EP2242486A1 - Encapsulation de la vitamine c dans des dendrimères solubles dans l'eau - Google Patents
Encapsulation de la vitamine c dans des dendrimères solubles dans l'eauInfo
- Publication number
- EP2242486A1 EP2242486A1 EP09720309A EP09720309A EP2242486A1 EP 2242486 A1 EP2242486 A1 EP 2242486A1 EP 09720309 A EP09720309 A EP 09720309A EP 09720309 A EP09720309 A EP 09720309A EP 2242486 A1 EP2242486 A1 EP 2242486A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- dendrimer
- vitamin
- conjugated
- molecule
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 title claims abstract description 530
- 239000000412 dendrimer Substances 0.000 title claims abstract description 335
- 229920000736 dendritic polymer Polymers 0.000 title claims abstract description 331
- 238000005538 encapsulation Methods 0.000 title claims description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title claims description 25
- 229960005070 ascorbic acid Drugs 0.000 title description 164
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims abstract description 93
- 229930003268 Vitamin C Natural products 0.000 claims abstract description 93
- 235000019154 vitamin C Nutrition 0.000 claims abstract description 93
- 239000011718 vitamin C Substances 0.000 claims abstract description 93
- 239000002537 cosmetic Substances 0.000 claims abstract description 21
- 230000015572 biosynthetic process Effects 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 23
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 17
- 230000003381 solubilizing effect Effects 0.000 claims description 16
- -1 C 6 alkene Chemical class 0.000 claims description 13
- 230000006870 function Effects 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- 229920001223 polyethylene glycol Polymers 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 230000008685 targeting Effects 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 7
- 239000002202 Polyethylene glycol Substances 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000003827 glycol group Chemical group 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 229940088594 vitamin Drugs 0.000 claims description 6
- 229930003231 vitamin Natural products 0.000 claims description 6
- 235000013343 vitamin Nutrition 0.000 claims description 6
- 239000011782 vitamin Substances 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 3
- 239000003963 antioxidant agent Substances 0.000 claims description 3
- 230000003078 antioxidant effect Effects 0.000 claims description 3
- 235000006708 antioxidants Nutrition 0.000 claims description 3
- QKWNIOMGXBERHJ-RXSVEWSESA-N azane;(2r)-2-[(1s)-1,2-dihydroxyethyl]-3,4-dihydroxy-2h-furan-5-one Chemical compound N.OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QKWNIOMGXBERHJ-RXSVEWSESA-N 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 230000003712 anti-aging effect Effects 0.000 claims description 2
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 2
- 230000001153 anti-wrinkle effect Effects 0.000 claims description 2
- 238000006664 bond formation reaction Methods 0.000 claims description 2
- 239000004094 surface-active agent Substances 0.000 claims description 2
- 150000003722 vitamin derivatives Chemical class 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 235000010323 ascorbic acid Nutrition 0.000 description 177
- 239000011668 ascorbic acid Substances 0.000 description 174
- 238000005481 NMR spectroscopy Methods 0.000 description 61
- 239000000243 solution Substances 0.000 description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 21
- 239000000178 monomer Substances 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 230000008901 benefit Effects 0.000 description 18
- 239000000523 sample Substances 0.000 description 17
- 238000003786 synthesis reaction Methods 0.000 description 17
- 239000007983 Tris buffer Substances 0.000 description 16
- 239000000126 substance Substances 0.000 description 15
- 150000001412 amines Chemical class 0.000 description 14
- 238000007306 functionalization reaction Methods 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 229940072107 ascorbate Drugs 0.000 description 11
- 238000004448 titration Methods 0.000 description 11
- 150000003141 primary amines Chemical group 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 230000002209 hydrophobic effect Effects 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 0.000 description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 7
- 229920002521 macromolecule Polymers 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 229920000642 polymer Polymers 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 150000003512 tertiary amines Chemical class 0.000 description 6
- JGJTXXOCEJMMCR-UHFFFAOYSA-N CC(O)COCCOCCO.CC1=CC=C(S(O)(=O)=O)C=C1 Chemical compound CC(O)COCCOCCO.CC1=CC=C(S(O)(=O)=O)C=C1 JGJTXXOCEJMMCR-UHFFFAOYSA-N 0.000 description 5
- 229920000587 hyperbranched polymer Polymers 0.000 description 5
- 231100000419 toxicity Toxicity 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- 239000013598 vector Substances 0.000 description 5
- GQWWGRUJOCIUKI-UHFFFAOYSA-N 2-[3-(2-methyl-1-oxopyrrolo[1,2-a]pyrazin-3-yl)propyl]guanidine Chemical compound O=C1N(C)C(CCCN=C(N)N)=CN2C=CC=C21 GQWWGRUJOCIUKI-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- 239000005711 Benzoic acid Substances 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 125000003368 amide group Chemical group 0.000 description 4
- 235000010233 benzoic acid Nutrition 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 125000004404 heteroalkyl group Chemical group 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000000033 nuclear magnetic resonance titration Methods 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 229910004298 SiO 2 Inorganic materials 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 125000004043 oxo group Chemical group O=* 0.000 description 3
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000003158 alcohol group Chemical group 0.000 description 2
- 230000002225 anti-radical effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 150000002605 large molecules Chemical class 0.000 description 2
- 230000033001 locomotion Effects 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- SENLDUJVTGGYIH-UHFFFAOYSA-N n-(2-aminoethyl)-3-[[3-(2-aminoethylamino)-3-oxopropyl]-[2-[bis[3-(2-aminoethylamino)-3-oxopropyl]amino]ethyl]amino]propanamide Chemical compound NCCNC(=O)CCN(CCC(=O)NCCN)CCN(CCC(=O)NCCN)CCC(=O)NCCN SENLDUJVTGGYIH-UHFFFAOYSA-N 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229920000962 poly(amidoamine) Polymers 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 230000004224 protection Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- SNBFDVVWWLGGFD-UHFFFAOYSA-N 1-[2-(2-hydroxyethoxy)ethoxy]propan-2-ol Chemical compound CC(O)COCCOCCO SNBFDVVWWLGGFD-UHFFFAOYSA-N 0.000 description 1
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-M L-ascorbate Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] CIWBSHSKHKDKBQ-JLAZNSOCSA-M 0.000 description 1
- 238000012565 NMR experiment Methods 0.000 description 1
- 229910020169 SiOa Inorganic materials 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000002929 anti-fatigue Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 235000019568 aromas Nutrition 0.000 description 1
- 238000013528 artificial neural network Methods 0.000 description 1
- 125000003289 ascorbyl group Chemical group [H]O[C@@]([H])(C([H])([H])O*)[C@@]1([H])OC(=O)C(O*)=C1O* 0.000 description 1
- XJMWHXZUIGHOBA-UHFFFAOYSA-N azane;propanoic acid Chemical class N.CCC(O)=O XJMWHXZUIGHOBA-UHFFFAOYSA-N 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000035587 bioadhesion Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- GHWVXCQZPNWFRO-UHFFFAOYSA-N butane-2,3-diamine Chemical compound CC(N)C(C)N GHWVXCQZPNWFRO-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000005202 decontamination Methods 0.000 description 1
- 230000003588 decontaminative effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000002059 diagnostic imaging Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000004452 microanalysis Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 210000000865 mononuclear phagocyte system Anatomy 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000010525 oxidative degradation reaction Methods 0.000 description 1
- 239000003973 paint Substances 0.000 description 1
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 238000002428 photodynamic therapy Methods 0.000 description 1
- 230000003711 photoprotective effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229920000333 poly(propyleneimine) Polymers 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 150000004672 propanoic acids Chemical class 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000017105 transposition Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
Definitions
- the present invention relates to the encapsulation of vitamin C using water-soluble dendrimers, and, in particular, to its method of preparation.
- Dendrimer is a molecule whose architecture resembles that of the branches of a tree. It is indeed a macromolecule of three-dimensional structure, related to a hyperbranched polymer, where the connected monomers are associated in a tree process around a central multivalent heart.
- Dendrimers generally take a very regular or spherical globular form, highly branched and multifunctionalized. They consist of three specific regions: a multivalent central core, a defined number (constituting the multivalence) of intermediate dendritic branches connected to the multivalent central heart where each dendritic branch consists of a number of branching generation, and the periphery consisting of a multitude of functional end groups.
- Dendrimers generally take a very regular or spherical globular form, highly branched and multifunctionalized.
- dendrimers are generally monodisperse, unlike hyperbranched polymers. Obtaining these regular structures that are the dendrimers requires synthetic methods other than ordinary polymerizations. Indeed, the synthesis of dendrimers is difficult because it requires many steps to protect the active location, which is an obstacle to the synthesis of significant amounts.
- obtaining dendrimers with defined and / or specifically functionalized multiple trees is a real challenge for chemists because it requires quantitative and clean reactions to avoid mixing on the branches.
- the hyperbranched polymers whose molecular architecture is irregular, are obtained by polymerization of multifunctional branched monomers in a disordered and unrestricted process.
- these macromolecules are adjustable: their structure, their flexibility, their porosity and their morphology can be optimized in order to obtain the desired properties.
- the control of the architecture of the dendrimers and the chemical nature of the terminal branches which can thus perform various functions arouse an increasing interest for many very promising applications, especially in the field of medicine as described for example in the article by Astruc, CR. Acad. ScL (1996), 322, Series 2b, pages 757-766 (2), but also from the food industry, aromas, paints, catalysis, decontamination, gene therapy, photodynamic therapy, biological sensors, nanoelectronics, etc.
- the vectorization of active molecules is today a major stake in the pharmaceutical and cosmetic fields, as described for example in the publication by Vandamme et al., J. Control. Release (2005), 102 (1), pages 23-38 (3). It corresponds to the transport of active molecules to a site of action which allows to modulate the pharmacokinetics and biodistribution of these molecules by promoting their presence at the sites of action while limiting their toxicity or impact on healthy tissue .
- the vectorization allows a protection of the active molecules vis-à-vis the medium in which they are introduced avoiding for example their metabolism or degradation, as described for example in the publication of Zhuo et al. J. Control. Release (1999) 57, p. 249 (4).
- Vitamins are of great interest, especially for manufacturers in the pharmaceutical and cosmetic fields. Indeed, they intervene in many biological and physiological processes and are essential for the organism.
- vitamin C or ascorbic acid (AA) has many properties.
- AA ascorbic acid
- Vitamin C also promotes the absorption of iron, which helps prevent the onset of anemia. It is also required in the synthesis of collagen in the skin and is essential for healing wounds. It is also a powerful anti-oxidant and antiradical that protects the body from free radicals, prevent oxidative degradation and aging.
- these applications, in particular cosmetics are numerous, also stimulating cellular metabolism and having a photoprotective effect.
- some vitamins, including vitamin C can not be synthesized by the human body, hence the need for an exogenous supply.
- vitamins are fragile compounds, easily degraded by light, heat, oxygen, etc.
- vitamin C the most fragile of all vitamins, is unstable in solution and is quickly eliminated by the body.
- Existing pharmaceutical and cosmetic products therefore have a limited time of use. To overcome this problem of instability, they use a very different formulation that does not allow a modulated release.
- this molecule is not currently vectorized, its dispersion is uncontrolled and nonspecific.
- conjugated dendrimer comprising at least one water-soluble dendrimer encapsulating at least one molecule of vitamin C.
- conjugated dendrimer means the combination of at least one water-soluble dendrimer with at least one vitamin C molecule.
- a vitamin C molecule may be associated with one or more dendrimers which may be identical or different, for example if the PEG chains of different dendrimers participate in the stabilization of vitamin C molecules.
- water-soluble dendrimer of the present invention, a dendrimer which can be dissolved in water, that is to say whose aqueous solution is clear.
- the NMR spectrum of this solution makes it possible to visualize all the groups present in the dendrimer. It may be, for example, dendrimers having on their surface hydrophilic and / or little hydrophobic functions, that is to say polar functions and / or functions capable of creating hydrogen bonds with the water molecules.
- the term "encapsulate” is understood to mean surrounding a molecule, for example in the form of a capsule or shell, making it possible to isolate it, stabilize it and / or This encapsulation can be done in the heart but also on the periphery of the dendrimer where the vitamin C molecules are turned towards the interior of the dendrimer and are thus stabilized and protected.
- Vitamin C molecules may for example be associated inside the dendrimer or on the surface thereof.
- the term "supramolecular bond” means the assembly of several distinct molecules by hydrogen, ionic, coordination and / or hydrophobic interaction bonds.
- the dendrimers of the present invention thus make it possible to stabilize the vitamin C molecules and / or to protect them from the external environment. Indeed, the vitamin C molecules are incorporated into a "capsule" protected by a hydrophilic crown. [25] Moreover, the dendrimers have the advantage of being unique molecules (that is to say of polydispersity equal to one), perfectly defined, with exact chemical formulas, and which can be characterized very precisely (for example by nuclear magnetic resonance (NMR) proton and / or carbon techniques, microanalysis, infrared spectrometry, or mass spectrometry).
- NMR nuclear magnetic resonance
- Dendrimers are therefore suitable molecules for biological applications that require a high purity and a great knowledge of the molecules introduced in a biological medium, for example their mode of assembly, operation, their stability or the way in which they could be metabolized. Indeed, biological applications are much more difficult to achieve in the case of polydispersed or polymolecular molecules such as hyperbranched polymers.
- the hyperbranched polymers comprise a mixture of hyperbranched molecules that do not have the same molecular weight and will not stabilize an identical number of biological molecules for each of them, which generates much more uncertainty and difficulties for them. adapt to biological use.
- the water-soluble dendrimers of the present invention appear to be suitable carriers for the transport of vitamin C molecules, i.e., ascorbic acid.
- the controlled multivalence of the dendrimers of the present invention can be used to attach one or more substances and / or targeting groups and solubilizing at the periphery. This attachment or association can be achieved by supramolecular bonds that allow the maintenance of vitamin C molecules in the heart and periphery of the dendrimers.
- the dendrimers of the present invention can behave like vectors of vitamin C. The vectorization aims at modifying the stability and the pharmacokinetic properties of the transported active principles such as the crossing of anatomical, physiological barriers, their targeting. The particular characteristics of dendrimers, and their globular form, make these new molecular architectures ideal carriers of charged molecules. Indeed, these molecules can be used in a large number of applications including the control of loosening of pharmaceutical or cosmetic products.
- the water-soluble dendrimer may have a symmetrical radial structure.
- the term "perfect" dendrimer means a dendrimer of symmetrical structure that has no defect, with a total and uniform functionalization of the branches.
- the high symmetry of the dendrimer architecture has been verified by different characterization methods (NMR, mass, etc.). These data are exposed in the "Examples" section.
- the water-soluble dendrimer may consist of g generations, g being an integer ranging from 0 to 10, preferably from 0 to 4, in order to respect a permissible size in the body.
- generation is understood to mean a repetition of branching units or monomers organized in a layer around the central core. A generation is counted from each division of a branch into at least two branches.
- the generation number g of the dendrimer corresponds to the number of concentric layers of monomer, but can also correspond to the number of sequences necessary for the synthesis of the dendrimer.
- the generation number g of the dendrimer induces a precise size of the dendrimer and also plays an important role in the conformation of the dendrimer.
- the water-soluble dendrimer can have a globular structure. It may be for example a lobe structure, an elliptical structure, a spherical structure, perfect or not perfect, preferably a perfect spherical structure.
- the dendrimers have a dendritic topology that is to say an architecture built according to a tree process around a central core multifunctional, analogically to a neural network dendritic.
- the connected units are repeated monomers organized in layers, also called generations. According to the dendrimers, beyond a certain number of generations, they can take a globular form if the molecular segments are flexible.
- the dendrimers of globular structure have the advantage of being able to accommodate molecules within their cavities with a larger capacity.
- the dendritic topology imposes dynamic cavities absent in a linear polymer, for example, whose topology is different.
- the term "cavities" within the meaning of the present invention means the spaces present between the branches of the dendrimers. Since a dendrimer is not fixed in solution, the cavities can be dynamic because of movement of the branches within the solution, guided by the movement
- the following comparative Table 1 details the different properties of a linear polymer and a dendrimer.
- the dendrimer may be preferred to obtain the various properties below which differ from those of a linear polymer.
- the main advantage of a globular dendrimer over a linear polymer is the size of its internal cavities which can be optimized to accommodate large molecules. Indeed, in the case of the dendrimer, the cavities can be large and organized so as to allow greater capacity of reception or encapsulation. On the other hand, in a linear polymer folded into a spherical ball, the structure is random and the cavities are not optimized.
- the water-soluble dendrimer may have a diameter of less than 200 A, preferably 10 A to 50 A. This diameter depends on the generation of the dendrimer.
- the water-soluble dendrimer may have a molecular weight ranging from 20 to 50,000 g / mol, for example from 500 to 15,000 g / mol, for example from 773 to 7168 g / mol .
- the water-soluble dendrimer of the present invention may be, for example, a dendrimer of the following formula (I):
- BT is the terminal branch, and p is the number of terminal units from the lower generation monomer where: p is an integer from 1 to 3, preferably p is 2 or 3, preferably p is 3;
- the term “multivalence” refers to the number of dendritic branches connected to the central core of the dendrimer.
- the term “dendritic branch” is intended to mean a branched branch. In particular, it may consist of a sequence of monomers Mi, identical or different, where each branch between the monomers is divided into two or more branches.
- the dendritic branch can be: [(M1) - (M2) ... 2 - (Mi) 2 A (M) H (OB].
- terminal branch is intended to mean that part of the dendritic branch constituted by the terminal unit located at the periphery of the dendrimer. It may be for example a last-generation monomer g of the dendrimer, a hydrophilic function, a dendron, etc.
- the terminal branch corresponds to: (BT).
- intermediate dendritic branch means that part of the dendritic branch connecting the multivalent central core A to the terminal branch BT.
- the intermediate dendritic branch corresponds to: [(M1) - (M2) 2 - ... - ].
- the term "dendron” is intended to mean a branched (for example non-terminal or internal) dendritic branch, for example, comprising 2 or more branches.
- the dendron may be a hyperbranched dendritic branch, that is to say comprising 3 or more ramifications.
- dendron mention may for example be made of pentafluorophenyl tris 3,4,5-tri (triethyleneoxy) benzoate (or PentaFluoroPhenyl tris 3,4,5-Tri (TriEthyleneGlycol) benzoate or PFPTTEG).
- alkyl in the sense of the present invention, a linear radical, branched or cyclic, saturated or unsaturated, optionally substituted, comprising 1 to 60 carbon atoms, for example 1 to 57 carbon atoms, by Example 1 to 28 carbon atoms, for example 1 to 22 carbon atoms, for example 1 to 6 carbon atoms.
- alkene in the sense of the present invention, an alkyl radical, as defined above, having at least one carbon-carbon double bond.
- alkyne in the sense of the present invention, an alkyl radical, as defined above, having at least one carbon-carbon triple bond.
- aryl means an aromatic system comprising at least one ring satisfying the Hekel aromaticity rule. Said aryl is optionally substituted, may be mono or polycyclic and may comprise from 6 to 10 carbon atoms.
- heteroalkyl in the sense of the present invention, an alkyl radical as defined above, said alkyl system comprising at least one heteroatom, in particular selected from the group consisting of sulfur, oxygen, nitrogen, silicon.
- the water-soluble dendrimer may have a hydrophobic central core and a hydrophilic crown.
- the hydrophobic core does not necessarily include only hydrophobic groups.
- the hydrophobic core may contain heteroatoms (for example N, O, S and / or Si).
- hydrophobic core means a core with a hydrophobic nature relative to the periphery of the dendrimer, which is hydrophilic.
- This hydrophobic core / hydrophilic crown system makes it possible, in particular, to maintain the vitamin C molecules in the heart of the dendrimer, thus avoiding their contact. with the external environment (or the biological environment) and therefore premature oxidation of these molecules, while allowing the release of active molecules of vitamin C, especially in a biological medium. ;
- these groups being located inside the dendrimer, this has the advantage of allowing a better encapsulation of vitamin C molecules inside the dendrimer, for example by hydrogen, ionic and / or coordination, and ; to avoid their contact with the external environment. In addition, this also makes it possible to increase the number of encapsulated vitamin C molecules.
- the water-soluble dendrimer may have at its periphery mainly free primary amine functions or ammonium functions.
- the dendrimers comprising free primary amines or peripheral ammonium functions have the advantage of being able to react either supramolecularly with ascorbic acid (for example by forming ammonium ascorbates), as demonstrated in FIG. the examples part, or covalently with other chemical groups in order to modify the periphery of the dendrimer and therefore its properties.
- they may be dendrimers comprising a DiAminoButane (DAB) core and poly (propylene) imine (PPI) branches, such as, for example, the dendrimers described in FIGS. 1 to 4, or poly dendrimers ( amido) amines (PAMAM), for example the dendrimers described in FIGS. 5 to 9.
- DAB DiAminoButane
- PPI poly (propylene) imine
- PAMAM poly dendrimers ( amido) amines
- the water-soluble dendrimer may have one of the structures following: DAB G2 ( Figure 1), DAB G3 ( Figure 2), DAB G4 (Figure 3), DAB G5 ( Figure 4), PAMAM GO ( Figure 5), PAMAM G1 (Figure 6), PAMAM G2 ( Figure 7), PAMAM G3 ( Figure 8), PAMAM G4 ( Figure 9), etc.
- DAB dendrimers G2, G3 DAB, DAB G5 PAMAM G1 and G4 PAMAM are commercially available, eg DAB dendrimers G2, G3 DAB, DAB G5 PAMAM G1 and G4 PAMAM are marketed by the company Sigma-Aldrich (Sigma-Aldrich Chemie GmbH, L 1 Isie Abeau Chesnes , 38297 Saint-Quentin Fallavier, France), respectively under the references No. 679895 (DAB G2), No. 469076 (DAB G3), No. 469092 (DAB G5), No. 597414 (PAMAM G1) and No. 597856 ( PAMAM G4).
- the water-soluble dendrimer may be functionalized at its periphery with at least one organic surface agent.
- surfactant a molecule present on the surface of the dendrimer for modulating its surface properties, for example: to modify its solubility to modulate its toxicity and its biodistribution, for example to avoid its recognition by the reticuloendothelial system ("stealth"), and / or to give it interesting bioadhesion properties when administered orally, ocularly, nasally, and / or to allow specific targeting of certain organs / fabrics, etc.
- the organic surface agent may be selected from the group consisting of: a pharmaceutical molecule, a targeting molecule or a solubilizing group.
- the organic surface agent may be a solubilizing group with polyethylene glycol chains.
- a dendron containing polyethylene glycol chains not only makes it possible to improve the encapsulation rate of vitamin C molecules. but also to promote the encapsulation inward of the dendrimer (for better protection), for example by making supramolecular bonds with the vitamin C molecules, despite the steric hindrance that may occur.
- This property was unexpected, and was highlighted by the inventors.
- the DAB G3 dendrimer functionalized by the PFPTTEG dendron can fix more than 150 molecules of vitamin C.
- this dendrimer (with a hyperramified dendron thus having a high steric hindrance) makes it possible to fix many more molecules. of vitamin C than the DAB G3 dendrimer functionalized by the MEAC ligand.
- Other examples of encapsulation yields of dendrimers according to the invention are given in the Examples section.
- the organic surface agent may be a solubilizing group corresponding to one of the following structures (II) or (III):
- n, n, r 2 and r 3 are independently an integer of 1 to 500, and
- R, Ri, R 2 and R 3 independently represent an alkyl to C 6 alkene C2 -C 6 alkyne C 2 -C 6, or a C 6 to C 10 optionally substituted.
- the solubilizing group may respond to one of the following structures (IV) or (V) in which:
- n, n, r, and 113 are 1 or 3, preferably n is 1 and n, n 2 and n 3 are 3;
- the water-soluble dendrimer according to the invention can be a DAB-dendrimer or a PAMAM-dendrimer functionalized with dendron pentafluorophenyl tris 3,4,5-tri (triethyleneoxy) benzoate (or PentaFluoroPhenyl tris 3 , 4,5-Tri (TMEthyleneGlycol) benzoate or PFPTTEG) or by the ligand 2,2- (methoxyethoxy) acetylchloride (MEAC).
- it may be the G3 DAB functionalized by the MEAC ligand (FIG. 10) or by the PFPTTEG dendron (FIG. 11).
- the water-soluble dendrimer may be a nona-ammonuim chloride dendrimer having the following structure:
- dendrimer which dendrimer is functionalized at its periphery by a solubilizing group corresponding to one of structures (II) or (III), preferably to structure (III), as follows:
- n, n 1 , n 2 and r 3 independently represent an integer from 1 to 500, and
- R 1, R 1, R 2 and R 3 independently represent C 1 -C 4 alkyl, C 2 -C 4 alkene, C 2 -C 4 alkyne, or optionally substituted C 1 -C 10 aryl.
- nona-ammonuim chloride dendrimer is not soluble in water, hence the advantage of previously functionalizing it with solubilizing groups, for example with the PFPTTEG dendron, for the encapsulation of vitamin C.
- solubilizing groups for example with the PFPTTEG dendron
- the water-soluble dendrimer can respond to the structure described in FIG. 12 ("nona-amine" dendrimer functionalized by the PFPTTEG dendron).
- the water-soluble dendrimer can make supramolecular bonds with the at least one molecule of vitamin C.
- the at least one vitamin C molecule can be maintained at the heart or at the periphery of the at least one water-soluble dendrimer.
- vitamin C can be contained in the heart or maintained on the surface of the dendrimer by supramolecular bonding, and especially by electrostatic bonding.
- the ascorbic acid molecules have a pKa equal to 4.11 at 25 ° C in water, and thus form ammonium ascorbates with the amines of the dendrimers when these two products are in solution.
- the vitamin C molecules also carry out hydrogen bonds between its alcohol functions and the amines of the dendrimers.
- the PEG groups can participate in the transport of the ascorbic acid molecules either by carrying out hydrogen bonds with the ascorbate molecules, or by keeping them at the hydrophobic core of the dendrimer.
- a dendrimer can contain up to 500 molecules of vitamin C.
- the average encapsulation number can be from 14 ( ⁇ 1) to 500 ( ⁇ 20) vitamin C molecules per dendrimer.
- this average encapsulation number can be adjusted according to the desired application. Indeed, depending on the amount of vitamin C added, we can encapsulate more or less up to a limit (which corresponds to the maximum number of vitamin C molecules that can be encapsulated).
- the release of vitamin C can be carried out in water, for example by exchange with water molecules, where the ascorbate molecules can be protonated before being released in the form of ascorbic acid. The release can also take place in other solvents where vitamin C is soluble, such as ethanol.
- the release could be controlled by performing a dialysis to study the kinetics of release.
- a porous semipermeable membrane with pores of identical and known diameters
- the small molecules, namely the Vitamin C molecules cross the membrane, while large molecules, the dendrimers, are retained inside the dialysis membrane.
- a quantification of these vitamin C molecules makes it possible to follow the kinetics of release.
- the release kinetics of vitamin C can be modified according to the pH since the pH influences the ratio between the number of ascorbic acid molecules and ascorbate.
- the invention also relates to a cosmetic composition comprising a conjugated dendrimer according to the invention.
- the conjugated dendrimer according to the invention can be formulated in a cosmetic product to ensure a modulated delivery of vitamin C on the skin for protective (anti-radical) and / or regenerative purposes.
- the invention also relates to a conjugated dendrimer according to the invention as an antioxidant and / or anti-inflammatory agent.
- the invention also relates to the use of the conjugated dendrimer according to the invention for the preparation of a cosmetic composition, for example anti-aging or anti-wrinkle.
- the invention also relates to a cosmetic care method comprising a step of applying to the skin a cosmetic composition comprising a conjugated dendrimer according to the invention.
- the invention also relates to a process for preparing a conjugated dendrimer comprising at least one water-soluble dendrimer encapsulating at least one vitamin C molecule, said method comprising a reaction step of said water-soluble dendrimer with said less one molecule of vitamin C in a solvent and at a temperature that facilitates the formation of supramolecular bonds of the dendrimer and the vitamin C molecule.
- water is the solvent which allows both solubility and formation links between the dendrimer and vitamin C.
- the combination of the dendrimer and the vitamin C molecule can proceed via at least one of the following bonds: Ammonium ascorbate with an amino function of the dendrimer, hydrogen bond formation between a hydroxyl function of vitamin C and an amino function of the dendrimer.
- the reaction step can be carried out in a solvent selected from the group comprising water, alcohols 1 R S -OH where R s is a C1-C6 alkyl radical, for example 1 ethanol, or a mixture thereof.
- a solvent selected from the group comprising water, alcohols 1 R S -OH where R s is a C1-C6 alkyl radical, for example 1 ethanol, or a mixture thereof.
- the solvent used can solubilize partially or completely ascorbic acid and the dendrimer.
- ascorbic acid is only partially soluble in ethanol. !
- the reaction step can be carried out during a reaction time of less than 1 minute, for example less than 30 seconds, for example less than 1 second.
- the reaction time can range from a few milliseconds to a few seconds, preferably from a few milliseconds to a second.
- the reaction step can be carried out at a temperature ranging from 3 to 90 ° C., preferably from 15 to 35 ° C., preferably from 20 to 30 ° C. In addition, an increase of temperature can help speed up the reaction rate.
- the reaction step can be carried out at a pH i ranging from 0 to 14, preferably at a pH of 6 to 8, preferably at a pH of 7.
- the pH can influence the rate of reaction, but especially the encapsulation efficiency, indeed, the pH has an influence on the formation of hydrogen bonds between ascorbic acid and the dendrimer.
- the method of preparation may comprise reacting in water a sufficient amount of vitamin C to achieve a concentration of less than 10 ⁇ 2 mg / ml, with an amount sufficient dendrimer to obtain a conjugated dendrimer having a vitamin C: dendrimer ratio of 14 to 500, the reaction being carried out at a pH of 6 to 8, preferably 7, and at a temperature of 25 ° C +/- 10 0 C preferably at a temperature of 25 ° C +/- 5 ° C.
- the method of preparation has the advantage of using green chemistry, the encapsulation can be entirely carried out in water. This has advantages both in terms of environmental preservation, lower cost of production, but also purity, allowing applications in many fields, including the pharmaceutical and cosmetic fields.
- the method of preparation may further comprise, prior to the reaction step, a functionalization step, of functionalizing the periphery of the dendrimer with an organic surface agent selected from the group comprising: a pharmaceutical molecule, a targeting molecule or a solubilizing group.
- Figure 1 shows the DAB G2 dendrimer.
- Figure 2 shows the DAB G3 dendrimer.
- Figure 3 shows the DAB G4 dendrimer.
- Figure 4 shows the DAB G5 dendrimer.
- Figure 5 shows the PAMAM GO dendrimer.
- Figure 6 shows the PAMAM G1 dendrimer.
- Figure 7 shows the PAMAM G2 dendrimer.
- Figure 8 shows the PAMAM G3 dendrimer.
- Figure 9 shows the PAMAM G4 dendrimer.
- Figure 10 shows the DAB G3 dendrimer functionalized by the MEAC.
- FIG. 11 represents the DAB G3 dendrimer functionalized by the PFPTTEG.
- Figure 12 shows the nona-amine dendrimer functionalized by PFPTTEG.
- FIG. 13 represents the graphs of variation of the chemical shift ⁇ (in ppm or parts per million) of the proton signals in 1 H NMR relative to the number N of ascorbic acid molecules (AA) per dendrimer: (a) represents the graph of removal of proton signals 1 to 4 of the DAB G2 dendrimer (in ppm) relative to N; and (b) the proton signal shielding graph A to C of I 1 AA (in ppm) relative to N.
- FIG. 13 represents the graphs of variation of the chemical shift ⁇ (in ppm or parts per million) of the proton signals in 1 H NMR relative to the number N of ascorbic acid molecules (AA) per dendrimer: (a) represents the graph of removal of proton signals 1 to 4 of the DAB G2 dendrimer (in ppm) relative to N; and (b) the proton signal shielding graph A to C of I 1 AA (in ppm) relative to N.
- FIG. 15 shows the graphs of variation of the chemical shift ⁇ (in ppm) of the proton signals in 1 H NMR relative to the number N of ascorbic acid molecules (AA) per dendrimer: (a) graph of removal of the signals of the protons 1 to 3 of the DAB G5 dendrimer in ppm relative to N; (b) shielding graph of proton signals A to C of AA in ppm relative to N.
- 16 represents the graphs of variation of the chemical shift ⁇ (in ppm) of the proton signals in 1 H NMR relative to the number N of ascorbic acid molecules (AA) per dendrimer: (a) graph of removal of the signals of the protons 1 to 4 and the 4 'of PAMAM G1 dendrimer in ppm relative to N; (b) shielding graph of proton signals A to C of the AA in ppm relative to the number N.
- FIG. 17 represents the graphs of variation of the chemical shift ⁇ (in ppm) of the proton signals in 1 H NMR relative to the number N of ascorbic acid molecules (AA) per dendrimer: (a) graph of removal of the signals of the protons 1 to 4 and the 2 'of PAMAM G4 dendrimer in ppm relative to N; (b) shielding graph of proton signals A to C of AA in ppm relative to N.
- FIG. 18 represents the graphs of variation of the chemical shift ⁇ (in ppm) of the proton signals in 1 H NMR relative to the number N of ascorbic acid molecules (AA) per dendrimer: (a) graph of removal of the signals of the protons 1 to 3 of the DAB G3 dendrimer functionalized by the MEAC ligand in ppm relative to N; (b) shielding graph of proton signals A to C of AA in ppm relative to N.
- FIG. 19 represents the graphs of variation of the chemical shift ⁇ (in ppm) of the proton signals in 1 H NMR relative to the number N of ascorbic acid molecules (AA) by dendrimer: (a) proton signal deblinding 1 to 3 of the DAB G3 dendrimer functionalized by the PFPTTEG dendron in ppm relative to N; and (b) shielding the proton signals A to C of the AA in ppm relative to N.
- - Figure 20 represents the graph of variation of the chemical shift ⁇ (or shielding) of the 1 H NMR signals of the protons A to C AA in ppm relative to the N number of AA molecules per non-amine dendrimer functionalized by the PFPTTEG dendron.
- Dendron 2,2- (methoxyethoxy) acetylchloride 210 mg: 1.38 mmol: 2 equiv. Per NH 2
- triethylamine 185 mg: 1.84 mmol: 1.5 equiv. Per NH 2
- DAB G3 97 mg: 57.5 ⁇ mol
- Tris 3,4,5-tri (triethyleneoxy) benzoic acid is synthesized according to the following reaction: a) K 2 CO 3 / acetone b) LiOKH 2 O / MeOH
- Pentafluorophenyl tris 3,4,5-tri (triethyleneoxy) benzoate is synthesized according to the following reaction: DCC / Diglyme
- the functionalization of the non-amine dendrimer is carried out according to the following reaction:
- PFPTTEG (226 mg: 286 ⁇ mol: 1.025 equivalents per amine) are dissolved in 50 ml of distilled dichloromethane, before adding triethylamine (56 mg: 558 ⁇ mol: 2 equivalents per amine). The mixture is stirred under nitrogen at room temperature for 12 hours.
- DAB G2 DAB generational 2
- DAB G3 DAB G3
- DAB G5 DAB generational 5
- PAMAM PAMAM generation 1 dendrimers
- Each sample E was prepared by adding a volume V of S1 solution of ascorbic acid in an NMR tube containing 5 mg of DAB G2 dendrimer in 300 ⁇ l of D2O. This dendrimer is marketed under the reference 679895 by Sigma-Aldrich (France).
- the volume V introduced, the ratio of the number of AA molecules introduced by DAB G2 dendrimer, and the mass of AA introduced into the NMR tube for each sample are detailed in Table 2 below.
- FIG. Chart (a) is a representation of the various ppm NMR data for all the hydrogens of the DAB G2 dendrimer as a function of the amount of ascorbic acid added.
- the protons of the dendrimer are numbered from 1 to 4 according to the diagram below, to better visualize the displacement of the NMR signals of each proton:
- curve 1 gives the chemical shift ⁇ in 1 H NMR of the hydrogen numbered 1 for each of the samples E1 to E15.
- the NMR data of the peak corresponding to the protons of the primary amines are not accessible; in fact, the NMR spectra are carried out in the solvent D 2 O, and these protons are in continuous exchange with the solvent, hence the absence of their signals.
- DAB G2 signals are progressively deblocked to a concentration of about 30 AA / DAB, which means that all primary and tertiary amines quaternized with AA, and some additional AAs have bound themselves to the dendrimer probably by hydrogen bonds with the protons of the primary amines at the periphery of the dendrimer.
- the AAs first settle on the periphery because curves 1 and 2 have an initial slope greater than those of curves 3 and 4.
- Chart (b) is the various NMR data in ppm of ascorbic acid hydrogens (AA) indexed from A to C as in the diagram below:
- the alcohol functions present on the ascorbic acid would then form hydrogen bonds with the amines of the dendrimer and would also allow them to encapsulate in his heart.
- An S2 solution of ascorbic acid is obtained by dissolving 104.5 mg of ascorbic acid (AA) in 1 ml of D 2 O.
- Each sample E was prepared by adding a volume V of solution S2 of ascorbic acid in an NMR tube containing 10 mg of DAB G3 dendrimer in 300 ⁇ l of D 2 O.
- This dendrimer is marketed under the reference 469076 by the company Sigma. AIdrich (France).
- Graph (a) shows the removal of the dendrimer hydrogens numbered from 1 to 4 as below:
- Chart (b) shows the various NMR data in ppm of the ascorbic acid hydrogens (AA) indexed from A to C as below:
- An S3 solution of ascorbic acid is obtained by dissolving 91.5 mg of ascorbic acid (AA) in 1.5 ml of D2O.
- Each sample E was prepared by adding a volume V of solution S3 of ascorbic acid in an NMR tube containing 5 mg of DAB G5 dendrimer in 300 ⁇ l of D 2 O.
- This dendrimer is marketed under the reference 469092 by Sigma AIdrich (France).
- Graph (a) shows the removal of the dendrimer hydrogens numbered from 1 to 4 as below:
- Chart (b) shows the various NMR data in ppm of ascorbic acid hydrogens (AA) indexed from A to C above.
- An S4 solution of ascorbic acid is obtained by dissolving 61.5 mg of ascorbic acid (AA) in 1 mL of D 2 O.
- Each sample E was prepared by adding a volume V of S4 solution of ascorbic acid in an NMR tube containing 5 mg of dendrimer PAMAM G1 in 300 ⁇ l of D 2 O.
- This dendrimer is marketed under the reference 597414 by Sigma-Aldrich (France).
- Graph (a) shows the removal of the dendrimer hydrogens numbered from 1 to 4 as below:
- Chart (b) shows the various NMR data in ppm of ascorbic acid hydrogens (AA) indexed from A to C above.
- Each sample E was prepared by adding a volume V of solution S5 of ascorbic acid in an NMR tube containing 5 mg of PAMAM G4 dendrimer in 300 ⁇ l of D 2 O.
- This dendrimer is marketed under the reference 597856 by Sigma. AIdrich (France).
- Graph (a) shows the removal of the dendrimer hydrogens numbered from 1 to 4 as below:
- Chart (b) shows the various NMR data in ppm of ascorbic acid hydrogens (AA) indexed from A to C above.
- PAMAM G4 signals are progressively deblocked to a concentration of 64 AA / PAMAM. It can be thought that the AA is initially encapsulated in the dendrimer, which generates only a weak removal. Then the signals 2 and 3 corresponding to the primary primary amines and internal tertiary amines are strongly deblinded, hence the presence of ammonium ascorbate in the heart and the periphery of the dendrimer.
- the amines react differently with the AA according to the generation to which they belong, this being explained by a congested access according to the depth of the amine at the heart of the dendrimer.
- DAB G5 and PAMAM G4 have an equivalent number of amino functions).
- Example 6 Encapsulation of Vitamin C Using Some Functionalized Dendrimers
- a polyethylene glycol chain graft at the periphery of a molecule have already been demonstrated many times. Indeed, this water-soluble, non-toxic and non-immunogenic polymer is very suitable for biological use thanks to its high water solubility and biocompatibility.
- An S6 solution of ascorbic acid is obtained by dissolving 49 mg of ascorbic acid (AA) in 2 mL of D 2 O.
- Each sample E was prepared by adding a volume V of solution S6 of ascorbic acid in an NMR tube containing 5 mg of DAB G3 dendrimer functionalized with the monomer MEAC in 300 ⁇ l of D 2 O.
- NMR titration of ascorbic acid with this functionalized dendrimer is performed to compare its vitamin C transport properties.
- the NMR data are detailed in the graphs shown in Figure 18.
- Graph (a) shows the removal of the dendrimer hydrogens numbered from 1 to 4 as below:
- Chart (b) shows the various NMR data in ppm of ascorbic acid hydrogens (AA) indexed from A to C above.
- this dendrimer carries the transport of vitamin C, with a yield similar to the non-functional DAB G3 dendrimer but with the advantages of much better solubility and biocompatibility. Indeed, this dendrimer can fix 16 molecules of ascorbate before appearance of ascorbic acid molecules, and up to 80 molecules of ascorbate before reaching a dynamic equilibrium. As for the NMR data of the dendron (5, 6 and 7), they do not vary at all during the titration; this means that monoethylene glycol branches do not participate in AA binding or encapsulation within the dendrimer. b) The DAB G3 dendrimer functionalized by the PFPTTEG dendron
- the PFPTTEG dendron is first synthesized according to Example 2 in order to perform the functionalization of the DAB G3 dendrimer according to the protocol described in Example 3.
- An S7 solution of ascorbic acid is obtained by dissolving 15.8 mg of ascorbic acid (AA) in 2 ml of D2O.
- Each sample E was prepared by adding a volume V of S7 solution of ascorbic acid in an NMR tube containing 5 mg of DAB G3 dendrimer functionalized with the PFPTTEG dendron in 300 ⁇ l of D 2 O.
- NMR titration of AA is performed to evaluate the transport capacity of vitamin C by the DAB G3 dendrimer functionalized with the PFPTTEG dendron.
- the dendrimer obtained is soluble in a wide range of more apolar solvents such as toluene and dichloromethane more polar such as water, methanol and acetonitrile.
- this functionalized dendrimer is soluble in water in all proportions, which is an additional advantage allowing a high yield of AA transported.
- NMR titration of ascorbic acid with this functionalized dendrimer is performed to compare its vitamin C transport properties. NMR data are detailed in the graphs shown in Figure 19.
- Graph (a) shows the removal of the dendrimer hydrogens numbered from 1 to 4 as below:
- the "nona-amine” dendrimer functionalized by the PFPTTEG dendron The PFPTTEG dendron is first synthesized according to Example 2 in order to carry out the functionalization, according to the protocol described in Example 4, of a new nine-branched water-soluble dendrimer, named here the non-amine dendrimer. .
- Each sample E was prepared by adding a volume V of S8 solution of ascorbic acid in an NMR tube containing 5 mg of "nona-amine" dendrimer functionalized by the PFPTTEG dendron in 300 ⁇ L of D2O.
- the amounts of AA introduced and the ratio of the number of dendrimer-introduced AA molecules in the NMR tube for each sample are detailed in the following Table 10.
- NMR titration of AA is performed with this new water-soluble functionalized dendrimer to identify the part of TEG chains of responsibility in the transport of vitamin C.
- the results are given in the proton deblinding graph of the AA presented in Figure 20.
- this dendrimer which is functionalized with PFPTTEG dendrons, it is possible to transport more than one hundred AAs.
- This molecule comprises 27 TEG chains, these latter create electrostatic bonds and a steric conformation favorable to the maintenance of the ascorbic acid molecules within the molecule, thus allowing their transport.
- This dendrimer being composed of no primary or tertiary amine, shows us a chemical composition and an ideal conformation for the encapsulation of vitamin C molecules thanks to its particular properties provided by its heart and its dendrons. d) Conclusion
- Ascorbic acid whose exogenous contribution is essential for the human body, has the potential to be transported by certain organic molecules through a cosmetic product. Indeed, three types of vectors have been tested, namely pure commercial dendrimers, these same dendrimers functionalized with ethylene glycol chains, as well as new water-soluble dendrimers also comprising ethylene glycol chains whose synthesis is entirely achieved. in the laboratory.
- the dendrimers and their particular properties allow excellent transport efficiency of the ascorbic acid molecules, especially when they are functionalized with a dendron comprising three triethylene glycol chains.
- the latter in fact perform hydrogen bonds with the ascorbic acid molecules and also allow them to encapsulate in the heart of the dendrimer, while providing solubility properties in water (as well as in a large number of solvents), biocompatibility, and especially stability.
- the PFPTTEG dendron clearly participates in a better encapsulation of the vitamin C molecules and also carries out hydrogen bonds with these same molecules which are then viewable by NMR.
- the chain of the MEAC group three times shorter than that of the PFPTTEG group, does not allow to see, in NMR, a participation of the MEAC group on the encapsulation of vitamin C molecules.
- the transport yields of the new water-soluble dendrimers functionalized with PEG chains differ according to whether the dendron is more or less imposing with longer or shorter chains.
- the two dendrimers functionalized with the PFPTTEG dendron lead to a better transport efficiency; indeed, thanks to their steric hindrance at the periphery of the dendrimers, they make it possible to keep the AA molecules inside the dendrimers, without interfering with the passage of AA molecules to his heart.
- the best performing dendrimer is the one whose synthesis is entirely carried out in the laboratory, namely the nona-amine functionalized by nine dendrons, ie 27 ethylene glycol chains.
- this dendrimer does not contain internal amines, should have a lower toxicity than those marketed.
- dendrimers appear to be suitable for the transport of ascorbic acid molecules in cosmetics thanks to their controlled multivalence which can be used to attach one or more substances (drugs, enzymes, contrast agents for medical imaging). , ... here vitamin C) as well as targeting and solubilizing groups on the periphery.
- this type of vector has the advantage of being able to be synthesized in different sizes by varying its generation.
- dendrimers are molecules with a well-defined structure (polymolecularity equal to one), they could provide a reproducible pharmacokinetic substance, a definite advantage for their future in application.
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0850372A FR2926548B1 (fr) | 2008-01-21 | 2008-01-21 | Encapsulation de la vitamine c dans des dendrimeres solubles dans l'eau |
PCT/FR2009/000064 WO2009112682A1 (fr) | 2008-01-21 | 2009-01-21 | Encapsulation de la vitamine c dans des dendrimères solubles dans l'eau |
Publications (1)
Publication Number | Publication Date |
---|---|
EP2242486A1 true EP2242486A1 (fr) | 2010-10-27 |
Family
ID=39847045
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP09720309A Withdrawn EP2242486A1 (fr) | 2008-01-21 | 2009-01-21 | Encapsulation de la vitamine c dans des dendrimères solubles dans l'eau |
Country Status (4)
Country | Link |
---|---|
US (1) | US20110021626A1 (fr) |
EP (1) | EP2242486A1 (fr) |
FR (1) | FR2926548B1 (fr) |
WO (1) | WO2009112682A1 (fr) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2673357A2 (fr) * | 2011-02-07 | 2013-12-18 | Life Technologies Corporation | Compositions et procédés de stabilisation de composés sensibles |
KR101491728B1 (ko) | 2012-12-14 | 2015-02-11 | 주식회사 휴메딕스 | 비타민 c와 비타민 b3의 컨쥬게이트 및 그를 포함하는 항산화제 |
WO2014190024A1 (fr) * | 2013-05-21 | 2014-11-27 | Virgil Percec | Synthèse modulaire de glycodendrimères amphiphiles de type janus et leur autoassemblage en glycodendrimèresomes |
CN114507515B (zh) * | 2022-02-21 | 2023-06-06 | 中国石油大学(华东) | 一种用于裂缝性地层的超分子凝胶堵漏剂及其制备方法与应用 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007048672A1 (fr) * | 2005-10-25 | 2007-05-03 | Evonik Degussa Gmbh | Preparation comprenant des polymeres hyperramifies |
WO2007149501A2 (fr) * | 2006-06-21 | 2007-12-27 | Dendritic Nano Technologies, Inc. | Procédé pour préparer des polymères dendritiques à l'aide d'une synthèse assistée par micro-ondes |
-
2008
- 2008-01-21 FR FR0850372A patent/FR2926548B1/fr not_active Expired - Fee Related
-
2009
- 2009-01-21 EP EP09720309A patent/EP2242486A1/fr not_active Withdrawn
- 2009-01-21 US US12/863,877 patent/US20110021626A1/en not_active Abandoned
- 2009-01-21 WO PCT/FR2009/000064 patent/WO2009112682A1/fr active Application Filing
Non-Patent Citations (1)
Title |
---|
See references of WO2009112682A1 * |
Also Published As
Publication number | Publication date |
---|---|
FR2926548B1 (fr) | 2010-09-03 |
FR2926548A1 (fr) | 2009-07-24 |
WO2009112682A1 (fr) | 2009-09-17 |
US20110021626A1 (en) | 2011-01-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Yang et al. | Polyethylene glycol–polyamidoamine dendritic micelle as solubility enhancer and the effect of the length of polyethylene glycol arms on the solubility of pyrene in water | |
Dhanikula et al. | Synthesis and evaluation of novel dendrimers with a hydrophilic interior as nanocarriers for drug delivery | |
Kannan et al. | Dynamics of cellular entry and drug delivery by dendritic polymers into human lung epithelial carcinoma cells | |
Dhanikula et al. | Influence of molecular architecture of polyether-co-polyester dendrimers on the encapsulation and release of methotrexate | |
WO1999032540A1 (fr) | Polymeres hyperbranches ou dendrimeres ayant un groupement particulier, procede de preparation, utilisation et compositions les comprenant | |
CN108623807B (zh) | 一种基于肉桂醛的响应型聚合物纳米粒子及其制备方法 | |
FR2772771A1 (fr) | Utilisation de polymeres hyperbranches et de dendrimeres comportant un groupement particulier, en tant qu'agent filmogene, les compositions filmogenes les comprenant et leur utilisation notamment en cosmetique ou en pharmacie | |
CN110218312B (zh) | 具有高效药物负载性能的聚合物的制备方法 | |
EP1668062B1 (fr) | Homopolyaminoacides telecheliques fonctionnalises par des groupements hydrophobes et leurs applications notamment therapeutiques | |
US20100029544A1 (en) | Composition | |
CA2408870A1 (fr) | Materiau a base de polymeres biodegradables et son procede de preparation | |
EP1848411A2 (fr) | Copolyhydroxyalkylglutamines fonctionnalises par des groupements hydrophobes et leurs applications notamment therapeutiques | |
WO2007051923A2 (fr) | Acides polyglutamiques fonctionnalises par des derives de l'histidine et des groupements hydrophobes et leurs applications notamment therapeutiques | |
EP2242486A1 (fr) | Encapsulation de la vitamine c dans des dendrimères solubles dans l'eau | |
EP1322296A1 (fr) | Suspension colloidale de particules submicroniques de vectorisation de principes actifs hydrophiles (insuline) et leur mode de preparation | |
FR2761601A1 (fr) | Compositions cosmetiques autobronzantes | |
CA2330498A1 (fr) | Polyetherester sequence non-reticule, sa preparation, et ses utilisations | |
FR3011470A1 (fr) | Composition antifongique comprenant un agent antifongique et du chitosane hydrophobise | |
CN113633785A (zh) | 一种智能响应性壳-核式聚电解质纳米凝胶的制备方法与应用 | |
EP1771498B1 (fr) | Polyaminoacides branches, fonctionnalises par des groupements hydrophobes et leurs applications notamment therapeutiques | |
CA2722050C (fr) | Micelles polymerisees | |
EP3004182A1 (fr) | Microparticules et nanoparticules auto-associatives composées de protéines | |
CN111607101A (zh) | 一种具有活性氧响应性的树状大分子及其制法和用途 | |
Wang et al. | Nanoscale amphiphilic star-like macromolecules with carboxy-, methoxy and amine-terminated chain ends | |
CA2754828A1 (fr) | Procede de preparation de complexes moleculaires entre adapalene et des cyclodextrines |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20100811 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK TR |
|
AX | Request for extension of the european patent |
Extension state: AL BA RS |
|
RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: BOISSELIER, ELODIE Inventor name: RUIZ ARANZAES, JAIME Inventor name: ASTRUC, DIDIER |
|
DAX | Request for extension of the european patent (deleted) | ||
17Q | First examination report despatched |
Effective date: 20111028 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20130801 |