 wherein 65-80\ of said tetracycline compound is released from said pellets in 60 minutes when suspended in water having a pH of 7,2 at ambient temperature (37 C) at a drug concentration of about 100 mg of drug/900 ml of water.
18. A pharmaceutical composition comprising 55-65\ wt minocycline hydrochloride, 9-12 It glycerol monostearate, 22-27 twt microcrystalline cellulose, and 3-6 twt povidone.
19. A pharmaceutical composition as claimed in claim 1 to 18 formulated as a capsule which contains a plurality of pellets.
20. A composition as claimed in claim 19 wherein said capsule is a hard gelatine capsule.
21. A pharmaceutical composition as claimed in any one of claims 1 to 20 being a controlled release l() pharmaceutical composition in oral dosage unit form.
22. A pharmaceutical composition according to any of the preceding claims, which reaches a peak concentration (Cmax) in serum of the tetracycline released in no more than 4 hours after administration in fasted state.
23. A pharmaceutical composition according to any of the preceding claims, which reaches a peak concentration (Cmax) in serum of the tetracycline released in 1-2 hours after administration in fasted state.
24. A pharmaceutical composition or capsule according to any of the preceding claims, which has a Cmax in the range 1000-2000 ng/ml and/or an AUC (extrapolated to infinity) in the range 15000-27000 ng x in/ml when 100 mg of the tetracycline is administered in fasted state.
25. A pharmaceutical composition as claimed in any preceding claim additionally comprising talc.
26. A process for the preparation of a pharmaceutical composition comprising (i) mixing a tetracycline or non-toxic additional salt thereof with an excipient selected from the group consisting of waxes; fats; esters of fatty acids with polyols; monoglycerides; diglycerides; triglycerides said excipient (or excipients) being present in an amount of 8-35 of the amount of the tetracycline (w/w); (ii) blending with at least one polymer selected from the group consisting of: microcrystalline cellulose; polyvinylpyrrolidone; hydroxypropylmethyl cellulose; methylcellulose; ethylcellulose; hydroxyethyl cellulose; hydroxypropyl cellulose; hydroxypropyl methylcellulose lO phthalate; cellulose acetate phthalate; hydroxypropyl methylcellulose succinate; a polymer or copolymer of (meth)acrylic acid or an ester thereof; sodium carboxymethyl-cellulose, said polymer (or polymers) being present in an amount of 20-100% of the amount of the Is tetracycline (w/w); (iii) adding a solution of polyvinyl pyrrolidone dissolved in Industrial Methylated Spirit/water (iv) granulating and then extruding the resulting mixture.
27. A process as claimed in claim 26 wherein an IMS/water solution of 5060 v/v is used. Is
28. A pharmaceutical composition substantially as hereinbefore described with reference to any of the
Examples.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0524368A GB2420708A (en) | 2003-09-30 | 2004-09-30 | Tetracycline controlled release pharmaceutical composition |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB0322848.3A GB0322848D0 (en) | 2003-09-30 | 2003-09-30 | Tetracycline controlled release pharmaceutical dosage form |
Publications (3)
Publication Number | Publication Date |
---|---|
GB0421759D0 GB0421759D0 (en) | 2004-11-03 |
GB2406517A true GB2406517A (en) | 2005-04-06 |
GB2406517B GB2406517B (en) | 2006-07-12 |
Family
ID=29287107
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GBGB0322848.3A Ceased GB0322848D0 (en) | 2003-09-30 | 2003-09-30 | Tetracycline controlled release pharmaceutical dosage form |
GB0421759A Expired - Fee Related GB2406517B (en) | 2003-09-30 | 2004-09-30 | Minocycline controlled release pharmaceutical composition |
GB0524368A Withdrawn GB2420708A (en) | 2003-09-30 | 2004-09-30 | Tetracycline controlled release pharmaceutical composition |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GBGB0322848.3A Ceased GB0322848D0 (en) | 2003-09-30 | 2003-09-30 | Tetracycline controlled release pharmaceutical dosage form |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB0524368A Withdrawn GB2420708A (en) | 2003-09-30 | 2004-09-30 | Tetracycline controlled release pharmaceutical composition |
Country Status (1)
Country | Link |
---|---|
GB (3) | GB0322848D0 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11103517B2 (en) | 2015-04-07 | 2021-08-31 | Dr. Reddy's Laboratories Ltd. | Pharmaceutical compositions for minocycline |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8722650B1 (en) | 2005-06-24 | 2014-05-13 | Medicis Pharmaceutical Corporation | Extended-release minocycline dosage forms |
US20080242642A1 (en) | 2007-04-02 | 2008-10-02 | Medicis Pharmaceutical Corporation | Minocycline oral dosage forms for the treatment of acne |
US8252776B2 (en) | 2007-04-02 | 2012-08-28 | Medicis Pharmaceutical Corporation | Minocycline oral dosage forms for the treatment of acne |
US9561241B1 (en) | 2011-06-28 | 2017-02-07 | Medicis Pharmaceutical Corporation | Gastroretentive dosage forms for minocycline |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1117270A (en) * | 1966-06-06 | 1968-06-19 | Ncr Co | A process for treating minute polymeric capsules |
CA1071935A (en) * | 1975-08-18 | 1980-02-19 | Takeda Chemical Industries Ltd. | Method of producing microcapsules with coacervated oil-and-fat as the wall material |
EP0841062A1 (en) * | 1995-07-21 | 1998-05-13 | Daiichi Pharmaceutical Co., Ltd. | Granular preparation and process for producing the same |
WO2000076481A1 (en) * | 1999-06-14 | 2000-12-21 | Cosmo S.P.A. | Mesalazine controlled release oral pharmaceutical compositions |
WO2003004009A1 (en) * | 2001-07-02 | 2003-01-16 | Geneva Pharmaceuticals, Inc. | Pharmaceutical composition |
-
2003
- 2003-09-30 GB GBGB0322848.3A patent/GB0322848D0/en not_active Ceased
-
2004
- 2004-09-30 GB GB0421759A patent/GB2406517B/en not_active Expired - Fee Related
- 2004-09-30 GB GB0524368A patent/GB2420708A/en not_active Withdrawn
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1117270A (en) * | 1966-06-06 | 1968-06-19 | Ncr Co | A process for treating minute polymeric capsules |
CA1071935A (en) * | 1975-08-18 | 1980-02-19 | Takeda Chemical Industries Ltd. | Method of producing microcapsules with coacervated oil-and-fat as the wall material |
EP0841062A1 (en) * | 1995-07-21 | 1998-05-13 | Daiichi Pharmaceutical Co., Ltd. | Granular preparation and process for producing the same |
WO2000076481A1 (en) * | 1999-06-14 | 2000-12-21 | Cosmo S.P.A. | Mesalazine controlled release oral pharmaceutical compositions |
WO2003004009A1 (en) * | 2001-07-02 | 2003-01-16 | Geneva Pharmaceuticals, Inc. | Pharmaceutical composition |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11103517B2 (en) | 2015-04-07 | 2021-08-31 | Dr. Reddy's Laboratories Ltd. | Pharmaceutical compositions for minocycline |
Also Published As
Publication number | Publication date |
---|---|
GB2420708A (en) | 2006-06-07 |
GB2406517B (en) | 2006-07-12 |
GB0322848D0 (en) | 2003-10-29 |
GB0524368D0 (en) | 2006-01-04 |
GB0421759D0 (en) | 2004-11-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0533297B1 (en) | Controlled-release pharmaceutical formulations | |
EP0825854B1 (en) | Pharmaceutical dosage form with multiple enteric polymer coatings for colonic delivery | |
CA1338439C (en) | Controlled release formulations of tetracycline compounds | |
TW499312B (en) | Immediate release tablet cores of insoluble drugs having sustained-release coating | |
EP0153105B1 (en) | Diffusion coated multiple-units dosage form | |
US4713248A (en) | Diffusion coated multiple-units dosage form | |
EP0827398B1 (en) | Pharmaceutical dosage form for colonic delivery | |
JP2019147832A (en) | Controlled release pharmaceutical compositions comprising fumaric acid ester | |
CZ30093A3 (en) | Pulsating systems for administering minocyclin once a day | |
IE66389B1 (en) | Pulsatile once-a-day delivery systems for minocycline | |
EP0470047A1 (en) | Sustained release formulations | |
JPH0761922A (en) | Release start controlling type pharmaceutical preparation | |
HU219449B (en) | Process for pnoncing of delayed release oral dosage forms for treatment of intestinal disorders | |
CA2570153A1 (en) | Granules for controlled release of tamsulosin | |
CN101669912A (en) | Slow-release composition containing tamsulosin and preparation thereof | |
GB2406517A (en) | Controlled release micropellets of tetracyclines | |
US20090136550A1 (en) | Modified release formulations of diltiazem | |
AU732210B2 (en) | Colonic delivery of weak acid drugs | |
WO2000056266A2 (en) | Taste masking coating compositions | |
AU627335B2 (en) | Aspirin granules with gastroprotectant coating | |
TR2023014802T2 (en) | MESALAZINE ENTERIC TABLET FORMULATION COMPOSITION | |
CA3230682A1 (en) | Oral formulation of a pyridinone derivate and use thereof in prophylaxis and/or treatment of intestinal fibrosis | |
EP4340847A1 (en) | Composition of mesalazine enteric tablet formulation | |
EA043403B1 (en) | PELLET WITH MULTILAYER STRUCTURE FOR SLOW RELEASE OF ACTIVE INGREDIENT INTO THE DISTAL SECTION OF THE COLON | |
EA043575B1 (en) | PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION WITH A CONTROLLED DISSOLUTION RATE, CONTAINING TIMED-RELEASE PELLETS CONTAINING TAMSULOSIN HYDROCHLORIDE |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 20130930 |