Ultra low dose doxepin and methods of using the same to treat sleep disorders

Abstract

The invention relates to doxepin, pharmaceutically acceptable salts and prodrugs of doxepin; compositions containing the same, and the use of any of the aforementioned for the treatment of sleep disorders.

1 . A method for treating insomnia comprising administering to a patient doxepin, a pharmaceutically acceptable salt thereof, or a prodrug thereof in a daily dosage ranging from about 0.0001 to about 0.49 milligrams. 
     
     
         2 . The method of  claim 1 , wherein the pharmaceutically acceptable salt of doxepin is the hydrochloride salt thereof. 
     
     
         3 . The method of  claim 1 , wherein the prodrug of doxepin is a prodrug ester. 
     
     
         4 . The method of  claim 1 , wherein the daily dosage is about 0.0001 to about 0.1 milligrams. 
     
     
         5 . The method of  claim 1 , wherein the daily dosage ranges from about 0.001 to about 0.1 milligrams. 
     
     
         6 . The method of  claim 1 , wherein the daily dosage is about 0.01 to about 0.099 milligrams. 
     
     
         7 . The method of  claim 1 , wherein the insomnia is a chronic insomnia or a non-chronic insomnia. 
     
     
         8 . The method of  claim 7 , wherein the non-chronic insomnia is a transient or a short term insomnia. 
     
     
         9 . The method of  claim 1 , wherein the insomnia is selected from the group consisting of onset insomnia and maintenance insomnia. 
     
     
         10 . The method of any of  claims 1 - 9 , wherein the patient is not suffering from depression. 
     
     
         11 . The method of any of  claims 1 - 9 , wherein the patient is suffering from depression. 
     
     
         12 . The method of  claim 1 , further comprising administering at least one of ramelteon, eszopiclone, zolpidem tartrate, or zaleplon. 
     
     
         13 . The method of  claim 1 , further comprising administering at least one additional sleep medication. 
     
     
         14 . The method of  claim 13 , wherein the at least one additional sleep medication is selected from a 5-HT2 antagonist, ketanserin, a H3 agonist, an orexin antagonist, a noradrenergic antagonist, a galanin agonist, a CRH antagonist, Gaboxadol, other GABA-A direct antagonists, a GABA reuptake inhibitor, tiagabine, a growth hormone, a growth hormone agonist, estrogen, an estrogen agonist, or a melatonin agonist. 
     
     
         15 . A composition comprising doxepin, a pharmaceutically acceptable salt thereof, or a prodrug of doxepin in a dosage of about 0.0001 milligrams to about 0.49 milligrams. 
     
     
         16 . The composition of  claim 15 , further comprising a pharmaceutically acceptable carrier. 
     
     
         17 . The composition of  claim 15 , wherein the pharmaceutically acceptable salt of doxepin is the hydrochloride salt thereof. 
     
     
         18 . The composition of  claim 15 , wherein the prodrug is an ester. 
     
     
         19 . The composition of  claim 15 , comprising a dosage of about 0.001 to about 0.1 milligrams of doxepin, a pharmaceutically acceptable salt of doxepin or a prodrug doxepin. 
     
     
         20 . The composition of  claim 15 , comprising a dosage of about 0.01 to about 0.099 milligrams of doxepin, a pharmaceutically acceptable salt of doxepin or a prodrug of doxepin. 
     
     
         21 . The composition of  claim 15 , wherein the composition is in a form suitable for oral or nasal administration. 
     
     
         22 . The composition of any of  claim 15 ,  16 ,  17 ,  18 ,  19 ,  20 , or  21 , further comprising at least one of ramelteon, eszopiclone, zolpidem tartrate, or zaleplon. 
     
     
         23 . The composition of any of  claim 15 ,  16 ,  17 ,  18 ,  19 ,  20 , or  21 , further comprising at least one additional sleep medication. 
     
     
         24 . The composition of  claim 25 , wherein the at least one additional sleep medication is selected from a 5-HT2 antagonist, ketanserin, a H3 agonist, an orexin antagonist, a noradrenergic antagonist, a galanin agonist, a CRH antagonist, Gaboxadol, other GABA-A direct antagonists, a GABA reuptake inhibitor, tiagabine, a growth hormone, a growth hormone agonist, estrogen, an estrogen agonist, or a melatonin agonist. 
     
     
         25 . A method of shortening the time required to achieve a maximum plasma concentration of doxepin in a patient receiving doxepin therapy comprising administering to the patient about 0.0001 milligrams to about 0.49 milligrams of doxepin in a pharmaceutical composition without food. 
     
     
         26 . A method of shortening the time required to achieve sleep onset comprising administering to the patient about 0.0001 milligrams to about 0.49 milligrams of doxepin in a pharmaceutical composition without food. 
     
     
         27 . A method of treating a sleep disorder comprising providing a patient with about 0.0001 milligrams to about 0.49 milligrams of doxepin and providing the patient with instructions to take the doxepin without food. 
     
     
         28 . A method of increasing the oral bioavailability of doxepin, comprising administering with food to a patient a pharmaceutical oral dosage form of doxepin in an amount of about 0.0001 milligrams to about 0.49 milligrams. 
     
     
         29 . A method of increasing the oral bioavailability of doxepin to a patient receiving doxepin therapy, comprising administering to the patient with food a pharmaceutical oral dosage form of doxepin comprising about 0.0001 milligrams to about 0.49 milligrams of doxepin, wherein the administration results in an AUC 0-∞ , that is greater than that achieved by the administration of the same amount of doxepin without food. 
     
     
         30 . A method of treating depression or anxiety, comprising administering about 0.0001 milligrams to about 0.49 milligrams of doxepin with food. 
     
     
         31 . A method of treating depression or anxiety, comprising providing a patient with doxepin in an amount of about 0.0001 milligrams to about 0.49 milligrams and providing the patient with instructions to take the doxepin with food. 
     
     
         32 . A method of treating depression or anxiety comprising providing a patient with doxepin in an amount of about 0.0001 milligrams to about 0.49 milligrams and providing the patient with information regarding a doxepin food effect. 
     
     
         33 . A method of decreasing the oral bioavailability of doxepin, comprising administering to a patient a pharmaceutical oral dosage form of doxepin comprising doxepin in an amount of about 0.0001 milligrams to about 0.49 milligrams without food. 
     
     
         34 . A method of decreasing the oral bioavailability of doxepin to a patient receiving doxepin therapy, comprising administering to the patient without food a pharmaceutical oral dosage form of doxepin comprising doxepin in an amount of about 0.0001 milligrams to about 0.49 milligrams, wherein the administration results in an AUC 0-∞  that is less than that achieved by the administration of the same amount of doxepin with food. 
     
     
         35 . A method of alleviating a doxepin food effect comprising administering about 0.0001 milligrams to about 0.49 milligrams of doxepin to a patient in need thereof, wherein the patient is in a non-fasted state. 
     
     
         36 . A method of alleviating a doxepin food effect comprising administering about 0.0001 milligrams to about 0.49 milligrams of doxepin to a patient in need thereof, wherein the patient is in a fasted state. 
     
     
         37 . A method of minimizing side effects associated with a doxepin therapy, comprising administering about 0.0001 milligrams to about 0.49 milligrams of doxepin to a patient with food. 
     
     
         38 . A method for improving the consistency of pharmacokinetics associated with doxepin therapy, in which a patient receives a multiple doxepin dosages over multiple days, comprising administering about 0.0001 milligrams to about 0.49 milligrams of doxepin to the patient in a fixed temporal relationship to food intake by the patient. 
     
     
         39 . A product comprising doxepin in an amount of about 0.0001 milligrams to about 0.49 milligrams and written instructions associated therewith to take the doxepin without food. 
     
     
         40 . A product comprising doxepin in an amount of about 0.0001 milligrams to about 0.49 milligrams and written instructions associated therewith to take the doxepin with food. 
     
     
         41 . A product comprising doxepin in an amount of about 0.0001 milligrams to about 0.49 milligrams and written information associated therewith regarding a doxepin food effect.