Combination therapy using low-dose doxepin for the improvement of sleep

Abstract

A composition comprising doxepin, or a pharmaceutically acceptable salt, or prodrug thereof, and a compound that enhances sleep onset, sleep maintenance or reduces early morning awakenings. These compositions are useful for treating multiple manifestations of insomnia.

We claim: 
     
         1 . A composition comprising doxepin, or a pharmaceutically acceptable salt or prodrug thereof, and one or more of a compound that promotes sleep onset. 
     
     
         2 . The composition of  claim 1 , wherein the compound that promotes sleep onset is selected from the group consisting of a GABA modulator, an H3 agonist, an orexin receptor antagonist, a melatonin agonist and a galanin agonist. 
     
     
         3 . The composition of  claim 1 , wherein said composition comprises doxepin in an amount of about 0.001 to about 10 mg. 
     
     
         4 . The composition of  claim 1 , wherein the one or more of a compound that promotes sleep onset in a dosage that is the same as the approved prescription dosage for that compound, the same as the clinical trial dosage for the compound, the same as a literature reported dosage for treating a sleep disorder, or the same as the dosage for the compound when used to treat a sleep disorder as a monotherapy. 
     
     
         5 . The composition of  claim 1 , wherein the one or more of a compound that promotes sleep onset in a dosage that is less than the approved prescription dosage for that compound to treat a sleep disorder, less than the clinical trial dosage for the compound for treating a sleep disorder, less than a literature reported dosage for treating a sleep disorder, less than the dosage for the compound when used to treat a sleep disorder as a monotherapy, or less than the monotherapy dosage of the compound required to achieve substantially the same sleep therapy benefit as the compound used in combination with doxepin. 
     
     
         6 . A method of reducing a side effect of a sleep medication, comprising:
 identifying a patient suffering from a side effect caused by a non-doxepin sleep medication;   providing the patient with doxepin in an amount of about 0.0001 to about 10 mg of doxepin, a pharmaceutically acceptable salt of doxepin, or a prodrug of doxepin; and   providing the patient with the non-doxepin sleep medication in a dosage less than the dosage which causes the side effect when the medication is used as sleep therapy alone.   
     
     
         7 . The method of  claim 6 , wherein the non-doxepin sleep medication is selected from the group consisting of a GABA modulator, an H3 agonist, an orexin receptor antagonist, a melatonin agonist and a galanin agonist. 
     
     
         8 . A composition comprising doxepin, or a pharmaceutically acceptable salt or prodrug thereof, and one or more of a compound that enhances gamma-aminobutyric acid (GABA) activity, a 5HT2a antagonist, a melatonin agonist, an ion channel blocker, a serotonin-2 antagonist/reuptake inhibitor (SARIs), a 5HT1a agonist, a GABA-B agonist and an orexin receptor antagonist. 
     
     
         9 . The composition of  claim 8 , wherein said compound that enhances GABA activity is selected from the group consisting of alprozolam, bromazepam, clobazam, clonazepam, clorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam, triazolam, indiplon, zopiclone, eszopiclone, zaleplon, zolpidem, gabaxadol, vigabatrin, tiagabine and estazolam. 
     
     
         10 . The composition of  claim 8 , wherein the 5HT2a antagonist is selected from the group consisting of ketanserin, risperidone, eplivanserin, pruvanserin, MDL 100907, APD125 and AVE 8488. 
     
     
         11 . The composition of  claim 8 , wherein the melatonin agonist is selected from the group consisting of melatonin, ramelteon and agomelatine. 
     
     
         12 . The composition of  claim 8 , wherein the ion channel blocker is selected from the group consisting of lamotrigine, gabapentin and pregabalin. 
     
     
         13 . The composition of  claim 8 , wherein the serotonin-2 antagonist/reuptake inhibitor (SARIs) is Org 50081, ritanserin, nefazodone, serzone or trazodone. 
     
     
         14 . The composition of  claim 8 , wherein the 5HT1a agonist is repinotan, sarizotan, eptapirone, buspirone or MN-305. 
     
     
         15 . The composition of  claim 8 , wherein the orexin receptor antagonist is orexin, a 1,3-biarylurea, SB-334867-a, ACT-078573 or a benzamide derivative. 
     
     
         16 . The composition of any  claim 8 , wherein said composition comprises doxepin, pharmaceutically acceptable salt or prodrug thereof, in a dosage of 0.01-49 mg. 
     
     
         17 . The composition of  claim 8 , wherein the dosage of doxepin is between about 0.5 mg and about 6 mg. 
     
     
         18 . A method for selecting a sleep drug therapy for a patient from among available therapies, comprising:
 evaluating whether the patient is in need of both sleep onset and sleep maintenance therapy, and if so;   selecting for the patient a composition of  claim 1 .   
     
     
         19 . A method for selecting a sleep drug therapy for a patient from among available therapies, comprising:
 evaluating whether the patient is in need of both sleep onset and sleep maintenance therapy, and if so;   selecting for the patient a composition of  claim 8 .