NZ749512B2 - Compositions and methods for the treatment of cancer - Google Patents
Compositions and methods for the treatment of cancer Download PDFInfo
- Publication number
- NZ749512B2 NZ749512B2 NZ749512A NZ74951217A NZ749512B2 NZ 749512 B2 NZ749512 B2 NZ 749512B2 NZ 749512 A NZ749512 A NZ 749512A NZ 74951217 A NZ74951217 A NZ 74951217A NZ 749512 B2 NZ749512 B2 NZ 749512B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- formula
- ghmatters
- compositions
- administration
- cancer
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title abstract description 226
- 201000011510 cancer Diseases 0.000 title abstract description 37
- 150000001875 compounds Chemical class 0.000 claims abstract description 73
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 28
- 239000006188 syrup Substances 0.000 claims abstract description 13
- 235000020357 syrup Nutrition 0.000 claims abstract description 13
- 239000007924 injection Substances 0.000 claims abstract description 10
- 238000007911 parenteral administration Methods 0.000 claims abstract description 10
- 230000000699 topical Effects 0.000 claims abstract description 10
- 238000002347 injection Methods 0.000 claims abstract description 9
- 229940100688 Oral Solution Drugs 0.000 claims abstract description 4
- 239000003814 drug Substances 0.000 claims description 69
- 230000003111 delayed Effects 0.000 claims description 38
- 239000003937 drug carrier Substances 0.000 claims description 17
- 206010017758 Gastric cancer Diseases 0.000 claims description 6
- 201000011549 stomach cancer Diseases 0.000 claims description 6
- 230000002459 sustained Effects 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 4
- 201000011231 colorectal cancer Diseases 0.000 claims description 4
- 201000000849 skin cancer Diseases 0.000 claims description 4
- 206010061424 Anal cancer Diseases 0.000 claims description 3
- 208000004818 Bowen's Disease Diseases 0.000 claims description 3
- 208000008443 Pancreatic Carcinoma Diseases 0.000 claims description 3
- 201000011165 anus cancer Diseases 0.000 claims description 3
- 201000002528 pancreatic cancer Diseases 0.000 claims description 3
- 239000003826 tablet Substances 0.000 abstract description 98
- 239000012453 solvate Substances 0.000 abstract description 20
- 150000004677 hydrates Chemical class 0.000 abstract description 19
- 239000007921 spray Substances 0.000 abstract description 11
- 238000001990 intravenous administration Methods 0.000 abstract description 7
- 239000007937 lozenge Substances 0.000 abstract description 6
- 206010028980 Neoplasm Diseases 0.000 abstract description 3
- 208000006641 Skin Disease Diseases 0.000 abstract description 3
- 201000008325 diseases of cellular proliferation Diseases 0.000 abstract description 3
- 238000000576 coating method Methods 0.000 description 62
- 239000011248 coating agent Substances 0.000 description 61
- 229940079593 drugs Drugs 0.000 description 60
- -1 rectal Substances 0.000 description 51
- 239000000463 material Substances 0.000 description 48
- 239000002552 dosage form Substances 0.000 description 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 43
- 239000003795 chemical substances by application Substances 0.000 description 38
- 239000010410 layer Substances 0.000 description 36
- 239000011780 sodium chloride Substances 0.000 description 35
- 235000002639 sodium chloride Nutrition 0.000 description 35
- 239000000243 solution Substances 0.000 description 32
- 150000003839 salts Chemical class 0.000 description 31
- 229920000642 polymer Polymers 0.000 description 30
- 239000000843 powder Substances 0.000 description 30
- 201000010099 disease Diseases 0.000 description 29
- 239000000314 lubricant Substances 0.000 description 27
- 230000003204 osmotic Effects 0.000 description 26
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 24
- 239000011324 bead Substances 0.000 description 23
- 239000000651 prodrug Substances 0.000 description 23
- 229940002612 prodrugs Drugs 0.000 description 23
- 229920002472 Starch Polymers 0.000 description 22
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 22
- 235000019698 starch Nutrition 0.000 description 22
- 239000004480 active ingredient Substances 0.000 description 21
- 239000003085 diluting agent Substances 0.000 description 21
- 239000008187 granular material Substances 0.000 description 21
- 238000000034 method Methods 0.000 description 20
- 239000011230 binding agent Substances 0.000 description 18
- 239000010408 film Substances 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 229920001223 polyethylene glycol Polymers 0.000 description 17
- 239000007787 solid Substances 0.000 description 17
- 239000011159 matrix material Substances 0.000 description 16
- 239000002245 particle Substances 0.000 description 16
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 16
- 230000001225 therapeutic Effects 0.000 description 16
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 15
- 229960001375 Lactose Drugs 0.000 description 15
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 15
- 229920002678 cellulose Polymers 0.000 description 15
- 239000001913 cellulose Substances 0.000 description 15
- 239000007884 disintegrant Substances 0.000 description 15
- 239000008101 lactose Substances 0.000 description 15
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 15
- 229940016286 microcrystalline cellulose Drugs 0.000 description 15
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 15
- 239000008108 microcrystalline cellulose Substances 0.000 description 15
- 239000000454 talc Substances 0.000 description 15
- 235000012222 talc Nutrition 0.000 description 15
- 229910052623 talc Inorganic materials 0.000 description 15
- 239000002775 capsule Substances 0.000 description 14
- 235000010980 cellulose Nutrition 0.000 description 13
- 238000007906 compression Methods 0.000 description 13
- 239000000945 filler Substances 0.000 description 13
- 239000007788 liquid Substances 0.000 description 13
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 13
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- 239000003981 vehicle Substances 0.000 description 13
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 12
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 12
- 235000019359 magnesium stearate Nutrition 0.000 description 12
- 239000012528 membrane Substances 0.000 description 12
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- 239000005720 sucrose Substances 0.000 description 12
- 235000000346 sugar Nutrition 0.000 description 12
- 108010010803 Gelatin Proteins 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 11
- 239000002671 adjuvant Substances 0.000 description 11
- 230000000240 adjuvant Effects 0.000 description 11
- 239000000969 carrier Substances 0.000 description 11
- 239000012530 fluid Substances 0.000 description 11
- 238000009472 formulation Methods 0.000 description 11
- 239000008273 gelatin Substances 0.000 description 11
- 229920000159 gelatin Polymers 0.000 description 11
- 235000019322 gelatine Nutrition 0.000 description 11
- 235000011852 gelatine desserts Nutrition 0.000 description 11
- 239000001993 wax Substances 0.000 description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- 241000282414 Homo sapiens Species 0.000 description 10
- 239000002202 Polyethylene glycol Substances 0.000 description 10
- 229940032147 Starch Drugs 0.000 description 10
- 239000000853 adhesive Substances 0.000 description 10
- 230000001070 adhesive Effects 0.000 description 10
- 229920001577 copolymer Polymers 0.000 description 10
- 235000019441 ethanol Nutrition 0.000 description 10
- 235000011187 glycerol Nutrition 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 229920001477 hydrophilic polymer Polymers 0.000 description 10
- 239000008107 starch Substances 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- 239000000443 aerosol Substances 0.000 description 9
- 230000002354 daily Effects 0.000 description 9
- 229920000609 methyl cellulose Polymers 0.000 description 9
- 235000010981 methylcellulose Nutrition 0.000 description 9
- 239000001923 methylcellulose Substances 0.000 description 9
- 235000021251 pulses Nutrition 0.000 description 9
- 229920003176 water-insoluble polymer Polymers 0.000 description 9
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2R,3R,4S,5R,6S)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2S,3R,4S,5R,6R)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2R,3R,4S,5R,6R)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 8
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 8
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 8
- 240000007472 Leucaena leucocephala Species 0.000 description 8
- 229960002900 Methylcellulose Drugs 0.000 description 8
- XAPRFLSJBSXESP-UHFFFAOYSA-N Oxycinchophen Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=C(O)C=1C1=CC=CC=C1 XAPRFLSJBSXESP-UHFFFAOYSA-N 0.000 description 8
- 229960004063 Propylene glycol Drugs 0.000 description 8
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 8
- 235000010443 alginic acid Nutrition 0.000 description 8
- 229920000615 alginic acid Polymers 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000007891 compressed tablet Substances 0.000 description 8
- 239000006185 dispersion Substances 0.000 description 8
- 239000000796 flavoring agent Substances 0.000 description 8
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 8
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 8
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 235000013772 propylene glycol Nutrition 0.000 description 8
- 239000004094 surface-active agent Substances 0.000 description 8
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 description 7
- 241000416162 Astragalus gummifer Species 0.000 description 7
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 7
- 229920001615 Tragacanth Polymers 0.000 description 7
- 229940116362 Tragacanth Drugs 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 239000001768 carboxy methyl cellulose Substances 0.000 description 7
- 230000001419 dependent Effects 0.000 description 7
- 235000014113 dietary fatty acids Nutrition 0.000 description 7
- 239000000194 fatty acid Substances 0.000 description 7
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 7
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 7
- 239000004615 ingredient Substances 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 239000000546 pharmaceutic aid Substances 0.000 description 7
- 239000004014 plasticizer Substances 0.000 description 7
- 239000003380 propellant Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 239000000829 suppository Substances 0.000 description 7
- 239000007916 tablet composition Substances 0.000 description 7
- 235000010487 tragacanth Nutrition 0.000 description 7
- 239000000196 tragacanth Substances 0.000 description 7
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-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 description 7
- 229920001817 Agar Polymers 0.000 description 6
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 6
- POULHZVOKOAJMA-UHFFFAOYSA-N Lauric acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 6
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 6
- 210000003491 Skin Anatomy 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 235000010419 agar Nutrition 0.000 description 6
- 239000002131 composite material Substances 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 6
- 235000010355 mannitol Nutrition 0.000 description 6
- 239000000594 mannitol Substances 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 239000011148 porous material Substances 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 238000005550 wet granulation Methods 0.000 description 6
- VVQNEPGJFQJSBK-UHFFFAOYSA-N 2-methyl-2-propenoic acid methyl ester Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 5
- GHASVSINZRGABV-UHFFFAOYSA-N 5-flurouricil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 5
- 229920002301 Cellulose acetate Polymers 0.000 description 5
- 229920002785 Croscarmellose sodium Polymers 0.000 description 5
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 5
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 5
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 5
- 239000001856 Ethyl cellulose Substances 0.000 description 5
- 229960002949 Fluorouracil Drugs 0.000 description 5
- RMAQACBXLXPBSY-UHFFFAOYSA-N Silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 5
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 5
- 229940081735 acetylcellulose Drugs 0.000 description 5
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 5
- 235000012216 bentonite Nutrition 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 239000001506 calcium phosphate Substances 0.000 description 5
- 239000003086 colorant Substances 0.000 description 5
- 238000009792 diffusion process Methods 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- 235000019325 ethyl cellulose Nutrition 0.000 description 5
- 229920001249 ethyl cellulose Polymers 0.000 description 5
- 238000011049 filling Methods 0.000 description 5
- 235000019634 flavors Nutrition 0.000 description 5
- 239000008079 hexane Substances 0.000 description 5
- 230000002503 metabolic Effects 0.000 description 5
- CERQOIWHTDAKMF-UHFFFAOYSA-N methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 5
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid group Chemical group C(CCCCCCC\C=C/CCCCCCCC)(=O)O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 5
- 239000004006 olive oil Substances 0.000 description 5
- 239000006187 pill Substances 0.000 description 5
- 229920002451 polyvinyl alcohol Polymers 0.000 description 5
- 239000003755 preservative agent Substances 0.000 description 5
- 230000002829 reduced Effects 0.000 description 5
- 229920003109 sodium starch glycolate Polymers 0.000 description 5
- 239000008109 sodium starch glycolate Substances 0.000 description 5
- 229940079832 sodium starch glycolate Drugs 0.000 description 5
- 235000010356 sorbitol Nutrition 0.000 description 5
- 239000000600 sorbitol Substances 0.000 description 5
- 238000005507 spraying Methods 0.000 description 5
- 150000008163 sugars Chemical class 0.000 description 5
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 4
- 239000005995 Aluminium silicate Substances 0.000 description 4
- PZZYQPZGQPZBDN-UHFFFAOYSA-N Aluminium silicate Chemical compound O=[Al]O[Si](=O)O[Al]=O PZZYQPZGQPZBDN-UHFFFAOYSA-N 0.000 description 4
- CJZGTCYPCWQAJB-UHFFFAOYSA-L Calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 4
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 4
- 229940105329 Carboxymethylcellulose Drugs 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- BJHIKXHVCXFQLS-UYFOZJQFSA-N Fructose Natural products OC[C@@H](O)[C@@H](O)[C@H](O)C(=O)CO BJHIKXHVCXFQLS-UYFOZJQFSA-N 0.000 description 4
- 229920002907 Guar gum Polymers 0.000 description 4
- 229940067606 Lecithin Drugs 0.000 description 4
- 229920001283 Polyalkylene terephthalate Polymers 0.000 description 4
- 235000021355 Stearic acid Nutrition 0.000 description 4
- RWQNBRDOKXIBIV-UHFFFAOYSA-N Thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 4
- QORWJWZARLRLPR-UHFFFAOYSA-H Tricalcium phosphate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 4
- HWKQNAWCHQMZHK-UHFFFAOYSA-N Trolnitrate Chemical compound [O-][N+](=O)OCCN(CCO[N+]([O-])=O)CCO[N+]([O-])=O HWKQNAWCHQMZHK-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 239000008272 agar Substances 0.000 description 4
- 235000012211 aluminium silicate Nutrition 0.000 description 4
- 239000000440 bentonite Substances 0.000 description 4
- 229910000278 bentonite Inorganic materials 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 239000008116 calcium stearate Substances 0.000 description 4
- 235000013539 calcium stearate Nutrition 0.000 description 4
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 4
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 4
- 239000004203 carnauba wax Substances 0.000 description 4
- 235000013869 carnauba wax Nutrition 0.000 description 4
- 239000004359 castor oil Substances 0.000 description 4
- 229940110456 cocoa butter Drugs 0.000 description 4
- 235000019868 cocoa butter Nutrition 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000007907 direct compression Methods 0.000 description 4
- 238000007908 dry granulation Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 150000004665 fatty acids Chemical class 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 239000007903 gelatin capsule Substances 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 125000005456 glyceride group Chemical group 0.000 description 4
- 235000010417 guar gum Nutrition 0.000 description 4
- 239000000665 guar gum Substances 0.000 description 4
- 229960002154 guar gum Drugs 0.000 description 4
- 238000007918 intramuscular administration Methods 0.000 description 4
- 235000010445 lecithin Nutrition 0.000 description 4
- 239000000787 lecithin Substances 0.000 description 4
- 230000003278 mimic Effects 0.000 description 4
- 238000000465 moulding Methods 0.000 description 4
- 235000008390 olive oil Nutrition 0.000 description 4
- 210000000056 organs Anatomy 0.000 description 4
- 239000003182 parenteral nutrition solution Substances 0.000 description 4
- 235000010987 pectin Nutrition 0.000 description 4
- 229920001277 pectin Polymers 0.000 description 4
- 239000001814 pectin Substances 0.000 description 4
- 229920001296 polysiloxane Polymers 0.000 description 4
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 4
- 230000002335 preservative Effects 0.000 description 4
- 239000008159 sesame oil Substances 0.000 description 4
- 235000011803 sesame oil Nutrition 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 239000007909 solid dosage form Substances 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- 239000008117 stearic acid Substances 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 4
- 235000015112 vegetable and seed oil Nutrition 0.000 description 4
- 239000008158 vegetable oil Substances 0.000 description 4
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-Dimethylaminophenol Substances CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- 244000215068 Acacia senegal Species 0.000 description 3
- 229920002126 Acrylic acid copolymer Polymers 0.000 description 3
- XJKJWTWGDGIQRH-BFIDDRIFSA-N Alginic acid Chemical compound O1[C@@H](C(O)=O)[C@@H](OC)[C@H](O)[C@H](O)[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](C)[C@@H](O)[C@H]1O XJKJWTWGDGIQRH-BFIDDRIFSA-N 0.000 description 3
- FMDFMIMQUYUJBM-UHFFFAOYSA-N C(C)(=O)OC1C(OCC1OC(C)=O)C Chemical compound C(C)(=O)OC1C(OCC1OC(C)=O)C FMDFMIMQUYUJBM-UHFFFAOYSA-N 0.000 description 3
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 3
- 229920001661 Chitosan Polymers 0.000 description 3
- LVGKNOAMLMIIKO-QXMHVHEDSA-N Ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 3
- 210000000887 Face Anatomy 0.000 description 3
- 229920000084 Gum arabic Polymers 0.000 description 3
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 3
- 239000005639 Lauric acid Substances 0.000 description 3
- 229920002774 Maltodextrin Polymers 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 208000008466 Metabolic Disease Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 229920000881 Modified starch Polymers 0.000 description 3
- 229920001800 Shellac Polymers 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- JNYAEWCLZODPBN-CTQIIAAMSA-N Sorbitan Chemical class OCC(O)C1OCC(O)[C@@H]1O JNYAEWCLZODPBN-CTQIIAAMSA-N 0.000 description 3
- DCXXMTOCNZCJGO-UHFFFAOYSA-N Stearin Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 3
- 240000000280 Theobroma cacao Species 0.000 description 3
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 3
- 235000010489 acacia gum Nutrition 0.000 description 3
- 239000000205 acacia gum Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 3
- 239000011149 active material Substances 0.000 description 3
- 239000003463 adsorbent Substances 0.000 description 3
- 239000000783 alginic acid Substances 0.000 description 3
- 229960001126 alginic acid Drugs 0.000 description 3
- 230000000111 anti-oxidant Effects 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 125000004429 atoms Chemical group 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 239000006172 buffering agent Substances 0.000 description 3
- 235000019438 castor oil Nutrition 0.000 description 3
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 3
- 238000005056 compaction Methods 0.000 description 3
- 239000002285 corn oil Substances 0.000 description 3
- 239000002385 cottonseed oil Substances 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 3
- 239000008121 dextrose Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 235000013399 edible fruits Nutrition 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 229940093471 ethyl oleate Drugs 0.000 description 3
- 239000003925 fat Substances 0.000 description 3
- 235000019197 fats Nutrition 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 235000013355 food flavoring agent Nutrition 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
- 230000002496 gastric Effects 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 239000000416 hydrocolloid Substances 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 230000002209 hydrophobic Effects 0.000 description 3
- 238000010348 incorporation Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000000391 magnesium silicate Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 238000001690 micro-dialysis Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000006072 paste Substances 0.000 description 3
- 239000000312 peanut oil Substances 0.000 description 3
- 230000035699 permeability Effects 0.000 description 3
- 229920001888 polyacrylic acid Polymers 0.000 description 3
- 229920000728 polyester Polymers 0.000 description 3
- 229920005862 polyol Polymers 0.000 description 3
- 150000003077 polyols Chemical class 0.000 description 3
- 235000019814 powdered cellulose Nutrition 0.000 description 3
- 229920003124 powdered cellulose Polymers 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000001294 propane Substances 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N rac-1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 3
- 239000011342 resin composition Substances 0.000 description 3
- 239000004208 shellac Substances 0.000 description 3
- 229940113147 shellac Drugs 0.000 description 3
- 235000013874 shellac Nutrition 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- 238000009491 slugging Methods 0.000 description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 239000002600 sunflower oil Substances 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- 230000002522 swelling Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000002194 synthesizing Effects 0.000 description 3
- 210000001519 tissues Anatomy 0.000 description 3
- 150000003626 triacylglycerols Chemical class 0.000 description 3
- 239000001069 triethyl citrate Substances 0.000 description 3
- 235000013769 triethyl citrate Nutrition 0.000 description 3
- 229920002554 vinyl polymer Polymers 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- OMDQUFIYNPYJFM-XKDAHURESA-N (2R,3R,4S,5R,6S)-2-(hydroxymethyl)-6-[[(2R,3S,4R,5S,6R)-4,5,6-trihydroxy-3-[(2S,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]methoxy]oxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O[C@H]2[C@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@H](O)[C@H](O)O1 OMDQUFIYNPYJFM-XKDAHURESA-N 0.000 description 2
- DBTMGCOVALSLOR-DEVYUCJPSA-N (2S,3R,4S,5R,6R)-4-[(2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-6-(hydroxymethyl)oxane-2,3,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](CO)O[C@H](O)[C@@H]2O)O)O[C@H](CO)[C@H]1O DBTMGCOVALSLOR-DEVYUCJPSA-N 0.000 description 2
- RPZANUYHRMRTTE-UHFFFAOYSA-N 2,3,4-trimethoxy-6-(methoxymethyl)-5-[3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxyoxane;1-[[3,4,5-tris(2-hydroxybutoxy)-6-[4,5,6-tris(2-hydroxybutoxy)-2-(2-hydroxybutoxymethyl)oxan-3-yl]oxyoxan-2-yl]methoxy]butan-2-ol Chemical compound COC1C(OC)C(OC)C(COC)OC1OC1C(OC)C(OC)C(OC)OC1COC.CCC(O)COC1C(OCC(O)CC)C(OCC(O)CC)C(COCC(O)CC)OC1OC1C(OCC(O)CC)C(OCC(O)CC)C(OCC(O)CC)OC1COCC(O)CC RPZANUYHRMRTTE-UHFFFAOYSA-N 0.000 description 2
- CWSZBVAUYPTXTG-UHFFFAOYSA-N 5-[6-[[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxymethyl]-3,4-dihydroxy-5-[4-hydroxy-3-(2-hydroxyethoxy)-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxyoxan-2-yl]oxy-6-(hydroxymethyl)-2-methyloxane-3,4-diol Chemical compound O1C(CO)C(OC)C(O)C(O)C1OCC1C(OC2C(C(O)C(OC)C(CO)O2)OCCO)C(O)C(O)C(OC2C(OC(C)C(O)C2O)CO)O1 CWSZBVAUYPTXTG-UHFFFAOYSA-N 0.000 description 2
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 2
- WNROFYMDJYEPJX-UHFFFAOYSA-K Aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N Benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- 210000004369 Blood Anatomy 0.000 description 2
- 235000017399 Caesalpinia tinctoria Nutrition 0.000 description 2
- 229960003563 Calcium Carbonate Drugs 0.000 description 2
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 2
- 229960004117 Capecitabine Drugs 0.000 description 2
- 229940063834 Carboxymethylcellulose Sodium Drugs 0.000 description 2
- 229940113118 Carrageenan Drugs 0.000 description 2
- 210000003169 Central Nervous System Anatomy 0.000 description 2
- 229920002101 Chitin Polymers 0.000 description 2
- DJHJJVWPFGHIPH-OODMECLYSA-N Chitin Chemical compound O[C@@H]1C(NC(=O)C)[C@H](O)OC(CO)[C@H]1COC[C@H]1C(NC(C)=O)[C@@H](O)[C@H](COC[C@H]2C([C@@H](O)[C@H](O)C(CO)O2)NC(C)=O)C(CO)O1 DJHJJVWPFGHIPH-OODMECLYSA-N 0.000 description 2
- 230000037242 Cmax Effects 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- NEFBYIFKOOEVPA-UHFFFAOYSA-K Dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 2
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 2
- PXBRQCKWGAHEHS-UHFFFAOYSA-N Dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 229920003134 Eudragit® polymer Polymers 0.000 description 2
- 230000036081 Excretion rate Effects 0.000 description 2
- 239000005715 Fructose Substances 0.000 description 2
- 229920000926 Galactomannan Polymers 0.000 description 2
- 241000237858 Gastropoda Species 0.000 description 2
- 241000206672 Gelidium Species 0.000 description 2
- 229920002148 Gellan gum Polymers 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000004705 High-molecular-weight polyethylene Substances 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 2
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 description 2
- 230000035809 INACTIVATION RATE Effects 0.000 description 2
- 229920001202 Inulin Polymers 0.000 description 2
- JYJIGFIDKWBXDU-MNNPPOADSA-N Inulin Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)OC[C@]1(OC[C@]2(OC[C@]3(OC[C@]4(OC[C@]5(OC[C@]6(OC[C@]7(OC[C@]8(OC[C@]9(OC[C@]%10(OC[C@]%11(OC[C@]%12(OC[C@]%13(OC[C@]%14(OC[C@]%15(OC[C@]%16(OC[C@]%17(OC[C@]%18(OC[C@]%19(OC[C@]%20(OC[C@]%21(OC[C@]%22(OC[C@]%23(OC[C@]%24(OC[C@]%25(OC[C@]%26(OC[C@]%27(OC[C@]%28(OC[C@]%29(OC[C@]%30(OC[C@]%31(OC[C@]%32(OC[C@]%33(OC[C@]%34(OC[C@]%35(OC[C@]%36(O[C@@H]%37[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O%37)O)[C@H]([C@H](O)[C@@H](CO)O%36)O)[C@H]([C@H](O)[C@@H](CO)O%35)O)[C@H]([C@H](O)[C@@H](CO)O%34)O)[C@H]([C@H](O)[C@@H](CO)O%33)O)[C@H]([C@H](O)[C@@H](CO)O%32)O)[C@H]([C@H](O)[C@@H](CO)O%31)O)[C@H]([C@H](O)[C@@H](CO)O%30)O)[C@H]([C@H](O)[C@@H](CO)O%29)O)[C@H]([C@H](O)[C@@H](CO)O%28)O)[C@H]([C@H](O)[C@@H](CO)O%27)O)[C@H]([C@H](O)[C@@H](CO)O%26)O)[C@H]([C@H](O)[C@@H](CO)O%25)O)[C@H]([C@H](O)[C@@H](CO)O%24)O)[C@H]([C@H](O)[C@@H](CO)O%23)O)[C@H]([C@H](O)[C@@H](CO)O%22)O)[C@H]([C@H](O)[C@@H](CO)O%21)O)[C@H]([C@H](O)[C@@H](CO)O%20)O)[C@H]([C@H](O)[C@@H](CO)O%19)O)[C@H]([C@H](O)[C@@H](CO)O%18)O)[C@H]([C@H](O)[C@@H](CO)O%17)O)[C@H]([C@H](O)[C@@H](CO)O%16)O)[C@H]([C@H](O)[C@@H](CO)O%15)O)[C@H]([C@H](O)[C@@H](CO)O%14)O)[C@H]([C@H](O)[C@@H](CO)O%13)O)[C@H]([C@H](O)[C@@H](CO)O%12)O)[C@H]([C@H](O)[C@@H](CO)O%11)O)[C@H]([C@H](O)[C@@H](CO)O%10)O)[C@H]([C@H](O)[C@@H](CO)O9)O)[C@H]([C@H](O)[C@@H](CO)O8)O)[C@H]([C@H](O)[C@@H](CO)O7)O)[C@H]([C@H](O)[C@@H](CO)O6)O)[C@H]([C@H](O)[C@@H](CO)O5)O)[C@H]([C@H](O)[C@@H](CO)O4)O)[C@H]([C@H](O)[C@@H](CO)O3)O)[C@H]([C@H](O)[C@@H](CO)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 JYJIGFIDKWBXDU-MNNPPOADSA-N 0.000 description 2
- 229940029339 Inulin Drugs 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 2
- 229920001543 Laminarin Polymers 0.000 description 2
- 239000005717 Laminarin Substances 0.000 description 2
- 210000003750 Lower Gastrointestinal Tract Anatomy 0.000 description 2
- 239000005913 Maltodextrin Substances 0.000 description 2
- GUBGYTABKSRVRQ-YOLKTULGSA-N Maltose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)O[C@H]1CO)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 GUBGYTABKSRVRQ-YOLKTULGSA-N 0.000 description 2
- 230000035888 Maximum plasma concentration Effects 0.000 description 2
- 235000016247 Mentha requienii Nutrition 0.000 description 2
- 235000002899 Mentha suaveolens Nutrition 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinylpyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 2
- 240000008962 Nicotiana tabacum Species 0.000 description 2
- 229960002715 Nicotine Drugs 0.000 description 2
- SNICXCGAKADSCV-JTQLQIEISA-N Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 2
- 229960002969 Oleic Acid Drugs 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- 229940067631 Phospholipids Drugs 0.000 description 2
- 210000002381 Plasma Anatomy 0.000 description 2
- 229920001225 Polyester resin Polymers 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- 229940068965 Polysorbates Drugs 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- 229920002305 Schizophyllan Polymers 0.000 description 2
- FEBUJFMRSBAMES-UHFFFAOYSA-N Scleroglucan Chemical compound OC1C(O)C(O)C(CO)OC1OCC1C(O)C(OC2C(C(OP)C(O)C(CO)O2)O)C(O)C(OC2C(C(CO)OC(P)C2O)O)O1 FEBUJFMRSBAMES-UHFFFAOYSA-N 0.000 description 2
- 239000004147 Sorbitan trioleate Substances 0.000 description 2
- 229960000391 Sorbitan trioleate Drugs 0.000 description 2
- 235000019486 Sunflower oil Nutrition 0.000 description 2
- FKHIFSZMMVMEQY-UHFFFAOYSA-N Talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 2
- 241000388430 Tara Species 0.000 description 2
- 235000009470 Theobroma cacao Nutrition 0.000 description 2
- 229940113082 Thymine Drugs 0.000 description 2
- 230000036201 Tissue concentration Effects 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N Triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- 229960002622 Triacetin Drugs 0.000 description 2
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K Trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- 240000006365 Vitis vinifera Species 0.000 description 2
- 235000014787 Vitis vinifera Nutrition 0.000 description 2
- 241000209149 Zea Species 0.000 description 2
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 2
- 229940093612 Zein Drugs 0.000 description 2
- 229920002494 Zein Polymers 0.000 description 2
- PRXRUNOAOLTIEF-XDTJCZEISA-N [2-[(2R,3S,4R)-4-hydroxy-3-[(Z)-octadec-9-enoyl]oxyoxolan-2-yl]-2-[(Z)-octadec-9-enoyl]oxyethyl] (Z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@@H](O)[C@@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-XDTJCZEISA-N 0.000 description 2
- 230000035507 absorption Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 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 2
- NIXOWILDQLNWCW-UHFFFAOYSA-M acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 2
- 230000001058 adult Effects 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminum Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 235000006682 bigleaf mint Nutrition 0.000 description 2
- 238000004166 bioassay Methods 0.000 description 2
- 229920001400 block copolymer Polymers 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000036760 body temperature Effects 0.000 description 2
- IJDNQMDRQITEOD-UHFFFAOYSA-N butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 235000010216 calcium carbonate Nutrition 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Inorganic materials [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 230000000271 cardiovascular Effects 0.000 description 2
- 235000010418 carrageenan Nutrition 0.000 description 2
- 229920001525 carrageenan Polymers 0.000 description 2
- 239000000679 carrageenan Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 239000008199 coating composition Substances 0.000 description 2
- 235000005822 corn Nutrition 0.000 description 2
- 235000005824 corn Nutrition 0.000 description 2
- 235000005687 corn oil Nutrition 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 235000012343 cottonseed oil Nutrition 0.000 description 2
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 2
- 230000004059 degradation Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- 229940038472 dicalcium phosphate Drugs 0.000 description 2
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 2
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 230000002708 enhancing Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 235000013312 flour Nutrition 0.000 description 2
- 230000004907 flux Effects 0.000 description 2
- 239000011888 foil Substances 0.000 description 2
- 230000002068 genetic Effects 0.000 description 2
- 201000002406 genetic disease Diseases 0.000 description 2
- 150000004676 glycans Polymers 0.000 description 2
- 229940075507 glyceryl monostearate Drugs 0.000 description 2
- 239000001087 glyceryl triacetate Substances 0.000 description 2
- 235000013773 glyceryl triacetate Nutrition 0.000 description 2
- 230000002489 hematologic Effects 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 2
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 2
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 2
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 230000004941 influx Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Chemical compound [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 2
- 235000019793 magnesium trisilicate Nutrition 0.000 description 2
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 2
- 229940099273 magnesium trisilicate Drugs 0.000 description 2
- 229940035034 maltodextrin Drugs 0.000 description 2
- 150000002734 metacrylic acid derivatives Chemical class 0.000 description 2
- CERQOIWHTDAKMF-UHFFFAOYSA-M methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 2
- 235000006679 mint Nutrition 0.000 description 2
- 235000019426 modified starch Nutrition 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- 229930015196 nicotine Natural products 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 235000021313 oleic acid Nutrition 0.000 description 2
- 230000000399 orthopedic Effects 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 235000019271 petrolatum Nutrition 0.000 description 2
- 239000008024 pharmaceutical diluent Substances 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
- 239000000049 pigment Substances 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 229920000233 poly(alkylene oxides) Polymers 0.000 description 2
- 229920000058 polyacrylate Polymers 0.000 description 2
- 229920001515 polyalkylene glycol Polymers 0.000 description 2
- 229920001610 polycaprolactone Polymers 0.000 description 2
- 239000004645 polyester resin Substances 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 150000004804 polysaccharides Polymers 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 229920002689 polyvinyl acetate Polymers 0.000 description 2
- 239000011118 polyvinyl acetate Substances 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 230000002035 prolonged Effects 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 2
- 230000000268 renotropic Effects 0.000 description 2
- 230000000241 respiratory Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 150000004760 silicates Chemical class 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- 239000008247 solid mixture Substances 0.000 description 2
- 238000007614 solvation Methods 0.000 description 2
- 235000019337 sorbitan trioleate Nutrition 0.000 description 2
- 239000003549 soybean oil Substances 0.000 description 2
- 238000001694 spray drying Methods 0.000 description 2
- 238000007910 systemic administration Methods 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 229920001169 thermoplastic Polymers 0.000 description 2
- 239000004416 thermosoftening plastic Substances 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- ZFOZVQLOBQUTQQ-UHFFFAOYSA-N tributyl 2-hydroxypropane-1,2,3-tricarboxylate Chemical compound CCCCOC(=O)CC(O)(C(=O)OCCCC)CC(=O)OCCCC ZFOZVQLOBQUTQQ-UHFFFAOYSA-N 0.000 description 2
- 235000019731 tricalcium phosphate Nutrition 0.000 description 2
- 239000011778 trisodium citrate Substances 0.000 description 2
- 235000019263 trisodium citrate Nutrition 0.000 description 2
- 239000000341 volatile oil Substances 0.000 description 2
- 229920003169 water-soluble polymer Polymers 0.000 description 2
- 229920001285 xanthan gum Polymers 0.000 description 2
- 239000005019 zein Substances 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- 229920000160 (ribonucleotides)n+m Polymers 0.000 description 1
- BOSAWIQFTJIYIS-UHFFFAOYSA-N 1,1,1-Trichloro-2,2,2-trifluoroethane Chemical compound FC(F)(F)C(Cl)(Cl)Cl BOSAWIQFTJIYIS-UHFFFAOYSA-N 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N 1,2,3-propanetrioltrinitrate Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- DCBSHORRWZKAKO-UHFFFAOYSA-N 1-monomyristoylglycerol Chemical compound CCCCCCCCCCCCCC(=O)OCC(O)CO DCBSHORRWZKAKO-UHFFFAOYSA-N 0.000 description 1
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- 239000000263 2,3-dihydroxypropyl (Z)-octadec-9-enoate Substances 0.000 description 1
- HDIFHQMREAYYJW-XGXNLDPDSA-N 2,3-dihydroxypropyl (Z,12R)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCC[C@@H](O)C\C=C/CCCCCCCC(=O)OCC(O)CO HDIFHQMREAYYJW-XGXNLDPDSA-N 0.000 description 1
- HJRDNARELSKHEF-CLFAGFIQSA-N 2-[2-[(Z)-octadec-9-enoyl]oxyethoxy]ethyl (Z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCCOCCOC(=O)CCCCCCC\C=C/CCCCCCCC HJRDNARELSKHEF-CLFAGFIQSA-N 0.000 description 1
- JNODDICFTDYODH-UHFFFAOYSA-N 2-hydroxytetrahydrofuran Chemical compound OC1CCCO1 JNODDICFTDYODH-UHFFFAOYSA-N 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N 2-stearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- YJISHJVIRFPGGN-UHFFFAOYSA-N 5-[5-[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxy-6-[[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxymethyl]-3,4-dihydroxyoxan-2-yl]oxy-6-(hydroxymethyl)-2-methyloxane-3,4-diol Chemical compound O1C(CO)C(OC)C(O)C(O)C1OCC1C(OC2C(C(O)C(OC)C(CO)O2)O)C(O)C(O)C(OC2C(OC(C)C(O)C2O)CO)O1 YJISHJVIRFPGGN-UHFFFAOYSA-N 0.000 description 1
- XLBPCYDDWIMTFH-UHFFFAOYSA-N 6-amino-1-fluoropyrimidin-2-one Chemical compound NC1=CC=NC(=O)N1F XLBPCYDDWIMTFH-UHFFFAOYSA-N 0.000 description 1
- 229960000583 Acetic Acid Drugs 0.000 description 1
- 208000009621 Actinic Keratosis Diseases 0.000 description 1
- 229940063655 Aluminum stearate Drugs 0.000 description 1
- 244000144725 Amygdalus communis Species 0.000 description 1
- 239000004382 Amylase Substances 0.000 description 1
- 102000013142 Amylases Human genes 0.000 description 1
- 108010065511 Amylases Proteins 0.000 description 1
- 240000005781 Arachis hypogaea Species 0.000 description 1
- 206010003119 Arrhythmia Diseases 0.000 description 1
- 229920003084 Avicel® PH-102 Polymers 0.000 description 1
- 229960000686 Benzalkonium Chloride Drugs 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BJQHLKABXJIVAM-UHFFFAOYSA-N Bis(2-ethylhexyl) phthalate Chemical compound CCCCC(CC)COC(=O)C1=CC=CC=C1C(=O)OCC(CC)CCCC BJQHLKABXJIVAM-UHFFFAOYSA-N 0.000 description 1
- 210000001124 Body Fluids Anatomy 0.000 description 1
- 210000000481 Breast Anatomy 0.000 description 1
- 229940043253 Butylated Hydroxyanisole Drugs 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N Butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- DJIRRVMQWKTPKX-UHFFFAOYSA-M COC(CC1COCC1CC(=O)[O-])=O Chemical compound COC(CC1COCC1CC(=O)[O-])=O DJIRRVMQWKTPKX-UHFFFAOYSA-M 0.000 description 1
- HRKLXZWNEKWBMF-UHFFFAOYSA-M COC(CCCCCCCCCCCC1COCC1CCCCCCCCCCCC(=O)[O-])=O Chemical compound COC(CCCCCCCCCCCC1COCC1CCCCCCCCCCCC(=O)[O-])=O HRKLXZWNEKWBMF-UHFFFAOYSA-M 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N C[N+](C)(C)CCO Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960005069 Calcium Drugs 0.000 description 1
- 229940073532 Candelilla Wax Drugs 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 206010007521 Cardiac arrhythmias Diseases 0.000 description 1
- 208000005846 Cardiomyopathy Diseases 0.000 description 1
- 235000014036 Castanea Nutrition 0.000 description 1
- 241001070941 Castanea Species 0.000 description 1
- WZNRVWBKYDHTKI-UHFFFAOYSA-N Cellulose, acetate 1,2,4-benzenetricarboxylate Chemical compound OC1C(O)C(O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O.OC1C(O)C(O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O.CC(=O)OCC1OC(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(COC(C)=O)O1.CC(=O)OCC1OC(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(COC(C)=O)O1.OC(=O)C1=CC(C(=O)O)=CC=C1C(=O)OCC1C(OC2C(C(OC(=O)C=3C(=CC(=CC=3)C(O)=O)C(O)=O)C(OC(=O)C=3C(=CC(=CC=3)C(O)=O)C(O)=O)C(COC(=O)C=3C(=CC(=CC=3)C(O)=O)C(O)=O)O2)OC(=O)C=2C(=CC(=CC=2)C(O)=O)C(O)=O)C(OC(=O)C=2C(=CC(=CC=2)C(O)=O)C(O)=O)C(OC(=O)C=2C(=CC(=CC=2)C(O)=O)C(O)=O)C(OC(=O)C=2C(=CC(=CC=2)C(O)=O)C(O)=O)O1 WZNRVWBKYDHTKI-UHFFFAOYSA-N 0.000 description 1
- 235000013912 Ceratonia siliqua Nutrition 0.000 description 1
- 240000008886 Ceratonia siliqua Species 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N Cetyl alcohol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 229960001927 Cetylpyridinium Chloride Drugs 0.000 description 1
- YMKDRGPMQRFJGP-UHFFFAOYSA-M Cetylpyridinium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 YMKDRGPMQRFJGP-UHFFFAOYSA-M 0.000 description 1
- 229960001231 Choline Drugs 0.000 description 1
- 244000223760 Cinnamomum zeylanicum Species 0.000 description 1
- 235000004310 Cinnamomum zeylanicum Nutrition 0.000 description 1
- 235000008733 Citrus aurantifolia Nutrition 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 240000002268 Citrus limon Species 0.000 description 1
- 235000013162 Cocos nucifera Nutrition 0.000 description 1
- 240000007170 Cocos nucifera Species 0.000 description 1
- 240000007154 Coffea arabica Species 0.000 description 1
- 235000010205 Cola acuminata Nutrition 0.000 description 1
- 240000001644 Cola acuminata Species 0.000 description 1
- 210000001072 Colon Anatomy 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000002528 Coronary Thrombosis Diseases 0.000 description 1
- 206010011091 Coronary artery thrombosis Diseases 0.000 description 1
- 241000723382 Corylus Species 0.000 description 1
- 235000007466 Corylus avellana Nutrition 0.000 description 1
- 229960001681 Croscarmellose Sodium Drugs 0.000 description 1
- 229960000913 Crospovidone Drugs 0.000 description 1
- UNXHWFMMPAWVPI-QWWZWVQMSA-N D-Threitol Natural products OC[C@@H](O)[C@H](O)CO UNXHWFMMPAWVPI-QWWZWVQMSA-N 0.000 description 1
- 229940099371 DIACETYLATED MONOGLYCERIDES Drugs 0.000 description 1
- 229940039227 DIAGNOSTIC AGENTS Drugs 0.000 description 1
- 208000007322 Death, Sudden, Cardiac Diseases 0.000 description 1
- 229940096516 Dextrates Drugs 0.000 description 1
- DOIRQSBPFJWKBE-UHFFFAOYSA-N Dibutyl phthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 description 1
- YUXIBTJKHLUKBD-UHFFFAOYSA-N Dibutyl succinate Chemical compound CCCCOC(=O)CCC(=O)OCCCC YUXIBTJKHLUKBD-UHFFFAOYSA-N 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- FLKPEMZONWLCSK-UHFFFAOYSA-N Diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N Diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- NIQCNGHVCWTJSM-UHFFFAOYSA-N Dimethyl phthalate Chemical compound COC(=O)C1=CC=CC=C1C(=O)OC NIQCNGHVCWTJSM-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 229960001484 Edetic Acid Drugs 0.000 description 1
- 230000035695 Efflux Effects 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- 229940009714 Erythritol Drugs 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N Erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- 240000000437 Eucalyptus leucoxylon Species 0.000 description 1
- 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 1
- 235000010705 Eucalyptus maculata Nutrition 0.000 description 1
- 235000009683 Eucalyptus polybractea Nutrition 0.000 description 1
- 235000009687 Eucalyptus sargentii Nutrition 0.000 description 1
- 229940012356 Eye Drops Drugs 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 235000016623 Fragaria vesca Nutrition 0.000 description 1
- 240000009088 Fragaria x ananassa Species 0.000 description 1
- 235000011363 Fragaria x ananassa Nutrition 0.000 description 1
- 229940068939 GLYCERYL MONOLAURATE Drugs 0.000 description 1
- 208000008665 Gastrointestinal Disease Diseases 0.000 description 1
- 210000001035 Gastrointestinal Tract Anatomy 0.000 description 1
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N Glyceryl behenate Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 description 1
- FETSQPAGYOVAQU-UHFFFAOYSA-N Glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 description 1
- UYXTWWCETRIEDR-UHFFFAOYSA-N Glyceryl tributyrate Chemical compound CCCC(=O)OCC(OC(=O)CCC)COC(=O)CCC UYXTWWCETRIEDR-UHFFFAOYSA-N 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 235000006200 Glycyrrhiza glabra Nutrition 0.000 description 1
- 240000005389 Glycyrrhiza glabra Species 0.000 description 1
- 229940031574 HYDROXYMETHYL CELLULOSE Drugs 0.000 description 1
- 210000003128 Head Anatomy 0.000 description 1
- IUJAMGNYPWYUPM-UHFFFAOYSA-N Hentriacontane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCC IUJAMGNYPWYUPM-UHFFFAOYSA-N 0.000 description 1
- 229920001612 Hydroxyethyl starch Polymers 0.000 description 1
- 208000001019 Inborn Errors Metabolism Diseases 0.000 description 1
- 206010062018 Inborn error of metabolism Diseases 0.000 description 1
- NNPPMTNAJDCUHE-UHFFFAOYSA-N Isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 1
- QWTDNUCVQCZILF-UHFFFAOYSA-N Isopentane Chemical compound CCC(C)C QWTDNUCVQCZILF-UHFFFAOYSA-N 0.000 description 1
- AXISYYRBXTVTFY-UHFFFAOYSA-N Isopropyl myristate Chemical compound CCCCCCCCCCCCCC(=O)OC(C)C AXISYYRBXTVTFY-UHFFFAOYSA-N 0.000 description 1
- 241000758791 Juglandaceae Species 0.000 description 1
- 235000014852 L-arginine Nutrition 0.000 description 1
- MTCFGRXMJLQNBG-REOHCLBHSA-N L-serine Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- 229960004873 LEVOMENTHOL Drugs 0.000 description 1
- 229960000448 Lactic acid Drugs 0.000 description 1
- 230000035832 Lag time Effects 0.000 description 1
- 230000035648 Lag-time Effects 0.000 description 1
- 229920000161 Locust bean gum Polymers 0.000 description 1
- 210000002751 Lymph Anatomy 0.000 description 1
- 229920002521 Macromolecule Polymers 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L Magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L Magnesium hydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N Malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N Maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 229940041616 Menthol Drugs 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- 230000036740 Metabolism Effects 0.000 description 1
- 206010061289 Metastatic neoplasm Diseases 0.000 description 1
- 210000004080 Milk Anatomy 0.000 description 1
- ARIWANIATODDMH-UHFFFAOYSA-N Monolaurin Chemical compound CCCCCCCCCCCC(=O)OCC(O)CO ARIWANIATODDMH-UHFFFAOYSA-N 0.000 description 1
- 210000000214 Mouth Anatomy 0.000 description 1
- 229920000715 Mucilage Polymers 0.000 description 1
- 210000003097 Mucus Anatomy 0.000 description 1
- 206010053643 Neurodegenerative disease Diseases 0.000 description 1
- 241000208125 Nicotiana Species 0.000 description 1
- 229940074730 OPHTHAMOLOGIC DIAGNOSTIC AGENTS Drugs 0.000 description 1
- 229940100467 POLYVINYL ACETATE PHTHALATE Drugs 0.000 description 1
- 229940066842 Petrolatum Drugs 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- 235000012550 Pimpinella anisum Nutrition 0.000 description 1
- 240000004760 Pimpinella anisum Species 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 239000004698 Polyethylene (PE) Substances 0.000 description 1
- 229940068918 Polyethylene Glycol 400 Drugs 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 229960003975 Potassium Drugs 0.000 description 1
- QEEAPRPFLLJWCF-UHFFFAOYSA-K Potassium citrate Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
- 229940069328 Povidone Drugs 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 201000001068 Prinzmetal angina Diseases 0.000 description 1
- 108010009736 Protein Hydrolysates Proteins 0.000 description 1
- 239000004373 Pullulan Substances 0.000 description 1
- 229920001218 Pullulan Polymers 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 229940100618 Rectal Suppository Drugs 0.000 description 1
- 240000001890 Ribes hudsonianum Species 0.000 description 1
- 235000016954 Ribes hudsonianum Nutrition 0.000 description 1
- 235000001466 Ribes nigrum Nutrition 0.000 description 1
- 240000007651 Rubus glaucus Species 0.000 description 1
- 235000011034 Rubus glaucus Nutrition 0.000 description 1
- 235000009122 Rubus idaeus Nutrition 0.000 description 1
- 239000004783 Serene Substances 0.000 description 1
- 229940083037 Simethicone Drugs 0.000 description 1
- CXQXSVUQTKDNFP-UHFFFAOYSA-N Simethicone Chemical compound C[Si](C)(C)O[Si](C)(C)O[Si](C)(C)C CXQXSVUQTKDNFP-UHFFFAOYSA-N 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 240000001016 Solanum tuberosum Species 0.000 description 1
- 229940075582 Sorbic Acid Drugs 0.000 description 1
- 239000004163 Spermaceti wax Substances 0.000 description 1
- GLDOVTGHNKAZLK-UHFFFAOYSA-N Stearyl alcohol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 1
- 210000002784 Stomach Anatomy 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 206010049418 Sudden cardiac death Diseases 0.000 description 1
- 229940072958 TETRAHYDROFURFURYL OLEATE Drugs 0.000 description 1
- 108060008443 TPPP Proteins 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- 235000015450 Tilia cordata Nutrition 0.000 description 1
- 235000011941 Tilia x europaea Nutrition 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N Trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940035893 Uracil Drugs 0.000 description 1
- 235000009499 Vanilla fragrans Nutrition 0.000 description 1
- 240000006722 Vanilla planifolia Species 0.000 description 1
- 235000012036 Vanilla tahitensis Nutrition 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Vitamin C Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 235000010724 Wisteria floribunda Nutrition 0.000 description 1
- GJCOSYZMQJWQCA-UHFFFAOYSA-N Xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-UHFFFAOYSA-N 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N Xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 Xylitol Drugs 0.000 description 1
- 235000006886 Zingiber officinale Nutrition 0.000 description 1
- 240000007329 Zingiber officinale Species 0.000 description 1
- NWGKJDSIEKMTRX-HSACVWGTSA-N [(2R)-2-[(2R,3R,4S)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] (E)-octadec-9-enoate Chemical compound CCCCCCCC\C=C\CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-HSACVWGTSA-N 0.000 description 1
- LWZFANDGMFTDAV-BURFUSLBSA-N [(2R)-2-[(2R,3R,4S)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O LWZFANDGMFTDAV-BURFUSLBSA-N 0.000 description 1
- ZNOZWUKQPJXOIG-XSBHQQIPSA-L [(2R,3S,4R,5R,6S)-6-[[(1R,3S,4R,5R,8S)-3,4-dihydroxy-2,6-dioxabicyclo[3.2.1]octan-8-yl]oxy]-4-[[(1R,3R,4R,5R,8S)-8-[(2S,3R,4R,5R,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-sulfonatooxyoxan-2-yl]oxy-4-hydroxy-2,6-dioxabicyclo[3.2.1]octan-3-yl]oxy]-5-hydroxy-2-( Chemical compound O[C@@H]1[C@@H](O)[C@@H](OS([O-])(=O)=O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H]2OC[C@H]1O[C@H](O[C@H]1[C@H]([C@@H](CO)O[C@@H](O[C@@H]3[C@@H]4OC[C@H]3O[C@H](O)[C@@H]4O)[C@@H]1O)OS([O-])(=O)=O)[C@@H]2O ZNOZWUKQPJXOIG-XSBHQQIPSA-L 0.000 description 1
- JLPULHDHAOZNQI-ZNEZQZEFSA-N [3-hexadecanoyloxy-2-[(9E,12E)-octadeca-9,12-dienoyl]oxypropyl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC JLPULHDHAOZNQI-ZNEZQZEFSA-N 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000003655 absorption accelerator Substances 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000002730 additional Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 230000000172 allergic Effects 0.000 description 1
- 235000020224 almond Nutrition 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 235000019418 amylase Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000259 anti-tumor Effects 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- 229940027983 antiseptics and disinfectants Quaternary ammonium compounds Drugs 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 125000000751 azo group Chemical group [*]N=N[*] 0.000 description 1
- 230000001580 bacterial Effects 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 229940092738 beeswax Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- SXFILQHETIJGQZ-UHFFFAOYSA-N but-3-enoic acid;phthalic acid Chemical compound OC(=O)CC=C.OC(=O)C1=CC=CC=C1C(O)=O SXFILQHETIJGQZ-UHFFFAOYSA-N 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- PUPZLCDOIYMWBV-UHFFFAOYSA-N butylene glycol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- 239000004204 candelilla wax Substances 0.000 description 1
- 235000013868 candelilla wax Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atoms Chemical group C* 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 201000008031 cardiomyopathy Diseases 0.000 description 1
- 230000001451 cardiotoxic Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 235000019219 chocolate Nutrition 0.000 description 1
- 230000001684 chronic Effects 0.000 description 1
- 235000017803 cinnamon Nutrition 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 229910052570 clay Inorganic materials 0.000 description 1
- 235000016213 coffee Nutrition 0.000 description 1
- 235000013353 coffee beverage Nutrition 0.000 description 1
- 235000020057 cognac Nutrition 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 201000002547 conjunctival squamous cell carcinoma Diseases 0.000 description 1
- 239000000599 controlled substance Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000005712 crystallization Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000007950 delayed release tablet Substances 0.000 description 1
- 229920003013 deoxyribonucleic acid Polymers 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- JAUGGEIKQIHSMF-UHFFFAOYSA-N dialuminum;dimagnesium;dioxido(oxo)silane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O.[O-][Si]([O-])=O JAUGGEIKQIHSMF-UHFFFAOYSA-N 0.000 description 1
- PWZFXELTLAQOKC-UHFFFAOYSA-A dialuminum;hexamagnesium;carbonate;hexadecahydroxide;tetrahydrate Chemical compound O.O.O.O.[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-]C([O-])=O PWZFXELTLAQOKC-UHFFFAOYSA-A 0.000 description 1
- 239000000385 dialysis solution Substances 0.000 description 1
- PYGXAGIECVVIOZ-UHFFFAOYSA-N dibutyl decanedioate Chemical compound CCCCOC(=O)CCCCCCCCC(=O)OCCCC PYGXAGIECVVIOZ-UHFFFAOYSA-N 0.000 description 1
- 229940031954 dibutyl sebacate Drugs 0.000 description 1
- 229960002097 dibutylsuccinate Drugs 0.000 description 1
- 229940042935 dichlorodifluoromethane Drugs 0.000 description 1
- IEPRKVQEAMIZSS-AATRIKPKSA-N diethyl fumarate Chemical compound CCOC(=O)\C=C\C(=O)OCC IEPRKVQEAMIZSS-AATRIKPKSA-N 0.000 description 1
- VKNUORWMCINMRB-UHFFFAOYSA-N diethyl malate Chemical compound CCOC(=O)CC(O)C(=O)OCC VKNUORWMCINMRB-UHFFFAOYSA-N 0.000 description 1
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 229960001826 dimethylphthalate Drugs 0.000 description 1
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 239000002706 dry binder Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 235000020673 eicosapentaenoic acid Nutrition 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 230000005684 electric field Effects 0.000 description 1
- 238000005370 electroosmosis Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 230000002255 enzymatic Effects 0.000 description 1
- 230000003628 erosive Effects 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- 239000000686 essence Substances 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- SUPCQIBBMFXVTL-UHFFFAOYSA-N ethyl 2-methylprop-2-enoate Chemical compound CCOC(=O)C(C)=C SUPCQIBBMFXVTL-UHFFFAOYSA-N 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-M ethyl carbonate Chemical compound CCOC([O-])=O CQDGTJPVBWZJAZ-UHFFFAOYSA-M 0.000 description 1
- 229960004667 ethyl cellulose Drugs 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- 235000001612 eucalyptus Nutrition 0.000 description 1
- 235000001617 eucalyptus Nutrition 0.000 description 1
- 235000001621 eucalyptus Nutrition 0.000 description 1
- 235000006356 eucalyptus Nutrition 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 239000003885 eye ointment Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 235000015203 fruit juice Nutrition 0.000 description 1
- 201000002146 gastrointestinal system disease Diseases 0.000 description 1
- 235000010492 gellan gum Nutrition 0.000 description 1
- 239000000216 gellan gum Substances 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 235000013531 gin Nutrition 0.000 description 1
- 235000008397 ginger Nutrition 0.000 description 1
- 229940049654 glyceryl behenate Drugs 0.000 description 1
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 description 1
- 229940074050 glyceryl myristate Drugs 0.000 description 1
- 229940046813 glyceryl palmitostearate Drugs 0.000 description 1
- 229960003711 glyceryl trinitrate Drugs 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 235000009754 grape Nutrition 0.000 description 1
- 235000012333 grape Nutrition 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000002440 hepatic Effects 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 239000010514 hydrogenated cottonseed oil Substances 0.000 description 1
- 235000019866 hydrogenated palm kernel oil Nutrition 0.000 description 1
- 239000008173 hydrogenated soybean oil Substances 0.000 description 1
- 229910001701 hydrotalcite Inorganic materials 0.000 description 1
- 229960001545 hydrotalcite Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000001341 hydroxy propyl starch Substances 0.000 description 1
- 229940050526 hydroxyethylstarch Drugs 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 235000013828 hydroxypropyl starch Nutrition 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000002757 inflammatory Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002664 inhalation therapy Methods 0.000 description 1
- 201000002450 inherited metabolic disease Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000266 injurious Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 239000001282 iso-butane Substances 0.000 description 1
- 229940074928 isopropyl myristate Drugs 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 229960000829 kaolin Drugs 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 238000010030 laminating Methods 0.000 description 1
- 229940094522 laponite Drugs 0.000 description 1
- 150000002605 large molecules Chemical class 0.000 description 1
- 125000000400 lauroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000014063 licorice root Nutrition 0.000 description 1
- 239000004571 lime Substances 0.000 description 1
- 230000000670 limiting Effects 0.000 description 1
- 235000011477 liquorice Nutrition 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 235000010420 locust bean gum Nutrition 0.000 description 1
- 239000000711 locust bean gum Substances 0.000 description 1
- 150000004668 long chain fatty acids Chemical class 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 239000011776 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- 235000012243 magnesium silicates Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000003211 malignant Effects 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 230000001404 mediated Effects 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000035786 metabolism Effects 0.000 description 1
- 230000001394 metastastic Effects 0.000 description 1
- 125000005395 methacrylic acid group Chemical group 0.000 description 1
- NXMXPVQZFYYPGD-UHFFFAOYSA-N methyl 2-methylprop-2-enoate;methyl prop-2-enoate Chemical compound COC(=O)C=C.COC(=O)C(C)=C NXMXPVQZFYYPGD-UHFFFAOYSA-N 0.000 description 1
- 125000004492 methyl ester group Chemical group 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 239000004200 microcrystalline wax Substances 0.000 description 1
- 235000019808 microcrystalline wax Nutrition 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 239000000025 natural resin Substances 0.000 description 1
- 230000001264 neutralization Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 230000003000 nontoxic Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 235000014571 nuts Nutrition 0.000 description 1
- REEZZSHJLXOIHL-UHFFFAOYSA-N octanoyl chloride Chemical compound CCCCCCCC(Cl)=O REEZZSHJLXOIHL-UHFFFAOYSA-N 0.000 description 1
- 125000001117 oleyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 125000006353 oxyethylene group Chemical group 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 235000019809 paraffin wax Nutrition 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 235000020232 peanut Nutrition 0.000 description 1
- 229960000292 pectin Drugs 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000002093 peripheral Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 239000011528 polyamide (building material) Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000001508 potassium citrate Substances 0.000 description 1
- 229960002635 potassium citrate Drugs 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000012254 powdered material Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N propylene oxide Chemical group CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective Effects 0.000 description 1
- 239000011253 protective coating Substances 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 230000000541 pulsatile Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 230000001698 pyrogenic Effects 0.000 description 1
- 239000006215 rectal suppository Substances 0.000 description 1
- 235000005227 red mallee Nutrition 0.000 description 1
- 230000001846 repelling Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 238000009490 roller compaction Methods 0.000 description 1
- 102220240796 rs553605556 Human genes 0.000 description 1
- 239000005060 rubber Substances 0.000 description 1
- 235000013533 rum Nutrition 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000012176 shellac wax Substances 0.000 description 1
- 235000020046 sherry Nutrition 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 231100000245 skin permeability Toxicity 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- WSWCOQWTEOXDQX-UHFFFAOYSA-N sorbic acid Chemical compound CC=CC=CC(O)=O WSWCOQWTEOXDQX-UHFFFAOYSA-N 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 235000019385 spermaceti wax Nutrition 0.000 description 1
- 238000005563 spheronization Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical class CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 1
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940012831 stearyl alcohol Drugs 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000001954 sterilising Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 235000020238 sunflower seed Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000013616 tea Nutrition 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 125000002640 tocopherol group Chemical group 0.000 description 1
- 235000019149 tocopherols Nutrition 0.000 description 1
- 229930003799 tocopherols Natural products 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- ILJSQTXMGCGYMG-UHFFFAOYSA-M triacetate(1-) Chemical compound CC(=O)CC(=O)CC([O-])=O ILJSQTXMGCGYMG-UHFFFAOYSA-M 0.000 description 1
- QZCLKYGREBVARF-UHFFFAOYSA-N tributyl 2-acetyloxypropane-1,2,3-tricarboxylate Chemical compound CCCCOC(=O)CC(C(=O)OCCCC)(OC(C)=O)CC(=O)OCCCC QZCLKYGREBVARF-UHFFFAOYSA-N 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- WEAPVABOECTMGR-UHFFFAOYSA-N triethyl 2-acetyloxypropane-1,2,3-tricarboxylate Chemical compound CCOC(=O)CC(C(=O)OCC)(OC(C)=O)CC(=O)OCC WEAPVABOECTMGR-UHFFFAOYSA-N 0.000 description 1
- 239000011791 tripotassium citrate Substances 0.000 description 1
- 235000015870 tripotassium citrate Nutrition 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 239000005418 vegetable material Substances 0.000 description 1
- XTXRWKRVRITETP-UHFFFAOYSA-N vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
- 229940117958 vinyl acetate Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 235000020234 walnut Nutrition 0.000 description 1
- 238000007601 warm air drying Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 235000015041 whisky Nutrition 0.000 description 1
- 235000014101 wine Nutrition 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 239000010457 zeolite Substances 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 235000014692 zinc oxide Nutrition 0.000 description 1
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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
Abstract
The invention relates to the compounds or its pharmaceutical acceptable polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula VI may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, lozenge, spray, intravenous, oral solution, buccal mucosal layer tablet, parenteral administration, syrup, or injection. Such compositions may be used to treat cancer, neoplasm, and skin diseases. ransmucosal, lozenge, spray, intravenous, oral solution, buccal mucosal layer tablet, parenteral administration, syrup, or injection. Such compositions may be used to treat cancer, neoplasm, and skin diseases.
Description
(12) Granted patent specificaon (19) NZ (11) 749512 (13) B2
(47) Publicaon date: 2021.12.24
(54) COMPOSITIONS AND METHODS FOR THE TREATMENT OF CANCER
(51) Internaonal Patent Classificaon(s):
A61K 31/505 A61K 31/506 A61P 31/00 C07H 19/06 C07H 19/067
(22) Filing date: (73) Owner(s):
2017.05.12 CELLIX BIO PRIVATE LIMITED
(23) Complete specificaon filing date: (74) Contact:
2017.05.12 Eagar & Associates Pty Ltd
(30) Internaonal Priority Data: (72) Inventor(s):
IN 201641022026 2016.06.28 KANDULA, Mahesh
IN 201641025259 2016.07.22
IN 201741006185 2017.02.21
(86) Internaonal Applicaon No.:
(87) Internaonal Publicaon number:
WO/2018/002739
(57) Abstract:
The invenon relates to the compounds or its pharmaceucal acceptable polymorphs, solvates,
enanomers, stereoisomers and hydrates thereof. The pharmaceucal composions comprising
an effecve amount of compounds of formula VI may be formulated for oral, buccal, rectal, topical,
transdermal, transmucosal, lozenge, spray, intravenous, oral soluon, buccal mucosal layer tablet,
parenteral administraon, syrup, or injecon. Such composions may be used to treat cancer,
neoplasm, and skin diseases.
NZ 749512 B2
COMPOSITIONS AND METHODS FOR THE TREATMENT
OF CANCER
PRIORITY
The present application claims the benefit Indian Provisional Patent Application No.
201641022026 filed on 28-June-2016, Indian Provisional Patent Application No.
201641025259 filed on 22-July-2016 and Indian Provisional Patent Application No.
201741006185 filed on 21- February-2017 the entire disclosure of which is relied on for all
purposes and is incorporated into this application by reference.
FIELD OF THE INVENTION
This disclosure generally relates to compounds and compositions for the treatment of
cancer. More particularly, this invention relates to treating subjects with a pharmaceutically
acceptable dose of compounds, crystals, solvates, enantiomer, stereoisomer, esters, salts,
hydrates, prodrugs, or mixtures thereof.
BACKGROUND OF THE INVENTION
The 5-Fluorouracil (5-FU) is still a widely used anticancer drug. Since 1957, it has
played an important role in the treatment of colon cancer and is used for patients with breast
and other cancers, like those of the head and neck.
5-FU is an effective chemotherapeutic drug developed as an inhibitor of TS, which
leads to a thymine less cell death. And it is also a pyrimidine analogue misincorporated into
RNA and DNA in place of uracil or thymine. However, its clinical application is greatly
limited due to drug resistance, which could result from various causes, including alteration
of drug influx and efflux, enhancement of drug inactivation and mutations of the drug target.
Unfortunately, in addition to its beneficial antitumor effects, 5-FU also possesses a
number of important toxicities. Acute coronary syndrome (ACS) precipitated by the
administration of 5-FU is a rare but well-established phenomenon and only one of several
17518482_1 (GHMatters) P115263.NZ
adverse cardiac effects related to this chemotherapeutic agent. Additional cardiotoxic effects
include cardiomyopathy, vasospastic angina, coronary thrombosis and dissection, malignant
arrhythmias, and sudden cardiac death.
SUMMARY OF THE INVENTION
The present invention provides compounds, compositions containing these
compounds and methods for using the same to treat, prevent and/or ameliorate the effects of
the conditions such as cancer.
[0006A] In a first aspect there is provided a compound of formula VI:
Formula VI
and pharmaceutically acceptable enantiomers and stereoisomers thereof;
wherein,
R , R , R represents CD , NULL,
1 3 5 2
17518482_1 (GHMatters) P115263.NZ
, , ,
, , , ,
, ,
, , ,
17518482_1 (GHMatters) P115263.NZ
, , ,
, , ,
or ;
R , R independently represents
17518482_1 (GHMatters) P115263.NZ
, or
R independently represents H, D,
17518482_1 (GHMatters) P115263.NZ
, or ;
wherein
n represents 0 to 12;
R is not H when R is NULL;
R and R independently represent
17518482_1 (GHMatters) P115263.NZ
[0006B] In a further aspect, there is provided a pharmaceutical composition comprising a
compound as defined herein and a pharmaceutically acceptable carrier.
[0006C] In a further aspect, there is provided a use of the pharmaceutical composition as
defined herein for the manufacture of a medicament for the treatment of colorectal cancer,
breast cancer, gastric cancer, oesophageal cancer, anal cancer, stomach cancer, pancreatic
cancer, skin cancers and Bowen's disease.
The invention herein provides compositions comprising of formula I or
pharmaceutical acceptable salts thereof. The invention also provides pharmaceutical
compositions comprising one or more compounds of formula I or intermediates thereof and
one or more of pharmaceutically acceptable salts, carriers, vehicles or diluents. These
compositions may be used in the treatment of cancer and its associated complications.
17518482_1 (GHMatters) P115263.NZ
R R O
O R R
O N N O
Formula I
In certain embodiments, the present invention relates to the compounds and
compositions of formula I, or pharmaceutically acceptable salts thereof,
17518482_1 (GHMatters) P115263.NZ
R R O
O R R
O N N O
Formula I
and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and
stereoisomers thereof;
Wherein,
R , R represents CD , CD , H, D, O, OD, CD CO, NULL,
1 3 3 2 3
, , ,
, , , ,
, , ,
, , ,
17518482_1 (GHMatters) P115263.NZ
, , ,
, , ,
, , ,
17518482_1 (GHMatters) P115263.NZ
or ;
R , R independently represents
17518482_1 (GHMatters) P115263.NZ
Within the proviso, Wherein
n represents 0 to 12;
R and R independently represents
17518482_1 (GHMatters) P115263.NZ
17518482_1 (GHMatters) P115263.NZ
The compositions are typically compounds of capecitabine in which the free
hydroxyl groups of capecitabine are conjugated with one of the selected fatty acid
compounds in an ester conjugate form. The invention also provides pharmaceutical
compositions comprising compositions of formula I and pharmaceutically acceptable
excipients.
In certain embodiments, the present invention relates to the compounds and
compositions of formula II, or pharmaceutically acceptable salts thereof,
Formula II
and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and
stereoisomers thereof;
Wherein,
R , R represents CD , CD , H, D, O, OD, CD CO, NULL,
1 3 3 2 3
, , ,
, , , ,
17518482_1 (GHMatters) P115263.NZ
, , ,
, , ,
, , ,
, , ,
, , ,
17518482_1 (GHMatters) P115263.NZ
or ;
R , R independently represents
17518482_1 (GHMatters) P115263.NZ
Within the proviso, Wherein
n represents 0 to 12;
R and R independently represents
17518482_1 (GHMatters) P115263.NZ
17518482_1 (GHMatters) P115263.NZ
In certain embodiments, the present invention relates to the compounds and
compositions of formula III, or pharmaceutically acceptable salts thereof,
Formula III
and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and
stereoisomers thereof;
Wherein,
R , R , R represents CD , CD , H, D, O, OD, CD CO, NULL,
1 3 5 3 2 3
, , ,
, , , ,
, , ,
17518482_1 (GHMatters) P115263.NZ
, , ,
, , ,
, , ,
, , ,
, , ,
, , ,
17518482_1 (GHMatters) P115263.NZ
, , ,
or ;
R , R independently represents
17518482_1 (GHMatters) P115263.NZ
Within the proviso, Wherein
n represents 0 to 12;
R independently represents NULL,
17518482_1 (GHMatters) P115263.NZ
In certain embodiments, the present invention relates to the compounds and
compositions of formula IV, or pharmaceutically acceptable salts thereof,
17518482_1 (GHMatters) P115263.NZ
Formula IV
and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and
stereoisomers thereof;
Wherein,
R , R , R , R represents CD , CD , H, D, O, OD, CD CO, NULL,
1 3 5 7 3 2 3
, , ,
, , , ,
, , ,
17518482_1 (GHMatters) P115263.NZ
, , ,
, , ,
, , ,
, , ,
17518482_1 (GHMatters) P115263.NZ
or ;
R , R , R , R independently represents
2 4 6 8
17518482_1 (GHMatters) P115263.NZ
Within the proviso, Wherein
n represents 0 to 12;
R and R independently represents
17518482_1 (GHMatters) P115263.NZ
17518482_1 (GHMatters) P115263.NZ
In certain embodiments, the present invention relates to the compounds and
compositions of formula V, or pharmaceutically acceptable salts thereof,
Formula V
and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and
stereoisomers thereof;
Wherein,
R , R , R represents CD , CD , H, D, O, OD, CD CO, NULL,
1 3 5 3 2 3
, , ,
, , , ,
17518482_1 (GHMatters) P115263.NZ
, , ,
, , ,
, , ,
, , ,
, , ,
17518482_1 (GHMatters) P115263.NZ
or ;
R , R , R independently represents
2 4 6
17518482_1 (GHMatters) P115263.NZ
Within the proviso, Wherein
n represents 0 to 12;
R and R independently represents
17518482_1 (GHMatters) P115263.NZ
17518482_1 (GHMatters) P115263.NZ
In certain embodiments, the present invention relates to the compounds and
compositions of formula VI, or pharmaceutically acceptable salts thereof,
Formula VI
and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and
stereoisomers thereof;
Wherein,
R , R , R represents CD , CD , H, D, O, OD, CD CO, NULL,
1 3 5 3 2 3
, , ,
, , , ,
17518482_1 (GHMatters) P115263.NZ
, , ,
, , ,
, , ,
, , ,
, , ,
, , ,
17518482_1 (GHMatters) P115263.NZ
, , ,
, , ,
or ;
R , R independently represents
17518482_1 (GHMatters) P115263.NZ
, or
R independently represents H, D, NULL,
17518482_1 (GHMatters) P115263.NZ
17518482_1 (GHMatters) P115263.NZ
Within the proviso,
Wherein
n represents 0 to 12;
R and R independently represents
17518482_1 (GHMatters) P115263.NZ
In certain embodiments, the present invention relates to the compounds and
compositions of formula II, or pharmaceutically acceptable salts thereof,
Formula VII
17518482_1 (GHMatters) P115263.NZ
and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and
stereoisomers thereof;
Wherein,
R , R represents CD , CD , H, D, O, OD, CD CO, NULL,
1 3 3 2 3
, , ,
, , , ,
, , ,
, , ,
, , ,
17518482_1 (GHMatters) P115263.NZ
, , ,
, , ,
, , ,
, , ,
, , ,
or ;
R , R independently represents
17518482_1 (GHMatters) P115263.NZ
17518482_1 (GHMatters) P115263.NZ
17518482_1 (GHMatters) P115263.NZ
Within the proviso,
Wherein
n represents 0 to 12;
R and R independently represents
17518482_1 (GHMatters) P115263.NZ
In certain embodiments, the present invention relates to the compounds and
compositions of formula VIII, or pharmaceutically acceptable salts thereof,
O N N
Formula VIII
and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and
stereoisomers thereof;
Wherein,
R represents CD , CD , H, D, O, OD, CD CO, NULL,
1 3 2 3
, , ,
17518482_1 (GHMatters) P115263.NZ
, , , ,
, , ,
, , ,
, , ,
, , ,
, , ,
17518482_1 (GHMatters) P115263.NZ
, , ,
, , ,
, , ,
or ;
R independently represents
17518482_1 (GHMatters) P115263.NZ
17518482_1 (GHMatters) P115263.NZ
17518482_1 (GHMatters) P115263.NZ
Within the proviso,
Wherein
n represents 0 to 12;
R and R independently represents
17518482_1 (GHMatters) P115263.NZ
The invention further provides methods for treating colorectal cancer, breast cancer
(metastatic or as monotherapy/combotherapy), gastric cancer, oesophageal cancer, anal,
breast, colorectal, oesophageal, stomach, pancreatic and skin cancers (especially head and
neck cancers), actinic keratoses, skin cancers and Bowen's disease and as eye drops for
treatment of ocular surface squamous neoplasia, when administered to patients, preferably
by oral, injection, rectal, aerosol, I.V, spray, solution, syrup, suppository, powder, i.v,
solution, syrup, nanoparticle, sachet administration.
Herein the application also provides a kit comprising any of the pharmaceutical
compositions disclosed herein. The kit may comprise instructions for use in the treatment of
cancer or its related complications.
The application also discloses a pharmaceutical composition comprising a
pharmaceutically acceptable carrier and any of the compositions herein. In some aspects,
the pharmaceutical composition is formulated for systemic administration, oral
administration, sustained release, parenteral administration, injection, subdermal
administration, or transdermal administration.
17518482_1 (GHMatters) P115263.NZ
Herein, the application additionally provides kits comprising the pharmaceutical
compositions described herein. The kits may further comprise instructions for use in the
treatment of cancer or its related complications.
The compositions described herein have several uses. The present application
provides, for example, methods of treating a patient suffering from cancer or its related
complications manifested from metabolic or genetic conditions or disorders, metabolic
diseases, chronic diseases or disorders; neurodegenerative disorders, metabolic condition,
Hepatology, Cancer, Respiratory, Hematological, Orthopedic, Cardiovascular, Renal, Skin,
Vascular or Ocular complications.
In the illustrative embodiments, examples of compounds of formula I, formula II,
formula III, formula IV, formula V, formula VI, formula VII and formula VIII are as set
forth below:
(1-1)
17518482_1 (GHMatters) P115263.NZ
(1-2)
(1-3)
(1-4)
(1-5)
17518482_1 (GHMatters) P115263.NZ
(1-6)
DETAILED DESCRIPTION OF THE INVENTION
Definitions
As used herein, the following terms and phrases shall have the meanings set forth
below. Unless defined otherwise, all technical and scientific terms used herein have the
same meaning as commonly understood to one of ordinary skill in the art.
The compounds of the present invention can be present in the form of
pharmaceutically acceptable salts. The compounds of the present invention can also be
present in the form of pharmaceutically acceptable esters (i.e., the methyl and ethyl esters of
the acids of formula I, formula II, formula III, formula IV, formula V, formula VI, formula
VII or formula VIII to be used as prodrugs). The compounds of the present invention can
also be solvated, i.e. hydrated. The solvation can be affected in the course of the
manufacturing process or can take place i.e. as a consequence of hygroscopic properties of
an initially anhydrous compound of formula I, formula II, formula III, formula IV, formula
V, formula VI, formula VII or formula VIII (hydration).
Compounds that have the same molecular formula but differ in the nature or
sequence of bonding of their atoms or the arrangement of their atoms in space are termed
"isomers." Isomers that differ in the arrangement of their atoms in space are termed
"stereoisomers." Diastereomers are stereoisomers with opposite configuration at one or
17518482_1 (GHMatters) P115263.NZ
more chiral centers which are not enantiomers. Stereoisomers bearing one or more
asymmetric centers that are non- superimposable mirror images of each other are termed
"enantiomers." When a compound has an asymmetric center, for example, if a carbon atom
is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be
characterized by the absolute configuration of its asymmetric center or centers and is
described by the R- and S-sequencing rules of Cahn, lngold and Prelog, or by the manner in
which the molecule rotates the plane of polarized light and designated as dextrorotatory or
levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either
individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the
enantiomers is called a "racemic mixture".
As used herein, the term “metabolic condition” refers to an Inborn errors of
metabolism (or genetic metabolic conditions) are genetic disorders that result from a defect
in one or more metabolic pathways; specifically, the function of an enzyme is affected and is
either deficient or completely absent. Metabolic or genetic disorders or condition associated
diseases include: Hepatic, Neurologic, Psychiatric, Hematologic, Respiratory, Renal,
Cardiovascular, Cancer, Musculoskeletal, Orthopedic and Gastrointestinal.
The term "polymorph" as used herein is art-recognized and refers to one crystal
structure of a given compound.
The phrases “parenteral administration” and “administered parenterally” as used
herein refer to modes of administration other than enteral and topical administration, such as
injections, and include without limitation intravenous, intramuscular, intrapleural,
intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital,
intracardiac, intradennal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-
articular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.
A “patient,” “subject,” or “host” to be treated by the subject method may mean
either a human or non-human animal, such as primates, mammals, and vertebrates.
17518482_1 (GHMatters) P115263.NZ
The phrase “pharmaceutically acceptable” is art-recognized. In certain
embodiments, the term includes compositions, polymers and other materials and/or dosage
forms which are, within the scope of sound medical judgment, suitable for use in contact
with the tissues of mammals, human beings and animals without excessive toxicity,
irritation, allergic response, or other problem or complication, commensurate with a
reasonable benefit/risk ratio.
The phrase “pharmaceutically acceptable carrier” is art-recognized, and includes,
for example, pharmaceutically acceptable materials, compositions or vehicles, such as a
liquid or solid filler, diluent, solvent or encapsulating material involved in carrying or
transporting any subject composition, from one organ, or portion of the body, to another
organ, or portion of the body. Each carrier must be “acceptable” in the sense of being
compatible with the other ingredients of a subject composition and not injurious to the
patient. In certain embodiments, a pharmaceutically acceptable carrier is non-pyrogenic.
Some examples of materials which may serve as pharmaceutically acceptable carriers
include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch
and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose,
ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc;
(8) cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil,
sunflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene
glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12)
esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as
magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water;
(17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer
solutions; and (21) other non-toxic compatible substances employed in pharmaceutical
formulations.
The term "polymorph" as used herein is art-recognized and refers to one crystal
structure of a given compound.
The term “prodrug” is intended to encompass compounds that, under physiological
conditions, are converted into the therapeutically active agents of the present invention. A
17518482_1 (GHMatters) P115263.NZ
common method for making a prodrug is to include selected moieties that are hydrolyzed
under physiological conditions to reveal the desired molecule. In other embodiments, the
prodrug is converted by an enzymatic activity of the host animal.
The term “prophylactic or therapeutic” treatment is art-recognized and includes
administration to the host of one or more of the subject compositions. If it is administered
prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted
state of the host animal) then the treatment is prophylactic, i.e., it protects the host against
developing the unwanted condition, whereas if it is administered after manifestation of the
unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate,
or stabilize the existing unwanted condition or side effects thereof).
The term "predicting" as used herein refers to assessing the probability according
to which a condition or disorder such as cancer or related diseases patient will suffer from
abnormalities or complication and/or death (i.e. mortality) within a defined time window
(predictive window) in the future. The mortality may be caused by the central nervous
system or complication. The predictive window is an interval in which the subject will
develop one or more of the said complications according to the predicted probability. The
predictive window may be the entire remaining lifespan of the subject upon analysis by the
method of the present invention. Preferably, however, the predictive window is an interval
of one month, six months or one, two, three, four, five or ten years after appearance of the
inflammatory complication (more preferably and precisely, after the sample to be analyzed
by the method of the present invention has been obtained). As will be understood by those
skilled in the art, such an assessment is usually not intended to be correct for 100% of the
subjects to be analyzed. The term, however, requires that the assessment will be valid for a
statistically significant portion of the subjects to be analyzed. Whether a portion is
statistically significant can be determined without further ado by the person skilled in the art
using various well known statistic evaluation tools, e.g., determination of confidence
intervals, p-value determination, Student's t-test, Mann- Whitney test, etc. Details are found
in Dowdy and Wearden, Statistics for Research, John Wiley & Sons, New York 1983.
Preferred confidence intervals are at least 90%, at least 95%, at least 97%, at least 98% or at
17518482_1 (GHMatters) P115263.NZ
least 99 %. The p-values are, preferably, 0.1, 0.05, 0.01, 0.005, or 0.0001. Preferably, the
probability envisaged by the present invention allows that the prediction will be correct for
at least 60%, at least 70%, at least 80%, or at least 90% of the subjects of a given cohort.
The term "treating" is art -recognized and includes preventing a disease, disorder
or condition from occurring in an animal which may be predisposed to the disease, disorder
and/or condition but has not yet been diagnosed as having it; inhibiting the disease, disorder
or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition,
e.g., causing regression of the disease, disorder and/or condition. Treating the disease or
condition includes ameliorating at least one symptom of the particular disease or condition,
even if the underlying pathophysiology is not affected, such as treating the cancer or
condition or disorders such as cancer condition of a subject by administration of an agent
even though such agent does not treat the cause of the condition. The term "treating", "treat"
or "treatment" as used herein includes curative, preventative (e.g., prophylactic), adjunct and
palliative treatment.
The phrase "therapeutically effective amount" is an art-recognized term. In certain
embodiments, the term refers to an amount of a salt or composition disclosed herein that
produces some desired effect at a reasonable benefit/risk ratio applicable to any medical
treatment. In certain embodiments, the term refers to that amount necessary or sufficient to
eliminate or reduce medical symptoms for a period of time. The effective amount may vary
depending on such factors as the disease or condition being treated, the particular targeted
constructs being administered, the size of the subject, or the severity of the disease or
condition. One of ordinary skill in the art may empirically determine the effective amount of
a particular composition without necessitating undue experimentation.
In certain embodiments, the pharmaceutical compositions described herein are
formulated in a manner such that said compositions will be delivered to a patient in a
therapeutically effective amount, as part of a prophylactic or therapeutic treatment. The
desired amount of the composition to be administered to a patient will depend on absorption,
17518482_1 (GHMatters) P115263.NZ
inactivation, and excretion rates of the drug as well as the delivery rate of the salts and
compositions from the subject compositions. It is to be noted that dosage values may also
vary with the severity of the condition to be alleviated. It is to be further understood that for
any particular subject, specific dosage regimens should be adjusted over time according to
the individual need and the professional judgment of the person administering or supervising
the administration of the compositions. Typically, dosing will be determined using
techniques known to one skilled in the art.
Additionally, the optimal concentration and/or quantities or amounts of any
particular salt or composition may be adjusted to accommodate variations in the treatment
parameters. Such treatment parameters include the clinical use to which the preparation is
put, e.g., the site treated, the type of patient, e.g., human or non-human, adult or child, and
the nature of the disease or condition.
In certain embodiments, the dosage of the subject compositions provided herein
may be determined by reference to the plasma concentrations of the therapeutic composition
or other encapsulated materials. For example, the maximum plasma concentration (Cmax)
and the area under the plasma concentration-time curve from time 0 to infinity may be used.
The term "solvate" as used herein, refers to a compound formed by solvation (e.g.,
a compound formed by the combination of solvent molecules with molecules or ions of the
solute).
When used with respect to a pharmaceutical composition or other material, the
term “sustained release” is art-recognized. For example, a subject composition which
releases a substance over time may exhibit sustained release characteristics, in contrast to a
bolus type administration in which the entire amount of the substance is made biologically
available at one time. For example, in particular embodiments, upon contact with body
fluids including blood, spinal fluid, mucus secretions, lymph or the like, one or more of the
pharmaceutically acceptable excipients may undergo gradual or delayed degradation (e.g.,
17518482_1 (GHMatters) P115263.NZ
through hydrolysis) with concomitant release of any material incorporated therein, e.g., an
therapeutic and/or biologically active salt and/or composition, for a sustained or extended
period (as compared to the release from a bolus). This release may result in prolonged
delivery of therapeutically effective amounts of any of the therapeutic agents disclosed
herein.
The phrases “systemic administration,” “administered systemically,” “peripheral
administration” and “administered peripherally” are art-recognized, and include the
administration of a subject composition, therapeutic or other material at a site remote from
the disease being treated. Administration of an agent for the disease being treated, even if
the agent is subsequently distributed systemically, may be termed “local” or “topical” or
“regional” administration, other than directly into the central nervous system, e.g., by
subcutaneous administration, such that it enters the patient’s system and, thus, is subject to
metabolism and other like processes.
The phrase “therapeutically effective amount” is an art-recognized term. In certain
embodiments, the term refers to an amount of a salt or composition disclosed herein that
produces some desired effect at a reasonable benefit/risk ratio applicable to any medical
treatment. In certain embodiments, the term refers to that amount necessary or sufficient to
eliminate or reduce medical symptoms for a period of time. The effective amount may vary
depending on such factors as the disease or condition being treated, the particular targeted
constructs being administered, the size of the subject, or the severity of the disease or
condition. One of ordinary skill in the art may empirically determine the effective amount
of a particular composition without necessitating undue experimentation.
The present disclosure also contemplates prodrugs of the compositions disclosed
herein, as well as pharmaceutically acceptable salts of said prodrugs.
This application also discloses a pharmaceutical composition comprising a
pharmaceutically acceptable carrier and the composition of a compound of Formula I,
17518482_1 (GHMatters) P115263.NZ
formula II, formula III, formula IV, formula V, formula VI, formula VII or formula VIII
may be formulated for systemic or topical or oral administration. The pharmaceutical
composition may be also formulated for oral administration, oral solution, injection,
subdermal administration, or transdermal administration. The pharmaceutical composition
may further comprise at least one of a pharmaceutically acceptable stabilizer, diluent,
surfactant, filler, binder, and lubricant.
In many embodiments, the pharmaceutical compositions described herein will
incorporate the disclosed compounds and compositions (Formula I, formula II, formula III,
formula IV, formula V, formula VI, formula VII or formula VIII ) to be delivered in an
amount sufficient to deliver to a patient a therapeutically effective amount of a compound of
formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII or
formula VIII or composition as part of a prophylactic or therapeutic treatment. The desired
concentration of formula I, formula II, formula III, formula IV, formula V, formula VI,
formula VII or formula VIII or its pharmaceutical acceptable salts will depend on
absorption, inactivation, and excretion rates of the drug as well as the delivery rate of the
salts and compositions from the subject compositions. It is to be noted that dosage values
may also vary with the severity of the condition to be alleviated. It is to be further
understood that for any particular subject, specific dosage regimens should be adjusted over
time according to the individual need and the professional judgment of the person
administering or supervising the administration of the compositions. Typically, dosing will
be determined using techniques known to one skilled in the art.
Additionally, the optimal concentration and/or quantities or amounts of any
particular compound of formula I, formula II, formula III, formula IV, formula V, formula
VI, formula VII or formula VIII may be adjusted to accommodate variations in the treatment
parameters. Such treatment parameters include the clinical use to which the preparation is
put, e.g., the site treated, the type of patient, e.g., human or non-human, adult or child, and
the nature of the disease or condition.
17518482_1 (GHMatters) P115263.NZ
The concentration and/or amount of any compound of formula I, formula II,
formula III, formula IV, formula V, formula VI, formula VII or formula VIII may be
readily identified by routine screening in animals, e.g., rats, by screening a range of
concentration and/or amounts of the material in question using appropriate assays. Known
methods are also available to assay local tissue concentrations, diffusion rates of the salts or
compositions, and local blood flow before and after administration of therapeutic
formulations disclosed herein. One such method is microdialysis, as reviewed by T. E.
Robinson et al., 1991, microdialysis in the neurosciences, Techniques, volume 7, Chapter 1.
The methods reviewed by Robinson may be applied, in brief, as follows. A microdialysis
loop is placed in situ in a test animal. Dialysis fluid is pumped through the loop. When
compounds with formula I, formula II, formula III, formula IV, formula V, formula VI,
formula VII or formula VIII such as those disclosed herein are injected adjacent to the loop,
released drugs are collected in the dialysate in proportion to their local tissue concentrations.
The progress of diffusion of the salts or compositions may be determined thereby with
suitable calibration procedures using known concentrations of salts or compositions.
In certain embodiments, the dosage of the subject compounds of formula I,
formula II, formula III, formula IV, formula V, formula VI, formula VII or formula VIII
provided herein may be determined by reference to the plasma concentrations of the
therapeutic composition or other encapsulated materials. For example, the maximum
plasma concentration (Cmax) and the area under the plasma concentration-time curve from
time 0 to infinity may be used.
Generally, in carrying out the methods detailed in this application, an effective
dosage for the compounds of formula I, formula II, formula III, formula IV, formula V,
formula VI, formula VII or formula VIII is in the range of about 0.01 mg/kg/day to about
100 mg/kg/day in single or divided. The compounds of formula I, formula II, formula III,
formula IV, formula V, formula VI, formula VII or formula VIII may be administered at a
dose of, for example, less than 0.2 mg/kg/day, 0.5 mg/kg/day, 1.0 mg/kg/day, 5 mg/kg/day,
mg/kg/day, 20 mg/kg/day, 30 mg/kg/day, or 40 mg/kg/day. Compounds of formula I,
17518482_1 (GHMatters) P115263.NZ
formula II, formula III, formula IV, formula V, formula VI, formula VII or formula VIII
may also be administered to a human patient at a dose of, for example, between 0.1 mg and
1000 mg, between 5 mg and 80 mg, or less than 1.0, 9.0, 12.0, 20.0, 50.0, 75.0, 100, 300,
400, 500, 800, 1000, 10,000, 20,000, 30,000 mg per day. In certain embodiments, the
compositions herein are administered at an amount that is less than 95%, 90%, 80%, 70%,
60%, 50%, 40%, 30%, 20%, or 10% of the compound of formula I, formula II, formula III,
formula IV, formula V, formula VI, formula VII or formula VIII required for the same
therapeutic benefit.
An effective amount of the compounds of formula I, formula II, formula III,
formula IV, formula V, formula VI, formula VII or formula VIII described herein refers to
the amount of one of said salts or compositions which is capable of inhibiting or preventing
a disease. For example cancer or any other metabolic condition or metabolic disorder or any
other medical condition.
The compositions provided by this application may be administered to a subject in
need of treatment by a variety of conventional routes of administration, including orally,
topically, parenterally, e.g., intravenously, subcutaneously or intramedullary. Further, the
compositions may be administered intranasally, as a rectal suppository, or using a "flash"
formulation, i.e., allowing the medication to dissolve in the mouth without the need to use
water. Furthermore, the compositions may be administered to a subject in need of treatment
by controlled release dosage forms, site specific drug delivery, transdermal drug delivery,
patch (active/passive) mediated drug delivery, by stereotactic injection, or in nanoparticles.
The compositions may be administered alone or in combination with
pharmaceutically acceptable carriers, vehicles or diluents, in either single or multiple doses.
Suitable pharmaceutical carriers, vehicles and diluents include inert solid diluents or fillers,
sterile aqueous solutions and various organic solvents. The pharmaceutical compositions
formed by combining the compositions and the pharmaceutically acceptable carriers,
vehicles or diluents are then readily administered in a variety of dosage forms such as
17518482_1 (GHMatters) P115263.NZ
tablets, powders, lozenges, syrups, injectable solutions and the like. These pharmaceutical
compositions can, if desired, contain additional ingredients such as flavorings, binders,
excipients and the like. Thus, for purposes of oral administration, tablets containing various
excipients such as L-arginine, sodium citrate, calcium carbonate and calcium phosphate may
be employed along with various disintegrates such as starch, alginic acid and certain
complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose,
gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium
lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a
similar type may also be employed as fillers in soft and hard filled gelatin capsules.
Appropriate materials for this include lactose or milk sugar and high molecular weight
polyethylene glycols. When aqueous suspensions or elixirs are desired for oral
administration, the essential active ingredient therein may be combined with various
sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or
suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin
and combinations thereof. The compounds of formula I, formula II, formula III, formula IV,
formula V, formula VI, formula VII or formula VIII may also comprise enterically coated
comprising of various excipients, as is well known in the pharmaceutical art.
For parenteral administration, solutions of the compositions may be prepared in
(for example) sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solutions
may be employed. Such aqueous solutions should be suitably buffered if necessary and the
liquid diluent first rendered isotonic with sufficient saline or glucose. These particular
aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and
intraperitoneal administration. In this connection, the sterile aqueous media employed are all
readily available by standard techniques known to those skilled in the art.
The formulations, for instance tablets, may contain e.g. 10 to 100, 50 to 250, 150 to
500 mg, or 350 to 800 mg e.g. 10, 50, 100, 300, 500, 700, 800 mg, 1 gram, 5 grams, 10
grams, 20 grams, 30 grams of the compounds of formula I, formula II, formula III, formula
IV, formula V, formula VI, formula VII or formula VIII disclosed herein, for instance,
17518482_1 (GHMatters) P115263.NZ
compounds of formula I, formula II, formula III, formula IV, formula V, formula VI,
formula VII or formula VIII or pharmaceutical acceptable salts of a compounds of formula
I, formula II, formula III, formula IV, formula V, formula VI, formula VII or formula VIII .
Generally, a composition as described herein may be administered orally, or
parenterally (e.g., intravenous, intramuscular, subcutaneous or intramedullary). Topical
administration may also be indicated, for example, where the patient is suffering from
gastrointestinal disorder that prevent oral administration, or whenever the medication is best
applied to the surface of a tissue or organ as determined by the attending physician.
Localized administration may also be indicated, for example, when a high dose is desired at
the target tissue or organ. For buccal administration the active composition may take the
form of tablets or lozenges formulated in a conventional manner.
The dosage administered will be dependent upon the identity of the cancer; the
type of host involved, including its age, health and weight; the kind of concurrent treatment,
if any; the frequency of treatment and therapeutic ratio.
Illustratively, dosage levels of the administered active ingredients are: intravenous,
0.1 to about 200 mg/kg; intramuscular, 1 to about 500 mg/kg; orally, 5 to about 1000 mg/kg;
intranasal instillation, 5 to about 1000 mg/kg; and aerosol, 5 to about 1000 mg/kg of host
body weight.
Expressed in terms of concentration, an active ingredient can be present in the
compositions of the present invention for localized use about the cutis, intranasally,
pharyngolaryngeally, bronchially, intravaginally, rectally, or ocularly in a concentration of
from about 0.01 to about 50% w/w of the composition; preferably about 1 to about 20% w/w
of the composition; and for parenteral use in a concentration of from about 0.05 to about
50% w/v of the composition and preferably from about 5 to about 20% w/v.
17518482_1 (GHMatters) P115263.NZ
The compositions of the present invention are preferably presented for
administration to humans and animals in unit dosage forms, such as tablets, capsules, pills,
powders, granules, suppositories, sterile parenteral solutions or suspensions, sterile non-
parenteral solutions of suspensions, and oral solutions or suspensions and the like,
containing suitable quantities of an active ingredient. For oral administration either solid or
fluid unit dosage forms can be prepared.
Powders are prepared quite simply by comminuting the active ingredient to a
suitably fine size and mixing with a similarly comminuted diluent. The diluent can be an
edible carbohydrate material such as lactose or starch. Advantageously, a sweetening agent
or sugar is present as well as flavoring oil.
Capsules are produced by preparing a powder mixture as hereinbefore described
and filling into formed gelatin sheaths. Advantageously, as an adjuvant to the filling
operation, a lubricant such as talc, magnesium stearate, calcium stearate and the like is
added to the powder mixture before the filling operation.
Soft gelatin capsules are prepared by machine encapsulation of slurry of active
ingredients with an acceptable vegetable oil, light liquid petrolatum or other inert oil or
triglyceride.
Tablets are made by preparing a powder mixture, granulating or slugging, adding a
lubricant and pressing into tablets. The powder mixture is prepared by mixing an active
ingredient, suitably comminuted, with a diluent or base such as starch, lactose, kaolin,
dicalcium phosphate and the like. The powder mixture can be granulated by wetting with a
binder such as corn syrup, gelatin solution, methylcellulose solution or acacia mucilage and
forcing through a screen. As an alternative to granulating, the powder mixture can be
slugged, i.e., ran through the tablet machine and the resulting imperfectly formed tablets
broken into pieces (slugs). The slugs can be lubricated to prevent sticking to the tablet-
17518482_1 (GHMatters) P115263.NZ
forming dies by means of the addition of stearic acid, a stearic salt, talc or mineral oil. The
lubricated mixture is then compressed into tablets.
Advantageously, the tablet can be provided with a protective coating consisting of
a sealing coat or enteric coat of shellac, a coating of sugar and methylcellulose and polish
coating of carnauba wax.
Fluid unit dosage forms for oral administration such as in syrups, elixirs and
suspensions can be prepared wherein each teaspoonful of composition contains a
predetermined amount of an active ingredient for administration. The water-soluble forms
can be dissolved in an aqueous vehicle together with sugar, flavoring agents and
preservatives to form syrup. An elixir is prepared by using a hydroalcoholic vehicle with
suitable sweeteners together with a flavoring agent. Suspensions can be prepared of the
insoluble forms with a suitable vehicle with the aid of a suspending agent such as acacia,
tragacanth, methylcellulose and the like.
For parenteral administration, fluid unit dosage forms are prepared utilizing an
active ingredient and a sterile vehicle, water being preferred. The active ingredient,
depending on the form and concentration used, can be either suspended or dissolved in the
vehicle. In preparing solutions the water- soluble active ingredient can be dissolved in water
for injection and filter sterilized before filling into a suitable vial or ampule and sealing.
Advantageously, adjuvants such as a local anesthetic, preservative and buffering agents can
be dissolved in the vehicle. Parenteral suspensions are prepared in substantially the same
manner except that an active, ingredient is suspended in the vehicle instead of being
dissolved and sterilization cannot be accomplished by filtration. The active ingredient can be
sterilized by exposure to cthylene oxide before suspending in the sterile vehicle.
Advantageously, a surfactant or wetting agent is included in the composition to facilitate
uniform distribution of the active ingredient.
17518482_1 (GHMatters) P115263.NZ
In addition to oral and parenteral administration, the rectal and vaginal routes can
be utilized. An active ingredient can be administered by means of a suppository. A vehicle
which has a melting point at about body temperature or one that is readily soluble can be
utilized. For example, cocoa butter and various polyethylene glycols (Carbowaxes) can
serve as the vehicle.
For intranasal instillation, a fluid unit dosage form is prepared utilizing an active
ingredient and a suitable pharmaceutical vehicle, preferably P.F. water, a dry powder can be
formulated when insufflation is the administration of choice.
For use as aerosols, the active ingredients can be packaged in a pressurized aerosol
container together with a gaseous or liquified propellant, for example,
dichlorodifluoromethane, carbon dioxide, nitrogen, propane, and the like, with the usual
adjuvants such as cosolvents and wetting agents, as may be necessary or desirable.
The term "unit dosage form" as used in the specification and claims refers to
physically discrete units suitable as unitary dosages for human and animal subjects, each
unit containing a predetermined quantity of active material calculated to produce the desired
therapeutic effect in association with the required pharmaceutical diluent, carrier or vehicle.
The specifications for the novel unit dosage forms of this invention are dictated by and are
directly dependent on (a) the unique characteristics of the active material and the particular
therapeutic effect to be achieved, and (b) the limitation inherent in the art of compounding
such an active material for therapeutic use in humans, as disclosed in this specification,
these being features of the present invention. Examples of suitable unit dosage forms in
accord with this invention are tablets, capsules, troches, suppositories, powder packets,
wafers, cachets, teaspoonfuls, tablespoonfuls, dropperfuls, ampules, vials, segregated
multiples of any of the foregoing, and other forms as herein described.
The tablets of the present invention contain one or more pharmaceutically active
agents that are released therefrom upon contact of the tablet with a liquid medium, for
17518482_1 (GHMatters) P115263.NZ
example a dissolution medium such as gastrointestinal fluids. "Water soluble," as used
herein in connection with non-polymeric materials, shall mean from sparingly soluble to
very soluble, i.e., not more than 100 parts water required to dissolve 1 part of the non-
polymeric, water soluble solute. See Remington, The Science and Practice of Pharmacy, pp
208-209 (2000). "Water soluble," as used herein in connection with polymeric materials,
shall mean that the polymer swells in water and can be dispersed at the molecular level or
dissolved in water.
As used herein, the term "modified release" shall apply to tablets, matrices,
particles, coatings, portions thereof, or compositions that alter the release of an
pharmaceutically active agent in any manner. Types of modified release include controlled,
prolonged, sustained, extended, delayed, pulsatile, repeat action, and the like. Suitable
mechanisms for achieving these types of modified release include diffusion, erosion, surface
area control via geometry and/or impermeable barriers, or other mechanisms known in the
art.
In one embodiment of the invention, the first pharmaceutically active agent and the
hydrophilic polymer are mixed with a powder containing a pharmaceutically-acceptable
carrier, which is also defined herein as the tablet matrix. In one embodiment, the powder has
an average particle size of about 50 microns to about 500 microns, such as between 50
microns and 300 microns. Particles in this size range are particularly useful for direct
compression processes. In embodiment, the components of powder are blended together, for
example as dry powders, and fed into the die cavity of an apparatus that applies pressure to
form a tablet core. Any suitable compacting apparatus may be used, including, but not
limited to, conventional unitary or rotary tablet press. In one embodiment, the tablet core
may be formed by compaction using a rotary tablet press (e.g., such as those commercially
available from Fette America Inc., Rockaway, N.J., or Manesty Machines LTD, Liverpool,
UK). In general, a metered volume of powder is filled into a die cavity (where the powder is
either gravity fed or mechanically fed from a feeder) of the rotary tablet press, and the cavity
rotates as part of a "die table" from the filling position to a compaction position. At the
17518482_1 (GHMatters) P115263.NZ
compaction position, the powder is compacted between an upper and a lower punch, then
the resulting tablet core is pushed from the die cavity by the lower punch and then guided to
an injection chute by a stationary "take-off bar.
In one embodiment of the invention, the tablet core may be a directly compressed
tablet core made from a powder that is substantially free of water-soluble polymeric binders
and hydrated polymers. As used herein, what is meant by "substantially free" is less than 5
percent, such as less than 1 percent, such as less than 0.1 percent, such as completely free
(e.g., 0 percent). This composition is advantageous for minimizing processing and material
costs and providing for optimal physical and chemical stability of the tablet core. In one
embodiment, the density of the tablet core is greater than about 0.9 g/cc.
The tablet core may have one of a variety of different shapes. For example, the
tablet core may be shaped as a polyhedron, such as a cube, pyramid, prism, or the like; or
may have the geometry of a space figure with some non-flat faces, such as a cone, truncated
cone, cylinder, sphere, torus, or the like. In certain embodiments, a tablet core has one or
more major faces. For example, the tablet core surface typically has opposing upper and
lower faces formed by contact with the upper and lower punch faces in the compression
machine. In such embodiments the tablet core surface typically further includes a "belly-
band" located between the upper and lower faces, and formed by contact with the die walls
in the compression machine.
As discussed above, the tablet core contains one or more hydrophilic polymers.
Suitable hydrophilic polymers include, but are not limited to, water swellable cellulose
derivatives, polyalkylene glycols, thermoplastic polyalkylene oxides, acrylic polymers,
hydrocolloids, clays, gelling starches, swelling cross-linked polymers, and mixtures thereof.
Examples of suitable water swellable cellulose derivatives include, but are not limited to,
sodium carboxymethylcellulose, cross-linked hydroxypropylcellulose, hydroxypropyl
cellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose,
hydroxybutylcellulose, hydroxyphenylcellulose, hydroxyethylcellulose (HEC),
17518482_1 (GHMatters) P115263.NZ
hydroxypentylcellulose, hydroxypropylethylcellulose, hydroxypropylbutylcellulose, and
hydroxypropylethylcellulose, and mixtures thereof. Examples of suitable polyalkylene
glycols include, but are not limited to, polyethylene glycol. Examples of suitable
thermoplastic polyalkylene oxides include, but are not limited to, poly(ethylene oxide).
Examples of suitable acrylic polymers include, but are not limited to, potassium
methacrylatedivinylbenzene copolymer, polymethylmethacrylate, high-molecular weight
crosslinked acrylic acid homopolymers and copolymers such as those commercially
available from Noveon Chemicals under the tradename CARBOPOL . Examples of
suitable hydrocolloids include, but are not limited to, alginates, agar, guar gum, locust bean
gum, kappa carrageenan, iota carrageenan, tara, gum arabic, tragacanth, pectin, xanthan
gum, gellan gum, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, gum
arabic, inulin, pectin, gelatin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin,
chitosan, and mixtures thereof. Examples of suitable clays include, but are not limited to,
smectites such as bentonite, kaolin, and laponite; magnesium trisilicate; magnesium
aluminum silicate; and mixtures thereof. Examples of suitable gelling starches include, but
are not limited to, acid hydrolyzed starches, swelling starches such as sodium starch
glycolate and derivatives thereof, and mixtures thereof. Examples of suitable swelling cross-
linked polymers include, but are not limited to, cross-linked polyvinyl pyrrolidone, cross-
linked agar, and cross-linked carboxymethylcellulose sodium, and mixtures thereof.
In one embodiment, an osmogen is incorporated into the tablet core in order to
draw water into the tablet upon contact with fluids, such as gastrointestinal fluids. An
osmogen as used herein is a water soluble component which preferentially draws water into
the tablet core for the purposes of distributing the water throughout the core, so that the
active ingredient contained in the core may be released. In one embodiment the osmogen is
a salt such as but not limited to sodium chloride, potassium chloride, sodium citrate, or
potassium citrate.
The carrier may contain one or more suitable excipients for the formulation of
tablets. Examples of suitable excipients include, but are not limited to, fillers, adsorbents,
17518482_1 (GHMatters) P115263.NZ
binders, disintegrants, lubricants, glidants, release-modifying excipients, superdisintegrants,
antioxidants, and mixtures thereof.
Suitable fillers include, but are not limited to, watersoluble compressible
carbohydrates such as sugars (e.g., dextrose, sucrose, maltose, and lactose), starches (e.g.,
corn starch), sugar-alcohols (e.g., mannitol, sorbitol, maltitol, erythritol, and xylitol), starch
hydrolysates (e.g., dextrins, and maltodextrins), and water insoluble plastically deforming
materials (e.g., microcrystalline cellulose or other cellulosic derivatives), and mixtures
thereof. Suitable adsorbents (e.g., to adsorb the liquid drug composition) include, but are
not limited to, water-insoluble adsorbents such as dicalcium phosphate, tricalcium
phosphate, silicified microcrystalline cellulose (e.g., such as distributed under the
PROSOLV brand (PenWest Pharmaceuticals, Patterson, N.Y.)), magnesium
aluminometasilicate (e.g., such as distributed under the NEUSILINTM brand (Fuji
Chemical Industries (USA) Inc., Robbinsville, N.J.), clays, silicas, bentonite, zeolites,
magnesium silicates, hydrotalcite, veegum, and mixtures thereof.
Suitable binders include, but are not limited to, dry binders such as polyvinyl
pyrrolidone and hydroxypropylmethylcellulose; wet binders such as water-soluble polymers,
including hydrocolloids such as acacia, alginates, agar, guar gum, locust bean, carrageenan,
carboxymethylcellulose, tara, gum arabic, tragacanth, pectin, xanthan, gellan, gelatin,
maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, inulin, whelan, rhamsan,
zooglan, methylan, chitin, cyclodextrin, chitosan, polyvinyl pyrrolidone, cellulosics,
sucrose, and starches; and mixtures thereof. Suitable disintegrants include, but are not
limited to, sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked
carboxymethylcellulose, starches, microcrystalline cellulose, and mixtures thereof.
Suitable lubricants include, but are not limited to, long chain fatty acids and their
salts, such as magnesium stearate and stearic acid, talc, glycerides waxes, and mixtures
thereof. Suitable glidants include, but are not limited to, colloidal silicon dioxide. Suitable
17518482_1 (GHMatters) P115263.NZ
release-modifying excipients include, but are not limited to, insoluble edible materials, pH-
dependent polymers, and mixtures thereof.
Suitable insoluble edible materials for use as release-modifying excipients include,
but are not limited to, water-insoluble polymers and low-melting hydrophobic materials,
copolymers thereof, and mixtures thereof. Examples of suitable water-insoluble polymers
include, but are not limited to, ethylcellulose, polyvinyl alcohols, polyvinyl acetate,
polycaprolactones, cellulose acetate and its derivatives, acrylates, methacrylates, acrylic acid
copolymers, copolymers thereof, and mixtures thereof. Suitable low-melting hydrophobic
materials include, but are not limited to, fats, fatty acid esters, phospholipids, waxes, and
mixtures thereof. Examples of suitable fats include, but are not limited to, hydrogenated
vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated
cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil, free fatty acids
and their salts, and mixtures thereof. Examples of suitable fatty acid esters include, but are
not limited to, sucrose fatty acid esters, mono-, di-, and triglycerides, glyceryl behenate,
glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate,
glyceryl myristate, GlycoWax-932, lauroyl macrogol-32 glycerides, stearoyl macrogol-32
glycerides, and mixtures thereof. Examples of suitable phospholipids include phosphotidyl
choline, phosphotidyl serene, phosphotidyl enositol, phosphotidic acid, and mixtures
thereof. Examples of suitable waxes include, but are not limited to, carnauba wax,
spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin
wax; fat-containing mixtures such as chocolate, and mixtures thereof. Examples of super
disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate
and cross-linked povidone (crospovidone). In one embodiment the tablet core contains up to
about 5 percent by weight of such super disintegrant.
Examples of antioxidants include, but are not limited to, tocopherols, ascorbic acid,
sodium pyrosulfite, butylhydroxytoluene, butylated hydroxyanisole, edetic acid, and edetate
salts, and mixtures thereof. Examples of preservatives include, but are not limited to, citric
17518482_1 (GHMatters) P115263.NZ
acid, tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, and sorbic acid, and
mixtures thereof.
The osmotic tablets of the present invention include an osmotic coating. An
osmotic coating is one that is semipermeable thereby allows water to be drawn into the
tablet core, e.g., for the purposes of releasing the active ingredient such as through a pre-
made hole in the coating or through coating itself it is semipermeable membrane. The
osmotic coating, thus, does not fully dissolve upon contact with water In one embodiment,
the osmotic coating contains a water soluble component such as a water solible film former
which aids in facilitating a further influx of water upon contact with water. In the current
invention the osmotic coating is applied via spray coating. Suitable spray coating techniques
include spray coating via a coating pan or fluid bed process such as Wurster coating or top
spray fluid bed coating as described in the text, "The Theory and Practice of Industrial
Pharmacy", Lachman, Leon et. al, 3rd ed. The osmotic coating may be applied using a
solution prepared with water, organic solvents, or mixtures thereof. Suitable organic
solvents include but are not limited to acetone, isopropanol, methylene chloride, hexane,
methanol, ethanol, and mixtures thereof. In one embodiment the polymer(s) are dissolved in
the coating solution. In one embodiment, the polymer(s) are dispersed, as is the case when
applying water insoluble polymers via a dispersion or as is the case when using
ethylcellulose dispersions.
In one embodiment in which the osmotic coating functions as a semipermeable
membrane (e.g., allowing water or solvent to pass into the core, but being impermeable to
dissolved pharmaceutically active agent, thereby preventing the passage of pharmaceutically
active agent therethrough) the film former is selected from water insoluble polymers, pH-
dependent polymers, water soluble polymers, and combinations thereof. In one embodiment,
the osmotic coating includes a water insoluble polymer and a pore forming material.
Examples of suitable water-insoluble polymers include ethylcellulose, polyvinyl alcohols,
polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates,
methacrylates, acrylic acid copolymers, and combinations thereof. In one embodiment, the
17518482_1 (GHMatters) P115263.NZ
water insoluble polymer is cellulose acetate. In one embodiment, the osmotic coating
includes from about 10 to about 100 weight percent of a water insoluble film former.
In one embodiment of the osmotic coating, the water insoluble polymer is
combined with a water soluble film former in order to create pores in the resulting semi-
permeable membrane. Examples of suitable film formers include, but are not limited to:
water soluble vinyl polymers such as polyvinylalcohol (PVA); water soluble
polycarbohydrates such as hydroxypropyl starch, hydroxyethyl starch, pullulan, methylethyl
starch, carboxymethyl starch, pre-gelatinized starches, and film-forming modified starches;
water swellable cellulose derivatives such as hydroxypropyl cellulose (HPC),
hydroxypropylmethyl cellulose (HPMC), methyl cellulose (MC),
hydroxyethylmethylcellulose (HEMC), hydroxybutylmethylcellulose (HBMC),
hydroxyethylethylcellulose (HEEC), and hydroxyethylhydroxypropylmethyl cellulose
(HEMPMC); water soluble copolymers such as methacrylic acid and methacrylate ester
copolymers, polyvinyl alcohol and polyethylene glycol copolymers, polyethylene oxide and
polyvinylpyrrolidone copolymers; and mixtures thereof.
In one embodiment, a pH dependent polymer is incorporated into the osmotic
coating. In one embodiment, the pH dependent polymer is used at a level of from about 10
to about 50 percent by weight of the osmotic coating. Suitable film-forming pH-dependent
polymers include, but are not limited to, enteric cellulose derivatives, such as for example
hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate,
and cellulose acetate phthalate; natural resins such as shellac and zein; enteric acetate
derivatives such as polyvinylacetate phthalate, cellulose acetate phthalate, and acetaldehyde
dimethylcellulose acetate; and enteric acrylate derivatives such as for example
polymethacrylate-based polymers such as poly(methacrylic acid, methyl methacrylate) 1:2
(commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT
STM), and poly(methacrylic acid, methyl methacrylate) 1:1 (commercially available from
Rohm Pharma GmbH under the tradename EUDRAGIT LTM); and combinations thereof.
In one embodiment, the osmotic coating has an average thickness of at least 5 microns, such
as from about 10 microns to about 200 microns, e.g. from about 20 microns to about 150
17518482_1 (GHMatters) P115263.NZ
microns, e.g. from about 30 to about 150 microns. In one embodiment, the osmotic coating
is free of porosity (e.g., wherein the pore volume is in a pore diameter range of less than
0.01 g/cc). In one embodiment, the average pore diameter of the osmotic coating is less than
about 0.2 microns (e.g., less than about 0.15 microns).
In one embodiment, the osmotic coating is substantially free of anpharmaceutically
active agent. In one embodiment the osmotic coating includes anpharmaceutically active
agent which is different than the pharmaceutically active agent included in the immediate
release coating. In one embodiment, the osmotic coating includes a plasticizer. In one
embodiment the plasticizer must be of sufficient quantity to withstand the compression force
of the immediate release coating. Suitable plasticizers include, but are not limited to:
polyethylene glycol; propylene glycol; glycerin; sorbitol; triethyl citrate; tributyl citrate;
dibutyl sebecate; vegetable oils such as castor oil, grape oil, olive oil, and sesame oil;
surfactants such as polysorbates, sodium lauryl sulfates, and dioctyl-sodium sulfosuccinates;
mono acetate of glycerol; diacetate of glycerol; triacetate of glycerol; natural gums;
triacetin; acetyltributyl citrate; diethyloxalate; diethylmalate; diethyl fumarate;
diethylmalonate; dioctylphthalate; dibutylsuccinate; glycerol tributyrate; hydrogenated
castor oil; fatty acids such as lauric acid; glycerides such as mono-, di-, and/or triglycerides,
which may be substituted with the same or different fatty acids groups such as, for example,
stearic, palmitic, and oleic and the like; and mixtures thereof. In one embodiment, the
plasticizer is triethyl citrate.
In one embodiment, at least about 50 percent of the cross-sectional area of the
osmotic coating used in tablets of this invention is striated, such as at least about 80% of the
cross-sectional area of the osmotic coating portion is striated. As used herein, "striated"
means non-homogeneous with respect to appearance and with respect to the internal
structure of the coating portion when viewed under any magnification and lighting
conditions, at which point striations or layers can be viewed. Compressed portions of a
pharmaceutical oral dosage forms do not display striated areas, wherein spray coated
portions display striations. For example a crosssection of the osmotic coating portion is
17518482_1 (GHMatters) P115263.NZ
striated, and nonuniform with respect to refractive properties when observed utilizing a light
microscope or a scanning electron microscope at a magnification of about 50 to about 400
times. The characteristic striations are indicative of the spray-coating process consisting of
multiple repetitions of the steps consisting of: (a) application via spraying of coating
solution; followed by (b) warm air drying, to a tumbling bed of tablets in a revolving coating
pan such that numerous layers of coating material are built up as each application of coating
material dries to form a layer. In one embodiment, the thickness of an individual striated
layer is the range of about 10 microns to about 15 microns.
In certain embodiments, the osmotic coating is semipermeable (e.g., containing a
plurality of small opening) and does not require the addition of an additional opening via
laser or other means. In one such embodiment, the semi-permeable membrane of the
osmotic coating also allows for the release of the active ingredient in the tablet core through
the membrane in a zero-order or first-order release manner.
In one embodiment, the immediate release coating has an average thickness of at
least 50 microns, such as from about 50 microns to about 2500 microns; e.g., from about
250 microns to about 1000 microns. In embodiment, the immediate release coating is
typically compressed at a density of more than about 0.9 g/cc, as measured by the weight
and volume of that specific layer.
In one embodiment, the immediate release coating contains a first portion and a
second portion, wherein at least one of the portions contains the second pharmaceutically
active agent. In one embodiment, the portions contact each other at a center axis of the
tablet. In one embodiment, the first portion includes the first pharmaceutically active agent
and the second portion includes the second pharmaceutically active agent.
In one embodiment, the first portion contains the first pharmaceutically active
agent and the second portion contains the second pharmaceutically active agent. In one
embodiment, one of the portions contains a third pharmaceutically active agent. In one
17518482_1 (GHMatters) P115263.NZ
embodiment one of the portions contains a second immediate release portion of the same
pharmaceutically active agent as that contained in the tablet core.
In one embodiment, the outer coating portion is prepared as a dry blend of
materials prior to addition to the coated tablet core. In another embodiment the outer coating
portion is included of a dried granulation including the pharmaceutically active agent.
In one embodiment, a suitable flavor or aroma agent may be added to the outer
coating. Examples of suitable flavor and aroma agents include, but are not limited to,
essential oils including distillations, solvent extractions, or cold expressions of chopped
flowers, leaves, peel or pulped whole fruit containing mixtures of alcohols, esters, aldehydes
and lactones; essences including either diluted solutions of essential oils, or mixtures of
synthetic chemicals blended to match the natural flavor of the fruit (e.g., strawberry,
raspberry, and black currant); artificial and natural flavors of brews and liquors (e.g.,
cognac, whisky, rum, gin, sherry, port, and wine); tobacco, coffee, tea, cocoa, and mint; fruit
juices including expelled juice from washed, scrubbed fruits such as lemon, orange, and
lime; mint; ginger; cinnamon; cacoe/ cocoa; vanilla; liquorice; menthol; eucalyptus;
aniseeds nuts (e.g., peanuts, coconuts, hazelnuts, chestnuts, walnuts, and colanuts); almonds;
raisins; and powder, flour, or vegetable material parts including tobacco plant parts (e.g., the
genus Nicotiana in amounts not contributing significantly to a level of therapeutic nicotine),
and mixtures thereof.
Formulations with different drug release mechanisms described above could be
combined in a final dosage form containing single or multiple units. Examples of multiple
units include multilayer tablets, capsules containing tablets, beads, or granules in a solid or
liquid form. Typical, immediate release formulations include compressed tablets, gels, films,
coatings, liquids and particles that can be encapsulated, for example, in a gelatin capsule.
Many methods for preparing coatings, covering or incorporating drugs, are known in the art.
The immediate release dosage, unit of the dosage form, i.e., a tablet, a plurality of
drug-containing beads, granules or particles, or an outer layer of a coated core dosage form,
17518482_1 (GHMatters) P115263.NZ
contains a therapeutically effective quantity of the active agent with conventional
pharmaceutical excipients. The immediate release dosage unit may or may not be coated,
and may or may not be admixed with the delayed release dosage unit or units (as in an
encapsulated mixture of immediate release drug-containing granules, particles or beads and
delayed release drug-containing granules or beads). A preferred method for preparing
immediate release tablets (e.g., as incorporated into a capsule) is by compressing a
drugcontaining blend, e.g., blend of granules, prepared using a direct, blend, wet-granulation
or dry-granulation process. Immediate release tablets may also be molded rather than
compressed, starting with a moist material containing a suitable water-soluble lubricant.
However, preferred tablets described herein are manufactured using compression rather than
molding. A preferred method for forming immediate release drug-containing blend is to mix
drug particles directly with one or more excipients such as diluents (or fillers), binders,
disintegrants, lubricants, glidants, and/or colorants. As an alternative to direct blending, a
drug-containing blend may be prepared by using a wet-granulation or dry-granulation
process. Beads containing the active agent may also be prepared by any one of a number of
conventional techniques, typically starting from a fluid dispersion. For example, a typical
method for preparing drug-containing beads involves blending the active agent with
conventional pharmaceutical excipients such as microcrystalline cellulose, starch,
polyvinylpyrrolidone, methylcellulose, talc, metallic stearates, and silicone dioxide. The
admixture is used to coat a bead core such as a sugar sphere (e.g., "non-parcil") having a
size of approximately 20 to 60 mesh.
An alternative procedure forpreparing drug beads is by blending tile drug with one
or more pharmaceutically acceptable excipients, such as microcrystalline cellulose, lactose,
cellulose, polyvinyl pyrrolidone, talc, magnesium stearate, and a disintegrant, extruding the
blend, spheronizing the extrudate, drying and optionally coating the bead to form immediate
release beads.
Extended release formulations are generally prepared as diffusion or osmotic
systems, for example, as described in "Remington—The Science and Practice of Pharmacy",
17518482_1 (GHMatters) P115263.NZ
20th. Ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000). A diffusion system
typically consists of one of two types of devices, reservoir and matrix, which are wellknown
and described in die art. The matrix devices are generally prepared by compressing the drug
with a slowly dissolving polymer carrier into a tablet form. The three major types of
materials used in the preparation of matrix devices are insoluble plastics, hydrophilic
polymers, and fatty compounds. Plastic matrices include, but are not limited to, methyl
acrylate-methyl methacrylate, polyvinyl chloride, and polyethylene. Hydrophilic polymers
include, but are not limited to, methylcellulose, hydroxypropylcellulose,
hydorxypropylmethylcellulose, sodium carboxymethylcellulose, and Carbopol 934, and
polyethylene oxides. Fatty compounds include, but are not limited to, various waxes such as
carnauba wax and glyceryl tristearate. Alternatively, extended release formulations can be
prepared using osmotic systems or by applying a semi-permeable coating to the dosage
form. In the latter case, the desired drug release profile can be achieved by combining, low
permeability and high permeability coating materials in suitable proportion.
An immediate release portion can be added to the extended release system by
means of either applying an immediate release layer on top of the extended release core;
using coating or compression processes or in a multiple unit system such as a capsule
containing extended and immediate release beads.
Extended release tablets containing hydrophilic polymers are prepared by
techniques commonly known in the art such as direct compression, wet granulation, or dry
granulation processes. These formulations usually incorporate polymers, diluents, binders,
and lubricants as well as the active pharmaceutical ingredient. The usual diluents include
inert powdered substances such as different kinds of starch, powdered, cellulose, especially
crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose,
grain flours and similar edible powders. Typical diluents include, for example, various types
of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as
sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful.
Typical tablet binders include substances such as starch, gelatin and sugars such as lactose,
17518482_1 (GHMatters) P115263.NZ
fructose, and glucose. Natural and synthetic gums, including acacia, alginates,
methylcellulose, and polyvinylpyrrolidine can also be used. Polyethylene glycol, hydrophilic
polymers, ethycellulose and waxes can also serve as binders. A lubricant is necessary in a
tablet formulation to prevent the tablet and punches from sticking in the die. The lubricant is
chosen from such slippery solids as tale, magnesium and calcium stearate, stearic acid and
hydrogenated vegetable oils. Extended release tablets containing wax materials are generally
prepared using methods known in the art such as a direct blend method, a congealing
method, and an aqueous dispersion method. In the congealing method, the drug is mixed
with a wax material and either spray-congealed or congealed and screened and processed.
Delayed release dosage formulations are created by coating a solid dosage form
with a film of a polymer which is insoluble in the acid environment of the stomach, but
soluble in the neutral environment of small intestines. The delayed release dosage units can
be prepared, for example, by coating a drug or a drug-containing composition with a
selected coating material. The drug-containing composition may be a tablet for
incorporation into a capsule, a tablet for use as an inner core in a "coated core" dosage form,
or a plurality of drug-containing beads, particles or granules, for incorporation into either a
tablet or capsule. Preferred coating materials include bioerodible, gradually hydrolyzable,
gradually water-soluble, and/or enzymatically degradable polymers, and may be
conventional "enteric" polymers. Enteric polymers, as will be appreciated by those skilled in
the art, become soluble in the higher pH environment of the lower gastrointestinal tract or
slowly erode as the dosage form passes through the gastrointestinal tract, while
enzymatically degradable polymers are degraded by bacterial enzymes present in the lower
gastrointestinal tract, particularly in the colon. Suitable coating materials for effecting
delayed release include, but are not limited to, cellulosic polymers such as hydroxypropyl
cellulose, hydoxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose,
hydroxypropyl methyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate,
methylcellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose
acetate trimellitate and carboxymethylcellulose sodium; acrylic acid polymers and
copolymers, preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl
17518482_1 (GHMatters) P115263.NZ
acrylate, methyl methacrylate and/or ethyl methacrylate, and other methacrylic resins that
are commercially available under the tradename EUDRAGITTM (Rohm Pharma; [0086]
Westerstadt, Germany), including EUDRAGITTM L30D-55 and LlOO-55 (soluble at pH
,5 and above). EUDRAGITTM 1,100D (soluble at pH 6.0 and above), EUDRAGITTM S
(soluble at pH 7.0 and above, as a result of a higher degree of esterification), and
EUDRAGITTM NE, RL and RS (water-insoluble polymers having different degrees of
permeability and expandability); vinyl polymers and copolymets such as polyvinyl
pyrrolidone, vinyl acetate, vinylacetate phthalate, vinylacetate crotonic acid copolymer, and
ethylene-vinyl acetate copolymer; enzymatically degradable polymers such as azo polymers,
pectin, chitosan, amylase and guar gum; zein and shellac. Combinations of different coating,
materials may also be used. Multi-layer coatings using different polymers may also be
applied. The preferred coating weights for particular coating materials may be readily
determined by those skilled in the art by evaluating individual release profiles for tablets,
beads and granules prepared with different quantities of various coating materials. It is the
combination of materials, method, and form of application that produce the desired release
characteristics, which one can determine only from the clinical studies.
The coating composition may include conventional additives, such as plasticizers,
pigments, colorants, stabilizing agents, glidants, etc. A plasticizer is normally present to
reduce the fragility of the coating, and will generally represent about 10 wt. % to 50 wt. %
relative to the dry weight of the polymer. Examples of typical plasticizers include
polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate,
dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, triethyl acetyl citrate,
castor oil and acetylated monoglycerides. A stabilizing agent is preferably used to stabilize
particles in the dispersion. Typical stabilizing agents are nonionic emulsifiers such as
sorbitan esters, polysorbates and polyvinylpyrrolidone. Glidants are recommended to reduce
sticking effects during film formation and drying, and will generally represent
approximately 25 wt. % to 100 wt. % of the polymer weight in the coating solution. One
effective glidant is talc. Other glidants such as magnesium stearate and glycerol
monostearates may also be used. Pigments such as titanium dioxide may also be used. Small
17518482_1 (GHMatters) P115263.NZ
quantities of an anti-foaming agent, such as a silicone (e.g., simethicone), may also be added
to the coating composition.
Alternatively, a delayed release tablet may be formulated by dispersing tire drug
within a matrix of a suitable material such as a hydrophilic polymer or a fatty compound.
Suitable hydrophilic polymers include, but are not limited to, polymers or copolymers of
cellulose, cellulose ester, acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, and
vinyl or enzymatically degradable polymers or copolymers as described above. These
hydrophilic polymers are particularly useful for providing a delayed release matrix. Fatty
compounds for use as a matrix material include, but are hot limited to, waxes (e,g. carnauba
wax) and glycerol tristearate. Once the active ingredient is mixed with the matrix material,
the mixture can be compressed into tablets.
A pulsed release dosage form is one that mimics a multiple dosing profile without
repeated dosing and typically allows at least a twofold reduction in dosing frequency as
compared to the drug presented as a conventional dosage form (e.g., as a solution or prompt
drug-releasing, conventional solid dosage form). A pulsed release profile is characterized by
a time period of no release (lag time) or reduced release followed by rapid drug release.
Each dosage form contains a therapeutically effective amount of active agent. In
one embodiment of dosage forms that mimic a twice daily dosing profile, approximately 30
wt. % to 70 wt. %, preferably 40 wt. % to 60 wt. %, of the total amount of active agent in
the dosage form is released in the initial pulse, and, correspondingly approximately 70 wt. %
to 3.0 wt. %, preferably 60 wt. % to 40 wt. %, of the total amount of active agent in the
dosage form is released in the second pulse. For dosage forms mimicking the twice daily
dosing profile, the second pulse is preferably released approximately 3 hours to less than 14
hours, and more preferably approximately 5 hours to 12 hours, following administration.
For dosage forms mimicking a three times daily dosing profile, approximately 25
wt. % to 40 wt. % of the total amount of active agent in the dosage form is released in the
17518482_1 (GHMatters) P115263.NZ
initial pulse, and approximately 25 wt. % to 40 wt. % of the total amount of active agent in
the dosage form is released in each of the second and third pulses. For dosage forms that
mimic a three times daily dosing profile, release of the second pulse preferably takes place
approximately 3 hours to 10 hours, and more preferably approximately 4 to 9 hours,
following oral administration. Release of the third pulse occurs about 2 hours to about 8
hours following the second pulse, which is typically about 5 hours to approximately 18
hours following oral administration.
The dosage form can be a closed capsule housing at least two drug-containing
dosage units, each dosage unit containing one or more compressed tablets, or may contain, a
plurality of beads, granules or particles, providing that each dosage unit has a different drug
release profile. The immediate release dosage unit releases drug substantially immediately
following oral administration to provide an initial dose. The delayed release dosage unit
releases drug approximately 3 hours to 14 hours following oral administration to provide a
second dose. Finally, an optional second delayed release dosage unit releases drug about 2
hours to 8 hours following the release of the second dose, which is typically 5 hours to 18
hours following oral administration.
Another dosage form contains a compressed tablet or a capsule having a drug-
containing immediate release dosage unit, a delayed release dosage unit and an optional
second delayed release dosage unit. In this dosage form, the immediate release dosage unit
contains a plurality of beads, granules particles that release drug substantially immediately
following oral administration to provide an initial dose. The delayed release dosage unit
contains a plurality of coated beads or granules, which release drug approximately 3 hours
to 14 hours following oral administration to provide a second dose.
An optional second delayed release dosage unit contains coated beads or granules
that release drug about 2 to 8 hours following administration of the initial delayed release
dose, which is typically 5 to 18 hours following oral administration. The beads or granules
in the delayed release dosage unites) are coated with a bioerodible polymeric material. This
17518482_1 (GHMatters) P115263.NZ
coating prevents the drug from being released until the appropriate time, i.e., approximately
3 hours to less than 14 hours following oral administration for the delayed release dosage
unit and at least 5 hours to approximately 18 hours following oral administration for the
optional second delayed release dosage unit. In this dosage form the components may be
admixed in the tablet or may be layered to form a laminated tablet.
Another dosage form is a tablet having a drug-containing immediate release dosage
unit, a delayed release dosage unit, and an optional second delayed release dosage unit,
wherein the immediate release dosage unit comprises an outer layer that releases the drug
substantially immediately following oral administration. The arrangement of the remaining
delayed release dosage(s), however, depends upon whether the dosage form is designed to
mimic twice daily dosing or three times daily dosing.
In the dosage form mimicking twice daily dosing, the delayed release dosage unit
contains an inner core that is coated with a bioerodible polymeric material. The coating is
applied such that release of the drug occurs approximately 3 hours to less than 14 hours
following oral administration. In this form, the outer layer completely surrounds the inner
core. In the dosage form mimicking three times a day dosing, the (first) delayed release
dose contains an internal layer that releases drug approximately 3 hours to less than 14 hours
following oral administration. This internal layer is surrounded by the outer layer. The
second delayed release dosage unit generally contains an inner core that releases the drug at
least 5 hours to approximately 18 hours following oral administration. Thus, the layers of
this tablet (starting from the external surface) contain an outer layer, an internal layer and an
inner core. The inner core contains delayed release beads or granules. Furthermore, the
internal layer contains the drug coated with a bioerodible polymeric material. Alternatively,
in this particular dosage form mimicking three times a day dosing, both the delayed release
dosage unit and second delayed release dosage units are surrounded by an inner layer. This
inner layer is free of active agent. Thus, the layers of this tablet (starting from the external
surface) comprise an outer layer, inner layer and an admixture of the delayed release dosage
units. The first delayed release pulse occurs once the inner layer is substantially eroded
17518482_1 (GHMatters) P115263.NZ
thereby releasing the admixture of the delayed release dosage units. The dose corresponding
to the (first) delayed release dosage unit is released immediately since the inner layer has
prevented access to this dose for the appropriate time, e.g., from approximately 3 hours to
hours. The second delayed release dose, however, is formulated to effectively delay
release for at least 5 hours to approximately 18 hours following oral administration.
For formulations mimicking twice daily dosing, it is preferred that the delayed
release dose is released approximately 3 hours to up to 14 hours, more preferably
approximately 5 hours to up to 12 hours, following oral administration. For formulations
mimicking three times daily dosing, it is preferred that the (first) delayed release dose is
released approximately 3 to 10 hours, preferably 4 hours to 9 hours, following oral
administration. For dosage forms containing a third dose, the third dose (i.e., the second
delayed release dose) is released at least 5 hours to approximately 18 hours following oral
administration.
In still another embodiment, a dosage form is provided which contains a coated
core-type delivery system wherein the outer layer contains an immediate release dosage unit
containing an active agent, such that the active agent therein is immediately released
following oral administration; an intermediate layer there under which surrounds a core; and
a core which contains immediate release beads or granules and delayed release beads or
granules, such that the second dose is provided by the immediate release beads or granules
and the third dose is provided by the delayed release beads or granules.
For purposes of transdermal (e.g., topical) administration, dilute sterile, aqueous or
partially aqueous solutions (usually in about 0.1% to 5% concentration), otherwise similar to
the above parenteral solutions, may be prepared.
Methods of preparing various pharmaceutical compositions with a certain amount
of one or more compounds of formula I, formula II, formula III, formula IV, formula V,
formula VI, formula VII or formula VIII or other active agents are known, or will be
17518482_1 (GHMatters) P115263.NZ
apparent in light of this disclosure, to those skilled in this art. For examples of methods of
preparing pharmaceutical compositions, see Remington's Pharmaceutical Sciences, Mack
Publishing Company, Easton, Pa., 19th Edition (1995).
In addition, in certain embodiments, subject compositions of the present
application maybe lyophilized or subjected to another appropriate drying technique such as
spray drying. The subject compositions may be administered once, or may be divided into a
number of smaller doses to be administered at varying intervals of time, depending in part
on the release rate of the compositions and the desired dosage.
Formulations useful in the methods provided herein include those suitable for oral,
nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral
administration. The formulations may conveniently be presented in unit dosage form and
may be prepared by any methods well known in the art of pharmacy. The amount of a
subject composition which may be combined with a carrier material to produce a single dose
may vary depending upon the subject being treated, and the particular mode of
administration.
Methods of preparing these formulations or compositions include the step of
bringing into association subject compositions with the carrier and, optionally, one or more
accessory ingredients. In general, the formulations are prepared by uniformly and intimately
bringing into association a subject composition with liquid carriers, or finely divided solid
carriers, or both, and then, if necessary, shaping the product.
The compounds of formula I, formula II, formula III, formula IV, formula V,
formula VI, formula VII or formula VIII described herein may be administered in inhalant
or aerosol formulations. The inhalant or aerosol formulations may comprise one or more
agents, such as adjuvants, diagnostic agents, imaging agents, or therapeutic agents useful in
inhalation therapy. The final aerosol formulation may for example contain 0.005-90% w/w,
17518482_1 (GHMatters) P115263.NZ
for instance 0.005-50%, 0.005-5% w/w, or 0.01-1.0% w/w, of medicament relative to the
total weight of the formulation.
It is desirable, but by no means required, that the formulations herein contain no
components which may provoke the degradation of stratospheric ozone. In particular it is
desirable that the formulations are substantially free of chlorofluorocarbons such as CCl3F,
CCl2F2 and CF3CCl3. As used to refer to ozone-damaging agents, “substantially free”
means less than 1% w/w based upon the propellant system, in particular less than 0.5%, for
example 0.1% or less.
The propellant may optionally contain an adjuvant having a higher polarity and/or
a higher boiling point than the propellant. Polar adjuvants which may be used include (e.g.,
C2-6) aliphatic alcohols and polyols such as ethanol, isopropanol and propylene glycol. In
general, only small quantities of polar adjuvants (e.g., 0.05-3.0% w/w) may be required to
improve the stability of the dispersion--the use of quantities in excess of 5% w/w may tend
to dissolve the medicament. The formulations described herein may contain less than 1%
w/w, e.g., about 0.1% w/w, of polar adjuvant. However, the formulations may be
substantially free of polar adjuvants, such as ethanol. Suitable volatile adjuvants include
saturated hydrocarbons such as propane, n-butane, isobutane, pentane and isopentane and
alkyl ethers such as dimethyl ether. In general, up to 50% w/w of the propellant may
comprise a volatile adjuvant, for example 1 to 30% w/w of a volatile saturated C1-C6
hydrocarbon.
Optionally, the aerosol formulations may further comprise one or more surfactants.
The surfactants must be physiologically acceptable upon administration by inhalation.
Within this category are included surfactants such as L-α-phosphatidylcholine (PC), 1,2-
dipalmitoylphosphatidycholine (DPPC), oleic acid, sorbitan trioleate, sorbitan mono-oleate,
sorbitan monolaurate, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20)
sorbitan monooleate, natural lecithin, oleyl polyoxyethylene (2) ether, stearyl
polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, block copolymers of
17518482_1 (GHMatters) P115263.NZ
oxyethylene and oxypropylene, synthetic lecithin, diethylene glycol dioleate,
tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glyceryl monooleate, glyceryl
monostearate, glyceryl monoricinoleate, cetyl alcohol, stearyl alcohol, polyethylene glycol
400, cetyl pyridinium chloride, benzalkonium chloride, olive oil, glyceryl monolaurate, corn
oil, cotton seed oil, and sunflower seed oil. Appropriate surfactants include lecithin, oleic
acid, and sorbitan trioleate.
Ophthalmic formulations, eye ointments, powders, solutions and the like, are also
contemplated as being within the scope of the disclosures herein.
Certain pharmaceutical compositions disclosed herein suitable for parenteral
administration comprise one or more subject compositions in combination with one or more
pharmaceutically acceptable sterile, isotonic, aqueous, or non-aqueous solutions,
dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into
sterile injectable solutions or dispersions just prior to use, which may contain antioxidants,
buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the
intended recipient or suspending or thickening agents.
Examples of suitable aqueous and non-aqueous carriers which may be employed in
the pharmaceutical compositions include water, ethanol, polyols (such as glycerol,
propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable
oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity may
be maintained, for example, by the use of coating materials, such as lecithin, by the
maintenance of the required particle size in the case of dispersions, and by the use of
surfactants.
Formulations suitable for oral administration may be in the form of capsules,
cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or
tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-
aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup,
17518482_1 (GHMatters) P115263.NZ
or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia), each
containing a predetermined amount of a subject composition as an active ingredient.
Subject compositions may also be administered as a bolus, electuary, or paste.
In solid dosage forms for oral administration (capsules, tablets, pills, dragees,
powders, granules and the like), the subject composition is mixed with one or more
pharmaceutically acceptable carriers and/or any of the following: (1) fillers or extenders,
such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as,
for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose
and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium
carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as
quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol
and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants,
such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and
pills, the pharmaceutical compositions may also comprise buffering agents. Solid
compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin
capsules using lactose or milk sugars, as well as high molecular weight polyethylene glycols
and the like.
A tablet may be made by compression or molding, optionally with one or more
accessory ingredients. Compressed tablets may be prepared using a binder (for example,
gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant
(for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),
surface-altering or dispersing agent. Molded tablets may be made by molding in a suitable
machine a mixture of the subject composition moistened with an inert liquid diluent.
Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may
optionally be scored or prepared with coatings and shells, such as enteric coatings and other
coatings well known in the pharmaceutical-formulating art.
17518482_1 (GHMatters) P115263.NZ
There has been widespread use of tablets since the latter part of the 19th century
and the majority of pharmaceutical dosage forms are marketed as tablets. Major reasons of
tablet popularity as a dosage form are simplicity, low cost and the speed of production.
Other reasons include stability of drug product, convenience in packaging, shipping and
dispensing. To the patient or consumer, tablets offer convenience of administration, ease of
accurate dosage, compactness, portability, blandness of taste, ease of administration and
elegant distinctive appearance.
Tablets may be plain, film or sugar coated, bisected, embossed, layered or
sustained- release. They can be made in a variety of sizes, shapes and colors. Tablets may be
swallowed, chewed or dissolved in the buccal cavity or beneath the tongue. They may be
dissolved in water for local or topical application. Sterile tablets are normally used for
parenteral solutions and for implantation beneath the skin.
In addition to the active or therapeutic ingredients, tablets may contain a number of
inert materials known as excipients. They may be classified according to the role they play
in the final tablet. The primary composition may include one or more of a filler, binder,
lubricant and glidant. Other excipients which give physical characteristics to the finished
tablet are coloring agents, and flavors (especially in the case of chewable tablets). Without
excipients most drugs and pharmaceutical ingredients cannot be directly-compressed into
tablets. This is primarily due to the poor flow and cohesive properties of most drugs.
Typically, excipients are added to a formulation to impart good flow and compression
characteristics to the material being compressed. Such properties are imparted through
pretreatment steps, such as wet granulation, slugging, spray drying spheronization or
crystallization.
Lubricants are typically added to prevent the tableting materials from sticking to
punches, minimize friction during tablet compression, and allow for removal of the
compressed tablet from the die. Such lubricants are commonly included in the final tablet
mix in amounts usually of about 1% by weight.
17518482_1 (GHMatters) P115263.NZ
Other desirable characteristics of excipients include the following: high-
compressibility to allow strong tablets to be made at low compression forces; impart
cohesive qualities to the powdered material; acceptable rate of disintegration; good flow
properties that can improve the flow of other excipients in the formula; and cohesiveness (to
prevent tablet from crumbling during processing, shipping and handling).
There are at least three commercially important processes for making compressed
tablets: wet granulation, direct compression and dry granulation (slugging or roller
compaction). The method of preparation and type of excipients are selected to give the tablet
formulation the desired physical characteristics that allow for the rapid compression of the
tablets. After compression, the tablets must have a number of additional attributes, such as
appearance, hardness, disintegrating ability and an acceptable dissolution profile. Choice of
fillers and other excipients will depend on the chemical and physical properties of the drug,
behavior of the mixture during processing and the properties of the final tablets.
Preformulation studies are done to determine the chemical and physical compatibility of the
active component with proposed excipients.
The properties of the drug, its dosage forms and the economics of the operation
will determine selection of the best process for tableting. Generally, both wet granulation
and direct compression are used in developing a tablet.
One formulation comprises the following: a compound of formula I, formula II,
formula III, formula IV, formula V, formula VI, formula VII or formula VIII , and a binder.
Examples of pharmaceutically acceptable binders include, but are not limited to, starches;
celluloses and derivatives thereof, e.g., microcrystalline cellulose, hydroxypropyl cellulose
hydroxylethyl cellulose and hydroxylpropylmethyl cellulose; sucrose; dextrose; corn syrup;
polysaccharides; and gelatin. The binder, e.g., may be present in an amount from about 1 %
to about 40% by weight of the composition such as 1 % to 30% or 1 % to 25% or 1 % to
%.
17518482_1 (GHMatters) P115263.NZ
Optionally, one, two, three or more diluents can be added to the formulations
disclosed herein. Examples of pharmaceutically acceptable fillers and pharmaceutically
acceptable diluents include, but are not limited to, confectioner's sugar, compressible sugar,
dextrates, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered
cellulose, sorbitol, sucrose and talc. The filler and/or diluent, e.g., may be present in an
amount from about 15% to about 40% by weight of the composition. In certain
embodiments, diluents are microcrystalline cellulose which is manufactured by the
controlled hydrolysis of alpha-cellulose, obtained as a pulp from fibrous plant materials,
with dilute mineral acid solutions. Following hydrolysis, the hydrocellulose is purified by
filtration and the aqueous slurry is spray dried to form dry, porous particles of a broad size
distribution. Suitable microcrystalline cellulose will have an average particle size of from
about 20 nm to about 200 nm. Microcrystalline cellulose is available from several suppliers.
Suitable microcrystalline cellulose includes Avicel PH 101, Avicel PH 102, Avicel PH 103,
Avicel PH 105 and Avicel PH 200, manufactured by FMC Corporation. The
microcrystalline cellulose may be present in a tablet formulation in an amount of from about
% to about 70% by weight. Another appropriate range of this material is from about 30%
to about 35% by weight; yet another appropriate range of from about 30% to about 32% by
weight. Another diluent is lactose. The lactose may be ground to have an average particle
size of between about 50 μm and about 500 μm prior to formulating. The lactose may be
present in the tablet formulation in an amount of from about 5% to about 40% by weight,
and can be from about 18% to about 35% by weight, for example, can be from about 20% to
about 25% by weight.
Optionally one, two, three or more disintegrants can be added to the formulations
described herein. Examples of pharmaceutically acceptable disintegrants include, but are not
limited to, starches; clays; celluloses; alginates; gums; cross-linked polymers, e.g., cross-
linked polyvinyl pyrrolidone, cross-linked calcium carboxymethylcellulose and cross-linked
sodium carboxymethylcellulose; soy polysaccharides; and guar gum. The disintegrant, e.g.,
may be present in an amount from about 2% to about 20%, e.g., from about 5% to about
%, e.g., about 7% about by weight of the composition. A disintegrant is also an optional
17518482_1 (GHMatters) P115263.NZ
but useful component of the tablet formulation. Disintegrants are included to ensure that the
tablet has an acceptable rate of disintegration. Typical disintegrants include starch
derivatives and salts of carboxymethylcellulose. Sodium starch glycolate is one appropriate
disintegrant for this formulation. In certain embodiments, the disintegrant is present in the
tablet formulation in an amount of from about 0% to about 10% by weight, and can be from
about 1% to about 4% by weight, for instance from about 1.5% to about 2.5% by weight.
Optionally one, two, three or more lubricants can be added to the formulations
disclosed herein. Examples of pharmaceutically acceptable lubricants and pharmaceutically
acceptable glidants include, but are not limited to, colloidal silica, magnesium trisilicate,
starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium
stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose
and microcrystalline cellulose. The lubricant, e.g., may be present in an amount from about
0.1% to about 5% by weight of the composition; whereas, the glidant, e.g., may be present
in an amount from about 0.1% to about 10% by weight. Lubricants are typically added to
prevent the tableting materials from sticking to punches, minimize friction during tablet
compression and allow for removal of the compressed tablet from the die. Such lubricants
are commonly included in the final tablet mix in amounts usually less than 1% by weight.
The lubricant component may be hydrophobic or hydrophilic. Examples of such lubricants
include stearic acid, talc and magnesium stearate. Magnesium stearate reduces the friction
between the die wall and tablet mix during the compression and ejection of the tablets. It
helps prevent adhesion of tablets to the punches and dies. Magnesium stearate also aids in
the flow of the powder in the hopper and into the die. It has a particle size range of 450-550
microns and a density range of 1.00-1.80 g/mL It is stable and does not polymerize within
the tableting mix. One lubricant, magnesium stearate may also be employed in the
formulation. In some aspects, the lubricant is present in the tablet formulation in an amount
of from about 0.25% to about 6%; also appropriate is a level of about 0.5% to about 4% by
weight; and from about 0.1% to about 2% by weight. Other possible lubricants include talc,
polyethylene glycol, silica and hardened vegetable oils. In an optional embodiment, the
17518482_1 (GHMatters) P115263.NZ
lubricant is not present in the formulation, but is sprayed onto the dies or the punches rather
than being added directly to the formulation.
Examples of useful excipients which can optionally be added to the composition
are described in the Handbook of Pharmaceutical Excipients, 3rd edition, Edited by
A.H.Kibbe, Published by: American Pharmaceutical Association, Washington DC, ISBN: 0-
917330X, or Handbook of Pharmaceutical Excipients (4th edition), Edited by Raymond
C Rowe - Publisher: Science and Practice.
Liquid dosage forms for oral administration include pharmaceutically acceptable
emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the
subject compositions, the liquid dosage forms may contain inert diluents commonly used in
the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers,
such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,
benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, corn,
peanut, sunflower, soybean, olive, castor, and sesame oils), glycerol, tetrahydrofuryl
alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Suspensions, in addition to the subject compositions, may contain suspending
agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and
sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar
and tragacanth, and mixtures thereof.
Formulations for rectal or vaginal administration may be presented as a
suppository, which may be prepared by mixing a subject composition with one or more
suitable non-irritating carriers comprising, for example, cocoa butter, polyethylene glycol, a
suppository wax, or a salicylate, and which is solid at room temperature, but liquid at body
temperature and, therefore, will melt in the appropriate body cavity and release the
encapsulated compound(s) and composition(s). Formulations which are suitable for vaginal
17518482_1 (GHMatters) P115263.NZ
administration also include pessaries, tampons, creams, gels, pastes, foams, or spray
formulations containing such carriers as are known in the art to be appropriate.
Dosage forms for transdermal administration include powders, sprays, ointments,
pastes, creams, lotions, gels, solutions, patches, and inhalants. A subject composition may
be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any
preservatives, buffers, or propellants that may be required. For transdermal administration,
the complexes may include lipophilic and hydrophilic groups to achieve the desired water
solubility and transport properties.
The ointments, pastes, creams and gels may contain, in addition to subject
compositions, other carriers, such as animal and vegetable fats, oils, waxes, paraffins, starch,
tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc
and zinc oxide, or mixtures thereof. Powders and sprays may contain, in addition to a
subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide,
calcium silicates and polyamide powder, or mixtures of such substances. Sprays may
additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile
unsubstituted hydrocarbons, such as butane and propane.
Methods of delivering a composition or compositions via a transdermal patch are
known in the art. Exemplary patches and methods of patch delivery are described in US
Patent Nos. 6,974,588, 6,564,093, 6,312,716, 6,440,454, 6,267,983, 6,239,180, and
6,103,275.
In one embodiment, a transdermal patch may comprise an outer backing foil, a
matrix and a protective liner wherein a) the composition or compositions are present in the
matrix in a solution (which may be oversaturated), b) the matrix may contain 1 to 5%
activated SiO2, and c) the matrix may have a moisture content of less than 0.7%. Moisture-
free matrix patches which contain activated silicon dioxide in the matrix show an enhanced
drug release into the skin.
17518482_1 (GHMatters) P115263.NZ
In another embodiment, a transdermal patch may comprise: a substrate sheet
comprising a composite film formed of a resin composition comprising 100 parts by weight
of a polyvinyl chloride-polyurethane composite and 2-10 parts by weight of a styrene-
ethylene-butylene-styrene copolymer, a first adhesive layer on the one side of the composite
film, and a polyalkylene terephthalate film adhered to the one side of the composite film by
means of the first adhesive layer, a primer layer which comprises a saturated polyester resin
and is formed on the surface of the polyalkylene terephthalate film; and a second adhesive
layer comprising a styrene-diene-styrene block copolymer containing a pharmaceutical
agent layered on the primer layer. A method for the manufacture of the above-mentioned
substrate sheet comprises preparing the above resin composition molding the resin
composition into a composite film by a calendar process, and then adhering a polyalkylene
terephthalate film on one side of the composite film by means of an adhesive layer thereby
forming the substrate sheet, and forming a primer layer comprising a saturated polyester
resin on the outer surface of the polyalkylene terephthalate film.
The pharmaceutical compositions herein can be packaged to produce a "reservoir
type" transdermal patch with or without a rate-limiting patch membrane. The size of the
patch and or the rate limiting membrane can be chosen to deliver the transdermal flux rates
desired. Such a transdermal patch can consist of a polypropylene/polyester impervious
backing member heat-sealed to a polypropylene porous/permeable membrane with a
reservoir there between. The patch can include a pharmaceutically acceptable adhesive (such
as a acrylate, silicone or rubber adhesive) on the membrane layer to adhere the patch to the
skin of the host, e.g., a mammal such as a human. A release liner such as a polyester release
liner can also be provided to cover the adhesive layer prior to application of the patch to the
skin as is conventional in the art. This patch assembly can be packaged in an aluminum foil
or other suitable pouch, again as is conventional in the art.
Alternatively, the compositions herein can be formulated into a "matrix-type"
transdermal patch. Drug Delivery Systems Characteristics and Biomedical Application, R. L
Juliano, ed., Oxford University Press. N.Y. (1980); and Controlled Drug Delivery, Vol. I
17518482_1 (GHMatters) P115263.NZ
Basic Concepts, Stephen D. Bruck (1983) describe the theory and application of methods
useful for transdermal delivery systems. The drug-matrix could be formed utilizing various
polymers, e.g. silicone, polyvinyl alcohol. The "drug matrix" may then be packaged into an
appropriate transdermal patch.
Another type of patch comprises incorporating the drug directly in a
pharmaceutically acceptable adhesive and laminating the drug-containing adhesive onto a
suitable backing member, e.g. a polyester backing membrane. The drug should be present at
a concentration which will not affect the adhesive properties, and at the same time deliver
the required clinical dose.
Transdermal patches may be passive or active. Passive transdermal drug delivery
systems currently available, such as the nicotine, estrogen and nitroglycerine patches,
deliver small-molecule drugs. Many of the newly developed proteins and peptide drugs are
too large to be delivered through passive transdermal patches and may be delivered using
technology such as electrical assist (iontophoresis) for large-molecule drugs.
Iontophoresis is a technique employed for enhancing the flux of ionized substances
through membranes by application of electric current. One example of an iontophoretic
membrane is given in U.S. Pat. No. 5,080,646 to Theeuwes. The principal mechanisms by
which iontophoresis enhances molecular transport across the skin are (a) repelling a charged
ion from an electrode of the same charge, (b) electroosmosis, the convective movement of
solvent that occurs through a charged pore in response the preferential passage of counter-
ions when an electric field is applied or (c) increase skin permeability due to application of
electrical current.
Methods and compositions for the treatment of cancer. Among other things, herein
is provided a method of treating cancer, comprising administering to a patient in need
thereof a therapeutically effective amount of compound of Formula I:
17518482_1 (GHMatters) P115263.NZ
R R O
O R R
O N N O
Formula I
and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and
stereoisomers thereof;
Wherein,
R , R represents CD , CD , H, D, O, OD, CD CO, NULL,
1 3 3 2 3
, , ,
, , , ,
, , ,
, , ,
17518482_1 (GHMatters) P115263.NZ
, , ,
, , ,
, , ,
17518482_1 (GHMatters) P115263.NZ
or ;
R , R independently represents
17518482_1 (GHMatters) P115263.NZ
Within the proviso, Wherein
n represents 0 to 12;
R and R independently represents
17518482_1 (GHMatters) P115263.NZ
17518482_1 (GHMatters) P115263.NZ
Methods and compositions for the treatment of cancer. Among other things, herein
is provided a method of treating cancer, comprising administering to a patient in need
thereof a therapeutically effective amount of compound of Formula II:
Formula II
and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and
stereoisomers thereof;
Wherein,
R , R represents CD , CD , H, D, O, OD, CD CO, NULL,
1 3 3 2 3
, , ,
, , , ,
, , ,
17518482_1 (GHMatters) P115263.NZ
, , ,
, , ,
, , ,
, , ,
17518482_1 (GHMatters) P115263.NZ
or ;
R , R independently represents
17518482_1 (GHMatters) P115263.NZ
Within the proviso, Wherein
n represents 0 to 12;
R and R independently represents
17518482_1 (GHMatters) P115263.NZ
17518482_1 (GHMatters) P115263.NZ
Methods and compositions for the treatment of cancer. Among other things, herein
is provided a method of treating cancer, comprising administering to a patient in need
thereof a therapeutically effective amount of compound of Formula III:
Formula III
and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and
stereoisomers thereof;
Wherein,
R , R , R represents CD , CD , H, D, O, OD, CD CO, NULL,
1 3 5 3 2 3
, , ,
, , , ,
17518482_1 (GHMatters) P115263.NZ
, , ,
, , ,
, , ,
, , ,
, , ,
, , ,
17518482_1 (GHMatters) P115263.NZ
, , ,
, , ,
or ;
R , R independently represents
17518482_1 (GHMatters) P115263.NZ
Within the proviso, Wherein
n represents 0 to 12;
R independently represents NULL,
17518482_1 (GHMatters) P115263.NZ
17518482_1 (GHMatters) P115263.NZ
Methods and compositions for the treatment of cancer. Among other things, herein
is provided a method of treating cancer, comprising administering to a patient in need
thereof a therapeutically effective amount of compound of Formula IV:
Formula IV
and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and
stereoisomers thereof;
Wherein,
R , R , R , R represents CD , CD , H, D, O, OD, CD CO, NULL,
1 3 5 7 3 2 3
, , ,
, , , ,
17518482_1 (GHMatters) P115263.NZ
, , ,
, , ,
, , ,
, , ,
, , ,
17518482_1 (GHMatters) P115263.NZ
or ;
R , R , R , R independently represents
2 4 6 8
17518482_1 (GHMatters) P115263.NZ
Within the proviso, Wherein
n represents 0 to 12;
R and R independently represents
17518482_1 (GHMatters) P115263.NZ
17518482_1 (GHMatters) P115263.NZ
Methods and compositions for the treatment of cancer. Among other things, herein
is provided a method of treating cancer, comprising administering to a patient in need
thereof a therapeutically effective amount of compound of Formula V:
Formula V
and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and
stereoisomers thereof;
Wherein,
R1, R3, R5 represents CD3, CD2, H, D, O, OD, CD3CO, NULL,
, , ,
, , , ,
17518482_1 (GHMatters) P115263.NZ
, , ,
, , ,
, , ,
, , ,
, , ,
17518482_1 (GHMatters) P115263.NZ
or ;
R , R , R independently represents
2 4 6
17518482_1 (GHMatters) P115263.NZ
Within the proviso, Wherein
n represents 0 to 12;
R and R independently represents
17518482_1 (GHMatters) P115263.NZ
17518482_1 (GHMatters) P115263.NZ
Methods and compositions for the treatment of cancer. Among other things, herein
is provided a method of treating cancer, comprising administering to a patient in need
thereof a therapeutically effective amount of compound of Formula VI:
Formula VI
and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and
stereoisomers thereof;
Wherein,
R , R , R represents CD , CD , H, D, O, OD, CD CO, NULL,
1 3 5 3 2 3
, , ,
, , , ,
17518482_1 (GHMatters) P115263.NZ
, , ,
, , ,
, , ,
, , ,
, , ,
, , ,
17518482_1 (GHMatters) P115263.NZ
, , ,
, , ,
or ;
R , R independently represents
, or
17518482_1 (GHMatters) P115263.NZ
R independently represents H, D, NULL,
17518482_1 (GHMatters) P115263.NZ
17518482_1 (GHMatters) P115263.NZ
Within the proviso,
Wherein
n represents 0 to 12;
R and R independently represents
17518482_1 (GHMatters) P115263.NZ
Methods and compositions for the treatment of cancer. Among other things, herein
is provided a method of treating cancer, comprising administering to a patient in need
thereof a therapeutically effective amount of compound of Formula VII:
Formula VII
and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and
stereoisomers thereof;
Wherein,
R , R represents CD , CD , H, D, O, OD, CD CO, NULL,
1 3 3 2 3
17518482_1 (GHMatters) P115263.NZ
, , ,
, , , ,
, , ,
, , ,
, , ,
, , ,
17518482_1 (GHMatters) P115263.NZ
, , ,
, , ,
, , ,
, , ,
or ;
R , R independently represents
17518482_1 (GHMatters) P115263.NZ
17518482_1 (GHMatters) P115263.NZ
17518482_1 (GHMatters) P115263.NZ
Within the proviso,
Wherein
n represents 0 to 12;
R and R independently represents
17518482_1 (GHMatters) P115263.NZ
Methods and compositions for the treatment of cancer. Among other things, herein
is provided a method of treating cancer, comprising administering to a patient in need
thereof a therapeutically effective amount of compound of Formula VIII:
O N N
Formula VIII
and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and
stereoisomers thereof;
Wherein,
R represents CD , CD , H, D, O, OD, CD CO, NULL,
1 3 2 3
, , ,
17518482_1 (GHMatters) P115263.NZ
, , , ,
, , ,
, , ,
, , ,
, , ,
, , ,
17518482_1 (GHMatters) P115263.NZ
, , ,
, , ,
, , ,
or ;
R independently represents
17518482_1 (GHMatters) P115263.NZ
17518482_1 (GHMatters) P115263.NZ
17518482_1 (GHMatters) P115263.NZ
Within the proviso,
Wherein
n represents 0 to 12;
R and R independently represents
17518482_1 (GHMatters) P115263.NZ
METHODS OF MAKING
Examples of synthetic pathways useful for making compounds of formulas’ are set
forth in example below and generalized in Example 1, Example 2:
Example 1:
Preparation of (2R,3R,4R,5R)(5-fluorooxo
(pentyloxycarbonylamino)pyrimidin-1(2H)-yl)methyl tetrahydrofuran-3,4-diyl
didodecanoate (Step-1):
To a stirred solution of pentyl 1-((2R,3R,4S,5R)-3,4-dihydroxymethyl tetrahydrofuran
yl)fluorooxo-1,2-dihydropyrimidinyl carbamate (5 g, 13.923 mmol), Lauric acid
(5.85 g, 29.239 mmol) in CH Cl (100 mL) was added DCC (8.61 g, 41.771 mmol), DMAP
17518482_1 (GHMatters) P115263.NZ
(84.9 mg, 0.696 mmol) and stirred at RT for 36 h. The progress of the reaction was
monitored by TLC. The reaction mixture was quenched with sat NaHCO solution (100
mL), extracted with CH Cl (100 mL). The combined organic layer was washed with water
(50 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure.
The crude compound was purified by column chromatography (silica gel 100-200 mesh,
eluted with 8% EtOAc in Hexane) to afford (2R,3R,4R,5R)(5-fluorooxo
(pentyloxycarbonylamino)pyrimidin-1(2H)-yl)methyltetrahydrofuran-3,4-diyl
didodecanoate (3.5 g, 34% yield) as off white solid.
Example 2:
Preparation of 4-amino((2R,3R,4S,5R)-3,4-dihydroxymethyltetrahydrofuran
yl)fluoropyrimidin-2(1H)-one (Step-1):
To a stirred solution of (2R,3R,4R,5R)(4-aminofluorooxopyrimidin-1(2H)-yl)
methyltetrahydrofuran-3,4-diyl-diacetate (20 g, 60.77 mmol) in MeOH (140 mL) was added
Diethyl amine (0.64 mL, 6.07 mmol) at RT under nitrogen atmosphere and stirred the
reaction mixture at 50 °C for 2 h. The progress of the reaction was monitored by TLC. The
17518482_1 (GHMatters) P115263.NZ
reaction mixture was diluted with Toluene (240 mL) at 50 °C, allowed to stir the reaction
mixture at RT for 30 min and the solid formed was filtered, washed with Toluene (10 mL)
followed by Hexane (10 mL), dried under vacuum to afford 4-amino((2R,3R,4S,5R)-3,4-
dihydroxymethyltetrahydrofuranyl)fluoropyrimidin-2(1H)-one (12 g, 80% yield) as
off white solid.
Preparation of (5Z,5'Z,8Z,8'Z,11Z,11'Z,14Z,14'Z,17Z,17'Z)-(2R,3R,4R,5R)(4-amino-
-fluorooxopyrimidin-1(2H)-yl)methyltetrahydrofuran-3,4-diyl bis(icosa-
,8,11,14,17-pentaenoate) (Step-2):
To a stirred solution of 4-amino((2R,3R,4S,5R)-3,4-dihydroxymethyl tetra hydrofuran-
2-yl)fluoropyrimidin-2(1H)-one (7 g, 28.56 mmol) in DMF (140 mL) was added DCC
(17.71 g, 85.68 mmol), DMAP (0.35 g, 2.85 mmol) followed by EPA (25.9 g, 85.68 mmol)
and stirred the reaction mixture at RT for 24 h. The progress of the reaction was monitored
by TLC. The reaction mixture was diluted with EtOAc (600 mL), filtered and the filtrate
was washed with water (4x300 mL) followed by brine (300 mL). The combined organic
layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure.
The crude compound was purified by column chromatography (silica gel 100-200 mesh,
eluted with 40% EtOAc in Hexane) followed by comb flash reverse phase column
purification to afford (5Z,5'Z,8Z,8'Z,11Z,11'Z,14Z,14'Z,17Z,17'Z)-(2R,3R,4R,5R)(4-
aminofluorooxopyrimidin-1(2H)-yl)methyltetrahydrofuran-3,4-diyl-bis(icosa-
,8,11,14,17-pentaenoate) (3 g, 13% yield) as Pale yellow liquid.
Preparation of (2R,3R,4R,5R)(4-dodecanamidofluorooxopyrimidin-1(2H)-yl)-
-methyltetrahydrofuran-3,4-diyldidodecanoate (Step-3):
To a stirred solution of 4-amino((2R,3R,4S,5R)-3,4-dihydroxymethyl tetra hydrofuran-
2-yl)fluoropyrimidin-2(1H)-one (12 g, 48.96 mmol) in CH Cl (102 mL), DMF (5 mL)
was added DCC (420 mg, 2.04 mmol), DMAP (7 mg, 0.06 mmol) followed by Lauric acid
(326 mg, 1.63 mmol) at 10-15 °C under nitrogen atmosphere and stirred the reaction mixture
at RT for 48 h. The progress of the reaction was monitored by TLC. The reaction mixture
was filtered through a pad of celite, washed with CH Cl (36 mL). The filtrate was washed
17518482_1 (GHMatters) P115263.NZ
with water (140 mL) followed by brine (140 mL), dried over anhydrous sodium sulphate and
concentrated under reduced pressure. The crude compound was purified by column
chromatography (silica gel 100-200 mesh, eluted with 20% EtOAc in Hexane) to afford
(2R,3R,4R,5R)(4-dodecanamidofluorooxopyrimidin-1(2H)-yl)
methyltetrahydrofuran-3,4-diyldidodecanoate (4.5 g, 11.6% yield) as Pale yellow semi-solid.
Example 3:
Synthesis of (2R,3R,4R,5R)(5-fluorooctanamidooxopyrimidin-1(2H)-yl)
methyltetrahydrofuran-3,4-diyl diacetate (3): To an ice cold solution of (2R,3R,4R,5R)-
2-(4-aminofluorooxopyrimidin-1(2H)-yl)methyltetrahydrofuran-3,4-diyl diacetate
(1, 10.0 g, 30.40 mmol) in dichloromethane (500 mL) was added 4-dimethylaminopyridine
(1.85 g, 15.20 mmol) and pyridine (25.0 mL, 243.16 mmol) and stirred for next 5 min. To
the above mixture octanoyl chloride (2, 6.45 mL, 36.47 mmol) was added dropwise at 0°C
and the reaction mixture was stirred at room temperature for 16h. After completion, reaction
mixture was filtered; the solid was washed with dichloromethane (100 mL), filtrate was
washed with brine (200 mL), saturated solution of sodium bicarbonate (200 mL) and 0.1 N
HCl solution (100 mL). Organic layer was separated and dried over anhydrous sodium
sulfate and solvent was removed under reduced pressure to get crude. The crude was
purified by silica gel (100-200 mesh) column chromatography eluting with 3% methanol in
dichloromethane to afford the desired product as light green crystalline solid. Yield: 11.50 g
(83%).
Example 4:
17518482_1 (GHMatters) P115263.NZ
Synthesis of methyl 9-((5-fluorooxo-2,3-dihydropyrimidinyl)amino)
oxononanoate (3): To an ice cold solution of 9-methoxyoxononanoic acid (2, 47.0 g,
232.69 mmol) in DMF (250 mL) was added 4-dimethylaminopyridine (88.37 g, 232.69
mmol) and DIPEA (137.7 mL, 775 mmol) and stirred the resulting reaction mass for next 5
minutes followed by the addition of 6-aminofluoropyrimidin-2(1H)-one (1, 20 g, 155
mmol). The resulting reaction mixture was stirred at room temperature for next 16h. After
completion of reaction (TLC monitoring), reaction mixture was poured into ice cold water
and the precipitate thus obtained was filtered and washed with water (3 x 100 mL), suck dry
under vacuum to get the desired compound as off-white solid. Yield 18.0 g (37%).
Synthesis of 9-((5-fluorooxo-2,3-dihydropyrimidinyl)amino)oxononanoic acid
(4): To an ice cold freshly prepared aqueous solution of 5% NaOH (375 mL) was added
methyl 9-((5-fluorooxo-2,3-dihydropyrimidinyl)amino)oxononanoate (3, 15 g,
47.92 mmol) portion wise at 0°C. The resulting reaction mixture was stirred at 0°C for next
-10 min. After completion of the reaction (TLC monitoring), the pH of reaction mass was
adjusted up to ~4 by using 6N HCl resulting in the precipitation of off-white solid. Solid
material was filtered off and washed with water (3 x 250 mL), suck dried under high
vacuum to get the desired product 4 as off-white solid. Yield: 11.0 g (76%).
EQUIVALENTS
The present disclosure provides among other things compositions and methods for
treating cancer and their complications. While specific embodiments of the subject
disclosure have been discussed, the above specification is illustrative and not restrictive.
Many variations of the systems and methods herein will become apparent to those skilled in
the art upon review of this specification. The full scope of the claimed systems and methods
should be determined by reference to the claims, along with their full scope of equivalents,
and the specification, along with such variations.
INCORPORATION BY REFERENCE
17518482_1 (GHMatters) P115263.NZ
All publications and patents mentioned herein, including those items listed above,
are hereby incorporated by reference in their entirety as if each individual publication or
patent was specifically and individually indicated to be incorporated by reference. In case
of conflict, the present application, including any definitions herein, will control.
17518482_1 (GHMatters) P115263.NZ
Claims (4)
1. A compound of formula VI: Formula VI and pharmaceutically acceptable enantiomers and stereoisomers thereof; wherein, R , R , R represents CD , NULL, 1 3 5 2 , , , , , , , , , 17518482_1 (GHMatters) P115263.NZ , , , , , , 17518482_1 (GHMatters) P115263.NZ , , , or ; R , R independently represents , or 17518482_1 (GHMatters) P115263.NZ R independently represents H, D, 17518482_1 (GHMatters) P115263.NZ , or ; wherein n represents 0 to 12; R is not H when R is NULL; R and R independently represent 17518482_1 (GHMatters) P115263.NZ
2. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
3. The pharmaceutical composition of claim 2, wherein said pharmaceutical composition is formulated for oral administration, delayed release or sustained release, transmucosal administration, syrup, topical administration, parenteral administration, injection, subdermal administration, oral solution, rectal administration, buccal administration or transdermal administration.
4. Use of a pharmaceutical composition of claim 3 for the manufacture of a medicament for the treatment of colorectal cancer, breast cancer, gastric cancer, oesophageal cancer, anal cancer, stomach cancer, pancreatic cancer, skin cancers and Bowen's disease. 17518482_1 (GHMatters) P115263.NZ
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN201641022026 | 2016-06-28 | ||
IN201641022026 | 2016-06-28 | ||
IN201641025259 | 2016-07-22 | ||
IN201641025259 | 2016-07-22 | ||
IN201741006185 | 2017-02-21 | ||
IN201741006185 | 2017-02-21 | ||
PCT/IB2017/052814 WO2018002739A1 (en) | 2016-06-28 | 2017-05-12 | Compositions and methods for the treatment of cancer |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ749512A NZ749512A (en) | 2021-08-27 |
NZ749512B2 true NZ749512B2 (en) | 2021-11-30 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20210078983A1 (en) | Compositions and methods for the treatment of cancer | |
WO2016046675A1 (en) | Compositions and methods for the treatment of neurological diseases | |
US9475747B1 (en) | Compositions and methods for the treatment of urea cycle disorders and gout | |
WO2017090007A1 (en) | Compositions and methods for the treatment of urea cycle disorders and hepatic diseases | |
AU2019313484A2 (en) | Compositions and methods for the treatment of cancer | |
WO2016046674A1 (en) | Compositions and methods for the treatment of moderate to severe pain | |
NZ749512B2 (en) | Compositions and methods for the treatment of cancer | |
US9932294B2 (en) | Compositions and methods for the treatment of multiple sclerosis | |
WO2017017585A1 (en) | Compound, composition and uses thereof | |
EP3212626B1 (en) | Three component salts of fumaric acid monomethyl ester with piperazine or ethylene diamine for the treatment of multiple sclerosis | |
WO2016046671A1 (en) | Compositions and methods for the treatment of lipid disorders | |
EP3240779B1 (en) | Compositions and methods for the treatment of epilepsy and neurological disorders | |
WO2014060942A2 (en) | Compositions and methods of for the treatment of multiple sclerosis and neurodegenerative diseases | |
WO2017221083A1 (en) | Compositions and methods for the treatment of viral infections | |
WO2016088132A9 (en) | Compositions and methods for the treatment of multiple sclerosis | |
WO2016203337A2 (en) | Compositions and methods for the treatment of cancer | |
WO2016203352A2 (en) | Compositions and methods for the treatment of cancer | |
WO2016046670A1 (en) | Compositions and methods for the treatment of renal diseases | |
WO2016067297A1 (en) | Salts of valproic acid with piperazine, ethylenediamine, lysine and/or eicosapentaenoic ecid (epa) amine derivatives for the treatment of epilepsy |