WO2003080135A1 - Therapeutic compositions comprising modified polysaccharides - Google Patents
Therapeutic compositions comprising modified polysaccharides Download PDFInfo
- Publication number
- WO2003080135A1 WO2003080135A1 PCT/GB2003/001208 GB0301208W WO03080135A1 WO 2003080135 A1 WO2003080135 A1 WO 2003080135A1 GB 0301208 W GB0301208 W GB 0301208W WO 03080135 A1 WO03080135 A1 WO 03080135A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- polysaccharide
- modified
- wound dressing
- wound
- modified polysaccharide
- Prior art date
Links
- 150000004676 glycans Chemical class 0.000 title claims abstract description 89
- 229920001282 polysaccharide Polymers 0.000 title claims abstract description 85
- 239000005017 polysaccharide Substances 0.000 title claims abstract description 85
- 239000000203 mixture Substances 0.000 title description 14
- 230000001225 therapeutic effect Effects 0.000 title description 6
- 206010052428 Wound Diseases 0.000 claims abstract description 50
- 208000027418 Wounds and injury Diseases 0.000 claims abstract description 50
- 125000003396 thiol group Chemical group [H]S* 0.000 claims abstract description 19
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- 230000001684 chronic effect Effects 0.000 claims abstract description 12
- 208000005592 lipodermatosclerosis Diseases 0.000 claims abstract description 12
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 claims abstract description 10
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims abstract description 10
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- 229920002101 Chitin Polymers 0.000 claims abstract description 3
- 229920001661 Chitosan Polymers 0.000 claims abstract description 3
- WCBPJVKVIMMEQC-UHFFFAOYSA-N 1,1-diphenyl-2-(2,4,6-trinitrophenyl)hydrazine Chemical group [O-][N+](=O)C1=CC([N+](=O)[O-])=CC([N+]([O-])=O)=C1NN(C=1C=CC=CC=1)C1=CC=CC=C1 WCBPJVKVIMMEQC-UHFFFAOYSA-N 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 16
- -1 Fe3+ ions Chemical class 0.000 claims description 12
- 150000001720 carbohydrates Chemical group 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 6
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
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- 208000004210 Pressure Ulcer Diseases 0.000 claims description 4
- 208000025865 Ulcer Diseases 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 231100000397 ulcer Toxicity 0.000 claims description 4
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical class O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 claims description 3
- 206010056340 Diabetic ulcer Diseases 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 239000011324 bead Substances 0.000 claims description 2
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- 239000000843 powder Substances 0.000 claims description 2
- 239000002759 woven fabric Substances 0.000 claims description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 abstract description 40
- 229910052742 iron Inorganic materials 0.000 abstract description 21
- 238000006243 chemical reaction Methods 0.000 abstract description 3
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 8
- 238000002835 absorbance Methods 0.000 description 8
- 239000003963 antioxidant agent Substances 0.000 description 8
- 235000006708 antioxidants Nutrition 0.000 description 8
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 7
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 7
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 7
- 239000003642 reactive oxygen metabolite Substances 0.000 description 7
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 6
- 210000002966 serum Anatomy 0.000 description 6
- 239000011701 zinc Substances 0.000 description 6
- 229910052725 zinc Inorganic materials 0.000 description 6
- HNSDLXPSAYFUHK-UHFFFAOYSA-N 1,4-bis(2-ethylhexyl) sulfosuccinate Chemical compound CCCCC(CC)COC(=O)CC(S(O)(=O)=O)C(=O)OCC(CC)CCCC HNSDLXPSAYFUHK-UHFFFAOYSA-N 0.000 description 5
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 5
- 239000012530 fluid Substances 0.000 description 5
- 230000036542 oxidative stress Effects 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- 230000035876 healing Effects 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
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- 241000894007 species Species 0.000 description 3
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 230000029663 wound healing Effects 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 description 2
- 239000000589 Siderophore Substances 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
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- 244000309466 calf Species 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 231100000749 chronicity Toxicity 0.000 description 2
- 229960000958 deferoxamine Drugs 0.000 description 2
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- 210000002950 fibroblast Anatomy 0.000 description 2
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- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical group CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- 102000016938 Catalase Human genes 0.000 description 1
- 108030002440 Catalase peroxidases Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
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- 206010011985 Decubitus ulcer Diseases 0.000 description 1
- 206010016717 Fistula Diseases 0.000 description 1
- 229920001503 Glucan Polymers 0.000 description 1
- 102000006587 Glutathione peroxidase Human genes 0.000 description 1
- 108700016172 Glutathione peroxidases Proteins 0.000 description 1
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 1
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 102000019197 Superoxide Dismutase Human genes 0.000 description 1
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
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- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
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- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
-
- 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
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/42—Use of materials characterised by their function or physical properties
-
- 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
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
- A61L15/28—Polysaccharides or their derivatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
Definitions
- the present invention relates to therapeutic compositions comprising chemically modified polysaccharides.processes suitable for the preparation of such modified polysaccharides, and the use of such modified polysaccharides in therapeutic applications such as wound treatment.
- oxidative stress Concentrations of reactive oxygen species such as hydroxyl radicals (OH), singlet oxygen ( 1 0 2 ), hydroperoxyl radicals ( OOH), superoxide radical anions ( O 2 ), and hydrogen peroxide (H 2 O 2 ) can rise in damaged tissues, producing a condition known as oxidative stress.
- the presence of a low level of reactive oxygen species may be advantageous in the early stages of wound healing by both attracting and activating macrophages which engulf and kill bacteria and release cytokines and growth factors.
- prolonged and more severe oxidative stress may delay healing because it will produce chronic inflammation, divert available energy supply towards antioxidant defence at the expense of tissue reconstruction, and increase levels of matrix metalloproteinases which cause tissue breakdown.
- elevated levels of reactive oxygen species can give rise to hydrogen peroxide-induced senescence or apoptosis (that is, programmed cell death) or tissue necrosis (that is, uncontrolled cell death and therefore permanent tissue damage).
- compositions comprising chemically modified polymers grafted with chemical groups that confer antioxidant activity as measured by a diphenylpicrylhydrazyl (DPPH) test and that also generate low levels of hydrogen peroxide by reaction with molecular oxygen in the wound bed to stimulate macrophage activity and fibroblast proliferation.
- the compositions may be used to promote the healing of chronic wounds.
- the polymer is a polymer bearing hydroxyl, carbonyl or amide functional groups, or a polysaccharide bearing hydroxyl functional groups, said functional groups having been converted to derivatives that are persistent free radicals or precursors of persistent free radicals, that is to say they are free radical scavenging antioxidant groups.
- compositions comprising polysaccharides grafted with antioxidants on at least one hydroxyl group of the polysaccharide.
- the compositions may be used inter alia to promote the healing of chronic wounds.
- the polysaccharide is hyaluronic acid and the antioxidant group comprises a phenol group.
- iron plays an important role.
- iron may play a role in catalysing the generation of the above-described reactive oxygen species, and thereby may contribute to wound chronicity.
- bacteria require iron for metabolism and can secrOete siderophores for the purpose of scavenging iron. It therefore appears that removal of free iron from the wound fluid, preferably without removal of other dissolved species such as zinc that promote wound healing, could assist in reducing both wound colonisation or infection by bacteria and wound chronicity.
- US-A-6156334 describes novel wound coverings comprising chelators such as the siderophore deferoxamine grafted onto a suitable carrier through a linker molecule, which remove interfering factors such as iron from the wound bed.
- chelators such as the siderophore deferoxamine grafted onto a suitable carrier through a linker molecule, which remove interfering factors such as iron from the wound bed.
- Foitzik A et al. in the Proceedings of the Joint Meeting of the European Tissue Repair Society/The Wound Healing Society. Bordeaux, 24 th - 28 th August 1999 describe treatment of chronic venous ulcers by means of a gauze dressing having deferoxamine coupled thereto.
- the resulting iron-absorbing dressing is expensive to manufacture, and its antioxidant properties and affinity for beneficial species such as zinc are unknown.
- EP-A-0556110 describes the use of thiol-grafted polymers to improve the adhesion of cosmetic and therapeutic compositions for application to the skin.
- the present invention provides a wound dressing comprising a chemically modified polysaccharide, wherein the polysaccharide is chemically modified by the introduction of one or more thiol groups.
- the thiol groups may replace hydroxyl groups of the saccharide units of the polysaccharide, or preferably the thiol groups are present on a side chain that is grafted onto the polysaccharide through an ester or ether linkage.
- the side chain has from 1 to 8 carbon atoms.
- a preferred side chain is 2- ethoxythiol, for example in a modified polysaccharide comprising a moiety of the following general formula.
- Such side chains of structure (III) can conveniently be formed by reacting a polysaccharide or a modified polysaccharide, for example hydroxyethyl cellulose, with Lawesson's reagent as described further below.
- a polysaccharide or a modified polysaccharide for example hydroxyethyl cellulose
- Lawesson's reagent as described further below.
- the chemically modified polysaccharide according to the present invention is a modified or derivatised glycan or aminoglycan.
- the modified or derivatised glycan is a modified or derivatised guluronomannuronan such as an alginate or alginate derivative.
- the modified or derivatised glycan is a modified or derivatised glucan such as cellulose or a cellulose derivative.
- the modified or derivatised glycan is a hydroxyalkyl cellulose for example hydroxyethyl cellulose
- the modified or derivatised aminoglycan is a modified or derivatised chitin/chitosan.
- the modified polysaccharide may comprise a mixture of two or more modified glycans, aminoglycans or derivatives thereof.
- At least 1% of the saccharide residues in the modified polysaccharide are modified in accordance with the invention by the introduction of a thiol group or a thiol-containing group. More preferably, at least 5% of the saccharide residues are so modified, and still more preferably at least 10% to 20% of the saccharide residues are so modified.
- the modified polysaccharide used in the present invention has a free radical activity, that is to say an antioxidant activity, of at least 15% in the diphenylpicrylhydrazyl (DPPH) test, measured as percentage reduction in absorbance at 524nm after 4 hours of a 0.5%w/v dispersion of the polysaccharide in lO /I DPPH, as described further hereinbelow in procedure 2.
- DPPH diphenylpicrylhydrazyl
- the percentage reduction in absorbance in the DPPH test is at least 25%, more preferably at least 50%, and most preferably at least 75%.
- the modified polysaccharide will absorb water or wound fluid and hence become wet, swell or become a gelatinous mass but will not spontaneously dissolve or disperse therein. That is to say, it is hydrophilic but has a solubility of preferably less than 1g/liter in water at 25°C. Low solubility renders such polysaccharides especially suitable for use as wound dressings to remove iron and reactive oxygen species from the wound fluid.
- the modified polysaccharide used in the present invention preferably forms complexes with iron selectively over zinc. That is to say, the molar fraction of the iron ions absorbed by the modified polysaccharide in the method of Procedure 1 is higher than the fraction of the zinc ions absorbed. More preferably, the stability constant of the polysaccharide complex with Fe 3+ ions is at least ten times the stability constant of the polysaccharide complex with Zn 2+ ions.
- a complex of the polysaccharide with Fe 3+ in water at neutral Ph has a stability constant of at least 10 3 , preferably at least 10 6 .
- the wound dressing and/or the modified polysaccharide used in the present invention may be provided in the form of beads, flakes, powder, and preferably in the form of a film, a fibrous pad, a web, a woven or non-woven fabric, a freeze- dried sponge, a foam or combinations thereof.
- Such formats are especially useful for wound dressings, which can easily be made by derivatisation of or by grafting of side chains onto polysaccharides already provided in the relevant formats.
- the antioxidant and iron sequestering properties of the polysaccharides used in the present invention suggest applications in a range of medical applications, including the treatment of acute surgical and traumatic wounds, burns, fistulas, venous ulcers, arterial ulcers, pressure sores (otherwise known as decubitus ulcers), diabetic ulcers, ulcers of mixed aetiology, and other chronic or necrotic wounds and inflammatory lesions and disorders.
- Another therapeutic application that is likely to be useful is in the treatment or prevention of lipodermatosclerosis (LDS).
- LDS is a pre-ulcerous discoloring and hardening of the skin in patients suffering from venous insufficiency leading ultimately to varicose ulcers. It is thought that excess iron plays a part in the mechanism of LDS, and therefore that the iron sequestering properties of these modified polysaccharides will be useful in the treatment and prevention of LDS.
- the wound dressing composition may also be in the form of a gel or viscous fluid for topical application.
- the wound dressing composition comprises at least about 1wt.% of the thiolated polysaccharide, more preferably at least about 10wt.%, more preferably at least about 50wt% of the thiolated polysaccharide.
- the wound dressing consists essentially of the thiolated polysaccharide.
- the wound dressing is sterile, and preferably it is packaged in a microorganism impermeable container.
- the present invention further provides the use of a modified polysaccharide, wherein the polysaccharide is chemically modified by the introduction of one or more thiol groups, for the preparation of a medicament for the treatment of a wound.
- the wound is a chronic wound. More preferably, the chronic wound is selected from the group consisting of ulcers of venous, arterial or mixed aetiology, decubitus ulcers, or diabetic ulcers.
- the present invention further provides the use of a modified polysaccharide, wherein the polysaccharide is chemically modified by the introduction of one or more thiol groups, for the preparation of a medicament for the treatment or prevention of lipodermatosclerosis.
- the present invention provides a method of treatment of a wound in a mammal comprising applying thereto a therapeutically effective amount of a modified polysaccharide, wherein the polysaccharide is chemically modified by the introduction of one or more thiol groups.
- the wound is a chronic wound.
- the present invention provides a method of treatment or prevention of lipodermatosclerosis in a mammal comprising applying to LDS skin, or to skin liable to develop LDS, a therapeutically effective amount of a modified polysaccharide, wherein the polysaccharide is chemically modified by the introduction of one or more thiol groups.
- Skin liable to develop LDS would include, for example, the lower leg of individuals suffering from venous insufficiency or varicose veins.
- the present invention further provides a process for the production of a modified polysaccharide comprising the step of reacting a polysaccharide or polysaccharide derivative with Lawesson's reagent having the structure (V):
- the Lawesson's reagent is reacted with said polysaccharide or polysaccharide derivative in an amount of at least 0.1 moles per mole of saccharide residues of the polysaccharide or polysaccharide derivative.
- the present invention further provides modified polysaccharides obtainable by processes according to the invention.
- the modified polysaccharides Preferably, the modified polysaccharides have structures as hereinbefore defined in relation to the first aspect of the invention.
- Figure 1 shows chromatograms of iron and zinc ion concentrations for a control serum (D) containing no added iron or zinc, a control serum containing added iron and zinc ions (A), and the serum A after treatment with a thiolated polysaccharide according to the present invention (E).
- the plots B and C relate to reference examples that are not considered further here.
- Figure 2 shows the absolute reduction in absorbance of DPPH at 524nm versus concentration of antioxidant for ascorbic acid (C, reference example), and a thiolated polysaccharide according to the invention (D).
- the absorbance of the starting DPPH solution was 0.506AU.
- Plots A and B relate to reference examples not considered further here.
- Example 1
- hydroxyethyl cellulose was modified by treatment with Lawesson's reagent as follows. Hydroxyethyl cellulose (10.3g, 50mmoles) was placed in a dry 250ml three-neck round bottomed flask with 150ml of anhydrous toluene. To this was added Lawesson's reagent (Aldrich Chemical Co. catalog number 22,743-9; 2.02g; ⁇ mmoles). The flask was fitted with a water condenser and the mixture was then stirred and heated under reflux in a nitrogen atmosphere for 4 hours.
- Lawesson's reagent Aldrich Chemical Co. catalog number 22,743-9; 2.02g; ⁇ mmoles
- the reaction mixture was then allowed to cool to 30°C before quenching with aqueous 1M potassium hydroxide (KOH) solution (100ml) to ensure complete hydrolysis of Lawesson's reagent. After standing for a further 15 minutes, liquid phases were decanted and collected for disposal. The remaining solid material was washed with aqueous 1M KOH (100ml x 3) and with aqueous 1M hydrochloric acid (100ml x 3), decanting the washings between each aliquot of wash solution. The remaining solid material was then washed with deionised water (100ml x 3) and with ethanol (100ml x 3). Centrifugation was necessary between washings.
- KOH potassium hydroxide
- the resultant pellets were placed on a tray and blast frozen before freeze drying. Yield of product was 4.03g.
- the degree of thiolation could be increased by increasing the initial proportion of Lawesson's reagent to polysaccharide; loss of product during washing could be decreased by using isopropanol/water mixtures as solvents for the alkaline, acidic, and neutral washes.
- the thiolated hydroxyethyl cellulose exhibited a high affinity for Fe 3+ and a particularly low affinity for Zn 2+ and also antioxidant properties as determined in procedures 1 and 2 described below.
- the results for this material are shown as graph E in Fig. 1 and as plot D in Fig. 2. Neither of these properties is observed for the unmodified hydroxyethyl cellulose starting material.
- modified polysaccharides according to the present invention to sequester iron ions selectively over zinc ions in aqueous media was determined as follows.
- the modified polysaccharide was added with stirring to a solution containing iron and/or zinc ions in a suitable matrix such as buffer, serum-containing buffer or cell culture medium that is intended to simulate wound fluid.
- a suitable matrix such as buffer, serum-containing buffer or cell culture medium that is intended to simulate wound fluid.
- ion chromatography was used to determine the levels of uncomplexed Fe 3+ and/or Zn 2+ ions remaining in solution.
- solutions of FeCI 3 .6H 2 0 and ZnS0 .7H 2 0 in water were added to Dulbecco's Modified Eagle's Medium (DMEM; Sigma Chemical Co. catalog number D 5546) containing 10% v/v calf serum (Sigma Chemical Co. catalog number N 4637) to produce final concentrations of 50 ppm Fe 3+ and 50 ppm Zn 2+ .
- DMEM Dulbecco's Modified Eagle's Medium
- N 4637 10% v/v calf serum
- the centrifuged solution was treated with 0.1ml of a 20% w/v solution of trichloroacetic acid (TCA) to give a final concentration of 2% w/v TCA.
- TCA trichloroacetic acid
- the tube was vortexed for 10 seconds and then centrifuged for 15 minutes or longer to remove solids.
- the supernatant (0.5ml) was added to a clean dry HPLC vial to which was added 0.5ml of 0.5M nitric acid (HN0 3 ) prepared in deionised water.
- Reagent 4-(2-pyridylazo) resorcinol monosodium salt (PAR) 0.12g/l
- modified polysaccharide under test (2.5mg; 5mg; & 25mg sample sizes) was suspended in 2.5ml of 0.1M pH 7.0 phosphate buffer.
- a solution of diphenylpicrylhydrazyl (DPPH) in methanol (10 "4 M) was added in an amount of DPPH diphenylpicrylhydrazyl
- DPPH control solution containing no test sample produced an absorbance reading of 0.506 AU.
- Ascorbic acid a well known antioxidant, provides a useful positive control substance for comparative purposes.
- Example 3 at its highest concentration (0.5% w/v) after 4 hours, as shown in Fig. 2.
- the unmodified hydroxyethyl cellulose exhibited much lower DPPH values of less than 15%.
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Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP03708359A EP1487508B1 (en) | 2002-03-25 | 2003-03-24 | Therapeutic compositions comprising modified polysaccharides |
AU2003212539A AU2003212539A1 (en) | 2002-03-25 | 2003-03-24 | Therapeutic compositions comprising modified polysaccharides |
DE60305169T DE60305169T2 (en) | 2002-03-25 | 2003-03-24 | THERAPEUTIC PREPARATIONS CONTAINED MODIFIED POLYSACCHARIDES |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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GB0207008.4 | 2002-03-25 | ||
GB0207008A GB2386900B (en) | 2002-03-25 | 2002-03-25 | Use in wound dressings of chemically modified polysaccharides |
Publications (1)
Publication Number | Publication Date |
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WO2003080135A1 true WO2003080135A1 (en) | 2003-10-02 |
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PCT/GB2003/001208 WO2003080135A1 (en) | 2002-03-25 | 2003-03-24 | Therapeutic compositions comprising modified polysaccharides |
Country Status (7)
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EP (1) | EP1487508B1 (en) |
AT (1) | ATE325627T1 (en) |
AU (1) | AU2003212539A1 (en) |
DE (1) | DE60305169T2 (en) |
ES (1) | ES2264524T3 (en) |
GB (1) | GB2386900B (en) |
WO (1) | WO2003080135A1 (en) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008008857A2 (en) * | 2006-07-11 | 2008-01-17 | University Of Utah Research Foundation | Thiolated macromolecules and methods of making and using thereof |
WO2008157285A1 (en) | 2007-06-13 | 2008-12-24 | Fmc Corporation | Biopolymer based implantable degradable devices |
WO2009132224A3 (en) * | 2008-04-24 | 2009-12-17 | Medtronic, Inc. | Rehydratable thiolated polysaccharide particles and sponge |
US8530632B2 (en) | 2008-04-24 | 2013-09-10 | Medtronic Xomed, Inc. | Chitosan-containing protective composition |
US8802652B2 (en) | 2008-04-24 | 2014-08-12 | Medtronic, Inc. | Rehydratable polysaccharide particles and sponge |
US9333220B2 (en) | 2008-04-24 | 2016-05-10 | Medtronic, Inc. | Method for treating the ear, nose, sinus or throat |
EP2614828B1 (en) | 2010-09-09 | 2016-10-19 | Bioregen Biomedical (Changzhou) Co., Ltd. | Low-modification biocompatible high polymer sulfhydryl-modified derivatives, cross-linked material thereof, and uses of said material |
US9597277B2 (en) | 2006-12-22 | 2017-03-21 | Croma-Pharma Gesellschaft M.B.H. | Use of polymers |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3368007B1 (en) | 2015-10-30 | 2020-03-18 | Croma-Pharma Gesellschaft m.b.H. | Therapeutic use of a sterile aqueous ophthalmic solution |
CN111375085B (en) * | 2018-12-27 | 2022-02-01 | 爱美客技术发展股份有限公司 | Fluid hemostatic gel and preparation method thereof |
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EP0556110A1 (en) * | 1992-02-10 | 1993-08-18 | Exsymol S.A.M. | Vector for therapeutic or cosmetic drugs for external use and therapeutic or cosmetic composition containing such a vector |
WO1994004129A2 (en) * | 1992-08-26 | 1994-03-03 | Beiersdorf Ag | Cosmetic and dermatological sunscreen compositions containing thiols and/or thiol derivates |
WO1994013333A1 (en) * | 1992-12-08 | 1994-06-23 | University College Cardiff Consultants Limited | Wound dressings |
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US3914214A (en) * | 1973-08-24 | 1975-10-21 | Us Agriculture | Thiolation of polysaccharides |
JPH0647604B2 (en) * | 1984-04-11 | 1994-06-22 | ダイセル化学工業株式会社 | Polysaccharide derivative |
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DE4210334A1 (en) * | 1992-03-30 | 1993-10-07 | Stoess & Co Gelatine | Biodegradable, water-resistant polymer material |
JP3547517B2 (en) * | 1995-03-15 | 2004-07-28 | 三洋化成工業株式会社 | Manufacturing method of water absorbent resin |
US6417347B1 (en) * | 2000-08-24 | 2002-07-09 | Scimed Life Systems, Inc. | High yield S-nitrosylation process |
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2002
- 2002-03-25 GB GB0207008A patent/GB2386900B/en not_active Expired - Fee Related
-
2003
- 2003-03-24 AT AT03708359T patent/ATE325627T1/en not_active IP Right Cessation
- 2003-03-24 WO PCT/GB2003/001208 patent/WO2003080135A1/en not_active Application Discontinuation
- 2003-03-24 EP EP03708359A patent/EP1487508B1/en not_active Expired - Lifetime
- 2003-03-24 ES ES03708359T patent/ES2264524T3/en not_active Expired - Lifetime
- 2003-03-24 AU AU2003212539A patent/AU2003212539A1/en not_active Abandoned
- 2003-03-24 DE DE60305169T patent/DE60305169T2/en not_active Expired - Lifetime
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EP0556110A1 (en) * | 1992-02-10 | 1993-08-18 | Exsymol S.A.M. | Vector for therapeutic or cosmetic drugs for external use and therapeutic or cosmetic composition containing such a vector |
WO1994004129A2 (en) * | 1992-08-26 | 1994-03-03 | Beiersdorf Ag | Cosmetic and dermatological sunscreen compositions containing thiols and/or thiol derivates |
WO1994013333A1 (en) * | 1992-12-08 | 1994-06-23 | University College Cardiff Consultants Limited | Wound dressings |
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Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008008857A2 (en) * | 2006-07-11 | 2008-01-17 | University Of Utah Research Foundation | Thiolated macromolecules and methods of making and using thereof |
WO2008008857A3 (en) * | 2006-07-11 | 2008-03-20 | Univ Utah Res Found | Thiolated macromolecules and methods of making and using thereof |
US9597277B2 (en) | 2006-12-22 | 2017-03-21 | Croma-Pharma Gesellschaft M.B.H. | Use of polymers |
WO2008157285A1 (en) | 2007-06-13 | 2008-12-24 | Fmc Corporation | Biopolymer based implantable degradable devices |
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 |
CN102083476A (en) * | 2008-04-24 | 2011-06-01 | 麦德托尼克公司 | Rehydratable thiolated polysaccharide particles and sponge |
AU2009240509B2 (en) * | 2008-04-24 | 2014-08-21 | Medtronic, Inc. | Rehydratable thiolated 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 |
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 |
WO2009132224A3 (en) * | 2008-04-24 | 2009-12-17 | Medtronic, Inc. | Rehydratable thiolated polysaccharide particles and sponge |
US10420794B2 (en) | 2008-04-24 | 2019-09-24 | Medtronic, Inc. | Polysaccharide particle mixture |
EP2614828B1 (en) | 2010-09-09 | 2016-10-19 | Bioregen Biomedical (Changzhou) Co., Ltd. | Low-modification biocompatible high polymer sulfhydryl-modified derivatives, cross-linked material thereof, and uses of said material |
Also Published As
Publication number | Publication date |
---|---|
DE60305169T2 (en) | 2007-03-01 |
AU2003212539A1 (en) | 2003-10-08 |
GB2386900B (en) | 2006-11-01 |
DE60305169D1 (en) | 2006-06-14 |
ATE325627T1 (en) | 2006-06-15 |
GB2386900A (en) | 2003-10-01 |
EP1487508A1 (en) | 2004-12-22 |
EP1487508B1 (en) | 2006-05-10 |
GB0207008D0 (en) | 2002-05-08 |
ES2264524T3 (en) | 2007-01-01 |
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