EP2007816A1 - Polysaccharides bifonctionnalises - Google Patents
Polysaccharides bifonctionnalisesInfo
- Publication number
- EP2007816A1 EP2007816A1 EP07731267A EP07731267A EP2007816A1 EP 2007816 A1 EP2007816 A1 EP 2007816A1 EP 07731267 A EP07731267 A EP 07731267A EP 07731267 A EP07731267 A EP 07731267A EP 2007816 A1 EP2007816 A1 EP 2007816A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- dextran
- group
- pharmaceutical composition
- composition according
- derivative
- 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.)
- Withdrawn
Links
- 229920001282 polysaccharide Polymers 0.000 title claims description 14
- 239000005017 polysaccharide Substances 0.000 title claims description 14
- 150000004676 glycans Chemical class 0.000 title claims 3
- 229920002307 Dextran Polymers 0.000 claims abstract description 77
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 39
- 125000001165 hydrophobic group Chemical group 0.000 claims abstract description 18
- 239000000203 mixture Substances 0.000 claims description 63
- 239000000243 solution Substances 0.000 claims description 56
- 239000002253 acid Substances 0.000 claims description 38
- 238000009472 formulation Methods 0.000 claims description 27
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- 108090000623 proteins and genes Proteins 0.000 claims description 26
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- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 19
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- 125000001483 monosaccharide substituent group Chemical group 0.000 claims description 8
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 claims description 8
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- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 claims description 7
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 7
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
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- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 239000000725 suspension Substances 0.000 claims description 6
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims description 6
- UMMQVDUMUMBTAV-YFKPBYRVSA-N (2s)-2-amino-3-(1h-imidazol-5-yl)propanamide Chemical compound NC(=O)[C@@H](N)CC1=CN=CN1 UMMQVDUMUMBTAV-YFKPBYRVSA-N 0.000 claims description 5
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- 238000000034 method Methods 0.000 claims description 5
- 239000002105 nanoparticle Substances 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 102000018386 EGF Family of Proteins Human genes 0.000 claims description 4
- 108010066486 EGF Family of Proteins Proteins 0.000 claims description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- ZQISRDCJNBUVMM-UHFFFAOYSA-N L-Histidinol Natural products OCC(N)CC1=CN=CN1 ZQISRDCJNBUVMM-UHFFFAOYSA-N 0.000 claims description 4
- ZQISRDCJNBUVMM-YFKPBYRVSA-N L-histidinol Chemical compound OC[C@@H](N)CC1=CNC=N1 ZQISRDCJNBUVMM-YFKPBYRVSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
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- 150000003624 transition metals Chemical class 0.000 claims description 4
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000004380 Cholic acid Substances 0.000 claims description 3
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- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 239000012620 biological material Substances 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- 150000001841 cholesterols Chemical class 0.000 claims description 3
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 claims description 3
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- 229960002471 cholic acid Drugs 0.000 claims description 3
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 claims description 3
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- 102000009024 Epidermal Growth Factor Human genes 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 108010057186 Insulin Glargine Proteins 0.000 description 1
- COCFEDIXXNGUNL-RFKWWTKHSA-N Insulin glargine Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(=O)NCC(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 COCFEDIXXNGUNL-RFKWWTKHSA-N 0.000 description 1
- FRCAFNBBXRWXQA-XRIGFGBMSA-N L-Histidinol dihydrochloride Chemical compound Cl.Cl.OC[C@@H](N)CC1=CN=CN1 FRCAFNBBXRWXQA-XRIGFGBMSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- FQYUMYWMJTYZTK-UHFFFAOYSA-N Phenyl glycidyl ether Chemical compound C1OC1COC1=CC=CC=C1 FQYUMYWMJTYZTK-UHFFFAOYSA-N 0.000 description 1
- 229920001218 Pullulan Polymers 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 229920001586 anionic polysaccharide Polymers 0.000 description 1
- 150000004836 anionic polysaccharides Chemical class 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- XAWDMXNJDWMHCN-KLXURFKVSA-N ethyl (2s)-2-amino-3-(1h-imidazol-5-yl)propanoate;dihydrochloride Chemical compound Cl.Cl.CCOC(=O)[C@@H](N)CC1=CN=CN1 XAWDMXNJDWMHCN-KLXURFKVSA-N 0.000 description 1
- 210000002436 femur neck Anatomy 0.000 description 1
- 125000000524 functional group Chemical class 0.000 description 1
- 229920001002 functional polymer Polymers 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 150000002410 histidine derivatives Chemical class 0.000 description 1
- 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 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000012606 in vitro cell culture Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 150000002519 isoleucine derivatives Chemical class 0.000 description 1
- 229940060975 lantus Drugs 0.000 description 1
- 150000002613 leucine derivatives Chemical class 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- VEEIFXWJNCAVEQ-RGMNGODLSA-N methyl (2s)-2-amino-3-(1h-imidazol-5-yl)propanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC1=CNC=N1 VEEIFXWJNCAVEQ-RGMNGODLSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 150000002993 phenylalanine derivatives Chemical class 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
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- 230000003449 preventive effect Effects 0.000 description 1
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Classifications
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- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A61P25/00—Drugs for disorders of the nervous system
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B11/00—Preparation of cellulose ethers
- C08B11/20—Post-etherification treatments of chemical or physical type, e.g. mixed etherification in two steps, including purification
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B15/00—Preparation of other cellulose derivatives or modified cellulose, e.g. complexes
- C08B15/05—Derivatives containing elements other than carbon, hydrogen, oxygen, halogens or sulfur
- C08B15/06—Derivatives containing elements other than carbon, hydrogen, oxygen, halogens or sulfur containing nitrogen, e.g. carbamates
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- 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
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- 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
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0021—Dextran, i.e. (alpha-1,4)-D-glucan; Derivatives thereof, e.g. Sephadex, i.e. crosslinked dextran
-
- 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
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
- C08B37/0027—2-Acetamido-2-deoxy-beta-glucans; Derivatives thereof
- C08B37/003—Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
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- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0045—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Galacturonans, e.g. methyl ester of (alpha-1,4)-linked D-galacturonic acid units, i.e. pectin, or hydrolysis product of methyl ester of alpha-1,4-linked D-galacturonic acid units, i.e. pectinic acid; Derivatives thereof
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- 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
- C08B37/0069—Chondroitin-4-sulfate, i.e. chondroitin sulfate A; Dermatan sulfate, i.e. chondroitin sulfate B or beta-heparin; Chondroitin-6-sulfate, i.e. chondroitin sulfate C; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0084—Guluromannuronans, e.g. alginic acid, i.e. D-mannuronic acid and D-guluronic acid units linked with alternating alpha- and beta-1,4-glycosidic bonds; Derivatives thereof, e.g. alginates
-
- 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
- C08B37/14—Hemicellulose; Derivatives thereof
-
- 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
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
Definitions
- the present invention relates to novel biodegradable polymers based on polysaccharides and more particularly on dextrans. These polymers are particularly useful for the administration of active principle (s) (PA) to humans or animals for therapeutic and / or prophylactic purposes. These polymers can also be used to potentiate and protect endogenous active ingredients.
- PA active principle
- PA such as proteins such as insulin, growth hormone,
- PAs such as growth factors such as Transforming Growth Factors or Bone Morphogenic Proteins, "cell culture in vitro,
- compositions that: • extend the release time of systemic PAs such as insulin or hGH,
- PA is a growth factor
- PA generally growth factors, used in the cell culture
- PLAGAs have been approved to date in the field of "Drug Delivery". These polymers form, in aqueous medium, dense solids which contain PA. In this case, the AP can be released for several weeks. which is one of the objectives sought.
- An example of a formulation is the Nutropin Depot developed by Alkermes and Genentech for the sustained release (2 weeks) of human growth hormone described in patent WO 95/29664.
- Atrix describes in US Pat. No. 5,990,194 the use of PLAGA for the release of a peptide, leuprolide under the name Atrigel which is an organic solvent-based formulation.
- Atrigel which is an organic solvent-based formulation.
- this technology has the following flaws: • The injection of an organic solvent. In the case of Atrigel, this solvent is classified as a CMR compound.
- compositions for the purpose of controlled release of pharmaceutical PAs employ crosslinkable polymers, but despite numerous research efforts, no biomaterial involved in pharmaceutical compositions can solve both the requirement of injectability and that of retention at the site of administration of the active ingredient to control its systemic or local release.
- the present invention relates to novel polysaccharides and more particularly to dextrans, bifunctionalized by at least one imidazolyl radical Im and at least one hydrophobic group Hy which make it possible to satisfy the abovementioned applications which have not found a solution to date.
- patent WO99 / 09067 discloses pectins (galacturonans) whose acids are modified with amines, and in particular, an amine carrying an imidazole nucleus. These mono-functionalized polymers are not amphiphilic.
- Biodex described in US Pat. No. 6,646,120 are modified by benzylamine which is a hydrophobic group. These polymers are not functionalized with an imidazolyl radical.
- Dellacherie et al. have also described hydrophobic functionalized dextrans (Durand, A. et al., Biomacromolecules 2006, 7, 958-964.) (Durand, Alain et al., Colloid Polym. Sci., 2006, 284, 536-545.) obtained by reaction of hydroxyl functions of dextran with epoxides (phenylglycidyl ether, 1,2-epoxyoctane or 1,2-epoxydodecane). The polymers described are therefore not bifunctionalized and do not have an imidazolyl radical.
- compositions insoluble in water by chemical modification of anionic polysaccharides by nucleophiles include histidine and some of its derivatives, but these polymers are monofunctional.
- the invention therefore relates to a polysaccharide bifunctionalized with at least one imidazolyl radical Im and at least one hydrophobic group Hy, said radical and group being each identical and / or different and grafted or bound to the polysaccharide by one or more linker arms R, Ri or Rh and functions F, Fi or Fh,
- the polysaccharide according to the invention is chosen from the group consisting of hyaluronans, alginates, chitosans, galacturonans, chondroitin sulphate, dextrans, carboxymethyldextrans or carboxymethylcelluloses.
- the polysaccharide according to the invention is chosen from the group consisting of hyaluronans, alginates, chitosans and carboxymethylextrans.
- the polysaccharide according to the invention is chosen from the group consisting of dextrans and carboxymethylextrans.
- the invention thus relates to a dextran and / or derived from dextran, bifunctionalized by at least one imidazolyl radical Im and at least one hydrophobic group Hy, said radical and group being each identical and / or different, and grafted or bound to dextran and / or derived from dextran by one or more R, Ri or Rh linkage arms and F, Fi or Fh functions,
- R represents a linking arm consisting of a chemical bond or a chain comprising between 1 and 18 carbon atoms, optionally branched and / or unsaturated comprising one or more heteroatoms, such as O, N and / or S,
- R will be called Ri when it bears an imidazolyl radical and Rh when it bears a hydrophobic group, Ri and Rh being identical or different,
- F represents a function chosen from the ester, thioester, amide, carbonate, carbamate, ether, thioether or amine functions
- Fi when it bears an imidazolyl radical and Fh when it bears a hydrophobic group, Fi and Fh being identical or different.
- Im represents an imidazolyl radical, optionally substituted on one of the carbons by a C1-C4 alkyl (C1-C4) alkyl group, of formula
- Hy represents a hydrophobic group chosen from the groups:
- dextran and / or derivative of dextran being amphiphilic when in solution.
- it is amphiphilic at acidic pH.
- dextran according to the invention is meant in the rest of the text dextran and dextran derivatives.
- the dextran derivatives are chosen from carboxylated derivatives.
- the carboxylated derivatives of dextran are more particularly chosen from carboxymethyldextrans and reaction products between succinic anhydride and dextran.
- the dextran and / or derivative of the bifunctionalized dextran can meet the following general formulas:
- n is between 1 and 3
- i represents the mole fraction of imidazolyl radical relative to a monosaccharide unit, between 0.1 and 0.9
- h represents the mole fraction of hydrophobic group relative to a monosaccharide unit of between 0.01 and 0.5.
- n is between 1 and 3
- i represents the mole fraction of imidazolyl radical relative to a monosaccharide unit, between 0 and 0.9
- k represents the mole fraction of hydrophobic group relative to a monosaccharide unit of between 0.01 and 0.5.
- dextrans bifunctionalized with at least one imidazolyl radical and at least one hydrophobic group according to the invention take up a mass at physiological pH while allowing the retention of PA in the polymer.
- the active ingredients are retained at the injection site in vivo without being degraded or denatured.
- the polymer can either form a solid or form a hydrogel.
- a hydrogel is a type of colloid obtained in an aqueous medium, in which a liquid contains a solid forming a thin network that extends throughout the system. The solid and liquid phases are continuous there.
- bifunctionalized dextrans Two types of bifunctionalized dextrans respond to this invention, cationic dextrans and anionic dextrans.
- the cationic dextrans according to the invention have the property of forming a homogeneous solution in a pH range of less than 6, and of massing at a pH close to physiological pH. At a pH close to the physiological pH, all or part of the imidazole segments charged and therefore hydrophilic will turn into neutral segments, resulting in its setting in mass.
- This caking effect can be combined with a physical crosslinking effect by coordinating the imidazolyl rings of the polymer, and possibly present on the active ingredient, with polyvalent transition metals such as zinc. This coordination takes place only at pH greater than 6.
- the anionic dextrans according to the invention have the property of forming a homogeneous solution at neutral pH and of taking up in mass at a pH close to physiological pH in the presence of transition metal salts.
- the dextrans according to the invention are amphiphilic and therefore solubilized in the form of micelles and / or nanoparticles.
- the massing induced by a physical crosslinking effect occurs by coordinating the imidazolyl rings of the polymer, and possibly present on the active principle, with polyvalent transition metals such as zinc.
- the following scheme shows the mode of action of metal salts at physiological pH with imidazoles carried by the polymer or PA.
- the injectable formulations will be carried out in the zones of pH in which said polymers form a homogeneous solution.
- the dextran and / or dextran derivative according to the invention is characterized in that the group R 1, when not a bond, is selected from the following groups:
- R2 being selected from alkyl radicals having from 1 to 18 carbon atoms.
- the dextran and / or dextran derivative according to the invention is characterized in that the group R 1 is a bond.
- the dextran and / or dextran derivative according to the invention is characterized in that the Imidazole-Ri group is chosen from the groups obtained by grafting an ester of histidine, histidinol, histidinamide or histamine.
- the dextran and / or dextran derivative according to the invention is characterized in that Hy will be selected from the group consisting of fatty acids, fatty alcohols, fatty amines, cholesterol derivatives of which cholic acid, phenols including alpha-tocopherol.
- the dextran and / or dextran derivative according to the invention is characterized in that the Rh group when it is not a bond is chosen from the groups:
- the dextran and / or dextran derivative according to the invention is characterized in that the Rh group is a bond. In one embodiment, the dextran and / or dextran derivative according to the invention is characterized in that the group Ri, when it is not a bond, is chosen from the groups
- R1 H, COOH, C00R2, C0NH2
- R2 being selected from alkyl radicals having from 1 to 18 carbon atoms.
- the dextran and / or dextran derivative according to the invention is characterized in that the Imidazole-Ri group is chosen from histidine esters, histidinol, histidine amidine or histamine.
- the dextran and / or dextran derivative according to the invention is characterized in that Hy will be selected from the group consisting of fatty acids, fatty alcohols, fatty amines, cholesterol derivatives of which cholic acid, phenols including alpha-tocopherol, hydrophobic amino acids.
- hydrophobic amino acids are chosen from tryptophan derivatives such as tryptophan ethyl ester, phenylalanine derivatives, leucine derivatives, valine derivatives and isoleucine derivatives.
- Dextran and / or dextran derivative may have a degree of polymerization m of between 10 and 10,000.
- it has a degree of polymerization m of between 10 and 1000.
- the invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising one of the dextrans and / or derivatives of dextran according to the invention as described above and at least one active ingredient.
- active principle is meant a product in the form of a single chemical entity or in the form of a combination having a physiological activity.
- Said active ingredient may be exogenous, ie it is provided by the composition according to the invention. It may also be endogenous, for example the growth factors that will be secreted in a wound during the first healing phase and that may be retained on said wound by the composition according to the invention.
- the invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising one of the dextrans and / or derivatives of dextran according to the invention as described above and a transition metal salt.
- the transition metal is selected from the group consisting of zinc, iron, copper and cobalt.
- the invention also relates to a pharmaceutical composition according to the invention as described above characterized in that it is in the form of a homogeneous solution or a suspension in water at a pH of less than 6.
- the invention also relates to a pharmaceutical composition according to the invention as described above characterized in that the homogeneous solution and / or the suspension at lower pH 6 consists of micelles and / or nanoparticles.
- nanoparticles means objects suspended in water whose average diameter is less than 600 nm.
- the invention also relates to a pharmaceutical composition according to the invention as described above, characterized in that it is in the form of a suspension of microparticles in water at a pH close to the physiological pH.
- microparticles are meant objects whose mean diameter is greater than 600 nm and by pH close to physiological pH, a pH of between 6 and 8.
- the invention also relates to a pharmaceutical composition according to the invention as described above characterized in that it is administrable intravenously, intramuscularly, intraosseous, subcutaneous, transdermal, ocular.
- the invention also relates to a pharmaceutical composition according to the invention as described above characterized in that it is administrable orally, nasally, vaginally, orally.
- the invention also relates to a pharmaceutical composition according to the invention as described above characterized in that it is in solid form.
- the invention also relates to a pharmaceutical composition according to the invention as described above, characterized in that it is obtained by setting in mass controlled by the pH.
- the caking is carried out at a pH greater than 6.5.
- the invention also relates to a pharmaceutical composition according to the invention as described above, characterized in that it is obtained by drying and / or lyophilization.
- the invention also relates to a pharmaceutical composition according to the invention as described above, characterized in that it is administrable in stent form, film or "coating" of implantable biomaterials implant.
- the invention also relates to a composition as described above characterized in that it undergoes a physical crosslinking at the injection site.
- the invention also relates to a composition as described above characterized in that it allows the retention of the active ingredient at the injection site.
- compositions according to the invention are obtained by conventional galenic techniques known to those skilled in the art and will be prepared either industrially or extemporaneously.
- the invention also relates to a pharmaceutical composition according to the invention as described above characterized in that the active ingredient is selected from the group consisting of proteins, glycoproteins, peptides and non-peptide therapeutic molecules.
- the proteins or glycoproteins are chosen from hormones such as insulin, hGH, among growth factors such as members of the super family of Transforming Growth Factors- ⁇ (TGF- ⁇ ), such as Bone Morphogenic Proteins (BMPs), Derived Growth Factors Platelets (PDGFs), Insulin Growth Factors (IGFs), Nerve Growth Factors (NGFs), Vascular Endothelial Growth Factors (VEGFs), Fibroblasts Growth Factors (FGFs), Epidermal Growth Factors (EGF), cytokines such as Interleukins (IL) or Interferons (IFN).
- TGF- ⁇ Transforming Growth Factors- ⁇
- BMPs Bone Morphogenic Proteins
- PDGFs Derived Growth Factors Platelets
- IGFs
- PAs such as growth factors such as TGFs, BMPs, PDGFs, NGFs, VEGFs, IGFs, FGFs, EGFs, systemic release of PAs such as proteins such as insulin, growth hormone, EPO, IL, IFN,
- compositions according to the invention as described above in which the active principle is chosen from the group consisting of proteins, glycoproteins, peptides and non-peptide therapeutic molecules comprise between 0.005% and 2% by weight of active principle. relative to the total weight of the composition.
- compositions comprise between 0.01% and 0.5% by weight of proteins, glycoproteins, peptides and non-peptide therapeutic molecules relative to the total weight of the composition.
- the invention thus relates to the use of dextrans and / or derivatives of dextrans and / or compositions according to the invention for the treatment or formulation of medicaments for the local treatment of bones weakened by osteoporosis.
- the composition comprises between 0.005% and 2% of BMP relative to the total weight of the composition.
- the composition comprises between 0.01% and 0.5% BMP relative to the total weight of the composition.
- the invention thus relates to the use of dextrans and / or derivatives of dextrans and / or compositions according to the invention for the treatment or the formulation of medicaments intended for the regeneration of nervous tissues.
- the composition comprises between 0.005% and 2% of NGF or TGF- ⁇ relative to the total weight of the composition.
- the composition comprises between 0.01% and 0.5% of NGF or TGF- ⁇ relative to the total weight of the composition.
- the invention thus relates to the use of dextrans and / or derivatives of dextrans and / or compositions according to the invention for the treatment or the formulation of drugs for the regeneration of cardiovascular tissues.
- the composition comprises between 0.005% and 2% of VEGF or TGF- ⁇ relative to the total weight of the composition.
- the composition comprises between 0.01% and 0.5% of VEGF or TGF- ⁇ relative to the total weight of the composition.
- the invention thus relates to the use of dextrans and / or derivatives of dextrans and / or compositions according to the invention for the treatment or the formulation of medicaments intended for the regeneration of skin tissues.
- the composition comprises between 0.005% and 2% of PDGF or FGF relative to the total weight of the composition.
- the composition comprises between:
- composition 0.01% and 0.5% of PDGF or FGF relative to the total weight of the composition
- the proteins are selected from the group consisting of insulin or hGH growth hormone.
- the non-peptide therapeutic molecules are chosen from the group consisting of anticancer agents such as Taxol or cis-platinum.
- the composition comprises between 0.005% and
- the composition comprises between 0.01% and 0.5% insulin or hGH growth hormone relative to the total weight of the composition.
- the active ingredient is selected from the group of peptides selected from leuprolide or short sequences of the ParaThyroidHormone (PTH).
- compositions according to the invention are either in liquid form (nanoparticles or microparticles suspended in water or in solvent mixtures), or in the form of powder, implant, film, gels or creams.
- the modes of administration envisaged are subcutaneous, intradermal, intramuscular, oral, nasal, vaginal, ocular, oral, etc.
- compositions according to the invention can thus be used to form an implant containing one or more pharmaceutical active principles for their controlled release for a long period of time.
- This application is particularly advantageous for the treatment of solid tumors with an anticancer agent or for cellular regeneration.
- the invention also relates to a physically crosslinked pharmaceutical composition at the injection site comprising an active ingredient selected from the group consisting of proteins, glycoproteins, peptides and non-peptide therapeutic molecules.
- the invention also relates to the use of dextrans and / or derivatives of bifunctionalized dextrans according to the invention for the preparation of pharmaceutical compositions as described above.
- the acid functions of a carboxymethyldextran are activated in the presence of N-methylmorpholine and isobutyl chloroformate in NMP. Benzylamine and then the ethyl ester Histidine is grafted onto this activated polymer.
- the resulting polymer has the following structure.
- the level of unmodified acids is zero.
- the acid functions of a carboxymethyldextran are activated in the presence of N-methylmorpholine and isobutyl chloroformate in DMF.
- the ethyl ester of histidine and dodecylamine are grafted onto this activated polymer.
- the resulting polymer has the following structure.
- R H or CH 9 CONHC 1 1,2 o 'u CH, COHisOEt
- the ethyl ester of histidine is 85% and the dodecylamine is 10%.
- the level of unmodified acids is 5%.
- Example 3 Synthesis of a carboxymethyldextran modified with histidinamide and benzylamine
- the acid functions of a carboxymethyldextran (average degree of acid per glycoside unit of 1.0) are activated in the presence of N-methylmorpholine and isobutyl chloroformate in the NMP. Histidinamide and benzylamine are grafted onto this activated polymer.
- the resulting polymer has the following structure.
- R H or CH 2 CONHBn or CH 2 COHisNH 2
- the level of unmodified acids is 5%.
- Example 4 Synthesis of a Histidine Ethyl Ester Modified Carboxymethyldextran and Tryptophan Ethyl Ester
- the acid functions of a carboxymethyldextran are activated in the presence of N -MethylMorpholine and isobutyl chloroformate in DMF at 0 ° C.
- the ethyl ester of histidine and the ethyl ester of tryptophan are grafted onto this activated polymer.
- the polymer obtained is characterized by a level of acid functional groups modified with: the ethyl ester of histidine of 70%,
- tryptophan ethyl ester 30% The level of unmodified acids is zero.
- the acid functions of a carboxymethyldextran are activated in the presence of N-methylmorpholine and isobutyl chloroformate in DMF at 0 ° C.
- the ethyl ester of histidine the ethyl ester of tryptophan are grafted onto this activated polymer.
- the polymer obtained is characterized by a level of acid functions modified by:
- the acid functions of a carboxymethyldextran (average degree of acid per glycoside unit of 1.0) are activated in the presence of N-methylmorpholine and isobutyl chloroformate in DMF at 0 ° C.
- the ethyl ester of histidine and benzylamine are grafted onto this activated polymer.
- the resulting polymer has the following structure.
- the level of acid functions modified by: the ethyl ester of histidine is 10%
- benzylamine is 45%.
- the level of unmodified acids is 45%.
- the acid functions of a carboxymethyldextran are activated in the presence of N-methylmorpholine and isobutyl chloroformate in DMF at 0 ° C.
- the ethyl ester of histidine ( 0.2 equivalents relative to acids) and benzylamine (0.45 equivalents relative to acids) are grafted onto this activated polymer.
- the resulting polymer has the following structure.
- R H or CH 7 CONHBn or CH, COHisOEt
- the ethyl ester of histidine is 30%, the benzylamine is 45%
- the level of unmodified acids is 25%.
- the polymer is prepared according to US6,646,120.
- the level of acid functions modified with benzylamine is 40%.
- the polymers described in the previous examples (1 to 8) were put in solution at acid pH, pH less than 6.
- the second column of the table describes the state of the solutions of polymers at acidic pH. Then, these acidic pH solutions are dispersed in buffered medium at neutral pH (PBS buffer).
- PBS buffer buffered medium at neutral pH
- the third column of the table describes the state of the solutions at neutral pH.
- the polymers described in the preceding examples (1 to 8) were solubilized in water, at acidic pH for polymers 1 to 5, at a neutral pH for polymers 6 to 8.
- ZnCl 2 is added to the acidic pH solution.
- the number of ZnCl2 is 1 to 2 imidazoles.
- the acidic solutions of polymers 1 to 5 containing ZnCl 2 are dispersed in buffered medium at neutral pH (PBS buffer).
- the solutions of polymers 6 to 8 at neutral pH are dispersed in a buffered medium at neutral pH (PBS buffer) containing ZnCl2.
- PBS buffer buffered medium at neutral pH
- the third column of the table describes the state of the neutral pH polymer solutions in the presence of ZnCl2.
- the sequestration of PDGF-BB in the solid at physiological pH was studied in the presence of ZnCl2.
- a solution of the polymer obtained in Example 1 was prepared at acidic pH (20 mg / ml).
- To 100 ⁇ l of the acid-acid polymer solution are added 0.02 mg of PDGF-BB and 6.5 mg of ZnCl 2.
- the acid solution is homogeneous and limpid.
- this solution is dispersed in buffered medium at neutral pH (10 volumes of 30 mM PBS buffer). The precipitate forms quickly.
- the PDGF-BB contained in the supernatant is assayed by ELISA after centrifugation of the heterogeneous medium.
- the concentration of PDGF-BB in the supernatant is less than 0.2 ⁇ g / ml whereas it is 2 ⁇ g / ml in the control without polymer. There is therefore a quasi-quantitative sequestration of the protein, greater than 90%, in the solid formed by the polymer at neutral pH in the presence of ZnCl 2.
- a solution No. 1 of the polymer obtained in Example 1 at a concentration of 50 mg / ml is prepared at pH 5.
- 1 mg / ml is prepared at pH 7.
- the osmolarity of each solution is adjusted to 300 mOsm by the addition of NaCl.
- These solutions are stored at 4 ° C.
- a solution No. 3 is prepared by mixing 0.9 ml of the solution No. 1 and 0.1 ml of the solution No. 2.
- the solution obtained is homogeneous and has a pH close to 5.
- the final solution No. 3 as described in Example 15 can be prepared extemporaneously from the polymer obtained in Example 1 lyophilized and lyophilized BMP-2.
- the osmolarity of the final solution is adjusted to 300 mOsm by addition of NaCl.
- the polymer has a buffering capacity and leads to a solution whose pH is close to 5. This final solution is clear.
- EXAMPLE 18 Polymer Formulation Obtained in Example 1 + ZnCl 2 + BMP-2
- the final solution No. 3 as described in Example 15 can be prepared extemporaneously from the polymer obtained in Example 1 and freeze-dried. Lyophilized BMP-2. In this case, the osmolarity of the final solution is adjusted to 300 mOsm by addition of ZnCl2. This final solution is crystal clear.
- Example 19 Polymer Formulation Obtained in Example 1 + BMP-2
- the formulation can be prepared extemporaneously by the solubilization of 0.1 mg of lyophilized BMP-2 in 1 ml of polymer solution obtained in Example 1 at 45 mg / ml at pH 5 and adjusted to 300 mOsm by the addition of NaCl. This final solution is crystal clear.
- Example 1 The polymer solution obtained in Example 1 at 45 mg / ml and at pH 5 as described in Example 17 is adjusted to 300 mOsm by the addition of ZnCl 2. Extemporaneously 0.1 mg of freeze-dried BMP-2 is dissolved in 1 ml of polymer solution. This final solution is also clear.
- EXAMPLE 21 Polymer Formulation Obtained in Example 1 + PDGF-BB It is in this case the preparation of a polymer formulation obtained in Example 1 and PDGF-BB. This formulation is prepared according to one of the six methods described in Examples 15 to 20. The formulation contains 45 mg of polymer and 0.1 mg of PDGF-BB per 1 ml of solution. This solution is clear and has a pH close to 5.
- This formulation is used in the treatment of diabetic foot ulcers.
- Example 22 Polymer Formulation Obtained in Example 1 + hGH
- Example 1 It is in this case the preparation of a polymer formulation obtained in Example 1 and hGH.
- This formulation is prepared according to one of the six methods described in Examples 15 to 20.
- the formulation contains 45 mg of polymer and 5 mg of hGH per 1 ml of solution. This solution is clear and has a pH close to 5.
- This formulation is injected once a week to patients.
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Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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FR0603130 | 2006-04-07 | ||
US79053206P | 2006-04-10 | 2006-04-10 | |
PCT/FR2007/000595 WO2007116143A1 (fr) | 2006-04-07 | 2007-04-06 | Polysaccharides bifonctionnalises |
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EP2007816A1 true EP2007816A1 (fr) | 2008-12-31 |
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EP07731267A Withdrawn EP2007816A1 (fr) | 2006-04-07 | 2007-04-06 | Polysaccharides bifonctionnalises |
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US (1) | US20080014250A1 (ru) |
EP (1) | EP2007816A1 (ru) |
JP (1) | JP2009532552A (ru) |
KR (1) | KR20090013179A (ru) |
CN (1) | CN101460523A (ru) |
AU (1) | AU2007235821A1 (ru) |
BR (1) | BRPI0710315A2 (ru) |
CA (1) | CA2648395A1 (ru) |
IL (1) | IL194489A0 (ru) |
MX (1) | MX2008012837A (ru) |
RU (1) | RU2008144129A (ru) |
WO (1) | WO2007116143A1 (ru) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8241620B2 (en) | 2005-09-26 | 2012-08-14 | Adocia | Complex polymere amphiphile-PDGF |
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FR2822834B1 (fr) * | 2001-04-02 | 2005-02-25 | Flamel Tech Sa | Suspension colloidale de nanoparticules a base de copolymeres amphiphile pour la vectorisation de principes actifs et leur mode de preparation |
FR2840614B1 (fr) | 2002-06-07 | 2004-08-27 | Flamel Tech Sa | Polyaminoacides fonctionnalises par de l'alpha-tocopherol et leurs applications notamment therapeutiques |
FR2843117B1 (fr) | 2002-07-30 | 2004-10-15 | Flamel Tech Sa | Polyaminoacides fonctionnalises par au moins un groupement hydrophobe et leurs applications notamment therapeutiques |
FR2860516B1 (fr) * | 2003-10-03 | 2006-01-13 | Flamel Tech Sa | Homopolyaminoacides telecheliques fonctionnalises par des groupements hydrophobes et leurs applications notamment therapeutiques |
FR2862536B1 (fr) * | 2003-11-21 | 2007-11-23 | Flamel Tech Sa | Formulations pharmaceutiques pour la liberation prolongee de principe(s) actif(s), ainsi que leurs applications notamment therapeutiques |
FR2914191A1 (fr) * | 2007-03-29 | 2008-10-03 | Proteins & Peptides Man | Composition angiogenique. |
FR2919188B1 (fr) * | 2007-07-27 | 2010-02-26 | Proteins & Peptides Man | Complexes entre un polymere amphiphile et une proteine osteogenique appartenant a la famille des bmps |
WO2009127940A1 (fr) * | 2008-04-14 | 2009-10-22 | Adocia | Composition osteogenique comprenant un complexe facteur de croissance/polymere amphiphile un sel soluble de cation e un support organique |
FR2933304A1 (fr) * | 2008-07-07 | 2010-01-08 | Adocia | Composition synergique osteogenique |
US8367640B2 (en) | 2008-09-26 | 2013-02-05 | Adocia | Complex consisted of a polysaccharide and an HBP |
FR2940802A1 (fr) * | 2008-10-10 | 2010-07-09 | Adocia | Complexe entre l'insuline humaine et un polymere amphiphile et utilisation de ce complexe pour la preparation d'une formulation d'insuline humaine rapide. |
FR2948573B1 (fr) * | 2009-07-31 | 2011-11-18 | Adocia | Nouvelle forme d'administration de complexes de proteines osteogeniques |
FR2943538B1 (fr) | 2009-03-27 | 2011-05-20 | Adocia | Formulation a action rapide d'insuline recombinante humaine |
US9018190B2 (en) | 2009-03-27 | 2015-04-28 | Adocia | Functionalized oligosaccharides |
US8529933B2 (en) | 2009-07-27 | 2013-09-10 | Warsaw Orthopedic, Inc. | Biphasic calcium phosphate cement for drug delivery |
FR2948572A1 (fr) * | 2009-07-31 | 2011-02-04 | Adocia | Nouvelle forme d'administration de proteines osteogeniques |
FR2956116A1 (fr) * | 2010-02-09 | 2011-08-12 | Adocia | Complexes polysaccharide/bmp-7 solubles a ph physiologique |
FR2958646B1 (fr) | 2010-04-07 | 2012-05-18 | Adocia | Polysaccharides comportant des groupes fonctionnels carboxyles substitues par un derive d'acide hydrophobe. |
CN102834117B (zh) * | 2010-02-09 | 2015-11-25 | 阿道恰公司 | 通过至少两个由至少三价的间隔物所携带的疏水基团进行官能化的阴离子多糖 |
FR2958647B1 (fr) * | 2010-04-08 | 2013-08-23 | Adocia | Polysaccharides comportant des groupes fonctionnels carboxyles substitues par un derive hydrophobe porte par un spacer au moins trivalent. |
KR101642939B1 (ko) * | 2010-08-31 | 2016-07-26 | 한화케미칼 주식회사 | 산화철 나노캡슐, 이의 제조방법 및 이를 포함하는 자기공명영상진단 조영제 |
DK2741765T3 (en) | 2011-08-10 | 2016-06-13 | Adocia | Injectable solution of at least one type of basal insulin |
FR2978918B1 (fr) * | 2011-08-10 | 2013-12-27 | Adocia | Solution injectable a ph7 comprenant au moins une insuline basale dont le pi est compris entre 5,8 et 8,5 |
US20130231281A1 (en) | 2011-11-02 | 2013-09-05 | Adocia | Rapid acting insulin formulation comprising an oligosaccharide |
US9198971B2 (en) | 2012-01-09 | 2015-12-01 | Adocia | Injectable solution at pH 7 comprising at least one basal insulin the pI of which is between 5.8 and 8.5 and a substituted co-polyamino acid |
FR3001896B1 (fr) * | 2013-02-12 | 2015-07-03 | Adocia | Solution injectable a ph 7 comprenant au moins une insuline basale dont le point isolectrique est compris entre 5,8 et 8,5 et un polymere anionique hydrophobise |
US20150314003A2 (en) | 2012-08-09 | 2015-11-05 | Adocia | Injectable solution at ph 7 comprising at least one basal insulin the isoelectric point of which is between 5.8 and 8.5 and a hydrophobized anionic polymer |
US9084806B2 (en) * | 2012-11-12 | 2015-07-21 | Research & Business Foundation Sungkyunkwan University | Hypoxia-responsive nanoparticle for therapy and imaging of hypoxia-involving diseases |
BR112015010799B1 (pt) | 2012-11-13 | 2023-01-17 | Adocia | Composição em solução aquosa, e, formulação farmacêutica |
FR3020947B1 (fr) | 2014-05-14 | 2018-08-31 | Adocia | Composition aqueuse comprenant au moins une proteine et un agent solubilisant, sa preparation et ses utilisations |
US9795678B2 (en) | 2014-05-14 | 2017-10-24 | Adocia | Fast-acting insulin composition comprising a substituted anionic compound and a polyanionic compound |
FR3043557B1 (fr) | 2015-11-16 | 2019-05-31 | Adocia | Composition a action rapide d'insuline comprenant un citrate substitue |
JP2023535243A (ja) | 2020-04-29 | 2023-08-17 | インテグリティ・バイオ-ケミカルズ,エルエルシー | 界面活性剤とともに組成したデキストリンまたはデキストランの脂肪酸反応生成物 |
CN113563493B (zh) * | 2021-07-01 | 2022-06-24 | 蚌埠医学院 | 疏水化多糖及其制备方法与应用 |
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US2931753A (en) * | 1953-11-18 | 1960-04-05 | Erskine | Organic ammonium salts of polysaccharide carboxylic acids |
US6174999B1 (en) * | 1987-09-18 | 2001-01-16 | Genzyme Corporation | Water insoluble derivatives of polyanionic polysaccharides |
DE4433101A1 (de) * | 1994-09-16 | 1996-03-21 | Bauer Kurt Heinz Prof Dr | Wasserlösliche Dextranfettsäureester und ihre Verwendung als Solubilisatoren |
FR2772382B1 (fr) * | 1997-12-11 | 2000-03-03 | Solutions | Derives de dextrane, leur procede de preparation et leurs applications comme medicaments a action biologique specifique |
FR2781485B1 (fr) * | 1998-07-21 | 2003-08-08 | Denis Barritault | Polymeres biocompatibles leur procede de preparation et les compositions les contenant |
US6630457B1 (en) * | 1998-09-18 | 2003-10-07 | Orthogene Llc | Functionalized derivatives of hyaluronic acid, formation of hydrogels in situ using same, and methods for making and using same |
SE9803482D0 (sv) * | 1998-10-13 | 1998-10-13 | Anders Holmberg | Ion exchange tumor targeting (IETT) |
-
2007
- 2007-04-06 EP EP07731267A patent/EP2007816A1/fr not_active Withdrawn
- 2007-04-06 RU RU2008144129/13A patent/RU2008144129A/ru not_active Application Discontinuation
- 2007-04-06 MX MX2008012837A patent/MX2008012837A/es unknown
- 2007-04-06 AU AU2007235821A patent/AU2007235821A1/en not_active Abandoned
- 2007-04-06 CN CNA2007800209797A patent/CN101460523A/zh active Pending
- 2007-04-06 KR KR1020087026683A patent/KR20090013179A/ko not_active Application Discontinuation
- 2007-04-06 JP JP2009503619A patent/JP2009532552A/ja not_active Withdrawn
- 2007-04-06 CA CA002648395A patent/CA2648395A1/fr not_active Abandoned
- 2007-04-06 BR BRPI0710315-8A patent/BRPI0710315A2/pt not_active IP Right Cessation
- 2007-04-06 WO PCT/FR2007/000595 patent/WO2007116143A1/fr active Application Filing
- 2007-04-09 US US11/783,402 patent/US20080014250A1/en not_active Abandoned
-
2008
- 2008-10-02 IL IL194489A patent/IL194489A0/en unknown
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See references of WO2007116143A1 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8241620B2 (en) | 2005-09-26 | 2012-08-14 | Adocia | Complex polymere amphiphile-PDGF |
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Publication number | Publication date |
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US20080014250A1 (en) | 2008-01-17 |
RU2008144129A (ru) | 2010-05-20 |
WO2007116143A1 (fr) | 2007-10-18 |
JP2009532552A (ja) | 2009-09-10 |
MX2008012837A (es) | 2008-10-17 |
AU2007235821A1 (en) | 2007-10-18 |
CA2648395A1 (fr) | 2007-10-18 |
BRPI0710315A2 (pt) | 2011-08-09 |
IL194489A0 (en) | 2009-08-03 |
KR20090013179A (ko) | 2009-02-04 |
CN101460523A (zh) | 2009-06-17 |
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