WO2006048773A1 - Reverse micelle composition for delivery of metal cations comprising a diglyceride and a phytosterol and method of preparation - Google Patents
Reverse micelle composition for delivery of metal cations comprising a diglyceride and a phytosterol and method of preparation Download PDFInfo
- Publication number
- WO2006048773A1 WO2006048773A1 PCT/IB2005/003605 IB2005003605W WO2006048773A1 WO 2006048773 A1 WO2006048773 A1 WO 2006048773A1 IB 2005003605 W IB2005003605 W IB 2005003605W WO 2006048773 A1 WO2006048773 A1 WO 2006048773A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- metal
- reverse micelles
- water
- activity
- reverse
- Prior art date
Links
- 239000000693 micelle Substances 0.000 title claims abstract description 92
- 229910052751 metal Inorganic materials 0.000 title claims abstract description 82
- 239000002184 metal Substances 0.000 title claims abstract description 82
- 230000002441 reversible effect Effects 0.000 title claims abstract description 77
- 238000000034 method Methods 0.000 title claims abstract description 47
- 239000000203 mixture Substances 0.000 title claims description 61
- 150000001768 cations Chemical class 0.000 title claims description 29
- 238000002360 preparation method Methods 0.000 title abstract description 24
- 229930182558 Sterol Natural products 0.000 claims abstract description 25
- 150000003432 sterols Chemical class 0.000 claims abstract description 25
- 235000003702 sterols Nutrition 0.000 claims abstract description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 45
- LGJMUZUPVCAVPU-UHFFFAOYSA-N beta-Sitostanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 LGJMUZUPVCAVPU-UHFFFAOYSA-N 0.000 claims description 40
- 229950005143 sitosterol Drugs 0.000 claims description 36
- NJKOMDUNNDKEAI-UHFFFAOYSA-N beta-sitosterol Natural products CCC(CCC(C)C1CCC2(C)C3CC=C4CC(O)CCC4C3CCC12C)C(C)C NJKOMDUNNDKEAI-UHFFFAOYSA-N 0.000 claims description 35
- KZJWDPNRJALLNS-VJSFXXLFSA-N sitosterol 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)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-VJSFXXLFSA-N 0.000 claims description 35
- 229910052712 strontium Inorganic materials 0.000 claims description 26
- 229910052720 vanadium Inorganic materials 0.000 claims description 25
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 claims description 23
- LEONUFNNVUYDNQ-UHFFFAOYSA-N vanadium atom Chemical compound [V] LEONUFNNVUYDNQ-UHFFFAOYSA-N 0.000 claims description 23
- 239000008213 purified water Substances 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 16
- 238000000527 sonication Methods 0.000 claims description 15
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 14
- 239000000194 fatty acid Substances 0.000 claims description 14
- 229930195729 fatty acid Natural products 0.000 claims description 14
- 150000004665 fatty acids Chemical class 0.000 claims description 14
- 229910052744 lithium Inorganic materials 0.000 claims description 11
- 238000007254 oxidation reaction Methods 0.000 claims description 11
- 230000003647 oxidation Effects 0.000 claims description 10
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 6
- 230000002210 biocatalytic effect Effects 0.000 claims description 5
- 229910052711 selenium Inorganic materials 0.000 claims description 5
- 239000011669 selenium Substances 0.000 claims description 5
- 229910052725 zinc Inorganic materials 0.000 claims description 5
- 239000011701 zinc Substances 0.000 claims description 5
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 4
- 229940076810 beta sitosterol Drugs 0.000 claims description 4
- 229910052804 chromium Inorganic materials 0.000 claims description 4
- 239000011651 chromium Substances 0.000 claims description 4
- 150000001982 diacylglycerols Chemical class 0.000 claims description 4
- 229910052737 gold Inorganic materials 0.000 claims description 4
- 239000010931 gold Substances 0.000 claims description 4
- 229910052750 molybdenum Inorganic materials 0.000 claims description 4
- 239000011733 molybdenum Substances 0.000 claims description 4
- 229910052758 niobium Inorganic materials 0.000 claims description 4
- 239000010955 niobium Substances 0.000 claims description 4
- 229910052707 ruthenium Inorganic materials 0.000 claims description 4
- 229910052718 tin Inorganic materials 0.000 claims description 4
- PWTCCMJTPHCGMS-KHPPLWFESA-N (2-acetyloxy-3-hydroxypropyl) (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(CO)OC(C)=O PWTCCMJTPHCGMS-KHPPLWFESA-N 0.000 claims description 3
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 claims description 3
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 claims description 3
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 3
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 claims description 3
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims description 3
- 229910052787 antimony Inorganic materials 0.000 claims description 3
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims description 3
- GUCVJGMIXFAOAE-UHFFFAOYSA-N niobium atom Chemical compound [Nb] GUCVJGMIXFAOAE-UHFFFAOYSA-N 0.000 claims description 3
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- 229910052697 platinum Inorganic materials 0.000 claims description 3
- WATWJIUSRGPENY-UHFFFAOYSA-N antimony atom Chemical compound [Sb] WATWJIUSRGPENY-UHFFFAOYSA-N 0.000 claims description 2
- 230000001747 exhibiting effect Effects 0.000 claims description 2
- AFSHUZFNMVJNKX-LLWMBOQKSA-N 1,2-dioleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](CO)OC(=O)CCCCCCC\C=C/CCCCCCCC AFSHUZFNMVJNKX-LLWMBOQKSA-N 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 235000005911 diet Nutrition 0.000 abstract description 9
- 230000000378 dietary effect Effects 0.000 abstract description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 36
- 235000015500 sitosterol Nutrition 0.000 description 31
- NLQLSVXGSXCXFE-UHFFFAOYSA-N sitosterol Natural products CC=C(/CCC(C)C1CC2C3=CCC4C(C)C(O)CCC4(C)C3CCC2(C)C1)C(C)C NLQLSVXGSXCXFE-UHFFFAOYSA-N 0.000 description 31
- KZJWDPNRJALLNS-VPUBHVLGSA-N (-)-beta-Sitosterol Natural products O[C@@H]1CC=2[C@@](C)([C@@H]3[C@H]([C@H]4[C@@](C)([C@H]([C@H](CC[C@@H](C(C)C)CC)C)CC4)CC3)CC=2)CC1 KZJWDPNRJALLNS-VPUBHVLGSA-N 0.000 description 30
- CSVWWLUMXNHWSU-UHFFFAOYSA-N (22E)-(24xi)-24-ethyl-5alpha-cholest-22-en-3beta-ol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(CC)C(C)C)C1(C)CC2 CSVWWLUMXNHWSU-UHFFFAOYSA-N 0.000 description 30
- KLEXDBGYSOIREE-UHFFFAOYSA-N 24xi-n-propylcholesterol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CCC)C(C)C)C1(C)CC2 KLEXDBGYSOIREE-UHFFFAOYSA-N 0.000 description 30
- LPZCCMIISIBREI-MTFRKTCUSA-N Citrostadienol Natural products CC=C(CC[C@@H](C)[C@H]1CC[C@H]2C3=CC[C@H]4[C@H](C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C LPZCCMIISIBREI-MTFRKTCUSA-N 0.000 description 30
- ARVGMISWLZPBCH-UHFFFAOYSA-N Dehydro-beta-sitosterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)CCC(CC)C(C)C)CCC33)C)C3=CC=C21 ARVGMISWLZPBCH-UHFFFAOYSA-N 0.000 description 30
- MJVXAPPOFPTTCA-UHFFFAOYSA-N beta-Sistosterol Natural products CCC(CCC(C)C1CCC2C3CC=C4C(C)C(O)CCC4(C)C3CCC12C)C(C)C MJVXAPPOFPTTCA-UHFFFAOYSA-N 0.000 description 30
- 241000700159 Rattus Species 0.000 description 29
- 230000000694 effects Effects 0.000 description 27
- 241001465754 Metazoa Species 0.000 description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 13
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 12
- 239000004006 olive oil Substances 0.000 description 12
- 235000008390 olive oil Nutrition 0.000 description 12
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 description 11
- RZRNAYUHWVFMIP-HXUWFJFHSA-N glycerol monolinoleate Natural products CCCCCCCCC=CCCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-HXUWFJFHSA-N 0.000 description 11
- 230000012010 growth Effects 0.000 description 11
- 241000196324 Embryophyta Species 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- 230000000638 stimulation Effects 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 235000019198 oils Nutrition 0.000 description 9
- 230000008569 process Effects 0.000 description 9
- 150000002739 metals Chemical class 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 7
- 230000003178 anti-diabetic effect Effects 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 229910052748 manganese Inorganic materials 0.000 description 7
- 239000011572 manganese Substances 0.000 description 7
- 239000004530 micro-emulsion Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 239000004094 surface-active agent Substances 0.000 description 7
- UUUGYDOQQLOJQA-UHFFFAOYSA-L vanadyl sulfate Chemical compound [V+2]=O.[O-]S([O-])(=O)=O UUUGYDOQQLOJQA-UHFFFAOYSA-L 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- UBXAKNTVXQMEAG-UHFFFAOYSA-L strontium sulfate Chemical compound [Sr+2].[O-]S([O-])(=O)=O UBXAKNTVXQMEAG-UHFFFAOYSA-L 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 229930091371 Fructose Natural products 0.000 description 5
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 5
- 239000005715 Fructose Substances 0.000 description 5
- 241000282414 Homo sapiens Species 0.000 description 5
- 238000000333 X-ray scattering Methods 0.000 description 5
- 210000000988 bone and bone Anatomy 0.000 description 5
- 206010012601 diabetes mellitus Diseases 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 229910021645 metal ion Inorganic materials 0.000 description 5
- 238000012544 monitoring process Methods 0.000 description 5
- 210000004877 mucosa Anatomy 0.000 description 5
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 239000000419 plant extract Substances 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- VGSSUFQMXBFFTM-UHFFFAOYSA-N (24R)-24-ethyl-5alpha-cholestane-3beta,5,6beta-triol Natural products C1C(O)C2(O)CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 VGSSUFQMXBFFTM-UHFFFAOYSA-N 0.000 description 4
- 208000023105 Huntington disease Diseases 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 208000001132 Osteoporosis Diseases 0.000 description 4
- LGJMUZUPVCAVPU-JFBKYFIKSA-N Sitostanol Natural products O[C@@H]1C[C@H]2[C@@](C)([C@@H]3[C@@H]([C@H]4[C@@](C)([C@@H]([C@@H](CC[C@H](C(C)C)CC)C)CC4)CC3)CC2)CC1 LGJMUZUPVCAVPU-JFBKYFIKSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000010907 mechanical stirring Methods 0.000 description 4
- 210000004400 mucous membrane Anatomy 0.000 description 4
- 210000002569 neuron Anatomy 0.000 description 4
- 235000021313 oleic acid Nutrition 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- LGJMUZUPVCAVPU-HRJGVYIJSA-N stigmastanol 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](C)CC[C@@H](CC)C(C)C)[C@@]2(C)CC1 LGJMUZUPVCAVPU-HRJGVYIJSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000002604 ultrasonography Methods 0.000 description 4
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 4
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 4
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 3
- AFSHUZFNMVJNKX-CLFAGFIQSA-N 1,2-dioleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(CO)OC(=O)CCCCCCC\C=C/CCCCCCCC AFSHUZFNMVJNKX-CLFAGFIQSA-N 0.000 description 3
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 3
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 244000068988 Glycine max Species 0.000 description 3
- 235000010469 Glycine max Nutrition 0.000 description 3
- 102000004877 Insulin Human genes 0.000 description 3
- 108090001061 Insulin Proteins 0.000 description 3
- 239000005642 Oleic acid Substances 0.000 description 3
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 3
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Natural products C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000002225 anti-radical effect Effects 0.000 description 3
- 239000011942 biocatalyst Substances 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- -1 etc. Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 125000005456 glyceride group Chemical group 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000008240 homogeneous mixture Substances 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 229940125396 insulin Drugs 0.000 description 3
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 3
- 210000004379 membrane Anatomy 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 150000004671 saturated fatty acids Chemical class 0.000 description 3
- 239000003784 tall oil Substances 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 235000015112 vegetable and seed oil Nutrition 0.000 description 3
- 239000008158 vegetable oil Substances 0.000 description 3
- 235000013311 vegetables Nutrition 0.000 description 3
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 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 2
- BTEISVKTSQLKST-UHFFFAOYSA-N Haliclonasterol Natural products CC(C=CC(C)C(C)(C)C)C1CCC2C3=CC=C4CC(O)CCC4(C)C3CCC12C BTEISVKTSQLKST-UHFFFAOYSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 238000010241 blood sampling Methods 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 230000030833 cell death Effects 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- KZJWDPNRJALLNS-FBZNIEFRSA-N clionasterol 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)CC[C@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-FBZNIEFRSA-N 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 230000002354 daily effect Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 235000019961 diglycerides of fatty acid Nutrition 0.000 description 2
- GZSOSUNBTXMUFQ-YFAPSIMESA-N diosmin Chemical compound C1=C(O)C(OC)=CC=C1C(OC1=C2)=CC(=O)C1=C(O)C=C2O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@H]2[C@@H]([C@H](O)[C@@H](O)[C@H](C)O2)O)O1 GZSOSUNBTXMUFQ-YFAPSIMESA-N 0.000 description 2
- 229960004352 diosmin Drugs 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000002296 dynamic light scattering Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- INHCSSUBVCNVSK-UHFFFAOYSA-L lithium sulfate Chemical compound [Li+].[Li+].[O-]S([O-])(=O)=O INHCSSUBVCNVSK-UHFFFAOYSA-L 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 239000002923 metal particle Substances 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 239000002086 nanomaterial Substances 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- 230000009826 neoplastic cell growth Effects 0.000 description 2
- 210000001577 neostriatum Anatomy 0.000 description 2
- 230000000324 neuroprotective effect Effects 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000011552 rat model Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 229960004586 rosiglitazone Drugs 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- XXUZFRDUEGQHOV-UHFFFAOYSA-J strontium ranelate Chemical compound [Sr+2].[Sr+2].[O-]C(=O)CN(CC([O-])=O)C=1SC(C([O-])=O)=C(CC([O-])=O)C=1C#N XXUZFRDUEGQHOV-UHFFFAOYSA-J 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 238000004627 transmission electron microscopy Methods 0.000 description 2
- 150000003626 triacylglycerols Chemical class 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- 150000003681 vanadium Chemical class 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- LGJMUZUPVCAVPU-ANOYILKDSA-N (3s,8r,9s,10s,13r,14s,17r)-17-[(2r,5s)-5-ethyl-6-methylheptan-2-yl]-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-ol Chemical class C1CC2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@H](CC)C(C)C)[C@@]1(C)CC2 LGJMUZUPVCAVPU-ANOYILKDSA-N 0.000 description 1
- ARYTXMNEANMLMU-UHFFFAOYSA-N 24alpha-methylcholestanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(C)C(C)C)C1(C)CC2 ARYTXMNEANMLMU-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 102000013563 Acid Phosphatase Human genes 0.000 description 1
- 108010051457 Acid Phosphatase Proteins 0.000 description 1
- 208000029483 Acquired immunodeficiency Diseases 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 208000020925 Bipolar disease Diseases 0.000 description 1
- 230000005653 Brownian motion process Effects 0.000 description 1
- SGNBVLSWZMBQTH-FGAXOLDCSA-N Campesterol Natural products O[C@@H]1CC=2[C@@](C)([C@@H]3[C@H]([C@H]4[C@@](C)([C@H]([C@H](CC[C@H](C(C)C)C)C)CC4)CC3)CC=2)CC1 SGNBVLSWZMBQTH-FGAXOLDCSA-N 0.000 description 1
- 240000007154 Coffea arabica Species 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 206010015548 Euthanasia Diseases 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 244000299507 Gossypium hirsutum Species 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229920002774 Maltodextrin Polymers 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 description 1
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 235000008331 Pinus X rigitaeda Nutrition 0.000 description 1
- 235000011613 Pinus brutia Nutrition 0.000 description 1
- 241000018646 Pinus brutia Species 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000005595 acetylacetonate group Chemical class 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 239000000956 alloy Substances 0.000 description 1
- 229910045601 alloy Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003529 anticholesteremic agent Substances 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 238000005537 brownian motion Methods 0.000 description 1
- 229910052793 cadmium Inorganic materials 0.000 description 1
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 description 1
- ARYTXMNEANMLMU-ATEDBJNTSA-N campestanol 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](C)CC[C@@H](C)C(C)C)[C@@]2(C)CC1 ARYTXMNEANMLMU-ATEDBJNTSA-N 0.000 description 1
- SGNBVLSWZMBQTH-PODYLUTMSA-N campesterol 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)CC[C@@H](C)C(C)C)[C@@]1(C)CC2 SGNBVLSWZMBQTH-PODYLUTMSA-N 0.000 description 1
- 235000000431 campesterol Nutrition 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000000975 co-precipitation Methods 0.000 description 1
- 238000004581 coalescence Methods 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- GPLRAVKSCUXZTP-UHFFFAOYSA-N diglycerol Chemical compound OCC(O)COCC(O)CO GPLRAVKSCUXZTP-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 210000004954 endothelial membrane Anatomy 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- KZJWDPNRJALLNS-STIDJNKJSA-N gamma-sitosterol Natural products CC[C@@H](CC[C@@H](C)[C@@H]1CC[C@H]2[C@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C KZJWDPNRJALLNS-STIDJNKJSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000000055 hyoplipidemic effect Effects 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000002486 insulinomimetic effect Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 230000003137 locomotive effect Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000011553 magnetic fluid Substances 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- 235000007079 manganese sulphate Nutrition 0.000 description 1
- 239000011702 manganese sulphate Substances 0.000 description 1
- SQQMAOCOWKFBNP-UHFFFAOYSA-L manganese(II) sulfate Chemical compound [Mn+2].[O-]S([O-])(=O)=O SQQMAOCOWKFBNP-UHFFFAOYSA-L 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000003818 metabolic dysfunction Effects 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- 229940035732 metformin and rosiglitazone Drugs 0.000 description 1
- 150000004704 methoxides Chemical class 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 239000007908 nanoemulsion Substances 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000004112 neuroprotection Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000002889 oleic acids Chemical class 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
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000002524 organometallic group Chemical class 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 230000033116 oxidation-reduction process Effects 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- 150000002940 palladium Chemical class 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 231100000683 possible toxicity Toxicity 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- GJAWHXHKYYXBSV-UHFFFAOYSA-N quinolinic acid Chemical compound OC(=O)C1=CC=CN=C1C(O)=O GJAWHXHKYYXBSV-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000004065 semiconductor Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 229940083492 sitosterols Drugs 0.000 description 1
- 238000001988 small-angle X-ray diffraction Methods 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007905 soft elastic gelatin capsule Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229910001631 strontium chloride Inorganic materials 0.000 description 1
- 229940079488 strontium ranelate Drugs 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- LSGOVYNHVSXFFJ-UHFFFAOYSA-N vanadate(3-) Chemical class [O-][V]([O-])([O-])=O LSGOVYNHVSXFFJ-UHFFFAOYSA-N 0.000 description 1
- 125000005287 vanadyl group Chemical group 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- 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
- A23L33/11—Plant sterols or derivatives thereof, e.g. phytosterols
-
- 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
- A61K31/28—Compounds containing heavy metals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- 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
- the present invention relates to a method for the preparation of reverse micelles based on sterols, acylglycerols and metal salt by mechanical stirring or sonication.
- Reverse micelles obtained by the method of the invention, are able to cross mucosa and then cellular membranes. They thus allow internalisation of metal ions by target cells. They are advantageously useful on the industrial level in the pharmaceutical and dietetic fields.
- the drug must be administered by a suitable and easy route, such as orally or rectally, and second the active ingredient must be delivered at the target cells under an active form.
- a suitable and easy route such as orally or rectally
- the active ingredient must be delivered at the target cells under an active form.
- “Cations with biocatalytic activity” is understood to cations having a direct biocatalytic activity, and cations capable of substituting for biocatalysts and so modifying certain pathological metabolic pathways.
- the example of vanadium may be mentioned, which by reason of its similar co-ordination chemistry may substitute for phosphate: thus both acid and alkaline phosphatases are inhibited by vanadyl and vanadate compounds; so too is tyrosine phosphatase which induces a stimulation of the phosphorylation of the tyrosine of the peripheral receptor of insulin as well as of the associated protein kinases.
- the present invention now provides a method for preparing reverse micelles, comprising one or more metal salts, such reverse micelles can be administered by any routes, in particular via mucosa and able to cross the cellular membranes.
- This process advantageously renders possible the control and optimisation of the composition comprising micelles for their later uses in the pharmaceutical and dietetic fields.
- the invention relates to a method for preparing reverse micelles based on sterols, acylglycerols and metal salt, intended to be used in the pharmaceutical and dietetic fields.
- the invention also relates to reverse micelles with an aqueous core of less or equal to 100 nm, wherein the said micelles are obtainable by a preparation method comprising:
- step (b) Stirring mixture obtained in step (a), at 40 0 C or less, and for a time sufficient to obtain formation of reverse micelles, said stirring being carried out mechanically at a speed from about 1000 to about 5000 r/min or by sonication.
- the reverse micellar system is characterized as a microemulsion comprising a dispersion of water-microdroplets in oil. This dispersion is stabilised by a surfactant (acylglycerol, more preferably diglycerol of fatty acids) at the water/oil interface.
- the reverse micellar phase can be defined as a system wherein water forms the internal phase and the hydrophobic tails of the lipids form the continuous phase.
- Reverse micelles containing oil(s), surfactant(s) and an aqueous phase are also characterized as water-in-oil microemulsions. The size of micelles is controlled by the quantity of solubilized water in the system.
- the ratio W (water)/(surfactant) weight ratio W (solubilized water in the mixture/the surfactant in the mixture).
- the ratio W (water)/(acylglycerol) is preferably less or equal to about 2.5, more preferably less or equal to 1 and more specifically from 0.01 to 0.2.
- the ratio W is preferably in the range from 0.05 to 0.18.
- the reverse micelles such as size of the core thereof, can be characterized by various methods:
- the compounds necessary for the preparation of the reverse micelles according to the invention comprise two lipids: a sterol and an acylglycerol, preferably a diglyceride of fatty acids, which acts as a surfactant.
- Reverse micelles according to the invention further comprises at least one metal cation.
- the ratios of the lipidic constituents can vary in a large extent, for instance the weight ratio sterol/acylglycerol can range from 0.01 to 1 (inclusive). According to a particular embodiment, an excess of acylglycerol (preferably diglyceride of fatty acids) can be used as compared to sterol (preferably sitosterol). More particularly, the weight ratio sterol/acylglycerol is more than or equal to 0.1 , more preferably from 0.1 to 0.2.
- Metal can be used at very low quantity compared to the two other components, advantageously in a molar ratio of 1/100 to 1/10000 compared to acylglycerol.
- Sitosterol can be identified by gas chromatographic analysis, and acylglycerol by high-pressure liquid chromatography (HPLC) using a light scattering detector, on a silica column (kromasil C18), in the presence of an eluent, e.g. isocratic acetonitrile.
- HPLC high-pressure liquid chromatography
- eluent e.g. isocratic acetonitrile
- Gas chromatography can also be used to identify diglycerides.
- Reverse micelles are dynamic systems. Brownian motion causes perpetual collisions of micelles, which lead to coalescence of micelles and to exchange of the aqueous cores. Separation and regeneration of micelles occur and allow chemical reactions between different solutions.
- the exchange rate between micelles increases in particular with temperature, the length of hydrocarbon chains of the surfactant, and W ratio (free water increases said exchange).
- size of the aqueous core of micelles ranges preferably from 5 to 100 nm.
- the relative quantity of water in the mixture (W) is preferably lower or equal to 2.5 and preferably lower or equal to 1 of the quantity of acylglycerol, preferably of diglyceride of fatty acids. According to a specific embodiment, the ratio W is preferably from 0.01 to 0.2.
- the invention relates to a method for preparing reverse micelles presenting an aqueous core of less or equal to 100 nm and comprising a water-soluble pharmaceutical active metal cation, wherein said method comprises the following steps :
- Step (b) of the process is of particular importance since it allows to obtain reverse micelles, which are then useful as a transport system for delivering drug at the target site in man or animal.
- step (a) The compounds constituting the reverse micelles are contacted during step (a).
- Compounds useful in the present invention will be described in more details below.
- Stirring of the mixture obtained by step (a) is more particularly carried out at a temperature less than or equal to 40 0 C, preferably ranging from 30 0 C to 38 0 C, more preferably from 30 0 C to 35 0 C 1 for a time sufficient to obtain formation of reverse micelles.
- the time sufficient can vary in particular upon the used stirring techniques, i.e., mechanical stirring at a speed from about 1000 to about 5000 r/min or sonication.
- the time of mechanical stirring or sonication is anyhow the time needed to convert the initial mixture into a monophasic reversed micellar solution. Stirring by sonication is preferred.
- the metal cation is first solubilized in purified water, which is then put into contact with the other constituents (step(a)).
- glycerol can, when introduced in large amount, prevent the formation of reverse micelles or break the micellar system. More specifically, no more than 1 %, and preferably no, glycerol (percent expressed by weight of glycerol / total amount by weight of water in the composition) is used for the preparation of the reverse micelles according to the present invention.
- sonication materials can be used at the laboratory or industrial scales.
- High-intensity ultrasound process is the most suitable process.
- materials of 400 W or 600 W with ultrasounds at 20 kHz give satisfactory results with a good homogeneity of the finished product and are thus preferred.
- Electronic control of temperature and emission duration of the process is also possible with that type of devices. Materials of the same type exist for industrial uses.
- temperature of the mixture must not exceed 40 0 C as to avoid degradation of the reactants. Temperature is preferably lower than about 38 0 C, even more preferably equal to or lower than about 35°C.
- the stirring speed necessary to obtain an optimal result depends on the viscosity of the mixture: stirring speed is preferably ranging from 1 000 to 5 000 r/minute.
- the implemented volumes, device, stirring speed and W ratio depend on and must be adapted with the pharmaceutically active metal cation introduced.
- the mixture is maintained at a temperature lower than approximately 40 0 C as to avoid degradation of the reactants, preferably at a temperature lower than approximately 35 0 C, even more preferably ranging between approximately 30 and 35°C.
- Another object of the invention relates to reverse micelles obtainable by the process according to the invention as described above.
- Acylglycerols more particularly acylglycerols of fatty acids, useful for the preparation of the reverse-micellar system according to the invention, can be isolated from the majority of plants and are majority components of plant and animal greasy substances.
- fatty acids number, their position on glycerol, their length of chain and the number of their possible unsaturations vary from one acylglycerol to another.
- Acylglycerols include in particular mono-, di- or triacylglycerols.
- mono-, di- or triglycerides used in the present invention present the following formula (I):
- - Ri is an acyl residue of a linear or branched, saturated or unsaturated fatty acid having between 14 and 24 carbon atoms, an hydrogen atom, or a mono-, di- or tri-galactose or glucose ;
- - R 2 is an acyl residue of a linear or branched, saturated or unsaturated fatty acid having between 2 and 18 carbon atoms,
- R 3 is an acyl residue of a linear or branched, saturated or unsaturated fatty acid having between 14 and 24 carbon atoms, or an hydrogen atom.
- At least one of Ri and R 3 represents an acyl residue of oleic acid (C18: 1[cis]-9).
- R 2 has one unsaturated bond (e.g; ethylenic bond) and has advantageously 18 carbon atoms, preferably R 2 is an oleic acid residue (oleoyl group), one of its positional isomers with respect to the double bond (cis-6, 7,9,11 and 13) or one of its iso-branched isomers.
- R 2 represents an acetyl group.
- R 3 represents an hydrogen atom.
- Acylglycerols used in the preparation of micelles according to the invention may be isolated from most plants.
- Unsaturated vegetable oils are particularly advantageously used as source of acylglycerols, especially olive oil from the first cold pressing.
- an oil containing a high concentration of oleic acid will be chosen as a useful source of acylglycerols according to the invention.
- Such an oil usually contains a high proportion of acylglycerols useful according to the invention.
- the preferred diglycerides of fatty acids are selected in the group consisting of 1,2-diolein and 1-oleoyl-2- acetyl glycerol.
- Acylglycerols and more particularly those which are found to be the most active in the applications sought after, also exist commercially. This is the case particularly for 1 -oleoyl-2-acetylglycerol and 1 ,2-dioleoylglycerol, which exist as commercial products with a high purity content.
- glyceride monooleate containing about 44 % of dioleic glycerides, from which about 14 % is 1,2-diolein.
- Such compound is pharmaceutically accepted (European
- Such product is for instance commercially available by Gattefosse Company under the name PECEOL®.
- the sterols useful for the preparation of the reverse-micellar system according to the invention can be any sterol, and preferably vegetable sterol.
- Sitosterol is the preferred sterol useful for the reverse-micellar system according to the invention.
- sitosterol incorporated in the reverse-micellar system of the invention can be [beta]- or [gamma]-sitosterol, preferably [beta]-sitosterol, or can be introduced in the form of a plant extract containing at least one of these two forms of sitosterol.
- Sitosterol is indeed a component of most plants.
- sitosterol which is extracted from soya
- the sitosterol generally represents from 50 to 70% by weight of the product and is generally found in a mixture with campesterol and sitostanol in respective proportions in the order of 15% each.
- Commercial sitosterol which is extracted from a variety of pine called tall oil can also be used, said tall-oil comprising an average of 75% by weigth of beta-sitosterol.
- said mixture comprises at least 50% sitosterol by weight of the mixture.
- beta-sitosterol having a purity higher than 95 %, or even 99 %, while proceeding in the following way: one carries out several successive recrystallizations with acetone of commercial mixture, which allows a pre-purification of beta-sitosterol by elimination of the campestanol and of the sitostanol present in the mixture.
- eluant mixtures such as methanol, in particular methanol 100% or mixtures of methanol and acetonitrile, in particular of mixtures 80-20 or any intermediate mixture making it possible to obtain sitosterol with a purity higher than 95 or even 99 %. This purity is determined by gas chromatography.
- Sitosterol and thus sitostanol can also be prepared by extraction from plants according to the techniques in the literature, for example p. 95 of the thesis presented at affiliated in November 1993 by Claude Cerdon entitled «Modulation de Ia production de sapogenines steroidiques en reponse a I'inhibition de Ia synthese de sterols».
- plants or products of plant origin with a relatively high free sitosterol content may be mentioned in particular olive oil, soya bean oil cotton leaves, coffee leaves, wheatgerm, for which the free sterol content and the percentage of sitosterol in the free sterol fraction are given in the table below:
- % is expressed by weight.
- the ratios of sterol and acylglycerol can vary in a large extent, for instance the weight ratio sterol/acylglycerol can range from 0.01 to 1 (inclusive).
- an excess of acylglycerol preferably diglyceride of fatty acids
- sterol preferably sitosterol
- the weight ratio sterol/acylglycerol is more than or equal to 0.1 , more preferably from 0.1 to 0.2.
- METAL Metal cations which may be used for preparing reverse-micellar system according to the invention are any cation in an oxidation state of at least 2, and whose biocatalytic activity is known or remains to be discovered.
- biocatalyst will indicate these metals exerting a catalytic activity on the biological systems.
- Metal ions play an essential part in approximately a third of the enzymes (Metal Ions in Biological Systems, Jenny P.GIusker, Amy K.Katz and Charles W.Bock, The Rigaku Journal, vol 16, N°2, 1999). They can have different types of actions : - modification of flows of electrons from the substrate or the enzyme, allowing the control of an enzymatic catalytic reaction,
- Metal M will be selected according to the desired biological activity.
- a metallic derivative of vanadium, niobium, molybdenum, selenium, chromium, zinc or titanium will more particularly be chosen.
- - niobium is advantageously in an oxidation state equal to 4 or 5, preferably 5,
- - vanadium is advantageously in an oxidation state equal to 3, 4 or 5, preferably 4,
- - selenium is advantageously in an oxidation state equal to 4 or 6, preferably 4, - molybdenum is in general in an oxidation state comprised between 3 and
- - chromium is preferably in an oxidation state equal to 3,
- - zinc is preferably in an oxidation state equal to 2, 3 or 4.
- the metal cation is selected in the group consisting of zinc, niobium, vanadium, selenium, molybdenum, chromium, antimony, tin, gold, ruthenium, palladium, platinum, lithium and strontium.
- particularly useful metal derivatives according to the invention are selected from sulphates, hydrates, halides, in particular chlorides, and any other water-soluble salt. It will be possible in some cases to use ammonium salts, methoxides of alkali metals or alkaline earth metals which can be advantageously dissolved in water or sometimes in alcohols. Organic metal derivatives like acetylacetonates, alkoxides or metal complexes with organic solvents, for example ethers, THF, DMF may also be used. These organic metal derivatives are generally soluble in organic solvents, more particularly in chlorinated solvents like chloroform or dichloromethane. Experiment shows that they can be collected by micelles in a reduced metal form in the aqueous core. However water-soluble salts will be preferred.
- Any metal having a water-soluble salt can be introduced into the reverse micelles according to the invention.
- the choice of metal will vary upon the desired therapeutic activity.
- a preferred metal is a metal exhibiting a biocatalytic activity. Metal can be used in very low amounts compared to the two other components, preferably in a molar ratio of 1/100 to 1/10 000 compared to acylglycerol.
- a therapeutic activity is obtained with amounts of metal divided by 1000 to 10000 compared to the activity obtained with a salt or an organic derivative of the same metal.
- the reverse micelles can be physically characterized by various methods: - X-Ray Scattering
- the reverse micelles of the invention improve bioavailability of the metal cation included therein, allowing its therapeutic or dietetic use with a reduced toxicity or a toxicity equal to zero. This is a considerable advantage compared to the state of the art. Due to its microemulsion nature, the reverse-micellar system allows to provide different types of formulations, comprising various excipients, vehicules or supports, which can be administered by various routes, including per mucosa, for example in a mouth or rectal administration, reverse micelles being then able to cross cellular membranes.
- mucosa and “mucosal” refer to a mucous tissue such as epithelium, lamina intestinal, and a layer of smooth muscle in the digestive tract.
- “Mucosal delivery”, “mucosal administration” and analogous terms as used herein refer to the administration of a composition to the mucosal tissue.
- “Mucosal delivery”, “mucosal administration” and analogous terms include, but are not limited to, the delivery of a composition through bronchi, gingival, lingual, nasal, oral, vaginal, rectal, and intestinal mucosal tissue.
- a reverse-micellar system can be used for the preparation of nanomaterials acting as microreactors which thereby enhance reactions of coprecipitations or chemical reductions of ions. They make it possible to prepare nanomaterials in a metastable state, which are usually not formed, in a massive state, at room temperature. It is thus possible to prepare, according to the process of the invention, reduced metal particles of copper, gold, silver, nickel, cadmium, etc., as well as semiconductors, alloys and magnetic fluids.
- the dynamic properties of the system make it possible to carry out reactions of reductions of ions in internal volumes of micelles whose size, form and reactivity are finely controlled thanks to the process according to the invention, as indicated above.
- aqueous core of a reverse-micellar system behaves as a nanoreactor, i.e. able, at room temperature, to transform a metal salt into a metal in a reduced ionic form, unstable in theory, but fully stable in the core of the micelles.
- the major therapeutic activity obtained with very low metal amounts (1 to 10 ⁇ g/kg/day in the animal, depending on metals) can be explained by the presence, inside the reverse micelles according to the invention, of metal in a free reduced metallic form, and by the specificity of the lipid components of micelle due to its cellular internalisation.
- This transformation of metal salt (in general a sulphate) into a reduced free metal particle is a fundamental element allowing metal to have a biological activity of intracellular enzymatic modulation.
- the activity results obtained in the animal for 4 metals, vanadium in the treatment of diabetes, manganese for an activity "SOD like", strontium to stimulate osseous growth and to treat the osteoporosis, and lithium for neuroprotection to treat in particular Huntington's disease show that any metai presenting a biological activity can be included in micelles according to the invention for the preparation of pharmaceutical compositions.
- the pharmaceutical composition contains reverse micelles as defined previously in a pharmaceutically acceptable support.
- the pharmaceutical composition may comprise a mixture of at least two types of micelles as defined previously, wherein each type comprises a metal cation distinct from the other type.
- Such a mixture provides, in certain cases, a synergistic effect: this is the case, in particular, when the composition contains a mixture of zinc and vanadium complex.
- a synergistic effect while using a pharmaceutical composition containing a mixture of these two types of complexes in the treatment of diabetes (cf. WO 96/23811 ).
- a further object of the invention concerns the use of reverse micelles as defined above for preparing a pharmaceutical composition intended for the delivery, more specifically the mucosal delivery, of one or more metal cation as defined above.
- the pharmaceutical composition is more particularly intended to prevent or treat one or more symptoms associated with a disease or disorder.
- Another object of the invention concerns methods for the delivery of one or more metal cations to an animal, said methods comprising administering to said animal a reverse micelle composition as defined above.
- the present invention provides methods for the mucosal delivery of one or more metal cations to an animal, said methods comprising mucosally administering to said animal a reverse micelle composition as defined above.
- the present invention provides methods for the prevention, treatment, or amelioration of one or more symptoms associated with a disease or disorder, said methods comprising in need thereof an effective amount of a reverse micelle composition as defined above and comprising one or more metal cations useful in the prevention, treatment or amelioration of one or more symptoms associated with said disease or disorder.
- the present invention provides methods for the prevention, treatment or amelioration of one or more symptoms associated with a disease or disorder, said methods comprising mucosally in need thereof an effective amount of a reverse micelle composition as defined above and comprising one or more metal cations useful in the prevention, treatment or amelioration of one or more symptoms associated with said disease or disorder.
- any excipient vehicle or carrier well-known to the person skilled in the art may be used.
- other additives well-known to the person skilled in the art such as stabilisers, drying agents, binders or pH buffers may be used.
- Preferred excipients in accordance with the invention promote adherence of the finished product to the mucosa.
- compositions of the invention can be administered in different ways, preferably via mucosal tissue, in particular via the oral route with a buccal or digestive absorption. It can also be the rectal route.
- the reverse micelle compositions of the invention are mucosally administered as a capsule, caplet, aerosol, spray, solution, suspension, emulsion, cachet, tablet, soft elastic gelatin capsule, aerosol, powder or granule.
- the compositions of the invention can be introduced in liquid form into capsules which releases their contents in the mouth.
- the reverse micelle compositions of the invention are administered to a mammal, more preferably a human to prevent or treat a disease or disorder.
- invention also relates to dietetic products, in particular dietetic products useful as food complements to control metabolic dysfunctions, by incorporating the reverse micelles previously defined, as well as a method to prepare these products.
- these products can be formed easily by contacting, in an oil particularly rich in diglycerides of fatty acids, beta- or gamma-sitosterol or a plant extract containing at least one of said two forms of sitosterol, a metal salt and purified water, and then agitating under the conditions of the process according to the invention as defined previously.
- oleic acid C18:1 contents of vegetable oils vary considerably according to the nature of the plant and its geographical origin.
- a vegetable oil in which the oleic acids account for at least 60% of the fatty acids.
- olive oil will be used, preferably oil of first cold pressure.
- Sitosterol will advantageously be introduced under the form of a plant extract.
- a plant extract obtained from soya, or preferably extracted from tall-oil.
- a dietetic product in particular, usable as a food complement with regulating activity of the glucidic metabolism and/or cardiovascular protective effect, one will use advantageously as metal salt, a salt of vanadium, in which vanadium is in an oxydation state equal to 4, in particular a vanadyl sulphate.
- Figure 1 antidiabetic activity assay on fructose rats of reverse micelles based on vanadium in comparison with reference drugs and controls: glycemia (mmol/l) during treatment (Day)
- Figure 2 antidiabetic activity assay on fructose rats of reverse micelles based on vanadium in comparison with reference drugs and controls: insulinemia ( ⁇ mol/ml) at DO and D21.
- Figure 3 adryamycin test on Wistar rats with reverse micelles based on manganese in comparison with controls: % of pow volume during treatment
- Figure 4 assessment of a stimulation activity of the osseous growth in growing rats with reverse micelles based on strontium in comparison with control and reference drug: femoral diameter (mm)
- Figure 5 assessment of a stimulation activity of the osseous growth in growing rats with reverse micelles based on strontium in comparison with control and reference drug: strontium amount in bone (expressed in ⁇ g/g)
- Figure 6 assessment of a stimulation activity of the osseous growth in growing rats with reverse micelles based on strontium in comparison with control and reference drug: strontium amount in plasma (expressed in ⁇ g/g)
- Figure 7A and B glycemia obtained on the STZ rats model at D3 and D7 respectively depending on W ratio of the administered reverse micelles containing vanadium
- Example 1 preparation of reverse micelles containing vanadium
- Peceol® (glyceride monooleate commercially available by Gattefosse) are added.
- Sonication of the mixture is carried out for 4 minutes, by monitoring the temperature at less than 38° C.
- the W ratio is 0.07.
- the obtained product is constituted of a homogeneous mixture of stable reverse micelles containing vanadium.
- the analysis by X-ray scattering shows a homogeneous micro emulsion with reverse micelles.
- Example 2 preparation of reverse micelles containing vanadium for the treatment of diabetic rats
- Sonication of the mixture is carried out in two times (3 minutes each), by monitoring the temperature at less than 38° C.
- the W ratio is 0.27.
- the obtained product is constituted of a homogeneous mixture of stable reverse micelles containing vanadium.
- the analysis by X-ray scattering shows a homogeneous micro emulsion with reverse micelles .
- Example 3 preparation of reverse micelles containing manganese for assessing a SOD-like activity in animals To 1.1 g of sitosterol solubilized in 2.2 ml of ethanol, 4.14 ml of purified water containing 313 ⁇ g of manganese sulphate (102 ⁇ g of metal manganese) and 40 ml of Peceol® are added.
- the mixture is stirred with a magnetic stirrer heating at 35°C for 15 minutes.
- the W ratio is 0.27.
- the obtained product is constituted of a homogeneous mixture of stable reverse micelles containing manganese.
- Example 4 preparation of reverse micelles containing strontium for assessing stimulation of the osseous growth activity in animals (NP 05 A)
- sitosterol solubilized in 20 ml of ethanol 20 ml of purified water containing 2570 mg of strontium sulphate (1229 mg of metal strontium), 48 ml of Peceol® and 160 ml of olive oil are added.
- the mixture is stirred with a magnetic stirrer heating at 35°C for 15 minutes.
- the W ratio is 0.85.
- Example 5 preparation of reverse micelles containing strontium for assessing stimulation of the osseous growth activity in animals (NP 05 B)
- Peceol® and 160 ml of olive oil are added.
- the mixture is stirred with a magnetic stirrer heating at 35°C for 15 minutes.
- the W ratio is 0.85.
- Example 6 preparation of reverse micelles containing strontium for assessing stimulation of the osseous growth activity in animals (NP 05 C) To 5 g of sitosterol solubilized in 20 ml of ethanol, 20 ml of purified water containing 26 mg of strontium sulphate (12.3 mg of metal strontium), 48 ml of Peceol® and 160 ml of olive oil are added.
- the mixture is stirred with a magnetic stirrer heating at 35°C for 15 minutes.
- the W ratio is 0.85.
- Example 7 preparation of reverse micelles containing vanadium (NP 01 A) To 1.1 g of sitosterol solubilized in 2.2 ml of ethanol, 1.5 ml of purified water containing 71 ⁇ g of vanadyl sulphate (22 ⁇ g of metal vanadium), 40 ml of olive oil (4% of diglycerides) are added.
- Sonication of the mixture is carried out for 4 minutes, by monitoring the temperature at less than 38 0 C.
- the W ratio is 2.33.
- Example 8 preparation of reverse micelles containing vanadium (NP 01 B) To 1.1 g of sitosterol solubilized in 2.2 ml of ethanol, 5.92 ml of purified water containing 85 ⁇ g of vanadyl sulphate (26 ⁇ g of metal vanadium), 40 ml of Peceol® are added.
- Sonication of the mixture is carried out for 4 minutes, by monitoring the temperature at less than 38° C.
- the W ratio is 0.38.
- Example 9 preparation of reverse micelles containing vanadium (NP 01 C)
- the mixture is stirred with a magnetic stirrer heating at 35°C for 15 minutes.
- the W ratio is 0.1.
- the model of the fructose rats is a non insulino dependent diabetes (NIDD) similar to the observed human type 2 diabetes.
- NIDD non insulino dependent diabetes
- the NP 01 product contains reverse micelles based on vanadium, prepared according to example 2. Its therapeutic activity is compared with two reference drugs: Metformin and Rosiglitazone.
- rats are weighed and a blood sampling is made to determine the basal values of the biochemical parameters.
- the rats are distributed randomly in groups of 10 rats.
- the drink water is then replaced by a solution of fructose 10% in distilled water. This solution is provided ad libitum for 21 days. They receive then again normal water for the following 21 days of the treatment.
- the treatment then starts for a 21 -day duration, with a daily administration: - Control group : 1 ml/kg of normal water per os
- - Metformin group 50 mg/kg of Metformin per os.
- Rosiglitazone group 5 mg/kg of Rosiglitazone per os
- blood sample At D7, blood sample.
- blood sample and end of the treatment At D 21 , blood sample and end of the treatment.
- NP 01 example 2 according to the invention
- insulinemia is the marker of insulino-resistance at the origin of unfavourable evolution of diabetes.
- the test with adryamycin is a specific test to highlight free anti-radicals activity of a substance.
- the product contains reverse micelles based on manganese prepared according to example 3.
- a second inflammatory phase begins on the 3rd day and lasts for 5 days.
- the vascular hyperpermeability arid the oedema which results therefrom, with a deterioration of the cells of endothelial membranes, are caused by the release of free radicals.
- the anti-inflammatory steroids and non steroids do not have any action during this second phase.
- the oedema is measured by plethysmography (expressed by % of pow volume).
- the control product Diosmine has a free anti-radical activity similar to Manganese superoxydismutase, (MnSOD); those products are the only products to exhibit an activity on this test.
- MnSOD Manganese superoxydismutase
- the product NP 02 prepared according to example 3 of the invention has a comparable free anti-radicals activity (even discreetly higher than the reference product).
- the objective of this study is the assessment of a stimulation activity of the osseous growth in growing rats.
- the product contains reverse micelles based on strontium prepared according to example 4.
- the animals are Wistar female rats of 200 g (average). Homogeneous batches of 10 rats are made up starting from their weight. The treatment is administered once per day during 6 weeks. Administered batches and products: - control batch (administration of olive oil by rectal route)
- the NP 05 products have a stimulation activity of the osseous growth higher than the reference product.
- the NP 05 C product has an activity higher than the reference product with 600 times less strontium metal.
- Strontium amount in bone (expressed in ⁇ g/g) - Figure 5 - SD stands for standard deviation
- the negative effect of strontium in the treatment of the osteoporosis is related to the important fixing of strontium in bone with the therapeutic amounts used (2 g per day for humans and 68.2 mg/kg for animals).
- the NP 05 product, in particular with the lowest strontium amounts (NP 05 C) does not induce any strontium fixing in bone.
- the plasmatic strontium rate of the NP 05 C batch prepared according to example 6 of the invention is similar to the rate of the untreated control batch.
- lithium protects cultured CNS neurons against glutamate mediated by NMDA receptors.
- the neuroprotective effect of lithium against striatal lesion in a rat model of Huntington's disease was assessed.
- This pharmacological activity is obtained with the same clinical doses that in the treatment of bipolar disorder: 500 mg to 1 000 mg per days of lithium carbonate (lithemia: 0,5 - 0,8 mEq/l.) in human, and 2-10 mg per day in mice or rats.
- Lithium has a high toxicity, and it is necessary to survey the lithemia every day because of the adverse effects. 6 rats receive by rectal route 2 ml/kg per day (product example 10: 10 ⁇ g Li) 24 h before and during 7 days after the unilaterally infusion of quinolinic acid into the striatum.
- Striatum is collected and cryosectionned using a Lecia CM 1850 cryostat. Sectins are treated with ethanol, cleared in xylene and then coverslipped using
- Sections containing NM neurons are analysed using a stereological program to compare the number of neurons on the lesion side versus the intact side.
- NP 03 significantly protects NM neurons from death following injection. In previous report, 20/30 % cell death was obtained in saline treated subjects. Here, only 9,2 % of cell death with NP 03 administration is obtained.
- the STZ rats model is a mix model for type 1 and type 2 diabetes. This model allows to obtain a quick response on antidiabetic activity of substances.
- Protocol Streptozotocine is administered to Wistar males rats from 250 to 300 g, by IV way in an amount of 50 mg/kg. 3 days after the administration of STZ, the animals glycemia lies between 20 and 30 mmol/l, and remains stable during the following 7 days. The studied products are administered daily for 7 days. Glycemia is measured at DO, D1 , D3 and D7.
- Each batch corresponds to 6 rats.
- Figures 7A and 7B represent the glycemia obtained at D3 and D7 respectively.
- ratio W ranges from 0.12 and 1.
- Higher sized micelles contain free water wherein metal is no longer under a reduced metallic form and remains in a sulphate form which produces a lower activity.
- Samples containing the relative quantities of peceol, sitosterol and ethanol given in the above examples were prepared by varying quantity of water in which metal ions were solubilized. A dilution scale was made by increasing quantity of water with increment of 0.3 %.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Botany (AREA)
- Immunology (AREA)
- Diabetes (AREA)
- Molecular Biology (AREA)
- Physical Education & Sports Medicine (AREA)
- Nutrition Science (AREA)
- Rheumatology (AREA)
- Biophysics (AREA)
- Dispersion Chemistry (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Polymers & Plastics (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Food Science & Technology (AREA)
- Mycology (AREA)
- Virology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- AIDS & HIV (AREA)
- Pain & Pain Management (AREA)
- Pulmonology (AREA)
- Communicable Diseases (AREA)
- Psychology (AREA)
Abstract
Description
Claims
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT05804076T ATE483454T1 (en) | 2004-11-02 | 2005-11-02 | REVERSED MICELLAR COMPOSITION FOR DELIVERING METAL CATIONS HAVING A DIGLYCERIDE AND A PHYTOSTEROL AND METHOD FOR PRODUCTION |
AU2005300253A AU2005300253B2 (en) | 2004-11-02 | 2005-11-02 | Reverse micelle composition for delivery of metal cations comprising a diglyceride and a phytosterol and method of preparation |
JP2007539653A JP4975631B2 (en) | 2004-11-02 | 2005-11-02 | Reverse micelle composition for delivery of metal cations and method of manufacture comprising diglyceride and phytosterol |
PL05804076T PL1807048T3 (en) | 2004-11-02 | 2005-11-02 | Reverse micelle composition for delivery of metal cations comprising a diglyceride and a phytosterol and method of preparation |
DE602005024036T DE602005024036D1 (en) | 2004-11-02 | 2005-11-02 | REVERSE-MICRO-COMPOSITION FOR DISPOSING METAL CATIONS WITH A DIGLYCERIDE AND A PHYTOSTEROL AND METHOD OF MANUFACTURE |
EP05804076A EP1807048B1 (en) | 2004-11-02 | 2005-11-02 | Reverse micelle composition for delivery of metal cations comprising a diglyceride and a phytosterol and method of preparation |
CA2584684A CA2584684C (en) | 2004-11-02 | 2005-11-02 | Reverse micelle composition for delivery of metal cations comprising a diglyceride and a phytosterol and method of preparation |
DK05804076.7T DK1807048T3 (en) | 2004-11-02 | 2005-11-02 | Reverse-micelle composition for delivery of metal ions comprising a diglyceride and a phytosterol and method |
EA200700994A EA012210B1 (en) | 2004-11-02 | 2005-11-02 | Reverse micelle composition for delivery of metal cations comprising a diglyceride and a phytosterol and method of preparation |
CN200580037670XA CN101102751B (en) | 2004-11-02 | 2005-11-02 | Reverse micelle composition for delivery of metal cations comprising a diglyceride and a phytosterol and method of preparation |
US11/718,511 US9173838B2 (en) | 2004-11-02 | 2005-11-02 | Reverse micelle compositions for delivery of metal cations comprising a diglyceride and a phytosterol and method of preparation |
IL182756A IL182756A (en) | 2004-11-02 | 2007-04-23 | Reverse micelle composition for delivery of metal cations comprising a diglyceride and a phytosterol and method of preparation |
HK07113627.7A HK1108368A1 (en) | 2004-11-02 | 2007-12-13 | Reverse micelle composition for delivery of metal cations comprising a diglyceride and a phytosterol and method of preparation |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP04025987.1 | 2004-11-02 | ||
EP04025987A EP1652512A1 (en) | 2004-11-02 | 2004-11-02 | Reverse micelle composition for delivery of metal cations comprising a diglyceride and a phytosterol and method of preparation |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2006048773A1 true WO2006048773A1 (en) | 2006-05-11 |
Family
ID=34927200
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2005/003605 WO2006048773A1 (en) | 2004-11-02 | 2005-11-02 | Reverse micelle composition for delivery of metal cations comprising a diglyceride and a phytosterol and method of preparation |
Country Status (17)
Country | Link |
---|---|
US (1) | US9173838B2 (en) |
EP (2) | EP1652512A1 (en) |
JP (1) | JP4975631B2 (en) |
CN (1) | CN101102751B (en) |
AT (1) | ATE483454T1 (en) |
AU (1) | AU2005300253B2 (en) |
CA (1) | CA2584684C (en) |
DE (1) | DE602005024036D1 (en) |
DK (1) | DK1807048T3 (en) |
EA (1) | EA012210B1 (en) |
ES (1) | ES2353804T3 (en) |
HK (1) | HK1108368A1 (en) |
IL (1) | IL182756A (en) |
PL (1) | PL1807048T3 (en) |
PT (1) | PT1807048E (en) |
WO (1) | WO2006048773A1 (en) |
ZA (1) | ZA200704286B (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011117333A2 (en) | 2010-03-24 | 2011-09-29 | Medesis Pharma | Reverse micelle system comprising metal ions and use thereof |
WO2012007387A1 (en) * | 2010-07-13 | 2012-01-19 | Medesis Pharma | Low- dose lithium for the treatment of neurodegenerative disorders |
EP2556833A1 (en) * | 2010-04-07 | 2013-02-13 | Fundação Arnaldo Vieira De Carvalho | Pharmaceutical composition for the treatment of alzheimer's disease, method for producing same and use thereof |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1652513A1 (en) * | 2004-11-02 | 2006-05-03 | Denderah Pharm Sa | Reverse micelles based on sterols and acylglycerols and therapeutic uses thereof |
EA201890255A1 (en) * | 2015-07-09 | 2018-07-31 | Медзис Фарма | PREPARATION OF CYANOMOSTIC METALLIC NANOPARTICLES IN A BIOCOMPATIBLE IN SITU TREATED MICELLAR SYSTEM |
CA3103704A1 (en) * | 2018-07-06 | 2020-01-09 | Medesis Pharma | Reverse micelle system for treatment and prevention of injury due to radiation exposure |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5252333A (en) * | 1987-04-27 | 1993-10-12 | Scotia Holdings Plc | Lithium salt-containing pharmaceutical compositions |
FR2729957A1 (en) * | 1995-01-31 | 1996-08-02 | Maurel Sante | ORGANOMETALLIC COMPLEXES BASED ON SITOSTEROLS AND ACYLGLYCEROLS AND PHARMACEUTICAL COMPOSITIONS AND DIETETIC PRODUCTS CONTAINING SAME. |
WO2000057721A2 (en) * | 1999-03-26 | 2000-10-05 | Akesis Pharmaceuticals, Inc. | Edible solids for treatment of glucose metabolism disorders |
US6129924A (en) * | 1996-07-03 | 2000-10-10 | Maurel Sante | Diglyceride and sterol based organometallic complexes and pharmaceutical compositions and dietetic products containing them |
US6365176B1 (en) * | 2000-08-08 | 2002-04-02 | Functional Foods, Inc. | Nutritional supplement for patients with type 2 diabetes mellitus for lipodystrophy |
EP1452175A1 (en) * | 2003-02-28 | 2004-09-01 | Medesis Pharma S.A. | Manganese based organometallic complexes, pharmaceutical compositions and dietetic products |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2658816A1 (en) * | 1990-02-27 | 1991-08-30 | Adir | NOVEL ALKALINOTERREUX METAL SALTS OF OXA-POLYACIDS, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
JPH119988A (en) * | 1997-06-26 | 1999-01-19 | Advanced Sukin Res Kenkyusho:Kk | Water-in-oil type microemulsion |
JPH1129464A (en) * | 1997-07-07 | 1999-02-02 | Advanced Sukin Res Kenkyusho:Kk | Water-in-oil type microemulsion mixed with cholesterol |
US6623765B1 (en) * | 2000-08-01 | 2003-09-23 | University Of Florida, Research Foundation, Incorporated | Microemulsion and micelle systems for solubilizing drugs |
RU2281652C2 (en) * | 2001-01-25 | 2006-08-20 | Унилевер Н.В. | Food microemulsion, method for production thereof and foodstuff containing the same |
US20030113366A1 (en) * | 2001-12-14 | 2003-06-19 | Macgregor Alexander | Reverse-micellar delivery system for controlled transportation and enhanced absorption of agents |
CN1457773A (en) * | 2003-06-02 | 2003-11-26 | 乐益 | Biguanide vanadium complex granular powder and/or capsule for curing diabetes and its use |
EP1652513A1 (en) * | 2004-11-02 | 2006-05-03 | Denderah Pharm Sa | Reverse micelles based on sterols and acylglycerols and therapeutic uses thereof |
-
2004
- 2004-11-02 EP EP04025987A patent/EP1652512A1/en not_active Withdrawn
-
2005
- 2005-11-02 CA CA2584684A patent/CA2584684C/en not_active Expired - Fee Related
- 2005-11-02 PL PL05804076T patent/PL1807048T3/en unknown
- 2005-11-02 ES ES05804076T patent/ES2353804T3/en active Active
- 2005-11-02 AT AT05804076T patent/ATE483454T1/en active
- 2005-11-02 JP JP2007539653A patent/JP4975631B2/en not_active Expired - Fee Related
- 2005-11-02 EP EP05804076A patent/EP1807048B1/en not_active Not-in-force
- 2005-11-02 DK DK05804076.7T patent/DK1807048T3/en active
- 2005-11-02 DE DE602005024036T patent/DE602005024036D1/en active Active
- 2005-11-02 CN CN200580037670XA patent/CN101102751B/en active Active
- 2005-11-02 PT PT05804076T patent/PT1807048E/en unknown
- 2005-11-02 US US11/718,511 patent/US9173838B2/en not_active Expired - Fee Related
- 2005-11-02 WO PCT/IB2005/003605 patent/WO2006048773A1/en active Application Filing
- 2005-11-02 EA EA200700994A patent/EA012210B1/en not_active IP Right Cessation
- 2005-11-02 AU AU2005300253A patent/AU2005300253B2/en not_active Ceased
-
2007
- 2007-04-23 IL IL182756A patent/IL182756A/en active IP Right Grant
- 2007-05-25 ZA ZA200704286A patent/ZA200704286B/en unknown
- 2007-12-13 HK HK07113627.7A patent/HK1108368A1/en not_active IP Right Cessation
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5252333A (en) * | 1987-04-27 | 1993-10-12 | Scotia Holdings Plc | Lithium salt-containing pharmaceutical compositions |
FR2729957A1 (en) * | 1995-01-31 | 1996-08-02 | Maurel Sante | ORGANOMETALLIC COMPLEXES BASED ON SITOSTEROLS AND ACYLGLYCEROLS AND PHARMACEUTICAL COMPOSITIONS AND DIETETIC PRODUCTS CONTAINING SAME. |
US6129924A (en) * | 1996-07-03 | 2000-10-10 | Maurel Sante | Diglyceride and sterol based organometallic complexes and pharmaceutical compositions and dietetic products containing them |
WO2000057721A2 (en) * | 1999-03-26 | 2000-10-05 | Akesis Pharmaceuticals, Inc. | Edible solids for treatment of glucose metabolism disorders |
US6365176B1 (en) * | 2000-08-08 | 2002-04-02 | Functional Foods, Inc. | Nutritional supplement for patients with type 2 diabetes mellitus for lipodystrophy |
EP1452175A1 (en) * | 2003-02-28 | 2004-09-01 | Medesis Pharma S.A. | Manganese based organometallic complexes, pharmaceutical compositions and dietetic products |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011117333A2 (en) | 2010-03-24 | 2011-09-29 | Medesis Pharma | Reverse micelle system comprising metal ions and use thereof |
WO2011117333A3 (en) * | 2010-03-24 | 2012-06-07 | Medesis Pharma | Reverse micelle microemulsion comprising metal ions and use thereof |
US9592218B2 (en) | 2010-03-24 | 2017-03-14 | Medesis Pharma | Reverse micelle system comprising metal ions and use thereof |
EP2556833A1 (en) * | 2010-04-07 | 2013-02-13 | Fundação Arnaldo Vieira De Carvalho | Pharmaceutical composition for the treatment of alzheimer's disease, method for producing same and use thereof |
EP2556833A4 (en) * | 2010-04-07 | 2013-09-04 | Fundacao Arnaldo Vieira De Carvalho | Pharmaceutical composition for the treatment of alzheimer's disease, method for producing same and use thereof |
WO2012007387A1 (en) * | 2010-07-13 | 2012-01-19 | Medesis Pharma | Low- dose lithium for the treatment of neurodegenerative disorders |
Also Published As
Publication number | Publication date |
---|---|
HK1108368A1 (en) | 2008-05-09 |
CA2584684C (en) | 2013-07-02 |
PT1807048E (en) | 2010-11-29 |
US9173838B2 (en) | 2015-11-03 |
ATE483454T1 (en) | 2010-10-15 |
EP1807048A1 (en) | 2007-07-18 |
EA200700994A1 (en) | 2007-10-26 |
US20090087477A1 (en) | 2009-04-02 |
JP2008519026A (en) | 2008-06-05 |
IL182756A0 (en) | 2007-07-24 |
ZA200704286B (en) | 2008-09-25 |
IL182756A (en) | 2011-02-28 |
EA012210B1 (en) | 2009-08-28 |
AU2005300253B2 (en) | 2010-09-09 |
JP4975631B2 (en) | 2012-07-11 |
EP1807048B1 (en) | 2010-10-06 |
ES2353804T3 (en) | 2011-03-07 |
DK1807048T3 (en) | 2011-01-10 |
DE602005024036D1 (en) | 2010-11-18 |
PL1807048T3 (en) | 2011-03-31 |
CN101102751B (en) | 2011-08-24 |
CN101102751A (en) | 2008-01-09 |
CA2584684A1 (en) | 2006-05-11 |
EP1652512A1 (en) | 2006-05-03 |
AU2005300253A1 (en) | 2006-05-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2584684C (en) | Reverse micelle composition for delivery of metal cations comprising a diglyceride and a phytosterol and method of preparation | |
EP0023349B1 (en) | Ubidecarenone composition enhancing the absorption | |
EP1807046B1 (en) | Reverse micelles based on phytosterols and acylglycerols and therapeutic use thereof | |
JPH11504028A (en) | Self-emulsifying compounds that create oil / water emulsions | |
TW200397B (en) | ||
CA2792136C (en) | Reverse micelle system comprising metal ions and use thereof | |
CN101103962A (en) | Vinpocetine oral self-micro-emulsification medicine-releasing system and preparation method thereof | |
NZ189297A (en) | Pgs inhibitor containing sterol glycosides | |
CN102552820A (en) | Method of preparing soft capsule of lipid-lowering and removing obstruction in the collaterals | |
CN115708829B (en) | Anti-osteoporosis pharmaceutical composition and application thereof | |
CN115708829A (en) | Anti-osteoporosis pharmaceutical composition and application thereof | |
Kalivianakis et al. | Detection of intestinal fat malabsorption due to impaired lipolysis by the 13 C-mixed triglyceride breath test in rats |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KN KP KR KZ LC LK LR LS LT LU LV LY MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2584684 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2005300253 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 182756 Country of ref document: IL |
|
WWE | Wipo information: entry into national phase |
Ref document number: 200580037670.X Country of ref document: CN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2007539653 Country of ref document: JP |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2005804076 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2005300253 Country of ref document: AU Date of ref document: 20051102 Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 3909/DELNP/2007 Country of ref document: IN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 200700994 Country of ref document: EA |
|
WWP | Wipo information: published in national office |
Ref document number: 2005804076 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 11718511 Country of ref document: US |