DK3116514T3 - Konjugater af en oligomer af hyaluronsyre eller salt deraf, fremgangsmåde til fremstilling deraf, og anvendelse deraf - Google Patents
Konjugater af en oligomer af hyaluronsyre eller salt deraf, fremgangsmåde til fremstilling deraf, og anvendelse deraf Download PDFInfo
- Publication number
- DK3116514T3 DK3116514T3 DK15719591.8T DK15719591T DK3116514T3 DK 3116514 T3 DK3116514 T3 DK 3116514T3 DK 15719591 T DK15719591 T DK 15719591T DK 3116514 T3 DK3116514 T3 DK 3116514T3
- Authority
- DK
- Denmark
- Prior art keywords
- hyaluronic acid
- group
- oligomer
- conjugates
- preparation according
- Prior art date
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- 229920002674 hyaluronan Polymers 0.000 title claims description 68
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 title claims description 58
- 229960003160 hyaluronic acid Drugs 0.000 title claims description 56
- 238000000034 method Methods 0.000 title claims description 23
- 238000002360 preparation method Methods 0.000 title claims description 21
- 150000003839 salts Chemical class 0.000 title claims description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 34
- 239000000203 mixture Substances 0.000 claims description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- 239000000758 substrate Substances 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- 150000004676 glycans Chemical class 0.000 claims description 10
- 229920001282 polysaccharide Polymers 0.000 claims description 10
- 239000005017 polysaccharide Substances 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 235000011054 acetic acid Nutrition 0.000 claims description 7
- 239000003638 chemical reducing agent Substances 0.000 claims description 7
- -1 cyanoborohydride Chemical compound 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 4
- 150000001735 carboxylic acids Chemical class 0.000 claims description 4
- QHXLIQMGIGEHJP-UHFFFAOYSA-N boron;2-methylpyridine Chemical compound [B].CC1=CC=CC=N1 QHXLIQMGIGEHJP-UHFFFAOYSA-N 0.000 claims description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 3
- 239000004310 lactic acid Substances 0.000 claims description 3
- 235000014655 lactic acid Nutrition 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 claims description 3
- 235000019260 propionic acid Nutrition 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 229910001413 alkali metal ion Inorganic materials 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 2
- 230000001093 anti-cancer Effects 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims description 2
- 150000001720 carbohydrates Chemical group 0.000 claims 4
- 238000004519 manufacturing process Methods 0.000 claims 3
- 125000000923 (C1-C30) alkyl group Chemical group 0.000 claims 2
- 101150007250 MOT1 gene Proteins 0.000 claims 2
- 125000003172 aldehyde group Chemical group 0.000 claims 2
- 238000000914 diffusion-ordered spectroscopy Methods 0.000 description 19
- 150000001299 aldehydes Chemical class 0.000 description 15
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 13
- KIUKXJAPPMFGSW-MNSSHETKSA-N hyaluronan Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)C1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H](C(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-MNSSHETKSA-N 0.000 description 13
- 125000005647 linker group Chemical group 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 229940099552 hyaluronan Drugs 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 239000012265 solid product Substances 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 8
- 238000006268 reductive amination reaction Methods 0.000 description 8
- 230000009467 reduction Effects 0.000 description 7
- 238000006722 reduction reaction Methods 0.000 description 7
- 230000004071 biological effect Effects 0.000 description 6
- 229920000642 polymer Polymers 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 150000002016 disaccharides Chemical class 0.000 description 5
- 125000003277 amino group Chemical group 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 3
- MSWZFWKMSRAUBD-IVMDWMLBSA-N glucosamine group Chemical group OC1[C@H](N)[C@@H](O)[C@H](O)[C@H](O1)CO MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- ALHNLFMSAXZKRC-UHFFFAOYSA-N benzene-1,4-dicarbohydrazide Chemical compound NNC(=O)C1=CC=C(C(=O)NN)C=C1 ALHNLFMSAXZKRC-UHFFFAOYSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 238000005538 encapsulation Methods 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 239000001294 propane Substances 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- 150000004044 tetrasaccharides Chemical class 0.000 description 2
- 150000004043 trisaccharides Chemical class 0.000 description 2
- 230000035899 viability Effects 0.000 description 2
- PIGCSKVALLVWKU-UHFFFAOYSA-N 2-Aminoacridone Chemical compound C1=CC=C2C(=O)C3=CC(N)=CC=C3NC2=C1 PIGCSKVALLVWKU-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229920002873 Polyethylenimine Polymers 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 239000007864 aqueous solution Substances 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
- 230000001588 bifunctional effect Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 239000002041 carbon nanotube Substances 0.000 description 1
- 229910021393 carbon nanotube Inorganic materials 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 239000013553 cell monolayer Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 210000000172 cytosol Anatomy 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 238000005570 heteronuclear single quantum coherence Methods 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 210000002901 mesenchymal stem cell Anatomy 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- 238000000569 multi-angle light scattering Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 210000001179 synovial fluid Anatomy 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Classifications
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biochemistry (AREA)
- Materials Engineering (AREA)
- Polymers & Plastics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Claims (19)
1. Konjugat af en oligomer af hyaluronsyre eller et salt deraf ifølge en hvilken som helst af de generelle formler I, II, III eller IV,
hvor R3 er COOR6 eller CH2OH, R4 er OH eller NHCOCH3, R6 er H+ eller er valgt fra gruppen omfattende ethvert af alkalimetalioner eller jordalkalimetaller, fortrinsvis Na+, K+, Mg2+ eller Li + ; R5 er valgt fra gruppen omfattende Ci-C30 alkyl, C3-C30 alkylaryl eller Ci-C30 alkylheteroaryl, valgfrit omfattende ét eller flere identiske eller forskellige heteroatomer valgt fra gruppen omfattende N, 0, S; X er 0 eller en NH-gruppe;
i tilfælde af at R3 er COOR6 er R4 OH, R1 er H, R2 er en hyaluronsyreoligomerrest; i tilfælde af at R3 er CH2OH er R4 NHCOCH3, R2 er OH, R1 er en hyaluronsyreoligomerrest; hyaluronsyreoligomerresten omfatter 1 til 17 saccharidringe, hvor saccharidringen er valgt fra gruppen bestående af β-(1,3)-D-glucuronsyre og β-(1,4)-2V-acetyl-D-glucosamin; substrat er et polysaccharid.
2. Konjugat ifølge krav 1, kendetegnet ved at polysaccharidet er valgt fra gruppen omfattende hyaluronsyre eller et farmaceutisk acceptabelt salt deraf.
3. Konjugat ifølge krav 2, kendetegnet ved at hyaluronsyre eller det farmaceutisk acceptable salt deraf har molekylevægten inden for intervallet 104 til 106 g.mot1, fortrinsvis 105 g.mot1.
4. Fremgangsmåde til fremstilling af konjugater af hyaluronsyreoligomeren ifølge den generelle formel I og II defineret i krav 1, kendetegnet ved at konjugaterne af hyaluronsyreoligomer-diaminolinker med den generelle formel V og VI
hvor R3 er COOR6 eller CH2OH, R4 er OH eller NHCOCH3, R6 er H eller et farmaceutisk acceptabelt salt;
R5 er valgt fra gruppen omfattende Ci-C30 alkyl, C3-C30 alkylaryl eller Ci-C30 alkylheteroaryl valgfrit omfattende ét eller flere identiske eller forskellige heteroatomer valgt fra gruppen omfattende N, 0, S; X er 0 eller en NH-gruppe; i tilfælde af at R3 er COOR6, så er R4 OH, R1 er H, R2 er en hyaluronsyreoligomerrest; i tilfælde af at R3 er -CH2OH, så er R4 NHCOCH3, R2 er OH, R1 er en hyaluronsyreoligomerrest; hyaluronsyreoligomerresten omfatter 1 til 17 saccharidringe, hvori saccharidringen er valgt fra gruppen bestående af β-(1,3)-D-glucuronsyre og β-(1,4)-2V-acetyl-D-glucosamin; reageres med mindst en aldehydgruppe af substratet i vand eller i en blanding af vand og et vandblandbart opløsningsmiddel.
5. Fremgangsmåde til fremstilling ifølge krav 4, kendetegnet ved at substratet er et polysaccharid, der fortrinsvis er valgt fra gruppen omfattende hyaluronsyre eller et farmaceutisk acceptabelt salt deraf.
6. Fremgangsmåde ifølge krav 5, kendetegnet ved at hyaluronsyre eller det farmaceutisk acceptable salt deraf har molekylevægten inden for intervallet 104 til 106 g.mol-1, fortrinsvis 105 g.mol-1.
7. Fremgangsmåde til fremstilling ifølge et hvilket som helst af kravene 4 til 6, kendetegnet ved at den udføres ved temperaturen 10 til 40°C, fortrinsvis ved temperaturen 20°C i 24 til 150 timer, fortrinsvis 60 til 80 timer.
8. Fremgangsmåde til fremstilling ifølge et hvilket som helst af kravene 4 til 7, kendetegnet ved at det vandblandbare opløsningsmiddel er valgt fra gruppen omfattende ethanol, isopropanol, methanol eller dimethylsulfoxid.
9. Fremgangsmåde til fremstilling af konjugater af hyaluronsyreoligomer ifølge de generelle formler III og IV defineret i krav 1, kendetegnet ved at den fortsætter som fremgangsmåden ifølge et hvilket som helst af kravene 4 til 8, idet konjugaterne af hyaluronsyreoligomer- diaminolinkeren med den generelle formel V og VI yderligere reageres med mindst en aldehydgruppe af substratet i tilstedeværelsen af et reduktionsmiddel.
10. Fremgangsmåde til fremstilling ifølge krav 9, kendetegnet ved at reduktionsmidlet er valgt fra gruppen omfattende cyanoborhydrid eller picolinboran.
11. Fremgangsmåde til fremstilling ifølge krav 9 eller krav 10, kendetegnet ved at mængden af reduktionsmidlet er inden for området 0,1 til 5 ækvivalenter, fortrinsvis 3 ækvivalenter, med hensyn til den molære mængde af hyaluronsyre-disaccharidet.
12. Fremgangsmåde til fremstilling ifølge et hvilket som helst af kravene 4 til 11, kendetegnet ved at konjugaterne af hyaluronsyreoligomer-diaminolinker med den generelle formel V og VI fremstilles på en sådan måde, at hyaluronsyreoligomeren reagerer ved dens afsluttende anomercenter i positionen 1 med et overskud af diaminolinker med den generelle formel H2N-X-R5-X-NH2, hvor R5 er valgt fra gruppen omfattende Ci-C30 alkyl, C2- C30 alkylaryl eller Ci-C30 alkylheteroaryl, valgfrit omfattende et eller flere identiske eller forskellige heteroatomer valgt fra gruppen omfattende N, O, S, og X er O eller en NH-gruppe ved pH i området fra 3 til 6, 99, hvorefter konjugatet af hyaluronsyreoligomer-diaminolinker med den generelle formel V og VI isoleres.
13. Fremgangsmåde til fremstilling ifølge krav 12, kendetegnet ved at reaktionen udføres ved pH i området 3 til 6, fortrinsvis inden for området fra 5 til 6.
14. Fremgangsmåde til fremstilling ifølge krav 12 eller 13, kendetegnet ved at reaktionen udføres i tilstedeværelsen af en carboxylsyre valgt fra gruppen omfattende eddikesyre, propansyre eller mælkesyre, fortrinsvis eddikesyre.
15. Fremgangsmåde til fremstilling ifølge krav 14, kendetegnet ved at mængden af carboxylsyren er inden for området fra 5 til 30 ækvivalenter, fortrinsvis inden for området fra 10 til 15 ækvivalenter med hensyn til den molære mængde af hyaluronsyre-disaccharidet som substratet.
16. Fremgangsmåde til fremstilling ifølge et hvilket som helst af kravene 12 til 15, kendetegnet ved at overskuddet af linkeren ligger inden for området fra 5 til 30 ækvivalenter, fortrinsvis 10 ækvivalenter, med hensyn til til den molære mængde af hyaluronsyre-disaccharidet som substratet.
17. Fremgangsmåde til fremstilling ifølge et hvilket som helst af kravene 12 til 16 kendetegnet ved at reaktionen udføres ved temperaturen 10 til 40°C, fortrinsvis ved temperaturen 20°C i 24 til 150 timer, fortrinsvis 60 til 80 timer.
18. Konjugaterne, der er defineret i krav 1 til 3, til anvendelse som bærere af biologisk aktive oligomerer i farmaci og biomedicin.
19. Konjugaterne, der er defineret i krav 1 til 3, til anvendelse i fremstillingen af materialer, der har en anticancereffekt.
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CZ2014-150A CZ305153B6 (cs) | 2014-03-11 | 2014-03-11 | Konjugáty oligomeru kyseliny hyaluronové nebo její soli, způsob jejich přípravy a použití |
PCT/CZ2015/000018 WO2015135511A1 (en) | 2014-03-11 | 2015-03-10 | Conjugates of oligomer of hyaluronic acid or of a salt thereof, method of preparation thereof and use thereof |
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- 2015-03-10 KR KR1020167025478A patent/KR102420500B1/ko active IP Right Grant
- 2015-03-10 RU RU2016139420A patent/RU2682509C2/ru active
- 2015-03-10 EP EP15719591.8A patent/EP3116514B1/en active Active
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AR100039A1 (es) | 2016-09-07 |
US10023658B2 (en) | 2018-07-17 |
US20170015759A1 (en) | 2017-01-19 |
RU2682509C2 (ru) | 2019-03-20 |
KR20160125999A (ko) | 2016-11-01 |
KR102420500B1 (ko) | 2022-07-13 |
RU2016139420A (ru) | 2018-04-11 |
PL3116514T3 (pl) | 2019-06-28 |
HUE043758T2 (hu) | 2019-09-30 |
ES2710801T3 (es) | 2019-04-26 |
CZ2014150A3 (cs) | 2015-05-20 |
JP2017508050A (ja) | 2017-03-23 |
EP3116514A1 (en) | 2017-01-18 |
BR112016020644A2 (da) | 2017-08-15 |
EP3116514B1 (en) | 2019-01-02 |
WO2015135511A1 (en) | 2015-09-17 |
JP6649892B2 (ja) | 2020-02-19 |
CZ305153B6 (cs) | 2015-05-20 |
RU2016139420A3 (da) | 2018-09-13 |
BR112016020644A8 (pt) | 2018-04-03 |
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