WO1998031712A2 - Chitosan-conjugates with acidic chelate-complex forming agents - Google Patents
Chitosan-conjugates with acidic chelate-complex forming agents Download PDFInfo
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- WO1998031712A2 WO1998031712A2 PCT/EP1998/000320 EP9800320W WO9831712A2 WO 1998031712 A2 WO1998031712 A2 WO 1998031712A2 EP 9800320 W EP9800320 W EP 9800320W WO 9831712 A2 WO9831712 A2 WO 9831712A2
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- Prior art keywords
- chitosan
- conjugates
- acid
- group
- agent
- Prior art date
Links
- 230000002378 acidificating effect Effects 0.000 title claims abstract description 8
- 150000004697 chelate complex Chemical class 0.000 title claims abstract description 6
- 238000004519 manufacturing process Methods 0.000 claims abstract description 8
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 6
- 229920001661 Chitosan Polymers 0.000 claims description 28
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 26
- 229960001484 edetic acid Drugs 0.000 claims description 26
- 239000002738 chelating agent Substances 0.000 claims description 16
- 150000001718 carbodiimides Chemical class 0.000 claims description 13
- 239000000227 bioadhesive Substances 0.000 claims description 12
- 239000011159 matrix material Substances 0.000 claims description 12
- 239000013543 active substance Substances 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 claims description 7
- 229960003330 pentetic acid Drugs 0.000 claims description 7
- 229940071106 ethylenediaminetetraacetate Drugs 0.000 claims description 5
- 239000003349 gelling agent Substances 0.000 claims description 5
- MGFYIUFZLHCRTH-UHFFFAOYSA-N nitrilotriacetic acid Chemical compound OC(=O)CN(CC(O)=O)CC(O)=O MGFYIUFZLHCRTH-UHFFFAOYSA-N 0.000 claims description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical group Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 4
- 102000004169 proteins and genes Human genes 0.000 claims description 4
- 108090000623 proteins and genes Proteins 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 3
- 239000008139 complexing agent Substances 0.000 claims description 2
- 229960005486 vaccine Drugs 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims 2
- 102000004196 processed proteins & peptides Human genes 0.000 claims 2
- 239000002537 cosmetic Substances 0.000 abstract description 5
- 229940045110 chitosan Drugs 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 229940079593 drug Drugs 0.000 description 6
- 150000001768 cations Chemical class 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 238000004132 cross linking Methods 0.000 description 5
- -1 poly(D- glucosamine) Polymers 0.000 description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- 230000000536 complexating effect Effects 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 108091005804 Peptidases Proteins 0.000 description 3
- 239000004365 Protease Substances 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical group 0.000 description 2
- MSWZFWKMSRAUBD-QZABAPFNSA-N beta-D-glucosamine Chemical group N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-QZABAPFNSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 0 CCC(C1NC(CN(*)CC([O-])=O)=O)OC(CO)C(COC)C1O Chemical compound CCC(C1NC(CN(*)CC([O-])=O)=O)OC(CO)C(COC)C1O 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 150000007942 carboxylates Chemical group 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 150000001767 cationic compounds Chemical class 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- FLASNYPZGWUPSU-SICDJOISSA-N chitosan Chemical compound O([C@@H]1[C@@H](CO)O[C@H]([C@@H]([C@H]1O)N)O[C@@H]1[C@@H](CO)O[C@H]([C@@H]([C@H]1O)N)O[C@@H]1[C@@H](CO)O[C@H]([C@@H]([C@H]1O)N)O[C@@H]1[C@@H](CO)O[C@H]([C@@H]([C@H]1O)N)O[C@@H]1[C@@H](CO)O[C@H]([C@@H]([C@H]1O)N)O[C@H]1[C@H](O)[C@H]([C@@H](O[C@@H]1CO)O[C@@H]1[C@H](O[C@@H](O[C@@H]2[C@H](O[C@@H](O)[C@H](N)[C@H]2O)CO)[C@H](N)[C@H]1O)CO)NC(=O)OC)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N FLASNYPZGWUPSU-SICDJOISSA-N 0.000 description 1
- 239000008406 cosmetic ingredient Substances 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 102000038379 digestive enzymes Human genes 0.000 description 1
- 108091007734 digestive enzymes Proteins 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 239000003337 fertilizer Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 150000002892 organic cations Chemical class 0.000 description 1
- 150000003141 primary amines Chemical group 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000008961 swelling 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
- C08B37/0006—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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/73—Polysaccharides
- A61K8/736—Chitin; Chitosan; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/08—Polysaccharides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/53—DNA (RNA) vaccination
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/57—Compounds covalently linked to a(n inert) carrier molecule, e.g. conjugates, pro-fragrances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
Definitions
- the invention described hereinafter relates to chitosan-conjugates with acidic chelate-complex forming agents, their crosslinked derivatives, the method of their manufacture and their use as a matrix having a variety of possible pharmaceu- tic, cosmetic and medical applications.
- EP-A-0 650 999 discloses chitosan adducts with acidic chelate forming agents.
- the viscosity of the resulting gels can be adjusted by the addition of salts of polyvalent metals and acids, in which chitosan is only moderately soluble or insoluble.
- JP-A-01239077 JAPIO-abstract No. 89-239077 discloses the addition of chitosan and ethylene diamine tetraacetic acid (EDTA) into fertilizers.
- EDTA ethylene diamine tetraacetic acid
- R represents a substituent selected from the group of -CH 2 COO " , -CH 2 CH 2 -N (-CH 2 COO ⁇ ) 2 and -CH 2 CH 2 -N ( -CH 2 COCf) -CH 2 CH 2 -N (-CH 2 COO " ) 2 .
- chitosan is reacted with EDTA in the presence of carbodiimides, i.e., by a carbodiimide mediated reaction.
- the negative ionic charge at the carboxylate group may be compensated by the respective positive charge provided by positively charged mono- or polyvalent counterions, such as protons, Li + , Na + , K + , Mg 2+ Ca 2+ , Zn 2+ and other positively charged inorganic or organic cations which may be represented by the cations to be complexed.
- positively charged mono- or polyvalent counterions such as protons, Li + , Na + , K + , Mg 2+ Ca 2+ , Zn 2+ and other positively charged inorganic or organic cations which may be represented by the cations to be complexed.
- the chitosan-conjugates according to the present invention are obtainable by reacting chitosan with an acidic chelate-complex forming agent (chelating agent) selected from the group of nitrilotriacetic acid (NTA) , ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA) in the presence of carbodiimides.
- chelating agent selected from the group of nitrilotriacetic acid (NTA) , ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA) in the presence of carbodiimides.
- the molar ratio of chitosan to chelating agents preferably is about 1:20 in case that no crosslinks should be present in the final product. In case that inter- and/or intramolecular crosslinking should be achieved the molar ratio of chitosan to chelating agent should be smaller than about 1:
- reaction is carried out in aqueous medium using l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride as the mediator.
- the chelating agent is covalently linked to the chitosan-structure by the formation of an amide bond.
- chitosan-ethylenediarriinetetraacetate conjugates comprising the following substructure within their overall structures:
- compositions relate to pharmaceutical compositions, cosmetical compositions and bioadhesive matrices comprising the chitosan-conjugates described above.
- the chitosan-conjugates are comprised in a bioadhesive matrix which can be used for the manufacture of medicaments for the administration or delivery of drugs, preferably of peptide- or protein- containing active agents (drugs) .
- the chitosan-conjugates of the present invention and in particular the chitosan-EDTA-conjugate can be used as a bioadhesive matrix system for the administration of peptide and protein drugs, as gelling agent for semi-solid drug dosage forms and cosmetics and as a complexing polymer for mono- or polyvalent cations, preferably for pharmaceutic and/or cosmetic applications .
- conjugates according to the present invention Prior to using the conjugates according to the present invention for the final purpose as gelling agent, matrix, complexing agent, etc. it may be necessary to neutralize the carboxylic acid groups in the conjugate using a suitable alkaline agent.
- the present invention relates to chitosan- ethylenediamine tetraacetate conjugates.
- At least one of the carboxylic acid moieties of EDTA is bound to the amine moiety of chitosan to form an amide.
- EDAC l-ethyl-3- (3-dimethylaminopropyl) car- bodiimide hydrochloride
- the amount of EDTA covalently bound to chitosan can be controlled by the ratio of chitosan to EDTA employed.
- a preferred molar ratio of chitosan to EDTA is about 1:20 inter- and intramolecular crosslinking can be avoided.
- the chitosan-conjugates according to the present invention are not susceptible against alkaline media, i.e., pH-values >7.
- alkaline media i.e., pH-values >7.
- the present invention also relates to such crosslinked chitosan- conjugates containing intra- and/or intermolecular crosslinks. Said crosslinks are also formed by covalent amide bonds.
- the intra- and/or intermolecular crosslinking i.e., the crosslinking reaction between two polymers and/or within one polymer can also be carried out in the presence of a carbodiimide, i.e., by a carbodiimide-mediated reaction.
- the crosslinked chitosan-chelating agent conjugates according to the present invention are obtainable by reacting chitosan with the chelating agents described above at a molar ratio of chitosan to chelating agent of less than about 1:20, in the presence of a carbodiimide as described above.
- the inter- and/or intramolecular crosslinked chitosan-conjugate can be used for the same purpose as the (uncrosslinked) chitosan- conjugate as described above, but may have different properties in terms of complexing activity, viscosity, gelling properties, drug-releasing (delivering) properties, etc.
- the chitosan-conjugates or its crosslinked derivatives bearing the substructure defined above or in case of the crosslinked derivatives bearing a substructure containing more than one amide bond in the moiety stemming from the chelating agent will bind polyvalent cations, inhibit zinc proteases, and exhibit bioadhesive and gelling properties. It is possible to use the conjugates of the present invention in bioadhesive matrix systems, as gelling agents and complexing polymer for polyvalent cations in pharmaceutical and cosmetic applications.
- the inhibition of protease by the chitosan-conjugates of the invention and particularly of the chitosan-EDTA conjugates enables the administration of all kinds of pharmaceutically active agents such as peptide- and protein-containing drugs.
- the advantage is most significant in the administration of vaccines (antigens) , DNA and RNA.
- the bioadhesive carrier matrix according to the present invention allows the oral administration of active agents which can up to now only be administered par- enterally.
- the active agents are incorporated into the inventive matrix and are sufficiently protected against an enzymatic attack by, for instance, digestive enzymes and are released in a controlled manner, as described above.
- the chitosan-conjugates according to the present invention and in particular the chitosan-EDTA conjugates inhibit various digesting enzymes, such as zinc protease, they are capable of complexing polyvalent cations, they represent a readily hy- drated and strongly swelling gelling agent and they have bioadhesive properties.
- the fraction of re- sidual primary amine moieties at chitosan is 0.1% ⁇ 0.03%
Abstract
The present invention relates to chitosan-conjugates with acidic chelate-complex forming agents, their method of manufacture and their use in the pharmaceutical and cosmetic fields.
Description
Chitosan-conjugates with acidic chelate-complex forming agents
The invention described hereinafter relates to chitosan-conjugates with acidic chelate-complex forming agents, their crosslinked derivatives, the method of their manufacture and their use as a matrix having a variety of possible pharmaceu- tic, cosmetic and medical applications.
EP-A-0 650 999 discloses chitosan adducts with acidic chelate forming agents. The viscosity of the resulting gels can be adjusted by the addition of salts of polyvalent metals and acids, in which chitosan is only moderately soluble or insoluble.
JP-A-01239077 (JAPIO-abstract No. 89-239077) discloses the addition of chitosan and ethylene diamine tetraacetic acid (EDTA) into fertilizers.
In general the present invention relates to chitosan [= poly(D- glucosamine) ] conjugates comprising the following substructure within their overall structures:
More particularly, the present invention relates to chitosan- ethylenediaminetetraacetate [= EDTA] conjugates comprising the following substructure within their overall structures:
In the structural formulae above the negative ionic charge at the carboxylate group may be compensated by the respective positive charge provided by positively charged mono- or polyvalent counterions, such as protons, Li+, Na+, K+, Mg 2+ Ca2+, Zn 2+ and other positively charged inorganic or organic cations which may be represented by the cations to be complexed.
The chitosan-conjugates according to the present invention are obtainable by reacting chitosan with an acidic chelate-complex forming agent (chelating agent) selected from the group of nitrilotriacetic acid (NTA) , ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA) in the presence of carbodiimides. The molar ratio of chitosan to chelating agents preferably is about 1:20 in case that no
crosslinks should be present in the final product. In case that inter- and/or intramolecular crosslinking should be achieved the molar ratio of chitosan to chelating agent should be smaller than about 1:20, as described below. In a preferred embodiment the reaction is carried out in aqueous medium using l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride as the mediator. The chelating agent is covalently linked to the chitosan-structure by the formation of an amide bond.
More particularly the invention relates to the production of chitosan-ethylenediarriinetetraacetate conjugates comprising the following substructure within their overall structures:
Further embodiments of the present invention relate to pharmaceutical compositions, cosmetical compositions and bioadhesive matrices comprising the chitosan-conjugates described above.
In a further preferred embodiment of this invention the chitosan-conjugates are comprised in a bioadhesive matrix which can be used for the manufacture of medicaments for the administration or delivery of drugs, preferably of peptide- or protein- containing active agents (drugs) .
The chitosan-conjugates of the present invention and in particular the chitosan-EDTA-conjugate can be used as a bioadhesive matrix system for the administration of peptide and protein drugs, as gelling agent for semi-solid drug dosage forms and cosmetics and as a complexing polymer for mono- or polyvalent cations, preferably for pharmaceutic and/or cosmetic applications .
Prior to using the conjugates according to the present invention for the final purpose as gelling agent, matrix, complexing agent, etc. it may be necessary to neutralize the carboxylic acid groups in the conjugate using a suitable alkaline agent.
In detail, the present invention relates to chitosan- ethylenediamine tetraacetate conjugates. At least one of the carboxylic acid moieties of EDTA is bound to the amine moiety of chitosan to form an amide. The reaction can be mediated by carbodiimides, such as l-ethyl-3- (3-dimethylaminopropyl) car- bodiimide hydrochloride [= EDAC] . The amount of EDTA covalently bound to chitosan can be controlled by the ratio of chitosan to EDTA employed. A preferred molar ratio of chitosan to EDTA is about 1:20 inter- and intramolecular crosslinking can be avoided. When the excess of EDTA is smaller than about 1:20 (molar ratio of D-glucosamine units to EDTA) during the coupling reaction, additional cross-links are generated since EDTA forms amide linkages with more than one amine moiety of chito- san by the formation of intra- and/or intermolecular links. Adjusting the ratio of chitosan to chelating agent allows to adjust the viscosity of the resulting gel. This, in turn allows to predetermine the retention/release rate of the active pharmaceutical or cosmetic ingredient which may be incorporated into said gel.
It is noteworthy that the chitosan-conjugates according to the present invention are not susceptible against alkaline media, i.e., pH-values >7.
Thus, as described above through the ratio of chitosan to EDTA employed, the amount of coupled EDTA and the extent of additional cross-linking can be controlled. Consequently, the present invention also relates to such crosslinked chitosan- conjugates containing intra- and/or intermolecular crosslinks. Said crosslinks are also formed by covalent amide bonds. Of course, the intra- and/or intermolecular crosslinking, i.e., the crosslinking reaction between two polymers and/or within one polymer can also be carried out in the presence of a carbodiimide, i.e., by a carbodiimide-mediated reaction.
The crosslinked chitosan-chelating agent conjugates according to the present invention are obtainable by reacting chitosan with the chelating agents described above at a molar ratio of chitosan to chelating agent of less than about 1:20, in the presence of a carbodiimide as described above. The inter- and/or intramolecular crosslinked chitosan-conjugate can be used for the same purpose as the (uncrosslinked) chitosan- conjugate as described above, but may have different properties in terms of complexing activity, viscosity, gelling properties, drug-releasing (delivering) properties, etc.
The chitosan-conjugates or its crosslinked derivatives bearing the substructure defined above or in case of the crosslinked derivatives bearing a substructure containing more than one amide bond in the moiety stemming from the chelating agent will bind polyvalent cations, inhibit zinc proteases, and exhibit bioadhesive and gelling properties. It is possible to use the conjugates of the present invention in bioadhesive matrix systems, as gelling agents and complexing polymer for polyvalent cations in pharmaceutical and cosmetic applications. The inhibition of protease by the chitosan-conjugates of the invention and particularly of the chitosan-EDTA conjugates enables the administration of all kinds of pharmaceutically active agents such as peptide- and protein-containing drugs. The advantage is most significant in the administration of vaccines (antigens) , DNA and RNA. The bioadhesive carrier matrix according to the present invention allows the oral administration of
active agents which can up to now only be administered par- enterally. The active agents are incorporated into the inventive matrix and are sufficiently protected against an enzymatic attack by, for instance, digestive enzymes and are released in a controlled manner, as described above.
The chitosan-conjugates according to the present invention, and in particular the chitosan-EDTA conjugates inhibit various digesting enzymes, such as zinc protease, they are capable of complexing polyvalent cations, they represent a readily hy- drated and strongly swelling gelling agent and they have bioadhesive properties.
What has been described above in relation to EDTA as the chelating agent also applies in case that NTA or DTPA is employed as the acidic chelating agent.
The invention is described by the following example without being limited thereto.
Example
To a 1% (m/v) aqueous chitosan-HCl solution at pH 4-5 is added a 20fold molar excess of EDTA (moles of D-glucosamine units of chitosan to moles of EDTA) . Then, the pH value is adjusted to 6.0 with 5 N NaOH, and l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride [= EDAC] is added to a final concentration of 0.1 M. The reaction mixture is stirred at room temperature for 12 hours, then neutralized with 5 N NaOH. The purifi- cation of the coupling product is effected by exhausting dialysis against deionized water, 0.05 N NaOH, and again deionized water. After lyophilization, the conjugate can be stored at room temperature.
In the coupling reaction thus described, the fraction of re- sidual primary amine moieties at chitosan is 0.1% ± 0.03%
(average of three determination runs; ± standard deviation) . By using a more than 20fold excess of EDTA, the degree of coupling
can be but marginally increased. Reaction mixtures containing a less than 20fold excess of EDTA result in lower degrees of coupling and the occurrence of cross-links since some EDTA molecules will react with more than one amine group of chitosan.
Claims
Claims :
Chitosan [= poly (D-glucosamine) ] conjugates comprising the following substructure within their overall structures:
The chitosan-conjugates according to claim 1 comprising the following structure within their overall structure:
Crosslinked chitosan-chelating agent conjugates obtainable by reacting chitosan with a chelating agent selected from the group consisting of nitrilotriacetic acid, ethyle- nediaminetetraacetic acid, diethylenetriaminepentaacetic acid at a molar ratio of chitosan: chelating agent of less than about 1:20 in the presence of a carbodiimide.
A method for the production of the chitosan-conjugates according to claim 1 or 2, by reacting chitosan with an acidic chelate-complex forming agent selected from the group consisting of nitrilotriacetic acid (NTA) , ethyle- nediaminetetraacetic acid (EDTA) and diethylenetriamine pentaacetic acid (DTPA) in the presence of carbodiimides.
The method according to claim 4, wherein the carbodiimide is l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydro- chloride.
6. The method according to claim 4 or 5 for the production of chitosan-ethylenediamine tetraacetate conjugates containing the following substructure within their overall structures:
characterized in that chitosan is reacted with EDTA in the presence of carbodiimides.
Method for the production of the crosslinked chitosan- conjugate according to claim 3 by reacting chitosan with a chelating agent selected from the group consisting of nitrilotriacetic acid, ethylenediaminetetraacetic acid, diethylenetriaminepentaacetic acid at a molar ratio of chitosan: chelating agent of less than about 1:20 in the presence of a carbodiimide.
A pharmaceutical composition comprising the chitosan- conjugate according to claim 1, 2 or 3.
The pharmaceutical composition according to claim 6 comprising chitosan-ethylenediaminetetraacetate conjugates bearing the substructure as defined in claim 2.
10. A cosmetical composition comprising the chitosan-conjugate according to claim 1, 2 or 3.
11. The cosmetical composition according to claim 10 compris- ing chitosan-ethylenediaminetetraacetate conjugates bearing the substructure as defined in claim 2.
12. A bioadhesive matrix comprising the chitosan-conjugate according to claim 1, 2 or 3.
13. The bioadhesive matrix according to claim 12 further comprising a pharmaceutically or cosmetically active agent.
14. The bioadhesive matrix according to claim 13, wherein the pharmaceutically active agent is selected from vaccines, DN or RNA.
15. The bioadhesive matrix according to claim 13, wherein the pharmaceutically active agent is selected from peptides, proteins, peptide-group containing or protein-group containing compounds .
16. Use of the bioadhesive matrix according to any of claims 12 to 15 for the manufacture of a medicament for the ad- ministration of active agents.
17. Use according to claim 16, wherein the active agent is selected from proteins, peptides, peptide-group or protein-group containing compounds.
18. Use of the chitosan-conjugates according to claim 1, 2 or 3 as complexing agent.
19. Use of the chitosan-conjugates according to claim 1, 2 or 3 as a gelling agent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP98907971A EP0954537A2 (en) | 1997-01-21 | 1998-01-21 | Chitosan-conjugates with acidic chelate-complex forming agents |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ATA79/97 | 1997-01-21 | ||
| AT0007997A ATA7997A (en) | 1997-01-21 | 1997-01-21 | METHOD FOR PRODUCING CHITOSAN ETHYLENE DIAMINE TETRAACETATE CONJUGATES |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO1998031712A2 true WO1998031712A2 (en) | 1998-07-23 |
| WO1998031712A3 WO1998031712A3 (en) | 1998-09-11 |
Family
ID=3480978
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1998/000320 WO1998031712A2 (en) | 1997-01-21 | 1998-01-21 | Chitosan-conjugates with acidic chelate-complex forming agents |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0954537A2 (en) |
| AT (1) | ATA7997A (en) |
| WO (1) | WO1998031712A2 (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000016811A2 (en) * | 1998-09-17 | 2000-03-30 | Schering Aktiengesellschaft | Mri contrast agent |
| US6896809B2 (en) | 2002-12-20 | 2005-05-24 | Providence Health System - Oregon | Methods for purifying chitosan |
| US7053068B2 (en) | 2001-08-31 | 2006-05-30 | Mucobiomer Biotechnologische Forschungs- Und Entwicklungs Gesmbh | Chitosan-thio-amidine conjugates and their cosmetic as well as pharmaceutic use |
| US8530632B2 (en) | 2008-04-24 | 2013-09-10 | Medtronic Xomed, Inc. | Chitosan-containing protective composition |
| WO2014102741A2 (en) | 2012-12-28 | 2014-07-03 | University Of The Witwatersrand, Johannesburg | Pharmaceutical dosage form |
| US8802652B2 (en) | 2008-04-24 | 2014-08-12 | Medtronic, Inc. | Rehydratable polysaccharide particles and sponge |
| US9198997B2 (en) | 2008-04-24 | 2015-12-01 | Medtronic, Inc. | Rehydratable thiolated polysaccharide particles and sponge |
| US9333220B2 (en) | 2008-04-24 | 2016-05-10 | Medtronic, Inc. | Method for treating the ear, nose, sinus or throat |
| US20180296461A1 (en) * | 2015-05-08 | 2018-10-18 | Cyra Consultora Limitada | Arsenic-chelating composition |
-
1997
- 1997-01-21 AT AT0007997A patent/ATA7997A/en not_active Application Discontinuation
-
1998
- 1998-01-21 EP EP98907971A patent/EP0954537A2/en not_active Withdrawn
- 1998-01-21 WO PCT/EP1998/000320 patent/WO1998031712A2/en not_active Application Discontinuation
Non-Patent Citations (6)
| Title |
|---|
| A. BERNKOP-SCHN]RCH ET AL.: "Intestinal peptide and protein delivery: Synthesis and evaluation of a chitosan-inhibitor conjugate" FARM VESTN, vol. 48, 1997, pages 218-219, XP002069753 * |
| A. BERNKOP-SCHN]RCH ET AL.: "Novel bioadhesive chitosan-edta conjugate rotects leucine enkephalin from degradation by aminopeptidase N" PHARMACEUTICAL RESEARCH, vol. 14, no. 7, July 1997, pages 917-922, XP002069752 * |
| C. VALENTA ET AL.: "Chitosan-EDTA conjugate: A novel polymer for topical used gels" FARM VESTN, vol. 48, 1997, pages 354-355, XP002069754 * |
| CHEMICAL ABSTRACTS, vol. 123, no. 16, 16 October 1995 Columbus, Ohio, US; abstract no. 217120, "Adsorption behaviors of some metal ions on chitosan modified with edta-type ligand" XP002069755 & INOUE K. ET AL.: BUNSEKI KAGAKU, vol. 44, no. 4, 1995, JP, pages 283-287, * |
| CHEMICAL ABSTRACTS, vol. 124, no. 24, 10 June 1996 Columbus, Ohio, US; abstract no. 320011, "adsorption behaviors of some complexane types of chemically modified chitosan for metal ions" XP002069756 & INOUE K. ET AL.: ADV. CHITIN SCI., vol. 1, 1996, pages 271-278, * |
| V. E. TIKHONOV ET AL.: "Metal-chelating chitin derivatives via reaction of chitosan with nitrilotriacetic acid" CARBOHYDRATE RESEARCH, vol. 290, 1996, pages 33-41, XP000596065 * |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000016811A2 (en) * | 1998-09-17 | 2000-03-30 | Schering Aktiengesellschaft | Mri contrast agent |
| WO2000016811A3 (en) * | 1998-09-17 | 2000-11-23 | Schering Ag | Mri contrast agent |
| US7053068B2 (en) | 2001-08-31 | 2006-05-30 | Mucobiomer Biotechnologische Forschungs- Und Entwicklungs Gesmbh | Chitosan-thio-amidine conjugates and their cosmetic as well as pharmaceutic use |
| US6896809B2 (en) | 2002-12-20 | 2005-05-24 | Providence Health System - Oregon | Methods for purifying chitosan |
| US8802652B2 (en) | 2008-04-24 | 2014-08-12 | Medtronic, Inc. | Rehydratable polysaccharide particles and sponge |
| US8530632B2 (en) | 2008-04-24 | 2013-09-10 | Medtronic Xomed, Inc. | Chitosan-containing protective composition |
| US9198997B2 (en) | 2008-04-24 | 2015-12-01 | Medtronic, Inc. | Rehydratable thiolated polysaccharide particles and sponge |
| US9333220B2 (en) | 2008-04-24 | 2016-05-10 | Medtronic, Inc. | Method for treating the ear, nose, sinus or throat |
| US9433636B2 (en) | 2008-04-24 | 2016-09-06 | Medtronic, Inc. | Protective gel based on chitosan and oxidized polysaccharide |
| US9561248B2 (en) | 2008-04-24 | 2017-02-07 | Medtronic, Inc. | Method for rehydrating polysaccharide particles |
| US10420794B2 (en) | 2008-04-24 | 2019-09-24 | Medtronic, Inc. | Polysaccharide particle mixture |
| WO2014102741A2 (en) | 2012-12-28 | 2014-07-03 | University Of The Witwatersrand, Johannesburg | Pharmaceutical dosage form |
| US20180296461A1 (en) * | 2015-05-08 | 2018-10-18 | Cyra Consultora Limitada | Arsenic-chelating composition |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0954537A2 (en) | 1999-11-10 |
| WO1998031712A3 (en) | 1998-09-11 |
| ATA7997A (en) | 1998-03-15 |
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