EP0949911A1 - Biodegradable ionic matrix of variable internal polarity with grafted polymer - Google Patents
Biodegradable ionic matrix of variable internal polarity with grafted polymerInfo
- Publication number
- EP0949911A1 EP0949911A1 EP97943009A EP97943009A EP0949911A1 EP 0949911 A1 EP0949911 A1 EP 0949911A1 EP 97943009 A EP97943009 A EP 97943009A EP 97943009 A EP97943009 A EP 97943009A EP 0949911 A1 EP0949911 A1 EP 0949911A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- matrix
- ionic
- matrix according
- molecules
- derivatives
- 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- Withdrawn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
- 239000011159 matrix material Substances 0.000 title claims abstract description 52
- 229920000578 graft copolymer Polymers 0.000 title description 3
- 229920000642 polymer Polymers 0.000 claims abstract description 34
- 230000003993 interaction Effects 0.000 claims abstract description 5
- 150000001720 carbohydrates Chemical class 0.000 claims abstract description 4
- 229920005862 polyol Polymers 0.000 claims abstract description 4
- 150000003077 polyols Chemical class 0.000 claims abstract description 4
- 239000000126 substance Substances 0.000 claims abstract description 4
- 125000003010 ionic group Chemical group 0.000 claims abstract 4
- 229920000768 polyamine Polymers 0.000 claims abstract 3
- 229920001477 hydrophilic polymer Polymers 0.000 claims abstract 2
- 239000000227 bioadhesive Substances 0.000 claims description 11
- 229920002472 Starch Polymers 0.000 claims description 10
- 235000019698 starch Nutrition 0.000 claims description 10
- 125000000129 anionic group Chemical group 0.000 claims description 9
- 239000008107 starch Substances 0.000 claims description 9
- -1 polyoxyethylene Polymers 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 229920000615 alginic acid Polymers 0.000 claims description 6
- 235000010443 alginic acid Nutrition 0.000 claims description 6
- 239000010410 layer Substances 0.000 claims description 5
- 229920001661 Chitosan Polymers 0.000 claims description 4
- 108091034117 Oligonucleotide Proteins 0.000 claims description 4
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 claims description 4
- 230000004071 biological effect Effects 0.000 claims description 4
- 229920001525 carrageenan Polymers 0.000 claims description 4
- 235000010418 carrageenan Nutrition 0.000 claims description 4
- 125000002091 cationic group Chemical group 0.000 claims description 4
- 229920000058 polyacrylate Polymers 0.000 claims description 4
- 210000001519 tissue Anatomy 0.000 claims description 4
- 241000894006 Bacteria Species 0.000 claims description 3
- 238000010521 absorption reaction Methods 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 150000001413 amino acids Chemical class 0.000 claims description 3
- 235000014633 carbohydrates Nutrition 0.000 claims description 3
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 3
- 229930195729 fatty acid Natural products 0.000 claims description 3
- 239000000194 fatty acid Substances 0.000 claims description 3
- 150000004665 fatty acids Chemical class 0.000 claims description 3
- 230000036571 hydration Effects 0.000 claims description 3
- 238000006703 hydration reaction Methods 0.000 claims description 3
- 230000002209 hydrophobic effect Effects 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- WDJUZGPOPHTGOT-OAXVISGBSA-N Digitoxin Natural products O([C@H]1[C@@H](C)O[C@@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@@](C)([C@H](C6=CC(=O)OC6)CC5)CC4)CC3)CC2)C[C@H]1O)[C@H]1O[C@@H](C)[C@H](O[C@H]2O[C@@H](C)[C@@H](O)[C@@H](O)C2)[C@@H](O)C1 WDJUZGPOPHTGOT-OAXVISGBSA-N 0.000 claims description 2
- 102000004190 Enzymes Human genes 0.000 claims description 2
- 108090000790 Enzymes Proteins 0.000 claims description 2
- 241001465754 Metazoa Species 0.000 claims description 2
- 102000016611 Proteoglycans Human genes 0.000 claims description 2
- 108010067787 Proteoglycans Proteins 0.000 claims description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 claims description 2
- 229930182558 Sterol Natural products 0.000 claims description 2
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- 229940035674 anesthetics Drugs 0.000 claims description 2
- 239000003242 anti bacterial agent Substances 0.000 claims description 2
- 230000002686 anti-diuretic effect Effects 0.000 claims description 2
- 230000002421 anti-septic effect Effects 0.000 claims description 2
- 239000000043 antiallergic agent Substances 0.000 claims description 2
- 229940088710 antibiotic agent Drugs 0.000 claims description 2
- 239000000935 antidepressant agent Substances 0.000 claims description 2
- 229940005513 antidepressants Drugs 0.000 claims description 2
- 229940124538 antidiuretic agent Drugs 0.000 claims description 2
- 229940121375 antifungal agent Drugs 0.000 claims description 2
- 239000000739 antihistaminic agent Substances 0.000 claims description 2
- 229940125715 antihistaminic agent Drugs 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 229940041181 antineoplastic drug Drugs 0.000 claims description 2
- 239000003963 antioxidant agent Substances 0.000 claims description 2
- 229940064004 antiseptic throat preparations Drugs 0.000 claims description 2
- 239000003443 antiviral agent Substances 0.000 claims description 2
- 229940121357 antivirals Drugs 0.000 claims description 2
- 229960005274 benzocaine Drugs 0.000 claims description 2
- 239000000496 cardiotonic agent Substances 0.000 claims description 2
- 230000003177 cardiotonic effect Effects 0.000 claims description 2
- 229940039227 diagnostic agent Drugs 0.000 claims description 2
- 239000000032 diagnostic agent Substances 0.000 claims description 2
- WDJUZGPOPHTGOT-XUDUSOBPSA-N digitoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)CC5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O WDJUZGPOPHTGOT-XUDUSOBPSA-N 0.000 claims description 2
- 229960000648 digitoxin Drugs 0.000 claims description 2
- 239000002934 diuretic Substances 0.000 claims description 2
- 229940030606 diuretics Drugs 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- 210000002615 epidermis Anatomy 0.000 claims description 2
- 239000003193 general anesthetic agent Substances 0.000 claims description 2
- 229940088597 hormone Drugs 0.000 claims description 2
- 239000005556 hormone Substances 0.000 claims description 2
- 210000000987 immune system Anatomy 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000002917 insecticide Substances 0.000 claims description 2
- 239000003589 local anesthetic agent Substances 0.000 claims description 2
- 229960005015 local anesthetics Drugs 0.000 claims description 2
- 244000005700 microbiome Species 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 210000000865 mononuclear phagocyte system Anatomy 0.000 claims description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims description 2
- 239000013047 polymeric layer Substances 0.000 claims description 2
- 230000005855 radiation Effects 0.000 claims description 2
- 230000002285 radioactive effect Effects 0.000 claims description 2
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 claims description 2
- 230000003637 steroidlike Effects 0.000 claims description 2
- 150000003432 sterols Chemical class 0.000 claims description 2
- 235000003702 sterols Nutrition 0.000 claims description 2
- 230000010415 tropism Effects 0.000 claims description 2
- 239000005526 vasoconstrictor agent Substances 0.000 claims description 2
- 229940124549 vasodilator Drugs 0.000 claims description 2
- 239000003071 vasodilator agent Substances 0.000 claims description 2
- 239000011782 vitamin Substances 0.000 claims description 2
- 235000013343 vitamin Nutrition 0.000 claims description 2
- 229940088594 vitamin Drugs 0.000 claims description 2
- 229930003231 vitamin Natural products 0.000 claims description 2
- 239000000341 volatile oil Substances 0.000 claims description 2
- 229920000881 Modified starch Polymers 0.000 claims 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims 1
- 239000012190 activator Substances 0.000 claims 1
- 229920006318 anionic polymer Polymers 0.000 claims 1
- 229940124599 anti-inflammatory drug Drugs 0.000 claims 1
- 150000007514 bases Chemical class 0.000 claims 1
- 229920006317 cationic polymer Polymers 0.000 claims 1
- 150000002334 glycols Chemical class 0.000 claims 1
- 150000001261 hydroxy acids Chemical class 0.000 claims 1
- 235000019426 modified starch Nutrition 0.000 claims 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 claims 1
- 150000003180 prostaglandins Chemical class 0.000 claims 1
- 150000003431 steroids Chemical class 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 238000000034 method Methods 0.000 description 24
- 238000003756 stirring Methods 0.000 description 24
- 239000000243 solution Substances 0.000 description 23
- 229920001282 polysaccharide Polymers 0.000 description 18
- 239000005017 polysaccharide Substances 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 17
- 239000002245 particle Substances 0.000 description 16
- 150000004804 polysaccharides Chemical class 0.000 description 16
- 239000013598 vector Substances 0.000 description 16
- 238000010348 incorporation Methods 0.000 description 13
- 239000012153 distilled water Substances 0.000 description 11
- 239000006185 dispersion Substances 0.000 description 10
- 238000000227 grinding Methods 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000004132 cross linking Methods 0.000 description 7
- 239000000178 monomer Substances 0.000 description 7
- 108090000765 processed proteins & peptides Proteins 0.000 description 7
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 6
- 238000010908 decantation Methods 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 102000004196 processed proteins & peptides Human genes 0.000 description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 description 6
- 239000012279 sodium borohydride Substances 0.000 description 6
- 229920001586 anionic polysaccharide Polymers 0.000 description 5
- 150000004836 anionic polysaccharides Chemical class 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N Lactic Acid Natural products CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 230000001588 bifunctional effect Effects 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 238000005342 ion exchange Methods 0.000 description 4
- 229920002521 macromolecule Polymers 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 229920001184 polypeptide Polymers 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 235000000346 sugar Nutrition 0.000 description 4
- 150000008163 sugars Chemical class 0.000 description 4
- 238000004448 titration Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229920002307 Dextran Polymers 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Natural products OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 235000003704 aspartic acid Nutrition 0.000 description 3
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 150000007942 carboxylates Chemical class 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 238000012412 chemical coupling Methods 0.000 description 3
- 238000007385 chemical modification Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000007822 coupling agent Substances 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 238000011068 loading method Methods 0.000 description 3
- 238000002493 microarray Methods 0.000 description 3
- 239000011859 microparticle Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 238000000935 solvent evaporation Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- PUVAFTRIIUSGLK-UHFFFAOYSA-M trimethyl(oxiran-2-ylmethyl)azanium;chloride Chemical class [Cl-].C[N+](C)(C)CC1CO1 PUVAFTRIIUSGLK-UHFFFAOYSA-M 0.000 description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 3
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 101000904173 Homo sapiens Progonadoliberin-1 Proteins 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 239000004100 Oxytetracycline Substances 0.000 description 2
- 239000004952 Polyamide Substances 0.000 description 2
- 102100024028 Progonadoliberin-1 Human genes 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 101000996723 Sus scrofa Gonadotropin-releasing hormone receptor Proteins 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 238000004873 anchoring Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000006065 biodegradation reaction Methods 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 150000001718 carbodiimides Chemical class 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 238000009795 derivation Methods 0.000 description 2
- 150000001991 dicarboxylic acids Chemical class 0.000 description 2
- XLXSAKCOAKORKW-UHFFFAOYSA-N gonadorelin Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 XLXSAKCOAKORKW-UHFFFAOYSA-N 0.000 description 2
- 229920002674 hyaluronan Polymers 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229920005615 natural polymer Polymers 0.000 description 2
- IWVCMVBTMGNXQD-PXOLEDIWSA-N oxytetracycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3[C@H](O)[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-PXOLEDIWSA-N 0.000 description 2
- 229960000625 oxytetracycline Drugs 0.000 description 2
- 235000019366 oxytetracycline Nutrition 0.000 description 2
- 229920002647 polyamide Polymers 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 239000013557 residual solvent Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 239000001384 succinic acid Substances 0.000 description 2
- 229940014800 succinic anhydride Drugs 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- UGHDGJHFWYZFKB-UHFFFAOYSA-N 2-hydroxyethyl-dimethyl-[3-(2-methylprop-2-enoylamino)propyl]azanium chloride Chemical compound [Cl-].CC(=C)C(=O)NCCC[N+](C)(C)CCO UGHDGJHFWYZFKB-UHFFFAOYSA-N 0.000 description 1
- KUDUQBURMYMBIJ-UHFFFAOYSA-N 2-prop-2-enoyloxyethyl prop-2-enoate Chemical class C=CC(=O)OCCOC(=O)C=C KUDUQBURMYMBIJ-UHFFFAOYSA-N 0.000 description 1
- KGIGUEBEKRSTEW-UHFFFAOYSA-N 2-vinylpyridine Chemical compound C=CC1=CC=CC=N1 KGIGUEBEKRSTEW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 102000055006 Calcitonin Human genes 0.000 description 1
- 108060001064 Calcitonin Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000208011 Digitalis Species 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 102000003951 Erythropoietin Human genes 0.000 description 1
- 108090000394 Erythropoietin Proteins 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 102400000321 Glucagon Human genes 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 238000012695 Interfacial polymerization Methods 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 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
- 241000509574 Paradeontacylix buri Species 0.000 description 1
- 229920000148 Polycarbophil calcium Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920000388 Polyphosphate Polymers 0.000 description 1
- 102000005157 Somatostatin Human genes 0.000 description 1
- 108010056088 Somatostatin Proteins 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 231100001259 acute cardiotoxicity Toxicity 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229920000229 biodegradable polyester Polymers 0.000 description 1
- 239000004622 biodegradable polyester Substances 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 239000003152 bradykinin antagonist Substances 0.000 description 1
- 238000012662 bulk polymerization Methods 0.000 description 1
- IRXBNHGNHKNOJI-UHFFFAOYSA-N butanedioyl dichloride Chemical compound ClC(=O)CCC(Cl)=O IRXBNHGNHKNOJI-UHFFFAOYSA-N 0.000 description 1
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 1
- 229960004015 calcitonin Drugs 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000005354 coacervation Methods 0.000 description 1
- 238000007334 copolymerization reaction Methods 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000007720 emulsion polymerization reaction Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- GKIPXFAANLTWBM-UHFFFAOYSA-N epibromohydrin Chemical compound BrCC1CO1 GKIPXFAANLTWBM-UHFFFAOYSA-N 0.000 description 1
- 229940105423 erythropoietin Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- QQNSNWTZOFOAKW-UHFFFAOYSA-N ethanol;trimethylazanium;chloride Chemical compound [Cl-].CCO.C[NH+](C)C QQNSNWTZOFOAKW-UHFFFAOYSA-N 0.000 description 1
- STVZJERGLQHEKB-UHFFFAOYSA-N ethylene glycol dimethacrylate Chemical class CC(=C)C(=O)OCCOC(=O)C(C)=C STVZJERGLQHEKB-UHFFFAOYSA-N 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000001879 gelation Methods 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229960004666 glucagon Drugs 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- YWGHUJQYGPDNKT-UHFFFAOYSA-N hexanoyl chloride Chemical compound CCCCCC(Cl)=O YWGHUJQYGPDNKT-UHFFFAOYSA-N 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000002433 hydrophilic molecules Chemical class 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 150000002734 metacrylic acid derivatives Chemical class 0.000 description 1
- 125000005395 methacrylic acid group Chemical group 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- TWJYXMZUQAMMKA-UHFFFAOYSA-N n,n-dimethyl-1-(oxiran-2-yl)methanamine Chemical class CN(C)CC1CO1 TWJYXMZUQAMMKA-UHFFFAOYSA-N 0.000 description 1
- SDZQEZNDOPDYPP-UHFFFAOYSA-N n,n-dimethylmethanamine;propan-1-amine Chemical compound CCCN.CN(C)C SDZQEZNDOPDYPP-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229960004368 oxytetracycline hydrochloride Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- UCUUFSAXZMGPGH-UHFFFAOYSA-N penta-1,4-dien-3-one Chemical class C=CC(=O)C=C UCUUFSAXZMGPGH-UHFFFAOYSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000002952 polymeric resin Substances 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 239000001205 polyphosphate Substances 0.000 description 1
- 235000011176 polyphosphates Nutrition 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910000679 solder Inorganic materials 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 description 1
- 229960000553 somatostatin Drugs 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 150000003440 styrenes Chemical class 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 239000000057 synthetic resin Substances 0.000 description 1
- 150000003567 thiocyanates Chemical class 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- UIYCHXAGWOYNNA-UHFFFAOYSA-N vinyl sulfide Chemical class C=CSC=C UIYCHXAGWOYNNA-UHFFFAOYSA-N 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
- A61K9/48—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
- A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
-
- 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
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
Definitions
- the present invention describes a new type of biodegradable particulate matrix and the preparation methods relating thereto.
- vector must be understood here in the broad sense, that is to say that it includes particles having a supporting role, for example when they are incorporated in a composition, either as such, or for transport, presentation. and / or the stabilization of active principle.
- vectorization strategies are based on the use of particulate vectors obtained by the techniques of solvent evaporation, emulsion polymerization, or coacervation (patent WO 93.02712). These are the vectors based on polyesters, polyamides, polypeptides, polyacrylates and derivatives, they are also the microparticles of peptide origin, of gelatins, of alginates, of polyamides obtained by gelation or by interfacial polymerization.
- the ideal vector for the internal incorporation of molecules can have the following characteristics: - a particulate structure obtained easily without using conventional and cumbersome techniques to be used, solvent evaporation or gelling or interfacial covalent crosslinking.
- Such a particulate vector must meet a certain number of requirements relating in particular to its payload, its biocompatibility, its non-toxicity and its biodegradability. It must not disturb physiological balances and must not be immunogenic.
- the only vectors that come close to these specifications are the microparticles of lactic / glycolic acid copolymer and the biodegradable ionic matrices.
- the matrix of these microparticles is made up of biodegradable polyesters from lactic acid and glycolic acid, two intermediates of cellular metabolism.
- the biodegradation rate is maximum for a lactic / glycolic ratio of 1/1 by weight.
- These particulate matrices are essentially prepared by the method known to those skilled in the art, called solvent evaporation described in the patent "WO 93-02712" and by "BENOIT in New Pharmaceutical Forms. Technological, Biopharmaceutical and Medical, P. BURI et al coordinators, Editions LAVOISIER Tec & Doc 1985 page 632 ". To obtain an internal charge to the particle with this type of technology, it is necessary to incorporate the active principle with the polymer from the initial phase of dispersion in organic solvent.
- the solubility of the active ingredient in the organic solvent determines the maximum capacity for incorporation into the particle.
- This process involves the presence of the active ingredient throughout the particle synthesis process, which is detrimental for radioactive and / or toxic products.
- the release of the active principle depends on the rate of biodegradation of the particle but also on the solubilization or diffusion properties of the molecule, therefore on its physical state. In practice, for many molecules, the release rate is not constant over time and turns out to be quite long, which limits the use of this type of vector.
- this technology does not allow the industrial preparation of particles smaller than 200 nm, which considerably restricts therapeutic applications and particularly limits the possibilities of parenteral administration. Finally, those skilled in the art know that it is impossible with this synthesis technique to completely eliminate the residual traces of solvent, which remains problematic.
- Biodegradable ionic matrices also called ion exchange resins, are constituted by a hydrophilic, swellable three-dimensional network, not soluble in water and derived by ionic functions giving them an ion exchange capacity generally between 0 , 1 and 10 mEq / g.
- Synthetic exchange resins are obtained by polymerization or copolymerization, in emulsion or reverse emulsion, of monomers comprising ionic functions, as described in patent WO 93/07862.
- the characteristics of these resins such as the size, the porosity of the ionic matrix, the ion exchange capacity, the swelling rate are controlled by the various parameters of the synthesis process such as the amount of water, the speed of agitation, the amount and type of solvent, the amount, type and concentration of the monomers.
- the monomers commonly used are:
- the unsaturated monoethylenic monomers such as styrenes, styrenes sulfonates, vinyl derivatives, acrylic and methacrylic esters.
- Unsaturated monoethylenic monomers with a protonable or basic function including vinyl-pyridine and its derivatives, derived acrylates and derived methacrylates such as acetate or methacrylamidopropylhydroxyethyl-dimethylammonium chloride.
- Unsaturated polyethylene monomers including ethylene glycol diacrylates, ethylene glycol dimethacrylates, polyvinyl ethylene glycol or glycerol, divinyl ketones, divinyl sulfides, vinyl derivatives with carboxylate or sulfate functions, vinyl derivatives with functions pyridine or ammonium.
- ethylene glycol diacrylates ethylene glycol dimethacrylates
- polyvinyl ethylene glycol or glycerol divinyl ketones
- divinyl sulfides vinyl derivatives with carboxylate or sulfate functions
- vinyl derivatives with functions pyridine or ammonium vinyl derivatives with functions
- Natural polymer resins are generally obtained from polysaccharides derived naturally by ionic functions, for example chitosan, hyaluronic acids, alginates, carrageenans.
- the most widely used technologies are based on the functionalization and crosslinking of biodegradable polysaccharides, for example starch, cellulose or dextran as described in the patent (Fr. 75.17633).
- the matrices thus obtained have ion exchange capacities of between 0.1 and 4 mEq / g.
- Great advantage of this type of polysaccharide matrices is their high capacity for incorporating molecules associated with high biocompatibility and good biodegradability. It should nevertheless be noted that the internal incorporation of weakly hydrophilic compounds is very difficult with this type of matrix.
- the present invention relates to a new type of biodegradable polymeric matrix intended for the transport of molecules and characterized in that the polarity of the ionic matrix can be modulated to allow the internal incorporation of water-soluble or hydrophobic molecules.
- the modulation of the polarity and of the hydrophobicity of the matrix is obtained by the derivation of the hydroxyl functions and / or by the covalent grafting of weakly water-soluble radicals. This substitution, which takes place in a homogeneous manner, can be introduced before, during or after the crosslinking of the polymer.
- the properties of the matrix can therefore be modified by chemical coupling of weakly water-soluble or lipidic reagents, that is to say in particular fatty acids with saturated hydrocarbon chains, straight or branched aliphatic and which comprises from 2 to 30 carbon atoms and preferably from 2 to 12, sterols, fatty amines, hydrophobic amino acids, alkoxy ethers.
- weakly water-soluble or lipidic reagents that is to say in particular fatty acids with saturated hydrocarbon chains, straight or branched aliphatic and which comprises from 2 to 30 carbon atoms and preferably from 2 to 12, sterols, fatty amines, hydrophobic amino acids, alkoxy ethers.
- the reaction is preferably carried out in water which allows maximum swelling of the matrix, added with acetic acid, from 0 to 60% or propionic acid from 0 to 10%.
- the bypass reagent is dispersed in the medium in the form of an emulsion by strong stirring at alkaline pH and at low temperature to avoid hydrolysis of the reagent.
- This new process makes it possible to avoid the use of conventional solvents of polysaccharides and fatty acids such as pyridine, which the person skilled in the art knows that elimination is always difficult, which can limit therapeutic applications.
- the different radicals are preferably grafted using labile bonds of ester type.
- matrices are also characterized in that their surface can be derived non-covalently by polymers after the internal loading of molecules.
- the particle can thus acquire a new character linked to the physicochemical properties of the surface-grafted polymer, for example bioadhesive or non-recognition by the reticuloendothelial system, or tropism for a tissue or activation of the immune system.
- bioadhesive power makes it possible to increase the residence time of the vector, therefore of the active principle at the site of absorption and / or action. It also makes it possible to obtain close contact between the vector and the membrane and to localize the vector in particular areas of the mucous membranes, of the tissues or of the organs chosen. It is therefore advantageous for certain applications to have bioadhesive particles.
- bioadhesive polymers used are of natural or semi-synthetic origin and have many polar groups, a high molecular weight and a very flexible carbon skeleton as described by "JUNGINGER in Pharmaceutical Industry (1991) volume 53 no. ll pl056-1065". They have a great hydration capacity.
- the most widely used polymers are, inter alia, polycarbophiles, alginates, polyacrylates, polyvinyl alcohols. These polymers can be grafted onto the polysaccharide matrix by covalent chemical coupling reactions from hydroxyl groups well known to those skilled in the art. These are techniques based on the use of coupling agents such as epichlorohydrin or bifunctional agents such as diepoxides, dialdehydes, dicarboxylates, diisothiocyanates. It can also be the carbodiimide technique for polymers having a carboxylate function.
- the matrices thus obtained are characterized by the presence of a peripheral layer of bioadhesive polymer of high molecular weight, from 6000 to 50,000 daltons.
- This grafting phase of a surface polymer cannot be carried out after the incorporation step to avoid any risk of chemical modification of the active principle.
- the internal incorporation of molecules is therefore carried out conventionally on matrices already provided with a polymeric covering, which poses many problems because polymers, among other bioadhesives, can interact strongly with certain molecules, in particular molecules of high molecular weight, peptides and polypeptides, charged molecules in general and hinder their incorporation into the matrix. To avoid these difficulties, it is therefore necessary to be able to graft the polymers after the incorporation of the molecules but without the risk of chemical modification.
- the innovative technology developed according to the present invention is characterized in that the polymers are coupled to molecular species called macromolecules allowing grafting onto the charged matrix, by coulombian interactions which are not likely to cause chemical modifications of the molecules of biological interest previously incorporated.
- macromolecules are generally low molecular weight, biodegradable polymers, of natural or synthetic origin, having numerous charges allowing anchoring by Coulomb interactions on the ionic matrix of opposite charge.
- macromolecules are polysaccharides naturally derived by ionic functions, for example chitosan, hyaluronic acids, alginates, carrageenans, polypeptides or functionalized derivatives of biodegradable polysaccharides, for example starch, cellulose or dextran , derivatives of polyglycolic polylactics as well as derivatives of polyacrylates, polymethacrylates and polyphosphates and more generally polymeric macromolecules of size between 5000 daltons and 50,000 daltons, of capacity between 0.2 and 15 mEq / g and having functions, such as hydroxyls or amines, capable of allowing the establishment of covalent bonds with the polymer, for example bioadhesive, by simple chemical reactions.
- ionic functions for example chitosan, hyaluronic acids, alginates, carrageenans, polypeptides or functionalized derivatives of biodegradable polysaccharides, for example starch, cellulose or dextran , derivative
- the polymers can be grafted onto the so-called macromolecular species, by covalent chemical coupling reactions, for example from the hydroxyl groups of the polysaccharides well known to those skilled in the art. These are techniques based on the use of coupling agents such as epichlorohydrin or bifunctional agents such as diepoxides, dialdehydes, dicarboxylates, diisothiocyanates. It can also be the carbodiimide technique for polymers having a carboxylate function.
- the present invention relates to a particulate matrix useful in particular for the transport of molecules with biological activity.
- These particles have a very important stability, a defined size which can be modulated according to the applications by the choice of the crosslinked and functionalized base matrix. They are suitable for the incorporation and transport or vectorization of various synthetic, semi-synthetic, recombinant or natural molecules. These particulate matrices can be used to allow or increase aqueous solubility and dispersibility. They can also be used to obtain a modulation of the modes of release of the molecules in time, to improve the physico-chemical stability of the sensitive molecules, to ensure the transport of the molecules within complex biological systems, eukaryotes or prokaryotes, intended to ensure chemical, photochemical, enzymatic, immunological reactions for pharmaceutical, cosmetological, diagnostic, study and research, fermentation applications. More particularly, the present invention relates to a particulate matrix characterized in that it comprises, in order, from the heart outwards successively:
- hydrophilic internal polymeric layer covering the central core with which it is associated by interactions of various natures, possibly ionic
- the central hydrophilic nucleus can be prepared by various methods well known to those skilled in the art.
- it is a polysaccharide, preferably biodegradable linear or branched, for example starches and their derivatives, cellulose, dextran, polysaccharides naturally derived by ionic functions for example chitosan, acids hyaluronic, alginates, carrageenans
- the ionic matrix is then obtained by crosslinking and derivation by methods well known to those skilled in the art.
- the crosslinking processes can be carried out by the use of coupling agents capable of reacting with the hydroxyl groups of the polysaccharides such as epichlorohydrin, epibromohydrin, bifunctionals such as diepoxides, dialdehydes, dichlorides of dicarboxylic acids, diisothicyanates , mixed anhydrides of dicarboxylic acids.
- the ionic character of the matrix is obtained by using a polymer already derived by ion exchangers or by grafting on neutral polymers of biocompatible and biodegradable ionic ligands, according to methods well known to those skilled in the art.
- the ionic ligands will preferably be chosen from natural molecules present in the body such as succinic acid, citric acid, phosphoric acid, glutamic acid, alanine, glycine.
- the glycidyl-trimethylammonium salts are also used, the glycidyldimethylamine salts.
- Certain basic ligands such as 2 (dimethylamino) ethano 2 (dirnethylamino) ethylamine, 2 (trimethylammonium) ethanol chloride, 3 (trimethylammonium) propylamine are grafted onto the matrix by a bifunctional coupla agent capable of establishing an ester bond or amide.
- succinic acid for coupling to the polysaccharide matrix, succinic acid, phosphorus oxychloride, thiocyanates and diepoxides are used.
- the grafting of the ion exchange functions can be carried out before, during or after the crosslinking step.
- the ionized matrix can be obtained in the form of particles by several methods.
- the first consists in mechanically grinding the gel obtained by mass polymerization.
- the second technique consists in directly producing the matrix in the form of particles by the polymerization technique in dispersion in a liquid immiscible with the reaction phase.
- These particles can be used for the administration of molecules by the oral per lingual, nasal, vaginal, rectal, cutaneous, ocular but also pulmonary and parenteral routes. They can also be used for any topical application.
- These new active principle vehicles are capable of encapsulating a large number of molecules with biological activity such as:
- cardiotonics such as digitoxin and digitalis and its derivatives - vasodilators
- This gel is taken up in 2 liters of water and the pH is adjusted to 5 by adding 2N HCl. The gel is then washed four times in 5 liters of distilled water. We obtain a matrix whose capacity, determined by titration is 1 positive charge for 4 sugars.
- Example 4 Preparation of crosslinked polysaccharide matrices which are weakly hydrophilic and functionalized with succinic acid:
- micromatrices by grinding the canonical matrices: 100 grams of gel prepared according to Example 1 are taken up in 5 liters of water and ground using an Ultraturrax turbine for 7 minutes at 4000 rpm. The micromatrices obtained have a size of between 5 and 25 microns.
- Example 6 Preparation of the micromatrices by grinding the anionic matrices:
- micromatrices obtained have a size of between 15 and 50 microns.
- micromatrices by grinding the matrices ionized by phosphate: 100 grams of gel prepared according to example 3 are taken up in 5 liters of water and ground using an Ultraturrax turbine for 7 minutes at 4000 rpm. The micromatrices obtained have a size of between 0.5 and 5 microns.
- micromatrices obtained have a size of between 50 and 500 microns.
- nanomatrices by grinding the anionic matrices: 100 grams of gel prepared according to Example 2 are taken up in 6 liters of water and ground using an Ultraturrax turbine for 3 minutes at 4000 rpm. This dispersion is then homogenized using a high pressure homogenizer of the Microfluidizer type at 100 bars. The nanomatrices obtained have a size between 50 and 150 nanometers.
- Example 11 Preparation of the nanomatrices by grinding the anionic matrices:
- nanomatrices by grinding the anionic matrices: 100 grams of gel prepared according to Example 4 are taken up in 8 liters of water and ground using an Ultraturrax turbine for 3 minutes at 4000 rpm. This dispersion is then homogenized using a high pressure homogenizer of the Microfluidizer type at 1200 bars. The nanomatrices obtained have a size between 150 and 500 nanometers.
- Example 14 according to the invention:
- Example 15 Ionic anchoring of a polymer derived by an anionic polysaccharide on cationic matrices:
- anionic micromatrices prepared according to example 9 are dispersed in 250 ml of distilled water.
- 10 grams of polymers derived from an anionic polysaccharide according to Example 14 are dispersed in 500 ml of distilled water.
- the microarray dispersion is then added slowly with stirring to the bioadhesive polymer solution. After 2 hours of stirring, the matrices covered with polymer are recovered by decantation and then washed twice with 2 liters of distilled water. 54 grams of cationic matrices with bioadhesive properties are thus obtained.
- Example 17 Loading of aspartic acid in cationic matrices:
- the polymer prepared according to Example 14 is anchored to the matrices prepared according to Example 16, following the process described according to Example 1.
Abstract
The invention concerns a particulate biodegradable matrix comprising: a biodegradable and hydrophilic core with a base of a carbohydrate or polyol or polyamine matrix, cross-linked and derived in the mass by variable amounts of ionic groups; a hydrophilic polymer layer, associated to the central core by chemical, for example ionic, interaction; surface molecules or polymers grafted on the external polymer layer by covalent bonds.
Description
MATRICE IONIQUE BIODÉGRADABLE DE POLARITÉ INTERNE MODULABLE À POLYMÈRE GREFFÉ MODULATED BIODEGRADABLE INTERNAL POLARITY ION MATRIX WITH GRAFTED POLYMER
La présente invention décrit un nouveau type de matrice particulaire biodégradable et les méthodes de préparation s'y reportant.The present invention describes a new type of biodegradable particulate matrix and the preparation methods relating thereto.
Aussi bien dans le domaine pharmaceutique que cosmétologique, l'emploi de nombreux principes actifs reste délicat et ne peut être envisagé que par la mise en place de stratégies de vectorisation. Pour faire pénétrer et réagir un composé à l'intérieur d'un système biologique ou biochimique, il existe un certain nombre de procédés. Il est parfois nécessaire de disposer de vecteur particulaire dans lequel le principe actif est incorporé afin d'en modifier le comportement.Both in the pharmaceutical and cosmetological fields, the use of numerous active ingredients remains delicate and can only be envisaged by the implementation of vectorization strategies. To make a compound penetrate and react inside a biological or biochemical system, there are a number of methods. It is sometimes necessary to have a particulate vector in which the active principle is incorporated in order to modify its behavior.
Ainsi l'incorporation dans un vecteur permet :Thus incorporation into a vector allows:
- de modifier la biodistribution de composés présentant une toxicité marquée pour un tissu - de modifier le mode de libération et le temps de résidence au site d'administration et/ou d'action- to modify the biodistribution of compounds having a marked toxicity for a tissue - to modify the mode of release and the time of residence at the site of administration and / or action
- d'améliorer la faible solubilité de certaines molécules dans les milieux physiologiques- to improve the low solubility of certain molecules in physiological media
- d'apporter une certaine protection et augmenter la demi-vie de la molécule incorporée dans le cas de composés ayant une demi vie trop faible dans l'organisme ou dans des systèmes biologiques ou biochimiques.- to provide a certain protection and to increase the half-life of the incorporated molecule in the case of compounds having a half-life which is too low in the organism or in biological or biochemical systems.
La notion de vecteur doit ici être entendue au sens large, c'est à dire qu'elle comprend des particules ayant un rôle de support, par exemple quand elles sont incorporées dans une composition, soit telles quelles, soit pour le transport, la présentation et/ou la stabilisation de principe actif. Ces stratégies de vectorisation sont basées sur l'utilisation de vecteurs particulaires obtenus par les techniques d'évaporation de solvant, de polymérisation en émulsion, ou coacervation (brevet WO 93.02712). Ce sont les vecteurs à base de polyesters, polyamides, polypeptides, polyacrylates et dérivés, ce sont aussi les microparticules d'origine peptidique, de gélatines, d'alginates, de polyamides obtenues par gélification ou par polymérisation interfaciale. Toutes ces techniques sont bien connues de l'homme de l'art. Elles sont discutées dans "Dossier Bioencapsulation, Biofutur, 1994 n° 132 p 1545". Ces vecteurs sont pour la plupart difficilement industrialisables et restent onéreux. Il faut souligner que les techniques d'évaporation conduisent à des vecteurs contenant des traces de solvants résiduels et présentent pour certains une toxicité non nulle. Enfin, on distingue les liposomes très utilisés en cosmétologie et pour lesquels apparaissent les premières applications pharmaceutiques mais dont la stabilité physico-chimique est toujours limitée.The concept of vector must be understood here in the broad sense, that is to say that it includes particles having a supporting role, for example when they are incorporated in a composition, either as such, or for transport, presentation. and / or the stabilization of active principle. These vectorization strategies are based on the use of particulate vectors obtained by the techniques of solvent evaporation, emulsion polymerization, or coacervation (patent WO 93.02712). These are the vectors based on polyesters, polyamides, polypeptides, polyacrylates and derivatives, they are also the microparticles of peptide origin, of gelatins, of alginates, of polyamides obtained by gelation or by interfacial polymerization. All of these techniques are well known to those skilled in the art. They are discussed in "Dossier Bioencapsulation, Biofutur, 1994 n ° 132 p 1545". These vectors are for the most part difficult to industrialize and remain expensive. It should be emphasized that evaporation techniques lead to vectors containing traces of residual solvents and for some have non-zero toxicity. Finally, a distinction is made between the liposomes widely used in cosmetology and for which the first pharmaceutical applications appear but whose physicochemical stability is always limited.
Ces différents types de technologies ont permis d'obtenir quelques résultats intéressants dans la résolution de certains problèmes de biodistribution et de pharmacocinétique. Ainsi des
formes de LHRH à libération prolongée ont été mises au point à partir de particules de copolymère polylactique/glycolique. Enfin des formes liposomales de Doxorubicine, qui sont caractérisées par une biodistribution modifiée permettent d'éviter le phénomène de cardiotoxicité aiguë comme décrit par "Bally et al. Cancer Chemotherapy and Pharmacology (1990) n°27 pl3-19" "Vaage et al, International Journal of Cancer (1992) n°51 p 942-948". Cependant, pour de nombreuses molécules, il n'existe pas de vecteur particulaire possédant une bonne capacité d'incorporation, modulable et facilement industrialisable.These different types of technology have made it possible to obtain some interesting results in the resolution of certain problems of biodistribution and pharmacokinetics. So LHRH sustained release forms have been developed from polylactic / glycolic copolymer particles. Finally, liposomal forms of Doxorubicin, which are characterized by a modified biodistribution, make it possible to avoid the phenomenon of acute cardiotoxicity as described by "Bally et al. Cancer Chemotherapy and Pharmacology (1990) n ° 27 pl3-19""Vaage et al, International Journal of Cancer (1992) n ° 51 p 942-948 ". However, for many molecules, there is no particulate vector having good incorporation capacity, which is modular and easily industrializable.
Le vecteur idéal permettant l'incorporation interne de molécules peut présenter les caractères suivants : - une structure particulaire obtenue aisément sans faire appel aux techniques classiques et lourdes à mettre en oeuvre, d'évaporation de solvant ou de gélification ou de réticulation covalente interfaciale.The ideal vector for the internal incorporation of molecules can have the following characteristics: - a particulate structure obtained easily without using conventional and cumbersome techniques to be used, solvent evaporation or gelling or interfacial covalent crosslinking.
- une capacité importante d'incorporation interne de molécules, suivie d'une bonne dispersabilité en milieu aqueux. - une stabilité d'incorporation élevée- a significant capacity for internal incorporation of molecules, followed by good dispersibility in an aqueous medium. - high incorporation stability
- une facilité de contrôle et de modulation des paramètres de libération.- ease of control and modulation of the release parameters.
- une facilité de dérivatisation de surface sans risque de modification de la structure du principe actif.- ease of surface derivatization without risk of modification of the structure of the active principle.
Un tel vecteur particulaire doit satisfaire à un certain nombre d'exigences touchant notamment à sa charge utile, sa biocompatibilité, sa non toxicité et sa biodégradabilité. Il ne doit pas perturber les équilibres physiologiques et ne doit pas être immunogène.Such a particulate vector must meet a certain number of requirements relating in particular to its payload, its biocompatibility, its non-toxicity and its biodegradability. It must not disturb physiological balances and must not be immunogenic.
Les seuls vecteurs qui se rapprochent de ce cahier des charges sont les microparticules de copolymère d'acide lactique/glycolique et les matrices ioniques biodégradables.The only vectors that come close to these specifications are the microparticles of lactic / glycolic acid copolymer and the biodegradable ionic matrices.
La matrice de ces microparticules est constituée de polyesters biodégradables issus de l'acide lactique et l'acide glycolique, deux intermédiaires du métabolisme cellulaire. La vitesse de biodégradation est maximale pour un rapport lactique/glycolique de 1/1 en poids. Ces matrices particulaires sont essentiellement préparées par la méthode connue de l'homme de l'art, dite de l'évaporation en solvant décrite dans le brevet "WO 93-02712" et par "BENOIT dans Formes Pharmaceutiques Nouvelles. Aspects Technologique, Biopharmaceutique et Médical, P. BURI et al coordonnateurs, Editions LAVOISIER Tec & Doc 1985 page 632". Pour obtenir un chargement interne à la particule avec ce type de technologie, il est nécessaire d'incorporer le principe actif avec le polymère dès la phase initiale de dispersion en solvant organique. La solubilité du principe actif dans le solvant organique détermine la capacité maximale d'incorporation dans la particule. Ce procédé implique la présence du principe actif tout au long du procédé de synthèse des particules, ce qui est pénalisant pour les produits radioactifs et/ou toxiques. Pour ce type de vecteur, la libération du principe actif dépend de la vitesse de biodégradation de la particule mais aussi des propriétés de solubilisation ou de diffusion de la molécule, donc de son état physique.
En pratique, pour de nombreuses molécule, la vitesse de libération n'est pas constante au cours du temps et s'avère assez longue, ce qui limite l'utilisation de ce type de vecteur. Concernant le contrôle de la taille des particules, cette technologie ne permet pas la préparation industrielle de particules de taille inférieure à 200 nm, ce qui restreint considérablement les applications thérapeutiques et limite particulièrement les possibilités d'administration parentérale. Enfin l'homme de l'art sait qu'il est impossible avec cette technique de synthèse, d'éliminer totalement les traces résiduelles de solvant, ce qui reste problématique.The matrix of these microparticles is made up of biodegradable polyesters from lactic acid and glycolic acid, two intermediates of cellular metabolism. The biodegradation rate is maximum for a lactic / glycolic ratio of 1/1 by weight. These particulate matrices are essentially prepared by the method known to those skilled in the art, called solvent evaporation described in the patent "WO 93-02712" and by "BENOIT in New Pharmaceutical Forms. Technological, Biopharmaceutical and Medical, P. BURI et al coordinators, Editions LAVOISIER Tec & Doc 1985 page 632 ". To obtain an internal charge to the particle with this type of technology, it is necessary to incorporate the active principle with the polymer from the initial phase of dispersion in organic solvent. The solubility of the active ingredient in the organic solvent determines the maximum capacity for incorporation into the particle. This process involves the presence of the active ingredient throughout the particle synthesis process, which is detrimental for radioactive and / or toxic products. For this type of vector, the release of the active principle depends on the rate of biodegradation of the particle but also on the solubilization or diffusion properties of the molecule, therefore on its physical state. In practice, for many molecules, the release rate is not constant over time and turns out to be quite long, which limits the use of this type of vector. Regarding the control of particle size, this technology does not allow the industrial preparation of particles smaller than 200 nm, which considerably restricts therapeutic applications and particularly limits the possibilities of parenteral administration. Finally, those skilled in the art know that it is impossible with this synthesis technique to completely eliminate the residual traces of solvent, which remains problematic.
Les matrices ioniques biodégradables, encore appelées résines d'échange d'ions sont constituées par un réseau tridimensionnel hydrophile, gonflable, non soluble dans l'eau et dérivé par des fonctions ioniques leur conférant une capacité d'échange d'ions généralement comprise entre 0,1 et 10 mEq/g.Biodegradable ionic matrices, also called ion exchange resins, are constituted by a hydrophilic, swellable three-dimensional network, not soluble in water and derived by ionic functions giving them an ion exchange capacity generally between 0 , 1 and 10 mEq / g.
On distingue principalement deux familles de résines : les résines synthétiques et les résines obtenues à partir de polymères naturels et/ou dérivés.There are mainly two families of resins: synthetic resins and resins obtained from natural polymers and / or derivatives.
Les résines échangeuses synthétiques sont obtenues par polymérisation ou copolymérisation, en émulsion ou émulsion inverse, de monomères comportant des fonctions ioniques, tel que décrit dans le brevet WO 93/07862. Les caractères de ces résines comme la taille, la porosité de la matrice ionique, la capacité d'échange d'ions, le taux de gonflement sont contrôlés par les différents paramètres du procédé de synthèse comme la quantité d'eau, la vitesse d'agitation, la quantité et le type de solvant, la quantité, le type et la concentration des monomères. Les monomères couramment utilisés sont :Synthetic exchange resins are obtained by polymerization or copolymerization, in emulsion or reverse emulsion, of monomers comprising ionic functions, as described in patent WO 93/07862. The characteristics of these resins such as the size, the porosity of the ionic matrix, the ion exchange capacity, the swelling rate are controlled by the various parameters of the synthesis process such as the amount of water, the speed of agitation, the amount and type of solvent, the amount, type and concentration of the monomers. The monomers commonly used are:
- Les monomères monoéthylèniques insaturés comme les styrènes, les styrènes sulfonates, les dérivés vinyliques, les esters acryliques et méthacryliques. Les monomères monoéthylèniques insaturés à fonction protonable ou basique incluant la vinyl-pyridine et ses dérivés, les acrylates dérivés et les méthacrylates dérivés comme l'acétate ou le chlorure de méthacrylamidopropylhydroxyethyl-diméthylammonium.- The unsaturated monoethylenic monomers such as styrenes, styrenes sulfonates, vinyl derivatives, acrylic and methacrylic esters. Unsaturated monoethylenic monomers with a protonable or basic function including vinyl-pyridine and its derivatives, derived acrylates and derived methacrylates such as acetate or methacrylamidopropylhydroxyethyl-dimethylammonium chloride.
- Les monomères polyéthylèniques insaturés incluant les diacrylates d'éthylène glycol, les diméthacrylates d'éthylène glycol, les polyvinyles d'éthylène glycol ou de glycérol, les divinylcétones, les divinylsulfides, les dérivés vinyliques à fonctions carboxylates ou sulfates, les dérivés vinyliques à fonctions pyridine ou ammonium. Cependant, l'emploi de ces polymères reste délicat en raison de leur biodégradabilité limitée ou nulle. Enfin, on ne peut pas éliminer totalement, dans l'état des techniques, les traces de solvants résiduels et de monomères résiduels ce qui peut induire des problèmes de toxicité.- Unsaturated polyethylene monomers including ethylene glycol diacrylates, ethylene glycol dimethacrylates, polyvinyl ethylene glycol or glycerol, divinyl ketones, divinyl sulfides, vinyl derivatives with carboxylate or sulfate functions, vinyl derivatives with functions pyridine or ammonium. However, the use of these polymers remains delicate because of their limited or zero biodegradability. Finally, the traces of residual solvents and residual monomers cannot be completely eliminated in the prior art, which can cause toxicity problems.
Les résines de polymère naturel sont généralement obtenues à partir de polysaccharides dérivés naturellement par des fonctions ioniques, par exemple le chitosane, les acides hyaluroniques, les alginates, les carraghénanes. Les technologies les plus usitées sont basées sur la fonctionnalisation et la réticulation de polysaccharides biodégradables, par exemple l'amidon, la cellulose ou le dextrane tel que décrit dans le brevet (Fr. 75.17633). Les matrices ainsi obtenues ont des capacités d'échange d'ions comprise entre 0.1 et 4 mEq/g. Le grand
avantage de ce type de matrices polysaccharidiques est leur grande capacité d'incorporation de molécules associée à une grande biocompatibilité et une bonne biodégradabilité. Il faut néanmoins noter que l'incorporation interne de composés faiblement hydrophiles est très difficile avec ce type de matrice. La présente invention concerne un nouveau type de matrice polymérique biodégradable destinée au transport de molécules et caractérisée en ce que la polarité de la matrice ionique peut être modulée pour permettre l'incorporation interne de molécules hydrosolubles on hydrophobes. La modulation de la polarité et de i'hydrophobie de la matrice est obtenue par la dérivation des fonctions hydroxyles et/ou par le greffage covalent de radicaux faiblement hydrosolubles. Cette substitution qui a lieu de manière homogène, peut être introduite avant, pendant ou après la réticulation du polymère. Les propriétés de la matrice peuvent donc être modifiées par couplage chimique de réactifs faiblement hydrosolubles ou lipidiques, c'est à dire notamment des acides gras à chaînes hydrocarbonées saturées, aliphatiques droites ou ramifiées et qui comprend de 2 à 30 atomes de carbones et de préférence de 2 à 12, des stérols, des aminés grasses, des acides aminés hydrophobes, des alkoxyéthers. Si ces réactions de greffage sont bien connues de l'homme de l'art, le procédé selon l'invention apporte une modification intéressante dans un mode de mise en oeuvre préféré en effectuant la réaction dans un milieu protique solvant de la matrice mais non solvant des molécules lipidiques. Ceci permet de limiter l'emploi des solvants organiques habituellement utilisés. Il a été trouvé que la réaction est réalisée préférentiellement dans l'eau qui permet un gonflement maximum de la matrice, additionnée d'acide acétique, de 0 à 60% ou d'acide propionique de 0 à 10%. Le réactif de dérivation est dispersé dans le milieu sous la forme d'une émulsion par agitation forte à pH alcalin et à basse température pour éviter l'hydrolyse du réactif. Ce nouveau procédé permet d'éviter l'emploi des solvants classiques des polysaccharides et des acides gras comme la pyridine, dont l'homme de l'art sait que l'élimination est toujours difficile, ce qui peut limiter les applications thérapeutiques. Pour maintenir une bonne dégradabilité de la matrice, les différents radicaux sont greffés préférentiellement à l'aide de liaisons labiles de type ester.Natural polymer resins are generally obtained from polysaccharides derived naturally by ionic functions, for example chitosan, hyaluronic acids, alginates, carrageenans. The most widely used technologies are based on the functionalization and crosslinking of biodegradable polysaccharides, for example starch, cellulose or dextran as described in the patent (Fr. 75.17633). The matrices thus obtained have ion exchange capacities of between 0.1 and 4 mEq / g. Great advantage of this type of polysaccharide matrices is their high capacity for incorporating molecules associated with high biocompatibility and good biodegradability. It should nevertheless be noted that the internal incorporation of weakly hydrophilic compounds is very difficult with this type of matrix. The present invention relates to a new type of biodegradable polymeric matrix intended for the transport of molecules and characterized in that the polarity of the ionic matrix can be modulated to allow the internal incorporation of water-soluble or hydrophobic molecules. The modulation of the polarity and of the hydrophobicity of the matrix is obtained by the derivation of the hydroxyl functions and / or by the covalent grafting of weakly water-soluble radicals. This substitution, which takes place in a homogeneous manner, can be introduced before, during or after the crosslinking of the polymer. The properties of the matrix can therefore be modified by chemical coupling of weakly water-soluble or lipidic reagents, that is to say in particular fatty acids with saturated hydrocarbon chains, straight or branched aliphatic and which comprises from 2 to 30 carbon atoms and preferably from 2 to 12, sterols, fatty amines, hydrophobic amino acids, alkoxy ethers. If these grafting reactions are well known to those skilled in the art, the method according to the invention provides an advantageous modification in a preferred embodiment by carrying out the reaction in a protic medium which is solvent for the matrix but not solvent. lipid molecules. This makes it possible to limit the use of the organic solvents usually used. It has been found that the reaction is preferably carried out in water which allows maximum swelling of the matrix, added with acetic acid, from 0 to 60% or propionic acid from 0 to 10%. The bypass reagent is dispersed in the medium in the form of an emulsion by strong stirring at alkaline pH and at low temperature to avoid hydrolysis of the reagent. This new process makes it possible to avoid the use of conventional solvents of polysaccharides and fatty acids such as pyridine, which the person skilled in the art knows that elimination is always difficult, which can limit therapeutic applications. To maintain good degradability of the matrix, the different radicals are preferably grafted using labile bonds of ester type.
Ces matrices sont aussi caractérisées en ce que leur surface peut être dérivée de façon non covalente par des polymères après le chargement interne de molécules. La particule peut ainsi acquérir un caractère nouveau lié aux propriétés physicochimiques du polymère greffé en surface, par exemple bioadhésif ou de non reconnaissance par le système réticuloendothélial, ou de tropisme pour un tissu ou d'activation du système immunitaire.These matrices are also characterized in that their surface can be derived non-covalently by polymers after the internal loading of molecules. The particle can thus acquire a new character linked to the physicochemical properties of the surface-grafted polymer, for example bioadhesive or non-recognition by the reticuloendothelial system, or tropism for a tissue or activation of the immune system.
Conférer un pouvoir bioadhésif permet d'augmenter le temps de résidence du vecteur, donc du principe actif au site d'absorption et/ou d'action. Il permet aussi d'obtenir un contact étroit entre le vecteur et la membrane et de localiser le vecteur dans des zones particulières des muqueuses, des tissus ou des organes choisis. Il est donc intéressant pour certaines applications de disposer de particules bioadhésives. Classiquement, les polymères bioadhésifs
utilisés sont d'origine naturelle ou semi-synthétique et présentent de nombreux groupes polaires, un poids moléculaire élevé et un squelette carboné très flexible comme décrit par "JUNGINGER in Pharmaceutical Industry (1991 ) volume 53 n°l l pl056- 1065". Ils sont dotés d'une grande capacité d'hydratation. Les polymères les plus utilisés sont entre autres les polycarbophiles, les alginates, les polyacrylates, les polyvinylalcools. Ces polymères peuvent être greffés sur la matrice polysaccharidique par des réactions de couplage chimique covalent à partir des groupements hydroxyles bien connues de l'homme de l'art. Ce sont des techniques basées sur l'emploi d'agents couplants comme l'épichlorhydrine ou bifonctionnels comme les diépoxydes, les dialdéhydes, les dicarboxylates, les diisothiocyanates. Ce peut être aussi la technique au carbodiimide pour les polymères possédant une fonction carboxylate. Les matrices ainsi obtenues sont caractérisées par la présence d'une couche périphérique de polymère bioadhésif de poids moléculaire élevé, de 6000 à 50 000 daltons.Giving a bioadhesive power makes it possible to increase the residence time of the vector, therefore of the active principle at the site of absorption and / or action. It also makes it possible to obtain close contact between the vector and the membrane and to localize the vector in particular areas of the mucous membranes, of the tissues or of the organs chosen. It is therefore advantageous for certain applications to have bioadhesive particles. Conventionally, bioadhesive polymers used are of natural or semi-synthetic origin and have many polar groups, a high molecular weight and a very flexible carbon skeleton as described by "JUNGINGER in Pharmaceutical Industry (1991) volume 53 no. ll pl056-1065". They have a great hydration capacity. The most widely used polymers are, inter alia, polycarbophiles, alginates, polyacrylates, polyvinyl alcohols. These polymers can be grafted onto the polysaccharide matrix by covalent chemical coupling reactions from hydroxyl groups well known to those skilled in the art. These are techniques based on the use of coupling agents such as epichlorohydrin or bifunctional agents such as diepoxides, dialdehydes, dicarboxylates, diisothiocyanates. It can also be the carbodiimide technique for polymers having a carboxylate function. The matrices thus obtained are characterized by the presence of a peripheral layer of bioadhesive polymer of high molecular weight, from 6000 to 50,000 daltons.
Cette phase de greffage d'un polymère en surface ne peut pas être réalisée après l'étape d'incorporation pour éviter tout risque de modification chimique du principe actif. L'incorporation interne des molécules est donc réalisée classiquement sur les matrices déjà dotées d'une couverture polymérique ce qui pose de nombreux problèmes car les polymères entre autres bioadhésifs, peuvent interagir fortement avec certaines molécules, en particulier les molécules de haut poids moléculaire, les peptides et polypeptides, les molécules chargées en général et gêner leur incorporation dans la matrice. Pour éviter ces difficultés, il est donc nécessaire de pouvoir greffer les polymères après l'incorporation des molécules mais sans risque de modification chimique. La technologie innovante développée selon la présente invention est caractérisée en ce que les polymères sont couplés à des espèces moléculaires dites macromolécules permettant le greffage sur la matrice chargée, par des interactions coulombiennes qui ne sont pas susceptibles d'entraîner des modifications chimiques des molécules d'intérêt biologique préalablement incorporées. Ces macromolécules sont généralement des polymères de bas poids moléculaire, biodégradables, d'origine naturelle ou synthétique, présentant de nombreuses charges permettant l'ancrage par interactions coulombiennes sur la matrice ionique de charge opposée. On distingue principalement comme macromolécules les polysaccharides dérivés naturellement par des fonctions ioniques, par exemple le chitosane, les acides hyaluroniques, les alginates, les carraghénanes, des polypeptides ou les dérivés fonctionnalisés de polysaccharides biodégradables, par exemple l'amidon, la cellulose ou le dextrane, les dérivés de polylactiques polyglycoliques ainsi que les dérivés de polyacrylates, de polyméthacrylates et de polyphosphates et plus généralement les macromolécules polymériques de taille comprise entre 5000 daltons et 50 000 daltons, de capacité comprise entre 0,2 et 15 mEq/g et présentant des fonctions, comme les hydroxyles ou les aminés, susceptibles de permettre l'établissement de liaisons covalentes avec le polymère par exemple bioadhésif par des réactions chimiques simples.
Les polymères peuvent être greffés sur les espèces dites macromoléculaires, par des réactions de couplage chimique covalent par exemple à partir des groupements hydroxyles des polysaccharides bien connues de l'homme de l'art. Ce sont les techniques basées sur l'emploi d'agents couplants comme l'épichlorhydrine ou bifonctionnels comme les diépoxydes, les dialdéhydes, les dicarboxylates, les diisothiocyanates. Ce peut être aussi la technique au carbodiimide pour les polymères possédant une fonction carboxylate.This grafting phase of a surface polymer cannot be carried out after the incorporation step to avoid any risk of chemical modification of the active principle. The internal incorporation of molecules is therefore carried out conventionally on matrices already provided with a polymeric covering, which poses many problems because polymers, among other bioadhesives, can interact strongly with certain molecules, in particular molecules of high molecular weight, peptides and polypeptides, charged molecules in general and hinder their incorporation into the matrix. To avoid these difficulties, it is therefore necessary to be able to graft the polymers after the incorporation of the molecules but without the risk of chemical modification. The innovative technology developed according to the present invention is characterized in that the polymers are coupled to molecular species called macromolecules allowing grafting onto the charged matrix, by coulombian interactions which are not likely to cause chemical modifications of the molecules of biological interest previously incorporated. These macromolecules are generally low molecular weight, biodegradable polymers, of natural or synthetic origin, having numerous charges allowing anchoring by Coulomb interactions on the ionic matrix of opposite charge. The main differences between macromolecules are polysaccharides naturally derived by ionic functions, for example chitosan, hyaluronic acids, alginates, carrageenans, polypeptides or functionalized derivatives of biodegradable polysaccharides, for example starch, cellulose or dextran , derivatives of polyglycolic polylactics as well as derivatives of polyacrylates, polymethacrylates and polyphosphates and more generally polymeric macromolecules of size between 5000 daltons and 50,000 daltons, of capacity between 0.2 and 15 mEq / g and having functions, such as hydroxyls or amines, capable of allowing the establishment of covalent bonds with the polymer, for example bioadhesive, by simple chemical reactions. The polymers can be grafted onto the so-called macromolecular species, by covalent chemical coupling reactions, for example from the hydroxyl groups of the polysaccharides well known to those skilled in the art. These are techniques based on the use of coupling agents such as epichlorohydrin or bifunctional agents such as diepoxides, dialdehydes, dicarboxylates, diisothiocyanates. It can also be the carbodiimide technique for polymers having a carboxylate function.
Plus particulièrement la présente invention concerne une matrice particulaire utile notamment pour le transport de molécules à activité biologique.More particularly the present invention relates to a particulate matrix useful in particular for the transport of molecules with biological activity.
Ces particules présentent une stabilité très importante, une taille définie qui peut être modulée en fonction des applications par le choix de la matrice réticulée et fonctionnalisée de base. Elles sont aptes à l'incorporation et au transport ou vectorisation, de molécules diverses synthétiques, hémisynthétiques, recombinantes ou naturelles. Ces matrices particulaires peuvent être utilisées pour permettre ou accroître la solubilité et la dispersabilité aqueuses. Elles peuvent être aussi utilisées pour obtenir une modulation des modes de libération des molécules dans le temps, pour améliorer la stabilité physico-chimique des molécules sensibles, pour assurer le transport des molécules au sein de systèmes biologiques complexes, eucaryotes ou procaryotes, destinés à assurer des réactions chimiques, photochimiques, enzymatiques, immunologiques pour des applications pharmaceutiques, cosmétologiques, diagnostiques, d'étude et de recherche, de fermentation. Plus particulièrement, la présente invention concerne une matrice particulaire caractérisée en ce qu'elle comporte dans l'ordre, du coeur vers l'extérieur successivement :These particles have a very important stability, a defined size which can be modulated according to the applications by the choice of the crosslinked and functionalized base matrix. They are suitable for the incorporation and transport or vectorization of various synthetic, semi-synthetic, recombinant or natural molecules. These particulate matrices can be used to allow or increase aqueous solubility and dispersibility. They can also be used to obtain a modulation of the modes of release of the molecules in time, to improve the physico-chemical stability of the sensitive molecules, to ensure the transport of the molecules within complex biological systems, eukaryotes or prokaryotes, intended to ensure chemical, photochemical, enzymatic, immunological reactions for pharmaceutical, cosmetological, diagnostic, study and research, fermentation applications. More particularly, the present invention relates to a particulate matrix characterized in that it comprises, in order, from the heart outwards successively:
- un noyau ionique interne à base d'hydrates de carbone ou de polyols réticulés, hydrophile non liquide et biodégradable, de polarité interne modulable- an internal ionic nucleus based on carbohydrates or crosslinked polyols, non-liquid and biodegradable hydrophilic, with modular internal polarity
- une couche polymérique interne hydrophile, recouvrant le noyau central auquel elle est associée par des interactions de diverses natures, éventuellement ioniques- a hydrophilic internal polymeric layer, covering the central core with which it is associated by interactions of various natures, possibly ionic
- des molécules ou des polymères de surface greffés sur la couche polymérique interne par des liaisons covalentes.- molecules or surface polymers grafted onto the internal polymer layer by covalent bonds.
Le noyau hydrophile central peut être préparé par différentes méthodes bien connues de l'homme de l'art. En particulier lorsqu'il s'agit d'un polysaccharide, de préférence biodégradable linéaire ou ramifié, par exemple d'amidons et leurs dérivés, de cellulose, de dextrane, de polysaccharides dérivés naturellement par des fonctions ioniques par exemple le chitosane, les acides hyaluroniques, les alginates, les carraghénanes, la matrice ionique est alors obtenue par réticulation et dérivation par des procédés bien connus de l'homme de l'art. Les procédés de réticulation peuvent être effectués par l'utilisation d'agents couplants capables de réagir avec les groupements hydroxyles des polysaccharides comme l'épichlorhydrine, l'épibromohydrine, bifonctionnels comme les diépoxydes, les dialdéhydes, les dichlorures d'acides dicarboxyliques, les diisothicyanates, les anhydrides mixtes d'acides dicarboxyliques.
Le caractère ionique de la matrice est obtenu en utilisant un polymère déjà dérivé par d échangeurs d'ions ou en réalisant le greffage sur des polymères neutres de ligands ioniqu biocompatibles et biodégradables, selon des procédés bien connus de l'homme de l'art. L ligands ioniques seront préférentiellement choisis parmi les molécules naturelles présent dans l'organisme comme l'acide succinique, l'acide citrique, l'acide phosphorique, l'aci glutamique, l'alanine, la glycine. On utilise aussi les sels de glycidyl-triméthylammonium, l sels de glycidyldiméthylamine. Certains ligands basiques comme le 2(diméthylamino)éthano le 2(dirnéthylamino)éthylamine, le chlorure de 2(triméthylammonium)éthanol, 3(triméthylammonium)propylamine sont greffés sur la matrice par un agent de coupla bifonctionnel capable d'établir une liaison ester ou amide. On utilise préférentiellement pour couplage sur la matrice polysaccharidique l'acide succinique, l'oxychlorure de phosphore, l thiocyanates, les diépoxydes. Le greffage des fonctions échangeuses d'ions peut être effect avant, durant ou après l'étape de réticulation.The central hydrophilic nucleus can be prepared by various methods well known to those skilled in the art. In particular when it is a polysaccharide, preferably biodegradable linear or branched, for example starches and their derivatives, cellulose, dextran, polysaccharides naturally derived by ionic functions for example chitosan, acids hyaluronic, alginates, carrageenans, the ionic matrix is then obtained by crosslinking and derivation by methods well known to those skilled in the art. The crosslinking processes can be carried out by the use of coupling agents capable of reacting with the hydroxyl groups of the polysaccharides such as epichlorohydrin, epibromohydrin, bifunctionals such as diepoxides, dialdehydes, dichlorides of dicarboxylic acids, diisothicyanates , mixed anhydrides of dicarboxylic acids. The ionic character of the matrix is obtained by using a polymer already derived by ion exchangers or by grafting on neutral polymers of biocompatible and biodegradable ionic ligands, according to methods well known to those skilled in the art. The ionic ligands will preferably be chosen from natural molecules present in the body such as succinic acid, citric acid, phosphoric acid, glutamic acid, alanine, glycine. The glycidyl-trimethylammonium salts are also used, the glycidyldimethylamine salts. Certain basic ligands such as 2 (dimethylamino) ethano 2 (dirnethylamino) ethylamine, 2 (trimethylammonium) ethanol chloride, 3 (trimethylammonium) propylamine are grafted onto the matrix by a bifunctional coupla agent capable of establishing an ester bond or amide. Preferably, for coupling to the polysaccharide matrix, succinic acid, phosphorus oxychloride, thiocyanates and diepoxides are used. The grafting of the ion exchange functions can be carried out before, during or after the crosslinking step.
La matrice ionisée peut être obtenue sous la forme de particules par plusieurs procédés. L premier consiste à broyer mécaniquement le gel obtenu par polymérisation en masse. L seconde technique consiste à réaliser directement la matrice sous forme de particules par l technique de polymérisation en dispersion dans un liquide non miscible avec la phas réactionnelle.The ionized matrix can be obtained in the form of particles by several methods. The first consists in mechanically grinding the gel obtained by mass polymerization. The second technique consists in directly producing the matrix in the form of particles by the polymerization technique in dispersion in a liquid immiscible with the reaction phase.
Ces particules peuvent être utilisées pour l'administration de molécules par les voies oral per linguale, nasale, vaginale, rectale, cutanée, oculaire mais aussi pulmonaire et parentéral Elles peuvent être aussi utilisées pour toute application topique. Ces nouveaux véhicules d principe actif sont capables d'encapsuler un grand nombre de molécules à activité biologiqu comme :These particles can be used for the administration of molecules by the oral per lingual, nasal, vaginal, rectal, cutaneous, ocular but also pulmonary and parenteral routes. They can also be used for any topical application. These new active principle vehicles are capable of encapsulating a large number of molecules with biological activity such as:
- les peptides et leurs dérivés, le glucagon, la somatostatine, la calcitonine, l'interféron et le interleukines, la LHRH, l'érythropoïétine, les antagonistes de la bradykinine, les polypeptide ainsi que les recombinants issus des biotechnologies- peptides and their derivatives, glucagon, somatostatin, calcitonin, interferon and interleukins, LHRH, erythropoietin, bradykinin antagonists, polypeptides as well as recombinants from biotechnology
- les anticorps- antibodies
- les protéoglycanes- proteoglycans
- les anticancéreux - les antibiotiques- anticancer drugs - antibiotics
- les antiviraux, et en particulier les analogues d'oligonucléotides et les inhibiteurs de l transcriptase inverse- antivirals, and in particular oligonucleotide analogs and reverse transcriptase inhibitors
- les antiprotéases- antiproteases
- les insecticides et antifongiques - les oligonucléotides, ADN et éléments de génome- insecticides and antifungals - oligonucleotides, DNA and genome elements
- les anesthésiques et anesthésiques locaux comme la benzocaïne- local anesthetics and anesthetics such as benzocaine
- les vasoconstricteurs- vasoconstrictors
- les cardiotoniques comme la digitoxine et la digitaline et ses dérivés
- les vasodilatateurs- cardiotonics such as digitoxin and digitalis and its derivatives - vasodilators
- les diurétiques et antidiurétiques- diuretics and antidiuretics
- les neuroleptiques- neuroleptics
- les antidépresseurs - les hormones et dérivés- antidepressants - hormones and derivatives
- les anti-inflammatoires stéroïdiens et non stéroïdiens- steroidal and nonsteroidal anti-inflammatory drugs
- les antihistaminiques- antihistamines
- les agents anti-allergiques- anti-allergic agents
- les antiseptiques- antiseptics
- les agents de diagnostic- diagnostic agents
- les vitamines- vitamins
- les antioxydants- antioxidants
- les acides aminés et les sels minéraux- amino acids and mineral salts
- les enzymes- enzymes
- les hydroxyacides et les huiles essentielles- hydroxy acids and essential oils
- les molécules à activité d'absorption des rayonnements UV ou d'hydratation de l'épiderme. La plupart des molécules à activité biologique peuvent être incorporées mais aussi les agents chromophores, fluorophores et/ou radiomarqués. Peuvent également être encapsulées les cellules animales et végétales, ainsi que les bactéries, levures et autres micro-organismes. Les domaines d'utilisation de ces particules innovantes sont très étendus aussi bien pour les applications pharmaceutiques, cosmétiques et d'hygiène qu'en biotechnologie, agroalimentaire, diagnostic et environnement.- molecules with absorption activity of UV radiation or hydration of the epidermis. Most molecules with biological activity can be incorporated, but also chromophoric, fluorophoric and / or radiolabelled agents. Can also be encapsulated animal and plant cells, as well as bacteria, yeasts and other microorganisms. The fields of use of these innovative particles are very wide as well for pharmaceutical, cosmetic and hygiene applications as in biotechnology, food industry, diagnostics and environment.
On comprendra mieux la présente invention et ses nombreux avantages en se référant aux cas particuliers suivants, donnés à titre d'exemple et qui ne sauraient en aucune façon limiter ladite invention. Toutes les parties indiquées dans les exemples sont des parties en volume et tous les pourcentages sont des pourcentages en poids.The present invention and its numerous advantages will be better understood by referring to the following particular cases, given by way of example and which in no way limit said invention. All the parts indicated in the examples are parts by volume and all the percentages are percentages by weight.
Exemple 1 selon l'invention :Example 1 according to the invention:
Préparation des matrices polysaccharidiques réticulées et cationiques : Dans un réacteur de 2,5 litres, on disperse 100 grammes d'amidon ayant un poids moléculaire d'environ 10 000 dans 300 ml d'eau contenant 1 gramme de borohydrure de sodium. Après 2 heures d'agitation, on ajoute 100 ml d'une solution de soude 4N. Lorsque la solution est homogène on ajoute 32 ml d'une solution aqueuse de chlorure de (2,3 époxypropyl)triméthylammonium à 75%. Après deux heures d'agitation, on ajoute 7 ml d'épichlorhydrine en maintenant l'agitation pendant encore 4 heures. La solution est alors laissée au repos pendant 40 heures. On obtient un gel translucide et cassant. Ce gel est repris dans 2 litres d'eau et le pH est ajusté à 5 par addition d'HCl 2N. Le gel est ensuite lavé quatre fois dans 5 litres d'eau distillée. On obtient une matrice dont la capacité, déterminée par titrage
est de 1 charge positive pour 4 sucres.Preparation of crosslinked and cationic polysaccharide matrices: In a 2.5 liter reactor, 100 grams of starch having a molecular weight of approximately 10,000 are dispersed in 300 ml of water containing 1 gram of sodium borohydride. After 2 hours of stirring, 100 ml of a 4N sodium hydroxide solution are added. When the solution is homogeneous, 32 ml of a 75% aqueous solution of (2,3 epoxypropyl) trimethylammonium chloride are added. After two hours of stirring, 7 ml of epichlorohydrin are added while stirring is continued for a further 4 hours. The solution is then left to stand for 40 hours. A translucent and brittle gel is obtained. This gel is taken up in 2 liters of water and the pH is adjusted to 5 by adding 2N HCl. The gel is then washed four times in 5 liters of distilled water. We obtain a matrix whose capacity, determined by titration is 1 positive charge for 4 sugars.
Exemple 2 selon l'invention :Example 2 according to the invention:
Préparation des matrices polysaccharidiques réticulées et anioniques : Dans un réacteur de 2,5 litres, on disperse 100 grammes d'amidon ayant un poid moléculaire d'environ 10 000 dans 300 ml d'eau contenant 1 gramme de borohydrure d sodium. Après 2 heures d'agitation, on ajoute 20 ml d'une solution de soude 0,2 N et on port la température à -1°C. Lorsque la solution est homogène on ajoute progressivement de faço concomitante 55 grammes de dichlorure d'acide succinique et 200 ml d'une solution de soud 4N en maintenant la température à -1°C. Après 4 heures d'agitation, le pH est ajusté à 5 pa addition d'HCl 2N. Le gel est ensuite lavé par décantation quatre fois dans 5 litres d'ea distillée. On obtient une matrice anionique réticulée par le succinate dont la capacité déterminé par titrage, est de 1 charge négative pour 4 sucres.Preparation of crosslinked and anionic polysaccharide matrices: In a 2.5 liter reactor, 100 grams of starch having a molecular weight of approximately 10,000 are dispersed in 300 ml of water containing 1 gram of sodium borohydride. After 2 hours of stirring, 20 ml of a 0.2 N sodium hydroxide solution are added and the temperature is brought to -1 ° C. When the solution is homogeneous, 55 grams of succinic acid dichloride and 200 ml of a 4N solder solution are gradually added concomitantly while maintaining the temperature at -1 ° C. After 4 hours of stirring, the pH is adjusted to 5 pa addition of 2N HCl. The gel is then washed by decantation four times in 5 liters of distilled water. An anionic matrix crosslinked with succinate is obtained, the capacity of which, determined by titration, is 1 negative charge for 4 sugars.
Exemple 3 selon l'invention :Example 3 according to the invention:
Préparation de matrices polysaccharidiques réticulées fonctionnalisées par l'acide phosphorique :Preparation of crosslinked polysaccharide matrices functionalized with phosphoric acid:
Dans un réacteur de 2,5 litres, on disperse 100 grammes d'amidon ayant un poids moléculaire d'environ 10000 dans 300 ml de NaCl 0.5M contenant 1 gramme de borohydrure de sodium. Après 2 heures d'agitation, on ajoute 20 ml d'une solution de soude 4N et on porte la température à 3°C. Lorsque la solution est homogène, on ajoute progressivement et en même temps 56 ml d'oxychlorure de phosphore et 500 ml d'une solution de soude 6N tout en maintenant la température à 3°C. Après 4 heures d'agitation, la solution est laissée au repos pendant 20 heures. On obtient un gel réticulé translucide. Ce gel est repris dans 2 litres d'eau et le pH est ajusté à 5 par addition d'HCl 2N. Le gel est ensuite lavé quatre fois dans 5 litres d'eau distillée. On obtient une matrice anionique dont la capacité déterminée par titrage, est de 1 charge négative pour 3 sucres.In a 2.5 liter reactor, 100 grams of starch having a molecular weight of approximately 10,000 are dispersed in 300 ml of 0.5M NaCl containing 1 gram of sodium borohydride. After 2 hours of stirring, 20 ml of a 4N sodium hydroxide solution are added and the temperature is brought to 3 ° C. When the solution is homogeneous, 56 ml of phosphorus oxychloride and 500 ml of a 6N sodium hydroxide solution are gradually added at the same time while maintaining the temperature at 3 ° C. After 4 hours of stirring, the solution is left to stand for 20 hours. A translucent crosslinked gel is obtained. This gel is taken up in 2 liters of water and the pH is adjusted to 5 by adding 2N HCl. The gel is then washed four times in 5 liters of distilled water. An anionic matrix is obtained, the capacity of which, determined by titration, is 1 negative charge for 3 sugars.
Exemple 4 selon l'invention : Préparation de matrices polysaccharidiques réticulées faiblement hydrophiles et fonctionnalisées par l'acide succinique :Example 4 according to the invention: Preparation of crosslinked polysaccharide matrices which are weakly hydrophilic and functionalized with succinic acid:
Dans un réacteur de 2,5 litres, on disperse 100 grammes d'amidon ayant un poids moléculaire d'environ 10 000 dans 300 ml d'eau contenant 1 gramme de borohydrure de sodium. Après 2 heures d'agitation on ajoute 100 ml d'une solution de soude 4N. Lorsque la solution est homogène on ajoute 6 ml d'épichlorhydrine en maintenant l'agitation pendant encore 4 heures. La solution est alors laissée au repos pendant 40 heures. On obtient un gel translucide et cassant. Ce gel est lavé dans 2 litres d'eau et le pH est ajusté à 6,8 par addition d'HCl 2N. Le gel est ensuite récupéré par décantation. Le gel est alors refroidi à 0°C et le pH
ajusté à 9 par une solution de NaOH 0,2N. Puis sous agitation on ajoute lentement 60 ml de solution de chlorure d'acide hexanoïque à 30% dans l'acide propionique en maintenant le pH constant à 9 puis 30 grammes d'anhydride succinique. A la fin de l'addition des réactifs, l'agitation est maintenue pendant 2 heures. Le gel est alors lavé par décantation quatre fois dans 2 litres d'eau distillée. On obtient une matrice faiblement hydrophile dérivée par l'acide succinique dont la capacité, déterminée par titrage, est de 1 charge pour 8 sucres.In a 2.5 liter reactor, 100 grams of starch having a molecular weight of about 10,000 are dispersed in 300 ml of water containing 1 gram of sodium borohydride. After 2 hours of stirring, 100 ml of a 4N sodium hydroxide solution are added. When the solution is homogeneous, 6 ml of epichlorohydrin are added while stirring is continued for a further 4 hours. The solution is then left to stand for 40 hours. A translucent and brittle gel is obtained. This gel is washed in 2 liters of water and the pH is adjusted to 6.8 by addition of 2N HCl. The gel is then recovered by decantation. The gel is then cooled to 0 ° C and the pH adjusted to 9 with a 0.2N NaOH solution. Then, with stirring, 60 ml of 30% hexanoic acid chloride solution in propionic acid are slowly added while keeping the pH constant at 9 and then 30 grams of succinic anhydride. At the end of the addition of the reagents, stirring is continued for 2 hours. The gel is then washed by decantation four times in 2 liters of distilled water. A weakly hydrophilic matrix obtained by succinic acid is obtained, the capacity of which, determined by titration, is 1 charge per 8 sugars.
Exemple 5 selon l'invention :Example 5 according to the invention:
Préparation des micromatrices par broyage des matrices canoniques : 100 grammes de gel préparé selon l'exemple 1, sont repris par 5 litres d'eau et broyés à l'aide d'une turbine Ultraturrax pendant 7 minutes à 4000 t/min. Les micromatrices obtenues ont une taille comprise entre 5 et 25 microns.Preparation of the micromatrices by grinding the canonical matrices: 100 grams of gel prepared according to Example 1 are taken up in 5 liters of water and ground using an Ultraturrax turbine for 7 minutes at 4000 rpm. The micromatrices obtained have a size of between 5 and 25 microns.
Exemple 6 selon l'invention : Préparation des micromatrices par broyage des matrices anioniques :Example 6 according to the invention: Preparation of the micromatrices by grinding the anionic matrices:
100 grammes de gel préparé selon l'exemple 2 sont repris par 5 litres d'eau et broyés à l'aide d'une turbine Ultraturrax pendant 7 minutes à 4000 t/min. Les micromatrices obtenues ont une taille comprise entre 15 et 50 microns.100 grams of gel prepared according to Example 2 are taken up in 5 liters of water and ground using an Ultraturrax turbine for 7 minutes at 4000 rpm. The micromatrices obtained have a size of between 15 and 50 microns.
Exemple 7 selon l'invention :Example 7 according to the invention:
Préparation des micromatrices par broyage des matrices ionisées par le phosphate : 100 grammes de gel préparé selon l'exemple 3 sont repris par 5 litres d'eau et broyés à l'aide d'une turbine Ultraturrax pendant 7 minutes à 4000 t/min. Les micromatrices obtenues ont une taille comprise entre 0,5 et 5 microns.Preparation of the micromatrices by grinding the matrices ionized by phosphate: 100 grams of gel prepared according to example 3 are taken up in 5 liters of water and ground using an Ultraturrax turbine for 7 minutes at 4000 rpm. The micromatrices obtained have a size of between 0.5 and 5 microns.
Exemple 8 selon l'invention :Example 8 according to the invention:
Préparation des micromatrices par broyage des matrices dérivées et ionisées par le succinate :Preparation of microarrays by grinding the matrices derived and ionized by succinate:
100 grammes de gel préparé selon l'exemple 4 sont repris par 5 litres d'eau et broyés à l'aide d'une turbine Ultraturrax pendant 7 minutes à 4000 t/min. Les micromatrices obtenues ont une taille comprise entre 50 et 500 microns.100 grams of gel prepared according to Example 4 are taken up in 5 liters of water and ground using an Ultraturrax turbine for 7 minutes at 4000 rpm. The micromatrices obtained have a size of between 50 and 500 microns.
Exemple 9 selon l'invention :Example 9 according to the invention:
Préparation des nanomatrices par broyage des matrices canoniques : 100 grammes de gel préparé selon l'exemple 1 sont repris par 10 litres d'eau et broyés à l'aide d'une turbine Ultraturrax pendant 3 minutes à 4000 t/min. Cette dispersion est alors homogénéisée à l'aide d'un homogénéisateur haute pression de type Microfluidizer à 1200 bars. Les nanomatrices obtenues ont une taille comprise entre 50 et 150 nanomètres.
Exemple 10 selon l'invention :Preparation of the nanomatrices by grinding the canonical matrices: 100 grams of gel prepared according to example 1 are taken up in 10 liters of water and ground using an Ultraturrax turbine for 3 minutes at 4000 rpm. This dispersion is then homogenized using a high pressure homogenizer of the Microfluidizer type at 1200 bars. The nanomatrices obtained have a size between 50 and 150 nanometers. Example 10 according to the invention:
Préparation des nanomatrices par broyage des matrices anioniques : 100 grammes de gel préparé selon l'exemple 2 sont repris par 6 litres d'eau et broyés l'aide d'une turbine Ultraturrax pendant 3 minutes à 4000 t/min. Cette dispersion est alor homogénéisée à l'aide d'un homogénéisateur haute pression de type Microfluidizer à 100 bars. Les nanomatrices obtenues ont une taille comprise entre 50 et 150 nanomètres.Preparation of the nanomatrices by grinding the anionic matrices: 100 grams of gel prepared according to Example 2 are taken up in 6 liters of water and ground using an Ultraturrax turbine for 3 minutes at 4000 rpm. This dispersion is then homogenized using a high pressure homogenizer of the Microfluidizer type at 100 bars. The nanomatrices obtained have a size between 50 and 150 nanometers.
Exemple 11 selon l'invention : Préparation des nanomatrices par broyage des matrices anioniques :Example 11 according to the invention: Preparation of the nanomatrices by grinding the anionic matrices:
100 grammes de gel préparé selon l'exemple 3 sont repris par 8 litres d'eau et broyés l'aide d'une turbine Ultraturrax pendant 3 minutes à 4000 t/min. Cette dispersion est alor homogénéisée à l'aide d'un homogénéisateur haute pression de type Microfluidizer à 10 bars. Les nanomatrices obtenues ont une taille comprise entre 50 et 1 0 nanomètres.100 grams of gel prepared according to Example 3 are taken up in 8 liters of water and ground using an Ultraturrax turbine for 3 minutes at 4000 rpm. This dispersion is then homogenized using a high pressure homogenizer of the Microfluidizer type at 10 bar. The nanomatrices obtained have a size between 50 and 10 nanometers.
Exemple 12 selon l'invention :Example 12 according to the invention:
Préparation des nanomatrices par broyage des matrices anioniques : 100 grammes de gel préparé selon l'exemple 4 sont repris par 8 litres d'eau et broyés à l'aide d'une turbine Ultraturrax pendant 3 minutes à 4000 t/min. Cette dispersion est alors homogénéisée à l'aide d'un homogénéisateur haute pression de type Microfluidizer à 1200 bars. Les nanomatrices obtenues ont une taille comprise entre 150 et 500 nanomètres.Preparation of the nanomatrices by grinding the anionic matrices: 100 grams of gel prepared according to Example 4 are taken up in 8 liters of water and ground using an Ultraturrax turbine for 3 minutes at 4000 rpm. This dispersion is then homogenized using a high pressure homogenizer of the Microfluidizer type at 1200 bars. The nanomatrices obtained have a size between 150 and 500 nanometers.
Exemple 13 selon l'invention :Example 13 according to the invention:
Préparation des matrices polysaccharidiques réticulées, cationiques par réticulation en émulsion :Preparation of crosslinked, cationic polysaccharide matrices by crosslinking in emulsion:
Dans un réacteur de 2,5 litres, on disperse 100 grammes d'amidon ayant un poids moléculaire d'environ 10 000 dans 300 ml d'eau contenant 1 gramme de borohydrure de sodium. Après 2 heures d'agitation, on ajoute 100 ml d'une solution de soude 4N. Lorsque la solution est homogène, on ajoute 32 ml d'une solution aqueuse de chlorure de (2,3époxypropyl) triméthylammonium à 75%. Après deux heures d'agitation, on ajoute 5 ml d'épichlorhydrine en maintenant l'agitation. La solution est dispersée dans deux litres de dichlorométhane sous agitation suffisante pour obtenir une dispersion de la phase aqueuse sous la forme de gouttelettes de taille comprise entre 50 et 500 microns. La dispersion est maintenue sous agitation à température ambiante pendant 14 heures. La dispersion est alors filtrée et les matrices sphériques reprises dans 2 litres d'éthanol 50% et le pH est ajusté à 5 par addition d'HCl 2N. Elles sont ensuite lavées 2 fois dans 5 litres d'éthanol 20% puis 2 fois dans 5 litres d'eau distillée à 50°C.
Exemple 14 selon l'invention:In a 2.5 liter reactor, 100 grams of starch having a molecular weight of about 10,000 are dispersed in 300 ml of water containing 1 gram of sodium borohydride. After 2 hours of stirring, 100 ml of a 4N sodium hydroxide solution are added. When the solution is homogeneous, 32 ml of a 75% aqueous solution of (2,3epoxypropyl) trimethylammonium chloride are added. After two hours of stirring, 5 ml of epichlorohydrin is added while stirring is continued. The solution is dispersed in two liters of dichloromethane with sufficient stirring to obtain a dispersion of the aqueous phase in the form of droplets of size between 50 and 500 microns. The dispersion is stirred at room temperature for 14 hours. The dispersion is then filtered and the spherical matrices taken up in 2 liters of 50% ethanol and the pH is adjusted to 5 by addition of 2N HCl. They are then washed twice in 5 liters of 20% ethanol and then twice in 5 liters of distilled water at 50 ° C. Example 14 according to the invention:
Préparation d'un polymère greffé sur un polysaccharide anionique :Preparation of a polymer grafted onto an anionic polysaccharide:
Dans un réacteur de 2,5 litres, on disperse 50 grammes d'amidon ayant un poids moléculaire d'environ 10 000 dans 200 ml d'eau contenant lg de borohydrure de sodium. Après 2 heures d'agitation, on ajoute 100 ml d'une solution de soude 4N. Lorsque la solution est homogène, on ajoute 25 grammes d'anhydride succinique. Après 2 heures d'agitation, on ajoute 150 grammes de 2-3 époxypropyléther d'hydroxypropylcellulose et on maintient sous agitation pendant 6 heures. La solution est alors laissée au repos pendant 30 heures. On obtient un gel translucide. Ce gel est repris dans 2 litres d'eau et le pH est ajusté à 5 par addition de HCl 2N. Le gel est ensuite lavé quatre fois dans 5 litres d'eau distillée par ultrafiltration. On obtient un polysaccharide anionique dérivé par l'hydroxypropylcellulose séché par lyophilisation.In a 2.5 liter reactor, 50 grams of starch having a molecular weight of about 10,000 are dispersed in 200 ml of water containing 1 g of sodium borohydride. After 2 hours of stirring, 100 ml of a 4N sodium hydroxide solution are added. When the solution is homogeneous, 25 grams of succinic anhydride are added. After 2 hours of stirring, 150 grams of 2-3 hydroxypropylcellulose epoxypropyl ether are added and stirring is continued for 6 hours. The solution is then left to stand for 30 hours. A translucent gel is obtained. This gel is taken up in 2 liters of water and the pH is adjusted to 5 by addition of 2N HCl. The gel is then washed four times in 5 liters of distilled water by ultrafiltration. An anionic polysaccharide derived from hydroxypropylcellulose dried by lyophilization is obtained.
Exemple 15 selon l'invention : Ancrage ionique d'un polymère dérivé par un polysaccharide anionique sur des matrices cationiques :Example 15 according to the invention: Ionic anchoring of a polymer derived by an anionic polysaccharide on cationic matrices:
50 grammes de micromatrices anioniques préparés selon l'exemple 9 sont dispersées dans 250 ml d'eau distillée. Parallèlement 10 grammes de polymères dérivés par un polysaccharide anionique selon l'exemple 14 sont dispersés dans 500 ml d'eau distillée. La dispersion de micromatrices est alors ajoutée lentement sous agitation à la solution de polymère bioadhésif. Après 2 heures d'agitation, les matrices recouvertes de polymère sont récupérées par décantation puis lavées 2 fois par 2 litres d'eau distillée. On obtient ainsi 54 grammes de matrices cationiques dotées de propriétés bioadhésives.50 grams of anionic micromatrices prepared according to example 9 are dispersed in 250 ml of distilled water. In parallel, 10 grams of polymers derived from an anionic polysaccharide according to Example 14 are dispersed in 500 ml of distilled water. The microarray dispersion is then added slowly with stirring to the bioadhesive polymer solution. After 2 hours of stirring, the matrices covered with polymer are recovered by decantation and then washed twice with 2 liters of distilled water. 54 grams of cationic matrices with bioadhesive properties are thus obtained.
Exemple 16 selon l'invention :Example 16 according to the invention:
Chargement de l'oxytétracycline dans les matrices anioniques :Loading of oxytetracycline in anionic matrices:
Dans un réacteur de 1 litre, 300 ml d'une solution de chlorhydrate d'oxytétracycline à 10% sont ajoutés lentement et sous agitation à 20 grammes de matrice polysaccharidique dérivée par le phosphate selon l'exemple 3, sous forme sèche lyophilisée. L'agitation est maintenue pendant 4 heures à température ambiante. Les matrices sont alors récupérées par décantation puis lavées 4 fois par 500 ml d'eau distillée. On récupère 28 grammes de matrice chargée à 40% d'oxytétracycline.In a 1 liter reactor, 300 ml of a 10% oxytetracycline hydrochloride solution are added slowly and with stirring to 20 grams of phosphate-derived polysaccharide matrix according to Example 3, in lyophilized dry form. Stirring is continued for 4 hours at room temperature. The matrices are then recovered by decantation and then washed 4 times with 500 ml of distilled water. 28 grams of matrix loaded with 40% oxytetracycline are recovered.
Exemple 17 selon l'invention : Chargement de l'acide aspartique dans les matrices cationiques :Example 17 according to the invention: Loading of aspartic acid in cationic matrices:
Dans un réacteur de 1 litre, 10 grammes d'acide aspartique sont mélangés à 20 grammes de matrice polysaccharidiques dérivée par le phosphate selon l'exemple 3, sous forme sèche lyophilisée. Le mélange est réhydraté lentement sous agitation par addition de 400ml d'eau
distillée à température ambiante. L'agitation est maintenue pendant 2 heures après réhydratation complète. Les particules de matrice sont alors récupérées par décantation puis lavées 4 fois par 500 ml d'eau distillée. On récupère 22 grammes de matrice chargée à 20% d'acide aspartique.In a 1 liter reactor, 10 grams of aspartic acid are mixed with 20 grams of polysaccharide matrix derived by phosphate according to Example 3, in dry lyophilized form. The mixture is rehydrated slowly with stirring by the addition of 400 ml of water distilled at room temperature. Agitation is maintained for 2 hours after complete rehydration. The matrix particles are then recovered by decantation and then washed 4 times with 500 ml of distilled water. 22 grams of matrix loaded with 20% aspartic acid are recovered.
Exemple 18 selon l'invention :Example 18 according to the invention:
Préparation de micromatrices contenant un principe actif et dérivées superficiellement par un polymère bioadhésif :Preparation of microarrays containing an active principle and derived surface by a bioadhesive polymer:
Le polymère préparé selon l'exemple 14, est ancré sur les matrices préparées selon l'exemple 16, en suivant le procédé décrit selon l'exemple 1 .
The polymer prepared according to Example 14 is anchored to the matrices prepared according to Example 16, following the process described according to Example 1.
Claims
R E V E N D I C A T I O N SR E V E N D I C A T I O N S
1 - Matrice particulaire biodégradable caractérisée en ce qu'elle comporte :1 - Biodegradable particulate matrix characterized in that it comprises:
- un noyau hydrophile et biodégradable à base d'une matrice d'hydrate de carbone ou de polyols ou de polyamines, réticulée et dérivée dans la masse par des taux variables de groupements ioniques- a hydrophilic and biodegradable core based on a matrix of carbohydrate or polyols or polyamines, crosslinked and derived in the mass by variable rates of ionic groups
- une couche polymérique hydrophile, associée au noyau central par des interactions chimiques, par exemple ioniques- a hydrophilic polymer layer, associated with the central nucleus by chemical interactions, for example ionic
- des molécules ou des polymères de surface greffés sur la couche polymérique externe par des liaisons covalentes.- molecules or surface polymers grafted onto the external polymeric layer by covalent bonds.
2 - Matrice particulaire selon la revendication 1 , caractérisée en ce qu'elle comporte un noyau non liquide et biodégradable à base d'une matrice d'hydrates de carbone ou de polyols ou de polyamines, réticulée et dérivée dans la masse par des taux variables de groupements ioniques et/ou lipophiles. 3 - Matrice particulaire selon la revendication 1 ou 2, caractérisée en ce que les groupements ioniques greffées sur la matrice sont des composés acides.2 - Particulate matrix according to claim 1, characterized in that it comprises a non-liquid and biodegradable core based on a matrix of carbohydrates or polyols or polyamines, crosslinked and derived in the mass by variable rates ionic and / or lipophilic groups. 3 - Particulate matrix according to claim 1 or 2, characterized in that the ionic groups grafted onto the matrix are acidic compounds.
4 - Matrice particulaire selon la revendication 1 ou 2, caractérisée en ce que les groupements ioniques greffés sur la matrice sont des composés basiques.4 - Particulate matrix according to claim 1 or 2, characterized in that the ionic groups grafted onto the matrix are basic compounds.
5 - Matrice selon l'une quelconque des revendications de 2 à 4, caractérisée en ce que le groupement lipophile greffé sur la matrice ionique est choisi parmi les acides gras à un taux variable ou parmi les polyoxyéthylèneglycols, les aminés grasses, les acides aminés hydrophobes, les stérols, les alkoxyéthers, et leurs mélanges.5 - Matrix according to any one of claims 2 to 4, characterized in that the lipophilic group grafted onto the ionic matrix is chosen from fatty acids at a variable rate or from polyoxyethylene glycols, fatty amines, hydrophobic amino acids , sterols, alkoxy ethers, and mixtures thereof.
6 - Matrice selon la revendication 3, caractérisée en ce que la couche de polymère associée au noyau anionique est choisie parmi des polymères cationiques d'origine naturelle ou dérivée, comme le chitosane ou les dérivés à groupements basiques de l'amidon.6 - Matrix according to claim 3, characterized in that the polymer layer associated with the anionic nucleus is chosen from cationic polymers of natural or derived origin, such as chitosan or derivatives with basic groups of starch.
7 - Matrice particulaire selon la revendication 4, caractérisée en ce que la couche de polymère associée au noyau cationique est choisie parmi des polymères anioniques naturels, dérivés ou synthétiques comme les alginates, les carraghénanes, les polyacrylates et les dérivés d'amidon à groupements acides. 8 - Matrice selon l'une quelconque des revendications de 1 à 7, caractérisée en ce que les polymères ou les molécules externes greffés sur le polymère associé au noyau, sont bioadhésifs ou furtifs vis-à-vis du système réticuloendothélial ou possèdent un tropisme pour un tissu ou sont activateurs du système immunitaire.7 - particulate matrix according to claim 4, characterized in that the polymer layer associated with the cationic nucleus is chosen from natural anionic polymers, derivatives or synthetics such as alginates, carrageenans, polyacrylates and starch derivatives with acid groups . 8 - Matrix according to any one of claims from 1 to 7, characterized in that the polymers or external molecules grafted onto the polymer associated with the nucleus, are bioadhesive or stealthy vis-à-vis the reticuloendothelial system or have a tropism for tissue or are activators of the immune system.
9 - Matrice selon l'une quelconque des revendications de 1 à 8, caractérisée en ce qu'elle comprend une entité à activité biologique choisie parmi :9 - Matrix according to any one of claims from 1 to 8, characterized in that it comprises an entity with biological activity chosen from:
- les anticorps, les protéoglycanes, les anticancéreux, les antibiotiques, les antiviraux, en particulier les analogues d'oligonucléotides et les inhibiteurs de la transcriptase inverse, les antiprotéases, les insecticides et antifongiques, les oligonucléotides, ADN et éléments de
génome, les anesthésiques et anesthésiques locaux comme la benzocaïne, le vasoconstricteurs, les cardiotoniques comme la digitoxine et ses dérivés, les vasodilatateurs les diurétiques et antidiurétiques, les prostaglandines, les neuroleptiques, les antidépresseurs les hormones et dérivés, les anti-inflammatoires stéroïdiens et non stéroïdiens, le antihistaminiques, les agents anti-allergiques, les antiseptiques, les agents de diagnostic, le vitamines, les anti-oxydants, les acides aminés et sels minéraux, les enzymes, le hydroxyacides et les huiles essentielles, les cellules animales et végétales, les levures, bactéries et autres micro-organismes, les molécules à activité d'absorption des rayonnements UV ou d'hydratation de l'épiderme. 10 - Matrice selon l'une quelconque des revendications de 1 à 8, caractérisée en ce q «'elle est marquée par un agent chromophore ou un agent fluorophore ou un agent radioactif.
- antibodies, proteoglycans, anticancer drugs, antibiotics, antivirals, in particular oligonucleotide analogs and reverse transcriptase inhibitors, antiproteases, insecticides and antifungals, oligonucleotides, DNA and elements of genome, local anesthetics and anesthetics like benzocaine, vasoconstrictors, cardiotonics like digitoxin and its derivatives, vasodilators diuretics and antidiuretics, prostaglandins, neuroleptics, antidepressants hormones and derivatives, steroidal anti-inflammatory drugs and not steroids, antihistamines, anti-allergic agents, antiseptics, diagnostic agents, vitamins, antioxidants, amino acids and minerals, enzymes, hydroxy acids and essential oils, animal and plant cells, yeasts, bacteria and other microorganisms, molecules with absorption activity for UV radiation or hydration of the epidermis. 10 - Matrix according to any one of claims from 1 to 8, characterized in that q "'it is marked by a chromophore agent or a fluorophore agent or a radioactive agent.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9611978 | 1996-09-27 | ||
FR9611978A FR2753902B1 (en) | 1996-09-27 | 1996-09-27 | NEW TYPE OF BIODEGRADABLE ION MATRIX OF MODULATED INTERNAL POLARITY WITH GRAFT POLYMER |
PCT/FR1997/001701 WO1998013030A1 (en) | 1996-09-27 | 1997-09-26 | Biodegradable ionic matrix of variable internal polarity with grafted polymer |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0949911A1 true EP0949911A1 (en) | 1999-10-20 |
Family
ID=9496258
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP97943009A Withdrawn EP0949911A1 (en) | 1996-09-27 | 1997-09-26 | Biodegradable ionic matrix of variable internal polarity with grafted polymer |
Country Status (6)
Country | Link |
---|---|
US (1) | US6346263B1 (en) |
EP (1) | EP0949911A1 (en) |
JP (1) | JP2001500888A (en) |
CA (1) | CA2266642A1 (en) |
FR (1) | FR2753902B1 (en) |
WO (1) | WO1998013030A1 (en) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6783838B2 (en) * | 2001-04-30 | 2004-08-31 | 3M Innovative Properties Company | Coated film laminate having an ionic surface |
AU2002362069A1 (en) * | 2001-12-14 | 2003-06-30 | Syed Rizvi | Feminine wipe for symptomatic treatment of vaginitis |
US20030232088A1 (en) * | 2002-06-14 | 2003-12-18 | Kimberly-Clark Worldwide, Inc. | Materials with both bioadhesive and biodegradable components |
WO2007038126A1 (en) * | 2005-09-21 | 2007-04-05 | Surmodics, Inc. | In vivo formed matrices including natural biodegradable polysaccharides and ophthalmic uses thereof |
US8512736B2 (en) * | 2005-09-21 | 2013-08-20 | Surmodics, Inc. | Coatings including natural biodegradable polysaccharides and uses thereof |
US8850784B2 (en) | 2005-11-16 | 2014-10-07 | Lorica International Corporation | Fire retardant compositions and methods and apparatuses for making the same |
US20080089923A1 (en) * | 2006-09-29 | 2008-04-17 | Burkstrand Michael J | Biodegradable ocular implants and methods for treating ocular conditions |
WO2009137689A2 (en) * | 2008-05-07 | 2009-11-12 | Surmodics, Inc. | Delivery of nucleic acid complexes from particles |
KR20120130166A (en) * | 2009-12-04 | 2012-11-29 | 마글레 홀딩 아베 | Microspheres of hydrolysed starch with endogenous, charged ligands |
US8901092B2 (en) | 2010-12-29 | 2014-12-02 | Surmodics, Inc. | Functionalized polysaccharides for active agent delivery |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2631826B1 (en) * | 1988-05-27 | 1992-06-19 | Centre Nat Rech Scient | PARTICULATE VECTOR USEFUL IN PARTICULAR FOR THE TRANSPORT OF BIOLOGICALLY ACTIVATED MOLECULES AND METHOD FOR THE PREPARATION THEREOF |
US5380536A (en) * | 1990-10-15 | 1995-01-10 | The Board Of Regents, The University Of Texas System | Biocompatible microcapsules |
US5275820A (en) * | 1990-12-27 | 1994-01-04 | Allergan, Inc. | Stable suspension formulations of bioerodible polymer matrix microparticles incorporating drug loaded ion exchange resin particles |
FR2702160B1 (en) * | 1993-03-02 | 1995-06-02 | Biovecteurs As | Synthetic particulate vectors and method of preparation. |
DE4428851C2 (en) * | 1994-08-04 | 2000-05-04 | Diagnostikforschung Inst | Nanoparticles containing iron, their production and application in diagnostics and therapy |
-
1996
- 1996-09-27 FR FR9611978A patent/FR2753902B1/en not_active Expired - Fee Related
-
1997
- 1997-09-26 CA CA002266642A patent/CA2266642A1/en not_active Abandoned
- 1997-09-26 US US09/269,499 patent/US6346263B1/en not_active Expired - Lifetime
- 1997-09-26 EP EP97943009A patent/EP0949911A1/en not_active Withdrawn
- 1997-09-26 JP JP10515356A patent/JP2001500888A/en active Pending
- 1997-09-26 WO PCT/FR1997/001701 patent/WO1998013030A1/en not_active Application Discontinuation
Non-Patent Citations (1)
Title |
---|
See references of WO9813030A1 * |
Also Published As
Publication number | Publication date |
---|---|
FR2753902A1 (en) | 1998-04-03 |
WO1998013030A1 (en) | 1998-04-02 |
JP2001500888A (en) | 2001-01-23 |
FR2753902B1 (en) | 1999-04-02 |
CA2266642A1 (en) | 1998-04-02 |
US6346263B1 (en) | 2002-02-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0687173B1 (en) | Synthetic particulate vectors and method for preparing same | |
US6395302B1 (en) | Method for the preparation of microspheres which contain colloidal systems | |
Gan et al. | Chitosan nanoparticle as protein delivery carrier—systematic examination of fabrication conditions for efficient loading and release | |
WO2008135563A1 (en) | Polyglutamic acids functionalized by cationic groups and hydrophobic groups and applications thereof, in particular therapeutic applications thereof | |
WO1994004261A1 (en) | Utilization of a transacylation reaction between an esterified polysaccharide and a polyaminated or polyhydroxylated substance for fabricating microparticles, microparticles thus obtained, methods and compositions containing them | |
FR2841137A1 (en) | VECTORIZATION SYSTEM COMPRISING HOMOGENEOUS SIZE NANOPARTICLES OF AT LEAST ONE POLYMER AND AT LEAST ONE POSITIVELY CHARGED POLYSACCHARIDE | |
EP1848411A2 (en) | Copolyhydroxyalkylglutamines which are functionalised with hydrophobic groups and applications thereof, such as in therapeutics | |
EP1835888B1 (en) | Cholanic acid-chitosan complex forming self-aggregates and preparation method thereof | |
WO2010084088A2 (en) | Starch nanoparticles for drug delivery systems | |
WO1998013030A1 (en) | Biodegradable ionic matrix of variable internal polarity with grafted polymer | |
WO2010084060A1 (en) | Starch copolymers and nanoparticles thereof for drug delivery systems | |
EP0542969B1 (en) | Biodegradable particulate vector and method of synthesis | |
CN113633785B (en) | Preparation method and application of intelligent responsive shell-core polyelectrolyte nanogel | |
JP2008088158A (en) | Method for producing hydrophilic active substance-containing fine particle | |
WO2001062805A1 (en) | Cationic polymers and matrices capable of being biologically eliminated with controlled degradation | |
JP2013512301A (en) | Acrylic or methacrylic polymer containing α-tocopherol graft | |
FR2968993A1 (en) | NANOPARTICLES COMPRISING AT LEAST ONE ACTIVE AND AT LEAST TWO POLYELECTROLYTES | |
WO1999001213A9 (en) | Microbeads prepared from cross-linked polysaccharide hydrogel capable of containing molecules of biological interest or cells | |
WO2006030111A2 (en) | Biodegradable polymer microparticles | |
CA2157384C (en) | Synthetic particulate vectors and process for their preparation | |
KR101551464B1 (en) | Hydrogel particle coated with lipid bilayer, and method for preparing thereof | |
FR2805269A1 (en) | New cationic polymers comprising polyhydroxylated backbone grafted with cationic ligands, are degradable in vivo at controlled rate and useful as carriers for e.g. drugs, vaccines or cosmetic agents | |
FR2803526A1 (en) | New stable polymeric matrices, useful e.g. for delivery, release and/or stabilization of drugs, comprising charged macromolecular hydrophilic matrix incorporating oppositely charged lipid phase |
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: 19990420 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE |
|
17Q | First examination report despatched |
Effective date: 20011025 |
|
RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: KAPPA BIOTECH SA |
|
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: 20030401 |