# US 12,109,302 B2 · Sustained release biodegradable intracanalicular inserts comprising a hydrogel and cyclosporine > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 12,109,302 B2 - Document ID: US12109302B2 - Status: Granted - Kind: B2 - Application number: 18/227,463 - Filed: 2023-07-28 - Published: 2024-02-08 - Granted: 2024-10-08 - Earliest claimed: 2020-09-24 - Assignees: Ocular Therapeutix, Inc. - Applicants: Ocular Therapeutix, Inc. - Inventors: Charles D. Blizzard; Rami El-Hayek; Michael Goldstein; Peter Jarrett; Andrew Vanslette - Web page: https://patentgrep.com/patent/US12109302B2 ## CPC - A61K 9/0051: {Ocular inserts or implants} - A61K 38/13: Cyclosporins - A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers - A61K 47/22: Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones - A61K 47/34: Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence) - A61P 27/00: Drugs for disorders of the senses - A61P 27/02: Ophthalmic agents - A61P 31/04: Antibacterial agents - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract Provided herein are sustained release biodegradable intracanalicular insert comprising a hydrogel and cyclosporine, methods of treating or preventing an ocular disease in a subject in need thereof by administering such inserts as well as methods of manufacturing such inserts. ## Claims ### Claim 1 A method of treating an ocular disease in a human subject in need thereof, the method comprising inserting into the canaliculus of the subject a sustained release biodegradable intracanalicular insert comprising a hydrogel and cyclosporine, wherein the cyclosporine is in the form of particles having d50 value of less than about 50 μm as measured by laser diffraction and wherein the cyclosporine particles are dispersed within the hydrogel, wherein the hydrogel comprises a polymer network comprising crosslinked polymer units that are identical or different which are polyethylene glycol units having two to ten arms, wherein the arms of the polyethylene glycol units are connected to a core molecule of pentaerythritol, the polymer network is formed by reacting an electrophilic group-containing multi-arm polymer precursor with a nucleophilic group-containing cross-linking agent, the electrophilic group is an N-hydroxysuccinimidyl (NHS) ester group, the nucleophilic group-containing crosslinking agent contains an amine group, wherein the ocular disease is selected from dry eye, blepharitis, allergic conjunctivitis, atopic keratoconjunctivitis or vernal keratoconjunctivitis. ### Claim 2 (depends on 1) The method of claim 1, wherein the nucleophilic group-containing cross-linking agent is a small molecule amine with a molecular weight below 1,000 Da. ### Claim 3 (depends on 1) The method of claim 1, wherein the nucleophilic group-containing crosslinking agent is a labeled trilysine. ### Claim 4 (depends on 1) The method of claim 1, wherein the cyclosporine particles have a d50 value ranging from 3 to 17 μm. ### Claim 5 (depends on 1) The method of claim 1, wherein the multi-arm polymer units comprise 4a20kPEG units and the cross-linking units comprise fluorescein-conjugated trilysine amide units. ### Claim 6 (depends on 1) The method of claim 1, wherein the polymer network is obtained by reacting 4a20kPEG-SG or 4a20kPEG-SAP with fluorescein-conjugated trilysine in a molar ratio ranging from about 1:2 to about 2:1. ### Claim 7 (depends on 1) The method of claim 1, wherein the insert in a dried state contains from about 15% to about 80% by weight of the cyclosporine based on the total weight of the insert and from about 20% to about 60% by weight polymer units based on the total weight of the insert. ### Claim 8 (depends on 1) The method of claim 1, wherein the insert in a dried state contains from about 40% to about 80% by weight of the cyclosporine based on the total weight of the insert. ### Claim 9 (depends on 8) The method of claim 8, wherein the insert in a dried state contains from 45% to 55% by weight of the cyclosporine based on the total weight of the insert. ### Claim 10 (depends on 1) The method of claim 1, wherein the insert contains a surfactant. ### Claim 11 (depends on 10) The method of claim 10, wherein the insert in a dried state contains from about 0.01% to about 5% by weight of a surfactant based on the total weight of the insert. ### Claim 12 (depends on 10) The method of claim 10, wherein the insert contains a non-ionic surfactant. ### Claim 13 (depends on 1) The method of claim 1, wherein the cyclosporine content as measured by HPLC after at least 3 months at a temperature of from 2 to 8° C. is from about 300 to about 410 μg by weight. ### Claim 14 (depends on 13) The method of claim 13, wherein the amount of impurities as measured by HPLC after at least 3 months of storage at a temperature of from 2 to 8° C. is not more than 3.0%. ### Claim 15 (depends on 1) The method of claim 1, wherein the insert is in the form of a fiber, wherein the fiber has an average length of about 1.5 mm to about 4.0 mm and an average diameter of not more than 0.8 mm in its dried state. ### Claim 16 (depends on 1) The method of claim 1, wherein the insert after at least 3 months at a temperature of from 2 to 8° C. is in the form of a fiber that has an average length of about 2.5 mm to about 2.9 mm and an average diameter of not more than 0.62 mm in its dried state. ### Claim 17 (depends on 1) The method of claim 1, wherein the insert is in the form of a fiber that has an average diameter of at least 1.0 mm in expanded state after 10 minutes of hydration or of at least 1.3 mm in equilibrium state after 24 hours of hydration in vitro in phosphate-buffered saline at a pH of 7.4 at 37° C. ### Claim 18 (depends on 1) The method of claim 1, wherein the insert disintegrates in the canaliculus within about 1 to about 6 months after insertion. ### Claim 19 (depends on 18) The method of claim 18, wherein the insert after insertion to the canaliculus releases a therapeutically effective amount of cyclosporine over a period of at least about 1 month after insertion. ### Claim 20 (depends on 19) The method of claim 19, wherein cyclosporine is released from the insert after insertion to a human subject at an average rate of about 0.1 μg/day to about 10 μg/day.