# US 10,441,626 B2 · Microparticles comprising GNRH made by PGSS > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,441,626 B2 - Document ID: US10441626B2 - Status: Granted - Kind: B2 - Application number: 15/027,754 - Filed: 2014-10-07 - Published: 2016-08-11 - Granted: 2019-10-15 - Earliest claimed: 2013-10-08 - Assignees: Ferring B.V. - Applicants: Ferring B.V. - Inventors: Gregoire Charles Joseph Schwach; Lars Schiefelbein; Andrew Naylor; Mark Andrew Whitaker; Nicholas John Arrowsmith - Web page: https://patentgrep.com/patent/US10441626B2 ## CPC - A61K 38/09: Luteinising hormone-releasing hormone [LHRH] {, i.e. Gonadotropin-releasing hormone [GnRH]}; Related peptides - A61K 9/1647: {Polyesters, e.g. poly(lactide-co-glycolide)} - A61K 38/22: Hormones (derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35) - A61P 13/08: of the prostate - A61P 35/00: Antineoplastic agents - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - 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 A pharmaceutical formulation comprising a solid matrix of one or more biodegradable polymers, the solid matrix including a pharmaceutically active substance or a pharmaceutically acceptable salt thereof distributed homogeneously or substantially homogeneously within the matrix; wherein the pharmaceutically active substance is, for example, a gonadotropin releasing hormone (GnRH), a GnRH agonist or a GnRH antagonist. ## Claims ### Claim 1 A pharmaceutical formulation comprising a solid matrix of one or more biodegradable polymers and a pharmaceutically active substance or a pharmaceutically acceptable salt thereof, wherein the active substance is distributed uniformly within the matrix on a micrometer scale and the active substance is chosen from gonadotropin releasing hormone (GnRH), a GnRH agonist, and a GnRH antagonist, wherein the formulation is made by a process comprising the steps of: (a) providing in a vessel the biodegradable polymer in solid form, the pharmaceutically active substance or salt thereof in solid form, and optionally an excipient; (b) adding a solvent to the vessel which includes the polymer in solid form and the pharmaceutically active substance in solid form; (c) adding a fluid which is capable of existing in a supercritical state to the vessel; (d) increasing the temperature and pressure in the vessel to convert the fluid to the supercritical state, optionally mixing the polymer, pharmaceutically active substance, and excipient (if present) prior to, during, and/or after conversion of the fluid to the supercritical state; (e) decreasing one or both of the temperature and pressure in the vessel to convert the fluid to a sub-critical state; and then increasing one or both of the temperature and pressure in the vessel to return the fluid to the supercritical state; and (f) recovering the solid matrix. ### Claim 2 (depends on 1) The pharmaceutical formulation according to claim 1, wherein the pharmaceutically active substance is degarelix. ### Claim 3 (depends on 2) The pharmaceutical formulation according to claim 2, wherein the amount of degarelix in the pharmaceutical formulation is from 5% to 40% by weight of the solid matrix. ### Claim 4 (depends on 1) The pharmaceutical formulation according to claim 1, further comprising one or more excipients. ### Claim 5 (depends on 4) The pharmaceutical formulation according to claim 4, wherein the one or more excipient is distributed homogeneously or substantially homogeneously within the matrix. ### Claim 6 (depends on 4) The pharmaceutical formulation according to claim 4, wherein the one or more excipient is chosen from a sugar, a sugar alcohol, an inorganic salt, and a synthetic polymer. ### Claim 7 (depends on 1) The pharmaceutical formulation according to claim 1, wherein the biodegradable polymer is polyhydroxy acid (PHA). ### Claim 8 (depends on 7) The pharmaceutical formulation according to claim 7, wherein the polyhydroxy acid (PHA) is chosen from poly(lactic acid) (PLA), poly(glycolic acid) (PGA), a copolymer of lactic and glycolic acid (PLGA), a copolymer of lactic and glycolic acid with poly(ethylene glycol), poly(e-caprolactone) (PCL), and poly(3-hydroxybutyrate) (PHB). ### Claim 9 (depends on 8) The pharmaceutical formulation according to claim 8, wherein the biodegradable polymer is a copolymer of lactic and glycolic acid (PLGA). ### Claim 10 (depends on 9) The pharmaceutical formulation according to claim 9, wherein the PLGA has a molar ratio of lactic acid:glycolic acid of from 90:10 to 10:90. ### Claim 11 (depends on 1) The pharmaceutical formulation according to claim 1, wherein the inherent viscosity of the one or more biodegradable polymer is from about 0.1 to about 0.5 dL/g. ### Claim 12 (depends on 1) The pharmaceutical formulation according to claim 1, wherein the solid matrix is in the form of microparticles. ### Claim 13 (depends on 12) The pharmaceutical formulation according to claim 12, wherein the microparticles have mean particle size from about 25 to about 65 μm expressed as the volume mean diameter (VMD). ### Claim 14 (depends on 1) The pharmaceutical formulation according to claim 1, wherein the formulation is in the form of a suspension. ### Claim 15 (depends on 14) The pharmaceutical formulation according to claim 14, wherein the formulation further comprises a pharmaceutically acceptable carrier. ### Claim 16 (depends on 1) The pharmaceutical formulation according to claim 1, wherein the formulation is in a form for intramuscular administration. ### Claim 17 (depends on 1) The pharmaceutical formulation according to claim 1, wherein the fluid added in step (c) is carbon dioxide. ### Claim 18 (depends on 17) The pharmaceutical formulation according to claim 17, wherein the solvent added in step (b) is an aprotic organic solvent. ### Claim 19 (depends on 18) The pharmaceutical formulation according to claim 18, wherein the aprotic organic solvent is chosen from dimethyl sulfoxide (DMSO), acetone, and an alcohol. ### Claim 20 (depends on 19) The pharmaceutical formulation according to claim 19, wherein the solid matrix is washed in water, a C1 to C8 alcohol, or a solution of a C1 to C8 alcohol in water. ### Claim 21 A method of treating prostate cancer or benign prostate hyperplasia comprising: administering to a patient in need thereof a pharmaceutical formulation comprising a solid matrix of one or more biodegradable polymers and a pharmaceutically active substance or a pharmaceutically acceptable salt thereof, wherein the active substance is distributed uniformly within the matrix on a micrometer scale and the active substance is chosen from gonadotropin releasing hormone (GnRH), a GnRH agonist, and a GnRH antagonist wherein the pharmaceutical formulation is made by a process comprising the steps of: (a) providing in a vessel the biodegradable polymer in solid form, the degarelix or salt thereof in solid form, and optionally an excipient; (b) adding a solvent to the vessel which includes the polymer in solid form and the degarelix in solid form; (c) adding a fluid which is capable of existing in the supercritical state to the vessel; (d) increasing the temperature and pressure in the vessel to convert the fluid to the supercritical state, optionally mixing the polymer, degarelix and excipient (if present) prior to, during, and/or after conversion of the fluid to the supercritical state; (e) decreasing one or both of the temperature and pressure in the vessel to convert the fluid to a sub-critical state; and then increasing one or both of the temperature and pressure in the vessel to return the fluid to the supercritical state; and (f) recovering the solid matrix. ### Claim 22 (depends on 1) The pharmaceutical formulation according to claim 1, further comprising after step (e), repeating step (e) one or more times. ### Claim 23 (depends on 1) The pharmaceutical formulation according to claim 1, further comprising after step (f), washing the solid matrix. ### Claim 24 (depends on 1) The pharmaceutical formulation according to claim 1, wherein the pharmaceutically active substance is triptorelin. ### Claim 25 (depends on 21) The pharmaceutical formulation according to claim 21, further comprising after step (e), repeating step (e) one or more times. ### Claim 26 (depends on 21) The pharmaceutical formulation according to claim 21, further comprising after step (f), washing the solid matrix. ### Claim 27 A method of making a pharmaceutical formulation comprising an active substance or pharmaceutically acceptable salt thereof is distributed uniformly within a matrix on a micrometer scale, the method comprising: (a) providing in a vessel a biodegradable polymer in solid form, the active substance or salt thereof in solid form, and optionally an excipient; (b) adding a solvent to the vessel which includes the polymer in solid form and the active substance or salt thereof in solid form; (c) adding a fluid which is capable of existing in the supercritical state to the vessel; (d) increasing the temperature and pressure in the vessel to convert the fluid to the supercritical state, optionally mixing the polymer, the active substance or salt thereof and excipient (if present) prior to, during, and/or after conversion of the fluid to the supercritical state; (e) decreasing one or both of the temperature and pressure in the vessel to convert the fluid to a sub-critical state; and then increasing one or both of the temperature and pressure in the vessel to return the fluid to the supercritical state; and (f) recovering the solid matrix.