MXPA06014586A - Drinkableimmediate release tablet made with direct compression of memantine or neramexane - Google Patents
Drinkableimmediate release tablet made with direct compression of memantine or neramexaneInfo
- Publication number
- MXPA06014586A MXPA06014586A MXPA/A/2006/014586A MXPA06014586A MXPA06014586A MX PA06014586 A MXPA06014586 A MX PA06014586A MX PA06014586 A MXPA06014586 A MX PA06014586A MX PA06014586 A MXPA06014586 A MX PA06014586A
- Authority
- MX
- Mexico
- Prior art keywords
- dosage form
- oral dosage
- solid oral
- immediate release
- release solid
- Prior art date
Links
- BUGYDGFZZOZRHP-UHFFFAOYSA-N Memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 title claims abstract description 91
- 229960004640 memantine Drugs 0.000 title claims abstract description 90
- OGZQTTHDGQBLBT-UHFFFAOYSA-N Neramexane Chemical compound CC1(C)CC(C)(C)CC(C)(N)C1 OGZQTTHDGQBLBT-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 229950004543 Neramexane Drugs 0.000 title claims abstract description 25
- 238000007907 direct compression Methods 0.000 title claims abstract description 6
- 239000006186 oral dosage form Substances 0.000 claims abstract description 58
- 239000007787 solid Substances 0.000 claims abstract description 57
- 239000004480 active ingredient Substances 0.000 claims abstract description 36
- 239000002552 dosage form Substances 0.000 claims abstract description 35
- 239000011248 coating agent Substances 0.000 claims abstract description 27
- 238000000576 coating method Methods 0.000 claims abstract description 26
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 claims abstract description 23
- 239000008101 lactose Substances 0.000 claims abstract description 23
- GUBGYTABKSRVRQ-XLOQQCSPSA-N 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 claims abstract description 23
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 20
- 238000005755 formation reaction Methods 0.000 claims abstract description 17
- 230000035852 Tmax Effects 0.000 claims abstract description 16
- 238000011068 load Methods 0.000 claims abstract description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 35
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 35
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 35
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 35
- 229960000967 Memantine hydrochloride Drugs 0.000 claims description 30
- LDDHMLJTFXJGPI-UHFFFAOYSA-N memantine hydrochloride Chemical group Cl.C1C(C2)CC3(C)CC1(C)CC2(N)C3 LDDHMLJTFXJGPI-UHFFFAOYSA-N 0.000 claims description 30
- 239000000463 material Substances 0.000 claims description 27
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 26
- 239000011780 sodium chloride Substances 0.000 claims description 26
- 229960001375 Lactose Drugs 0.000 claims description 22
- WSVLPVUVIUVCRA-RJMJUYIDSA-N (2R,3R,4S,5R,6S)-2-(hydroxymethyl)-6-[(2R,3S,4R,5R)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol;hydrate 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)OC(O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-RJMJUYIDSA-N 0.000 claims description 18
- 229960001021 Lactose Monohydrate Drugs 0.000 claims description 18
- -1 1-aminocyclohexane compound Chemical class 0.000 claims description 15
- 201000010099 disease Diseases 0.000 claims description 15
- 239000000945 filler Substances 0.000 claims description 15
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 14
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 14
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 claims description 13
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 13
- 235000019359 magnesium stearate Nutrition 0.000 claims description 13
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 12
- 206010001897 Alzheimer's disease Diseases 0.000 claims description 11
- 239000007884 disintegrant Substances 0.000 claims description 10
- 239000000314 lubricant Substances 0.000 claims description 10
- 238000011049 filling Methods 0.000 claims description 8
- 208000004296 Neuralgia Diseases 0.000 claims description 7
- 239000000454 talc Substances 0.000 claims description 6
- 229910052623 talc Inorganic materials 0.000 claims description 6
- CLUKHUGGXSIGRX-UHFFFAOYSA-N methanesulfonic acid;1,3,3,5,5-pentamethylcyclohexan-1-amine Chemical group CS(O)(=O)=O.CC1(C)CC(C)(C)CC(C)(N)C1 CLUKHUGGXSIGRX-UHFFFAOYSA-N 0.000 claims description 5
- 229960001681 Croscarmellose Sodium Drugs 0.000 claims description 4
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- 239000003086 colorant Substances 0.000 claims description 4
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 4
- 239000003381 stabilizer Substances 0.000 claims description 3
- 230000000181 anti-adherence Effects 0.000 claims description 2
- 239000003911 antiadherent Substances 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims description 2
- 239000008184 oral solid dosage form Substances 0.000 claims description 2
- 229920001577 copolymer Polymers 0.000 claims 1
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 108
- 238000009472 formulation Methods 0.000 abstract description 29
- 238000004090 dissolution Methods 0.000 abstract description 28
- PAFZNILMFXTMIY-UHFFFAOYSA-N Cyclohexylamine Chemical class NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 abstract description 18
- 239000004615 ingredient Substances 0.000 abstract description 5
- 230000002354 daily Effects 0.000 abstract description 4
- 239000007909 solid dosage form Substances 0.000 abstract description 2
- 239000003826 tablet Substances 0.000 description 122
- 239000003814 drug Substances 0.000 description 34
- 230000035492 administration Effects 0.000 description 30
- 229940079593 drugs Drugs 0.000 description 29
- 125000004432 carbon atoms Chemical group C* 0.000 description 25
- 150000001875 compounds Chemical class 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- 238000007906 compression Methods 0.000 description 16
- 238000000034 method Methods 0.000 description 16
- 230000036470 plasma concentration Effects 0.000 description 15
- 230000037242 Cmax Effects 0.000 description 14
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 13
- RWRDLPDLKQPQOW-UHFFFAOYSA-N pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 238000002156 mixing Methods 0.000 description 11
- 239000007912 modified release tablet Substances 0.000 description 9
- 241000282414 Homo sapiens Species 0.000 description 8
- 210000002381 Plasma Anatomy 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 8
- 125000002947 alkylene group Chemical group 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 230000000275 pharmacokinetic Effects 0.000 description 8
- 230000036912 Bioavailability Effects 0.000 description 7
- 230000035888 Maximum plasma concentration Effects 0.000 description 7
- 125000003342 alkenyl group Chemical group 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 230000035514 bioavailability Effects 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 238000010521 absorption reaction Methods 0.000 description 6
- 238000007792 addition Methods 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000009826 distribution Methods 0.000 description 6
- 125000004435 hydrogen atoms Chemical class [H]* 0.000 description 6
- 239000011159 matrix material Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000004448 titration Methods 0.000 description 6
- 210000004369 Blood Anatomy 0.000 description 5
- 230000035683 MEAN RESIDENCE TIME Effects 0.000 description 5
- 229920002472 Starch Polymers 0.000 description 5
- 229940032147 Starch Drugs 0.000 description 5
- 239000007899 abuse-deterrent tablet Substances 0.000 description 5
- 231100000494 adverse effect Toxicity 0.000 description 5
- 125000000304 alkynyl group Chemical group 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 238000007922 dissolution test Methods 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- OVDULOGIHPNNKW-UHFFFAOYSA-N 1-(1,3,3,5,5-pentamethylcyclohexyl)pyrrolidine Chemical compound C1C(C)(C)CC(C)(C)CC1(C)N1CCCC1 OVDULOGIHPNNKW-UHFFFAOYSA-N 0.000 description 4
- 230000035533 AUC Effects 0.000 description 4
- 230000036663 AUC0-8 Effects 0.000 description 4
- 108010076119 Caseins Proteins 0.000 description 4
- 206010012289 Dementia Diseases 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- HOKKHZGPKSLGJE-GSVOUGTGSA-N NMDA Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 4
- 125000004450 alkenylene group Chemical group 0.000 description 4
- 125000003710 aryl alkyl group Chemical group 0.000 description 4
- 239000005018 casein Substances 0.000 description 4
- 235000021240 caseins Nutrition 0.000 description 4
- 235000010980 cellulose Nutrition 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 239000001913 cellulose Substances 0.000 description 4
- 150000004677 hydrates Chemical class 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 238000002553 single reaction monitoring Methods 0.000 description 4
- 125000003107 substituted aryl group Chemical group 0.000 description 4
- HNJBEVLQSNELDL-UHFFFAOYSA-N 2-Pyrrolidone Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 3
- 230000036680 AUC0-t Effects 0.000 description 3
- ORILYTVJVMAKLC-UHFFFAOYSA-N Adamantane Chemical class C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 3
- 230000037217 Elimination half-life Effects 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 206010061536 Parkinson's disease Diseases 0.000 description 3
- 229910052770 Uranium Inorganic materials 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- 230000003111 delayed Effects 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 150000003840 hydrochlorides Chemical class 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000006011 modification reaction Methods 0.000 description 3
- 230000003287 optical Effects 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000005204 segregation Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000002194 synthesizing Effects 0.000 description 3
- 230000001225 therapeutic Effects 0.000 description 3
- 229910052721 tungsten Inorganic materials 0.000 description 3
- 229910052727 yttrium Inorganic materials 0.000 description 3
- SNIOPGDIGTZGOP-UHFFFAOYSA-N 1,2,3-propanetrioltrinitrate Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 2
- 208000005881 Bovine Spongiform Encephalopathy Diseases 0.000 description 2
- 206010057668 Cognitive disease Diseases 0.000 description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N Cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
- ZFGMDIBRIDKWMY-PASTXAENSA-N Heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- RUUUZPJNWLBOMQ-UHFFFAOYSA-N N,1,3,3,5,5-hexamethylcyclohexan-1-amine Chemical compound CNC1(C)CC(C)(C)CC(C)(C)C1 RUUUZPJNWLBOMQ-UHFFFAOYSA-N 0.000 description 2
- 102000004868 N-methyl-D-aspartate receptors Human genes 0.000 description 2
- 108090001041 N-methyl-D-aspartate receptors Proteins 0.000 description 2
- 229940014995 Nitroglycerin Drugs 0.000 description 2
- 239000000006 Nitroglycerin Substances 0.000 description 2
- 229960002460 Nitroprusside Drugs 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Octadecanoic acid Natural products CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000004429 atoms Chemical group 0.000 description 2
- 150000003976 azacycloalkanes Chemical class 0.000 description 2
- 230000000903 blocking Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 201000008779 central nervous system disease Diseases 0.000 description 2
- 230000000875 corresponding Effects 0.000 description 2
- 238000001784 detoxification Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 230000003628 erosive Effects 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 230000002496 gastric Effects 0.000 description 2
- 229960003711 glyceryl trinitrate Drugs 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- 230000002209 hydrophobic Effects 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate Chemical class CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 2
- ASPOIVQEUUCDQT-UHFFFAOYSA-N nitroprusside Chemical compound O=N[Fe-2](C#N)(C#N)(C#N)(C#N)C#N ASPOIVQEUUCDQT-UHFFFAOYSA-N 0.000 description 2
- 231100001079 no serious adverse effect Toxicity 0.000 description 2
- 230000036963 noncompetitive Effects 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000005554 pickling Methods 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000000284 resting Effects 0.000 description 2
- 231100000486 side effect Toxicity 0.000 description 2
- 230000000391 smoking Effects 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 201000009032 substance abuse Diseases 0.000 description 2
- 230000002459 sustained Effects 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 238000000844 transformation Methods 0.000 description 2
- 230000001131 transforming Effects 0.000 description 2
- 229910052720 vanadium Inorganic materials 0.000 description 2
- PUSNGFYSTWMJSK-GSZQVNRLSA-N (2R,3R,4S,5R,6R)-2,3,4-trimethoxy-6-(methoxymethyl)-5-[(2S,3R,4S,5R,6R)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxyoxane;1-[[(2R,3R,4S,5R,6S)-3,4,5-tris(2-hydroxypropoxy)-6-[(2R,3R,4S,5R,6R)-4,5,6-tris(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)oxan- 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](OC)O[C@@H]1COC.CC(O)CO[C@@H]1[C@@H](OCC(C)O)[C@H](OCC(C)O)[C@@H](COCC(O)C)O[C@H]1O[C@H]1[C@H](OCC(C)O)[C@@H](OCC(C)O)[C@H](OCC(C)O)O[C@@H]1COCC(C)O PUSNGFYSTWMJSK-GSZQVNRLSA-N 0.000 description 1
- NEVCGYUBKUPZRL-UHFFFAOYSA-N (3,3,5,5-tetramethylcyclohexyl)methanamine Chemical compound CC1(C)CC(CN)CC(C)(C)C1 NEVCGYUBKUPZRL-UHFFFAOYSA-N 0.000 description 1
- OIWONFBTWNCEIA-NXEZZACHSA-N (3R,5R)-3-ethyl-1,1,5-trimethylcyclohexane Chemical compound CC[C@@H]1C[C@@H](C)CC(C)(C)C1 OIWONFBTWNCEIA-NXEZZACHSA-N 0.000 description 1
- PYOLJOJPIPCRDP-UHFFFAOYSA-N 1,1,3-trimethylcyclohexane Chemical compound CC1CCCC(C)(C)C1 PYOLJOJPIPCRDP-UHFFFAOYSA-N 0.000 description 1
- WCBGLHDVUJFUDO-UHFFFAOYSA-N 1,3,3-trimethyl-5,5-dipropylcyclohexan-1-amine Chemical compound CCCC1(CCC)CC(C)(C)CC(C)(N)C1 WCBGLHDVUJFUDO-UHFFFAOYSA-N 0.000 description 1
- QTXWDXKTMLBHIW-UHFFFAOYSA-N 1,3,3-trimethylcyclohexan-1-amine Chemical compound CC1(C)CCCC(C)(N)C1 QTXWDXKTMLBHIW-UHFFFAOYSA-N 0.000 description 1
- PMNUOTQOFZGNNQ-UHFFFAOYSA-N 1,3,5-trimethylcyclohexan-1-amine Chemical compound CC1CC(C)CC(C)(N)C1 PMNUOTQOFZGNNQ-UHFFFAOYSA-N 0.000 description 1
- MGNZXYYWBUKAII-UHFFFAOYSA-N 1,3-Cyclohexadiene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 1
- BADMBUCXLGEWNJ-UHFFFAOYSA-N 1,3-dimethyl-3-propylcyclohexan-1-amine Chemical compound CCCC1(C)CCCC(C)(N)C1 BADMBUCXLGEWNJ-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N 1,4-Butanediol, dimethanesulfonate Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- UVJHQYIOXKWHFD-UHFFFAOYSA-N 1,4-Cyclohexadiene Chemical compound C1C=CCC=C1 UVJHQYIOXKWHFD-UHFFFAOYSA-N 0.000 description 1
- AEWYCWAJLDLBGX-UHFFFAOYSA-N 1-(1,3,3,5-tetramethylcyclohexyl)pyrrolidine Chemical compound C1C(C)CC(C)(C)CC1(C)N1CCCC1 AEWYCWAJLDLBGX-UHFFFAOYSA-N 0.000 description 1
- QVEQDLBYFRYKKW-UHFFFAOYSA-N 1-(1,3,5-trimethylcyclohexyl)pyrrolidine Chemical compound C1C(C)CC(C)CC1(C)N1CCCC1 QVEQDLBYFRYKKW-UHFFFAOYSA-N 0.000 description 1
- ZNVKFZVNJWBJGZ-UHFFFAOYSA-N 1-(1-ethyl-3,3,5,5-tetramethylcyclohexyl)pyrrolidine Chemical compound C1CCCN1C1(CC)CC(C)(C)CC(C)(C)C1 ZNVKFZVNJWBJGZ-UHFFFAOYSA-N 0.000 description 1
- LODZBBPOQRJCTJ-UHFFFAOYSA-N 1-(3,3,5,5-tetramethyl-1-propylcyclohexyl)pyrrolidine Chemical compound C1CCCN1C1(CCC)CC(C)(C)CC(C)(C)C1 LODZBBPOQRJCTJ-UHFFFAOYSA-N 0.000 description 1
- JURFVVKQIRIWBJ-UHFFFAOYSA-N 1-(3,3-diethyl-1,5,5-trimethylcyclohexyl)pyrrolidine Chemical compound C1C(CC)(CC)CC(C)(C)CC1(C)N1CCCC1 JURFVVKQIRIWBJ-UHFFFAOYSA-N 0.000 description 1
- VZMMNFHWJMVOSI-UHFFFAOYSA-N 1-(3-ethyl-1,3,5,5-tetramethylcyclohexyl)pyrrolidine Chemical compound C1C(CC)(C)CC(C)(C)CC1(C)N1CCCC1 VZMMNFHWJMVOSI-UHFFFAOYSA-N 0.000 description 1
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Abstract
The present invention relates to an immediate release solid oral dosage form containing 1-aminocyclohexanes, preferably memantine or neramexane, and optionally a pharmaceutically acceptable coating, wherein the active ingredient exhibits dose proportionality and is released at a dissolution rate of more than about 80%within about the first 60 minutes following entry of said form into a use environment. The dosage form is direct compressed and has a hardness with the range of between about 3 and 40Kp, exhibits and average Tmax within the range of about 2 to about 8 hours with an acitve ingredient load within the range of about 2.5 to about 150 mg. The formulation allows for dose-proportional compositions for once daily of b.i.d. dosing, while maintaining steady average range of Tmax. The solid dosage form obtained by direct compression may be a drinkable tablet and optionally may not contain lactose in order to reduce the formation of adduct.
Description
FORMULATIONS FOR IMMEDIATE RELEASE OF MEMORANDUM ORAL DOSAGE FORMS
FIELD OF THE INVENTION The present invention relates to solid, pharmaceutical oral dosage forms of compositions of 1-aminocyclohexane compounds which have an immediate release profile, possess advantageous stability profiles and additionally rapidly disintegrate in aqueous solutions. The invention is particularly suitable for solid pharmaceutical dosage forms of 1-aminocyclohexane compounds in which a therapeutically effective amount of the active ingredient is available in the environment of use shortly after administration. These compositions can be provided as dispersible tablets for administration as an aqueous oral solution. In one embodiment, the active ingredient is preferably 1-aminocyclohexane, memantine. In another preferred embodiment, the 1-aminocyclohexane is neramexane.
BACKGROUND OF THE INVENTION The 1-aminocyclohexanes such as memantine (l-amino-3,5-dimethyladamantane) and neramexane (l-amino-1, 3,3,5,5-pentamethylcyclohexane) are non-competitive NMDA receptor antagonists, moderate affinity with strong dependence on voltage and fast blocking / unblocking kinetics. Therefore, there is an existing and continuing need in the art for solid oral formulations of 1-aminocyclohexane compounds and more preferably hydrochloride
memantine (l-amino-3,5-dimethyladamantane hydrochloride) and neramexane mesylate (l-amino-1 mesylate, 3,3,5,5-pentamethylcyclohexane). The solid oral drug compositions or preparations have various release profiles such as an immediate release profile referred to by the FDA guidelines ("Dissolution Testing of Immediate Relay Solid Oral Dosage Forms", issued on 8/1997). , section IV-A) or an extended release profile referred to by the FDA guidelines ("Extended Oral Dosage Forms: Development, Evaluation, and Application of In Vitro / In Vivo Correlations", Food and Drug Administration, CDER, September 1997, page 17). In dissolution test line lines for immediate release profiles, materials which dissolve at least 80% in the first 30 to 60 minutes in solution qualify as immediate release profiles. Therefore, solid dosage forms of immediate release allow the release of most or all of the active ingredient for a short period of time, for example 60 minutes or less, and perform rapid absorption of the possible drug. In contrast, solid oral dosage forms of extended release allow the release of active ingredient over an extended period of time in an effort to maintain therapeutically effective plasma concentrations over similarly extended time intervals, improve compliance of the dosage or modify other pharmacokinetic properties of the active ingredient. The patent of E.U.A. No. 5,382,601 provides solid pharmaceutical dosage forms containing memantine, which have an extended biphasic release profile, with a portion of the drug that is released from
immediate, followed by a sustained release of the rest. The matrix of this formulation contains the casein salt water-soluble and insoluble in water, preferably sodium and calcium caseinate. However, casein has an unpleasant taste; it is associated with an undesirable effect of exacerbating certain side effects, as described in the patent of E.U.A. No. 6,413,556; and exhibits instability when the pH varies. Another concern regarding casein is the possibility of contamination or transmission of bovine spongiform encephalitis (BSE) or another infectious agent since casein is a product derived from animals. A general method for preparing modified-release N-methyl-D-aspartate (NMDA) receptor antagonists has been described in the U.S.A. No 6, 194,000. This method involves preparing an instant release component and a modified release component to arrive at a final formulation. The patent describes formulations consisting of encapsulated spheres previously coated using organic solvent based systems. However, this patent does not specifically describe compositions containing memantine or neramexane. The patent also does not show how the release rates affect the Tmax (time for maximum plasma concentration) and whether this procedure will result in proportional dose formulations. Currently, a dosing regimen of memantine is used twice a day using immediate release tablets not proportional to the dose. After oral administration in man, memantine is completely absorbed (absolute bioavailability of approximately 100%). The time for maximum plasma concentrations (Cmax) after oral doses of 10 to 40
mg of memantine vary between 3 and 7 hours, where peak plasma concentrations (Cma) after a single oral dose of 20 mg vary between 22 and 46 ng / ml. The values of AUC and Cmax of memantine increase proportionally with the dose over the dosage range of 5 to 40 mg. The elimination half-life (Ti / 2) of
memantine is approximately 60-80 hours. There is a need for memantine formulations proportional to the dose which are easily obtained with immediate release formulations. The advantages of dose-proportional, immediate-release formulations include improved ease of administration by allowing implements in the dose without increasing the
The number of tablets that need to be administered, and increased flexibility in the administration of the medicament by allowing the target drug to be administered either as multiple of lower strength formulations or as a higher strength formulation. Another advantage of the formulations proportional to the dose of highly soluble and highly permeable medicines, particularly those
of memantine and neramexane, is that the bioavailability of multiple forces, for example 10 mg versus 80 mg, is considered identical and in accordance with the guidelines of "Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate." Reléase Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System ", US Department of Health and Human Services, Food and Drug Administration. The administration of increasing doses of medication is often required as part of a titration regimen for dose increase to the desired therapeutic dose because such regimens result in improved tolerability. In fact, the current guide lines for the use of memantine in the treatment of
Alzheimer's recommended that memantine be administered at an initial dose of 5 mg / day and that it be increased to a dose of 20 mg / day with weekly increments in the 5 mg dose. Dosage-proportional formulations are especially important for the treatment of diseases, both for neuropathic pain, which requires titration by dose increase, up to higher doses. The existing formulations of immediate release, proportional to the dose of different forces of memantine ranging from 2.5 mg to 80 mg would therefore allow ease and convenience in dosing during the titration phase by dose increase as well as drug maintenance at higher therapeutic dose levels.
BRIEF DESCRIPTION OF THE INVENTION According to the present invention, it has now been found that 1-aminociclohexanes, such as memantine (l-amino-3,5-dimethyladamantane) and neramexane (l-amino-1, 3,3,5 , 5-pentamethylcyclohexane) and its salts, which include the hydrochloride salt, bromohydrate, mesylate as well as other pharmaceutically acceptable salts, can be formulated in an immediate release dosage form with dose proportional bioavailability and advantageous stability profiles wherein the Dosage forms preferably disintegrate rapidly. The formulation of the present invention includes 1-aminocyclohexanes, such as memantine (l-amino-3,5-dimethyladamantane) and neramexane (1-amino-1,3,5,5,5-pentamethylcyclohexane) and optionally a pharmaceutically acceptable coating. , and one or more excipients to be administered in a single oral dosage form, preferably once a day. Alternatively, the dosage form can be
administer twice a day, with approximately 4 to approximately 8 hours between each administration. Preferably, the dosage form is a tablet or an aqueous solution of the dispersed tablet. Specifically, the present invention provides a dosage form which immediately releases the active agent, for example memantine or neramexane, at a rate of about 80% or more within the first 60 minutes after the entry of the dosage form into an environment of use. Preferably, the dosage form is released to this extent within the first 30 minutes, more preferably within the first 15 minutes. In the present invention, the Tmax for the memantine-containing dosage forms is obtained in a time interval that averages from about 3 hours to about 7 hours after the entry of the dosage forms into the environment of use. Preferably, the time interval averages between about 4 hours and about 6 hours. The Tmax of the dosage forms containing neramexane is obtained at a time interval that averages from about 2 hours to about 8 hours after the entry of the dosage form into the environment of use. Preferably, the time interval averages between about 3 and about 8 hours. In specific embodiments wherein the active ingredient is memantine hydrochloride, the active ingredient of the present invention is usually present in amounts ranging from about 2% w / w to about 20% w / w. Preferably, the amounts vary from about 3.2% w / w to about 10% w / w, more preferably from about 3.9% w / w
up to about 8.4% w / w, based on the weight of the complete dosage form. In specific embodiments wherein the active ingredient is meramexane mesylate, the active ingredient of the present invention is usually present in amounts ranging from about 2% w / w to about 50% w / w. Preferably, the amounts range from about 2% w / w to about 40% w / w, more preferably from about 3% w / w to about 25% w / w. In the present invention, the preferred optional pharmaceutically acceptable coating contains hydroxypropylmethylcellulose such as Opadry ™ (Colorcon, West Point, PA) or Sepifilm ™ (Seppic, NJ) present in amounts ranging from about 2% w / w to about 7% w / w. , preferably from about 2% w / w to about 5% w / w. In suitable embodiments, the formulation contains filler materials such as starch and starch derivatives, hydrated sugar alcohols, calcium phosphates and cellulose-based excipients and derivatives thereof. The oral dosage form of the present invention may additionally comprise one or more pharmaceutically acceptable carriers, excipients, antibiotics, stabilizing agents, binders, colorants, disintegrants, fluidizers and lubricants. In another embodiment of the present invention, the dosage forms contain excipients having improved stability, forming less than 3.0% w / w of lactose adduct, preferably less than 2.5% w / w, by storage
for 36 months at room temperature. The present invention discovered the formation of lactose adduct, which is not a reaction of anticipated adduct formation. A person skilled in the art will recognize that an adduct, such as a lactose adduct, is formed by the Maillard reaction between the analogous active ingredient of 1-aminocyclohexane and a lactose excipient. In one embodiment, dosage forms containing microcrystalline cellulose filler material, which is present in amounts ranging from about 10% w / w to about 35% w / w, wherein the compositions additionally comprise lactose monohydrate, preferably from about 18% w / w to about 22% w / w. Such a dosage form has less than 3% adduct formation, in 36 months. In alternative embodiments, where lactose (or any other reducing agent) is not present, the microcrystalline cellulose filler material is present in amounts ranging from about 20% w / w to about 95% w / w, preferably at amounts ranging from about 60% w / w to about 90% w / w. Such dosage forms exhibit less than 0.5% adduct formation in 36 months. In another embodiment of the present invention, the dosage forms contain the magnesium stearate lubricant, which is present in amounts ranging from about 0% to about 2% w / w, preferably in amounts ranging from about 0.2% to about 0.5% p / p. In another embodiment, the dosage forms contain an excipient which supports the disintegration of the formulation. This excipient may be based on
starch or derivatives thereof, based on cellulose or derivatives thereof, or based on pyrrolidone or a derivative thereof, in amounts ranging from about 0.2 to 10% w / w. In a preferred embodiment, the composition is in the form of a tablet. The tablet form has a hardness of from about 3 to about 40 Kp. Preferably, the hardness is from about 4 to about 30 Kp. A person skilled in the art will recognize that the hardness of the tablet is also related to the shape and size of the tablets.
BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph of memantine-mediated plasma concentrations (ng / ml) after administration of two 10 mg memantine hydrochloride immediate release tablets of the present invention, separated by four hours (black circle) in subjects of healthy masculine and feminine gender, young with respect to time (hours) elapsed since administration. The results of two modified release tablets (white circle and inverted triangle) are also shown in the graphs. Figure 2 is a graph of the logarithm of mean plasma concentrations of memantine (ng / ml) after administration of two 10 mg immediate-release memantine hydrochloride tablets separated by four hours (treatment A, 30 min release) (black circle) or modified release tablets (treatments B and C, release 6 hours and 12 hours), tablets (white circle and inverted triangle) in subjects of the male genders
and healthy, young women against the time elapsed (hours) since the administration. Figure 3 shows the mean plasma concentrations of memantine (ng / ml) after the administration of two memantine hydrochloride immediate release tablets of 10 mg of the present invention with a difference of four hours (treatment A) (circle black) or modified release tablets prepared using the matrix formula containing HPMC (treatments B and C) (white circle and inverted triangle) in subjects of the healthy, young male and female gender, against time (hours) during first 24 hours after administration. Figure 4 shows the dissolution of memantine hydrochloride tablets of 5 mg. The solution is shown as a dissolved percentage with respect to time (hours). Figure 5 shows the dissolution of memantine hydrochloride tablets of 10 mg. The solution is shown as the dissolved percentage with respect to time (hours). Figure 6 shows the dissolution of memantine hydrochloride tablets of 15 mg. The solution is shown as the dissolved percentage with respect to time (hours). Figure 7a shows the dissolution of memantine hydrochloride tablets of 20 mg, lot A. The solution is shown as the percentage dissolved with respect to time (hours). Figure 7b shows the dissolution of memantine hydrochloride tablets of 20 mg, lot B. The solution is shown as the percentage dissolved with
with respect to time (hours). Figure 8 shows the dissolution of 80 mg memantine hydrochloride tablets. The solution is shown as the dissolved percentage with respect to time (hours). Figure 9 presents a graph of the dissolution of memantine with microcrystalline cellulose (ie, lactose free) at a strength of 5 mg using Prosolv ™ (a mixture of microcrystalline cellulose and colloidal silicon dioxide) and at a strength of 20 mg using Avicel ™ ( microcrystalline cellulose) against time (hours) from its administration.
DETAILED DESCRIPTION OF THE INVENTION In accordance with the present invention, there is provided an immediate release pharmaceutical composition for the administration of 1-aminocyclohexane, preferably memantine or neramexane and a pharmaceutically acceptable salt thereof, to a human or animal subject, wherein the The composition includes oral solid dosage forms, preferably in the form of a tablet. In the present invention, the pharmaceutical compositions comprise a therapeutically effective amount of 1-aminocyclohexane, preferably memantine (free base) or neramexane (free base) or a pharmaceutically acceptable salt thereof, preferably the hydrochloride salt and optionally a pharmaceutically acceptable coating, as well as, optionally one or more carriers, fillers, antiadherents, excipients, stabilizing agents, binders, colorants, disintegrants, fluidizers and lubricants (all, pharmaceutically acceptable).
Memantine (l-amino-3,5-dimethyladamantane) and neramexane (1-amino-1, 3,3,5,5-pentamethylcyclohexane) can be considered an analog of 1-aminocyclohexane (described, for example, in US Patent Nos. 4,122,193; 4,273,774; 5,061, 703) and are systemically active, non-competitive NMDA receptor agonists having a low to moderate affinity for the receptor and a strong voltage dependency and fast blocking / unblocking kinetics. These pharmacological characteristics allow memantine and neramexane to block sustained activation of the receptor under pathological conditions and rapidly leave the NMDA channel during normal physiological channel activation. Memantine and salts thereof (eg, hydrochloride salt, MW 215.77) are indicated for the treatment of CNS diseases such as Alzheimer's disease. Memantine has been approved in the United States for the treatment of Alzheimer's disease and has now been approved outside the United States as an oral formulation for Alzheimer's disease and Parkinson's disease and has been commercially available since 1982. It is currently under investigation for the treatment of neuropathic pain. The 1-aminocyclohexane compounds of the present invention having NMDA antagonist activity can be represented in the general formula (I):
where:
R * is - (A) n- (CR'R2) m-NR3R4, n and m are integers, and n + m = 0, 1 or 2, A is selected from the group consisting of lower alkyl of 1 to 6 carbon atoms , linear or branched, straight or branched alkenyl of 2 to 6 carbon atoms and straight and branched alkynyl of 2 to 6 lower carbon atoms; 1 2 R and R are independently selected from the group consisting of hydrogen, linear or branched lower alkyl of 1 to 6 carbon atoms, lower straight or branched alkenyl of 2 to 6 lower carbon atoms, lower alkynyl of 2 to 6 lower carbon atoms linear or branched, substituted aryl and arylalkyl; R3 and R4 are independently selected from the group consisting of hydrogen, linear or branched lower alkyl of 1 to 6 carbon atoms, lower straight or branched alkenyl of 2-6 carbon atoms and lower alkynyl of 2 to 6 lower carbon atoms linear or branched, or together they form alkylene of 2 to 10 carbon atoms or alkenylene of 2 to 10 carbon atoms, or together with N form a
azacycloalkane or azacycloalkene of 3 to 7 members, which includes substituted (C 1-6 -alkyl) alkyl, alkenyl of 2 to 6 carbon atoms, azacycloalkane or azacycloalkene of 3 to 7 members; or independently R3 or R4 can be linked with Rp, Rq, Rr or Rs to form an alkylene chain -CH (R6) - (CH2) t-, where t = 0 or 1 and the left side of the alkylene chain is attached to U or Y and the right side of the alkylene chain is attached to N or R6 is selected from the group consisting of hydrogen, linear or branched lower alkyl of 1 to 6 carbon atoms, linear lower 2 to 6 carbon alkenyl or branched, linear or branched lower alkyl alkynyl of 2 to 6 carbon atoms, aryl, substituted aryl and arylalkyl; or independently R3 or R4 is
can bind with R5 to form an alkylene chain represented by the formula -CH2-CH2-CH2- (CH2) t-, or an alkenylene chain represented by the formulas -CH = CH-CH2 (CH2) t-, -CH = C = CH- (CH2) t. or -CH2-CH = CH- (CH2) t, where t = 0 or 1, and the left side of the alkylene or alkenylene chain is attached to W and the right side of the alkylene chain is attached to N; R5 is independently selected from the group consisting of hydrogen, linear or branched lower alkyl of 1 to 6 carbon atoms, straight or branched lower carbon atom of 2 to 6 alkenyl and linear or branched lower alkynyl of 2 to 6 carbon atoms, or R5 is combined with the carbon to which it is attached and the next carbon of the adjacent ring to form a double bond; Rp, Rq, Rr and Rs are independently selected from the group consisting of hydrogen, linear or branched lower alkyl of 1 to 6 carbon atoms, straight or branched lower alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms linear or branched lower carbon, cycloalkyl of 3 to 6 carbon atoms and aryl, substituted aryl and arylalkyl, or Rp, Rq, Rr and Rs independently can form a double bond with U or with Y or to which they are attached, or Rp, Rq, Rr and Rs can be combined together to represent a lower alkylene - (CH2) X or a lower alkenylene bridge where x is 2-5, inclusive, alkylene bridge which, in turn, can be combined with R5 to form a alkylene bridge - (CH2) and additional lower or lower alkenylene, wherein x is 1-3, inclusive; and the ring defined by U-V-W-X-Y-Z represents an optionally unsaturated cyclohexane ring wherein U, W and Y represent carbon atoms and V, W and Z each independently represent a carbon atom, CH or CH2 (or the
- In definitions of U, W, Y on the one hand and V, X and Z can be inverted, which include the corresponding placement of the groups R, R *, R5, Rp, Rq, Rr and Rs, it being understood that the requirements of The valence of the ring atoms are respected and include optical isomers, diastereoisomers, polymorphic forms, enantiomers, hydrates, pharmaceutically acceptable salts and mixtures of compounds within the formula (I). The ring defined by U-V-W-X-Y-Z is preferably selected from the group consisting of cyclohexane, cyclohex-2-ene, cyclohex-3-ene, cyclohex-l, 4-diene, cyclohex-l, 5-diene, cyclohex-2,4-diene and cyclohex-2,5-diene. The compounds of formula I can be adamantyl substances. Non-limiting examples of 1-aminocyclohexane compounds used according to the invention include 1-aminoalkylcyclohexane derivatives which are selected from the group consisting of: 1-amino-1, 3,5-trimethylcyclohexane; 1-amino-1 (trans), 3 (trans), 5-trimethylcyclohexane; 1-amino-1 (cis), 3 (cis), 5-trimethylcyclohexane; 1-amino-1,3,3,5-trimethylcyclohexane; l-amino-l, 3,3,5,5-pentamethylcyclohexane (neramexane), 1-amino-1, 3,5,5-tetramethyl-3-ethylcyclohexane, l-amino-1, 5,5-trimethyl-3 , 3-diethylcyclohexane, 1-amino-1,5,5-trimethyl-cis-3-ethylcyclohexane, 1-amino- (1S, 5S) cis-3-ethyl-1, 5,5-trimethylcyclohexane, 1-amino- 1, 5, 5-trimethyl-trans-3-ethylcyclohexane, 1-amino- (1R, 5S) trans-3-ethyl-1,5,5-trimethylcyclohexane;
l -amino-l-ethyl-3,3,5,5-tetramethylcyclohexane, l-amino-l-propyl-3,3,5,5-tetramethylcyclohexane, N-methyl-1-amino-1,3,3, 5,5-pentamethylcyclohexane, N-ethyl-l-amino-1, 3,3,5,5-pentamethylcyclohexane, N- (1, 3,3, 5, 5-pentamethylcyclohexyl) pyrrolidine, 3,3,5,5 -tetramethylcyclohexylmethylamine, l-amino-l-propyl-3,3,5,5-tetramethylcyclohexane, l-amino-l, 3,3,5- (trans) -tetramethylcyclohexane (axial amino group) 3-propyl hemihydrate l, 3,5,5-tetramethylcyclohexylamine, l-amino-l, 3,5,5-tetramethyl-3-ethylcyclohexane, l-amino-l, 3,5-trimethylcyclohexane, 1-amino-1,3-dimethyl- 3-propylcyclohexane, l-amino-l, 3 (trans), 5 (trans) -trimethyl-3- (cis) -propylcyclohexane,
1 - . 1 - . 1 - . 1-amino- 1, 3-dimethyl-3-ethylcyclohexane, 1-amino-1, 3,3-trimethylcyclohexane, cis-3-ethyl-1 (trans) -3 (trans) -5-trimethylcyclohexamine, 1-amino- 1, 3 (trans) -dimethylcyclohexane, 1, 3,3-trimethyl-5,5-dipropylcyclohexylamine, 1-amino-1-methyl-3 (trans) -propylcyclohexane, 1-methyl-3 (cis) -propylcyclohexylamine, 1 -amino-l-methyl-3 (trans) -ethylcyclohexane, l-amino-l, 3,3-trimethyl-5 (cis) -ethylcyclohexane, 1-amino-1,3,3-trimethyl-5 (trans) - ethylcyclohexane,
cis -3-propyl-1,5,5-trimethylcyclohexylamine, trans-3-propyl-l, 5,5-trimethylcyclohexylamine, N-ethyl-l, 3,3,5,5-pentamethylcyclohexylamine, N-methyl- 1 - amino-1, 3,3,5,5-pentamethylcyclohexane, 1-amino-1-methylcyclohexane, N, N-dimethyl-1-amino-1, 3,3,5,5-pentamethylcyclohexane,
2- (3,3,5,5-tetramethylcyclohexyl) ethylamine, 2-methyl-1- (3,3,5,5-tetramethylcyclohexyl) propyl-2-amine, 2- (1, 3,3,5 hemihydrate , 5-pentamethylcyclohexyl-1) -ethylamine,
N- (1, 3,3,5,5-pentamethylcyclohexyl) -pyrrolidine, 1-amino-1,3 (trans), 5 (trans) -trimethylcyclohexane, 1-amino-1,3 (cis), 5 (cis) ) -trimethylcyclohexane, l-amino- (lR, SS) trans-5-ethyl-l, 3,3-trimethylcyclohexane,
1-amino- (1 S, SS) cis-5-ethyl- 1, 3, -trimethylcyclohexane, 1-amino-1,5,5-trimethyl-3 (cis) -isopropyl-cyclohexane, 1-amino-1, 5,5-trimethyl-3 (trans) -isopropyl-cyclohexane,
1-amino-1-methyl-3 (cis) -ethyl-cyclohexane, l-amino-l-methyl-3 (cis) -methyl-cyclohexane, 1-amino-5,5-diethyl- 1, 3, 3 - trimethyl-cyclohexane, l-amino-l, 3,3,5,5-pentamethylcyclohexane, l-amino-l, 5,5-trimethyl-3,3-diethylcyclohexane, l-amino-l-ethyl-3,3, 5,5-tetramethylcyclohexane, N-ethi 1- 1 -amino- 1,3,3,5,5-pentamethylcyclohexane,
N- (1, 3,5-trimethylcyclohexyl) pyrrolidine or piperidine, N- [1, 3 (trans), 5 (trans) -trimethylcyclohexyl] pyrrolidine or piperidine, N- [1, 3 (cis), 5 (cis) -trimethylcyclohexyl] pyrrolidine or piperidine, N- (1, 3,3,5-tetramethylcyclohexyl) pyrrolidine or piperidine, N- (1, 3,3,5,5-pentamethylcyclohexyl) pyrrolidine or piperidine, N- (1, 3, 5,5-tetramethyl-3-ethylcyclohexyl) pyrrolidine or piperidine, N- (1, 5,5-trimethyl-3,3-diethylcyclohexyl) pyrrolidine or piperidine, N- (1, 3,3-trimethyl-cis-5- ethylcyclohexyl) pyrrolidine or piperidine, N - [(l S, SS) cis-5-ethyl-l, 3,3-trimethylcyclohexyl] pyrrolidine or piperidine, N- (l, 3,3-trimethyl-trans-5-ethylcyclohexyl) pyrrolidine or piperidine, N - [(lR, SS) trans-5-ethyl, 3,3-trimethylcyclohexyl] pyrrolidine or piperidine, N- (l-ethyl-3,3,5,5-tetramethylcyclohexyl) pyrrolidine or piperidine, N - (1-propyl-3,3,5,5-tetramethylcyclohexyl) pyrrolidine or piperidine, N- (1, 3,3,5,5-pentamethylcyclohexyl) pyrrolidine, its optical isomers, diastereoisomers, enantiomers, hydrates, its pharmaceutical salts Y mixtures thereof. Neramexane (l-amino-1, 3,3,5,5-pentamethylcyclohexane) is described in the document No. 6,034,134, which is incorporated herein by reference in its entirety. Some 1-aminocyclohexane derivatives of the general formula (I) include three axial alkyl substituents, for example Rp, Rr and R5 all together form compounds (termed 1-aminoadamantanes) illustrated by the formulas Ilb
Some 1-aminocyclohexane derivatives of formula (I) wherein n + m = 0, U, V, W, X, Y, and Z form a cyclohexane ring and one or both of R3 and R4 independently bind to the cyclohexane ring via Alkylene bridges formed by Rp, Rq, Rr, Rs or R5 are represented by the following formulas IlIa-IIIc:
Illa Hlb nic where Rq, Rr, Rs Rr and R5 are as defined above for the formula (I), R6 is hydrogen, lower alkyl straight or branched carbon atoms, alkenyl of 2 to 6 atoms of linear or branched lower carbon, linear or branched lower alkyl alkynyl of 2 to 6 carbon atoms, aryl, substituted aryl or arylalkyl, and is saturated or can be combined with R6 to form a carbon-
hydrogen with the carbon of the ring to which it is attached, 1 = 0 or 1 and k = 0, 1 or 2 and represents a single or double bond. Non-limiting examples of 1-aminocyclohexane compounds used in accordance with the invention include 1-aminodamantane and its derivatives which are selected from the group consisting of: 1-amino-3-phenylalanine, 1-amino-methyladamantane, 1-amino-3 , 5-dimethyladamantane (memantine), 1-amino-3-ethyladamantane, 1-amino-3-isopropyladamantane, 1-amino-3-n-butyladamantane, l-amino-3,5-diethyladamantane, 1-amino-3, 5-diisopropyladamantane, 1-amino-3, 5-di-n-butyladamantane, 1-amino-3-methyl-5-ethyladamantane, 1-N-methylamino-3, 5-dimethyladamantane, 1-N-ethylamino-3, 5-dimethyladamantane, lN-isopropyl-3,5-dimethyladamantane, lN, N-dimethylamino-3,5-dimethyladamantane, lN-methyl-N-isopropylamino-3-methyl-5-ethyladamantane, 1-amino-3-butyl- 5-phenylalanomane, 1-amino-3-pentyladamantane, 1-amino-3, 5-dipentyladamantane,
l-amino-3-pentyl-5-hexylanediamine, l-amino-3-pentyl-5-cyclohexylardamantane, l-amino-3-pentyl-5-phenylalanine, 1-amino-3-hexylanediamine, 1-amino-3, 5-dihexylamdamantane, l-amino-3-hexyl-5-cyclohexyldamantane,
1 - . 1 - . 1 - . 1 - . 1 - . 1-amino-3-hexyl-5-phenylamanamane, 1-amino-3-cyclohexyldamantane, 1-amino-3,5-dicyclohexyldamantane, l-amino-3-cyclohexyl-5-phenylalanine,
1-amino-3, 5-diphenylammantane, 1-amino-3,5,7-trimethyladamantane, 1-amino-3, 5-dimethyl-7-ethyladamantane,
1-amino-3, 5-diethyl-7-methyladamantane, derivatives of 1-N-pyrrolidino and 1-N-piperidine, l-amino-3-methyl-5-propyladamantane,
1-amino-3-methyl-5-butyladamantane 1-amino-3-methyl-5-pentyladamantane, 1-amino-3-methyl-5-hexylamantane, l-amino-3-methyl-5-cyclohexylamantane,
1-amino-3-methyl-5-phenylamanamantane, 1-amino-3-ethyl-5-propyladamantane, 1-amino-3-ethyl-5-butyladamantane,
1 - . 1-amino-3-ethyl-5-pentyladamantane, 1-amino-3-ethyl-5-hexylardamantane, l-amino-3-ethyl-5-cyclohexylamantane, 1-amino-3-ethyl-5-phenylalanine, 1 - amino-3-propyl-5-butyladamantane, l-amino-3-propyl-5-pentyladamantane, 1-amino-3-propyl-5-hexylanediamine, 1-amino-3-propyl-5-cyclohexylanediamine, 1-amino- 3-propyl-5-phenylamanamantane, 1-amino-3-butyl-5-pentyladamantane, 1-amino-3-butyl-5-hexylamantane, l-amino-3-butyl-5-cyclohexyldamantane, its optical isomers, diastereomers, enantiomers, hydrates, N-methyl,?,? - dimethyl, N-ethyl, N-propyl derivatives, their pharmaceutically acceptable salts and mixtures thereof. Memantine (1-amino-3, 5-dimethyladamantane) for example is the subject matter of the patents of US Pat. Nos. 4,122,193 and 4,273,774, both incorporated herein by reference in their entirety. Neramexane, for example, is the subject matter of the patent of E. U. A. No. 6,034,134, incorporated herein in its entirety. The 1-aminodamantane compounds of the formulas Ilb and lid, which include memantine, are generally prepared by alkylation of halogenated adamantanes, preferably bromine or chlordamantanes. The adamantanes di- or tri-
substituted adamantanes are obtained by additional processes of halogenation and alkylation. The amino group is introduced either by oxidation with chromium oxide or bromination with HBr or bromination with bromine and reaction with formamide followed by hydrolysis. The amino function can be rented according to generally accepted methods. The methylation can be carried out, for example, by reaction with chloromethyl formate and subsequent reduction. The ethyl group can be introduced by reduction of the respective acetamide. For more details regarding the synthesis see, for example, the patents of E.U.A. Nos. 5,061,703 and 6,034,134. Additional synthesis techniques for the above compounds can be found in the applications of E.U.A. published Nos. 2003/0166634 and 2004/0034055, all incorporated as a reference in their entirety. According to the invention, the 1-aminocyclohexane derivatives of formula (I) can be applied as such or they can be used in the form of their pharmaceutically acceptable salts. Suitable salts of the compound include, but are not limited to, acid addition salts such as those made with hydrochloric, methylsulfonic, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, pyruvic acids, malonic, succinic, maleic, fumaric, maleic, tartaric, citric, benzoic, carbonic, cinnamic, mandelic, methanesulfonic, ethanesulfonic, hydroxyethane sulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexansulfamic, salicylic, p-aminosalicylic, 2-phenoxybenzoic and 2-acetoxybenzoic; salts made with saccharin. In a preferred embodiment, the salt is memantine hydrochloride (Ci2H2iN-HCl, MW 215.77). In another preferred embodiment, the salt is neramexane mesylate (CnH23N-CH403S, MW 265.42). The terms "sales"
they may also include addition salts of free acids. All of these salts (or other similar salts) can be prepared by convenient means. All of said salts are acceptable provided they are non-toxic and do not substantially interfere with the desired pharmacological activity. The present invention also includes all individual enantiomers, diastereoisomers, racemates and other isomers of these compounds, wherein said structural variations are possible. The invention also includes all polymorphic and solvate forms, such as hydrates and those formed with organic solvents, of these compounds. Such isomers, polymorphic forms and solvates can be prepared by methods known in the art, for example by crystallization from different solvents or by regiospecific or enantioselective synthesis and resolution, based on the description provided herein. The present invention includes derivatives of the compound of the present invention. Examples of derivatives applicable to the invention include, but are not limited to, structurally related compounds consisting of a tricyclic 10-carbon ring having an amino group such as the nitroxymethanamine derivatives (such as nitroprusside, nitroglycerin or a derivative that generates NO of nitroprusside or nitroglycerin and U.S. Patent Nos. 5,234,956 and 5,455,279). In a preferred embodiment, the active ingredient is memantine hydrochloride. The active ingredient is present in generally varying amounts, from about 2.5 mg to about 80 mg, preferably ranging from about 5 mg to about 60 mg. In
a preferred embodiment, the compositions contain between about 2% and about 20% w / w of memantine; preferably, from about 3.2% to about 10% w / w of memantine; more preferably from about 3.9% to about 8.4% w / w of memantine. In another preferred embodiment, the active ingredient is neramexane mesylate. The active ingredient is present in amounts that vary widely from about 6.25 mg to about 150 mg, preferably ranging from about 12.5 mg to about 125 mg. The active ingredient, for example neramexane mesylate in the oral dosage form of the present invention is usually present in amounts ranging from about 2% w / w to about 50% w / w. Preferably, the amounts range from about 2% w / w to about 40% w / w, more preferably from about 3% w / w to about 25% w / w. Optionally, the immediate release dosage form has a coating applied or deposited over the entire surface of a unit release core. The immediate release of the drug is carried out by any of the various methods known in the art which include the use of a very thin layer or coating, which, by virtue of its thinness (ie, less than about 100 microns) is penetrated quickly by the gastric fluid allowing rapid leaching of the drug. In the present invention, examples of coating materials that rapidly disintegrate and disperse include lactose and microcrystalline cellulose, colloidal silicon dioxide, hydrophilic polymers such as hydroxypropylmethylcellulose,
PVA, methacrylates (for example Eudragit ™ Rohm Pharma Polymer, Piscataway, NJ), natural polymers such as xanthan gum and combinations thereof (for example Prosolv ™, which contains microcrystalline cellulose and colloidal silicon dioxide). In formulations with a lactose-free environment, colloidal silicon dioxide may be necessary in addition to the use of microcrystalline cellulose, for example Avicel ™. These materials may also be present as excipients in addition to the common auxiliary agents and additives or fillers including tableting aids., colorants, binders, fillers, fluidizers and lubricants (all pharmaceutically acceptable). In a preferred embodiment of the invention, hydroxypropylmethylcellulose is used as a coating material. The optional coating material is present in amounts ranging from about 1 mg to about 70 mg, preferably from about 3 mg to about 60 mg, more preferably from about 3 mg to about 40 mg. In a preferred embodiment, the compositions contain from about 2% w / w to about 5% w / w of coating material containing hydroxypropylmethylcellulose; more preferably from about 2% to about 4% w / w of coating material containing hydroxypropylmethylcellulose. The fillers or disintegrants act to modify the dissolution pattern. Examples of such fillers include lactose monohydrate, microcrystalline cellulose, Prosolv ™, hydroxypropylmethylcellulose and combinations thereof. When lactose monohydrate is used, it counteracts the ingredients
less soluble of the composition and thus acts as a disintegrant, while microcrystalline cellulose and a similar type filler material, when used in a lactose-free environment, may require additional disintegrants such as croscarmellose sodium. Disintegrants and dosage forms may additionally contain an excipient to support the disintegration of the formulation. A person skilled in the art recognizes that these excipients may be based on starch, based on cellulose or based on pyrrolidone or a derivative thereof, in amounts ranging from about 0.2 to 10%. When hydroxypropylmethylcellulose or ethylcellulose is used in a matrix tablet, the dissolution rates are much lower than the immediate release rate that is targeted, that is because the hydrophobic matrix tablets that result when these polymers release the drug by polymeric erosion mechanism. Since the erosion from a hydrophobic matrix is very slow, the dissolution rate of the easily soluble active ingredient is also slow. In one embodiment of the present invention in a formulation containing memantine, lactose monohydrate is used as a filler. The lactose monohydrate is present in amounts ranging from about 40 mg to about 1400 mg, preferably from about 80 mg to about 1050 mg. In another embodiment, the compositions contain from about 50% to about 80% w / w of lactose monohydrate, preferably from about 60% w / w to about 75% w / w. The lactose adduct formation is less than 3% w / w,
more preferably less than 2.5% w / w. In a preferred embodiment of the invention containing memantine, microcrystalline cellulose (MCC) is used as a filler. In formulations containing lactose monohydrate, MCC is used as an additional filler material present in amounts ranging from about 13 mg to about 420 mg, preferably from about 25 to about 315 mg per unit dose. In one embodiment, MCC is present in amounts from about 10% w / w to about 35% w / w, preferably from about 18% w / w to about 22% w / w. If MCC is used as the filling material in the absence of lactose monohydrate, MCC is present in an amount ranging from about 50 mg to about 1600 mg, preferably from about 100 mg to about 1200 mg per unit dose. In a preferred embodiment, the compositions contain from about 20% w / w to about 95% w / w microcrystalline cellulose; more preferably, from about 60% w / w to about 90% w / w. The microcrystalline cellulose provides the desired dissolution profiles with a formulation and with acceptable or improved processing properties. A person skilled in the art will recognize that these formulations based on microcrystalline cellulose contain disintegrants. The disintegrants are excipients based on starch, based on cellulose or based on pyrrolidone, or based on a derivative of any of the foregoing, in amounts ranging from about 0.2 to 10% w / w. Other excipients such as these can also be used in combination
such as talc (a non-stick), starch, dicalcium phosphate, mannitol, croscarmellose sodium, colloidal silicon dioxide, sodium starch glycolate. The use of the soluble disintegrants or fillers allows a rapid disintegration of the tablets which exposes a large surface area and the drug leads to a faster dissolution of said medicament. Additionally, the dosage forms contain excipients that form less than 3.0% adduct, preferably less than 2.5%, even 0% in lactose-free formulations. A person skilled in the art will recognize that substances such as memantine and neramexane adducts result from the Maillard reaction. Adducts such as lactose or other reducing sugar adducts can be formed with the amines in adamantane derivatives. The tablets according to this invention can be prepared by conventional mixing, comminution and tableting technique which are well known in the pharmaceutical formulation industry. The immediate release tablet, for example, can be manufactured by direct compression by punches and dies coupled in a rotary press for tabletting, ejection or compression molding, granulation followed by compression or formation of a paste and expulsion of the paste in a mold or cut of the extrudate in short lengths followed by compression. As mentioned in the foregoing, the immediate release component can be applied as a coating on the core by spraying, dipping or pan-coating, or as an additional layer by tabletting or compression. Preferably, the process used to prepare tablets is direct compression of the mixture, usually, direct mixing is a
difficult procedure and problems may occur such as segregation of the mixture, low compressibility or low content uniformity. However, none of the formulations described in this invention nor any of the processes for their preparation present these problems, or said problems are substantially less significant. Spectroscopic methods of near IR show good distribution of the drugs in the tablets. When making tablets by direct compression, the addition of lubricants can be useful and sometimes it is important to promote the flow of powder and to avoid the "fragmentation" of the tablet (the rupture of a portion of the tablet) when the pressure is released. Useful lubricants are magnesium stearate and hydrogenated vegetable oil (preferably hydrogenated and refined triglycerides of stearic and palmitic acids). In a preferred embodiment, magnesium stearate is used as a lubricant in an amount from about 0 mg to about 6 mg, preferably from about 0.3 mg to about 4.0 mg. In a preferred embodiment, the compositions contain from about 0% w / w to about 2% w / w magnesium stearate; more preferably, from about 0.2% w / w to about 0.5% w / w magnesium stearate. Additional excipients may be added to improve the hardness of the tablet, the fluidity of the powder and to reduce the friability of the tablet and the adhesion to the die wall. The hardness of the tablet is affected linearly by different compression forces, shape and size of the tablet. As the compression forces (kN) increase, there is a linear increase in the hardness of the tablet (Kp).
Preferably, the hardness values range from about 3 to about 40 Kp, more preferably from about 4 to about 30 Kp. In addition, at a lower compression and therefore lower hardness values, for example less than 3 Kp, the logo and product identification can be erased from the engraving and "eliminated" which makes reading difficult and aesthetically less pleasant. At higher compression and hardness values, the deletion is eliminated without affecting the solution at 30 minutes (see example 1). the plasma concentration of the immediate-release memantine formulations proportional to the dose have a maximum plasma concentration time (Tmax) in human patients ranging from about 3 to about 7 hours, with a higher frequency that averages between about 4 and about 6. hours, and an in vitro release rate of greater than about 80% in about 60 minutes, more preferably in about 30 minutes. The plasma concentration of the proportional immediate release formulations in the neramexane dose have a maximum plasma concentration time (Tmax) ranging from about 2 to about 8 hours, with a higher frequency that averages between about 2 and about 7 hours at a rate of in vitro release greater than about 80% in about 60 minutes, more preferably in about 30 minutes. The pharmaceutical formulations of the present invention allow the compositions to be proportional to the doses and the modification of the Cmax to the
change the strength of the formulation without substantially affecting the drug's Tmax. The 30 minute immediate release formulations described in the present invention provide desired Tmax without compromising the initial peak (Cmax), which is characteristic of the memantine or neramexane salts. In addition, a long value allows either an administration twice a day, or preferably once a day, for an immediate release dosage form and obtains a relatively high Cmax which is considered essential for the pharmacological efficacy of the product . For example, the Cma for 20 mg of memantine (administered as two tablets of 10 mg, with a difference of 4 hours) can be in the range of approximately 15 to approximately 40 ng / ml with an average value of approximately 25 ng / ml. If the dosage form of memantine or neramexane is administered twice a day, administrations are separated by approximately 4 hours, the average Tmax is approximately 8 hours ± 2 hours. In addition, the proportionality of the dose allows titration by dose increase to begin with lower doses for patients using an essentially identical formulation composition and by essentially varying only the weight content of memantine or neramexane to obtain different strengths. In accordance with the present invention, there is provided an immediate release pharmaceutical composition for daily administration once a day or, if preferred, twice a day, of memantine or a pharmaceutically acceptable salt thereof, preferably its HC1 salt, a a human or animal subject. In accordance with the present invention a pharmaceutical release composition is provided
Immediate for administration once a day, or if preferred, twice a day, of neramexane or a pharmaceutically acceptable salt thereof, preferably its mesylate salt, to a human or animal subject. In an alternative embodiment of the invention, the rapid dissolution profile of the tablets allows ingestible solutions to be elaborated for patients incapable of ingesting tablets. The memantine and neramexane formulations of the invention are suitable for the treatment of CNS diseases including but not limited to the treatment of Alzheimer's disease, Parkinson's disease, AIDS dementia (U.S. Patent No. 5,506,231, see also Parsons et al., Neuropharmacology 1999 June; 38 (6); 735-67), neuropathic pain (U.S. Patent No. 5,334,618), cerebral ischemia, epilepsy, glaucoma, hepatic encephalopathy, multiple sclerosis, stroke, depression (US patent No 6,479,553), tardive dyskinesia, malaria, Borna virus, hepatitis C (U.S. Patent Nos. 6,034,134 and 6,071,966). Additional pathologies for the treatment in which memantine is suitable are described in the patents of US Pat. Nos. 5,614,560 and 6,444,702. Accordingly, the present invention additionally provides a method for the therapeutic or prophylactic treatment of CNS disorders in a human or animal subject, the method includes administering to the subject a composition according to the present invention. As used herein, the term "adduct formation" refers to the formation of a compound with a particular formation of a composition by a solid phase reaction. The general term "adduct" for a
A compound, also called an addition compound, results from the direct combination of two or more different compounds. For example, in the present invention, the formation of a lactose adduct can be produced with formulations containing lactose. Such adduct formation impairs the efficacy of the product and increases the risks of other side effects. As used herein, a "therapeutically effective amount" means the amount of a compound that, when administered to a mammal to treat a condition, disorder or condition, is sufficient to carry out said treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated. According to the present invention in one embodiment, a therapeutically effective amount of memantine is an amount effective to treat CNS disorders, which includes Alzheimer's disease or Parkinson's disease. Other uses include, but are not limited to, the treatment of dementia and depression. The effective amount of the drug for pharmacological action and therefore the strength of the tablet depends on the disease itself, for example in Alzheimer's disease, the patient is initially given a dose of 5 mg and the dosage is progressively increased up to 10 mg twice a day or up to 20 mg once a day. Titration procedures by raising similar doses, but starting with higher base amounts (for example, starting values ranging from about 12 to about 15 mg, and titrating by dose increase to about 80 mg) are useful for pain relief , for example neuropathic pain. This titration can be facilitated by providing a selection of tablets that
present standard or common doses, for example 5 mg, 10 mg, 15 mg, 20 mg, 40 mg and 80 mg of active substance. Therefore, it is important to have a formulation proportional to the dose. As used herein, the term "pharmaceutically acceptable" refers to biologically or pharmacologically compatible for in vivo use and preferably means approved by a regulatory agency of federal or state government or included in the U. S-Pharmacopeia or other pharmacopoeia generally recognized for use in animals, and more particularly in humans. As used herein, the term "treating" and its derivatives are used herein to mean the release or alleviation of pain in a hypersensitive mammal or in a mammal suffering from a CNS disorder, e.g. dementia or disease of Parkinson. The term "treat" may mean releasing or relieving the intensity and / or duration of a manifestation of disease experienced by a subject in response to a given stimulus (e.g., pressure, tissue damage, cold temperature, etc.). For example, in relation to dementia, the term "treat" may mean releasing or alleviating cognitive impairment (such as memory impairment or orientation) or impairment of overall functioning (activities of daily living, ADL) or decrease or reversal of the progressive deterioration in ADL or cognitive impairment. Within the meaning of the present invention, the term "treating" also means suppressing, delaying the onset (i.e., the period before the clinical manifestation of a disease) or reducing the risk of developing or worsening a disease. The term "protect" is used herein to mean avoiding a delay or treating, or all, as appropriate, the development or continuation or aggravation of a disease in a subject. Inside of the
In the ing of the present invention, dementia is associated by a CNS disorder that includes, without limitation, neurodegenerative diseases such as Alzheimer's disease (AD). The term "pickling" refers to the detachment of material (such as a film fragment) from the surface of one tablet upon contact with another object and its adherence to the surface of the other object (such as another tablet or tool) (see Pharmaceutical Dosage Forms: Tablets volume 3, edited by HA Lieberman and L. Lachman, pp. 101 and 272 (Marcel Dekker, Inc. 1982)). The pickling can occur, for example, when the tablets are compressed or placed in a rotating drum. The material that is separated can obscure or hide logos, monograms, letters and numbering which are intended to appear on the surface of the tablet. The term "dose proportional", as used herein, refers to the relationship between the dose of a drug and its bioavailability. For example, in the present invention, twice the amount of the same composition for making a dosage form that will be delivered twice the drug, will provide the same bioavailability (ie AUC and Cmax) as a dose of the dosage form. The proportionality of the dose of the present invention is applied to a wide range of doses as discussed in detail herein. The term "about" or "about" s within a range of error acceptable to the particular value, determined by a person ordinarily skilled in the art, which will depend, in part, on how the value is ured or determined, ie, the limitations of the urement system. For example,
"approximately" may within 1 or more than 1 standard deviations, as practiced in the art, alternatively, "approximately" with respect to the compositions may more or less a range of up to 20%, preferably from up to 10%, more preferably up to 5%. Alternatively, particularly with respect to biological systems or processes, the term may within an order of magnitude, preferably within 5 multiples and more preferably within 2 multiples of a value. When particular values are described in the application and the claims, unless otherwise stated, the term "approximately" s within a range of error acceptable to the particular value. For example, with reference to a period of time, for example hours, the current values (+ 20%) are more applicable. Therefore, 6 hours can be, for example, 4.8 hours, 5.5 hours, 6.5 hours, 7.2 hours as well as the usual 6 hours. The term "use environment," when applied to formulations, s the gastric fluids of a patient in whom the formulation is administered or a simulated dissolution medium. EXAMPLES The present invention will be better understood with reference to the following examples, which are provided as exemplary of the invention and in no way limitation. EXAMPLE 1 Preparation of Modified Release Tablets of Hydrochloride
memantine The present example describes the process of developing immediate release tablets of memantine hydrochloride in dosages of 2.5, 5, 10, 15, 20, 40, 60 and 80 mg. MATERIALS AND METHODS The following tables provide for the constitution of immediate release tablets that include the active components, coating agent and other excipients for the specified dosage forms with specific target release time periods. Tables 1 and 2 provide the constitution of the tablets with lactose and contain the same data expressed respectively in absolute terms (mg) or relative (%, w / w).
Table 1 Proportional dose formulations 2.5 mg to 80 mg (with lactose / MCC)
For the proportional dose formulations of Table 1, the percentage w / w for each active ingredient and excipients are as identified in Table 2
Table 2 Weights in% w / w of the tablet (lactose / MMC)
Table 3a-3c and table 4 also provide in the constitution of lactose-free tablets and contain the same data expressed respectively in absolute terms (mg) or relative (% w / w)
Table 3a Proportional formulations at doses of 2.5 mg to 80 mg (without lactose)
* The weight of the core can be adjusted with filling materials to +/- 10%, based on the densities of the filling materials. Prosolv ™ is a mixture of microcrystalline cellulose and colloidal silicon dioxide
Table 3b Proportional formulations at a dose of 6.25 mg 125 mg (without lactose)
Exact composition of the formula (Composition in mg per tablet)
* The weight of the core can be adjusted with recycled materials to +/- 10%, based on the densities of the filling materials.
Table 3c. Formulations proportional to the dose of 10 mg to 80 mg for memantine tablets, 10 mg to 80 mg of high drug loading (lactose free) with a smaller tablet size Composition in mg per tablet
* The weight of the core can be adjusted with filling materials to +/- 10%, based on the densities of the filling materials. ** The colloidal silicon dioxide may not be used For the proportional dose formulations of Table 3 c, the percentage w / w for each of the active ingredients and excipients is identified in Table 4.
Table 4. Weights in% w / w of the tablet (without lactose) of all potencies, including a high drug load
The test batches of each of the tablets are prepared according to the procedures indicated in the following.
Preparation of the combination for tablet preparation (lactose / MC s) Approximately half of the amount of microcrystalline cellulose and active drug is placed in a cone mixer of 20 cubic feet Colloidal silicon dioxide is sieved with the rest of the cellulose microcrystalline through a 0.71 mm sieve and added to the cone mixer of 20 cubic feet.The components are mixed for 6 minutes with the intensifier bar turned off.Lactose monohydrate (when requested in the formula) and talcum powder They are screened through 0.71 mm and added to the cone mixer.The contents of the mixer are mixed for 20 minutes with the intensifier bar turned off.The magnesium stearate is sieved through a filter of approximately 0.8 mm and is added to the cone mixer The mix is combined for an additional 5 minutes with the intensifier bar turned off A person skilled in the art will recognize that for the MCC and other materials fill, the above procedures can be modified. A person skilled in the art will recognize that alternating addition and mixing methods are also acceptable. During the process of making the tablets, before compression in the form of a tablet, an initial batch of mixed product is combined for 2 hours, with samples that are obtained over the period of time. The samples are tested for segregation. Compression of the tablets The mixture is compressed using a rotary tablet press. The tablets are compressed at different compression forces ranging from 5 to 25 Kp and are tested for hardness of physical properties, dissolution, thickness, friability and uniformity of content. For dissolution tests,
Tablets of different hardness are tested using USP apparatus II using 900 ml with pH 1.2 buffer. The tablets are passed through a tablet dust remover and a metal verifier after compression. The tablets are then coated in a perforated coating pan. Tests are also carried out to study the effect of the coating on the solution and stability. The tablets are coated with Opadry (containing hydroxypropylmethylcellulose) material. A dissolution test apparatus at 100 rpm is used to generate results. Alternative dissolution methods, for example 50 rpm using an appropriate USP device is also acceptable. Samples are collected after various levels of weight gain (based on the amount of coating) and tested for dissolution at 15, 30 and 45 minutes. To determine stability, the coated tablets are placed in a chamber under 40 ° C / 75% RH accelerated conditions in an open container, for three months. The dissolution test is carried out at 15, 30 and 45 minutes. Near IR spectroscopy. The near infrared (near IR) for the immediate release formulation of memantine is performed with an Infrared Chemical Imaging System (Spectral Dimension, Olney, MD). The cross section of the tablet is measured and a single channel image at 1692 nm is used as a marker for memantine. The domain rich in memantine is measured by showing the distribution of the active ingredient. Different batches of memantine immediate release tablets are analyzed in triplicate. The data analysis shows that the distribution of memantine between the different lots is similar.
Results and Discussion The samples obtained during the 2-hour mixing test do not present perceivable mixing separation. The results show that the ingredients of the formula allow a good distribution of the active ingredient and that, once combined, the active ingredient remains uniformly distributed through the matrix of the tablet. A mixing time of 20 minutes (400 revolutions) is selected as the preferred mixing time. A lack of significant displacements in the particle size distribution is observed regardless of the mixing time, which indicates that no measurable particle attrition is carried out during mixing. The results are well within the limits of the uniformity tests of USP content for tablets. The results of the effect of the compression force on the hardness of the tablet show that as the compression force (kN) increases, there is also a linear increase in the hardness of the tablet (kP). Similarly, as the compression force increases, there is a linear decrease in tablet thickness (inches). An unfavorable development during compression is the appearance of adhesions between tablets. Lower punches are recorded with the force of the tablet (5, 10 or 20) and the upper punches with "FP". The adhesion to the punches, particularly the "P" is observed at lower compression forces. The production of harder tablets eliminates the problem of adhesion. The effect of the hardness of the tablet in the solution is further evaluated. The data show that hardness has an effect on dissolution. This effect is observed only for the 15 minute time point, which is related
with the disintegration of the tablets. Complete release is obtained for the 30 minute time point. The proposed dissolution specification for the product is not less than 80% dissolved in 30 minutes. Based on the data, a higher tablet hardness is required to avoid that the adhesion has no effect on the dissolution specification. The data for hardness and dissolution values are presented in tables 5a and 5b and in the following tables 6a and 6b.
Table 5 Dissolution of non-coated core tablets of memantine hydrochloride of different hardness
Table 5 Solution of neuramexan mesylate core tablets of different hardness (lactose-free filler)
Table 6 Dissolution of the tablets coated with memantine hydrochloride, different hardness
Table 6b Solution of neramexan mesylate coated tablets
The friability of the tablet is tested since the product is coated with film to mask the characteristic taste of the drug. Generally, the friability values are very low, indicating good mechanical integrity for the tablets. The content of the tablet is observed to determine uniformity, and in all cases the tablets have a low variability content. The initial dissolution test is also carried out. Memantine hydrochloride is highly soluble and a highly permeable drug. An objective solution of not less than 80% in 30 minutes is desired in order to support a classification in the biopharmaceutical classification system (BCS) class 1 for the drug. The tablets also show a rapid dissolution (greater than 80% in 30 minutes) even at very high hardness (20 Kp for 20 mg tablets).
The results of the study also show that the coating process and the coating level have no effect on the dissolution and stability of the final products. No significant changes were observed after three months under extreme conditions, demonstrating the stability of the formulations. The designed dry mixing process is very resistant to mixing segregation and is not sensitive to the particle size distribution of the active principle or the mixture. The tablets show good mechanical integrity (with a compressive force of 10 kN for 5 mg tablets) and a good uniformity of content. Two methods are used to reduce the agglomeration of memantine particles: 1) increase in the proportion of diluents compared to the drug, which reduces the available trajectory for interaction; 2) when mixing the active principle and the diluents for an appropriate time.
EXAMPLE 2 Pharmacokinetic Study of Memantine The present example demonstrates the bioavailability of immediate release memantine tablets compared to modified release memantine tablets.
MATERIALS AND METHODS The study design in the present example is an open-label, single-center, 57-day study in 24 healthy and young subjects, with ages ranging from 18 to 35 years. Subjects underwent evaluation for inclusion in the
study, consisting of a complete medical history, a complete physical examination with vital signs, a 12-electrode ECG, clinical laboratory evaluations consisting of CBC (including differential), clinical chemistry, urinalysis, RPR / VDRL, HIV testing 1 and 2, an analysis of drugs of abuse (including alcohol and nicotine), anti-HCV antibodies and HbsAg. The subjects of the female gender underwent the ß-hCG serum test for pregnancy performed at the time of the analysis for inclusion in the test and a urine pregnancy test on day -1. The inclusion criteria include informed consent, normal physical examination, and belonging to a group of healthy adults between 18 and 35 years of age, without smoking habit, within 15% of the ideal body weight in relation to height and a heart rate. in sitting position not less than 50 beats per minute by palpitation, and a heart rate of not less than 50 beats per minute, recorded by ECG. Criteria for exclusion include hypersensitivity to memantine or other NMDA antagonists, presence of any clinically significant disease, systolic blood pressure at rest greater than 180 mmHg or less than 100 mmHg, or resting resting blood pressure greater than 100 mmHg or less 60 mmHg at the time of initial analysis, significant abnormalities on the ECG, history of alcohol or substance abuse, positive results of drug abuse tests, caffeine intake within 48 hours or alcohol within 72 hours hours before the test, participation in other clinical investigations within the last 30 days of the study, clinical conditions associated with memantine, concomitant medications and the fact that women breastfeed or not.
There are three treatment regimens that include a 10 mg tablet of memantine hydrochloride immediate release (IR) (30 minute solution, ie, treatment A), one 20 mg tablet of modified release memantine hydrochloride (MR) (formulation I, 6 hour solution, ie treatment B) and a second 20 mg tablet of modified release memantine hydrochloride (formulation II, 12 hour solution, ie treatment C). Modified release formulations contain different compositions to obtain release rates < 70% drug release in approximately 6 hours and approximately 12 hours. Subjects received all three treatments on study days 1, 22 and 43 in a cross-way separated by a detoxification period of 21 days based on randomized treatment sequences. The immediate release treatment is administered on day 1 at 0800 and 1200 hours. Modified release treatments are administered on day 1 at 0800 hours. After the detoxification periods, the subjects undergo cross-exchange for the other treatment (MR or IR). Formulations B and C are set forth in detail in the co-pending application filed simultaneously with the present application, proxy file number 03269/1200817-US1. The subjects were included in a non-smoking environment at approximately 1900 hours on days -1, 21 and 42. There were a total of six overnight stays for each subject (days -1, 1, 21, 22, 42 and 43). The subjects underwent both diet and fluid control and did not receive concomitant medications. During the course of the study, vital signs and adverse events were recorded. Blood samples are obtained from each subject during the development of the study
for the determination of memantine at 1, 22 and 43 days of study after administration of the drug at 0800 hours in the following times: hour 0.0 (before the dose), every hour during the first 12 hours, 14, 24 , 36, 48, 72, 96, 144, 192, 240, 288 and 336 hours after the dose. During the development of the study approximately 390 ml of blood was collected from each subject (including before the study, after the study and a follow-up clinical analysis). A total of 72 plasma samples were collected during the study for pharmacokinetic analysis. The blood samples for the determination of memantine concentration are collected by a qualified phlebotomist using Vacutainer ™ with green top tubes, of 5 ml previously cooled (containing sodium heparin as an anticoagulant). Approximately 5 ml of blood are collected directly in 5 ml freshly-capped Vacutainer ™ tubes with green cap (which contain sodium heparin) after dosing on days 1, 22 and 43. Blood samples are centrifuged in the following 30 minutes from the time of extraction at 2,500 g for 10 minutes at 4 ° C and the plasma is harvested and transferred into forest-coded polypropylene tubes previously cooled. The samples are then frozen instantly in an isopropyl alcohol / dry ice bath and stored in a freezer at -70 ° C. Bioanalytical procedures. The bioanalytical procedure used to measure plasma concentrations of memantine is validated to demonstrate precision, linearity, reproducibility and precision of analytical procedures. A LC / MS / MS method (liquid chromatography / mass spectroscopy / tandem mass spectroscopy) is developed for the determination of memantine in
human plasma. After the addition of 10 ng of internal standard of [H6] -memantine and 0.5M sodium carbonate buffer to plasma standards and samples, the compounds are extracted with ethyl acetate. The organic layer is isolated and dried at room temperature under vacuum in a sample concentrator (Savant). The dry residue is analyzed after reconstitution in mobile phase. The components of the reconstituted samples are separated on a Zorbax SB-C8 column (150 x 4.6 mm, 3.5 μ) and detected by chemical ionization at atmospheric pressure (APCI) with selected reaction monitoring (SRM) in ion mode positive. The SRM uses precursor positive product ions of m / z 180 -_? 163 and m / z 186 169 to monitor memantine and its internal standard, respectively. The protonated molecular ions of memantine and [2H] -memantine are the precursor ions for the SRM mode. The ratio of peak ion height of memantine product to its internal standard is the response used for quantification. The plasma standards of the method validation show an accuracy of + 8.2% deviation and the accuracy does not exceed 7.6% CV. The precision for the determination of memantine in plasma quality controls is within + 8.8% deviation with an accuracy that does not exceed 9.8% CV. The lower limit of quantification of the method is 0.5 ng / ml. Pharmacokinetic analysis. Pharmacokinetic parameters were calculated using the WinNonlin program (version 3.3, Pharsight Corporation, Mountain View, CA). The following parameters were determined from the plasma concentrations of memantine after the administration of a single dose: the area under the plasma concentration time curve (AUC0.t ,, AUC0-24i and AUC0-8),
the maximum plasma concentration (Cmax), the maximum plasma concentration time (Tmax), the elimination half-life (? ^) and the mean residence time (MRT). The maximum plasma concentrations (Cmax) and the time of maximum concentration (Tmax) for memantine were determined by observation. The first order velocity constant, ??, which describes the terminal decline in plasma, is calculated by WinNonlin (version 3.3) using logarithmic linear regression of the terminal linear phase of the memantine mean-time plasma concentration curves. The estimates of terminal elimination half-life (Tm), in hours, are calculated with equation 1: T 0.693. , i1 / 2 = equation 1
The low area of plasma concentration versus time curve to the last measurable concentration at time t (AUC0-t) or at 24 hours (AUCo-24) is calculated by numerical integration using the linear trapezoidal rule (equation 2).
A UC0_ = ¿0.5 · (C, - C,.,) · (T, -) Equation 2 = 2
where C i is the plasma concentration at the corresponding sampling time point t ,. The area under the curve of plasma concentration-time to the infinite moment (AUCo-8) of memantine is calculated using the following (equation 3):
AUC0_8 = -4C C0_, equation 3
where Ciast is the last measurable concentration in the profile of
concentration-time.
MRT is calculated using the following (equation 4):
MRT = ^ UMC cuacjon 4 AUC0_8
where AUMC is the area below the first moment curve.
The descriptive statistics for the pharmacokinetic parameters of
Memantine Cmax, tmax, AUC0-t, AUCo-24, AUCo-8, n and MRT are provided for
subjects who completed the study.
RESULTS
Adverse events. There are no serious adverse events reported.
Nineteen (82.6%) of the twenty-three subjects reported a total of 42 adverse events
emerging in the treatment after the administration of treatments A, B and C.
There are no differences in the number of adverse events observed with treatment
any. A total of 14, 12 and 16 adverse events were observed after the
treatments A, B and C, respectively. The most common adverse events (ie,
that occur in three or more subjects) were headache, dizziness, flatulence and infection.
Pharmacokinetic results. The mean plasma concentrations of
memantine are illustrated in Figure 1 (linear scale) and Figure 2 (scale
semilogarithmic). The graphs in figures 1 and 2 show the results of three treatments. In FIG. 3, the differences are additionally shown. Figure 3 shows the mean plasma concentrations of memantine during the first 24 hours after dosing. The concentration of memantine peak is highest after the administration of the IR formulation (treatment A) and the lowest after the administration of formulation II MR (treatment C). The mean (+ SD) of pharmacokinetic parameters of memantine after treatments A, B and C are listed in table 7.
Table 7
Table 8 below shows the statistical comparisons of memantine parameters
Table 8
The absorption of memantine from modified release tablets is delayed compared to an immediate release tablet. The speed and the degree of absorption of memantine are reduced after administration of the modified release formulations compared to the formulation of
immediate release. Importantly, the absorption rate (Tmax) is delayed by 8.2 hours for the IR tablet (ie, twice a day administered approximately 4 hours after the administration of the first tablet up to 12.1 hours and 19.3 for the tablets I and II modified release, respectively). The 90% confidence intervals for the comparison of the logarithmic transformations of Cmax, AUC0-24, AUCo-t and AUC0-8 for treatment A (tablet IR) versus treatment B (formulation I MR) show a mean Cmax value significantly greater but not in the values of the AUC parameter. The 90% confidence intervals for the comparison of the logarithmic transformations of Cmax, AUCo-24, AUC0-t and AUC0-8 for treatment A (IR tablet) versus treatment C (formulation II MR) are significantly higher in the mean values of Cmax and AUC. These results demonstrate that IR tablets improve bioavailability compared to modified release formulations. There are no statistically significant effects with respect to gender based on the elimination half-life and the adjustment in weight of the Cmax, AUC0- t and AUC0-8 values after administration of the IR formulation.
DISCUSSION In this study, it was found that single daily doses of 20 mg of memantine, administered as two doses of 10 mg of immediate-release tablet, separated by a 4-hour interval, are safe and well tolerated. There was no
serious adverse events observed in this study. The speed and the degree of absorption of memantine is greater after the administration of the immediate release tablets. The Cmax values averaged 24.92, 20.37 and 17.48 ng / ml for the immediate-release tablet (treatment A, 30-minute release), formulation I of the modified-release tablet (treatment B, 6-hour release) and formulation II of the Modified release tablet (treatment C, 12 hour release), respectively. The average AUCo-8 1969, 1827 and 1730 ng.h / ml for the immediate-release tablet (treatment A), the modified release tablet formulation I (treatment B) and the modified release tablet formulation II (treatment C) ), respectively. The mean Tmax was 8.2 hours, 12.1 hours and 19.3 hours, for treatments A, B and C, respectively. The delayed Tmax for two modified release formulations is indicative of a slower absorption rate compared to the immediate release tablets. These results demonstrate that the desired release characteristics are obtained for both modified and immediate release formulations.
EXAMPLE 3 Preparation of 30 minute immediate release tablets of memantine hydrochloride The present example demonstrates the constitution of memantine tablets of immediate release for 30 minutes, with and without lactose monohydrate.
The methods for producing the tablets are the same as those described in Example 1. Specifically, the tablets are comprised of the following active components, coating agent and other excipients as presented below in Tables 9 and 10. Tables 9 and 10, which summarizes the tablets with lactose monohydrate, contain the same data expressed respectively in absolute terms (mg) or relative (% w / w).
Table 9 30 min release tablets with lactose monohydrate / MCC (weights in mg / tablet)
For the formulations proportional to the dose in Table 10, the percentage intervals for each ingredient are identified in Table 9.
Table 10 Weights in% w / w of tablet with lactose monohydrate
Tables 1 1 and 12, which summarize the tablets with lactose, contain the same data expressed, respectively, in absolute terms (mg) or relative (% W / W) -
Table 11 Release tablets of 30 min, lactose-free (weights in mg / tablet)
For formulations proportional to the dose in Table 1 1, the percentage ranges for each ingredient are identified in Table 2.
Table 12 Pesos% p / p tablet
Figures 4, 5, 6, 7 and 8 show the dissolution of IR tablets of
minutes for 5 mg, 10 mg, 15 mg, two batches of 20 mg and 80 mg, respectively, for the formulation containing lactose monohydrate and MCC. Figure 9 shows the dissolution of 5 mg and 20 mg of lactose-free formulations. In Figure 7, another batch of 20 mg shows 15 minutes is approximately 65% at the initial time point, but greater than 80% at stability. This variation is a variation from one batch to another. The results show that more than 80% of the drug is released in 30 minutes and in many cases more than 80% of the drug is released in 15 minutes.
Adduct formation. An adduct is formed as a result of reaction between memantine with lactose monohydrate and similar excipients, known as reducing sugars. The adduct is not formed in single formulations without lactose / MCC. The adduct formation is detected using the CLAR method with an evaporative light scattering detector. The product stored under ambient conditions for 40 months contains an adduct concentration of up to about 2.5%. In the table 13 the adduct data are presented.
Table 13
It is determined that the adduct concentration is less than about 3%, preferably less than about 2.5% are rated according to ICH Q3B (R) guidelines, FDA Guidelines Rockville, MD. The present invention is not limited in scope by the specific embodiments described herein. In fact, various modifications of the invention, in addition to those described herein, will become apparent to those skilled in the art from the foregoing description and the appended figures. Said modifications are intended to be within the scope of the appended claims. It should also be understood that all values are approximate and are provided for description. Patents, patent applications, publications, product descriptions and protocols are mentioned in this application, the descriptions of which are hereby incorporated by reference in their entirety for all purposes.
Claims (42)
1. An immediate release solid oral dosage form, characterized in that it comprises: (i) an active ingredient that is selected from the group consisting of a 1-aminocyclohexane compound and a pharmaceutically acceptable salt thereof, and (ii) optionally, a pharmaceutically coated acceptable, the dosage form presents dose proportionality and releases the active ingredient at a rate greater than about 80% within about the first 60 minutes after the entry of the form to the environment of use, wherein the dosage form exhibits a Average Tmax within the range of about 2 to about 8 hours with a loading of active ingredient within the range of about 2.5 to about 150 mg and wherein the dosage form is obtained through direct compression.
2. The immediate-release solid oral dosage form according to claim 1, characterized in that the oral dosage form releases the active ingredient at a rate of more than about 80% within the first 30 minutes after the entry of the active form. environment of use.
3. The immediate-release solid oral dosage form according to claim 2, characterized in that the oral dosage form releases the active ingredient at a rate of more than about 80% within the first 15 minutes after the entry of the active form. environment of use.
4. The immediate release solid oral dosage form according to claim 1, characterized in that the active ingredient is memantine hydrochloride.
5. The immediate release solid oral dosage form according to claim 1, characterized in that the active ingredient is neramexane mesylate.
6. The immediate release solid oral dosage form according to claim 4, characterized in that the active ingredient is present in an amount within the range of from about 2% w / w to about 20% w / w.
7. The immediate release solid oral dosage form according to claim 6, characterized in that the active ingredient is present in an amount in the range of about 3.2% w / w to about 10% w / w.
8. The immediate release solid oral dosage form according to claim 6, characterized in that the active ingredient is present in an amount within the range from about 3.9% w / w to about 8.4% w / w.
9. The immediate release solid oral dosage form according to claim 1, characterized in that the pharmaceutically acceptable coating contains hydroxypropylmethylcellulose.
10. The immediate release solid oral dosage form according to claim 1, characterized in that the pharmaceutically acceptable coating contains a copolymer of methacrylic acid-ethyl acrylate.
1. The immediate release solid oral dosage form according to claim 1, characterized in that the pharmaceutically acceptable coating is present in an amount in the range from about 2% w / w to about 7% w / w.
12. The immediate release solid oral dosage form according to claim 11, characterized in that the pharmaceutically acceptable coating is present in an amount within the range of from about 2% w / w to about 5% w / w.
13. The immediate release solid oral dosage form according to claim 1, characterized in that it further comprises one or more carriers, excipients, antiadherents, fillers, stabilizing agents, binders, colorants, disintegrants, fluidizers and lubricants, pharmaceutically acceptable
14. The immediate release solid oral dosage form according to claim 1, characterized in that it further comprises a pharmaceutically acceptable filling material.
15. The immediate release solid oral dosage form according to claim 1, characterized in that it presents an adduct formation to a degree less than 3% w / w.
16. The immediate release solid oral dosage form according to claim 1, characterized in that it has an adduct formation to a degree less than 2.5% w / w.
17. The immediate release solid oral dosage form according to claim 1, characterized in that it presents an adduct formation to a degree less than 0.5% w / w.
18. The immediate release solid oral dosage form according to claim 14, characterized in that the pharmaceutically acceptable filling material is microcrystalline cellulose.
19. The oral solid dosage form of immediate release of according to claim 18, characterized in that the microcrystalline cellulose is present in an amount within the range from about 10% w / w to about 35% w / w, and wherein the solid oral dosage form additionally comprises lactose monohydrate.
20. The immediate release solid oral dosage form according to claim 19, characterized in that the microcrystalline cellulose is present in an amount in the range of about 18% w / w to about 22% w / w.
21. The immediate release solid oral dosage form according to claim 18, characterized in that the microcrystalline cellulose is present in an amount within the range from about 20% w / w to about 95% w / w, wherein the dosage form Oral solid is lactose-free.
22. The immediate release solid oral dosage form according to claim 21, characterized in that the microcrystalline cellulose is present in amounts ranging from about 60% w / w to about 90% w / w.
23. The immediate release solid oral dosage form according to claim 1, characterized in that the oral dosage form solid has a hardness within the range of between about 3 and about 40 Kp.
24. The immediate release solid oral dosage form according to claim 23, characterized in that the solid oral dosage form has a hardness in the range of between about 4 and about 30 Kp.
25. The immediate release solid oral dosage form according to claim 1, characterized in that it also comprises a lubricant.
26. The immediate-release solid oral dosage form according to claim 25, characterized in that the lubricant is magnesium stearate.
27. The immediate release solid oral dosage form according to claim 26, characterized in that the magnesium stearate is present in an amount within the range of from about 0% to about 2% w / w.
28. The immediate release solid oral dosage form according to claim 27, characterized in that the magnesium stearate it is present in an amount within the range of from about 0.2% to about 0.5% w / w.
29. The immediate release solid oral dosage form according to claim 1, characterized in that the solid oral dosage form is a tablet.
30. The immediate release solid oral dosage form according to claim 1, characterized in that the solid oral dosage form comprises: a) between about 2% w / w and about 10% w / w memantine hydrochloride; b) between about 2% w / w and about 5% w / w of hydroxypropylmethylcellulose; c) between about 10% w / w and about 35% w / w microcrystalline cellulose; d) between about 50% w / w and about 70% w / w lactose monohydrate; e) between about 0% w / w and about 3% w / w of colloidal silicon dioxide; f) between about 3% w / w and about 5% w / w talc; and g) between about 0% w / w and about 2% w / w of magnesium stearate.
31. The immediate release solid oral dosage form according to claim 1, characterized in that the solid oral dosage form comprises: a) between about 3.2% w / w and about 10% w / w memantine hydrochloride; b) between about 2% w / w and about 4% w / w hydroxypropylmethylcellulose; c) between about 18% w / w and about 22% w / w microcrystalline cellulose; between about 65% w / w and about 70% w / w lactose monohydrate; e) between about 0% w / w and about 0.5% w / w of colloidal silicon dioxide; f) between about 4% w / w and about 5% w / w talc; and g) between about 0.2% w / w and about 0.5% w / w magnesium stearate.
32. The immediate release solid oral dosage form according to claim 1, characterized in that the solid oral dosage form comprises: a) between about 2% w / w and about 10% w / w of memantine hydrochloride; b) between about 2% w / w and about 5% w / w of hydroxypropylmethylcellulose; c) between about 20% w / w and about 95% w / w microcrystalline cellulose; d) between about 0% w / w and about 3% w / w of colloidal silicon dioxide; e) between about 0% w / w and about 5% w / w talc; and f) between about 0% w / w and about 2% w / w magnesium stearate; g) between about 0% w / w and about 3% w / w croscarmellose sodium.
33. The immediate release solid oral dosage form according to claim 1, characterized in that the solid oral dosage form comprises: a) between about 3.2% w / w and about 10% w / w memantine hydrochloride; b) between about 2% w / w and about 4% w / w hydroxypropylmethylcellulose; c) between approximately 60% w / w and approximately 90% w / w microcrystalline cellulose; d) between about 0% w / w and about 0.5% w / w colloidal silicon dioxide; e) between about 4% w / w and about 5% w / w talc; f) between about 0.2% w / w and about 0.5% w / w magnesium stearate; g) between about 1.8% w / w and about 2.2% w / w croscarmellose sodium.
34. The immediate release solid oral dosage form according to claim 1, characterized in that the solid oral dosage form does not contain lactose.
35. The use of an active ingredient that is selected from the group consisting of memantine and a pharmaceutically acceptable salt of memantine and optionally a pharmaceutically acceptable coating, for preparing an immediate release solid oral dosage form, according to claims 1 to 33, to treat mild, moderate or severe Alzheimer's disease.
36. The use of an active ingredient that is selected from the group consisting of neramexane and a pharmaceutically acceptable salt of neramexane and optionally a pharmaceutically acceptable coating, to prepare a form immediate release solid oral dosage system according to claims 1 to 3 for treating mild, moderate or severe Alzheimer's disease.
37. The use of an active ingredient that is selected from the group consisting of memantine and a pharmaceutically acceptable salt of memantine and optionally a pharmaceutically acceptable coating, for preparing an immediate release solid oral dosage form according to claims 1 to 33, for treat neuropathic pain.
38. The use of an active ingredient that is selected from the group consisting of neramexane and a pharmaceutically acceptable neramexane salt and optionally a pharmaceutically acceptable coating, for preparing an immediate release solid oral dosage form according to claims 1 to 3, for treat neuropathic pain.
39. A method for treating a disorder that is selected from the group consisting of mild, moderate or severe Alzheimer's dementia and neuropathic pain, wherein the method is characterized in that it comprises administering the immediate release solid oral dosage form in accordance with claim 1 .
40. The method according to claim 39, characterized in that the administration is once a day.
41. The method according to claim 40, characterized in that the administration is a dosage twice a day.
42. The method according to claim 41, characterized in that the dosage form is administered with a difference of about 4 hours.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US60/581,244 | 2004-06-17 |
Publications (1)
Publication Number | Publication Date |
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MXPA06014586A true MXPA06014586A (en) | 2008-10-03 |
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