US20040167098A1 - Cross-linked polysaccharides - Google Patents
Cross-linked polysaccharides Download PDFInfo
- Publication number
- US20040167098A1 US20040167098A1 US10/787,736 US78773604A US2004167098A1 US 20040167098 A1 US20040167098 A1 US 20040167098A1 US 78773604 A US78773604 A US 78773604A US 2004167098 A1 US2004167098 A1 US 2004167098A1
- Authority
- US
- United States
- Prior art keywords
- cross
- polysaccharide
- linked
- product
- product according
- 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.)
- Abandoned
Links
- 229920001282 polysaccharide Polymers 0.000 title claims abstract description 28
- 239000005017 polysaccharide Substances 0.000 title claims abstract description 28
- 150000004676 glycans Chemical class 0.000 title abstract 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 27
- 229920000768 polyamine Polymers 0.000 claims abstract description 9
- 239000002537 cosmetic Substances 0.000 claims abstract description 6
- 125000003277 amino group Chemical group 0.000 claims abstract description 4
- 238000004132 cross linking Methods 0.000 claims description 29
- 150000004804 polysaccharides Chemical class 0.000 claims description 23
- 229920002674 hyaluronan Polymers 0.000 claims description 19
- -1 iron ions Chemical class 0.000 claims description 16
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 11
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 8
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 8
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 8
- 229920000615 alginic acid Polymers 0.000 claims description 7
- 235000010443 alginic acid Nutrition 0.000 claims description 7
- 150000004781 alginic acids Chemical class 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 4
- 230000003213 activating effect Effects 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 229920002678 cellulose Polymers 0.000 claims description 4
- 235000010980 cellulose Nutrition 0.000 claims description 4
- 229910052802 copper Inorganic materials 0.000 claims description 4
- 239000010949 copper Substances 0.000 claims description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- 229910052742 iron Inorganic materials 0.000 claims description 4
- 229910052725 zinc Inorganic materials 0.000 claims description 4
- 239000011701 zinc Substances 0.000 claims description 4
- FBPINGSGHKXIQA-UHFFFAOYSA-N 2-amino-3-(2-carboxyethylsulfanyl)propanoic acid Chemical compound OC(=O)C(N)CSCCC(O)=O FBPINGSGHKXIQA-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 239000001913 cellulose Substances 0.000 claims description 3
- 229920000669 heparin Polymers 0.000 claims description 3
- 229960002897 heparin Drugs 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 229920001661 Chitosan Polymers 0.000 claims description 2
- 229920000045 Dermatan sulfate Polymers 0.000 claims description 2
- 229920001503 Glucan Polymers 0.000 claims description 2
- 229920002971 Heparan sulfate Polymers 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical class [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000000010 aprotic solvent Substances 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 125000000623 heterocyclic group Chemical group 0.000 claims 1
- 239000004615 ingredient Substances 0.000 claims 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 claims 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 50
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical compound NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 description 30
- 239000000047 product Substances 0.000 description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- 239000000499 gel Substances 0.000 description 20
- 238000000034 method Methods 0.000 description 17
- 229960003160 hyaluronic acid Drugs 0.000 description 13
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 12
- AONKRVVHOIQJQI-UHFFFAOYSA-M 3-(chloromethyl)-2h-pyridin-2-ylium;iodide Chemical compound [I-].ClCC1=CC=CN=[C+]1 AONKRVVHOIQJQI-UHFFFAOYSA-M 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 11
- 229920002521 macromolecule Polymers 0.000 description 10
- 230000008569 process Effects 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 238000005406 washing Methods 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000012190 activator Substances 0.000 description 6
- 239000003431 cross linking reagent Substances 0.000 description 6
- 150000002016 disaccharides Chemical group 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 229920000642 polymer Polymers 0.000 description 6
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 6
- 238000004626 scanning electron microscopy Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 230000008961 swelling Effects 0.000 description 5
- 239000000783 alginic acid Substances 0.000 description 4
- 229960001126 alginic acid Drugs 0.000 description 4
- 229920006037 cross link polymer Polymers 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 229910021645 metal ion Inorganic materials 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 229920002125 Sokalan® Polymers 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 125000002091 cationic group Chemical group 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- NAQMVNRVTILPCV-UHFFFAOYSA-N hexane-1,6-diamine Chemical compound NCCCCCCN NAQMVNRVTILPCV-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 210000004623 platelet-rich plasma Anatomy 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Inorganic materials O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- GYLDXXLJMRTVSS-UHFFFAOYSA-N CCCCNC(C)=O Chemical compound CCCCNC(C)=O GYLDXXLJMRTVSS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 229920002385 Sodium hyaluronate Polymers 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000005452 bending Methods 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 150000002118 epoxides Chemical class 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 229920000193 polymethacrylate Polymers 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 229940010747 sodium hyaluronate Drugs 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- KIUKXJAPPMFGSW-YXBJCWEESA-N (2s,4s,5r,6s)-6-[(2s,3r,5s,6r)-3-acetamido-2-[(3s,4r,5r,6r)-6-[(3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H](C(O[C@@H]3[C@@H]([C@@H](O)C(O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)C(C(O)=O)O1 KIUKXJAPPMFGSW-YXBJCWEESA-N 0.000 description 1
- JFOIBTLTZWOAIC-UHFFFAOYSA-N (4-nitrophenyl) 2,2,2-trifluoroacetate Chemical compound [O-][N+](=O)C1=CC=C(OC(=O)C(F)(F)F)C=C1 JFOIBTLTZWOAIC-UHFFFAOYSA-N 0.000 description 1
- DPEYHNFHDIXMNV-UHFFFAOYSA-N (9-amino-3-bicyclo[3.3.1]nonanyl)-(4-benzyl-5-methyl-1,4-diazepan-1-yl)methanone dihydrochloride Chemical compound Cl.Cl.CC1CCN(CCN1Cc1ccccc1)C(=O)C1CC2CCCC(C1)C2N DPEYHNFHDIXMNV-UHFFFAOYSA-N 0.000 description 1
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 1
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 description 1
- 229920001287 Chondroitin sulfate Polymers 0.000 description 1
- 229910021592 Copper(II) chloride Inorganic materials 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 229910017358 Fe2(SO4) Inorganic materials 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 229920002593 Polyethylene Glycol 800 Polymers 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000000181 anti-adherent effect Effects 0.000 description 1
- 229910001422 barium ion Inorganic materials 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical compound C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 159000000011 group IA salts Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000001483 monosaccharide substituent group Chemical group 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000004848 polyfunctional curative Substances 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 150000004992 toluidines Chemical class 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- QJDRFICTELBSSO-UHFFFAOYSA-N triazol-4-ylidenemethanone Chemical compound O=C=C1C=NN=N1 QJDRFICTELBSSO-UHFFFAOYSA-N 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/73—Polysaccharides
- A61K8/731—Cellulose; Quaternized cellulose derivatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B15/00—Preparation of other cellulose derivatives or modified cellulose, e.g. complexes
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B15/00—Preparation of other cellulose derivatives or modified cellulose, e.g. complexes
- C08B15/005—Crosslinking of cellulose derivatives
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B31/00—Preparation of derivatives of starch
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B31/00—Preparation of derivatives of starch
- C08B31/003—Crosslinking of starch
- C08B31/006—Crosslinking of derivatives of starch
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0084—Guluromannuronans, e.g. alginic acid, i.e. D-mannuronic acid and D-guluronic acid units linked with alternating alpha- and beta-1,4-glycosidic bonds; Derivatives thereof, e.g. alginates
Definitions
- the present invention refers to a cross-linking process of carboxylated polysaccharides.
- the process of the invention provides a high degree of reproducibility of the obtained products, in terms of cross-linking degree, homogeneity of the distribution of the cross-linking chains, and chemico-physical characteristics of the products and the technological characteristics of the articles obtained therefrom.
- the invention further refers to the products obtainable by said process and their applications in the medical, pharmaceutical and dermo-cosmetic field.
- Macromolecules are used in the preparation of pharmaceutical formulations as thickening agents, lubricants, gastro-resistant film coating agents, particularly in the preparation of capsules, gel, colloids and of different devices (e.g. contact lenses, gauzes, etc.). Macromolecules are also used in the preparation of controlled-release formulations of active ingredients.
- Said macromolecules belong to different chemical families and may be either synthetic, or natural or semi-synthetic.
- Examples of synthetic macromolecules include polyvinylpyrrolidone, polyoxyethylenealkyl ethers, polyvinyl alcohols, polymethacrylates.
- Examples of natural macromolecules include native hyaluronic acid (HY) and cellulose.
- Examples of semi-synthetic macromolecules include carboxyalkylcelluloses, widely used in the food and personal care industries. These macromolecules are characterized by a linear or poorly branched structure.
- cross-linking A very important modification for increasing the chemical, enzymatic and mechanical strength is provided by cross-linking, which may be carried out both on synthetic and natural (more or less already modified) polymers.
- cross-linked polymers include polymers used for the gastro-protection of tablets or capsules (polymethacrylates), as well as polymers used as emulsifiers, suspending agents, tablet hardeners (Carbopol), cross-linked hyaluronic acids, hereinafter discussed.
- a gradual degradation for instance for the controlled release of a medicament, may be desirable.
- This resistance is particularly important when the macromolecule is present in compositions/articles that must last for a long time, e.g. substitutes of the synovial liquid, films, sponges or gels as tissular antiadhesives in different kinds of surgery; in tissular engineering (artificial organs); artificial skins, in the treatment of burns and generally in aesthetic surgery;
- composition of the different production batches must be kept constant within very narrow limits; this implies that the production methods are standardized and that the base components have a very low intrinsic variability.
- a possible cause of dishomogeneity for macromolecules derives from the dispersion of molecular weights. Said dishomogeneity becomes even higher as a consequence of cross-linking. This may be a serious drawback depending on the field of use and the applicative purposes of the final product.
- EP-A-566118 discloses cross-linked polysaccharides to be used as super-absorbents for diapers and similar articles.
- the process described therein is based on the cross-linking of cellulose by formation of intermolecular amides, esters or ethers between polyamines, polyols or mixtures thereof and the carboxy group of polysaccharides.
- the reaction is carried out by heating at about 80° C. the mixture of the polysaccharide with the polyol and/or polyamine. This process is certainly economic and suitable for large scale production where the reproducibility requirements are less stringent.
- U.S. Pat. No. 5,465,055 discloses cross-linked polysaccharides (hyaluronic acid and alginic acid) obtained by esterification of COOH of the polysaccharide and OH groups of other molecules, without insertion of cross-linking arms.
- WO 91/9119 discloses microcapsules for islets of Langerhans as biohybrid organs, consisting of alginic acid cross-linked with barium ions.
- EP 190215 discloses the cross-linking of different polymers (carboxylated starches, dextran, celluloses) with di- or poly-functional epoxides.
- polyalcohols are disclosed in U.S. Pat. No. 4,957,744;
- divinylsulfone is disclosed in U.S. Pat. Nos. 4 , 605 , 691 , 4 , 636 , 524 ;
- aldehydes are disclosed in U.S. Pat. Nos. 4,713,448 and 4,582,865;
- carboxamides are disclosed in U.S. Pat. No. 5,356,833;
- the invention refers to a process for the preparation of cross-linked polysaccharides containing carboxy groups, allowing complete control of cross-linking degree as well as high reproducibility in terms of constant characteristics of the final product.
- the process of the invention comprises:
- the obtained cross-linked polysaccharide may be subjected to sulphation or hemisuccinylation of the free hydroxy groups.
- the products obtainable by the process of the invention may also be complexed with metal ions such as zinc, copper or iron ions.
- the carboxy-containing polysaccharide which may be used according to the invention may be of natural, synthetic or semi-synthetic origin.
- said polysaccharides include Hyaluronic acids (obtained from tissues or bacteria), carboxymethyldextran, carboxymethylcellulose, carboxymethyl-starch, alginic acids, cellulosic acid, N-carboxy-methyl or butyl glucans or chitosans; heparins with different molecular weights, optionally desulphated and succinylated, dermatan sulphates, Chondroitin sulphates, heparan sulphates, polyacrylic acids.
- Hyaluronic acids carboxymethylcellulose, heparins, alginic acids and polyacrylic acids are particularly preferred.
- the carboxy activating agents are usually those used in the peptide chemistry: examples of suitable agents include carbonyldiimidazole, carbonyltriazole, chloromethylpyridylium iodide (CMP-J), hydroxybenzotriazole, p-nitrophenol p-nitrophenyltrifluoroacetate, N-hydroxysuccinimide and the like.
- CMP-J chloromethylpyridylium iodide
- hydroxybenzotriazole p-nitrophenol p-nitrophenyltrifluoroacetate
- N-hydroxysuccinimide and the like.
- chloromethylpyridylium iodide is particularly preferred.
- the polyamines have preferably the following general formula:
- R 1 and R 2 which are the same or different, are hydrogen, C 1 -C 6 alkyl, phenyl or benzyl groups
- A is a C 2 -C 10 alkylene chain, preferably a C 2 -C 6 alkylene chain, optionally substituted by hydroxy, carboxy, halogen, alkoxy, amino groups; a polyoxyalkylene chain of formula
- n is 2 or 3 and m is an integer from 2 to 10; a C 5 -C 7 cycloalkyl group; an aryl or hetaryl group, preferably 1, 3 or 1,4-disubstituted benzene.
- A is preferably C 2 -C 6 linear alkylene or a chain of formula
- the cross-linking reaction is preferably carried out in a solvent selected from tetrahydrofuran, dimethylformamide or dimethyl sulfoxide, and the polysaccharide is preferably salified with a lipophilic cation, for example tetralkylammonium or other lipophilic organic bases.
- inorganic salts such as sodium salts
- suitable organic lipophilic salts may be carried out by known ion-exchange methods in homogeneous phase or by precipitation of the acidic component, followed by recovering of the latter and salification with the desired organic base.
- the activation reaction of the carboxy groups is carried out in homogeneous phase and in anhydrous polar aprotic solvent.
- the polyamine diluted in the same anhydrous solvent is added to the solution of the activated ester, keeping the temperature from 0° C. to 30° C.
- the cross-linking reaction times range from 1 to 12 hours, also depending on the optional presence of suitable basic substances (e.g. triethylamine).
- the final product is recovered by precipitation of the organic salt adding a different solvent to the reaction solvent or by evaporation of the latter, followed by centrifugation, washing with distilled water, repeated dispersions in the solutions of the desired alkali (for instance sodium, potassium), subsequent washing with water and final drying of the alkaline salt under vacuum or by lyophilization.
- a different solvent for instance sodium, potassium
- dispersions in the solutions of the desired alkali for instance sodium, potassium
- the cross-linking degree may range within wide limits and may be adjusted by changing the amount of the carboxy activating agents, since the activation and the cross-linking reaction are substantially quantitative.
- the cross-linked polysaccharides obtained according to the invention may be subjected to sulphation reaction of the hydroxy groups possibly present, usually by reaction with the pyridine-sulfur trioxide complex in dimethylformamide.
- the reaction is carried out in heterogeneous phase at a temperature of 0-10° C. for times ranging from about 0.5 to about 6 hours.
- the sulphation degree obtained is comprised within wide limits with respect to the total of the hydroxy groups and it may be adjusted by changing the temperature and reaction times.
- the sulphation degree (defined as equivalents of sulphate groups/g) may range from 1 ⁇ 10 ⁇ 6 to 6 ⁇ 10 ⁇ 6 , preferably it is of 2 ⁇ 10 ⁇ 6 eq/g for a cross-linking degree of 0.5.
- cross-linked polymers obtained according to the invention are able to complex metal ions such as zinc, copper or iron ions.
- Said complexes may be obtained by dissolving or dispersing until complete swelling the product in water and adding under stirring, preferably at room temperature, a concentrated solution of an organic or inorganic metal salt, e.g. CuCl 2 , ZnCl 2 , Fe 2 (SO 4 ); after stirring for 12-24 hours, the complex is recovered by centrifugation or by precipitation following the addition of a different solvent (for example ethanol or acetone) or evaporation under vacuum; the recovered crude product is thoroughly washed with distilled water so as to remove the excess ions. The complexes are then lyophilized.
- the content of metal ions varies depending on the used operative conditions, particularly the polymer to ion molar ratios; concentration and pH of the solutions; reaction times and particularly cross-linking degree.
- the process of the invention by suitably adjusting the cross-linking and/or sulphation degree, allows the preparation of cross-linked carboxylated polysaccharides in a wide range of shapes, characterized by different properties such as viscoelasticity, hydration degree, complexing ability towards metal ions, ability to form hydrogels, moldability in films or sponges, mechanical strength of the final materials.
- the molar ratio was 1 to 1 as carboxymethyl cellulose has one functional carboxylic group per disaccharide unit. After 20 minutes the solution was added with 2 ml of cross-linking 1,3-diaminopropane (0.006 moles), and immediately after also with 0.5 ml of triethylamine. A solid, jelly-like product formed which was washed with DMF, then placed in H 2 O to completely swell.
- TBA salt of alginic has been prepared from the sodium salt by ionic exchange on strong cationic resin (Dovex) in H + form (i.e. acidic form), followed by neutralization with tetrabutylammonium hydroxide (TBA-OH) and final liophylisation.
- Dovex strong cationic resin
- TBA-OH tetrabutylammonium hydroxide
- Hyaluronic acid sodium salt (1 ⁇ 10 ⁇ 3 mol., with reference to the disaccharidic unit) were transformed in TBA salt, according to one of the following methods:
- a) 1% aqueous solution of sodium hyaluronate is transformed in H + form by H + cationic strong resin (Amberlite IR 120); the final solution is treated by a 0.5% solution of TBA-OH to about pH 9.
- TBA salt is then dissolved in 15 ml of anhydrous DMF, under N 2 , and—at 0° C.-0.02 g of cloromethypyridylium Iodide (CMPJ) in 2 ml of anhydrous DFM, are added dropwise to the stored solution of TBA salt.
- CMPJ cloromethypyridylium Iodide
- d 1,3-diaminopropane
- the reaction mixture was stirred for at least 30′ and the solvent was then removed under reduced pressure, the residue was then taken up with DMF, which was subsequently removed by distillation; the residue was then treated with ethanol, ethanol-water and finally with water.
- SD Silicone (Swelling Degree, in water and r.t., after 15′; gravimetric determination; calculated according to: SD ⁇ W s - Wd Wd ⁇ 100 ,
- Cross-linking degree 0.05 (5% of initially available carboxy groups).
- Activator chloromethylpyridylium iodide.
- the final product after lyophilisation, shows at the scanning microscope an irregular pattern with smooth zones alternating to spongy zones.
- the cross-linking degree was 0.3 (30% of initially available carboxy groups)
- hyaluronic acid tributylammonium salt (HY TBA) (1 ⁇ 10 ⁇ 3 mol., with reference to the disaccharide unit) were dissolved under stirring in 30 ml of DMF under nitrogen.
- CMPJ chloromethylpyridylium iodide
- the obtained product had a cross-linking degree of 0.5 and showed at the scanning microscope a grainy aspect interspaced by large meshes. At higher magnitudes, the two morphologies appear identical and show round-shaped protrusions a few microns in diameter.
- IR film; cm ⁇ 1 ): 1740 (— CO OH); 1630 (— CO —NH—); 1610 (— CO O ⁇ ); 1560 (—CO—NH—);
- NMR (13 C; ppm): 29.3 and 39.8 (—CH 2 —CH 2 —CH 2 — propanediamine link); 172.5
- the IR spectrum shows, in addition to the bands of the starting product, a peak at 1260 cm ⁇ 1 and a stronger band at 1025 cm ⁇ 1 .
- the rheological properties are characterised by dynamic elastic modules G′ (2500 Pa with 20 mg and 1000 Pa with 10 mg at 10 Hz) which are always higher than the dynamic viscous modules G′′ (600 Pa with 20 mg and 150 Pa with 10 mg at 10 Hz) and much higher than the corresponding values obtained with non-sulphated HY (13 at 50%—example 5).
- This compound has a thrombin time (TT) higher (61 ⁇ 5”) than the control (14.0′′) and the corresponding not cross-linked (14.6′′).
Abstract
A product having application in the medical, pharmaceutical and dermo-cosmetic fields comprising a cross-linked polysaccharide in which cross-linkage exists only through amide bonds between carboxy groups of the polysaccharide and amino groupss of a polyamine.
Description
- The present invention refers to a cross-linking process of carboxylated polysaccharides.
- The process of the invention provides a high degree of reproducibility of the obtained products, in terms of cross-linking degree, homogeneity of the distribution of the cross-linking chains, and chemico-physical characteristics of the products and the technological characteristics of the articles obtained therefrom.
- The reproducibility is particularly important for the applications in the medical, pharmaceutical and dermo-cosmetic fields.
- The invention further refers to the products obtainable by said process and their applications in the medical, pharmaceutical and dermo-cosmetic field.
- The use of macromolecules in the medical/pharmaceutical field and, more recently, in the dermatological-cosmetic field, is well established. Macromolecules are used in the preparation of pharmaceutical formulations as thickening agents, lubricants, gastro-resistant film coating agents, particularly in the preparation of capsules, gel, colloids and of different devices (e.g. contact lenses, gauzes, etc.). Macromolecules are also used in the preparation of controlled-release formulations of active ingredients.
- Reviews of their characteristics and pharmaceutical uses are reported in
- 1) C. Flansch et Al. Editors—“Comprehensive Medicinal Chemistry”—Pergamon Press, Oxford, 1990-Vol. 1-6;
- 2) A. Wade and P. J. Wellers Editors—“Handbook of Pharmaceutical Excipients”—Ed. 1994—The Pharmaceutical Press.
- Said macromolecules belong to different chemical families and may be either synthetic, or natural or semi-synthetic.
- Examples of synthetic macromolecules include polyvinylpyrrolidone, polyoxyethylenealkyl ethers, polyvinyl alcohols, polymethacrylates. Examples of natural macromolecules include native hyaluronic acid (HY) and cellulose.
- Examples of semi-synthetic macromolecules include carboxyalkylcelluloses, widely used in the food and personal care industries. These macromolecules are characterized by a linear or poorly branched structure.
- A very important modification for increasing the chemical, enzymatic and mechanical strength is provided by cross-linking, which may be carried out both on synthetic and natural (more or less already modified) polymers.
- Examples of cross-linked polymers include polymers used for the gastro-protection of tablets or capsules (polymethacrylates), as well as polymers used as emulsifiers, suspending agents, tablet hardeners (Carbopol), cross-linked hyaluronic acids, hereinafter discussed.
- For the considered applications, and particularly for the preparation of invasive medical devices which have to be administered parenterally, said polymers must meet a number of requirements, of technical and regulatory kind.
- The technical requirements include:
- 1) high biocompatibility;
- 2) resistance to enzymatic systems, both tissular or plasmatic (for injectable compositions) and gastrointestinal (for oral compositions).
- In some cases a gradual degradation, for instance for the controlled release of a medicament, may be desirable.
- This resistance is particularly important when the macromolecule is present in compositions/articles that must last for a long time, e.g. substitutes of the synovial liquid, films, sponges or gels as tissular antiadhesives in different kinds of surgery; in tissular engineering (artificial organs); artificial skins, in the treatment of burns and generally in aesthetic surgery;
- 3) moldability into different shapes (gels, films, sponges, etc.);
- 4) possibility to be sterilized chemically or physically without changing the product structure.
- According to the regulatory requisites, the composition of the different production batches must be kept constant within very narrow limits; this implies that the production methods are standardized and that the base components have a very low intrinsic variability.
- A possible cause of dishomogeneity for macromolecules derives from the dispersion of molecular weights. Said dishomogeneity becomes even higher as a consequence of cross-linking. This may be a serious drawback depending on the field of use and the applicative purposes of the final product.
- EP-A-566118 (Kimberly-Clark) discloses cross-linked polysaccharides to be used as super-absorbents for diapers and similar articles.
- The process described therein is based on the cross-linking of cellulose by formation of intermolecular amides, esters or ethers between polyamines, polyols or mixtures thereof and the carboxy group of polysaccharides.
- The reaction is carried out by heating at about 80° C. the mixture of the polysaccharide with the polyol and/or polyamine. This process is certainly economic and suitable for large scale production where the reproducibility requirements are less stringent.
- U.S. Pat. No. 5,465,055 discloses cross-linked polysaccharides (hyaluronic acid and alginic acid) obtained by esterification of COOH of the polysaccharide and OH groups of other molecules, without insertion of cross-linking arms.
- WO 91/9119 discloses microcapsules for islets of Langerhans as biohybrid organs, consisting of alginic acid cross-linked with barium ions.
- EP 190215 discloses the cross-linking of different polymers (carboxylated starches, dextran, celluloses) with di- or poly-functional epoxides.
- The following cross-linking agents for hyaluronic acids have been proposed:
- polyfunctional epoxides are disclosed in U.S. Pat. Nos. 4,716,224, 4,772,419, 4,716,154;
- polyalcohols are disclosed in U.S. Pat. No. 4,957,744;
- divinylsulfone is disclosed in U.S. Pat. Nos.4,605,691, 4,636,524;
- aldehydes are disclosed in U.S. Pat. Nos. 4,713,448 and 4,582,865;
- carboxamides are disclosed in U.S. Pat. No. 5,356,833;
- polycarboxylic acids are disclosed in EP-A-718312.
- The invention refers to a process for the preparation of cross-linked polysaccharides containing carboxy groups, allowing complete control of cross-linking degree as well as high reproducibility in terms of constant characteristics of the final product.
- The process of the invention comprises:
- a) activation of the carboxy groups of the polysaccharide by reaction with suitable carboxy activating agents in anhydrous aprotic solvent;
- b) reaction of the carboxy activated polysaccharide with a polyamine.
- The obtained cross-linked polysaccharide, if desired, may be subjected to sulphation or hemisuccinylation of the free hydroxy groups.
- The products obtainable by the process of the invention may also be complexed with metal ions such as zinc, copper or iron ions.
- The carboxy-containing polysaccharide which may be used according to the invention may be of natural, synthetic or semi-synthetic origin. Examples of said polysaccharides include Hyaluronic acids (obtained from tissues or bacteria), carboxymethyldextran, carboxymethylcellulose, carboxymethyl-starch, alginic acids, cellulosic acid, N-carboxy-methyl or butyl glucans or chitosans; heparins with different molecular weights, optionally desulphated and succinylated, dermatan sulphates, Chondroitin sulphates, heparan sulphates, polyacrylic acids.
- Hyaluronic acids, carboxymethylcellulose, heparins, alginic acids and polyacrylic acids are particularly preferred.
- Said cross-linked polymers, obtained by different methods, are known and have been proposed for several uses (see, for instance, EP 566118, WO91/9119, U.S. Pat. No. 5,465,055, EP 190215, EP 718312, U.S. Pat. No. 4,716,224 discussed above).
- The carboxy activating agents are usually those used in the peptide chemistry: examples of suitable agents include carbonyldiimidazole, carbonyltriazole, chloromethylpyridylium iodide (CMP-J), hydroxybenzotriazole, p-nitrophenol p-nitrophenyltrifluoroacetate, N-hydroxysuccinimide and the like. The use of chloromethylpyridylium iodide is particularly preferred.
- The polyamines have preferably the following general formula:
- R1—NH—A—NH—R2
- wherein R1 and R2, which are the same or different, are hydrogen, C1-C6 alkyl, phenyl or benzyl groups, A is a C2-C10 alkylene chain, preferably a C2-C6 alkylene chain, optionally substituted by hydroxy, carboxy, halogen, alkoxy, amino groups; a polyoxyalkylene chain of formula
- [(CH2)n—O—(CH2)n]m
- wherein n is 2 or 3 and m is an integer from 2 to 10; a C5-C7 cycloalkyl group; an aryl or hetaryl group, preferably 1, 3 or 1,4-disubstituted benzene. A is preferably C2-C6 linear alkylene or a chain of formula
- [(CH2)n—O—(CH2)n]m.
- The cross-linking reaction is preferably carried out in a solvent selected from tetrahydrofuran, dimethylformamide or dimethyl sulfoxide, and the polysaccharide is preferably salified with a lipophilic cation, for example tetralkylammonium or other lipophilic organic bases.
- The transformation of inorganic salts such as sodium salts, into suitable organic lipophilic salts may be carried out by known ion-exchange methods in homogeneous phase or by precipitation of the acidic component, followed by recovering of the latter and salification with the desired organic base.
- The activation reaction of the carboxy groups is carried out in homogeneous phase and in anhydrous polar aprotic solvent.
- The polyamine diluted in the same anhydrous solvent, is added to the solution of the activated ester, keeping the temperature from 0° C. to 30° C. The cross-linking reaction times range from 1 to 12 hours, also depending on the optional presence of suitable basic substances (e.g. triethylamine).
- Generally, the final product is recovered by precipitation of the organic salt adding a different solvent to the reaction solvent or by evaporation of the latter, followed by centrifugation, washing with distilled water, repeated dispersions in the solutions of the desired alkali (for instance sodium, potassium), subsequent washing with water and final drying of the alkaline salt under vacuum or by lyophilization.
- The cross-linking degree (C.L.D) may range within wide limits and may be adjusted by changing the amount of the carboxy activating agents, since the activation and the cross-linking reaction are substantially quantitative.
- The cross-linked polysaccharides obtained according to the invention may be subjected to sulphation reaction of the hydroxy groups possibly present, usually by reaction with the pyridine-sulfur trioxide complex in dimethylformamide.
- The reaction is carried out in heterogeneous phase at a temperature of 0-10° C. for times ranging from about 0.5 to about 6 hours.
- The sulphation degree obtained is comprised within wide limits with respect to the total of the hydroxy groups and it may be adjusted by changing the temperature and reaction times. Generally, the sulphation degree (defined as equivalents of sulphate groups/g) may range from 1×10−6 to 6×10−6, preferably it is of 2×10−6 eq/g for a cross-linking degree of 0.5.
- The cross-linked polymers obtained according to the invention, optionally sulphated, are able to complex metal ions such as zinc, copper or iron ions.
- Said complexes may be obtained by dissolving or dispersing until complete swelling the product in water and adding under stirring, preferably at room temperature, a concentrated solution of an organic or inorganic metal salt, e.g. CuCl2, ZnCl2, Fe2(SO4); after stirring for 12-24 hours, the complex is recovered by centrifugation or by precipitation following the addition of a different solvent (for example ethanol or acetone) or evaporation under vacuum; the recovered crude product is thoroughly washed with distilled water so as to remove the excess ions. The complexes are then lyophilized. The content of metal ions varies depending on the used operative conditions, particularly the polymer to ion molar ratios; concentration and pH of the solutions; reaction times and particularly cross-linking degree.
- The process of the invention, by suitably adjusting the cross-linking and/or sulphation degree, allows the preparation of cross-linked carboxylated polysaccharides in a wide range of shapes, characterized by different properties such as viscoelasticity, hydration degree, complexing ability towards metal ions, ability to form hydrogels, moldability in films or sponges, mechanical strength of the final materials.
- This allows their use in many medical fields, in the human and veterinary field, and in dermo-cosmetology.
- The following examples further illustrate the invention.
- Carboxymethylcellulose Gel 100% Cross-Linked with 1,3-diaminopropane.
- 1.2×10−3 moles, with reference to the disaccharide unit of carboxymethyl cellulare TBA salt, were dissolved in 30 ml of DMF under N2 and with stirring. 0.32 g of chloromethylpyridylium iodide (1.2×10−3 moles) dissolved in 2 ml of DMF were added dropwise to the solution kept at a temperature of 0° C. with ice.
- The molar ratio was 1 to 1 as carboxymethyl cellulose has one functional carboxylic group per disaccharide unit. After 20 minutes the solution was added with 2 ml of cross-linking 1,3-diaminopropane (0.006 moles), and immediately after also with 0.5 ml of triethylamine. A solid, jelly-like product formed which was washed with DMF, then placed in H2O to completely swell.
- Alternating washings with EtOH and H2O were then carried out. After the last washing with EtOH, the product was freeze-dried.
- I.R. (film; cm−1): 1650(—CO—NH—); no bending —COO− at 1.400 about.
-
- where:
- Ws=weight of hydrated gel; Wd=weight of dry gel): 7.000
- SEM (Scanning Electron Microscopy): the structure looks compact, with 15-35 μpers.
- The product surface, by rabbit PRP (Platelet Rich Plasma) exposure, shows a very reduced presence of platelets or aggregates in comparison with equivalent product obtained by low density polypropylene (EC reference standard).
- Carboxymethyl Cellulose Gel 50% Cross-Linked with 1,3-diaminopropane.
- 1.2×10−3 moles, referred to the disaccharide unit of carboxymethyl cellulose, were dissolved in 30 ml of DMF under N2 and with stirring. 0.24 g of chloromethylpyridylium iodide (1.2×10−3 moles) dissolved in 2 ml of DMF were added dropwise to the solution kept at a temperature of 0° C. with ice. The molar ratio was 2/1.
- After 20 minutes the solution was added with 2 ml of cross-linking 1,3-diaminopropane (3×10−3 moles), and immediately after also with 0.5 ml of triethylamine. A solid, jelly-like product formed which was washed with DMF, then placed in H2O to completely swell.
- Alternating washings with EtOH and H2O were then carried out. After the last washing with EtOH the product was freeze-dried.
- I.R. (film; cm−1): 1650(—CO—NH—); no bending —COO− at 1.400 about.
- SD: 8.000
- SEM: presence of 13-25 μpers.
- Platelet adhesion: as reported in Example 1.
- Alginic acid gel 50% (100% with reference to disaccharide units) cross-linked with 1,3-diaminopropane.
- The TBA salt of alginic has been prepared from the sodium salt by ionic exchange on strong cationic resin (Dovex) in H+ form (i.e. acidic form), followed by neutralization with tetrabutylammonium hydroxide (TBA-OH) and final liophylisation.
- 1.2×10−3 moles, refered to the monosaccharide unit, were dissolved in 30 ml of DMF under N2 and under stirring. 0.36 g of chloromethylpyridylium iodide (1.2×10−3 moles) dissolved in 2 ml of DMF were added dropwise to the solution kept at a temperature of 0° C. with ice. The molar ratio was 1/1.
- After 20 minutes the solution was added with 6×10−3 moles of cross-linking 1,3-diaminopropane (0.024 moles), and immediately after also with 0.5 ml of triethylamine. A solid, jelly-like product formed which was washed with DMF, then placed in H2O to completely swell.
- Alternating washings with EtOH and H2O were then carried out. After the last washing with EtOH the product was freeze-dried.
- IR (film; cm−1): 1635 (broad) (—CO—NH—): 1.400, about (—COO−).
- SD: 5.000
- SEM: the structure looks compact and without pores.
- Preparation of hyaluronic acid cross-linked with C.L.D. =0.05 (5% of available carboxy groups). Cross-linking agent: 1,3-propanediamine.
- Hyaluronic acid sodium salt (1×10−3 mol., with reference to the disaccharidic unit) were transformed in TBA salt, according to one of the following methods:
- a) 1% aqueous solution of sodium hyaluronate is transformed in H+ form by H+ cationic strong resin (Amberlite IR 120); the final solution is treated by a 0.5% solution of TBA-OH to about pH=9.
- b) 1% aqueous solution of sodium hyaluronate is transformed in TBA salt solution by treating with a cationic weak resin in TBA+ form. (Amberlite IRC 50)
- In both cases, the final solutions are liophylised. The TBA salt is then dissolved in 15 ml of anhydrous DMF, under N2, and—at 0° C.-0.02 g of cloromethypyridylium Iodide (CMPJ) in 2 ml of anhydrous DFM, are added dropwise to the stored solution of TBA salt.
- The reaction mixture was then added with 0.1 ml of triethylamine and, then, dropwise, with a solution of 1,3-diaminopropane (d=0.88, in large excess, so as to make cross-linking of the activated carboxy groups easier) in 2 ml of anhydrous DMF. When the addition was over, the reaction mixture was stirred for at least 30′ and the solvent was then removed under reduced pressure, the residue was then taken up with DMF, which was subsequently removed by distillation; the residue was then treated with ethanol, ethanol-water and finally with water.
- The product was then lyophilised and the residue subjected to analysis.
- IR (film; cm−1): 1630 (—CO—NH); 1740 (—COOH, polysaccharide); 3200 (—NH—).
-
- where:
- Ws=weight of hydrated gel; Wd=weight of dry gel): 31.000
- Cross-linking degree: 0.05 (5% of initially available carboxy groups).
- Preparation of hyaluronic acid cross-linked with C.L.D. =0.05 (5% of the available carboxy groups). Cross-linking agent: 1,6-diaminohexane.
- Activator: chloromethylpyridylium iodide.
- According to the procedure and conditions reported in Example 4, using the same HY and the same activator, but 1,6-diaminohexane instead of 1,3-diaminopropane, the cross-linked derivative was obtained.
- IR (film; cm−1): 1630 (—CO—NH); 1740 (—COOH polysaccharide); 3200 (—NH—).
- Preparation of cross-linked hyaluronic acid, with C.L.D. =0.05 (5% of the available carboxy groups). Cross-linking agent: 0.0′-bis-(2-aminopropyl)PEG500. Activator: chloromethylpyridylium iodide
- According to the procedure and conditions reported in Example 4 and using the same activator, but 0.0′-bis-(2-aminopropyl)PEG500 instead of 1,3-diaminopropane, the cross-linked derivative was obtained.
- IR (film; cm−1): 1630 (—CO—NH); 1740 (—COOH polysaccharide); 3200 (—NH—)
- SD: 31.000
- Preparation of cross-linked hyaluronic acids, with C.L.D.=0.3 (30% of the available carboxy groups). Cross-linking agent: 1,3-propanediamine. Activator: chloromethylpyridylium iodide.
- 0.6 g of hyaluronic acid tributylammonium salt (1×10−3 mol., with reference to the disaccharide unit) were dissolved under stirring in 30 ml of DMF under nitrogen. 0.08 g of chloromethylpyridylium iodide (3.5×10−4 mol) dissolved in 2 ml of DMF were added dropwise to the stirred solution kept at 0° C. The molar ratio was therefore about 3/1.
- After 20 minutes 2 ml of 1,3-diaminopropane (0.024 mol) were added, followed immediately by 0.5 ml of triethylamine. A solid, gelatinous product was obtained, the product was then swelled with water and washed again with ethanol.
- The final product, after lyophilisation, shows at the scanning microscope an irregular pattern with smooth zones alternating to spongy zones.
- The cross-linking degree was 0.3 (30% of initially available carboxy groups)
- IR (film; cm−1): 1740 (—COOH); 1630 (—CO—NH); 1610 (—COO—); 1560 (—CO—NH—)
- Preparation of hyaluronic acid cross-linked with C.L.D.=0.5 (50% of the available carboxy groups). Cross-linking agent: 1,3-propanediamine. Activator: chloromethylpyridylium iodide.
- 0.6 g of hyaluronic acid tributylammonium salt (HY TBA) (1×10−3 mol., with reference to the disaccharide unit) were dissolved under stirring in 30 ml of DMF under nitrogen. 0.15 g of chloromethylpyridylium iodide (CMPJ) (6×10−6 mol) dissolved in 2 ml of DMF were added dropwise to the solution, kept at 0° C. The molar ratio was 2HY.TBA:1 CMPJ. After 20 minutes, 2 ml of 1,3 diaminopropane (0.024 mol.) were added to the solution.
- 0.5 ml of triethylamine were added thereafter.
- A solid, gelly-like product was obtained and thoroughly washed with DMF.
- After evaporating DMF, the product was swelled in water and washed with ethanol before lyophilization.
- The obtained product had a cross-linking degree of 0.5 and showed at the scanning microscope a grainy aspect interspaced by large meshes. At higher magnitudes, the two morphologies appear identical and show round-shaped protrusions a few microns in diameter.
- IR (film; cm−1): 1740 (—COOH); 1630 (—CO—NH—); 1610 (—COO−); 1560 (—CO—NH—);
- The gels were subjected to swelling in PBS and the max swelling ability was evaluated.
- SD=23.500
-
- The rheological properties evaluated on Bohlin VOR Rheometer, at the temperature of 23±0.1° C., show that the dynamic elastic module G′ (100 Pa at 10 Hz) identical at the two considered concentrations (10 and 20 mg/ml) is always higher than the viscous dynamic module (G″ 40 Pa for 20 mg at 10 Hz and 20 Pa for 10 mg at 10 Hz).
- According to the methods disclosed in the previous examples, the cross-linked hyaluronic acid derivatives having the characteristics summarised in the following table 1, were obtained, starting from 1×10−3 mol (0.6 g) of hyaluronic acid tributylammonium salt.
- The obtained derivatives had the following properties:
TABLE 1 Scanning Cross- Amount Cross- Electron linking agent (g) of linking Microscopy Ex (mol) CMPJ (mol) degree SD NMR (13) (ppm) I.R. (film) (cm−1) (SEM) 9 1,3-propane- diamine (0.024) 0.6 g (1.210−3) (100%) 13.200 Homogeneouns, ondulated morphology. 10 0,0′-1-bis-(-2-di- 0.15 g (50%) 9.000 Alternating aminopropyl) (6 × 10−4) smooth areas PEG 500 (0.022) and meshes, circular protrusions a few microns in size. 11 0,0′-bis (2-amino- 0.15 g (50%) 6.100 Two propyl) - (6 × 10−4) morphologically PEG 800 (0.022) different zones, a first one ondulated and a second with hole-like structures. 12 1,6-diamino- hexane (0.023) 0.15 g (6 × 10−4) (50%) 8.000 169.46(—CO—NH— of cross- linking); 74.04/76.80/83.17/80.41(—CH2—of cross-linking arm) Smooth surface with protrusions having a few microns in size. - Sulphation of 50% cross-linked HY,
- The derivative obtained in example 8 was dispersed in 5 ml DMF under strong stirring and nitrogen atmosphere.
- A solution of 1 g of SO3/pyridine in mol of DMF was added at 0° C. and stirred for 3 hours. The reaction was blocked by adding an excess of H2O (50 ml) and the pH adjusted to 9 with 0.1M NaOH.
- The product was thoroughly washed with ethanol and H2O and then lyophilized.
- The IR spectrum shows, in addition to the bands of the starting product, a peak at 1260 cm−1 and a stronger band at 1025 cm−1.
- The gel swells in PBS with SD=33.000. Higher resolution 13C NMR spectrum shows the signals in H2O at 37° C. reported in table 2. The intensity of the NMR signals at 29.3 and 38.8 ppm (—CH2—) and the signal at 172.5 ppm (CONH) confirm a cross-linking degree of about 50%.
- The rheological properties are characterised by dynamic elastic modules G′ (2500 Pa with 20 mg and 1000 Pa with 10 mg at 10 Hz) which are always higher than the dynamic viscous modules G″ (600 Pa with 20 mg and 150 Pa with 10 mg at 10 Hz) and much higher than the corresponding values obtained with non-sulphated HY (13 at 50%—example 5). This compound has a thrombin time (TT) higher (61±5”) than the control (14.0″) and the corresponding not cross-linked (14.6″).
- The compound was also active in the PRP test using stressed rabbit.
TABLE 2 Table: 13C Chemical shift C-1 C-2 C-3 C-4 C-5 x-C═O y-CH3 103.5 57.3 85.4 71.3 78.7 178.0 25.3 ppm C-1′ C-2′ C-3′ C-4′ C-5′ 6-C═O 105.9 75.2 76.4 82.8 78.6 176.2 ppm 1-CH2 2-CH2 3-CH2 6′-C═O CROSS-LINKING 39.8 29.3 39.8 172.5 ppm - Sulphation of Alginic Acid GEL
- The cross-linked product after treatment with EtOH was freeze-dried to remove completely humidity and subjected to sulphation of the alcohol groups.
- 100 mg of cross-linked product dispersed in 5 ml of DMF were added with a SO3-pyridine solution of (800 mg in 2 ml of DMF). The reaction should be carried out at 0° C., under nitrogen and with constant stirring for 2 hours.
- It is mandatory for the product not to adsorb humidity, as it inhibits the reaction.
- After 2 hours H2O was added pH was adjusted to 9 by a 1M solution of NaOH, thereby freeing pyridine.
- The thus sulphated product was purified in EtOH.
- The analysis of purified products, shows:
- IR (film; cm−1) 1263 (stretching SO)
- Equivalents of SO3 groups/g gel (by toluidine complexes):
- 5% cross linked gel: 6×10−5
- 50% cross linked gel: 2×10−5
- 100% cross linked gel: 3×10−5
- SD
- 5% cross linked gel: 19×103
- 50% cross linked gel: 9×10−3
- 100% cross linked gel: 7×10−3
- Using the same methodology, the sulphated derivatives of 50% cross-linked products according to example 10, 11 and 12, have been synthetized.
- Colorimetric characteristics of the sulphated derivatives are reported in table 3 together with that of the products deriving from examples 8 and 13.
TABLE 3 CROSSLINKED POLYMER (50% CROSS-LINKING ΔHa Tg DEGREE) [J/g] [° C.] ΔHb [J/g] Wt % water C.L.Hyal-1,3 (Ex. 8) 276 51 42 12 C.L.HyalS-1,3 (Ex. 13) 357 64 53 16 C.L.Hyal-1,6 (Ex. 12) 327 64 58 16 C.L.HyalS-1,6 465 64 65 20 5 C.L.Hyal-P500.2NH2 (Ex. 10) 239 45 72 10 6 C.L.HyalS-P500.2NH2 384 69 113 16 7 C.L.Hyal-P800.2NH2 (Ex. 11) 179 73 30 10 8 C.L.HyalS-P800.2NH2 206 76 52 10 Hyal ITBA 164 — 130 5 - Suphation of Carboxymethylcellulose Gel.
- Following the procedure and conditions reported in Example 14, the sulphated derivative was obtained.
- Equivalents of SO3 Groups/g:
- a—CMC 5% cross linked: 8×10−6
- b—CMC 50% cross linked: 7×10−6
- c—CMC 100% cross linked: 4×10−6
- SD
- a: 20×10−3
- b: 12×10−3
- c: 9×10−3
Claims (7)
1. A product having application in the medical, pharmaceutical and dermo-cosmetic fields comprising a cross-linked polysaccharide in which cross-linkage exists only through amide bonds between carboxy groups of the polysaccharide and amino groupss of a polyamine.
2. A product according to claim 1 in which it is complexed with zinc, copper or iron ions.
3. A product according to claim 1 in which the it sulfated with a pyridine-sulfur trioxide complex.
4. A pharmaceutical composition in which the principal ingredient is a product according to claim 1 .
5. A product having application in the medical, pharmaceutical and dermo-cosmetic fields comprising a cross-linked polysaccharide in which cross-linking occurs only through amide bonds between carboxy groups of the polysaccharide and amino groups of a polyamine in which the polysaccharide is selected from the group consisting of hyaluronic acids, carboxymethyldextran, carboxymethylcellulose, carboxymethylstarch, alginic acids, cellulose acid, N-carboxymethyl or butyl glucans or chitosans, heparins with different molecular weights, optionally desulfated and succinylated, dermatan sulfates, chodroitin sulfates and heparin sulfates obtained by (a) reacting the carboxy groups of a polysaccharide in an aqueous aprotic solvent using a suitable carboxy activating agent, (b) reacting the carboxy activated polysaccharide with a polyamine selected from the group having the formula R1—NH-A-NH—R2 herein R1 and R2, which may be the same or different, are hydrogen, C1-C6 alkyl, phenyl, or benzyl groups; A is a C2-C10 alkylene chain; a polyoxylene chain of the formula [(CH2)n]m wherein n is 2 or 3 and m is an interger from 2 to 10, a C5-C7 cycloalkyl group or an aryl or heterocyclic group and (c) recovering the resultant cross-linked polsaccharide.
6. A product according to claim 4 in which it is complexed with zinc, copper or iron ions.
7. A product according to claim 4 in which it is sulfated with a pyridine-sulfur trioxide complex.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/787,736 US20040167098A1 (en) | 1998-11-11 | 2004-02-26 | Cross-linked polysaccharides |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITMI98A002443 | 1998-11-11 | ||
IT1998MI002443A IT1303738B1 (en) | 1998-11-11 | 1998-11-11 | CARBOXYLATE POLYSACCHARIDE CROSS-LINKING PROCESS. |
US09/830,744 US6734298B1 (en) | 1998-11-11 | 1999-11-09 | Cross-linking process of carboxylated polysaccharides |
US10/787,736 US20040167098A1 (en) | 1998-11-11 | 2004-02-26 | Cross-linked polysaccharides |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/830,744 Division US6734298B1 (en) | 1998-11-11 | 1999-11-09 | Cross-linking process of carboxylated polysaccharides |
Publications (1)
Publication Number | Publication Date |
---|---|
US20040167098A1 true US20040167098A1 (en) | 2004-08-26 |
Family
ID=11381036
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/830,744 Expired - Lifetime US6734298B1 (en) | 1998-11-11 | 1999-11-09 | Cross-linking process of carboxylated polysaccharides |
US10/787,736 Abandoned US20040167098A1 (en) | 1998-11-11 | 2004-02-26 | Cross-linked polysaccharides |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/830,744 Expired - Lifetime US6734298B1 (en) | 1998-11-11 | 1999-11-09 | Cross-linking process of carboxylated polysaccharides |
Country Status (25)
Country | Link |
---|---|
US (2) | US6734298B1 (en) |
EP (1) | EP1137670B1 (en) |
JP (1) | JP2002529549A (en) |
KR (1) | KR100685454B1 (en) |
CN (1) | CN1144818C (en) |
AT (1) | ATE291590T1 (en) |
AU (1) | AU756158B2 (en) |
BR (1) | BR9915238A (en) |
CA (1) | CA2350665A1 (en) |
CZ (1) | CZ303485B6 (en) |
DE (1) | DE69924407T2 (en) |
DK (1) | DK1137670T3 (en) |
ES (1) | ES2237971T3 (en) |
HK (1) | HK1041010B (en) |
HU (1) | HU227731B1 (en) |
IL (1) | IL143064A0 (en) |
IT (1) | IT1303738B1 (en) |
NO (1) | NO20012316L (en) |
NZ (1) | NZ511308A (en) |
PT (1) | PT1137670E (en) |
RU (1) | RU2230073C2 (en) |
SI (1) | SI1137670T1 (en) |
TR (1) | TR200101325T2 (en) |
WO (1) | WO2000027886A1 (en) |
ZA (1) | ZA200103800B (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012017288A3 (en) * | 2010-08-04 | 2012-03-29 | Carlo Ghisalberti | Supramolecular complexes of polyanionic polymers and spermidine in tissue maintenance and repair |
KR20170122179A (en) | 2015-02-27 | 2017-11-03 | 각코호우징 조쇼 가쿠엔 | Polysaccharide derivatives having membrane permeable peptide chains |
Families Citing this family (65)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ITPD980037A1 (en) * | 1998-02-25 | 1999-08-25 | Fidia Advanced Biopolymers Srl | SULFATED HYALURONIC ACID AND ITS DERIVATIVES COVALENTLY LINKED TO SYNTHETIC POLYMERS FOR THE PREPARATION OF BIOMATERIALS AND FOR COATING |
IT1303738B1 (en) | 1998-11-11 | 2001-02-23 | Aquisitio S P A | CARBOXYLATE POLYSACCHARIDE CROSS-LINKING PROCESS. |
IT1303735B1 (en) * | 1998-11-11 | 2001-02-23 | Falorni Italia Farmaceutici S | CROSS-LINKED HYALURONIC ACIDS AND THEIR MEDICAL USES. |
FR2799196B1 (en) * | 1999-10-04 | 2002-02-08 | Sod Conseils Rech Applic | CROSSLINKED COPOLYMERS BASED ON NON-CROSSLINKED POLYCARBOXYLIC COPOLYMERS |
KR100375299B1 (en) * | 2000-10-10 | 2003-03-10 | 주식회사 엘지생명과학 | Crosslinked derivatives of hyaluronic acid by amide formation and their preparation methods |
US6500947B1 (en) | 2001-08-24 | 2002-12-31 | Weyerhaeuser Company | Superabsorbent polymer |
KR100493461B1 (en) * | 2002-02-27 | 2005-06-07 | 재단법인서울대학교산학협력재단 | Natural polymers bonded adhesion molecular, their preparation and their use |
FR2839312A1 (en) * | 2002-05-03 | 2003-11-07 | Roquette Freres | Production of an amidated amylaceous material, e.g. useful in papermaking, comprises reacting a dry or semidry carboxy-functional amylaceous material with an amine at elevated temperature in the absence of solvent |
KR20040009891A (en) * | 2002-07-26 | 2004-01-31 | 주식회사 엘지생명과학 | Hyaluronic Acid Derivative Gel and Method for Preparing the Same |
KR100523953B1 (en) * | 2002-08-27 | 2005-10-25 | 주식회사 엘지생명과학 | Microbeads of natural polysaccharide and hyaluronic acid and processes for preparing the same |
DE10256558A1 (en) * | 2002-12-04 | 2004-09-16 | Supramol Parenteral Colloids Gmbh | Esters of polysaccharide aldonic acids, process for their preparation and use for coupling to active pharmaceutical ingredients |
EP1595892A4 (en) | 2003-02-21 | 2007-06-20 | Terumo Corp | Crosslinkable polysaccharide derivative, process for producing the same, crosslinkable polysaccharide composition and medical treatment material |
FR2861734B1 (en) | 2003-04-10 | 2006-04-14 | Corneal Ind | CROSSLINKING OF LOW AND HIGH MOLECULAR MASS POLYSACCHARIDES; PREPARATION OF INJECTABLE SINGLE PHASE HYDROGELS; POLYSACCHARIDES AND HYDROGELS OBTAINED |
JP4669919B2 (en) * | 2003-06-06 | 2011-04-13 | コスモテック株式会社 | Medical composition |
US8519058B2 (en) | 2004-02-23 | 2013-08-27 | E I Du Pont De Nemours And Company | Crosslinked polymers containing biomass derived materials |
JP4566189B2 (en) * | 2004-03-15 | 2010-10-20 | テルモ株式会社 | Anti-adhesive material |
KR100863870B1 (en) | 2004-06-21 | 2008-10-15 | 에보닉 스톡하우젠 게엠베하 | Water absorbing polysaccharide and method for producing the same |
ITMI20041373A1 (en) | 2004-07-09 | 2004-10-09 | Lima Lto S P A | N-METHYL-CARBOXYMETHYLCELLULOSE ACID ALGINIC OR CARBOXYMETALAMIDE |
US7541396B2 (en) | 2004-12-29 | 2009-06-02 | Weyerhaeuser Nr Company | Method for making carboxyalkyl cellulose |
US7241836B2 (en) * | 2004-12-29 | 2007-07-10 | Weyerhaeuser Co. | Method of crosslinking a mixture of carboxylated polymers using a triazine crosslinking activator |
US7393905B2 (en) * | 2004-12-29 | 2008-07-01 | Weyerhaeuser Company | Crosslinked mixed carboxylated polymer network |
US7300965B2 (en) | 2004-12-29 | 2007-11-27 | Weyerhaeuser Company | Mixed polymer network |
US7230049B2 (en) * | 2004-12-29 | 2007-06-12 | Weyerhaeuser Co. | Method of crosslinking a carboxylated polymer using a triazine crosslinking activator |
US20060142476A1 (en) * | 2004-12-29 | 2006-06-29 | Weerawarna S A | Crosslinked carboxylated polymer |
AU2006286158A1 (en) * | 2005-09-02 | 2007-03-08 | Colbar Lifescience Ltd. | Cross-linked polysaccharide and protein matrices and methods for their preparation |
RU2486907C2 (en) * | 2006-12-04 | 2013-07-10 | Джонс Хопкинс Юниверсити | Imidised biopolymer adhesive and hydrogel |
KR100825519B1 (en) | 2007-01-05 | 2008-04-25 | 주식회사 바이오폴리메드 | A chitosan based polymer conjugate and a method for producing the same |
US20080293637A1 (en) * | 2007-05-23 | 2008-11-27 | Allergan, Inc. | Cross-linked collagen and uses thereof |
US20110077737A1 (en) * | 2007-07-30 | 2011-03-31 | Allergan, Inc. | Tunably Crosslinked Polysaccharide Compositions |
US8697044B2 (en) | 2007-10-09 | 2014-04-15 | Allergan, Inc. | Crossed-linked hyaluronic acid and collagen and uses thereof |
JP5670196B2 (en) | 2007-11-16 | 2015-02-18 | バイセプト セラピューティクス、インク. | Compositions and methods for treating purpura |
US8394784B2 (en) | 2007-11-30 | 2013-03-12 | Allergan, Inc. | Polysaccharide gel formulation having multi-stage bioactive agent delivery |
US8394782B2 (en) | 2007-11-30 | 2013-03-12 | Allergan, Inc. | Polysaccharide gel formulation having increased longevity |
US8357795B2 (en) | 2008-08-04 | 2013-01-22 | Allergan, Inc. | Hyaluronic acid-based gels including lidocaine |
ES2829971T3 (en) | 2008-09-02 | 2021-06-02 | Tautona Group Lp | Hyaluronic acid threads and / or derivatives thereof, methods to manufacture them and uses thereof |
US8361926B2 (en) * | 2008-11-25 | 2013-01-29 | Evonik Stockhausen, Llc | Water-absorbing polysaccharide and method for producing the same |
EP2413894B1 (en) * | 2009-04-02 | 2017-01-04 | Allergan, Inc. | Hair-like shaped hydrogels for soft tissue augmentation |
US20110172180A1 (en) | 2010-01-13 | 2011-07-14 | Allergan Industrie. Sas | Heat stable hyaluronic acid compositions for dermatological use |
US9114188B2 (en) | 2010-01-13 | 2015-08-25 | Allergan, Industrie, S.A.S. | Stable hydrogel compositions including additives |
KR101764451B1 (en) | 2010-03-12 | 2017-08-02 | 알러간 인더스트리 에스에이에스 | A Fluid Composition Comprising A Hyaluronan Polymer and Mannitol For Improving Skin Condition |
PL3078388T3 (en) | 2010-03-22 | 2019-08-30 | Allergan, Inc. | Cross-linked hydrogels for soft tissue augmentation |
US8889123B2 (en) | 2010-08-19 | 2014-11-18 | Allergan, Inc. | Compositions and soft tissue replacement methods |
US9005605B2 (en) | 2010-08-19 | 2015-04-14 | Allergan, Inc. | Compositions and soft tissue replacement methods |
US8883139B2 (en) | 2010-08-19 | 2014-11-11 | Allergan Inc. | Compositions and soft tissue replacement methods |
US8697057B2 (en) | 2010-08-19 | 2014-04-15 | Allergan, Inc. | Compositions and soft tissue replacement methods |
KR102312056B1 (en) | 2011-06-03 | 2021-10-12 | 알러간 인더스트리 에스에이에스 | Dermal filler compositions including antioxidants |
US9393263B2 (en) | 2011-06-03 | 2016-07-19 | Allergan, Inc. | Dermal filler compositions including antioxidants |
US20130096081A1 (en) | 2011-06-03 | 2013-04-18 | Allergan, Inc. | Dermal filler compositions |
US9408797B2 (en) | 2011-06-03 | 2016-08-09 | Allergan, Inc. | Dermal filler compositions for fine line treatment |
US9662422B2 (en) | 2011-09-06 | 2017-05-30 | Allergan, Inc. | Crosslinked hyaluronic acid-collagen gels for improving tissue graft viability and soft tissue augmentation |
US20130244943A1 (en) | 2011-09-06 | 2013-09-19 | Allergan, Inc. | Hyaluronic acid-collagen matrices for dermal filling and volumizing applications |
CN103113495A (en) * | 2013-02-03 | 2013-05-22 | 江苏天竹化工科技有限公司 | Photopolymerizable hyaluronic acid derivative and preparation method thereof |
ITUD20130119A1 (en) * | 2013-09-12 | 2015-03-13 | Limacorporate Spa | BIOCOMPATIBLE IDROGEL FOR BIOMEDICAL OR PHARMACEUTICAL USE, INTERMEDIATE POLYMER TO REALIZE THE BIOCOMPATIBLE IDROGEL AND ITS APPLICATION METHOD |
ES2811269T3 (en) | 2014-01-31 | 2021-03-11 | Seikagaku Kogyo Co Ltd | Diamine crosslinking agent, acid polysaccharide crosslinking body and medical material |
ES2761558T3 (en) | 2014-09-30 | 2020-05-20 | Allergan Ind Sas | Stable hydrogel compositions including additives |
ES2938482T3 (en) | 2015-01-16 | 2023-04-11 | Seikagaku Kogyo Co Ltd | Cross-linked chondroitin sulfate, composition containing the same and treatment agent for eye disease |
WO2016128783A1 (en) | 2015-02-09 | 2016-08-18 | Allergan Industrie Sas | Compositions and methods for improving skin appearance |
WO2016159159A1 (en) * | 2015-03-31 | 2016-10-06 | キユーピー株式会社 | Hyaluronic acid derivative and manufacturing method therefor and cosmetics, food composition, and pharmaceutical composition containing hyaluronic acid derivative |
CZ306479B6 (en) * | 2015-06-15 | 2017-02-08 | Contipro A.S. | A method of crosslinking polysaccharides by using photolabile protecting groups |
GB201511218D0 (en) | 2015-06-25 | 2015-08-12 | Goe Ip As | Reservoir treatments |
CN105566511B (en) * | 2016-01-27 | 2017-11-03 | 天津医科大学 | Electric charge overturns pulullan polysaccharide derivative and its preparation method and use |
CN110961057A (en) * | 2020-01-16 | 2020-04-07 | 江苏罗格斯生物科技有限公司 | Green biological hydrogel conveying system and preparation method thereof |
RU2743941C1 (en) * | 2020-07-29 | 2021-03-01 | Федеральное государственное бюджетное учреждение науки Институт химии Дальневосточного отделения Российской академии наук (ИХ ДВО РАН) | Method for producing biopolymeric hydrogel |
CN114230678B (en) * | 2021-12-13 | 2023-09-01 | 珠海通桥医疗科技有限公司 | Photocrosslinked hydrogel embolism system for intravascular treatment and application method |
CN114507359A (en) * | 2022-02-17 | 2022-05-17 | 浙江大学 | Preparation method of modified material of lignosulfonate and application of modified material in nano pesticide |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5616568A (en) * | 1993-11-30 | 1997-04-01 | The Research Foundation Of State University Of New York | Functionalized derivatives of hyaluronic acid |
US5944753A (en) * | 1991-08-16 | 1999-08-31 | Galin; Miles A. | Medicament coated refractive anterior chamber ocular implant |
US6831172B1 (en) * | 1998-11-11 | 2004-12-14 | Farmila-Thea Farmaceutici S.P.A. | Cross-linked hyaluronic acids and medical uses thereof |
Family Cites Families (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5257102A (en) * | 1975-11-06 | 1977-05-11 | Sumitomo Chemical Co | Process for preparing carboxylic acid amide |
US4716224A (en) * | 1984-05-04 | 1987-12-29 | Seikagaku Kogyo Co. Ltd. | Crosslinked hyaluronic acid and its use |
SE442820B (en) * | 1984-06-08 | 1986-02-03 | Pharmacia Ab | GEL OF THE CROSS-BOND HYALURONIC ACID FOR USE AS A GLASS BODY SUBSTITUTE |
US4636524A (en) * | 1984-12-06 | 1987-01-13 | Biomatrix, Inc. | Cross-linked gels of hyaluronic acid and products containing such gels |
US4582865A (en) * | 1984-12-06 | 1986-04-15 | Biomatrix, Inc. | Cross-linked gels of hyaluronic acid and products containing such gels |
US4605691A (en) * | 1984-12-06 | 1986-08-12 | Biomatrix, Inc. | Cross-linked gels of hyaluronic acid and products containing such gels |
SE8501022L (en) * | 1985-03-01 | 1986-09-02 | Pharmacia Ab | FORMAT CREATES AND PROCEDURES FOR ITS PREPARATION |
US4713448A (en) * | 1985-03-12 | 1987-12-15 | Biomatrix, Inc. | Chemically modified hyaluronic acid preparation and method of recovery thereof from animal tissues |
IT1184161B (en) * | 1985-03-14 | 1987-10-22 | Franco Conti | CHITOSAN DERIVATIVES CONSTITUTED BY COORDINATION COMPLEXES WITH FERROUS IONS |
IT1198449B (en) * | 1986-10-13 | 1988-12-21 | F I D I Farmaceutici Italiani | ESTERS OF POLYVALENT ALCOHOLS OF HYALURONIC ACID |
IT1219587B (en) * | 1988-05-13 | 1990-05-18 | Fidia Farmaceutici | SELF-CROSS-LINKED CARBOXYLY POLYSACCHARIDES |
CZ714489A3 (en) * | 1989-12-18 | 1993-03-17 | Kery Vladimir | method of binding biologically active substances containing an amine group to polysaccharides |
WO1991016881A1 (en) * | 1990-05-04 | 1991-11-14 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Colonic drug delivery system |
JP2855307B2 (en) * | 1992-02-05 | 1999-02-10 | 生化学工業株式会社 | Photoreactive glycosaminoglycans, cross-linked glycosaminoglycans and methods for producing them |
CA2076732C (en) * | 1992-04-17 | 2006-05-09 | Kimberly-Clark Worldwide, Inc. | Modified polysaccharides having improved absorbent properties and process for the preparation thereof |
US5550189A (en) * | 1992-04-17 | 1996-08-27 | Kimberly-Clark Corporation | Modified polysaccharides having improved absorbent properties and process for the preparation thereof |
JP3107726B2 (en) * | 1994-05-13 | 2000-11-13 | 株式会社クラレ | Water-swellable polymer gel |
US5690961A (en) * | 1994-12-22 | 1997-11-25 | Hercules Incorporated | Acidic polysaccharides crosslinked with polycarboxylic acids and their uses |
JP4018181B2 (en) * | 1995-11-07 | 2007-12-05 | 生化学工業株式会社 | Glycosaminoglycan derivative and process for producing the same |
JPH09176204A (en) * | 1995-12-28 | 1997-07-08 | Kazukiyo Kobayashi | Functional material containing sialoglycochain and its synthesis |
JPH09278803A (en) * | 1996-04-09 | 1997-10-28 | Kuraray Co Ltd | Medical treatment material |
JP3413062B2 (en) * | 1996-06-19 | 2003-06-03 | キヤノン株式会社 | Polymer compound containing sugar chain polymer compound and decomposition method thereof |
FR2752843B1 (en) * | 1996-08-30 | 1998-10-16 | Sod Conseils Rech Applic | CROSSLINKED COPOLYMERS BASED ON POLYCARBOXYLIC POLYMERS AND THEIR USE AS SUPPORTS OF PHARMACEUTICAL COMPOSITIONS |
EP0927196B1 (en) * | 1996-09-19 | 2008-11-05 | The Regents Of The University Of Michigan | Polymers containing polysaccharides such as alginates or modified alginates |
US6630457B1 (en) * | 1998-09-18 | 2003-10-07 | Orthogene Llc | Functionalized derivatives of hyaluronic acid, formation of hydrogels in situ using same, and methods for making and using same |
IT1303738B1 (en) | 1998-11-11 | 2001-02-23 | Aquisitio S P A | CARBOXYLATE POLYSACCHARIDE CROSS-LINKING PROCESS. |
-
1998
- 1998-11-11 IT IT1998MI002443A patent/IT1303738B1/en active
-
1999
- 1999-11-09 TR TR2001/01325T patent/TR200101325T2/en unknown
- 1999-11-09 RU RU2001112487/04A patent/RU2230073C2/en not_active IP Right Cessation
- 1999-11-09 US US09/830,744 patent/US6734298B1/en not_active Expired - Lifetime
- 1999-11-09 EP EP99971819A patent/EP1137670B1/en not_active Revoked
- 1999-11-09 ES ES99971819T patent/ES2237971T3/en not_active Expired - Lifetime
- 1999-11-09 WO PCT/EP1999/008480 patent/WO2000027886A1/en active IP Right Grant
- 1999-11-09 HU HU0104075A patent/HU227731B1/en not_active IP Right Cessation
- 1999-11-09 BR BR9915238-0A patent/BR9915238A/en not_active Application Discontinuation
- 1999-11-09 PT PT99971819T patent/PT1137670E/en unknown
- 1999-11-09 IL IL14306499A patent/IL143064A0/en not_active IP Right Cessation
- 1999-11-09 JP JP2000581063A patent/JP2002529549A/en active Pending
- 1999-11-09 NZ NZ511308A patent/NZ511308A/en not_active IP Right Cessation
- 1999-11-09 CZ CZ20011651A patent/CZ303485B6/en not_active IP Right Cessation
- 1999-11-09 KR KR1020017005930A patent/KR100685454B1/en not_active IP Right Cessation
- 1999-11-09 DE DE69924407T patent/DE69924407T2/en not_active Expired - Lifetime
- 1999-11-09 DK DK99971819T patent/DK1137670T3/en active
- 1999-11-09 CN CNB99813144XA patent/CN1144818C/en not_active Expired - Fee Related
- 1999-11-09 CA CA002350665A patent/CA2350665A1/en not_active Abandoned
- 1999-11-09 AT AT99971819T patent/ATE291590T1/en active
- 1999-11-09 SI SI9930767T patent/SI1137670T1/en unknown
- 1999-11-09 AU AU13803/00A patent/AU756158B2/en not_active Ceased
-
2001
- 2001-05-10 NO NO20012316A patent/NO20012316L/en not_active Application Discontinuation
- 2001-05-10 ZA ZA200103800A patent/ZA200103800B/en unknown
-
2002
- 2002-04-11 HK HK02102741.6A patent/HK1041010B/en not_active IP Right Cessation
-
2004
- 2004-02-26 US US10/787,736 patent/US20040167098A1/en not_active Abandoned
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5944753A (en) * | 1991-08-16 | 1999-08-31 | Galin; Miles A. | Medicament coated refractive anterior chamber ocular implant |
US5616568A (en) * | 1993-11-30 | 1997-04-01 | The Research Foundation Of State University Of New York | Functionalized derivatives of hyaluronic acid |
US5874417A (en) * | 1993-11-30 | 1999-02-23 | The Research Foundation Of State University Of New York | Functionalized derivatives of hyaluronic acid |
US6831172B1 (en) * | 1998-11-11 | 2004-12-14 | Farmila-Thea Farmaceutici S.P.A. | Cross-linked hyaluronic acids and medical uses thereof |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012017288A3 (en) * | 2010-08-04 | 2012-03-29 | Carlo Ghisalberti | Supramolecular complexes of polyanionic polymers and spermidine in tissue maintenance and repair |
KR20170122179A (en) | 2015-02-27 | 2017-11-03 | 각코호우징 조쇼 가쿠엔 | Polysaccharide derivatives having membrane permeable peptide chains |
US10793603B2 (en) | 2015-02-27 | 2020-10-06 | Josho Gakuen Educational Foundation | Polysaccharide derivative having membrane-permeable peptide chain |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6734298B1 (en) | Cross-linking process of carboxylated polysaccharides | |
KR100674177B1 (en) | Cross-linked hyaluronic acids and medical uses thereof | |
Gómez-Mascaraque et al. | Oxidized dextrins as alternative crosslinking agents for polysaccharides: application to hydrogels of agarose–chitosan | |
US7651702B2 (en) | Crosslinking hyaluronan and chitosanic polymers | |
EP1163274B1 (en) | Process for cross-linking hyaluronic acid to polymers | |
US8575129B2 (en) | Amides of hyaluronic acid and the derivatives thereof and a process for their preparation | |
US7683038B2 (en) | Percarboxylated polysaccharides, and a process for their preparation | |
Bam et al. | Design of biostable scaffold based on collagen crosslinked by dialdehyde chitosan with presence of gallic acid | |
AU2001252180B2 (en) | Clathrate complexes formed by hyaluronic acid derivatives and use thereof as pharmaceuticals | |
US20110117198A1 (en) | Compositions of semi-interpenetrating polymer network | |
WO2013164782A1 (en) | Shape-memory cross-linked polysaccharides | |
de Azevedo | Aldehyde-functionalized chitosan and cellulose: chitosan composites: application as drug carriers and vascular bypass grafts | |
MXPA01004723A (en) | Cross-linking process of carboxylated polysaccharides | |
RU2659175C1 (en) | Composition on the basis of bacterial cellulose and hyaluronic acid | |
EP4341303A1 (en) | Mixtures of polysaccharides and polyaminosaccharides with improved rheological properties | |
López-Saucedo et al. | Hydrogels Based on Natural and/or Synthetic Polymers |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |
|
AS | Assignment |
Owner name: SIGMA ITALIA SPA, ITALY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:FARMILA-THEA FARMACEUTICI S.P.A.;REEL/FRAME:019140/0399 Effective date: 20060921 |