EP1370244A1 - Novel tablets and capsules and a process for its preparation - Google Patents
Novel tablets and capsules and a process for its preparationInfo
- Publication number
- EP1370244A1 EP1370244A1 EP02702234A EP02702234A EP1370244A1 EP 1370244 A1 EP1370244 A1 EP 1370244A1 EP 02702234 A EP02702234 A EP 02702234A EP 02702234 A EP02702234 A EP 02702234A EP 1370244 A1 EP1370244 A1 EP 1370244A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- tablet
- weight
- capsule
- active ingredient
- microcrystalline cellulose
- 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.)
- Withdrawn
Links
- 239000002775 capsule Substances 0.000 title claims abstract description 77
- 238000000034 method Methods 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 108
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 62
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 62
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 62
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 60
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 50
- 235000012239 silicon dioxide Nutrition 0.000 claims abstract description 50
- 239000004480 active ingredient Substances 0.000 claims abstract description 38
- WMUIIGVAWPWQAW-XMMPIXPASA-N (2r)-2-ethoxy-3-[4-(2-phenoxazin-10-ylethoxy)phenyl]propanoic acid Chemical group C1=CC(C[C@@H](OCC)C(O)=O)=CC=C1OCCN1C2=CC=CC=C2OC2=CC=CC=C21 WMUIIGVAWPWQAW-XMMPIXPASA-N 0.000 claims description 36
- 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 claims description 28
- 229930195725 Mannitol Natural products 0.000 claims description 28
- 239000000594 mannitol Substances 0.000 claims description 28
- 235000010355 mannitol Nutrition 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 20
- -1 polymorph Substances 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 239000002245 particle Substances 0.000 claims description 5
- 101000945318 Homo sapiens Calponin-1 Proteins 0.000 claims description 4
- 101000652736 Homo sapiens Transgelin Proteins 0.000 claims description 4
- 102100031013 Transgelin Human genes 0.000 claims description 4
- 238000007907 direct compression Methods 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 239000002207 metabolite Substances 0.000 claims description 4
- 239000000651 prodrug Substances 0.000 claims description 4
- 229940002612 prodrug Drugs 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- JJAHTWIKCUJRDK-UHFFFAOYSA-N succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate Chemical compound C1CC(CN2C(C=CC2=O)=O)CCC1C(=O)ON1C(=O)CCC1=O JJAHTWIKCUJRDK-UHFFFAOYSA-N 0.000 claims description 4
- 125000000637 arginyl group Chemical class N[C@@H](CCCNC(N)=N)C(=O)* 0.000 claims 1
- 239000007858 starting material Substances 0.000 abstract description 4
- 239000003826 tablet Substances 0.000 description 71
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 46
- 239000000454 talc Substances 0.000 description 26
- 229910052623 talc Inorganic materials 0.000 description 26
- 235000012222 talc Nutrition 0.000 description 26
- 235000019359 magnesium stearate Nutrition 0.000 description 23
- 150000001483 arginine derivatives Chemical class 0.000 description 22
- 239000000203 mixture Substances 0.000 description 14
- 239000000843 powder Substances 0.000 description 12
- 238000002156 mixing Methods 0.000 description 11
- 238000009826 distribution Methods 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000000332 continued effect Effects 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 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 3
- 241001465754 Metazoa Species 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 239000004475 Arginine Substances 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- WMUIIGVAWPWQAW-DEOSSOPVSA-N (2s)-2-ethoxy-3-{4-[2-(10h-phenoxazin-10-yl)ethoxy]phenyl}propanoic acid Chemical compound C1=CC(C[C@H](OCC)C(O)=O)=CC=C1OCCN1C2=CC=CC=C2OC2=CC=CC=C21 WMUIIGVAWPWQAW-DEOSSOPVSA-N 0.000 description 1
- UPHOPMSGKZNELG-UHFFFAOYSA-N 2-hydroxynaphthalene-1-carboxylic acid Chemical class C1=CC=C2C(C(=O)O)=C(O)C=CC2=C1 UPHOPMSGKZNELG-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 229920000856 Amylose Polymers 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 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 1
- 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 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 229940122355 Insulin sensitizer Drugs 0.000 description 1
- 150000000994 L-ascorbates Chemical class 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 239000003741 agents affecting lipid metabolism Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 159000000013 aluminium salts Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 229940124326 anaesthetic agent Drugs 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 230000000578 anorexic effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000000507 anthelmentic effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
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- 229940005513 antidepressants Drugs 0.000 description 1
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- 229940125708 antidiabetic agent Drugs 0.000 description 1
- 239000000729 antidote Substances 0.000 description 1
- 229940075522 antidotes Drugs 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000002255 antigout agent Substances 0.000 description 1
- 229960002708 antigout preparations Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 229940033495 antimalarials Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000003904 antiprotozoal agent Substances 0.000 description 1
- 239000003200 antithyroid agent Substances 0.000 description 1
- 229940043671 antithyroid preparations Drugs 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 230000003190 augmentative effect Effects 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 150000001642 boronic acid derivatives Chemical class 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
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- 230000003291 dopaminomimetic effect Effects 0.000 description 1
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- 238000003379 elimination reaction Methods 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000004083 gastrointestinal agent Substances 0.000 description 1
- 229940125695 gastrointestinal agent Drugs 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 150000002315 glycerophosphates Chemical class 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
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- 239000003326 hypnotic agent Substances 0.000 description 1
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- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 239000004041 inotropic agent Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000003149 muscarinic antagonist Substances 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 230000000701 neuroleptic effect Effects 0.000 description 1
- 150000002823 nitrates Chemical class 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
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000008184 oral solid dosage form Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical class OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910052700 potassium Chemical class 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
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- 150000003873 salicylate salts Chemical class 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 238000005029 sieve analysis Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 229940125706 skeletal muscle relaxant agent Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
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- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- 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
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/485—Inorganic compounds
-
- 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
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
Definitions
- Novel tablets and capsules and a process for its preparation Novel tablets and capsules and a process for its preparation.
- the present invention relates to novel tablets and capsules with relatively low amounts of the active ingredient.
- the present invention further relates to tablets and capsules comprising as the active ingredient (-) 3-[4-[2-(phenoxazin-10-yl) ethoxy]phenyl]-2-ethoxypropanoic acid or a pharmaceutically acceptable salt thereof.
- (2S)(-)-3-[4-[2-(phenoxazin-10-yl) ethoxy]phenyl]-2-ethoxypropanoic acid in the following (-) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid) and pharmaceutically ac- ceptable salts thereof has been found useful in the treatment of type 2 diabetes acting as an insulin sensitizer as disclosed in eg PCT Publication WO 99/19313, WO 00/50414 and WO 00/63192, which are incorporated herein by reference.
- compositions containing (-) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid as active ingredient or a pharmaceutically acceptable salt thereof are described in WO01/74363.
- One object of the present invention is to provide tablets and capsules having improved homogeneity.
- Another object of the present invention is to provide tablets and capsules having improved homogeneity with respect to the content of active ingredient. Another object of the present invention is to provide tablets and capsules having improved homogeneity with respect to the distribution of active ingredient.
- Another object of the present invention is to provide tablets and capsules having a low content of active ingredient.
- a still further object of the present invention is to provide tablets and capsules being supe- rior to the known art.
- a tablet or capsule wherein the content of active ingredient in the tablet or capsule is between about 3 % (weight/weight) and about 0.001 % (weight/weight) can be prepared with improved homogenous distribution of the active ingredient if microcrystalline cellulose and silicon dioxide are used as some of the starting materials.
- a tablet or capsule wherein the content of active ingredient in the tablet or capsule is not more than about 2 % (weight/weight) can be prepared with improved homogenous distribution of the active ingredient if microcrystalline cellulose and silicon dioxide are used as some of the starting materials.
- any sort of microcrystalline cellulose can be used for the preparation of the tablets and capsules according to the present invention.
- the microcrystalline cellulose used for the preparation of the tablets and capsules according to the present invention has a bulk density above 0.35 g/ml.
- the microcrystalline cellulose used for the preparation of the tablets and capsules according to the present invention has a particle size above about 50 micrometer.
- a tablet or capsule according to the present invention comprises preferably microcrystalline cellulose in an amount of at least 20 %, more preferred of at least 30 % and even more preferred of at least 40 % (weight/weight) and most preferred in an amount of at least 45% (weight/weight).
- the tablet or capsule according to the invention comprises microcrystalline cellulose in amounts ranging from 20% to 80% (weight/weight) , amounts from 30% to 70% are preferred while amounts from 40% to 60% are even more preferred and amounts ranging from 45% to 55% are especially preferred.
- any sort of silicone dioxide can be used for the preparation of the tablets and cap- sules according to the present invention.
- the silicone dioxide used for the preparation of the tablets and capsules according to the present invention has a particle size from about 1 namometer to about 100 micrometer.
- a tablet or capsule according to the present invention comprises preferably an amount of silicone dioxide in the range from 0.1 to 5 %, preferably in the range from 0.2% to 3%, even more preferred in the range from 0.5% to 1 ,5% (weight/weight).
- the tablet or capsule further comprises mannitol.
- the tablet or capsule comprises mannitol in an amount of at least 20%, preferably at least 30% an even more pre- ferred at lest 40% (weight/weight) and most preferred in an amount of at least 45%
- the tablet or capsule comprises mannitol in amounts ranging from 20% to 80% (weight/weight) , amounts from 30% to 70%) are preferred while amounts from 40% to 60% are even more preferred and amounts ranging from 45% to 55% are especially preferred.
- the tablet or capsule comprises mannitol and microcrystalline cellulose in proportions between 2:8 and 8:2, preferably between 3:5 and 5:3, more preferred between 4:6 and 6:4, and even more preferred between 45:55 and 55:45.
- the tablet or capsule comprises talc in the range from 0.1 to 10 % (weight/weight).
- the tablet or capsule comprises micro- crystalline cellulose in an amount ranging from 45% to 55% and silicon dioxide in an amount from 0,5%) to 1 ,5%(weight/weight).
- the tablet or capsule comprises: (i) an active ingredient selected from the group consisting of (-) 3-[4-[2-(phenoxazin-10-yl) ethoxy]phenyl]-2- ethoxypropanoic acid, pharmaceutically acceptable salt, ester, metabolite, hydrate, solvate, polymorph, and pro-drug form thereof, (ii) microcrystalline cellulose; and (iii) silicon dioxide, wherein the amount of said active ingredient is between about 0.01% and about 2,0% (weight/weight); the amount of said microcrystalline cellulose is between about 40% and about 50%) (weight/weight); and the amount of said silicone dioxide is between about 0.8% and about 1.2% (weight/weight).
- an active ingredient selected from the group consisting of (-) 3-[4-[2-(phenoxazin-10-yl) ethoxy]phenyl]-2- ethoxypropanoic acid, pharmaceutically acceptable salt, ester, metabolite, hydrate, solvate, polymorph, and pro-d
- Non-limiting examples of a formulation according to invention include the following (expressed as % weight/ total weight of each ingredient):
- the tablets or capsules are prepared using one of the commercial products marketed under the designations ProSolv HD 90, Pro- Solv SMCC 50, and ProSolv SMCC 90 by the firm PenWest, each of which contain both microcrystalline cellulose and silicon dioxide.
- the tablets or capsules have a relative standard deviation (RSD) for the content of active ingredient in the tablet or capsule which is not more than about 4%.
- RSD relative standard deviation
- the RSD value is not more than about 3 %, more preferred the RSD value is not more than about 2,5 %, and even more preferred the RSD value is not more than about 2 %, especially preferred the RSD value is not more than about 1 ,5 %, and even more preferred the RSD value is not more than about 1 %.
- the relative standard deviation (RSD) for the content of active ingredient in the tablets of the present invention can be determined as described in the United States Pharmacopeia (USP 24) 2000, chapter 905 using the test for Uniformity of Dosage Units, ⁇ 905>, USP XV.
- the bulk and tapped density can be determined as described in method BTD-8, Handbook of Pharmaceutical Excipients, 2nd ed., 1994. Particle size distribution can be determined by Sieve analysis using US standard sieves.
- the tablets and capsules according to the present invention can be prepared in a manner known perse. More specifically, the tablets and capsules may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practise of Pharmacy, 19 th edition, 1995. According to a preferred feature of the present invention, the tablet or capsule ac- cording to the present invention are prepared by direct compression. Direct compression has the advantage that it is possible to first mix all the ingredients which are to be present in the final tablet or capsule and then to subject the mixture to direct compression.
- the active ingredient present in the tablets and capsules of the present invention can be any pharmaceutical such as analgesics and anti-inflammatory agents, anthelminthics, anti- arrhythmic agents, antibacterial agents, anticoaglants, antidepressants, antidiabetic agents, antiepileptics, antifungal agents, antigout agents, antihypertensive agents, antimalarials, an- timigraine gents, antimuscarinic agents, antineoplastic agents, immunosuppressants, anti- protozoal agents, antithyroid agents, antiviral agents, anxiolytic sedatives, hypnotics, neuro- leptics, beta-adrenoceptor blocking agents, calcium regulating agents, cardiac inotropic agents, chelating agents, antidotes, antagonists, corticosteroids, diuretics, dopaminergic an- tiparkinsonian agents, gastro-intestinal agents, anaesthetics, hormones, lipid regulating agents, , anti
- An example of a specific medicaments is (-) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid and pharmaceutically acceptable salts thereof.
- Pharmaceutically acceptable salts forming part of this invention include salts such as alkali metal salts like Li, Na, and K salts, alkaline earth metal salts like Ca and Mg salts, salts of organic bases such as lysine, arginine, guanidine, diethanolamine, choline and the like, ammonium or substituted ammonium salts, aluminium salts.
- Salts may include acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulplionates, benzoates, salicy- lates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketogluta- rates and the like.
- Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.
- the present invention also encompasses esters, metabolites, hydrates, solvates, poly- morphs, and pro-drug forms of (-) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid.
- (-) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine is used in the present invention.
- Another example of a specific medicament is 5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2- quinazolinyl]methoxy]phenyl-methyl]thiazolidine-2,4-dione and pharmaceutically acceptable salts thereof as active ingredient as described in PCT Publication WO 97/41097.
- the present invention also encompasses esters, metabolites, hydrates, solvates, polymorphs, and pro- drug forms of 5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl- methyl]thiazolidine-2,4-dione.
- suitable carriers present in the tablets and capsules according to the present invention are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatine, lactose, terra alba, sucrose, mannitol, sorbitol, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
- the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
- the tablets and capsules may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
- the tablets and capsules of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
- the tablets and capsules can be sterilized and mixed, if desired, with auxiliary agents, emul- sifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds.
- the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge.
- Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
- Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch.
- the tablets and capsules of the invention may be administered to a mammal, especially a human in need of such treatment, prevention, elimination, alleviation or amelioration of various diseases as mentioned above.
- mammals include also animals, both domestic animals, e.g. household pets, and non-domestic animals such as wildlife.
- the exact dosage of the tablets and capsules will depend upon the mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
- the powder mixture is compressed into tablets on a tabletting machine.
- the tablet weight is EXAMPLE 6
- the powder mixture is compressed into tablets on a tabletting machine.
- the tablet weight is EXAMPLE 8
- the powder mixture is compressed into tablets on a tabletting machine.
- the tablet weight is 110 mg.
- the powder mixture is compressed into tablets on a tabletting machine.
- the tablet weight is 110 mg.
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Abstract
Tablets and capsules wherein the content of active ingredient in the tablet or capsule is not more than about 3 % (weight/weight) can be prepared if microcrystalline cellulose and silicon dioxide are used as some of the starting materials.
Description
Novel tablets and capsules and a process for its preparation.
FIELD OF THE INVENTION
The present invention relates to novel tablets and capsules with relatively low amounts of the active ingredient. The present invention further relates to tablets and capsules comprising as the active ingredient (-) 3-[4-[2-(phenoxazin-10-yl) ethoxy]phenyl]-2-ethoxypropanoic acid or a pharmaceutically acceptable salt thereof.
BACKGROUND OF THE INVENTION
In US patent 5,948,438 and US patent 6,106,865 oral solid dosage forms comprising micro- crystalline cellulose and a compressibility augmenting agent such as silicon dioxide are described.
(2S)(-)-3-[4-[2-(phenoxazin-10-yl) ethoxy]phenyl]-2-ethoxypropanoic acid (in the following (-) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid) and pharmaceutically ac- ceptable salts thereof has been found useful in the treatment of type 2 diabetes acting as an insulin sensitizer as disclosed in eg PCT Publication WO 99/19313, WO 00/50414 and WO 00/63192, which are incorporated herein by reference. Pharmaceutical compositions containing (-) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid as active ingredient or a pharmaceutically acceptable salt thereof are described in WO01/74363.
One object of the present invention is to provide tablets and capsules having improved homogeneity.
Another object of the present invention is to provide tablets and capsules having improved homogeneity with respect to the content of active ingredient. Another object of the present invention is to provide tablets and capsules having improved homogeneity with respect to the distribution of active ingredient.
Another object of the present invention is to provide tablets and capsules having a low content of active ingredient. A still further object of the present invention is to provide tablets and capsules being supe- rior to the known art.
SUMMARY OF THE INVENTION
It has now been found that a tablet or capsule wherein the content of active ingredient in the tablet or capsule is between about 3 % (weight/weight) and about 0.001 % (weight/weight) can be prepared with improved homogenous distribution of the active ingredient if microcrystalline cellulose and silicon dioxide are used as some of the starting materials. Surprisingly, it has now been found that a tablet or capsule wherein the content of active ingredient in the tablet or capsule is not more than about 2 % (weight/weight) can be prepared with improved homogenous distribution of the active ingredient if microcrystalline cellulose and silicon dioxide are used as some of the starting materials. Using these starting materials, it is even possible to prepare tablets and capsules wherein the content of active ingredient in the tablet or capsule is not more than about 1 %, not more than about 0.5 %, not more than about 0.05 %, not more than about 0.01 %, and even not more than about 0.005 % (weight/weight).
It is a further object of the present invention to provide a tablet or capsule with improved homogenous distribution which comprises microcrystalline cellulose and silicon dioxide and (-) 3-[4-[2-(phenoxazin-10-yl) ethoxy]phenyl]-2-ethoxypropanoic acid or a pharmaceutically ac- ceptable salt thereof.
MORE DETAILED DESCRIPTION OF THE PRESENT INVENTION
Generally, any sort of microcrystalline cellulose can be used for the preparation of the tablets and capsules according to the present invention. However, it is preferred that the microcrystalline cellulose used for the preparation of the tablets and capsules according to the present invention has a bulk density above 0.35 g/ml. Furthermore, it is preferred that the microcrystalline cellulose used for the preparation of the tablets and capsules according to the present invention has a particle size above about 50 micrometer. A tablet or capsule according to the present invention comprises preferably microcrystalline cellulose in an amount of at least 20 %, more preferred of at least 30 % and even more preferred of at least 40 % (weight/weight) and most preferred in an amount of at least 45% (weight/weight). For example, the tablet or capsule according to the invention comprises microcrystalline cellulose in amounts ranging from 20% to 80% (weight/weight) , amounts from 30% to 70% are preferred while amounts
from 40% to 60% are even more preferred and amounts ranging from 45% to 55% are especially preferred.
Similarly, any sort of silicone dioxide can be used for the preparation of the tablets and cap- sules according to the present invention. However, it is preferred that the silicone dioxide used for the preparation of the tablets and capsules according to the present invention has a particle size from about 1 namometer to about 100 micrometer. A tablet or capsule according to the present invention comprises preferably an amount of silicone dioxide in the range from 0.1 to 5 %, preferably in the range from 0.2% to 3%, even more preferred in the range from 0.5% to 1 ,5% (weight/weight).
In another embodiment according to the present invention, the tablet or capsule further comprises mannitol. In a preferred embodiment according to the invention, the tablet or capsule comprises mannitol in an amount of at least 20%, preferably at least 30% an even more pre- ferred at lest 40% (weight/weight) and most preferred in an amount of at least 45%
(weight/weight). In preferred embodiments of the invention, the tablet or capsule comprises mannitol in amounts ranging from 20% to 80% (weight/weight) , amounts from 30% to 70%) are preferred while amounts from 40% to 60% are even more preferred and amounts ranging from 45% to 55% are especially preferred.
In another embodiment of the present invention, the tablet or capsule comprises mannitol and microcrystalline cellulose in proportions between 2:8 and 8:2, preferably between 3:5 and 5:3, more preferred between 4:6 and 6:4, and even more preferred between 45:55 and 55:45.
In another embodiment of the present invention, the tablet or capsule comprises talc in the range from 0.1 to 10 % (weight/weight).
In a further preferred embodiment of the invention, the tablet or capsule comprises micro- crystalline cellulose in an amount ranging from 45% to 55% and silicon dioxide in an amount from 0,5%) to 1 ,5%(weight/weight).
In another embodiment of the invention, the tablet or capsule comprises: (i) an active ingredient selected from the group consisting of (-) 3-[4-[2-(phenoxazin-10-yl) ethoxy]phenyl]-2- ethoxypropanoic acid, pharmaceutically acceptable salt, ester, metabolite, hydrate, solvate,
polymorph, and pro-drug form thereof, (ii) microcrystalline cellulose; and (iii) silicon dioxide, wherein the amount of said active ingredient is between about 0.01% and about 2,0% (weight/weight); the amount of said microcrystalline cellulose is between about 40% and about 50%) (weight/weight); and the amount of said silicone dioxide is between about 0.8% and about 1.2% (weight/weight).
Non-limiting examples of a formulation according to invention include the following (expressed as % weight/ total weight of each ingredient):
Active ingredient 1%
Microcrystalline cellulose 97.8-98.2%
Silicon dioxide 0.8-1.2%
Active ingredient 1 %
Microcrystalline cellulose 47%
Silicon dioxide 1%
Mannitol 47%
Talc 4%
Active ingredient 1%
Microcrystalline cellulose 45.2%
Silicon dioxide 0.8%
Mannitol 49%
Talc 4%
Active ingredient 0.5%
Microcrystalline cellulose 98.3-98.7%
Silicon dioxide 0.8-1.2%
Active ingredient 2%
Microcrystalline cellulose 96.8-97.2%
Silicon dioxide 0.8-1.2%
Active ingredient 0.2%
Microcrystalline cellulose 98.6-99.0%
Silicon dioxide 0.8-1.2
Active ingredient 2% Microcrystalline cellulose 46.5%
Silicon dioxide 1%
Mannitol 46.5%
Talc 4
In a preferred embodiment of the present invention, the tablets or capsules are prepared using one of the commercial products marketed under the designations ProSolv HD 90, Pro- Solv SMCC 50, and ProSolv SMCC 90 by the firm PenWest, each of which contain both microcrystalline cellulose and silicon dioxide.
In one aspect of the present invention, the tablets or capsules have a relative standard deviation (RSD) for the content of active ingredient in the tablet or capsule which is not more than about 4%. Preferably, the RSD value is not more than about 3 %, more preferred the RSD value is not more than about 2,5 %, and even more preferred the RSD value is not more than about 2 %, especially preferred the RSD value is not more than about 1 ,5 %, and even more preferred the RSD value is not more than about 1 %.
The relative standard deviation (RSD) for the content of active ingredient in the tablets of the present invention can be determined as described in the United States Pharmacopeia (USP 24) 2000, chapter 905 using the test for Uniformity of Dosage Units, <905>, USP XV.
The bulk and tapped density can be determined as described in method BTD-8, Handbook of Pharmaceutical Excipients, 2nd ed., 1994. Particle size distribution can be determined by Sieve analysis using US standard sieves.
The tablets and capsules according to the present invention can be prepared in a manner known perse. More specifically, the tablets and capsules may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practise of Pharmacy, 19th edition, 1995. According to a preferred feature of the present invention, the tablet or capsule ac- cording to the present invention are prepared by direct compression. Direct compression has
the advantage that it is possible to first mix all the ingredients which are to be present in the final tablet or capsule and then to subject the mixture to direct compression.
The active ingredient present in the tablets and capsules of the present invention can be any pharmaceutical such as analgesics and anti-inflammatory agents, anthelminthics, anti- arrhythmic agents, antibacterial agents, anticoaglants, antidepressants, antidiabetic agents, antiepileptics, antifungal agents, antigout agents, antihypertensive agents, antimalarials, an- timigraine gents, antimuscarinic agents, antineoplastic agents, immunosuppressants, anti- protozoal agents, antithyroid agents, antiviral agents, anxiolytic sedatives, hypnotics, neuro- leptics, beta-adrenoceptor blocking agents, calcium regulating agents, cardiac inotropic agents, chelating agents, antidotes, antagonists, corticosteroids, diuretics, dopaminergic an- tiparkinsonian agents, gastro-intestinal agents, anaesthetics, hormones, lipid regulating agents, , anti-angina agents, vitamins, anti-asthma agents, skeletal muscle relaxants, stimulants, anoretics, sympatomimetics, thrombolytic agents, and vasodilators.
An example of a specific medicaments is (-) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid and pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts forming part of this invention include salts such as alkali metal salts like Li, Na, and K salts, alkaline earth metal salts like Ca and Mg salts, salts of organic bases such as lysine, arginine, guanidine, diethanolamine, choline and the like, ammonium or substituted ammonium salts, aluminium salts. Salts may include acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulplionates, benzoates, salicy- lates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketogluta- rates and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.
The present invention also encompasses esters, metabolites, hydrates, solvates, poly- morphs, and pro-drug forms of (-) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid.
In a preferred embodiment, (-) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine is used in the present invention.
Another example of a specific medicament is 5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2- quinazolinyl]methoxy]phenyl-methyl]thiazolidine-2,4-dione and pharmaceutically acceptable salts thereof as active ingredient as described in PCT Publication WO 97/41097. The present invention also encompasses esters, metabolites, hydrates, solvates, polymorphs, and pro- drug forms of 5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl- methyl]thiazolidine-2,4-dione.
Examples of suitable carriers present in the tablets and capsules according to the present invention are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatine, lactose, terra alba, sucrose, mannitol, sorbitol, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The tablets and capsules may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents. The tablets and capsules of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
The tablets and capsules can be sterilized and mixed, if desired, with auxiliary agents, emul- sifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds.
If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge.
Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch.
The tablets and capsules of the invention may be administered to a mammal, especially a human in need of such treatment, prevention, elimination, alleviation or amelioration of
various diseases as mentioned above. Such mammals include also animals, both domestic animals, e.g. household pets, and non-domestic animals such as wildlife.
The exact dosage of the tablets and capsules will depend upon the mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
The present invention will further be illustrated with the following non-exhaustive examples.
EXAMPLE 1
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt 3.860g
Microcrystalline cellulose with 2% silicon dioxide 1423g Mannitol 1423g
Magnesium stearate 30g
Talc 120g
Manufacture: (-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt, and 200g of microcrystalline cellulose with silicon dioxide is mixed in a drum mixer for 5 minutes. Mannitol and the rest of microcrystalline cellulose with silicon dioxide is added and mixing is continued for 10 minutes. Magnesium stearate and talc are added and mixed for further 5 minutes. The powder mixture is compressed into tablets on a tabletting machine. The tablet weight is 110 mg.
The results from test for content uniformity according to USP gave the following results: Mean content of (-) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid in each tablet: 0.0973mg RSD: 1.17%
EXAMPLE 2
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt 3.860g
Microcrystalline cellulose with 2% silicon dioxide 2846g
Magnesium stearate 30g
Talc 120g
Manufacture:
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt, and 200g of microcrystalline cellulose with silicon dioxide is mixed in a drum mixer for 5 minutes. The rest of microcrystalline cellulose with silicon dioxide is added and mixing is continued for 10 minutes. Magnesium stearate and talc are added and mixed for further 5 minutes. The powder mixture is compressed into tablets on a tabletting machine. The tablet weight is 110 mg.
The results from test for content uniformity according to USP gave the following results: Mean content of (-) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid in each tablet: 0.103mg
RSD: 1.85%
EXAMPLE 3
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt 3.860g
Microcrystalline cellulose with 2% silicon dioxide 1708 g
Mannitol 1138 g
Magnesium stearate 30g
Talc 120 g
Manufacture:
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt, and 200g of microcrystalline cellulose with silicon dioxide is mixed in a drum mixer for 5 minutes. Mannitol and the rest of microcrystalline cellulose with silicon dioxide is added and mixing is con- tinued for 10 minutes. Magnesium stearate and talc are added and mixed for further 5 minutes.
The powder mixture is compressed into tablets on a tabletting machine. The tablet weight is 110 mg.
EXAMPLE 4
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt 3.860g
Microcrystalline cellulose with 2% silicon dioxide 1138 g Mannitol 1708 g
Magnesium stearate 30g
Talc 120 g
Manufacture: (-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt, and 200g of microcrystalline cellulose with silicon dioxide is mixed in a drum mixer for 5 minutes. Mannitol and the rest of microcrystalline cellulose with silicon dioxide is added and mixing is continued for 10 minutes. Magnesium stearate and talc are added and mixed for further 5 minutes. The powder mixture is compressed into tablets on a tabletting machine. The tablet weight is 110 mg.
EXAMPLE 5
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt 3.860g
Microcrystalline cellulose with 2% silicon dioxide 1897 g
Mannitol 949 g
Magnesium stearate 30g
Talc 120 g
Manufacture:
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt, and 200g of microcrystalline cellulose with silicon dioxide ismixed in a drum mixer for 5 minutes. Mannitol and the rest of microcrystalline cellulose with silicon dioxide is added and mixing is con- tinued for 10 minutes. Magnesium stearate and talc are added and mixed for further 5 minutes.
The powder mixture is compressed into tablets on a tabletting machine. The tablet weight is
EXAMPLE 6
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt 3.860g
Microcrystalline cellulose with 2% silicon dioxide 949 g Mannitol 1897 g
Magnesium stearate 30g
Talc 120 g
Manufacture: (-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt, and 200g of microcrystalline cellulose with silicon dioxide is mixed in a drum mixer for 5 minutes. Mannitol and the rest of microcrystalline cellulose with silicon dioxide is added and mixing is continued for 10 minutes. Magnesium stearate and talc are added and mixed for further 5 minutes. The powder mixture is compressed into tablets on a tabletting machine. The tablet weight is 110 mg.
EXAMPLE 7
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt 3.860g
Microcrystalline cellulose with 2% silicon dioxide 407 g
Mannitol 2439 g
Magnesium stearate 30g
Talc 120 g
Manufacture:
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt, and 200g of microcrystalline cellulose with silicon dioxide is mixed in a drum mixer for 5 minutes. Mannitol and the rest of microcrystalline cellulose with silicon dioxide is added and mixing is con- tinued for 10 minutes. Magnesium stearate and talc are added and mixed for further 5 minutes.
The powder mixture is compressed into tablets on a tabletting machine. The tablet weight is
EXAMPLE 8
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt 3.860g
Microcrystalline cellulose with 2% silicon dioxide 2439 g Mannitol 407 g
Magnesium stearate 30g
Talc 120 g
Manufacture: (-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt, and 200g of microcrystalline cellulose with silicon dioxide is mixed in a drum mixer for 5 minutes. Mannitol and the rest of microcrystalline cellulose with silicon dioxide is added and mixing is continued for 10 minutes. Magnesium stearate and talc are added and mixed for further 5 minutes. The powder mixture is compressed into tablets on a tabletting machine. The tablet weight is 110 mg.
EXAMPLE 9
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt 3.860g
Microcrystalline cellulose 90 g
Lactose, monohydrate 2885
Silica, colloidal anhydrous 6 g
Magnesium stearate 15 g
Manufacture:
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt, and 90 g of microcrystalline cellulose is mixed in a drum mixer for 5 minutes. Lactose and silica is added and mixing is continued for 10 minutes. Magnesium stearate is added and mixed for further 5 minutes.
The powder mixture is compressed into tablets on a tabletting machine. The tablet weight is 110 mg.
EXAMPLE 10
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt 19.30g
Microcrystalline cellulose with 2% silicon dioxide 1693 g Mannitol 1138 g
Magnesium stearate 30g
Talc 120 g
Manufacture: (-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt, and 200g of microcrystalline cellulose with silicon dioxide is mixed in a drum mixer for 5 minutes. Mannitol and the rest of microcrystalline cellulose with silicon dioxide is added and mixing is continued for 10 minutes. Magnesium stearate and talc are added and mixed for further 5 minutes. The powder mixture are compressed into tablets on a tabletting machine. The tablet weight is 110 mg.
EXAMPLE 11
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt 1.930g
Microcrystalline cellulose with 2% silicon dioxide 950 g
Mannitol 1898 g
Magnesium stearate 30g
Talc 120 g
Manufacture:
(-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt, and 200g of microcrystalline cellulose with silicon dioxide is mixed in a drum mixer for 5 minutes. Mannitol and the rest of microcrystalline cellulose with silicon dioxide is added and mixing is con- tinued for 10 minutes. Magnesium stearate and talc are added and mixed for further 5 minutes.
The powder mixture is compressed into tablets on a tabletting machine. The tablet weight is 110 mg.
Claims
1. A tablet or capsule containing microcrystalline cellulose and silicon dioxide and active ingredient in an amount between about 3 % and about 0.001 % (weight/ weight).
2. A tablet or capsule, according to claim 1 , wherein the content of active ingredient is not more than about 2 % (weight/weight).
3. A tablet or capsule, according to claim 1 , wherein the content of active ingredient is not more than about 1 %( weight/weight).
4. A tablet or capsule, according to any one of the preceding claims, wherein the content of active ingredient is not more than about 0.5 %( weight/weight).
5. A tablet or capsule, according to any one of the preceding claims, wherein the content of active ingredient is not more than about 0.05 %( weight/weight).
6. A tablet or capsule, according to any one of the preceding claims, wherein the content of active ingredient is not more than about 0.01 % (weight/weight).
7. A tablet or capsule, according to any one of the preceding claims, wherein the content of active ingredient is not more than about 0.005 %( weight/weight).
8. A tablet or capsule, according to any one of the preceding claims, wherein the active in- gredient is (-) 3-[4-[2-(phenoxazin-10-yl) ethoxy]phenyl]-2-ethoxypropanoic acid or a pharmaceutically acceptable salt thereof.
9. A tablet or capsule, according to any one of the preceding claims, wherein the active ingredient is (-) 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, arginine salt
10. A tablet or capsule, according to any one of the preceding claims, which further comprises mannitol.
11. A tablet or capsule according to any one of the preceding claims comprising mannitol and microcrystalline cellulose in proportions between 2:8 and 8:2, preferably between 3:5 an 5:3, even more preferred between 4:6 and 6:4, and most preferred between 45:55 and 55:45.
12. A tablet or capsule according to any one of the preceding claims comprising silicon dioxide in the range from 0.1 to 5 %, preferably in the range from 0.2% to 3%, and even more preferred in the range from 0.5% to 1 ,5% (weight/weight).
13. A tablet or capsule according to any one of the preceding claims comprising microcrystalline cellulose in an amount ranging from 45% to 55% and silicon dioxid in an amount ranging from 0,5% to 1 ,5% (weight/weight).
14. A tablet or capsule, according to any one of the preceding claims, wherein the microcrystalline cellulose has a bulk density above 0.35 g/ml.
15. A tablet or capsule according to any one of the preceding claims, wherein the microcrystalline cellulose has a particle size above about 50 micrometer.
16. A tablet or capsule according to any one of the preceding claims, wherein the silicone dioxide has a particle size from about 1 namometer to about 100 micrometer.
17. A tablet or capsule according to any one of the preceding claims containing ProSolv HD 90, ProSolv SMCC 50, and ProSolv SMCC 90 (from PenWest).
18. A tablet or capsule according to any one of the preceding claims for which the relative standard deviation (RSD) for the content of active ingredient in the tablet or capsule is not more than about 4%.
19. A tablet or capsule according to any one of the preceding claim for which the RSD value is not more than about 3 %.
20. A tablet or capsule according to any one of the preceding claims for which the RSD value is not more than about 2,5 %.
21. A tablet or capsule according to any one of the preceding claims for which the RSD value is not more than about 2 %.
22. A tablet or capsule according to any one of the preceding claims for which the RSD value is not more than about 1 ,5 %.
23. A tablet or capsule according to any one of the preceding claims for which the RSD value is not more than about 1 %.
24. A process for preparing a tablet or capsule according to any one of the preceding claims which process is characterized in that the tablets or capsules are prepared by direct compression.
25. A tablet or capsule which comprises microcrystalline cellulose and silicon dioxide and wherein the active ingredient is (-) 3-[4-[2-(phenoxazin-10-yl) ethoxy]phenyl]-2- ethoxypropanoic acid or a pharmaceutically acceptable salt thereof.
26. A tablet or capsule comprising: (i) an active ingredient selected from the group consist- ing of (-) 3-[4-[2-(phenoxazin-10-yl) ethoxy]phenyl]-2-ethoxypropanoic acid, pharmaceutically acceptable salt, ester, metabolite, hydrate, solvate, polymorph, and pro-drug form thereof.; (ii) microcrystalline cellulose; and (iii) silicon dioxide, wherein the amount of said active ingredient is between about 0.01 % and about 2,0% (weight/weight); the amount of said microcrystalline cellulose is between about 40% and about 50% (weight/weight); and the amount of said silicone dioxide is between about 0.8% and about 1.2%
(weight/weight).
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK200100413 | 2001-03-12 | ||
| DKPA200100413 | 2001-03-12 | ||
| PCT/DK2002/000163 WO2002072069A1 (en) | 2001-03-12 | 2002-03-12 | Novel tablets and capsules and a process for its preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1370244A1 true EP1370244A1 (en) | 2003-12-17 |
Family
ID=8160361
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP02702234A Withdrawn EP1370244A1 (en) | 2001-03-12 | 2002-03-12 | Novel tablets and capsules and a process for its preparation |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP1370244A1 (en) |
| WO (1) | WO2002072069A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1638554A1 (en) * | 2003-06-27 | 2006-03-29 | Dr. Reddy's Research Foundation | Compositions comprising balaglitazone and further antidiabetic compounds |
| EP3185900A4 (en) * | 2014-08-25 | 2018-05-02 | Aimmune Therapeutics, Inc. | Egg protein formulations and methods of manufacture thereof |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU5957480A (en) * | 1979-07-26 | 1981-01-29 | American Cyanamid Company | Diethyl carbamazine resinate |
| IL110376A (en) * | 1993-08-02 | 1998-08-16 | Bristol Myers Squibb Co | Pharmaceutical compositions containing ifetroban salts and methods for the preparation thereof |
| AU5397496A (en) * | 1995-03-28 | 1996-10-16 | Janssen Pharmaceutica N.V. | Low dose ridogrel formulations and their use for the treatme nt of inflammatory bowel diseases |
| TWI249526B (en) * | 1998-03-13 | 2006-02-21 | Aventis Pharma Inc | Novel processes for the preparation of (R)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol |
| AU2001244098A1 (en) * | 2000-04-04 | 2001-10-15 | Novo-Nordisk A/S | Pharmaceutical composition containing 3-(4(2-phenoxazin-10-yl)ethoxy)phenyl)-2-ethoxy propanoicacid |
| US6855333B1 (en) * | 2000-10-03 | 2005-02-15 | Mutual Pharmaceutical Co., Inc. | Stabilization of solid thyroid drug formulations |
-
2002
- 2002-03-12 EP EP02702234A patent/EP1370244A1/en not_active Withdrawn
- 2002-03-12 WO PCT/DK2002/000163 patent/WO2002072069A1/en not_active Ceased
Non-Patent Citations (1)
| Title |
|---|
| See references of WO02072069A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2002072069A1 (en) | 2002-09-19 |
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