WO2012034544A2 - Method of preparation of highly substituted hyaluronic acid amides - Google Patents
Method of preparation of highly substituted hyaluronic acid amides Download PDFInfo
- Publication number
- WO2012034544A2 WO2012034544A2 PCT/CZ2011/000089 CZ2011000089W WO2012034544A2 WO 2012034544 A2 WO2012034544 A2 WO 2012034544A2 CZ 2011000089 W CZ2011000089 W CZ 2011000089W WO 2012034544 A2 WO2012034544 A2 WO 2012034544A2
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- WO
- WIPO (PCT)
- Prior art keywords
- hyaluronic acid
- added
- hours
- preparation according
- kda
- Prior art date
Links
- 229920002674 hyaluronan Polymers 0.000 title claims abstract description 55
- 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 class 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 abstract description 47
- 229960003160 hyaluronic acid Drugs 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 title claims abstract description 20
- 238000006467 substitution reaction Methods 0.000 claims abstract description 21
- 230000002378 acidificating effect Effects 0.000 claims abstract description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 45
- 239000011541 reaction mixture Substances 0.000 claims description 41
- 238000006243 chemical reaction Methods 0.000 claims description 31
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 29
- KIUKXJAPPMFGSW-MNSSHETKSA-N hyaluronan Chemical class 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 claims description 13
- 150000003141 primary amines Chemical class 0.000 claims description 8
- -1 amide derivatives of hyaluronic acid Chemical class 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 125000005270 trialkylamine group Chemical group 0.000 claims description 2
- TUCNEACPLKLKNU-UHFFFAOYSA-N acetyl Chemical compound C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 claims 1
- 239000000539 dimer Substances 0.000 claims 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
- 239000012048 reactive intermediate Substances 0.000 claims 1
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 28
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 26
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 238000005481 NMR spectroscopy Methods 0.000 description 20
- HEMHJVSKTPXQMS-DYCDLGHISA-M Sodium hydroxide-d Chemical compound [Na+].[2H][O-] HEMHJVSKTPXQMS-DYCDLGHISA-M 0.000 description 13
- 238000001816 cooling Methods 0.000 description 13
- 238000004090 dissolution Methods 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 13
- 239000011780 sodium chloride Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 230000009435 amidation Effects 0.000 description 10
- 238000007112 amidation reaction Methods 0.000 description 10
- OYBOVXXFJYJYPC-UHFFFAOYSA-N 3-azidopropan-1-amine Chemical compound NCCCN=[N+]=[N-] OYBOVXXFJYJYPC-UHFFFAOYSA-N 0.000 description 9
- 238000005570 heteronuclear single quantum coherence Methods 0.000 description 9
- 229940099552 hyaluronan Drugs 0.000 description 9
- 239000000017 hydrogel Substances 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- IKXNIQJDNKPPCH-UHFFFAOYSA-N hydron;prop-2-yn-1-amine;chloride Chemical compound [Cl-].[NH3+]CC#C IKXNIQJDNKPPCH-UHFFFAOYSA-N 0.000 description 5
- 230000015556 catabolic process Effects 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 3
- 238000004132 cross linking Methods 0.000 description 3
- 238000000914 diffusion-ordered spectroscopy Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- BMVXCPBXGZKUPN-UHFFFAOYSA-N 1-hexanamine Chemical compound CCCCCCN BMVXCPBXGZKUPN-UHFFFAOYSA-N 0.000 description 1
- 208000032544 Cicatrix Diseases 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 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
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001337 aliphatic alkines Chemical class 0.000 description 1
- AEMOLEFTQBMNLQ-WAXACMCWSA-N alpha-D-glucuronic acid Chemical group O[C@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-WAXACMCWSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000000560 biocompatible material Substances 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 230000006196 deacetylation Effects 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 125000000600 disaccharide group Chemical group 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000001879 gelation Methods 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical compound NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 230000037387 scars Effects 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- 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
Definitions
- the technical solution relates to the method of preparation of highly substituted amide derivatives of hyaluronic acid, which can be used in medicine, pharmacy and for preparation of hydrogels in tissue engineering.
- Hyaluronic acid is a linear heteropolysaccharide, composed of repetitive disaccharide units of D-glucuronic acid and N-acetyl-D-glueosamine.
- This npn r branched polysaccharide when isolated from natural source, may have molecular weight within the range from 50 000 to 5 000 000 Da, depending on the isolation method and teh source material.
- Hyaluronic acid is the main component of intercellular substance and due to its visco-elastic properties is essential part of rhedlogical,' physiological arid biological functions in organism. Due to its high lubrication capacity, ability of high sorptibh and water retention it is often applied in eye surgery. Hyaluronic acid eliminates free oxygen radicals and affects the proliferation and differentiation of cells. Furthermore, it prevents collagen deposition and in that way promotes healing of wounds and prevents formation of scars.
- th ' complications consist especially in a very quick degradation thereof in solutions and in the relatively poor mechanical properties thereof.
- Chemical modification of hyaluronan allows to improve these properties and at the same time to increase its resistance to degradation.
- hydrogels are hydrophilic polymer networks which can be used for controlled distribution of medicaments, bioactive and other substances in organisms, in the form of scaffolds or cutaneous filling substances.
- An important condition for the preparation of hydrogels is the stability of the derivatives which are used as input precursors for the cross-linking reaction.
- the low degree of hyaluronan ariiide derivatives can be increased by an application of specific reaction conditions.
- the main' subject matter 'of his invention is a method of preparation of hyaluronic acid amides,' where highly substituted products are obtained by selective amidation of hyaluronic 1 acid earboxylic group.
- the principle of the reaction consists in the activation of hyaluronan carbbxy!ic group by ethylchloroformiate in the presence of a base, wherein the resulting intermediate - activated hyalurprian - consequently reacts with a primary amine R-NH 2 and hyaluronic acid amide is formed ⁇ according to Scheme 1 :
- R is an alkyl linear or branched chain Ci - C30, optionally containing aromatic or heteroaromatic groups.
- the preparation is preferably carried out in a polar aprotic environment, particularly in dimethylsulphoxide.
- the hyaluronic acid is preferably in an acidic form and has a weight average molecular weight within the range 10 to 500 kDa, particularly within the range 350 to 500 kDa.
- the reaction is carried out at 25 °C for 8 to 24 hours, preferably for 12 hours.
- the degree of substitution of hyaluronic acid in the method of preparation according to the invention is preferably controlled 'by the molar quantity of Ihe added amine R-NH 2 , wherein the primary amine is preferably added to the reaction mixtiire at time 0.1 to 2 hours after the addition of ethylchloroformiate and in the molar quantity of 3' to 5 equivalents with respect to the molar amount of hyaluronan dimer.
- the primary amine R-NH 2 can be for example CH ⁇ C-CH 2 -NH 2> NH 2 -CH 2 -CH 2 i -CH 2 -N 3 or NH 2 (CH 2 ) 5 -CH 3 .
- the molar amount of the added ethylchloroformiate is in a molar ratio Of 3 to 5 equivalents with respect to the molar amount of hyaluronan dimer.
- the base used in the method of 'the invention can be trialkylamine, such as triethylamine, preferably in the molar amount in a molar ratio of 3 to 5 equivalents with respect to the molar amount of hyaluronan dimer.
- ⁇ ' 1 trialkylamine, such as triethylamine, preferably in the molar amount in a molar ratio of 3 to 5 equivalents with respect to the molar amount of hyaluronan dimer.
- Hyaluronan amide derivatives prepared by this method show a controllable degree of substitution within the range from ' 10 to 99%.
- the substitution degree is controlled by the molar ratio of the primary amine, ethylcfiloroformiate and the base.
- Amide derivatives are highly stable to degradation and hydrolysis and therefore, they can be used for the preparation of stable hydrogels. In case of a high substitution degree only a very small amount of catalyst is needed for the cross-linking reaction.
- hyaluronic acid (acidic ' fo' m) having the molecular weight of 100 kDa and polydispersion of 1.9 was dissolved in 50 mL of DMSO at 60°C. After the dissolution, the hyaluronic acid solution was allowed to cool to the roorrt temperature. After cooling, 0.922 mL of triethylamine (5 eq) was added' 'and the reaction mixture was stirred for 10 minutes. Then 0.378 mL of ethylchlorofohniate' (3 eq) was added arid the reaction mixture was stirred for 1 hour.
- hyaluronic acid (acidic form) having the molecular weight of 248 kDa and polydispersion of 1.6 was dissolved in 50 mL of DMSO at- 60°C. After the dissolution, the hyaluronic acid solution was allowed to cool to the room temperature. After cooling, 0.922 mL of triethylamine (5 eq) was added and the reaction mixture was stirred for 10 minutes. Then 0.378 mL of ethylchloroformiate (3 eq) was added and the reaction mixture was stirred for 1 hour.
- hyaluronic acid (acidic form) having the molecular weight of 366 kDa and polydispersion of 1.6 was dissolved in 50 mL of DMSO ; at 60°C. After the dissolution, the hyaluronic acid solution was allowed to cool to the room temperature. After cooling, 0.922 mL of triethylamine (3 eq) was added and the reaction mixture was stirred for 10 minutes. Then 0.378 mL of ethylchlorofprmiate, (3, eq) was added 3 ⁇ 4trid the reaction mixture was stirred for 1 hour.
- hyaluronic acid (acidic form) having the molecular weight of 393 kDa and polydispersion of 1.6 was dissolved in 50 mL of DMSO at 60°C. After the dissolution, the hyaluronic acid solution was allowed tp cool to the room temperature. After cooling, 0.922 mL of triethylamine (5 eq) was added and the reaction mixture was stirred for 10 minutes. Then 0.378 mL of ethylchlorofoimiate, (3 eq) was added and the reaction mixture was stirred for 1 hour.
- hyaluronic acid (acidic ⁇ form) having the molecular weight of 485 kDa and polydispersion of 1.6 was dissolved ih 50 mL of DMSO at 60°C. After the dissolution, the hyaluronic acid solution was allowed to cool to the room temperature. After cooling, 0.922 mL of triethylamine (5 eq) was added and the reaction mixture was stirred for 10 minutes. Then 0.378 mL of ethylchloroformiate (3 eq) was added and the reaction mixture was stirred for 1 hour.
- hyaluronic acid (acidic form) having the molecular weight of 42 kDa and polydispersion of 1.6 was dissolved in 50 mL of DMSO at 60°C. After the dissolution, the hyaluronic acid solution was allowed to cool to the room temperature. After cooling, 0.922 mL of triethylamine (3 eq) was added and the reaction mixture was stirred for 10 minutes. Then 0.378 mL of ethylchloroformiate (4 eq) was added and the reaction mixture was stirred for 1 hour.
- hyaluronic acid (acidic form) having the molecular weight of 42 kDa and polydispersion of 1.6 was dissolved in 50 mL of DMSO at 60°C. After the dissolution, the hyaluronic acid solution was allowed to cool to the room temperature. After cooling, 0.922 mL of triethylamine (3 eq) was added and the reaction mixture was stirred for 10 minutes. Then 0.378 mL of ethylchloroformiate (5 eq) was added and the reaction mixture was stirred for 1 hour.
- hyaluronic acid (acidic form) having the molecular weight of 72 kDa and polydispersion of 1.7 was dissolved in 50 mL of DMSO at 60°C. After the dissolution, the hyaluronic acid solution was allowed to cool to the room temperature. After cooling, 0.922 mL of triethylamine (3 eq) was added and the reaction mixture was stirred for 10 minutes. Then ⁇ .378 mL of ethylchloroformiate ; (5,eq) was added , and the reaction mixture was stirred for 1 hour.
- hyaluronic acid (acidic form) having the molecular weight of 70 kDa and polydispersion of 1.7 was dissolved in 50 mL of DMSO at 60°C. After the dissolution, the hyaluronic acid solution was allowed to cool to the room temperature. After cooling, 0.922 mL of triethylamine (3 eq) was added and the reaction mixture was stirred for 10 minutes. Then 0.378 mL of ethylc oroformiate (5 eq) was added and the reaction mixture was stirred for 1 hour.
- hyaluronic acid (acidic form) having the molecular weight of 393 kDa and polydispersion of 1.7 was dissolved in 50 mL of DMSO at 60°C. After the dissolution, the hyaluronic acid solution was allowed to cool to the room temperature. After cooling, 0.922 mL of triethylamine (3 eq) was added and the reaction mixture was stirred for 10 minutes. Then 0.378 mL of ethylchloroformiate (3 eq) was added and the reaction mixture was stirred for 1 hour.
- hyaluronic acid (acidic form) having the molecular weight of 485 kDa and polydispersion of 1.7 was dissolved in 50 mL of DMSO at 60°C. After the dissolution, the hyaluronic acid solution was allowed to cool to the room temperature. After cooling, 0.922 mL of triethylamine (3 eq) was added and the reaction mixture was stirred for 10 minutes. Then 0.378 mL of ethylchloroformiaie (3 eq) was added arid the reaction mixture was stirred for 1 hour.
- hyaluronic acid (acidic ' form) having the molecular weight of 485 kDa and polydispersion of 1.7 was dissolved in 50 mL of DMSO at 60°C. After the dissolution, the hyaluronic acid solution was allowed to. cool to the room temperature. After cooling, 0.922 mL of triethylamine (5 eq) was added and the reaction mixture was stirred for 10 minutes. Then 0.378 mL of ethylchloroformiate (3 eq) was added and the reaction mixture was stirred for 1 hour.
- DOSY NMR log D (2.03 ppm CH5-CO-NH-Polymer)—10.5 m 2 /s
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- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CZ2010-687A CZ305040B6 (cs) | 2010-09-14 | 2010-09-14 | Způsob přípravy vysoce substituovaných amidů kyseliny hyaluronové |
| CZPV2010-687 | 2010-09-14 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2012034544A2 true WO2012034544A2 (en) | 2012-03-22 |
| WO2012034544A3 WO2012034544A3 (en) | 2012-05-03 |
Family
ID=45047494
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CZ2011/000089 WO2012034544A2 (en) | 2010-09-14 | 2011-09-08 | Method of preparation of highly substituted hyaluronic acid amides |
Country Status (3)
| Country | Link |
|---|---|
| AR (1) | AR082965A1 (cs) |
| CZ (1) | CZ305040B6 (cs) |
| WO (1) | WO2012034544A2 (cs) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017108015A1 (en) | 2015-12-23 | 2017-06-29 | Contipro A.S. | Fluorescent cypate conjugate of hyaluronic acid or salt thereof, hydrophobized conjugate, methods of perparation and use thereof |
| US10414832B2 (en) | 2015-06-26 | 2019-09-17 | Contipro A.S | Derivatives of sulfated polysaccharides, method of preparation, modification and use thereof |
| US10617711B2 (en) | 2014-06-30 | 2020-04-14 | Contipro A.S. | Antitumor composition based on hyaluronic acid and inorganic nanoparticles, method of preparation thereof and use thereof |
| US10618984B2 (en) | 2016-06-27 | 2020-04-14 | Contipro A.S. | Unsaturated derivatives of polysaccharides, method of preparation thereof and use thereof |
| US10689464B2 (en) | 2015-03-09 | 2020-06-23 | Contipro A.S. | Self-supporting, biodegradable film based on hydrophobized hyaluronic acid, method of preparation and use thereof |
| US10759878B2 (en) | 2015-06-15 | 2020-09-01 | Contipro A.S. | Method of crosslinking of polysaccharides using photoremovable protecting groups |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000001733A1 (en) | 1998-07-06 | 2000-01-13 | Fidia Advanced Biopolymers S.R.L. | Amides of hyaluronic acid and the derivatives thereof and a process for their preparation |
| WO2008031525A1 (en) | 2006-09-11 | 2008-03-20 | Fidia Farmaceutici S.P.A. | Hyaluronic acid derivatives obtained via 'click chemistry' crosslinking |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20040009891A (ko) * | 2002-07-26 | 2004-01-31 | 주식회사 엘지생명과학 | 히알루론산의 유도체 겔 및 그 제조방법 |
| EP1790665B1 (en) * | 2004-09-07 | 2014-11-05 | Chugai Seiyaku Kabushiki Kaisha | Process for producing water-soluble modified hyaluronic acid |
| CN101367884A (zh) * | 2008-09-25 | 2009-02-18 | 复旦大学 | 一种半胱胺修饰的巯基化透明质酸偶合物及其制备方法和应用 |
-
2010
- 2010-09-14 CZ CZ2010-687A patent/CZ305040B6/cs not_active IP Right Cessation
-
2011
- 2011-09-08 WO PCT/CZ2011/000089 patent/WO2012034544A2/en active Application Filing
- 2011-09-13 AR ARP110103318A patent/AR082965A1/es unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000001733A1 (en) | 1998-07-06 | 2000-01-13 | Fidia Advanced Biopolymers S.R.L. | Amides of hyaluronic acid and the derivatives thereof and a process for their preparation |
| WO2008031525A1 (en) | 2006-09-11 | 2008-03-20 | Fidia Farmaceutici S.P.A. | Hyaluronic acid derivatives obtained via 'click chemistry' crosslinking |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10617711B2 (en) | 2014-06-30 | 2020-04-14 | Contipro A.S. | Antitumor composition based on hyaluronic acid and inorganic nanoparticles, method of preparation thereof and use thereof |
| US10689464B2 (en) | 2015-03-09 | 2020-06-23 | Contipro A.S. | Self-supporting, biodegradable film based on hydrophobized hyaluronic acid, method of preparation and use thereof |
| US10759878B2 (en) | 2015-06-15 | 2020-09-01 | Contipro A.S. | Method of crosslinking of polysaccharides using photoremovable protecting groups |
| US10414832B2 (en) | 2015-06-26 | 2019-09-17 | Contipro A.S | Derivatives of sulfated polysaccharides, method of preparation, modification and use thereof |
| WO2017108015A1 (en) | 2015-12-23 | 2017-06-29 | Contipro A.S. | Fluorescent cypate conjugate of hyaluronic acid or salt thereof, hydrophobized conjugate, methods of perparation and use thereof |
| US10618984B2 (en) | 2016-06-27 | 2020-04-14 | Contipro A.S. | Unsaturated derivatives of polysaccharides, method of preparation thereof and use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| AR082965A1 (es) | 2013-01-23 |
| CZ305040B6 (cs) | 2015-04-08 |
| WO2012034544A3 (en) | 2012-05-03 |
| CZ2010687A3 (cs) | 2012-03-21 |
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