# US 12,595,342 B2 · Chitosan-based beads, and preparation, compositions and uses thereof > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 12,595,342 B2 - Document ID: US12595342B2 - Status: Granted - Kind: B2 - Application number: 17/790,180 - Filed: 2021-11-22 - Published: 2023-03-02 - Granted: 2026-04-07 - Earliest claimed: 2020-11-23 - Assignees: KiOmed Pharma - Applicants: Kiomed Pharma - Inventors: Mickaël Chausson; Sandrine Emilia Gautier; Laurence Hermitte; Antoine Rabeux; Guillermo Rocasalbas - Web page: https://patentgrep.com/patent/US12595342B2 ## CPC - C08J 3/075: Macromolecular gels - C08L 5/08: Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof - A61L 27/48: with macromolecular fillers - A61L 27/52: Hydrogels or hydrocolloids - C08B 37/003: {Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof} - C08B 37/0072: {Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates} - C08J 3/24: Crosslinking, e.g. vulcanising, of macromolecules (mechanical aspects B29C35/00; crosslinking agents C08K) - A61L 2400/06: Flowable or injectable implant compositions - A61L 2430/34: for soft tissue reconstruction - C08J 2305/08: Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof - C08J 2405/08: Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof - C08J: WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H (working, e.g. shaping, of plastics B29) - C08L: COMPOSITIONS OF MACROMOLECULAR COMPOUNDS (compositions based on polymerisable monomers C08F, C08G; artificial filaments or fibres D01F; textile treating compositions D06) - 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 (preservation of bodies or disinfecting characterised by the agents employed A01N; preserving, e.g. sterilising, food or foodstuffs A23; preparations for medical, dental or toiletry purposes A61K) - C08B: POLYSACCHARIDES; DERIVATIVES THEREOF (polysaccharides containing less than six saccharide radicals attached to each other by glycosidic linkages C07H; fermentation or enzyme-using processes C12P19/00; sugar industry C13; production of cellulose D21) ## Abstract The invention relates to beads and a composition comprising an aqueous phase comprising a plurality of beads, the beads comprising or consisting in a hydrogel matrix comprising at least one carboxyalkyl chitosan having glucosamine units, N-acetyl-glucosamine units and glucosamine units substituted with a carboxyalkyl group, the carboxyalkyl chitosan being crosslinked by covalent bonds between the carboxyalkyl chitosan chains and/or co-crosslinked by covalent bonds with one or more other polymers. The invention also relates to processes for their preparation and applications thereof. ## Claims ### Claim 1 A method of aesthetic treatment or aesthetic care comprising administering to a human or animal in need thereof, by injection or implantation at a site in need of aesthetic treatment or aesthetic care, a composition comprising a plurality of beads dispersed within an aqueous phase, wherein the plurality of beads comprise a hydrogel matrix, wherein the hydrogel matrix comprises at least one carboxyalkyl chitosan having glucosamine units, N-acetyl-glucosamine units, and glucosamine units substituted with a carboxyalkyl group, said at least one carboxyalkyl chitosan having a degree of substitution with a group of carboxyalkyl greater than 50%, expressed in number of moles of the substituent with respect to the number of moles of total units, wherein the at least one carboxyalkyl chitosan is crosslinked by covalent bonds between chains of the at least one carboxyalkyl chitosan and/or co-crosslinked by covalent bonds with one or more other polymers, and wherein said plurality of beads remain integral in the aqueous phase. ### Claim 2 (depends on 1) The method of claim 1, wherein the aqueous phase comprises one or more polymers. ### Claim 3 (depends on 1) The method of claim 1, wherein the at least one carboxyalkyl chitosan is co-crosslinked by covalent bonds with another polymer. ### Claim 4 (depends on 1) The method of claim 1, wherein the aqueous phase and/or the plurality of beads are in the form of a hydrogel with a pH and osmolality in balance with a physiological medium. ### Claim 5 (depends on 1) The method of claim 1, wherein said at least one carboxyalkyl chitosan has a degree of substitution with a group of carboxyalkyl that is in a range of greater than 50% to 200%, expressed in the number of moles of the substituent with respect to the number of moles of total units. ### Claim 6 (depends on 1) The method of claim 1, wherein the hydrogel matrix further comprises at least one polymer optionally crosslinking on itself by covalent bonds or cross-linked by covalent bonds with said at least one carboxyalkyl chitosan. ### Claim 7 (depends on 1) The method of claim 1, wherein the hydrogel matrix further comprises at least hyaluronan optionally crosslinking on itself by covalent bonds or cross-linked by covalent bonds with said at least one carboxyalkyl chitosan. ### Claim 8 (depends on 1) The method of claim 1, wherein crosslinking is formed by a crosslinking agent forming said covalent bonds. ### Claim 9 (depends on 1) The method of claim 1, wherein the crosslinking agent is selected from the group consisting of crosslinking biopolymers, polysaccharides, 1,4 butanediol diglycidyl ether, 1-bromo-3,4-epoxybutane, 1-bromo-4,5-epoxypentane, 1-chloro-2,3-epithio-propane, 1-bromo-2,3-epithiopropane, 1-bromo-3,4-epithio-butane, 1-bromo-4,5-epithiopentane, 2,3-dibromopropanol, 2,4-dibromobutanol, 2,5-dibromopentanol, 2,3-dibromopro-panethiol, 2,4-dibromobutanethiol, 2,5-dibromopentane-thiol epichlorohydrin, 2,3-dibromopropanol, 1-chloro-2,3-epithiopropane, dimethylaminopropylcarbodiimide, gallic acid, epigallocatechine gallate, curcumin, tannic acid, genipine, diisocyanate compounds, hexamethylene diisocyanate, toluene diisocyanate, and divinyl sulfone. ### Claim 10 (depends on 1) The method of claim 1, wherein said composition is formulated as an injectable suspension, ready for instillation or implantable in humans or animals. ### Claim 11 (depends on 1) The method of claim 1, wherein the plurality of beads further comprises one or more active agents. ### Claim 12 (depends on 1) The method of claim 1, wherein the administering comprises the injection by subcutaneous or intradermal route of said composition. ### Claim 13 (depends on 1) The method of claim 1, wherein said method is for repairing or filling at least one body liquid or tissue requiring a repair or filling. ### Claim 14 (depends on 1) The method of claim 1, wherein said method is for cosmetic medicine, plastic surgery, internal surgery, or dermatology. ### Claim 15 (depends on 1) The method of claim 1 further comprising: preparing an aqueous solution comprising said at least one carboxyalkyl chitosan, at least one crosslinking agent, and, optionally, the one or more other polymers; forming droplets of the aqueous solution; and crosslinking the at least one carboxyalkyl chitosan and the one or more other polymers, if present in the aqueous solution, with the at least one crosslinking agent within the droplets; thereby preparing said plurality of beads. ### Claim 16 (depends on 15) The method of claim 15, further comprising placing the droplets in the presence of an aqueous phase that optionally comprises an organic solvent. ### Claim 17 (depends on 15) The method of claim 15 further comprising coagulating the droplets, in the presence of at least one coagulation agent before crosslinking them. ### Claim 18 (depends on 15) The method of claim 15 further comprising subjecting the plurality of beads to purification steps by washing and balancing the pH and osmolality in a physiologically acceptable medium. ### Claim 19 (depends on 15) The method of claim 15 further comprising selecting said plurality beads based on their dimensions. ### Claim 20 (depends on 15) The method of claim 15 further comprising associating the plurality of beads with an aqueous phase, a lipophilic phase, a hydrolipidic phase, or another solid phase, optionally comprising one or more polymers. ### Claim 21 (depends on 1) The method of claim 1, wherein said method is for volumization indications of skin tissue for cosmetic purposes and medication delivery indications, by injection. ### Claim 22 (depends on 1) The method of claim 1, wherein said method is for providing a volumizing or remodelling effect of the outline of the face or body. ### Claim 23 (depends on 1) The method of claim 1, wherein said method is a method for treating lipoatrophies. ### Claim 24 (depends on 1) The method of claim 1, wherein said method is a method of treatment or of cosmetic care by filling cutaneous tissue. ### Claim 25 (depends on 24) The method of claim 24, wherein said method comprises a subcutaneous, intradermal, intra-mucosal, or intramuscular injection of said composition. ### Claim 26 (depends on 1) The method of claim 1, wherein said method comprises the treatment of skin by multiple injections by an intradermal route. ### Claim 27 (depends on 1) The method of claim 1, wherein said method is a method of treatment of appearance of skin wrinkles and/or fine lines, or of enhancement of skin appearance with a rejuvenated look. ### Claim 28 (depends on 1) The method of claim 1, wherein said method is for one or more tissues or organs affected by excessive temperature or burn. ### Claim 29 (depends on 1) The method of claim 1, wherein said injection or implantation is for aesthetic or cosmetic purposes subsequent to an accident or a surgical procedure. ### Claim 30 (depends on 1) The method of claim 1, wherein said method comprises the injection or implantation of said composition in a dermal tissue, an epithelial tissue, a conjunctive tissue, a muscular tissue, an adipose tissue, or a nerve tissue. ### Claim 31 (depends on 1) The method of claim 1, wherein said method is for cutaneous volumisation by injection in the dermis or hypodermis. ### Claim 32 (depends on 1) The method of claim 1, wherein said plurality of beads are microbeads or nanobeads. ### Claim 33 (depends on 1) The method of claim 1, wherein said at least one carboxyalkyl chitosan has a degree of acetylation higher than 30% and up to 80%, expressed as the number of moles of N-acetyl groups with respect to the number of moles of total glucosamine units. ### Claim 34 (depends on 1) The method of claim 1, wherein said composition is sterile and comprises said plurality of beads integral in said aqueous phase. ### Claim 35 (depends on 1) The method of claim 1, wherein said composition is formulated as a subcutaneous or intradermal injectable composition or subcutaneous or intradermal implantable composition. ### Claim 36 (depends on 1) The method of claim 1, wherein said plurality of beads have an average volume diameter from 1 μm to 450 μm under their hydrated form. ### Claim 37 (depends on 1) The method of claim 1, wherein said plurality of beads have an average diameter from 20 μm to 450 μm under their hydrated form. ### Claim 38 (depends on 1) The method of claim 1, wherein said plurality of beads have an average volume diameter from 25 μm to 250 μm under their hydrated form. ### Claim 39 (depends on 1) The method of claim 1, wherein said plurality of beads have an average volume diameter between 1 μm and 20 μm under their hydrated form. ### Claim 40 (depends on 1) The method of claim 1, wherein said plurality of beads have an average volume diameter lower than 1000 nm. ### Claim 41 (depends on 1) The method of claim 1, wherein said plurality of beads remain integral in the aqueous phase after injection via a 27-gauge needle.