ES2322008A1 - Process of obtaining and biomedical applications of alternating polyesters constituted by units of glycolic acid and aliphatic hydroxyiaids (Machine-translation by Google Translate, not legally binding) - Google Patents
Process of obtaining and biomedical applications of alternating polyesters constituted by units of glycolic acid and aliphatic hydroxyiaids (Machine-translation by Google Translate, not legally binding) Download PDFInfo
- Publication number
- ES2322008A1 ES2322008A1 ES200702065A ES200702065A ES2322008A1 ES 2322008 A1 ES2322008 A1 ES 2322008A1 ES 200702065 A ES200702065 A ES 200702065A ES 200702065 A ES200702065 A ES 200702065A ES 2322008 A1 ES2322008 A1 ES 2322008A1
- Authority
- ES
- Spain
- Prior art keywords
- acid
- baselineskip
- units
- polyesters
- aliphatic
- 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.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 28
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical group OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 229920000728 polyester Polymers 0.000 title claims abstract description 16
- 230000008569 process Effects 0.000 title abstract description 21
- 125000001931 aliphatic group Chemical group 0.000 title abstract description 4
- 239000004005 microsphere Substances 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 14
- 229940079593 drug Drugs 0.000 claims abstract description 14
- -1 aliphatic hydroxy acids Chemical group 0.000 claims abstract description 13
- WHBMMWSBFZVSSR-UHFFFAOYSA-N 3-hydroxybutyric acid Chemical compound CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 claims abstract description 8
- 150000001261 hydroxy acids Chemical class 0.000 claims abstract description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract 4
- 150000003839 salts Chemical class 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 13
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- 239000011159 matrix material Substances 0.000 claims description 4
- 238000006068 polycondensation reaction Methods 0.000 claims description 2
- 230000003252 repetitive effect Effects 0.000 claims description 2
- 229920000229 biodegradable polyester Polymers 0.000 claims 2
- 239000004622 biodegradable polyester Substances 0.000 claims 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 229920000642 polymer Polymers 0.000 abstract description 31
- 239000000463 material Substances 0.000 abstract description 14
- 230000015572 biosynthetic process Effects 0.000 abstract description 12
- 229920001634 Copolyester Polymers 0.000 abstract description 11
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 238000002360 preparation method Methods 0.000 abstract description 8
- IWHLYPDWHHPVAA-UHFFFAOYSA-N 6-hydroxyhexanoic acid Chemical class OCCCCCC(O)=O IWHLYPDWHHPVAA-UHFFFAOYSA-N 0.000 abstract description 5
- 239000003960 organic solvent Substances 0.000 abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 230000015556 catabolic process Effects 0.000 description 11
- 238000006731 degradation reaction Methods 0.000 description 11
- 150000002148 esters Chemical class 0.000 description 10
- 239000000178 monomer Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000006116 polymerization reaction Methods 0.000 description 9
- SJZRECIVHVDYJC-UHFFFAOYSA-N 4-hydroxybutyric acid Chemical compound OCCCC(O)=O SJZRECIVHVDYJC-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 6
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 229940006015 4-hydroxybutyric acid Drugs 0.000 description 5
- XEFQLINVKFYRCS-UHFFFAOYSA-N Triclosan Chemical compound OC1=CC(Cl)=CC=C1OC1=CC=C(Cl)C=C1Cl XEFQLINVKFYRCS-UHFFFAOYSA-N 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 229960003500 triclosan Drugs 0.000 description 5
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229920001577 copolymer Polymers 0.000 description 4
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 229920000954 Polyglycolide Polymers 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000012455 biphasic mixture Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 230000009477 glass transition Effects 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000005014 poly(hydroxyalkanoate) Substances 0.000 description 3
- 229920000903 polyhydroxyalkanoate Polymers 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 3
- 230000009257 reactivity Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 description 3
- FMHKPLXYWVCLME-UHFFFAOYSA-N 4-hydroxy-valeric acid Chemical compound CC(O)CCC(O)=O FMHKPLXYWVCLME-UHFFFAOYSA-N 0.000 description 2
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 229930188620 butyrolactone Natural products 0.000 description 2
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 229960005215 dichloroacetic acid Drugs 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229920001519 homopolymer Polymers 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000012719 thermal polymerization Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- CDIIZULDSLKBKV-UHFFFAOYSA-N 4-chlorobutanoyl chloride Chemical compound ClCCCC(Cl)=O CDIIZULDSLKBKV-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 241000589513 Burkholderia cepacia Species 0.000 description 1
- 108010067770 Endopeptidase K Proteins 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 235000000421 Lepidium meyenii Nutrition 0.000 description 1
- 240000000759 Lepidium meyenii Species 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000012382 advanced drug delivery Methods 0.000 description 1
- 239000000956 alloy Substances 0.000 description 1
- 229910045601 alloy Inorganic materials 0.000 description 1
- 229940061720 alpha hydroxy acid Drugs 0.000 description 1
- 150000001280 alpha hydroxy acids Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000002902 bimodal effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 238000011138 biotechnological process Methods 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 238000002701 cell growth assay Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 159000000006 cesium salts Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003245 coal Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- ISLJZDYAPAUORR-UHFFFAOYSA-N ethyl n-[2-[(5-nitrothiophene-2-carbonyl)amino]thiophene-3-carbonyl]carbamate Chemical compound C1=CSC(NC(=O)C=2SC(=CC=2)[N+]([O-])=O)=C1C(=O)NC(=O)OCC ISLJZDYAPAUORR-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 125000005843 halogen group Chemical class 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid group Chemical group C(CCCCC)(=O)O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 235000012902 lepidium meyenii Nutrition 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 229910001510 metal chloride Inorganic materials 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 238000000879 optical micrograph Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920000070 poly-3-hydroxybutyrate Polymers 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 239000004632 polycaprolactone Substances 0.000 description 1
- 229920006149 polyester-amide block copolymer Polymers 0.000 description 1
- 229920006254 polymer film Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical class O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000007151 ring opening polymerisation reaction Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 238000001878 scanning electron micrograph Methods 0.000 description 1
- 238000004621 scanning probe microscopy Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 238000002411 thermogravimetry Methods 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
- C08G63/06—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from hydroxycarboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/78—Preparation processes
- C08G63/80—Solid-state polycondensation
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Polymers & Plastics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Polyesters Or Polycarbonates (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
Proceso de obtención y aplicaciones biomédicas de poliésteres alternantes constituidos por unidades de ácido glicólico e hidroxiácidos alifáticos.Obtaining process and biomedical applications of alternating polyesters consisting of acid units glycolic and aliphatic hydroxy acids.
La presente invención se refiere a un nuevo proceso de síntesis de copoliésteres derivados del ácido glicólico e hidroxiácidos de naturaleza alifática que permite su obtención con rendimientos elevados y pesos moleculares adecuados a su utilización posterior. El proceso descrito permite sintetizar estos copoliésteres de secuencia regular de una forma muy simple al requerirse un número muy reducido de etapas.The present invention relates to a new synthesis process of glycolic acid derived copolyesters and hydroxy acids of an aliphatic nature that allow obtaining them with high yields and molecular weights appropriate to its subsequent use The described process allows to synthesize these regular sequence copolyesters in a very simple way by a very small number of stages is required.
En general, los poliésteres constituyen el grupo de polímeros de mayor aplicación en el ámbito de la biomedicina, abarcando aplicaciones tan diversas como suturas quirúrgicas bioabsorbibles, fijaciones óseas, sistemas dosificadores de fármacos, o andamios temporales. La función que estos materiales tienen que cumplir al estar en contacto con el medio fisiológico es mantener sus propiedades y biocompatibilidad, durante el período de tiempo en el cual son usados. Una vez transcurrido dicho tiempo, los productos de degradación generados debido al proceso de reabsorción biodegradativo deben de ser eliminados del organismo.In general, polyesters constitute the group of polymers of greater application in the field of biomedicine, covering applications as diverse as surgical sutures bioabsorbable, bone fixations, dosing systems drugs, or temporary scaffolding. The function that these materials they have to comply by being in contact with the physiological environment is maintain its properties and biocompatibility, during the period of time in which they are used. Once this time has elapsed, the degradation products generated due to the resorption process Biodegradative should be removed from the body.
Dentro de la familia de los poliésteres son precisamente los polímeros constituidos por unidades de ácido glicólico/glicolida los más utilizados para las aplicaciones anteriormente indicadas. En este entorno, también tienen una elevada relevancia los homopolímeros y/o copolímeros derivados de ácido 6-hidroxihexanoico/caprolactona, ácido 4-hidroxibutanoico/butirolactona y ácido 3-hidroxibutanoico. La presente invención permite preparar una familia de copoliésteres degradables y biocompatibles con unas propiedades que pueden modularse en función del número de grupos metileno del hidroxiácido seleccionado.Within the family of polyesters are precisely polymers consisting of acid units glycolic / glycolide the most used for applications previously indicated. In this environment, they also have a high relevance homopolymers and / or copolymers derived from acid 6-hydroxyhexanoic / caprolactone, acid 4-hydroxybutanoic / butyrolactone and acid 3-hydroxybutanoic. The present invention allows prepare a family of degradable and biocompatible copolyesters with properties that can be modulated based on the number of methylene groups of the selected hydroxy acid.
Los polímeros biodegradables presentan gran interés para su empleo en el sector biomédico debido a dos factores primordiales: a) la posibilidad de que el material se elimine de forma natural una vez que ha terminado su función y, b) la mayor severidad en los requerimientos de seguridad y biocompatibilidad que deben presentar los biomateriales. Las aplicaciones pueden variar ampliamente desde su empleo como suturas quirúgicas bioabsorbibles hasta su utilización en ingeniería de tejidos o como sistemas liberadores de fármacos. En esta última aplicación, los materiales poliméricos son idóneos, al ser prácticamente imposible retener durante un tiempo apreciable un fármaco en una matriz constituida por un compuesto de bajo peso molecular. El agente activo puede variar desde un factor de crecimiento de naturaleza peptídica hasta un agente antitumoral, un antibiótico o un compuesto preventivo de la trombosis.Biodegradable polymers have great interest for employment in the biomedical sector due to two factors paramount: a) the possibility that the material is removed from naturally once you have finished your function and, b) the greatest severity of safety and biocompatibility requirements that They must present the biomaterials. Applications may vary. widely since its use as bioabsorbable surgical sutures until used in tissue engineering or as systems drug releasers In this last application, the materials Polymers are suitable, being virtually impossible to retain for a considerable time a drug in a matrix constituted for a compound of low molecular weight. The active agent can vary from a growth factor of a peptide nature to an antitumor agent, an antibiotic or a preventive compound of thrombosis
Es importante que un polímero que vaya a ser empleado como sistema liberador pueda procesarse en forma de pequeñas microesferas, en cuyo interior pueda distribuirse uniformemente el agente activo. Entre los métodos más habituales de preparación puede considerarse la extracción o evaporación de una fase orgánica que está finamente dispersada en una fase acuosa (Jain, R., Shah, N. H., Malick, A. W., Rhodes, C. T. Drug Development and Industrial Pharmacy 28, 703-727, 1998), hallándose el polímero y el fármaco disueltos en la primera. Las microesferas deben presentar una estructura porosa y un tamaño de poro controlable para poder ejercer satisfactoriamente su función como sistema de transferencia de materia con el medio circundante.It is important that a polymer to be used as a releasing system can be processed in the form of small microspheres, into which the active agent can be distributed evenly. Among the most common methods of preparation can be the extraction or evaporation of an organic phase that is finely dispersed in an aqueous phase (Jain, R., Shah, NH, Malick, AW, Rhodes, CT Drug Development and Industrial Pharmacy 28, 703 -727, 1998), the polymer and drug being dissolved in the first. The microspheres must have a porous structure and a controllable pore size in order to successfully perform their function as a matter transfer system with the surrounding environment.
Actualmente los polihidroxialcanoatos constituyen la principal familia de polímeros sintéticos utilizados en biomedicina. Concretamente la poliglicolida es el material más empleado en aplicaciones clínicas, especialmente como sutura quirúrgica bioabsorbible (Schmitt, E. E., Polistina, R. A., U. S. Pat. 3,297,033, 1967). La polilactida presenta una menor velocidad de degradación y una mayor facilidad de procesado, factores ambos que amplían su aplicabilidad. Por ejemplo, la rápida degradación de la poliglicolida puede generar una respuesta inflamatoria que dificulta la reparación de tejidos cuando la cantidad implantada es elevada. Por otra parte es difícil preparar microesferas de poliglicolida, idóneas para su utilización como matrices liberadoras de fármacos, debido a su muy limitada solubilidad. La policaprolactona es uno de los materiales más empleados como sistema liberador debido a su reducida temperatura de transición vítrea que le confiere una naturaleza gomosa, su baja temperatura de fusión, su reducida velocidad de degradación y su capacidad para formar aleaciones compatibles con una amplia variedad de polímeros (Pitt, C. G., Marks, T. A., Schindler, A., Baker, R. Controlled Release of Bioactive Materials, Academic Press Inc.: New York, 1980). Copolímeros de lactida, glicolida y \varepsilon-caprolactona son también ampliamente utilizados como sistemas liberadores de fármacos y en ingeniería de tejidos (Tamber, H., Johansen, P., Merkle, H. P., Gander, B. Advanced Drug Delivery Reviews, 357, 57, 2005).Currently, polyhydroxyalkanoates constitute the main family of synthetic polymers used in biomedicine. Specifically, polyglycolide is the most commonly used material in clinical applications, especially as a bioabsorbable surgical suture (Schmitt, EE, Polistina, RA, US Pat. 3,297,033, 1967). The polylactide has a lower degradation rate and a greater ease of processing, both factors that extend its applicability. For example, the rapid degradation of polyglycolide can generate an inflammatory response that makes tissue repair difficult when the implanted amount is high. On the other hand, it is difficult to prepare polyglycolide microspheres, suitable for use as drug-releasing matrices, due to their very limited solubility. Polycaprolactone is one of the most used materials as a releasing system due to its reduced glass transition temperature that gives it a rubbery nature, its low melting temperature, its low degradation rate and its ability to form alloys compatible with a wide variety of polymers (Pitt, CG, Marks, TA, Schindler, A., Baker, R. Controlled Release of Bioactive Materials , Academic Press Inc .: New York, 1980). Lactide, glycolide and? -Caprolactone copolymers are also widely used as drug delivery systems and tissue engineering (Tamber, H., Johansen, P., Merkle, HP, Gander, B. Advanced Drug Delivery Reviews , 357, 57, 2005).
A pesar de que el poli(3-hidroxibutirato) se produce por procesos biotecnológicos, su utilización biomédica es restringida debido a su excesivamente lenta velocidad de degradación en el cuerpo humano. Copolímeros de ácido 3-hidroxibutírico y ácido 4-hidroxibutírico pueden producirse también naturalmente (Choi, M. H., Yoon, S. C., Lenz, R. W. Applied and Environmental Microbiology, 1570, 65, 1999) aunque por el momento sus aplicaciones continúan poco estudiadas al igual que ocurre con el homopolímero de ácido 4-hidroxibutírico.Although poly (3-hydroxybutyrate) is produced by biotechnological processes, its biomedical use is restricted due to its excessively slow degradation rate in the human body. Copolymers of 3-hydroxybutyric acid and 4-hydroxybutyric acid can also occur naturally (Choi, MH, Yoon, SC, Lenz, RW Applied and Environmental Microbiology , 1570, 65, 1999) although for the moment their applications are still poorly studied as well as occurs with the homopolymer of 4-hydroxybutyric acid.
Los polihidroxialcanoatos de origen natural son producidos intracelularmente por distintos microorganismos, acumulándose en forma granular como fuente de carbón y de reserva energética. La composición de los polímeros y copolímeros depende de las condiciones de fermentación y de los monómeros empleados. El resto de lo polihidroxialcanoatos sintéticos para usos médicos suelen prepararse mediante la polimerización térmica en maca por apertura de anillo de glicolida, lactida o caprolactona.The naturally occurring polyhydroxyalkanoates are produced intracellularly by different microorganisms, accumulating in granular form as a source of coal and reserve energetic The composition of polymers and copolymers depends on the fermentation conditions and the monomers used. He rest of the synthetic polyhydroxyalkanoates for medical uses usually prepared by thermal polymerization in maca by ring opening of glycolide, lactide or caprolactone.
Recientemente se ha desarrollado un proceso para la síntesis de poliésteres derivados de \alpha-hidroxiácidos, principalmente poliglicólico y poliláctico (Epple, M., Herzberg, O. Journal of Biomedical Materials Research, 43, 83-88, 1998; Herzberg, O., Epple, M. European Journal of Inorganic Chemistry, 6, 1395-1406, 2001). Este último puede considerarse alternativo a la polimerización por apertura de anillo aunque los pesos moleculares obtenidos son muy reducidos. El proceso está basado en la polimerización térmica de sales metálicas de derivados halogenados de los ácidos glicólico y láctico.Recently, a process has been developed for the synthesis of polyesters derived from α-hydroxy acids, mainly polyglycolic and polylactic (Epple, M., Herzberg, O. Journal of Biomedical Materials Research , 43, 83-88, 1998; Herzberg, O. , Epple, M. European Journal of Inorganic Chemistry , 6, 1395-1406, 2001). The latter can be considered as an alternative to ring opening polymerization although the molecular weights obtained are very low. The process is based on the thermal polymerization of metal salts of halogenated derivatives of glycolic and lactic acids.
El método se ha intentado extender, aunque sin éxito, a la preparación de poliésteres derivados de \omega-hidroxiácidos.The method has been tried to extend, although without success, to the preparation of polyesters derived from ? -hydroxy acids.
Por el contrario, el proceso ha resultado satisfactorio cuando se aplica a la síntesis de varios tipos de poliesteramidas regulares que incluyen unidades de ácido glicólico (Vera, M., Rodríguez-Galan, A., Puiggalí, J. Macromolecular Rapid Communications, 25, 812-817, 2004). También, se ha conseguido aplicar el método para la preparación de copoliésteres alternantes constituidos por ácido 4-hidroxibutírico y distintos hidroxiácidos alifáticos (Martínez-Palau, M., Franco, L., Ramis, X., Puiggalí, J. Macromolecular Chemistry & Physics, 207, 90 2006). En este caso, el monómero de partida dispone de un terminal derivado del cloruro de 4-clorobutirilo. La reactividad del mismo es reducida por lo que la cinética de la policondensación térmica es lenta. El proceso, sin embargo, se ha mostrado efectivo para la obtención de una serie de copoliésteres alifáticos que tienen en común la presencia de unidades de 4-hidroxibutirato. Recientemente se ha solicitado una patente relativa a su síntesis y a sus aplicaciones en el campo de la biomedicina (Martínez Palau, M., Franco, L., Rodriguez Galán, A., Puiggalí, J., Patente Española con número de solicitud P200502217).On the contrary, the process has been satisfactory when applied to the synthesis of several types of regular polyesteramides that include glycolic acid units (Vera, M., Rodríguez-Galan, A., Puiggalí, J. Macromolecular Rapid Communications , 25, 812-817, 2004). Also, it has been possible to apply the method for the preparation of alternating copolyesters consisting of 4-hydroxybutyric acid and various aliphatic hydroxy acids (Martínez-Palau, M., Franco, L., Ramis, X., Puiggalí, J. Macromolecular Chemistry & Physics , 207, 90 2006). In this case, the starting monomer has a terminal derived from 4-chlorobutyryl chloride. Its reactivity is reduced, so the kinetics of thermal polycondensation are slow. The process, however, has proven effective in obtaining a series of aliphatic copolyesters that have in common the presence of 4-hydroxybutyrate units. Recently a patent has been applied for its synthesis and its applications in the field of biomedicine (Martínez Palau, M., Franco, L., Rodriguez Galán, A., Puiggalí, J., Spanish Patent with application number P200502217) .
El proceso que aquí describimos permite preparar copoliésteres de secuencia regular y que incluyen en este caso unidades de ácido glicólico, garantizándose asimismo un peso molecular adecuado. La síntesis de estos copoliésteres se consigue utilizando un monómero representativo de la secuencia que se prepara a partir del cloruro de 2-cloroacetilo. El monómero se caracteriza además por la presencia de un átomo de halógeno y una sal metálica como terminales. El monómero resultante es mucho más reactivo que el estudiado anteriormente (Martínez-Palau, M., Franco, L., Ramis, X., Puiggalí, J. Macromolecular Chemistry & Physics, 207, 90 2006), derivado del cloruro de 4-clorobutirilo. De esta forma, el nuevo proceso se distingue del proceso aplicado para la obtención de copoliésteres alternantes derivados de ácido 4-hidroxibutírico, en primer lugar por la familia distinta de copoliésteres que se producen y en segundo lugar por la mayor reactividad del nuevo sistema que repercute en unas condiciones de reacción más suaves y en un aumento de los tamaños moleculares de los polímeros resultantes.The process described here allows to prepare copolyesters of regular sequence and which in this case include glycolic acid units, also guaranteeing a suitable molecular weight. The synthesis of these copolyesters is achieved using a representative monomer of the sequence that is prepared from 2-chloroacetyl chloride. The monomer is further characterized by the presence of a halogen atom and a metal salt as terminals. The resulting monomer is much more reactive than the one studied previously (Martínez-Palau, M., Franco, L., Ramis, X., Puiggalí, J. Macromolecular Chemistry & Physics , 207, 90 2006), derived from 4- chloride chlorobutyryl In this way, the new process is distinguished from the process applied to obtain alternating copolyesters derived from 4-hydroxybutyric acid, firstly by the different family of copolyesters that are produced and secondly by the greater reactivity of the new system that affects in milder reaction conditions and in an increase in the molecular sizes of the resulting polymers.
La presente invención se refiere a un nuevo método de preparación de poliésteres constituidos por unidades de ácido glicólico y distintos hidroxiácidos alifáticos. El proceso se basa en una polimerización de sales metálicas de derivados clorados. Los productos obtenidos son novedosos por su secuencia regular, siendo particularmente interesante el derivado del ácido 6-hidroxihexanoico por sus potenciales aplicaciones en el ámbito biomédico.The present invention relates to a new Polyester preparation method consisting of units of glycolic acid and various aliphatic hydroxy acids. The process is based on a polymerization of metal salts of chlorinated derivatives. The products obtained are novel by their regular sequence, the acid derivative being particularly interesting 6-hydroxyhexanoic by its potential applications in the biomedical field.
Los productos son semicristalinos y se caracterizan por su degradabilidad, su baja temperatura de transición vítrea, y su reducida citotoxicidad. Su solubilidad en disolventes orgánicos permite que puedan prepararse en forma de microesferas por el método de evaporación de mezclas bifásicas.The products are semi-crystalline and are characterized by its degradability, its low temperature of glass transition, and its reduced cytotoxicity. Its solubility in Organic solvents allow them to be prepared in the form of microspheres by the evaporation method of biphasic mixtures.
Los poliésteres se caracterizan por la unidad repetitiva -[OCH_{2}COOCHR(CH_{2})_{n-2}CO]-, siendo más interesantes aquellos con R = H y valores 3 y 6 de n. Éstos corresponden a derivados de ácido propiónico y de ácido 6-hidroxihexanoico/\varepsilon-caprolactona que son unidades frecuentes en los polímeros actualmente utilizados en biomedicina. Los comonómeros son \omega-hidroxiácidos cuando R corresponde a un átomo de hidrógeno. Se considera también los comonómeros correspondientes a los ácidos 3-hidroxibutírico (n = 3 y R = CH_{3}) y 4-hidroxivalérico (n = 4 y R = CH_{3}).Polyesters are characterized by the repetitive unit - [OCH 2 COOCHR (CH 2) n-2 CO] -, those with R = H and values 3 and 6 of n being more interesting. These correspond to derivatives of propionic acid and 6-hydroxyhexanoic acid / ε-caprolactone which are frequent units in the polymers currently used in biomedicine. The comonomers are? -Hydroxy acids when R corresponds to a hydrogen atom. The comonomers corresponding to 3-hydroxybutyric acids ( n = 3 and R = CH 3) and 4-hydroxyvaleric acid ( n = 4 and R = CH 3) are also considered.
En el esquema adjunto se ilustra el procedimiento que se ha utilizado para la obtención de los mencionados poliésteres alternantes. El proceso descrito no es idóneo para el derivado del ácido 4-hidroxibutírico (n = 4 y R = H) debido a su elevada tendencia a ciclar, dando lugar a la butirolactona, en el transcurso de la síntesis.The attached scheme illustrates the procedure that has been used to obtain the mentioned alternating polyesters. The process described is not suitable for 4-hydroxybutyric acid derivative (n = 4 and R = H) due to its high tendency to cycle, giving rise to to butyrolactone, in the course of the synthesis.
Para obtener estos copoliésteres con secuencia regular se hace reaccionar el cloruro de 2-cloroacetilo con el hidroxiácido apropiado en un disolvente orgánico. El producto que se recupera por destilación en un horno de bolas, se disuelve o se suspende en agua, y se neutraliza con un bicarbonato metálico (preferentemente de sodio, potasio o cesio) hasta un pH cercano a 8. La correspondiente sal se recupera del medio de reacción y tras lavarse adecuadamente constituye el monómero que se utiliza en las polimerizaciones.To obtain these copolyesters with sequence regular the chloride is reacted from 2-Chloroacetyl with the appropriate hydroxy acid in a organic solvent The product that is recovered by distillation in a ball oven, dissolves or is suspended in water, and neutralize with a metallic bicarbonate (preferably sodium, potassium or cesium) to a pH close to 8. The corresponding salt is recover from the reaction medium and after washing properly it constitutes the monomer that is used in the polymerizations.
El producto suele ser higroscópico por lo que se debe tener especial cuidado en eliminar la humedad tanto si se quiere almacenar como si se quiere polimerizar, evitando de esta forma posibles degradaciones posteriores.The product is usually hygroscopic so it special care must be taken to remove moisture whether want to store as if you want to polymerize, avoiding this form possible later degradations.
Las polimerizaciones tienen como fuerza motor la formación de cloruro metálico, al establecerse nuevos enlaces éster entre los monómeros. La temperatura de fusión del monómero, la cinética de la reacción de condensación y la temperatura óptima de polimerización dependen de las sales metálicas empleadas. En general, se observa que tanto la temperatura de fusión como la de polimerización decrecen con el tamaño del catión. La reacción tiene preferentemente lugar en estado líquido al ser superior la temperatura de polimerización y al tener además el polímero final un bajo punto de fusión. Sin embargo, la reacción puede iniciarse en estado sólido en una primera etapa donde se efectúa el proceso a reducida temperatura. La orientación adecuada de los grupos reactivos en el sólido cristalino permite que se forme rápidamente un prepolímero. En este caso, puede efectuarse una segunda etapa a mayor temperatura que transcurre exclusivamente en fase líquida y permite la agitación (magnética o mecánica) del medio.The polymerizations have the driving force as formation of metallic chloride, when new ester bonds are established between the monomers. The melting temperature of the monomer, the kinetics of the condensation reaction and the optimum temperature of polymerization depend on the metal salts used. In In general, it is observed that both the melting temperature and the temperature of polymerization decrease with cation size. The reaction has preferably place in a liquid state when the polymerization temperature and also having the final polymer a low melting point However, the reaction can be initiated in solid state in a first stage where the process is carried out to reduced temperature The proper orientation of the groups reagents in the crystalline solid allows it to form quickly a prepolymer In this case, a second stage can be carried out higher temperature that occurs exclusively in the liquid phase and allows agitation (magnetic or mechanical) of the medium.
La polimerización avanza en la mayoría de los casos hasta unos pesos moleculares adecuados para las posteriores aplicaciones. Las viscosidades intrínsecas medidas en ácido dicloroacético a 25ºC pueden llegar a ser superiores a 1.0 dL/g. Los monómeros que deben polimerizarse a las temperaturas más elevadas, pueden en algunos casos sufrir una cierta degradación a tiempos de reacción elevados que limita el tamaño molecular.Polymerization advances in most of the cases up to appropriate molecular weights for subsequent Applications. Intrinsic viscosities measured in acid dichloroacetic acid at 25 ° C may be greater than 1.0 dL / g. The monomers that should polymerize at the highest temperatures, they may in some cases suffer some degradation in times of elevated reaction that limits molecular size.
Los polímeros se obtienen en forma de composite con una matriz polimérica que ocluye la sal metálica. Ésta puede eliminarse mediante un simple lavado con agua dando lugar a un material de naturaleza porosa. También puede procederse a la disolución parcial del producto de reacción, por ejemplo mediante diclorometano, y a la precipitación del polímero con metanol.The polymers are obtained in the form of a composite with a polymer matrix that occludes the metal salt. This can be removed by a simple wash with water giving rise to a material of porous nature. It is also possible to partially dissolve the reaction product, for example by dichloromethane, and to precipitate the polymer with methanol.
La solubilidad de estos poliésteres en disolventes orgánicos permite que puedan prepararse microesferas de los mismos por el método de evaporación de mezclas bifásicas. Las microesferas pueden incorporar diferentes fármacos y por tanto ser utilizadas como sistemas dosificadores. Una disolución de polímero y el fármaco apropiado en un disolvente orgánico volátil como el diclorometano se dispersa finamente en una fase acuosa, manteniendo una vigorosa agitación mecánica. Se añade asimismo un surfactante como el alcohol polivinílico y cloruro sódico. La agitación se mantiene hasta la evaporación completa de la fase orgánica, recuperándose el polímero por centrifugación. Para las aplicaciones de dosificación, se efectúa un tamizado y se selecciona la fracción con diámetros comprendidos entre unos 45 y 80 \mum ya que se considera la más apropiada. El proceso permite obtener microesferas de tamaño uniforme, superficie rugosa y porosidad controlable.The solubility of these polyesters in organic solvents allow microspheres of the same by the evaporation method of biphasic mixtures. The microspheres can incorporate different drugs and therefore be used as dosing systems. A solution of polymer and the appropriate drug in a volatile organic solvent such as Dichloromethane is dispersed finely in an aqueous phase, keeping a vigorous mechanical agitation. A surfactant is also added such as polyvinyl alcohol and sodium chloride. Agitation is maintains until the complete evaporation of the organic phase, recovering the polymer by centrifugation. For applications dosing, screening is done and the fraction is selected with diameters between about 45 and 80 µm since it Consider the most appropriate. The process allows to obtain microspheres uniform size, rough surface and controllable porosity.
Los siguientes ejemplos no pretenden ser limitantes, sino describir un proceso concreto de obtención del polímero con formación de cloruro metálico como fuerza motor y la preparación de microesferas de polímero con la incorporación de un fármaco. Adicionalmente se demuestra la degradabilidad del material, se ilustra su idoneidad como sistema liberador y su reducida toxicidad.The following examples are not intended to be limitations, but describe a specific process of obtaining the polymer with metal chloride formation as the driving force and the preparation of polymer microspheres with the incorporation of a drug. Additionally, the degradability of the material, its suitability as a liberating system and its reduced toxicity
Se disuelve cloruro de cloroacetilo (7.2 ml, 69 mmol) en 50 mL de cloroformo anhidro. Esta solución se adiciona lentamente a un matraz de 250 mL conteniendo 50 mL de una solución de ácido 6-hidroxihexanoico (76 mmol, 1.1 eq) en cloroformo. La adición se lleva a cabo durante un periodo de 1 h bajo agitación vigorosa y manteniendo el matraz a 0ºC mediante un baño de agua y sal. Para neutralizar los gases de ácido clorhídrico producidos durante la reacción se utiliza un tubo de salida de gases relleno de hidróxido sódico. Posteriormente, la mezcla de reacción se mantiene en agitación a temperatura ambiente durante otras tres horas y se efectúa un lavado con agua mediante un embudo de extracción. Tras evaporar la fase orgánica se obtiene un aceite que se purifica en un horno de vidrio para destilación al vacío en tubo de bolas. Finalmente, se obtiene un aceite incoloro con un rendimiento del 50% que corresponde al producto deseado.Chloroacetyl Chloride Dissolves (7.2 ml, 69 mmol) in 50 mL of anhydrous chloroform. This solution is added. slowly to a 250 mL flask containing 50 mL of a solution of 6-hydroxyhexanoic acid (76 mmol, 1.1 eq) in chloroform. The addition is carried out over a period of 1 h under vigorous stirring and keeping the flask at 0 ° C by water and salt bath. To neutralize hydrochloric acid gases produced during the reaction a gas outlet tube is used sodium hydroxide filler. Subsequently, the reaction mixture it is kept under stirring at room temperature for another three hours and a water wash is performed using a funnel extraction. After evaporating the organic phase an oil is obtained that it is purified in a glass oven for vacuum distillation in a tube of balls. Finally, a colorless oil is obtained with a 50% yield corresponding to the desired product.
Infrarrojo: 3047 (OH, ácido), 2941 y 2869 (CH_{2}), 1737 (C=O, éster), 1703 (C=O, ácido), 1243 y 1173 (C-O, éster) cm^{-1}.Infrared: 3047 (OH, acid), 2941 and 2869 (CH2), 1737 (C = O, ester), 1703 (C = O, acid), 1243 and 1173 (C-O, ester) cm -1.
^{1}H NMR (CDCl_{3}, TMS): \delta = 4.20 (triplete, 2H, COOCH_{2}), 4.06 (singulete, 2H, ClCH_{2}COO), 2.38 (triplete, 2H, CH_{2}COOH), 1.69 (multiplete, 4H, CH_{2}CH_{2}CH_{2}CH_{2}COOH), 1.44 (multiplete, 2H, CH_{2}CH_{2}CH_{2}COOH) ppm.1 H NMR (CDCl 3, TMS): δ = 4.20 (triplet, 2H, COOCH 2), 4.06 (singlet, 2H, ClCH 2 COO), 2.38 (triplet, 2H, C H 2 COOH), 1.69 (multiplet, 4H, C H 2 CH 2 C H 2 CH 2 COOH), 1.44 (multiplet, 2H, C H 2 CH_ {2 CH2COOH) ppm.
^{13}C NMR (CDCl_{3}, TMS): \delta = 179.6
(COOH), 167.4 (ClCH_{2}COO), 65.9 (COOCH_{2}),
40.8 (ClCH_{2}) 33.7 (CH_{2}CO
OH), 28.1
(COOCH_{2}CH_{2}), 25.2 (CH_{2}CH_{2}COOH),
24.1 (CH_{2}CH_{2}CH_{2}COOH) ppm.13 C NMR (CDCl 3, TMS): δ = 179.6 (COOH), 167.4 (ClCH 2 C OO), 65.9 (COO C H 2), 40.8 (Cl C H 2 }) 33.7 ( C H 2 CO
OH), 28.1 (COOCH 2 C H 2), 25.2 ( C H 2 CH 2 COOH), 24.1 ( C H 2 CH 2 CH 2 COOH) ppm.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Estos compuestos se prepararan mediante la neutralización de una solución acuosa del ácido 6-(2-cloroacetoxi)hexanoico con la correspondiente solución 1M de bicarbonato sódico, potásico o césico. La solución se mantiene a una temperatura de 0ºC durante todo el proceso de adición. Cuando se alcanza un pH de 8 la mezcla de reacción se congela y liofiliza. Las sales de sodio y potasio se purifican mediante repetidos lavados con acetato de etilo. Los monómeros finales se guardan en un desecador al vacío. La elevada reactividad de algunos productos puede causar que se produzca una cierta cantidad de oligómeros durante el proceso de recuperación y/o almacenaje. Los rendimientos que se indican se han calculado incluyendo las cantidades de prepolímero formado, mientras que los datos espectroscópicos corresponden únicamente a las sales orgánicas sintetizadas.These compounds will be prepared by neutralization of an aqueous acid solution 6- (2-Chloroacetoxy) hexanoic acid with the corresponding 1M solution of sodium bicarbonate, potassium or Césico The solution is maintained at a temperature of 0 ° C for The whole process of addition. When a pH of 8 is reached the mixture reaction is frozen and lyophilized. The sodium and potassium salts are Purify by repeated washing with ethyl acetate. The Final monomers are stored in a vacuum desiccator. High reactivity of some products may cause a certain amount of oligomers during the recovery process and / or storage. The indicated returns have been calculated including the amounts of prepolymer formed, while the spectroscopic data correspond only to salts organic synthesized.
Sal de sodio: El rendimiento final es cercano al 97%. Sodium salt : The final yield is close to 97%.
Infrarrojo: 2937 y 2855 (CH_{2}), 1732 (C=O, éster), 1560 (C=O, sal), 1293 y 1263 (C-O, sal), 1189 y 1166 (C-O, éster) cm^{-1}.Infrared: 2937 and 2855 (CH2), 1732 (C = O, ester), 1560 (C = O, salt), 1293 and 1263 (C-O, salt), 1189 and 1166 (C-O, ester) cm -1.
^{1}H NMR (DMSO): \delta = 4.32 (singulete,
2H, ClCH_{2}COO), 4.02 (triplete, 2H, COOCH_{2}), 1.87
(triplete, 2H, CH_{2}COO
Na), 1.45 (multiplete, 4H,
CH_{2}CH_{2}CH_{2}CH_{2}COONa), 1.26
(multiplete, 2H, CH_{2}CH_{2}CH_{2}COONa) ppm.1 H NMR (DMSO): δ = 4.32 (singlet, 2H, ClCH 2 COO), 4.02 (triplet, 2H, COOCH 2), 1.87 (triplet, 2H, CH 2 COO
Na), 1.45 (multiplet, 4H, C H 2 CH 2 C H 2 CH 2 COONa), 1.26 (multiplet, 2H, C H 2 CH 2 CH 2 2} COONa) ppm.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Sal de potasio: El rendimiento final es cercano al 75%. Potassium salt : The final yield is close to 75%.
Infrarrojo: 2929 y 2859 (CH_{2}), 1734 (C=O, éster), 1561 (C=O, sal), 1295 y 1267 (C-O, sal), 1192 y 1165 (C-O, éster) cm^{-1}.Infrared: 2929 and 2859 (CH2), 1734 (C = O, ester), 1561 (C = O, salt), 1295 and 1267 (C-O, salt), 1192 and 1165 (C-O, ester) cm -1.
^{1}H NMR (DMSO): \delta = 4.32 (singulete,
2H, ClCH_{2}COO), 4.02 (triplete, 2H, COOCH_{2}), 1.91
(triplete, 2H, CH_{2}
COOK), 1.51 (multiplete, 4H,
CH_{2}CH_{2}CH_{2}CH_{2}COOK), 1.29
(multiplete, 2H, CH_{2}CH_{2}CH_{2}COOK) ppm.1 H NMR (DMSO): δ = 4.32 (singlet, 2H, ClCH 2 COO), 4.02 (triplet, 2H, COOCH 2), 1.91 (triplet, 2H, CH 2)
COOK), 1.51 (multiplet, 4H, C H 2 CH 2 C H 2 CH 2 COOK), 1.29 (multiplet, 2H, C H 2 CH 2 CH 2 2} COOK) ppm.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Sal de cesio: El rendimiento final es prácticamente cuantitativo. Cesium salt : The final yield is practically quantitative.
Infrarrojo: 2940 y 2864 (CH_{2}), 1739 (C=O, éster), 1559 (C=O, sal), 1286 (C-O, sal), 1190 y 1149 (C-O, éster) cm^{-1}.Infrared: 2940 and 2864 (CH2), 1739 (C = O, ester), 1559 (C = O, salt), 1286 (C-O, salt), 1190 and 1149 (C-O, ester) cm -1.
^{1}H NMR (DMSO): \delta = 4.31 (singulete,
2H, ClCH_{2}COO), 4.01 (triplete, 2H, COOCH_{2}), 1.83
(triplete, 2H, CH_{2}COO
Cs), 1.50 (multiplete, 4H,
CH_{2}CH_{2}CH_{2}CH_{2}COOCs), 1.27
(multiplete, 2H, CH_{2}CH_{2}CH_{2}COOCs) ppm.1 H NMR (DMSO): δ = 4.31 (singlet, 2H, ClCH 2 COO), 4.01 (triplet, 2H, COOCH 2), 1.83 (triplet, 2H, CH 2 COO
Cs), 1.50 (multiplet, 4H, C H 2 CH 2 C H 2 CH 2 COOCs), 1.27 (multiplet, 2H, C H 2 CH 2 CH 2 2} COOCs) ppm.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
En un tubo de reacción provisto de agitación se
introduce la sal potásica del ácido
6-(2-cloroacetoxi)hexanoico triturada y
previamente secada en un desecador al vacío. En una primera fase se
calienta al vacío el matraz hasta una temperatura de 70ºC durante 2
h y en una segunda fase se calienta el matraz hasta una temperatura
de 100ºC durante 2 h. Tras enfriar hasta temperatura ambiente, se
obtiene una masa sólida blanca que corresponde a la mezcla de
polímero y cloruro potásico. El polímero se disuelve en
diclorometano, se separa del cloruro mediante centrifugación, se
recupera por precipitación con metanol y se lava abundantemente con
agua, metanol y éter etílico. La viscosidad intrínseca (medida en
ácido dicloroacético a 25ºC) corresponde a 1.05 dL/g mientras que
el peso molecular promedio en peso determinado mediante GPC es
superior a 44 000 g/mol. El rendimiento de polimerización es cercano
al
80%.In a reaction tube provided with stirring, the potassium salt of the crushed 6- (2-chloroacetoxy) hexanoic acid previously dried in a vacuum desiccator is introduced. In a first phase the flask is heated under vacuum to a temperature of 70 ° C for 2 h and in a second phase the flask is heated to a temperature of 100 ° C for 2 h. After cooling to room temperature, a white solid mass is obtained that corresponds to the polymer and potassium chloride mixture. The polymer is dissolved in dichloromethane, separated from the chloride by centrifugation, recovered by precipitation with methanol and washed thoroughly with water, methanol and ethyl ether. The intrinsic viscosity (measured in dichloroacetic acid at 25 ° C) corresponds to 1.05 dL / g while the weight average molecular weight determined by GPC is greater than 44,000 g / mol. The polymerization yield is close to
80%
Infrarrojo: 2941 y 2871 (CH_{2}), 1735 (C=O, éster), 1148 (C-O, éster) cm^{-1}.Infrared: 2941 and 2871 (CH2), 1735 (C = O, ester), 1148 (C-O, ester) cm -1.
^{1}H NMR (DMSO): \delta = 4.58 (singulete, 2H, OCH_{2}COO), 4.02 (triplete, 2H, OCH_{2}), 2.32 (triplete, 2H, CH_{2}COO), 1.49 (multiplete, 4H, CH_{2}CH_{2}CH_{2}CH_{2}COO), 1.28 (multiplete, 2H, CH_{2}CH_{2}CH_{2}COO) ppm.1 H NMR (DMSO): δ = 4.58 (singlet, 2H, OCH 2 COO), 4.02 (triplet, 2H, OCH 2), 2.32 (triplet, 2H, CH 2 COO) , 1.49 (multiplet, 4H, C H 2 CH 2 C H 2 CH 2 COO), 1.28 (multiplet, 2H, C H 2 CH 2 CH 2 COO) ppm.
^{13}C NMR (DMSO): \delta = 172.59 (CO, 6HH), 168.01 (CO, Glc), 64.62 (OCH_{2}), 60.67 (COOCH_{2}COO), 33.07 (CH_{2}COO), 27.82 (OCH_{2}CH_{2}), 24.76 (CH_{2}CH_{2}COO), 24.12 (CH_{2}CH_{2}CH_{2}COO) ppm.13 C NMR (DMSO): δ = 172.59 (CO, 6HH), 168.01 (CO, Glc), 64.62 (OCH 2), 60.67 (COO C H 2 COO), 33.07 ( C H_ {2} COO), 27.82 (OCH 2 CH 2), 24.76 ( C H 2 CH 2 COO), 24.12 ( C H 2 CH 2 CH 2 COO) ppm .
El análisis térmico diferencial de barrido muestra que el polímero presenta una temperatura de fusión cercana a los 63ºC y una temperatura de transición vítrea de -37ºC. El análisis termogravimétrico indica que el polímero puede procesarse desde el estado fundido al estar la temperatura de inicio de descomposición por encima de los 300ºC.Differential thermal scanning analysis shows that the polymer has a near melting temperature at 63 ° C and a glass transition temperature of -37 ° C. He thermogravimetric analysis indicates that the polymer can be processed from the molten state to the start temperature of decomposition above 300 ° C.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Las microesferas del polímero se preparan por el método de evaporación de una mezcla constituida por una fase orgánica y una fase acuosa. 2 g de polímero se disuelven en 45 cm^{3} de diclorometano, añadiéndose la cantidad apropiada del fármaco. La solución resultante se dispersa en 500 cm^{3} de una solución acuosa que contiene 4 g de alcohol polivinílico (grado de hidrólisis 87-89%, peso molecular promedio en peso de 13000-23000 g/mol) y 5 g de cloruro sódico, la adición se efectúa mientras se agita mecánicamente a una velocidad de 1.300 rpm. La mezcla bifásica se mantiene en agitación hasta que todo el diclorometano se evapora. Las microesferas se separaran por filtración, al igual que tras los sucesivos lavados con agua.The polymer microspheres are prepared by the evaporation method of a mixture consisting of a phase Organic and an aqueous phase. 2 g of polymer dissolve in 45 cm 3 of dichloromethane, adding the appropriate amount of drug. The resulting solution is dispersed in 500 cm 3 of a aqueous solution containing 4 g of polyvinyl alcohol (degree of hydrolysis 87-89%, weight average molecular weight of 13000-23000 g / mol) and 5 g of sodium chloride, the addition is done while mechanically stirring at a speed of 1,300 rpm. The biphasic mixture is kept under stirring until All dichloromethane evaporates. The microspheres will be separated by filtration, as after successive washing with water.
El análisis granulométrico realizado mediante tamices con tamaños de poro de 1000, 500, 250, 125, 100, 80 y 45 \mum muestra una curva bimodal con una fracción significativa de microesferas con diámetros comprendidos entre 45 y 80 \mum que se considera la más idónea para su empleo como sistema liberador. La observación mediante microscopía de barrido revela que las partículas presentan una forma esférica y una superficie rugosa.The granulometric analysis performed by sieves with pore sizes of 1000, 500, 250, 125, 100, 80 and 45 um shows a bimodal curve with a significant fraction of microspheres with diameters between 45 and 80 µm which are considered the most suitable for use as a liberating system. The Scanning microscopy observation reveals that particles have a spherical shape and a surface rough.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Las microesferas de poli(Glc-alt-6HH) se degradan hidrolíticamente en condiciones fisiológicas simuladas mediante un tampón fosfato de pH 7.4 y una temperatura de 37ºC. De esta forma, tras 7 y 25 días de exposición se observa una caída del peso molecular promedio en peso desde un valor inicial de 44.000 g/mol hasta unos valores finales de 30.000 y 20.000 g/mol, respectivamente. En estas condiciones, la degradación transcurre por tanto a una velocidad moderada.Poly (Gl- alt- 6HH) microspheres are hydrolytically degraded under simulated physiological conditions by a phosphate buffer of pH 7.4 and a temperature of 37 ° C. Thus, after 7 and 25 days of exposure, a drop in the average molecular weight by weight is observed from an initial value of 44,000 g / mol to final values of 30,000 and 20,000 g / mol, respectively. Under these conditions, degradation takes place at a moderate speed.
Los estudios de degradación realizados con películas del polímero de 200 \mum de espesor corroboran que la muestra es susceptible al ataque hidrolítico aunque el proceso es lento. De esta forma, tras 120 días de exposición se detecta una pérdida de peso del 6% y una caída del peso molecular en peso hasta un valor de 15.000 g/mol. En condiciones aceleradas producidas por un incremento de la temperatura del medio, hasta un valor de 50ºC, los cambios anteriores se observan tras sólo 28 días de exposición.Degradation studies conducted with 200 µm thick polymer films corroborate that the sample is susceptible to hydrolytic attack although the process is slow. In this way, after 120 days of exposure a 6% weight loss and a molecular weight drop in weight to a value of 15,000 g / mol. In accelerated conditions produced by an increase in the temperature of the medium, up to a value of 50 ° C, the above changes are observed after only 28 days of exposition.
El polímero se degrada fácilmente por la acción de enzimas como la lipasa de Pseudomonas cepacia y la proteinasa K. Se observa la degradación completa de películas de 200 \mum de espesor expuestas a estos medios después de 5 y 10 días, respectivamente.The polymer is easily degraded by the action of enzymes such as Pseudomonas cepacia lipase and proteinase K. The complete degradation of 200 µm thick films exposed to these media is observed after 5 and 10 days, respectively.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
La siguiente figura ilustra la cinética de liberación del fármaco triclosán en un medio celular (medio Eagle modificado por Dulbecco conteniendo un 7.5% (peso/volumen) de bicarbonato sódico y 10% (volumen/volumen) de suero fetal bovino a pH 7.4) para las microesferas de dos poliésteres representativos de la familia considerada, concretamente los que incorporan unidades de ácido 6-hidroxihexanoico (poli(Glc-alt-6HH)) o de ácido 4-hidroxibutírico (poli(Glc-alt-4HB)) como comonómeros. Se observa, un comportamiento diferente que está de acuerdo con las características de los correspondientes polímeros. De esta forma, el triclosán se libera más lentamente en el polímero de naturaleza más hidrofóbica (poli(Glc-alt-6HH)). Concretamente, tras 50 horas de exposición, un 80% de la carga inicial se libera en el medio cuando se utiliza poli(Glc-alt-4HB) como matriz polimérica, mientras que se requieren 110 horas para liberar un 62% cuando se utiliza poli(Glc-alt-6HH). Estos tiempos son claramente insuficientes para producir una degradación hidrolítica acusada de los correspondientes polímeros. La presente invención permite consecuentemente preparar una familia de materiales con distintas cinéticas de liberación.The following figure illustrates the release kinetics of the triclosan drug in a cellular medium (Dulbecco-modified Eagle medium containing 7.5% (weight / volume) of sodium bicarbonate and 10% (volume / volume) of bovine fetal serum at pH 7.4) for the microspheres of two representative polyesters of the family considered, specifically those incorporating units of 6-hydroxyhexanoic acid (poly (Gl- alt- 6HH)) or 4-hydroxybutyric acid (poly (Gl- alt -4HB)) as comonomers. It is observed, a different behavior that is in accordance with the characteristics of the corresponding polymers. In this way, triclosan is released more slowly in the polymer of a more hydrophobic nature (poly (Gl- alt- 6HH)). Specifically, after 50 hours of exposure, 80% of the initial charge is released in the medium when poly (Gl- alt -4HB) is used as a polymer matrix, while 110 hours are required to release 62% when poly is used (Glc- alt -6HH). These times are clearly insufficient to produce a marked hydrolytic degradation of the corresponding polymers. The present invention consequently allows to prepare a family of materials with different release kinetics.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Los ensayos de citotoxicidad se realizaron de acuerdo con la norma ISO-140320, evaluando la toxicidad de los productos liberados por el material tras su incubación durante 50 días en un medio de cultivo celular (DMEM, medio Eagle modificado por Dulbecco conteniendo un 7.5% (peso/volumen) de bicarbonato sódico y 10% (volumen/volumen) de suero fetal bovino a pH 7.4). La extracción se realizó a 37ºC en atmósfera húmeda con 5% CO_{2} y 95% aire. Las células utilizadas en los ensayos tanto de citotoxicidad como de adherencia fueron fibroblastos de ratón L-929 (EACC, Sigma-Aldrich, UK). Las pruebas realizadas demuestran una baja toxicidad de los extractos y una adecuada proliferación y adherencia celular sobre el polímero.Cytotoxicity tests were performed in according to ISO-140320, evaluating the toxicity of the products released by the material after its incubation for 50 days in a cell culture medium (DMEM, half Eagle modified by Dulbecco containing 7.5% (weight / volume) of sodium bicarbonate and 10% (volume / volume) of fetal bovine serum at pH 7.4). Extraction was performed at 37 ° C in humid atmosphere with 5% CO2 and 95% air. The cells used in both cytotoxicity and adhesion tests were L-929 mouse fibroblasts (EACC, Sigma-Aldrich, UK). The tests performed demonstrate low toxicity of extracts and adequate cell proliferation and adhesion on the polymer.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Figura 1. Micrografías de SEM mostrando la morfología microesferas de poli(Glc-alt-6HH) cargadas con triclosan.Figure 1. SEM micrographs showing the morphology microspheres of poly (Glc- alt -6HH) loaded with triclosan.
Figura 2. Liberación de triclosán en un medio de cultivo celular a partir de dos polímeros representativos de la serie.Figure 2. Triclosan release in a medium of cell culture from two representative polymers of the Serie.
Figura 3. Micrografía óptica mostrando la proliferación celular sobre un film de poli(Glc-alt-6HH) tras 72 de exposición. Se puede observar como las células L-929 se mantienen perfectamente adheridas formando monocapa sobre el nuevo material. Aumento 100x.Figure 3. Optical micrograph showing cell proliferation on a poly (Glc- alt- 6HH) film after 72 exposure. It can be seen how L-929 cells remain perfectly attached forming monolayer on the new material. 100x magnification
Claims (5)
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ES200702065A ES2322008B1 (en) | 2007-07-19 | 2007-07-19 | PROCESS OF OBTAINING AND BIOMEDICAL APPLICATIONS OF ALTERNATE POLYESTERS CONSTITUTED BY UNITS OF GLYCOLIC ACID AND ALIFATIC HYDROXIACIDES. |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ES200702065A ES2322008B1 (en) | 2007-07-19 | 2007-07-19 | PROCESS OF OBTAINING AND BIOMEDICAL APPLICATIONS OF ALTERNATE POLYESTERS CONSTITUTED BY UNITS OF GLYCOLIC ACID AND ALIFATIC HYDROXIACIDES. |
Publications (2)
Publication Number | Publication Date |
---|---|
ES2322008A1 true ES2322008A1 (en) | 2009-06-15 |
ES2322008B1 ES2322008B1 (en) | 2010-03-11 |
Family
ID=40739876
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ES200702065A Active ES2322008B1 (en) | 2007-07-19 | 2007-07-19 | PROCESS OF OBTAINING AND BIOMEDICAL APPLICATIONS OF ALTERNATE POLYESTERS CONSTITUTED BY UNITS OF GLYCOLIC ACID AND ALIFATIC HYDROXIACIDES. |
Country Status (1)
Country | Link |
---|---|
ES (1) | ES2322008B1 (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6548569B1 (en) * | 1999-03-25 | 2003-04-15 | Metabolix, Inc. | Medical devices and applications of polyhydroxyalkanoate polymers |
-
2007
- 2007-07-19 ES ES200702065A patent/ES2322008B1/en active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6548569B1 (en) * | 1999-03-25 | 2003-04-15 | Metabolix, Inc. | Medical devices and applications of polyhydroxyalkanoate polymers |
Non-Patent Citations (8)
Title |
---|
FUKUZAKI, H. et al. "{}Direct copolymerization of glycolic acid with lactones in the absence of catalysts"{}. European Polymer Journal, 1990, Volumen 26, Número 4, páginas 457-461 (Ver Figura 1). * |
FUKUZAKI, H. et al. "Direct copolymerization of glycolic acid with lactones in the absence of catalysts". European Polymer Journal, 1990, Volumen 26, Número 4, páginas 457-461 (Ver Figura 1). * |
MARTINEZ-PALAU M. et al. "{}Poly[(4-hydroxybutyric acid)-alt- (glycolic acid)]: Synthesis by Thermal Polycondensation of Metal Salts of 4-Chlorobutyric Acid Carboxymethyl Ester"{}. Macromolecular Chemistry and Physics, 2006, Volumen 207, páginas 90-103 (Ver páginas 90 y 91). * |
MARTINEZ-PALAU M. et al. "Poly[(4-hydroxybutyric acid)-alt- (glycolic acid)]: Synthesis by Thermal Polycondensation of Metal Salts of 4-Chlorobutyric Acid Carboxymethyl Ester". Macromolecular Chemistry and Physics, 2006, Volumen 207, páginas 90-103 (Ver páginas 90 y 91). * |
POUTON, C.W. et al. "{}Biosynthetic polyhydroxyalkanoates and their potential in drug delivery"{}. Advanced Drug Delivery Reviews, 1996, Volumen 18, páginas 133-162. * |
POUTON, C.W. et al. "Biosynthetic polyhydroxyalkanoates and their potential in drug delivery". Advanced Drug Delivery Reviews, 1996, Volumen 18, páginas 133-162. * |
RODRÍGUEZ-GALÁN, A. et al. "{}Synthesis of Poly(ester amide)s Derived from Glycolic Acid and the Amino Acids: beta-alanine or 4-Aminobutyric Acid"{}. Macromolecular Chemistry and Physics, 2003, Volumen 204, Número 17, páginas 2078-2089 (ver página 2079). * |
RODRÍGUEZ-GALÁN, A. et al. "Synthesis of Poly(ester amide)s Derived from Glycolic Acid and the Amino Acids: beta-alanine or 4-Aminobutyric Acid". Macromolecular Chemistry and Physics, 2003, Volumen 204, Número 17, páginas 2078-2089 (ver página 2079). * |
Also Published As
Publication number | Publication date |
---|---|
ES2322008B1 (en) | 2010-03-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
ES2394953T3 (en) | Polyhydroxyalkanoate compositions with controlled degradation rates | |
ES2375637T3 (en) | RESTORABLE POLY (ETERES-ESTERS) AND ITS USE FOR THE PRODUCTION OF MEDICAL IMPLANTS. | |
Ying et al. | Scaffolds from electrospun polyhydroxyalkanoate copolymers: fabrication, characterization, bioabsorption and tissue response | |
Ghalia et al. | Biodegradable poly (lactic acid)-based scaffolds: synthesis and biomedical applications | |
JP4410857B2 (en) | Monomers derived from hydroxy acids and polymers prepared therefrom | |
US6867248B1 (en) | Polyhydroxyalkanoate compositions having controlled degradation rates | |
US6878758B2 (en) | Polyhydroxyalkanoate compositions having controlled degradation rates | |
Bourke et al. | Polymers derived from the amino acid L-tyrosine: polycarbonates, polyarylates and copolymers with poly (ethylene glycol) | |
ES2305512T3 (en) | BIODEGRADABLE COPOLYMERS OF VARIOUS BLOCKS, SEGMENTED AND SEPARATE PHASES | |
US6828357B1 (en) | Polyhydroxyalkanoate compositions having controlled degradation rates | |
KR100668046B1 (en) | Preparation and characterization of polyethyleneglycol/polyesters as biocompatible themo-sensitive materials | |
ES2628931T3 (en) | Multi-block segmented copolymers of biodegradable separate phases and release of biologically active polypeptides | |
JP4680900B2 (en) | Degradable and biocompatible block copolymer | |
KR100408458B1 (en) | Porous Scaffolds for Tissue Engineering made from the Biodegradable Glycolide/ε-Caprolactone Copolymer | |
ES2322008B1 (en) | PROCESS OF OBTAINING AND BIOMEDICAL APPLICATIONS OF ALTERNATE POLYESTERS CONSTITUTED BY UNITS OF GLYCOLIC ACID AND ALIFATIC HYDROXIACIDES. | |
ES2282025B1 (en) | PROCESS OF OBTAINING AND BIOMEDICAL APPLICATIONS OF ALTERNATE POLYESTERS CONSTITUTED BY UNITS OF 4-HYDROXIBUTRIC ACID AND ALIFATIC HYDROXIACIDES. | |
Vert | Poly (lactic acid) s | |
JP2005518469A (en) | Biodegradable polymeric materials for bioclinical applications | |
Rizzarelli et al. | Analytical methods in resorbable polymer development and degradation tracking | |
Woodard | Degradable PCL-PLLA Semi-interpenetrating Network (Semi-IPN) Shape Memory Polymer (SMP) Scaffolds for Cranial Bone Defect Repair | |
Kohn et al. | Polymers derived from L-Tyrosine | |
Fischer et al. | 1.1 Poly (glycolic acid): A Status Report on Synthesis, Applications and Limitations | |
NAIR et al. | MENG DENG |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EC2A | Search report published |
Date of ref document: 20090615 Kind code of ref document: A1 |
|
FG2A | Definitive protection |
Ref document number: 2322008B1 Country of ref document: ES |