# US 10,441,548 B2 · Aggregating microparticles for medical therapy > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,441,548 B2 - Document ID: US10441548B2 - Status: Granted - Kind: B2 - Application number: 15/349,985 - Filed: 2016-11-11 - Published: 2017-05-18 - Granted: 2019-10-15 - Earliest claimed: 2015-11-12 - Assignees: Graybug Vision, Inc. - Applicants: Graybug Vision, Inc. - Inventors: Yun Yu; Joshua Kays; Ming Yang; Jeffrey L. Cleland - Web page: https://patentgrep.com/patent/US10441548B2 ## CPC - A61K 9/5089: {Processes} - A61K 9/0048: {Eye, e.g. artificial tears} - A61K 9/1641: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers} - A61K 9/1647: {Polyesters, e.g. poly(lactide-co-glycolide)} - A61K 9/5026: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates} - A61K 9/5031: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)} - A61K 31/382: having six-membered rings, e.g. thioxanthenes (thiothixene A61K31/496) - A61K 31/404: Indoles, e.g. pindolol - A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol - A61K 31/542: ortho- or peri-condensed with heterocyclic ring systems - A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers - A61P 27/02: Ophthalmic agents - A61P 27/06: Antiglaucoma agents or miotics - A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)} - A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin - A61K 47/36: Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin - 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 The present invention is a surface treated drug-loaded solid (e.g., non-porous) microparticle that aggregates in vivo to form a consolidated larger particle for medical therapy. In one embodiment, the particles are used for ocular therapy. Processes for producing the surface treated microparticle and injectable formulations which include the surface treated microparticle are also provided. When used in the eye, long-term consistent intraocular delivery can be achieved without disrupting vision and minimizing undesirable inflammatory responses. ## Claims ### Claim 1 Surface-modified solid aggregating microparticles comprising at least one biodegradable polymer, a surfactant, and a therapeutic agent that is encapsulated in the biodegradable polymer wherein the microparticles have a mean diameter between 10 μm and 60 μm that: (i) have a solid core with less than 10% porosity by ratio of void space to total volume; (ii) contain from about 0.001 percent to about 1 percent surfactant and have been surface-modified to contain less surfactant than a microparticle prior to the surface modification wherein the surface has been modified at a temperature less than about 18° C.; and (iii) are capable of aggregating in vivo to form at least one pellet of at least 500 μm in vivo capable of sustained drug delivery in vivo for at least one month. ### Claim 2 (depends on 1) The surface modified solid aggregating microparticles of claim 1 suitable for injection. ### Claim 3 (depends on 1) The surface modified solid aggregating microparticles of claim 1 suitable for a delivery route selected from the group consisting of intravitreal, intrastromal, intracameral, subtenon, sub-retinal, retrobulbar, peribulbar, suprachoroidal, subchoroidal, conjunctival, subconjunctival, episcleral, posterior juxtascleral, circumcorneal, and tear duct injections. ### Claim 4 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet is capable of sustained drug delivery for at least two months. ### Claim 5 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet is capable of sustained drug delivery for at least three months. ### Claim 6 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet is capable of sustained drug delivery for at least four months. ### Claim 7 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet is capable of sustained drug delivery for at least five months. ### Claim 8 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet is capable of sustained drug delivery for at least six months. ### Claim 9 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet is capable of sustained drug delivery for at least seven months. ### Claim 10 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the surface modification is carried out at a pH between about 6 and about 8. ### Claim 11 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the surface modification is carried out at a pH between about 6.5 and about 7.5. ### Claim 12 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the surface modification is carried out at a temperature of less than 16° C. ### Claim 13 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the surface modification is carried out at a temperature of less than 10° C. ### Claim 14 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the surface modification is carried out at a temperature of less than 8° C. ### Claim 15 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the surface modification is carried out at a temperature of less than 5° C. ### Claim 16 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the solid core comprises a biodegradable polymer with less than 8 percent porosity. ### Claim 17 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the solid core comprises a biodegradable polymer with less than 7 percent porosity. ### Claim 18 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the solid core comprises a biodegradable polymer with less than 6 percent porosity. ### Claim 19 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the solid core comprises a biodegradable polymer with less than 5 percent porosity. ### Claim 20 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the solid core comprises a biodegradable polymer with less than 4 percent porosity. ### Claim 21 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the solid core comprises a biodegradable polymer with less than 3 percent porosity. ### Claim 22 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the solid core comprises a biodegradable polymer with less than 2 percent porosity. ### Claim 23 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the therapeutic agent is a pharmaceutical drug. ### Claim 24 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the therapeutic agent is a biologic drug. ### Claim 25 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the therapeutic agent is sunitinib, or its pharmaceutically acceptable salt. ### Claim 26 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the therapeutic agent is a tyrosine kinase inhibitor. ### Claim 27 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles have a mean diameter between about 20 and 30 μm. ### Claim 28 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles have a mean diameter between about 20 and 50 μm. ### Claim 29 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles have a mean diameter between about 25 and 35 μm. ### Claim 30 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles have a mean diameter between about 20 and 40 μm. ### Claim 31 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles have a mean diameter between about 25 and 40 μm. ### Claim 32 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet has a diameter of at least 600 μm. ### Claim 33 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet has a diameter at least 700 μm. ### Claim 34 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet has a diameter of at least 1 mm. ### Claim 35 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet has a diameter of at least 1.5 mm. ### Claim 36 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet has a diameter of at least 2 mm. ### Claim 37 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet has a diameter of at least 3 mm. ### Claim 38 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet has a diameter of at least 4 mm. ### Claim 39 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet has a diameter of at least 5 mm. ### Claim 40 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet is capable of releasing not more than about 10 percent by weight of the therapeutic agent in vivo over a 24 hour period. ### Claim 41 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet is capable of releasing not more than about 15 percent by weight of the therapeutic agent in vivo over a 24 hour period. ### Claim 42 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet is capable of releasing not more than about 10 percent by weight of the therapeutic agent in vivo over a 12 hour period. ### Claim 43 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet is capable of releasing not more than about 15 percent by weight of the therapeutic agent in vivo over a 12 hour period. ### Claim 44 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles have a drug loading of 1-40 percent by weight. ### Claim 45 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles have a drug loading of 5-25 percent by weight. ### Claim 46 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles have a drug loading of 5-15 percent by weight. ### Claim 47 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles have a drug loading of 0.1-5 percent by weight. ### Claim 48 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles comprise poly(lactide-co-glycolide). ### Claim 49 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles comprise poly(lactide-co-glycolide) covalently linked to polyethylene glycol. ### Claim 50 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles comprise more than one biodegradable polymer. ### Claim 51 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles comprise both poly(lactide-co-glycolide) and poly(lactide-co-glycolide) covalently linked to polyethylene glycol. ### Claim 52 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles comprise poly(lactic acid). ### Claim 53 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles comprise poly(lactic acid) covalently linked to polyethylene glycol. ### Claim 54 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles comprise both poly(lactic acid) and poly(lactic acid) covalently linked to polyethylene glycol. ### Claim 55 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles comprise both poly(lactic acid) and poly(lactide-co-glycolide) covalently linked to polyethylene glycol. ### Claim 56 (depends on 1) The surface-modified solid aggregating microparticles of claim 1 wherein the surfactant comprises polyvinyl alcohol. ### Claim 57 (depends on 1) An injectable material that comprises the microparticles of claim 1 in a pharmaceutically acceptable carrier for administration in vivo. ### Claim 58 (depends on 57) The injectable material of claim 57, further comprising a compound that inhibits aggregation of microparticles prior to injection. ### Claim 59 (depends on 58) The injectable material of claim 58 wherein the compound is a sugar. ### Claim 60 (depends on 59) The injectable material of claim 59 wherein the sugar is mannitol. ### Claim 61 (depends on 57) The injectable material of claim 57, further comprising a viscosity enhancer. ### Claim 62 (depends on 61) The injectable material of claim 61, wherein the viscosity enhancer comprises hyaluronic acid. ### Claim 63 (depends on 61) The injectable material of claim 61, wherein the viscosity enhancer comprises sodium hyaluronate. ### Claim 64 (depends on 57) The injectable material of claim 57, wherein the injectable material has a range of concentration of the surface-modified solid aggregating microparticles of about 100-600 mg/ml. ### Claim 65 (depends on 57) The injectable material of claim 57, wherein the injectable material has a range of concentration of the surface-modified solid aggregating microparticles of about 500 or less mg/ml. ### Claim 66 (depends on 57) The injectable material of claim 57, wherein the injectable material has a range of concentration of the surface-modified solid aggregating microparticles of about 300 or less mg/ml. ### Claim 67 (depends on 57) The injectable material of claim 57, wherein the injectable material has a range of concentration of the surface-modified solid aggregating microparticles of about 200 or less mg/ml. ### Claim 68 (depends on 57) The injectable material of claim 57, wherein the injectable material has a range of concentration of the surface-modified solid aggregating microparticles of about 150 or less mg/ml. ### Claim 69 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the surface modification is carried out on wet microparticles. ### Claim 70 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the surface treated microparticles are capable of releasing a therapeutic agent over a longer period of time compared to non-surface treated microparticles. ### Claim 71 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the surface-modified solid aggregating microparticles are more hydrophobic than the microparticles prior to the surface modification. ### Claim 72 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the surface-modified solid aggregating microparticles are less inflammatory than non-surface treated microparticles. ### Claim 73 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the therapeutic agent is sunitinib malate. ### Claim 74 (depends on 73) The surface-modified solid aggregating microparticles of claim 73, wherein the microparticles comprise both poly(lactide-co-glycolide) and poly(lactide-co-glycolide) covalently linked to polyethylene glycol. ### Claim 75 (depends on 74) The surface-modified solid aggregating microparticles of claim 74, wherein the microparticles have a mean diameter between about 20 and 30 μm. ### Claim 76 (depends on 74) The surface-modified solid aggregating microparticles of claim 74, wherein the microparticles have a mean diameter between about 20 and 40 μm. ### Claim 77 (depends on 74) The surface-modified solid aggregating microparticles of claim 74, wherein the surfactant comprises polyvinyl alcohol. ### Claim 78 (depends on 1) The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles comprise poly(lactide-co-glycolide), poly(lactic acid), and poly(lactide-co-glycolide) covalently linked to polyethylene glycol.