CA2758556A1 - Pharmaceutical composition of amphetamine mixed salts - Google Patents
Pharmaceutical composition of amphetamine mixed salts Download PDFInfo
- Publication number
- CA2758556A1 CA2758556A1 CA2758556A CA2758556A CA2758556A1 CA 2758556 A1 CA2758556 A1 CA 2758556A1 CA 2758556 A CA2758556 A CA 2758556A CA 2758556 A CA2758556 A CA 2758556A CA 2758556 A1 CA2758556 A1 CA 2758556A1
- Authority
- CA
- Canada
- Prior art keywords
- pharmaceutical composition
- release pharmaceutical
- modified
- modified release
- composition according
- 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
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 95
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical group C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 title claims abstract description 55
- 229940025084 amphetamine Drugs 0.000 title claims description 23
- 150000003839 salts Chemical class 0.000 title claims description 14
- 239000004480 active ingredient Substances 0.000 claims abstract description 95
- 239000008188 pellet Substances 0.000 claims abstract description 92
- 239000000203 mixture Substances 0.000 claims abstract description 58
- 239000002702 enteric coating Substances 0.000 claims abstract description 44
- 238000009505 enteric coating Methods 0.000 claims abstract description 44
- 239000011230 binding agent Substances 0.000 claims abstract description 42
- 229920000642 polymer Polymers 0.000 claims abstract description 37
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 31
- 238000004519 manufacturing process Methods 0.000 claims abstract description 31
- 230000005465 channeling Effects 0.000 claims abstract description 29
- 238000004090 dissolution Methods 0.000 claims abstract description 18
- 230000000541 pulsatile effect Effects 0.000 claims abstract description 16
- 238000000338 in vitro Methods 0.000 claims abstract description 13
- 239000002552 dosage form Substances 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims description 53
- 229940079593 drug Drugs 0.000 claims description 52
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 44
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 33
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 33
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 33
- 229960003943 hypromellose Drugs 0.000 claims description 23
- 229920001477 hydrophilic polymer Polymers 0.000 claims description 21
- 239000004014 plasticizer Substances 0.000 claims description 20
- 239000011253 protective coating Substances 0.000 claims description 20
- 239000011248 coating agent Substances 0.000 claims description 19
- 238000000576 coating method Methods 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 13
- 229930195725 Mannitol Natural products 0.000 claims description 13
- 230000000181 anti-adherent effect Effects 0.000 claims description 13
- 239000003911 antiadherent Substances 0.000 claims description 13
- 239000000594 mannitol Substances 0.000 claims description 13
- 235000010355 mannitol Nutrition 0.000 claims description 13
- PYHRZPFZZDCOPH-QXGOIDDHSA-N (S)-amphetamine sulfate Chemical compound [H+].[H+].[O-]S([O-])(=O)=O.C[C@H](N)CC1=CC=CC=C1.C[C@H](N)CC1=CC=CC=C1 PYHRZPFZZDCOPH-QXGOIDDHSA-N 0.000 claims description 12
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 12
- 229920001577 copolymer Polymers 0.000 claims description 12
- 239000001069 triethyl citrate Substances 0.000 claims description 12
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims description 12
- 235000013769 triethyl citrate Nutrition 0.000 claims description 12
- 239000012530 fluid Substances 0.000 claims description 11
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 10
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 10
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 10
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 10
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 10
- 239000002202 Polyethylene glycol Substances 0.000 claims description 10
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 10
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 10
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 10
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 10
- 229920003064 carboxyethyl cellulose Polymers 0.000 claims description 10
- 229920003090 carboxymethyl hydroxyethyl cellulose Polymers 0.000 claims description 10
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 10
- 239000012141 concentrate Substances 0.000 claims description 10
- 239000006185 dispersion Substances 0.000 claims description 10
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 10
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 10
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 10
- 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 10
- 229920000609 methyl cellulose Polymers 0.000 claims description 10
- 239000001923 methylcellulose Substances 0.000 claims description 10
- 235000010981 methylcellulose Nutrition 0.000 claims description 10
- 229920001223 polyethylene glycol Polymers 0.000 claims description 10
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 10
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 10
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 10
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 10
- VHKVKWTWHZUFIA-DGOKBZBKSA-N (2s)-1-phenylpropan-2-amine;(2s,3s,4s,5r)-2,3,4,5-tetrahydroxyhexanedioic acid Chemical compound C[C@H](N)CC1=CC=CC=C1.OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O VHKVKWTWHZUFIA-DGOKBZBKSA-N 0.000 claims description 8
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 8
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 8
- ZFOZVQLOBQUTQQ-UHFFFAOYSA-N Tributyl citrate Chemical compound CCCCOC(=O)CC(O)(C(=O)OCCCC)CC(=O)OCCCC ZFOZVQLOBQUTQQ-UHFFFAOYSA-N 0.000 claims description 8
- PYHRZPFZZDCOPH-UHFFFAOYSA-N amphetamine sulfate Chemical compound OS(O)(=O)=O.CC(N)CC1=CC=CC=C1.CC(N)CC1=CC=CC=C1 PYHRZPFZZDCOPH-UHFFFAOYSA-N 0.000 claims description 8
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims description 8
- 239000002775 capsule Substances 0.000 claims description 8
- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 claims description 8
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 claims description 8
- KWTSXDURSIMDCE-UHFFFAOYSA-N 1-phenylpropan-2-amine Chemical compound CC(N)CC1=CC=CC=C1 KWTSXDURSIMDCE-UHFFFAOYSA-N 0.000 claims description 7
- 229940052370 dextroamphetamine saccharate Drugs 0.000 claims description 7
- -1 glidants Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- OJNSNSZTGUACNI-IBFUIWIBSA-N N[C@H](CC(O)=O)C(O)=O.CC(N)CC1=CC=CC=C1.CC(N)CC1=CC=CC=C1 Chemical compound N[C@H](CC(O)=O)C(O)=O.CC(N)CC1=CC=CC=C1.CC(N)CC1=CC=CC=C1 OJNSNSZTGUACNI-IBFUIWIBSA-N 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- 229940052327 amphetamine aspartate Drugs 0.000 claims description 6
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 6
- 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 claims description 5
- 229920003134 Eudragit® polymer Polymers 0.000 claims description 5
- 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 claims description 5
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 claims description 5
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 5
- 229930006000 Sucrose Natural products 0.000 claims description 5
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 5
- 239000002535 acidifier Substances 0.000 claims description 5
- 239000008121 dextrose Substances 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 239000007884 disintegrant Substances 0.000 claims description 5
- 239000008103 glucose Substances 0.000 claims description 5
- 239000004615 ingredient Substances 0.000 claims description 5
- 239000008101 lactose Substances 0.000 claims description 5
- 239000000314 lubricant Substances 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 5
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 201000003631 narcolepsy Diseases 0.000 claims description 5
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- 239000000811 xylitol Substances 0.000 claims description 5
- 235000010447 xylitol Nutrition 0.000 claims description 5
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 5
- 229960002675 xylitol Drugs 0.000 claims description 5
- QZCLKYGREBVARF-UHFFFAOYSA-N Acetyl tributyl citrate Chemical compound CCCCOC(=O)CC(C(=O)OCCCC)(OC(C)=O)CC(=O)OCCCC QZCLKYGREBVARF-UHFFFAOYSA-N 0.000 claims description 4
- PYGXAGIECVVIOZ-UHFFFAOYSA-N Dibutyl decanedioate Chemical compound CCCCOC(=O)CCCCCCCCC(=O)OCCCC PYGXAGIECVVIOZ-UHFFFAOYSA-N 0.000 claims description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical class CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 4
- 229960002380 dibutyl phthalate Drugs 0.000 claims description 4
- 229940031954 dibutyl sebacate Drugs 0.000 claims description 4
- 229940075507 glyceryl monostearate Drugs 0.000 claims description 4
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims description 4
- 235000013772 propylene glycol Nutrition 0.000 claims description 4
- 229920003138 Eudragit® L 30 D-55 Polymers 0.000 claims description 3
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 claims description 3
- 238000005507 spraying Methods 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims 1
- 239000010410 layer Substances 0.000 description 19
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- 239000012729 immediate-release (IR) formulation Substances 0.000 description 8
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- 230000001419 dependent effect Effects 0.000 description 5
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- 238000013268 sustained release Methods 0.000 description 5
- 239000012730 sustained-release form Substances 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 4
- 229940119751 dextroamphetamine sulfate Drugs 0.000 description 4
- 230000009977 dual effect Effects 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 229940047812 adderall Drugs 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 238000013270 controlled release Methods 0.000 description 3
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- 238000009506 drug dissolution testing Methods 0.000 description 3
- 238000013265 extended release Methods 0.000 description 3
- 210000000936 intestine Anatomy 0.000 description 3
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- 239000000758 substrate Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- DAWXRFCLWKUCNS-MNTSKLTCSA-N (2s)-2-aminobutanedioic acid;1-phenylpropan-2-amine;hydrate Chemical compound O.OC(=O)[C@@H](N)CC(O)=O.CC(N)CC1=CC=CC=C1.CC(N)CC1=CC=CC=C1 DAWXRFCLWKUCNS-MNTSKLTCSA-N 0.000 description 2
- 229940081735 acetylcellulose Drugs 0.000 description 2
- 229940030922 amphetamine aspartate monohydrate Drugs 0.000 description 2
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- 229940099242 dexedrine Drugs 0.000 description 2
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- 210000000813 small intestine Anatomy 0.000 description 2
- KWTSXDURSIMDCE-MRVPVSSYSA-N (R)-amphetamine Chemical compound C[C@@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-MRVPVSSYSA-N 0.000 description 1
- SOFQDLYSFOWTJX-UHFFFAOYSA-N 1-phenylpropan-2-amine;sulfuric acid Chemical compound OS(O)(=O)=O.CC(N)CC1=CC=CC=C1 SOFQDLYSFOWTJX-UHFFFAOYSA-N 0.000 description 1
- 229920000856 Amylose Polymers 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-N 0.000 description 1
- 206010017943 Gastrointestinal conditions Diseases 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical class NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 1
- 206010062519 Poor quality sleep Diseases 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 229920002494 Zein Polymers 0.000 description 1
- IYKJEILNJZQJPU-UHFFFAOYSA-N acetic acid;butanedioic acid Chemical compound CC(O)=O.OC(=O)CCC(O)=O IYKJEILNJZQJPU-UHFFFAOYSA-N 0.000 description 1
- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 description 1
- GAMPNQJDUFQVQO-UHFFFAOYSA-N acetic acid;phthalic acid Chemical compound CC(O)=O.OC(=O)C1=CC=CC=C1C(O)=O GAMPNQJDUFQVQO-UHFFFAOYSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940002345 amphetamine saccharate Drugs 0.000 description 1
- 229940008238 amphetamine sulfate Drugs 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
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- 230000006399 behavior Effects 0.000 description 1
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
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- 230000008859 change Effects 0.000 description 1
- 239000011247 coating layer Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 229940099340 desoxyn Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229960000632 dexamfetamine Drugs 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000005095 gastrointestinal system Anatomy 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
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- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 229950005223 levamfetamine Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- VOBHXZCDAVEXEY-JSGCOSHPSA-N lisdexamfetamine Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](C)CC1=CC=CC=C1 VOBHXZCDAVEXEY-JSGCOSHPSA-N 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- TWXDDNPPQUTEOV-FVGYRXGTSA-N methamphetamine hydrochloride Chemical compound Cl.CN[C@@H](C)CC1=CC=CC=C1 TWXDDNPPQUTEOV-FVGYRXGTSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
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- 239000008203 oral pharmaceutical composition Substances 0.000 description 1
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- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
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- 230000002035 prolonged effect Effects 0.000 description 1
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- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
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Classifications
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- 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
- 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
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
Abstract
The present invention relates to an orally administrable modified release pharmaceutical composition comprising pellets containing one or more active ingredients, more specifically the present invention is directed to dosage form comprising one or more amphetamine salts, which comprising: (a) an inert core; (b) a first layer, said layer comprises at least one pharmaceutically active ingredient and at least one hydrophilic binder; and (c) a modified enteric coating, said modified enteric coating comprises an enteric polymer and a channeling agent, wherein said composition provides: a continuous release of the pharmaceutically active ingredient at pH less than 5.5, and a pulsatile release of the pharmaceutically active ingredient at pH 6.0 or more;
and has an in vitro dissolution profile of at least 95% of the active ingredient dissolved within 4 hours after administration. A method of manufacturing the modified release pharmaceutical composition is also disclosed.
and has an in vitro dissolution profile of at least 95% of the active ingredient dissolved within 4 hours after administration. A method of manufacturing the modified release pharmaceutical composition is also disclosed.
Description
, PHARMACEUTICAL COMPOSITION OF AMPHETAMINE
MIXED SALTS
FIELD OF THE INVENTION
The present invention relates to an orally administrable modified release pharmaceutical composition comprising pellets containing one or more active ingredients, more specifically the present invention is directed to dosage form comprising one or more amphetamine salts.
BACKGROUND OF THE INVENTION
Continued development and improvement of modified release pharmaceutical compositions has long been a focus in the field of pharmaceutical formulations.
Advantages of a modified release composition include increased convenience of administration, and a more consistent therapeutic effect throughout a desired period of time.
Amphetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.
Amphetamines are non-catecholamine, sympathominetic amines with central nervous system stimulant activity, which have been widely utilized in treating narcolepsy and Attention Deficit Hyperactivity Disorder (ADHD). The amphetamine salts generally include the neutral sulfate salts of dextroamphetamine and amphetamine, the dextro isomer of amphetamine saccharate and d,l-amphetamine aspartate.
Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat, Desoxyn, ProCentra, and Vyvanse, as well as Benzedrine.
Currently marketed oral amphetamine products to treat narcolepsy and/or ADHD
include both immediate-release and modified-release forms. The Dexedrine product is marketed as a sustained-release formulation with dextroamphetamine sulfate as the only active ingredient.
Adderall is an immediate release composition and Adderall XR , a once daily sustained-release, are single-entity dosage forms containing a mixture of four amphetamine salts: dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrate and amphetamine sulfate, which is indicated for treatment of ADHD in children from 3-10 years of age.
Adderall is also known like an immediate release composition, which includes a mixture of four amphetamine salts.
Drug absorption is different in various segments of the gastrointestinal system. For example, it drug absorption is moderately slow in the stomach, rapid in the small intestine, and sharply declines in the large intestine. Compensation for changing absorption characteristics in the gastrointestinal tract may be important for some drugs.
The mixture of amphetamine salts is well known. For example, see the following references: CA2605185, CA2651890, W020050044238, W02007133203, US2006204575, CA2348090 (US 6322819), CA2432178 (US 6287599) CA2348090 (US6322819) discloses a multiple pulsed dose drug delivery system for pharmaceutically active amphetamine salts, comprising immediate-release pellets for releasing in the stomach and an enteric delayed-release pellets releasing in the small intestine, and a person skilled in the art would recognize an inherent food effect.
CA2432178 (US6287599) discloses pharmaceutical composition comprising at least one pharmaceutically active agent that is pH dependent, at least one non-pH
dependent sustained release agent, and at least one pH dependent agent that increases the dissolution rate of the at least one pharmaceutically active agent at pH in excess of 5.5.
US6384020 (SHIRE LAB INC.) discloses an immediate-release oral dosage form in delivering amphetamines and their salts. This dosage form solves particular process problems and has an adequate stability profile. However, this reference does not teach how to make a sustained-release formulation.
MIXED SALTS
FIELD OF THE INVENTION
The present invention relates to an orally administrable modified release pharmaceutical composition comprising pellets containing one or more active ingredients, more specifically the present invention is directed to dosage form comprising one or more amphetamine salts.
BACKGROUND OF THE INVENTION
Continued development and improvement of modified release pharmaceutical compositions has long been a focus in the field of pharmaceutical formulations.
Advantages of a modified release composition include increased convenience of administration, and a more consistent therapeutic effect throughout a desired period of time.
Amphetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.
Amphetamines are non-catecholamine, sympathominetic amines with central nervous system stimulant activity, which have been widely utilized in treating narcolepsy and Attention Deficit Hyperactivity Disorder (ADHD). The amphetamine salts generally include the neutral sulfate salts of dextroamphetamine and amphetamine, the dextro isomer of amphetamine saccharate and d,l-amphetamine aspartate.
Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat, Desoxyn, ProCentra, and Vyvanse, as well as Benzedrine.
Currently marketed oral amphetamine products to treat narcolepsy and/or ADHD
include both immediate-release and modified-release forms. The Dexedrine product is marketed as a sustained-release formulation with dextroamphetamine sulfate as the only active ingredient.
Adderall is an immediate release composition and Adderall XR , a once daily sustained-release, are single-entity dosage forms containing a mixture of four amphetamine salts: dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrate and amphetamine sulfate, which is indicated for treatment of ADHD in children from 3-10 years of age.
Adderall is also known like an immediate release composition, which includes a mixture of four amphetamine salts.
Drug absorption is different in various segments of the gastrointestinal system. For example, it drug absorption is moderately slow in the stomach, rapid in the small intestine, and sharply declines in the large intestine. Compensation for changing absorption characteristics in the gastrointestinal tract may be important for some drugs.
The mixture of amphetamine salts is well known. For example, see the following references: CA2605185, CA2651890, W020050044238, W02007133203, US2006204575, CA2348090 (US 6322819), CA2432178 (US 6287599) CA2348090 (US6322819) discloses a multiple pulsed dose drug delivery system for pharmaceutically active amphetamine salts, comprising immediate-release pellets for releasing in the stomach and an enteric delayed-release pellets releasing in the small intestine, and a person skilled in the art would recognize an inherent food effect.
CA2432178 (US6287599) discloses pharmaceutical composition comprising at least one pharmaceutically active agent that is pH dependent, at least one non-pH
dependent sustained release agent, and at least one pH dependent agent that increases the dissolution rate of the at least one pharmaceutically active agent at pH in excess of 5.5.
US6384020 (SHIRE LAB INC.) discloses an immediate-release oral dosage form in delivering amphetamines and their salts. This dosage form solves particular process problems and has an adequate stability profile. However, this reference does not teach how to make a sustained-release formulation.
, . CA 02758556 2011-11-17 There are other references which disclose different amphetamine dosage forms with a plurality of modified release units, particularly extended release dosage forms, mixed salts of amphetamine extended release capsules, where it is formulated by mixing two types of pellets, immediate release pellets and delayed release pellets in 1:
1 ratio to have a dual type of release. The immediate release pellets releases the amphetamine salts immediately after ingestion and the delayed release pellets release the amphetamine salts once the pellets reache the intestine.
A number of factors may influence the efficacy of pulse drug release and thus, represent a source of variability. Such factors include the complexity of the process for drug formulation, reproducibility of the manufacturing process, and uniformity of the product produced by the manufacturing process. One of the disadvantages of the manufacturing process used to prepare such pulse drug release formulations is the filling of two or more pellets requires specialized filling machines and change parts and could bring variability in dissolution if the correct amount of each type of pellets is not filled.
In addition, gastrointestinal transit times vary not only from patient-to-patient but also within patients as a result of food intake (i.e. fed or fasted states), stress, and illness.
Thus, while a variety of formulations have been proposed in consideration of one or more of these factors, improved formulations are still desirable.
Therefore, accordingly to a need exist to overcome the existing drawbacks by modified release formulation of amphetamine mixed salts.
SUMMARY OF THE INVENTION
An aspect of the present invention is directed to a modified release pharmaceutical composition comprising pellets containing one or more active ingredients, said pellets comprising:
(a) an inert core;
(b) a first layer disposed over the inert core, said layer comprises at least one pharmaceutically active ingredient and at least one hydrophilic binder; and (c) a modified enteric coating disposed over the first layer, said modified enteric coating comprises an enteric polymer and a channeling agent, wherein said composition provides: a continuous release of the pharmaceutically active ingredient once the dosage form is exposed to a media of pH less than 5.5; and a pulsatile release of the pharmaceutically active ingredient at pH 6.0 or more.
Preferably, the pharmaceutically active ingredient is selected from the group consisting of amphetamine salts, and more preferably, amphetamine base salts.
More preferably, the amphetamine salts are selected from the group consisting of:
amphetamine sulphate, dextroamphetamine sulphate, dextroamphetamine saccharate, amphetamine aspartate and mixtures thereof.
Another aspect of the present invention is directed to a modified release pharmaceutical composition which provides a dual type of release:
- a continuous release of the pharmaceutically active ingredient at a pH less than 5.5, and - a pulsatile release of the pharmaceutically active ingredient at pH 6.0 or more.
Preferably, the dual type of release of said modified release pharmaceutical composition is provided from a single type of pellets containing one or more active ingredients.
Yet another aspect of the present invention is directed to a modified release pharmaceutical composition comprising pellets containing one or more active ingredients which comprising: an inert core; a first layer disposed over the inert core and a modified enteric coating disposed over the drug layered pellet, wherein said composition provides: a continuous release of the pharmaceutically active ingredient at pH
less than 5.5, and a pulsatile release of the pharmaceutically active ingredient at pH
6.0 or more, and has an in vitro dissolution profile of at least 95% of the active ingredient dissolved within 4 hours of administration as measured by USP Type II Apparatus (sinkers), with 750 ml of 0,08 N HCI for 2hrs, and then 200m1 of buffer concentrate added to make pH
6.0 for the next two hours, at 37 deg. C., at a paddle speed of 50 rpm.
Preferably, the inert core comprises at least one pharmaceutically acceptable excipient selected from the group consisting of: inert water soluble, inert water insoluble, swellable . . CA 02758556 2011-11-17 material and mixtures thereof. More preferably, the pellet further comprises a seal coat disposed between the inert core and the first layer.
Also, preferably the first layer disposed over the inert core comprises at least one pharmaceutically active ingredient and at least one hydrophilic binder, which is selected from the group consisting of: hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, hypromellose, and combinations thereof. More preferably, the hydrophilic binder is hypromellose.
Another aspect of the present invention is directed to a modified release pharmaceutical composition with a dual type of release from a single type of pellets containing one ore more active ingredients comprising: an inert core; a first layer disposed over the inert core, and a modified enteric coating disposed over the drug layered pellet, wherein said modified enteric coating comprises an enteric polymer, a channeling agent and at least one pharmaceutically acceptable excipient.
Preferably, the modified enteric coating comprises an enteric polymer selected from the group consisting of: ammonialkyl methacrylate copolymers, methacrylate copolymers, and a combination thereof. More preferably, the enteric polymer is Eudragit L3OD 558.
Also, preferably the channeling agent of the modified enteric coating is selected from the group consisting of: hydrophilic excipients or hydrophilic polymers, comprising one or more of glucose, mannitol, lactose, xylitol, dextrose, sucrose and combinations thereof.
More preferably, the channeling agent is mannitol.
Preferably, one or more pharmaceutically acceptable excipients are selected from the group consisting of: binders, plasticizers, lubricants, disintegrants, diluents, glidants, anti adherents and acidifying agents. More preferably, the plasticizer is triethyl citrate.
More preferable, the modified release pharmaceutical composition comprising pellets containing one or more active ingredients, which comprises: about 50 %w/w to about 90 %w/w of an inert core, about 2 %w/w to about 15 % w/w of a pharmaceutically active ingredient, about 1.0 %w/w to about 12.0 %w/w of an enteric polymer, about 0.1 %w/w to about 3.0 % w/w of a channeling agent, about 0.1 %w/w to about 3 %w/w of a hydrophilic binder, about 0.1 %w/w to about 3.0 % w/w of Plasacryle, and about 0.1 %w/w to about 2.0 % w/w of a plasticizer, all based on the total weight of the modified release pharmaceutical composition.
Yet, another aspect of the present invention is directed to a modified release pharmaceutical composition comprising pellets containing one or more active ingredients, the composition comprising: an inert core; a first layer disposed over the inert core, said layer comprises at least one pharmaceutically active ingredient and at least one hydrophilic binder; a protective coating disposed over the first (drug) layered core, said coating comprises a hydrophilic polymer and at least one pharmaceutically acceptable excipient; and a modified enteric coating disposed over the protective coating, said modified enteric coating comprises an enteric polymer, a channeling agent, and at least one pharmaceutically acceptable excipient, wherein said composition provides continuous release of the active ingredient at pH less than 5.5, and pulsatile release of the pharmaceutically active ingredient at pH 6.0 or more.
Preferably, pellet further comprises a protective coating disposed over the first layer, in between the first layer and the modified enteric coating.
Also, preferably the hydrophilic polymer is selected from the group consisting of:
hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, hypromellose, and combinations thereof. More preferably, the hydrophilic polymer of the protective coating is hypromellose and one of pharmaceutically acceptable excipients is colloidal silicon dioxide.
Further aspect of the present invention is directed to modified release pharmaceutical composition comprising pellets containing one or more active ingredients and at least one pharmaceutically acceptable excipient, wherein said composition has an in vitro dissolution profile of at least 95% of the active ingredient dissolved within 4 hours of administration as measured by USP Type II Apparatus (sinkers), with 750 ml of 0,08 N
1 ratio to have a dual type of release. The immediate release pellets releases the amphetamine salts immediately after ingestion and the delayed release pellets release the amphetamine salts once the pellets reache the intestine.
A number of factors may influence the efficacy of pulse drug release and thus, represent a source of variability. Such factors include the complexity of the process for drug formulation, reproducibility of the manufacturing process, and uniformity of the product produced by the manufacturing process. One of the disadvantages of the manufacturing process used to prepare such pulse drug release formulations is the filling of two or more pellets requires specialized filling machines and change parts and could bring variability in dissolution if the correct amount of each type of pellets is not filled.
In addition, gastrointestinal transit times vary not only from patient-to-patient but also within patients as a result of food intake (i.e. fed or fasted states), stress, and illness.
Thus, while a variety of formulations have been proposed in consideration of one or more of these factors, improved formulations are still desirable.
Therefore, accordingly to a need exist to overcome the existing drawbacks by modified release formulation of amphetamine mixed salts.
SUMMARY OF THE INVENTION
An aspect of the present invention is directed to a modified release pharmaceutical composition comprising pellets containing one or more active ingredients, said pellets comprising:
(a) an inert core;
(b) a first layer disposed over the inert core, said layer comprises at least one pharmaceutically active ingredient and at least one hydrophilic binder; and (c) a modified enteric coating disposed over the first layer, said modified enteric coating comprises an enteric polymer and a channeling agent, wherein said composition provides: a continuous release of the pharmaceutically active ingredient once the dosage form is exposed to a media of pH less than 5.5; and a pulsatile release of the pharmaceutically active ingredient at pH 6.0 or more.
Preferably, the pharmaceutically active ingredient is selected from the group consisting of amphetamine salts, and more preferably, amphetamine base salts.
More preferably, the amphetamine salts are selected from the group consisting of:
amphetamine sulphate, dextroamphetamine sulphate, dextroamphetamine saccharate, amphetamine aspartate and mixtures thereof.
Another aspect of the present invention is directed to a modified release pharmaceutical composition which provides a dual type of release:
- a continuous release of the pharmaceutically active ingredient at a pH less than 5.5, and - a pulsatile release of the pharmaceutically active ingredient at pH 6.0 or more.
Preferably, the dual type of release of said modified release pharmaceutical composition is provided from a single type of pellets containing one or more active ingredients.
Yet another aspect of the present invention is directed to a modified release pharmaceutical composition comprising pellets containing one or more active ingredients which comprising: an inert core; a first layer disposed over the inert core and a modified enteric coating disposed over the drug layered pellet, wherein said composition provides: a continuous release of the pharmaceutically active ingredient at pH
less than 5.5, and a pulsatile release of the pharmaceutically active ingredient at pH
6.0 or more, and has an in vitro dissolution profile of at least 95% of the active ingredient dissolved within 4 hours of administration as measured by USP Type II Apparatus (sinkers), with 750 ml of 0,08 N HCI for 2hrs, and then 200m1 of buffer concentrate added to make pH
6.0 for the next two hours, at 37 deg. C., at a paddle speed of 50 rpm.
Preferably, the inert core comprises at least one pharmaceutically acceptable excipient selected from the group consisting of: inert water soluble, inert water insoluble, swellable . . CA 02758556 2011-11-17 material and mixtures thereof. More preferably, the pellet further comprises a seal coat disposed between the inert core and the first layer.
Also, preferably the first layer disposed over the inert core comprises at least one pharmaceutically active ingredient and at least one hydrophilic binder, which is selected from the group consisting of: hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, hypromellose, and combinations thereof. More preferably, the hydrophilic binder is hypromellose.
Another aspect of the present invention is directed to a modified release pharmaceutical composition with a dual type of release from a single type of pellets containing one ore more active ingredients comprising: an inert core; a first layer disposed over the inert core, and a modified enteric coating disposed over the drug layered pellet, wherein said modified enteric coating comprises an enteric polymer, a channeling agent and at least one pharmaceutically acceptable excipient.
Preferably, the modified enteric coating comprises an enteric polymer selected from the group consisting of: ammonialkyl methacrylate copolymers, methacrylate copolymers, and a combination thereof. More preferably, the enteric polymer is Eudragit L3OD 558.
Also, preferably the channeling agent of the modified enteric coating is selected from the group consisting of: hydrophilic excipients or hydrophilic polymers, comprising one or more of glucose, mannitol, lactose, xylitol, dextrose, sucrose and combinations thereof.
More preferably, the channeling agent is mannitol.
Preferably, one or more pharmaceutically acceptable excipients are selected from the group consisting of: binders, plasticizers, lubricants, disintegrants, diluents, glidants, anti adherents and acidifying agents. More preferably, the plasticizer is triethyl citrate.
More preferable, the modified release pharmaceutical composition comprising pellets containing one or more active ingredients, which comprises: about 50 %w/w to about 90 %w/w of an inert core, about 2 %w/w to about 15 % w/w of a pharmaceutically active ingredient, about 1.0 %w/w to about 12.0 %w/w of an enteric polymer, about 0.1 %w/w to about 3.0 % w/w of a channeling agent, about 0.1 %w/w to about 3 %w/w of a hydrophilic binder, about 0.1 %w/w to about 3.0 % w/w of Plasacryle, and about 0.1 %w/w to about 2.0 % w/w of a plasticizer, all based on the total weight of the modified release pharmaceutical composition.
Yet, another aspect of the present invention is directed to a modified release pharmaceutical composition comprising pellets containing one or more active ingredients, the composition comprising: an inert core; a first layer disposed over the inert core, said layer comprises at least one pharmaceutically active ingredient and at least one hydrophilic binder; a protective coating disposed over the first (drug) layered core, said coating comprises a hydrophilic polymer and at least one pharmaceutically acceptable excipient; and a modified enteric coating disposed over the protective coating, said modified enteric coating comprises an enteric polymer, a channeling agent, and at least one pharmaceutically acceptable excipient, wherein said composition provides continuous release of the active ingredient at pH less than 5.5, and pulsatile release of the pharmaceutically active ingredient at pH 6.0 or more.
Preferably, pellet further comprises a protective coating disposed over the first layer, in between the first layer and the modified enteric coating.
Also, preferably the hydrophilic polymer is selected from the group consisting of:
hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, hypromellose, and combinations thereof. More preferably, the hydrophilic polymer of the protective coating is hypromellose and one of pharmaceutically acceptable excipients is colloidal silicon dioxide.
Further aspect of the present invention is directed to modified release pharmaceutical composition comprising pellets containing one or more active ingredients and at least one pharmaceutically acceptable excipient, wherein said composition has an in vitro dissolution profile of at least 95% of the active ingredient dissolved within 4 hours of administration as measured by USP Type II Apparatus (sinkers), with 750 ml of 0,08 N
HCI for 2hrs and then 200m1 of buffer concentrate added to make pH 6.0 for the next two hours, at 37 deg. C, at a paddle speed of 50 rpm.
Preferably, the modified release pharmaceutical composition comprising pellets containing one or more active ingredients, which comprises: about 50 %w/w to about 90 %w/w of an inert core, about 2 %w/w to about 15 % w/w of a pharmaceutically active ingredient, about 1.0 %w/w to about 12.0 %w/w of an enteric polymer, about 0.1 %w/w to about 3.0 % w/w of a channeling agent, about 0.1 %w/w to about 3 %w/w of a hydrophilic binder, about 1.0 %w/w to about 8.0 % w/w of a hydrophilic polymer, about 0.1 %w/w to about 2.0 % w/w of an anti-adherent, about 0.1 %w/w to about 3.0 A w/w of Plasacryle, and about 0.1 %w/w to about 2.0 % w/w of a plasticizer, all based on the total weight of the modified release pharmaceutical composition.
Preferably, said pharmaceutical composition has an in vitro dissolution profile:
- about 10% to about 40% of the pharmaceutically active ingredient is released after 60 min;
- about 40% to about 50% of the pharmaceutically active ingredient is released after 120 min;
- about 80% to about 100% of the pharmaceutically active ingredient is released after 180 min; and - about 100% of the pharmaceutically active ingredient is released after 240 min, as measured by Apparatus USP Type II (sinkers), with 750 ml of 0.08 N HCI for 2hrs and then 200m1 of buffer concentrate added to make pH 6.0 for the next two hours, at a paddle speed of 50rpm.
Another aspect of the present invention is directed to a modified release pharmaceutical composition comprising pellets containing one or more active ingredients and at least one pharmaceutically acceptable excipient, wherein the in vitro dissolution profile of said composition provides at least 95% of the active ingredient dissolved within 4 hours, which is substantially the same as provided by an equivalent dose of Adderal XR, as measured by USP Type II Apparatus(sinkers), with 750 ml of 0,08 N HCI for 2hrs and then 200m1 of buffer concentrate added to make pH 6.0 for the next two hours, at 37 deg. C., at a paddle speed of 50 rpm.
Preferably, the modified release pharmaceutical composition comprising pellets containing one or more active ingredients, which comprises: about 50 %w/w to about 90 %w/w of an inert core, about 2 %w/w to about 15 % w/w of a pharmaceutically active ingredient, about 1.0 %w/w to about 12.0 %w/w of an enteric polymer, about 0.1 %w/w to about 3.0 % w/w of a channeling agent, about 0.1 %w/w to about 3 %w/w of a hydrophilic binder, about 1.0 %w/w to about 8.0 % w/w of a hydrophilic polymer, about 0.1 %w/w to about 2.0 % w/w of an anti-adherent, about 0.1 %w/w to about 3.0 A w/w of Plasacryle, and about 0.1 %w/w to about 2.0 % w/w of a plasticizer, all based on the total weight of the modified release pharmaceutical composition.
Preferably, said pharmaceutical composition has an in vitro dissolution profile:
- about 10% to about 40% of the pharmaceutically active ingredient is released after 60 min;
- about 40% to about 50% of the pharmaceutically active ingredient is released after 120 min;
- about 80% to about 100% of the pharmaceutically active ingredient is released after 180 min; and - about 100% of the pharmaceutically active ingredient is released after 240 min, as measured by Apparatus USP Type II (sinkers), with 750 ml of 0.08 N HCI for 2hrs and then 200m1 of buffer concentrate added to make pH 6.0 for the next two hours, at a paddle speed of 50rpm.
Another aspect of the present invention is directed to a modified release pharmaceutical composition comprising pellets containing one or more active ingredients and at least one pharmaceutically acceptable excipient, wherein the in vitro dissolution profile of said composition provides at least 95% of the active ingredient dissolved within 4 hours, which is substantially the same as provided by an equivalent dose of Adderal XR, as measured by USP Type II Apparatus(sinkers), with 750 ml of 0,08 N HCI for 2hrs and then 200m1 of buffer concentrate added to make pH 6.0 for the next two hours, at 37 deg. C., at a paddle speed of 50 rpm.
. . CA 02758556 2011-11-17 Further aspect of the present invention is directed to a modified release pharmaceutical composition comprising pellets containing one or more active ingredients and at least one pharmaceutically acceptable excipient, wherein the modified enteric coating allows to release the active ingredient in such a way that less than 50% of the active ingredient is released in the stomach and substantially the same amount of the remaining active ingredient is released in the intestine.
Preferable, the pulsatile release provides a release of amphetamine salts from about 2 hours to about 4 hours after administration.
Yet, another aspect of the present invention is directed to a method of manufacturing a modified release pharmaceutical composition, wherein the method comprises the following steps:
1) Drug layering:
a) loading a sugar spheres or optionally seal coated pellets in a coating equipment;
b) dissolving the active ingredient;
c) mixing the active ingredient with a hydrophilic binder and at least one pharmaceutically acceptable excipient;
d) spraying solution comprising the active ingredient, a binder and at least one pharmaceutically acceptable excipient onto the sugar spheres or seal coated pellets to obtain a drug layered pellet;
2) Protective coating:
e) dissolving a hydrophilic polymer and at least one pharmaceutically acceptable excipient;
f) loading the drug layered pellets in a fluid bed processor;
g) coating drug layered pellets with solution of step (e) to obtain sub-coated pellets;
3) Modified enteric coating:
h) dissolving a channeling agent;
i) preparing a dispersion solution; adding enteric polymer to solution of step (h);
j) adding an enteric polymer and at least one pharmaceutically acceptable excipient to solution of step (i);
Preferable, the pulsatile release provides a release of amphetamine salts from about 2 hours to about 4 hours after administration.
Yet, another aspect of the present invention is directed to a method of manufacturing a modified release pharmaceutical composition, wherein the method comprises the following steps:
1) Drug layering:
a) loading a sugar spheres or optionally seal coated pellets in a coating equipment;
b) dissolving the active ingredient;
c) mixing the active ingredient with a hydrophilic binder and at least one pharmaceutically acceptable excipient;
d) spraying solution comprising the active ingredient, a binder and at least one pharmaceutically acceptable excipient onto the sugar spheres or seal coated pellets to obtain a drug layered pellet;
2) Protective coating:
e) dissolving a hydrophilic polymer and at least one pharmaceutically acceptable excipient;
f) loading the drug layered pellets in a fluid bed processor;
g) coating drug layered pellets with solution of step (e) to obtain sub-coated pellets;
3) Modified enteric coating:
h) dissolving a channeling agent;
i) preparing a dispersion solution; adding enteric polymer to solution of step (h);
j) adding an enteric polymer and at least one pharmaceutically acceptable excipient to solution of step (i);
. . CA 02758556 2011-11-17 k) loading sub-coated pellets in a fluid bed processor;
I) applying a solution of step (j) onto the sub-coated pellets of step (2) to obtain modified enteric coated pellets.
Preferably, the layers are applied as a solution/ dispersion of coating ingredients. The modified release pharmaceutical composition preferably is in the form of a capsule.
The present invention is further related to use of said pharmaceutical composition for the treatment or prevention of narcolepsy and Attention-Deficit/Hyperactivity Disorder (ADHD).
These and other aspects, advantages and features of the present invention become clear when detailed description and examples are provided.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows dissolution profiles for modified release composition versus time for an example compared to Adderall XR .
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an orally administrable modified release pharmaceutical composition comprising pellets containing one or more active ingredients which comprising: an inert core; a first layer disposed over the inert core, and a modified enteric coating disposed over the first layer, wherein said composition provides:
- continuous release of the pharmaceutically active ingredient at an pH less than 5.5, and - pulsatile release of the pharmaceutically active ingredient at pH 6.0 or more.
A controlled release pharmaceutical composition means a pharmaceutical composition including at least one active pharmaceutical ingredient which is formulated with at least one pharmaceutically acceptable film forming polymer and optionally with at least one pharmaceutically acceptable excipient, where the pharmaceutical composition shows a pH-dependent or a pH-independent reproducible release profile.
I) applying a solution of step (j) onto the sub-coated pellets of step (2) to obtain modified enteric coated pellets.
Preferably, the layers are applied as a solution/ dispersion of coating ingredients. The modified release pharmaceutical composition preferably is in the form of a capsule.
The present invention is further related to use of said pharmaceutical composition for the treatment or prevention of narcolepsy and Attention-Deficit/Hyperactivity Disorder (ADHD).
These and other aspects, advantages and features of the present invention become clear when detailed description and examples are provided.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows dissolution profiles for modified release composition versus time for an example compared to Adderall XR .
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an orally administrable modified release pharmaceutical composition comprising pellets containing one or more active ingredients which comprising: an inert core; a first layer disposed over the inert core, and a modified enteric coating disposed over the first layer, wherein said composition provides:
- continuous release of the pharmaceutically active ingredient at an pH less than 5.5, and - pulsatile release of the pharmaceutically active ingredient at pH 6.0 or more.
A controlled release pharmaceutical composition means a pharmaceutical composition including at least one active pharmaceutical ingredient which is formulated with at least one pharmaceutically acceptable film forming polymer and optionally with at least one pharmaceutically acceptable excipient, where the pharmaceutical composition shows a pH-dependent or a pH-independent reproducible release profile.
. . CA 02758556 2011-11-17 The term "controlled release pharmaceutical composition", as referred to herein, is defined to mean oral pharmaceutical compositions which when administered releases the active ingredient at a relatively constant rate and provide plasma concentrations of the active ingredient that remain substantially invariant with time within the therapeutic range of the active ingredient over a 24-hour period and encompasses "prolonged release", "extended release", "modified release", "delayed release" and "sustained release" compositions.
The term "modified release" as referred to herein, means that the escape of the drug from the tablet has been modified in some way. Usually this is to slow the release of the drug so that the medicine doesn't have to be taken too often and therefore improves compliance. The other benefit from modifying release is that the drug release is controlled and there are smaller peaks and troughs in blood levels therefore reducing the chance of peak effects and increasing the likelihood of therapeutic effectiveness for longer periods of time.
The term "continuous release", means that a term applied to a drug that is designed to deliver a dose of a medication over an extended period. The most common device for this purpose is a soft, soluble capsule containing minute pellets of the drug for release at different rates in the GI tract, depending on the thickness and nature of the oil, fat, wax, or resin coating on the pellets. Another system consists of a porous plastic carrier impregnated with the drug and a surfactant to facilitate the entry of GI
fluids that slowly leach out of the drug. Ion exchange resins that bind to drugs and liquids containing suspensions of slow-release drug granules are also used to provide medication over an extended period.
The term "pulsatile release" means that a drug is delivered in one or more doses that fluctuate between a maximum and minimum dose over a predetermined time intervals.
This can be represented by a dose release profile having one or more distinct peaks or valleys. However, two or more pulsed releases may produce an overlapping, overall, or composite release profile that appears or effectively is constant. The need for pulsatile release may include the desire to avoid drug degradation in the stomach or first pass metabolism. Pulsatile release can be achieved via coating of multiparticulates with pH
The term "modified release" as referred to herein, means that the escape of the drug from the tablet has been modified in some way. Usually this is to slow the release of the drug so that the medicine doesn't have to be taken too often and therefore improves compliance. The other benefit from modifying release is that the drug release is controlled and there are smaller peaks and troughs in blood levels therefore reducing the chance of peak effects and increasing the likelihood of therapeutic effectiveness for longer periods of time.
The term "continuous release", means that a term applied to a drug that is designed to deliver a dose of a medication over an extended period. The most common device for this purpose is a soft, soluble capsule containing minute pellets of the drug for release at different rates in the GI tract, depending on the thickness and nature of the oil, fat, wax, or resin coating on the pellets. Another system consists of a porous plastic carrier impregnated with the drug and a surfactant to facilitate the entry of GI
fluids that slowly leach out of the drug. Ion exchange resins that bind to drugs and liquids containing suspensions of slow-release drug granules are also used to provide medication over an extended period.
The term "pulsatile release" means that a drug is delivered in one or more doses that fluctuate between a maximum and minimum dose over a predetermined time intervals.
This can be represented by a dose release profile having one or more distinct peaks or valleys. However, two or more pulsed releases may produce an overlapping, overall, or composite release profile that appears or effectively is constant. The need for pulsatile release may include the desire to avoid drug degradation in the stomach or first pass metabolism. Pulsatile release can be achieved via coating of multiparticulates with pH
, CA 02758556 2011-11-17 dependent and/or barrier membrane coating systems, followed by blending of the multiparticulates to achieve desired release profiles.
"Immediate" and "delayed" release" refer to the onset of release in relationship to administration of the drug. "Immediate" means that the release of drug begins very soon, within a relatively short time after administration, e.g. a few minutes or less. "Delayed"
means that the release of drug is postponed, and begins or is triggered some period of time after administration (e.g., the lag time), typically a relatively long period of time, e.g.
more than one hour.
The terms "pellet" refer to a discrete component of a dosage form. For example, a capsule shell is filled with a plurality of beads or pellets. As used herein, pellet means any discrete component of a dosage form.
A drug delivery system of the invention typically may comprise a core seed or matrix, which may or may not be loaded with drug, and one or more coating layers comprising drug, and/or comprising a layer have release characteristics which control the onset and release characteristics of the drug.
An inert core comprises at least one pharmaceutically acceptable excipient selected from the group consisting of: inert water soluble, inert water insoluble, swellable material and mixtures thereof. Preferably, the inert core is made of sugar spheres and more preferably the pellet further comprises a seal coat disposed between the inert core and the first layer.
The term "active ingredient" refers to an Active Pharmaceutical Ingredients (API) which are active chemicals used in the manufacturing of drugs. The active agent can be a therapeutic, a prophylactic, or a diagnostic agent.
According to the present invention the pharmaceutically active ingredient is selected from the group consisting of Amphetamine base salts, wherein the amphetamine salts are selected from the group consisting of: amphetamine sulphate, dextroamphetamine sulphate, dextroamphetamine saccharate, amphetamine aspartate and mixtures thereof.
"Immediate" and "delayed" release" refer to the onset of release in relationship to administration of the drug. "Immediate" means that the release of drug begins very soon, within a relatively short time after administration, e.g. a few minutes or less. "Delayed"
means that the release of drug is postponed, and begins or is triggered some period of time after administration (e.g., the lag time), typically a relatively long period of time, e.g.
more than one hour.
The terms "pellet" refer to a discrete component of a dosage form. For example, a capsule shell is filled with a plurality of beads or pellets. As used herein, pellet means any discrete component of a dosage form.
A drug delivery system of the invention typically may comprise a core seed or matrix, which may or may not be loaded with drug, and one or more coating layers comprising drug, and/or comprising a layer have release characteristics which control the onset and release characteristics of the drug.
An inert core comprises at least one pharmaceutically acceptable excipient selected from the group consisting of: inert water soluble, inert water insoluble, swellable material and mixtures thereof. Preferably, the inert core is made of sugar spheres and more preferably the pellet further comprises a seal coat disposed between the inert core and the first layer.
The term "active ingredient" refers to an Active Pharmaceutical Ingredients (API) which are active chemicals used in the manufacturing of drugs. The active agent can be a therapeutic, a prophylactic, or a diagnostic agent.
According to the present invention the pharmaceutically active ingredient is selected from the group consisting of Amphetamine base salts, wherein the amphetamine salts are selected from the group consisting of: amphetamine sulphate, dextroamphetamine sulphate, dextroamphetamine saccharate, amphetamine aspartate and mixtures thereof.
In addition to the pharmaceutically active ingredient(s), the pharmaceutical composition according to the present invention contains at least one enteric polymer, at least one channeling agent, at least one hydrophilic polymer and at least one pharmaceutically acceptable excipient.
An enteric polymers that may be used in the oral modified release pharmaceutical composition is selected from the group, but are not limited to: ammonialkyl methacrylate copolymers, methacrylate copolymers, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl nnethylcellulose phthalate (HPMCP), polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, shellac, zein, polymethacrylates containing carboxyl groups, amylose acetate phthalate, styrene maleic acid copolymer, and cellulose acetate succinate and a combination thereof.
Examples of commercially available enteric material are available under the trade names EUDRAGIT . Preferably, the enteric polymer is EUDRAGITO L 30D-55 (methacrylic acid/ethyl acrylate copolymer), but similar enteric polymer may also be employed.
The present invention includes pharmaceutical composition producing a modified release having channels. The channels act as controlled transmission passages through the polymer.
The channeling agent is selected from the group consisting, but not limited to:
hydrophilic excipients or hydrophilic polymers, comprising one or more of glucose, mannitol, lactose, xylitol, dextrose, sucrose and combinations thereof.
Preferably, the channeling agent is mannitol, but similar channeling agent may also be employed.
Hydrophilic polymers that may be used in the oral modified release pharmaceutical composition is selected from the group, but are not limited to: hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, hypromellose, and combinations thereof.
In addition to the active ingredients and listed polymers the pharmaceutical composition of the present invention contains the pharmaceutically acceptable excipients added to the composition for a variety of purposes. One or more pharmaceutically acceptable excipients may be present in the composition of the present invention, but not limited to:
diluents, binders, lubricants, disintegrants, glidants, and acidifying agents.
As understood by a person skilled in the art, these excipients are conventional excipients which are well known in the pharmaceutical art.
The hydrophilic binder is selected from the group consisting of: hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, hypromellose, and a combination thereof. Preferably, the hydrophilic binder is hypromellose, but similar hydrophilic binders may also be employed.
According to the present invention the plasticizer of the modified enteric coating is selected from the group consisting of: diethylphthalate, dibutylphthalate, dibutylsebacate, tributyl citrate, triethyl citrate, acetyltributyl citrate, propylene glycols, glyceryl monostearate, and a combination thereof. Preferably the plasticizer is triethyl citrate, but similar plasticizer may also be employed.
Oral dosage forms which may be employed with the present invention include pellets in a capsule or in any other suitable solid form.
During drug development, in vitro dissolution testing is an important tool in the evaluation of the 'best' formulation. Dissolution testing is also utilized to define the biopharmaceutical characteristics and to identify possible risks such as potential food effects on bioavailability or interaction with other drugs. The simulation of specific gastrointestinal conditions which may lead to potential therapeutic failure or adverse events seems to be another point of interest during drug development. At this stage various models and test conditions for in vitro dissolution studies are applied to learn about the biopharmaceutical characteristics of early formulations and about the discriminating power of the test system.
Drug release and drug release profiles are measures or representations of the manner and timing by which a formulation releases or delivers active ingredients (drug) to a receiving environment (e.g. the stomach, intestines, etc.) upon administration. Various methods are known for evaluating drug release and producing release profiles, including in vitro tests which model the in vivo behavior of a formulation. These include USP
dissolution testing for immediate release and controlled release solid dosage forms.
According to an aspect of the present invention, the method of manufacturing a modified release pharmaceutical composition comprising a single type of pellets containing one or more active ingredients which comprising: an inert core; a first layer; and a modified enteric coating, wherein said method comprises the following steps:
1) Drug layering:
a) loading a sugar spheres or seal coated pellets in a coating equipment;
b) dissolving the active ingredient;
c) mixing the active ingredient with a hydrophilic binder and at least one pharmaceutically acceptable excipient;
d) spraying solution comprising the active ingredient, a binder and at least one pharmaceutically acceptable excipient onto the sugar spheres or seal coated pellets to obtain a drug layered pellet;
2) Protective coating:
e) dissolving a hydrophilic polymer and at least one pharmaceutically acceptable excipient;
f) loading the drug layered pellets in a fluid bed processor;
g) coating drug layered pellets with solution of step (e) to obtain sub-coated pellets;
3) Modified enteric coating:
h) dissolving a channeling agent;
i) preparing a dispersion solution; adding enteric polymer to solution of step (h);
j) adding an enteric polymer and at least one pharmaceutically acceptable excipient to solution of step (i);
k) loading sub-coated pellets in a fluid bed processor;
I) applying a solution of step (j) onto the sub-coated pellets of step (2) to obtain modified enteric coated pellets; and optionally m) filing obtained pellets into a suitable sized capsule.
An enteric polymers that may be used in the oral modified release pharmaceutical composition is selected from the group, but are not limited to: ammonialkyl methacrylate copolymers, methacrylate copolymers, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl nnethylcellulose phthalate (HPMCP), polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, shellac, zein, polymethacrylates containing carboxyl groups, amylose acetate phthalate, styrene maleic acid copolymer, and cellulose acetate succinate and a combination thereof.
Examples of commercially available enteric material are available under the trade names EUDRAGIT . Preferably, the enteric polymer is EUDRAGITO L 30D-55 (methacrylic acid/ethyl acrylate copolymer), but similar enteric polymer may also be employed.
The present invention includes pharmaceutical composition producing a modified release having channels. The channels act as controlled transmission passages through the polymer.
The channeling agent is selected from the group consisting, but not limited to:
hydrophilic excipients or hydrophilic polymers, comprising one or more of glucose, mannitol, lactose, xylitol, dextrose, sucrose and combinations thereof.
Preferably, the channeling agent is mannitol, but similar channeling agent may also be employed.
Hydrophilic polymers that may be used in the oral modified release pharmaceutical composition is selected from the group, but are not limited to: hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, hypromellose, and combinations thereof.
In addition to the active ingredients and listed polymers the pharmaceutical composition of the present invention contains the pharmaceutically acceptable excipients added to the composition for a variety of purposes. One or more pharmaceutically acceptable excipients may be present in the composition of the present invention, but not limited to:
diluents, binders, lubricants, disintegrants, glidants, and acidifying agents.
As understood by a person skilled in the art, these excipients are conventional excipients which are well known in the pharmaceutical art.
The hydrophilic binder is selected from the group consisting of: hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, hypromellose, and a combination thereof. Preferably, the hydrophilic binder is hypromellose, but similar hydrophilic binders may also be employed.
According to the present invention the plasticizer of the modified enteric coating is selected from the group consisting of: diethylphthalate, dibutylphthalate, dibutylsebacate, tributyl citrate, triethyl citrate, acetyltributyl citrate, propylene glycols, glyceryl monostearate, and a combination thereof. Preferably the plasticizer is triethyl citrate, but similar plasticizer may also be employed.
Oral dosage forms which may be employed with the present invention include pellets in a capsule or in any other suitable solid form.
During drug development, in vitro dissolution testing is an important tool in the evaluation of the 'best' formulation. Dissolution testing is also utilized to define the biopharmaceutical characteristics and to identify possible risks such as potential food effects on bioavailability or interaction with other drugs. The simulation of specific gastrointestinal conditions which may lead to potential therapeutic failure or adverse events seems to be another point of interest during drug development. At this stage various models and test conditions for in vitro dissolution studies are applied to learn about the biopharmaceutical characteristics of early formulations and about the discriminating power of the test system.
Drug release and drug release profiles are measures or representations of the manner and timing by which a formulation releases or delivers active ingredients (drug) to a receiving environment (e.g. the stomach, intestines, etc.) upon administration. Various methods are known for evaluating drug release and producing release profiles, including in vitro tests which model the in vivo behavior of a formulation. These include USP
dissolution testing for immediate release and controlled release solid dosage forms.
According to an aspect of the present invention, the method of manufacturing a modified release pharmaceutical composition comprising a single type of pellets containing one or more active ingredients which comprising: an inert core; a first layer; and a modified enteric coating, wherein said method comprises the following steps:
1) Drug layering:
a) loading a sugar spheres or seal coated pellets in a coating equipment;
b) dissolving the active ingredient;
c) mixing the active ingredient with a hydrophilic binder and at least one pharmaceutically acceptable excipient;
d) spraying solution comprising the active ingredient, a binder and at least one pharmaceutically acceptable excipient onto the sugar spheres or seal coated pellets to obtain a drug layered pellet;
2) Protective coating:
e) dissolving a hydrophilic polymer and at least one pharmaceutically acceptable excipient;
f) loading the drug layered pellets in a fluid bed processor;
g) coating drug layered pellets with solution of step (e) to obtain sub-coated pellets;
3) Modified enteric coating:
h) dissolving a channeling agent;
i) preparing a dispersion solution; adding enteric polymer to solution of step (h);
j) adding an enteric polymer and at least one pharmaceutically acceptable excipient to solution of step (i);
k) loading sub-coated pellets in a fluid bed processor;
I) applying a solution of step (j) onto the sub-coated pellets of step (2) to obtain modified enteric coated pellets; and optionally m) filing obtained pellets into a suitable sized capsule.
The following Example 1 illustrates the preferred embodiment but not limiting the present invention.
Example 1, Modified Release Pharmaceutical Composition of Amphetamine Mixed Salts The required quantities of amphetamine salts: Amphetamine sulphate, Dextroamphetamine sulfate, Dextroamphetamine saccharate and Amphetamine aspartate are dissolved in purified water to make 15.7% w/w solution (amphetamine salts mixture). The mixture of amphetamine salts may be in a 1:1:1:1 ratio.
The modified release composition comprises about 2.0 %w/w to about 15 % w/w of the pharmaceutically active amphetamine salts. Preferably, the modified release composition comprises about 2.0 %w/w to about 4.0 % w/w of each amphetamine salt, more preferably about 2.96 %w/w.
A suitable binder adhere particles of the selected composition to a core.
Suitable binders include, for example, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, hypromellose, and a combination thereof. In present embodiment, the binder is hypromellose. The modified release composition comprises about 0.1 %w/w to about 3.0 % w/w of the binder, preferably about 2.36 %w/w.
A protective coating layer may be disposed on the inert core before and/or after coating of the active agent. The inert core may be coated with a protective layer comprising a second binder (sub-coat) and/or an active agent-coated core may be coated with a protective layer comprising a third binder (outer-coat), by coating techniques such as pan coating or fluid bed coating using solutions of polymers in water or suitable organic solvents or by using aqueous polymer dispersions.
The pellet further comprises a seal coat disposed between the inert core and the first layer.
Example 1, Modified Release Pharmaceutical Composition of Amphetamine Mixed Salts The required quantities of amphetamine salts: Amphetamine sulphate, Dextroamphetamine sulfate, Dextroamphetamine saccharate and Amphetamine aspartate are dissolved in purified water to make 15.7% w/w solution (amphetamine salts mixture). The mixture of amphetamine salts may be in a 1:1:1:1 ratio.
The modified release composition comprises about 2.0 %w/w to about 15 % w/w of the pharmaceutically active amphetamine salts. Preferably, the modified release composition comprises about 2.0 %w/w to about 4.0 % w/w of each amphetamine salt, more preferably about 2.96 %w/w.
A suitable binder adhere particles of the selected composition to a core.
Suitable binders include, for example, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, hypromellose, and a combination thereof. In present embodiment, the binder is hypromellose. The modified release composition comprises about 0.1 %w/w to about 3.0 % w/w of the binder, preferably about 2.36 %w/w.
A protective coating layer may be disposed on the inert core before and/or after coating of the active agent. The inert core may be coated with a protective layer comprising a second binder (sub-coat) and/or an active agent-coated core may be coated with a protective layer comprising a third binder (outer-coat), by coating techniques such as pan coating or fluid bed coating using solutions of polymers in water or suitable organic solvents or by using aqueous polymer dispersions.
The pellet further comprises a seal coat disposed between the inert core and the first layer.
The sugar spheres or seal coated pellets is loaded in a bottom spray fluid bed processor.
A mixture comprising said pharmaceutically active amphetamine salts and a binder is sprayed over the sugar spheres or seal coated inert core in an amount sufficient to provide an Amphetamine drug layered pellets.
The required quantity of hypromellose is dissolved in purified water and to this solution colloidal silicon dioxide is dispersed to make 6.8% w/w protective coating solution. The modified release composition comprises about 1 %w/w to about 8 % w/w of the hypromellose, preferably about 7.9 %w/w and about 0.1 %w/w to about 2.0 % w/w of the colloidal silicon dioxide, preferably 1.2%w/w.
Amphetamine drug layered pellets are loaded in a bottom spray fluid bed processor. The protective coating solution is sprayed on the drug layered pellets to obtain Amphetamine sub coated pellets.
The required quantity of mannitol is dissolved in purified water. The modified release composition comprises about 0.1 %w/w to about 3.0 % w/w of mannitol, preferably about 2.20 %w/w. To this solution the Plasacryle is dispersed and stirred for 45 minutes. The modified release composition comprise about 0.1 %w/w to about 3.0 % w/w of Plasacryle, preferably about 2.20 %w/w. Further to said dispersion the Eudragit L3OD
55 is added. The modified release composition comprises about 1.0%w/w to about 12.0% w/w of Eudragit L3OD 550, preferably about 11.1%w/w.
Further the triethyl citrate is added to make 15% w/w dispersion for the modified enteric coating. The modified release composition comprises about 0.1%w/w to about 2.0 A) w/w of triethyl citrate, preferably about 1.1 %w/w. The modified enteric coating dispersion is stirred for 30 minutes before using. Amphetamine sub-coated pellets are loaded in a bottom spray fluid bed processor. The modified enteric coating dispersion is sprayed over the Amphetamine drug layered pellets to obtain modified enteric coated pellets.
A mixture comprising said pharmaceutically active amphetamine salts and a binder is sprayed over the sugar spheres or seal coated inert core in an amount sufficient to provide an Amphetamine drug layered pellets.
The required quantity of hypromellose is dissolved in purified water and to this solution colloidal silicon dioxide is dispersed to make 6.8% w/w protective coating solution. The modified release composition comprises about 1 %w/w to about 8 % w/w of the hypromellose, preferably about 7.9 %w/w and about 0.1 %w/w to about 2.0 % w/w of the colloidal silicon dioxide, preferably 1.2%w/w.
Amphetamine drug layered pellets are loaded in a bottom spray fluid bed processor. The protective coating solution is sprayed on the drug layered pellets to obtain Amphetamine sub coated pellets.
The required quantity of mannitol is dissolved in purified water. The modified release composition comprises about 0.1 %w/w to about 3.0 % w/w of mannitol, preferably about 2.20 %w/w. To this solution the Plasacryle is dispersed and stirred for 45 minutes. The modified release composition comprise about 0.1 %w/w to about 3.0 % w/w of Plasacryle, preferably about 2.20 %w/w. Further to said dispersion the Eudragit L3OD
55 is added. The modified release composition comprises about 1.0%w/w to about 12.0% w/w of Eudragit L3OD 550, preferably about 11.1%w/w.
Further the triethyl citrate is added to make 15% w/w dispersion for the modified enteric coating. The modified release composition comprises about 0.1%w/w to about 2.0 A) w/w of triethyl citrate, preferably about 1.1 %w/w. The modified enteric coating dispersion is stirred for 30 minutes before using. Amphetamine sub-coated pellets are loaded in a bottom spray fluid bed processor. The modified enteric coating dispersion is sprayed over the Amphetamine drug layered pellets to obtain modified enteric coated pellets.
A modified release pharmaceutical composition comprising pellets containing one ore more active ingredients which comprises: from about 50 %w/w to about 90 %w/w of an inert core, about 2 %w/w to about 15 % w/w of a pharmaceutically active ingredient, about 1 %w/w to about 12 % w/w of an enteric polymer, about 0.1 %w/w to about 3.0 %
w/w of a channeling agent, about 0.1 %w/w to about 3 %w/w of a hydrophilic binder, about 0.1 %w/w to about 3.0 % w/w of Plasacryle, and about 0.1 %w/w to about 2.0 %
w/w of a plasticizer, all based on the total weight of the modified release pharmaceutical composition.
The modified enteric coated pellets further are incorporated into a capsule.
The formulation and manufacturing steps of Example 1 is set out in Table 1.
Table 1 FORMULATION AND MANUFACTORING OF AMPHETAMINE MIXED SALTS
I. Drug layering No. Ingredients % w/w Function 1. Inert core (seal coated spheres) 85.8 Substrate for coating 2. Amphetamine sulphate 2.96 Active ingredient 3. Dextroamphetamine sulfate 2.96 Active ingredient 4. Amphetamine aspartate monohydrate 2.96 Active ingredient 5. Dextramphetamine Saccharate 2.96 Active ingredient Hypromellose 2.36 Binder Purified water Quantity sufficient Dispersing agent to make 15.7%
6. w/w TOTAL 100.0 II. Sub Coating/ Protective Coating =
No. Ingredients % wlw Function 1. Drug layered pellets 90.9 Substrate for coating Hypromellose 7.90 Protective coating 2.
polymer 3. Colloidal silicon dioxide 1.20 Anti adherent Purified water Quantity sufficient Dispersing agent 4 . to make 6.8%
w/w TOTAL 100.0 III. Modified enteric coating No. Ingredients % Wm/ Function 1. Sub coated pellets 83.3 Substrate 2. Eudragit L-30D 55 11.1 Ph dependant polymer 3. Mannitol 2.20 Channeling agent 4. Plasacryl 2.20 Anti adherent 5. Triethyl citrate 1.10 Plasticizer Purified water Quantity sufficient Dispersing agent 6. to make15% w/w TOTAL 100.0 The pharmaceutical composition obtained from Example 1 was subsequently tested for in vitro dissolution rate, measured by Apparatus (USP Type II with sinkers), using the following parameters:
Media: 750 ml of 0.08N HCI for 2hrs and 200 ml of buffer concentrate added to make pH 6.0 for the next two hours;
Speed: 50 RPM
A modified release pharmaceutical composition, wherein the in vitro dissolution profile of said composition provides at least 95% of the active ingredient dissolved within 4 hours, which is substantially the same as provided by an equivalent dose of Adderal XR, as measured by USP Type II Apparatus(sinkers), with 750 ml of 0,08 N HCI for 2hrs and then 200m1 of buffer concentrate added to make pH 6.0 for the next two hours, at 37 deg. C., at a paddle speed of 50 rpm as illustrated in FIG. 1 and described below.
w/w of a channeling agent, about 0.1 %w/w to about 3 %w/w of a hydrophilic binder, about 0.1 %w/w to about 3.0 % w/w of Plasacryle, and about 0.1 %w/w to about 2.0 %
w/w of a plasticizer, all based on the total weight of the modified release pharmaceutical composition.
The modified enteric coated pellets further are incorporated into a capsule.
The formulation and manufacturing steps of Example 1 is set out in Table 1.
Table 1 FORMULATION AND MANUFACTORING OF AMPHETAMINE MIXED SALTS
I. Drug layering No. Ingredients % w/w Function 1. Inert core (seal coated spheres) 85.8 Substrate for coating 2. Amphetamine sulphate 2.96 Active ingredient 3. Dextroamphetamine sulfate 2.96 Active ingredient 4. Amphetamine aspartate monohydrate 2.96 Active ingredient 5. Dextramphetamine Saccharate 2.96 Active ingredient Hypromellose 2.36 Binder Purified water Quantity sufficient Dispersing agent to make 15.7%
6. w/w TOTAL 100.0 II. Sub Coating/ Protective Coating =
No. Ingredients % wlw Function 1. Drug layered pellets 90.9 Substrate for coating Hypromellose 7.90 Protective coating 2.
polymer 3. Colloidal silicon dioxide 1.20 Anti adherent Purified water Quantity sufficient Dispersing agent 4 . to make 6.8%
w/w TOTAL 100.0 III. Modified enteric coating No. Ingredients % Wm/ Function 1. Sub coated pellets 83.3 Substrate 2. Eudragit L-30D 55 11.1 Ph dependant polymer 3. Mannitol 2.20 Channeling agent 4. Plasacryl 2.20 Anti adherent 5. Triethyl citrate 1.10 Plasticizer Purified water Quantity sufficient Dispersing agent 6. to make15% w/w TOTAL 100.0 The pharmaceutical composition obtained from Example 1 was subsequently tested for in vitro dissolution rate, measured by Apparatus (USP Type II with sinkers), using the following parameters:
Media: 750 ml of 0.08N HCI for 2hrs and 200 ml of buffer concentrate added to make pH 6.0 for the next two hours;
Speed: 50 RPM
A modified release pharmaceutical composition, wherein the in vitro dissolution profile of said composition provides at least 95% of the active ingredient dissolved within 4 hours, which is substantially the same as provided by an equivalent dose of Adderal XR, as measured by USP Type II Apparatus(sinkers), with 750 ml of 0,08 N HCI for 2hrs and then 200m1 of buffer concentrate added to make pH 6.0 for the next two hours, at 37 deg. C., at a paddle speed of 50 rpm as illustrated in FIG. 1 and described below.
In present embodiment a modified release pharmaceutical composition exhibits the following dissolution profile:
- about 10% to about 40% of the mixed amphetamine salts is released after 60 min;
- about 40% to about 50% of the mixed amphetamine salts is released after 120 min;
- about 80% to about 100% of the mixed amphetamine salts is released after 180 min;
- about 100% of the mixed amphetamine salts is released after 240 min, as measured by USP Type II Apparatus(sinkers), with 750 ml of 0,08 N HCI for 2hrs and then 200m1 of buffer concentrate added to make pH 6.0, at a paddle speed of 50 rpm.
The dissolution results are set out in Table 2.
Table 2 Dissolution rate of Amphetamine mixed salts pharmaceutical composition of Example 1.
Time Adderal XR 30 mg (mm) A60144B Example 1 Table 2 shows a comparison of the dissolution parameters for the pharmaceutical composition of the present invention compared to Adderall XR .
- about 10% to about 40% of the mixed amphetamine salts is released after 60 min;
- about 40% to about 50% of the mixed amphetamine salts is released after 120 min;
- about 80% to about 100% of the mixed amphetamine salts is released after 180 min;
- about 100% of the mixed amphetamine salts is released after 240 min, as measured by USP Type II Apparatus(sinkers), with 750 ml of 0,08 N HCI for 2hrs and then 200m1 of buffer concentrate added to make pH 6.0, at a paddle speed of 50 rpm.
The dissolution results are set out in Table 2.
Table 2 Dissolution rate of Amphetamine mixed salts pharmaceutical composition of Example 1.
Time Adderal XR 30 mg (mm) A60144B Example 1 Table 2 shows a comparison of the dissolution parameters for the pharmaceutical composition of the present invention compared to Adderall XR .
Claims (69)
1. A modified release pharmaceutical composition comprising pellets containing one or more active ingredients, said pellets comprising:
(a) an inert core;
(b) a first layer disposed over the inert core, said layer comprises at least one pharmaceutically active ingredient and at least one hydrophilic binder; and (c) a modified enteric coating disposed over the first layer, said modified enteric coating comprises an enteric polymer and a channeling agent, wherein said composition provides: a continuous release of the pharmaceutically active ingredient once the dosage form is exposed to a media of pH less than 5.5, and a pulsatile release of the pharmaceutically active ingredient at pH 6.0 or more.
(a) an inert core;
(b) a first layer disposed over the inert core, said layer comprises at least one pharmaceutically active ingredient and at least one hydrophilic binder; and (c) a modified enteric coating disposed over the first layer, said modified enteric coating comprises an enteric polymer and a channeling agent, wherein said composition provides: a continuous release of the pharmaceutically active ingredient once the dosage form is exposed to a media of pH less than 5.5, and a pulsatile release of the pharmaceutically active ingredient at pH 6.0 or more.
2. A modified release pharmaceutical composition comprising pellets containing one ore more active ingredients, said pellets comprising:
(a) an inert core;
(b) a first layer disposed over the inert core, said layer comprises at least one pharmaceutically active ingredient and at least one hydrophilic binder; and (c) a modified enteric coating disposed over the first layer, said modified enteric coating comprises an enteric polymer and a channeling agent, wherein said composition provides: a continuous release of the pharmaceutically active ingredient once the dosage form is exposed to a media of pH less than 5.5, and a pulsatile release of the pharmaceutically active ingredient at pH 6.0 or more;
and has an in vitro dissolution profile of at least 95% of the active ingredient dissolved within 4 hours of administration as measured by USP Type II Apparatus (sinkers), with 750 ml of 0,08 N HCl for 2hrs, and then 200ml of buffer concentrate added to make pH 6.0 for the next two hours, at 37 deg. C., at a paddle speed of 50 rpm.
(a) an inert core;
(b) a first layer disposed over the inert core, said layer comprises at least one pharmaceutically active ingredient and at least one hydrophilic binder; and (c) a modified enteric coating disposed over the first layer, said modified enteric coating comprises an enteric polymer and a channeling agent, wherein said composition provides: a continuous release of the pharmaceutically active ingredient once the dosage form is exposed to a media of pH less than 5.5, and a pulsatile release of the pharmaceutically active ingredient at pH 6.0 or more;
and has an in vitro dissolution profile of at least 95% of the active ingredient dissolved within 4 hours of administration as measured by USP Type II Apparatus (sinkers), with 750 ml of 0,08 N HCl for 2hrs, and then 200ml of buffer concentrate added to make pH 6.0 for the next two hours, at 37 deg. C., at a paddle speed of 50 rpm.
3. The modified release pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutically active ingredient is selected from the group consisting of Amphetamine base salts.
4. The modified release pharmaceutical composition according to claim 3, wherein the amphetamine salts are selected from the group consisting of: amphetamine sulphate, dextroamphetamine sulphate, dextroamphetamine saccharate, amphetamine aspartate and mixtures thereof.
5. The modified release pharmaceutical composition according to any one of claims 1 to 4, wherein the inert core comprises at least one pharmaceutically acceptable excipient selected from the group consisting of: inert water soluble, inert water insoluble, swellable material and mixtures thereof.
6. The modified release pharmaceutical composition according to any one of claims 1 to 5, wherein inert core is made of sugar spheres.
7. The modified release pharmaceutical composition according to any one of claims 1 to 6, wherein the pellet further comprises a seal coat disposed between the inert core and the first layer.
8. The modified release pharmaceutical composition according to any one of claims 1 to 7, wherein the hydrophilic binder is selected from the group consisting of:
hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, hypromellose, and a combination thereof.
hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, hypromellose, and a combination thereof.
9. The modified release pharmaceutical composition according to any one of claims 1 to 8, wherein the hydrophilic binder is hypromellose.
10. The modified release pharmaceutical composition according to any one of claims 1 to 9, wherein the modified enteric coating comprises an enteric polymer selected from the group consisting of: ammonialkyl methacrylate copolymers, methacrylate copolymers, and a combination thereof.
11. The modified release pharmaceutical composition according to claim 10, wherein the enteric polymer of the modified enteric coating is Eudragit L30D 55®.
12. The modified release pharmaceutical composition according to any one of claims 1 to 11, wherein the channeling agent is selected from the group consisting of:
hydrophilic excipients or hydrophilic polymers, comprising one or more of glucose, mannitol, lactose, xylitol, dextrose, sucrose and combinations thereof.
hydrophilic excipients or hydrophilic polymers, comprising one or more of glucose, mannitol, lactose, xylitol, dextrose, sucrose and combinations thereof.
13. The modified release pharmaceutical composition according to any one of claims 1 to 12, wherein the channeling agent is mannitol.
14. The modified release pharmaceutical composition according to any one of claims 1 to 13, wherein the modified enteric coating further comprises at least one pharmaceutically acceptable excipient.
15. The modified release pharmaceutical composition according to claim 14, wherein at least one pharmaceutically acceptable excipient is selected from the group consisting of:
binders, plasticizers, lubricants, disintegrants, diluents, glidants, anti-adherents and acidifying agents.
binders, plasticizers, lubricants, disintegrants, diluents, glidants, anti-adherents and acidifying agents.
16. The modified release pharmaceutical composition according to claim 15, wherein the plasticizer of the modified enteric coating is selected from the group consisting of:
diethylphthalate, dibutylphthalate, dibutylsebacate, tributyl citrate, triethyl citrate, acetyltributyl citrate, propylene glycols, glyceryl monostearate, and a combination thereof.
diethylphthalate, dibutylphthalate, dibutylsebacate, tributyl citrate, triethyl citrate, acetyltributyl citrate, propylene glycols, glyceryl monostearate, and a combination thereof.
17. The modified release pharmaceutical composition according to claim 15 or 16, wherein the plasticizer is triethyl citrate.
18. The modified release pharmaceutical composition according to any one of claims 15 to 17 wherein the anti-adherent is Plasacryl ®.
19. A modified release pharmaceutical composition comprising pellets containing one or more active ingredients, said pellets comprise: about 50 %w/w to about 90 %w/w of an inert core, about 2 %w/w to about 15 % w/w of a pharmaceutically active ingredient, about 1.0 %w/w to about 12.0 %w/w of an enteric polymer, about 0.1 %w/w to about 3.0 % w/w of a channeling agent, a hydrophilic binder, an anti-adherent, and a plasticizer, all based on the total weight of the modified release pharmaceutical composition.
20. A modified release pharmaceutical composition comprising pellets containing one or more active ingredients, said pellets comprising:
(a) an inert core;
(b) a first layer disposed over the inert core, said layer comprises at least one pharmaceutically active ingredient and at least one hydrophilic binder;
(c) a protective coating disposed over the first layer, said coating comprises a hydrophilic polymer and at least one pharmaceutically acceptable excipient;
and (d) a modified enteric coating disposed over the protective coating, said modified enteric coating comprises an enteric polymer, a channeling agent, and at least one pharmaceutically acceptable excipient, wherein said composition provides: a continuous release of the active ingredient at pH
less than pH 5.5, and a pulsatile release of the pharmaceutically active ingredient at pH
6.0 or more.
(a) an inert core;
(b) a first layer disposed over the inert core, said layer comprises at least one pharmaceutically active ingredient and at least one hydrophilic binder;
(c) a protective coating disposed over the first layer, said coating comprises a hydrophilic polymer and at least one pharmaceutically acceptable excipient;
and (d) a modified enteric coating disposed over the protective coating, said modified enteric coating comprises an enteric polymer, a channeling agent, and at least one pharmaceutically acceptable excipient, wherein said composition provides: a continuous release of the active ingredient at pH
less than pH 5.5, and a pulsatile release of the pharmaceutically active ingredient at pH
6.0 or more.
21. The modified release pharmaceutical composition according to claim 20, wherein said pellet further comprises a protective coating disposed over the first layer, in between the first layer and the modified enteric coating.
22. The modified release pharmaceutical composition according to any one of claims 20 to 21, wherein the hydrophilic polymer is selected from the group consisting of:
hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, hypromellose, and combinations thereof.
hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, hypromellose, and combinations thereof.
23. The modified release pharmaceutical composition according to claim 22, wherein the hydrophilic polymer of the protective coating is hypromellose.
24. The modified release pharmaceutical composition according to any one of claims 20 to 23, wherein one of pharmaceutically acceptable excipients is colloidal silicon dioxide.
25. The modified release pharmaceutical composition according to any one of claims 20 to 24 wherein the pharmaceutically active ingredient is selected from the group consisting of Amphetamine base salts.
26. The modified release pharmaceutical composition according to claim 25, wherein the amphetamine salts are selected from the group consisting of: amphetamine sulphate, dextroamphetamine sulphate, dextroamphetamine saccharate, amphetamine aspartate and mixtures thereof.
27. The modified release pharmaceutical composition according to any one of claims 20 to 26, wherein the inert core comprises at least one pharmaceutically acceptable excipient selected from the group consisting of: inert water soluble, inert water insoluble, swellable material and mixtures thereof.
28. The modified release pharmaceutical composition according to any one of claims 20 to 27, wherein inert core is made of sugar spheres.
29. The modified release pharmaceutical composition according to any one of claims 20 to 28, wherein the pellet further comprises a seal coat disposed between the inert core and the first layer.
30. The modified release pharmaceutical composition according to any one of claims 20 to 29, wherein the hydrophilic binder is selected from the group consisting of:
hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, hypromellose, and combinations thereof.
hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, hypromellose, and combinations thereof.
31. The modified release pharmaceutical composition according to any one of claims 20 to 30, wherein the hydrophilic binder is hypromellose.
32. The modified release pharmaceutical composition according to any one of claims 20 to 31, wherein the modified enteric coating comprises an enteric polymer selected from the group consisting of: ammonialkyl methacrylate copolymers, methacrylate copolymers, and combinations thereof.
33. The modified release pharmaceutical composition according to claim 32, wherein the enteric polymer of the modified enteric coating is Eudragit L3OD 55®.
34. The modified release pharmaceutical composition according to any one of claims 20 to 33, wherein the channeling agent is selected from the group consisting of:
hydrophilic excipients or hydrophilic polymers, comprising one or more of glucose, mannitol, lactose, xylitol, dextrose, sucrose and combinations thereof.
hydrophilic excipients or hydrophilic polymers, comprising one or more of glucose, mannitol, lactose, xylitol, dextrose, sucrose and combinations thereof.
35. The modified release pharmaceutical composition according to claim 34, wherein the channeling agent is mannitol.
36. The modified release pharmaceutical composition according to any one of claims 20 to 35, wherein one or more pharmaceutically acceptable excipients are selected from the group consisting of: binders, plasticizers, lubricants, disintegrants, diluents, glidants, anti-adherents and acidifying agents.
37. The modified release pharmaceutical composition according to claim 36, wherein the plasticizer of the modified enteric coating is selected from the group consisting of:
diethylphthalate, dibutylphthalate, dibutylsebacate, tributyl citrate, triethyl citrate, acetyltributyl citrate, propylene glycols, glyceryl monostearate, and a combination thereof.
diethylphthalate, dibutylphthalate, dibutylsebacate, tributyl citrate, triethyl citrate, acetyltributyl citrate, propylene glycols, glyceryl monostearate, and a combination thereof.
38. The modified release pharmaceutical composition according to claim 36 or 37, wherein the plasticizer is triethyl citrate.
39. The modified release pharmaceutical composition according to any one of claims 36 to 38 wherein the anti-adherent is Plasacryl®.
40. The modified release pharmaceutical composition for oral administration according to any one of claims 1 to 39, wherein the continuous release of the active ingredient at pH less than 5.5 and the pulsatile release of the active ingredient at pH 6.0 or more, is achieved from a single pellet.
41. A modified release pharmaceutical composition for oral administration according to claim 1, 19 or 20 wherein an in vitro dissolution provides:
- about 10% to about 40% of the mixed amphetamine salts is released after 60 min;
- about 40% to about 50% of the mixed amphetamine salts is released after 120 min;
- about 80% to about 100% of the mixed amphetamine salts is released after 180 min;
- about 100% of the mixed amphetamine salts is released after 240 min, as measured by USP Type II Apparatus(sinkers), with 750 ml of 0,08 N HCI for 2hrs and then 200ml of buffer concentrate added to make pH 6.0 for the next two hours, at 37 deg. C., at a paddle speed of 50 rpm.
- about 10% to about 40% of the mixed amphetamine salts is released after 60 min;
- about 40% to about 50% of the mixed amphetamine salts is released after 120 min;
- about 80% to about 100% of the mixed amphetamine salts is released after 180 min;
- about 100% of the mixed amphetamine salts is released after 240 min, as measured by USP Type II Apparatus(sinkers), with 750 ml of 0,08 N HCI for 2hrs and then 200ml of buffer concentrate added to make pH 6.0 for the next two hours, at 37 deg. C., at a paddle speed of 50 rpm.
42. A modified release pharmaceutical composition according to claim 1, 19 or wherein the in vitro dissolution profile of said composition provides at least 95% of the active ingredient dissolved within 4 hours, which is substantially the same as provided by an equivalent dose of Adderal ® XR, as measured by USP Type II
Apparatus(sinkers), with 750 ml of 0,08 N HCl for 2hrs and then 200ml of buffer concentrate added to make pH 6.0 for the next two hours, at 37 deg. C., at a paddle speed of 50 rpm.
Apparatus(sinkers), with 750 ml of 0,08 N HCl for 2hrs and then 200ml of buffer concentrate added to make pH 6.0 for the next two hours, at 37 deg. C., at a paddle speed of 50 rpm.
43. The modified release pharmaceutical composition according to any one of claims 1 to 42, wherein the pulsatile release provides a release of amphetamine salts from about 2 hours to about 4 hours after administration.
44. The modified release pharmaceutical composition according to any one of claims 1 to 43, wherein said composition is in the form of a capsule.
45. A method of manufacturing a modified release pharmaceutical composition of claim 1 or 19 which comprising:
(a) an inert core;
(b) a first layer disposed over the inert core, said layer comprises at least one pharmaceutically active ingredient and at least one hydrophilic binder; and (c) a modified enteric coating disposed over the first layer, said modified enteric coating comprises an enteric polymer and a channeling agent, wherein said composition provides: a continuous release of the pharmaceutically active ingredient at pH less than 5.5, and a pulsatile release of the pharmaceutically active ingredient at pH 6.0 or more.
(a) an inert core;
(b) a first layer disposed over the inert core, said layer comprises at least one pharmaceutically active ingredient and at least one hydrophilic binder; and (c) a modified enteric coating disposed over the first layer, said modified enteric coating comprises an enteric polymer and a channeling agent, wherein said composition provides: a continuous release of the pharmaceutically active ingredient at pH less than 5.5, and a pulsatile release of the pharmaceutically active ingredient at pH 6.0 or more.
46. A method of manufacturing a modified release pharmaceutical composition of claim 20, wherein the method comprises the following steps:
1) Drug layering:
a) loading sugar spheres or optionally seal coated pellets in a coating equipment;
b) dissolving the active ingredient;
c) mixing the active ingredient with a hydrophilic binder and at least one pharmaceutically acceptable excipient;
d) spraying solution comprising the active ingredient, a binder and at least one pharmaceutically acceptable excipient onto the sugar spheres or seal coated pellets to obtain a drug layered pellet;
2) Protective coating:
e) dissolving a hydrophilic polymer and at least one pharmaceutically acceptable excipient;
f) loading the drug layered pellets in a fluid bed processor;
g) coating drug layered pellets with solution of step (e) to obtain sub-coated pellets;
3) Modified enteric coating:
h) dissolving a channeling agent;
i) preparing a dispersion solution; adding an enteric polymer to solution of step (h);
j) adding at least one pharmaceutically acceptable excipient to solution of step (i);
k) loading sub-coated pellets in a fluid bed processor;
I) applying a solution of step (j) onto the sub-coated pellets of step (2) to obtain modified enteric coated pellets.
1) Drug layering:
a) loading sugar spheres or optionally seal coated pellets in a coating equipment;
b) dissolving the active ingredient;
c) mixing the active ingredient with a hydrophilic binder and at least one pharmaceutically acceptable excipient;
d) spraying solution comprising the active ingredient, a binder and at least one pharmaceutically acceptable excipient onto the sugar spheres or seal coated pellets to obtain a drug layered pellet;
2) Protective coating:
e) dissolving a hydrophilic polymer and at least one pharmaceutically acceptable excipient;
f) loading the drug layered pellets in a fluid bed processor;
g) coating drug layered pellets with solution of step (e) to obtain sub-coated pellets;
3) Modified enteric coating:
h) dissolving a channeling agent;
i) preparing a dispersion solution; adding an enteric polymer to solution of step (h);
j) adding at least one pharmaceutically acceptable excipient to solution of step (i);
k) loading sub-coated pellets in a fluid bed processor;
I) applying a solution of step (j) onto the sub-coated pellets of step (2) to obtain modified enteric coated pellets.
47. The method of manufacturing according to claim 46, wherein the layers are applied as a solution/ dispersion of coating ingredients.
48. The method of manufacturing according to any one of claims 45 to 47, wherein the active ingredient is selected from the group consisting of Amphetamine base salts.
49. The method of manufacturing according to claim 48, wherein the amphetamine salts are selected from the group consisting of: amphetamine sulphate, dextroamphetamine sulphate, dextroamphetamine saccharate, amphetamine aspartate and mixtures thereof.
50. The method of manufacturing according to any one of claims 45 to 49, wherein the inert core is made of a sugar spheres.
51. The method of manufacturing according to any one of claims 45 to 50, wherein the hydrophilic binder is selected from the group consisting of: hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, hypromellose, and combinations thereof.
52. The method of manufacturing according to claim 51, wherein the hydrophilic binder is hypromellose.
53. The method of manufacturing according to any one of claims 45 to 52, wherein the modified enteric coating comprises an enteric polymer selected from the group consisting of: ammonialkyl methacrylate copolymers, methacrylate copolymers, and combinations thereof.
54. The method of manufacturing according to claim 53, wherein the enteric polymer of the modified enteric coating is Eudragit L30D 55®.
55. The method of manufacturing according to any one of claims 45 to 54 wherein the channeling agent is selected from the group consisting of: hydrophilic excipients or hydrophilic polymers and comprising one or more of glucose, mannitol, lactose, xylitol, dextrose, sucrose and combinations thereof.
56. The method of manufacturing according to claim 56, wherein the channeling agent is mannitol.
57. The method of manufacturing according to any one of claims 45 to 56, wherein the modified enteric coating further comprises at least one pharmaceutically acceptable excipient.
58. The method of manufacturing according to claim 57, wherein at least one pharmaceutically acceptable excipient is selected from the group consisting of: binders, plasticizers, lubricants, disintegrants, diluents, glidants, anti-adherents and acidifying agents.
59. The method of manufacturing according to claim 58, wherein the plasticizer is selected from the group consisting of: diethylphthalate, dibutylphthalate, dibutylsebacate, tributyl citrate, triethyl citrate, acetyltributyl citrate, propylene glycols, glyceryl monostearate, and combinations thereof.
60. The method of manufacturing according to claim 59, wherein the plasticizer is triethyl citrate.
61. The method of manufacturing according to any one of claims 45 to 60, wherein the anti-adherent of the enteric coating is Plasacry®l.
62. The method of manufacturing according to claim 46, wherein said pellet further comprises a protective coating disposed over the first layer, in between the first layer and the modified enteric coating.
63. The method of manufacturing according to any one of claims 46 to 62, wherein said protective coating comprises a hydrophilic polymer and at least one pharmaceutically acceptable excipient.
64. The method of manufacturing according to any one of claims 46 to 63, wherein the hydrophilic polymer is selected from the group consisting of: hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, hypromellose, and combinations thereof.
65. The method of manufacturing according to claim 64, wherein the hydrophilic polymer of the protective coating is hypromellose.
66. The method of manufacturing according to any one of claims 46 to 65, wherein an anti-adherent of the protective coating is colloidal silicon dioxide.
67. A method of manufacturing of a modified release pharmaceutical composition comprising pellets containing one or more active ingredients, said pellets comprises:
about 50 %w/w to about 90 %w/w of an inert core, about 2 %w/w to about 15 %
w/w of a pharmaceutically active ingredient, about 1.0 %w/w to about 12.0 %w/w of an enteric polymer, about 0.1 %w/w to about 3.0 % w/w of a channeling agent, a hydrophilic binder, a hydrophilic polymer, an anti-adherent, a Plasacryl®, and a plasticizer, all based on the total weight of the modified release pharmaceutical composition.
about 50 %w/w to about 90 %w/w of an inert core, about 2 %w/w to about 15 %
w/w of a pharmaceutically active ingredient, about 1.0 %w/w to about 12.0 %w/w of an enteric polymer, about 0.1 %w/w to about 3.0 % w/w of a channeling agent, a hydrophilic binder, a hydrophilic polymer, an anti-adherent, a Plasacryl®, and a plasticizer, all based on the total weight of the modified release pharmaceutical composition.
68. Use of a therapeutically effective amount of Amphetamine mixed salts, for the preparation of a modified release pharmaceutical composition according to any one of claims 1 to 45 for the treatment of narcolepsy and Attention-Deficit/Hyperactivity Disorder (ADHD).
69. Use of the modified release pharmaceutical composition according to any one of claims 1 to 45 for the treatment of narcolepsy and Attention-Deficit/Hyperactivity Disorder (ADHD) in human.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA2758556A CA2758556A1 (en) | 2011-11-17 | 2011-11-17 | Pharmaceutical composition of amphetamine mixed salts |
| PCT/CA2012/001067 WO2013071421A1 (en) | 2011-11-17 | 2012-11-16 | Pharmaceutical composition of amphetamine mixed salts |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA2758556A CA2758556A1 (en) | 2011-11-17 | 2011-11-17 | Pharmaceutical composition of amphetamine mixed salts |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2758556A1 true CA2758556A1 (en) | 2013-05-17 |
Family
ID=48428888
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2758556A Abandoned CA2758556A1 (en) | 2011-11-17 | 2011-11-17 | Pharmaceutical composition of amphetamine mixed salts |
Country Status (2)
| Country | Link |
|---|---|
| CA (1) | CA2758556A1 (en) |
| WO (1) | WO2013071421A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9545399B2 (en) | 2012-08-15 | 2017-01-17 | Tris Pharma, Inc. | Methylphenidate extended release chewable tablet |
| US9675704B2 (en) | 2006-03-16 | 2017-06-13 | Tris Pharma, Inc. | Modified release formulations containing drug-ion exchange resin complexes |
| US11590081B1 (en) | 2017-09-24 | 2023-02-28 | Tris Pharma, Inc | Extended release amphetamine tablets |
| US11590228B1 (en) | 2015-09-08 | 2023-02-28 | Tris Pharma, Inc | Extended release amphetamine compositions |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR102467968B1 (en) * | 2014-10-08 | 2022-11-16 | 신세틱 바이오로직스, 인코퍼레이티드 | Beta-lactamase formulations and uses thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8707416D0 (en) * | 1987-03-27 | 1987-04-29 | Wellcome Found | Pharmaceutical formulations |
| US20010055613A1 (en) * | 1998-10-21 | 2001-12-27 | Beth A. Burnside | Oral pulsed dose drug delivery system |
| IL130602A0 (en) * | 1999-06-22 | 2000-06-01 | Dexcel Ltd | Stable benzimidazole formulation |
| IN192159B (en) * | 2000-05-15 | 2004-02-28 | Ranbaxy Lab Ltd | |
| US20080020041A1 (en) * | 2004-10-19 | 2008-01-24 | Ayres James W | Enteric Coated Compositions that Release Active Ingredient(s) in Gastric Fluid and Intestinal Fluid |
| CN102791258B (en) * | 2010-02-03 | 2018-05-08 | 图必制药公司 | Alleviating prolongation delivery formulations of Rasagiline and application thereof |
| US20110229564A1 (en) * | 2010-03-22 | 2011-09-22 | Amneal Pharmaceuticals, L.L.C. | Pharmaceutical Compositions Of Carvedilol Salts And Process For Preparation Thereof |
-
2011
- 2011-11-17 CA CA2758556A patent/CA2758556A1/en not_active Abandoned
-
2012
- 2012-11-16 WO PCT/CA2012/001067 patent/WO2013071421A1/en active Application Filing
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10086087B2 (en) | 2006-03-16 | 2018-10-02 | Tris Pharma, Inc. | Modified release formulations containing drug-ion exchange resin complexes |
| US9675704B2 (en) | 2006-03-16 | 2017-06-13 | Tris Pharma, Inc. | Modified release formulations containing drug-ion exchange resin complexes |
| US9675703B2 (en) | 2006-03-16 | 2017-06-13 | Tris Pharma, Inc | Modified release formulations containing drug - ion exchange resin complexes |
| US10507203B2 (en) | 2012-08-15 | 2019-12-17 | Tris Pharma, Inc | Methylphenidate extended release chewable tablet |
| US9844544B2 (en) | 2012-08-15 | 2017-12-19 | Tris Pharma, Inc | Methylphenidate extended release chewable tablet |
| US9844545B2 (en) | 2012-08-15 | 2017-12-19 | Tris Pharma, Inc. | Methylphenidate extended release chewable tablet |
| US9545399B2 (en) | 2012-08-15 | 2017-01-17 | Tris Pharma, Inc. | Methylphenidate extended release chewable tablet |
| US10857143B2 (en) | 2012-08-15 | 2020-12-08 | Tris Pharma, Inc | Methylphenidate extended release chewable tablet |
| US11103495B2 (en) | 2012-08-15 | 2021-08-31 | Tris Pharma, Inc | Methylphenidate extended release chewable tablet |
| US11103494B2 (en) | 2012-08-15 | 2021-08-31 | Tris Pharma, Inc | Methylphenidate extended release chewable tablet |
| US11633389B2 (en) | 2012-08-15 | 2023-04-25 | Tris Pharma, Inc | Methylphenidate extended release chewable tablet |
| US11590228B1 (en) | 2015-09-08 | 2023-02-28 | Tris Pharma, Inc | Extended release amphetamine compositions |
| US11590081B1 (en) | 2017-09-24 | 2023-02-28 | Tris Pharma, Inc | Extended release amphetamine tablets |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2013071421A1 (en) | 2013-05-23 |
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