WO2015011724A2 - A novel omega -3 fatty acid composition with a plant extract - Google Patents
A novel omega -3 fatty acid composition with a plant extract Download PDFInfo
- Publication number
- WO2015011724A2 WO2015011724A2 PCT/IN2014/000483 IN2014000483W WO2015011724A2 WO 2015011724 A2 WO2015011724 A2 WO 2015011724A2 IN 2014000483 W IN2014000483 W IN 2014000483W WO 2015011724 A2 WO2015011724 A2 WO 2015011724A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition
- omega
- fatty acid
- atleast
- epa
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 177
- 235000020660 omega-3 fatty acid Nutrition 0.000 title claims abstract description 143
- 229940012843 omega-3 fatty acid Drugs 0.000 title claims abstract description 138
- 239000000419 plant extract Substances 0.000 title claims abstract description 63
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 title claims abstract description 58
- 239000006014 omega-3 oil Substances 0.000 claims abstract description 82
- 239000004094 surface-active agent Substances 0.000 claims abstract description 63
- 238000000034 method Methods 0.000 claims abstract description 24
- 230000009246 food effect Effects 0.000 claims abstract description 18
- 235000021471 food effect Nutrition 0.000 claims abstract description 17
- 230000008569 process Effects 0.000 claims abstract description 10
- -1 mono- Chemical compound 0.000 claims description 141
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 62
- 229930195729 fatty acid Natural products 0.000 claims description 62
- 239000000194 fatty acid Substances 0.000 claims description 62
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 50
- 239000004359 castor oil Substances 0.000 claims description 44
- 235000019438 castor oil Nutrition 0.000 claims description 44
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 44
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 27
- 229920000053 polysorbate 80 Polymers 0.000 claims description 27
- 244000119298 Emblica officinalis Species 0.000 claims description 24
- 235000015489 Emblica officinalis Nutrition 0.000 claims description 24
- 150000004665 fatty acids Chemical group 0.000 claims description 23
- 244000179886 Moringa oleifera Species 0.000 claims description 18
- 235000011347 Moringa oleifera Nutrition 0.000 claims description 18
- 239000003921 oil Substances 0.000 claims description 18
- 239000002736 nonionic surfactant Substances 0.000 claims description 17
- 229920001223 polyethylene glycol Polymers 0.000 claims description 17
- 239000002775 capsule Substances 0.000 claims description 16
- 239000002202 Polyethylene glycol Substances 0.000 claims description 14
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 14
- 239000012736 aqueous medium Substances 0.000 claims description 14
- 239000007903 gelatin capsule Substances 0.000 claims description 13
- 240000007551 Boswellia serrata Species 0.000 claims description 11
- 240000003890 Commiphora wightii Species 0.000 claims description 11
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 11
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 11
- 210000002381 plasma Anatomy 0.000 claims description 11
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 11
- 210000002966 serum Anatomy 0.000 claims description 11
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 10
- 239000002245 particle Substances 0.000 claims description 10
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 10
- 150000002148 esters Chemical class 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 claims description 8
- 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 claims description 8
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 8
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 8
- 230000001965 increasing effect Effects 0.000 claims description 8
- 230000002195 synergetic effect Effects 0.000 claims description 8
- 150000003904 phospholipids Chemical class 0.000 claims description 7
- 235000011067 sorbitan monolaureate Nutrition 0.000 claims description 7
- 235000018062 Boswellia Nutrition 0.000 claims description 6
- 241000533293 Sesbania emerus Species 0.000 claims description 6
- 230000000996 additive effect Effects 0.000 claims description 6
- 239000012141 concentrate Substances 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 6
- 235000003717 Boswellia sacra Nutrition 0.000 claims description 5
- 235000012035 Boswellia serrata Nutrition 0.000 claims description 5
- 240000007154 Coffea arabica Species 0.000 claims description 5
- 240000007311 Commiphora myrrha Species 0.000 claims description 5
- 235000006965 Commiphora myrrha Nutrition 0.000 claims description 5
- 239000004863 Frankincense Substances 0.000 claims description 5
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 5
- 229920002690 Polyoxyl 40 HydrogenatedCastorOil Polymers 0.000 claims description 5
- 229930006000 Sucrose Natural products 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 235000021588 free fatty acids Nutrition 0.000 claims description 5
- 235000011187 glycerol Nutrition 0.000 claims description 5
- 239000007764 o/w emulsion Substances 0.000 claims description 5
- 229920001451 polypropylene glycol Polymers 0.000 claims description 5
- 239000005720 sucrose Substances 0.000 claims description 5
- 235000007460 Coffea arabica Nutrition 0.000 claims description 4
- AHANXAKGNAKFSK-PDBXOOCHSA-N all-cis-icosa-11,14,17-trienoic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCCCC(O)=O AHANXAKGNAKFSK-PDBXOOCHSA-N 0.000 claims description 4
- 229920001400 block copolymer Polymers 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- IQLUYYHUNSSHIY-HZUMYPAESA-N eicosatetraenoic acid Chemical compound CCCCCCCCCCC\C=C\C=C\C=C\C=C\C(O)=O IQLUYYHUNSSHIY-HZUMYPAESA-N 0.000 claims description 4
- PRHHYVQTPBEDFE-UHFFFAOYSA-N eicosatrienoic acid Natural products CCCCCC=CCC=CCCCCC=CCCCC(O)=O PRHHYVQTPBEDFE-UHFFFAOYSA-N 0.000 claims description 4
- 235000013305 food Nutrition 0.000 claims description 4
- 235000020777 polyunsaturated fatty acids Nutrition 0.000 claims description 4
- 150000003626 triacylglycerols Chemical class 0.000 claims description 4
- YUFFSWGQGVEMMI-JLNKQSITSA-N (7Z,10Z,13Z,16Z,19Z)-docosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCCCC(O)=O YUFFSWGQGVEMMI-JLNKQSITSA-N 0.000 claims description 3
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- 208000003556 Dry Eye Syndromes Diseases 0.000 claims description 3
- 206010013774 Dry eye Diseases 0.000 claims description 3
- 208000035150 Hypercholesterolemia Diseases 0.000 claims description 3
- 206010061218 Inflammation Diseases 0.000 claims description 3
- 208000002193 Pain Diseases 0.000 claims description 3
- 239000003945 anionic surfactant Substances 0.000 claims description 3
- 206010003246 arthritis Diseases 0.000 claims description 3
- 230000001804 emulsifying effect Effects 0.000 claims description 3
- 230000004054 inflammatory process Effects 0.000 claims description 3
- DTOSIQBPPRVQHS-UHFFFAOYSA-N α-Linolenic acid Chemical compound CCC=CCC=CCC=CCCCCCCCC(O)=O DTOSIQBPPRVQHS-UHFFFAOYSA-N 0.000 claims description 3
- LGHXTTIAZFVCCU-SSVNFBSYSA-N (2E,4E,6E,8E)-octadeca-2,4,6,8-tetraenoic acid Chemical compound CCCCCCCCC\C=C\C=C\C=C\C=C\C(O)=O LGHXTTIAZFVCCU-SSVNFBSYSA-N 0.000 claims description 2
- OQOCQFSPEWCSDO-JLNKQSITSA-N 6Z,9Z,12Z,15Z,18Z-Heneicosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCCC(O)=O OQOCQFSPEWCSDO-JLNKQSITSA-N 0.000 claims description 2
- 235000021294 Docosapentaenoic acid Nutrition 0.000 claims description 2
- OPGOLNDOMSBSCW-CLNHMMGSSA-N Fursultiamine hydrochloride Chemical compound Cl.C1CCOC1CSSC(\CCO)=C(/C)N(C=O)CC1=CN=C(C)N=C1N OPGOLNDOMSBSCW-CLNHMMGSSA-N 0.000 claims description 2
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 claims description 2
- 239000003093 cationic surfactant Substances 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 230000035622 drinking Effects 0.000 claims description 2
- 235000019387 fatty acid methyl ester Nutrition 0.000 claims description 2
- OQOCQFSPEWCSDO-UHFFFAOYSA-N heneicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCCC(O)=O OQOCQFSPEWCSDO-UHFFFAOYSA-N 0.000 claims description 2
- 238000011065 in-situ storage Methods 0.000 claims description 2
- 239000007937 lozenge Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000006186 oral dosage form Substances 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 125000000075 primary alcohol group Chemical group 0.000 claims description 2
- 150000003333 secondary alcohols Chemical class 0.000 claims description 2
- JIWBIWFOSCKQMA-UHFFFAOYSA-N stearidonic acid Natural products CCC=CCC=CCC=CCC=CCCCCC(O)=O JIWBIWFOSCKQMA-UHFFFAOYSA-N 0.000 claims description 2
- 150000003509 tertiary alcohols Chemical class 0.000 claims description 2
- 206010052904 Musculoskeletal stiffness Diseases 0.000 claims 2
- 208000035475 disorder Diseases 0.000 claims 2
- 241000723377 Coffea Species 0.000 claims 1
- 239000012895 dilution Substances 0.000 claims 1
- 238000010790 dilution Methods 0.000 claims 1
- MBMBGCFOFBJSGT-KUBAVDMBSA-N all-cis-docosa-4,7,10,13,16,19-hexaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O MBMBGCFOFBJSGT-KUBAVDMBSA-N 0.000 description 37
- JAZBEHYOTPTENJ-JLNKQSITSA-N all-cis-5,8,11,14,17-icosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O JAZBEHYOTPTENJ-JLNKQSITSA-N 0.000 description 30
- 235000020673 eicosapentaenoic acid Nutrition 0.000 description 30
- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 description 30
- 229960005135 eicosapentaenoic acid Drugs 0.000 description 30
- 239000011734 sodium Substances 0.000 description 27
- 229910052708 sodium Inorganic materials 0.000 description 27
- 239000007788 liquid Substances 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- 235000020669 docosahexaenoic acid Nutrition 0.000 description 22
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 21
- 238000010521 absorption reaction Methods 0.000 description 21
- 235000021323 fish oil Nutrition 0.000 description 21
- 238000009472 formulation Methods 0.000 description 21
- 229940090949 docosahexaenoic acid Drugs 0.000 description 19
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 18
- 239000003240 coconut oil Substances 0.000 description 16
- 235000019198 oils Nutrition 0.000 description 16
- 241000196324 Embryophyta Species 0.000 description 14
- DTMGIJFHGGCSLO-FIAQIACWSA-N ethyl (4z,7z,10z,13z,16z,19z)-docosa-4,7,10,13,16,19-hexaenoate;ethyl (5z,8z,11z,14z,17z)-icosa-5,8,11,14,17-pentaenoate Chemical compound CCOC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CC.CCOC(=O)CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CC DTMGIJFHGGCSLO-FIAQIACWSA-N 0.000 description 14
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 13
- 235000019864 coconut oil Nutrition 0.000 description 13
- 239000000284 extract Substances 0.000 description 13
- 239000004615 ingredient Substances 0.000 description 13
- 125000000217 alkyl group Chemical group 0.000 description 12
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 12
- 229940068968 polysorbate 80 Drugs 0.000 description 12
- 229960004418 trolamine Drugs 0.000 description 12
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 11
- 229920002582 Polyethylene Glycol 600 Polymers 0.000 description 10
- 229920002675 Polyoxyl Polymers 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 230000036541 health Effects 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 235000020937 fasting conditions Nutrition 0.000 description 7
- 229940115970 lovaza Drugs 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 108010004103 Chylomicrons Proteins 0.000 description 6
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 6
- 229920002125 Sokalan® Polymers 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 5
- 235000015872 dietary supplement Nutrition 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 230000000055 hyoplipidemic effect Effects 0.000 description 5
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 5
- 230000000704 physical effect Effects 0.000 description 5
- 229920000136 polysorbate Polymers 0.000 description 5
- 239000011591 potassium Substances 0.000 description 5
- 229910052700 potassium Inorganic materials 0.000 description 5
- 239000000344 soap Substances 0.000 description 5
- 210000002784 stomach Anatomy 0.000 description 5
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- ULUAUXLGCMPNKK-UHFFFAOYSA-N Sulfobutanedioic acid Chemical compound OC(=O)CC(C(O)=O)S(O)(=O)=O ULUAUXLGCMPNKK-UHFFFAOYSA-N 0.000 description 4
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000012377 drug delivery Methods 0.000 description 4
- 238000004945 emulsification Methods 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 235000019197 fats Nutrition 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 210000004379 membrane Anatomy 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 239000008389 polyethoxylated castor oil Substances 0.000 description 4
- 229940068977 polysorbate 20 Drugs 0.000 description 4
- 229940068965 polysorbates Drugs 0.000 description 4
- 229940035044 sorbitan monolaurate Drugs 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- DVSZKTAMJJTWFG-SKCDLICFSA-N (2e,4e,6e,8e,10e,12e)-docosa-2,4,6,8,10,12-hexaenoic acid Chemical compound CCCCCCCCC\C=C\C=C\C=C\C=C\C=C\C=C\C(O)=O DVSZKTAMJJTWFG-SKCDLICFSA-N 0.000 description 3
- CUNWUEBNSZSNRX-RKGWDQTMSA-N (2r,3r,4r,5s)-hexane-1,2,3,4,5,6-hexol;(z)-octadec-9-enoic acid Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O CUNWUEBNSZSNRX-RKGWDQTMSA-N 0.000 description 3
- RZRILSWMGXWSJY-UHFFFAOYSA-N 2-[bis(2-hydroxyethyl)amino]ethanol;sulfuric acid Chemical compound OS(O)(=O)=O.OCCN(CCO)CCO RZRILSWMGXWSJY-UHFFFAOYSA-N 0.000 description 3
- GZJLLYHBALOKEX-UHFFFAOYSA-N 6-Ketone, O18-Me-Ussuriedine Natural products CC=CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O GZJLLYHBALOKEX-UHFFFAOYSA-N 0.000 description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- 0 CN***C1*(**)C1* Chemical compound CN***C1*(**)C1* 0.000 description 3
- 241000238424 Crustacea Species 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- BACYUWVYYTXETD-UHFFFAOYSA-N N-Lauroylsarcosine Chemical compound CCCCCCCCCCCC(=O)N(C)CC(O)=O BACYUWVYYTXETD-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 235000020661 alpha-linolenic acid Nutrition 0.000 description 3
- 230000001315 anti-hyperlipaemic effect Effects 0.000 description 3
- 230000003078 antioxidant effect Effects 0.000 description 3
- 239000013060 biological fluid Substances 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- KAUVQQXNCKESLC-UHFFFAOYSA-N docosahexaenoic acid (DHA) Natural products COC(=O)C(C)NOCC1=CC=CC=C1 KAUVQQXNCKESLC-UHFFFAOYSA-N 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 239000008203 oral pharmaceutical composition Substances 0.000 description 3
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 3
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 3
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 3
- 229940113124 polysorbate 60 Drugs 0.000 description 3
- 230000000069 prophylactic effect Effects 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 3
- 108700004121 sarkosyl Proteins 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 230000001839 systemic circulation Effects 0.000 description 3
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- WLMZUANPXHJWCH-UHFFFAOYSA-N 2-[bis(2-hydroxyethyl)amino]ethanol;dodecanoic acid Chemical compound OCCN(CCO)CCO.CCCCCCCCCCCC(O)=O WLMZUANPXHJWCH-UHFFFAOYSA-N 0.000 description 2
- OAVHXBONEDQFLJ-UHFFFAOYSA-N 4-ethoxy-4-oxo-3-sulfobutanoic acid Chemical compound CCOC(=O)C(S(O)(=O)=O)CC(O)=O OAVHXBONEDQFLJ-UHFFFAOYSA-N 0.000 description 2
- 241000251468 Actinopterygii Species 0.000 description 2
- 241000972773 Aulopiformes Species 0.000 description 2
- 240000002791 Brassica napus Species 0.000 description 2
- 235000011293 Brassica napus Nutrition 0.000 description 2
- 206010013911 Dysgeusia Diseases 0.000 description 2
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 244000124853 Perilla frutescens Species 0.000 description 2
- 229920002535 Polyethylene Glycol 1500 Polymers 0.000 description 2
- 229920000604 Polyethylene Glycol 200 Polymers 0.000 description 2
- 229920002556 Polyethylene Glycol 300 Polymers 0.000 description 2
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 2
- 229920001219 Polysorbate 40 Polymers 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 108010077895 Sarcosine Proteins 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 2
- IYFATESGLOUGBX-YVNJGZBMSA-N Sorbitan monopalmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O IYFATESGLOUGBX-YVNJGZBMSA-N 0.000 description 2
- 244000077923 Vaccinium vitis idaea Species 0.000 description 2
- 235000017606 Vaccinium vitis idaea Nutrition 0.000 description 2
- IJCWFDPJFXGQBN-RYNSOKOISA-N [(2R)-2-[(2R,3R,4S)-4-hydroxy-3-octadecanoyloxyoxolan-2-yl]-2-octadecanoyloxyethyl] octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCCCCCCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCCCCCCCCCCCC IJCWFDPJFXGQBN-RYNSOKOISA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 235000004279 alanine Nutrition 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- 150000005215 alkyl ethers Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003833 bile salt Substances 0.000 description 2
- 229940093761 bile salts Drugs 0.000 description 2
- 210000001772 blood platelet Anatomy 0.000 description 2
- 229960001631 carbomer Drugs 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 208000029078 coronary artery disease Diseases 0.000 description 2
- 108010011222 cyclo(Arg-Pro) Proteins 0.000 description 2
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 2
- 229960003964 deoxycholic acid Drugs 0.000 description 2
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- WODOUQLMOIMKAL-FJSYBICCSA-L disodium;(2s)-2-(octadecanoylamino)pentanedioate Chemical compound [Na+].[Na+].CCCCCCCCCCCCCCCCCC(=O)N[C@H](C([O-])=O)CCC([O-])=O WODOUQLMOIMKAL-FJSYBICCSA-L 0.000 description 2
- YHAIUSTWZPMYGG-UHFFFAOYSA-L disodium;2,2-dioctyl-3-sulfobutanedioate Chemical compound [Na+].[Na+].CCCCCCCCC(C([O-])=O)(C(C([O-])=O)S(O)(=O)=O)CCCCCCCC YHAIUSTWZPMYGG-UHFFFAOYSA-L 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 2
- 229940043264 dodecyl sulfate Drugs 0.000 description 2
- 235000013399 edible fruits Nutrition 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 235000004626 essential fatty acids Nutrition 0.000 description 2
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 2
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 2
- 229940093471 ethyl oleate Drugs 0.000 description 2
- 238000001125 extrusion Methods 0.000 description 2
- 235000019688 fish Nutrition 0.000 description 2
- 235000004426 flaxseed Nutrition 0.000 description 2
- 230000037406 food intake Effects 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 229960002989 glutamic acid Drugs 0.000 description 2
- 241000411851 herbal medicine Species 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 229960004488 linolenic acid Drugs 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 235000012054 meals Nutrition 0.000 description 2
- 239000000693 micelle Substances 0.000 description 2
- 235000016709 nutrition Nutrition 0.000 description 2
- 230000035764 nutrition Effects 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- 229940096992 potassium oleate Drugs 0.000 description 2
- MLICVSDCCDDWMD-KVVVOXFISA-M potassium;(z)-octadec-9-enoate Chemical compound [K+].CCCCCCCC\C=C/CCCCCCCC([O-])=O MLICVSDCCDDWMD-KVVVOXFISA-M 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 235000019515 salmon Nutrition 0.000 description 2
- 229940043230 sarcosine Drugs 0.000 description 2
- 235000010413 sodium alginate Nutrition 0.000 description 2
- 239000000661 sodium alginate Substances 0.000 description 2
- 229940005550 sodium alginate Drugs 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- CAVXVRQDZKMZDB-UHFFFAOYSA-M sodium;2-[dodecanoyl(methyl)amino]ethanesulfonate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CCS([O-])(=O)=O CAVXVRQDZKMZDB-UHFFFAOYSA-M 0.000 description 2
- 235000011078 sorbitan tristearate Nutrition 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000003760 tallow Substances 0.000 description 2
- 210000002978 thoracic duct Anatomy 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
- AVBJHQDHVYGQLS-AWEZNQCLSA-N (2s)-2-(dodecanoylamino)pentanedioic acid Chemical compound CCCCCCCCCCCC(=O)N[C@H](C(O)=O)CCC(O)=O AVBJHQDHVYGQLS-AWEZNQCLSA-N 0.000 description 1
- ZNRLADRSOXNJKR-INIZCTEOSA-N (2s)-2-[methyl(tetradecanoyl)amino]propanoic acid Chemical compound CCCCCCCCCCCCCC(=O)N(C)[C@@H](C)C(O)=O ZNRLADRSOXNJKR-INIZCTEOSA-N 0.000 description 1
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 1
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 1
- KAKVFSYQVNHFBS-UHFFFAOYSA-N (5-hydroxycyclopenten-1-yl)-phenylmethanone Chemical compound OC1CCC=C1C(=O)C1=CC=CC=C1 KAKVFSYQVNHFBS-UHFFFAOYSA-N 0.000 description 1
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- FFJCNSLCJOQHKM-CLFAGFIQSA-N (z)-1-[(z)-octadec-9-enoxy]octadec-9-ene Chemical compound CCCCCCCC\C=C/CCCCCCCCOCCCCCCCC\C=C/CCCCCCCC FFJCNSLCJOQHKM-CLFAGFIQSA-N 0.000 description 1
- ICLYJLBTOGPLMC-KVVVOXFISA-N (z)-octadec-9-enoate;tris(2-hydroxyethyl)azanium Chemical compound OCCN(CCO)CCO.CCCCCCCC\C=C/CCCCCCCC(O)=O ICLYJLBTOGPLMC-KVVVOXFISA-N 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- WGIMXKDCVCTHGW-UHFFFAOYSA-N 2-(2-hydroxyethoxy)ethyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCCOCCO WGIMXKDCVCTHGW-UHFFFAOYSA-N 0.000 description 1
- CTPDSKVQLSDPLC-UHFFFAOYSA-N 2-(oxolan-2-ylmethoxy)ethanol Chemical compound OCCOCC1CCCO1 CTPDSKVQLSDPLC-UHFFFAOYSA-N 0.000 description 1
- FKOKUHFZNIUSLW-UHFFFAOYSA-N 2-Hydroxypropyl stearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(C)O FKOKUHFZNIUSLW-UHFFFAOYSA-N 0.000 description 1
- MOKBFXZQXUZAMV-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCOCCOCCOCCOCCOCCOCCOCCO MOKBFXZQXUZAMV-UHFFFAOYSA-N 0.000 description 1
- JDKIORRVWBZTQQ-UHFFFAOYSA-N 2-[bis(2-hydroxyethyl)amino]ethanol;tridecyl hydrogen sulfate Chemical compound OCCN(CCO)CCO.CCCCCCCCCCCCCOS(O)(=O)=O JDKIORRVWBZTQQ-UHFFFAOYSA-N 0.000 description 1
- HJDITXMCJQRQLU-UHFFFAOYSA-N 2-[dodecanoyl(methyl)amino]acetate;tris(2-hydroxyethyl)azanium Chemical class OCCN(CCO)CCO.CCCCCCCCCCCC(=O)N(C)CC(O)=O HJDITXMCJQRQLU-UHFFFAOYSA-N 0.000 description 1
- TWJNQYPJQDRXPH-UHFFFAOYSA-N 2-cyanobenzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1C#N TWJNQYPJQDRXPH-UHFFFAOYSA-N 0.000 description 1
- BHIZVZJETFVJMJ-UHFFFAOYSA-N 2-hydroxypropyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCC(C)O BHIZVZJETFVJMJ-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- LIFHMKCDDVTICL-UHFFFAOYSA-N 6-(chloromethyl)phenanthridine Chemical compound C1=CC=C2C(CCl)=NC3=CC=CC=C3C2=C1 LIFHMKCDDVTICL-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- GJCOSYZMQJWQCA-UHFFFAOYSA-N 9H-xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 241000208229 Burseraceae Species 0.000 description 1
- 108010076119 Caseins Proteins 0.000 description 1
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- 241000555825 Clupeidae Species 0.000 description 1
- 241001454694 Clupeiformes Species 0.000 description 1
- 244000060011 Cocos nucifera Species 0.000 description 1
- 235000013162 Cocos nucifera Nutrition 0.000 description 1
- 241000195493 Cryptophyta Species 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 206010015137 Eructation Diseases 0.000 description 1
- FPVVYTCTZKCSOJ-UHFFFAOYSA-N Ethylene glycol distearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCOC(=O)CCCCCCCCCCCCCCCCC FPVVYTCTZKCSOJ-UHFFFAOYSA-N 0.000 description 1
- 241000239366 Euphausiacea Species 0.000 description 1
- 206010016260 Fatty acid deficiency Diseases 0.000 description 1
- 241000276438 Gadus morhua Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108010007979 Glycocholic Acid Proteins 0.000 description 1
- 108010035713 Glycodeoxycholic Acid Proteins 0.000 description 1
- WVULKSPCQVQLCU-UHFFFAOYSA-N Glycodeoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCC(O)=O)C)C1(C)C(O)C2 WVULKSPCQVQLCU-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 229930195714 L-glutamate Natural products 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- 240000006240 Linum usitatissimum Species 0.000 description 1
- 235000004431 Linum usitatissimum Nutrition 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- 108010013563 Lipoprotein Lipase Proteins 0.000 description 1
- 102000043296 Lipoprotein lipases Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- SMEROWZSTRWXGI-UHFFFAOYSA-N Lithocholsaeure Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 SMEROWZSTRWXGI-UHFFFAOYSA-N 0.000 description 1
- 241000834128 Lopholatilus chamaeleonticeps Species 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 241000220214 Moringaceae Species 0.000 description 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-N Myristic acid Natural products CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 1
- 235000021360 Myristic acid Nutrition 0.000 description 1
- 241000237536 Mytilus edulis Species 0.000 description 1
- QZXSMBBFBXPQHI-UHFFFAOYSA-N N-(dodecanoyl)ethanolamine Chemical compound CCCCCCCCCCCC(=O)NCCO QZXSMBBFBXPQHI-UHFFFAOYSA-N 0.000 description 1
- RFDAIACWWDREDC-UHFFFAOYSA-N Na salt-Glycocholic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCC(O)=O)C)C1(C)C(O)C2 RFDAIACWWDREDC-UHFFFAOYSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- DIOYAVUHUXAUPX-KHPPLWFESA-N Oleoyl sarcosine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)N(C)CC(O)=O DIOYAVUHUXAUPX-KHPPLWFESA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 235000019482 Palm oil Nutrition 0.000 description 1
- 102000019280 Pancreatic lipases Human genes 0.000 description 1
- 108050006759 Pancreatic lipases Proteins 0.000 description 1
- 235000004347 Perilla Nutrition 0.000 description 1
- 235000004348 Perilla frutescens Nutrition 0.000 description 1
- 241001537211 Perna canaliculus Species 0.000 description 1
- 241000269980 Pleuronectidae Species 0.000 description 1
- 229920002696 Polyoxyl 40 castor oil Polymers 0.000 description 1
- 229920002700 Polyoxyl 60 hydrogenated castor oil Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 1
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 1
- 241001107098 Rubiaceae Species 0.000 description 1
- DQBKCNUKYYQDPA-KVVVOXFISA-N S(=O)(=O)(O)C(C(=O)O)CCCCCC\C=C/CCCCCCCC.N(CCO)(CCO)CCO Chemical compound S(=O)(=O)(O)C(C(=O)O)CCCCCC\C=C/CCCCCCCC.N(CCO)(CCO)CCO DQBKCNUKYYQDPA-KVVVOXFISA-N 0.000 description 1
- 240000005481 Salvia hispanica Species 0.000 description 1
- 235000001498 Salvia hispanica Nutrition 0.000 description 1
- 241000269821 Scombridae Species 0.000 description 1
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- BHTRKEVKTKCXOH-UHFFFAOYSA-N Taurochenodesoxycholsaeure Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCCS(O)(=O)=O)C)C1(C)CC2 BHTRKEVKTKCXOH-UHFFFAOYSA-N 0.000 description 1
- WBWWGRHZICKQGZ-UHFFFAOYSA-N Taurocholic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCCS(O)(=O)=O)C)C1(C)C(O)C2 WBWWGRHZICKQGZ-UHFFFAOYSA-N 0.000 description 1
- WPMWEFXCIYCJSA-UHFFFAOYSA-N Tetraethylene glycol monododecyl ether Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCO WPMWEFXCIYCJSA-UHFFFAOYSA-N 0.000 description 1
- 102000000591 Tight Junction Proteins Human genes 0.000 description 1
- 108010002321 Tight Junction Proteins Proteins 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 235000021068 Western diet Nutrition 0.000 description 1
- 241000269959 Xiphias gladius Species 0.000 description 1
- FGUZFFWTBWJBIL-XWVZOOPGSA-N [(1r)-1-[(2s,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] 16-methylheptadecanoate Chemical compound CC(C)CCCCCCCCCCCCCCC(=O)O[C@H](CO)[C@H]1OC[C@H](O)[C@H]1O FGUZFFWTBWJBIL-XWVZOOPGSA-N 0.000 description 1
- NCHJGQKLPRTMAO-XWVZOOPGSA-N [(2R)-2-[(2R,3R,4S)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] 16-methylheptadecanoate Chemical compound CC(C)CCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NCHJGQKLPRTMAO-XWVZOOPGSA-N 0.000 description 1
- ZBNRGEMZNWHCGA-PDKVEDEMSA-N [(2r)-2-[(2r,3r,4s)-3,4-bis[[(z)-octadec-9-enoyl]oxy]oxolan-2-yl]-2-hydroxyethyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC ZBNRGEMZNWHCGA-PDKVEDEMSA-N 0.000 description 1
- NWGKJDSIEKMTRX-BFWOXRRGSA-N [(2r)-2-[(3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)C1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-BFWOXRRGSA-N 0.000 description 1
- HVUMOYIDDBPOLL-XGKPLOKHSA-N [2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XGKPLOKHSA-N 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229940023476 agar Drugs 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 206010064930 age-related macular degeneration Diseases 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000008051 alkyl sulfates Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 235000019513 anchovy Nutrition 0.000 description 1
- 230000000489 anti-atherogenic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 230000000026 anti-ulcerogenic effect Effects 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229940069765 bean extract Drugs 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- MKHVZQXYWACUQC-UHFFFAOYSA-N bis(2-hydroxyethyl)azanium;dodecyl sulfate Chemical compound OCCNCCO.CCCCCCCCCCCCOS(O)(=O)=O MKHVZQXYWACUQC-UHFFFAOYSA-N 0.000 description 1
- QZUFUZCFYQJWBG-UHFFFAOYSA-N bis(2-hydroxyethyl)azanium;tetradecyl sulfate Chemical compound OCCNCCO.CCCCCCCCCCCCCCOS(O)(=O)=O QZUFUZCFYQJWBG-UHFFFAOYSA-N 0.000 description 1
- 235000019519 canola oil Nutrition 0.000 description 1
- 239000000828 canola oil Substances 0.000 description 1
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 1
- 229940096529 carboxypolymethylene Drugs 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 229960000800 cetrimonium bromide Drugs 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 229940080284 cetyl sulfate Drugs 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
- 230000002113 chemopreventative effect Effects 0.000 description 1
- RUDATBOHQWOJDD-BSWAIDMHSA-N chenodeoxycholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-BSWAIDMHSA-N 0.000 description 1
- 229960001091 chenodeoxycholic acid Drugs 0.000 description 1
- 235000020235 chia seed Nutrition 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 235000019416 cholic acid Nutrition 0.000 description 1
- 229960002471 cholic acid Drugs 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 235000012716 cod liver oil Nutrition 0.000 description 1
- 239000003026 cod liver oil Substances 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 239000004064 cosurfactant Substances 0.000 description 1
- 230000000254 damaging effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 235000018823 dietary intake Nutrition 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 229940079886 disodium lauryl sulfosuccinate Drugs 0.000 description 1
- SXBBFOVRSQCYFE-SQKCAUCHSA-L disodium;(2s)-2-(tetradecanoylamino)pentanedioate Chemical compound [Na+].[Na+].CCCCCCCCCCCCCC(=O)N[C@H](C([O-])=O)CCC([O-])=O SXBBFOVRSQCYFE-SQKCAUCHSA-L 0.000 description 1
- KHIQYZGEUSTKSB-UHFFFAOYSA-L disodium;4-dodecoxy-4-oxo-3-sulfobutanoate Chemical compound [Na+].[Na+].CCCCCCCCCCCCOC(=O)C(S(O)(=O)=O)CC([O-])=O.CCCCCCCCCCCCOC(=O)C(S(O)(=O)=O)CC([O-])=O KHIQYZGEUSTKSB-UHFFFAOYSA-L 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229960000878 docusate sodium Drugs 0.000 description 1
- 235000013345 egg yolk Nutrition 0.000 description 1
- 210000002969 egg yolk Anatomy 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 210000001842 enterocyte Anatomy 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 230000004373 eye development Effects 0.000 description 1
- 235000020988 fatty fish Nutrition 0.000 description 1
- 229940075000 frankincense extract Drugs 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 230000002178 gastroprotective effect Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229930182478 glucoside Chemical class 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- RFDAIACWWDREDC-FRVQLJSFSA-N glycocholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 RFDAIACWWDREDC-FRVQLJSFSA-N 0.000 description 1
- 229940099347 glycocholic acid Drugs 0.000 description 1
- WVULKSPCQVQLCU-BUXLTGKBSA-N glycodeoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 WVULKSPCQVQLCU-BUXLTGKBSA-N 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000009437 guggulu extract Substances 0.000 description 1
- 230000007407 health benefit Effects 0.000 description 1
- 230000002443 hepatoprotective effect Effects 0.000 description 1
- 239000012676 herbal extract Substances 0.000 description 1
- LPTIRUACFKQDHZ-UHFFFAOYSA-N hexadecyl sulfate;hydron Chemical compound CCCCCCCCCCCCCCCCOS(O)(=O)=O LPTIRUACFKQDHZ-UHFFFAOYSA-N 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 229940106134 krill oil Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 229940033355 lauric acid Drugs 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
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 125000002669 linoleoyl 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])=C([H])\C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940040461 lipase Drugs 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- SMEROWZSTRWXGI-HVATVPOCSA-N lithocholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 SMEROWZSTRWXGI-HVATVPOCSA-N 0.000 description 1
- 150000004668 long chain fatty acids Chemical class 0.000 description 1
- 235000004213 low-fat Nutrition 0.000 description 1
- 235000020640 mackerel Nutrition 0.000 description 1
- 208000002780 macular degeneration Diseases 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229940037627 magnesium lauryl sulfate Drugs 0.000 description 1
- HBNDBUATLJAUQM-UHFFFAOYSA-L magnesium;dodecyl sulfate Chemical compound [Mg+2].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O HBNDBUATLJAUQM-UHFFFAOYSA-L 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000007909 melt granulation Methods 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 239000010658 moringa oil Substances 0.000 description 1
- OBMBYGXRLQQDHH-KVVVOXFISA-N morpholin-4-ium;(z)-octadec-9-enoate Chemical compound C1COCCN1.CCCCCCCC\C=C/CCCCCCCC(O)=O OBMBYGXRLQQDHH-KVVVOXFISA-N 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 235000020638 mussel Nutrition 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 239000007908 nanoemulsion Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- YZUUTMGDONTGTN-UHFFFAOYSA-N nonaethylene glycol Chemical compound OCCOCCOCCOCCOCCOCCOCCOCCOCCO YZUUTMGDONTGTN-UHFFFAOYSA-N 0.000 description 1
- 239000002417 nutraceutical Substances 0.000 description 1
- 235000021436 nutraceutical agent Nutrition 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 208000015380 nutritional deficiency disease Diseases 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- ZHALDANPYXAMJF-UHFFFAOYSA-N octadecanoate;tris(2-hydroxyethyl)azanium Chemical compound OCC[NH+](CCO)CCO.CCCCCCCCCCCCCCCCCC([O-])=O ZHALDANPYXAMJF-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- 235000021032 oily fish Nutrition 0.000 description 1
- FATBGEAMYMYZAF-KTKRTIGZSA-N oleamide Chemical compound CCCCCCCC\C=C/CCCCCCCC(N)=O FATBGEAMYMYZAF-KTKRTIGZSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229960002969 oleic acid Drugs 0.000 description 1
- FATBGEAMYMYZAF-UHFFFAOYSA-N oleicacidamide-heptaglycolether Natural products CCCCCCCCC=CCCCCCCCC(N)=O FATBGEAMYMYZAF-UHFFFAOYSA-N 0.000 description 1
- 125000002811 oleoyl 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])=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
- 229940055577 oleyl alcohol Drugs 0.000 description 1
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 1
- 235000021301 omega-3 deficiency Nutrition 0.000 description 1
- 229940118617 omtryg Drugs 0.000 description 1
- 229940100688 oral solution Drugs 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000010525 oxidative degradation reaction Methods 0.000 description 1
- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 description 1
- 239000002540 palm oil Substances 0.000 description 1
- 229940116369 pancreatic lipase Drugs 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920000056 polyoxyethylene ether Polymers 0.000 description 1
- 229920000259 polyoxyethylene lauryl ether Polymers 0.000 description 1
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 description 1
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 description 1
- 229940101027 polysorbate 40 Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229940068984 polyvinyl alcohol Drugs 0.000 description 1
- ONQDVAFWWYYXHM-UHFFFAOYSA-M potassium lauryl sulfate Chemical compound [K+].CCCCCCCCCCCCOS([O-])(=O)=O ONQDVAFWWYYXHM-UHFFFAOYSA-M 0.000 description 1
- 229940116985 potassium lauryl sulfate Drugs 0.000 description 1
- 229940114930 potassium stearate Drugs 0.000 description 1
- GUAZCMSGQCEOKY-UHFFFAOYSA-M potassium;2-(methylamino)ethanesulfonate Chemical compound [K+].CNCCS([O-])(=O)=O GUAZCMSGQCEOKY-UHFFFAOYSA-M 0.000 description 1
- MQOCIYICOGDBSG-UHFFFAOYSA-M potassium;hexadecanoate Chemical compound [K+].CCCCCCCCCCCCCCCC([O-])=O MQOCIYICOGDBSG-UHFFFAOYSA-M 0.000 description 1
- ANBFRLKBEIFNQU-UHFFFAOYSA-M potassium;octadecanoate Chemical compound [K+].CCCCCCCCCCCCCCCCCC([O-])=O ANBFRLKBEIFNQU-UHFFFAOYSA-M 0.000 description 1
- DQFWABVCOIFBPO-UHFFFAOYSA-M potassium;tetradecyl sulfate Chemical compound [K+].CCCCCCCCCCCCCCOS([O-])(=O)=O DQFWABVCOIFBPO-UHFFFAOYSA-M 0.000 description 1
- 229920003124 powdered cellulose Polymers 0.000 description 1
- 235000019814 powdered cellulose Nutrition 0.000 description 1
- 239000000955 prescription drug Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 229940026235 propylene glycol monolaurate Drugs 0.000 description 1
- 229940093625 propylene glycol monostearate Drugs 0.000 description 1
- 239000001944 prunus armeniaca kernel oil Substances 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 150000003235 pyrrolidines Chemical class 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 1
- 229960003147 reserpine Drugs 0.000 description 1
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
- 235000019512 sardine Nutrition 0.000 description 1
- 229940046303 sodium cetostearyl sulfate Drugs 0.000 description 1
- 229940080236 sodium cetyl sulfate Drugs 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- BTURAGWYSMTVOW-UHFFFAOYSA-M sodium dodecanoate Chemical compound [Na+].CCCCCCCCCCCC([O-])=O BTURAGWYSMTVOW-UHFFFAOYSA-M 0.000 description 1
- 229940082004 sodium laurate Drugs 0.000 description 1
- 229940075560 sodium lauryl sulfoacetate Drugs 0.000 description 1
- 229950005425 sodium myristyl sulfate Drugs 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 229940045870 sodium palmitate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229940080350 sodium stearate Drugs 0.000 description 1
- IWIUXJGIDSGWDN-UQKRIMTDSA-M sodium;(2s)-2-(dodecanoylamino)pentanedioate;hydron Chemical compound [Na+].CCCCCCCCCCCC(=O)N[C@H](C([O-])=O)CCC(O)=O IWIUXJGIDSGWDN-UQKRIMTDSA-M 0.000 description 1
- DONVGTHTQJQEDC-UHFFFAOYSA-M sodium;2-(2-oxopentadecylamino)acetate Chemical compound [Na+].CCCCCCCCCCCCCC(=O)CNCC([O-])=O DONVGTHTQJQEDC-UHFFFAOYSA-M 0.000 description 1
- ZUFONQSOSYEWCN-UHFFFAOYSA-M sodium;2-(methylamino)acetate Chemical compound [Na+].CNCC([O-])=O ZUFONQSOSYEWCN-UHFFFAOYSA-M 0.000 description 1
- KKDONKAYVYTWGY-UHFFFAOYSA-M sodium;2-(methylamino)ethanesulfonate Chemical compound [Na+].CNCCS([O-])(=O)=O KKDONKAYVYTWGY-UHFFFAOYSA-M 0.000 description 1
- UKSFMDODPANKJI-UHFFFAOYSA-M sodium;2-[methyl(octadecanoyl)amino]ethanesulfonate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC(=O)N(C)CCS([O-])(=O)=O UKSFMDODPANKJI-UHFFFAOYSA-M 0.000 description 1
- IZWPGJFSBABFGL-GMFCBQQYSA-M sodium;2-[methyl-[(z)-octadec-9-enoyl]amino]ethanesulfonate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC(=O)N(C)CCS([O-])(=O)=O IZWPGJFSBABFGL-GMFCBQQYSA-M 0.000 description 1
- UAJTZZNRJCKXJN-UHFFFAOYSA-M sodium;2-dodecoxy-2-oxoethanesulfonate Chemical compound [Na+].CCCCCCCCCCCCOC(=O)CS([O-])(=O)=O UAJTZZNRJCKXJN-UHFFFAOYSA-M 0.000 description 1
- HFQQZARZPUDIFP-UHFFFAOYSA-M sodium;2-dodecylbenzenesulfonate Chemical compound [Na+].CCCCCCCCCCCCC1=CC=CC=C1S([O-])(=O)=O HFQQZARZPUDIFP-UHFFFAOYSA-M 0.000 description 1
- GGXKEBACDBNFAF-UHFFFAOYSA-M sodium;hexadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCC([O-])=O GGXKEBACDBNFAF-UHFFFAOYSA-M 0.000 description 1
- GGHPAKFFUZUEKL-UHFFFAOYSA-M sodium;hexadecyl sulfate Chemical compound [Na+].CCCCCCCCCCCCCCCCOS([O-])(=O)=O GGHPAKFFUZUEKL-UHFFFAOYSA-M 0.000 description 1
- CLBALUNQCMWJSU-UHFFFAOYSA-L sodium;hexadecyl sulfate;octadecyl sulfate Chemical compound [Na+].CCCCCCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCCCCCCCOS([O-])(=O)=O CLBALUNQCMWJSU-UHFFFAOYSA-L 0.000 description 1
- BKHIPXYILWCYCA-KVVVOXFISA-M sodium;hydron;(z)-2-sulfonatooctadec-9-enoate Chemical compound [H+].[Na+].CCCCCCCC\C=C/CCCCCCC(C([O-])=O)S([O-])(=O)=O BKHIPXYILWCYCA-KVVVOXFISA-M 0.000 description 1
- NWZBFJYXRGSRGD-UHFFFAOYSA-M sodium;octadecyl sulfate Chemical compound [Na+].CCCCCCCCCCCCCCCCCCOS([O-])(=O)=O NWZBFJYXRGSRGD-UHFFFAOYSA-M 0.000 description 1
- UPUIQOIQVMNQAP-UHFFFAOYSA-M sodium;tetradecyl sulfate Chemical compound [Na+].CCCCCCCCCCCCCCOS([O-])(=O)=O UPUIQOIQVMNQAP-UHFFFAOYSA-M 0.000 description 1
- 229940057429 sorbitan isostearate Drugs 0.000 description 1
- 229950006451 sorbitan laurate 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
- 235000011071 sorbitan monopalmitate Nutrition 0.000 description 1
- 239000001570 sorbitan monopalmitate Substances 0.000 description 1
- 229940031953 sorbitan monopalmitate Drugs 0.000 description 1
- 229960005078 sorbitan sesquioleate Drugs 0.000 description 1
- 239000001589 sorbitan tristearate Substances 0.000 description 1
- 229960004129 sorbitan tristearate Drugs 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000005563 spheronization Methods 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000007619 statistical method Methods 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
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 235000021335 sword fish Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- BHTRKEVKTKCXOH-AYSJQVDDSA-N taurochenodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)C1C2C2CC[C@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)CC1 BHTRKEVKTKCXOH-AYSJQVDDSA-N 0.000 description 1
- WBWWGRHZICKQGZ-GIHLXUJPSA-N taurocholic acid Chemical compound C([C@@H]1C[C@H]2O)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@H](O)C1 WBWWGRHZICKQGZ-GIHLXUJPSA-N 0.000 description 1
- QBYUNVOYXHFVKC-GBURMNQMSA-N taurolithocholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)CC1 QBYUNVOYXHFVKC-GBURMNQMSA-N 0.000 description 1
- UWHCKJMYHZGTIT-UHFFFAOYSA-N tetraethylene glycol Chemical compound OCCOCCOCCOCCO UWHCKJMYHZGTIT-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001578 tight junction Anatomy 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 229940093609 tricaprylin Drugs 0.000 description 1
- 229940117013 triethanolamine oleate Drugs 0.000 description 1
- 229940029614 triethanolamine stearate Drugs 0.000 description 1
- 125000005457 triglyceride group Chemical group 0.000 description 1
- VLPFTAMPNXLGLX-UHFFFAOYSA-N trioctanoin Chemical compound CCCCCCCC(=O)OCC(OC(=O)CCCCCCC)COC(=O)CCCCCCC VLPFTAMPNXLGLX-UHFFFAOYSA-N 0.000 description 1
- 150000004072 triols Chemical class 0.000 description 1
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 description 1
- 229960001661 ursodiol Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
- 239000002888 zwitterionic surfactant Substances 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/115—Fatty acids or derivatives thereof; Fats or oils
- A23L33/12—Fatty acids or derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/32—Burseraceae (Frankincense family)
- A61K36/324—Boswellia, e.g. frankincense
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/32—Burseraceae (Frankincense family)
- A61K36/328—Commiphora, e.g. mecca myrrh or balm of Gilead
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/47—Euphorbiaceae (Spurge family), e.g. Ricinus (castorbean)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/74—Rubiaceae (Madder family)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Definitions
- This invention relates to omega-3 fatty acid composition of enhanced bioavailability comprising omega-3 fatty acids, a plant extract and at least one surfactant.
- This invention also relates to omega-3 fatty acid composition substantially free of food effects comprising Omega-3 fatty acids, a plant extract and at least one surfactant.
- This invention also relates to process of preparing composition comprising omega-3 fatty acids, a plant extract and at least one surfactant.
- Omega-3 fatty acids also called n-3 poly unsaturated fatty acids (PUFA)
- PUFA n-3 poly unsaturated fatty acids
- These fatty acids have a number of beneficial effects, among which is lowering elevated blood triglyceride levels down to more clinically acceptable values (Harris et. al., "Omega-3 fatty acids and coronary heart disease risk: Clinical and mechanistic perspectives" Atherosclerosis. 2008 March; 197(1): 12-24).
- Omega-3 fatty acids may improve cognitive function and delay the onset of Alzheimer's disease
- Omega-3 fatty acids delivers ingredients essential for eye development and which may protect against age related macular degeneration and help dry eye syndrome and also contains essential fatty acids which may improve the nutrition of the skin and associated inflammatory conditions.
- Omega -3 fatty acids may also help in reducing pain, stiffness and inflammation associated with arthritis and other joint conditions. Omega-3 fatty acids have also been shown to be important in pregnant women and infants, where their depletion may lead to visual or central nervous system problems Omega-3 fatty acids cannot be manufactured in the human body and are therefore called essential fatty acids. They need to be obtained from the diet of an individual.
- the two major health promoting omega-3 polyunsaturated fatty acids are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). EPA and DHA are naturally found in certain cold-water fatty fish such as salmon, tuna, and mackerel.
- ALA alpha-linolenic acid
- EPA EPA and DHA
- omega-3 fatty acids Because of the wide range of known health benefits related to omega-3 fatty acids, a number of international organizations and agencies proposed recommendations for omega-3 fatty acids, as well as fish intake for health promotion and prevention of various chronic diseases. Although the intake of omega-3 fatty acids has proven to be crucial, it has been found that omega-3 fatty acids are deficient in the typical Western diet. The omega-3 deficiency situation is even worse among the poor and malnourished.
- omega-3 fatty acid deficiencies are through dietary supplementation, which is a convenient way to add them to the diet.
- Nutritional supplements are especially useful in individuals who struggle to meet their nutrient needs because of inadequate dietary intakes.
- omega-3 fatty acids and uses thereof, including in pharmaceutical, nutritional or dietary supplement products is known in art.
- One such form of omega-3 fatty acid is a concentrate of omega-3, long chain, polyunsaturated fatty acids from fish oil containing DHA and EPA and is sold under the trademark Lovaza®.
- Such a form of omega-3 fatty acid is described in U.S. Patent Nos. 5,502,077, 5,656,667 and 5,698,594.
- WO2013103902 discloses DPA-enriched compositions of omega-3 polyunsaturated fatty acids in free acid form
- WO2013148136 describes composition comprising Omega-3 fatty acid esters, free of Omega-3 free fatty acids
- U.S. Patent Nos. 7652068 discloses highly purified omega-3 fatty acid formulations containing greater than 85% omega-3 fatty acids by weight.
- omega-3 fatty acid formulation The bioavailability and thus the therapeutic efficacy of an omega-3 fatty acid formulation is affected by the form in which it is administered.
- the amount of absorption of omega-3 fatty acid in gastro intestinal tract depends upon the chemical and physical form of the fish oil.
- omega-3 fatty acid supplements There are several omega-3 fatty acid supplements available. Current dietary supplements, nutraceuticals, and prescribed drugs containing Omega-3 fatty acid esters have a food effect, with poor absorption when taken while fasting or with a low fat meal.
- compositions with enhanced bioavailability of omega-3 fatty acids which can be administered without food effects
- Extracts from plants such as Amla (Phyllanthus emblica), Green coffee bean (Coffea arabica), Drumstick tree or Horseradish tree (Moringa oleiferd), Guggul or Mukul myrrh tree ⁇ Commiphora wightii), Frankincense (Boswellia serata) are known for antidiabetic, hypolipidemic, antibacterial, antioxidant, antiulcerogenic, hepatoprotective, gastroprotective, and chemopreventive properties. Various studies have been documented for these plant extracts having Antihyperlipidimic activities.
- Amla Emblica officinalis
- family: euphorbiaceac Jeevangi Santoshkumar., et al :A study of anti-hyperlipidemia, hypolipedimic and anti-atherogenic activity of fruit of emblica officinalis (amla) in high fat fed albino rats); Green coffee bean ⁇ Coffea arabica), family: Rubiaceae (Gaafar M.
- a herbal medicine for hyperlipidemia A pre- clinical report); Guggul or Mukul myrrh tree ⁇ Commiphora wightii), family: burseraccac (Singh RB., et al: Hypolipidemic and antioxidant effects of Commiphora mukul as an adjunct to dietary therapy in patients with hypercholesterolemia.); Frankincense (Boswellia seratd), family: Burseraceae (Dashti GH.,et al : The effect of frankincense extract on accumulation of fatty streaks in coronary arteries of high-cholesterol fed male rabbits)
- compositions comprising omega-3 fatty acid and plant extract should have good physical stability; the physical properties of this composition should be made ideal to provide high patient compliance.
- These plant extracts may prevent oxidative degradation of Omega-3 fatty acid that occurs over time can result in an unpleasant aftertaste following administration.
- This invention relates to a composition
- a composition comprising omega-3 fatty acids and a plant extract and atleast one surfactant suitable for oral administration.
- the invention relates to a composition
- a composition comprising omega-3 fatty acids and a plant extract and atleast one surfactant for oral administration, where in the composition is substantially free of food effects.
- the formulation upon administration of a pharmaceutical formulation of the invention to a mammal, the formulation exhibits an absorption profile (e.g., C max and AUC, or max, AUC, and T max ) under fed conditions which is similar to, the absorption profile of the same composition administered under fasting conditions.
- the mammal is a human.
- Yet another objective of the invention relates to a composition
- a composition comprising omega-3 fatty acids and a plant extract, and atleast one surfactant, wherein exhibits enhanced bioavailability
- Yet another objective of the invention relates to a composition
- a composition comprising omega-3 fatty acids and a plant extract, and atleast one surfactant, wherein the said composition forms micelles in aqueous medium having D90 less than lOOnm
- composition suitable for prophylactic or therapeutic treatment known for omega-3fatty acids for a subject in need thereof comprising omega-3 fatty acids and a plant extract and atleast one surfactant for oral administration.
- omega-3 fatty acid composition comprising Plant extracts wherein the plant extracts may provide synergistic and/ or additive effect on antihyperlipidemic property of omega-3 fatty acids.
- FIG. 1 is an illustration of the particle size of the self-emulsified droplets in gastric environment.
- FIG. 2 is an illustration of the comparative oral pharmacokinetic profile of the omega-3 fatty acid present in fish oil with omega-3 fatty acid given as novel preconcentrate formulation.
- FIG. 3 is an illustration of the comparative oral pharmacokinetic profile of "EPA" concentration in Fast state and Fed state of Omega-3 fatty acid KMS formulation.
- FIG. 4 is an illustration of the comparative oral pharmacokinetic profile of EPA concentration in fast state with omega-3 fatty acid KMS formulation vs lovaza DETAILED DESCRIPTION OF THE INVENTION:
- omega-3 fatty acids includes natural and synthetic omega-3 fatty acids, as well as pharmaceutically-acceptable esters, free acids, triglycerides, derivatives, conjugates (see, e.g., Zaloga et al., U.S. Patent Application Publication No. 2004/0254357, and Horrobin et al, U.S. Pat. No. 6,245,811, each hereby incorporated by reference), precursors, salts, and mixtures thereof.
- omega-3 fatty acid oils include, but are not limited to, omega-3 polyunsaturated, long-chain fatty acids such as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), a-linolenic acid (ALA), heneicosapentaenoic acid (HP A), docosapentaenoic acid (DP A), eicosatetraenoic acid (ETA), eicosatrienoic acid (ETE), and octadecatetraenoic acid (i.e., stearidonic acid, STA); esters of omega-3 fatty acids with glycerol such as mono-, di- and triglycerides; and esters of the omega-3 fatty acids and a primary, secondary and/or tertiary alcohol, such as, for example, fatty acid methyl esters and fatty acid ethyl esters.
- omega-3 fatty acids, esters, triglycerides, derivatives, conjugates, precursors, salts and/or mixtures thereof according to the present disclosure can be used in their pure form and/or as a component of an oil, for example, as marine oil (e.g., fish oil and purified fish oil concentrates), algae oils, microbial oils and plant-based oils.
- marine oil e.g., fish oil and purified fish oil concentrates
- algae oils e.g., microbial oils and plant-based oils.
- plant plant extracf'or “Herbal extract”
- plant plant extracf'or “Herbal extract”
- plant extract means an extract, juice, or concentrate from any part of a plant, such as the seed, leaf, fruit, flower, stem, root, tuber, bark, etc.
- food effect refers to a somewhat unpredictable phenomenon that can influence the absorption of active ingredients from the gastrointestinal tract following oral administration.
- a food effect can be designated negative when absorption is decreased, or positive when absorption is increased and manifested as an increase in oral bioavailability (as reflected by total exposure).
- “food effects” can refer to changes in maximum concentration, or the time to reach maximum concentration, independently of overall absorption. As a result, some active ingredients have to be taken in either fasted or fed conditions to achieve the optimum effect. However, many drugs are unaffected by food, and thus, can be taken in either a fasted or a fed condition.
- the presence or absence of a food effect may be quantified by making Area under the Curve (AUC) and/or C max measurements according to methods well known in the art.
- AUC measurements and C max measurements are made by taking timed biological fluid samples and plotting the serum concentration of Omega-3 fatty (or the active agent thereof) against time.
- the values obtained represent a number of values taken from subjects across a patient population and are therefore expressed as mean values expressed over the entire patient population. By comparing the mean AUC and/or C max values, one can determine whether Omega-3 fatty exhibits a food effect.
- M C max refers to maximum concentration of omega-3 fatty acids in blood or serum following the ingestion of a dose of omega-3 fatty acids.
- T max refers to the time following ingestion required for the level of omega-3 fatty acids in blood or serum to reach C max .
- AUC refers to the area under the curve of a plot of the blood/serum concentration of omega-3 fatty acids against time from the time omega-3 fatty acids is ingested until the concentration is below the detection limit.
- AUC is a measure of the total patient exposure to omega-3 fatty acids.
- Bioavailability is a measurement of the rate and extent to which a drug reaches the systemic circulation
- bioavailability refers to "relative bioavailability" between composition of present invention comprising omega-3 fatty acid Plant extracts and an unformulated Omega-3 fatty acid.
- preconcentrate here in refers to a composition which when diluted with aqueous solution forms dispersions
- aqueous medium refers to any solution or suspension, that comprises water or phosphate buffered saline pH 7.4 or fluid having an acidic pH or a biological fluid such as for example and without limitation, stomach acid or the aqueous medium comprises simulated stomach acid comprising 0.1 N HC 1.
- composition wherein composition comprises omega-3 fatty acids, a plant extract and atleast one surfactant suitable for oral administration.
- composition with enhanced bioavailability of omega -3 fatty acids comprising omega-3 fatty acids, a plant extract and atleast one surfactant is provided.
- composition substantially free of food effects comprising omega-3 fatty acids, a plant extract and atleast one surfactant is provided.
- Omega-3 fatty acids used herein may be derived from either marine source or plant source.
- Omega-3 fatty acids may be derived from a marine species, such as a fish oil or crustacean.
- fish known to have high levels of omega-3 fatty acids include so-called "oily fish” such as salmon, tuna, swordfish, halibut, tilefish, cod fish (including cod liver oil), anchovies, and sardines.
- crustaceans are also known to have high levels of omega-3 fatty acids, including krill, a crustacean in the Antarctic (the source of krill oil) and the New Zealand green-lipped mussel, (also known as Perna canaliculus) but not limited to them
- Omega-3 fatty acids may be may be derived from a vegetable source, in particular seed oils, including perilla seeds (Linnaean name Perilla frutescens); chia seeds (Salviahispanica); flax seeds (Linum usitatissimum); lingon berry seeds (Vaccinium vitis-idaea); and rape seeds (Brassicanapus), more commonly called canola oil but not limited to them
- the composition comprises about 10% to about 98% (w/w) of omega-3 fatty acids in total composition. Preferably about 20% w/w of omega-3 fatty acids, More preferably about 30% w/w of the omega-3 fatty acids.
- Omega-3 fatty acids used herein is preferably either eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) or both
- Omega -3 fatty acids comprising "EPA” and "DHA” used herein may be of esterified, triglyceride, phospholipid or free fatty acid forms
- Omega-3 fatty acids comprising "EPA” and “DHA” used herein is preferably in esterified form.
- the weight ratio of EP A:DHA of the fatty acid oil mixture ranges from about 1 : 10 to about 10:1, from about 1 :8 to about 8: 1, from about 1 :6 to about 6:1, from about 1 :5 to about 5: 1 , from about 1:4 to about 4:1, from about 1 :3 to about 3:1, or from about 1 :2 to about 2:1. More preferably from about 1 :3 to about 3: 1
- the content of EPA and DHA, taken together is atleast above 10% w/w; atleast above 20%w/w; atleast about 30%w/w; atleast about 40% w/w; atleast about 50%w/w of omega -3 fatty acids in the total composition. Preferably about 50% w/w of omeg-3 fatty acids in total composition.
- the content of EPA alone is atleast above 10% w/w of the total composition. Preferably above 20% w/w of the total composition; more preferably above 30% w/w of the total composition.
- the content of DHA alone is atleast above 5% w/w of omega-3 fatty acids in the total composition.
- the composition comprises a plant extract; wherein the plant extract is select from the group consisting of extracts from Amla (Phyllanthus emblica), Green coffee bean (Coffea arabica), Drumstick tree or Horseradish tree (Moringa oleifera), Guggul or Mukul myrrh tree ⁇ Commiphora wightii), Frankincense (Boswellia serata)
- the plant extract may exert additive effect and/or synergistic effect on antihyperlipidemic activity of omega- 3 fatty acids.
- plant extract comprises about 1 % to about 50 %( w/w), of the total composition.
- the plant extract is preferably Amla (Phyllanthus emblica).
- plant extract comprises about 1 % to about 50 % (w/w), of the total composition; wherein the plant extract is Amla.
- composition comprising omega-3 fatty acids and a plant extract and atleast one surfactant.
- a surfactant may, for example, lower the surface tension of a liquid or the surface tension between two liquids.
- surfactants according to the present disclosure may lower the surface tension between the fatty acid oil mixture and an aqueous solution.
- surfactants are molecules with at least one hydrophilic part and at least one hydrophobic (i.e., lipophilic) part.
- Surfactant properties may be reflected in the hydrophilic- lipophilic balance (HLB) value of the surfactant, wherein the HLB value is a measure of the degree of hydrophilic versus lipophilic properties of a surfactant.
- HLB hydrophilic- lipophilic balance
- the HLB value normally ranges from 0 to 20, where a HLB value of 0 represents high hydrophilic character, and a HLB of 20 represents high lipophilic character.
- Surfactants are often used in combination with other surfactants, wherein the HLB values are additive.
- the HLB value of surfactant mixtures may be calculated as follows:
- said surfactant is selected from the group consisting of nonionic surfactants, cationic surfactants, anionic surfactants, zwitterionic surfactants, or combinations thereof.
- non-ionic surfactants are selected from a group having a hydrophobic group and a reactive hydrogen atom, for example aliphatic alcohols, acids, amides and alkyl phenols, with alkylene oxides, especially ethylene oxide either alone or in combination with propylene oxide.
- nonionic surfactant compounds include, but are not limited to, Polyoxyethylene glycol sorbitan alkyl esters, Polyoxyethylene Stearates, Polyoxyethylene Castor Oil Derivatives, Sorbitan Esters (Sorbitan Fatty Acid Esters , polyoxyethylene sorbitan fatty acid esters), Polyoxylglycerides, sucrose fatty acid esters, block copolymers of polyethylene glycol and polypropylene glycol, ethylene glycol fatty acid esters, poly(ethylene glycol) fatty acid esters, propylene glycol fatty acid esters (propylene glycol monolaurate), poly(propylene glycol) fatty acid esters, glycol fatty acid esters, trimethylolpropane fatty acid esters, pentaerythritol fatty acid esters, glucoside derivatives, glycerin alkyl ether fatty acid esters, trimethylolpropane oxyethylene alkyl ethers, fatty acid amides
- Polysorbates are a class of oily liquids derived from PEG-ylated sorbitan (a derivative of sorbitol) esterified with fatty acids. Common brand names for polysorbates include Tween®. Tween-20, Tween-60 and Tween-80, for example, are available from AkzoNobel (Strawinskylaan 2555 1077 ZZ, Amsterdam, the Netherlands).
- Exemplary polysorbates include polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate ), polysorbate 60(polyoxyethylene (20) sorbitan monostearate ), and polysorbate 80 (polyoxyethylene (20) sorbitan monooleate).
- Polyoxyethylene Castor Oil Derivatives include Polyoxyl 5 castor oil(PEG-5 castor oil; polyoxyethylene 5 castor oil.), Polyoxyl 9 castor oil(PEG-9 castor oil; polyoxyethylene 9 castor oil), Polyoxyl 15 castor oil(PEG-15 castor oil; polyoxyethylene 15 castor oil), Polyoxyl 35 castor oil(Cremophor EL; Kolliphor EL; PEG-35 castor oil; polyethoxylated castor oil; polyoxyethylene 35 castor oil), Polyoxyl 40 castor oil(PEG-40 castor oil; polyoxyethylene 40 castor oil), Polyoxyl 40 hydrogenated castor oil(Cremophor RH 40; PEG-40 hydrogenated castor oil; polyethoxylated hydrogenated castor oil; polyoxyethylene 40 hydrogenated castor oil), Polyoxyl 60 castor oil(PEG-60 castor oil; polyoxyethylene 60 castor oil), Polyoxyl 60 hydrogenated castor oil(PEG-60 hydrogenated castor oil; polyoxyethylene 60 hydrogenated castor oil;
- Sorbitan Esters Sorbitan Fatty Acid Esters
- Sorbitan monoisostearate Arlacel 987; Crill 6; sorbitan isostearate
- Sorbitan monolaurate sorbitan laurate; sorbitani lauras; Span 20
- Sorbitan monooleate Arlacel 80
- Sorbitan monopalmitate Span 40.
- Sorbitan monostearate Span 60
- Sorbitan sesquiisostearate Sorbitan sesquioleate
- Sorlacel C Arlacel 83; Crill 43
- Sorbitan trilaurate Span 25
- Sorbitan trioleate Span 85
- Sorbitan tristearate Span 65
- Polyoxylglycerides include but not limited to Caprylocaproyl polyoxylglycerides (Labrasol; macro golglyceridorum caprylocaprates; PEG 400 caprylic/ capric glycerides), Lauroyl polyoxylglycerides(Gelucire 44/14; hydrogenated coconut oil PEG 1500 esters),Linoleoyl polyoxylglycerides (Corn oil PEG 300 esters; LabrafilM2125CS), Oleoyl polyoxylglycerides (Apricot kernel oil PEG 300 esters), Stearoyl polyoxylglycerides(Gelucire 50/13; hydrogenated palm oil PEG 1500 ester)
- anionic surfactants are selected from a group include, but are not limited to, N-acyl-L-glutamic acid diethanolamine, N-acyl-L-glutamic acid triethanolamine, sodium N- acyl-L-glutamate, sodium alkanesulfonate, ammonium alkyl (C 12> C 14 , Ci 6 ) sulfate, alkyl (Cn, C , C15) sulfuric acid triethanolamine, alkyl (C » , C13, C15) sulfuric acid triethanolamine, alkyl (C 12 to C 14 ) sulfuric acid triethanolamine, liquid alkylsulfuric acid triethanolamine, sodium alkyl (Ci 2 , C 13 ) sulfate, liquid sodium alkylsulfate, sodium isoethionate, sodium lacto-isostearate, disodium undecylenoylamido ethyl sulfosuccinate, triethanolamine sulfoole
- surfactants also include, but are not limited to the bile acids (e.g., cholic acid, chenodeoxycholic acid, glycocholic acid, glycodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid, taurolithocholic acid, deoxycholic acid, lithocholic acid, and ursodeoxycholic acid and salts thereof, e.g., sodium, potassium, lithium), natural emulsifiers (e.g.
- acacia agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g.
- carboxy polymethylene polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer
- carrageenan cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose), polyoxyethylene esters (e.g. polyoxyethylene monostearate [Myrj 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. Cremophor), polyoxyethylene ethers, (e.g.
- polyoxyethylene lauryl ether [Brij 30]), poly(vinyl-pyrrolidone), diethyl ene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyllaurate, sodium lauryl sulfate, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium or combinations thereof.
- Atleast one surfactant preferably selected from group of Polyoxyethylene glycol sorbitan alkyl esters, Polyoxyethylene Castor Oil Derivatives, Sorbitan Esters (Sorbitan Fatty Acid Esters , polyoxyethylene sorbitan fatty acid esters), Polyoxylglycerides, sucrose fatty acid esters, block copolymers of polyethylene glycol and polypropylene glycol or combinations thereof.
- Atleast one surfactant is selected from group of Polyoxyethylene glycol sorbitan alkyl esters such as Tween 20, Tween 60 Tween80.
- Atleast one surfactant is selected from group of Sorbitan Fatty Acid Esters such as Span 20, Span 60. More preferably atleast one surfactant is selected from a group of Polyoxyethylene Castor Oil derivatives such as PEG-35 castor oil, PEG-40 castor oil.
- the total amount of surfactants present in the composition do not exceed 50% w/w of the total composition.
- the value of HLB of the Surfactants present is in the composition should be from about 8 - 18. More preferably above 12.
- composition comprising omega-3 fatty acids and a plant extract and atleast one surfactant optionally may contain co surfactants and other pharmaceutically acceptable excipients
- compositions of the present disclosure further comprise at least one co-surfactant.
- co-surfactant means a substance added to the compostion in combination with the at least one surfactant to affect, e.g., increase or enhance, emulsification and/or stability of the compostion, for example to aid in forming an emulsion.
- the at least one co-surfactant is hydrophilic.
- co-surfactants suitable for the present disclosure include, but are not limited to, short chain alcohols comprising from 1 to 6 carbons (e.g., ethanol), benzyl alcohol, alkane diols and triols (e.g., propylene glycol, glycerol, polyethylene glycols such as PEG 600 and PEG 400), glycol ethers such as tetraglycol and glycofurol (e.g., tetrahydrofurfuryl PEG ether), pyrrolidine derivatives such as N-methylpyrrolidone (e.g., Pharmasolve®) and 2-pyrrolidone (e.g., Soluphor® P), and bile salts, for example sodium deoxycholate. Further examples include ethyl oleate. Additional oils
- Synergistic composition further comprise at least one additional oil, such as medium chain triglyceride (MCT) oil and long chain triglyceride (LCT) oil
- MCT medium chain triglyceride
- LCD long chain triglyceride
- composition can be a preconcentrate or an emulsion.
- the preconcentrates produce dispersions when contacted with aqueous medium generating self-nanoemulsifying drug delivery systems (SNEDDS), self- microemulsifying drug delivery systems (SMEDDS), or self emulsifying drug delivery systems (SEDDS).
- SNEDDS self-nanoemulsifying drug delivery systems
- SMEDDS self- microemulsifying drug delivery systems
- SEDDS self emulsifying drug delivery systems
- the compostion is preferably self-nanoemulsifying drug delivery systems (SNEDDS)
- composition forms micelles in aqueous medium having D 90 less than 500nm, D 90 less than 300nm, more preferably D 90 less than lOOnm.
- composition comprising omega-3 fatty acids and a plant extract and atleast one surfactant for oral administration, wherein the composition forms particle size D90 less than lOOnm when contacted with aqueous medium.
- particle size are preferably between 20nm to about 90nm.
- the aqueous medium may be any solution or suspension, that comprises water or phosphate buffered saline pH 7.4 or fluid having an acidic pH or a biological fluid such as for example and without limitation, stomach acid or the aqueous medium comprises simulated stomach acid comprising 0.1N HC1.
- omega-3 fatty acids from the gastrointestinal tract involves the conversion of large fat globules to the smaller size micellar droplets by action of bile salts. The smaller droplets are then acted upon by pancreatic lipase that coverts the triglyceride within fat to fatty acids that traverse easily through the phospholipid bilayer. Thus absorption of omega-3 fatty acid from gastrointestinal tract depends widely upon its emulsification and conversion to smaller droplets.
- the self-emulsifying composition of this invention comprising omega-3 fatty acids, a plant extract and atleast one surfactant which rapidly form an oil-in-water emulsion when introduced into the aqueous media under mild agitation.
- the digestive motility of the stomach and intestine provides the agitation necessary for self-emulsification in vivo.
- the self-emulsification process occurs spontaneously.
- the spontaneous formation of micro/nano emulsion advantageously presents the drug in a dissolved form and the resultant small droplets size provides a large interfacial surface area for drug release and absorption.
- Main mechanisms include increasing membrane fluidity to facilitate transcellular absorption, opening tight junction to allow paracellular transport, inhibiting P-gp and/or CYP450 to increase intracellular concentration and residence time by surfactants, and stimulating lipoprotein/chylomicron production by lipid.
- the formulation upon administration of a pharmaceutical formulation of the invention to a mammal, the formulation exhibits an absorption profile (e.g., Cmax and AUC, or Cmax, AUC, and Tmax) under fed conditions which is similar, or bioequivalent to, the absorption profile of the same composition administered under fasting conditions.
- the mammal is a human.
- the synergistic composition comprising omega-3 fatty acid extract and a Plant extract; where in the composition is substantially free of food effect.
- the free fatty acids are absorbed / transported into the intestinal enterocytes; rapidly re esterified, and enters the systemic circulation via the thoracic duct as chylomicrons.
- the chylomicrons Following transit through the thoracic duct, the chylomicrons enter the plasma.
- the normal half-life of a chylomicron in the circulation is approximately 10 minutes.
- Lipoprotein lipase present on the endothelial surfaces of capillary beds, hydrolyzes the triglyceride core of the chylomicron, liberating the fatty acids for tissue uptake.
- omega-3 fatty acids into the systemic circulation can be directly measured by determining the plasma levels of their free form and the total levels after liberating the free fatty acid form from its esterified form (chylomicrons).
- the fatty acid composition of the serum phospholipids correlates with levels incorporated in membranes (e.g., erythrocyte, monocyte, and thrombocyte membranes) (See, e.g. Katan, MB, et al., J Lipid Res. 1997; 38:2012-22 and Tremoli, E et al., Am J Clin Nutr. 1995; 67:607-13).
- the omega-3 fatty acid composition of erythrocyte and thrombocyte membranes correlates with whole body content of these compounds. Analysis of blood phospholipids is, therefore, an appropriate way to assess the performance of products intended to increase total body stores of omega-3 fatty acids. Analysis of plasma phospholipids has been described, e.g.
- omega-3 fatty acids comprising EPA and DHA
- the increase of EPA and DHA in plasma or in serum phospholipids may be used as a measure of absorption.
- measures of absorption may be used as a measure of oral bioavailability.
- the of substantially composition is substantially free of food effect such that when administered orally the difference between AUCo- t value for EPA in the blood plasma of the human under a fed state and AUC 0-t value under a fasted state when administered orally to a human is not more than 15%, wherein t is 24 hours from the administration of the pharmaceutical composition.
- the of the composition is substantially free of food effect such that when administered orally the difference between C max value for EPA in the blood plasma of the human under a fed state and C max value under a fasted state when administered orally to a human is not more than 10%, wherein t is 24 hours from the administration of the pharmaceutical composition.
- inventions provide for a method of enhancing bioavailability of an omega-3 fatty acid in a subject in need of treatment with an omega-3 fatty acid, comprising orally administering an emulsion or self- emulsifying composition of this invention to the subject, wherein the oral absorption and/or oral bioavailability is enhanced compared to the oral absorption and/or oral bioavailability unformulated omega-3 fatty acid.
- an increase in absorption is exhibited by an increase in AUC of the total omega-3 fatty acids measured.
- the omega-3 fatty acids which is measured are EPA and/or DHA.
- the blood serum level of total EPA and/or DHA is increased; preferably the blood serum level of total EPA and/or DHA is increased by at least about 2, 3 or 4- fold compared to the blood serum level of total EPA and/or DHA of unformulated omega-3 fatty acid. More preferably atleast 2 fold Increase in total EPA and/or DHA compared to of unformulated omega-3 fatty acid.
- composition in another embodiment relates to process of preparing composition comprising omega-3 fatty acid, a plant extract and atleast one surfactant.
- the method of preparing involves mixing the plant extract with Surfactant, to the mixture optionally cosurfactants was added and mixed. The mixture obtained was added slowly to the oil containing omega-3 fatty acids and homogenized if needed.
- the pharmaceutical composition of the present invention is filled into capsules.
- Preferred capsules are gelatin capsules which may be soft or hard.
- the soft gelatin capsule is a capsule which is manufactured and filled in one single operation.
- the hard gelatin capsule consists of two pieces, a cap and a body, one fitting inside the other.
- the hard gelatin capsules are produced empty and filled in a separate operation step.
- the pharmaceutical composition is filled into capsules such as Soft gelatin capsules, but capsules from alternative materials such as methylcellulose- based shells, and hard gelatin capsules may also be used.
- liquid composition optionally converted into solid form through but not limited to process such as spray drying, Melt granulation, Adsorption to solid carriers, Melt extrusion/extrusion spheronization.
- the solid particles obtained can be filled into hard gelatin capsules or can be manufactures as tablets with suitable excipients.
- Another objective of the invention relates to method of administering a composition comprising omega-3 fatty acids and a plant extract and atleast one surfactant.
- composition is formulated as both ready-to-use aqueous solutions and or a Non-aqueous preconcentrate.
- composition may be diluted with suitable solutions immediately before administration.
- composition of present invention is filled into single dosage forms suitable for oral administration, such as capsules, drinking ampoules and dose cushions, or may be formulated as other suitable oral dosage forms such as chewable soft pills and chewy-base lozenges.
- the pharmaceutical composition may be dissolved in e.g. a glass of water, thus allowing the pre-concentrate to form an emulsion which may be taken as an oral solution.
- the compositions intended for dissolution prior to administration may be filled e.g. into soft gelatin capsules, plastic or aluminum cushions, or plastic or glass ampoules. This feature is particularly advantageous for high dose compositions which would require a large capsule, for patients who have difficulty in swallowing capsules, and for pediatric patients.
- pre-concentrate filed in soft gelatin capsules transforms into an oil-in- water emulsion upon contact with the gastrointestinal fluids, whereby the omega-3 fatty acid is released.
- the composition will form an in situ oil-in-water emulsion in the gastrointestinal tract (GI tract).
- composition suitable for prophylactic or therapeutic treatment known for omega-3fatty acids for a subject in need thereof comprising omega-3 fatty acids and a plant extract and atleast one surfactant for oral administration.
- omega-3 fatty acid composition comprising Plant extracts wherein the plant extracts may provide synergistic and/ or additive effect on antihyperlipidemic property of omega-3 fatty acids.
- synergistic composition provide both, Plant extracts and Omega-3 fatty acids together in a stable form.
- Yet another embodiment is to have a composition, plant extracts which protects the highly labile omega-3 fatty acid molecules from oxidation and also from the damaging effect of light and air.
- the composition of present invention is stable for the FDA recommended period
- the omega-3 fatty acid in this composition is very palatable, and would minimize or eliminate an unpleasant smell and/ or an unpleasant aftertaste, and/or burping in the patient.
- composition containing omega-3 fatty acids with varying amounts of EPA and DHA , surfactants , plant extracts and other excipients in Table 1- 11 and process of preparing such compostions.
- Polysorbate 80 (Tween 80) 1 1 1 1 1 1 1 1 1
- Polysorbate 80 (Tween 80) 29.39 34.62 28
- Polysorbate 80 (Tween 80) 29.30 25.26
- Polysorbate 80 (Tween 80) 19.35
- Polysorbate 80 (Tween 80) - - - 35 25 35
- Polyethylene Glycol (PEG 600) 1.65 1.67 0.82
- Polysorbate 80 (Tween 80) ⁇ 7.5 9.27 8.62 7.5 10.09
- Step 1 A plant extract if present in the composition is mixed with a surfactant
- Step 2 To the mixture obtained in step 1 other excipients present in the compostion is added and mixed
- Step 3 To the mixture obtained in step 2, fish oil was added slowly and mixed.
- Step 4 The mixture obtained from step 3 was homogenized if needed. Relative bioavailability studies:
- a comparative pharmacokinetic study of the novel preconcentrate formulation suggested in the invention against polyunsaturated fatty acid with similar omega-3 fatty acid content was carried out in Sprague dawley rats at unimolar dose i.e similar amount of omega-3 fatty acid was administered to the different groups treated with preconcentrate formulation and the unformulated fatty acid.
- the design of study offered a weight to weight comparison of the omega-3 fatty acid bioavailability given as novel formulated preconcentrate and unformulated fatty acid.
- the collection of the blood carried out at defined time interval and plasma separated from it by centrifuging at 4000 rpm speed for 10 min. The plasma samples were analyzed using a validated LC-MS/MS method.
- Results in Table 14 shows more than 2 times improvement in C max and AUC for the preconcentrate formulation prepared according to our invention.
- FIG: 2 Enhanced bioavailability is illustrated in FIG: 2.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Mycology (AREA)
- Botany (AREA)
- Alternative & Traditional Medicine (AREA)
- Microbiology (AREA)
- Medical Informatics (AREA)
- Biotechnology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Polymers & Plastics (AREA)
- Food Science & Technology (AREA)
- Nutrition Science (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Dispersion Chemistry (AREA)
- Medicines Containing Plant Substances (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
Abstract
A composition comprising omega-3 fatty acid, a plant extracts at least one surfactant and a process to process to prepare such composition is disclosed. The composition disclosed herein has enhanced bioavailability of omega -3 fatty acids and is substantially free of food effects.
Description
A novel Omega -3 fatty acid composition with a Plant extract FIELD OF INVENTION
This invention relates to omega-3 fatty acid composition of enhanced bioavailability comprising omega-3 fatty acids, a plant extract and at least one surfactant.
This invention also relates to omega-3 fatty acid composition substantially free of food effects comprising Omega-3 fatty acids, a plant extract and at least one surfactant.
This invention also relates to process of preparing composition comprising omega-3 fatty acids, a plant extract and at least one surfactant.
BACKGROUND OF THE INVENTION AND RELATED PRIOR ARTS Omega -3 fatty acids:
Omega-3 fatty acids, also called n-3 poly unsaturated fatty acids (PUFA), have long been suspected of having beneficial effects in humans, particularly with regards to reducing the risk of coronary heart disease, reducing obesity, improving diabetic parameters including blood glucose levels, and improving other parameters of the metabolic syndrome. These fatty acids have a number of beneficial effects, among which is lowering elevated blood triglyceride levels down to more clinically acceptable values (Harris et. al., "Omega-3 fatty acids and coronary heart disease risk: Clinical and mechanistic perspectives" Atherosclerosis. 2008 March; 197(1): 12-24).
Omega-3 fatty acids may improve cognitive function and delay the onset of Alzheimer's disease, Omega-3 fatty acids delivers ingredients essential for eye development and which may protect against age related macular degeneration and help dry eye syndrome and also contains essential fatty acids which may improve the nutrition of the skin and associated inflammatory conditions.
Omega -3 fatty acids may also help in reducing pain, stiffness and inflammation associated with arthritis and other joint conditions. Omega-3 fatty acids have also been shown to be important in pregnant women and infants, where their depletion may lead to visual or central nervous system problems
Omega-3 fatty acids cannot be manufactured in the human body and are therefore called essential fatty acids. They need to be obtained from the diet of an individual. The two major health promoting omega-3 polyunsaturated fatty acids are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). EPA and DHA are naturally found in certain cold-water fatty fish such as salmon, tuna, and mackerel. They can also be derived in the body from alpha-linolenic acid (ALA), which is an omega-3 fatty acid found in certain seeds and plant-based oils. However, the body is very inefficient at converting ALA into EPA and DHA. This table lists several different names for the most common omega-3 fatty acids found in nature.
Because of the wide range of known health benefits related to omega-3 fatty acids, a number of international organizations and agencies proposed recommendations for omega-3 fatty acids, as well as fish intake for health promotion and prevention of various chronic diseases. Although the intake of omega-3 fatty acids has proven to be crucial, it has been found that omega-3 fatty acids
are deficient in the typical Western diet. The omega-3 deficiency situation is even worse among the poor and malnourished.
One approach to alleviating omega-3 fatty acid deficiencies is through dietary supplementation, which is a convenient way to add them to the diet. Nutritional supplements are especially useful in individuals who struggle to meet their nutrient needs because of inadequate dietary intakes. Various forms of omega-3 fatty acids and uses thereof, including in pharmaceutical, nutritional or dietary supplement products is known in art. One such form of omega-3 fatty acid is a concentrate of omega-3, long chain, polyunsaturated fatty acids from fish oil containing DHA and EPA and is sold under the trademark Lovaza®. Such a form of omega-3 fatty acid is described in U.S. Patent Nos. 5,502,077, 5,656,667 and 5,698,594.
WO2013103902 discloses DPA-enriched compositions of omega-3 polyunsaturated fatty acids in free acid form
WO2013148136 describes composition comprising Omega-3 fatty acid esters, free of Omega-3 free fatty acids
U.S. Patent Nos. 7652068 discloses highly purified omega-3 fatty acid formulations containing greater than 85% omega-3 fatty acids by weight.
The bioavailability and thus the therapeutic efficacy of an omega-3 fatty acid formulation is affected by the form in which it is administered. The amount of absorption of omega-3 fatty acid in gastro intestinal tract depends upon the chemical and physical form of the fish oil.
There are several omega-3 fatty acid supplements available. Current dietary supplements, nutraceuticals, and prescribed drugs containing Omega-3 fatty acid esters have a food effect, with poor absorption when taken while fasting or with a low fat meal. One such drug sold under trade name OMYTRYG® when administered under fasted condition, on average the peak (Cmax) and total (AUC0-72h) exposure were lower by up to 20 to 80-fold, respectively, for total plasma EPA, and lower by up to 2 to 4-fold, respectively, for total plasma DHA, in comparison
to those observed under fed condition (high-fat high-calorie meal). Therefore, OMTRYG should be taken with food.
Therefore a need arises for compositions with enhanced bioavailability of omega-3 fatty acids and which can be administered without food effects
Plants Extracts:
In recent years, the use of various plant extract for the prevention of disease, alleviating the effects thereof, or for treating diseases have been gradually increasing in all societies. Throughout the human history, there have been and still are attempts for treating many diseases by using some plant extracts. According to the records of the World Health Organization (WHO), a large proportion of the world's population (70-80%) makes use of plant extracts for therapeutic or prophylactic purposes. Additionally, around 25% of prescription drugs in developed countries are composed of plant based active agents (vinblastine, reserpine, quinine, aspirin, etc.) (Farnsworth et al.,1985). Particularly following the end of the 1990s, the discovery of new areas of use for medical and aromatic plant extracts and the increasing demand for natural products have increased the use potential thereof day by day.
Many plant derivatives and domestic remedies have been screened for their hypolipidemic action. More than 70 medicinal plants have been documented to have significant hypolipidemic action. During the last decade, an increase in the use of medicinal plants has been observed in metropolitan areas of developed countries. Medicinal plants play a major role in hypolipidemic activity. The advantages of herbal medicines reported are effectiveness, safety, affordability and acceptability
Extracts from plants such as Amla (Phyllanthus emblica), Green coffee bean (Coffea arabica), Drumstick tree or Horseradish tree (Moringa oleiferd), Guggul or Mukul myrrh tree {Commiphora wightii), Frankincense (Boswellia serata) are known for antidiabetic, hypolipidemic, antibacterial, antioxidant, antiulcerogenic, hepatoprotective, gastroprotective, and chemopreventive properties.
Various studies have been documented for these plant extracts having Antihyperlipidimic activities. Amla (Emblica officinalis), family: euphorbiaceac (Jeevangi Santoshkumar., et al :A study of anti-hyperlipidemia, hypolipedimic and anti-atherogenic activity of fruit of emblica officinalis (amla) in high fat fed albino rats); Green coffee bean {Coffea arabica), family: Rubiaceae (Gaafar M. Ahmed., et al: Effect of green and degree of roasted arabic coffee on hyperlipidemia and antioxidant status in diabetic rat); Drumstick tree or Horseradish tree (Moringa oleifera), family: Moringaceae (Rajanandh MG., et al: Moringa oleifera Lam. A herbal medicine for hyperlipidemia: A pre- clinical report); Guggul or Mukul myrrh tree {Commiphora wightii), family: burseraccac (Singh RB., et al: Hypolipidemic and antioxidant effects of Commiphora mukul as an adjunct to dietary therapy in patients with hypercholesterolemia.); Frankincense (Boswellia seratd), family: Burseraceae (Dashti GH.,et al : The effect of frankincense extract on accumulation of fatty streaks in coronary arteries of high-cholesterol fed male rabbits)
Attempts were to make to include these plant extacts in our Omega-3 fatty acid preparation to have a synergistic effect and/or additive effect to antihyperlipedimic property of omega-3 fatty acids.
The compositions comprising omega-3 fatty acid and plant extract should have good physical stability; the physical properties of this composition should be made ideal to provide high patient compliance. However, it is quite difficult to provide the above described conditions in the formulations comprising plant extract. Due to some characteristic chemical, biological and physical properties of the plant extract used in the formulation, some problems are encountered in obtaining a formulation comprising said substances as well as having a good physical stability and ideal physical properties in terms of patient compliance. Physical properties and physical stability of the formulation are directly affected by the characteristic features of the plant extracts comprised therein.
Under the light of the foregoing, it would be desirable to provide a formulation, as well as a process for the preparation of this formulation, comprising combinations of plant extracts, being
capable to retain the physical stability for a long time, and having ideal physical properties in terms of patient compliance.
These plant extracts may prevent oxidative degradation of Omega-3 fatty acid that occurs over time can result in an unpleasant aftertaste following administration.
SUMMARY AND OBJECTIVES OF THE INVENTION:
This invention relates to a composition comprising omega-3 fatty acids and a plant extract and atleast one surfactant suitable for oral administration.
More particularly, the invention relates to a composition comprising omega-3 fatty acids and a plant extract and atleast one surfactant for oral administration, where in the composition is substantially free of food effects.
Yet another object of the invention, upon administration of a pharmaceutical formulation of the invention to a mammal, the formulation exhibits an absorption profile (e.g., Cmax and AUC, or max, AUC, and Tmax) under fed conditions which is similar to, the absorption profile of the same composition administered under fasting conditions. In some embodiments, the mammal is a human.
Yet another objective of the invention relates to a composition comprising omega-3 fatty acids and a plant extract, and atleast one surfactant, wherein exhibits enhanced bioavailability
Yet another objective of the invention relates to a composition comprising omega-3 fatty acids and a plant extract, and atleast one surfactant, wherein the said composition forms micelles in aqueous medium having D90 less than lOOnm
Another objective of the invention relates to the process of preparing a composition comprising omega-3 fatty acids and a plant extract and atleast one surfactant for oral administration.
Another objective of the invention relates to method of administering a composition comprising omega-3 fatty acids and a plant extract and atleast one surfactant.
Another aspect of the invention provides a composition suitable for prophylactic or therapeutic treatment known for omega-3fatty acids for a subject in need thereof, said composition comprising omega-3 fatty acids and a plant extract and atleast one surfactant for oral administration.
Another aspect of the invention provides an omega-3 fatty acid composition comprising Plant extracts wherein the plant extracts may provide synergistic and/ or additive effect on antihyperlipidemic property of omega-3 fatty acids.
BRIEF DESCRIPTION OF THE DRAWINGS
A clear understanding of some of the features of the invention summarized above may be carried out by reference to the appended drawings, which illustrate the objective of the invention, although it will be understood that such drawings depict observation with one of the preferred embodiments of the invention and, therefore, are not to be considered as limiting its scope with regard to other embodiments which the invention is capable of contemplating. Accordingly:
FIG. 1 is an illustration of the particle size of the self-emulsified droplets in gastric environment.
FIG. 2 is an illustration of the comparative oral pharmacokinetic profile of the omega-3 fatty acid present in fish oil with omega-3 fatty acid given as novel preconcentrate formulation.
FIG. 3 is an illustration of the comparative oral pharmacokinetic profile of "EPA" concentration in Fast state and Fed state of Omega-3 fatty acid KMS formulation.
FIG. 4 is an illustration of the comparative oral pharmacokinetic profile of EPA concentration in fast state with omega-3 fatty acid KMS formulation vs lovaza
DETAILED DESCRIPTION OF THE INVENTION:
Before the present invention is disclosed and described, it is to be understood that this invention is not limited to the particular materials disclosed herein, but is extended to equivalents thereof as would be recognized by those ordinarily skilled in the relevant arts. It should also be understood that terminology employed herein is used for the purpose of describing particular embodiments only and is not intended to be limiting.
The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.
The term "or" means "and/or".
The terms "comprising", "having", "including", and "containing" are to be construed as open- ended terms (i.e., meaning "including, but not limited to").
The terms "approximately" and "about" mean to be nearly the same as a referenced number or value. As used herein, the terms "approximately" and "about" should be generally understood to encompass ±10% of a specified amount, frequency or value.
The term "formulation" and "composition" may be used interchangeably herein.
The term "omega-3 fatty acids" includes natural and synthetic omega-3 fatty acids, as well as pharmaceutically-acceptable esters, free acids, triglycerides, derivatives, conjugates (see, e.g., Zaloga et al., U.S. Patent Application Publication No. 2004/0254357, and Horrobin et al, U.S. Pat. No. 6,245,811, each hereby incorporated by reference), precursors, salts, and mixtures thereof. Examples of omega-3 fatty acid oils include, but are not limited to, omega-3 polyunsaturated, long-chain fatty acids such as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), a-linolenic acid (ALA), heneicosapentaenoic acid (HP A), docosapentaenoic acid (DP A), eicosatetraenoic acid (ETA), eicosatrienoic acid (ETE), and octadecatetraenoic acid (i.e., stearidonic acid, STA); esters of omega-3 fatty acids with glycerol such as mono-, di- and
triglycerides; and esters of the omega-3 fatty acids and a primary, secondary and/or tertiary alcohol, such as, for example, fatty acid methyl esters and fatty acid ethyl esters. The omega-3 fatty acids, esters, triglycerides, derivatives, conjugates, precursors, salts and/or mixtures thereof according to the present disclosure can be used in their pure form and/or as a component of an oil, for example, as marine oil (e.g., fish oil and purified fish oil concentrates), algae oils, microbial oils and plant-based oils.
The term "Fatty acid oil", "omega -3 fatty acid", "Fish oil" or "active ingredient" may be used interchangeably therein unless the content clearly dictates otherwise.
The term "plant", "plant extracf'or "Herbal extract" " may be used interchangeably therein unless the content clearly dictates otherwise.
As used herein, the term "plant extract" means an extract, juice, or concentrate from any part of a plant, such as the seed, leaf, fruit, flower, stem, root, tuber, bark, etc.,
The term "food effect" refers to a somewhat unpredictable phenomenon that can influence the absorption of active ingredients from the gastrointestinal tract following oral administration. A food effect can be designated negative when absorption is decreased, or positive when absorption is increased and manifested as an increase in oral bioavailability (as reflected by total exposure).
Alternatively, "food effects" can refer to changes in maximum concentration, or the time to reach maximum concentration, independently of overall absorption. As a result, some active ingredients have to be taken in either fasted or fed conditions to achieve the optimum effect. However, many drugs are unaffected by food, and thus, can be taken in either a fasted or a fed condition.
The presence or absence of a food effect may be quantified by making Area under the Curve (AUC) and/or Cmax measurements according to methods well known in the art. Typically AUC measurements and Cmax measurements are made by taking timed biological fluid samples and plotting the serum concentration of Omega-3 fatty (or the active agent thereof) against time.
The values obtained represent a number of values taken from subjects across a patient population and are therefore expressed as mean values expressed over the entire patient population. By comparing the mean AUC and/or Cmax values, one can determine whether Omega-3 fatty exhibits a food effect.
The term MCmax" refers to maximum concentration of omega-3 fatty acids in blood or serum following the ingestion of a dose of omega-3 fatty acids.
The term "Tmax" refers to the time following ingestion required for the level of omega-3 fatty acids in blood or serum to reach Cmax., the term "AUC" refers to the area under the curve of a plot of the blood/serum concentration of omega-3 fatty acids against time from the time omega-3 fatty acids is ingested until the concentration is below the detection limit. "AUC" is a measure of the total patient exposure to omega-3 fatty acids.
Bioavailability is a measurement of the rate and extent to which a drug reaches the systemic circulation
The term "bioavailability" disclosed here in refers to "relative bioavailability" between composition of present invention comprising omega-3 fatty acid Plant extracts and an unformulated Omega-3 fatty acid.
The term "preconcentrate" here in refers to a composition which when diluted with aqueous solution forms dispersions
As used herein, the term "aqueous medium" refers to any solution or suspension, that comprises water or phosphate buffered saline pH 7.4 or fluid having an acidic pH or a biological fluid such as for example and without limitation, stomach acid or the aqueous medium comprises simulated stomach acid comprising 0.1 N HC 1.
COMPOSTIONS:
In one embodiment composition is provided wherein composition comprises omega-3 fatty acids, a plant extract and atleast one surfactant suitable for oral administration.
In another embodiment composition with enhanced bioavailability of omega -3 fatty acids comprising omega-3 fatty acids, a plant extract and atleast one surfactant is provided.
In another embodiment composition substantially free of food effects comprising omega-3 fatty acids, a plant extract and atleast one surfactant is provided.
In one embodiment Omega-3 fatty acids used herein may be derived from either marine source or plant source.
In one embodiment Omega-3 fatty acids may be derived from a marine species, such as a fish oil or crustacean. Examples of fish known to have high levels of omega-3 fatty acids include so-called "oily fish" such as salmon, tuna, swordfish, halibut, tilefish, cod fish (including cod liver oil), anchovies, and sardines. Several crustaceans are also known to have high levels of omega-3 fatty acids, including krill, a crustacean in the Antarctic (the source of krill oil) and the New Zealand green-lipped mussel, (also known as Perna canaliculus) but not limited to them
In one embodiment Omega-3 fatty acids may be may be derived from a vegetable source, in particular seed oils, including perilla seeds (Linnaean name Perilla frutescens); chia seeds (Salviahispanica); flax seeds (Linum usitatissimum); lingon berry seeds (Vaccinium vitis-idaea); and rape seeds (Brassicanapus), more commonly called canola oil but not limited to them
In one embodiment the composition comprises about 10% to about 98% (w/w) of omega-3 fatty acids in total composition. Preferably about 20% w/w of omega-3 fatty acids, More preferably about 30% w/w of the omega-3 fatty acids.
In one embodiment Omega-3 fatty acids used herein is preferably either eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) or both
In one embodiment Omega -3 fatty acids comprising "EPA" and "DHA" used herein may be of esterified, triglyceride, phospholipid or free fatty acid forms
In one embodiment Omega-3 fatty acids comprising "EPA" and "DHA" used herein is preferably in esterified form.
In one embodiments of the present disclosure, the weight ratio of EP A:DHA of the fatty acid oil mixture ranges from about 1 : 10 to about 10:1, from about 1 :8 to about 8: 1, from about 1 :6 to about 6:1, from about 1 :5 to about 5: 1 , from about 1:4 to about 4:1, from about 1 :3 to about 3:1, or from about 1 :2 to about 2:1. More preferably from about 1 :3 to about 3: 1
In one embodiment the content of EPA and DHA, taken together, is atleast above 10% w/w; atleast above 20%w/w; atleast about 30%w/w; atleast about 40% w/w; atleast about 50%w/w of omega -3 fatty acids in the total composition. Preferably about 50% w/w of omeg-3 fatty acids in total composition.
In one embodiment the content of EPA alone is atleast above 10% w/w of the total composition. Preferably above 20% w/w of the total composition; more preferably above 30% w/w of the total composition.
In one embodiment the content of DHA alone is atleast above 5% w/w of omega-3 fatty acids in the total composition. Preferably above 10%w/w of the total composition; more preferably above 15% w/w of the total composition.
In one embodiment the composition comprises a plant extract; wherein the plant extract is select from the group consisting of extracts from Amla (Phyllanthus emblica), Green coffee bean (Coffea arabica), Drumstick tree or Horseradish tree (Moringa oleifera), Guggul or Mukul myrrh tree {Commiphora wightii), Frankincense (Boswellia serata)
In one embodiment the plant extract may exert additive effect and/or synergistic effect on antihyperlipidemic activity of omega- 3 fatty acids.
In one embodiment plant extract comprises about 1 % to about 50 %( w/w), of the total composition.
In one embodiment the plant extract is preferably Amla (Phyllanthus emblica).
In one embodiment plant extract comprises about 1 % to about 50 % (w/w), of the total composition; wherein the plant extract is Amla.
In one embodiment composition comprising omega-3 fatty acids and a plant extract and atleast one surfactant. SURFACTANTS:
A surfactant may, for example, lower the surface tension of a liquid or the surface tension between two liquids. For example, surfactants according to the present disclosure may lower the surface tension between the fatty acid oil mixture and an aqueous solution. Chemically speaking, surfactants are molecules with at least one hydrophilic part and at least one hydrophobic (i.e., lipophilic) part. Surfactant properties may be reflected in the hydrophilic- lipophilic balance (HLB) value of the surfactant, wherein the HLB value is a measure of the degree of hydrophilic versus lipophilic properties of a surfactant. The HLB value normally ranges from 0 to 20, where a HLB value of 0 represents high hydrophilic character, and a HLB of 20 represents high lipophilic character. Surfactants are often used in combination with other surfactants, wherein the HLB values are additive. The HLB value of surfactant mixtures may be calculated as follows:
HLBA (fraction of surfactant A) + HLBB (fraction of surfactant B) = HLBA+B mixture
In certain embodiments, said surfactant is selected from the group consisting of nonionic surfactants, cationic surfactants, anionic surfactants, zwitterionic surfactants, or combinations thereof.
In one embodiment non-ionic surfactants are selected from a group having a hydrophobic group and a reactive hydrogen atom, for example aliphatic alcohols, acids, amides and alkyl phenols, with alkylene oxides, especially ethylene oxide either alone or in combination with propylene oxide.
Examples of nonionic surfactant compounds include, but are not limited to, Polyoxyethylene glycol sorbitan alkyl esters, Polyoxyethylene Stearates, Polyoxyethylene Castor Oil Derivatives, Sorbitan Esters (Sorbitan Fatty Acid Esters , polyoxyethylene sorbitan fatty acid esters), Polyoxylglycerides, sucrose fatty acid esters, block copolymers of polyethylene glycol and polypropylene glycol, ethylene glycol fatty acid esters, poly(ethylene glycol) fatty acid esters, propylene glycol fatty acid esters (propylene glycol monolaurate), poly(propylene glycol) fatty acid esters, glycol fatty acid esters, trimethylolpropane fatty acid esters, pentaerythritol fatty acid esters, glucoside derivatives, glycerin alkyl ether fatty acid esters, trimethylolpropane oxyethylene alkyl ethers, fatty acid amides, alkylolamides, alkylamine oxides, lanolin and its derivatives, castor oil derivatives, hardened castor oil derivatives, sterols and its derivatives, polyoxyethylene alkyl ethers, polyoxyethylene alkyl allyl ethers, polyoxyethylene alkylamine, polyoxyethylene fatty acid amides, polyoxyethylene alkylolamides, polyoxyethylene diethanolamine fatty acid esters, polyoxyethylene trimethylolpropane fatty acid esters, polyoxyethylene alkyl ether fatty acid esters, polyoxyethylene polyoxypropylene glycols, polyoxyethylene polyoxypropylene alkyl ethers, polyoxyethylene polyoxypropylene polyhydric alcohol ethers, glycerin fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, Carbomer, or combinations thereof.
Examples of are typically the Polyoxyethylene Sorbitan Fatty Acid Esters, polysorbates. Polysorbates are a class of oily liquids derived from PEG-ylated sorbitan (a derivative of sorbitol) esterified with fatty acids. Common brand names for polysorbates include Tween®. Tween-20, Tween-60 and Tween-80, for example, are available from AkzoNobel
(Strawinskylaan 2555 1077 ZZ, Amsterdam, the Netherlands). Exemplary polysorbates include polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate ), polysorbate 60(polyoxyethylene (20) sorbitan monostearate ), and polysorbate 80 (polyoxyethylene (20) sorbitan monooleate).
Examples of Polyoxyethylene Castor Oil Derivatives include Polyoxyl 5 castor oil(PEG-5 castor oil; polyoxyethylene 5 castor oil.), Polyoxyl 9 castor oil(PEG-9 castor oil; polyoxyethylene 9 castor oil), Polyoxyl 15 castor oil(PEG-15 castor oil; polyoxyethylene 15 castor oil), Polyoxyl 35 castor oil(Cremophor EL; Kolliphor EL; PEG-35 castor oil; polyethoxylated castor oil; polyoxyethylene 35 castor oil), Polyoxyl 40 castor oil(PEG-40 castor oil; polyoxyethylene 40 castor oil), Polyoxyl 40 hydrogenated castor oil(Cremophor RH 40; PEG-40 hydrogenated castor oil; polyethoxylated hydrogenated castor oil; polyoxyethylene 40 hydrogenated castor oil), Polyoxyl 60 castor oil(PEG-60 castor oil; polyoxyethylene 60 castor oil), Polyoxyl 60 hydrogenated castor oil(PEG-60 hydrogenated castor oil; polyoxyethylene 60 hydrogenated castor oil), Polyoxyl 100 castor oil(PEG-100 hydrogenated castor oil; polyoxyethylene 100 hydrogenated castor oil), Polyoxyl 100 hydrogenated castor oil(polyoxyethylene 100 hydrogenated castor oil), Polyoxyl 200 castor oil(polyoxyethylene 200 castor oil; PEG-200 castor oil;), Polyoxyl 200 hydrogenated castor oil(PEG-200 hydrogenated castor oil; polyoxyethylene 200 hydrogenated castor oil).
Examples of Sorbitan Esters (Sorbitan Fatty Acid Esters) include Sorbitan monoisostearate (Arlacel 987; Crill 6; sorbitan isostearate), Sorbitan monolaurate (sorbitan laurate; sorbitani lauras; Span 20), Sorbitan monooleate(Arlacel 80), Sorbitan monopalmitate(Span 40.),Sorbitan monostearate (Span 60),Sorbitan sesquiisostearate, Sorbitan sesquioleate (Arlacel C; Arlacel 83; Crill 43),Sorbitan trilaurate (Span 25),Sorbitan trioleate (Span 85), Sorbitan tristearate (Span 65)
Examples of Polyoxylglycerides include but not limited to Caprylocaproyl polyoxylglycerides (Labrasol; macro golglyceridorum caprylocaprates; PEG 400 caprylic/ capric glycerides), Lauroyl polyoxylglycerides(Gelucire 44/14; hydrogenated coconut oil PEG 1500 esters),Linoleoyl polyoxylglycerides (Corn oil PEG 300 esters; LabrafilM2125CS), Oleoyl
polyoxylglycerides (Apricot kernel oil PEG 300 esters), Stearoyl polyoxylglycerides(Gelucire 50/13; hydrogenated palm oil PEG 1500 ester)
In one embodiment anionic surfactants are selected from a group include, but are not limited to, N-acyl-L-glutamic acid diethanolamine, N-acyl-L-glutamic acid triethanolamine, sodium N- acyl-L-glutamate, sodium alkanesulfonate, ammonium alkyl (C12> C14, Ci6) sulfate, alkyl (Cn, C , C15) sulfuric acid triethanolamine, alkyl (C » , C13, C15) sulfuric acid triethanolamine, alkyl (C12 to C14) sulfuric acid triethanolamine, liquid alkylsulfuric acid triethanolamine, sodium alkyl (Ci2, C13) sulfate, liquid sodium alkylsulfate, sodium isoethionate, sodium lacto-isostearate, disodium undecylenoylamido ethyl sulfosuccinate, triethanolamine sulfooleate, sodium sulfooleate, disodium oleamide sulfosuccinate, potassium oleate, sodium oleate, morpholine oleate, oleoyl sarcosine, oleoyl methyltaurine sodium salt, potassium-containing soap base, liquid base for potassium soap, potassium soap, carboxylated polyoxyethylene tridodecyl ether, sodium salt (3 ethyle oxide "E.O.") of carboxylated polyoxyethylene tridodecyl ether, triethanolamine N-hydrogenated tallow fatty-acyl-L-glutamate, sodium N-hydrogenated tallow fatty-acyl- L-glutamate, sodium hydrogenated coconut fatty acid glyceryl sulfate, sodium diundecylenoylamido ethyl sulfosuccinate, sodium stearyl sulfate, potassium stearate, triethanolamine stearate, sodium stearate, sodium N-stearoyl-L-glutamate, disodium stearoyl- L- glutamate, stearoyl methyltaurine sodium salt, sodium dioctyl sulfosuccinate, liquid sodium dioctyl sulfosuccinate, liquid disodium polyoxyethylene monooleylamido sulfosuccinate (2 E.O.), disodium polyoxyethylene lauroyl ethanolamide sulfosuccinate (5 E.O.), disodium lauryl sulfosuccinate, diethanolamide cetyl sulfate, sodium cetyl sulfate, soap base, sodium cetostearyl sulfate, triethanolamine tridecyl sulfate, potassium palmitate, sodium palmitate, palmitoyl methyltaurine sodium salt, liquid castor oil fatty acid sodium salt (30%), ammonium polyoxyethylene alkyl ether sulfate (3 E.O.), liquid diethanolamine polyoxyethylene alkyl (CI 2, CI 3) ether sulfate, liquid triethanolamine polyoxyethylene alkyl ether sulfate (3 E.O.), triethanolamine polyoxyethylene alkyl (CI 1, CI 3, CI 5) ether sulfate (1 E.O.), triethanolamine polyoxyethylene alkyl (CI 2, CI 3) ether sulfate (3 E.O.), liquid sodium polyoxyethylene alkyl ether sulfate (3 E.O.), sodium polyoxyethylene alkyl (CI 1, C13, C15) ether sulfate (1 E.O.), sodium polyoxyethylene alkyl (CI 1 to CI 5) ether sulfate (3 E.O.), sodium polyoxyethylene alkyl (CI 2, CI 3) ether sulfate (3 E.O.), sodium polyoxyethylene alkyl (CI 2 to CI 4) ether sulfate (3
E.O.), sodium polyoxyethylene alkyl (C12 to C15) ether sulfate (3 E.O.), disodium polyoxyethylene alkyl (CI 2 to CI 4) sulfosuccinate (7 E.O.), sodium polyoxyethylene undecyl ether sulfate, liquid sodium polyoxyethylene octyl phenyl ether sulfate, ammonium polyoxyethylene oleyl ether sulfate, disodium polyoxyethylene lauryl sulfosuccinate, sodium polyoxyethylene nonyl phenyl ether sulfate, sodium polyoxyethylene pentadecyl ether sulfate, triethanolamine polyoxyethylene myristyl ether sulfate, sodium polyoxyethylene myristyl ether sulfate, sodium polyoxyethylene myristyl ether sulfate (3 E.O.), liquid sodium polyoxyethylene lauryl ether acetate (16 E.O.), ammonium polyoxyethylene lauryl ether sulfate (2 E.O.), triethanolamine polyoxyethylene lauryl ether sulfate, sodium polyoxyethylene lauryl ether sulfate, diethanolamine myristyl sulfate, sodium myristyl sulfate, potassium myristyl sulfate, sodium N- myristoyl- L-glutamate, sodium myristoylmethylaminoacetate, liquid myristoyl methyl- -alanine sodium salt, myristoyl methyltaurine sodium salt, medicinal soaps, triethanolamine/magnesium coco alkyl sulfate, triethanolamine N-coconut oil fatty-acyl-L- glutamate, sodium N-coconut oil fatty-acyl-L-glutamate, sodium coconut oil fatty acid ethyl ester sulfonate, coconut oil fatty acid potassium salt, liquid coconut oil fatty acid potassium salt, sodium N-coconut oil fatty/hydro genated fatty-acyl-L-glutamate, coconut oil fatty acid sarcosine, coconut oil fatty acid sarcosine triethanolamine salt, coconut oil fatty acid sarcosine sodium salt, coconut oil fatty acid triethanolamine salt, liquid triethanolamine salt of cocbnut oil fatty acid, coconut oil fatty acid sodium salt, coconut oil fatty acid methyl alanine sodium salt, liquid coconut oil fatty acid methyl alanine sodium salt, coconut oil fatty acid methyltaurine potassium salt, coconut oil fatty acid methyltaurine sodium salt, sodium laurylamino dipropionate, liquid sodium laurylamino dipropionate (30%), sodium lauryl sulfoacetate; sodium lauryl benzenesulfonate, lauryl sulfate, ammonium lauryl sulate, potassium lauryl sulfate, diethanolamine lauryl sulfate, triethanolamine lauryl sulfate, sodium lauryl sulfate, magnesium lauryl sulfate, monoethanolainine lauryl sulfate, potassium laurate, lauric acid triethanolamine, liquid lauric acid triethanolamine, sodium laurate, lauric acid/myristic acid triethanolamine, lauroyl-L-glutamic acid triethanolamine, sodium N- lauroyl-L-glutamate, lauroyl sarcosine, lauroyl sarcosine potassium, liquid lauroyl sarcosine triethanolamine salt, lauroyl sarcosine sodium, liquid lauroyl methyl-.beta. -alanine sodium salt, lauroyl methyltaurine sodium salt, liquid lauroyl methyltaurine sodium salt, or combinations thereof.
In another embodiment surfactants also include, but are not limited to the bile acids (e.g., cholic acid, chenodeoxycholic acid, glycocholic acid, glycodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid, taurolithocholic acid, deoxycholic acid, lithocholic acid, and ursodeoxycholic acid and salts thereof, e.g., sodium, potassium, lithium), natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose), polyoxyethylene esters (e.g. polyoxyethylene monostearate [Myrj 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. Cremophor), polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [Brij 30]), poly(vinyl-pyrrolidone), diethyl ene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyllaurate, sodium lauryl sulfate, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium or combinations thereof.
In one embodiment atleast one surfactant preferably selected from group of Polyoxyethylene glycol sorbitan alkyl esters, Polyoxyethylene Castor Oil Derivatives, Sorbitan Esters (Sorbitan Fatty Acid Esters , polyoxyethylene sorbitan fatty acid esters), Polyoxylglycerides, sucrose fatty acid esters, block copolymers of polyethylene glycol and polypropylene glycol or combinations thereof.
More preferably atleast one surfactant is selected from group of Polyoxyethylene glycol sorbitan alkyl esters such as Tween 20, Tween 60 Tween80.
More preferably atleast one surfactant is selected from group of Sorbitan Fatty Acid Esters such as Span 20, Span 60.
More preferably atleast one surfactant is selected from a group of Polyoxyethylene Castor Oil derivatives such as PEG-35 castor oil, PEG-40 castor oil.
In one embodiment the total amount of surfactants present in the composition do not exceed 50% w/w of the total composition.
In one embodiment the value of HLB of the Surfactants present is in the composition should be from about 8 - 18. More preferably above 12.
In one embodiment composition comprising omega-3 fatty acids and a plant extract and atleast one surfactant optionally may contain co surfactants and other pharmaceutically acceptable excipients
OTHER PHARMACEUTICAL EXCIPIENTS: Co- Surfactant
In some embodiments, compositions of the present disclosure further comprise at least one co- surfactant. As used herein the term "co-surfactant" means a substance added to the compostion in combination with the at least one surfactant to affect, e.g., increase or enhance, emulsification and/or stability of the compostion, for example to aid in forming an emulsion. In some embodiments, the at least one co-surfactant is hydrophilic.
Examples of co-surfactants suitable for the present disclosure include, but are not limited to, short chain alcohols comprising from 1 to 6 carbons (e.g., ethanol), benzyl alcohol, alkane diols and triols (e.g., propylene glycol, glycerol, polyethylene glycols such as PEG 600 and PEG 400), glycol ethers such as tetraglycol and glycofurol (e.g., tetrahydrofurfuryl PEG ether), pyrrolidine derivatives such as N-methylpyrrolidone (e.g., Pharmasolve®) and 2-pyrrolidone (e.g., Soluphor® P), and bile salts, for example sodium deoxycholate. Further examples include ethyl oleate.
Additional oils
In some embodiments, Synergistic composition further comprise at least one additional oil, such as medium chain triglyceride (MCT) oil and long chain triglyceride (LCT) oil
PARTICLE SIZE:
In another embodiment composition can be a preconcentrate or an emulsion.
In another embodiment the composition produce dispersions when contacted with aqueous medium
In another embodiment the preconcentrates produce dispersions when contacted with aqueous medium generating self-nanoemulsifying drug delivery systems (SNEDDS), self- microemulsifying drug delivery systems (SMEDDS), or self emulsifying drug delivery systems (SEDDS).
In another embodiment the compostion is preferably self-nanoemulsifying drug delivery systems (SNEDDS)
In another embodiment composition the composition forms micelles in aqueous medium having D90 less than 500nm, D90 less than 300nm, more preferably D90 less than lOOnm.
In another embodiment composition comprising omega-3 fatty acids and a plant extract and atleast one surfactant for oral administration, wherein the composition forms particle size D90 less than lOOnm when contacted with aqueous medium.
In one embodiment particle size are preferably between 20nm to about 90nm.
In on embodiment the aqueous medium may be any solution or suspension, that comprises water or phosphate buffered saline pH 7.4 or fluid having an acidic pH or a biological fluid such as for
example and without limitation, stomach acid or the aqueous medium comprises simulated stomach acid comprising 0.1N HC1.
BIOAVAILABILITY:
Absorption of omega-3 fatty acids from the gastrointestinal tract involves the conversion of large fat globules to the smaller size micellar droplets by action of bile salts. The smaller droplets are then acted upon by pancreatic lipase that coverts the triglyceride within fat to fatty acids that traverse easily through the phospholipid bilayer. Thus absorption of omega-3 fatty acid from gastrointestinal tract depends widely upon its emulsification and conversion to smaller droplets.
The self-emulsifying composition of this invention comprising omega-3 fatty acids, a plant extract and atleast one surfactant which rapidly form an oil-in-water emulsion when introduced into the aqueous media under mild agitation. The digestive motility of the stomach and intestine provides the agitation necessary for self-emulsification in vivo. The self-emulsification process occurs spontaneously. The spontaneous formation of micro/nano emulsion advantageously presents the drug in a dissolved form and the resultant small droplets size provides a large interfacial surface area for drug release and absorption. Main mechanisms include increasing membrane fluidity to facilitate transcellular absorption, opening tight junction to allow paracellular transport, inhibiting P-gp and/or CYP450 to increase intracellular concentration and residence time by surfactants, and stimulating lipoprotein/chylomicron production by lipid.
In one embodiment of the invention, upon administration of a pharmaceutical formulation of the invention to a mammal, the formulation exhibits an absorption profile (e.g., Cmax and AUC, or Cmax, AUC, and Tmax) under fed conditions which is similar, or bioequivalent to, the absorption profile of the same composition administered under fasting conditions. In some embodiments, the mammal is a human.
In another embodiment the synergistic composition comprising omega-3 fatty acid extract and a Plant extract; where in the composition is substantially free of food effect.
After rapid and complete hydrolysis of omega-3 fatty acids in the intestine, the free fatty acids are absorbed / transported into the intestinal enterocytes; rapidly re esterified, and enters the systemic circulation via the thoracic duct as chylomicrons. Following transit through the thoracic duct, the chylomicrons enter the plasma. The normal half-life of a chylomicron in the circulation is approximately 10 minutes. Lipoprotein lipase, present on the endothelial surfaces of capillary beds, hydrolyzes the triglyceride core of the chylomicron, liberating the fatty acids for tissue uptake.
The absorption of omega-3 fatty acids into the systemic circulation can be directly measured by determining the plasma levels of their free form and the total levels after liberating the free fatty acid form from its esterified form (chylomicrons).
In addition, the fatty acid composition of the serum phospholipids correlates with levels incorporated in membranes (e.g., erythrocyte, monocyte, and thrombocyte membranes) (See, e.g. Katan, MB, et al., J Lipid Res. 1997; 38:2012-22 and Tremoli, E et al., Am J Clin Nutr. 1995; 67:607-13). The omega-3 fatty acid composition of erythrocyte and thrombocyte membranes, in turn, correlates with whole body content of these compounds. Analysis of blood phospholipids is, therefore, an appropriate way to assess the performance of products intended to increase total body stores of omega-3 fatty acids. Analysis of plasma phospholipids has been described, e.g. by Harris, W. et al. Clinical Biochemistry 43 (2010) 338-340; Harris, W. et al., American Journal of Clinical Nutrition 2007; 86: 1621-5; Cao, J. et al., Clinical Chemistry 52:12 2265-2271 (2006); Harris, W. et al., Preventive Medicine 39 (2004) 212-220; and Park, Y. et al., Journal of Lipid Research 44, 2003 455-463.
Thus, when investigating the absorption of omega-3 fatty acids comprising EPA and DHA (e.g., from omega-3-acid ethyl esters comprising EPA and DHA ethyl esters), the increase of EPA and DHA in plasma or in serum phospholipids may be used as a measure of absorption. These measures of absorption may be used as a measure of oral bioavailability.
In one embodiment the of substantially composition is substantially free of food effect such that when administered orally the difference between AUCo-t value for EPA in the blood plasma of
the human under a fed state and AUC 0-t value under a fasted state when administered orally to a human is not more than 15%, wherein t is 24 hours from the administration of the pharmaceutical composition.
In one embodiment the of the composition is substantially free of food effect such that when administered orally the difference between Cmax value for EPA in the blood plasma of the human under a fed state and Cmax value under a fasted state when administered orally to a human is not more than 10%, wherein t is 24 hours from the administration of the pharmaceutical composition.
Other embodiments of the invention provide for a method of enhancing bioavailability of an omega-3 fatty acid in a subject in need of treatment with an omega-3 fatty acid, comprising orally administering an emulsion or self- emulsifying composition of this invention to the subject, wherein the oral absorption and/or oral bioavailability is enhanced compared to the oral absorption and/or oral bioavailability unformulated omega-3 fatty acid.
In some embodiments, an increase in absorption is exhibited by an increase in AUC of the total omega-3 fatty acids measured.
In some embodiments, the omega-3 fatty acids which is measured are EPA and/or DHA.
In some embodiments, the blood serum level of total EPA and/or DHA is increased; preferably the blood serum level of total EPA and/or DHA is increased by at least about 2, 3 or 4- fold compared to the blood serum level of total EPA and/or DHA of unformulated omega-3 fatty acid. More preferably atleast 2 fold Increase in total EPA and/or DHA compared to of unformulated omega-3 fatty acid.
MANUFACTURING PROCESS:
In another embodiment the composition relates to process of preparing composition comprising omega-3 fatty acid, a plant extract and atleast one surfactant.
The method of preparing involves mixing the plant extract with Surfactant, to the mixture optionally cosurfactants was added and mixed. The mixture obtained was added slowly to the oil containing omega-3 fatty acids and homogenized if needed.
In one embodiment the pharmaceutical composition of the present invention is filled into capsules. Preferred capsules are gelatin capsules which may be soft or hard. The soft gelatin capsule is a capsule which is manufactured and filled in one single operation. The hard gelatin capsule consists of two pieces, a cap and a body, one fitting inside the other. The hard gelatin capsules are produced empty and filled in a separate operation step.
In a one embodiment of the invention, the pharmaceutical composition is filled into capsules such as Soft gelatin capsules, but capsules from alternative materials such as methylcellulose- based shells, and hard gelatin capsules may also be used.
In one embodiment the liquid composition optionally converted into solid form through but not limited to process such as spray drying, Melt granulation, Adsorption to solid carriers, Melt extrusion/extrusion spheronization. The solid particles obtained can be filled into hard gelatin capsules or can be manufactures as tablets with suitable excipients.
METHOD OF ADMINISTRATION:
Another objective of the invention relates to method of administering a composition comprising omega-3 fatty acids and a plant extract and atleast one surfactant.
In one embodiment composition is formulated as both ready-to-use aqueous solutions and or a Non-aqueous preconcentrate.
In another embodiment composition may be diluted with suitable solutions immediately before administration.
In one embodiment composition of present invention is filled into single dosage forms suitable for oral administration, such as capsules, drinking ampoules and dose cushions, or may be
formulated as other suitable oral dosage forms such as chewable soft pills and chewy-base lozenges.
In an alternative embodiment of the invention, the pharmaceutical composition may be dissolved in e.g. a glass of water, thus allowing the pre-concentrate to form an emulsion which may be taken as an oral solution. The compositions intended for dissolution prior to administration may be filled e.g. into soft gelatin capsules, plastic or aluminum cushions, or plastic or glass ampoules. This feature is particularly advantageous for high dose compositions which would require a large capsule, for patients who have difficulty in swallowing capsules, and for pediatric patients.
In another embodiment, pre-concentrate filed in soft gelatin capsules transforms into an oil-in- water emulsion upon contact with the gastrointestinal fluids, whereby the omega-3 fatty acid is released. Thus, the composition will form an in situ oil-in-water emulsion in the gastrointestinal tract (GI tract).
USE:
Another aspect of the invention provides a composition suitable for prophylactic or therapeutic treatment known for omega-3fatty acids for a subject in need thereof, said composition comprising omega-3 fatty acids and a plant extract and atleast one surfactant for oral administration.
Another aspect of the invention provides an omega-3 fatty acid composition comprising Plant extracts wherein the plant extracts may provide synergistic and/ or additive effect on antihyperlipidemic property of omega-3 fatty acids.
In another embodiment the synergistic composition provide both, Plant extracts and Omega-3 fatty acids together in a stable form.
Yet another embodiment is to have a composition, plant extracts which protects the highly labile omega-3 fatty acid molecules from oxidation and also from the damaging effect of light and air.
In one embodiment the composition of present invention is stable for the FDA recommended period In another embodiment the omega-3 fatty acid in this composition is very palatable, and would minimize or eliminate an unpleasant smell and/ or an unpleasant aftertaste, and/or burping in the patient.
In view of the teachings presented herein, other modifications and variations of the present inventions will be readily apparent to those of skill in the art. The foregoing discussion and description are illustrative of some embodiments of the present invention, but are not meant to be limitations on the practice thereof.
The invention will be more fully understood by the following examples which are illustrative but not limiting of compositions in accordance with the present invention.
EXAMPLE: 1
Illustrates the composition containing omega-3 fatty acids with varying amounts of EPA and DHA , surfactants , plant extracts and other excipients in Table 1- 11 and process of preparing such compostions.
EPA: DHA ratio in fish oil in each composition mentioned in the parenthesis in each table alongside of fish oil.
TABLE: 1
Ingredients Ex -1 E -2
% w/w % w/w
Fish oil (35: 25) 94.33 57.14
Amla Extract - 0.57
Polysorbate 20(Tween 20) - 3.8
Polysorbate 80(Tween 80) 0.94 26.66
Polyethylene Glycol (PEG 600) - 1.90
Purified water 4.71 4.76
Total 100 100
TABLE: 2
Ingredients Ex-3
% w/w
Fish oil (55:20) 78.95
Polysorbate 80 (Tween 80) 10.09
Sorbitan monolaurate (Span 20) 10.09
Polyethylene Glycol (PEG 600) 0.88
Total 100
TABLE: 3
Ingredients Ex-4 Ex-5 Ex-6 Ex-7 Ex-8 Ex-9
% w/w % w/w % w/w % w/w % w/w % w/w
Fish oil (35: 25) 70.72 97.06 74.25 59.40 49.5 70.72
Amla Extract 28.29 1.94 24.75 39.60 49.5 28.28
Polysorbate 80 (Tween 80) 1 1 1 1 1 1
Total 100 100 100 100 100 100 TABLE: 4
Ingredients Ex-10 Ex-11 Ex-12
% w/w % w/w % w/w
Fish oil (35: 25) 37.75 44.47 60
Amla Extract 15.10 - 6
Polysorbate 20 (Tween 20) 13.97 16.46 4
Polysorbate 80 (Tween 80) 29.39 34.62 28
Polyethylene Glycol (PEG 600) 3.78 4.45 2
Total 100 100 100
TABLE: 5
Ingredients Ex-13 Ex-14
% w/w % w/w
Fish oil (10:40) 67.70 67.74
Polysorbate 80 (Tween 80) 29.30 25.26
Polyethylene Glycol (PEG 600) 3 3
Purified water - 4
Total 100 100
TABLE: 6
Ingredients Ex-15
% w/w
Fish oil (10:60) 67.74
Polysorbate 60 (Tween 60) 9.68
Polysorbate 80 (Tween 80) 19.35
Tricaprylin (MCT) 3.23
Total 100
TABLE: 7
Ingredients Ex-16 Ex-17 Ex-18 Ex-19 Ex-20 Ex-21
% w/w % w/w % w/w % w/w % w/w % w/w
Fish oil (35: 25) 83.33 46.47 60.61 50 50 50
Plant Extract
Guggul extract - 4.65 - - - ■ -
Boswellia serata - - 6.06 - - -
Moringa Extract - - - 5 - -
Moringa oleifera 16.67 - - - -
Moringa oil - - - - 10 -
Green Coffee bean extract - - - - - 5
Surfactant
Polysorbate 20 (Tween 20) - - - - 10 -
Polysorbate 80 (Tween 80) - - - 35 25 35
Polysorbate 60 (Tween 60) - 2.32 3.03 - - -
Other excipients
Sodium alginate 30.30 - -
Carbomer - 46.47 - - - -
(Pemelun TF2 (0.25 % solution))
NaOH 18% Solution - 0.08 - - - -
Polyethylene Glycol (PEG 600) - - - - 5 -
Purified water - - - 10 - 10
Total 100 100 100 100 100 100
TABLE: 8
Ingredients Ex-22 Ex-23 Ex-24 Ex-25 Ex-26 Ex-27
% w/w % w/w % w/w % w/w % w/w % w/w
Fish oil (52:22) 54.55 54.55 54.55 63.67 67.05 68.81
Amla Extract 5.45 5.45 5.45 2 3.83 3.67
Polysorbate 80(Tween 80) 37.36 - 5.45 16.18 9.96 9.54
Polyethylene Glycol(PEG 600) 2.64 - - 5.45 5.75 5.5
Polyoxyl 35 castor oil (KoUiphor EL) - 40 27.73 12.73 13.41 12.84
Polyoxylglycerides(Labrasol) - - 1.36 - -
Total 100 100 100 100 100 100
TABLE: 9
Ingredients Ex-28 Ex-29 Ex-30 Ex-31 Ex-32
% w/w % w/w % w/w % w/w % w/w
Fish oil (52:22) 75 74.69 74.38 75.19 74.35
Amla Extract 5 4.98 4.96 4.96 4.90
Polysorbate 80(Tween 80) 7.5 7.47 7.44 7.52 7.43
Polyethylene Glycol(PEG 600) 1.67 1.66 1.65 1.50 1.49
Polyoxyl 35 castor oil (KoUiphor EL) 10.83 10.79 10.74 10.83 10.71
Lauroglycol - 0.41 0.83 - 1.12
Total 100 100 100 100 100 TABLE: 10
Ingredients Ex-33 Ex-34 Ex-35
% w/w % w/w % w/w
Fish oil (52:22) 74.07 75 74.07
Amla Extract 4.94 5 4.94
Polysorbate 80 (Tween 80) 8.23 7.5 7.41
Sorbitan monolaurate (Span 20) - - 11.52
Polyethylene Glycol (PEG 600) 1.65 1.67 0.82
KoUiphor EL 11.11 10.83 -
Lipase Filterate - - 1.23
Total 100 100 100
TABLE: 11
Ingredients Ex-36 Ex-37 Ex-38 Ex-39 Ex-40
% w/w % w/w % w/w % w/w % w/w
Fish oil (52:22) 75 72.58 77.59 75 78.95
Amla Extract 5 4.83 5.17 5 -
Polysorbate 80 (Tween 80) · 7.5 9.27 8.62 7.5 10.09
Sorbitan monolaurate (Span 20) 11.67 9.27 7.76 7.5 10.09
Polyethylene Glycol (PEG 600) 0.83 0.81 0.86 1.25 0.88
Total 100 100 100 100 100
Method of preparing the composition containing ingredients from table 1-11:
Step 1: A plant extract if present in the composition is mixed with a surfactant
Step 2: To the mixture obtained in step 1 other excipients present in the compostion is added and mixed
Step 3: To the mixture obtained in step 2, fish oil was added slowly and mixed.
Step 4: The mixture obtained from step 3 was homogenized if needed. Relative bioavailability studies:
EXAMPLE: 2
Illustrates relative bioavailability studies of omega-3-acid ethyl esters 1.2 g soft gelatin capsules of KMS Health Center PVT LTD, Chennai, India prepared according to example 34 under fasting and fed condition; to demonstrate the food effect on this formulation
TABLE 12- Relative bioavailability studies of KMS formulation in fast and fed state.
# Geometric mean *Median
Results in Table 12 shows that oral pharmaceutical composition containing 1.2g of omega -3 fatty acid Capsules prepared according to Example 34 has increase AUCo-t and Cmax to about 13.65% and 10.25% respectively, under fed condition compared to fasting condition.
However, the effect of food on bioavailability (both AUC0-t and Cmax) of oral pharmaceutical composition containing 1.2g of omega-3 fatty acid capsules prepared according to Example 34 is found to be modest and is not of clinically significance
Relative bioavailability of KMS formulation in fast and fed state is illustrated in FIG: 3 EXAMPLE: 3
Illustrates relative bioavailability studies of omega-3-acid ethyl esters 1.2 g soft gelatin capsules of KMS Health Center PVT LTD, Chennai, India prepared according to example 34 and lovaza® (omega-3 -acid ethyl esters) capsules 1 g of Glaxosmithkline, RTP, NC 27709 (four capsules as single dose) in health, adult, human subjects under fed condition. TABLE 13: Relative bioavailability in fed condition
# Geometric mean * Median
Results in Table 12 shows that oral pharmaceutical composition 1.2g of omega -3 fatty acid Capsules prepared according to Example 34 has increase AUC0-t and Cmax to about 15.12% and 22.69% respectively, under fed condition compared to Lovaza®. EXAMPLE 4:
Relative bioavailability in fasting condition
Relative bioavailability studies of omega-3-acid ethyl esters 1.2 g soft gelatin capsules of KMS Health Center PVT LTD, Chennai, India prepared according to example 34 and lovaza® (omega-3-acid ethyl esters) capsules 1 g of Glaxosmithkline, RTP, NC 27709 (four capsules as single dose) in health, adult, human subjects under fasting condition is studied.
The statistical analysis was not performed as there are no EPA concentrations obtained for lovaza of under fasting conditions. EPA concentration of lovaza® vs KMS formulation in fasting condition is illustrated in FIG: 4
EXAMPLE 5:
Enhanced bioavailability
A comparative pharmacokinetic study of the novel preconcentrate formulation suggested in the invention against polyunsaturated fatty acid with similar omega-3 fatty acid content was carried out in Sprague dawley rats at unimolar dose i.e similar amount of omega-3 fatty acid was administered to the different groups treated with preconcentrate formulation and the unformulated fatty acid. The design of study offered a weight to weight comparison of the omega-3 fatty acid bioavailability given as novel formulated preconcentrate and unformulated fatty acid. The collection of the blood carried out at defined time interval and plasma separated from it by centrifuging at 4000 rpm speed for 10 min. The plasma samples were analyzed using a validated LC-MS/MS method.
TABLE 14:
Results in Table 14 shows more than 2 times improvement in Cmax and AUC for the preconcentrate formulation prepared according to our invention.
Enhanced bioavailability is illustrated in FIG: 2.
Claims
1. A novel composition of enhanced bioavailability comprising
(a) omega-3 fatty acid consisting atleast about 30%w/w of EPA and/or DHA of the total composition
(b) atleast one surfactant preferably selected from a group of nonionic surfactants with a concentration range of 1% to 50%w/w of the total compostion
wherein the composition forms particle size D90 less than lOOnm when contacted with aqueous medium; wherein the said composition can be taken with or without food.
2. A novel composition of claim 1, wherein Omega -3 fatty acids comprising "EPA" and "DHA" used herein may be of esterified, triglyceride, phospholipid or free fatty acid forms. More preferably in preferably in esterified form.
3. A novel composition of claim 1, where in concentration of EPA alone is atleast above 10% w/w of the total composition.
4. A novel composition of claim 1, where in concentration of DHA alone is atleast above 10% w/w of the total composition.
5. A novel composition comprising omega-3 fatty acids of claim 1, where in the weight ratio of EPA:DHA in omega-3 fatty acid oil mixture ranges from about 1 :10 to about 10:1, from about 1 :8 to about 8:1, from about 1 :6 to about 6:1, from about 1:5 to about 5:1, from about 1 :4 to about 4:1, from about 1:3 to about 3:1, or from about 1:2 to about 2:1.
6. A weight ratio of EPA: DHA in omega-3 fatty acid oil mixture of claim 5, is preferably from about 1 :6 to about 6:1
. A novel composition of claim 1, where in omega -3 fatty acid further may contain other polyunsaturated fatty acids such as a-linolenic acid (ALA), heneicosapentaenoic acid (HP A), docosapentaenoic acid (DP A), eicosatetraenoic acid (ETA), eicosatrienoic acid (ETE), and octadecatetraenoic acid (i.e., stearidonic acid, STA); esters of omega-3 fatty acids with glycerol such as mono-, di- and triglycerides; and esters of the omega-3 fatty acids and a primary, secondary and/or tertiary alcohol, such as, for example, fatty acid methyl esters and fatty acid ethyl esters or combinations thereof.
8. A novel composition of claim 1, wherein a nonionic surfactant selected from a group of group of Polyoxyethylene glycol sorbitan alkyl esters, Polyoxyethylene Stearates, Polyoxyethylene Castor Oil Derivatives, Sorbitan Esters (Sorbitan Fatty Acid Esters , polyoxyethylene sorbitan fatty acid esters), Polyoxylglycerides, sucrose fatty acid esters, block copolymers of polyethylene glycol and polypropylene glycol or combinations thereof.
9. A novel composition of claim 1 , where in nonionic surfactant is preferably selected from group of Polyoxyethylene glycol sorbitan alkyl esters such as Tween 20, Tween 60, Tween 80 etc.
10. A novel composition of claim 1, where in nonionic surfactant is preferably selected from group of Sorbitan Fatty Acid Esters such as Span 20, span 60 etc.
11. A novel composition of claim 1, where in nonionic surfactant is preferably selected from group of Polyoxyethylene Castor Oil derivatives such as PEG-35 castor oil, PEG-40 castor oil etc.
12. A novel composition of claim 1, optionally contains additional Surfactant selected from a nonionic surfactants, cationic surfactants, anionic surfactants, zwitterion surfactants, or combinations thereof.
13. A novel composition of claim 1, has an HLB value between 8-18.
14. An HLB value of novel composition of claim 13, is preferably above 12.
15. A novel composition of claim 1, further comprises a therapeutically effective amount of plant extract where in plant extract is selected from Amla (Phyllanthus emblica), Green coffee bean {Coffea arabica), Drumstick tree or Horseradish tree (Moringa oleifera), Guggul or Mukul myrrh tree {Commiphora wightii), Frankincense (Boswellia serata)
16. A novel composition comprising plant extract of claim 15, where in plant extract comprises about 1 % to about 50 % (w/w), of the total composition.
17. A plant extract of claim 16, where in plant extract is preferably Amla (Phyllanthus emblica).
18. A novel composition of enhanced bioavailability comprising
(a) omega-3 fatty acid consisting atleast about 30%w/w of EPA and/or DHA of the total composition;
(b) atleast one surfactant preferably selected from a group of nonionic surfactants with a concentration range of 1% to 50%w/w of the total composition;
wherein the composition forms particle size D90 less than lOOnm when contacted with aqueous medium;
wherein the difference between AUC0-t value for EPA in the blood plasma of the human under a fed state and AUC 0.t value under a fasted state when administered orally to a human is not more than 15%, wherein t is 24 hours from the administration of the pharmaceutical composition;
wherein the difference between Cmax value for EPA in the blood plasma of the human under a fed state and Craax value under a fasted state when administered orally to a human is not more than 10%, wherein t is 24 hours from the administration of the pharmaceutical composition.
19. A novel composition substantially free of food effects comprising
(a) omega-3 fatty acid consisting atleast about 30%w/w of EPA and/or DHA of the total composition;
(b) atleast one surfactant preferably selected from a group of nonionic surfactants with a concentration range of 1% to 50%w/w of the total composition;
wherein the composition forms particle size D90 less than lOOnm when contacted with aqueous medium;
wherein the blood serum level of total EPA of novel composition is increased, at least about 2 fold to the blood serum level of total EPA of omega-3 fatty acid alone.
20. A process of preparing novel composition comprising mixing (a) omega-3 fatty acid consisting atleast about 30%w/w of EPA and/or DHA of the total composition and (b atleast one surfactant preferably selected from a group of nonionic surfactants with a concentration range of 1% to 50%w/w of the total composition and optionally homogenizing the mixture if needed.
21. A method of administering a composition comprising (a) omega-3 fatty acid consisting atleast about 30%w/w of EPA and/or DHA of the total composition (b) atleast one surfactant preferably selected from a group of nonionic surfactants with a concentration range of 1% to 50%w/w of the total composition; wherein the composition is either ready-to-use aqueous solutions and or a non-aqueous preconcentrate.
22. A method of administering a composition according to claim 21, wherein a non-aqueous preconcentrate may be diluted with suitable solutions immediately before administration.
23. A method of administering a composition according to claim 21, wherein a non-aqueous preconcentrate is filled into single dosage forms suitable for oral administration, such as capsules, drinking ampoules and dose cushions, or may be formulated as other suitable oral dosage forms such as chewable soft pills and chewy-base lozenges.
24. A method of administering a composition according to claim 21, wherein a non-aqueous pre-concentrate filed in soft gelatin capsules ; where in, the composition will form an in situ oil-in-water emulsion in the gastrointestinal tract (GI tract).
25. A method of treating and/or preventing hyperlipidemia and/or hypercholesterolemia, age related macular disorders, dry eye syndrome, Alzheimer's disease; pain, stiffness and inflammation associated with arthritis and other joint conditions comprises administering a composition comprising (a) omega-3 fatty acid consisting atleast about 30%w/w of EPA and/or DHA of the total composition (b) atleast one surfactant preferably selected from a group of nonionic surfactants with a concentration range of 1% to 50%w/w of the total composition to a subject in need thereof.
26. A method of treating and/or preventing hyperlipidemia and/or hypercholesterolemia, age related macular disorders, dry eye syndrome, Alzheimer's disease; pain, stiffness and inflammation associated with arthritis and other joint conditions as in claim 25 further comprises a plant extract; wherein the plant extract exerts additive effect and/or synergistic effect to omega-3 fatty acids.
27. A novel self emulsifying composition comprising
(a) omega-3 fatty acid consisting atleast about 30%w/w of EPA and/or DHA of the total composition;
(b) atleast one surfactant preferably selected from a group of nonionic surfactants with a concentration range of 1% to 50%w/w of the total composition;
(c) Optionally a plant extract selected from a group of Amla {Phyllanthus emblica), Green coffee bean (Coffea arabicd), Drumstick tree or Horseradish tree (Moringa oleiferd), Guggul or Mukul myrrh tree (Commiphora wightii), Frankincense
(Boswellia serata)
wherein the composition forms particle size D90 less than lOOnm when contacted with aqueous medium wherein the composition is substantially free of food effects with enhanced bioavailability
8. A self-emulsifying composition capable of forming an oil-in-water emulsion upon dilution with an aqueous solution, having particle size D90 less than lOOnm comprising
(a) omega-3 fatty acid consisting atleast about 30%w/w of EPA and/or DHA of the total composition; 1
(b) atleast one surfactant preferably selected from a group of nonionic surfactants with a concentration range of 1% to 50%w/w of the total composition;
Wherein the non-ionic surfactant is selected from a group of Polyoxyethylene glycol sorbitan alkyl esters, Polyoxyethylene Stearates, Polyoxyethylene Castor Oil Derivatives, Sorbitan Esters (Sorbitan Fatty Acid Esters , polyoxyethylene sorbitan fatty acid esters), Polyoxylglycerides, sucrose fatty acid esters, block copolymers of polyethylene glycol and polypropylene glycol or combinations thereof.
Where in the said composition can be taken with or without food.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN3261CH2013 | 2013-07-22 | ||
IN3261/CHE/2013 | 2013-07-22 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2015011724A2 true WO2015011724A2 (en) | 2015-01-29 |
WO2015011724A3 WO2015011724A3 (en) | 2015-03-26 |
Family
ID=51900928
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IN2014/000483 WO2015011724A2 (en) | 2013-07-22 | 2014-07-22 | A novel omega -3 fatty acid composition with a plant extract |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2015011724A2 (en) |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104839711A (en) * | 2015-04-29 | 2015-08-19 | 刘祥义 | Horseradish tree leaf superfine powder production method |
CN106072611A (en) * | 2016-06-20 | 2016-11-09 | 威海百合生物技术股份有限公司 | A kind of heterogeneous diluted composition containing unsaturated fatty acid |
WO2016191433A1 (en) * | 2015-05-25 | 2016-12-01 | Mycell Technologies, Llc | Mono and di-glyceride esters of omega-3 fatty acid emulsions |
WO2017218418A1 (en) * | 2016-06-13 | 2017-12-21 | The Board Of Regents Of The University Of Texas System | Compositions and methods for modeling heart failure with preserved ejection fraction |
WO2018061011A1 (en) * | 2016-09-29 | 2018-04-05 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd | Method for extraction of an agent from a plant source |
IT201700045343A1 (en) * | 2017-04-26 | 2018-10-26 | Micro Sphere Sa | PROCESS FOR THE PREPARATION OF A FOOD AND SUPPLEMENTARY SUPPLEMENTER SO OBTAINED |
EP3496709A4 (en) * | 2016-08-12 | 2020-04-08 | Pharmako Biotechnologies PTY Limited | Omega-3 compositions and methods relating thereto |
EP3585375A4 (en) * | 2017-02-27 | 2021-01-13 | Focus Laboratories, Inc. | Formulations containing omega-3 fatty acids or esters thereof and maqui berry extract and therapeutic uses thereof |
US11666618B2 (en) | 2016-09-29 | 2023-06-06 | Yissun Research Development Company Of The Hebrew University Of Jerusalem Ltd. | Method for selective extraction of cannabinoids from a plant source |
US11819490B2 (en) | 2016-09-29 | 2023-11-21 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. | Dilutable formulations of cannabinoids and processes for their preparation |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5502077A (en) | 1988-08-11 | 1996-03-26 | Norsk Hydro A.S. | Fatty acid composition |
US6245811B1 (en) | 1995-05-01 | 2001-06-12 | Scotia Holdings Plc | Fatty acid esters as bioactive compounds |
US20040254357A1 (en) | 2002-12-19 | 2004-12-16 | Zaloga Gary P. | Fatty acid phenolic conjugates |
US7652068B2 (en) | 2005-12-20 | 2010-01-26 | Cenestra Llc | Omega 3 fatty acid formulations |
WO2013103902A1 (en) | 2012-01-06 | 2013-07-11 | Omthera Pharmaceuticals, Inc. | Dpa-enriched compositions of omega-3 polyunsaturated fatty acids in free acid form |
WO2013148136A1 (en) | 2012-03-30 | 2013-10-03 | Sancilio & Company, Inc. | Omega-3 fatty acid ester compositions |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100587551B1 (en) * | 1997-12-10 | 2006-06-08 | 싸이클로스포린 테라퓨틱스 리미티드 | Pharmaceutical compositions containing an omega-3 fatty acid oil |
US20120021077A1 (en) * | 2007-07-18 | 2012-01-26 | Bhushan Patwardhan | Synergistic herbal composition for treatment of rheumatic and musculo-skeletal disorders (rmsds) |
WO2009066303A2 (en) * | 2007-11-22 | 2009-05-28 | Ganga Raju Gokaraju | New synergistic phytochemical composition for the treatment of obesity |
KR101841756B1 (en) * | 2009-03-09 | 2018-03-23 | 프로노바 바이오파마 너지 에이에스 | Compositions comprising a fatty acid oil mixture and a surfactant, and methods and uses thereof |
US8618168B2 (en) * | 2009-05-22 | 2013-12-31 | Mochida Pharmaceutical Co., Ltd. | Self-emulsifying composition of OMEGA3 fatty acid |
ES2661812T3 (en) * | 2009-10-16 | 2018-04-04 | Mochida Pharmaceutical Co., Ltd. | Compositions |
CN101961352A (en) * | 2010-10-27 | 2011-02-02 | 南通迈特生物工程有限公司 | Self-emulsified fish oil soft capsules without fishy smell |
-
2014
- 2014-07-22 WO PCT/IN2014/000483 patent/WO2015011724A2/en active Application Filing
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5502077A (en) | 1988-08-11 | 1996-03-26 | Norsk Hydro A.S. | Fatty acid composition |
US5656667A (en) | 1988-08-11 | 1997-08-12 | Norsk Hydro As | Fatty acid composition |
US5698594A (en) | 1988-08-11 | 1997-12-16 | Norsk Hydro A.S | Treatment and prevention of risk factors for cardiovascular diseases |
US6245811B1 (en) | 1995-05-01 | 2001-06-12 | Scotia Holdings Plc | Fatty acid esters as bioactive compounds |
US20040254357A1 (en) | 2002-12-19 | 2004-12-16 | Zaloga Gary P. | Fatty acid phenolic conjugates |
US7652068B2 (en) | 2005-12-20 | 2010-01-26 | Cenestra Llc | Omega 3 fatty acid formulations |
WO2013103902A1 (en) | 2012-01-06 | 2013-07-11 | Omthera Pharmaceuticals, Inc. | Dpa-enriched compositions of omega-3 polyunsaturated fatty acids in free acid form |
WO2013148136A1 (en) | 2012-03-30 | 2013-10-03 | Sancilio & Company, Inc. | Omega-3 fatty acid ester compositions |
Non-Patent Citations (8)
Title |
---|
CAO, J. ET AL., CLINICAL CHEMISTRY, vol. 52, 2006, pages 12 2265 - 2271 |
HARRIS, W. ET AL., AMERICAN JOURNAL OF CLINICAL NUTRITION, vol. 86, 2007, pages 1621 - 5 |
HARRIS, W. ET AL., CLINICAL BIOCHEMISTRY, vol. 43, 2010, pages 338 - 340 |
HARRIS, W. ET AL., PREVENTIVE MEDICINE, vol. 39, 2004, pages 212 - 220 |
HARRIS: "Omega-3 fatty acids and coronary heart disease risk: Clinical and mechanistic perspectives", ATHEROSCLEROSIS, vol. 197, no. 1, March 2008 (2008-03-01), pages 12 - 24 |
KATAN, MB ET AL., J LIPID RES., vol. 38, 1997, pages 2012 - 22 |
PARK, Y. ET AL., JOURNAL OF LIPID RESEARCH, vol. 44, 2003, pages 455 - 463 |
TREMOLI, E ET AL., AM J CLIN NUTR., vol. 67, 1995, pages 607 - 13 |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104839711A (en) * | 2015-04-29 | 2015-08-19 | 刘祥义 | Horseradish tree leaf superfine powder production method |
WO2016191433A1 (en) * | 2015-05-25 | 2016-12-01 | Mycell Technologies, Llc | Mono and di-glyceride esters of omega-3 fatty acid emulsions |
CN107645910A (en) * | 2015-05-25 | 2018-01-30 | 麦赛尔科技有限责任公司 | The list of omega-3 fatty acid emulsion and two glyceride |
WO2017218418A1 (en) * | 2016-06-13 | 2017-12-21 | The Board Of Regents Of The University Of Texas System | Compositions and methods for modeling heart failure with preserved ejection fraction |
CN106072611A (en) * | 2016-06-20 | 2016-11-09 | 威海百合生物技术股份有限公司 | A kind of heterogeneous diluted composition containing unsaturated fatty acid |
EP3496709A4 (en) * | 2016-08-12 | 2020-04-08 | Pharmako Biotechnologies PTY Limited | Omega-3 compositions and methods relating thereto |
AU2017301077B2 (en) * | 2016-08-12 | 2022-07-07 | Pharmako Biotechnologies Pty Limited | Omega-3 compositions and methods relating thereto |
US11224628B2 (en) | 2016-09-29 | 2022-01-18 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. | Method for extraction of an agent from a plant source |
WO2018061011A1 (en) * | 2016-09-29 | 2018-04-05 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd | Method for extraction of an agent from a plant source |
US11666618B2 (en) | 2016-09-29 | 2023-06-06 | Yissun Research Development Company Of The Hebrew University Of Jerusalem Ltd. | Method for selective extraction of cannabinoids from a plant source |
US11819490B2 (en) | 2016-09-29 | 2023-11-21 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. | Dilutable formulations of cannabinoids and processes for their preparation |
US11819491B2 (en) | 2016-09-29 | 2023-11-21 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. | Dilutable formulations of cannabinoids and processes for their preparation |
EP3585375A4 (en) * | 2017-02-27 | 2021-01-13 | Focus Laboratories, Inc. | Formulations containing omega-3 fatty acids or esters thereof and maqui berry extract and therapeutic uses thereof |
IT201700045343A1 (en) * | 2017-04-26 | 2018-10-26 | Micro Sphere Sa | PROCESS FOR THE PREPARATION OF A FOOD AND SUPPLEMENTARY SUPPLEMENTER SO OBTAINED |
Also Published As
Publication number | Publication date |
---|---|
WO2015011724A3 (en) | 2015-03-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2015011724A2 (en) | A novel omega -3 fatty acid composition with a plant extract | |
US11523999B2 (en) | Compositions comprising a fatty aged oil mixture and a free fatty acid, and methods and uses thereof | |
KR101904388B1 (en) | Coated capsules and tablets of a fatty acid oil mixture | |
KR102275447B1 (en) | SELF-EMULSIFYING COMPOSITION OF ω-3 FATTY ACID | |
JP2021107433A (en) | SELF-EMULSION COMPOSITION OF ω3 FATTY ACID | |
US20110262534A1 (en) | polysaccharide capsule enclosing a fatty acid oil-containing emulsion | |
TWI694823B (en) | A composition comprising a lipid compound, a triglyceride, and a surfactant, and methods of using the same | |
CA2589656A1 (en) | Stable compositions of fenofibrate with fatty acid esters | |
US20220193018A1 (en) | Omega-3 compositions and methods relating thereto | |
JP2022531685A (en) | Liquid oral preparation of methylnaltrexone | |
TW201938143A (en) | Self-emulsifying formulation and self-emulsifying composition of [omega]3 fatty acid exhibiting excellent self-emulsifying property, composition dispersing ability, emulsification stability and absorbability |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 14799219 Country of ref document: EP Kind code of ref document: A2 |