Methods of treating circadian rhythm phase disorders

• US 5,707,652 A
• Filed: 06/07/1995
• Issued: 01/13/1998
• Est. Priority Date: 12/04/1990
• Status: Expired due to Term

• Current Assignee: State of Oregon
• Original Assignee: State of Oregon
• Inventors: Parrott, Keith A., Ayres, James W., Sack, Robert L., Lewy, Alfred J.
• Primary Examiner(s): Rose, Shep K.
• Application Number:
  US08/480,558
• Time in Patent Office: 951 Days
• Field of Search: 514/415, 514/419, 424/457, 424/458, 424/468, 424/469, 424/470, 424/471, 424/472
• US Class Current: 424/457
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/4045 Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/5047 Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5078 with drug-free core
• CPC Class Codes: 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

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

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.

2. The dosage form of claim 1 wherein the formulation releases melatonin over a period of about 3 to about 12 hours.

3. 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.

4. The dosage form of claim 1 wherein the formulation produces a normal nighttime plasma melatonin concentration in an animal.

5. 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.

6. 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.

7. 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.

8. The dosage form of claim 5 wherein the core comprises about 0.3 % by weight of melatonin.

9. The dosage form of claim 1 that is orally administered.

10. 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.

11. The method of claim 10 wherein the animal is a human.

12. The method of claim 11 wherein the human is elderly.

13. The method of claim 11 wherein the human is an Alzheimer'"'"'s disease patient.

14. 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.

15. 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.

16. 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.

17. 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.

18. 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.

19. The method of claim 18 wherein the human is elderly.

20. The method of claim 18 wherein the human is afflicted with a melatonin deficiency disorder.

21. The method of claim 18, wherein the human is an Alzheimer'"'"'s disease patient.