# US 9,040,086 B2 · Timed, sustained release systems for propranolol > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 9,040,086 B2 - Document ID: US9040086B2 - Status: Granted - Kind: B2 - Application number: 11/500,892 - Filed: 2006-08-09 - Published: 2006-11-30 - Granted: 2015-05-26 - Earliest claimed: 2001-10-04 - Assignees: Aptalis Pharmatech, Inc. - Applicants: Phillip J. Percel; Krishna S. Vishnupad; Gopi M. Venkatesh - Inventors: Phillip J. Percel; Krishna S. Vishnupad; Gopi M. Venkatesh - Web page: https://patentgrep.com/patent/US9040086B2 ## CPC - A61K 9/5084: {Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs (tablets containing such a mixture A61K9/2077)} - A61K 9/5078: {with drug-free core} - A61K 31/138: Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine (atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377) - 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) ## Abstract A unit dosage form, such as a capsule or the like for delivering drugs into the body in a circadian release fashion, is comprising of one or more populations of propranolol-containing particles (beads, pellets, granules, etc.). Each bead population exhibits a pre-designed rapid or sustained release profile with or without a predetermined lag time of 3 to 5 hours. Such a circadian rhythm release cardiovascular drug delivery system is designed to provide a plasma concentration-time profile, which varies according to physiological need during the day, i.e., mimicking the circadian rhythm and severity/manifestation of a cardiovascular disease, predicted based on pharmaco-kinetic and pharmaco-dynamic considerations and in vitro/in vivo correlations. ## Claims ### Claim 1 A timed, sustained-release (TSR) pharmaceutical formulation comprising timed, sustained release beads, wherein said TSR beads comprise: a) a core comprising propranolol or a pharmaceutically acceptable salt thereof; b) a first membrane comprising a first water insoluble polymer surrounding said core; c) a second outer membrane comprising a mixture of a second water insoluble polymer and an enteric polymer; wherein said formulation provides a lag time in propranolol blood plasma concentration of about 2 to about 6 hours, wherein said formulation comprises about 80 mg, about 120 mg, or about 160 mg of propranolol or a pharmaceutically acceptable salt thereof, wherein said formulation provides a maximum blood plasma concentration (Cmax) between about 10 and about 14 hours following administration. ### Claim 2 (depends on 1) The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation comprises about 160 mg of propranolol or a pharmaceutically acceptable salt thereof, and provides a maximum blood plasma concentration (Cmax) within the range of 80% to 125% of about 177 ng/mL of propranolol between about 10 and about 14 hours following administration and an AUC0-T within the range of 80% to 125% of about 3417 ng·hr/mL. ### Claim 3 (depends on 1) The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation comprises about 120 mg of propranolol or a pharmaceutically acceptable salt thereof, and provides a maximum blood plasma concentration (Cmax) within the range of 80% to 125% of about 130 ng/ml, of propranolol between about 10 and about 14 hours following administration and an AUC0-T within the range of 80% to 125% of about 2270 ng·hr/mL. ### Claim 4 (depends on 1) The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation comprises about 80 mg of propranolol or a pharmaceutically acceptable salt thereof, and provides a maximum blood plasma concentration (Cmax) within the range of 80% to 125% of about 81 ng/mL of propranolol between about 10 and about 14 hours following administration and an AUC0-T within the range of 80% to 125% of about 1443 ng·hr/mL. ### Claim 5 (depends on 1) The pharmaceutical formulation of claim 1 wherein the first and second water insoluble polymers are independently selected from the group consisting of ethylcellulose, polyvinyl acetate, neutral copolymers based on ethyl acrylate and methylmethacrylate, and copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups. ### Claim 6 (depends on 1) The pharmaceutical formulation of claim 1 wherein the enteric polymer is selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, pH-sensitive methacrylic acid-methamethacrylate copolymers and shellac. ### Claim 7 (depends on 1) The pharmaceutical formulation of claim 1 whereby the first and second water insoluble polymers are ethylcellulose and the enteric polymer is a pH sensitive methacrylic acid-methamethacrylate copolymer. ### Claim 8 (depends on 1) A method of propranolol therapy which comprises administering orally to a human in need thereof the pharmaceutical formulation of claim 1. ### Claim 9 (depends on 2) A method of propranolol therapy which comprises administering orally to a human in need thereof the pharmaceutical formulation of claim 2. ### Claim 10 (depends on 3) A method of propranolol therapy which comprises administering orally to a human in need thereof the pharmaceutical formulation of claim 3. ### Claim 11 (depends on 4) A method of propranolol therapy which comprises administering orally to a human in need thereof the pharmaceutical formulation of claim 4. ### Claim 12 (depends on 1) A method of decreasing blood pressure during the early waking hours comprising orally administering once daily before bedtime to a human in need thereof the pharmaceutical formulation of claim 1. ### Claim 13 (depends on 2) A method of decreasing blood pressure during the early waking hours comprising orally administering once daily before bedtime to a human in need thereof the pharmaceutical formulation of claim 2. ### Claim 14 (depends on 3) A method of decreasing blood pressure during the early waking hours comprising orally administering once daily before bedtime to a human in need thereof the pharmaceutical formulation of claim 3. ### Claim 15 (depends on 4) A method of decreasing blood pressure during the early waking hours comprising orally administering once daily before bedtime to a human in need thereof the pharmaceutical formulation of claim 4. ### Claim 16 (depends on 1) A method of preventing angina during the early waking hours comprising orally administering once daily before bedtime to a human in need thereof the pharmaceutical formulation of claim 1. ### Claim 17 (depends on 2) A method of preventing angina during the early waking hours comprising orally administering once daily before bed time to a human in need thereof the pharmaceutical formulation of claim 2. ### Claim 18 (depends on 3) A method of preventing angina during the early waking hours comprising orally administering once daily before bedtime to a human in need thereof the pharmaceutical formulation of claim 3. ### Claim 19 (depends on 4) A method of preventing angina during the early waking hours comprising orally administering once daily before bedtime to a human in need thereof the pharmaceutical formulation of claim 4.