US20230302192A1 - Powder for achieving hemostasis - Google Patents
Powder for achieving hemostasis Download PDFInfo
- Publication number
- US20230302192A1 US20230302192A1 US18/327,140 US202318327140A US2023302192A1 US 20230302192 A1 US20230302192 A1 US 20230302192A1 US 202318327140 A US202318327140 A US 202318327140A US 2023302192 A1 US2023302192 A1 US 2023302192A1
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- US
- United States
- Prior art keywords
- chitosan
- composition
- groups
- aldehyde
- powder
- 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.)
- Pending
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- 239000000843 powder Substances 0.000 title claims abstract description 97
- 230000023597 hemostasis Effects 0.000 title description 5
- 229920001661 Chitosan Polymers 0.000 claims abstract description 213
- 239000000203 mixture Substances 0.000 claims abstract description 58
- 238000000034 method Methods 0.000 claims abstract description 19
- 230000000740 bleeding effect Effects 0.000 claims abstract description 11
- 239000002245 particle Substances 0.000 claims description 28
- 239000003431 cross linking reagent Substances 0.000 claims description 27
- 150000001299 aldehydes Chemical class 0.000 claims description 26
- 229920001477 hydrophilic polymer Polymers 0.000 claims description 20
- 125000003277 amino group Chemical group 0.000 claims description 18
- 229920000642 polymer Polymers 0.000 claims description 17
- 125000002843 carboxylic acid group Chemical group 0.000 claims description 14
- -1 poly(ethylene glycol) Polymers 0.000 claims description 14
- 229920001223 polyethylene glycol Polymers 0.000 claims description 14
- 125000003172 aldehyde group Chemical group 0.000 claims description 8
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 claims description 6
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 5
- ZNZYKNKBJPZETN-WELNAUFTSA-N Dialdehyde 11678 Chemical compound N1C2=CC=CC=C2C2=C1[C@H](C[C@H](/C(=C/O)C(=O)OC)[C@@H](C=C)C=O)NCC2 ZNZYKNKBJPZETN-WELNAUFTSA-N 0.000 claims description 4
- 125000003700 epoxy group Chemical group 0.000 claims description 4
- 239000000178 monomer Substances 0.000 claims description 4
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 3
- 229940015043 glyoxal Drugs 0.000 claims description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 3
- 229920002125 Sokalan® Polymers 0.000 claims description 2
- 229920002401 polyacrylamide Polymers 0.000 claims description 2
- 125000000524 functional group Chemical group 0.000 claims 4
- 229920002818 (Hydroxyethyl)methacrylate Polymers 0.000 claims 1
- 150000003839 salts Chemical class 0.000 abstract description 23
- 230000000712 assembly Effects 0.000 abstract description 3
- 238000000429 assembly Methods 0.000 abstract description 3
- AZKVWQKMDGGDSV-BCMRRPTOSA-N Genipin Chemical compound COC(=O)C1=CO[C@@H](O)[C@@H]2C(CO)=CC[C@H]12 AZKVWQKMDGGDSV-BCMRRPTOSA-N 0.000 description 12
- AZKVWQKMDGGDSV-UHFFFAOYSA-N genipin Natural products COC(=O)C1=COC(O)C2C(CO)=CCC12 AZKVWQKMDGGDSV-UHFFFAOYSA-N 0.000 description 12
- 239000007789 gas Substances 0.000 description 11
- 150000002118 epoxides Chemical class 0.000 description 10
- 208000032843 Hemorrhage Diseases 0.000 description 8
- 125000003396 thiol group Chemical group [H]S* 0.000 description 8
- 125000000129 anionic group Chemical group 0.000 description 7
- 150000003141 primary amines Chemical group 0.000 description 7
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 6
- 150000001718 carbodiimides Chemical class 0.000 description 6
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000012530 fluid Substances 0.000 description 6
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 5
- 239000004593 Epoxy Substances 0.000 description 5
- 238000003381 deacetylation reaction Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- 230000006196 deacetylation Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 210000001124 body fluid Anatomy 0.000 description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 description 3
- 230000021615 conjugation Effects 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- PMNLUUOXGOOLSP-UHFFFAOYSA-N 2-mercaptopropanoic acid Chemical compound CC(S)C(O)=O PMNLUUOXGOOLSP-UHFFFAOYSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 208000000624 Esophageal and Gastric Varices Diseases 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 2
- 238000006845 Michael addition reaction Methods 0.000 description 2
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 2
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 208000025865 Ulcer Diseases 0.000 description 2
- 206010052428 Wound Diseases 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000010839 body fluid Substances 0.000 description 2
- 230000036760 body temperature Effects 0.000 description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229940001468 citrate Drugs 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000004132 cross linking Methods 0.000 description 2
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 description 2
- 229910000071 diazene Inorganic materials 0.000 description 2
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229940049920 malate Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 229950006780 n-acetylglucosamine Drugs 0.000 description 2
- 229920005615 natural polymer Polymers 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229920000671 polyethylene glycol diacrylate Polymers 0.000 description 2
- 229920002338 polyhydroxyethylmethacrylate Polymers 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 229920001059 synthetic polymer Polymers 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 231100000397 ulcer Toxicity 0.000 description 2
- 238000011144 upstream manufacturing Methods 0.000 description 2
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- UWFRVQVNYNPBEF-UHFFFAOYSA-N 1-(2,4-dimethylphenyl)propan-1-one Chemical compound CCC(=O)C1=CC=C(C)C=C1C UWFRVQVNYNPBEF-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 239000004971 Cross linker Substances 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 206010051012 Gastric varices Diseases 0.000 description 1
- 208000012671 Gastrointestinal haemorrhages Diseases 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000003570 air Substances 0.000 description 1
- 238000010976 amide bond formation reaction Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-QZABAPFNSA-N beta-D-glucosamine Chemical compound N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-QZABAPFNSA-N 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000012650 click reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical class C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 208000030304 gastrointestinal bleeding Diseases 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 125000002791 glucosyl group Chemical class C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000002439 hemostatic effect Effects 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 150000001261 hydroxy acids Chemical class 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 210000001819 pancreatic juice Anatomy 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 229920000447 polyanionic polymer Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
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- 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
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
- A61L26/0023—Polysaccharides
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/722—Chitin, chitosan
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/16—Biologically active materials, e.g. therapeutic substances
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- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
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- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
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- A—HUMAN NECESSITIES
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2202/00—Special media to be introduced, removed or treated
- A61M2202/06—Solids
- A61M2202/064—Powder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2210/00—Anatomical parts of the body
- A61M2210/10—Trunk
- A61M2210/1042—Alimentary tract
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
- A61M25/01—Introducing, guiding, advancing, emplacing or holding catheters
- A61M25/09—Guide wires
Definitions
- Gastrointestinal bleeding affects millions of people annually. Certain cases of internal bleeding cannot be controlled effectively by current hemostatic technologies such as clips, cautery, or band ligation. Wounds, surgical sites, diseased tissue, ulcer beds and gastric varices, among others, are locations where conventional means of hemostasis ray to fail, leading to extended hospital stay or death.
- the present disclosure pertains to methods of treating or preventing bleeding at a tissue site comprising applying a chitosan powder composition to the tissue site, wherein the chitosan powder composition comprises a chitosan salt, a crosslinked chitosan, a derivatized chitosan, or a combination thereof.
- the tissue site may be a body lumen, for example a site in the gastrointestinal tract.
- the chitosan powder may be applied, for example, via a catheter or other suitable device.
- the powder r ay be fluidized in a gas (e.g., CO 2 , nitrogen, air, etc.) to form a fluidized powder and blown onto the tissue site.
- a gas e.g., CO 2 , nitrogen, air, etc.
- the fluidized powder may exit the catheter at a velocity ranging from 1.5 to 50 m/s, among other possible velocities.
- the present disclosure pertains to powder compositions for application to a tissue site, where the powder compositions comprise first particles comprising chitosan, a chitosan salt or a derivatized chitosan admixed with second particles that comprise a crosslinking agent that covalently or non-covalently interacts with the first particles upon exposure to moisture.
- the first particles may comprise a chitosan salt and the crosslinking agent may be a polyanionic crosslinking agent.
- the first particles may comprise chitosan or a chitosan salt and the crosslinking agent may be a covalent crosslinking agent.
- covalent crosslinking agents include, for instance, a multifunctional epoxy, a multifunctional aldehyde, multifunctional acrylate, genipin, or a derivatized polymer (e.g., an aldehyde derivatized polymer, an epoxy derivatized polymer, acrylate derivatized polymer or a genipin derivatized polymer), among other possibilities.
- the first particles may comprise a derivatized chitosan and the second particles may comprise a covalent crosslinking agent.
- the first particles may comprise thiol-modified chitosan and the second particles may comprise a molecule having a plurality of unsaturated groups.
- the present disclosure pertains to powder compositions for application to a tissue site that comprise derivatized chitosan.
- the derivatized chitosan reacts with cysteine groups in tissue upon exposure to moisture.
- the derivatized chitosan may be chitosan derivatized with a multifunctional aldehyde
- the derivatized chitosan may be chitosan derivatized with a multifunctional epoxide
- the derivatized chitosan may be chitosan derivatized with a multifunctional acrylate
- the derivatized chitosan may be chitosan derivatized with genipin.
- the derivatized chitosan may interact with thiol groups in tissue upon exposure to moisture.
- the derivatized chitosan may be chitosan derivatized with unsaturated groups or the derivatized chitosan may be derivatized with thiol groups, among other possibilities.
- the present disclosure pertains to powder compositions for application to a tissue site that comprise a chitosan salt.
- the chitosan salt ionically crosslinks with negative charged species in tissue or blood.
- the disclosure pertains to catheter assemblies, which are preloaded with a chitosan powder composition and which are configured to deliver the chitosan powder composition a tissue site.
- the present disclosure pertains to methods of treating a tissue site (e.g., a wound, a surgical site, a diseased tissue site, an ulcer bed, a gastric varix, etc.), in which a chitosan powder is applied to the tissue site.
- the chitosan powder may be applied, for example, to address existing bleeding or to prevent or minimize future bleeding that may occur.
- the tissue site is tissue that surrounds a body lumen, for example, a wall of the gastrointestinal tract.
- the chitosan powder may contain, for example, chitosan, a chitosan salt, crosslinked chitosan, derivatized chitosan, or natural or synthetic polymer blends containing the same.
- the chitosan powder may comprise, for example, a chitosan salt, a crosslinked chitosan a derivatized chitosan or a combination thereof.
- the chitosan powder may be applied to a tissue site via a catheter.
- catheter assemblies in which a powder may be fluidized in a gas (e.g., compressed air, nitrogen, carbon dioxide, etc.) to form fluidized powder, which is then blown onto the tissue site.
- a catheter assembly may be provided, which includes (a) a catheter having a lumen extending therethrough, a proximal end, and a distal end having an exit orifice, and (b) a reservoir containing a chitosan powder.
- the catheter assembly may be configured to deliver the chitosan powder from the reservoir, through the lumen, and out the exit orifice.
- the catheter assembly may include a pressurized reservoir that contains a pressurized gas for delivering the chitosan powder from the reservoir, through the lumen, and out the exit orifice.
- the pressurized reservoir may be positioned upstream of the reservoir and the pressurized gas passed through the chitosan powder, thereby fluidizing the chitosan powder in the gas for deliver); of through the lumen and out the exit orifice.
- the catheter is operated such that the fluidized powder exits the catheter at a velocity ranging from 15 m/s to 50 m/s.
- the chitosan powder may be applied through an endoscope.
- a system may be provided, which includes a catheter having a proximal end and a distal end that is partially loaded with chitosan powder (with a remaining volume being air).
- the catheter may also include a seal, such as a plug, cap, or other mechanism for retaining the chitosan powder on the proximal and distal ends of the catheter.
- the system may further be provided with a mechanism for breaking the proximal seal and for applying gas to the catheter at sufficient pressure to fluidize the powder in the catheter, eject the distal seal, and disperse the fluidized chitosan powder from the distal end of the catheter and onto the treatment site.
- chitosan powder When applied to a tissue site, chitosan powder in accordance with the present disclosure acts as a barrier to bleeding associated with the tissue site.
- the chitosan powder acts as a barrier by absorbing liquids, which, for example, may be bodily fluids such as blood or gastrointestinal fluids (e.g., pancreatic juices, biliary fluid, saliva, etc.) that are present at the tissue site, or may be fluid such as saline, phosphate buffered saline, or contrast fluid that is applied to the tissue site prior to, concurrently with, or subsequent to application of the chitosan powder.
- the chitosan powder may be used to achieve hemostasis at sites of active bleeding or can be used as a preventative over clipped areas, suture sites, or other having the potential for bleeding, among other uses.
- the present disclosure pertains to chitosan powders, that may be used to for hemostasis, among other possible uses.
- Chitosan powders for use in the present disclosure may be of any suitable particle size.
- the particle size may range, for example, from less than 1 ⁇ m to 1000 ⁇ m (e.g., ranging from 1 ⁇ m to 2.5 ⁇ m to 5 ⁇ m to 10 ⁇ m to 25 ⁇ m to 50 ⁇ m to 100 ⁇ m to 250 ⁇ m to 500 ⁇ m to 1000 ⁇ m), among other possibilities.
- a chitosan powder having particles sized between 50 ⁇ m and 425 ⁇ m performs well when dispensed through an 8 French catheter.
- chitosan powder may contain, for example, chitosan, a chitosan salt, derivatized chitosan, or crosslinked chitosan, and, optionally, a natural or synthetic polymer.
- Chitosan is a modified polysaccharide containing randomly distributed ⁇ -(1-4)-linked D-glucosamine and N-acetyl-D-glucosamine monomer units. Chitosan is produced commercially by the alkaline N-deacetylation of chitin, which is a cellulose-like polymer consisting primarily of unbranched chains of modified glucose, specifically N-acetyl-D-glucosamine.
- the degree of deacetylation in commercial chitosans typically ranges from 75 to 100% although essentially any degree of deacetylation is possible.
- Chitosan is positively charged in acidic to neutral solutions with a charge density that is dependent on the pH and the degree of deacetylation.
- the pka value of chitosan generally ranges from 6.1 to 7.0, depending on the degree of deacetylation.
- chitosan is generally soluble in aqueous acidic solutions (e.g., pH ⁇ 6.5 or less).
- chitosan salts include chitosan halides such as chitosan fluoride, chitosan chloride, chitosan bromide, chitosan iodide, chitosan phosphate, chitosan nitrate, chitosan sulfate, chitosan salts of organic mono-acids such as formate, acetate, propionate, butyrate, chitosan salts of organic diacids such as oxalate, malonate, succinate, maleate, or glutarate, or salts of hydro acids such as glycolate, lactate, tartrate, malate, citrate, or gluconate.
- chitosan halides such as chitosan fluoride, chitosan chloride, chitosan bromide, chitosan iodide, chitosan phosphate, chitosan nitrate, chitosan
- modified chitosans may be employed, which exhibit enhanced properties, including enhanced adhesion.
- a thiol-modified chitosan may be formed by reaction of chitosan with a molecule having one or more thiol groups and one or more additional groups (e.g., carboxylic acid groups, which may also be referred to herein as carboxyl groups) for bonding to the chitosan.
- carboxylic acid groups of thiolactic acid may be reacted with primary amine groups on the chitosan through suitable chemistry to form a covalent amide bond.
- carbodiimide conjugation works by activating carboxylic acid groups with a suitable carbodiimide, such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), dicyclohexylcarbodiimide (DCC), N,N′-diisopropylcarbodiimide (DIC), for direct conjugation to primary amines (e.g., primary amine groups on the chitosan) via amide bond formation.
- a suitable carbodiimide such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), dicyclohexylcarbodiimide (DCC), N,N′-diisopropylcarbodiimide (DIC), for direct conjugation to primary amines (e.g., primary amine groups on the chitosan) via amide bond formation.
- EDC 1-ethyl-3-(3-dimethyla
- carbonyldiimidazole can be used in non-aqueous conditions to activate carboxylic acids for direct conjugation to primary amines (e.g., primary amine groups on the chitosan) via amide bonds.
- primary amines e.g., primary amine groups on the chitosan
- thiols on the modified chitosan can provide enhanced attachment by interacting and forming covalent bonds with cysteine-rich tissue.
- modified chitosans include chitosan modified with groups that allow for covalent reaction with tissue, including groups that are reactive with amine groups found in tissue.
- a multifunctional (e.g., difunctional, trifunctional, etc.) reactive molecule such as a multifunctional aldehyde molecule can be reacted with amine groups on chitosan to form aldehyde-modified chitosan (chitosan having pendant aldehyde groups).
- a multifunctional (e.g., difunctional, trifunctional, etc.) reactive molecule such as a multifunctional epoxide molecule, can be reacted with amine groups on chitosan to form epoxy-modified chitosan chitosan having pendant epoxide groups).
- a multifunctional (e.g., difunctional, trifunctional, etc.) reactive molecule such as a multifunctional acrylate molecule or another molecule having one or more groups that react with chitosan and has at least one acrylate group such as PEG diacrylate
- a multifunctional reactive molecule such as a multifunctional acrylate molecule or another molecule having one or more groups that react with chitosan and has at least one acrylate group such as PEG diacrylate
- thiol groups on thiol modified chitosan via michael addition click reaction under body temperature in physiological pH conditions to form a chitosan-PEG crosslinked network (i.e., chitosan-PEG crosslinked gel having excess pendant thiol groups amendable to covalently linking to tissue).
- a multifunctional (e.g., difunctional, trifunctional, etc.) reactive molecule such as genipin
- genipin can be reacted with amine groups on chitosan to form genipin-modified chitosan (i.e., chitosan having pendant genipin groups).
- the multifunctional reactive molecule e.g., multifunctional aldehyde molecule, a multifunctional epoxide molecule, or genipin
- the multifunctional reactive molecule may be reacted with chitosan in relative amounts such that multifunctional reactive molecule is provided in a lx molar minimum relative to the number of moles of amine groups on the chitosan, such that all or essentially all of the amine groups are reacted and have pendant reactive groups.
- Example of multifunctional aldehydes include glutaraldehyde, glyoxal, and aldehyde terminated hydrophilic polymers.
- Example of multifunctional epoxides include 4-butanediol diglycidyl ether, ethylene glycol diglycidyl ether, and epoxide terminated hydrophilic polymers.
- Hydrophilic polymers which may be provided with aldehyde or epoxide termination include poly(ethylene glycol) (PEG), also referred to as poly(ethylene oxide) (PEO), polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), polyacrylamide, poly(acrylic acid), and poly(hydroxyethyl methacrylate) (PHEMA).
- Suitable hydrophilic polymers may range, for example, from 2 to 250 monomers in length, among other possibilities.
- a modified chitosan may be formed by reacting a reactive synthetic molecule such as PEG diepoxide or a PEG dialdehyde with chitosan in relative amounts such that the reactive molecule is provided in a 1 ⁇ molar minimum relative to the number of moles of amine groups on the chitosan, such that all or essentially all of the amine groups of the chitosan are reacted and have pendant epoxide-terminated PEG groups or aldehyde-terminated PEG groups.
- a reactive synthetic molecule such as PEG diepoxide or a PEG dialdehyde
- the chitosan may be directly oxidized, thereby forming aldehyde groups on the chitosan.
- a chitosan powder may be employed in which chitosan, chitosan salt, modified chitosan, or a combination thereof, is non-covalently crosslinked or covalently crosslinked, either before application to a tissue site, or at the time of application to a tissue site.
- an ionic crosslinker such as a multifunctional anionic molecule having two or more anionic groups (e.g., carboxylic acid groups, or sulfonate groups) may be provided in order to ionically crosslink the chitosan via positively charged amine groups located on the chitosan.
- multifunctional anionic molecules include organic diacids such as oxalate, malonate, succinate, maleate, or glutarate, or salts of hydroxyacids such as tartrate, malate, or citrate.
- multifunctional anionic molecules also include polyanionic polymers.
- the multifunctional anionic molecule is combined and ionically crosslinked with the chitosan prior to applying to tissue, grinding the crosslinked product into a powder if desired or necessary.
- the multifunctional anionic molecule is ionically crosslinked on the tissue surface.
- a multifunctional anionic molecule e.g., citric acid, among others
- chitosan in powder form and the mixture applied to tissue.
- a moisture rich environment e.g., provided by body fluid and/or a separately applied fluid
- liquid will be absorbed and the powder constituents will dissolve and crosslink, creating a firmer more cohesive gel with less particulate over the application site.
- chitosan or modified chitosan may be covalently crosslinked prior to administration, and subsequently applied to tissue.
- chitosan or modified chitosan may be reacted with a multifunctional molecule having two or more groups (e.g., carboxylic acid groups, amine groups, epoxy groups, or aldehyde groups) that are reactive with the chitosan (e.g., reactive with the amine groups on the chitosan or carboxymethyl groups on the modified chitosan).
- groups e.g., carboxylic acid groups, amine groups, epoxy groups, or aldehyde groups
- a biocompatible hydrophilic polymer (e.g., one the hydrophilic polymers listed above, among others) having terminal carboxylic acid groups may be reacted with primary amine groups on the chitosan through any suitable chemistry (e.g., using carbodiimide or carbonyldiimidazole chemistry) in order to covalently crosslink the chitosan.
- carboxylic acid groups of a PEG dicarboxylate may be reacted with amine groups of chitosan using carbodiimide or carbonyldiimidazole chemistry, thereby covalently crosslinking the chitosan.
- a derivatized chitosan (e.g., a chitosan derivatized with carboxylic acid groups) is crosslinked with a biocompatible hydrophilic polymer (e.g., one the hydrophilic polymers listed above, among others) having terminal amine groups through any suitable chemistry (e.g., using carbodiimide or carbonyldiimidazole chemistry) in order to covalently crosslink the chitosan.
- amine groups of a PEG diamine may be reacted with carboxylic acid groups of carboxymethyl chitosan using carbodiimide or carbonyldiimidazole chemistry, thereby covalently crosslinking the chitosan.
- the resulting product is subsequently applied to tissue, after grinding the product into a powder, if desired or necessary. This should generally improve the overall structural integrity of the powder.
- a chitosan powder is provided, which become covalently crosslinked upon administration to tissue.
- a first powder comprising a multifunctional (e.g., difunctional, trifunctional, etc.) reactive molecule that reacts with amines, for example, genipin, a multifunctional aldehyde molecule, or a multifunctional epoxide molecule, such as those described above (e.g., PEG diepoxide, PEG dialdehyde or any small molecule dialdehyde or small molecule diepoxide that is a solid), may be admixed with chitosan or a chitosan salt powder and applied to tissue in dry form.
- a multifunctional reactive molecule that reacts with amines
- amines for example, genipin, a multifunctional aldehyde molecule, or a multifunctional epoxide molecule, such as those described above (e.g., PEG diepoxide, PEG dialdehyde or any small molecule dialdehyde or small molecule diepoxide that is a solid)
- the multifunctional reactive molecule is a modified chitosan such as those described above, which may be selected, for example, from the aldehyde-modified chitosan (chitosan having pendant aldehyde groups), epoxy-modified chitosan (i.e., chitosan having pendant epoxide groups) and genipin-modified chitosan (i.e., chitosan having pendant genipin groups) described above.
- aldehyde-modified chitosan chitosan having pendant aldehyde groups
- epoxy-modified chitosan i.e., chitosan having pendant epoxide groups
- genipin-modified chitosan i.e., chitosan having pendant genipin groups
- the powder constituents dissolve, allowing the multifunctional reactive molecule to crosslink with amines found on the chitosan or the chitosan salt, and to also react with amines found in tissue.
- a first powder comprising a thiol-modified chitosan such as that described above may be admixed a second powder that comprises a molecule that comprises two or more unsaturated groups and applied to tissue in dry form.
- molecules that comprises two or more unsaturated groups include acrylate-terminated hydrophilic polymers.
- Hydrophilic polymers which may be provided with unsaturated termination include those hydrophilic polymers described above.
- a particular example of a molecule that comprises two or more unsaturated groups is PEG diacrylate. Applying such a powder to tissue and subsequently mixing with saline in situ will follow a Michael addition reaction scheme. At body temperature and the pH of saline (7,4) the two powders crosslink to form a cohesive patch.
- the first powder or the second powder may include a catalyst, such as a base or a nucleophile).
- a method of treating or preventing bleeding at a tissue site comprising: applying chitosan powder to the tissue site, wherein the chitosan powder comprises a chitosan salt, a crosslinked chitosan, a derivatized chitosan, or a combination thereof.
- Aspect A2 The method of aspect A1, wherein the tissue site is in a body lumen.
- Aspect A3 The method of aspect A2, wherein the body lumen is the gastrointestinal tract.
- Aspect A4 The method of any of aspects A1-A3, wherein the chitosan powder is applied via a catheter.
- Aspect A5 The method of any of aspects A1-A4, wherein the powder is fluidized in a gas to form a fluidized powder and blown onto the tissue site.
- Aspect A6 The method of aspect A6, wherein the fluidized gas is CO 2 .
- Aspect A7 The method of any aspects A6-A7, wherein the fluidized powder exits the catheter at a velocity ranging from 15 to 50 m/s.
- a preloaded catheter assembly comprising: a catheter having a lumen extending therethrough, a proximal end, and a distal end having an exit orifice, a reservoir comprising a chitosan powder, wherein the catheter assembly is configured to deliver the chitosan powder from the reservoir, through the lumen, and out the exit orifice.
- Aspect B2 The preloaded catheter of aspect B1, wherein the catheter assembly further comprises a pressurized reservoir comprising a pressurized gas for delivering the chitosan powder from the reservoir, through the lumen, and out the exit orifice.
- Aspect B3 The preloaded catheter of aspect B2, wherein the pressurized reservoir is positioned upstream of the reservoir and the pressurized gas passes through the chitosan powder, thereby fluidizing the chitosan powder in gas for delivery of through the lumen and out the exit orifice.
- the chitosan powder comprises chitosan, a chitosan salt, crosslinked chitosan, derivatized chitosan, or a combination thereof.
- a powder composition for application to a tissue site comprising first particles comprising chitosan, a chitosan salt or a derivatized chitosan admixed with second particles that comprise a crosslinking agent that covalently or non-covalently interacts with the first particles upon exposure to moisture.
- Aspect C2 The composition of aspect C1, wherein the first particles comprise a chitosan salt.
- Aspect C3 The composition of aspect C2, wherein the crosslinking agent is a polyanionic crosslinking agent.
- Aspect C4 The composition of aspect C1, wherein the first particles comprise chitosan or a chitosan salt and the crosslinking agent is a covalent crosslinking agent.
- Aspect C5. The composition of aspect C4, wherein the covalent crosslinking agent is selected from a multifunctional epoxy, a multifunctional aldehyde, and genipin.
- composition of aspect C4, wherein the covalent crosslinking agent is a derivatized polymer.
- composition of aspect C6, wherein the derivatized polymer is selected from an aldehyde derivatized polymer, epoxy derivatized polymer, and a genipin derivatized polymer.
- Aspect C8 The composition of aspect C6, wherein the derivatized polymer is derivatized chitosan.
- Aspect C9 The composition of aspect C8, wherein the derivatized chitosan selected from aldehyde derivatized chitosan, epoxy derivatized chitosan, and genipin derivatized chitosan.
- Aspect C10 The composition of aspect C1, wherein the first particles comprise a derivatized chitosan.
- Aspect C11 The composition of aspect C10, wherein the second particles comprise a covalent crosslinking agent.
- Aspect C12 The composition of aspect C11, wherein the covalent crosslinking agent is a polymeric crosslinking agent.
- composition of aspect C10 wherein the first particles comprise thiol-modified chitosan and the second particles comprise a molecule having a plurality of unsaturated groups.
- Aspect C14 The composition of aspect C13, wherein the molecule having a plurality of unsaturated groups is a hydrophilic polymer having unsaturated end groups.
- a powder composition for application to a tissue site comprising chitosan crosslinked with a multifunctional carboxylated polymer.
- Aspect D2 The composition of aspect D1, wherein the carboxylated polymer is a hydrophilic polymer having carboxylic acid end groups.
- Aspect D3 The composition of aspect D1 or D2, chitosan is crosslinked with the multifunctional carboxylated polymer using a diimide coupling.
- a powder composition for application to a tissue site comprising derivatized chitosan.
- Aspect E3 The powder of aspect E1, wherein the derivatized chitosan reacts with primary amine groups in tissue upon exposure to moisture.
- Aspect E4 The powder of aspect E2, wherein the derivatized chitosan is chitosan derivatized with a multifuctional aldehyde.
- Aspect E5 The powder of aspect E2, wherein the derivatized chitosan is chitosan derivatized with a multifunctional epoxide.
- Aspect E6 The powder of aspect E2, wherein the derivatized chitosan is chitosan derivatized with genipin.
- Aspect E7 The powder of aspect E1, wherein the derivatized chitosan interacts with thiol groups in tissue upon exposure to moisture.
- Aspect E8 The powder of aspect E7, wherein the derivatized chitosan is chitosan derivatized with unsaturated groups.
- Aspect E9 The powder of aspect E7, wherein the derivatized chitosan is derivatized with thiol groups.
- Aspect E11 The powder of aspect E10, wherein the chitosan is derivatized using diimide (e.g., EDC or DCC) coupling.
- diimide e.g., EDC or DCC
- Chitosan obtained from Sigma Aldrich is suspended in water at a concentration of 2 wt % Chitosan and 98 wt % water. The mixture is stirred using a mechanical mixer at room temperature. Acetic acid is then added during the stirring such that the pH levels out near 5.0 after 5 hours of stirring. 2 wt % citric acid (relative to the weight of chitosan initially used) is added to the container and mixed for an additional 5 hours. This process forms a gel which is subsequently dried. The dried gel is then ground into a fine powder for use.
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Abstract
In various aspects, the present disclosure pertains to methods of treating or preventing bleeding at a tissue site comprising applying a chitosan powder composition to the tissue site, In various aspects, the present disclosure pertains to chitosan powder compositions for application to a tissue site, where the powder compositions comprise a chitosan salt, a crosslinked chitosan, a derivatized chitosan, or a combination thereof. In various aspects, the disclosure pertains to catheter assemblies, which are preloaded with a chitosan powder composition and which are configured to deliver the chitosan powder composition a tissue site.
Description
- This application claims the benefit of U.S. Provisional Application No. 62/616,751, filed Jan. 12, 2018, entitled “Powder for Achieving Hemostasis,” the disclosure of which is hereby corporate by reference in its entirety.
- Gastrointestinal bleeding affects millions of people annually. Certain cases of internal bleeding cannot be controlled effectively by current hemostatic technologies such as clips, cautery, or band ligation. Wounds, surgical sites, diseased tissue, ulcer beds and gastric varices, among others, are locations where conventional means of hemostasis ray to fail, leading to extended hospital stay or death.
- In various aspects, the present disclosure pertains to methods of treating or preventing bleeding at a tissue site comprising applying a chitosan powder composition to the tissue site, wherein the chitosan powder composition comprises a chitosan salt, a crosslinked chitosan, a derivatized chitosan, or a combination thereof.
- In various embodiments, the tissue site may be a body lumen, for example a site in the gastrointestinal tract. When the tissue site is a body lumen, the chitosan powder may be applied, for example, via a catheter or other suitable device.
- In various embodiments, which may be used in conjunction with the above aspects and embodiments, the powder r ay be fluidized in a gas (e.g., CO2, nitrogen, air, etc.) to form a fluidized powder and blown onto the tissue site. In such embodiments, the fluidized powder may exit the catheter at a velocity ranging from 1.5 to 50 m/s, among other possible velocities.
- In various aspects, the present disclosure pertains to powder compositions for application to a tissue site, where the powder compositions comprise first particles comprising chitosan, a chitosan salt or a derivatized chitosan admixed with second particles that comprise a crosslinking agent that covalently or non-covalently interacts with the first particles upon exposure to moisture.
- In some embodiments, the first particles may comprise a chitosan salt and the crosslinking agent may be a polyanionic crosslinking agent. For example, the first particles may comprise chitosan or a chitosan salt and the crosslinking agent may be a covalent crosslinking agent. Examples of covalent crosslinking agents include, for instance, a multifunctional epoxy, a multifunctional aldehyde, multifunctional acrylate, genipin, or a derivatized polymer (e.g., an aldehyde derivatized polymer, an epoxy derivatized polymer, acrylate derivatized polymer or a genipin derivatized polymer), among other possibilities.
- In some embodiments, which may be used in conjunction with the above aspects and embodiments, the first particles may comprise a derivatized chitosan and the second particles may comprise a covalent crosslinking agent. In one particular example, the first particles may comprise thiol-modified chitosan and the second particles may comprise a molecule having a plurality of unsaturated groups.
- In various aspects, the present disclosure pertains to powder compositions for application to a tissue site that comprise derivatized chitosan.
- In some embodiments, the derivatized chitosan reacts with cysteine groups in tissue upon exposure to moisture. For example, the derivatized chitosan may be chitosan derivatized with a multifunctional aldehyde, the derivatized chitosan may be chitosan derivatized with a multifunctional epoxide, the derivatized chitosan may be chitosan derivatized with a multifunctional acrylate, or the derivatized chitosan may be chitosan derivatized with genipin.
- In some embodiments, which may be used in conjunction with the above aspects and embodiments, the derivatized chitosan may interact with thiol groups in tissue upon exposure to moisture.
- In some embodiments, which may be used in conjunction with the above aspects and embodiments, the derivatized chitosan may be chitosan derivatized with unsaturated groups or the derivatized chitosan may be derivatized with thiol groups, among other possibilities.
- In various aspects, the present disclosure pertains to powder compositions for application to a tissue site that comprise a chitosan salt.
- In some embodiments, the chitosan salt ionically crosslinks with negative charged species in tissue or blood.
- In various aspects, which may be used in conjunction with the above aspects and embodiments, the disclosure pertains to catheter assemblies, which are preloaded with a chitosan powder composition and which are configured to deliver the chitosan powder composition a tissue site.
- These and other aspects and embodiments are further described in the detailed description to follow.
- In various aspects, the present disclosure pertains to methods of treating a tissue site (e.g., a wound, a surgical site, a diseased tissue site, an ulcer bed, a gastric varix, etc.), in which a chitosan powder is applied to the tissue site. The chitosan powder may be applied, for example, to address existing bleeding or to prevent or minimize future bleeding that may occur. In various embodiments, the tissue site is tissue that surrounds a body lumen, for example, a wall of the gastrointestinal tract. The chitosan powder may contain, for example, chitosan, a chitosan salt, crosslinked chitosan, derivatized chitosan, or natural or synthetic polymer blends containing the same. As discussed in more detail below, in particular embodiments, the chitosan powder may comprise, for example, a chitosan salt, a crosslinked chitosan a derivatized chitosan or a combination thereof.
- In various embodiments, the chitosan powder may be applied to a tissue site via a catheter. Examples include catheter assemblies in which a powder may be fluidized in a gas (e.g., compressed air, nitrogen, carbon dioxide, etc.) to form fluidized powder, which is then blown onto the tissue site. For example, a catheter assembly may be provided, which includes (a) a catheter having a lumen extending therethrough, a proximal end, and a distal end having an exit orifice, and (b) a reservoir containing a chitosan powder. The catheter assembly may be configured to deliver the chitosan powder from the reservoir, through the lumen, and out the exit orifice. In certain embodiments, the catheter assembly may include a pressurized reservoir that contains a pressurized gas for delivering the chitosan powder from the reservoir, through the lumen, and out the exit orifice. For example, the pressurized reservoir may be positioned upstream of the reservoir and the pressurized gas passed through the chitosan powder, thereby fluidizing the chitosan powder in the gas for deliver); of through the lumen and out the exit orifice. In certain embodiments, the catheter is operated such that the fluidized powder exits the catheter at a velocity ranging from 15 m/s to 50 m/s. Where applied to the gastrointestinal tract, the chitosan powder may be applied through an endoscope.
- In various aspects, the present disclosure pertains to catheters that are preloaded with a chitosan powder. For example, a system may be provided, which includes a catheter having a proximal end and a distal end that is partially loaded with chitosan powder (with a remaining volume being air). The catheter may also include a seal, such as a plug, cap, or other mechanism for retaining the chitosan powder on the proximal and distal ends of the catheter. The system may further be provided with a mechanism for breaking the proximal seal and for applying gas to the catheter at sufficient pressure to fluidize the powder in the catheter, eject the distal seal, and disperse the fluidized chitosan powder from the distal end of the catheter and onto the treatment site.
- When applied to a tissue site, chitosan powder in accordance with the present disclosure acts as a barrier to bleeding associated with the tissue site. The chitosan powder acts as a barrier by absorbing liquids, which, for example, may be bodily fluids such as blood or gastrointestinal fluids (e.g., pancreatic juices, biliary fluid, saliva, etc.) that are present at the tissue site, or may be fluid such as saline, phosphate buffered saline, or contrast fluid that is applied to the tissue site prior to, concurrently with, or subsequent to application of the chitosan powder. The chitosan powder may be used to achieve hemostasis at sites of active bleeding or can be used as a preventative over clipped areas, suture sites, or other having the potential for bleeding, among other uses.
- In various aspects, the present disclosure pertains to chitosan powders, that may be used to for hemostasis, among other possible uses.
- Chitosan powders for use in the present disclosure may be of any suitable particle size. In various embodiments, the particle size may range, for example, from less than 1 μm to 1000 μm (e.g., ranging from 1 μm to 2.5 μm to 5 μm to 10 μm to 25 μm to 50 μm to 100 μm to 250 μm to 500 μm to 1000 μm), among other possibilities. In this regard, a chitosan powder having particles sized between 50 μm and 425 μm performs well when dispensed through an 8 French catheter.
- As noted above, chitosan powder may contain, for example, chitosan, a chitosan salt, derivatized chitosan, or crosslinked chitosan, and, optionally, a natural or synthetic polymer.
- Chitosan is a modified polysaccharide containing randomly distributed β-(1-4)-linked D-glucosamine and N-acetyl-D-glucosamine monomer units. Chitosan is produced commercially by the alkaline N-deacetylation of chitin, which is a cellulose-like polymer consisting primarily of unbranched chains of modified glucose, specifically N-acetyl-D-glucosamine.
- The degree of deacetylation in commercial chitosans typically ranges from 75 to 100% although essentially any degree of deacetylation is possible. Chitosan is positively charged in acidic to neutral solutions with a charge density that is dependent on the pH and the degree of deacetylation. The pka value of chitosan generally ranges from 6.1 to 7.0, depending on the degree of deacetylation. Thus, while typically substantially insoluble in distilled water, chitosan is generally soluble in aqueous acidic solutions (e.g., pH ˜6.5 or less).
- Examples of chitosan salts include chitosan halides such as chitosan fluoride, chitosan chloride, chitosan bromide, chitosan iodide, chitosan phosphate, chitosan nitrate, chitosan sulfate, chitosan salts of organic mono-acids such as formate, acetate, propionate, butyrate, chitosan salts of organic diacids such as oxalate, malonate, succinate, maleate, or glutarate, or salts of hydro acids such as glycolate, lactate, tartrate, malate, citrate, or gluconate.
- In various embodiments, modified chitosans may be employed, which exhibit enhanced properties, including enhanced adhesion. For instance, a thiol-modified chitosan may be formed by reaction of chitosan with a molecule having one or more thiol groups and one or more additional groups (e.g., carboxylic acid groups, which may also be referred to herein as carboxyl groups) for bonding to the chitosan. In a specific example, carboxylic acid groups of thiolactic acid may be reacted with primary amine groups on the chitosan through suitable chemistry to form a covalent amide bond. For example, carbodiimide conjugation works by activating carboxylic acid groups with a suitable carbodiimide, such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), dicyclohexylcarbodiimide (DCC), N,N′-diisopropylcarbodiimide (DIC), for direct conjugation to primary amines (e.g., primary amine groups on the chitosan) via amide bond formation. Similarly, carbonyldiimidazole (CDI) can be used in non-aqueous conditions to activate carboxylic acids for direct conjugation to primary amines (e.g., primary amine groups on the chitosan) via amide bonds. The thiols on the modified chitosan can provide enhanced attachment by interacting and forming covalent bonds with cysteine-rich tissue.
- Other examples of modified chitosans include chitosan modified with groups that allow for covalent reaction with tissue, including groups that are reactive with amine groups found in tissue. For example, a multifunctional (e.g., difunctional, trifunctional, etc.) reactive molecule such as a multifunctional aldehyde molecule can be reacted with amine groups on chitosan to form aldehyde-modified chitosan (chitosan having pendant aldehyde groups). As another example, a multifunctional (e.g., difunctional, trifunctional, etc.) reactive molecule, such as a multifunctional epoxide molecule, can be reacted with amine groups on chitosan to form epoxy-modified chitosan chitosan having pendant epoxide groups). As another example, a multifunctional (e.g., difunctional, trifunctional, etc.) reactive molecule, such as a multifunctional acrylate molecule or another molecule having one or more groups that react with chitosan and has at least one acrylate group such as PEG diacrylate, can be reacted with thiol groups on thiol modified chitosan via michael addition click reaction under body temperature in physiological pH conditions to form a chitosan-PEG crosslinked network (i.e., chitosan-PEG crosslinked gel having excess pendant thiol groups amendable to covalently linking to tissue). As another example, a multifunctional (e.g., difunctional, trifunctional, etc.) reactive molecule, such as genipin, can be reacted with amine groups on chitosan to form genipin-modified chitosan (i.e., chitosan having pendant genipin groups). In certain specific embodiments, the multifunctional reactive molecule (e.g., multifunctional aldehyde molecule, a multifunctional epoxide molecule, or genipin) may be reacted with chitosan in relative amounts such that multifunctional reactive molecule is provided in a lx molar minimum relative to the number of moles of amine groups on the chitosan, such that all or essentially all of the amine groups are reacted and have pendant reactive groups.
- Example of multifunctional aldehydes include glutaraldehyde, glyoxal, and aldehyde terminated hydrophilic polymers. Example of multifunctional epoxides include 4-butanediol diglycidyl ether, ethylene glycol diglycidyl ether, and epoxide terminated hydrophilic polymers. Hydrophilic polymers which may be provided with aldehyde or epoxide termination include poly(ethylene glycol) (PEG), also referred to as poly(ethylene oxide) (PEO), polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), polyacrylamide, poly(acrylic acid), and poly(hydroxyethyl methacrylate) (PHEMA). Suitable hydrophilic polymers may range, for example, from 2 to 250 monomers in length, among other possibilities.
- In certain specific embodiments, a modified chitosan may be formed by reacting a reactive synthetic molecule such as PEG diepoxide or a PEG dialdehyde with chitosan in relative amounts such that the reactive molecule is provided in a 1× molar minimum relative to the number of moles of amine groups on the chitosan, such that all or essentially all of the amine groups of the chitosan are reacted and have pendant epoxide-terminated PEG groups or aldehyde-terminated PEG groups.
- In some embodiments, the chitosan may be directly oxidized, thereby forming aldehyde groups on the chitosan.
- In some embodiments, a chitosan powder may be employed in which chitosan, chitosan salt, modified chitosan, or a combination thereof, is non-covalently crosslinked or covalently crosslinked, either before application to a tissue site, or at the time of application to a tissue site.
- For instance, in some embodiments, an ionic crosslinker such as a multifunctional anionic molecule having two or more anionic groups (e.g., carboxylic acid groups, or sulfonate groups) may be provided in order to ionically crosslink the chitosan via positively charged amine groups located on the chitosan. Examples of multifunctional anionic molecules include organic diacids such as oxalate, malonate, succinate, maleate, or glutarate, or salts of hydroxyacids such as tartrate, malate, or citrate. Examples of multifunctional anionic molecules also include polyanionic polymers.
- In some embodiments, the multifunctional anionic molecule is combined and ionically crosslinked with the chitosan prior to applying to tissue, grinding the crosslinked product into a powder if desired or necessary. In some embodiments, the multifunctional anionic molecule is ionically crosslinked on the tissue surface. For example, a multifunctional anionic molecule (e.g., citric acid, among others) may be combined with chitosan in powder form and the mixture applied to tissue. When this mixture contacts a moisture rich environment (e.g., provided by body fluid and/or a separately applied fluid), liquid will be absorbed and the powder constituents will dissolve and crosslink, creating a firmer more cohesive gel with less particulate over the application site.
- In some embodiments, chitosan or modified chitosan may be covalently crosslinked prior to administration, and subsequently applied to tissue. For instance, chitosan or modified chitosan may be reacted with a multifunctional molecule having two or more groups (e.g., carboxylic acid groups, amine groups, epoxy groups, or aldehyde groups) that are reactive with the chitosan (e.g., reactive with the amine groups on the chitosan or carboxymethyl groups on the modified chitosan). For example, a biocompatible hydrophilic polymer (e.g., one the hydrophilic polymers listed above, among others) having terminal carboxylic acid groups may be reacted with primary amine groups on the chitosan through any suitable chemistry (e.g., using carbodiimide or carbonyldiimidazole chemistry) in order to covalently crosslink the chitosan. In one specific embodiment, carboxylic acid groups of a PEG dicarboxylate may be reacted with amine groups of chitosan using carbodiimide or carbonyldiimidazole chemistry, thereby covalently crosslinking the chitosan. As another example, a derivatized chitosan (e.g., a chitosan derivatized with carboxylic acid groups) is crosslinked with a biocompatible hydrophilic polymer (e.g., one the hydrophilic polymers listed above, among others) having terminal amine groups through any suitable chemistry (e.g., using carbodiimide or carbonyldiimidazole chemistry) in order to covalently crosslink the chitosan. In one specific embodiment, amine groups of a PEG diamine may be reacted with carboxylic acid groups of carboxymethyl chitosan using carbodiimide or carbonyldiimidazole chemistry, thereby covalently crosslinking the chitosan. The resulting product is subsequently applied to tissue, after grinding the product into a powder, if desired or necessary. This should generally improve the overall structural integrity of the powder.
- In some embodiments, a chitosan powder is provided, which become covalently crosslinked upon administration to tissue.
- For example, a first powder comprising a multifunctional (e.g., difunctional, trifunctional, etc.) reactive molecule that reacts with amines, for example, genipin, a multifunctional aldehyde molecule, or a multifunctional epoxide molecule, such as those described above (e.g., PEG diepoxide, PEG dialdehyde or any small molecule dialdehyde or small molecule diepoxide that is a solid), may be admixed with chitosan or a chitosan salt powder and applied to tissue in dry form. In certain embodiments, the multifunctional reactive molecule is a modified chitosan such as those described above, which may be selected, for example, from the aldehyde-modified chitosan (chitosan having pendant aldehyde groups), epoxy-modified chitosan (i.e., chitosan having pendant epoxide groups) and genipin-modified chitosan (i.e., chitosan having pendant genipin groups) described above. Once the admixed powder becomes wet (e.g., due to body fluid and/or application of a fluid), the powder constituents dissolve, allowing the multifunctional reactive molecule to crosslink with amines found on the chitosan or the chitosan salt, and to also react with amines found in tissue.
- As another example, a first powder comprising a thiol-modified chitosan such as that described above may be admixed a second powder that comprises a molecule that comprises two or more unsaturated groups and applied to tissue in dry form. Examples of molecules that comprises two or more unsaturated groups include acrylate-terminated hydrophilic polymers. Hydrophilic polymers which may be provided with unsaturated termination include those hydrophilic polymers described above. A particular example of a molecule that comprises two or more unsaturated groups is PEG diacrylate. Applying such a powder to tissue and subsequently mixing with saline in situ will follow a Michael addition reaction scheme. At body temperature and the pH of saline (7,4) the two powders crosslink to form a cohesive patch. In certain embodiments, the first powder or the second powder may include a catalyst, such as a base or a nucleophile).
- Various further aspects of the present disclosure are provided in the following enumerated paragraphs:
- Aspect A1. A method of treating or preventing bleeding at a tissue site comprising: applying chitosan powder to the tissue site, wherein the chitosan powder comprises a chitosan salt, a crosslinked chitosan, a derivatized chitosan, or a combination thereof.
- Aspect A2. The method of aspect A1, wherein the tissue site is in a body lumen.
- Aspect A3. The method of aspect A2, wherein the body lumen is the gastrointestinal tract.
- Aspect A4. The method of any of aspects A1-A3, wherein the chitosan powder is applied via a catheter.
- Aspect A5. The method of any of aspects A1-A4, wherein the powder is fluidized in a gas to form a fluidized powder and blown onto the tissue site.
- Aspect A6. The method of aspect A6, wherein the fluidized gas is CO2.
- Aspect A7. The method of any aspects A6-A7, wherein the fluidized powder exits the catheter at a velocity ranging from 15 to 50 m/s.
- Aspect B1. A preloaded catheter assembly comprising: a catheter having a lumen extending therethrough, a proximal end, and a distal end having an exit orifice, a reservoir comprising a chitosan powder, wherein the catheter assembly is configured to deliver the chitosan powder from the reservoir, through the lumen, and out the exit orifice.
- Aspect B2. The preloaded catheter of aspect B1, wherein the catheter assembly further comprises a pressurized reservoir comprising a pressurized gas for delivering the chitosan powder from the reservoir, through the lumen, and out the exit orifice.
- Aspect B3. The preloaded catheter of aspect B2, wherein the pressurized reservoir is positioned upstream of the reservoir and the pressurized gas passes through the chitosan powder, thereby fluidizing the chitosan powder in gas for delivery of through the lumen and out the exit orifice.
- Aspect B4. The preloaded catheter of aspect B1, the chitosan powder comprises chitosan, a chitosan salt, crosslinked chitosan, derivatized chitosan, or a combination thereof.
- Aspect C1. A powder composition for application to a tissue site, the powder composition comprising first particles comprising chitosan, a chitosan salt or a derivatized chitosan admixed with second particles that comprise a crosslinking agent that covalently or non-covalently interacts with the first particles upon exposure to moisture.
- Aspect C2. The composition of aspect C1, wherein the first particles comprise a chitosan salt.
- Aspect C3. The composition of aspect C2, wherein the crosslinking agent is a polyanionic crosslinking agent.
- Aspect C4. The composition of aspect C1, wherein the first particles comprise chitosan or a chitosan salt and the crosslinking agent is a covalent crosslinking agent.
- Aspect C5. The composition of aspect C4, wherein the covalent crosslinking agent is selected from a multifunctional epoxy, a multifunctional aldehyde, and genipin.
- Aspect C6. The composition of aspect C4, wherein the covalent crosslinking agent is a derivatized polymer.
- Aspect C7. The composition of aspect C6, wherein the derivatized polymer is selected from an aldehyde derivatized polymer, epoxy derivatized polymer, and a genipin derivatized polymer.
- Aspect C8. The composition of aspect C6, wherein the derivatized polymer is derivatized chitosan.
- Aspect C9. The composition of aspect C8, wherein the derivatized chitosan selected from aldehyde derivatized chitosan, epoxy derivatized chitosan, and genipin derivatized chitosan.
- Aspect C10. The composition of aspect C1, wherein the first particles comprise a derivatized chitosan.
- Aspect C11. The composition of aspect C10, wherein the second particles comprise a covalent crosslinking agent.
- Aspect C12. The composition of aspect C11, wherein the covalent crosslinking agent is a polymeric crosslinking agent.
- Aspect C13. The composition of aspect C10, wherein the first particles comprise thiol-modified chitosan and the second particles comprise a molecule having a plurality of unsaturated groups.
- Aspect C14. The composition of aspect C13, wherein the molecule having a plurality of unsaturated groups is a hydrophilic polymer having unsaturated end groups.
- Aspect D1. A powder composition for application to a tissue site, the powder composition comprising chitosan crosslinked with a multifunctional carboxylated polymer.
- Aspect D2. The composition of aspect D1, wherein the carboxylated polymer is a hydrophilic polymer having carboxylic acid end groups.
- Aspect D3. The composition of aspect D1 or D2, chitosan is crosslinked with the multifunctional carboxylated polymer using a diimide coupling.
- Aspect E1. A powder composition for application to a tissue site, the powder composition comprising derivatized chitosan.
- Aspect E2. The powder of aspect E1, wherein the derivatized chitosan reacts with tissue upon exposure to moisture.
- Aspect E3. The powder of aspect E1, wherein the derivatized chitosan reacts with primary amine groups in tissue upon exposure to moisture.
- Aspect E4. The powder of aspect E2, wherein the derivatized chitosan is chitosan derivatized with a multifuctional aldehyde.
- Aspect E5. The powder of aspect E2, wherein the derivatized chitosan is chitosan derivatized with a multifunctional epoxide.
- Aspect E6. The powder of aspect E2, wherein the derivatized chitosan is chitosan derivatized with genipin.
- Aspect E7. The powder of aspect E1, wherein the derivatized chitosan interacts with thiol groups in tissue upon exposure to moisture.
- Aspect E8. The powder of aspect E7, wherein the derivatized chitosan is chitosan derivatized with unsaturated groups.
- Aspect E9. The powder of aspect E7, wherein the derivatized chitosan is derivatized with thiol groups.
- Aspect E10. The powder of aspect E9, wherein the chitosan is derivatized with a compound comprising a carboxylic acid group and a thiol group.
- Aspect E11. The powder of aspect E10, wherein the chitosan is derivatized using diimide (e.g., EDC or DCC) coupling.
- Chitosan obtained from Sigma Aldrich is suspended in water at a concentration of 2 wt % Chitosan and 98 wt % water. The mixture is stirred using a mechanical mixer at room temperature. Acetic acid is then added during the stirring such that the pH levels out near 5.0 after 5 hours of stirring. 2 wt % citric acid (relative to the weight of chitosan initially used) is added to the container and mixed for an additional 5 hours. This process forms a gel which is subsequently dried. The dried gel is then ground into a fine powder for use.
Claims (21)
1-20. (canceled)
21. A composition comprising:
first particles comprising chitosan derivatized with a multifunctional aldehyde; and
second particles comprising a covalent crosslinking agent;
wherein the composition is in the form of a powder.
22. The composition of claim 21 , wherein the chitosan derivatized with the multifunctional aldehyde comprises pendant aldehyde groups.
23. The composition of claim 21 , wherein the multifunctional aldehyde comprises glutaraldehyde, glyoxal, or an aldehyde terminated hydrophilic polymer.
24. The composition of claim 23 , wherein the multifunctional aldehyde comprises the aldehyde terminated hydrophilic polymer, and wherein the aldehyde terminated hydrophilic polymer comprises poly(ethylene glycol), polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylamide, poly(acrylic acid), or poly(hydroxyethyl methacrylate.
25. The composition of claim 21 , wherein the multifunctional aldehyde is poly(ethylene glycol) dialdehyde.
26. The composition of claim 21 , wherein the covalent crosslinking agent is a polymeric crosslinking agent.
27. The composition of claim 21 , wherein the covalent crosslinking agent comprises a multifunctional molecule having two or more functional groups.
28. The composition of claim 27 , wherein the covalent crosslinking agent is a biocompatible hydrophilic polymer having terminal carboxylic acid groups.
29. The composition of claim 27 , wherein the two or more functional groups include carboxylic acid groups, amine groups, epoxy groups, and/or aldehyde groups.
30. The composition of claim 21 , wherein the first particles have a size ranging from 100 μm to 500 μm.
31. A method of treating or preventing bleeding at a tissue site comprising applying the composition of claim 21 to the tissue site via a catheter, wherein the tissue site is tissue of a gastrointestinal tract.
32. The method of claim 31 , wherein the composition is fluidized in a gas to form a fluidized powder and blown onto the tissue site.
33. The method of claim 32 , wherein the gas is CO2.
34. The method of claim 32 , wherein the fluidized powder exits the catheter at a velocity ranging from 15 m/s to 50 m/s.
35. The method of claim 31 , wherein the composition is applied to the tissue site via the catheter through an endoscope.
36. A composition comprising:
first particles comprising chitosan derivatized with a multifunctional aldehyde; and
second particles comprising a covalent crosslinking agent, wherein the cross-linking agent comprises a multifunctional polymer comprising two or more functional groups chosen from carboxylic acid groups, amine groups, epoxy groups, aldehyde groups, or combinations thereof;
wherein the composition is in the form of a powder.
37. The composition of claim 36 , wherein the chitosan derivatized with a multifunctional aldehyde comprises chitosan derivatized with glutaraldehyde, chitosan derivatized with glyoxal, or chitosan derivatized with an aldehyde terminated hydrophilic polymer.
38. The composition of claim 37 , wherein the aldehyde terminated hydrophilic polymer is approximately 2 monomers to 250 monomers in length.
39. A method of treating or preventing bleeding at a tissue site, the method comprising administering a composition to the tissue site, wherein the composition is in the form of a powder and comprises:
first particles comprising chitosan derivatized with a multifunctional aldehyde; and
second particles comprising a covalent crosslinking agent, wherein the covalent crosslinking agent comprises a multifunctional polymer comprising two or more functional groups chosen from carboxylic acid groups, amine groups, epoxy groups, aldehyde groups, or combinations thereof.
40. The method of claim 39 , wherein the covalent crosslinking agent is a biocompatible hydrophilic polymer having terminal amine groups.
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