EP4251695A1 - Organic material with pore-forming, anti-inflammatory and anticoagulant properties and the method of its preparation - Google Patents
Organic material with pore-forming, anti-inflammatory and anticoagulant properties and the method of its preparationInfo
- Publication number
- EP4251695A1 EP4251695A1 EP21897295.8A EP21897295A EP4251695A1 EP 4251695 A1 EP4251695 A1 EP 4251695A1 EP 21897295 A EP21897295 A EP 21897295A EP 4251695 A1 EP4251695 A1 EP 4251695A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- base
- admixture
- string
- active admixture
- mixture
- 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.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims abstract description 95
- 230000002429 anti-coagulating effect Effects 0.000 title claims abstract description 21
- 230000003110 anti-inflammatory effect Effects 0.000 title claims abstract description 19
- 239000011368 organic material Substances 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title description 2
- 239000000463 material Substances 0.000 claims abstract description 131
- 230000008569 process Effects 0.000 claims abstract description 66
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims abstract description 27
- KANJSNBRCNMZMV-ABRZTLGGSA-N fondaparinux Chemical compound O[C@@H]1[C@@H](NS(O)(=O)=O)[C@@H](OC)O[C@H](COS(O)(=O)=O)[C@H]1O[C@H]1[C@H](OS(O)(=O)=O)[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O[C@@H]4[C@@H]([C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O4)NS(O)(=O)=O)[C@H](O3)C(O)=O)O)[C@@H](COS(O)(=O)=O)O2)NS(O)(=O)=O)[C@H](C(O)=O)O1 KANJSNBRCNMZMV-ABRZTLGGSA-N 0.000 claims abstract description 26
- 229960001318 fondaparinux Drugs 0.000 claims abstract description 26
- 229920000669 heparin Polymers 0.000 claims abstract description 26
- 229960002897 heparin Drugs 0.000 claims abstract description 26
- 102000009027 Albumins Human genes 0.000 claims abstract description 20
- 108010088751 Albumins Proteins 0.000 claims abstract description 20
- KXNPVXPOPUZYGB-XYVMCAHJSA-N argatroban Chemical compound OC(=O)[C@H]1C[C@H](C)CCN1C(=O)[C@H](CCCN=C(N)N)NS(=O)(=O)C1=CC=CC2=C1NC[C@H](C)C2 KXNPVXPOPUZYGB-XYVMCAHJSA-N 0.000 claims abstract description 20
- 229960003856 argatroban Drugs 0.000 claims abstract description 20
- UHKAJLSKXBADFT-UHFFFAOYSA-N 1,3-indandione Chemical compound C1=CC=C2C(=O)CC(=O)C2=C1 UHKAJLSKXBADFT-UHFFFAOYSA-N 0.000 claims abstract description 17
- UESSERYYFWCTBU-UHFFFAOYSA-N 4-(n-phenylanilino)benzaldehyde Chemical compound C1=CC(C=O)=CC=C1N(C=1C=CC=CC=1)C1=CC=CC=C1 UESSERYYFWCTBU-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229940050528 albumin Drugs 0.000 claims abstract description 16
- OIRCOABEOLEUMC-GEJPAHFPSA-N bivalirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)CNC(=O)CNC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 OIRCOABEOLEUMC-GEJPAHFPSA-N 0.000 claims abstract description 9
- 229960001500 bivalirudin Drugs 0.000 claims abstract description 9
- 108010055460 bivalirudin Proteins 0.000 claims abstract description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 90
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 90
- 239000000203 mixture Substances 0.000 claims description 49
- -1 poly(tetrafluoroethylene) Polymers 0.000 claims description 41
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 34
- 239000008240 homogeneous mixture Substances 0.000 claims description 30
- 230000007704 transition Effects 0.000 claims description 29
- 239000011888 foil Substances 0.000 claims description 28
- 229920003023 plastic Polymers 0.000 claims description 28
- 239000004033 plastic Substances 0.000 claims description 28
- 239000011541 reaction mixture Substances 0.000 claims description 28
- 229920001343 polytetrafluoroethylene Polymers 0.000 claims description 24
- 238000001816 cooling Methods 0.000 claims description 22
- 239000002033 PVDF binder Substances 0.000 claims description 21
- 229920002981 polyvinylidene fluoride Polymers 0.000 claims description 21
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- 239000007864 aqueous solution Substances 0.000 claims description 18
- 239000004743 Polypropylene Substances 0.000 claims description 16
- 229920001155 polypropylene Polymers 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- 238000009835 boiling Methods 0.000 claims description 15
- 238000004440 column chromatography Methods 0.000 claims description 15
- 238000010992 reflux Methods 0.000 claims description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 14
- 125000004122 cyclic group Chemical group 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 239000008187 granular material Substances 0.000 claims description 12
- 229920000139 polyethylene terephthalate Polymers 0.000 claims description 12
- 239000005020 polyethylene terephthalate Substances 0.000 claims description 12
- 229910052724 xenon Inorganic materials 0.000 claims description 11
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 claims description 11
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 10
- 229910052786 argon Inorganic materials 0.000 claims description 10
- 239000012298 atmosphere Substances 0.000 claims description 10
- 229920002492 poly(sulfone) Polymers 0.000 claims description 10
- 229920006324 polyoxymethylene Polymers 0.000 claims description 10
- 239000004814 polyurethane Substances 0.000 claims description 10
- 229920001577 copolymer Polymers 0.000 claims description 9
- 239000011521 glass Substances 0.000 claims description 9
- HCDGVLDPFQMKDK-UHFFFAOYSA-N hexafluoropropylene Chemical group FC(F)=C(F)C(F)(F)F HCDGVLDPFQMKDK-UHFFFAOYSA-N 0.000 claims description 9
- BFKJFAAPBSQJPD-UHFFFAOYSA-N tetrafluoroethene Chemical group FC(F)=C(F)F BFKJFAAPBSQJPD-UHFFFAOYSA-N 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 229920002313 fluoropolymer Polymers 0.000 claims description 8
- 239000004811 fluoropolymer Substances 0.000 claims description 8
- 239000011261 inert gas Substances 0.000 claims description 8
- 238000001953 recrystallisation Methods 0.000 claims description 8
- 239000004417 polycarbonate Substances 0.000 claims description 6
- 229920000515 polycarbonate Polymers 0.000 claims description 6
- 238000003490 calendering Methods 0.000 claims description 4
- 239000000919 ceramic Substances 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 239000002798 polar solvent Substances 0.000 claims description 4
- 229920005573 silicon-containing polymer Polymers 0.000 claims description 4
- 229910001220 stainless steel Inorganic materials 0.000 claims description 4
- 239000010935 stainless steel Substances 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- 239000012528 membrane Substances 0.000 abstract description 47
- 238000006213 oxygenation reaction Methods 0.000 abstract description 34
- 210000004369 blood Anatomy 0.000 abstract description 29
- 239000008280 blood Substances 0.000 abstract description 29
- 238000010276 construction Methods 0.000 abstract description 9
- 238000007664 blowing Methods 0.000 abstract 3
- 229920005601 base polymer Polymers 0.000 abstract 1
- 239000002861 polymer material Substances 0.000 abstract 1
- 239000011148 porous material Substances 0.000 description 62
- 208000007536 Thrombosis Diseases 0.000 description 22
- 230000003247 decreasing effect Effects 0.000 description 18
- 230000001965 increasing effect Effects 0.000 description 18
- 239000000047 product Substances 0.000 description 17
- 239000012300 argon atmosphere Substances 0.000 description 16
- 238000000576 coating method Methods 0.000 description 16
- 238000000926 separation method Methods 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 239000011248 coating agent Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 13
- 239000003146 anticoagulant agent Substances 0.000 description 10
- 229940127219 anticoagulant drug Drugs 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 9
- 238000012258 culturing Methods 0.000 description 8
- 230000000399 orthopedic effect Effects 0.000 description 8
- 210000003491 skin Anatomy 0.000 description 8
- 210000004927 skin cell Anatomy 0.000 description 8
- 239000003868 thrombin inhibitor Substances 0.000 description 7
- 229940123900 Direct thrombin inhibitor Drugs 0.000 description 6
- 108090000190 Thrombin Proteins 0.000 description 6
- 229960004072 thrombin Drugs 0.000 description 6
- 210000001772 blood platelet Anatomy 0.000 description 5
- 238000004113 cell culture Methods 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 229920002635 polyurethane Polymers 0.000 description 5
- 102000009123 Fibrin Human genes 0.000 description 4
- 108010073385 Fibrin Proteins 0.000 description 4
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 229950003499 fibrin Drugs 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 206010053567 Coagulopathies Diseases 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000035602 clotting Effects 0.000 description 3
- 210000003527 eukaryotic cell Anatomy 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 229920000098 polyolefin Polymers 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 206010014522 Embolism venous Diseases 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 239000004809 Teflon Substances 0.000 description 2
- 229920006362 Teflon® Polymers 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 239000004019 antithrombin Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 239000010839 body fluid Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000005345 coagulation Methods 0.000 description 2
- 230000015271 coagulation Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- 230000014508 negative regulation of coagulation Effects 0.000 description 2
- 210000000440 neutrophil Anatomy 0.000 description 2
- 230000036542 oxidative stress Effects 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 239000004810 polytetrafluoroethylene Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 230000035882 stress Effects 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 208000004043 venous thromboembolism Diseases 0.000 description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 229920000536 2-Acrylamido-2-methylpropane sulfonic acid Polymers 0.000 description 1
- XHZPRMZZQOIPDS-UHFFFAOYSA-N 2-Methyl-2-[(1-oxo-2-propenyl)amino]-1-propanesulfonic acid Chemical compound OS(=O)(=O)CC(C)(C)NC(=O)C=C XHZPRMZZQOIPDS-UHFFFAOYSA-N 0.000 description 1
- 102000004411 Antithrombin III Human genes 0.000 description 1
- 108090000935 Antithrombin III Proteins 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 108010074860 Factor Xa Proteins 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 206010062506 Heparin-induced thrombocytopenia Diseases 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 108010094028 Prothrombin Proteins 0.000 description 1
- 102100027378 Prothrombin Human genes 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 229940122388 Thrombin inhibitor Drugs 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229960005348 antithrombin iii Drugs 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-QZABAPFNSA-N beta-D-glucosamine Chemical compound N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-QZABAPFNSA-N 0.000 description 1
- 230000032770 biofilm formation Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 230000001687 destabilization Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000002598 diffusion tensor imaging Methods 0.000 description 1
- 230000000678 effect on lipid Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- WQPDUTSPKFMPDP-OUMQNGNKSA-N hirudin Chemical class C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(OS(O)(=O)=O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H]1NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]2CSSC[C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@H](C(NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N2)=O)CSSC1)C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)CSSC1)C(C)C)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 WQPDUTSPKFMPDP-OUMQNGNKSA-N 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003100 immobilizing effect Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 150000002617 leukotrienes Chemical class 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000010687 lubricating oil Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 229920000447 polyanionic polymer Polymers 0.000 description 1
- 229920000867 polyelectrolyte Polymers 0.000 description 1
- 239000013047 polymeric layer Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229940039716 prothrombin Drugs 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000012959 renal replacement therapy Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 238000012876 topography Methods 0.000 description 1
- ZTWTYVWXUKTLCP-UHFFFAOYSA-N vinylphosphonic acid Chemical compound OP(O)(=O)C=C ZTWTYVWXUKTLCP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L75/00—Compositions of polyureas or polyurethanes; Compositions of derivatives of such polymers
- C08L75/04—Polyurethanes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
- A61L33/06—Use of macromolecular materials
- A61L33/08—Polysaccharides
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K5/00—Use of organic ingredients
- C08K5/16—Nitrogen-containing compounds
- C08K5/34—Heterocyclic compounds having nitrogen in the ring
- C08K5/3412—Heterocyclic compounds having nitrogen in the ring having one nitrogen atom in the ring
- C08K5/3415—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K5/00—Use of organic ingredients
- C08K5/36—Sulfur-, selenium-, or tellurium-containing compounds
- C08K5/43—Compounds containing sulfur bound to nitrogen
- C08K5/435—Sulfonamides
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L27/00—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a halogen; Compositions of derivatives of such polymers
- C08L27/02—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a halogen; Compositions of derivatives of such polymers not modified by chemical after-treatment
- C08L27/12—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a halogen; Compositions of derivatives of such polymers not modified by chemical after-treatment containing fluorine atoms
- C08L27/16—Homopolymers or copolymers or vinylidene fluoride
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L27/00—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a halogen; Compositions of derivatives of such polymers
- C08L27/02—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a halogen; Compositions of derivatives of such polymers not modified by chemical after-treatment
- C08L27/12—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a halogen; Compositions of derivatives of such polymers not modified by chemical after-treatment containing fluorine atoms
- C08L27/18—Homopolymers or copolymers or tetrafluoroethene
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L81/00—Compositions of macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing sulfur with or without nitrogen, oxygen or carbon only; Compositions of polysulfones; Compositions of derivatives of such polymers
- C08L81/06—Polysulfones; Polyethersulfones
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L2201/00—Properties
- C08L2201/02—Flame or fire retardant/resistant
Definitions
- the object of the invention is an organic material with pore-forming, anti inflammatory and anticoagulant properties, intended in particular for the construction of medical devices, in particular for the construction of components in direct contact with blood, and a method for obtaining it.
- Materials with pore-forming properties are used to make selective membranes, that is, membranes that only allow particles of a certain size to pass through. Such materials are used, among other things, to make membranes for use in the manufacture of everyday objects such as: tents, jackets, filters, but also osmotic membranes for medical applications: in filters for renal replacement therapy and in oxygenators for blood oxygenation.
- PL225257 patent description presents a membrane system for local immobilization of eukaryotic cells, having a support and at least one bilayer formed successively from one polyelectrolyte layer comprising polysaccharide hydrogels, especially sodium alginate containing in its structure incorporated fullerenol and protein A, characterized in that the first layer is applied directly to the group of isolated cells then seated on a support made of the same material in terms of composition, and a second polymeric layer of aliphatic secondary and tertiary amines - containing ethyl or methyl groups with incorporated fullerenol.
- a single layer is applied directly to a group of isolated eukaryotic cells, and it allows eukaryotic cells to be isolated from the external environment, particularly microorganisms, while not restricting nutrient transport across the membrane, allowing for directed growth.
- PL212620 patent description presents a specially modified polyolefin membrane (PP, PE) and a method of modifying microporous polyolefin membranes intended for the isolation of Gram(+) bacteria, consisting in that a solution of polycation, selected from the group consisting of aliphatic amino acids, especially protein amino acids, preferably polar and dissolved in NaCl solution, is introduced into the structure of polyolefin membrane of high porosity in a known way, preferably by soaking, and then the solution of polyanion, selected from the group consisting of polymeric secondary and tertiary amines, especially methylamine and ethylamine, preferably containing 100% methyl or ethyl groups, dissolved in a solution of NaCl.
- a solution of polycation selected from the group consisting of aliphatic amino acids, especially protein amino acids, preferably polar and dissolved in NaCl solution
- polyanion selected from the group consisting of polymeric secondary and tertiary amine
- PL197199 patent description presents a polymeric proton-conducting membrane based on hydrated poly(perfluorosulfonic acid), characterized in that it is a reaction product of radiation-induced grafting of poly(perfluorosulfonic acid) with vinylphosphonic acid used in an amount of 1 to 40% by weight or 2-acrylamido-2-methylpropanesulfonic acid used in an amount of 1 to 40% by weight.
- PL165872 patent description presents a method for producing a multilayer porous membrane of polytetrafluoroethylene containing at least two layers having pores of different average diameters, which includes the steps of: filling the extruder barrel with at least two different types of fine polytetrafluoroethylene powders, with a liquid lubricant mixed with each.
- EP0409496 patent description presents a process for preparing microporous membranes containing at least a partially crystalline aromatic polymer containing ether or thioether and ketone bonds in the chain.
- the process allows membranes to be made from certain aromatic polymers with high melting points, such as PEDK.
- polypropylene (PP) and polyurethane (PU) have mainly been used as pore forming materials in medical applications.
- polyurethane was used as a porous material for the construction of membranes
- polypropylene was used for the construction of elements for separation of membrane layers (spacers).
- spacers the high efficiency of such membranes in terms of gas exchange, they have limitations mainly related to the initiation of inflammatory reaction from the low bioinertness of these materials. This affected the formation of progressively growing thrombi on the membrane surface.
- the amount of thrombi is already so high that the device is no longer suitable for further operation (does not perform its function) and the entire oxygenator system must be replaced.
- the anti inflammatory effects of albumins include inhibition of leukotriene production by neutrophils and thrombocytes and decreased sensitivity of neutrophils to inflammatory cytokines.
- their anticoagulant effect is through activation of antithrombin III and inhibition of thrombocyte aggregation.
- argatroban a synthetic analogue of hirudin, which is a small-molecule direct thrombin inhibitor (DTI) used for anticoagulant therapy in patients with heparin-induced thrombocytopenia type II who require parenteral anticoagulant therapy.
- DTI direct thrombin inhibitor
- DTI direct specific thrombin inhibitors
- Bivalirudin is also known - an anticoagulant from a group of direct specific thrombin inhibitors (DTI). DTIs block the active site responsible for the main thrombin action and/or the external site where the substrate is recognized and spatially correctly oriented. The action of these inhibitors is direct and does not depend on the presence of antithrombin. Unlike indirect DTI inhibitors, they can inhibit fibrin-bound thrombin, which prevents thrombin from splitting fibrinogen to fibrin monomers, activating factors XIII, V, VIII, and stimulating thrombocytes to aggregate.
- a compound with an anticoagulant effect is also fondaparinux - an organic chemical compound, an oligosaccharide. It is a synthetic pentasaccharide with a sequence identical with the pentasaccharide hydrolysis products of fondaparinux, and contains an additional methyl group at the reducing end. It is a selective inhibitor of factor Xa.
- Fondaparinux is used as an anticoagulant to prevent the formation of thrombi and is used as standard in patients undergoing surgery and immobilized due to disease, in venous thromboembolism, acute coronary syndromes.
- Heparin an organic chemical compound, a polysaccharide composed primarily of N-sulfate and O-sulfate of glycosaminoglycan made up of D-glucosamine and L-iduronic acid radical linked into an unbranched chain, also exhibits anticoagulant activity.
- Heparin is a natural agent that, by inhibiting the transition of prothrombin to thrombin, causes a potent blood anticoagulant effect and, due to its effect on lipids through lipase activation, is also used as an anticoagulant used for anticoagulant coatings. When released in a controlled manner, it can also inhibit thrombocyte aggregation and adhesion (sticking to surfaces) to blood vessel walls.
- Heparin is trapped by the vessel walls and increases their negative charge, making it difficult for thrombocytes to adhere and preventing the formation of wall clots. Heparin is used as an anticoagulant to prevent thrombus formation, standard treatment for patients undergoing surgery and immobilized due to disease, in venous thromboembolism, acute coronary syndromes.
- the essence of the invention is an organic material with pore-forming, anti-inflammatory and anticoagulant properties, comprising:
- - base in the form of a fluoropolymer, preferably poly(tetrafluoroethylene) (PTFE, Teflon) or polyvinylidene fluoride (PVDF) or a copolymer of tetrafluoroethylene and hexafluoropropylene (FEP), and
- PTFE poly(tetrafluoroethylene)
- PVDF polyvinylidene fluoride
- FEP hexafluoropropylene
- the essence thereof is an organic material with pore-forming, anti-inflammatory and anticoagulant properties, comprising:
- - base in the form of polypropylene (PP) or polyurethane (PU) or polyethylene terephthalate (PET) or polycarbonate (PC) or polyoxymethylene (POM) or polysulfone (PSU) or silicone or fluoropolymer, preferably poly (tetrafluoroethylene) (PTFE) or polyvinylidene fluoride (PVDF) or a copolymer of tetrafluoroethylene and hexafluoropropylene (FEP),
- PP polypropylene
- PU polyurethane
- PET polyethylene terephthalate
- PC polycarbonate
- POM polyoxymethylene
- PSU polysulfone
- silicone or fluoropolymer preferably poly (tetrafluoroethylene) (PTFE) or polyvinylidene fluoride (PVDF) or a copolymer of tetrafluoroethylene and hexafluoropropylene (FEP),
- the essence of the invention also comprises a method for obtaining an organic material with pore-forming, anti-inflammatory and anticoagulant properties, in the first variant, characterized in that a base material in the form of a fluoropolymer, preferably poly(tetrafluoroethylene) (PTFE) or polyvinylidene fluoride (PVDF) or a copolymer of tetrafluoroethylene and hexafluoropropylene (FEP) is extruded on a linear head in the form of a string, preferably with a diameter of 2 to 10 mm, or on a cross head in the form of a tube, preferably with an outer diameter of 2 to 10 mm, or on a flat head in the form of a foil preferably with a thickness of 0.1 to 3 mm, then the process of immobilization of active admixture in the form of albumin or argatroban or bivalimdin or fondaparinux or heparin to the steric structure of the material thus
- the essence of the invention also comprises a method for obtaining an organic material with pore-forming, anti-inflammatory and anticoagulant properties, in a second variation, characterized in that a polar solvent and an acid selected from the following ones are introduced into a reactor of a non-reactive material in an inert gas atmosphere: sulfuric acid VI, hydrochloric acid or acetic acid, in proportions from 2 ⁇ 0.002 to 7 ⁇ 0.002, preferably 5 ⁇ 0.002, and then per 50 mL of a mixture thus formed, 4-(diphenylamino)benzaldehyde in an amount from 0.2 g to 0.7 g and 1.3-indandione in a quantity of 0.01 g to 0.08 g are added and stirred until a homogeneous mixture is obtained in no less than 1 minute, after which the suspension is washed with inert gas for at least 5 minutes, preferably not more than 60 minutes, heated to boiling under a reflux condenser in an inert gas atmosphere and stirred intensely at 100-1000 r
- the resulting mixture is cooled to 20 to 35°C and subjected to column chromatography in a S1O2 bed and in the mobile phase of the mixture of hexane and methylene chloride, in amounts of hexane from 0.5 to 2 times the volume of the mixture, and methylene chloride from 0,5 to 2 times the volume of the reaction mixture. It is then vacuum-dried for at least 20 hours, preferably 24 hours to a constant weight, after which it is recrystallized from chloroform.
- the product after recrystallization from chloroform is placed in a homogenizer and the base is introduced as: polypropylene (PP) or polyurethane (PU) or polyethylene terephthalate (PET) or polycarbonate (PC) or polyoxymethylene (POM) or polysulfone (PSU) or silicone or fluoropolymer, preferably poly(tetrafluoroethylene) (PTFE) or polyvinylidene fluoride (PVDF) or a copolymer of tetrafluoroethylene and hexafluoropropylene (FEP), in the proportion of the base- recrystallizate from 50 ⁇ 2 to 5000 ⁇ 2, preferably 100 ⁇ 2, and then mixed to a homogeneous mixture and dried for at least 20 hours at 80-110°C, after which the material is extruded on a linear head is extruded on a linear head in the form of a string, preferably with an outer diameter of 2 to 10 mm, or
- the method according to the invention in the second variant is carried out in a glass, ceramic or stainless steel reactor.
- the method according to the invention in the second variant is carried out in a reactor in the form of a round-bottomed three-necked flask, due to its good functional properties.
- argon or nitrogen or xenon is used as the inert gas.
- anhydrous ethanol is used as the polar solvent.
- the base material is added in the form of a crushed material or aggregate or most preferably granulate.
- a cyclic decrease and increase of the stress is applied, which increases the efficiency of the immobilization of the active admixture in the pores of the material.
- the chemical structure of macromolecules of materials obtained by the method according to the invention affects their good pore-forming properties and at the same time ensures its biocompatibility and bioinertness (full neutrality).
- these materials are used to manufacture membranes for oxygenators, the risk of inducing inflammation is reduced, and thus the process of coagulation on the membrane slows down.
- the method according to the invention makes it possible to obtain materials with a pore size in the nano range so that a single molecule of oxygen and carbon dioxide is able to penetrate the pores, and at the same time so that the pores are smaller than the macromolecular packets of which body fluids are composed, which in effect makes it possible to effectively oxygenate the blood without the risk of blood molecules penetrating the pores.
- the solution according to the invention makes it possible to obtain membranes with a very wide range of pore sizes from nano/micro scale (application especially for oxygenation, gas exchange) to macro pore size of even tenths of a millimeter (application as waterproof, breathable materials).
- the method according to the invention makes it possible to precisely control the size of the pores formed.
- an immobilized active admixture allows its concentration on the piece contact surface to remain constant throughout the application of the materials (planned product life). The possibility of excessive leaching of the active admixture is minimized, and because of the diffusion-controlled release of the active admixture, its contact concentration on the product surface is constant.
- the active admixture into the material according to the invention also gives the material the desired anti-coagulant and anti-inflammatory properties.
- Substances used as active admixture, as noted above, have strong anticoagulant effect.
- the active admixture is embedded both in the pores of the material and in microcracks formed as equilibrium defects during the material formation stage. This significantly improves the surface continuity of the material structure and thus prevents organic material from depositing in pores and microcracks and significantly reduces coagulation.
- Example 1 A method for preparing an organic material with pore-forming, anti-inflammatory and anticoagulant properties with the addition of an active admixture according to the invention will be further explained by means of the following examples.
- Example 1 A method for preparing an organic material with pore-forming, anti-inflammatory and anticoagulant properties with the addition of an active admixture according to the invention will be further explained by means of the following examples.
- the material in the form of PTFE granules is extruded on a linear head in the form of a string, with a diameter of 2 mm and then after initial cooling in a bath containing a supersaturated aqueous solution of albumin to a temperature 20°C lower than the plastic transition temperature, it is stretched on calenders to obtain a 10-fold elongation.
- a supersaturated aqueous solution of albumin to a temperature 20°C lower than the plastic transition temperature
- calenders cyclic decreasing and increasing of tension in the range of 60 ⁇ 90% of tension is used to obtain a 10-fold elongation.
- Its elongation process is carried out in two directions to form a flat foil from the string. This type of process yields an albumin-to-base ratio of 1:100.
- the Teflon-based material thus obtained can be used as a thrombus filter in medical equipment due to its high biocompatibility.
- the resulting pores are characterized by sizes ranging from 1 nanometer to 300 micrometers. Systems having pore sizes between 75 and 150 micrometers are ideal for cell culture. Systems with pores in the order of nanometers can be used to create gas-permeable membranes for example in a blood oxygenation and oxygenation process.
- the material in the form of PVDF granules and aggregate is extruded on a flat head in the form of a foil with a thickness of 0,1 mm, after which the process of immobilization of argatroban to the steric structure of the material so obtained is carried out in such a way that, after initial cooling in a bath containing a supersaturated aqueous solution of argatroban to a temperature of 20°C lower than the plastic transition temperature, it is elongated on calenders so as to obtain a 15-fold elongation. The elongation process is carried out in two directions to obtain a foil. This type of process yields an argatroban-to-base ratio of 1:140.
- the polyvinylidene fluoride -based material thus obtained can be used as a thrombus filter in medical equipment due to its high biocompatibility.
- the resulting pores are characterized by sizes ranging from 1 nanometer to 300 micrometers. Systems having pore sizes between 75 and 150 micrometers are ideal for cell culture. Systems with pores in the order of nanometers can be used to create gas-permeable membranes for example in a blood oxygenation and oxygenation process.
- the material in the form of crushed FEP is extruded on a cross head in the form of a tube with an outer diameter of 3 mm, after which the process of immobilization of bivalimdin to the steric structure of the material so obtained is carried out in such a way that, after initial cooling in a bath containing a supersaturated aqueous solution of bivalimdin to a temperature 15°C higher than the plastic transition temperature, it is stretched on calenders so as to obtain a 5-fold elongation. During calendering, cyclic decreasing and increasing of tension in the range of 60 ⁇ 90% of tension is used to obtain a 5-fold elongation. This type of process yields a bivalimdin-to-base ratio of 1:1200.
- the material thus obtained based on a copolymer of tetrafluoroethylene and hexafluoropropylene can be used as a thrombus filter in medical equipment due to its high biocompatibility.
- the resulting pores are characterized by sizes ranging from 1 nanometer to 300 micrometers. Systems having pore sizes between 75 and 150 micrometers are ideal for cell culture. Systems with pores in the order of nanometers can be used to create gas- permeable membranes for example in a blood oxygenation and oxygenation process.
- the PTFE granules are extruded on a flat head in the form of a 1 mm thick foil, after which the process of immobilization of the fondaparinux into the steric structure of the material so obtained is carried out, in such a way that, after initial cooling of the material in a bath containing a supersaturated aqueous solution of the fondaparinux to a temperature 20°C lower than the plastic transition temperature, it is stretched by cyclically increasing and decreasing the tension in the range of 60 ⁇ 90% on the calenders until a 15-fold elongation is obtained and fondaparinux is incorporated into the steric structure of the material.
- This type of process yields a fondaparinux-to-base ratio of 1:1200.
- the poly(tetrafluoroethylene)-based material thus obtained can be used as a thrombus filter in medical equipment due to its high biocompatibility, or as a semi-permeable coating for rainproofing with high single molecule water vapor separation properties, or as a breathable material in contact with skin, for example for making wound dressing plasters, kinesiology tapes, orthopedic insoles, etc.
- the resulting pores are characterized by sizes ranging from 1 nanometer to 150 micrometers. Systems having pore sizes between 75 and 150 micrometers are ideal for culturing skin cells. Systems having pores in the order of nanometers can be used to create gas-permeable membranes in blood oxygenation and oxygenation process, for example.
- the PVDF granules are extruded on a flat head in the form of a 0.1 mm thick foil, followed by a process of immobilization of heparin into the steric structure of the material so obtained, in such a way that, after the material is initially cooled in a bath containing a supersaturated aqueous solution of heparin to a temperature of 20°C below the plastic transition temperature, it is stretched on calenders until a 5-fold elongation and incorporation of heparin into the steric structure of the material. The elongation process is carried out in two directions to obtain a foil. This type of process yields a heparin-to-base ratio of 1:800.
- the PVDF-based material thus obtained can be used as a thrombus filter in medical equipment due to its high biocompatibility or as a semi-permeable coating for rainproofing with high single molecule water vapor separation properties or as a breathable material in contact with the skin, for example for the manufacture of wound dressing plasters, kinesiology tapes, orthopedic insoles, etc.
- the resulting pores are characterized by sizes ranging from 1 nanometer to 150 micrometers. Systems having pore sizes between 75 and 150 micrometers are ideal for culturing skin cells. Systems having pores in the order of nanometers can be used to create gas-permeable membranes in blood oxygenation and oxygenation, for example.
- the crushed FEP is extruded on a linear head in the form of a string with a diameter of 5 mm, and then the process of immobilization of heparin into the steric structure of the material so obtained is carried out in such a way that, after initial cooling of the material in a bath containing a supersaturated aqueous solution of heparin to a temperature of 30°C below the plastic transition temperature, it is stretched by cyclically increasing and decreasing the tension in the range of 60 ⁇ 90% on the calenders until a 5-fold elongation is obtained and heparin is incorporated into the steric structure of the material.
- the elongation process is carried out in two directions to form a flat foil from the string. This type of process yields a heparin-to-base ratio of 1 :200.
- the FEP-based material thus obtained can be used as a thrombus filter in medical equipment due to its high biocompatibility or as a semi-permeable coating for rainproofing with high single molecule water vapor separation properties or as a breathable material in contact with the skin, for example for the manufacture of wound dressing plasters, kinesiology tapes, orthopedic insoles, etc.
- the resulting pores are characterized by sizes ranging from 1 nanometer to 150 micrometers. Systems having pore sizes between 75 and 150 micrometers are ideal for culturing skin cells. Systems having pores in the order of nanometers can be used to create gas-permeable membranes in blood oxygenation and oxygenation, for example.
- the PVDF granules are extruded on a flat head in the form of a 0.1 mm thick foil, after which the process of immobilizing the fondaparinux into the steric structure of the material so obtained is carried out, in such a way that, after the material is initially cooled in a bath containing a supersaturated aqueous solution of fondaparinux to a temperature 25 °C below the plastic transition temperature, it is stretched on calenders until a 5-fold elongation is obtained and the fondaparinux is incorporated into the steric structure of the material.
- This type of process yields a fondaparinux/base ratio of 1:800.
- the PVDF-based material thus obtained can be used as a thrombus filter in medical equipment due to its high biocompatibility or as a semi-permeable coating for rainproofing with high single molecule water vapor separation properties or as a breathable material in contact with the skin, for example for the manufacture of wound dressing plasters, kinesiology tapes, orthopedic insoles, etc.
- the resulting pores are characterized by sizes ranging from 1 nanometer to 150 micrometers. Systems having pore sizes between 75 and 150 micrometers are ideal for culturing skin cells. Systems having pores in the order of nanometers can be used to create gas-permeable membranes, for example, in blood oxygenation and oxygenation.
- the system After obtaining a homogeneous mixture, the system is cooled down to 20°C and subjected to column chromatography in a S1O2 bed and in the mobile phase of the mixture of hexane and methylene chloride, in an amount of hexane equal to 0.5 times the volume of the reaction mixture and methylene chloride equal to 0.5 times the volume of the reaction mixture.
- the product is then vacuum-dried for 24 hours to a constant mass, after which it is recrystallized from chloroform, the recry stallizate is placed in a homogenizer and 25 g of crushed PTFE is added.
- the system is mixed until a homogeneous mixture is obtained and dried for 20 hours at 80°C.
- the material is extruded on a linear head in the form of a string with a diameter of 3 mm, after cooling in a bath containing a supersaturated aqueous solution of albumin to a temperature 20°C lower than the plastic transition temperature, it is stretched by cyclic increasing and decreasing the tension in the range of 60 ⁇ 90% on calenders until an 8 -fold elongation is obtained and albumin is incorporated into the steric structure of the material.
- the elongation process is carried out linearly maintaining the form of the string. This type of process yields an albumin-to-base ratio of 1:150.
- the poly(tetrafluoroethylene) based material thus obtained can be used as a thrombus filter in medical equipment or as a semi-permeable coating for rain protection with high single molecule water vapor separation properties.
- the material obtained in this way makes it possible to create pores with a range of 150 micrometers.
- the system After obtaining a homogeneous mixture, the system is cooled down to 25°C and subjected to column chromatography in a S1O2 bed and in a mobile phase of the mixture of hexane and methylene chloride, in an amount of hexane equal to 1 times the volume of the reaction mixture, and of methylene chloride equal to 1 times the volume of the reaction mixture.
- the product is then vacuum-dried to a constant mass for 24 hours, followed by recrystallization from chloroform, the recry stallizate is placed in a homogenizer and 50 g of PP aggregate is added.
- the system is mixed until a homogeneous mixture is obtained and dried for 20 hours at 100°C.
- the material is extruded on a cross head in the form of a tube with a diameter of 9 mm, after cooling in a bath containing a supersaturated aqueous solution of albumin to a temperature of 25°C lower than the plastic transition temperature, it is stretched by cyclic increasing and decreasing the tension in the range of 60 ⁇ 90% on calenders until 7-fold elongation is obtained and albumin is incorporated into the steric structure of the material.
- This type of process yields an albumin-to-base ratio of 1:350.
- the polypropylene-based material thus obtained can be used as a thrombus filter in medical equipment or as a semi-permeable coating for rainproofing with high single molecule water vapor separation properties.
- the material obtained in this way makes it possible to create pores of 30 micrometers.
- the system After obtaining a homogeneous mixture, the system is cooled down to 30°C and subjected to column chromatography in a S1O2 bed and in a mobile phase of the mixture of hexane and methylene chloride, in an amount of hexane equal to 2 times the volume of the reaction mixture, and of methylene chloride equal to 2 times the volume of the reaction mixture.
- the product is then vacuum-dried for 24 hours to a constant mass, after which it is recrystallized from chloroform, the recry stallizate is placed in a homogenizer and 28 g of PU granulate is added.
- the system is mixed until a homogeneous mixture is obtained and dried for 24 hours at 110°C.
- the material is extruded on a flat head in the form of a foil with a thickness of 0.1 mm, after cooling in a bath containing a supersaturated aqueous solution of albumin to a temperature 20°C lower than the plastic transition temperature, it is stretched by cyclic increasing and decreasing the tension in the range of 60 ⁇ 90% on calenders until a 15-fold elongation is obtained and albumin is incorporated into the steric structure of the material.
- the elongation process is carried out in two directions to obtain a foil. This type of process yields an albumin-to-base ratio of 1:150.
- the resulting polyurethane -based material can be used as a thrombus filter in medical equipment due to its high biocompatibility or as a semi-permeable coating for rainproofing with high single molecule water vapor separation properties or as a breathable material in contact with the skin for example: wound dressing plasters, kinesiology tapes, orthopedic insoles, etc.
- the resulting pores are characterized by sizes ranging from 1 nanometer to 150 micrometers. Systems having pore sizes between 75 and 150 micrometers are ideal for culturing skin cells. Systems with pores in the order of nanometers can be used to create gas- permeable membranes for example in a blood oxygenation and oxygenation process.
- the system After obtaining a homogeneous mixture, the system is cooled down to 25°C and subjected to column chromatography in a S1O2 bed and in a mobile phase of the mixture of hexane and methylene chloride, in an amount of hexane equal to 1.5 times the volume of the reaction mixture, and of methylene chloride equal to 1.5 times the volume of the reaction mixture.
- the product is then vacuum-dried to a constant mass for 24 hours, followed by recrystallization from chloroform, the recry stallizate is placed in a homogenizer and 42 g of crushed PET is added. The system is mixed until a homogeneous mixture is obtained and dried for 20 hours at 80°C.
- the material is extruded on a flat head in the form of a foil with a thickness of 1 mm and after cooling in a bath containing a supersaturated aqueous solution of argatroban to a temperature 30°C lower than the plastic transition temperature, it is stretched by cyclic increasing and decreasing the tension in the range of 60 ⁇ 90% on calenders until a 10-fold elongation is obtained and argatroban is incorporated into the steric structure of the material.
- This type of process yields an argatroban-to-base ratio of 1:150.
- the poly(ethylene terephthalate) -based material thus obtained can be used as a thrombus filter in medical equipment or as a semi-permeable coating for rainproofing with high single molecule water vapor separation properties.
- the material obtained in this way makes it possible to create pores in the range of 150 micrometers.
- the system After obtaining a homogeneous mixture, the system is cooled down to 25°C and subjected to column chromatography in a S1O2 bed and in a mobile phase of the mixture of hexane and methylene chloride, in an amount of hexane equal to 1 times the volume of the reaction mixture, and of methylene chloride equal to 1 times the volume of the reaction mixture.
- the product is then vacuum-dried to a constant mass for 24 hours, followed by recrystallization from chloroform, the recry stallizate is placed in a homogenizer and 40 g of PC aggregate is added. The system is mixed until a homogeneous mixture is obtained and dried for 20 hours at 100°C.
- the material is extruded on a linear head in the form of an 8 mm diameter string, and after cooling in a bath containing a supersaturated aqueous argatroban solution to a temperature 10°C lower than the plastic transition temperature, it is stretched by cyclically increasing and decreasing the tension in the range of 60 ⁇ 90% on calenders until a 10-fold elongation is obtained and argatroban is incorporated into the steric structure of the material. Its elongation process is carried out in two directions to form a flat foil from the string. This type of process yields an argatroban-to-base ratio of 1:150.
- the polycarbonate-based material thus obtained can be used as a water filter or as a semi-permeable coating for rain protection with high single molecule water vapor separation properties.
- the resulting pores are characterized by sizes ranging from 1 to 300 micrometers.
- the system After obtaining a homogeneous mixture, the system is cooled down to 30°C and subjected to column chromatography in a S1O2 bed and in a mobile phase of the mixture of hexane and methylene chloride, in an amount of hexane equal to 2 times the volume of the reaction mixture, and of methylene chloride equal to 2 times the volume of the reaction mixture.
- the product is then vacuum-dried for 24 hours to a constant mass, after which it is recrystallized from chloroform, the recry stallizate is placed in a homogenizer and 28 g of POM granulate.
- the system is mixed until a homogeneous mixture is obtained and dried for 24 hours at 110°C.
- the material is extruded on a linear head in the form of an 2 mm diameter string, and after cooling in a bath containing a supersaturated aqueous argatroban solution to 15°C below the plastic transition temperature, it is stretched by cyclically increasing and decreasing the tension in the range of 60 ⁇ 90% on calenders until a 15-fold elongation is obtained and argatroban is incorporated into the steric structure of the material. Its elongation process is carried out in two directions to form a flat foil from the string. This type of process yields an argatroban-to-base ratio of 1:350.
- the polyoxymethylene -based material thus obtained can be used as a thrombus filter in medical equipment due to its high biocompatibility.
- the resulting pores are characterized by sizes ranging from 1 nanometer to 300 micrometers. Systems having pore sizes between 75 and 150 micrometers are ideal for cell culture. Systems with pores in the order of nanometers can be used to create gas-permeable membranes for example in a blood oxygenation and oxygenation process.
- the system After obtaining a homogeneous mixture, the system is cooled down to 30°C and subjected to column chromatography in a S1O2 bed and in a mobile phase of the mixture of hexane and methylene chloride, in an amount of hexane equal to 0.5 times the volume of the reaction mixture and of methylene chloride equal to 0.5 times the volume of the reaction mixture.
- the product is then vacuum-dried for 24 hours to a constant mass, after which it is recrystallized from chloroform, the recrystallizate is placed in a homogenizer and 25 g of ground PSU is added. The system is mixed until a homogeneous mixture is obtained and dried for 20 hours at 80°C.
- the material is extruded on a linear head in the form of a string with a diameter of 3 mm, and after cooling in a bath containing a supersaturated aqueous solution of bivalirudin to a temperature 20°C lower than the plastic transition temperature, it is stretched by cyclic increasing and decreasing the tension in the range of 60 ⁇ 90% on calenders until a 10-fold elongation is obtained and bivalirudin is incorporated into the steric structure of the material.
- the elongation process is carried out linearly maintaining the form of the string. This type of process yields a bivalirudin-to-base ratio of 1:250.
- the polysulfone-based material thus obtained can be used as a thrombus filter in medical equipment due to its high biocompatibility.
- the resulting pores are characterized by sizes ranging from 1 nanometer to 300 micrometers. Systems having pore sizes between 75 and 150 micrometers are ideal for cell culture. Systems with pores in the order of nanometers can be used to create gas-permeable membranes for example in a blood oxygenation and oxygenation process.
- the system After obtaining a homogeneous mixture, the system is cooled down to 25°C and subjected to column chromatography in a S1O2 bed and in the mobile phase of the mixture of hexane and methylene chloride in a quantity of hexane equal to 1 times the volume of the reaction mixture and methylene chloride equal to 1 times the volume of the reaction mixture.
- the product is then vacuum-dried for 24 hours to a constant mass, after which it is recrystallized from chloroform, the recry stallizate is placed in a homogenizer and 25 g of ground PVDF is added.
- the system is mixed until a homogeneous mixture is obtained and dried for 20 hours at 100°C.
- the material is extruded on a linear head in the form of a string with a diameter of 2 mm, and after cooling in a bath containing a supersaturated aqueous solution of bivalimdin to a temperature 20°C lower than the plastic transition temperature, it is stretched by cyclic increasing and decreasing the tension in the range of 60 ⁇ 90% on the calenders until a 20-fold elongation is obtained and bivalimdin is incorporated into the steric structure of the material.
- the elongation process is carried out linearly maintaining the form of the string. This type of process yields a bivalirudin-to-base ratio of 1:80.
- the PVDF-based material thus obtained can be used as a thrombus filter in medical equipment due to its high biocompatibility, or as a semi-permeable coating for rainproofing with high single molecule water vapor separation properties, or as a breathable material in contact with skin, for example for making: wound dressing plasters, kinesiology tapes, orthopedic insoles, etc.
- the resulting pores are characterized by sizes ranging from 1 nanometer to 150 micrometers. Systems having pore sizes between 75 and 150 micrometers are ideal for culturing skin cells. Systems with pores in the order of nanometers can be used to create gas-permeable membranes for example in a blood oxygenation and oxygenation process.
- the system After obtaining a homogeneous mixture, the system is cooled down to 30°C and subjected to column chromatography in a S1O2 bed and in a mobile phase of the mixture of hexane and methylene chloride, in an amount of hexane equal to 2 times the volume of the reaction mixture, and of methylene chloride equal to 2 times the volume of the reaction mixture.
- the product is then vacuum-dried for 24 hours to a constant mass, after which it is recrystallized from chloroform, the recry stallizate is placed in a homogenizer and 28 g of FEP granulate.
- the system is mixed until a homogeneous mixture is obtained and dried for 24 hours at 110°C.
- the material is extruded on a cross head in the form of a tube with an outer diameter of 10 mm, after cooling in a bath containing a supersaturated aqueous solution of fondaparinux to a temperature of 15°C lower than the plastic transition temperature, it is stretched by cyclic increasing and decreasing the tension in the range of 60 ⁇ 90% on calenders until a 5-fold elongation is obtained and fondaparinux is incorporated into the steric structure of the material.
- This type of process yields a fondaparinux-to-base ratio of 1:1200.
- the FEP-based material thus obtained can be used as a thrombus filter in medical equipment due to its high biocompatibility or as a semi-permeable coating for rainproofing with high single molecule water vapor separation properties or as a breathable material in contact with the skin, for example for: wound dressing plasters, kinesiology tapes, orthopedic insoles, etc.
- the resulting pores are characterized by sizes ranging from 1 nanometer to 150 micrometers. Systems having pore sizes between 75 and 150 micrometers are ideal for culturing skin cells. Systems with pores in the order of nanometers can be used to create gas-permeable membranes for example in a blood oxygenation and oxygenation process.
- the system After obtaining a homogeneous mixture, the system is cooled down to 20°C and subjected to column chromatography in a S1O2 bed and in a mobile phase of the mixture of hexane and methylene chloride, in an amount of hexane equal to 0.5 times the volume of the reaction mixture, and of methylene chloride equal to 0.5 times the volume of the reaction mixture.
- the product is then vacuum-dried for 24 hours to a constant mass, after which it is recrystallized from chloroform, the recrystallizate is placed in a homogenizer and 21 g of PTFE granulate is added.
- the system is mixed until a homogeneous mixture is obtained and dried for 20 hours at 80°C.
- the material is extruded on a linear head in the form of a 3 mm diameter string, and after cooling in a bath containing a supersaturated aqueous fondaparinux solution to 20°C below the plastic transition temperature, it is stretched by cyclically increasing and decreasing the tension in the range of 60 ⁇ 90% on calenders until a 7-fold elongation is obtained and fondaparinux is incorporated into the steric structure of the material. Its elongation process is carried out in two directions to form a flat foil from the string. This type of process yields a fondaparinux/base ratio of 1:150.
- the poly(tetrafluoroethylene) based material thus obtained can be used as a thrombus filter in medical equipment or as a semi-permeable coating for rain protection with high single molecule water vapor separation properties.
- the material obtained in this way makes it possible to create pores in the range of 150 micrometers.
- the system After obtaining a homogeneous mixture, the system is cooled down to 25°C and subjected to column chromatography in a S1O2 bed and in a mobile phase of the mixture of hexane and methylene chloride, in an amount of hexane equal to 1 times the volume of the reaction mixture, and of methylene chloride equal to 1 times the volume of the reaction mixture.
- the product is then vacuum-dried to a constant mass for 24 hours, followed by recrystallization from chloroform, the recry stallizate is placed in a homogenizer and 45 g of PP aggregate is added.
- the system is mixed until a homogeneous mixture is obtained and dried for 20 hours at 100°C.
- the material is extruded on a linear head in the form of an 8 mm diameter string, and after cooling in a bath containing a supersaturated heparin solution to 10°C below the plastic transition temperature, it is stretched by cyclically increasing and decreasing the tension in the range of 60 ⁇ 90% on calenders until a 10-fold elongation is obtained and heparin is incorporated into the steric structure of the material.
- the elongation process is carried out linearly maintaining the form of the string. This type of process yields a heparin-to-base ratio of 1:350.
- the polypropylene-based material thus obtained can be used as a thrombus filter in medical equipment or as a semi-permeable coating for rainproofing with high single molecule water vapor separation properties.
- the material obtained in this way makes it possible to create pores in the range of 30 micrometers.
- the system After obtaining a homogeneous mixture, the system is cooled down to 30°C and subjected to column chromatography in a S1O2 bed and in a mobile phase of a mixture of hexane and methylene chloride, in an amount of hexane equal to 2 times the volume of the reaction mixture, and of methylene chloride equal to 2 times the volume of the reaction mixture.
- the product is then vacuum-dried for 24 hours to a constant mass, after which it is recrystallized from chloroform, the recry stallizate is placed in a homogenizer and 28 g of PU granulate is added.
- the system is mixed until a homogeneous mixture is obtained and dried for 24 hours at 110°C.
- the material is extruded on a flat head in the form of a foil with a thickness of 0.1 mm and after cooling in a bath containing a supersaturated aqueous heparin solution to a temperature 30°C lower than the plastic transition temperature, it is stretched by cyclic increasing and decreasing the tension in the range of 60 ⁇ 90% on calenders until a 15- fold elongation is obtained and heparin is incorporated into the steric structure of the material.
- the elongation process is carried out in two directions to obtain a foil. This type of process yields a heparin-to-base ratio of 1:150.
- the polyurethane-based material thus obtained can be used as a thrombus filter in medical equipment due to its high biocompatibility, or as a semi-permeable coating for rainproofing with high single molecule water vapor separation properties, or as a breathable material in contact with skin, for example for making: wound dressing plasters, kinesiology tapes, orthopedic insoles, etc.
- the resulting pores are characterized by sizes ranging from 1 nanometer to 150 micrometers. Systems having pore sizes between 75 and 150 micrometers are ideal for culturing skin cells. Systems with pores in the order of nanometers can be used to create gas-permeable membranes for example in a blood oxygenation and oxygenation process.
- the system After obtaining a homogeneous mixture, the system is cooled down to 25°C and subjected to column chromatography in a S1O2 bed and in a mobile phase of the mixture of hexane and methylene chloride, in an amount of hexane equal to 1.5 times the volume of the reaction mixture, and of methylene chloride equal to 1.5 times the volume of the reaction mixture.
- the product is then vacuum-dried to a constant mass for 24 hours, followed by recrystallization from chloroform, the recry stallizate is placed in a homogenizer and 50 g of crushed PET is added. The system is mixed until a homogeneous mixture is obtained and dried for 20 hours at 80°C.
- the material is extruded on a flat head in the form of a foil with a thickness of 1 mm and after cooling in a bath containing a supersaturated aqueous heparin solution to a temperature 30°C lower than the plastic transition temperature, it is stretched by cyclic increasing and decreasing the tension in the range of 60 ⁇ 90% on calenders until a 10-fold elongation is obtained and heparin is incorporated into the steric structure of the material.
- the elongation process is carried out in two directions to obtain a foil. This type of process yields a heparin-to-base ratio of 1:150.
- the poly(ethylene terephthalate) -based material thus obtained can be used as a thrombus filter in medical equipment or as a semi-permeable coating for rainproofing with high single molecule water vapor separation properties.
- the material obtained in this way makes it possible to create pores in the range of 150 micrometers.
- the method according to the invention makes it possible to obtain materials with pore forming, anti-inflammatory and anticoagulant properties, especially for the construction of medical equipment, in particular for components which are in direct contact with blood.
- the solution can be used to obtain blood oxygenation membranes and other gas-selective membranes.
Abstract
The object of the invention is an organic material with blowing, anti-inflammatory and anticoagulant properties characterized in that it comprises a base polymeric material and an active admixture in the form of albumin or argatroban or bivalirudin or fondaparinux or heparin, embedded in the microstructure of the base material in a base-active admixture ratio from 80÷1 to 1200÷1 and, in case of some types of base polymer materials, also from 4- (diphenylamino)benzaldehyde admixture in a base-active admixture ratio from 50÷1 to 5000÷1 and 1,3-indandione admixture in a base-active admixture ratio from 50÷1 to 5000÷1. The object of the invention is also a method for obtaining an organic material having blowing, anti-inflammatory and anticoagulant properties based on the fact that the base polymeric material is extruded on a linear head in the form of a string, or on a cross head in the form of a tube, or on a flat head in the form of a film, Then the process of immobilization of active admixture in the form of albumin, argatroban, bivalirudin, fondaparinux or heparin to the steric structure of the material obtained in such a way that its content in the material in the base-active admixture ratio is from 80÷1 to 1200÷1. The method according to the invention makes it possible to obtain materials with blowing, anti-inflammatory and anticoagulant properties, especially for the construction of medical equipment, in particular for components which are in direct contact with blood. Among other applications, the solution can be used to obtain blood oxygenation membranes and other gas-selective membranes.
Description
ORGANIC MATERIAL WITH PORE-FORMING, ANTI-INFLAMMATORY AND ANTICOAGULANT PROPERTIES AND THE METHOD OF ITS PREPARATION
The object of the invention is an organic material with pore-forming, anti inflammatory and anticoagulant properties, intended in particular for the construction of medical devices, in particular for the construction of components in direct contact with blood, and a method for obtaining it.
Materials with pore-forming properties are used to make selective membranes, that is, membranes that only allow particles of a certain size to pass through. Such materials are used, among other things, to make membranes for use in the manufacture of everyday objects such as: tents, jackets, filters, but also osmotic membranes for medical applications: in filters for renal replacement therapy and in oxygenators for blood oxygenation.
The most common, high-tech - in non-medical applications - pore-forming material (used, for example, in the manufacture of jackets), from which membranes were made is poly (tetrafluoroethylene) .
However, in medical applications, i.e. for the construction of medical devices, from the current state of the art various materials are known, including materials for the construction of porous membranes used in devices having direct contact with body fluids.
For example, PL225257 patent description presents a membrane system for local immobilization of eukaryotic cells, having a support and at least one bilayer formed successively from one polyelectrolyte layer comprising polysaccharide hydrogels, especially sodium alginate containing in its structure incorporated fullerenol and protein A, characterized in that the first layer is applied directly to the group of isolated cells then seated on a support made of the same material in terms of composition, and a second polymeric layer of aliphatic secondary and tertiary amines - containing ethyl or methyl groups with incorporated fullerenol. In this system, a single layer is applied directly to a group of isolated eukaryotic cells, and it allows eukaryotic cells to be isolated from the external environment, particularly microorganisms, while not restricting nutrient transport across the membrane, allowing for directed growth.
PL212620 patent description presents a specially modified polyolefin membrane (PP, PE) and a method of modifying microporous polyolefin membranes intended for the isolation of Gram(+) bacteria, consisting in that a solution of polycation, selected from the group consisting of aliphatic amino acids, especially protein amino acids, preferably polar and dissolved in NaCl solution, is introduced into the structure of polyolefin membrane of high porosity in a known way, preferably by soaking, and then the solution of polyanion, selected from the group consisting of polymeric secondary and tertiary amines, especially methylamine and ethylamine, preferably containing 100% methyl or ethyl groups, dissolved in a solution of NaCl.
Also PL197199 patent description presents a polymeric proton-conducting membrane based on hydrated poly(perfluorosulfonic acid), characterized in that it is a reaction product of
radiation-induced grafting of poly(perfluorosulfonic acid) with vinylphosphonic acid used in an amount of 1 to 40% by weight or 2-acrylamido-2-methylpropanesulfonic acid used in an amount of 1 to 40% by weight.
PL165872 patent description presents a method for producing a multilayer porous membrane of polytetrafluoroethylene containing at least two layers having pores of different average diameters, which includes the steps of: filling the extruder barrel with at least two different types of fine polytetrafluoroethylene powders, with a liquid lubricant mixed with each.
EP0409496 patent description presents a process for preparing microporous membranes containing at least a partially crystalline aromatic polymer containing ether or thioether and ketone bonds in the chain. The process allows membranes to be made from certain aromatic polymers with high melting points, such as PEDK.
The type of materials from which the membranes known from the above solutions were made allows - for steric reasons - their use for blood oxygenation, however their significant biochemical limitations significantly limit this application. This is because these membranes did not contain additives to provide anticoagulant release, which was a significant disadvantage in such applications. Moreover, due to their structure, they are characterized by developed surface topography on the micrometer scale, which was the reason for their negative effects on living organisms. At the cellular level, these membranes cause steric damage to cell membranes, resulting in cell destabilization. Furthermore, membranes cannot inhibit thrombus formation and do not protect against bacterial biofilm formation.
So far, polypropylene (PP) and polyurethane (PU) have mainly been used as pore forming materials in medical applications. For example, in devices used in the process of oxygenation of blood, polyurethane was used as a porous material for the construction of membranes, and polypropylene was used for the construction of elements for separation of membrane layers (spacers). Despite the high efficiency of such membranes in terms of gas exchange, they have limitations mainly related to the initiation of inflammatory reaction from the low bioinertness of these materials. This affected the formation of progressively growing thrombi on the membrane surface. In this case, in order to maintain the effectiveness of blood oxygenation, it was necessary to increase the oxygen concentration, which induces oxidative stress and intensifies the clotting process, triggering an unfavorable cascade of rapidly consecutive adverse factors, because the oxygen concentration must be constantly increased to maintain the blood saturation level, and this intensifies oxidative stress and enhances clotting.
After crossing a certain threshold, the amount of thrombi is already so high that the device is no longer suitable for further operation (does not perform its function) and the entire oxygenator system must be replaced.
Consequently, there was a need to develop new membrane materials, especially for medical applications, that would allow for a high level of pore-forming properties, while also ensuring their biocompatibility and bioinertness (neutrality) when in contact with patient blood. The reason for using new materials for the membrane in the oxygenator is the need to reduce the risk of inducing inflammation, thereby slowing down the clotting process on the membrane and extending the life of the device.
Various compounds with anticoagulant activity are known from the state of the art. Among others, we know albumins - blood proteins produced in the liver and responsible for maintaining oncotic pressure in blood vessels, transport of substances poorly soluble in plasma (fatty acids, some hormones, calcium ions) and buffering blood. The anti inflammatory effects of albumins include inhibition of leukotriene production by neutrophils and thrombocytes and decreased sensitivity of neutrophils to inflammatory cytokines. On the other hand, their anticoagulant effect is through activation of antithrombin III and inhibition of thrombocyte aggregation. Also known is argatroban, a synthetic analogue of hirudin, which is a small-molecule direct thrombin inhibitor (DTI) used for anticoagulant therapy in patients with heparin-induced thrombocytopenia type II who require parenteral anticoagulant therapy. The first mechanism of DTI action involves blocking the active site of thrombin, whereas the second involves inhibition of the fibrin binding site, where the substrate is recognized and spatially correctly oriented. The action of these inhibitors is direct and does not depend on the presence of antithrombin. Unlike indirect DTI inhibitors, they can inhibit fibrin-bound thrombin. Bivalirudin is also known - an anticoagulant from a group of direct specific thrombin inhibitors (DTI). DTIs block the active site responsible for the main thrombin action and/or the external site where the substrate is recognized and spatially correctly oriented. The action of these inhibitors is direct and does not depend on the presence of antithrombin. Unlike indirect DTI inhibitors, they can inhibit fibrin-bound thrombin, which prevents thrombin from splitting fibrinogen to fibrin monomers, activating factors XIII, V, VIII, and stimulating thrombocytes to aggregate. A compound with an anticoagulant effect is also fondaparinux - an organic chemical compound, an oligosaccharide. It is a synthetic pentasaccharide with a sequence identical with the pentasaccharide hydrolysis products of fondaparinux, and contains an additional methyl group at the reducing end. It is a selective inhibitor of factor Xa. Fondaparinux is used as an anticoagulant to prevent the formation of thrombi and is used as standard in patients undergoing surgery and immobilized due to disease, in venous thromboembolism, acute coronary syndromes. Heparin, an organic chemical compound, a polysaccharide composed primarily of N-sulfate and O-sulfate of glycosaminoglycan made up of D-glucosamine and L-iduronic acid radical linked into an unbranched chain, also exhibits anticoagulant activity. Heparin is a natural agent that, by inhibiting the transition of prothrombin to thrombin, causes a potent blood anticoagulant effect and, due to its effect on lipids through lipase activation, is also used as an anticoagulant used for anticoagulant coatings. When released in a controlled manner, it can also inhibit thrombocyte aggregation and adhesion (sticking to surfaces) to blood vessel walls. Heparin is trapped by the vessel walls and increases their negative charge, making it difficult for thrombocytes to adhere and preventing the formation of wall clots. Heparin is used as an anticoagulant to prevent thrombus formation, standard treatment for patients undergoing surgery and immobilized due to disease, in venous thromboembolism, acute coronary syndromes.
So far, however, there are no known materials with pore-forming, anti-inflammatory and anticoagulant properties, containing immobilized in their composition active admixtures of albumin, argatroban, bivalirudin, fondaparinux or heparin, semi -permeable to gases, especially for the construction of membranes used in medical gas exchange systems,
especially for blood oxygenation (oxygenators) and effective ways of obtaining such materials, and their development has become the aim of the authors of the present invention.
In a first variation of the invention, the essence of the invention is an organic material with pore-forming, anti-inflammatory and anticoagulant properties, comprising:
- base in the form of a fluoropolymer, preferably poly(tetrafluoroethylene) (PTFE, Teflon) or polyvinylidene fluoride (PVDF) or a copolymer of tetrafluoroethylene and hexafluoropropylene (FEP), and
- active admixture in the form of albumin or argatroban or bivalimdin or fondaparinux or heparin, embedded in the micro structure of the base material, in the proportion base-active admixture from 80÷1 to 1200÷1, preferably 150÷1.
In a second variation of the invention, the essence thereof is an organic material with pore-forming, anti-inflammatory and anticoagulant properties, comprising:
- base in the form of polypropylene (PP) or polyurethane (PU) or polyethylene terephthalate (PET) or polycarbonate (PC) or polyoxymethylene (POM) or polysulfone (PSU) or silicone or fluoropolymer, preferably poly (tetrafluoroethylene) (PTFE) or polyvinylidene fluoride (PVDF) or a copolymer of tetrafluoroethylene and hexafluoropropylene (FEP),
- 4-(diphenylamino)benzaldehyde admixture in a base-to-admixture ratio from 50÷1 to 5000÷1, preferably 100÷1,
- admixture of 1,3-indandione in a base-to-admixture ratio from 50÷1 to 5000÷1, preferably 100÷1, and
- active admixture in the form of albumin or argatroban or bivalimdin or fondaparinux or heparin, embedded in the micro structure of the base material, in the proportion base-active admixture from 80÷1 to 1200÷1, preferably 150÷1.
The essence of the invention also comprises a method for obtaining an organic material with pore-forming, anti-inflammatory and anticoagulant properties, in the first variant, characterized in that a base material in the form of a fluoropolymer, preferably poly(tetrafluoroethylene) (PTFE) or polyvinylidene fluoride (PVDF) or a copolymer of tetrafluoroethylene and hexafluoropropylene (FEP) is extruded on a linear head in the form of a string, preferably with a diameter of 2 to 10 mm, or on a cross head in the form of a tube, preferably with an outer diameter of 2 to 10 mm, or on a flat head in the form of a foil preferably with a thickness of 0.1 to 3 mm, then the process of immobilization of active admixture in the form of albumin or argatroban or bivalimdin or fondaparinux or heparin to the steric structure of the material thus obtained is carried out in a manner ensuring its content in the material in the ratio base-active admixture from 80÷1 to 1200÷1, preferably 150÷1, in such a way, that after initial cooling in a bath containing a supersaturated aqueous solution of the active admixture to a temperature ±30°C from the plastic transition temperature, preferably below the plastic transition temperature, it is stretched on calenders (by known methods of forming fibers or foils) to obtain an elongation of 5÷20 times, preferably 10 times, which results in the formation of micropores in which the active admixture immobilizes, whereby in a variant with an extruded string, the elongation process is carried out linearly - maintaining the string form, or in two directions - forming a flat foil from the string.
The essence of the invention also comprises a method for obtaining an organic material with pore-forming, anti-inflammatory and anticoagulant properties, in a second
variation, characterized in that a polar solvent and an acid selected from the following ones are introduced into a reactor of a non-reactive material in an inert gas atmosphere: sulfuric acid VI, hydrochloric acid or acetic acid, in proportions from 2÷0.002 to 7÷0.002, preferably 5÷0.002, and then per 50 mL of a mixture thus formed, 4-(diphenylamino)benzaldehyde in an amount from 0.2 g to 0.7 g and 1.3-indandione in a quantity of 0.01 g to 0.08 g are added and stirred until a homogeneous mixture is obtained in no less than 1 minute, after which the suspension is washed with inert gas for at least 5 minutes, preferably not more than 60 minutes, heated to boiling under a reflux condenser in an inert gas atmosphere and stirred intensely at 100-1000 rpm, preferably 350-450 rpm for at least 18 hours, preferably not more than 30 hours. After the mixing process, the resulting mixture is cooled to 20 to 35°C and subjected to column chromatography in a S1O2 bed and in the mobile phase of the mixture of hexane and methylene chloride, in amounts of hexane from 0.5 to 2 times the volume of the mixture, and methylene chloride from 0,5 to 2 times the volume of the reaction mixture. It is then vacuum-dried for at least 20 hours, preferably 24 hours to a constant weight, after which it is recrystallized from chloroform. The product after recrystallization from chloroform (recry stallizate) is placed in a homogenizer and the base is introduced as: polypropylene (PP) or polyurethane (PU) or polyethylene terephthalate (PET) or polycarbonate (PC) or polyoxymethylene (POM) or polysulfone (PSU) or silicone or fluoropolymer, preferably poly(tetrafluoroethylene) (PTFE) or polyvinylidene fluoride (PVDF) or a copolymer of tetrafluoroethylene and hexafluoropropylene (FEP), in the proportion of the base- recrystallizate from 50÷2 to 5000÷2, preferably 100÷2, and then mixed to a homogeneous mixture and dried for at least 20 hours at 80-110°C, after which the material is extruded on a linear head is extruded on a linear head in the form of a string, preferably with an outer diameter of 2 to 10 mm, or on a cross head in the form of a tube, preferably with an outer diameter of 2 to 10 mm, or on a flat head in the form of a foil preferably with a thickness of 0.1 to 3 mm, and in the next step the process of immobilization of active admixture in the form of albumin or argatroban or bivalirudin or fondaparinux or heparin to the steric structure of the material thus obtained is carried out in a manner ensuring its content in the material in the ratio base-active admixture from 80÷1 to 1200÷1, preferably 150÷1, in such a way, that after initial cooling in a bath containing a supersaturated aqueous solution of the active admixture to a temperature ±30°C from the plastic transition temperature, preferably below the plastic transition temperature, it is stretched on calenders (by known methods of forming fibers or foils) to obtain an elongation of 5÷20 times, preferably 10 times, which results in the formation of micropores in which the active admixture immobilizes, whereby in a variant with an extruded string, the elongation process is carried out linearly - maintaining the string form, or in two directions - forming a flat foil from the string.
Preferably, the method according to the invention in the second variant is carried out in a glass, ceramic or stainless steel reactor.
Preferably, the method according to the invention in the second variant is carried out in a reactor in the form of a round-bottomed three-necked flask, due to its good functional properties.
Preferably, in the method according to the invention in the second variant, argon or nitrogen or xenon is used as the inert gas.
Preferably, in the method according to the invention in the second variant, anhydrous ethanol is used as the polar solvent.
Preferably, in the method according to the first or second variant, the base material is added in the form of a crushed material or aggregate or most preferably granulate.
Preferably, in the method according to the first or second variant, during the calendering step during the immobilization of the active admixture, a cyclic decrease and increase of the stress is applied, which increases the efficiency of the immobilization of the active admixture in the pores of the material.
The chemical structure of macromolecules of materials obtained by the method according to the invention affects their good pore-forming properties and at the same time ensures its biocompatibility and bioinertness (full neutrality). When these materials are used to manufacture membranes for oxygenators, the risk of inducing inflammation is reduced, and thus the process of coagulation on the membrane slows down. The method according to the invention makes it possible to obtain materials with a pore size in the nano range so that a single molecule of oxygen and carbon dioxide is able to penetrate the pores, and at the same time so that the pores are smaller than the macromolecular packets of which body fluids are composed, which in effect makes it possible to effectively oxygenate the blood without the risk of blood molecules penetrating the pores.
In addition to the above advantages, the solution according to the invention makes it possible to obtain membranes with a very wide range of pore sizes from nano/micro scale (application especially for oxygenation, gas exchange) to macro pore size of even tenths of a millimeter (application as waterproof, breathable materials). The method according to the invention makes it possible to precisely control the size of the pores formed.
The use of an immobilized active admixture allows its concentration on the piece contact surface to remain constant throughout the application of the materials (planned product life). The possibility of excessive leaching of the active admixture is minimized, and because of the diffusion-controlled release of the active admixture, its contact concentration on the product surface is constant.
Introduction of the active admixture into the material according to the invention also gives the material the desired anti-coagulant and anti-inflammatory properties. Substances used as active admixture, as noted above, have strong anticoagulant effect. The active admixture is embedded both in the pores of the material and in microcracks formed as equilibrium defects during the material formation stage. This significantly improves the surface continuity of the material structure and thus prevents organic material from depositing in pores and microcracks and significantly reduces coagulation.
The introduction of 4-(diphenylamino)benzaldehyde and 1,3-indandione admixtures in the second variant of the invention results in a reduction of the internal stresses of the material which results in a better orientation of the macromolecules during processing and pore formation, which is ultimately observed as a smooth outer structure so that there are no mechanical steric centers for thrombus formation due to the uniformity of the material as well as the absence of sharp edges around the pores and cracks.
A method for preparing an organic material with pore-forming, anti-inflammatory and anticoagulant properties with the addition of an active admixture according to the invention will be further explained by means of the following examples.
Example 1
The material in the form of PTFE granules is extruded on a linear head in the form of a string, with a diameter of 2 mm and then after initial cooling in a bath containing a supersaturated aqueous solution of albumin to a temperature 20°C lower than the plastic transition temperature, it is stretched on calenders to obtain a 10-fold elongation. During calendering, cyclic decreasing and increasing of tension in the range of 60÷90% of tension is used to obtain a 10-fold elongation. Its elongation process is carried out in two directions to form a flat foil from the string. This type of process yields an albumin-to-base ratio of 1:100.
The Teflon-based material thus obtained can be used as a thrombus filter in medical equipment due to its high biocompatibility. The resulting pores are characterized by sizes ranging from 1 nanometer to 300 micrometers. Systems having pore sizes between 75 and 150 micrometers are ideal for cell culture. Systems with pores in the order of nanometers can be used to create gas-permeable membranes for example in a blood oxygenation and oxygenation process.
Example 2
The material in the form of PVDF granules and aggregate is extruded on a flat head in the form of a foil with a thickness of 0,1 mm, after which the process of immobilization of argatroban to the steric structure of the material so obtained is carried out in such a way that, after initial cooling in a bath containing a supersaturated aqueous solution of argatroban to a temperature of 20°C lower than the plastic transition temperature, it is elongated on calenders so as to obtain a 15-fold elongation. The elongation process is carried out in two directions to obtain a foil. This type of process yields an argatroban-to-base ratio of 1:140.
The polyvinylidene fluoride -based material thus obtained can be used as a thrombus filter in medical equipment due to its high biocompatibility. The resulting pores are characterized by sizes ranging from 1 nanometer to 300 micrometers. Systems having pore sizes between 75 and 150 micrometers are ideal for cell culture. Systems with pores in the order of nanometers can be used to create gas-permeable membranes for example in a blood oxygenation and oxygenation process.
Example 3
The material in the form of crushed FEP is extruded on a cross head in the form of a tube with an outer diameter of 3 mm, after which the process of immobilization of bivalimdin to the steric structure of the material so obtained is carried out in such a way that, after initial cooling in a bath containing a supersaturated aqueous solution of bivalimdin to a temperature 15°C higher than the plastic transition temperature, it is stretched on calenders so as to obtain a 5-fold elongation. During calendering, cyclic decreasing and increasing of tension in the range of 60÷90% of tension is used to obtain a 5-fold elongation. This type of process yields a bivalimdin-to-base ratio of 1:1200.
The material thus obtained, based on a copolymer of tetrafluoroethylene and hexafluoropropylene can be used as a thrombus filter in medical equipment due to its high biocompatibility. The resulting pores are characterized by sizes ranging from 1 nanometer to 300 micrometers. Systems having pore sizes between 75 and 150 micrometers are ideal for
cell culture. Systems with pores in the order of nanometers can be used to create gas- permeable membranes for example in a blood oxygenation and oxygenation process.
Example 4
The PTFE granules are extruded on a flat head in the form of a 1 mm thick foil, after which the process of immobilization of the fondaparinux into the steric structure of the material so obtained is carried out, in such a way that, after initial cooling of the material in a bath containing a supersaturated aqueous solution of the fondaparinux to a temperature 20°C lower than the plastic transition temperature, it is stretched by cyclically increasing and decreasing the tension in the range of 60÷90% on the calenders until a 15-fold elongation is obtained and fondaparinux is incorporated into the steric structure of the material. This type of process yields a fondaparinux-to-base ratio of 1:1200.
The poly(tetrafluoroethylene)-based material thus obtained can be used as a thrombus filter in medical equipment due to its high biocompatibility, or as a semi-permeable coating for rainproofing with high single molecule water vapor separation properties, or as a breathable material in contact with skin, for example for making wound dressing plasters, kinesiology tapes, orthopedic insoles, etc. The resulting pores are characterized by sizes ranging from 1 nanometer to 150 micrometers. Systems having pore sizes between 75 and 150 micrometers are ideal for culturing skin cells. Systems having pores in the order of nanometers can be used to create gas-permeable membranes in blood oxygenation and oxygenation process, for example.
Example 5
The PVDF granules are extruded on a flat head in the form of a 0.1 mm thick foil, followed by a process of immobilization of heparin into the steric structure of the material so obtained, in such a way that, after the material is initially cooled in a bath containing a supersaturated aqueous solution of heparin to a temperature of 20°C below the plastic transition temperature, it is stretched on calenders until a 5-fold elongation and incorporation of heparin into the steric structure of the material. The elongation process is carried out in two directions to obtain a foil. This type of process yields a heparin-to-base ratio of 1:800.
The PVDF-based material thus obtained can be used as a thrombus filter in medical equipment due to its high biocompatibility or as a semi-permeable coating for rainproofing with high single molecule water vapor separation properties or as a breathable material in contact with the skin, for example for the manufacture of wound dressing plasters, kinesiology tapes, orthopedic insoles, etc. The resulting pores are characterized by sizes ranging from 1 nanometer to 150 micrometers. Systems having pore sizes between 75 and 150 micrometers are ideal for culturing skin cells. Systems having pores in the order of nanometers can be used to create gas-permeable membranes in blood oxygenation and oxygenation, for example.
Example 6
The crushed FEP is extruded on a linear head in the form of a string with a diameter of 5 mm, and then the process of immobilization of heparin into the steric structure of the material so obtained is carried out in such a way that, after initial cooling of the material in a bath
containing a supersaturated aqueous solution of heparin to a temperature of 30°C below the plastic transition temperature, it is stretched by cyclically increasing and decreasing the tension in the range of 60÷90% on the calenders until a 5-fold elongation is obtained and heparin is incorporated into the steric structure of the material. The elongation process is carried out in two directions to form a flat foil from the string. This type of process yields a heparin-to-base ratio of 1 :200.
The FEP-based material thus obtained can be used as a thrombus filter in medical equipment due to its high biocompatibility or as a semi-permeable coating for rainproofing with high single molecule water vapor separation properties or as a breathable material in contact with the skin, for example for the manufacture of wound dressing plasters, kinesiology tapes, orthopedic insoles, etc. The resulting pores are characterized by sizes ranging from 1 nanometer to 150 micrometers. Systems having pore sizes between 75 and 150 micrometers are ideal for culturing skin cells. Systems having pores in the order of nanometers can be used to create gas-permeable membranes in blood oxygenation and oxygenation, for example.
Example 7
The PVDF granules are extruded on a flat head in the form of a 0.1 mm thick foil, after which the process of immobilizing the fondaparinux into the steric structure of the material so obtained is carried out, in such a way that, after the material is initially cooled in a bath containing a supersaturated aqueous solution of fondaparinux to a temperature 25 °C below the plastic transition temperature, it is stretched on calenders until a 5-fold elongation is obtained and the fondaparinux is incorporated into the steric structure of the material. This type of process yields a fondaparinux/base ratio of 1:800.
The PVDF-based material thus obtained can be used as a thrombus filter in medical equipment due to its high biocompatibility or as a semi-permeable coating for rainproofing with high single molecule water vapor separation properties or as a breathable material in contact with the skin, for example for the manufacture of wound dressing plasters, kinesiology tapes, orthopedic insoles, etc. The resulting pores are characterized by sizes ranging from 1 nanometer to 150 micrometers. Systems having pore sizes between 75 and 150 micrometers are ideal for culturing skin cells. Systems having pores in the order of nanometers can be used to create gas-permeable membranes, for example, in blood oxygenation and oxygenation.
Example 8
50 mL of a mixture of anhydrous ethanol and sulfuric acid (VI) in proportions of 5÷0.002 is introduced into a glass reactor in the form of a dried round-bottomed triple-necked flask in an argon atmosphere and 0.2 g of 4-(diphenylamino)benzaldehyde and 0.01 g of 1,3-indandione are added. The whole mixture is stirred for 5 minutes and washed with argon for 10 minutes. It is then heated to boiling under a reflux condenser in an argon atmosphere and stirred intensely at 400 rpm for 24 hours. After obtaining a homogeneous mixture, the system is cooled down to 20°C and subjected to column chromatography in a S1O2 bed and in the mobile phase of the mixture of hexane and methylene chloride, in an amount of hexane equal to 0.5 times the volume of the reaction mixture and methylene chloride equal to 0.5 times the volume of the reaction mixture. The product is then vacuum-dried for 24 hours to a constant
mass, after which it is recrystallized from chloroform, the recry stallizate is placed in a homogenizer and 25 g of crushed PTFE is added. The system is mixed until a homogeneous mixture is obtained and dried for 20 hours at 80°C. The material is extruded on a linear head in the form of a string with a diameter of 3 mm, after cooling in a bath containing a supersaturated aqueous solution of albumin to a temperature 20°C lower than the plastic transition temperature, it is stretched by cyclic increasing and decreasing the tension in the range of 60÷90% on calenders until an 8 -fold elongation is obtained and albumin is incorporated into the steric structure of the material. The elongation process is carried out linearly maintaining the form of the string. This type of process yields an albumin-to-base ratio of 1:150.
The poly(tetrafluoroethylene) based material thus obtained can be used as a thrombus filter in medical equipment or as a semi-permeable coating for rain protection with high single molecule water vapor separation properties. The material obtained in this way makes it possible to create pores with a range of 150 micrometers.
Example 9
50 mL of a mixture of anhydrous ethanol and acetic acid in proportions of 6÷0.002 is introduced into a glass reactor in the form of a dried round-bottomed triple-necked flask in a xenon atmosphere and 0.7 g of 4-(diphenylamino)benzaldehyde and 0.01 g of 1,3-indandione are added. The whole mixture is stirred for 3 minutes and washed with xenon for 30 minutes. It is then heated to boiling under a reflux condenser in xenon atmosphere and stirred intensely at 100 rpm for 30 hours. After obtaining a homogeneous mixture, the system is cooled down to 25°C and subjected to column chromatography in a S1O2 bed and in a mobile phase of the mixture of hexane and methylene chloride, in an amount of hexane equal to 1 times the volume of the reaction mixture, and of methylene chloride equal to 1 times the volume of the reaction mixture. The product is then vacuum-dried to a constant mass for 24 hours, followed by recrystallization from chloroform, the recry stallizate is placed in a homogenizer and 50 g of PP aggregate is added. The system is mixed until a homogeneous mixture is obtained and dried for 20 hours at 100°C. The material is extruded on a cross head in the form of a tube with a diameter of 9 mm, after cooling in a bath containing a supersaturated aqueous solution of albumin to a temperature of 25°C lower than the plastic transition temperature, it is stretched by cyclic increasing and decreasing the tension in the range of 60÷90% on calenders until 7-fold elongation is obtained and albumin is incorporated into the steric structure of the material. This type of process yields an albumin-to-base ratio of 1:350.
The polypropylene-based material thus obtained can be used as a thrombus filter in medical equipment or as a semi-permeable coating for rainproofing with high single molecule water vapor separation properties. The material obtained in this way makes it possible to create pores of 30 micrometers.
Example 10
50 mL of a mixture of anhydrous ethanol and hydrochloric acid in a ratio of 5÷0.002 is introduced into a dried ceramic reactor in an argon atmosphere and 0.2 g of 4- (diphenylamino)benzaldehyde and 0.08 g of 1,3-indandione are added. The whole mixture is stirred for 2 minutes and washed with argon for 60 minutes. It is then heated to boiling under
a reflux condenser in an argon atmosphere and stirred intensely at 1000 rpm for 24 hours. After obtaining a homogeneous mixture, the system is cooled down to 30°C and subjected to column chromatography in a S1O2 bed and in a mobile phase of the mixture of hexane and methylene chloride, in an amount of hexane equal to 2 times the volume of the reaction mixture, and of methylene chloride equal to 2 times the volume of the reaction mixture. The product is then vacuum-dried for 24 hours to a constant mass, after which it is recrystallized from chloroform, the recry stallizate is placed in a homogenizer and 28 g of PU granulate is added. The system is mixed until a homogeneous mixture is obtained and dried for 24 hours at 110°C. The material is extruded on a flat head in the form of a foil with a thickness of 0.1 mm, after cooling in a bath containing a supersaturated aqueous solution of albumin to a temperature 20°C lower than the plastic transition temperature, it is stretched by cyclic increasing and decreasing the tension in the range of 60÷90% on calenders until a 15-fold elongation is obtained and albumin is incorporated into the steric structure of the material. The elongation process is carried out in two directions to obtain a foil. This type of process yields an albumin-to-base ratio of 1:150.
The resulting polyurethane -based material can be used as a thrombus filter in medical equipment due to its high biocompatibility or as a semi-permeable coating for rainproofing with high single molecule water vapor separation properties or as a breathable material in contact with the skin for example: wound dressing plasters, kinesiology tapes, orthopedic insoles, etc. The resulting pores are characterized by sizes ranging from 1 nanometer to 150 micrometers. Systems having pore sizes between 75 and 150 micrometers are ideal for culturing skin cells. Systems with pores in the order of nanometers can be used to create gas- permeable membranes for example in a blood oxygenation and oxygenation process.
Example 11
50 mL of a mixture of anhydrous ethanol and sulfuric acid (VI) in proportions of 2÷0.002 is introduced into a glass reactor in the form of a dried round-bottomed triple-necked flask in an argon atmosphere and 0.2 g of 4-(diphenylamino)benzaldehyde and 0.01 g of 1,3-indandione are added. The whole mixture is stirred for 3 minutes and washed with argon for 10 minutes. It is then heated to boiling under a reflux condenser in an argon atmosphere and stirred intensely at 500 rpm for 24 hours. After obtaining a homogeneous mixture, the system is cooled down to 25°C and subjected to column chromatography in a S1O2 bed and in a mobile phase of the mixture of hexane and methylene chloride, in an amount of hexane equal to 1.5 times the volume of the reaction mixture, and of methylene chloride equal to 1.5 times the volume of the reaction mixture. The product is then vacuum-dried to a constant mass for 24 hours, followed by recrystallization from chloroform, the recry stallizate is placed in a homogenizer and 42 g of crushed PET is added. The system is mixed until a homogeneous mixture is obtained and dried for 20 hours at 80°C. The material is extruded on a flat head in the form of a foil with a thickness of 1 mm and after cooling in a bath containing a supersaturated aqueous solution of argatroban to a temperature 30°C lower than the plastic transition temperature, it is stretched by cyclic increasing and decreasing the tension in the range of 60÷90% on calenders until a 10-fold elongation is obtained and argatroban is incorporated into the steric structure of the material. This type of process yields an argatroban-to-base ratio of 1:150.
The poly(ethylene terephthalate) -based material thus obtained can be used as a thrombus filter in medical equipment or as a semi-permeable coating for rainproofing with high single molecule water vapor separation properties. The material obtained in this way makes it possible to create pores in the range of 150 micrometers.
Example 12
50 mL of a mixture of anhydrous ethanol and acetic acid is introduced in a xenon atmosphere in proportions of 7÷0,002 is introduced to a dried stainless steel reactor and 0.7 g of 4- (diphenylamino)benzaldehyde and 0.01 g of 1,3-hidandione are added. The whole mixture is stirred 4 minutes and washed with xenon for 30 minutes. It is then heated to boiling under a reflux condenser in xenon atmosphere and stirred intensely at 750 rpm for 30 hours. After obtaining a homogeneous mixture, the system is cooled down to 25°C and subjected to column chromatography in a S1O2 bed and in a mobile phase of the mixture of hexane and methylene chloride, in an amount of hexane equal to 1 times the volume of the reaction mixture, and of methylene chloride equal to 1 times the volume of the reaction mixture. The product is then vacuum-dried to a constant mass for 24 hours, followed by recrystallization from chloroform, the recry stallizate is placed in a homogenizer and 40 g of PC aggregate is added. The system is mixed until a homogeneous mixture is obtained and dried for 20 hours at 100°C. The material is extruded on a linear head in the form of an 8 mm diameter string, and after cooling in a bath containing a supersaturated aqueous argatroban solution to a temperature 10°C lower than the plastic transition temperature, it is stretched by cyclically increasing and decreasing the tension in the range of 60÷90% on calenders until a 10-fold elongation is obtained and argatroban is incorporated into the steric structure of the material. Its elongation process is carried out in two directions to form a flat foil from the string. This type of process yields an argatroban-to-base ratio of 1:150.
The polycarbonate-based material thus obtained can be used as a water filter or as a semi-permeable coating for rain protection with high single molecule water vapor separation properties. The resulting pores are characterized by sizes ranging from 1 to 300 micrometers.
Example 13
50 mL of a mixture of anhydrous ethanol and hydrochloric acid in proportions of 5÷0.002 is introduced into a glass reactor as a dried round -bottomed triple-necked flask in an argon atmosphere and 0.2 g of 4-(diphenylamino)benzaldehyde and 0.08 g of 1,3-indandione are added. The whole mixture is stirred for 5 minutes and washed with argon for 60 minutes. It is then heated to boiling under a reflux condenser in an argon atmosphere and stirred intensely at 450 rpm for 24 hours. After obtaining a homogeneous mixture, the system is cooled down to 30°C and subjected to column chromatography in a S1O2 bed and in a mobile phase of the mixture of hexane and methylene chloride, in an amount of hexane equal to 2 times the volume of the reaction mixture, and of methylene chloride equal to 2 times the volume of the reaction mixture. The product is then vacuum-dried for 24 hours to a constant mass, after which it is recrystallized from chloroform, the recry stallizate is placed in a homogenizer and 28 g of POM granulate. The system is mixed until a homogeneous mixture is obtained and dried for 24 hours at 110°C. The material is extruded on a linear head in the form of an 2 mm diameter string, and after cooling in a bath containing a supersaturated aqueous argatroban
solution to 15°C below the plastic transition temperature, it is stretched by cyclically increasing and decreasing the tension in the range of 60÷90% on calenders until a 15-fold elongation is obtained and argatroban is incorporated into the steric structure of the material. Its elongation process is carried out in two directions to form a flat foil from the string. This type of process yields an argatroban-to-base ratio of 1:350.
The polyoxymethylene -based material thus obtained can be used as a thrombus filter in medical equipment due to its high biocompatibility. The resulting pores are characterized by sizes ranging from 1 nanometer to 300 micrometers. Systems having pore sizes between 75 and 150 micrometers are ideal for cell culture. Systems with pores in the order of nanometers can be used to create gas-permeable membranes for example in a blood oxygenation and oxygenation process.
Example 14
50 mL of a mixture of anhydrous ethanol and sulfuric acid (VI) is introduced into a dried stainless steel reactor in proportions of a 5÷0.002 in an argon atmosphere and 0.2 g of 4- (diphenylamino)benzaldehyde and 0.01 g of 1,3-indandione are added. The whole mixture is stirred for 6 minutes and washed with argon for 10 minutes. It is then heated to boiling under a reflux condenser in an argon atmosphere and stirred intensely at 400 rpm for 24 hours. After obtaining a homogeneous mixture, the system is cooled down to 30°C and subjected to column chromatography in a S1O2 bed and in a mobile phase of the mixture of hexane and methylene chloride, in an amount of hexane equal to 0.5 times the volume of the reaction mixture and of methylene chloride equal to 0.5 times the volume of the reaction mixture. The product is then vacuum-dried for 24 hours to a constant mass, after which it is recrystallized from chloroform, the recrystallizate is placed in a homogenizer and 25 g of ground PSU is added. The system is mixed until a homogeneous mixture is obtained and dried for 20 hours at 80°C. The material is extruded on a linear head in the form of a string with a diameter of 3 mm, and after cooling in a bath containing a supersaturated aqueous solution of bivalirudin to a temperature 20°C lower than the plastic transition temperature, it is stretched by cyclic increasing and decreasing the tension in the range of 60÷90% on calenders until a 10-fold elongation is obtained and bivalirudin is incorporated into the steric structure of the material. The elongation process is carried out linearly maintaining the form of the string. This type of process yields a bivalirudin-to-base ratio of 1:250.
The polysulfone-based material thus obtained can be used as a thrombus filter in medical equipment due to its high biocompatibility. The resulting pores are characterized by sizes ranging from 1 nanometer to 300 micrometers. Systems having pore sizes between 75 and 150 micrometers are ideal for cell culture. Systems with pores in the order of nanometers can be used to create gas-permeable membranes for example in a blood oxygenation and oxygenation process.
Example 15
50 mL of a mixture of anhydrous ethanol and acetic acid in proportions of 5÷0.002 is introduced into a dried round-bottomed triple-necked flask in nitrogen atmosphere and 0.7 g of 4-(diphenylamino)benzaldehyde and 0.01 g of 1,3-indandione are added. The whole mixture is stirred for 8 minutes and washed with nitrogen for 30 minutes. It is then heated to
boiling under a reflux condenser in nitrogen atmosphere and stirred intensely at 350 rpm for 30 hours. After obtaining a homogeneous mixture, the system is cooled down to 25°C and subjected to column chromatography in a S1O2 bed and in the mobile phase of the mixture of hexane and methylene chloride in a quantity of hexane equal to 1 times the volume of the reaction mixture and methylene chloride equal to 1 times the volume of the reaction mixture. The product is then vacuum-dried for 24 hours to a constant mass, after which it is recrystallized from chloroform, the recry stallizate is placed in a homogenizer and 25 g of ground PVDF is added. The system is mixed until a homogeneous mixture is obtained and dried for 20 hours at 100°C. The material is extruded on a linear head in the form of a string with a diameter of 2 mm, and after cooling in a bath containing a supersaturated aqueous solution of bivalimdin to a temperature 20°C lower than the plastic transition temperature, it is stretched by cyclic increasing and decreasing the tension in the range of 60÷90% on the calenders until a 20-fold elongation is obtained and bivalimdin is incorporated into the steric structure of the material. The elongation process is carried out linearly maintaining the form of the string. This type of process yields a bivalirudin-to-base ratio of 1:80.
The PVDF-based material thus obtained can be used as a thrombus filter in medical equipment due to its high biocompatibility, or as a semi-permeable coating for rainproofing with high single molecule water vapor separation properties, or as a breathable material in contact with skin, for example for making: wound dressing plasters, kinesiology tapes, orthopedic insoles, etc. The resulting pores are characterized by sizes ranging from 1 nanometer to 150 micrometers. Systems having pore sizes between 75 and 150 micrometers are ideal for culturing skin cells. Systems with pores in the order of nanometers can be used to create gas-permeable membranes for example in a blood oxygenation and oxygenation process.
Example 16
50 mL of a mixture of anhydrous ethanol and hydrochloric acid in proportions of 4÷0.002 is introduced into a dried round-bottomed triple-necked flask in nitrogen atmosphere and 0.2 g of 4-(diphenylamino)benzaldehyde and 0.08 g of 1,3-indandione are added. The whole mixture is stirred for 1 minute and washed with nitrogen for 60 minutes. It is then heated to boiling under a reflux condenser in nitrogen atmosphere and stirred intensely at 450 rpm for 24 hours. After obtaining a homogeneous mixture, the system is cooled down to 30°C and subjected to column chromatography in a S1O2 bed and in a mobile phase of the mixture of hexane and methylene chloride, in an amount of hexane equal to 2 times the volume of the reaction mixture, and of methylene chloride equal to 2 times the volume of the reaction mixture. The product is then vacuum-dried for 24 hours to a constant mass, after which it is recrystallized from chloroform, the recry stallizate is placed in a homogenizer and 28 g of FEP granulate. The system is mixed until a homogeneous mixture is obtained and dried for 24 hours at 110°C. The material is extruded on a cross head in the form of a tube with an outer diameter of 10 mm, after cooling in a bath containing a supersaturated aqueous solution of fondaparinux to a temperature of 15°C lower than the plastic transition temperature, it is stretched by cyclic increasing and decreasing the tension in the range of 60÷90% on calenders until a 5-fold elongation is obtained and fondaparinux is incorporated into the steric structure of the material. This type of process yields a fondaparinux-to-base ratio of 1:1200.
The FEP-based material thus obtained can be used as a thrombus filter in medical equipment due to its high biocompatibility or as a semi-permeable coating for rainproofing with high single molecule water vapor separation properties or as a breathable material in contact with the skin, for example for: wound dressing plasters, kinesiology tapes, orthopedic insoles, etc. The resulting pores are characterized by sizes ranging from 1 nanometer to 150 micrometers. Systems having pore sizes between 75 and 150 micrometers are ideal for culturing skin cells. Systems with pores in the order of nanometers can be used to create gas-permeable membranes for example in a blood oxygenation and oxygenation process.
Example 17
50 mL of a mixture of anhydrous ethanol and sulfuric acid (VI) in proportions of 5÷0.002 is introduced into a glass reactor in the form of a dried round-bottomed triple-necked flask in an argon atmosphere and 0.2 g of 4-(diphenylamino)benzaldehyde and 0.01 g of 1,3- indandione are added. The whole mixture is stirred for 5 minutes and washed with argon for 10 minutes. It is then heated to boiling under a reflux condenser in an argon atmosphere and stirred intensely at 400 rpm for 24 hours. After obtaining a homogeneous mixture, the system is cooled down to 20°C and subjected to column chromatography in a S1O2 bed and in a mobile phase of the mixture of hexane and methylene chloride, in an amount of hexane equal to 0.5 times the volume of the reaction mixture, and of methylene chloride equal to 0.5 times the volume of the reaction mixture. The product is then vacuum-dried for 24 hours to a constant mass, after which it is recrystallized from chloroform, the recrystallizate is placed in a homogenizer and 21 g of PTFE granulate is added. The system is mixed until a homogeneous mixture is obtained and dried for 20 hours at 80°C. The material is extruded on a linear head in the form of a 3 mm diameter string, and after cooling in a bath containing a supersaturated aqueous fondaparinux solution to 20°C below the plastic transition temperature, it is stretched by cyclically increasing and decreasing the tension in the range of 60÷90% on calenders until a 7-fold elongation is obtained and fondaparinux is incorporated into the steric structure of the material. Its elongation process is carried out in two directions to form a flat foil from the string. This type of process yields a fondaparinux/base ratio of 1:150.
The poly(tetrafluoroethylene) based material thus obtained can be used as a thrombus filter in medical equipment or as a semi-permeable coating for rain protection with high single molecule water vapor separation properties. The material obtained in this way makes it possible to create pores in the range of 150 micrometers.
Example 18
50 mL of a mixture of anhydrous ethanol and acetic acid in proportions of 6÷0.002 is introduced into a glass reactor in the form of a dried round-bottomed triple-necked flask in a xenon atmosphere and 0.7 g of 4-(diphenylamino)benzaldehyde and 0.01 g of 1,3-indandione are added. The whole mixture is stirred for 3 minutes and washed with xenon for 30 minutes. It is then heated to boiling under a reflux condenser in a xenon atmosphere and stirred intensely at 100 rpm for 30 hours. After obtaining a homogeneous mixture, the system is cooled down to 25°C and subjected to column chromatography in a S1O2 bed and in a mobile phase of the mixture of hexane and methylene chloride, in an amount of hexane equal to 1
times the volume of the reaction mixture, and of methylene chloride equal to 1 times the volume of the reaction mixture. The product is then vacuum-dried to a constant mass for 24 hours, followed by recrystallization from chloroform, the recry stallizate is placed in a homogenizer and 45 g of PP aggregate is added. The system is mixed until a homogeneous mixture is obtained and dried for 20 hours at 100°C. The material is extruded on a linear head in the form of an 8 mm diameter string, and after cooling in a bath containing a supersaturated heparin solution to 10°C below the plastic transition temperature, it is stretched by cyclically increasing and decreasing the tension in the range of 60÷90% on calenders until a 10-fold elongation is obtained and heparin is incorporated into the steric structure of the material. The elongation process is carried out linearly maintaining the form of the string. This type of process yields a heparin-to-base ratio of 1:350.
The polypropylene-based material thus obtained can be used as a thrombus filter in medical equipment or as a semi-permeable coating for rainproofing with high single molecule water vapor separation properties. The material obtained in this way makes it possible to create pores in the range of 30 micrometers.
Example 19
50 mL of a mixture of anhydrous ethanol and hydrochloric acid in a ratio of 5÷0.002 is introduced into a dried ceramic reactor in an argon atmosphere and 0.2 g of 4- (diphenylamino)benzaldehyde and 0.08 g of 1,3-indandione are added. The whole mixture is stirred 2 minutes and washed with argon for 60 minutes. It is then heated to boiling under a reflux condenser in an argon atmosphere and stirred intensely at 1000 rpm for 24 hours. After obtaining a homogeneous mixture, the system is cooled down to 30°C and subjected to column chromatography in a S1O2 bed and in a mobile phase of a mixture of hexane and methylene chloride, in an amount of hexane equal to 2 times the volume of the reaction mixture, and of methylene chloride equal to 2 times the volume of the reaction mixture. The product is then vacuum-dried for 24 hours to a constant mass, after which it is recrystallized from chloroform, the recry stallizate is placed in a homogenizer and 28 g of PU granulate is added. The system is mixed until a homogeneous mixture is obtained and dried for 24 hours at 110°C. The material is extruded on a flat head in the form of a foil with a thickness of 0.1 mm and after cooling in a bath containing a supersaturated aqueous heparin solution to a temperature 30°C lower than the plastic transition temperature, it is stretched by cyclic increasing and decreasing the tension in the range of 60÷90% on calenders until a 15- fold elongation is obtained and heparin is incorporated into the steric structure of the material. The elongation process is carried out in two directions to obtain a foil. This type of process yields a heparin-to-base ratio of 1:150.
The polyurethane-based material thus obtained can be used as a thrombus filter in medical equipment due to its high biocompatibility, or as a semi-permeable coating for rainproofing with high single molecule water vapor separation properties, or as a breathable material in contact with skin, for example for making: wound dressing plasters, kinesiology tapes, orthopedic insoles, etc. The resulting pores are characterized by sizes ranging from 1 nanometer to 150 micrometers. Systems having pore sizes between 75 and 150 micrometers are ideal for culturing skin cells. Systems with pores in the order of nanometers can be used to
create gas-permeable membranes for example in a blood oxygenation and oxygenation process.
Example 20
50 mL of a mixture of anhydrous ethanol and sulfuric acid (VI) in proportions of 2÷0.002 is introduced into a glass reactor in the form of a dried round-bottomed triple-necked flask in an argon atmosphere and 0.2 g of 4-(diphenylamino)benzaldehyde and 0.01 g of 1,3-hidandione are added. The whole mixture is stirred 3 minutes and washed with argon for 10 minutes. It is then heated to boiling under a reflux condenser in an argon atmosphere and stirred intensely at 500 rpm for 24 hours. After obtaining a homogeneous mixture, the system is cooled down to 25°C and subjected to column chromatography in a S1O2 bed and in a mobile phase of the mixture of hexane and methylene chloride, in an amount of hexane equal to 1.5 times the volume of the reaction mixture, and of methylene chloride equal to 1.5 times the volume of the reaction mixture. The product is then vacuum-dried to a constant mass for 24 hours, followed by recrystallization from chloroform, the recry stallizate is placed in a homogenizer and 50 g of crushed PET is added. The system is mixed until a homogeneous mixture is obtained and dried for 20 hours at 80°C. The material is extruded on a flat head in the form of a foil with a thickness of 1 mm and after cooling in a bath containing a supersaturated aqueous heparin solution to a temperature 30°C lower than the plastic transition temperature, it is stretched by cyclic increasing and decreasing the tension in the range of 60÷90% on calenders until a 10-fold elongation is obtained and heparin is incorporated into the steric structure of the material. The elongation process is carried out in two directions to obtain a foil. This type of process yields a heparin-to-base ratio of 1:150.
The poly(ethylene terephthalate) -based material thus obtained can be used as a thrombus filter in medical equipment or as a semi-permeable coating for rainproofing with high single molecule water vapor separation properties. The material obtained in this way makes it possible to create pores in the range of 150 micrometers.
The method according to the invention makes it possible to obtain materials with pore forming, anti-inflammatory and anticoagulant properties, especially for the construction of medical equipment, in particular for components which are in direct contact with blood. Among other applications, the solution can be used to obtain blood oxygenation membranes and other gas-selective membranes.
Claims
1. An organic material with pore-forming, anti-inflammatory and anticoagulant properties, characterized in that it comprises:
- base in the form of a fluoropolymer, preferably poly(tetrafluoroethylene) or polyvinylidene fluoride or a copolymer of tetrafluoroethylene and hexafluoropropylene, and
- active admixture in the form of albumin or argatroban or bivalimdin or fondaparinux or heparin, embedded in the microstmcture of the base material, in the proportion base-active admixture from 80÷1 to 1200÷1, preferably 150÷1.
2. An organic material with pore-forming, anti-inflammatory and anticoagulant properties, characterized in that it comprises:
- base in the form of polypropylene (PP) or polyurethane (PU) or poly(ethylene terephthalate) (PET) or polycarbonate (PC) or polyoxymethylene (POM) or polysulfone (PSU) or silicone or fluoropolymer, preferably poly(tetrafluoroethylene) (PTFE) or polyvinylidene fluoride (PVDF) or a copolymer of tetrafluoroethylene and hexafluoropropylene (FEP),
- 4-(diphenylamino)benzaldehyde admixture in a base-to-admixture ratio from 50÷1 to 5000÷1, preferably 100÷1,
- admixture of 1,3-indandione in a base-to-admixture ratio from 50÷1 to 5000÷1, preferably 100÷1, and
- active admixture in the form of albumin or argatroban or bivalimdin or fondaparinux or heparin, embedded in the microstmcture of the base material, in the proportion base-active admixture from 80÷1 to 1200÷1, preferably 150÷1.
3. A method for obtaining an organic material with pore-forming, anti-inflammatory and anticoagulant properties characterized in that a base material in the form of a fluoropolymer, preferably poly(tetrafluoroethylene) or a copolymer of tetrafluoroethylene and hexafluoropropylene is extmded on a linear head in the form of a string, preferably with a diameter of 2 to 10 mm, or on a cross head in the form of a tube, preferably with an outer diameter of 2 to 10 mm, or on a flat head in the form of a foil preferably with a thickness of 0.1 to 3 mm, then the process of immobilization of active admixture in the form of albumin or argatroban or bivalirudin or fondaparinux or heparin to the steric structure of the material thus obtained is carried out in a manner ensuring its content in the material in the base-active admixture ratio from 80÷1 to 1200÷1, preferably 150÷1, in such a way, that after initial cooling in a bath containing a supersaturated aqueous solution of the active admixture to a temperature ±30°C from the plastic transition temperature, preferably below the plastic transition temperature, it is stretched on calenders to obtain an elongation of 5÷20 times, preferably 10 times, whereby in a variant with an extruded string, the elongation process is carried out linearly - maintaining the string form, or in two directions - forming a flat foil from the string.
4. A method for obtaining an organic material with pore-forming, anti-inflammatory and anticoagulant properties, characterized in that a polar solvent and an acid selected from the following ones are introduced into a reactor of a non-reactive material in an inert gas atmosphere: sulfuric acid VI, hydrochloric acid or acetic acid, in proportions from 2÷0.002 to
7÷0.002, preferably 5÷0.002, and then 4-(diphenylamino)benzaldehyde in an amount from 0.2 g to 0.7 g and 1,3-indandione in an amount from 0.01 g to 0, 08 g is added to the resulting mixture and stirred until a homogeneous mixture is obtained for not less than 1 minute, after which the suspension is washed with inert gas for at least 5 minutes, preferably not more than 60 minutes, heated to boiling under a reflux condenser in an inert gas atmosphere and stirred intensely at 100-1000 rpm, preferably 350 to 450 rpm, for at least 18 hours, preferably not more than 30 hours, and after the mixing process the resulting mixture is cooled to a temperature of 20 to 35°C and subjected to column chromatography in a S1O2 bed and in the mobile phase of a mixture of hexane and methylene chloride, in an amount of hexane from 0.5 to 2 times the volume of the mixture, and methylene chloride from 0.5 to 2 times the volume of the reaction mixture, then vacuum-dried for at least 20 hours, preferably 24 hours to constant weight, followed by recrystallization from chloroform, after which the product after recrystallization from chloroform (recry stallizate) is placed in a homogenizer and the base is introduced as: polypropylene (PP) or polyurethane (PU) or poly (ethylene terephthalate) (PET) or polycarbonate (PC) or polyoxymethylene (POM) or polysulfone (PSU) or silicone or fluoropolymer, preferably poly(tetrafluoroethylene) (PTFE) or polyvinylidene fluoride (PVDF) or a copolymer of tetrafluoroethylene and hexafluoropropylene (FEP), in the proportion of the base-recrystallizate from 50÷2 to 5000÷2, preferably 100÷2, and then mixed to a homogeneous mixture and dried for at least 20 hours at 80-110°C, after which the material is extruded on a linear head in the form of a string, preferably with an outer diameter of 2 to 10 mm, or on a cross head in the form of a tube, preferably with an outer diameter of 2 to 10 mm, or on a flat head in the form of a foil preferably with a thickness of 0.1 to 3 mm, and in the next step the process of immobilization of active admixture in the form of albumin or argatroban or bivalirudin or fondaparinux or heparin to the steric structure of the material thus obtained is carried out in a manner ensuring its content in the material in the ratio base-active admixture from 80÷1 to 1200÷1, preferably 150÷1, in such a way, that after initial cooling in a bath containing a supersaturated aqueous solution of the active admixture to a temperature ±30°C from the plastic transition temperature, preferably below the plastic transition temperature, it is stretched on calenders to obtain an elongation of 5÷20 times, preferably 10 times, whereby in a variant with an extruded string, the elongation process is carried out linearly - maintaining the string form, or in two directions - forming a flat foil from the string.
5. A method according to claim 4 characterized in that it is conducted in a glass, ceramic or stainless steel reactor.
6. A method according to claim 4 characterized in that it is carried out in a round-bottomed triple-neck flask reactor.
7. A method according to claim 4 characterized in that argon or nitrogen or xenon is used as inert gas.
8. A method according to claim 4 characterized in that anhydrous ethanol is used as polar solvent.
9. A method according to claim 3 or 4 characterized in that the base material is added in the form of crushed fraction or aggregate or most preferably granulate.
10. A method according to claim 3 or 4 characterized in that at the calendering stage during the immobilization of the active admixture, a cyclic decrease and increase of tension is applied.
Applications Claiming Priority (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PL436102A PL240231B1 (en) | 2020-11-27 | 2020-11-27 | Organic material with pore-forming, anti-inflammatory and anticoagulant properties and method of preparation thereof |
PL436106A PL240234B1 (en) | 2020-11-27 | 2020-11-27 | Organic material with pore-forming, anti-inflammatory and anticoagulant properties and method of preparation thereof |
PL436109A PL240887B1 (en) | 2020-11-27 | 2020-11-27 | Organic material with pore-forming, anti-inflammatory and anticoagulant properties and method of preparation thereof |
PL436107A PL240885B1 (en) | 2020-11-27 | 2020-11-27 | Organic material with pore-forming, anti-inflammatory and anticoagulant properties and method of preparation thereof |
PL436111A PL240909B1 (en) | 2020-11-27 | 2020-11-27 | Organic material with pore-forming, anti-inflammatory and anticoagulant properties and method of preparation thereof |
PL436104A PL243070B1 (en) | 2020-11-27 | 2020-11-27 | Organic material with pore-forming, anti-inflammatory and anticoagulant properties and method of preparation thereof |
PL436105A PL240233B1 (en) | 2020-11-27 | 2020-11-27 | Organic material with pore-forming, anti-inflammatory and anticoagulant properties and method of preparation thereof |
PL436108A PL240886B1 (en) | 2020-11-27 | 2020-11-27 | Organic material with pore-forming, anti-inflammatory and anticoagulant properties and method of preparation thereof |
PL436103A PL240232B1 (en) | 2020-11-27 | 2020-11-27 | Organic material with pore-forming, anti-inflammatory and anticoagulant properties and method of preparation thereof |
PL436110A PL240908B1 (en) | 2020-11-27 | 2020-11-27 | Organic material with pore-forming, anti-inflammatory and anticoagulant properties and method of preparation thereof |
PCT/IB2021/061010 WO2022113015A1 (en) | 2020-11-27 | 2021-11-26 | Organic material with pore-forming, anti-inflammatory and anticoagulant properties and the method of its preparation |
Publications (1)
Publication Number | Publication Date |
---|---|
EP4251695A1 true EP4251695A1 (en) | 2023-10-04 |
Family
ID=81755665
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP21897295.8A Pending EP4251695A1 (en) | 2020-11-27 | 2021-11-26 | Organic material with pore-forming, anti-inflammatory and anticoagulant properties and the method of its preparation |
Country Status (2)
Country | Link |
---|---|
EP (1) | EP4251695A1 (en) |
WO (1) | WO2022113015A1 (en) |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5413694A (en) * | 1977-07-01 | 1979-02-01 | Sumitomo Electric Industries | Composite blood vessel prosthesis and method of producing same |
US7807210B1 (en) * | 2000-10-31 | 2010-10-05 | Advanced Cardiovascular Systems, Inc. | Hemocompatible polymers on hydrophobic porous polymers |
KR100491700B1 (en) * | 2002-03-22 | 2005-05-27 | 주식회사 뉴하트바이오 | Method for immobilization of antithrombotic proteins on polytetrafluoroethylene surface by plasma treatment |
JP5217026B2 (en) * | 2006-02-28 | 2013-06-19 | 株式会社日本ステントテクノロジー | Stent and manufacturing method thereof |
CN101745327B (en) * | 2009-12-29 | 2012-09-05 | 浙江大学 | Method for fixing biological molecules on polymer microporous membrane surface |
CN103240006A (en) * | 2013-05-10 | 2013-08-14 | 天津大学 | Bovine serum albumin-polycarbonate composite membrane and preparation method thereof |
PL231827B1 (en) * | 2017-02-27 | 2019-04-30 | Univ Slaski | Organic bacteriostatic material |
-
2021
- 2021-11-26 EP EP21897295.8A patent/EP4251695A1/en active Pending
- 2021-11-26 WO PCT/IB2021/061010 patent/WO2022113015A1/en unknown
Also Published As
Publication number | Publication date |
---|---|
WO2022113015A1 (en) | 2022-06-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20030073158A1 (en) | Degradable porous materials with high surface areas | |
Genevro et al. | Glucomannan asymmetric membranes for wound dressing | |
JP2006523733A5 (en) | ||
WO2007111205A1 (en) | Porous bioabsorbable material and method of producing the same | |
Zhao et al. | Highly hemo-compatible, mechanically strong, and conductive dual cross-linked polymer hydrogels | |
Lin et al. | Immobilization of heparin on PVDF membranes with microporous structures | |
Zhang et al. | Anticoagulant Hydrogel Tubes with Poly (ɛ‐Caprolactone) Sheaths for Small‐Diameter Vascular Grafts | |
He et al. | Membranes for extracorporeal membrane oxygenator (ECMO): History, preparation, modification and mass transfer | |
WO2012029020A1 (en) | Implantable prosthetic device and solvent casting method for manufacturing the same | |
EP4251695A1 (en) | Organic material with pore-forming, anti-inflammatory and anticoagulant properties and the method of its preparation | |
Yuan et al. | Bioabsorbable poly (4-hydroxybutyrate)(P4HB) fibrous membranes as a potential dermal substitute | |
BR102015031933B1 (en) | process for obtaining asymmetric membranes, membranes thus obtained and use | |
WO2022113019A1 (en) | A membrane made of organic material with pore-forming, anti-inflammatory and anticoagulant properties and the method of obtaining it | |
PL240234B1 (en) | Organic material with pore-forming, anti-inflammatory and anticoagulant properties and method of preparation thereof | |
PL240231B1 (en) | Organic material with pore-forming, anti-inflammatory and anticoagulant properties and method of preparation thereof | |
PL243070B1 (en) | Organic material with pore-forming, anti-inflammatory and anticoagulant properties and method of preparation thereof | |
PL240233B1 (en) | Organic material with pore-forming, anti-inflammatory and anticoagulant properties and method of preparation thereof | |
JP2012082245A (en) | Method for manufacturing silk fibroin porous body | |
PL240232B1 (en) | Organic material with pore-forming, anti-inflammatory and anticoagulant properties and method of preparation thereof | |
US6979700B2 (en) | Non-degradable porous materials with high surface areas | |
Cai et al. | Hierarchically Porous Films Architectured by Self-Assembly of Prolamins at the Air–Liquid Interface | |
PL240909B1 (en) | Organic material with pore-forming, anti-inflammatory and anticoagulant properties and method of preparation thereof | |
PL240940B1 (en) | Membrane made of organic material with pore-forming, anti-inflammatory and anticoagulant properties and method of preparation thereof | |
PL240908B1 (en) | Organic material with pore-forming, anti-inflammatory and anticoagulant properties and method of preparation thereof | |
JP2957023B2 (en) | Biocompatible substrate |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE |
|
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 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE |
|
17P | Request for examination filed |
Effective date: 20230613 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
DAV | Request for validation of the european patent (deleted) | ||
DAX | Request for extension of the european patent (deleted) |