US20170135999A1 - Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations - Google Patents
Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations Download PDFInfo
- Publication number
- US20170135999A1 US20170135999A1 US15/343,902 US201615343902A US2017135999A1 US 20170135999 A1 US20170135999 A1 US 20170135999A1 US 201615343902 A US201615343902 A US 201615343902A US 2017135999 A1 US2017135999 A1 US 2017135999A1
- Authority
- US
- United States
- Prior art keywords
- formulation
- methylphenidate
- coating
- release
- drug
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 269
- 238000009472 formulation Methods 0.000 title claims abstract description 250
- 238000013270 controlled release Methods 0.000 title claims abstract description 111
- 239000003814 drug Substances 0.000 title claims abstract description 86
- 229940079593 drug Drugs 0.000 title claims abstract description 81
- 230000007423 decrease Effects 0.000 title description 4
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims abstract description 125
- 230000000694 effects Effects 0.000 claims abstract description 20
- 230000002035 prolonged effect Effects 0.000 claims abstract description 13
- DUGOZIWVEXMGBE-UHFFFAOYSA-N Methylphenidate Chemical compound C=1C=CC=CC=1C(C(=O)OC)C1CCCCN1 DUGOZIWVEXMGBE-UHFFFAOYSA-N 0.000 claims description 125
- 239000011324 bead Substances 0.000 claims description 125
- 229960001344 methylphenidate Drugs 0.000 claims description 98
- 238000000576 coating method Methods 0.000 claims description 81
- 239000011248 coating agent Substances 0.000 claims description 70
- JUMYIBMBTDDLNG-OJERSXHUSA-N hydron;methyl (2r)-2-phenyl-2-[(2r)-piperidin-2-yl]acetate;chloride Chemical compound Cl.C([C@@H]1[C@H](C(=O)OC)C=2C=CC=CC=2)CCCN1 JUMYIBMBTDDLNG-OJERSXHUSA-N 0.000 claims description 67
- 230000036470 plasma concentration Effects 0.000 claims description 55
- 239000000463 material Substances 0.000 claims description 29
- 239000000758 substrate Substances 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 21
- 230000002209 hydrophobic effect Effects 0.000 claims description 20
- 229960001033 methylphenidate hydrochloride Drugs 0.000 claims description 20
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 19
- 229920001577 copolymer Polymers 0.000 claims description 17
- 230000002051 biphasic effect Effects 0.000 claims description 15
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 13
- 230000009471 action Effects 0.000 claims description 13
- 229920003145 methacrylic acid copolymer Polymers 0.000 claims description 13
- 229940117841 methacrylic acid copolymer Drugs 0.000 claims description 12
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 10
- 230000007935 neutral effect Effects 0.000 claims description 9
- 238000005507 spraying Methods 0.000 claims description 9
- 125000005395 methacrylic acid group Chemical group 0.000 claims description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 7
- 235000021152 breakfast Nutrition 0.000 claims description 7
- 239000002702 enteric coating Substances 0.000 claims description 7
- 238000009505 enteric coating Methods 0.000 claims description 7
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 7
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 7
- 230000004584 weight gain Effects 0.000 claims description 7
- 235000019786 weight gain Nutrition 0.000 claims description 7
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 6
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 6
- 210000002784 stomach Anatomy 0.000 claims description 4
- 230000007012 clinical effect Effects 0.000 claims description 2
- 239000013583 drug formulation Substances 0.000 abstract description 4
- 238000011282 treatment Methods 0.000 description 136
- 238000012360 testing method Methods 0.000 description 67
- 229940099204 ritalin Drugs 0.000 description 49
- 238000010521 absorption reaction Methods 0.000 description 40
- 238000004090 dissolution Methods 0.000 description 40
- 239000012730 sustained-release form Substances 0.000 description 34
- 238000013268 sustained release Methods 0.000 description 33
- 239000000047 product Substances 0.000 description 27
- 239000006185 dispersion Substances 0.000 description 26
- 235000020937 fasting conditions Nutrition 0.000 description 26
- 239000004014 plasticizer Substances 0.000 description 24
- 239000013543 active substance Substances 0.000 description 23
- 210000002381 plasma Anatomy 0.000 description 23
- 239000002775 capsule Substances 0.000 description 22
- 239000012530 fluid Substances 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical group CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 20
- 238000000540 analysis of variance Methods 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 239000002552 dosage form Substances 0.000 description 18
- 229920000058 polyacrylate Polymers 0.000 description 15
- 239000003795 chemical substances by application Substances 0.000 description 13
- 239000003826 tablet Substances 0.000 description 13
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 12
- 239000011162 core material Substances 0.000 description 12
- 210000001035 gastrointestinal tract Anatomy 0.000 description 12
- -1 spheroids Substances 0.000 description 12
- 239000001069 triethyl citrate Substances 0.000 description 12
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 12
- 235000013769 triethyl citrate Nutrition 0.000 description 12
- 239000001856 Ethyl cellulose Substances 0.000 description 11
- 210000004369 blood Anatomy 0.000 description 11
- 239000008280 blood Substances 0.000 description 11
- 229920001249 ethyl cellulose Polymers 0.000 description 11
- 235000019325 ethyl cellulose Nutrition 0.000 description 11
- 229960004667 ethyl cellulose Drugs 0.000 description 11
- 230000006870 function Effects 0.000 description 11
- 239000007903 gelatin capsule Substances 0.000 description 11
- 229920000642 polymer Polymers 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- 239000004615 ingredient Substances 0.000 description 10
- 229920003161 Eudragit® RS 30 D Polymers 0.000 description 9
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 description 9
- 230000008030 elimination Effects 0.000 description 9
- 238000003379 elimination reaction Methods 0.000 description 9
- 239000002245 particle Substances 0.000 description 9
- 238000005070 sampling Methods 0.000 description 9
- 238000007619 statistical method Methods 0.000 description 9
- 229920003151 Eudragit® RL polymer Polymers 0.000 description 8
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 8
- 239000008186 active pharmaceutical agent Substances 0.000 description 8
- 229940088679 drug related substance Drugs 0.000 description 8
- 239000000454 talc Substances 0.000 description 8
- 229910052623 talc Inorganic materials 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- 229920003152 Eudragit® RS polymer Polymers 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- 229920013820 alkyl cellulose Polymers 0.000 description 7
- 230000002902 bimodal effect Effects 0.000 description 7
- 230000001419 dependent effect Effects 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- 238000009506 drug dissolution testing Methods 0.000 description 6
- 235000013305 food Nutrition 0.000 description 6
- 230000002496 gastric effect Effects 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 description 6
- 239000011159 matrix material Substances 0.000 description 6
- 239000007921 spray Substances 0.000 description 6
- 229920000178 Acrylic resin Polymers 0.000 description 5
- 239000004925 Acrylic resin Substances 0.000 description 5
- 230000030136 gastric emptying Effects 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000008188 pellet Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 229920003134 Eudragit® polymer Polymers 0.000 description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 4
- ZFOZVQLOBQUTQQ-UHFFFAOYSA-N Tributyl citrate Chemical compound CCCCOC(=O)CC(O)(C(=O)OCCCC)CC(=O)OCCCC ZFOZVQLOBQUTQQ-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 230000003935 attention Effects 0.000 description 4
- 230000036765 blood level Effects 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 4
- 210000004051 gastric juice Anatomy 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 4
- 229920003157 Eudragit® RL 30 D Polymers 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000012754 barrier agent Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 238000004364 calculation method Methods 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 239000012738 dissolution medium Substances 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 230000009246 food effect Effects 0.000 description 3
- 230000009477 glass transition Effects 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 208000013403 hyperactivity Diseases 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- 239000003456 ion exchange resin Substances 0.000 description 3
- 229920003303 ion-exchange polymer Polymers 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 230000035699 permeability Effects 0.000 description 3
- 239000000049 pigment Substances 0.000 description 3
- 125000001453 quaternary ammonium group Chemical group 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 2
- PYGXAGIECVVIOZ-UHFFFAOYSA-N Dibutyl decanedioate Chemical compound CCCCOC(=O)CCCCCCCCC(=O)OCCCC PYGXAGIECVVIOZ-UHFFFAOYSA-N 0.000 description 2
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 2
- 229920003138 Eudragit® L 30 D-55 Polymers 0.000 description 2
- 229920003136 Eudragit® L polymer Polymers 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 2
- 229920001800 Shellac Polymers 0.000 description 2
- 229920002494 Zein Polymers 0.000 description 2
- 230000003542 behavioural effect Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 description 2
- 230000001079 digestive effect Effects 0.000 description 2
- 229940126534 drug product Drugs 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 238000013265 extended release Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 235000021471 food effect Nutrition 0.000 description 2
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
- 239000001087 glyceryl triacetate Substances 0.000 description 2
- 235000013773 glyceryl triacetate Nutrition 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 239000004922 lacquer Substances 0.000 description 2
- 235000012054 meals Nutrition 0.000 description 2
- 238000002483 medication Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 2
- 239000004926 polymethyl methacrylate Substances 0.000 description 2
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 description 2
- 230000008092 positive effect Effects 0.000 description 2
- 239000003368 psychostimulant agent Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000004208 shellac Substances 0.000 description 2
- 229940113147 shellac Drugs 0.000 description 2
- 235000013874 shellac Nutrition 0.000 description 2
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- 230000000391 smoking effect Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 239000004408 titanium dioxide Substances 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 229960002622 triacetin Drugs 0.000 description 2
- 229920003169 water-soluble polymer Polymers 0.000 description 2
- 239000005019 zein Substances 0.000 description 2
- 229940093612 zein Drugs 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- SJIXRGNQPBQWMK-UHFFFAOYSA-N 2-(diethylamino)ethyl 2-methylprop-2-enoate Chemical compound CCN(CC)CCOC(=O)C(C)=C SJIXRGNQPBQWMK-UHFFFAOYSA-N 0.000 description 1
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 1
- VKNASXZDGZNEDA-UHFFFAOYSA-N 2-cyanoethyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OCCC#N VKNASXZDGZNEDA-UHFFFAOYSA-N 0.000 description 1
- SFPNZPQIIAJXGL-UHFFFAOYSA-N 2-ethoxyethyl 2-methylprop-2-enoate Chemical class CCOCCOC(=O)C(C)=C SFPNZPQIIAJXGL-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 229920002126 Acrylic acid copolymer Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 229920003137 Eudragit® S polymer Polymers 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 206010027603 Migraine headaches Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229920006243 acrylic copolymer Polymers 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229920003144 amino alkyl methacrylate copolymer Polymers 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001062 anti-nausea Effects 0.000 description 1
- 230000003579 anti-obesity Effects 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000003434 antitussive agent Substances 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 239000002830 appetite depressant Substances 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 208000013404 behavioral symptom Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000037058 blood plasma level Effects 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 239000000168 bronchodilator agent Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical class [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000005587 carbonate group Chemical group 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- 239000008199 coating composition Substances 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 230000003931 cognitive performance Effects 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 239000000599 controlled substance Substances 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 239000000850 decongestant Substances 0.000 description 1
- 229940124581 decongestants Drugs 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 229940099371 diacetylated monoglycerides Drugs 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 239000012943 hotmelt Substances 0.000 description 1
- 229920001600 hydrophobic polymer Polymers 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 230000005032 impulse control Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 239000001034 iron oxide pigment Substances 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000007775 late Effects 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 238000009115 maintenance therapy Methods 0.000 description 1
- 239000013563 matrix tablet Substances 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- 150000002734 metacrylic acid derivatives Chemical class 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000005397 methacrylic acid ester group Chemical group 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 230000037023 motor activity Effects 0.000 description 1
- 239000004081 narcotic agent Substances 0.000 description 1
- 238000002670 nicotine replacement therapy Methods 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000003605 opacifier Substances 0.000 description 1
- 229940100691 oral capsule Drugs 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical class OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 238000005498 polishing Methods 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 229920002744 polyvinyl acetate phthalate Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 201000004645 pyromania Diseases 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 239000002195 soluble material Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229920003176 water-insoluble polymer Polymers 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4458—Non condensed piperidines, e.g. piperocaine only substituted in position 2, e.g. methylphenidate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
- A61K9/2846—Poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2893—Tablet coating processes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5089—Processes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
Definitions
- Sustained release dosage forms are central in the search for improved therapy, both through improved patient compliance and decreased incidences of adverse drug reactions. It is the intent of all sustained release formulations to provide a longer period of pharmacologic action after administration than is ordinarily obtained after administration of immediate-release dosage forms. Sustained release compositions may be used to delay absorption of a medicament until it has reached certain portions of the alimentary tract, and maintain a desired concentration of said medicament in the blood stream for a longer duration than would occur if conventional rapid release dosage forms are administered. Such longer periods of response provide for many therapeutic benefits that are not achieved with corresponding short acting, immediate release preparations.
- therapy may be continued without interrupting the sleep of the patient, which is of special importance, for example, when treating a patient for moderate to severe pain (e.g., a post-surgery patient, a cancer patient, etc.), or for those patients who experience migraine headaches on awakening, as well as for the debilitated patient for whom sleep is essential.
- moderate to severe pain e.g., a post-surgery patient, a cancer patient, etc.
- a further general advantage of longer acting drug preparations is improved patient compliance resulting from the avoidance of missed doses through patient forgetfulness.
- a controlled release dosage form will ideally provide therapeutic concentration of the drug in blood that is maintained throughout the dosing interval with a reduction in the peak/trough concentration ratio.
- compositions which provide for sustained release of pharmacologically active substances contained in the compositions after oral administration to humans and animals.
- Sustained release formulations known in the art include specially coated pellets, coated tablets and capsules, and ion exchange resins, wherein the slow release of the active medicament is brought about through selective breakdown of the coating of the preparation or through compounding with a special matrix to affect the release of a drug.
- Some sustained release formulations provide for related sequential release of a single dose of an active compound at predetermined periods after administration.
- Sustained release dosage forms are central in the search for improved therapy, both through improved patient compliance and decreased incidences of adverse drug reactions.
- a controlled release dosage form will provide therapeutic concentration of the drug in blood that is maintained throughout the dosing interval with a reduction in the peak/trough concentration ration.
- Central to the development process are the many variables that influence the in vivo release and subsequent absorption of the active ingredients from the gastrointestinal tract.
- Controlled release formulations known in the art include specially coated beads or pellets, coated tablets and ion exchange resins, wherein the slow release of the active drug is brought about through selective breakdown of the coating of the preparation or through formulation with a special matrix to affect the release of the drug.
- Some controlled release formulations provide for sequential release of a single dosage of an active medicament at predetermined periods after administration.
- Attention Deficit Disorders are the most common psychiatric disorders in children (Campbell et al. 1992) with reported rates ranging from 4% to 9% (Aman et al. 1983). Attention Deficit Disorder (ADD) is characterized by inattention and impulsivity and may be present with hyperactivity (ADHD) (Shaywitz et al. 1984). Other characteristics may include aggressiveness, stealing, lying, truancy, setting fires, running away, explosiveness, cognitive and learning problems as well as poor social skills (Campbell et al. 1992). It is four to five times more frequent in boys than girls (Campbell et al. 1992).
- Stimulant medication such as amphetamines
- Stimulant medication have been shown to be the most effective agents in the treatment of children with disorders of activity modulation and attention regulation and result in significant improvement in 70 to 80 per cent of affected children (Shaywitz et al. 1984).
- Positive effects of stimulants have been documented in a variety of areas including behavioral, social, perceptual performance, motor activity, impulse control, attention regulation and cognitive performance (Barkley 1977, Kavale 1983, Offenbacher et al. 1983, Rosenthalet al 1978).
- Methylphenidate ⁇ dl-threo-methyl-2-phenyl-2-(2-piperidyl) acetate ⁇ is the psychostimulant used most frequently in the treatment of hyperactivity and attention deficit disorder. It appears to have a higher incidence of positive effects and a lower incidence of adverse effects than other psychostimulants.
- the efficacy of methylphenidate (“MPH”) in improving attention and behavioral symptoms has been supported by many studies.
- Immediate release methylphenidate preparations because of their short half-life, require frequent administration at short intervals to ensure adequate treatment throughout a child's school day.
- the rapid onset and offset of immediate release methylphenidate preparations means that a medicated child with attention deficit disorder will be maximally affected only for relatively brief periods during the day. Due to its short half-life, MPH is usually given twice per day, usually once after breakfast and once during the school day, an event that some children and some school personnel apparently avoid, resulting in poor compliance with prescribed regimens (Brown et al., 1985; Firestone 1982).
- Ritalin® SR sustained release methylphenidate
- ADHD Attention Deficit Hyperactivity Disorder
- MLR multi-layer release
- the present invention is directed in part to a controlled release product which is intended to combined both a rapid onset and sustained plasma concentrations throughout the day.
- the formulations of the present invention provide a rapid onset, a prolonged action, followed by rapid offset of effect, i.e., a “square wave” profile.
- the invention is directed in part to controlled/modified release formulations based on a multi-layered release (“MLR”) technology.
- the drug product can be in a tablet or a multiparticulate formulation contained within an oral gelatin capsule.
- each bead contains a series of layers with different characteristics—an outer immediate release layer, a release delaying layer (enteric coat), a controlled release layer over an immediate release layer.
- the MLR formulation is designed such that upon oral administration, the formulation provides a rapid dissolution and absorption of the outer layer of the formulation which contains a portion of the drug in immediate release form, thereby resulting in a rapid rise of the drug to therapeutic plasma levels. This is followed by a period of no absorption (due to an enteric coating), followed thereafter by a controlled release of the drug from the formulation to maintain plasma levels. After absorption of the drug from an immediate release core, plasma levels then rapidly decrease.
- the plasma level of the drug when plotted on a time/concentration curve, takes the appearance of a “square wave”.
- the formulation provides a time to maximum plasma concentration at about 0.5 to about 4 hours after oral administration and provides effective blood levels for at least about 6 hours after administration.
- the formulation exhibits a “plateau” in the blood plasma curve which lasts from about 2 hours to about 6 hours.
- Other embodiments exhibit a “plateau” which lasts from about 6 hours to about 12 hours.
- the “plateau” is characterized by a stabilized plasma concentration, wherein the plasma level at the end of the measured interval does not differ by more than 20%, preferably by no more than 10% of the plasma concentration at the beginning of the measured interval.
- the formulation exhibits a bimodal release of active agent from the dosage form.
- Bimodal release of the active agent is characterized by the active agent being release from the dosage form by more than one distinct release rate.
- the release rates can be separated by a no-release or a substantially no-release interval, although this is not always necessary.
- the formulation exhibits a biphasic absorption of the active agent.
- Biphasic absorption of the active agent is characterized by the active agent being absorbed through a natural barrier (e.g. the mucosal lining of the gastro-intestinal tract) by more than one distinct absorption rate.
- the absorption rates can be separated by a no-absorption or a substantially no-absorption interval, although this is not always necessary.
- a formulation can exhibit both biphasic absorption and bimodal release of the active agent, with the biphasic absorption being a function of the bimodal release rate. However, biphasic absorption is not always attributed to release rate and can occur in a formulation not exhibiting bimodal release.
- the formulation exhibits bimodal release and/or biphasic absorption to provide a “plateau” in the blood plasma curve which lasts from about 2 hours to about 6 hours.
- Other embodiments exhibit bimodal release and/or biphasic absorption to provide a “plateau” which lasts from about 6 hours to about 12 hours.
- Other embodiments maintain effective plasma levels of the active agent for about 16 to about 18 hours after administration of the dosage form.
- an acrylic resin is utilized to provide the controlled slow release of therapeutically active ingredients over a predetermined or a specified period of time, the acrylic resin thereby comprising a significant part of the “base composition”.
- Base compositions prepared from such acrylic resins provide sustained release of therapeutically active ingredients over a period of time from five hours and for as much as 24 hours after administration, generally oral administration, in humans or animals.
- formulations of the invention are composed of:
- the controlled/modified release drug formulations of the invention consist of a plurality of beads, each containing an immediate-release component in combination with an enteric coated controlled-release component to produce a delay in the absorption process.
- the drug product is an oral capsule containing beads. Each bead contains a series of layers with different release characteristics—an outer immediate release layer; a release delaying layer; a controlled release layer; and an immediate release core.
- the final product is a capsule containing multi-layer release (MLR) beads which have both immediate release and controlled release components. It is made up of a controlled release bead which is enteric coated to delay dissolution until after gastric emptying.
- the enteric coated controlled release bead has an immediate release topcoat to provide an initial rate of absorption of the drug.
- the immediate release component represents 40% of the total dose per bead and the controlled release component represents 60%.
- This formulation is designed to produce a rapid rise to therapeutic plasma levels after oral administration, due to the rapid dissolution and absorption of the outer layer, followed by a period of reduced absorption and then controlled release of the immediate release core, to maintain therapeutic plasma levels. After absorption of the immediate release core, plasma levels would then decrease according to the elimination kinetics of the drug.
- the results of a bioavailability study of this formulation indicate a biphasic release profile that is consistent with the pharmaceutical rationale discussed herein.
- the bead size of the formulations can be adjusted in order to obtain a desired pharmacokinetic profile based on the correlation between gastric emptying and bead size.
- a smaller bead size exhibits faster gastric emptying as compared to a larger bead size.
- pH-dependent for purposes of the present invention is defined as having characteristics (e.g. dissolution) which vary according to environmental pH (e.g., due to changes in the in-vitro dissolution media, or due to passage of the dosage form through the gastrointestinal tract.
- pH-independent for purposes of the present invention is defined as having characteristics (e.g., dissolution) which are substantially unaffected by pH, in that a difference, at any given time, between an amount of methylphenidate released at one pH and an amount released at any other pH, when measured in-vitro using the USP Paddle Method of U.S. Pharmacopeia XXII (1990) at 100 rpm in 900 ml aqueous buffer, is no greater than 10%.
- FIG. 1 is a graphical comparison of the mean plasma concentration of methylphenidate when test subjects are treated with Formulation 1 and Ritalin® as a function of time when given under fasting conditions.
- FIG. 2 is a graphical comparison of the mean plasma concentration of methylphenidate when test subjects are treated with Formulation 1 and Ritalin® as a function of time when given under fed conditions.
- FIG. 3 is a graphical comparison of the mean plasma concentration of methylphenidate when test subjects are treated with Formulation 1 as a function of time when given under fasting and fed conditions.
- FIG. 4 is a graphical comparison of the mean plasma concentration of methylphenidate when test subjects are treated with Ritalin® as a function of time when given under fasting and fed conditions.
- FIG. 5 is a graphical comparison of the mean plasma concentration of methylphenidate when test subjects are treated with Formulation 2 under fasting and fed conditions, and Ritalin® SR under fasting conditions, as a function of time.
- FIG. 6 is a graphical comparison of the mean plasma concentration of methylphenidate when test subjects are treated with Formulation 3 under fasting and fed conditions, and Ritalin® SR under fasting conditions, as a function of time.
- FIG. 7 is a graphical comparison of the mean plasma concentration of methylphenidate when test subjects are treated with Formulations 2 and 3 under fasting conditions as a function of time.
- FIG. 8 is a graphical comparison of the mean plasma concentration of methylphenidate when test subjects are treated with Formulations 2 and 3 under fed conditions as a function of time.
- the drug used in the formulations of the invention may be selected from a wide variety of pharmaceutically active drugs such as diabetes drugs, attention deficit hyperactivity controlled drugs, analgesics, anti-obesity preparations, anti-inflammatories, antihistamines, antitussives, decongestants, antinausea agents, narcotics, bronchodilators, cardiovasculars, central nervous system (CNS) drugs, nicotine replacement therapy, nitrates, sleeping aids/sedatives, vitamins, etc.
- pharmaceutically active drugs such as diabetes drugs, attention deficit hyperactivity controlled drugs, analgesics, anti-obesity preparations, anti-inflammatories, antihistamines, antitussives, decongestants, antinausea agents, narcotics, bronchodilators, cardiovasculars, central nervous system (CNS) drugs, nicotine replacement therapy, nitrates, sleeping aids/sedatives, vitamins, etc.
- the controlled/modified release preparations of the present invention may be used in conjunction with any multiparticulate system, such as granules, spheroids, beads, pellets, ion-exchange resin beads, and other multiparticulate systems in order to obtain a desired sustained-release of the therapeutically active agent.
- Beads, granules, spheroids, or pellets, etc., prepared in accordance with the present invention can be presented in a capsule or in any other suitable unit dosage form.
- An amount of the multiparticulates effective to provide the desired dose of drug over time may be placed in a capsule, may be contained in a packet and sprinkled onto food, or may be incorporated in any other suitable oral solid form, such as a tablet.
- the present invention can be in the form of a matrix tablet.
- the formulation be prepared such that an initial immediate release of drug provides an early onset of effect, which onset is analogous to an immediate release formulation, and that the formulation further provide a sustained release component which maintains therapeutically effective levels of the drug in the plasma for the desired amount of time, followed by a relatively rapid drop-off in blood plasma levels relative to typical sustained release formulations.
- the plasma level of the drug from the formulations of the present invention have the appearance of a “square wave”.
- the immediate release component preferably represents from about 30% to about 40% of the total dose and the controlled release component preferably represents from about 60% to about 70% of the total dose of methylphenidate contained in the formulations of the present invention.
- the immediate release component represents about 40% of the total dose and the controlled release component represents about 60% of the total dose of methylphenidate contained in the formulation.
- methylphenidate it is desired that the onset of action occurs from about 0.5 to about 4 hours, and preferably from about 0.5 to about 2 hours after the oral dosage form is administered, and it is further desired that the dosage form no longer provides effective plasma levels of methylphenidate from about 8 to about 12, more preferably from about 8 to about 10 hours, after oral administration of the dose.
- the dose of methylphenidate can be administered to a child in the morning before school begins, provides the desired effect at the start of the school day, with the pharmacologic action of the drug not waning until after the school day ends, and preferably before dinner so that the drug does not have the side effect of acting as an appetite suppressant.
- the formulations of the present invention are designed to produce a rapid rise to therapeutic plasma levels after oral administration, due to the rapid dissolution and absorption of the outer layer, followed by a period of reduced absorption and then controlled release of the immediate release core, to maintain therapeutic plasma levels. After absorption of the immediate release core, plasma levels would then decrease according to the elimination kinetics of the drug.
- Bioavailability in a more meaningful sense, is the degree, or amount, to which a drug substance is absorbed into the systemic circulation in order to be available to a target tissue site. To be absorbed, an active drug substance must be in a solution.
- the time required for a given proportion of an active drug substance contained in a dosage unit to enter into solution in appropriate physiological fluids is known as the dissolution time.
- the dissolution time for an active substance from a dosage unit is determined as the proportion of the amount of active drug substance released from the dosage unit over a specified time by a test method conducted under standardized conditions.
- the physiological fluids of the gastrointestinal tract are the media for determining dissolution time. The present state of the art dissolution time for pharmaceutical compositions, and these test procedures are described in official compendia world wide.
- the dissolution time determined for a pharmacologically active substance from a specific composition is relatively constant and reproducible.
- factors affecting the dissolution time are the surface area of the drug substance presented to the dissolution solvent medium, the pH of the solution, the solubility of the substance in the specific solvent medium, and the driving forces of the saturation concentration of dissolved materials in the solvent medium.
- the dissolution concentration of an active drug substance is dynamically modified in this steady state as components are removed from the dissolution medium through absorption across the tissue site.
- the saturation level of the dissolved materials is replenished from the dosage form reserve to maintain a relatively uniform and constant dissolution concentration in the solvent medium, providing for a steady state absorption.
- the transport across a tissue absorption site in the gastrointestinal tract is influenced by the Donnan osmotic equilibrium forces on both sides of the membrane, since the direction of the driving force is the difference between the concentrations of active substance on either side of the membrane, i.e. the amount dissolved in the gastrointestinal fluids and the amount present in the blood. Since the blood levels are constantly being modified by dilution, circulatory changes, tissue storage, metabolic conversion and systemic excretion, the flow of active materials is directed from the gastrointestinal tract into the blood stream.
- dissolution time determined for a dosage form is one of the important fundamental characteristics for consideration when evaluating whether a controlled release formulation should be tested in vivo.
- the in-vitro dissolution of the drug at various time points for formulations in accordance with the present invention is provided below:
- the drug is incorporated into or onto a substrate and a sustained release coating is applied thereto.
- the drug may be contained within or on a substrate as follows: (i) incorporated into matrix spheroids (e.g., together with a pharmaceutically acceptable spheronizing agent such as microcrystalline cellulose), (ii) coated onto inert pharmaceutically acceptable beads (e.g., nonpareil beads); (iii) incorporated into a normal release tablet core; or (iv) incorporated into a tablet core which comprises a matrix including a sustained release carrier material. Thereafter, a sustained release coating is applied onto substrates such as those mentioned in (i)-(iv) above.
- the dosage forms of the present invention may optionally be coated with one or more materials suitable for the regulation of release or for the protection of the formulation.
- coatings are provided to permit either pH-dependent or pH-independent release, e.g., when exposed to gastrointestinal fluid.
- a pH-dependent coating serves to release the drug in desired areas of the gastro-intestinal (GI) tract, e.g., the stomach or small intestine.
- GI gastro-intestinal
- the coating is designed to achieve optimal release regardless of pH-changes in the environmental fluid, e.g., the GI tract. It is also possible to formulate compositions which release a portion of the dose in one desired area of the GI tract, e.g., the stomach, and release the remainder of the dose in another area of the GI tract, e.g., the small intestine.
- Formulations according to the invention that utilize pH-dependent coatings to obtain formulations may also impart a repeat-action effect whereby unprotected drug is coated over the enteric coat and is released in the stomach, while the remainder, being protected by the enteric coating, is released further down the gastrointestinal tract.
- Coatings which are pH-dependent may be used in accordance with the present invention include shellac, cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), hydroxypropylmethylcellulose phthalate, and methacrylic acid ester copolymers, zein, and the like.
- the substrate e.g., tablet core bead, matrix particle
- the substrate comprising the drug is coated with a hydrophobic material selected from (i) an alkylcellulose; (ii) an acrylic polymer; or (iii) mixtures thereof.
- the coating may be applied in the form of an organic or aqueous solution or dispersion.
- the coating may be applied to obtain a weight gain from about 2 to about 25% of the substrate in order to obtain a desired sustained release profile.
- Such formulations are described, e.g., in detail in U.S. Pat. Nos. 5,273,760 and 5,286,493, assigned to the Assignee of the present invention and hereby incorporated by reference.
- the particles are preferably film coated with a material that permits release of the drug so as to achieve, in combination with the other stated properties, a desired in-vitro release rate and in-vivo plasma levels.
- the sustained release coating formulations of the present invention should be capable of producing a strong, continuous film that is smooth and elegant, capable of supporting pigments and other coating additives, non-toxic, inert, and tack-free.
- sustained release formulations and coatings which may be used in accordance with the present invention include Assignee's U.S. Pat. Nos. 5,324,351; 5,356,467, and 5,472,712, hereby incorporated by reference in their entirety.
- Cellulosic materials and polymers including alkylcelluloses, provide hydrophobic materials well suited for coating the beads according to the invention.
- one preferred alkylcellulosic polymer is ethylcellulose, although the artisan will appreciate that other cellulose and/or alkylcellulose polymers may be readily employed, singly or in any combination, as all or part of a hydrophobic coating according to the invention.
- Aquacoat® One commercially available aqueous dispersion of ethylcellulose is Aquacoat® (FMC Corp., Philadelphia, Pa., U.S.A.). Aquacoat® is prepared by dissolving the ethylcellulose in a water-immiscible organic solvent and then emulsifying the same in water in the presence of a surfactant and a stabilizer. After homogenization to generate submicron droplets, the organic solvent is evaporated under vacuum to form a pseudolatex. The plasticizer is not incorporated in the pseudolatex during the manufacturing phase. Thus, prior to using the same as a coating, it is necessary to intimately mix the Aquacoat® with a suitable plasticizer prior to use.
- aqueous dispersion of ethylcellulose is commercially available as Surelease® (Colorcon, Inc., West Point, Pa., U.S.A.). This product is prepared by incorporating plasticizer into the dispersion during the manufacturing process. A hot melt of a polymer, plasticizer (dibutyl sebacate), and stabilizer (oleic acid) is prepared as a homogeneous mixture, which is then diluted with an alkaline solution to obtain an aqueous dispersion which can be applied directly onto substrates.
- Surelease® Colorcon, Inc., West Point, Pa., U.S.A.
- the hydrophobic material comprising the controlled release coating may comprise a pharmaceutically acceptable acrylic polymer, including but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.
- acrylic acid and methacrylic acid copolymers including but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acrylic acid), poly(methacryl
- the acrylic polymer is comprised of one or more ammonio methacrylate copolymers.
- Ammonio methacrylate copolymers are well known in the art, and are described in NF XVII as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.
- methacrylic acid ester-type polymers are useful for preparing pH-dependent coatings which may be used in accordance with the present invention.
- methacrylic acid copolymer or polymeric methacrylates commercially available as Eudragit® from Rohm Tech, Inc.
- Eudragit® E is an example of a methacrylic acid copolymer which swells and dissolves in acidic media.
- Eudragit® L is a methacrylic acid copolymer which does not swell at about pH ⁇ 5.7 and is soluble at about pH>6.
- Eudragit® S does not swell at about pH ⁇ 6.5 and is soluble at about pH>7.
- Eudragit® RL and Eudragit® RS are water swellable, and the amount of water absorbed by these polymers is pH-dependent, however, dosage forms coated with Eudragit® RL and RS are pH-independent.
- the acrylic coating comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma under the Tradenames Eudragit® RL30D and Eudragit® RS30D, respectively.
- Eudragit® RL30D and Eudragit® RS30D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1:20 in Eudragit® RL30D and 1:40 in Eudragit® RS30D.
- the mean molecular weight is about 150,000.
- the code designations RL (high permeability) and RS (low permeability) refer to the permeability properties of these agents.
- Eudragit® RL/RS mixtures are insoluble in water and in digestive fluids. However, coatings formed from the same are swellable and permeable in aqueous solutions and digestive fluids.
- the Eudragit® RL/RS dispersions of the present invention may be mixed together in any desired ratio in order to ultimately obtain a sustained release formulation having a desirable dissolution profile. Desirable sustained release formulations may be obtained, for instance, from a retardant coating derived from 100% Eudragit® RL, 50% Eudragit® RL and 50% Eudragit® RS, and 10% Eudragit® RL: 90% Eudragit® RS. Of course, one skilled in the art will recognize that other acrylic polymers may also be used, such as, for example, Eudragit® L.
- the coating comprises an aqueous dispersion of a hydrophobic material such as an alkylcellulose or an acrylic polymer
- the inclusion of an effective amount of a plasticizer in the aqueous dispersion of hydrophobic material will further improve the physical properties of the sustained release coating.
- a plasticizer into an ethylcellulose coating containing sustained release coating before using the same as a coating material.
- the amount of plasticizer included in a coating solution is based on the concentration of the film-former, e.g., most often from about 1 to about 50 percent by weight of the film-former. Concentration of the plasticizer, however, can only be properly determined after careful experimentation with the particular coating solution and method of application.
- plasticizers for ethylcellulose include water insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, and triacetin, although it is possible that other water-insoluble plasticizers (such as acetylated monoglycerides, phthalate esters, castor oil, etc.) may be used.
- Triethyl citrate is an especially preferred plasticizer for the aqueous dispersions of ethyl cellulose of the present invention.
- plasticizers for the acrylic polymers of the present invention include, but are not limited to citric acid esters such as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate, and possibly 1,2-propylene glycol.
- Other plasticizers which have proved to be suitable for enhancing the elasticity of the films formed from acrylic films such as Eudragit® RL/RS lacquer solutions include polyethylene glycols, propylene glycol; diethyl phthalate, castor oil, and triacetin.
- Triethyl citrate is an especially preferred plasticizer for the aqueous dispersions of ethyl cellulose of the present invention.
- aqueous dispersion of hydrophobic material When the aqueous dispersion of hydrophobic material is used to coat a substrate including the drug, for example, inert pharmaceutical beads such as nu pariel 18/20 beads, a plurality of the resultant stabilized solid controlled release beads may thereafter be placed in a gelatin capsule in an amount sufficient to provide an effective controlled release dose when ingested and contacted by an environmental fluid, e.g., gastric fluid or dissolution media.
- the substrate may be a tablet core coated with the sustained release coating, and optionally a further film-forming agent or colorant, such as Opadry®.
- an aqueous dispersion of an hydrophobic polymer such as an alkylcellulose is applied to the substrate, it is preferred that the coated substrate is cured at a temperature above the glass transition temperature of the plasticized polymer and at a relative humidity above ambient conditions, until an endpoint is reached at which the coated formulation attains a dissolution profile which is substantially unaffected by exposure to storage conditions, e.g., of elevated temperature and/or humidity.
- the curing time is about 24 hours or more, and the curing conditions may be, for example, about 60° C. and 85% relative humidity.
- Detailed information concerning the stabilization of such formulations is set forth in U.S. Pat. Nos. 5,273,760; 5,681,585; and 5,472,712; all of which are hereby incorporated by reference in their entireties.
- the coated substrate is cured at a temperature above the glass transition temperature of the plasticized polymer until an endpoint is reached at which the coated formulation attains a dissolution profile which is substantially unaffected by exposure to storage conditions, e.g., of elevated temperature and/or humidity.
- the curing time is about 24 hours or more, and the curing temperature may be, for example, about 45° C.
- Detailed information concerning the stabilization of such formulations is set forth in U.S. Pat. Nos. 5,286,493; 5,580,578; and 5,639,476; all of which are hereby incorporated by reference in their entireties.
- the sustained release profile of the coated formulations of the invention can be altered, for example, by varying the amount of overcoating with the aqueous dispersion of hydrophobic material, altering the manner in which the plasticizer is added to the aqueous dispersion of hydrophobic material, by varying the amount of plasticizer relative to hydrophobic material, by the inclusion of additional ingredients or excipients, by altering the method of manufacture, etc.
- the dissolution profile of the ultimate product may also be modified, for example, by increasing or decreasing the thickness of the retardant coating.
- Spheroids or beads coated with a therapeutically active agent are prepared, e.g., by dissolving the therapeutically active agent in water and then spraying the solution onto a substrate, for example, nu panel 18/20 beads, using a Wuster insert.
- additional ingredients are also added prior to coating the beads in order to assist the binding of the drug to the beads, and/or to color the solution, etc.
- a product which includes hydroxypropylmethylcellulose, etc. with or without colorant e.g., Opadry®, commercially available from Colorcon, Inc.
- the resultant coated substrate in this example beads, may then be optionally overcoated with a barrier agent, to separate the therapeutically active agent from the hydrophobic controlled release coating.
- a barrier agent is one which comprises hydroxypropylmethylcellulose.
- any film-former known in the art may be used. It is preferred that the barrier agent does not affect the dissolution rate of the final product.
- the beads may then be overcoated with an aqueous dispersion of the hydrophobic material.
- the aqueous dispersion of hydrophobic material preferably further includes an effective amount of plasticizer, e.g. triethyl citrate, Pre-formulated aqueous dispersions of ethyl-cellulose, such as Aquacoat® or Surelease®, may be used. If Surelease is used, it is not necessary to separately add a plasticizer. Alternatively, pre-formulated aqueous dispersions of acrylic polymers such as Eudragit can be used.
- the coating solutions of the present invention preferably contain, in addition to the film-former, plasticizer, and solvent system (i.e., water), a colorant to provide elegance and product distinction.
- Color may be added to the solution of the therapeutically active agent instead, or in addition to the aqueous dispersion of hydrophobic material.
- color be added to Aquacoat via the use of alcohol or propylene glycol based color dispersions, milled aluminum lakes and opacifiers such as titanium dioxide by adding color with shear to water soluble polymer solution and then using low shear to the plasticized Aquacoat.
- any suitable method of providing color to the formulations of the present invention may be used.
- Suitable ingredients for providing color to the formulation when an aqueous dispersion of an acrylic polymer is used include titanium dioxide and color pigments, such as iron oxide pigments. The incorporation of pigments, may, however, increase the retard effect of the coating.
- the plasticized aqueous dispersion of hydrophobic material may be applied onto the substrate comprising the therapeutically active agent by spraying using any suitable spray equipment known in the art.
- a Wurster fluidized-bed system is used in which an air jet, injected from underneath, fluidizes the core material and effects drying while the acrylic polymer coating is sprayed on.
- a further overcoat of a film-former such as Opadry, is optionally applied to the beads. This overcoat is provided, if at all, in order to substantially reduce agglomeration of the beads.
- the release of the drug from the sustained release formulation of the present invention can be further influenced, i.e., adjusted to a desired rate, by the addition of one or more release-modifying agents, or by providing one or more passageways through the coating.
- the ratio of hydrophobic material to water soluble material is determined by, among other factors, the release rate required and the solubility characteristics of the materials selected.
- the release-modifying agents which function as pore-formers may be organic or inorganic, and include materials that can be dissolved, extracted or leached from the coating in the environment of use.
- the pore-formers may comprise one or more hydrophilic materials such as hydroxypropylmethylcellulose.
- the sustained release coatings of the present invention can also include erosion-promoting agents such as starch and gums.
- the sustained release coatings of the present invention can also include materials useful for making microporous lamina in the environment of use, such as polycarbonates comprised of linear polyesters of carbonic acid in which carbonate groups reoccur in the polymer chain.
- the release-modifying agent may also comprise a semi-permeable polymer.
- the release-modifying agent is selected from hydroxypropylmethylcellulose, lactose, metal stearates, and mixtures of any of the foregoing.
- the sustained release coatings of the present invention may also include an exit means comprising at least one passageway, orifice, or the like.
- the passageway may be formed by such methods as those disclosed in U.S. Pat. Nos. 3,845,770; 3,916,889; 4,063,064; and 4,088,864 (all of which are hereby incorporated by reference).
- the passageway can have any shape such as round, triangular, square, elliptical, irregular, etc.
- the substrate of the present invention may be prepared by a spheronizing agent together with the active agent ingredient that can be spheronized to form spheroids.
- Microcrystalline cellulose is preferred.
- a suitable microcrystalline cellulose is, for example, the material sold as Avicel PH 101 (Trade Mark, FMC Corporation).
- the spheroids may also contain a binder. Suitable binders, such as low viscosity, water soluble polymers, will be well known to those skilled in the pharmaceutical art. However, water soluble hydroxy lower alkyl cellulose, such as hydroxypropylcellulose, are preferred.
- the spheroids may contain a water insoluble polymer, especially an acrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethyl acrylate copolymer or ethyl cellulose.
- the sustained-release coating will generally include a water insoluble material such as (a) a wax, either alone or in admixture with a fatty alcohol; or (b) shellac or zein.
- the controlled/modified release methylphenidate formulation is prepared as a multilayered release (MLR) formulation comprising coated inert beads.
- MLR multilayered release
- IR immediate release
- HPMC HPMC
- Opadry® Clear Formmula No: YS-1-7006
- a controlled release coating is applied to the IR beads, which converts the same into controlled release (CR) beads. This is accomplished by spraying a solution of Eudragit® RS 30 D, triethyl citrate (plasticizer) and talc (glidant), onto the IR beads.
- the coated beads are cured in order to obtain a stabilized release rate of the therapeutically active agent.
- the CR coating utilizes an acrylic resin to control the release of the drug
- the CR beads at this stage are subjected to oven curing at a temperature above the Tg of the plasticized acrylic polymer of the required time period, the optimum values of the temperature and time for the particular formulation being determined experimentally.
- the stabilized products is obtained via oven curing conducted at a temperature of about 40-50° C. for a time period of about 12 to about 24 hours or longer.
- An enteric coating is then applied onto the CR beads to convert the same into enteric coated CR (ECCR) beads. This is accomplished by spraying a solution of Eudragit® L 30 D-55 dispersion, triethyl citrate (plasticizer) and talc (glidant) onto the CR beads.
- an immediate release coating is applied onto the ECCR beads (referred to as, e.g., an IR Topcoat). This is accomplished by spraying a solution of methylphenidate in water over EC CR beads.
- an effective amount of the drug in immediate release form is included in the drug formulation.
- the immediate release form of the drug is included in an amount which is effective to shorten the time to maximum concentration of the drug in the blood (e.g., plasma), such that time to T max is shortened to a time of, e.g., from about 0.5 to about 2 hours.
- the time to onset of action is significantly reduced, and is the same or earlier than that of the reference standard immediate release treatment (e.g., Ritalin IR).
- an effective amount of the drug in immediate release form may be coated onto the substrates (e.g., multiparticulates or tablets) of the present invention.
- the immediate release layer can be overcoated on top of the controlled release coating.
- the immediate release layer may be coated onto the surface of substrates wherein the drug is incorporated in a controlled release matrix.
- the immediate release portion of the drug dose may be incorporated into the gelatin capsule via inclusion of the sufficient amount of immediate release drug as a powder or granulate within the capsule.
- the gelatin capsule itself may be coated with an immediate release layer of the drug.
- the beads are then filled into hard gelatin capsules at a strength of 20 mg.
- Dissolution testing was conducted on the bead filled IR capsules using USP Apparatus 1 (basket method) in 500 mL of simulated gastric juice without enzyme, 100 rpm at 37° C. The results are as follows:
- the controlled-release coating is manufactured as follows:
- the beads were then filled into hard gelatin capsules at a 20 mg strength.
- Dissolution testing was conducted on the bead filled CR capsules using the following USP Apparatus (basket method).
- the capsules were placed into 500 mL of simulated gastric juice without enzyme, for first 2 hours at 100 rpm and 37TC and then placed into 500 mL simulated intestinal fluid without enzyme for the remainder of the testing period.
- the results are as follows:
- the method of manufacturing the controlled-release beads in Examples 3 and 4 is similar to the method described under Example 2, by varying the proportion of beads and Eudragit® RS 30 D.
- the cured beads were filled into hard gelatin capsules at a strength of 20 mg.
- Fluid Bed Dryer with 1 mm spray nozzle and the beads are coated to a weight gain of ⁇ 9%.
- the beads were then filled into hard gelatin capsules at a 20 mg strength.
- Dissolution testing was conducted on the bead filled CR filled capsules using USP Apparatus 1 (basket method) 500 mL at 100 rpm and 37° C. using SGF without enzyme for the first 2 hours and SIF without enzyme for the rest of the testing period. Results are shown below:
- the (IR ⁇ EC ⁇ CR Beads) formulation hereinafter referred to as Formulation 1, is a capsule containing multi-layer release beads which have both immediate release and controlled release components. It is made up of a controlled release bead which is enteric coated to delay dissolution until after gastric emptying.
- the enteric coated controlled release bead has an immediate release topcoat to provide an initial rate of absorption equal to or greater than Ritalin® IR immediate release tablets.
- the immediate release component represent 40% of the total dose per bead and the controlled release component represents 60%.
- the beads were then filled into a hard gelatin capsule to a 20 mg strength.
- Dissolution testing was conducted on the bead filled capsules of Formulation 1 using USP Apparatus 1 (basket method) 100 rpm, 500 mL at 3.7° C.—simulated gastric juice without enzyme 1st and 2nd hours; 3rd hour onwards simulated intestinal fluid without enzyme.
- the enteric-coated controlled release beads (EC ⁇ CR) beads described in Example 5 may be mixed with the immediate release (IR) beads described in Example 1 in varying proportions and placed in capsules to obtain the final blended dosage form, (IR+EC ⁇ CR Blend), hereinafter referred to as Formulation 2.
- Formulation 2 was designed to provide a faster rate of absorption of the controlled release portion than Formulation 1.
- the immediate release component represents 35% of the total dose per capsule and the controlled release component represents 65%:
- the IR ⁇ CR Beads formulation hereinafter referred to as Formulation 3, is a capsule containing single beads made up of an immediate release topcoat and a controlled release core, and is designed to provide an intermediate rate of absorption of the controlled release portion between that of the controlled release formulations of Formulations 1 and 2.
- the immediate release component represents 30% of the total dose per bead and the controlled release component represents 70%.
- the immediate release topcoat is applied to CR beads as described in Example 6A for Formulation 1.
- Methylphenidate MLR capsules The bioavailability of Methylphenidate MLR capsules was investigated in a four-way blind study which compared the Formulation 1 20 mg single dosage formulation under fed and fasted conditions with two doses (4 hours apart) of Ritalin® IR.
- Treatment 1 Test Product: methylphenidate controlled-release, Formulation 1, 20 mg capsule, in the morning under fasting conditions.
- Treatment 2 Reference Product: methylphenidate immediate-release, Ritalin® (Novartis), 10 mg tablet in the morning and 4 hours later, under fasting conditions.
- Treatment 3 Test Product: methylphenidate controlled-release, Formulation 1, 20 mg capsule, administered 5 minutes after a high fat breakfast.
- Treatment 4 Reference Product: methylphenidate immediate-release, Ritalin® (Novartis), 10 mg tablet in the morning and 4 hours later, administered 5 minutes after a high fat breakfast.
- Plasma samples (1 ⁇ 5 mL each) were taken from each subject within one hour prior to dosing and at 0.250, 0.500, 0.750, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.00, 6.00, 7.00, 8.00, 10.0, 12.0, 16.0, 24.0 hours post-dose for the Formulation 1 and at pre-dose, 0.250, 0.500, 0.750, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.00, 6.00, 7.00, 8.00, 10.0, 12.0, 16.0, 24.0 hours post-dose for the Ritulin® IR. Plasma was harvested from each blood sample and stored in a ⁇ 20° C. freezer until assayed for plasma methylphenidate concentration. Assay of plasma methylphenidate concentrations was performed using gas chromatography/mass spectrometry (GC/MS).
- GC/MS gas chromatography/mass spectrometry
- the mean plasma concentrations, standard deviations and coefficients of variation are shown as a function of time in Tables 12 and 13, for fasting and fed conditions, respectively.
- FIG. 1 presents the mean plasma concentration versus time for Formulation 1 and Ritalin® underlasting conditions.
- FIG. 2 presents the mean plasma concentration versus time for Formulation 1 and Ritalin® under fed conditions.
- FIG. 3 presents the mean plasma concentration versus time for Formulation 1 under fed and fasting conditions.
- FIG. 4 presents the mean plasma concentration versus time for Ritalin® under fed and fasting conditions.
- Pharmacokinetic parameters were calculated based on the data from the four-way study.
- AUC 0-t (pg ⁇ h/mL), AUC 0-inf (pg ⁇ h/mL), AUC 0inf (%), C max (pg/mL), T max (hours), T 1/2 el (hours), K el (hour ⁇ 1 ), TLIN (hours) and LQCT (hours) were calculated as described below.
- Time deviations during sampling for drugs with a T max ⁇ 4 hours were treated as follows: between 0 and 6 hours post dose, the sampling time was used in the statistical analysis if the delay between the actual and scheduled time of blood collection was ⁇ 10%. Above 6 hours post dose, the sampling time was used in the statistical analysis if the delay between the actual and scheduled time of plasma collection was ⁇ 15%. When sampling times were used when previously described acceptance criteria, the corrected sampling items were used when performing pharmacokinetic parameters calculations. Sampling times are present in concentration tables and graphs of statistical report.
- the mean, standard deviation (SD), and coefficient of variation (CV) were calculated for plasma concentrations of methylphenidate for each sampling time and treatment.
- the mean, SD, and CV were calculated for the AUC 0-t (pg ⁇ h/mL), AUC 0-inf (pg ⁇ h/mL), C max (pg/mL), T max (hours), T 1/2 el (hours), K el (hour ⁇ 1 ) , TLIN (hours) and LQCT (hours). The calculation of these pharmacokinetic parameters is explained below.
- AUC 0-t was calculated using the linear trapezoidal rule.
- the AUC 0-t was derived where t is the time (t) of the last measurable (non-zero) concentration (C t ) for each treatment.
- the AUC 0-inf was calculated as:
- TLIN the time point where log-linear elimination begins
- LQCT the last quantifiable concentration time
- the plasma concentration of unchanged methylphenidate following administration of the controlled release formulation Formulation 1 reached the maximum concentration (C max ) at a mean of 3.27 hours under fasting conditions and 7.29 hours under fed conditions reflecting a biphasic absorption profile.
- the plasma concentration of unchanged methylphenidate following administration of two doses of the immediate release formulation (Ritalin® IR) reached the maximum concentration (C max ) at 5.96 hours under fasting conditions and 3.54 hours under fed conditions.
- the T max was 1.71 hours under fasting conditions and 1.63 hours under fed conditions.
- the ANOVA and Duncan's Multiple Range Test performed on the T max data detected a statistically significant difference between treatments for this parameter.
- Duncan's Multiple Range Test detected statistically significant differences between treatments 1 and 2, treatments 3 and 4, and treatments 1 and 3 for this parameter.
- the ANOVA and Duncan's Multiple Range Test performed on the T 1/2 el data detected a statistically significant difference between treatments for this parameter.
- Duncan's Multiple Range Test detected no statistically significant differences between treatments 1 and 3 for T 1/2 el .
- Duncan's Multiple Range Test detected statistically significant differences between treatments 1 and 2 and treatments 3 and 4 for this parameter.
- the AUC and C max ratios of controlled release methylphenidate 20 mg Formulation 1 under fed and fasted conditions are summarized in Table 19 below.
- a comparison of the AUC and C max ratios for immediate release methylphenidate 10 mg (Ritalin® IR) and Formulation 1 under fasting conditions are summarized in Table 20 below.
- Table 21 shows the comparative ratios for immediate release methylphenidate 10 mg (Ritalin® IR) and Formulation 1 under fed conditions.
- Treatment 1 (Formulation 1, fasting) versus Treatment 3 (Formulation 1, fed)
- the ANOVAs detected statistically significant differences between treatments for ln-transformed AUC 0-t , AUC 0-inf and C max , and untransformed T max , K el , T 1/2 el .
- Duncan's Multiple Range Test detected statistically significant differences between treatments 1 and 3 for ln-transformed AUC 0-t , and AUC 0-inf and untransformed T max .
- Duncan's Multiple Range Test detected no statistically significant differences between treatments for ln-transformed C max and untransformed K el and T 1/2 el .
- Plasma MPH concentrations at 12 hours were higher on Formulation 1 than on Ritalin IR in all subjects, under both fed and fasted conditions.
- a biphasic profile was apparent under fasted conditions in 7-10/12 subjects and in 8-10/12 under fed conditions.
- the mean curve showing a stable plateau under fasted conditions is therefore not fully representative of the individual profiles.
- the enteric coat therefore gave rise to a biphasic profile in some subjects even under fasted conditions.
- Formulation 1 had a more prolonged mean plasma MPH concentration time profile than two doses of Ritalin IR. An across study comparison indicates that Formulation 1 also has a more prolonged profile than Ritalin SR.
- Formulation 1 had a mean initial rate of rise of plasma MPH that is similar to Ritalin IR and a relatively flat plateau until 8 hours post-dose.
- Formulation 1 results in both a fast initial rate of rise of plasma methylphenidate concentration, and a prolonged duration. The transformation from a prolonged plateau profile under fasted conditions to a biphasic profile under fed conditions, is as predicted. Formulation 1 therefore has the potential to meet the dual objectives of rapid onset and prolonged duration that are considered desirable characteristics of a controlled release methylphenidate formulation for the treatment of ADD/ADHD.
- results indicate the potential for a single morning dose of this formulation to produce clinical effects that are at least equivalent to those of two doses of immediate-release methylphenidate given at breakfast and lunchtime, with a duration of action that may reduce the need for a third dose of immediate release methylphenidate later in the day.
- Treatment 1 Test Product: methylphenidate controlled-release, Formulation 2, 20 mg capsule, in the morning under fasting conditions.
- Treatment 2 Test Product: methylphenidate controlled-release, Formulation 2, 20 mg capsule, in the morning, under fed conditions.
- Treatment 3 Test Product: methylphenidate controlled-release, Formulation 3, 20 mg capsule, under fasting conditions.
- Treatment 4 Test Product: methylphenidate controlled-release, Formulation 3, 20 mg capsule, under fed conditions.
- Reference Product methylphenidate slow-release 20 mg tablet Ritalin SR (Novartis) under fasting conditions.
- Plasma samples (1 ⁇ 5 mL each) were taken from each subject within one hour prior to dosing and at 0.250, 0.500, 0.750, 1.00, 1.50, 2.00, 2.50, 3.00, 150, 4.00, 4.50, 5.00, 6.00, 7.00, 8.00, 10.0, 12.0, 16.0, 24.0 hours post-dose. Plasma was harvested from each blood sample and stored in a ⁇ 20 C freezer until assayed for plasma methylphenidate concentration.
- FIGS. 5-8 The data is presented graphically in FIGS. 5-8 .
- FIG. 5 presents the mean plasma concentration versus time for Formulation 2 under fasting and fed conditions and Ritalin® under fasting conditions.
- FIG. 6 presents the mean plasma concentration versus time for Formulation 3 under fasting and fed conditions and Ritalin® under fasting conditions.
- FIG. 7 presents the mean plasma concentration versus time for Formulations 2 and 3 under fasting conditions.
- FIG. 8 presents the mean plasma concentration versus time for Formulations 2 and 3 under fed conditions.
- the ANOVA and Duncan's Multiple Range Test performed on the ln-transformed T max data detected a statistically significant difference between treatments for this parameter.
- Duncan's Multiple Range Test detected statistically significant differences between treatments 1 and 2, and treatments 3 and 4 for this parameter.
- Duncan's Multiple Range Test did not detect statistically significant differences between treatments for T max when comparing treatments 1 vs. 3 or treatments 3 vs. 5.
- the ANOVA performed on the K el data show a statistically significant difference between treatments for this parameter. Statistically significant differences were not detected by Duncan's Multiple Range Test, between treatments for K el when comparing treatments 1 and 2, treatments 3 and 4, or treatments 1 and 5 . However, Duncan's Multiple Range Test detected statistically significant differences between treatments 3 and 5 for this parameter.
- Treatment 1 Treatment 3 AUC 0-t Treatment 1 vs. vs. vs. vs. (pg ⁇ h/mL) Treatment 2 Treatment 4 Treatment 5 Treatment 5 Ratio 89.21% 88.23% 101.82% 100.63% 90% 84.03% to 83.10% to 95.91% to 94.81% to Geometric 94.71% 93.67% 108.10% 106.81% C.I.
- the ANOVAs detected statistically significant differences between fed and fasting conditions, treatments 1 and 2, for the ln-transformed AUC 0-t , AUC 0-inf and C max and untransformed T max , T 1/2el and K el .
- Duncan's Multiple Range Test detected statistically significant differences between treatments 1 and 2 for ln-transformed AUC 0-1 and AUC 0-inf and untransformed T max .
- Duncan's Multiple Range Test detected no statistically significant differences between treatments for ln-transformed C max and untransformed T 1/2el and K el .
- the ANOVAs detected statistically significant differences between treatments for ln-transformed AUC 0-t , AUC 0-inf and C max and untransformed T max , T 1/2el and K el .
- Duncan's Multiple Range Test detected statistically significant differences between treatments 3 and 4 for ln-transformed AUC 0-t , AUC 0-inf and C max and untransformed T max .
- Duncan's Multiple Range Test detected no statistically significant differences between treatments for untransformed T 1/2el and K el .
- the ANOVAs detected statistically significant differences between treatments for ln-transformed AUC 0-t , AUC 0-inf and C max and untransformed T max , T 1/2el and K el .
- Duncan's Multiple Range Test detected statistically significant differences between treatments 3 and 5 for ln-transformed C max and untransformed T 1/2el and K el .
- Duncan's Multiple Range Test detected no statistically significant differences between treatments for ln-transformed AUC 0-t and AUC 0-inf and untransformed T max .
- Formulation 3 is bioequivalent to the reference product Ritalin SR® under fasting conditions.
- Bioavailability of Formulations 1 and 2 are similar under fasted and fed conditions (fasted: 49.8 vs. 51.2 ng.h/mL; fed: 55.7 vs. 57.9 ng.h/mL).
- Bioavailability of Formulation 3 relative to Ritalin SR® is acceptable under fasted conditions (Relative AUC inf 100.8% -fed conditions not tested).
- Formulations 1 and 3 Bioavailability of Formulations 1 and 3 are similar under fasted and fed conditions (fasted: 50,0 versus 51.2 ng/hmL; fed: 56.3 versus 57.9ng ⁇ h/mL). Note also that Formulations 2 and 3 have almost identical AUC values.
- Formulation 3 does not contain an enteric coat, this suggests that food slows the initial release from the IR component of formulations that contain an enteric coat, both when the enteric coat is part of the same bead (underneath the IR coat in the case of Formulation 1) and when it is in a separate bead (as for Formulation 2).
- the T max of the mean curve of Formulation 3 occurs at a similar time to that of Ritalin SR® under fed and fasted conditions.
- the T max of the second absorption phase under fed conditions is substantially delayed relative to Ritalin SR®.
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Neurosurgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Biomedical Technology (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Psychology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention is directed to oral modified/controlled release drug formulations which provide a rapid initial onset of effect and a prolonged duration of effect. Preferably, the peak concentration is lower than that provided by the reference standard for immediate release formulations of the drug, and the duration of effect falls rapidly at the end of the dosing interval.
Description
- This application is a continuation of U.S. Application Ser. No. 10/156,622, filed May 28, 2002, which is a continuation of U.S. Application Ser. No. 09/465,159, filed Dec. 16, 1999, no U.S. Pat. No. 6,419,960, which claims priority to U.S. Provisional Application No. 60/112,617, filed Dec. 17, 1998, the disclosures of which are hereby incorporated by reference in their entireties.
- Sustained release dosage forms are central in the search for improved therapy, both through improved patient compliance and decreased incidences of adverse drug reactions. It is the intent of all sustained release formulations to provide a longer period of pharmacologic action after administration than is ordinarily obtained after administration of immediate-release dosage forms. Sustained release compositions may be used to delay absorption of a medicament until it has reached certain portions of the alimentary tract, and maintain a desired concentration of said medicament in the blood stream for a longer duration than would occur if conventional rapid release dosage forms are administered. Such longer periods of response provide for many therapeutic benefits that are not achieved with corresponding short acting, immediate release preparations. Thus, therapy may be continued without interrupting the sleep of the patient, which is of special importance, for example, when treating a patient for moderate to severe pain (e.g., a post-surgery patient, a cancer patient, etc.), or for those patients who experience migraine headaches on awakening, as well as for the debilitated patient for whom sleep is essential. A further general advantage of longer acting drug preparations is improved patient compliance resulting from the avoidance of missed doses through patient forgetfulness.
- Unless conventional rapid acting drug therapy is carefully administered at frequent intervals to maintain effective steady state blood levels of the drug, peaks and valleys in the blood level of the active drug occurs because of the rapid absorption, systemic excretion of the compound and through metabolic inactivation, thereby producing special problems in maintenance therapy of the patient. In view of this, it is considered a goal of many skilled in the art that a controlled release dosage form will ideally provide therapeutic concentration of the drug in blood that is maintained throughout the dosing interval with a reduction in the peak/trough concentration ratio. Central to the development process are the many variables that influence the in vivo release and subsequent absorption of the active ingredients from the gastrointestinal tract.
- It is known in the pharmaceutical art to prepare compositions which provide for sustained release of pharmacologically active substances contained in the compositions after oral administration to humans and animals. Sustained release formulations known in the art include specially coated pellets, coated tablets and capsules, and ion exchange resins, wherein the slow release of the active medicament is brought about through selective breakdown of the coating of the preparation or through compounding with a special matrix to affect the release of a drug. Some sustained release formulations provide for related sequential release of a single dose of an active compound at predetermined periods after administration.
- Sustained release dosage forms are central in the search for improved therapy, both through improved patient compliance and decreased incidences of adverse drug reactions. Ideally, a controlled release dosage form will provide therapeutic concentration of the drug in blood that is maintained throughout the dosing interval with a reduction in the peak/trough concentration ration. Central to the development process are the many variables that influence the in vivo release and subsequent absorption of the active ingredients from the gastrointestinal tract.
- Controlled release formulations known in the art include specially coated beads or pellets, coated tablets and ion exchange resins, wherein the slow release of the active drug is brought about through selective breakdown of the coating of the preparation or through formulation with a special matrix to affect the release of the drug. Some controlled release formulations provide for sequential release of a single dosage of an active medicament at predetermined periods after administration.
- While controlled and/or sustained release compositions have constituted a definite advance in the art, improvements in these compositions have been sought, particularly for preparations available for conditions such as Attention Deficit Hyperactivity Disorder (ADHD), diabetes etc.
- Attention Deficit Disorders are the most common psychiatric disorders in children (Campbell et al. 1992) with reported rates ranging from 4% to 9% (Aman et al. 1983). Attention Deficit Disorder (ADD) is characterized by inattention and impulsivity and may be present with hyperactivity (ADHD) (Shaywitz et al. 1984). Other characteristics may include aggressiveness, stealing, lying, truancy, setting fires, running away, explosiveness, cognitive and learning problems as well as poor social skills (Campbell et al. 1992). It is four to five times more frequent in boys than girls (Campbell et al. 1992).
- Stimulant medication, such as amphetamines, have been shown to be the most effective agents in the treatment of children with disorders of activity modulation and attention regulation and result in significant improvement in 70 to 80 per cent of affected children (Shaywitz et al. 1984). Positive effects of stimulants have been documented in a variety of areas including behavioral, social, perceptual performance, motor activity, impulse control, attention regulation and cognitive performance (Barkley 1977, Kavale 1983, Offenbacher et al. 1983, Rosenthalet al 1978).
- Methylphenidate {dl-threo-methyl-2-phenyl-2-(2-piperidyl) acetate} is the psychostimulant used most frequently in the treatment of hyperactivity and attention deficit disorder. It appears to have a higher incidence of positive effects and a lower incidence of adverse effects than other psychostimulants. The efficacy of methylphenidate (“MPH”) in improving attention and behavioral symptoms has been supported by many studies.
- Immediate release methylphenidate preparations, because of their short half-life, require frequent administration at short intervals to ensure adequate treatment throughout a child's school day. The rapid onset and offset of immediate release methylphenidate preparations means that a medicated child with attention deficit disorder will be maximally affected only for relatively brief periods during the day. Due to its short half-life, MPH is usually given twice per day, usually once after breakfast and once during the school day, an event that some children and some school personnel apparently avoid, resulting in poor compliance with prescribed regimens (Brown et al., 1985; Firestone 1982). Compliance is a major problem for children who require a midday or midafternoon dose as many schools prohibit children from taking medications during the school day and others often insist that all medications be given by a nurse. Poor compliance in taking medication may explain, in part, the variable and conflicting results reported in many studies of the effect of medication on improving the behavior of hyperactive children. These limitations of immediate release methylphenidate led to interest in products with longer effective periods of action. These limitations of immediate release methylphenidate preparations led to interest in products with longer effective periods of action.
- A sustained release form of methylphenidate (Ritalin® SR) is commercially available. As a result of many clinical trials, various opinion leaders in treatment of attention deficit hyperactivity disorder have made the following comments regarding Ritalin® SR (sustained release methylphenidate) produced by Ciba-Geigy: (i) Ritalin® SR does not have a sufficiently early onset of effect to allow for behavioral management in the early morning; (ii) Ritalin® SR does not have the beneficial late effects that would be produced by a lunch time dose of immediate release methylphenidate, thus defeating the purpose of using an SR formulation; (iii) The effects of Ritalin® SR are inconsistent or erratic over the course of the day.
- There is a need in the art to develop drug formulations which provide a rapid onset, a prolonged action, followed by rapid offset of effect in order to overcome the deficiencies of the current state of the art.
- It is an object of the present invention to provide new oral dosage formulations of methylphenidate or similarly acting drugs which results in improved patient compliance.
- It is an object of the present invention to provide new oral dosage formulations which represent improvements over currently available preparations available for conditions such as Attention Deficit Hyperactivity Disorder (ADHD).
- It is an object of the present invention to provide new oral dosage formulations of methylphenidate or similarly acting drugs which ensure adequate treatment throughout a child's school day.
- It is an object of the present invention to provide new oral dosage formulations which allow a child with attention deficit disorder to be maximally treated throughout the daytime, while being administered only once, i.e., in the morning.
- It is a further object of the present invention to provide new controlled/modified release oral dosage formulations which provide a rapid onset and rapid offset with an extended release of active medicaments incorporated therein.
- It is yet another object of the present invention to provide new controlled/modified release oral dosage formulations which are useful in all types of pharmaceutically active ingredients and which can extend the time of release of all such ingredients.
- It is yet another object of the present invention to provide an oral controlled release formulation which combines both a rapid onset and sustained plasma concentrations throughout the day, followed by a rapid drop-off of plasma concentrations of drug to below minimum effective concentrations.
- It is yet another object of the present invention to provide a “multi-layer release” (MLR) technology which is useful for all types of pharmaceutically active ingredients and which can extend the duration of action for a desired length of time.
- To address the above-mentioned deficiencies as well as other goals, the present invention is directed in part to a controlled release product which is intended to combined both a rapid onset and sustained plasma concentrations throughout the day. Significantly, the formulations of the present invention provide a rapid onset, a prolonged action, followed by rapid offset of effect, i.e., a “square wave” profile.
- The invention is directed in part to controlled/modified release formulations based on a multi-layered release (“MLR”) technology. The drug product can be in a tablet or a multiparticulate formulation contained within an oral gelatin capsule.
- In the case of beads, encapsulated in a capsule, each bead contains a series of layers with different characteristics—an outer immediate release layer, a release delaying layer (enteric coat), a controlled release layer over an immediate release layer. The MLR formulation is designed such that upon oral administration, the formulation provides a rapid dissolution and absorption of the outer layer of the formulation which contains a portion of the drug in immediate release form, thereby resulting in a rapid rise of the drug to therapeutic plasma levels. This is followed by a period of no absorption (due to an enteric coating), followed thereafter by a controlled release of the drug from the formulation to maintain plasma levels. After absorption of the drug from an immediate release core, plasma levels then rapidly decrease. By virtue of the release of the drug from the MLR formulation, the plasma level of the drug, when plotted on a time/concentration curve, takes the appearance of a “square wave”.
- In certain further preferred embodiments, the formulation provides a time to maximum plasma concentration at about 0.5 to about 4 hours after oral administration and provides effective blood levels for at least about 6 hours after administration.
- In certain further preferred embodiments, the formulation exhibits a “plateau” in the blood plasma curve which lasts from about 2 hours to about 6 hours. Other embodiments exhibit a “plateau” which lasts from about 6 hours to about 12 hours. The “plateau” is characterized by a stabilized plasma concentration, wherein the plasma level at the end of the measured interval does not differ by more than 20%, preferably by no more than 10% of the plasma concentration at the beginning of the measured interval.
- In certain further preferred embodiments, the formulation exhibits a bimodal release of active agent from the dosage form. Bimodal release of the active agent is characterized by the active agent being release from the dosage form by more than one distinct release rate. In some embodiments, the release rates can be separated by a no-release or a substantially no-release interval, although this is not always necessary.
- In certain further preferred embodiments, the formulation exhibits a biphasic absorption of the active agent. Biphasic absorption of the active agent is characterized by the active agent being absorbed through a natural barrier (e.g. the mucosal lining of the gastro-intestinal tract) by more than one distinct absorption rate. In some embodiments, the absorption rates can be separated by a no-absorption or a substantially no-absorption interval, although this is not always necessary. A formulation can exhibit both biphasic absorption and bimodal release of the active agent, with the biphasic absorption being a function of the bimodal release rate. However, biphasic absorption is not always attributed to release rate and can occur in a formulation not exhibiting bimodal release.
- In other preferred embodiments the formulation exhibits bimodal release and/or biphasic absorption to provide a “plateau” in the blood plasma curve which lasts from about 2 hours to about 6 hours. Other embodiments exhibit bimodal release and/or biphasic absorption to provide a “plateau” which lasts from about 6 hours to about 12 hours. Other embodiments maintain effective plasma levels of the active agent for about 16 to about 18 hours after administration of the dosage form.
- In certain preferred embodiments, an acrylic resin is utilized to provide the controlled slow release of therapeutically active ingredients over a predetermined or a specified period of time, the acrylic resin thereby comprising a significant part of the “base composition”. Base compositions prepared from such acrylic resins provide sustained release of therapeutically active ingredients over a period of time from five hours and for as much as 24 hours after administration, generally oral administration, in humans or animals.
- In other embodiments of the invention, the formulations of the invention are composed of:
- (i) a mixture of immediate release particles (e.g., beads) and enteric coated immediate release particles (e.g., beads); (ii) a mixture of immediate release particles (e.g., beads) and enteric coated controlled release particles (e.g., beads) or (iii) a mixture of immediate release particles (e.g., beads) and controlled release particles (e.g., beads). In each such instance, the mixture of particles possessing different release properties are blended together and filled into hard gelatin capsules.
- In certain preferred embodiments, the controlled/modified release drug formulations of the invention consist of a plurality of beads, each containing an immediate-release component in combination with an enteric coated controlled-release component to produce a delay in the absorption process. The drug product is an oral capsule containing beads. Each bead contains a series of layers with different release characteristics—an outer immediate release layer; a release delaying layer; a controlled release layer; and an immediate release core. The final product is a capsule containing multi-layer release (MLR) beads which have both immediate release and controlled release components. It is made up of a controlled release bead which is enteric coated to delay dissolution until after gastric emptying. The enteric coated controlled release bead has an immediate release topcoat to provide an initial rate of absorption of the drug. In certain embodiments, the immediate release component represents 40% of the total dose per bead and the controlled release component represents 60%. This formulation is designed to produce a rapid rise to therapeutic plasma levels after oral administration, due to the rapid dissolution and absorption of the outer layer, followed by a period of reduced absorption and then controlled release of the immediate release core, to maintain therapeutic plasma levels. After absorption of the immediate release core, plasma levels would then decrease according to the elimination kinetics of the drug. The results of a bioavailability study of this formulation indicate a biphasic release profile that is consistent with the pharmaceutical rationale discussed herein.
- In other embodiments of the invention, the bead size of the formulations can be adjusted in order to obtain a desired pharmacokinetic profile based on the correlation between gastric emptying and bead size. A smaller bead size exhibits faster gastric emptying as compared to a larger bead size.
- Other objects and advantages of the present invention will be apparent from the further reading of the specification and of the appended claims.
- The term “pH-dependent” for purposes of the present invention is defined as having characteristics (e.g. dissolution) which vary according to environmental pH (e.g., due to changes in the in-vitro dissolution media, or due to passage of the dosage form through the gastrointestinal tract.
- The term “pH-independent” for purposes of the present invention is defined as having characteristics (e.g., dissolution) which are substantially unaffected by pH, in that a difference, at any given time, between an amount of methylphenidate released at one pH and an amount released at any other pH, when measured in-vitro using the USP Paddle Method of U.S. Pharmacopeia XXII (1990) at 100 rpm in 900 ml aqueous buffer, is no greater than 10%.
- The following drawings are illustrative of embodiments of the invention and are not meant to limit the scope of the invention as encompassed by the claims.
-
FIG. 1 is a graphical comparison of the mean plasma concentration of methylphenidate when test subjects are treated with Formulation 1 and Ritalin® as a function of time when given under fasting conditions. -
FIG. 2 is a graphical comparison of the mean plasma concentration of methylphenidate when test subjects are treated with Formulation 1 and Ritalin® as a function of time when given under fed conditions. -
FIG. 3 is a graphical comparison of the mean plasma concentration of methylphenidate when test subjects are treated with Formulation 1 as a function of time when given under fasting and fed conditions. -
FIG. 4 is a graphical comparison of the mean plasma concentration of methylphenidate when test subjects are treated with Ritalin® as a function of time when given under fasting and fed conditions. -
FIG. 5 is a graphical comparison of the mean plasma concentration of methylphenidate when test subjects are treated withFormulation 2 under fasting and fed conditions, and Ritalin® SR under fasting conditions, as a function of time. -
FIG. 6 is a graphical comparison of the mean plasma concentration of methylphenidate when test subjects are treated withFormulation 3 under fasting and fed conditions, and Ritalin® SR under fasting conditions, as a function of time. -
FIG. 7 is a graphical comparison of the mean plasma concentration of methylphenidate when test subjects are treated withFormulations -
FIG. 8 is a graphical comparison of the mean plasma concentration of methylphenidate when test subjects are treated withFormulations - The drug used in the formulations of the invention may be selected from a wide variety of pharmaceutically active drugs such as diabetes drugs, attention deficit hyperactivity controlled drugs, analgesics, anti-obesity preparations, anti-inflammatories, antihistamines, antitussives, decongestants, antinausea agents, narcotics, bronchodilators, cardiovasculars, central nervous system (CNS) drugs, nicotine replacement therapy, nitrates, sleeping aids/sedatives, vitamins, etc.
- The controlled/modified release preparations of the present invention may be used in conjunction with any multiparticulate system, such as granules, spheroids, beads, pellets, ion-exchange resin beads, and other multiparticulate systems in order to obtain a desired sustained-release of the therapeutically active agent. Beads, granules, spheroids, or pellets, etc., prepared in accordance with the present invention can be presented in a capsule or in any other suitable unit dosage form. An amount of the multiparticulates effective to provide the desired dose of drug over time may be placed in a capsule, may be contained in a packet and sprinkled onto food, or may be incorporated in any other suitable oral solid form, such as a tablet. On the other hand, the present invention can be in the form of a matrix tablet. With respect to all such optional formulations, it is desired that the formulation be prepared such that an initial immediate release of drug provides an early onset of effect, which onset is analogous to an immediate release formulation, and that the formulation further provide a sustained release component which maintains therapeutically effective levels of the drug in the plasma for the desired amount of time, followed by a relatively rapid drop-off in blood plasma levels relative to typical sustained release formulations. Viewed as an in vivo time/concentration plot, the plasma level of the drug from the formulations of the present invention have the appearance of a “square wave”. The immediate release component preferably represents from about 30% to about 40% of the total dose and the controlled release component preferably represents from about 60% to about 70% of the total dose of methylphenidate contained in the formulations of the present invention. In certain preferred embodiments, including the MLR embodiments of the invention, the immediate release component represents about 40% of the total dose and the controlled release component represents about 60% of the total dose of methylphenidate contained in the formulation.
- In the case of methylphenidate, it is desired that the onset of action occurs from about 0.5 to about 4 hours, and preferably from about 0.5 to about 2 hours after the oral dosage form is administered, and it is further desired that the dosage form no longer provides effective plasma levels of methylphenidate from about 8 to about 12, more preferably from about 8 to about 10 hours, after oral administration of the dose. In this manner, the dose of methylphenidate can be administered to a child in the morning before school begins, provides the desired effect at the start of the school day, with the pharmacologic action of the drug not waning until after the school day ends, and preferably before dinner so that the drug does not have the side effect of acting as an appetite suppressant.
- The formulations of the present invention are designed to produce a rapid rise to therapeutic plasma levels after oral administration, due to the rapid dissolution and absorption of the outer layer, followed by a period of reduced absorption and then controlled release of the immediate release core, to maintain therapeutic plasma levels. After absorption of the immediate release core, plasma levels would then decrease according to the elimination kinetics of the drug.
- It is generally recognized that the mere presence of an active substance in the gastrointestinal fluids does not, by itself, insure bioavailability. Bioavailability, in a more meaningful sense, is the degree, or amount, to which a drug substance is absorbed into the systemic circulation in order to be available to a target tissue site. To be absorbed, an active drug substance must be in a solution. The time required for a given proportion of an active drug substance contained in a dosage unit to enter into solution in appropriate physiological fluids is known as the dissolution time. The dissolution time for an active substance from a dosage unit is determined as the proportion of the amount of active drug substance released from the dosage unit over a specified time by a test method conducted under standardized conditions. The physiological fluids of the gastrointestinal tract are the media for determining dissolution time. The present state of the art dissolution time for pharmaceutical compositions, and these test procedures are described in official compendia world wide.
- Although there are many diverse factors which influence the dissolution of a drug substance from its carrier, the dissolution time determined for a pharmacologically active substance from a specific composition is relatively constant and reproducible. Among the different factors affecting the dissolution time are the surface area of the drug substance presented to the dissolution solvent medium, the pH of the solution, the solubility of the substance in the specific solvent medium, and the driving forces of the saturation concentration of dissolved materials in the solvent medium. Thus, the dissolution concentration of an active drug substance is dynamically modified in this steady state as components are removed from the dissolution medium through absorption across the tissue site. Under physiological conditions, the saturation level of the dissolved materials is replenished from the dosage form reserve to maintain a relatively uniform and constant dissolution concentration in the solvent medium, providing for a steady state absorption.
- The transport across a tissue absorption site in the gastrointestinal tract is influenced by the Donnan osmotic equilibrium forces on both sides of the membrane, since the direction of the driving force is the difference between the concentrations of active substance on either side of the membrane, i.e. the amount dissolved in the gastrointestinal fluids and the amount present in the blood. Since the blood levels are constantly being modified by dilution, circulatory changes, tissue storage, metabolic conversion and systemic excretion, the flow of active materials is directed from the gastrointestinal tract into the blood stream.
- Notwithstanding the diverse factors influencing both dissolution and absorption of a drug substance, in many cases an important correlation can be established between the in vitro dissolution time determined for a dosage form and the in vivo bioavailability. This correlation is so firmly established in the art that dissolution time has become generally descriptive of bioavailability potential for many classes of active components contained in a particular dosage form. In view of this relationship, the dissolution time determined for a composition is one of the important fundamental characteristics for consideration when evaluating whether a controlled release formulation should be tested in vivo.
- With the above in mind, the in-vitro dissolution of the drug at various time points for formulations in accordance with the present invention is provided below:
-
Time (hours) % Drug Dissolved 0.25 0-45% 1 5-50% 4 40-90% 8 NLT 60% 12 NLT 80% - In certain preferred embodiments of the present invention, the in-vitro dissolution of the drug at various time points for formulations in accordance with the present invention is provided below:
-
Time % Drug (hours) Dissolved 0.25 0-45% 1 10-50% 4 30-80% 8 NLT 65% 12 NLT 80% - In certain preferred embodiments, the drug is incorporated into or onto a substrate and a sustained release coating is applied thereto. For example, the drug may be contained within or on a substrate as follows: (i) incorporated into matrix spheroids (e.g., together with a pharmaceutically acceptable spheronizing agent such as microcrystalline cellulose), (ii) coated onto inert pharmaceutically acceptable beads (e.g., nonpareil beads); (iii) incorporated into a normal release tablet core; or (iv) incorporated into a tablet core which comprises a matrix including a sustained release carrier material. Thereafter, a sustained release coating is applied onto substrates such as those mentioned in (i)-(iv) above. The dosage forms of the present invention may optionally be coated with one or more materials suitable for the regulation of release or for the protection of the formulation. In one embodiment, coatings are provided to permit either pH-dependent or pH-independent release, e.g., when exposed to gastrointestinal fluid. A pH-dependent coating serves to release the drug in desired areas of the gastro-intestinal (GI) tract, e.g., the stomach or small intestine. When a pH-independent coating is desired, the coating is designed to achieve optimal release regardless of pH-changes in the environmental fluid, e.g., the GI tract. It is also possible to formulate compositions which release a portion of the dose in one desired area of the GI tract, e.g., the stomach, and release the remainder of the dose in another area of the GI tract, e.g., the small intestine.
- Formulations according to the invention that utilize pH-dependent coatings to obtain formulations may also impart a repeat-action effect whereby unprotected drug is coated over the enteric coat and is released in the stomach, while the remainder, being protected by the enteric coating, is released further down the gastrointestinal tract. Coatings which are pH-dependent may be used in accordance with the present invention include shellac, cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), hydroxypropylmethylcellulose phthalate, and methacrylic acid ester copolymers, zein, and the like.
- In certain preferred embodiments, the substrate (e.g., tablet core bead, matrix particle) comprising the drug is coated with a hydrophobic material selected from (i) an alkylcellulose; (ii) an acrylic polymer; or (iii) mixtures thereof. The coating may be applied in the form of an organic or aqueous solution or dispersion. The coating may be applied to obtain a weight gain from about 2 to about 25% of the substrate in order to obtain a desired sustained release profile. Such formulations are described, e.g., in detail in U.S. Pat. Nos. 5,273,760 and 5,286,493, assigned to the Assignee of the present invention and hereby incorporated by reference. The particles are preferably film coated with a material that permits release of the drug so as to achieve, in combination with the other stated properties, a desired in-vitro release rate and in-vivo plasma levels. The sustained release coating formulations of the present invention should be capable of producing a strong, continuous film that is smooth and elegant, capable of supporting pigments and other coating additives, non-toxic, inert, and tack-free.
- Other examples of sustained release formulations and coatings which may be used in accordance with the present invention include Assignee's U.S. Pat. Nos. 5,324,351; 5,356,467, and 5,472,712, hereby incorporated by reference in their entirety.
- Cellulosic materials and polymers, including alkylcelluloses, provide hydrophobic materials well suited for coating the beads according to the invention. Simply by way of example, one preferred alkylcellulosic polymer is ethylcellulose, although the artisan will appreciate that other cellulose and/or alkylcellulose polymers may be readily employed, singly or in any combination, as all or part of a hydrophobic coating according to the invention.
- One commercially available aqueous dispersion of ethylcellulose is Aquacoat® (FMC Corp., Philadelphia, Pa., U.S.A.). Aquacoat® is prepared by dissolving the ethylcellulose in a water-immiscible organic solvent and then emulsifying the same in water in the presence of a surfactant and a stabilizer. After homogenization to generate submicron droplets, the organic solvent is evaporated under vacuum to form a pseudolatex. The plasticizer is not incorporated in the pseudolatex during the manufacturing phase. Thus, prior to using the same as a coating, it is necessary to intimately mix the Aquacoat® with a suitable plasticizer prior to use.
- Another aqueous dispersion of ethylcellulose is commercially available as Surelease® (Colorcon, Inc., West Point, Pa., U.S.A.). This product is prepared by incorporating plasticizer into the dispersion during the manufacturing process. A hot melt of a polymer, plasticizer (dibutyl sebacate), and stabilizer (oleic acid) is prepared as a homogeneous mixture, which is then diluted with an alkaline solution to obtain an aqueous dispersion which can be applied directly onto substrates.
- The hydrophobic material comprising the controlled release coating may comprise a pharmaceutically acceptable acrylic polymer, including but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.
- In certain preferred embodiments, the acrylic polymer is comprised of one or more ammonio methacrylate copolymers. Ammonio methacrylate copolymers are well known in the art, and are described in NF XVII as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.
- In order to obtain a desirable dissolution profile, it may be necessary to incorporate two or more ammonio methacrylate copolymers having differing physical properties, such as different molar ratios of the quaternary ammonium groups to the neutral (meth)acrylic esters.
- Certain methacrylic acid ester-type polymers are useful for preparing pH-dependent coatings which may be used in accordance with the present invention. For example, there are a family of copolymers synthesized from diethylaminoethyl methacrylate and other neutral methacrylic esters, also known as methacrylic acid copolymer or polymeric methacrylates, commercially available as Eudragit® from Rohm Tech, Inc. There are several different types of Eudragit®. For example, Eudragit® E is an example of a methacrylic acid copolymer which swells and dissolves in acidic media. Eudragit® L is a methacrylic acid copolymer which does not swell at about pH<5.7 and is soluble at about pH>6. Eudragit® S does not swell at about pH<6.5 and is soluble at about pH>7. Eudragit® RL and Eudragit® RS are water swellable, and the amount of water absorbed by these polymers is pH-dependent, however, dosage forms coated with Eudragit® RL and RS are pH-independent.
- In certain preferred embodiments, the acrylic coating comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma under the Tradenames Eudragit® RL30D and Eudragit® RS30D, respectively. Eudragit® RL30D and Eudragit® RS30D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1:20 in Eudragit® RL30D and 1:40 in Eudragit® RS30D. The mean molecular weight is about 150,000. The code designations RL (high permeability) and RS (low permeability) refer to the permeability properties of these agents. Eudragit® RL/RS mixtures are insoluble in water and in digestive fluids. However, coatings formed from the same are swellable and permeable in aqueous solutions and digestive fluids.
- The Eudragit® RL/RS dispersions of the present invention may be mixed together in any desired ratio in order to ultimately obtain a sustained release formulation having a desirable dissolution profile. Desirable sustained release formulations may be obtained, for instance, from a retardant coating derived from 100% Eudragit® RL, 50% Eudragit® RL and 50% Eudragit® RS, and 10% Eudragit® RL: 90% Eudragit® RS. Of course, one skilled in the art will recognize that other acrylic polymers may also be used, such as, for example, Eudragit® L.
- In embodiments of the present invention where the coating comprises an aqueous dispersion of a hydrophobic material such as an alkylcellulose or an acrylic polymer, the inclusion of an effective amount of a plasticizer in the aqueous dispersion of hydrophobic material will further improve the physical properties of the sustained release coating. For example, because ethylcellulose has a relatively high glass transition temperature and does not form flexible films under normal coating conditions, it is preferable to incorporate a plasticizer into an ethylcellulose coating containing sustained release coating before using the same as a coating material. Generally, the amount of plasticizer included in a coating solution is based on the concentration of the film-former, e.g., most often from about 1 to about 50 percent by weight of the film-former. Concentration of the plasticizer, however, can only be properly determined after careful experimentation with the particular coating solution and method of application.
- Examples of suitable plasticizers for ethylcellulose include water insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, and triacetin, although it is possible that other water-insoluble plasticizers (such as acetylated monoglycerides, phthalate esters, castor oil, etc.) may be used. Triethyl citrate is an especially preferred plasticizer for the aqueous dispersions of ethyl cellulose of the present invention.
- Examples of suitable plasticizers for the acrylic polymers of the present invention include, but are not limited to citric acid esters such as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate, and possibly 1,2-propylene glycol. Other plasticizers which have proved to be suitable for enhancing the elasticity of the films formed from acrylic films such as Eudragit® RL/RS lacquer solutions include polyethylene glycols, propylene glycol; diethyl phthalate, castor oil, and triacetin. Triethyl citrate is an especially preferred plasticizer for the aqueous dispersions of ethyl cellulose of the present invention.
- It has further been found that the addition of a small amount of talc reduces the tendency of the aqueous dispersion to stick during processing, and acts as a polishing agent.
- When the aqueous dispersion of hydrophobic material is used to coat a substrate including the drug, for example, inert pharmaceutical beads such as nu pariel 18/20 beads, a plurality of the resultant stabilized solid controlled release beads may thereafter be placed in a gelatin capsule in an amount sufficient to provide an effective controlled release dose when ingested and contacted by an environmental fluid, e.g., gastric fluid or dissolution media. Alternatively, the substrate may be a tablet core coated with the sustained release coating, and optionally a further film-forming agent or colorant, such as Opadry®.
- In formulations where an aqueous dispersion of an hydrophobic polymer such as an alkylcellulose is applied to the substrate, it is preferred that the coated substrate is cured at a temperature above the glass transition temperature of the plasticized polymer and at a relative humidity above ambient conditions, until an endpoint is reached at which the coated formulation attains a dissolution profile which is substantially unaffected by exposure to storage conditions, e.g., of elevated temperature and/or humidity. Generally, in such formulations the curing time is about 24 hours or more, and the curing conditions may be, for example, about 60° C. and 85% relative humidity. Detailed information concerning the stabilization of such formulations is set forth in U.S. Pat. Nos. 5,273,760; 5,681,585; and 5,472,712; all of which are hereby incorporated by reference in their entireties.
- In formulations where an aqueous dispersion of an acrylic polymer is applied to the substrate, it is preferred that the coated substrate is cured at a temperature above the glass transition temperature of the plasticized polymer until an endpoint is reached at which the coated formulation attains a dissolution profile which is substantially unaffected by exposure to storage conditions, e.g., of elevated temperature and/or humidity. Generally, the curing time is about 24 hours or more, and the curing temperature may be, for example, about 45° C. Detailed information concerning the stabilization of such formulations is set forth in U.S. Pat. Nos. 5,286,493; 5,580,578; and 5,639,476; all of which are hereby incorporated by reference in their entireties.
- The sustained release profile of the coated formulations of the invention can be altered, for example, by varying the amount of overcoating with the aqueous dispersion of hydrophobic material, altering the manner in which the plasticizer is added to the aqueous dispersion of hydrophobic material, by varying the amount of plasticizer relative to hydrophobic material, by the inclusion of additional ingredients or excipients, by altering the method of manufacture, etc. The dissolution profile of the ultimate product may also be modified, for example, by increasing or decreasing the thickness of the retardant coating.
- Spheroids or beads coated with a therapeutically active agent are prepared, e.g., by dissolving the therapeutically active agent in water and then spraying the solution onto a substrate, for example,
nu panel 18/20 beads, using a Wuster insert. Optionally, additional ingredients are also added prior to coating the beads in order to assist the binding of the drug to the beads, and/or to color the solution, etc. For example, a product which includes hydroxypropylmethylcellulose, etc. with or without colorant (e.g., Opadry®, commercially available from Colorcon, Inc.) may be added to the solution and the solution mixed (e.g., for about 1 hour) prior to application of the same onto the beads. The resultant coated substrate, in this example beads, may then be optionally overcoated with a barrier agent, to separate the therapeutically active agent from the hydrophobic controlled release coating. An example of a suitable barrier agent is one which comprises hydroxypropylmethylcellulose. However, any film-former known in the art may be used. It is preferred that the barrier agent does not affect the dissolution rate of the final product. - The beads may then be overcoated with an aqueous dispersion of the hydrophobic material. The aqueous dispersion of hydrophobic material preferably further includes an effective amount of plasticizer, e.g. triethyl citrate, Pre-formulated aqueous dispersions of ethyl-cellulose, such as Aquacoat® or Surelease®, may be used. If Surelease is used, it is not necessary to separately add a plasticizer. Alternatively, pre-formulated aqueous dispersions of acrylic polymers such as Eudragit can be used.
- The coating solutions of the present invention preferably contain, in addition to the film-former, plasticizer, and solvent system (i.e., water), a colorant to provide elegance and product distinction. Color may be added to the solution of the therapeutically active agent instead, or in addition to the aqueous dispersion of hydrophobic material. For example, color be added to Aquacoat via the use of alcohol or propylene glycol based color dispersions, milled aluminum lakes and opacifiers such as titanium dioxide by adding color with shear to water soluble polymer solution and then using low shear to the plasticized Aquacoat. Alternatively, any suitable method of providing color to the formulations of the present invention may be used. Suitable ingredients for providing color to the formulation when an aqueous dispersion of an acrylic polymer is used include titanium dioxide and color pigments, such as iron oxide pigments. The incorporation of pigments, may, however, increase the retard effect of the coating.
- The plasticized aqueous dispersion of hydrophobic material may be applied onto the substrate comprising the therapeutically active agent by spraying using any suitable spray equipment known in the art. In a preferred method, a Wurster fluidized-bed system is used in which an air jet, injected from underneath, fluidizes the core material and effects drying while the acrylic polymer coating is sprayed on. A sufficient amount of the aqueous dispersion of hydrophobic material to obtain a predetermined sustained release of the therapeutically active agent (i.e., drug) when the coated substrate is exposed to aqueous solutions, e.g. gastric fluid, is preferably applied, taking into account the physical characteristics of the therapeutically active agent, the manner of incorporation of the plasticizer, etc. After coating with the hydrophobic material, a further overcoat of a film-former, such as Opadry, is optionally applied to the beads. This overcoat is provided, if at all, in order to substantially reduce agglomeration of the beads.
- The release of the drug from the sustained release formulation of the present invention can be further influenced, i.e., adjusted to a desired rate, by the addition of one or more release-modifying agents, or by providing one or more passageways through the coating. The ratio of hydrophobic material to water soluble material is determined by, among other factors, the release rate required and the solubility characteristics of the materials selected.
- The release-modifying agents which function as pore-formers may be organic or inorganic, and include materials that can be dissolved, extracted or leached from the coating in the environment of use. The pore-formers may comprise one or more hydrophilic materials such as hydroxypropylmethylcellulose.
- The sustained release coatings of the present invention can also include erosion-promoting agents such as starch and gums.
- The sustained release coatings of the present invention can also include materials useful for making microporous lamina in the environment of use, such as polycarbonates comprised of linear polyesters of carbonic acid in which carbonate groups reoccur in the polymer chain.
- The release-modifying agent may also comprise a semi-permeable polymer. In certain preferred embodiments, the release-modifying agent is selected from hydroxypropylmethylcellulose, lactose, metal stearates, and mixtures of any of the foregoing.
- The sustained release coatings of the present invention may also include an exit means comprising at least one passageway, orifice, or the like. The passageway may be formed by such methods as those disclosed in U.S. Pat. Nos. 3,845,770; 3,916,889; 4,063,064; and 4,088,864 (all of which are hereby incorporated by reference). The passageway can have any shape such as round, triangular, square, elliptical, irregular, etc.
- The substrate of the present invention may be prepared by a spheronizing agent together with the active agent ingredient that can be spheronized to form spheroids. Microcrystalline cellulose is preferred. A suitable microcrystalline cellulose is, for example, the material sold as Avicel PH 101 (Trade Mark, FMC Corporation). In such embodiments, in addition to the active ingredients and spheronizing agent, the spheroids may also contain a binder. Suitable binders, such as low viscosity, water soluble polymers, will be well known to those skilled in the pharmaceutical art. However, water soluble hydroxy lower alkyl cellulose, such as hydroxypropylcellulose, are preferred. Additionally (or alternatively) the spheroids may contain a water insoluble polymer, especially an acrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethyl acrylate copolymer or ethyl cellulose. In such embodiments, the sustained-release coating will generally include a water insoluble material such as (a) a wax, either alone or in admixture with a fatty alcohol; or (b) shellac or zein.
- In a particular preferred embodiment of the invention, the controlled/modified release methylphenidate formulation is prepared as a multilayered release (MLR) formulation comprising coated inert beads. A summary of one method of manufacturing such a formulation is outlined as follows. First, immediate release (IR) drug-coated beads are prepared by spraying a solution of methylphenidate in water over sugar beads in a fluid bed dryer with a drug load of about 8%. The spray process is carried out in a fluid bed dryer, equipped with a Wurster column. A clear overcoat of HPMC is applied using an Opadry® material (e.g., Opadry® Clear (Formula No: YS-1-7006)), to a weight gain of about 1%. Next, a controlled release coating is applied to the IR beads, which converts the same into controlled release (CR) beads. This is accomplished by spraying a solution of Eudragit® RS 30 D, triethyl citrate (plasticizer) and talc (glidant), onto the IR beads. Next, the coated beads are cured in order to obtain a stabilized release rate of the therapeutically active agent. In preferred embodiments of the present invention where the CR coating utilizes an acrylic resin to control the release of the drug, the CR beads at this stage are subjected to oven curing at a temperature above the Tg of the plasticized acrylic polymer of the required time period, the optimum values of the temperature and time for the particular formulation being determined experimentally. In certain embodiments of the present invention, the stabilized products is obtained via oven curing conducted at a temperature of about 40-50° C. for a time period of about 12 to about 24 hours or longer. An enteric coating is then applied onto the CR beads to convert the same into enteric coated CR (ECCR) beads. This is accomplished by spraying a solution of Eudragit® L 30 D-55 dispersion, triethyl citrate (plasticizer) and talc (glidant) onto the CR beads. Finally, an immediate release coating is applied onto the ECCR beads (referred to as, e.g., an IR Topcoat). This is accomplished by spraying a solution of methylphenidate in water over EC CR beads.
- Results of initial studies show that this formulation is stable under room temperature (25° C., 60% RH) and accelerated conditions (40° C., 75% RH).
- In certain preferred embodiments of the present invention, an effective amount of the drug in immediate release form is included in the drug formulation. The immediate release form of the drug is included in an amount which is effective to shorten the time to maximum concentration of the drug in the blood (e.g., plasma), such that time to Tmax is shortened to a time of, e.g., from about 0.5 to about 2 hours. By including an amount of immediate release drug in the formulation, the time to onset of action is significantly reduced, and is the same or earlier than that of the reference standard immediate release treatment (e.g., Ritalin IR). In such embodiments, an effective amount of the drug in immediate release form may be coated onto the substrates (e.g., multiparticulates or tablets) of the present invention. For example, where the extended release of the drug from the formulation is due to a controlled release coating, the immediate release layer can be overcoated on top of the controlled release coating. On the other hand, the immediate release layer may be coated onto the surface of substrates wherein the drug is incorporated in a controlled release matrix. Where a plurality of the sustained release substrates comprising an effective unit dose of the drug (e.g., multiparticulate systems including pellets, spheres, beads and the like) are incorporated into a hard gelatin capsule, the immediate release portion of the drug dose may be incorporated into the gelatin capsule via inclusion of the sufficient amount of immediate release drug as a powder or granulate within the capsule. Alternatively, the gelatin capsule itself may be coated with an immediate release layer of the drug. One skilled in the art would recognize still other alternative manners of incorporating the immediate release drug portion into the unit dose. Such alternatives are deemed to be encompassed by the appended claims.
- The following examples illustrate various aspects of the present invention. They are not to be construed to limit the claims in any manner whatsoever.
-
-
TABLE 1 Ingredients % Methylphenidate hydrochloride 15.0 Sugar bead 14/1880.0 Opadry ® clear YS-1-7006 5.0 Water q.s. Total 100.0 - 1. Charge Niro-Aeromatic Strea 1 Fluid Bed Wurster Coater with 14/18 mesh Nupareil® PG (sugar spheres NF).
- 2. Coat the beads at 60° C. by spraying a solution of methylphenidate hydrochloride (12% w/w) and Opadry clear (4% w/w) in water.
- 3. Once the coating is completed, allow the beads to dry at 60° C. for 2 or 3 minutes.
- 4. Cool the beads in a shallow pan at room temperature.
- 5. Break agglomerates, if any.
- 6. Sift the beads through
Tyler 10 mesh sieve (1.77 mm opening) and then throughTyler 20 mesh sieve (850 micrometer opening) to remove fines. - 7. Apply top coat to beads by spraying a solution of coloured Opadry clear solution (4% w/w) to a theoretical weight gain of 1% w/w.
- After the completion of the overcoat, the beads are then filled into hard gelatin capsules at a strength of 20 mg.
- Dissolution testing was conducted on the bead filled IR capsules using USP Apparatus 1 (basket method) in 500 mL of simulated gastric juice without enzyme, 100 rpm at 37° C. The results are as follows:
-
TABLE 2 Time % Methylphenidate (minutes) HCl dissolved 10 92.7 20 95.7 30 97.7 45 98.5 - The dissolution results as set forth in the above table indicate that 98.5% of the methylphenidate hydrochloride was dissolved in 45 minutes.
-
-
TABLE 3 Ingredients % Methylphenidate IR beads 86.20 Eudragit ® RS 30 D 8.63 Triethyl citrate 1.72 Talc 3.45 Water q.s. Total 100.0 - The controlled-release coating is manufactured as follows:
- 1. The Eudragit® RS 30 D is plasticized with triethyl citrate and talc approximately 30 minutes.
- 2. A load of the IR beads is charged into a Wurster insert of an Aeromatic Fluid Bed Dryer with 1 mm spray nozzle and the beads are coated to a weight gain of ˜8%.
- 3. Upon completion of the coating, the beads are cured for 24 hours at 40-45° C.
- The beads were then filled into hard gelatin capsules at a 20 mg strength.
- Dissolution testing was conducted on the bead filled CR capsules using the following USP Apparatus (basket method). The capsules were placed into 500 mL of simulated gastric juice without enzyme, for first 2 hours at 100 rpm and 37TC and then placed into 500 mL simulated intestinal fluid without enzyme for the remainder of the testing period. The results are as follows:
-
TABLE 4 Time Methylphenidate (hours) HCl dissolved 1 6.9 2 16.2 3 26.1 4 35.7 6 59.8 8 74.7 12 75.4 18 82.5 24 92.8 - The dissolution results as set forth in the above table indicate that 92.8% of methylphenidate hydrochloride dissolved in 24 hours.
- By adjusting the amount of Eudragit® RS 30 D applied, The release rate can be adjusted. This effect is illustrated in Examples 3 and 4 below:
-
TABLE 5 % Ingredients Example 3 Example 4 Methylphenidate HCl IR Bead 91.2 94.0 Eudragit ® RS 30 D 5.8 3.9 Triethyl citrate 1.0 0.7 Talc 2.0 1.4 Water — — Total 100.0 100.0 - The method of manufacturing the controlled-release beads in Examples 3 and 4 is similar to the method described under Example 2, by varying the proportion of beads and Eudragit® RS 30 D.
- The cured beads were filled into hard gelatin capsules at a strength of 20 mg.
- The dissolution results, conducted under conditions identical to those found under Example 2, are shown below:
-
TABLE 6 Time % Methylphenidae HCl dissolved (hours) Example 3 Example 4 1 18.7 49.5 2 35.1 73.3 3 49.0 81.5 4 60.6 85.2 6 75.7 90.4 8 77.3 90.7 12 82.1 92.8 - The dissolution results as set forth in the above table, indicate that 82.1% and 92.8% respectively of methylphenidate hydrochloride is dissolved in 12 hours. However, the release of drug from Example 4 was significantly faster at
time points -
-
TABLE 7 Ingredients % Methylphenidate CR beads 83.2 Eudragit ® L 30 D55 9.9 Triethyl citrate 2.0 Talc 4.9 Water q.s. Total 100.0 - The enteric coating procedure is described below:
- 1. The Eudragie L 30 D 55 is plasticized with triethyl citrate and talc approximately 30 minutes.
- 2. A load of the methylphenidate CR beads is charged into a Wurster insert of an Aeromatic
- Fluid Bed Dryer with 1 mm spray nozzle and the beads are coated to a weight gain of ˜9%.
- 3. Upon completion of the coating, the beads are cured for 18 hours at 40° C.
- 4. The cured beads are then sieved through
Tyler 10 mesh (1.7 mm opening) andTyler 20 mesh (850 micrometer opening) sieves to remove any fines. - The beads were then filled into hard gelatin capsules at a 20 mg strength.
- Dissolution testing was conducted on the bead filled CR filled capsules using USP Apparatus 1 (basket method) 500 mL at 100 rpm and 37° C. using SGF without enzyme for the first 2 hours and SIF without enzyme for the rest of the testing period. Results are shown below:
-
TABLE 8 Time % Methylphenidate HCl dissolved (hours) Lot 1 Lot 2Lot 31 0.4 1.0 2.0 2 2.2 5.4 7.4 3 18.8 27.8 61.3 4 36.7 48.3 87.0 6 59.5 75.5 98.8 8 76.9 90.1 100.0 12 82.3 99.6 — - The dissolution results as set forth in the above table indicate that very little drug is dissolved in gastric juice after enteric coating and that the dissolution profile of the CR beads has been modified.
- Examples 6A, 6B and 6C below set forth the formulations developed and tested in clinical studies.
- The (IR·EC·CR Beads) formulation, hereinafter referred to as Formulation 1, is a capsule containing multi-layer release beads which have both immediate release and controlled release components. It is made up of a controlled release bead which is enteric coated to delay dissolution until after gastric emptying. The enteric coated controlled release bead has an immediate release topcoat to provide an initial rate of absorption equal to or greater than Ritalin® IR immediate release tablets. The immediate release component represent 40% of the total dose per bead and the controlled release component represents 60%.
-
TABLE 9 Ingredients % Enteric coated Controlled Release 91.4 Methylphenidate HCl beads Methylphenidate hydrochloride USP 6.5 Opadry ® clear YS-1-7006 2.1 Water q.s. Total 100.0 - The application of an immediate release coat on the top of Enteric Coated CR beads is described below:
- 1. Dissolve methylphenidate HCl USP and Opadry in water with stirring.
- 2. Load EC·CR beads into a Wurster insert of an Aeromatic Fluid Bed Dryer.
- 3. Spray the beads with the coating solution using a 1 mm spray nozzle at a temperature of not more than 50° C.
- 4. Once the coating is completed, cool the beads at room temperature and pass through Tyler sieves 10 and 20 mesh to remove fines.
- The beads were then filled into a hard gelatin capsule to a 20 mg strength.
- Dissolution testing was conducted on the bead filled capsules of Formulation 1 using USP Apparatus 1 (basket method) 100 rpm, 500 mL at 3.7° C.—simulated gastric juice without enzyme 1st and 2nd hours; 3rd hour onwards simulated intestinal fluid without enzyme.
- The results are as follows:
-
TABLE 10 Time % Methylphenidate (hours) HCl dissolved 5 minutes 37.0 10 minutes 38.0 15 minutes 39.0 30 minutes 40.0 60 minutes 40.0 2 40.1 3 51.4 4 61.0 6 75.6 8 87.0 12 87.5 - The dissolution results as set forth in the above table indicate a rapid onset on dissolution, followed by prolonged action.
- The enteric-coated controlled release beads (EC·CR) beads described in Example 5 may be mixed with the immediate release (IR) beads described in Example 1 in varying proportions and placed in capsules to obtain the final blended dosage form, (IR+EC·CR Blend), hereinafter referred to as
Formulation 2.Formulation 2 was designed to provide a faster rate of absorption of the controlled release portion than Formulation 1. The immediate release component represents 35% of the total dose per capsule and the controlled release component represents 65%: - Dissolution testing was performed and the comparative results are shown in Table 11 below.
- The IR·CR Beads formulation, hereinafter referred to as
Formulation 3, is a capsule containing single beads made up of an immediate release topcoat and a controlled release core, and is designed to provide an intermediate rate of absorption of the controlled release portion between that of the controlled release formulations ofFormulations 1 and 2. The immediate release component represents 30% of the total dose per bead and the controlled release component represents 70%. - The immediate release topcoat is applied to CR beads as described in Example 6A for Formulation 1.
- The dissolution profiles of Formulations 1-3 and Ritalin® SR, used as a comparator, are shown in Table 11 below.
Hours 1 and 2 are in 500 ml of simulated gastric fluid. Simulated intestinal fluid (500 ml) is used from the third hour onwards. The results of the dissolution testing confirmed the anticipated in vitro dissolution profile. -
TABLE 11 Comparative Dissolution of Formulations Time (Hours) Ritalin SR Formulation 1 Formulation 2Formulation 310 min 21.4 38.0 32.0 28.6 30 min 31.4 40.0 36.7 34.0 1 45.7 40.0 38.2 40.5 2 62.3 40.1 40.4 57.6 3 75.8 51.4 68.1 70.6 4 79.5 61.0 86.4 79.5 6 88.0 75.6 95.4 89.6 8 90.7 87.0 96.2 92.7 12 91.3 87.5 97.0 93.1 - The bioavailability of Methylphenidate MLR capsules was investigated in a four-way blind study which compared the Formulation 1 20 mg single dosage formulation under fed and fasted conditions with two doses (4 hours apart) of Ritalin® IR.
- Healthy male volunteers were given a single dose of 20 mg Formulation 1 or two doses of
immediate release methylphenidate 10 mg administered four hours apart under both fed and fasting conditions (n=12). “Fed” conditions indicates the test formulation was given to the subjects after they had eaten a high-fat breakfast. Following an overnight fast of at least 10.0 hours, each of the normal, healthy, non-smoking, male subjects were given the following treatments according toWilliams design 4 treatment randomization scheme. - Treatment 1: Test Product: methylphenidate controlled-release,
Formulation 1, 20 mg capsule, in the morning under fasting conditions. - Treatment 2: Reference Product: methylphenidate immediate-release, Ritalin® (Novartis), 10 mg tablet in the morning and 4 hours later, under fasting conditions.
- Treatment 3: Test Product: methylphenidate controlled-release,
Formulation 1, 20 mg capsule, administered 5 minutes after a high fat breakfast. - Treatment 4: Reference Product: methylphenidate immediate-release, Ritalin® (Novartis), 10 mg tablet in the morning and 4 hours later, administered 5 minutes after a high fat breakfast.
- There was a seven day washout period between the study periods. During each study period, blood samples (1×5 mL each) were taken from each subject within one hour prior to dosing and at 0.250, 0.500, 0.750, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.00, 6.00, 7.00, 8.00, 10.0, 12.0, 16.0, 24.0 hours post-dose for the Formulation 1 and at pre-dose, 0.250, 0.500, 0.750, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.00, 6.00, 7.00, 8.00, 10.0, 12.0, 16.0, 24.0 hours post-dose for the Ritulin® IR. Plasma was harvested from each blood sample and stored in a −20° C. freezer until assayed for plasma methylphenidate concentration. Assay of plasma methylphenidate concentrations was performed using gas chromatography/mass spectrometry (GC/MS).
- The mean plasma concentrations, standard deviations and coefficients of variation are shown as a function of time in Tables 12 and 13, for fasting and fed conditions, respectively.
- This data is presented graphically in
FIGS. 1-4 .FIG. 1 presents the mean plasma concentration versus time for Formulation 1 and Ritalin® underlasting conditions.FIG. 2 presents the mean plasma concentration versus time for Formulation 1 and Ritalin® under fed conditions.FIG. 3 presents the mean plasma concentration versus time for Formulation 1 under fed and fasting conditions.FIG. 4 presents the mean plasma concentration versus time for Ritalin® under fed and fasting conditions. -
TABLE 12 Mean Plasma Concentrations (pg/mL) of Methylphenidate: Formulation 1 and Ritalin ® IR (fasting) Formulation 1 Ritalin Sample Concen- Concen- Time (h) tration SD (±) CV (%) tration SD (±) CV (%) 0.000 0.00 0.00 0.00 0.00 0.250 0.00 0.00 — 0.00 0.00 0.500 817.53 801.84 98.08 883.96 686.65 77.68 0.750 2268.79 1128.12 49.72 2485.74 828.38 33.33 1.00 3108.79 756.66 24.34 3468.74 1172.28 33.80 1.50 3597.88 740.36 20.58 4388.04 998.86 22.76 2.00 3675.60 1315.29 35.78 4289.39 1144.40 26.68 2.50 3469.81 882.62 25.44 4121.37 1014.57 24.62 3.00 3573.56 1031.61 28.87 3528.56 863.25 24.46 3.50 3637.01 1008.73 27.74 3020.93 716.36 23.71 4.00 3604.03 1071.59 29.73 2747.91 698.95 25.44 4.50 3494.44 1069.13 30.60 2958.49 799.89 27.04 5.00 3446.41 1069.50 31.03 4394.22 1603.40 36.49 5.50 — — — 5525.84 1766.58 31.97 6.00 3421.13 1166.25 34.09 5927.06 1955.99 33.00 6.50 — — 5528.41 1758.49 31.81 7.00 3422.32 958.42 28.00 4860.45 1482.24 30.50 8.00 3338.59 724.49 21.70 3795.34 1500.79 39.54 10.0 2858.42 612.21 21.42 2223.48 926.11 41.65 12.0 2073.97 536.08 25.85 1334.71 523.37 39.21 16.0 1180.67 502.11 42.53 455.86 287.79 63.13 24.0 275.87 201.51 73.04 55.10 99.99 181.46 -
TABLE 13 Mean Plasma Concentrations (pg/mL) of Methylphenidate: Formulation 1 and Ritalin ® IR (fed) Formulation 1 Ritalin Sample Concen- Concen- Time (h) tration SD (±) CV (%) tration SD (±) CV (%) 0.000 0.00 0.00 — 0.00 0.00 0.250 0.00 0.00 — 53.12 133.84 251.95 0.500 291.66 271.58 93.11 1256.61 1602.66 127.54 0.750 910.22 653.80 71.83 2984.60 3406.53 114.14 1.00 1580.66 983.13 62.20 3400.39 2301.87 67.69 1.50 2760.68 797.24 28.88 5205.16 1882.17 36.16 2.00 3098.73 874.49 28.22 5146.55 1617.43 31.43 2.50 3655.68 982.31 26.87 5157.11 1227.99 23.81 3.00 3625.88 797.55 22.00 4546.61 932.94 20.52 3.50 3717.71 951.58 25.60 4184.34 1080.71 25.83 4.00 3650.63 875.97 23.99 3652.57 1023.22 28.01 4.50 3627.41 835.40 23.03 3811.27 1103.83 28.96 5.00 3430.14 783.72 22.85 5158.45 1714.53 33.24 5.50 — — — 5982.98 1618.65 27.05 6.00 3418.03 937.07 27.42 6228.81 1591.64 25.55 6.50 — — — 6054.32 1919.95 31.71 7.00 4218.94 775.86 18.39 5538.57 1741.02 31.43 8.00 4679.67 1126.52 24.07 4350.90 1611.95 37.05 10.0 3858.58 1045.56 27.10 2577.66 896.59 34.78 12.0 2610.98 902.53 34.57 1521.52 611.54 40.19 16.0 1372.86 737.71 53.74 577.90 334.26 57.84 24.0 334.79 306.63 91.59 94.23 144.99 153.86 - Pharmacokinetic parameters were calculated based on the data from the four-way study. AUC0-t (pg·h/mL), AUC0-inf (pg·h/mL), AUC0inf (%), Cmax (pg/mL), Tmax (hours), T1/2 el (hours), Kel (hour−1), TLIN (hours) and LQCT (hours) were calculated as described below.
- For purposes of the present invention, the following terms are meant to have the following meanings:
-
- AUC0-t Area under the concentration-time curve from time zero to the time of the last non-zero concentration (this corresponds to the area under the concentration-time curve, over the dosing interval of the test formulation for both controlled-release and immediate-release formulations)
- AUC0-inf Area under the concentration-time curve from time zero to infinity
- C.I. Confidence interval
- CV Coefficient of variation
- Cmax Maximum observed concentration
- Kel Elimination rate constant
- LQCT The last quantifable concentration time
- SD Standard deviation
- TLIN The time point where log-linear elimination begins
- T1/2 el Time for observed Cmax
- Sampling Time Time post dose of plasma collection based on parameters to be studied
- Scheduled Time The predetermined (clock) time at which the samples are to be taken
- Actual time The exact (clock) time at which the sample was taken
- Time deviations during sampling for drugs with a Tmax≦4 hours were treated as follows: between 0 and 6 hours post dose, the sampling time was used in the statistical analysis if the delay between the actual and scheduled time of blood collection was <10%. Above 6 hours post dose, the sampling time was used in the statistical analysis if the delay between the actual and scheduled time of plasma collection was <15%. When sampling times were used when previously described acceptance criteria, the corrected sampling items were used when performing pharmacokinetic parameters calculations. Sampling times are present in concentration tables and graphs of statistical report.
- The mean, standard deviation (SD), and coefficient of variation (CV) were calculated for plasma concentrations of methylphenidate for each sampling time and treatment. As well, the mean, SD, and CV were calculated for the AUC0-t (pg·h/mL), AUC0-inf (pg·h/mL), Cmax (pg/mL), Tmax (hours), T1/2 el (hours), Kel (hour−1) , TLIN (hours) and LQCT (hours). The calculation of these pharmacokinetic parameters is explained below.
- Areas under the Concentration-Time Curves
- AUC0-t was calculated using the linear trapezoidal rule.
- The AUC0-t was derived where t is the time (t) of the last measurable (non-zero) concentration (Ct) for each treatment.
- The AUC0-inf was calculated as:
-
- Where Ct=the last non-zero concentration for that treatment, AUC0-t=the AUC from time zero to the time of the last non-zero concentration for that treatment and Kel=the elimination rate constant.
- The maximum observed concentration, Cmax, and the observed time to reach peak concentration, Tmax, was determined for each subject and for each treatment.
- To calculate the elimination rate constant (Kel), linear regression analyses were performed on the natural log (Ln) of plasma concentration values (y) versus time (x). Calculations were made between a time point where log-linear elimination phase begins (LQCT) occurred. The Kel was taken as the slope multiplied by (−1) and the apparent half-life (T1/2 el) as 0.693/Kel.
- TLIN, the time point where log-linear elimination begins, and LQCT, the last quantifiable concentration time were determined for each subject and for each treatment.
- Percent drug absorbed was calculated at each sampling time (t) by Modified Wagner-Nelson's method, as implemented in Kinetica software, version 2.0.1 according to the following formula:
-
- All ANOVAs were performed with the SAS General Linear Models Procedure (GLM). For all analyses, effects were considered statistically significant if the probability associated with ‘F’ was less than 0.050. Based on the pairwise comparisons of the ln-transformed AUC0-t, AUC0-inf and Cmax data, the relative ratios of the geometric means, calculated according to the formulation “e(X-Y)×100”, as well as the 90% geometric confidence intervals were determined.
- The plasma concentration of unchanged methylphenidate following administration of the controlled release formulation Formulation 1 reached the maximum concentration (Cmax) at a mean of 3.27 hours under fasting conditions and 7.29 hours under fed conditions reflecting a biphasic absorption profile. The plasma concentration of unchanged methylphenidate following administration of two doses of the immediate release formulation (Ritalin® IR) reached the maximum concentration (Cmax) at 5.96 hours under fasting conditions and 3.54 hours under fed conditions. When the determination of C was restricted to the first dose of immediate release methylphenidate, the Tmax was 1.71 hours under fasting conditions and 1.63 hours under fed conditions.
- The complete pharmacokinetic parameters of controlled
release methylphenidate 20 mg Formulation 1 andimmediate release methylphenidate 10 mg (Ritalin® IR) under fed and fasted conditions are summarized in Tables 14 and 15 below. -
TABLE 14 Pharmacokinetic Parameters for Formulation 1 Formulation 1 Formulation 1 (fasting) (fed) CV Parameters Mean ± SD CV (%) Mean ± SD (%) AUC0-t 48493.80 ± 13430.27 27.69 54686.38 ± 15118.66 27.65 (pg.h/mL) AUC0-inf 51213.86 ± 13260.14 26.59 57931.47 ± 16762.54 28.94 (pg.h/mL) Cmax (pg/mL) 4410.25 ± 1188.68 26.95 4879.37 ± 1027.85 21.07 Tmax (h) 3.27 ± 2.54 77.64 7.29 ± 1.29 17.65 Kel (h−1) 0.1672 ± 0.0339 20.25 0.1812 ± 0.0392 21.65 T1/2 el (h) 4.32 ± 0.96 22.18 4.06 ± 1.25 30.91 -
TABLE 15 Pharmacokinetic Parameters for Ritalin ® IR RITALIN ® RITALIN ® (fasting) (fed) CV Parameters Mean ± SD CV (%) Mean ± SD (%) AUC0-t 44644.22 ± 13806.82 30.93 52781.49 ± 15194.94 28.79 (pg.h/mL) AUC0-inf 46466.23 ± 14012.73 30.16 54783.17 ± 15311.08 27.95 (pg.h/mL) Cmax (pg/mL) 6536.04 ± 1669.29 25.54 7571.74 ± 1534.58 20.27 Tmax (h) 5.96 ± 0.54 9.09 3.54 ± 2.42 68.43 Kel (h−1) 0.2481 ± 0.0550 22.17 0.2449 ± 0.0719 29.37 T1/2 el (h) 2.93 ± 0.71 24.10 3.08 ± 0.96 31.26 - The results of the ANOVA and Duncan's Multiple Range Test performed on the ln-transformed AUC0-t data show a statistically significant difference between treatments for this parameter. According to Duncan's Multiple Range Test, the AUC0-t of treatment 1 was significantly different from the AUC0-t of
treatments treatments -
TABLE 16 AUC0-t TRT 1 vs. TRT 3 vs.TRT 1 vs. (pg · h/mL) TRT 2TRT 4TRT 3Ratio 109.90% 104.08% 88.65% 90% 102.59% to 97.15% to 82.75% to Geometric C.I. 117.74% 111.50% 94.97% - The results of the ANOVA and Duncan's Multiple Range Test performed on the ln-transformed AUC0-inf data show a statistically significant difference between treatments for this parameter. According to Duncan's Multiple Range Test, the AUC0-inf of treatment 1 was significantly different from the AUC0-inf of
treatments treatments -
TABLE 17 AUC0-inf (pg · h/mL) TRT 1 vs. TRT 2TRT 3 vs.TRT 4TRT 1 vs. TRT 3Ratio 111.65% 105.86% 88.85% 90% 104.09% to 98.70% to 82.84% to Geometric 119.95% 113.55% 95.30% C.I. - The results of the ANOVA and Duncan's Multiple Range Test performed on the ln-transformed Cmax data show a statistically significant difference between treatments for this parameter. According to Duncan's Multiple Range Test, the Cmax of treatment 1 was not significantly different from the Cmax of
treatment 3. However, Duncan's Multiple Range Test detected statistically significant differences for Cmax when comparingtreatments 1 and 2 andtreatments -
TABLE 18 Cmax (pg/mL) TRT 1 vs. TRT 2TRT 3 vs.TRT 4TRT 1 vs. TRT 3Ratio 67.48% 64.38% 89.37% 90% Geometric 60.28% to 57.51% to 79.83% to C.I. 75.54% 72.07% 100.04% - The ANOVA and Duncan's Multiple Range Test performed on the Tmax data detected a statistically significant difference between treatments for this parameter. Duncan's Multiple Range Test detected statistically significant differences between
treatments 1 and 2,treatments treatments 1 and 3 for this parameter. - The ANOVA and Duncan's Multiple Range Test performed on the T1/2 el data detected a statistically significant difference between treatments for this parameter. Duncan's Multiple Range Test detected no statistically significant differences between
treatments 1 and 3 for T1/2 el. However, Duncan's Multiple Range Test detected statistically significant differences betweentreatments 1 and 2 andtreatments - The results of the ANOVA and Duncan's Multiple Range Test performed on the Kel data show a statistically significant difference between treatments for this parameter. Statistically significant differences were detected by Duncan's Multiple Range Test between
treatments 1 and 2 andtreatments treatments 1 and 3. - The AUC and Cmax ratios of controlled
release methylphenidate 20 mg Formulation 1 under fed and fasted conditions are summarized in Table 19 below. A comparison of the AUC and Cmax ratios forimmediate release methylphenidate 10 mg (Ritalin® IR) and Formulation 1 under fasting conditions are summarized in Table 20 below. Table 21 shows the comparative ratios forimmediate release methylphenidate 10 mg (Ritalin® IR) and Formulation 1 under fed conditions. - Treatment 1 (Formulation 1, fasting) versus Treatment 3 (Formulation 1, fed)
- The ANOVAs detected statistically significant differences between treatments for ln-transformed AUC0-t, AUC0-inf and Cmax, and untransformed Tmax, Kel, T1/2 el. Duncan's Multiple Range Test detected statistically significant differences between
treatments 1 and 3 for ln-transformed AUC0-t, and AUC0-inf and untransformed Tmax. However, Duncan's Multiple Range Test detected no statistically significant differences between treatments for ln-transformed Cmax and untransformed Kel and T1/2 el. All formulation ratios, as well as 90% geometric confidence intervals of the relative mean AUC0-t, AUC0-inf and Cmax of the test product (Formulation 1, fasting) to reference product (Formulation 1, fed) were found to be within 80 to 125%. This is summarized in Table 19 below: -
TABLE 19 Formulation 1 (Fed) vs. Formulation 1 (Fast) AUC0-t AUC0-inf Cmax Ratio1 112.80% 112.54% 111.90% 90% 105.29%-120.84% 104.93%-120.71% 99.96%-125.27% Geometric C.I.2 1Calculated using geometric means according to the formula: e[Formulation 1(fed) −Formulation 1 (fasting)] × 100 290% Geometric Confidence Interval using In-transformed data
Treatment 1 (Formulation 1, fasting) versus Treatment 2 (Ritalin®, fasting) - The ANOVAs detected statistically significant differences between treatments for ln-transformed AUC0-1, AUC0-inf and Cmax, and untransformed Tmax, Kel, T1/2 el . Duncan's Multiple Range Test detected statistically significant differences between
treatments 1 and 2 for all parameters. With the exception of Cmax, all formulation ratios as well as 90% geometric confidence intervals of the relative mean AUC0-t and AUC0-inf of the test product (Formulation 1) to reference product (Ritalin) were found to be within the 80 to 125%. This is summarized in Table 20 below: -
TABLE 20 Formulation 1 (Fast) vs Ritalin ® (Fast) AUC0-t AUC0-inf Cmax Ratio1 109.90% 111.65% 67.48% 90% 102.59%-117.74% 104.09%-119.75% 60.28%-75.54% Geometric C.I.2 1Calculated using geometric means according to the formula: e[Formulation 1 (fast) − Ritalin IR (fast)] × 100 290% Geometric Confidence Interval using log-transformed data
Treatment 3 (Formulation 1, fed) versus Treatment 4 (Ritalin, fed) - The ANOVAs detected statistically significant differences between treatments for ln-transformed AUC0-t, AUC0-inf and Cmax, and untransformed Tmax, Kel, T1/2 el. Duncan's Multiple Range Test detected statistically significant differences between
treatments -
TABLE 21 Formulation 1 (Fed) vs. Ritalin ® IR (Fed) AUC0-t AUC0-inf Cmax Ratio1 104.08% 105.86% 64.38% 90% Geometric 97.15%-111.50% 98.70%-113.55% 57.51%-72.07% C.I.2 1Calculated using geometric means according to the formula: e[Formulation 1 (fed) − Ritalin IR (fed)] × 100 290% Geometric Confidence Interval using log-transformed data - Review of individual plasma MPH time curves indicates the following:
- Plasma MPH concentrations at 12 hours were higher on Formulation 1 than on Ritalin IR in all subjects, under both fed and fasted conditions.
- A biphasic profile was apparent under fasted conditions in 7-10/12 subjects and in 8-10/12 under fed conditions. The mean curve showing a stable plateau under fasted conditions is therefore not fully representative of the individual profiles. The enteric coat therefore gave rise to a biphasic profile in some subjects even under fasted conditions.
- Under fasted conditions the apparent rate of rise of plasma MPH was equivalent to, or faster than, that of Ritalin IR in 8/12 subjects under fasted conditions and 4-5/12 subjects under fed conditions. The mean curves which demonstrate an equivalent rate of rise under fasted conditions and a slower rise under fed conditions were therefore largely reflective of the individual profiles.
- The bioavailability of Formulation 1 relative to Ritalin IR was acceptable under both fed and fasted conditions (Relative AUCinf 106% and 112%). There was an increase in AUC of both Formulation 1 and Ritalin when given with food (13.1% and 17.9% respectively).
- Formulation 1 had a more prolonged mean plasma MPH concentration time profile than two doses of Ritalin IR. An across study comparison indicates that Formulation 1 also has a more prolonged profile than Ritalin SR.
- Under fasted conditions Formulation 1 had a mean initial rate of rise of plasma MPH that is similar to Ritalin IR and a relatively flat plateau until 8 hours post-dose.
- Under fed conditions, the initial rise in plasma MPH from Formulation 1 was slower than under fasted conditions and the plateau showed a biphasic profile. This was consistent with predictions that the enteric coat would delay release of the controlled release component and that this delay would be longer under fed conditions (allowing the initial plasma concentration peak, due to the IR component, to fall prior to the start of release from the controlled release component).
- Formulation 1 results in both a fast initial rate of rise of plasma methylphenidate concentration, and a prolonged duration. The transformation from a prolonged plateau profile under fasted conditions to a biphasic profile under fed conditions, is as predicted. Formulation 1 therefore has the potential to meet the dual objectives of rapid onset and prolonged duration that are considered desirable characteristics of a controlled release methylphenidate formulation for the treatment of ADD/ADHD.
- An initial pilot bioavailability study completed in adult healthy volunteers has confirmed that a single 20 mg dose of this formulation has an equivalent extent of absorption to two doses of immediate release methylphenidate (10 mg) given 4 hours apart. Maximal plasma concentrations with the controlled release formulation are similar to those attained with the first dose of immediate release methylphenidate and from approximately 10 hours post-dose, are higher than those following the second dose of immediate release methylphenidate.
- The results indicate the potential for a single morning dose of this formulation to produce clinical effects that are at least equivalent to those of two doses of immediate-release methylphenidate given at breakfast and lunchtime, with a duration of action that may reduce the need for a third dose of immediate release methylphenidate later in the day.
- A five-way blind study was conducted which compared a single dose of
Formulation Formulation Ritalin SR 20 mg single dose fasted. According to the published literature and anecdotal comments from physicians, Ritalin SR is used in less than 20% of methylphenidate treated patients. - Twelve healthy male volunteers were given a single dose of either 20
mg Formulation 2 orFormulation 3 administered four hours apart under both fed and fasting conditions (n=12), or slow-release 20 mg methylphenidate (Ritalin SR) under fasting conditions. “Fed” conditions indicates the test formulation was given to the subjects after they had eaten a high-fat breakfast. Following an overnight fast of at least 10.0 hours, each of the normal, healthy, non-smoking, male subjects were given the following treatments according to Williams design 5 treatment randomization scheme. - Treatment 1: Test Product: methylphenidate controlled-release,
Formulation - Treatment 2: Test Product: methylphenidate controlled-release,
Formulation - Treatment 3: Test Product: methylphenidate controlled-release,
Formulation - Treatment 4: Test Product: methylphenidate controlled-release,
Formulation - Treatment 5: Reference Product: methylphenidate slow-
release 20 mg tablet Ritalin SR (Novartis) under fasting conditions. - There was a seven day washout period between the study periods. During each study period, blood samples (1×5 mL each) were taken from each subject within one hour prior to dosing and at 0.250, 0.500, 0.750, 1.00, 1.50, 2.00, 2.50, 3.00, 150, 4.00, 4.50, 5.00, 6.00, 7.00, 8.00, 10.0, 12.0, 16.0, 24.0 hours post-dose. Plasma was harvested from each blood sample and stored in a −20 C freezer until assayed for plasma methylphenidate concentration.
- The data is presented graphically in
FIGS. 5-8 .FIG. 5 presents the mean plasma concentration versus time forFormulation 2 under fasting and fed conditions and Ritalin® under fasting conditions.FIG. 6 presents the mean plasma concentration versus time forFormulation 3 under fasting and fed conditions and Ritalin® under fasting conditions.FIG. 7 presents the mean plasma concentration versus time forFormulations FIG. 8 presents the mean plasma concentration versus time forFormulations - The complete pharmacokinetic parameters of controlled
release methylphenidate 20 mg (Formulation 2 and 3) under fed and fasting conditions, and forslow release methylphenidate 20 mg (Ritalin® SR) under fasting conditions are summarized in Tables 22-24 below. -
TABLE 22 Pharmacokinetic Parameters for Formulation 2Treatment 1, Fasting Treatment 2, Fed Parameters Means ± SD CV (%) Mean ± SD CV (%) AUC0-t (pg · h/mL) 48190.73 ± 11668.71 24.21 53452.63 ± 12820.39 23.98 AUC0-inf (pg · h/mL) 49787.07 ± 12053.23 24.21 55690.49 ± 12691.52 22.79 Cmax (pg · h/mL) 7498.57 ± 1968.38 26.25 6879.09 ± 1486.53 21.61 Tmax (h) 3.63 ± 0.57 15.70 6.42 ± 1.08 16.89 Kel (h−1) 0.2391 ± 0.0428 17.91 0.2321 ± 0.0342 14.75 T1/2 (h) 3.00 ± 0.64 21.32 3.05 ± 0.48 15.74 -
TABLE 23 Pharmacokinetic Parameters for Formulation 3Treatment 3,Fasting Treatment 4, Fed Parameters Means ± SD CV (%) Mean ± SD CV (%) AUCo-t (pg · h/mL) 48057.06 ± 14743.87 30.68 54128.75 ± 14787.94 27.32 AUC0-inf (pg · h/mL) 49984.68 ± 14873.03 29.76 56315.66 ± 14779.59 26.24 Cmax (pg · h/mL) 6080.97 ± 2048.60 33.69 6959.07 ± 1559.34 22.41 Tmax (h) 3.46 ± 0.89 25.76 4.42 ± 0.56 12.62 Kel (h−1) 0.2009 ± 0.0468 23.32 0.2057 ± 0.0390 18.97 T1/2 (h) 3.65 ± 0.97 26.52 3.49 ± 0.70 20.01 -
TABLE 24 Pharmacokinetic Parameters for Ritalin SR ® Parameters Mean ± SD CV (%) AUC0-t (pg · h/mL) 47404.51 ± 12754.66 26.91 AUC0-inf (pg · h/mL) 49252.17 ± 12841.52 26.07 Cmax (pg/mL) 6783.09 ± 1496.65 22.06 Tmax (h) 3.50 ± 0.43 12.18 Kel (h−1) 0.2282 ± 0.0320 14.01 T1/2 el (h) 3.10 ± 0.47 15.14 - The results of the ANOVA and Duncan's Multiple Range Test performed on the ln-transformed Cmax data show a statistically significant difference between treatments for this parameter. According to Duncan's Multiple Range Test, the Cmax of
treatment 3 was significantly different from the Cmax oftreatments 4 and 5. However, Duncan's Multiple Range Test did not detect statistically significant differences between treatments for Cmax when comparing treatment 1 vs.treatment 2 or treatment 1 vs treatment 5. The statistical analyses performed on the data are summarized in Table 25 below: -
TABLE 25 TRT 1 vs. TRT 3 vs.TRT 1 vs. TRT 3 vs.Cmax (pg/mL) TRT 2TRT 4TRT 5 TRT 5 Ratio 103.73% 84.78% 109.25% 87.40% 90% Geometric 98.94% to 78.59% to 101.28% to 81.05% to C.I. 115.14% 91.45% 117.85% 94.26% - The ANOVA and Duncan's Multiple Range Test performed on the ln-transformed Tmax data detected a statistically significant difference between treatments for this parameter. Duncan's Multiple Range Test detected statistically significant differences between
treatments 1 and 2, andtreatments treatments 3 vs. 5. - The ANOVA performed on the T1/2 el data detected a statistically significant difference between treatments for this parameter. Duncan's Multiple Range Test detected no statistically significant differences between
treatments 1 and 2,treatments treatments 3 and 5 for this parameter. - The ANOVA performed on the Kel data show a statistically significant difference between treatments for this parameter. Statistically significant differences were not detected by Duncan's Multiple Range Test, between treatments for Kel when comparing
treatments 1 and 2,treatments treatments 3 and 5 for this parameter. - The ANOVA and Duncan's Multiple Range Test performed on the ln-transformed AUC0-t, data show a statistically significant difference between treatments for this parameter. According to Duncan's Multiple Range Test, the AUC0-t of
treatments 1 and 3 was significantly different from the AUC0-1 oftreatments treatment 3 vs treatment 5. The statistical analyses performed on the data are summarized below in Table 26: -
TABLE 26 Treatment 3Treatment 1 Treatment 3AUC0-t Treatment 1 vs. vs. vs. vs. (pg · h/mL) Treatment 2Treatment 4Treatment 5 Treatment 5 Ratio 89.21% 88.23% 101.82% 100.63% 90% 84.03% to 83.10% to 95.91% to 94.81% to Geometric 94.71% 93.67% 108.10% 106.81% C.I. - The ANOVA and Duncan's Multiple Range Test performed on the ln-transformed AUC0-inf data show a statistically significant difference between treatments for this parameter. According to Duncan's Multiple Range Test, the AUC0-inf of
treatments 1 and 3 was significantly different from the AUC0-inf oftreatments treatment 3, ortreatment 3 vs treatment 5. The statistical analyses performed on the data are summarized below in Table 27: -
TABLE 27 AUC0-inf TRT 1 vs. TRT 3 vs.TRT 1 vs. TRT 3 vs.(pg · h/mL) TRT 2TRT 4TRT 5 TRT 5 Ratio 88.33% 88.14% 101.14% 100.82% 90% 83.50% to 83.32% to 95.61% to 95.33% to Geometric 93.44% 93.24% 106.99% 106.63% C.I.
Treatment 1 (Formulation 2, Fasting) vs. Treatment 2 (Formulation 2, Fed) - The ANOVAs detected statistically significant differences between fed and fasting conditions,
treatments 1 and 2, for the ln-transformed AUC0-t, AUC0-inf and Cmax and untransformed Tmax, T1/2el and Kel. Duncan's Multiple Range Test detected statistically significant differences betweentreatments 1 and 2 for ln-transformed AUC0-1 and AUC0-inf and untransformed Tmax. However, Duncan's Multiple Range Test detected no statistically significant differences between treatments for ln-transformed Cmax and untransformed T1/2el and Kel. All formulation ratios, as well as 90% geometric confidence intervals of the relative mean AUC0-t, AUC0-inf and Cmax were found to be within the 80% to 125%, as is shown in Table 28 below. Thus, it appears that food increases the extent of absorption of methylphenidate forFormulation 2. However, this food effect was less than 20% on average. -
TABLE 28 Formulation 2, Fed versus FastingAUC0-t AUC0-inf Cmax Ratio1 112.09% 113.21% 93.69% 90% Geometric C.I.2 105.58% to 107.03% to 119.76% 86.85% to 119.00% 101.07% 1Calculated using geometric means according to the formula: e(Formulation 2(Fed)−Formulation 2 (Fasting)) × 100 290% Geometric Confidence Interval using In-transformed data
Treatment 3 (Formulation 3, Fasting) vs. Treatment 4 (Formulation 3, Fed) - The ANOVAs detected statistically significant differences between treatments for ln-transformed AUC0-t, AUC0-inf and Cmax and untransformed Tmax, T1/2el and Kel. Duncan's Multiple Range Test detected statistically significant differences between
treatments Formulation 3. However, this food effect was less than 20% on average. -
TABLE 29 Formulation 3, Fed versus FastingAUC0-t AUC0-inf Cmax Ratio1 113.35% 113.45% 117.96% 90% Geometric 106.76% to 107.25% to 120.01% 109.35% to C.I.2 120.33% 127.25% 1Calculated using geometric means according to the formula: e(Formulation 3 (fed)−Formulation 3 (Fasting)) × 100 290% Geometric Confidence Interval using In-transformed data
Treatment 1 (Formulation 2, Fasting) vs. Treatment 5 (Ritalin SR® , Fasting) - The ANOVAs detected statistically significant differences between treatments for ln-transformed AUC0-t, AUC0-inf and Cmax and untransformed Tmax, T1/2el and Kel. Duncan's Multiple Range Test detected no statistically significant differences between treatments 1 and 5 for all parameters. All formulation ratios, as well as 90% geometric confidence intervals of the relative mean AUC0-t, AUC0-inf and Cmax of the test to reference product were found to be within the 80% to 125%, as shown in Table 30 below. Thus,
Formulation 2 is bioequivalent to the reference product Ritalin SR® under fasting conditions. -
TABLE 30 Formulation 2 (Fasting) versus Ritalin SR (Fasting) AUC0-t AUC0-inf Cmax Ratio1 101.82% 101.14% 106.99% 90% Geometric C.I.2 95.91% to 95.61% to 106.99% 101.28 to 108.10% 117.85% 1Calculated using geometric means according to the formula: e(Formulation 2 (fast)−Ritalin SR (Fast)) × 100 290% Geometric Confidence Interval using In-transformed data
Treatment 3 (Formulation 3, Fasting) vs. Treatment 5 (Ritalin SR®, Fasting) - The ANOVAs detected statistically significant differences between treatments for ln-transformed AUC0-t, AUC0-inf and Cmax and untransformed Tmax, T1/2el and Kel. Duncan's Multiple Range Test detected statistically significant differences between
treatments 3 and 5 for ln-transformed Cmax and untransformed T1/2el and Kel. However, Duncan's Multiple Range Test detected no statistically significant differences between treatments for ln-transformed AUC0-t and AUC0-inf and untransformed Tmax. All formulation ratios, as well as 90% geometric confidence intervals of the relative mean AUC0-t, AUC0-inf and Cmax of the test to reference product were found to be within the 80% to 125%, as shown in Table 31 below. Thus,Formulation 3 is bioequivalent to the reference product Ritalin SR® under fasting conditions. -
TABLE 31 Formulation 3 (Fasting) versus Ritalin SR (Fasting) AUC0-t AUC0-inf Cmax Ratio1 101.63% 100.82% 87.40% 90% Geometric C.I.2 94.81% to% 95.33% to 106.63% 81.05 to 106.81 94.26% 1Calculated using geometric means according to the formula: e(Formulation (fast)−Ritalin SR (Fast)) × 100 290% Geometric Confidence Interval using In-transformed data - The bioavailability of
Formulation 2 relative to Ritalin SR® is acceptable under fasted conditions (Relative AUCinf 101% -Fed conditions not tested) - The bioavailability of Ritalin SR® under fasted conditions is similar to that of Ritalin® IR, as discussed in Example 7 (AUCinf 29.2 vs. 46.5 ng.h/mL, respectively). Literature data which indicates that Ritalin® IR and SR are absorbed at equivalent rates suggests that comparisons between the studies presented in Examples 7 and 8 are reasonable.
- Bioavailability of
Formulations 1 and 2 are similar under fasted and fed conditions (fasted: 49.8 vs. 51.2 ng.h/mL; fed: 55.7 vs. 57.9 ng.h/mL). - From the mean curves of
Formulation 2 and Ritalin SR®, the initial rate of rise of plasma MPH concentration is slightly faster forFormulation 2 compared to Ritalin SR®. Under fed conditions, the rate of rise of plasma MPH withFormulation 2 decreased and Tmax was delayed in comparison to bothFormulation 2 fasted and Ritalin SR® fasted. - Bioavailability of
Formulation 3 relative to Ritalin SR® is acceptable under fasted conditions (Relative AUCinf 100.8% -fed conditions not tested). - Bioavailability of
Formulations 1 and 3 are similar under fasted and fed conditions (fasted: 50,0 versus 51.2 ng/hmL; fed: 56.3 versus 57.9ng·h/mL). Note also thatFormulations - From the mean curves for
Formulation 3 and Ritalin SR®, the initial rate of rise of plasma MPH concentrations is slightly faster forFormulation 3 compared to Ritalin SR®. - In contrast to
Formulation 2, the effect of food on the initial rate of concentration rise is minimal. SinceFormulation 3 does not contain an enteric coat, this suggests that food slows the initial release from the IR component of formulations that contain an enteric coat, both when the enteric coat is part of the same bead (underneath the IR coat in the case of Formulation 1) and when it is in a separate bead (as for Formulation 2). - Also in contrast to
Formulation 2, the Tmax of the mean curve ofFormulation 3 occurs at a similar time to that of Ritalin SR® under fed and fasted conditions. For Formulation 2 (and Formulation 1) the Tmax of the second absorption phase under fed conditions is substantially delayed relative to Ritalin SR®. -
- 1. Formulation 1 has both a fast initial rate of rise, at least under fasted conditions and a prolonged duration. The transformation from a prolonged plateau profile under fasted conditions to a biphasic profile under fed conditions, is as predicted. Since these conditions represent the extremes of “food stress”, one might predict that administration in association with normal meals and times would provide an intermediate profile. It is also possible that gastric emptying in children on a normal meal schedule will be faster than in adults fed a high fat meal—this will tend to make the second absorption phase occur earlier and produce lower concentrations from 12 hours onwards. Formulation 1 therefore meets the dual objectives of rapid onset and prolonged duration.
- 2.
Formulation 2 is also very similar to Ritalin SR® under fasted conditions but shows a delayed peak under fed conditions such that plasma MPH concentrations are higher than Ritalin SR®(fasted) from 6 hours post dose onwards. The controlled release component inFormulation 2 is faster releasing than the one in Formulation 1 and plasma MPH concentrations are lower forFormulation 2 from about 10 hours post dose. - 3. Overall, Formulation 3 (non-enteric coated) has a profile very similar to Ritalin SR® under both fed and fasted conditions. The IR component of
Formulation 3 provides some increase in initial absorption rate relative to Ritalin SR® under fasted conditions. Since concentrations later in the day are similar for the two formulations, this confirms the concept that a fast initial rise and higher concentrations later in the day are not possible at the same dose, unless a delay is introduced into the release of a component of the total dose. - The examples provided above are not meant to be exclusive. Many other variations of the present invention would be obvious to those skilled in the art, and are contemplated to be within the scope of the appended claims.
Claims (17)
1. An oral controlled release formulation comprising
a plurality of substrates comprising a portion of an effective dose of a drug in an immediate release form,
a hydrophobic material coated onto the surface of said substrates in an amount sufficient to retard the release of said drug,
an enteric coating applied over said hydrophobic coating in an amount sufficient to substantially delay the release of said drug from said substrate until after said formulation passes through the stomach,
the formulation further comprising the remaining portion of the effective dose in an immediate release form.
2-13. (canceled)
14. A method for preparing an oral controlled release formulation comprising
preparing immediate release drug-coated inert beads by spraying a solution of a drug onto said inert beads;
applying a controlled release coating to said immediate release drug-coated inert beads to convert the same into controlled release beads;
applying an enteric coating onto said controlled release coating; and
applying an immediate release overcoat of said drug onto the surface of said enteric coated beads.
15.-20. (canceled)
21. A method of treating ADHD in a child: comprising administering encapsulated multi-layer release beads comprising an effective dose of methylphenidate hydrochloride to the child.
22. The oral controlled release formulation of claim 1 , wherein the drug is methylphenidate hydrochloride, and the formulation comprises a plurality of encapsulated multi-layered release beads comprising an effective dose of methylphenidate hydrochloride, each bead comprising
a core,
a coating of a copolymer of acrylic and methacrylic esters having a molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters of 1:20 coated over the core,
a coating of a methacrylic acid copolymer which does not swell at about pH<5.7 and is soluble at about pH>6 coated over the coating of the copolymer of acrylic and methacrylic esters having a molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters of 1:20, and
a methylphenidate hydrochloride coating coated over the coating of the methacrylic acid copolymer which does not swell at about pH<5.7 and is soluble at about pH>6,
wherein from about 60% to about 70% of the methylphenidate hydrochloride in the bead is in the core,
from about 30% to about 40% of the methylphenidate hydrochloride in the bead is in the methylphenidate hydrochrloride coating coated over the coatings of the methacrylic acid copolymer which does not swell at about pH<5.7 and is soluble at about pH>6,
the coating of the methacrylic acid copolymer which does not swell at about pH<5.7 and is soluble at about pH>6 is in an amount sufficient to provide a drop in methylphenidate plasma concentration at 4 hours after oral administration of the formulation under fasted conditions to a child, and
the formulation provides effective methylphenidate plasma concentrations for about 12 hours after said oral administration.
23. The oral controlled release formulation of claim 22 , wherein the core comprises about 60% of the methylphenidate hydrochloride in the bead.
24. The oral controlled release formulation of claim 23 , wherein the copolymer of acrylic and methacrylic esters having the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters of 1:20 is coated over the core to obtain a weight gain from about 2% to about 25%.
25. The oral controlled release formulation of claim 24 , wherein the effects of methylphenidate on the child are consistent over the course of the day, despite the drop in methylphenidate plasma concentration.
26. The oral controlled release formulation of claim 1 , wherein the drug is methylphenidate hydrochloride, and the formulation comprises a plurality of encapsulated multi-layered release beads comprising an effective dose of methylphenidate hydrochloride, each bead comprising
a core comprising from about 60% to about 70% of the methylphenidate hydrochloride in the bead,
a coating of a copolymer of acrylic and methacrylic esters having a molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters of 1:20 coated over the core,
a coating of a methacrylic acid copolymer which does not swell at about pH<5.7 and is soluble at about pH>6 coated over the coating of the copolymer of acrylic and methacrylic esters having a molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters of 1:20, and
the remaining methylphenidate hydrochloride in the bead in an immediate release coating coated over the coating of the methacrylic acid copolymer which does not swell at about pH<5.7 and is soluble at about pH>6,
wherein the formulation provides a peak in methylphenidate plasma concentration at about 8 after oral administration under fed conditions and effective methylphenidate plasma concentrations for about 12 hours after said oral administration.
27. The oral controlled release formulation of claim 26 , wherein the core comprises about 60% of the methylphenidate hydrochloride in the bead.
28. The oral controlled release formulation of claim 27 , wherein the copolymer of acrylic and methacrylic esters having the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters of 1:20 is coated over the core to obtain a weight gain from about 2% to about 25%.
29. The oral controlled release formulation of claim 28 , wherein the coating of the methacrylic acid copolymer which does not swell at about pH<5.7 and is soluble at about pH>6 in an amount sufficient to provide a drop in methylphenidate plasma concentration at 4 hours after oral administration of the formulation under fasted conditions to a child.
30. The oral controlled release formulation of claim 29 , wherein the effects of methylphenidate on the child are consistent over the course of the day, despite the drop in methylphenidate plasma concentration.
31. The oral controlled release formulation of claim 1 , wherein the drug is methylphenidate hydrochloride, and the formulation provides
a clinical effect that is at least equivalent to two doses of immediate-release methylphenidate given at breakfast and lunchtime, with a duration of action that may reduce the need for a third dose of immediate release methylphenidate later in the day,
a fast initial rate of rise of plasma methylphenidate concentration and prolonged duration, which includes a biphasic profile under fed conditions, the formulation providing a maximal plasma concentration similar to that attained with the first dose of immediate release methylphenidate and from about 10 hours post-dose having a plasma concentration higher than those following a second dose of immediate release methylphenidate, and
a rapid offset of action at the end of the dosing interval.
32. The oral controlled release formulation of claim 22 , wherein the methylphenidate hydrochloride coating coated over the coating of the methacrylic acid copolymer which does not swell at about pH<5.7 and is soluble at about pH>6 comprises hydroxypropylmethyl cellulose.
33. The method of claim 26 , wherein the immediate release coating coated over the coating of the methacrylic acid copolymer which does not swell at about pH<5.7 and is soluble at about pH>6 comprises hydroxypropylmethylcellulose.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15/343,902 US20170135999A1 (en) | 1998-12-17 | 2016-11-04 | Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations |
Applications Claiming Priority (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11261798P | 1998-12-17 | 1998-12-17 | |
US09/465,159 US6419960B1 (en) | 1998-12-17 | 1999-12-16 | Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations |
US10/156,622 US7247318B2 (en) | 1998-12-17 | 2002-05-28 | Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations |
US11/879,646 US7438930B2 (en) | 1998-12-17 | 2007-07-17 | Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations |
US12/283,431 US8580310B2 (en) | 1998-12-17 | 2008-09-11 | Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations |
US14/049,677 US9066869B2 (en) | 1998-12-17 | 2013-10-09 | Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations |
US14/718,814 US9801823B2 (en) | 1998-12-17 | 2015-05-21 | Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations |
US15/343,377 US9949931B2 (en) | 1998-12-17 | 2016-11-04 | Methods of treating attention deficit hyperactivity disorder |
US15/343,902 US20170135999A1 (en) | 1998-12-17 | 2016-11-04 | Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/343,377 Division US9949931B2 (en) | 1998-12-17 | 2016-11-04 | Methods of treating attention deficit hyperactivity disorder |
Publications (1)
Publication Number | Publication Date |
---|---|
US20170135999A1 true US20170135999A1 (en) | 2017-05-18 |
Family
ID=22344918
Family Applications (11)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/465,159 Expired - Lifetime US6419960B1 (en) | 1998-12-17 | 1999-12-16 | Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations |
US10/156,622 Expired - Lifetime US7247318B2 (en) | 1998-12-17 | 2002-05-28 | Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations |
US11/879,646 Expired - Fee Related US7438930B2 (en) | 1998-12-17 | 2007-07-17 | Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations |
US12/283,431 Expired - Lifetime US8580310B2 (en) | 1998-12-17 | 2008-09-11 | Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations |
US14/049,677 Expired - Fee Related US9066869B2 (en) | 1998-12-17 | 2013-10-09 | Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations |
US14/718,814 Expired - Fee Related US9801823B2 (en) | 1998-12-17 | 2015-05-21 | Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations |
US15/343,377 Expired - Fee Related US9949931B2 (en) | 1998-12-17 | 2016-11-04 | Methods of treating attention deficit hyperactivity disorder |
US15/343,902 Abandoned US20170135999A1 (en) | 1998-12-17 | 2016-11-04 | Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations |
US15/344,026 Expired - Fee Related US10022330B2 (en) | 1998-12-17 | 2016-11-04 | Methods of preparing oral controlled release formulations |
US15/714,542 Expired - Fee Related US10463624B2 (en) | 1998-12-17 | 2017-09-25 | Controlled release formulations |
US15/714,706 Expired - Fee Related US10039719B2 (en) | 1998-12-17 | 2017-09-25 | Methods of treating attention deficit hyperactivity disorder |
Family Applications Before (7)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/465,159 Expired - Lifetime US6419960B1 (en) | 1998-12-17 | 1999-12-16 | Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations |
US10/156,622 Expired - Lifetime US7247318B2 (en) | 1998-12-17 | 2002-05-28 | Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations |
US11/879,646 Expired - Fee Related US7438930B2 (en) | 1998-12-17 | 2007-07-17 | Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations |
US12/283,431 Expired - Lifetime US8580310B2 (en) | 1998-12-17 | 2008-09-11 | Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations |
US14/049,677 Expired - Fee Related US9066869B2 (en) | 1998-12-17 | 2013-10-09 | Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations |
US14/718,814 Expired - Fee Related US9801823B2 (en) | 1998-12-17 | 2015-05-21 | Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations |
US15/343,377 Expired - Fee Related US9949931B2 (en) | 1998-12-17 | 2016-11-04 | Methods of treating attention deficit hyperactivity disorder |
Family Applications After (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/344,026 Expired - Fee Related US10022330B2 (en) | 1998-12-17 | 2016-11-04 | Methods of preparing oral controlled release formulations |
US15/714,542 Expired - Fee Related US10463624B2 (en) | 1998-12-17 | 2017-09-25 | Controlled release formulations |
US15/714,706 Expired - Fee Related US10039719B2 (en) | 1998-12-17 | 2017-09-25 | Methods of treating attention deficit hyperactivity disorder |
Country Status (12)
Country | Link |
---|---|
US (11) | US6419960B1 (en) |
EP (1) | EP1143937B1 (en) |
JP (1) | JP4172917B2 (en) |
AT (1) | ATE268595T1 (en) |
AU (1) | AU2122700A (en) |
CA (1) | CA2355854C (en) |
DE (1) | DE69917937T2 (en) |
DK (1) | DK1143937T3 (en) |
ES (1) | ES2224740T3 (en) |
PT (1) | PT1143937E (en) |
SI (1) | SI1143937T1 (en) |
WO (1) | WO2000035426A2 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9974752B2 (en) | 2014-10-31 | 2018-05-22 | Purdue Pharma | Methods and compositions particularly for treatment of attention deficit disorder |
US10722473B2 (en) | 2018-11-19 | 2020-07-28 | Purdue Pharma L.P. | Methods and compositions particularly for treatment of attention deficit disorder |
Families Citing this family (94)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5266331A (en) * | 1991-11-27 | 1993-11-30 | Euroceltique, S.A. | Controlled release oxycodone compositions |
US20080075781A1 (en) * | 1992-11-25 | 2008-03-27 | Purdue Pharma Lp | Controlled release oxycodone compositions |
US20070275062A1 (en) * | 1993-06-18 | 2007-11-29 | Benjamin Oshlack | Controlled release oxycodone compositions |
ATE411011T3 (en) | 1998-11-02 | 2008-10-15 | Elan Pharma Int Ltd | MULTIPARTICULAR COMPOSITION OF METHYLPHENIDATE WITH MODIFIED RELEASE |
US20060240105A1 (en) * | 1998-11-02 | 2006-10-26 | Elan Corporation, Plc | Multiparticulate modified release composition |
US20090149479A1 (en) * | 1998-11-02 | 2009-06-11 | Elan Pharma International Limited | Dosing regimen |
US7083808B2 (en) * | 1998-12-17 | 2006-08-01 | Euro-Celtique S.A. | Controlled/modified release oral methylphenidate formulations |
US6419960B1 (en) | 1998-12-17 | 2002-07-16 | Euro-Celtique S.A. | Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations |
US6673367B1 (en) | 1998-12-17 | 2004-01-06 | Euro-Celtique, S.A. | Controlled/modified release oral methylphenidate formulations |
US10179130B2 (en) | 1999-10-29 | 2019-01-15 | Purdue Pharma L.P. | Controlled release hydrocodone formulations |
MXPA02004293A (en) | 1999-10-29 | 2002-10-31 | Euro Celtique Sa | Controlled release hydrocodone formulations. |
ATE312595T1 (en) | 2000-01-19 | 2005-12-15 | Mannkind Corp | FORMULATION WITH MULTIPLE PULSED RELEASE OF ACTIVE INGREDIENTS |
GB0007419D0 (en) * | 2000-03-27 | 2000-05-17 | Smithkline Beecham Gmbh | Composition |
US7674480B2 (en) * | 2000-06-23 | 2010-03-09 | Teva Pharmaceutical Industries Ltd. | Rapidly expanding composition for gastric retention and controlled release of therapeutic agents, and dosage forms including the composition |
US6344215B1 (en) * | 2000-10-27 | 2002-02-05 | Eurand America, Inc. | Methylphenidate modified release formulations |
KR101167465B1 (en) | 2000-10-30 | 2012-07-27 | 유로-셀티크 소시에떼 아노뉨 | Controlled release hydrocodone formulations |
JP3943342B2 (en) * | 2001-03-26 | 2007-07-11 | 富士通株式会社 | Medical treatment information creation program, pharmaceutical information processing program, medical treatment information creation method, pharmaceutical information system |
JP2004525955A (en) * | 2001-04-05 | 2004-08-26 | コッラジェネックス ファーマシューチカルス インコーポレイテッド | Controlled transmission of tetracycline compounds and tetracycline derivatives |
US20110104214A1 (en) * | 2004-04-15 | 2011-05-05 | Purdue Pharma L.P. | Once-a-day oxycodone formulations |
UA81224C2 (en) * | 2001-05-02 | 2007-12-25 | Euro Celtic S A | Dosage form of oxycodone and use thereof |
US20030099711A1 (en) * | 2001-08-29 | 2003-05-29 | David Meadows | Sustained release preparations |
FR2830447B1 (en) * | 2001-10-09 | 2004-04-16 | Flamel Tech Sa | MICROPARTICULAR ORAL GALENIC FORM FOR DELAYED AND CONTROLLED RELEASE OF PHARMACEUTICAL ACTIVE INGREDIENTS |
US8101209B2 (en) | 2001-10-09 | 2012-01-24 | Flamel Technologies | Microparticulate oral galenical form for the delayed and controlled release of pharmaceutical active principles |
US20040037879A1 (en) * | 2001-11-02 | 2004-02-26 | Adusumilli Prasad S. | Oral controlled release forms useful for reducing or preventing nicotine cravings |
DK1443917T3 (en) * | 2001-11-07 | 2006-07-17 | Synthon Bv | Tamsulosin tablets |
CA2480826C (en) | 2002-04-09 | 2012-02-07 | Flamel Technologies | Oral pharmaceutical formulation in the form of microcapsule aqueous suspension allowing modified release of active ingredient(s) |
BR0309093A (en) * | 2002-04-09 | 2005-02-09 | Flamel Tech Sa | Oral pharmaceutical formulation in aqueous microcapsule suspension allowing modified release of amoxicillin |
CA2395819A1 (en) * | 2002-08-13 | 2004-02-13 | Bernard Charles Sherman | Dual-spike release formulation for oral drug delivery |
US6913768B2 (en) | 2002-09-24 | 2005-07-05 | Shire Laboratories, Inc. | Sustained release delivery of amphetamine salts |
US20080220074A1 (en) * | 2002-10-04 | 2008-09-11 | Elan Corporation Plc | Gamma radiation sterilized nanoparticulate docetaxel compositions and methods of making same |
US7988993B2 (en) | 2002-12-09 | 2011-08-02 | Andrx Pharmaceuticals, Inc. | Oral controlled release dosage form |
US8133507B2 (en) | 2002-12-13 | 2012-03-13 | Durect Corporation | Oral drug delivery system |
DE10361596A1 (en) | 2003-12-24 | 2005-09-29 | Grünenthal GmbH | Process for producing an anti-abuse dosage form |
DE102005005446A1 (en) | 2005-02-04 | 2006-08-10 | Grünenthal GmbH | Break-resistant dosage forms with sustained release |
NZ546148A (en) | 2003-09-26 | 2009-05-31 | Alza Corp | Drug coating providing high drug loading and methods for providing the same |
AU2004280240B2 (en) * | 2003-10-08 | 2010-04-22 | SpecGx LLC | Methylphenidate solution and associated methods of administration and production |
ES2359375T3 (en) * | 2003-11-04 | 2011-05-20 | Supernus Pharmaceuticals, Inc. | DOSAGE FORMS OF DAILY SINGLE DOSE OF TROSPIO. |
US8007827B2 (en) * | 2004-04-02 | 2011-08-30 | Impax Laboratories, Inc. | Pharmaceutical dosage forms having immediate release and/or controlled release properties |
SI1591109T1 (en) * | 2004-04-30 | 2008-10-31 | Topotarget Germany Ag | Formulation comprising histone deacetylase inhibitor exhibiting biphasic release |
US20050265955A1 (en) * | 2004-05-28 | 2005-12-01 | Mallinckrodt Inc. | Sustained release preparations |
ES2261006B1 (en) * | 2004-06-10 | 2007-11-01 | Laboratorios Rubio, S.A. | PELLET MULTICAPA CONTROLLED RELEASE OF METHYLPHENIDATE |
US9308164B2 (en) * | 2004-06-30 | 2016-04-12 | Sovereign Pharmaceuticals, Llc | Hyoscyamine dosage form |
DE102004032049A1 (en) | 2004-07-01 | 2006-01-19 | Grünenthal GmbH | Anti-abuse, oral dosage form |
ES2314693T3 (en) * | 2004-08-23 | 2009-03-16 | PEJO ISERLOHN HEILMITTEL-UND DIAT-GMBH & CO.KG | PHARMACEUTICAL COMPOSITION CONTAINING PSYCHOSTIMULANTS. |
US8541026B2 (en) | 2004-09-24 | 2013-09-24 | Abbvie Inc. | Sustained release formulations of opioid and nonopioid analgesics |
WO2006063078A2 (en) * | 2004-12-08 | 2006-06-15 | Elan Corporation, Plc | Topiramate pharmaceuticals composition |
DE102005005449A1 (en) | 2005-02-04 | 2006-08-10 | Grünenthal GmbH | Process for producing an anti-abuse dosage form |
JP2008535922A (en) * | 2005-04-12 | 2008-09-04 | エラン・ファルマ・インターナショナル・リミテッド | Controlled release composition comprising cephalosporin for treating bacterial infections |
FR2886150B1 (en) * | 2005-05-24 | 2007-08-24 | Flamel Technologies Sa | ORAL PHARMACEUTICAL FORM BASED ON AT LEAST ONE ACTIVE INGREDIENT WHOSE SOLUBILITY VARIES IN ACCORDANCE WITH THE CONDITIONS OF GASTRIC PH |
US20100136106A1 (en) * | 2005-06-08 | 2010-06-03 | Gary Liversidge | Modified Release Famciclovir Compositions |
US20070020333A1 (en) * | 2005-07-20 | 2007-01-25 | Chin-Chih Chiang | Controlled release of hypnotic agents |
EP2289497A1 (en) * | 2005-11-10 | 2011-03-02 | Circ Pharma Research and Development Limited | Once-daily administration of central nervous system drugs |
CA2645855C (en) | 2006-03-16 | 2015-02-03 | Tris Pharma, Inc. | Modified release formulations containing drug-ion exchange resin complexes |
US20070253927A1 (en) * | 2006-04-13 | 2007-11-01 | Gwenaelle Jegou | Cosmetic compositions comprising at least one dielectrophile monomer and at least one radical initiator |
CA2671200A1 (en) * | 2006-07-21 | 2008-01-24 | Lab International Srl | Hydrophilic abuse deterrent delivery system |
CA2706658A1 (en) | 2007-12-06 | 2009-06-18 | Durect Corporation | Methods useful for the treatment of pain, arthritic conditions or inflammation associated with a chronic condition |
CN102170874A (en) | 2008-08-06 | 2011-08-31 | 高思福斯中心(控股)有限公司 | Compositions and methods for treating psychiatric disorders |
US20100260844A1 (en) * | 2008-11-03 | 2010-10-14 | Scicinski Jan J | Oral pharmaceutical dosage forms |
WO2011020032A2 (en) * | 2009-08-13 | 2011-02-17 | Kudco Ireland, Ltd. | Pharmaceutical dosage form |
US20110052700A1 (en) * | 2009-08-31 | 2011-03-03 | Depomed, Inc. | Gastric retentive pharmaceutical compositions for immediate and extended release of levosulpiride |
CA2812570A1 (en) * | 2010-09-24 | 2012-03-29 | QRxPharma Ltd. | Controlled release formulations of opioids |
PH12013501345A1 (en) * | 2010-12-23 | 2022-10-24 | Purdue Pharma Lp | Tamper resistant solid oral dosage forms |
US9283214B2 (en) | 2011-03-23 | 2016-03-15 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
US8916588B2 (en) | 2011-03-23 | 2014-12-23 | Ironshore Pharmaceuticals & Development, Inc. | Methods for treatment of attention deficit hyperactivity disorder |
EP4316488A3 (en) | 2011-03-23 | 2024-02-28 | Ironshore Pharmaceuticals & Development, Inc. | Methods and compositions for treatment of attention deficit disorder |
US9603809B2 (en) | 2011-03-23 | 2017-03-28 | Ironshore Pharmaceuticals & Development, Inc. | Methods of treatment of attention deficit hyperactivity disorder |
US9119809B2 (en) | 2011-03-23 | 2015-09-01 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
US9498447B2 (en) | 2011-03-23 | 2016-11-22 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
US10905652B2 (en) | 2011-03-23 | 2021-02-02 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
US10292937B2 (en) | 2011-03-23 | 2019-05-21 | Ironshore Pharmaceuticals & Development, Inc. | Methods of treatment of attention deficit hyperactivity disorder |
US11241391B2 (en) | 2011-03-23 | 2022-02-08 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
US8927010B2 (en) | 2011-03-23 | 2015-01-06 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
GB201111712D0 (en) | 2011-07-08 | 2011-08-24 | Gosforth Ct Holdings Pty Ltd | Pharmaceutical compositions |
US20130028972A1 (en) | 2011-07-29 | 2013-01-31 | Grunenthal Gmbh | Tamper-resistant tablet providing immediate drug release |
SI2736495T1 (en) | 2011-07-29 | 2017-12-29 | Gruenenthal Gmbh | Tamper-resistant tablet providing immediate drug release |
DE102012105528A1 (en) * | 2012-06-25 | 2014-01-02 | Hennig Arzneimittel Gmbh & Co. Kg | Pharmaceutical form for the release of active substances |
AU2013302657B2 (en) | 2012-08-15 | 2018-08-09 | Tris Pharma, Inc. | Methylphenidate extended release chewable tablet |
EP3530268B1 (en) * | 2012-10-09 | 2021-12-15 | Attentive Therapeutics, Inc. | Therapeutic treatment |
US10751287B2 (en) | 2013-03-15 | 2020-08-25 | Purdue Pharma L.P. | Tamper resistant pharmaceutical formulations |
US9572885B2 (en) | 2013-03-15 | 2017-02-21 | Durect Corporation | Compositions with a rheological modifier to reduce dissolution variability |
JP6449871B2 (en) | 2013-07-12 | 2019-01-09 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | Anti-modified dosage form containing ethylene-vinyl acetate polymer |
SI3277278T1 (en) | 2015-04-02 | 2020-04-30 | Theravance Biopharma R&D Ip, Llc | Combination dosage form of a mu opioid receptor antagonist and an opioid agent |
US11590228B1 (en) | 2015-09-08 | 2023-02-28 | Tris Pharma, Inc | Extended release amphetamine compositions |
WO2017042325A1 (en) | 2015-09-10 | 2017-03-16 | Grünenthal GmbH | Protecting oral overdose with abuse deterrent immediate release formulations |
US9875113B2 (en) * | 2015-12-09 | 2018-01-23 | Quanta Computer Inc. | System and method for managing BIOS setting configurations |
GB201610101D0 (en) * | 2016-06-09 | 2016-07-27 | Attenborough Dental Laboratories Ltd | Multicellular lay-up process |
JP7258561B2 (en) | 2016-07-06 | 2023-04-17 | オリエント ファーマ シーオー.,エルティーディー. | Oral dosage form having a drug composition, a barrier layer and a drug layer |
EP3372225A1 (en) * | 2017-03-09 | 2018-09-12 | Develco Pharma Schweiz AG | Novel dosage form |
US11590081B1 (en) | 2017-09-24 | 2023-02-28 | Tris Pharma, Inc | Extended release amphetamine tablets |
WO2019071272A1 (en) * | 2017-10-06 | 2019-04-11 | Adare Pharmaceuticals, Inc. | Pharmaceutical compositions for the treatment of the attention-deficit/hyperactivity disorder (adhd) |
BR112020006995A2 (en) * | 2017-10-13 | 2020-10-06 | Grünenthal GmbH | modified release abuse deterrence dosage forms |
CN111557929B (en) * | 2020-05-15 | 2021-12-07 | 河南中帅医药科技股份有限公司 | Dexmethylphenidate hydrochloride multiple-release preparation and preparation method thereof |
WO2023043852A1 (en) * | 2021-09-14 | 2023-03-23 | Nulixir Inc. | Stable non-aqueous compositions of functional ingredients and methods of making the same |
WO2024081554A2 (en) * | 2022-10-10 | 2024-04-18 | Corino Therapeutics, Inc. | Modified release tolcapone formulations |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5639476A (en) * | 1992-01-27 | 1997-06-17 | Euro-Celtique, S.A. | Controlled release formulations coated with aqueous dispersions of acrylic polymers |
US5837284A (en) * | 1995-12-04 | 1998-11-17 | Mehta; Atul M. | Delivery of multiple doses of medications |
US5885616A (en) * | 1997-08-18 | 1999-03-23 | Impax Pharmaceuticals, Inc. | Sustained release drug delivery system suitable for oral administration |
US6730325B2 (en) * | 1998-11-02 | 2004-05-04 | Elan Corporation, Plc | Multiparticulate modified release composition |
Family Cites Families (47)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4256108A (en) | 1977-04-07 | 1981-03-17 | Alza Corporation | Microporous-semipermeable laminated osmotic system |
JPS55149211A (en) | 1979-05-10 | 1980-11-20 | Takeda Chem Ind Ltd | Production of gradually releasable preparation |
GB2186485B (en) | 1986-02-13 | 1988-09-07 | Ethical Pharma Ltd | Slow release formulation |
AU591248B2 (en) * | 1986-03-27 | 1989-11-30 | Kinaform Technology, Inc. | Sustained-release pharaceutical preparation |
US4842867A (en) | 1986-05-09 | 1989-06-27 | Alza Corporation | Pulsed drug delivery of doxylamine |
GB8613689D0 (en) | 1986-06-05 | 1986-07-09 | Euro Celtique Sa | Pharmaceutical composition |
DE3769707D1 (en) | 1986-06-17 | 1991-06-06 | Recordati Chem Pharm | THERAPEUTIC SYSTEM WITH REGULATED DELIVERY OF ACTIVE SUBSTANCES. |
IT1213080B (en) | 1986-06-17 | 1989-12-07 | Recordati Chem Pharm | THERAPEUTIC SYSTEMS FOR THE CONTROLLED SALE OF DRUGS. |
US4786503A (en) | 1987-04-06 | 1988-11-22 | Alza Corporation | Dosage form comprising parallel lamine |
EP0325086A3 (en) | 1987-11-23 | 1990-10-31 | Jago Research Ag | Novel methods for obtaining therapeutic systems with controlled release of the drug |
DE3827214A1 (en) | 1988-08-11 | 1990-02-15 | Roehm Gmbh | RETARDED MEDICAMENT AND METHOD FOR THE PRODUCTION THEREOF |
US5202128A (en) * | 1989-01-06 | 1993-04-13 | F. H. Faulding & Co. Limited | Sustained release pharmaceutical composition |
US5133974A (en) * | 1989-05-05 | 1992-07-28 | Kv Pharmaceutical Company | Extended release pharmaceutical formulations |
US5643602A (en) | 1989-11-22 | 1997-07-01 | Astra Aktiebolag | Oral composition for the treatment of inflammatory bowel disease |
IE61651B1 (en) | 1990-07-04 | 1994-11-16 | Zambon Spa | Programmed release oral solid pharmaceutical dosage form |
US5156850A (en) | 1990-08-31 | 1992-10-20 | Alza Corporation | Dosage form for time-varying patterns of drug delivery |
AU1992592A (en) | 1991-05-24 | 1993-01-08 | Pharmavene, Inc. | Treatment of drug withdrawal symptoms and drug craving with type b monoamine oxidase inhibitors |
EP0520119A1 (en) * | 1991-06-17 | 1992-12-30 | Spirig Ag Pharmazeutische Präparate | New oral diclofenac composition |
US5326570A (en) | 1991-07-23 | 1994-07-05 | Pharmavene, Inc. | Advanced drug delivery system and method of treating psychiatric, neurological and other disorders with carbamazepine |
US5273760A (en) * | 1991-12-24 | 1993-12-28 | Euroceltigue, S.A. | Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer |
US5286493A (en) | 1992-01-27 | 1994-02-15 | Euroceltique, S.A. | Stabilized controlled release formulations having acrylic polymer coating |
US5324351A (en) | 1992-08-13 | 1994-06-28 | Euroceltique | Aqueous dispersions of zein and preparation thereof |
JPH072650A (en) | 1993-06-18 | 1995-01-06 | Tanabe Seiyaku Co Ltd | Release part control type preparation |
IL110014A (en) | 1993-07-01 | 1999-11-30 | Euro Celtique Sa | Solid controlled-release oral dosage forms of opioid analgesics |
US5395626A (en) | 1994-03-23 | 1995-03-07 | Ortho Pharmaceutical Corporation | Multilayered controlled release pharmaceutical dosage form |
US6077533A (en) * | 1994-05-25 | 2000-06-20 | Purdue Pharma L.P. | Powder-layered oral dosage forms |
US5658590A (en) | 1995-01-11 | 1997-08-19 | Eli Lilly And Company | Treatment of attention-deficit/hyperactivity disorder |
JPH11509226A (en) | 1995-07-14 | 1999-08-17 | メデバ・ユアラプ・リミテッド | Composition comprising D-threo-methylphenidate and another medicament |
GB9514451D0 (en) | 1995-07-14 | 1995-09-13 | Chiroscience Ltd | Sustained-release formulation |
AU702801B2 (en) | 1995-07-14 | 1999-03-04 | Darwin Discovery Limited | Therapeutic use of D-threo-methylphenidate |
US5922736A (en) | 1995-12-04 | 1999-07-13 | Celegene Corporation | Chronic, bolus administration of D-threo methylphenidate |
US5773031A (en) | 1996-02-27 | 1998-06-30 | L. Perrigo Company | Acetaminophen sustained-release formulation |
CA2231195C (en) * | 1996-07-08 | 2003-01-21 | Edward Mendell Co., Inc. | Sustained release matrix for high-dose insoluble drugs |
DK0957899T3 (en) | 1996-08-16 | 2003-04-22 | Alza Corp | Dosage form to provide increasing dose of drug |
DE69735581T2 (en) | 1996-09-30 | 2007-01-25 | Alza Corp., Palo Alto | DOSAGE FOR A DELAYED AND INCREASING INGREDIENTS |
US5851579A (en) | 1996-10-28 | 1998-12-22 | Eastman Chemical Company | Aqueous enteric coating compositions |
US6919373B1 (en) | 1996-11-12 | 2005-07-19 | Alza Corporation | Methods and devices for providing prolonged drug therapy |
DK0946151T3 (en) | 1996-11-25 | 2006-08-28 | Alza Corp | Dosage form with increasing dose release |
DE19718012C1 (en) | 1997-04-29 | 1998-10-08 | Jenapharm Gmbh | Process for the production of orally applicable solid pharmaceutical forms with controlled release of active substances |
US6372254B1 (en) | 1998-04-02 | 2002-04-16 | Impax Pharmaceuticals Inc. | Press coated, pulsatile drug delivery system suitable for oral administration |
US5945123A (en) * | 1998-04-02 | 1999-08-31 | K-V Pharmaceutical Company | Maximizing effectiveness of substances used to improve health and well being |
WO1999062496A1 (en) * | 1998-06-03 | 1999-12-09 | Alza Corporation | Methods and devices for providing prolonged drug therapy |
US6419960B1 (en) | 1998-12-17 | 2002-07-16 | Euro-Celtique S.A. | Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations |
US7083808B2 (en) * | 1998-12-17 | 2006-08-01 | Euro-Celtique S.A. | Controlled/modified release oral methylphenidate formulations |
US6673367B1 (en) | 1998-12-17 | 2004-01-06 | Euro-Celtique, S.A. | Controlled/modified release oral methylphenidate formulations |
WO2003005951A2 (en) | 2001-07-10 | 2003-01-23 | Teva Pharmaceutical Industries Ltd. | Drug delivery system for zero order, zero order-biphasic, ascending or descending drug delivery |
WO2010077925A2 (en) | 2008-12-16 | 2010-07-08 | Teva Pharmaceutical Industries Ltd. | Drug delivery system for zero order, zero order biphasic, ascending or descending drug delivery of methylphenidate |
-
1999
- 1999-12-16 US US09/465,159 patent/US6419960B1/en not_active Expired - Lifetime
- 1999-12-17 AT AT99965601T patent/ATE268595T1/en active
- 1999-12-17 SI SI9930617T patent/SI1143937T1/en unknown
- 1999-12-17 AU AU21227/00A patent/AU2122700A/en not_active Abandoned
- 1999-12-17 WO PCT/IB1999/002095 patent/WO2000035426A2/en active IP Right Grant
- 1999-12-17 JP JP2000587747A patent/JP4172917B2/en not_active Expired - Lifetime
- 1999-12-17 CA CA002355854A patent/CA2355854C/en not_active Expired - Lifetime
- 1999-12-17 EP EP99965601A patent/EP1143937B1/en not_active Expired - Lifetime
- 1999-12-17 PT PT99965601T patent/PT1143937E/en unknown
- 1999-12-17 DK DK99965601T patent/DK1143937T3/en active
- 1999-12-17 ES ES99965601T patent/ES2224740T3/en not_active Expired - Lifetime
- 1999-12-17 DE DE69917937T patent/DE69917937T2/en not_active Expired - Lifetime
-
2002
- 2002-05-28 US US10/156,622 patent/US7247318B2/en not_active Expired - Lifetime
-
2007
- 2007-07-17 US US11/879,646 patent/US7438930B2/en not_active Expired - Fee Related
-
2008
- 2008-09-11 US US12/283,431 patent/US8580310B2/en not_active Expired - Lifetime
-
2013
- 2013-10-09 US US14/049,677 patent/US9066869B2/en not_active Expired - Fee Related
-
2015
- 2015-05-21 US US14/718,814 patent/US9801823B2/en not_active Expired - Fee Related
-
2016
- 2016-11-04 US US15/343,377 patent/US9949931B2/en not_active Expired - Fee Related
- 2016-11-04 US US15/343,902 patent/US20170135999A1/en not_active Abandoned
- 2016-11-04 US US15/344,026 patent/US10022330B2/en not_active Expired - Fee Related
-
2017
- 2017-09-25 US US15/714,542 patent/US10463624B2/en not_active Expired - Fee Related
- 2017-09-25 US US15/714,706 patent/US10039719B2/en not_active Expired - Fee Related
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5639476A (en) * | 1992-01-27 | 1997-06-17 | Euro-Celtique, S.A. | Controlled release formulations coated with aqueous dispersions of acrylic polymers |
US5837284A (en) * | 1995-12-04 | 1998-11-17 | Mehta; Atul M. | Delivery of multiple doses of medications |
US5885616A (en) * | 1997-08-18 | 1999-03-23 | Impax Pharmaceuticals, Inc. | Sustained release drug delivery system suitable for oral administration |
US6730325B2 (en) * | 1998-11-02 | 2004-05-04 | Elan Corporation, Plc | Multiparticulate modified release composition |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10507186B2 (en) | 2014-10-31 | 2019-12-17 | Purdue Pharma L.P. | Methods and compositions particularly for treatment of attention deficit disorder |
US10111839B2 (en) | 2014-10-31 | 2018-10-30 | Purdue Pharma | Methods and compositions particularly for treatment of attention deficit disorder |
US10292939B2 (en) | 2014-10-31 | 2019-05-21 | Purdue Pharma L.P. | Methods and compositions particularly for treatment of attention deficit disorder |
US10292938B2 (en) | 2014-10-31 | 2019-05-21 | Purdue Pharma L.P. | Methods and compositions particularly for treatment of attention deficit disorder |
US10449159B2 (en) | 2014-10-31 | 2019-10-22 | Purdue Pharma L.P. | Methods and compositions particularly for treatment of attention deficit disorder |
US10500162B2 (en) | 2014-10-31 | 2019-12-10 | Purdue Pharma L.P. | Methods and compositions particularly for treatment of attention deficit disorder |
US9974752B2 (en) | 2014-10-31 | 2018-05-22 | Purdue Pharma | Methods and compositions particularly for treatment of attention deficit disorder |
US10512612B2 (en) | 2014-10-31 | 2019-12-24 | Purdue Pharma L.P. | Methods and compositions particularly for treatment of attention deficit disorder |
US10512613B2 (en) | 2014-10-31 | 2019-12-24 | Purdue Pharma L.P. | Methods and compositions particularly for treatment of attention deficit disorder |
US10568841B2 (en) | 2014-10-31 | 2020-02-25 | Purdue Pharma L.P. | Methods and compositions particularly for treatment of attention deficit disorder |
US10688060B2 (en) | 2014-10-31 | 2020-06-23 | Purdue Pharma L.P. | Methods and compositions particularly for treatment of attention deficit disorder |
US11896722B2 (en) | 2014-10-31 | 2024-02-13 | Purdue Pharma L.P. | Methods and compositions particularly for treatment of attention deficit disorder |
US10722473B2 (en) | 2018-11-19 | 2020-07-28 | Purdue Pharma L.P. | Methods and compositions particularly for treatment of attention deficit disorder |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10039719B2 (en) | Methods of treating attention deficit hyperactivity disorder | |
US6673367B1 (en) | Controlled/modified release oral methylphenidate formulations | |
US7083808B2 (en) | Controlled/modified release oral methylphenidate formulations | |
EP1023896B1 (en) | Opioid formulations for treating pain | |
US7740881B1 (en) | Method of treating humans with opioid formulations having extended controlled release |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO PAY ISSUE FEE |