# US 5,707,652 A · Methods of treating circadian rhythm phase disorders > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 5,707,652 A - Document ID: US5707652A - Status: Granted - Kind: A - Application number: 08/480,558 - Filed: 1995-06-07 - Granted: 1998-01-13 - Earliest claimed: 1990-12-04 - Assignees: State of Oregon - Inventors: Alfred J. Lewy; Robert L. Sack; Keith A. Parrott; James W. Ayres - Web page: https://patentgrep.com/patent/US5707652A ## CPC - A61K 9/5047: {Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose} - A61K 9/5078: {with drug-free core} - 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 31/40: having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil - A61K 31/4045: Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - 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 Methods for treating circadian rhythm disorders and sleep disorders are described. The method involves oral administration of a sustained release composition of melatonin to produce a normal melatonin pattern when the normal pattern has been disrupted or is missing. ## Claims ### Claim 1 A dosage form comprising a sustained release melatonin formulation having a total dose of melatonin that is less than 1 mg, wherein a portion of the total dose of melatonin provided is in a sustained-release form and a portion of the total dose of melatonin provided is in an immediate release form, wherein the formulation provides at least 1% bioavailable melatonin and wherein the dosage form produces a plasma concentration profile for melatonin that mimics the normal nighttime melatonin plasma concentration profile when administered to a human. ### Claim 2 (depends on 1) The dosage form of claim 1 wherein the formulation releases melatonin over a period of about 3 to about 12 hours. ### Claim 3 (depends on 1) The dosage form of claim 1 wherein the formulation produces plasma melatonin concentrations in an animal that are from about 10 to about 600 pg/mL over a period of at least 3 hours. ### Claim 4 (depends on 1) The dosage form of claim 1 wherein the formulation produces a normal nighttime plasma melatonin concentration in an animal. ### Claim 5 (depends on 1) A dosage form of claim 1 wherein the sustained release melatonin formulation comprises: (a) a sugar-based core comprising less than 1 mg of melatonin where the melatonin is about 0.05 to 2% by weight of the core; and (b) about 5 to 25% by weight of ethylcellulose coating comprising ethylcellulose and a plasticizer. ### Claim 6 (depends on 5) The dosage form of claim 5 wherein the plasticizer is an alkyl sebacate or a trialkyl citrate, where each alkyl is the same or different and represents straight or branched chain alkyl groups having 1-6 carbon atoms. ### Claim 7 (depends on 5) The dosage form of claim 5 wherein the core additionally contains from about 0.05 to 1% by weight of polyvinylpyrrolidone and 0.01 to 1% by weight of hydroxypropylcellulose. ### Claim 8 (depends on 5) The dosage form of claim 5 wherein the core comprises about 0.3 % by weight of melatonin. ### Claim 9 (depends on 1) The dosage form of claim 1 that is orally administered. ### Claim 10 (depends on 1) A method for treating an animal suffering from a melatonin deficiency, the method comprising the step of administering to the animal an effective dose of the dosage form of claim 1. ### Claim 11 (depends on 10) The method of claim 10 wherein the animal is a human. ### Claim 12 (depends on 11) The method of claim 11 wherein the human is elderly. ### Claim 13 (depends on 11) The method of claim 11 wherein the human is an Alzheimer's disease patient. ### Claim 14 (depends on 11) The method according to claim 11 wherein the dosage form is administered to a human from about 4 to about 17 hours before a time characterized as the human's endogenous melatonin onset time. ### Claim 15 (depends on 11) The method according to claim 11 wherein the dosage form is administered to the human from about 6 to about 19 hours before a time characterized as the onset time of the human's normal or desired sleep phase. ### Claim 16 (depends on 1) The dosage form of claim 1 wherein the portion of the total dose of melatonin that is in a sustained-release form comprises from about 0.1 to about 0.9 mg melatonin. ### Claim 17 (depends on 1) The dosage form of claim 1 wherein the portion of the total dose of melatonin that is in an immediate release form comprises from about 0.01 to about 0.09 mg melatonin. ### Claim 18 (depends on 1) A method for inducing sleep in a human, the method comprising administering an amount of melatonin less than 1 mg to the human in an oral dosage form according to claim 1 designed to provide a sustained release of melatonin over time, wherein the dosage form is administered at a time that produces a plasma concentration profile for melatonin that mimics the normal nighttime plasma melatonin concentration profile during the human's sleep phase and produces sleep in the human. ### Claim 19 (depends on 18) The method of claim 18 wherein the human is elderly. ### Claim 20 (depends on 18) The method of claim 18 wherein the human is afflicted with a melatonin deficiency disorder. ### Claim 21 (depends on 18) The method of claim 18, wherein the human is an Alzheimer's disease patient.