WO2014145045A1

WO2014145045A1 - Compositions and methods for transmucosal absorption

Info

Publication number: WO2014145045A1
Application number: PCT/US2014/029688
Authority: WO
Inventors: Seth Lederman
Original assignee: Tonix Pharmaceuticals, Inc.
Priority date: 2013-03-15
Filing date: 2014-03-14
Publication date: 2014-09-18

Abstract

The invention provides compositions and methods for administering compounds for transmucosal absorption. The compositions and methods have a number of surprising pharmacokinetic benefits over oral administration of a compound.

Description

Compositions and Methods for Transmucosal Absorption Related Application

[0001] This application claims priority and benefit from U.S. Provisional Patent Application 61/792,819, filed March 15, 2013, the contents and disclosures of which are hereby incorporated by reference in their entirety.

Background of the Invention

[0002] Doxepin, or (£'/Z)-3-(dibenzo[^,g]oxepin-l l(6H)-ylidene)-N,N-dimethylpropan- 1 -amine, was approved by the U.S. Food and Drug Administration as an oral medication for the treatment depression and has been marketed under trade names including:

Aponal®, Adapine®, Doxal®, Deptran®, Sinquan® and Sinequan®). Doxepin is a tricyclic antidepressant that is formulated as an irrational mixture of E (trans) and Z (cis) stereoisomers: 85%: 15%, respectively (Haritos VS, et al.

Pharmacogenetics. 2000 Oct;10(7):591-603.). Doxepin was developed and approved in the U.S. as an oral medication for the treatment of insomnia and sleep maintenance and marketed under the tradename,Silenor®. Doxepin was also developed and approved in topical forms to treat itch and are marketed under tradenames including; Zonalon® and Xepin®). Doxepin is used off-label to treat anxiety disorders and chronic idiopathic uricaria. Doxepin is a mixture of mixture of E (trans) and Z (cis) stereoisomers. Imipramine, or 3-(10,l l-dihydro-5H-dibenzo[^,/]azepin-5-yl)-N,N-dimethylpropan-l- amine, was first approved by the U.S. Food and Drug Administration for the treatment of depression.

[0003] Imipramine (also known as melipramine) has been sold under tradenames including: Antideprin®, Deprimin®, Deprinol®, Depsol®, Depsonil®,

Dynaprin®, Eupramin®, Imipramil® Irmin®, Janimine®, Melipramin®,

Surplix®, Tofranil®. Imipramine is a tricyclic antidepressant of the dibenzazepine group. Imipramine is mainly used in the treatment of major depression, but is also used to treat enuresis, migraines, ADHD, post concussive syndrome, panic attacks, chronic pain, and Kleine-Levin syndrome. In pediatric patients, it is commonly used to treat pavor nocturnus and nocturnal enuresis. [0004] Cyclobenzaprine is a structural analogue to doxepin and imipramine that has been has been studied for fibromyalgia and other uses where the object of therapy is to have high dose-intensity during sleep and rapid clearance and low blood levels the next day. Studies have shown cyclobenzaprine to also be effective in the treatment of fibromyalgia syndrome, post- traumatic stress disorder (PTSD), traumatic brain injury (TBI), generalized anxiety disorder and depression.

Furthermore, the utility of cyclobenzaprine as an agent for improving the quality of sleep, as a sleep deepener, or for treating sleep disturbances has been investigated. Treatment with cyclobenzaprine may be particularly useful in treating sleep disturbances caused by, exacerbated by, or associated with fibromyalgia syndrome, prolonged fatigue, chronic fatigue, chronic fatigue syndrome, a sleep disorder, a psychogenic pain disorder, chronic pain syndrome (type II), the administration of a drug, autoimmune disease, stress or anxiety, or for treating an illness caused by or exacerbated by sleep disturbances, and symptoms of such illness. See, for example, U.S. Patent Nos. 6,395,788 and 6,358,944, incorporated herein by reference..

[0005] Despite the broad therapeutic usefulness of doxepin and imipramine, these agents often cause fatigue, somnolence, a groggy feeling, or cognitive impairment in individuals, which is not desirable during normal periods of wakefulness. Doxepin can only be used at low doses for sleep because otherwise next morning grogginess results. As an oral agent, imipramine is only

recommended for long-term usage, where the goal of therapy is to have prolonged, high levels of drugs and active metabolites in the plasma at tissue sites of action and in the body. No pulsatile therapeutic regimens are approves such that daily dosing would have high blood levels at night and low blood levels during the day. Thus, improved formulations of doxepin, E-doxepin, Z-doxepin and imipramine are desirable.

Summary of the Invention

[0006] In some embodiments, the invention provides a composition comprising doxepin, wherein the composition is suitable for transmucosal absorption. In some embodiments, the invention provides a composition comprising doxepin and a basifying agent, wherein the composition is suitable for transmucosal absorption.

[0007] In some embodiments, the invention provides a composition comprising imipramine, wherein the composition is suitable for transmucosal absorption. In some embodiments, the invention provides a composition comprising imipramine and a basifying agent, wherein the composition is suitable for transmucosal absorption.

[0008] In certain embodiments, the basifying agent is selected from the group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate and trisodium citrate. [0009] In certain embodiments, the transmucosal absorption is oral absorption. In certain embodiments, the composition is suitable for sublingual administration. In further embodiments, the composition is in a form selected from the group consisting of a sublingual tablet, a sublingual film, a sublingual powder, and a sublingual spray solution. [0010] In certain embodiments, the composition is suitable for buccal administration. In further embodiments, the composition is in a form selected from the group consisting of a buccal tablet, a lozenge, a buccal powder, and a buccal spray solution.

[0011] In certain embodiments, the transmucosal absorption is intranasal absorption. In further embodiments, the composition is in a form of a nasal spray solution. In certain embodiments, the transmucosal absorption is pulmonary absorption. In further embodiments, the composition is in a form selected from the group consisting of an aerosolized composition and an inhalable dry powder. [0012] In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 50 + 25% x 10^~9 mL^"1 10 minutes after administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 125 + 25% x 10^"9 mL^"1 15 minutes after administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 150 + 25% x 10^"9 mL^"1 20 minutes after administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 300 + 25% x 10^"9 mL^"1 30 minutes after administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 450 + 25% x 10^"9 mL^"1 45 minutes after administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 600 + 25% x 10^"9 mL^"1 1 hour after administration. In some

embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 700 + 25% x 10^"9 mL^"1 2 hours after administration. In some

embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 750 + 25% x 10^"9 mL^"1 2.5 (150 min) hours after administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 850 + 25% x 10^"9 mL^"1 3 hours after administration. In some

embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 900 + 25% x 10^"9 mL^"1 3.3 hours (200 min) after administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 950 + 25% x 10^~9 mL^"1 3.7 (220 min) hours after administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 1000 + 25% x 10^"9 mL^"1 4 hours after administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 1000 + 25% x 10^"9 mL^"1 4.33 (260 min) hours after administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 1050 + 25% x 10^"9 mL^"1 4.67 hours (280 min) after administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 1000 + 25% x 10^"9 mL^"1 5 hours after administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 1000 + 25% x 10^"9 mL^"1 5.5 hours after administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 900 + 25% x 10^"9 mL^"1 6 hours after administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 700 + 25% x 10^"9 mL^"1 8 hours after administration. In some

embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of less than or equal to 650 + 25% x 10^"9 mL^"1 10 hours after administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of less than or equal to 500 + 25% x 10^"9 mL^"1 12 hours after administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of less than or equal to 500 + 25% x 10^"9 mL^"1 14 hours after administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of less than or equal to 350 + 25% x 10^~9 mL^"1 16 hours after administration. In some

embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of less than or equal to 350 + 25% x 10^"9 mL^"1 18 hours after administration. In some

embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of less than or equal to 300 + 25% x 10^"9 mL^"1 20 hours after administration. In some

embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of less than or equal to 300 + 25% x 10^"9 mL^"1 22 hours after administration. In some

embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of less than or equal to 300 + 25% x 10^"9 mL^"1 24 hours after administration. In some

embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of less than or equal to 200 + 25% x 10^"9 mL^"1 36 hours after administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of less than or equal to 150 + 25% x 10^"9 mL^"1 48 hours after administration. In some

embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of less than or equal to 100 + 25% x 10^"9 mL^"1 72 hours after administration. In some

embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 2.0 + 25% x 10^"9 mL^"1 30 minutes after administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 2.0 + 25% x 10^"9 mL^"1 45 minutes after administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 2.0 + 25% x 10^"9 mL^"1 1 hour after administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 2.0 + 25% x 10^"9 mL^"1 2 hours after administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 2.0 + 25% x 10^"9 mL^"1 3 hours after administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of less than or equal to 5.0 +

25% x 10 -^"7 mL -^"1 8 hours after administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of less than or equal to 5.0 +

25% x 10 -^"7 mL -^"1 10 hours after administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of less than or equal to 5.0 + 25% x 10 -^"7 mL -^"1 12 hours after administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of less than or equal to 5.0 +

25% x 10 -^"7 mL -^"1 14 hours after administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of less than or equal to 5.0 +

25% x 10 -^"7 mL -^"1 16 hours after administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of less than or equal to 5.0 +

25% x 10 -^"7 mL -^"1 18 hours after administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of less than or equal to 5.0 +

25% x 10 -^"7 mL -^"1 20 hours after administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of less than or equal to 5.0 + 25% x 10 -^"7 mL -^"1 22 hours after administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of less than or equal to 5.0 +

25% x 10 -^"7 mL -^"1 24 hours after administration.

[0013] In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnAUCo-8h of greater than or equal to 5 + 25% x 10^"6 mL^"1 hr. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnAUCo-∞h of greater than or equal to 20 + 25% x 10^"6 mL^"1 hr. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC_max* of greater than or equal to 1.0 + 25% x 10^"6 mL^"1. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a partial AUCo-20min of greater than or equal to 37 + 25% ng hr L^"1, an AUCo-30min of greater than or equal to 128 + 25% ng hr L^"1, an AUCo-45min of greater than or equal to 333 + 25% ng hr L^"1, an AUCo-ih of greater than or equal to 614 + 25% ng hr L^"1, an AUCo-2h of greater than or equal to 2098 + 25% ng hr L^"1, an AUCo-2.5h of greater than or equal to 2955 + 25% ng hr L^"1, an AUC₀-₃h of greater than or equal to 3931 + 25% ng hr L^"1. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a partial AUCo-20min of greater than or equal to 23 + 25% ng hr L^"1, an AUCo-₃omin of greater than or equal to 86 + 25% ng hr L^"1, an AUCo-45min of greater than or equal to 223 + 25% ng hr L^"1, an AUCo-ih of greater than or equal to 405 + 25% ng hr L^"1, an AUCo-2h of greater than or equal to 1478 + 25% ng hr L^"1, an AUCo-2.5h of greater than or equal to 2167 + 25% ng hr L^"1. In some embodiments, the dnAUCo-20min is about 0.02 + 25% x 10^"6 hr mL^"1, the dnAUC₀-₃₀min is about 0.05 + 25% x 10^"6 hr mL^"1, the dnAUC₀-45min is about 0.15 + 25% x 10^"6 hr mL^"1, the dnAUC₀-i_h is about 0.25 + 25% x 10^"6 hr mL^"1, the dnAUC₀-_2h is about 0.9 + 25% x 10^"6 hr mL^"1, the dnAUC₀-₂.5h is about 1.2 + 25% x 10^"6 hr mL^"1, the dnAUC₀-_3h is about 1.5 + 25% x 10^"6 hr mL^"1, the dnAUC_{3 3h} is about 1.8 + 25% x 10^"6 hr mL^"1, dnAUC₀-₃.7h is about 2.3 + 25% x 10^"6 hr mL^"1, the dnAUC₀-₄h is about 2.6 + 25% x 10^"6 hr mL^"1, the dnAUC₀-_{4 3}h is about 3.0 + 25% x 10^"6 hr mL^"1, the dnAUCo- ₄.7h is about 3.3 + 25% x 10^"6 hr mL^"1, the dnAUCo-5h is about 3.7 + 25% x 10^"6 hr mL^"1, the dnAUCo-s.sh is about 4.2 + 25% x 10^"6 hr mL^"1, the dnAUC₀-₆h is about 4.7 + 25% x 10^"6 hr mL^"1, the dnAUC₀-_8h is 6.30 + 25% x 10^"6 hr mL^"1, the dnAUC₀-i2h is about 20 + 25% x 10^"6 hr mL^"1, and the dnAUC₀-∞h is about 25 + 25% x 10^"6 hr mL^"1.

[0014] In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dbmnAUCo-20min of greater than or equal to 1.0 + 25% x 10^"6 kg hr mL^"1. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dbmnAUCo-30min of greater than or equal to 3.5 + 25% x 10^"6 kg hr mL^"1. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dbmnAUCo-45min of greater than or equal to 10 + 25% x 10^"6 kg hr mL^"1. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dbmnAUCo-ih of greater than or equal to 18 + 25% x 10^"6 kg hr mL^"1. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dbmnAUCo-2h of greater than or equal to 60 + 25% x 10^"6 kg hr mL^"1. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dbmnAUCo-2.5h of greater than or equal to 85 + 25% x 10^"6 kg hr mL^"1. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dbmnAUCo-3h of greater than or equal to 115 + 25% x 10^"6 kg hr mL^"1. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dbmnAUCs jh of greater than or equal to 135 + 25% x 10^"6 kg hr mL^"1. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has adbmnAUCo-3.7h of greater than or equal to 160 + 25% x 10^"6 kg hr mL^"1. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dbmnAUCo-4h of greater than or equal to 180 + 25% x 10^"6 kg hr mL^"1. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dbmnAUCo-4.3h of greater than or equal to 210 + 25% x 10^"6 kg hr mL^"1. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dbmnAUCo-4.7h of greater than or equal to 230 + 25% x 10^"6 kg hr mL^"1. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dbmnAUCo-5h of greater than or equal to 250 + 25% x 10^"6 kg hr mL^"1. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dbmnAUCo-s.s_h of greater than or equal to 290 + 25% x 10^"6 kg hr mL^"1. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dbmnAUCo-6h of greater than or equal to 330 + 25% x 10^"6 kg hr mL^"1. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dbmnAUCo-8h is 440 + 25% x 10^"6 kg hr mL^"1. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dbmnAUCo-i2h of greater than or equal to 1500 + 25% x 10^"6 kg hr mL^"1. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dbmnAUCo-inf of greater than or equal to 1800 + 25% x 10^"6 kg hr mL^"1

[0015] In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a plasma concentration of 50% or less of the C_max 8 hours after administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a plasma concentration of 50% or less of the C_max 12 hours after administration.

[0016] In some embodiments, doxepin is present in a composition of the invention in an amount from 0.1 mg to 10 mg, for example, from 0.1 mg to 5 mg. In certain embodiments, the doxepin is present in an amount of about 2.4 mg, less than about 2.4 mg, about 4.8 mg, or less than about 4.8 mg. In certain

embodiments, the doxepin is present in an amount of about 2.8 mg, less than about 2.8 mg, about 5.6 mg, or less than about 5.6 mg. In certain embodiments, the doxepin is present in an amount of about 4.5 mg, less than about 5 mg, about 9 mg, or less than about 10 mg.

[0017] In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the composition affords a C_max of doxepin greater than or equal to 10 ng/mL. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the composition affords a C_max of doxepin greater than or equal to 15 ng/mL, greater than or equal to 20 ng/mL, greater than or equal to 25 ng/mL or greater than or equal to 30 ng/mL. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the composition affords a C_max of doxepin greater than or equal to 2.5 ng/mL, greater than or equal to 3 ng/mL, greater than or equal to 4 ng/mL, greater than or equal to 10 ng/mL. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the composition affords a C_max of doxepin greater than or equal to 2.74 ng/mL, greater than or equal to 3.20 ng/mL, greater than or equal to 5.13 ng/mL or greater than or equal to 10.27 ng/mL. [0018] In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the composition affords a C_max of doxepin greater than or equal to 10 ng/mL, greater than or equal to 15 ng/mL, greater than or equal to 20 ng/mL, greater than or equal to 25 ng/mL, or greater than or equal to 30 ng/mL above the baseline level of doxepin in the individual immediately prior to administration. In some embodiments relating to repeated, repetitive, daily and chronic dosing, a composition is characterized in that, when administered by transmucosal absorption, the composition affords a C_max of doxepin greater than or equal to 10 ng/mL, greater than or equal to 15 ng/mL, greater than or equal to 20 ng/mL, greater than or equal to 25 ng/mL, or greater than or equal to 30 ng/mL above the baseline level of doxepin in the individual immediately prior to administration. In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the composition affords a C_max of doxepin greater than or equal to 2.74 ng/ml, greater than or equal to 3.20 ng/ml, greater than or equal to 5.13 ng/ml, or greater than or equal to 10.27 ng/ml above the baseline level of doxepin in the individual immediately prior to administration. In some embodiments relating to repeated, repetitive, daily and chronic dosing, a composition is characterized in that, when administered by transmucosal absorption, the composition affords a C_max of doxepin greater than or equal to 10 ng/ml, greater than or equal to 15 ng/ml, greater than or equal to 20 ng/ml, greater than or equal to 25 ng/ml, or greater than or equal to 30 ng/ml above the baseline level of doxepin in the individual immediately prior to administration.

[0019] In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the composition affords a t_max of doxepin of less than 4.70 hours. [0020] In some embodiments, a composition is characterized in that, when administered by transmucosal absorption, the composition affords a plasma level of doxepin that decreases by at least 50%, by at least 60%, by at least 70%, by at least 80% the C_max by 8 hours after administration.

[0021] In some embodiments, the invention provides a method for treating a disease or condition in an individual in need thereof comprising administering a composition as described herein by transmucosal absorption. An exemplary disease or condition is post- traumatic stress disorder (PTSD). In further embodiments, administration of the composition treats the development of PTSD following a traumatic event, the initiation of PTSD following a traumatic event, the consolidation of PTSD following a traumatic event, or the perpetuation of PTSD following a traumatic event. In certain embodiments, the disease or condition is selected from the group consisting of fibromyalgia, depression, traumatic brain injury, sleep disorder, non-restorative sleep, chronic pain, muscle spasm, acute pain, and anxiety disorder. [0022] In some embodiments, the basifying agent useful in methods of the invention is selected from the group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, tripotassium citrate, dipotassium citrate, trisodium citrate and disodium citrate.

[0023] In some embodiments, the oral absorption in a method of the invention is sublingual absorption. In certain embodiments, the composition is in a form selected from the group consisting of a sublingual tablet, a sublingual film, a sublingual powder, and a sublingual spray solution.

[0024] In some embodiments, the oral absorption in a method of the invention is buccal absorption. In certain embodiments, the composition is selected from the group consisting of a buccal tablet, a lozenge, a buccal powder, and a buccal spray solution.

[0025] In some embodiments, the transmucosal absorption useful in a method of the invention is intranasal absorption. In certain embodiments, the composition is in a form of a nasal spray solution. [0026] In some embodiments, the transmucosal absorption useful in a method of the invention is pulmonary absorption. In certain embodiments, the composition is in a form selected from the group consisting of an aerosolized composition and an inhalable dry powder.

[0027] In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of greater than or equal to 8.0 + 25% x 10^" mL^"1 15 minutes after administration, greater than or equal to 1.0 + 25% x 10^"6 mL^"1 30 minutes after administration, greater than or equal to 1.0 + 25% x 10^"6 mL^"1 45 minutes after administration, greater than or equal to 1.0 + 25% x 10^"6 mL^"1 1 hour after administration, greater than or equal to 1.0 + 25% x 10^"6 mL^"1 2 hours after administration, or greater than or equal to 1.0 x mL^" 3 hours after administration. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of less than or equal to 5.0 + 25% x 10^" mL^"1 8 hours after administration. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of less than or equal to 5.0

+ 25% x 10 -^"7 mL -^"1 10 hours after administration. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of less than or equal to 5.0 + 25% x 10 -^"7 mL -^"1 12 hours after administration. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of less than or equal to 5.0 + 25% x 10 -^"7 mL -^"1 14 hours after administration. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of less than or equal to 5.0 + 25% x 10^" mL^"1 16 hours after administration. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of less than or equal to 5.0 + 25% x 10 -^"7 mL -^"1 18 hours after administration. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of less than or equal to 5.0 + 25% x 10 -^"7 mL -^"1 20 hours after administration. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of less than or equal to 5.0 + 25% x 10 -^"7 mL -^"1 22 hours after administration. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of less than or equal to 5.0 + 25% x 10^" mL^"1 24 hours after administration. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of greater than or equal to 50 + 25% x 10^"9 mL^"1 10 minutes after administration. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of greater than or equal to 150 + 25% x 10^"9 mL^"1 20 minutes after administration. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of greater than or equal to 300 + 25% x 10^"9 mL^"1 30 minutes after administration. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of greater than or equal to 450 + 25% x 10^"9 mL^"1 45 minutes after administration. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of greater than or equal to 600 + 25% x 10^"9 mL^"1 1 hour after administration. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of greater than or equal to 700 + 25% x 10^"9 mL^"1 2 hours after administration. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of greater than or equal to 750 + 25% x 10^"9 mL^"1 2.5 hours after administration. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of greater than or equal to 850 + 25% x 10^"9 mL^"1 3 hours after administration. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of greater than or equal to 900 + 25% x 10^"9 mL^"1 3.3 hours after administration. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of greater than or equal to 950 + 25% x 10^"9 mL^"1 3.7 hours after administration. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of greater than or equal to 1000 + 25% x 10^"9 mL^"1 4 hours after administration. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of greater than or equal to 1050 + 25% x 10^"9 mL^"1 4.33 hours after administration. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of less than or equal to 1050 + 25% x 10^"9 mL^"1 4.67 hours after administration. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of less than or equal to 1000 + 25% x 10^"9 mL^"1 5 hours after administration. In some

embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of less than or equal to 1000 + 25% x 10^"9 mL^"1 5.5 hours after administration. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of less than or equal to 900 + 25% x 10^"9 mL^"1 6 hours after administration. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of less than or equal to 700 + 25% x 10^"9 mL^"1 8 hours after administration. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of less than or equal to 500 + 25% x 10^"9 mL^"1 12 hours after administration. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of less than or equal to 350 + 25% x 10^"9 mL^"1 16 hours after administration. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of less than or equal to 300 + 25% x 10^"9 mL^"1 24 hours after administration. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of less than or equal to 180 + 25% x 10^"9 mL^"1 36 hours after administration. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of less than or equal to 140 + 25% x 10^"9 mL^"1 48 hours after administration. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC* of less than or equal to 90 + 25% x 10^"9 mL^"1 72 hours after

administration.

[0028] In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnAUCo-8h of greater than or equal to 5 mL^"1 hr. In some embodiments, the doxepin or imipramine has a dnAUCo-∞h of greater than or equal to 20 mL^"1 hr. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC_max* of greater than or equal to 1.0 + 25% x 10^"6 mL^"1. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnAUCo-8h of greater than or equal to 6.3 + 25% x lO^ hr mL^"1. In some embodiments, the doxepin or imipramine has a dnAUCo-∞h of greater than or equal to 25 + 25% x 10^"6 hr mL^"1. In some embodiments, the invention provides a method wherein the doxepin or imipramine has a dnC_max* of greater than or equal to 1.1 + 25% x 10^"6 mL^"1.

[0029] In some embodiments, the invention provides a method wherein the doxepin or imipramine has a plasma concentration of 50% or less of the C_max 4 hours after administration, 50% or less of the C_max 6 hours after administration,

50% or less of the C_max 8 hours after administration, or 50% or less of the C_max 12 hours after administration.

[0030] In some embodiments, the invention provides a method wherein the doxepin is present in the composition in an amount from 0.1 mg to 10 mg. In certain embodiments, the doxepin is present in the composition in an amount from 0.1 mg to 5 mg, for example, in an amount of about 2.4 mg, in an amount of less than about 2.4 mg, in an amount of about 4.8 mg, or in an amount of less than about 4.8 mg or in an amount of about 2.8 mg, in an amount of less than about 2.8 mg, in an amount of about 5.6 mg, or in an amount of less than about 5.6 mg, in an amount of about 9.0 mg, in an amount of less than about 10 mg [0031] In some embodiments, the invention provides a method wherein a composition affords a C_max of doxepin greater than or equal to 10 ng/mL, greater than or equal to 15 ng/mL, greater than or equal to 20 ng/mL, greater than or equal to 25 ng/mL, greater than or equal to 30 ng/mL, greater than or equal to 40 ng/mL, greater than or equal to 50 ng/mL, greater than or equal to 60 ng/mL, greater than or equal to 70 ng/mL, greater than or equal to 80 ng/mL, greater than or equal to 90 ng/mL, greater than or equal to 100 ng/mL, greater than or equal to 120 ng/mL, greater than or equal to 140 ng/mL, greater than or equal to 150 ng/mL, greater than or equal to 160 ng/mL, greater than or equal to 170 ng/mL, greater than or equal to 180 ng/mL, greater than or equal to 190 ng/mL, greater than or equal to 200 ng/mL, greater than or equal to 220 ng/mL, greater than or equal to 240 ng/mL, greater than or equal to 260 ng/mL, or greater than or equal to 280 ng/mL. In some embodiments, the invention provides a method wherein a composition affords a C_max of doxepin greater than or equal to 2.74 ng/ml, greater than or equal to 3.20 ng/ml, greater than or equal to 5.13 ng/ml, greater than or equal to 10.27 ng/ml, greater than or equal to 2 ng/ml, greater than or equal to 3 ng/ml.

[0032] In some embodiments, the invention provides a method wherein a composition affords a C_max of doxepin greater than or equal to 10 ng/mL above the baseline level, greater than or equal to 15 ng/mL above the baseline level, greater than or equal to 20 ng/mL above the baseline level, greater than or equal to 25 ng/mL above the baseline level, greater than or equal to 30 ng/mL above the baseline level, greater than or equal to 40 ng/mL above the baseline level, greater than or equal to 50 ng/mL above the baseline level, greater than or equal to 60 ng/mL above the baseline level, greater than or equal to 70 ng/mL above the baseline level, greater than or equal to 80 ng/mL above the baseline level, greater than or equal to 90 ng/mL above the baseline level, greater than or equal to 100 ng/mL above the baseline level, greater than or equal to 120 ng/mL above the baseline level, greater than or equal to 140 ng/mL above the baseline level, greater than or equal to 150 ng/mL above the baseline level, greater than or equal to 160 ng/mL above the baseline level, greater than or equal to 170 ng/mL above the baseline level, greater than or equal to 180 ng/mL above the baseline level, greater than or equal to 190 ng/mL above the baseline level, greater than or equal to 200 ng/mL above the baseline level, greater than or equal to 220 ng/mL above the baseline level, greater than or equal to 240 ng/mL above the baseline level, greater than or equal to 260 ng/mL above the baseline level, or greater than or equal to 280 ng/mL above the baseline level of doxepin in the individual immediately prior to administration. In some embodiments relating to repeated, repetitive, daily and chronic dosing, the invention provides a method wherein a composition affords a Cmax of doxepin greater than or equal to 10 ng/mL above the baseline level, greater than or equal to 15 ng/mL above the baseline level, greater than or equal to 20 ng/mL above the baseline level, greater than or equal to 25 ng/mL above the baseline level, greater than or equal to 30 ng/mL above the baseline level, greater than or equal to 40 ng/mL above the baseline level, greater than or equal to 50 ng/mL above the baseline level, greater than or equal to 60 ng/mL above the baseline level, greater than or equal to 70 ng/mL above the baseline level, greater than or equal to 80 ng/mL above the baseline level, greater than or equal to 90 ng/mL above the baseline level, greater than or equal to 100 ng/mL above the baseline level, greater than or equal to 120 ng/mL above the baseline level, greater than or equal to 140 ng/mL above the baseline level, greater than or equal to 150 ng/mL above the baseline level, greater than or equal to 160 ng/mL above the baseline level, greater than or equal to 170 ng/mL above the baseline level, greater than or equal to 180 ng/mL above the baseline level, greater than or equal to 190 ng/mL above the baseline level, greater than or equal to 200 ng/mL above the baseline level, greater than or equal to 220 ng/mL above the baseline level, greater than or equal to 240 ng/mL above the baseline level, greater than or equal to 260 ng/mL above the baseline level, or greater than or equal to 280 ng/mL above the baseline level, of doxepin in the individual immediately prior to administration. In some embodiments, the invention provides a method wherein a composition affords a C_max of doxepin greater than or equal to 2.74 ng/ml above the baseline level, greater than or equal to 3.20 ng/ml above the baseline level, greater than or equal to 5.13 ng/ml above the baseline level, greater than or equal to 10.27 ng/ml above the baseline level, greater than or equal to 2 ng/ml above the baseline level, greater than or equal to 3 ng/ml above the baseline level, 10 ng/ml, greater than or equal to 15 ng/ml above the baseline level, greater than or equal to 20 ng/ml above the baseline level, greater than or equal to 25 ng/ml above the baseline level, greater than or equal to 30 ng/ml above the baseline level, greater than or equal to 40 ng/ml above the baseline level.

[0033] In some embodiments, the invention provides a method wherein a composition affords a t_max of doxepin of less than 4 hours, less than 3 hours, less than 2 hours, less than 1 hour, less than 45 minutes, less than 30 minutes, less than 15 minutes, less than 10 minutes, or less than 5 minutes.

[0034] In some embodiments, the invention provides a method wherein the composition affords a plasma level of doxepin that decreases by at least 50% of the C_max by 8 hours after administration, by at least 60% of the C_max by 8 hours after administration, by at least 70% of the C_max by 8 hours after administration, by at least 80% of the C_max by 8 hours after administration, by at least 90% of the C_max by 8 hours after administration, or by at least 95% of the C_max by 8 hours after administration. [0035] In some embodiments, the invention provides a composition comprising doxepin for transmucosal administration comprising from about 2 to about 20 mg of doxepin or a salt thereof, the formulation affording a C_max of doxepin from about 20 to about 200 ng/mL from about 0.05 to about 2.5 hours after

administration, and a minimum doxepin plasma concentration from about 1 to about 5 ng/mL from about 22 to about 26 hours after administration, wherein the composition is administered for four days or more of daily administration. In some embodiments, the invention provides a composition comprising doxepin for transmucosal administration comprising from about 2 to about 20 mg of doxepin or a salt thereof, the formulation affording a C_max of doxepin from about 1.0 ng/ml to about 30.0 ng/ml from about 2 to about 5.0 hours after administration, and a minimum plasma concentration from about 1 to about 5 ng/ml from about 22 to about 26 hours after administration, wherein the composition is administered for four days or more of daily administration, and wherein the composition is administered within two hours of sleep. ng/ml.

[0036] In some embodiments, the invention provides a composition comprising doxepin for transmucosal administration comprising from about 2 to about 20 mg of doxepin or a salt thereof, the formulation affording a dnC_mi_n(24)* of doxepin from about 100 + 25% x 10^"9 mL^"1 to about 1000 + 25% x 10^"9 mL^"1 about 22 to about 26 hours after administration, wherein the composition is administered for four days or more of daily administration, and wherein the composition is administered within two hours of sleep. In some embodiments, the invention provides a composition comprising doxepin for transmucosal administration comprising from about 2 to about 20 mg of doxepin or a salt thereof, the formulation affording a dnC_mi_n(24)* of doxepin less then or equal to 300 + 25% x 10^"9 mL^"1 (calculated using the mean C_mi_n(24) of 706.55 pg/mL at 24 hours and the dnC_min(24)* was ((706.55 pg/mL)/(2.4 mg)) = 294.40 pg/(mg mL), or 300 + 25% x 10^"9 mL^"1) at 24 hours or between 22 to about 26 hours after administration, wherein the composition is administered for four days or more of daily

administration, and wherein the composition is administered within two hours of sleep. [0037] In some embodiments, the invention provides a method for reducing the symptoms of fibromyalgia in a human patient, comprising administering a transmucosal dosage formulation comprising from about 2 to about 20 mg of doxepin or a salt thereof, said formulation affording a C_max of doxepin from about 20 to about 200 ng/mL from about 0.05 to about 2.5 hours after administration, and a minimum plasma concentration from about 1 to about 5 ng/mL from about 22 to about 26 hours after administration, wherein the composition is administered for four days or more of daily administration, and wherein the composition is administered within two hours of sleep.

[0038] In some embodiments, the invention provides a method for reducing the symptoms of fibromyalgia in a human patient, comprising administering a transmucosal dosage formulation comprising of about 2.4 mg of doxepin or a salt thereof, said formulation affording in a single dose study, a C_max of doxepin of about 2.74 μg mL ¹ at about 4.70 hours after administration, and a minimum plasma concentration of about 706.55 ng mL^"1 at about 24 hours after

administration, wherein the composition is administered for four days or more of daily administration, and wherein the composition is administered within two hours of sleep.

[0039] In some embodiments, the invention provides a method for reducing the symptoms of PTSD in a human patient, comprising administering a transmucosal dosage formulation comprising from about 2 to about 20 mg of doxepin or a salt thereof, said formulation affording a C_max of doxepin from about 1.0 ng/ml to about 30.0 ng/ml from about 2 to about 5.0 hours after administration, and a minimum plasma concentration from about 1 to about 5 ng/ml from about 22 to about 26 hours after administration, wherein the composition is administered for four days or more of daily administration, and wherein the composition is administered within two hours of sleep.

[0040] In some embodiments, the invention provides a method for reducing the symptoms of muscle spasm and acute painful musculoskeletal conditions, including local pain and restriction of movement, in a human patient, comprising administering a transmucosal dosage formulation comprising from about 2 to about 20 mg of doxepin or a salt thereof, said formulation affording a C_max of doxepin from about 1.0 ng/ml to about 30.0 ng/ml from about 2 to about 5.0 hours after administration.

[0041] In some embodiments, the invention provides a composition comprising imipramine for transmucosal administration comprising from about 2 to about 25 mg of imipramine or a salt thereof, said formulation affording a C_max of imipramine from about 20 to about 200 ng/mL from about 0.05 to about 2.5 hours after administration, and a minimum imipramine plasma concentration from about 1 to about 5 ng/mL from about 22 to about 26 hours after administration, wherein the composition is administered for four days or more of daily administration. In some embodiments, the invention provides a composition comprising imipramine for transmucosal administration comprising from about 2 to about 25 mg of imipramine or a salt thereof, said formulation affording a C_max of imipramine from about 20 to about 200 ng/mL from about 0.05 to about 5 hours after administration, and a minimum imipramine plasma concentration from about 1 to about 5 ng/mL from about 22 to about 26 hours after administration, wherein the composition is administered for four days or more of daily administration.

[0042] In some embodiments, the invention provides a method for reducing the symptoms of fibromyalgia in a human patient, comprising administering a transmucosal dosage formulation comprising from about 2 to about 25 mg of imipramine or a salt thereof, said formulation affording a C_max of imipramine from about 20 to about 200 ng/mL from about 0.05 to about 2.5 hours after

administration, and a minimum plasma concentration from about 1 to about 5 ng/mL from about 22 to about 26 hours after administration, wherein the composition is administered for four days or more of daily administration, and wherein the composition is administered within two hours of sleep. In some embodiments, the invention provides a method for reducing the symptoms of fibromyalgia in a human patient, comprising administering a transmucosal dosage formulation comprising from about 7.5 to about 50 mg of imipramine or a salt thereof, said formulation affording a C_max of imipramine from about 3 to about 90 ng/ml from about 2 to about 5 hours after administration, and a minimum imipramine plasma concentration from about 3 to about 15 ng/ml from about 22 to about 26 hours after administration, wherein the composition is administered for four days or more of daily administration.

Detailed Description of the Invention

[0043] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, pharmacology, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology,

microbiology, genetics and protein and nucleic acid chemistry, described herein, are those well known and commonly used in the art. [0044] The methods and techniques of the present invention are generally performed, unless otherwise indicated, according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout this specification. [0045] Chemistry terms used herein are used according to conventional usage in the art, as exemplified by "The McGraw-Hill Dictionary of Chemical Terms", Parker S., Ed., McGraw-Hill, San Francisco, C.A. (1985).

[0046] All of the above, and any other publications, patents and published patent applications referred to in this application are specifically incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control.

[0047] Throughout this specification, the word "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of a stated integer (or components) or group of integers (or components), but not the exclusion of any other integer (or components) or group of integers (or

components).

[0048] The singular forms "a," "an," and "the" include the plurals unless the context clearly dictates otherwise.

[0049] The term "including" is used to mean "including but not limited to." "Including" and "including but not limited to" are used interchangeably.

[0050] A "patient", "subject", or "individual" are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats). [0051] "Treating" a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms associated with a disease or condition described herein. [0052] "Administering" or "administration of a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or an agent can be administered sublingually or intranasally, by inhalation into the lung or rectally. Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods. In some aspects, the administration includes both direct administration, including self-administration, and indirect administration, including the act of prescribing a drug. For example, as used herein, a physician who instructs a patient to self- administer a drug, or to have the drug administered by another and/or who provides a patient with a prescription for a drug is

administering the drug to the patient.

[0053] The invention provides compositions and methods for administering compounds for transmucosal absorption. The compositions and methods have a number of surprising pharmacokinetic benefits in comparison to the oral administration of a compound, which results predominantly in the absorption of compounds in the stomach, small intestine and colon.

[0054] Each embodiment described herein may be used individually or in combination with any other embodiment described herein.

Compounds [0055] The compounds useful in embodiments of the present invention include doxepin and imipramine. In some embodiments, the compounds are micronized. In alternative embodiments, the compounds are not micronized. In some embodiments, the compounds may be present in one or more crystal isoforms.

[0056] As used herein, "doxepin" includes doxepin, or one of its pure isomers E- doxepin or Z-doxepin, and pharmaceutically acceptable salts of doxepin (e.g., doxepin HC1, E-doxepin HC1, and Z-doxepin HC1). In some embodiments, doxepin may be modified by the covalent addition of lysine or by binding to albumin. [0057] As used herein, "imipramine" includes imipramine and pharmaceutically acceptable salts of imipramine (e.g., imipramine HC1). In some embodiments, imipramine may be modified by the covalent addition of lysine or by binding to albumin. [0058] The skilled worker will appreciate that doxepin and imipramine can be used interchangeably in the compositions and methods of the invention.

Doses

[0059] A "therapeutically effective amount" of a drug or agent is an amount of a drug or an agent that, when administered to a subject will have the intended therapeutic effect, e.g. reducing the symptoms of fibromyalgia or post- traumatic stress disorder (PTSD) or treating the development of fibromyalgia or posttraumatic stress disorder (PTSD). The full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Generally, doxepin or imipramine therapy can be carried out indefinitely to alleviate the symptoms of interest and frequency of dosage may be changed to be taken as needed. Thus, a therapeutically effective amount may be administered in one or more administrations. The precise effective amount needed for a subject will depend upon, for example, the subject's size, health and age, the nature and extent of the cognitive impairment, and the therapeutics or combination of therapeutics selected for administration, and the mode of administration. The skilled worker can readily determine the effective amount for a given situation by routine experimentation. Generally, a therapeutically effective amount of the doxepin or imipramine administered to a subject is between 0.1 mg and 20.0 mg, between 0.1 mg and 5.0 mg, between 0.1 mg and 4.0 mg, or between 0.1 and 3.0 mg, or between 1 and 50 mg or between 1 and 75 mg. In some embodiments, a therapeutically effective amount is about 0.1 mg, 0.5 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5.0 mg, 5.1 mg, 5.2 mg, 5.3 mg, 5.4 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0 mg, 11.0 mg, 12.0 mg, 13.0 mg, 14.0 mg, 15.0 mg, 16.0 mg, 17.0 mg, 18.0 mg, 19.0 mg, or 20.0 mg. In some embodiments, a therapeutically effective amount is about 21.0 mg, 22.0 mg, 23.0 mg, 24.0 mg, 25.0 mg, 26.0 mg, 27.0 mg, 28.0 mg, 28.0 mg, 29.0 mg, 30.0 mg, 31.0 mg, 32.0 mg, 33.0 mg, 34.0 mg, 35.0 mg, 36.0 mg, 37.0 mg, 38.0 mg, 39.0 mg, 40.0 mg, 41.0 mg, 42.0 mg, 43.0 mg, 44.0 mg, 45.0 mg, 46.0 mg, 47.0 mg, 48.0 mg, 49.0 mg, or 50.0 mg. In some embodiments, doxepin or imipramine is present in a composition of the invention in an amount from 1 mg to 25 mg, for example, from 1 mg to 10 mg. In certain embodiments, doxepin or imipramine is present in an amount of about 8 mg, less than about 16 mg, about 16 mg, or less than about 24 mg.

Administration

[0060] Appropriate methods of administering a substance, a compound or an agent to a subject will depend, for example, on the age of the subject, whether the subject is active or inactive at the time of administering, whether the subject is experiencing symptoms of a disease or condition at the time of administering, the extent of the symptoms, and the chemical and biological properties of the compound or agent (e.g. solubility, digestibility, bioavailability, stability and toxicity). In some embodiments, the compound is administered for transmucosal absorption. Absorption properties of compounds of the invention through transmucosal delivery cannot be predicted without experimentation. The suitability of compounds of the invention for transmucosal absorption is a surprising feature. Transmucosal absorption can occur through any mucosa.

Exemplary mucosa include oral mucosa (e.g., buccal mucosa and sublingual mucosa), nasal mucosa, rectal mucosa, and pulmonary mucosa. In some embodiments, a composition is suitable for transmucosal absorption. In some embodiments, a composition is formulated for transmucosal absorption.

[0061] Methods of administering compositions for transmucosal absorption are well known in the art. For example, a composition may be administered for buccal absorption through buccal tablets, lozenges, buccal powders, and buccal spray solutions. A composition may be administered for sublingual absorption through sublingual tablets, sublingual films, liquids, sublingual powders, and sublingual spray solutions. A composition may be administered for intranasal absorption through nasal sprays. A composition may be administered for pulmonary absorption through aerosolized compositions and inhalable dried powders. When administered via sprays or aerosolized compositions, a composition may be prepared with saline as a solution, employ benzyl alcohol or other suitable preservatives, or include absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents.

[0062] Doses and dosing regimens can be determined by one of skill in the art according to the needs of a subject to be treated. The skilled worker may take into consideration factors such as the age or weight of the subject, the severity of the disease or condition being treated, and the response of the subject to treatment. A composition of the invention can be administered, for example, as needed or on a daily basis. In some embodiments, a composition can be administered

immediately prior to sleep or several hours before sleep. Administration prior to sleep may be beneficial by providing the therapeutic effect before the onset of the symptoms of the disease or condition being treated. Dosing may take place over varying time periods. For example, a dosing regimen may last for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, or longer. In some embodiments, a dosing regimen will last 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer.

Therapeutic uses

[0063] The compounds of the invention may be employed for treating or preventing the development of fibromyalgia syndrome, also known as fibrositis (see, e.g., Moldofsky et al,. J Rheumatol 38(12):2653-2663 (2011) and Thomas, J Rheumatol 38(12):2499-2500 (2011)). Fibromyalgia is a chronic, noninflammatory rheumatic disorder. The American College of Rheumatology (ACR) published a classification criteria for fibromyalgia in 1990 (Wolfe, F., et al., Arthritis and Rheumatism 33:160-172 (1990)). Subsequently, a modification to the ACR criteria been published (Wolfe et al., J Rheumatol 38(6): 1113-22 (2011)). Diagnostic criteria have also been published by an international network of working groups called, "Outcome Measures in Rheumatology" clinical trials or OMERACT (Mease P, et al. J Rheumatol. 2009;36(10):2318-29). Fibromyalgia is traditionally characterized by stiffness or diffuse pain, aches, muscle soreness, sleep disturbances or fatigue. The pain is generally widespread and generally localized at specific "tender points," which may bring on widespread pain and muscle spasm when touched. Other symptoms include mental and emotional disturbances such as poor concentration and irritability, neuropsychiatric symptoms such as depression and anxiety, joint swelling, headache, numbness. Fibromyalgia is associated with nonrefreshing sleep, tiredness, sleepiness, reflux, mental fog and cognitive impairments including difficulty multi-tasking.

Fibromyalgia also is often comorbid with sleep disorders, fatigue, non-restorative sleep, anxiety, and depression. The compositions and methods of the invention can be used to treat any one of the above-identified conditions, and any combination thereof. [0064] Some practitioners further classify fibromyalgia into two categories- primary or secondary-concomitant fibromyalgia. Generally, primary fibromyalgia syndrome can be considered fibromyalgia occurring in the absence of another significant condition whereas secondary-concomitant fibromyalgia can be considered fibromyalgia occurring in the presence of another significant medical disorder, which may have been caused by or is merely associated with the patient's fibromyalgia. Secondary or concomitant fibromyalgia can include fibromyalgia in patients with classical or definite rheumatoid arthritis, osteoarthritis of the knee or hand, low back pain syndromes, cervical pain syndromes, cancer pain syndromes, temporomandibular joint disorders, migraine headaches, menopause, post- traumatic stress disorder and interstitial cystitis or painful bladder syndrome (or combinations thereof).

[0065] The compounds of the invention also may be employed for treating or preventing the development (either the initiation, consolidation or perpetuation) of a PTSD symptom following a traumatic event. A traumatic event is defined as a direct personal experience that involves actual or threatened death or serious injury, or other threat to one's physical integrity, or witnessing an event that involves death, injury, or a threat to the physical integrity of another person; or learning about unexpected or violent death, serious harm, or threat of death or injury experienced by a family member or other close associate. Traumatic events that are experienced directly include, but are not limited to, military combat, violent personal assault (sexual assault, physical attack, robbery, mugging), being kidnapped, being taken hostage, terrorist attack, torture, incarceration as a prisoner of war or in a concentration camp, natural or manmade disasters, severe automobile accidents, or being diagnosed with a life-threatening illness. For children, sexually traumatic events may include developmentally inappropriate sexual experiences without threatened or actual violence or injury. Witnessed events include, but are not limited to, observing the serious injury or unnatural death of another person due to violent assault, accident, war, or disaster or unexpectedly witnessing a dead body or body parts. Events experienced by others that are learned about may include, but are not limited to, violent personal assault, serious accident, or serious injury experienced by a family member or a close friend, learning about the sudden, unexpected death of a family member or a close friend, or learning that one's child has a life-threatening disease. The disorder may be especially severe or long lasting when the stressor is of human design (e.g., torture or rape). The initiation of a PTSD symptom typically occurs immediately following the traumatic event, during which the symptoms of PTSD appear and become increasingly severe. One theory of how PTSD develops is that there is a type of "learning" or reinforcement process during which the memories of the trauma are engrained in the mind. As these memories become more fixed (a process called consolidation), symptoms such as flashbacks and nightmares grow in severity and frequency. Interventions during this critical time may prevent some patients from developing full-blown PTSD. The consolidation of a PTSD symptom typically occurs during the weeks and months following a traumatic event. A person's memories of that event become consolidated into highly vivid and concrete memories that are re-experienced with increasing frequency either as flashbacks or nightmares. During this time, hyperarousal symptoms and avoidant behavior can become increasingly severe and disabling. The perpetuation of a PTSD symptom occurs once traumatic memories are consolidated, and the re- experienced symptoms (flashbacks and nightmares) and hyperarousal symptoms become persistent and remain at a level that is functionally disabling to the patient.

[0066] The compositions and methods of the invention may be used to treat different phases of PTSD development at various time intervals after a traumatic event. For example, treating the initiation phase of PTSD may require the administration of a composition of the invention soon after the traumatic event, for example within the first week, within the second week, within the third week, or within the fourth week or later. By contrast, when treating the consolidation phase of PTSD, the skilled worker may be able to administer a composition of the invention later after the traumatic event and later during the development of the symptoms, for example, within the first month, within the second month, or within the third month or later. The perpetuation phase of PTSD may be treated with a composition of the invention administered 3 months or longer after the traumatic event, for example within the third month, within the fourth month, within the fifth month, or later. As a result of treatment at the initiation, consolidation, or perpetuation phase, PTSD symptoms will be ameliorated or be eliminated.

[0067] The compositions and methods of the invention also can be used to treat traumatic brain injury (TBI). TBI is associated with sleep disorders, sleep disturbances, fatigue, non-restorative sleep, anxiety, and depression. The compositions and methods of the invention also can be used to treat any of the above conditions, in combination with or independently of treating TBI.

[0068] The compositions and methods of the invention also can be used to chronic traumatic encephalopathy (CTE). CTE is associated with sleep disorders, sleep disturbances, fatigue, non-restorative sleep, anxiety, and depression. The compositions and methods of the invention also can be used to treat any of the above conditions, in combination with or independently of treating CTE.

[0069] The compositions and methods of the invention may be used to treat sleep disorders or sleep disturbances. A "sleep disorder" may be any one of four major categories of sleep dysfunction (DSM-IV, pp. 551-607; see also The International Classification of Sleep Disorders: (ICSD) Diagnostic and Coding Manual, 1990, American Sleep Disorders Association). One category, primary sleep disorders, comprises sleep disorders that do not result from another mental disorder, a substance, or a general medical condition. They include without limitation primary insomnia, primary hypersomnia, narcolepsy, circadian rhythm sleep disorder, nightmare disorder, sleep terror disorder, sleepwalking disorder, REM sleep behavior disorder, sleep paralysis, day/night reversal and other related disorders; sub stance- induced sleep disorders; and sleep disorders due to a general medical condition. Primary insomnia non-restorative sleep is described by the DSM-IV-TR as a type of primary insomnia wherein the predominant problem is waking up feeling unrefreshed or nonrefreshed. A second category comprises those sleep disorders attributable to substances, including medications and drugs of abuse. A third category comprises sleep disturbances arising from the effects of a general medical condition on the sleep/wake system. A fourth category of sleep disorders comprises those resulting from an identifiable mental disorder such as a mood or anxiety disorder. A fifth category of sleep disorders comprises those described as non-restorative sleep. One definition of non-restorative sleep is in the DSM-IV- TR as a type of primary insomnia (A1.3) wherein the predominant problem is waking up feeling unrefreshed or nonrefreshed. Symptoms of each category of sleep disorder are known in the art. A "sleep disturbance" may be an impairment in refreshing sleep. Such a clinical diagnosis may be made based on a patient's self described feeling of fatigue upon waking or the patient's report of poor quality sleep. Such impediments to good quality sleep may be described as shallow sleep or frequent awakenings which may be associated with an increase in the Cyclic Alternating Pattern (CAP) A2 or A3 rate or cycle duration or an increase in the normalized CAP A2 + A3 which is determined by CAP (A2+A3)/CAP

(A1+A2+A3) in non-REM sleep (see, e.g., Moldofsky et al,. J Rheumatol

38(12):2653-2663 (2011) and Thomas, J Rheumatol 38(12):2499-2500 (2011)), alpha rhythm contamination in non-REM sleep, or absence of delta waves during deeper physically restorative sleep. Such "sleep disturbances" may or may not rise to the level of a "sleep disorder" as defined in the DSM-IV, although they may share one or more symptom in common. Symptoms of sleep disturbances are known in the art. Among the known symptoms are groggy or spacey feelings, tiredness, feelings of being run down, and having difficulty concentrating during waking hours. Among the sleep-related conditions that may be treated with the methods and compositions of the invention are dyssomnias (e.g., intrinsic sleep disorders such as sleep state misperception, psychophysiological insomnia, idiopathic insomnia, obstructive sleep apnea syndrome, central sleep apnea syndrome, central alveolar hypoventilation syndrome, restless leg syndrome, and periodic limb movement disorder; extrinsic sleep disorders such as environmental sleep disorder, adjustment sleep disorder, limit-setting sleep disorder, stimulant- dependent sleep disorder, alcohol-dependent sleep disorder, toxin-induced sleep disorder, sleep onset association disorder, hypnotic dependent sleep disorder, inadequate sleep hygiene, altitude insomnia, insufficient sleep syndrome, nocturnal eating syndrome, and nocturnal drinking syndrome; and circadian rhythm sleep disorders such as jet lag syndrome, delayed sleep phase syndrome, advanced sleep phase syndrome, shift work sleep disorder, non-24 hour sleep-wake disorder, and irregular sleep-wake patterns), parasomnias (e.g., arousal disorders such as sleepwalking, confusional arousals, and sleep terrors and sleep-wake transition disorders such as rhythmic movement disorder, sleep talking and sleep starts, and nocturnal leg cramps), and sleep disorders associated with medical or psychiatric conditions or disorders. Basifying agents

[0070] The compositions of the invention may include a basifying agent in addition to a compound useful in the compositions of the invention. As used herein, a "basifying agent" refers to an agent (e.g., a substance that increases the local pH of the liquid near a mucosal surface including potassium dihydrogen phosphate (monopotassium phosphate, monobasic potassium phosphate, KH₂PO₄), dipotassium hydrogen phosphate (dipotassium phosphate, dibasic potassium phosphate, K₂HPO₄), tripotassium phosphate (K₃PO₄), sodium dihydrogen phosphate (mo no sodium phosphate, monobasic sodium phosphate, NaH₂P0₄), disodium hydrogen phosphate (disodium phosphate, dibasic sodium phosphate, Na₂HP0₄), trisodium phosphate (Na₃P0₄), bicarbonate or carbonate salts, dipotassium citrate, tripotassium citrate, disodium citrate, trisodium citrate, borate, hydroxide, silicate, nitrate, dissolved ammonia, the conjugate bases of some organic acids (including bicarbonate), and sulfide) that raises the pH of a solution containing a compound (e.g., doxepin or imipramine ) useful in the compositions and methods of the invention. The solution of interest is the layer of aqueous material overlying a mucous membrane. Therefore the basifying agent is sometimes an ingredient (and excipient) in a tablet, and the basifying agent exerts its effects during the time the tablet is being dispersed in the mucous material, while parts of the formulation are dissolving in the mucous material and for a period of time after the tablet is dissolved in the mucous material. Surprisingly, the addition of a basifying agent to a composition of the invention improves the pharmacokinetic properties of the composition. This is exemplified by doxepin HCl as one particular compound useful in the methods and compositions of the invention. A basifying agent with particular effects on doxepin HCl is dipotassium hydrogen phosphate (K₂HPO₄). Another basifying agent with particular effects on doxepin HCl is potassium dihydrogen phosphate (KH₂PO₄). Another basifying agent with particular effects on doxepin HCl is disodium hydrogen phosphate (Na₂HP0₄). Another basifying agent with particular effects on doxepin HCl is tripotassium citrate. Another basifying agent with particular effects on doxepin HCl is trisodium citrate. In some embodiments, imipramine HCl is a particular compound useful in the methods and compositions of the invention. A basifying agent with particular effects on imipramine HCl is K₂HPO₄. Another basifying agent with particular effects on imipramine HCl is Na₂HPC«4. Another basifying agent with particular effects on imipramine HCl is KH₂PO_4. Another basifying agent with particular effects on imipramine HCl is tripotassium citrate. Another basifying agent with particular effects on imipramine HCl is trisodium citrate.

[0071] Doxepin HCl has an acid dissociation constant (or pKa) for the amine group of approximately 8.5 at 25° C, indicating that at pH 8.5, the compound is 50% ionized or protonated (and 50% un-ionized or free base) (M. L. Cotton, G. R. B. Down, Anal. Profiles Drug Subs. 17, 41-72 (1988)). The pH of an aqueous solution of doxepin HCl from 10 gm/100 mL (0.32 molar) to 30 gm/100 mL (0.96 molar) is between approximately 3.1 and 3.3, thereby providing a condition wherein nearly all the doxepin is ionized and soluble. The skilled worker, with this knowledge in hand, would therefore look to maintain doxepin at a low pH, maximizing its solubility. However, ionized doxepin may not have optimal absorption by and across mucosal surfaces because of its charge. This problem is solved by combining the doxepin with a basifying agent. Indeed, we have discovered that combining doxepin HC1 with a basifying agent such as dipotassium hydrogen phosphate (K₂HPO₄) or potassium dihydrogen phosphate (KH₂PO₄) improves the pharmacokinetic properties of a composition comprising doxepin for transmucosal absorption. In experiments with oral and intravenous solutions containing doxepin and a basifying agent, the pH was adjusted to about pH 7.1 to pH 7.4. In experiments with tablet formulations containing doxepin and a basifying agent, the addition of the basifying agent results in a higher pH when the tablet is dissolved in water. Combining doxepin with a basifying agent also enhances the uptake of doxepin by transmucosal absorption. The effects of a basifying agent like K₂HPO₄ or KH₂PO₄ on the transmucosal pharmacokinetic properties of a composition comprising doxepin are remarkable because doxepin HC1 in a solution at 2.5 mg/ml at 7.4 containing K₂HPO₄ or KH₂PO₄ appears to be close to its saturation point where doxepin falls out of solution, or becomes insoluble, presumably because the concentration of doxepin free base increases relative to ionized doxepin. Without wishing to be bound by theory, it is possible that the basifying agent increases the pH of the microenvironment local to the mucosal membrane and brings more of the doxepin into an un-ionized or free-base state at the mucosal surface, which helps drive doxepin across mucosa and into the bloodstream, thereby offsetting any decrease in the solubility of doxepin resulting from the basifying agent action in the solution near the mucous membrane.

Without wishing to be bound by theory, the basifying agent may create a transition state involving hydration of the free base, such that the free base is formed in situ near the mucosal surface and crosses the mucosal membrane.

[0072] A basifying agent useful in the compositions and methods of the invention may be any agent that increases the pH of a solution containing a compound useful in the methods and compositions of the invention. Exemplary basifying agents include potassium dihydrogen phosphate (monopotassium phosphate, monobasic potassium phosphate, KH₂PO₄), dipotassium hydrogen phosphate (dipotassium phosphate, dibasic potassium phosphate, K₂HPO₄), tripotassium phosphate (K₃PO₄), sodium dihydrogen phosphate (monosodium phosphate, monobasic sodium phosphate, NaH₂P0₄), disodium hydrogen phosphate (disodium phosphate, dibasic sodium phosphate, Na₂HP0₄), trisodium phosphate (Na₃P0₄), sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, potassium citrate and sodium citrate. In some embodiments, a composition of the invention has a molar ratio of a compound (e.g., doxepin or imipramine) to a basifying agent of 1:1, 1:2, 1:3, 1:4, 1:5 1:6, 1.7, 1.8, 1.9 or 2.0. In some embodiments, the ratio of doxepin HC1 (2.4 mg, MW 275.387) to K₂HPO₄ (1.05 mg, MW 174.2) is 0.69.

Doxepin and imipramine metabolism

[0073] Doxepin rapidly distributes out of the vasculature after intravenous (IV) bolus administration in humans. The pharmacokinetic properties of intravenous and oral doxepin have been studied. The intravenous administration of 22.12 mg free base doxepin (with a ratio of 16:84 Z:E-doxepin) resulted in plasma C_max for for Z and E-isomers of -18 and -37 ng/ml, respectively, and C_max for for N- desmethyldoxepin Z and E isomers of 1.5 and 1.8 ng/ml, respectively. The oral administration of 75 mg free base doxepin resulted in plasma C_max for for Z and E- isomers of C_max 4.3 and 20.4 ng/ml, respectively, and C_max for for N- desmethyldoxepin Z and E isomers of 5.4 and 3.3 ng/ml, respectively. These data show that doxepin is metabolized by the liver and that the metabolites are present in plasma. (Yan JH, et al. et al. Absolute bioavailability and stereoselective pharmacokinetics of doxepin. Xenobiotica. 2002 Jul;32(7):615-23.

PMID:12162857).

[0074] Doxepin and its pure isomers E-doxepin or Z-doxepin and imipramine are structurally related to each other and also to cyclobenzaprine. Doxepin differs from cyclobenzaprine chemically by having an oxygen instead of a carbon at position either 10 or 11 in the cyclobenzaprine central cycloheptene ring (such that doxepin has an oxepin ring.) Imipramine differs from cyclobenzaprine chemically by having a nitrogen at position 5 in the cyclobenzaprine central cycloheptyl ring (such that imipramine has an azepin ring) and also a single bond beteween this nitrogen and the dimethyl-propanamine chain. However, changes in chemical structure can affect drug actions on normal or pathological tissues as well as absorption, disposition, metabolism and excretion. Doxepin is the active pharmaceutical ingredient of tricyclic anti-depressants (TCAs) such as Adapin®, and Sinequan®. Imipramine (also known as melipramine) is the active

pharmaceutical ingredient of tricyclic anti-depressants (TCAs) such as Imipramine has been sold under tradenames including: Antideprin®, Deprimin®, Deprinol®, Depsol®, Depsonil®, Dynaprin®, Eupramin®, Imipramil® Irmin®, Janimine®, Melipramin®, Surplix®, Tofranil®. Doxepin and Imipramine, are rapidly partitioned out of plasma. The pharmacokinetics of IV administration of doxepin or imipramine can be described by a two-compartment model containing a plasma "central" compartment and a "peripheral" compartment (Yan JH, et. al. Absolute bioavailability and stereoselective pharmacokinetics of doxepin. Xenobiotica. 2002 Jul;32(7):615-23. PMID: 12162857).

[0075] Neither cyclobenzaprine nor amitriptyline is an effective long-term treatment for fibromyalgia in any formulation that has been tested, for example currently available formulations were not effective over six months of treatment (Carette, S. Arthritis Rheum. 1994 Jan;37(l):32-40). Cyclobenzaprine is not an effective treatment for fibromyalgia in a twelve week study (Bennett et al., Arthritis Rheum. 31: 1535-1542 (1988)). In general, cyclobenzaprine is not recommended for long-term use. We hypothesized that the side effects of fatigue, somnolence and grogginess have overwhelmed the treatment effects from cyclobenzaprine or amitriptyline, but it was not known how to shorten the plasma half-life of either cyclobenzaprine or amitriptyline. In addition, we have shown for the first time that the ineffectiveness of cyclobenzaprine may be due to the metabolism of cyclobenzaprine by the liver. Whereas amitriptyline was known to be metabolized to nortriptyline, and the delayed plasma half life of nortriptyline has been reported (Bhatt, Biomed Chromatogr 24(11): 1247-54 (2010)), the manner in which nortriptyline accumulation may decrease efficacy of bedtime amitriptyline as a chronic treatment was not understood. Doxepin and imipramine suffer from the same problems.

[0076] Doxepin is metabolized by the liver by both hydroxylation and demethylation (Ereshefsky L, et al. Pharmacokinetic factors affecting

antidepressant drug clearance and clinical effect: evaluation of doxepin and imipramine-new data and review. Clin Chem. 1988 May;34(5):863-80. PMID: 3286056.) Doxepin is demethylated into N-desmethyldoxepin (Luo H, et al. The quaternary ammonium- linked glucuronide of doxepin: a major metabolite in depressed patients treated with doxepin. Drug Metab Dispos. 1991 19(3):722-4.) Commercial preparations of the oral anti-depressant doxepin product contain 15% of the more active cis-doxepin (or Z-doxepin) and 85% of the trans-isomer or (E- doxepin). Since doxepine is a mixture of isomers, it has been further studied that doxepin is demethylated into E- N-desmethyldoxepin and Z- N-desmethyldoxepin (Adamczyk M, et al. Ther Drug Monit. 1995 17(4):371-6.) While the average ratio of Z- to E-doxepin isomers in plasma of 15:85, the mean plasma levels of Z-N- desmethyldoxepin in exceed those of the trans-isomer at every time point after 10 h. Since the Z-N-desmethyldoxepin is believed to be pharmacologically active, this accumulation is thought to prolong a stable therapeutic effect in depression (Midha KK, et al. Stereoselective pharmacokinetics of doxepin isomers. Eur J Clin Pharmacol. 1992;42(5):539-44. PMID: 1607001).

[0077] The N-demethylation of doxepin isomers, E-doxepin and Z-doxepin is mainly catalyzed by hepatic CYP2C19. (Hartter S, et al. Pharm Res. 2002

19(7): 1034-7 and Haritos VS, et al. Pharmacogenetics. 2000 10(7):591-603' Hartter S, et al. The N-demethylation of the doxepin isomers is mainly catalyzed by the polymorphic CYP2C19. Pharm Res. 2002 Jul;19(7): 1034-7. PMID:

12180536; and Haritos VS, et al. Role of cytochrome P450 2D6 (CYP2D6) in the stereo specific metabolism of E- and Z-doxepin. Pharmacogenetics. 2000

Oct;10(7):591-603. PMID: 11037801]

[0078] More than one metabolic process contributes to the enrichment of Z-N- desmethyldoxepin observed in the plasma of subjects on doxepin therapy. Study of the individual doxepin isomers has shown that significant amounts of Z-N- desmethyldoxepin were formed and excreted after dosing with E-doxepin and only a small amount of E-N-desmethyldoxepin was formed from Z-doxepin in most, but not all, subjects. One component of the enrichment may be due to a transition state in the demethylation process that favors the production of Z-N-desmethyldoxepin (Ghabrial H, et al. 1991 Drug Metab Dispos. 19(3):596-9.)

[0079] Another factor in that appears to favor Z-N-desmethyldoxepin is stereoselective oxidation in which enzymes includine CYP2D6 may catalyze hydroxylation with a preference for the E-isomers. A relatively more rapid metabolism of E-isomeric forms, and a slower metabolism of the Z-isomers could contribute to the apparent enrichment of Z-N-desmethyldoxepin in humans

(Haritos VS, et al. Pharmacogenetics. 2000 10(7):591-603.) A major implication of sublingual/transmucosal doxepin is that transmucosal delivery of doxepin and in particular, E-doxepin, will have reduced demethylation and oxidation by liver enzymes. [0080] Similarly, imipramine is metabolized by the liver by both hydroxylation and demethylation (Ereshefsky L, et al. Pharmacokinetic factors affecting antidepressant drug clearance and clinical effect: evaluation of doxepin and imipramine-new data and review. Clin Chem. 1988 May;34(5):863-80. PMID: 3286056). Imipramine is subject to P450 mediated N-demethylation to

desipramine (also known as desmethylimipramine), or 3-(10,l l-dihydro-5H- dibenzo[b Jazepin-5-yl)-N-methylpropan-l-amine. Desipramine is also a tricyclic antidepressant (TCA), active metabolite that is sold under trade names including Norpramin® and Pertofane®. Imipramine administered by oral tablet resulted in predominately desipramine because of first pass hepatic metabolism (Rigal J, et al. The influence of the route of administration of imipramine on imipramine and desipramine blood levels. J Clin Psychopharmacol. 1989 Oct;9(5):364-7.)

Imipramine and desipramine are also also converted into 2- hydroxydesipramine. (Sutfin TA, et al. The analysis and disposition of imipramine and its active metabolites in man. Psychopharmacology (Berl). 1984;82(4):310-7. PMID:

6427820). Pharmacokinetic properties

[0081] Transmucosal absorption of a compound useful in the compositions and methods of the invention has a number of beneficial effects on the pharmacokinetic properties of the compound. Transmucosal delivery allows a compound of the invention to be absorbed more rapidly than if administered orally, resulting in a shorter time to therapeutic concentrations of doxepin or imipramine in the plasma. In some embodiments, the compositions of the invention afford therapeutic concentrations of doxepin or imipramine in the plasma at less than 3.3 hours, less than 3 hours, less than 2.5 hours, less than 2 hours, less than 1 hour, less than 45 minutes, less than 30 minutes, or less than 20 minutes. In some embodiments, the compositions of the invention afford increased concentrations of doxepin or imipramine in the plasma, relative to oral doses, at time less than or equal to 3.3 hours, less than or equal to 3 hours, less than or equal to 2.5 hours, less than or equal to 2 hours, less than or equal to 1 hour, less than or equal to 45 minutes, less than or equal to 30 minutes, or less than or equal to 20 minutes. In some embodiments, the compositions of the invention afford increased AUCs of doxepin or imipramine in the plasma, relative to oral doses, at times 0 to 3.3 hours, 0 to 3 hours, 0 to 2.5 hours, 0 to 2 hours, 0 to 1 hour, 0 to 45 minutes, 0 to 30 minutes, or 0 to 20 minutes. In some embodiments, the compositions of the invention afford increased dose-normalized concentrations (dnC*) of doxepin or imipramine in the plasma, relative to oral doses, at time less than or equal to 3.3 hours, less than or equal to 3 hours, less than or equal to 2.5 hours, less than or equal to 2 hours, less than or equal to 1 hour, less than or equal to 45 minutes, less than or equal to 30 minutes, or less than or equal to 20 minutes. In some embodiments, the

compositions of the invention afford increased dose normalized AUCs (dnAUC*) of doxepin or imipramine in the plasma, relative to oral doses, at times 0 to 3.3 hours, 0 to 3 hours, 0 to 2.5 hours, 0 to 2 hours, 0 to 1 hour, 0 to 45 minutes, 0 to 30 minutes, or 0 to 20 minutes. Transmucosal delivery allows a compound of the invention to be absorbed more rapidly than if administered orally, resulting in a shorter time to maximum concentration, or t_max. In some embodiments, the compositions of the invention afford a t_max of doxepin or imipramine of less than 5 hours, less than 4 hours, less than 3.5 hours, less than 3 hours, less than 2.5 hours, less than 2 hours, less than 1.5 hours, less than 1 hour, less than 45 minutes, less than 30 minutes, less than 15 minutes, less than 10 minutes, or less than 5 minutes. In some embodiments, the compositions of the invention afford a t_max of doxepin or imipramine of about 5 hours, about 4 hours, about 3 hours, about 2.5 hours, about 2 hours, about 1.5 hours, about 1 hour, about 45 minutes, about 30 minutes, about 15 minutes, about 10 minutes, or about 5 minutes.

[0082] Transmucosal absorption also produces higher plasma concentrations of a compound as compared to oral administration. A plasma concentration may be an individual plasma concentration or a mean plasma concentration when observing multiple individuals. The higher plasma concentrations produced by transmucosal absorption may be determined by measuring the plasma concentration of the compound being administered or by calculating the ratio of the plasma

concentration and the dose administered, which is the dose-normalized plasma concentration (C) or dnC*, measured in mL^"1. The dnC* is calculated by determining the ratio of plasma level to dose administered. For example, if 2.4 mg of doxepin or imipramine is administered and the plasma level is 2.4 ng/mL at 3 hours, the dnC* at 3 hours is ((2.4 ng/mL)/(2.4 mg)) = 1.0 x 10^"6 mL^"1. The dnC* can be measured either at fixed time points or at a variable time point, e.g., the time point corresponding to C_max. The dose normalized concentration of doxepin dnC* of doxepin in plasma after ingestion of 5 mg immediate release doxepin was: at 20 min was 0.00; at 30 min was 1.95 x 10^"9 mL^"1; at 45 min was 19.31 x 10^"9 mL^"1; at 1 hour was 50.00 x 10^"9 mL^"1; at 2 hour was 378.65 x 10^"9 mL^"1; at 2.5 hours (150 min) was 510.94 x 10^"9 mL^"1; at 3 hours was 625.29 x 10^"9 mL^"1 x 10^"9 mL^"1; at 3.3 hours (200 min) was 698.49 x 10^"9 mL^"1; at 3.67 hours (220 min) was 818.31 x 10^"9 mL^"1; at 4 hours was 848.33 x 10^"9 mL^"1; at 4.33 hours (260 min) was 968.09 x 10^"9 mL^"1; at 4.67 hours (280 min) was 933.95 x 10^"9 mL^"1; at 5 hours was 932.86 x 10^"9 mL^"1; at 5.5 hours (330 min) was 920.94 x 10^"9 mL^"1; at 6 hours was 953.40 x 10^"9 mL^"1; at 8 hours was 801.23 x 10^"9 mL^"1; at 12 hours was 516.73 x 10^"9 mL^"1; at 16 hours was 347.39 x 10^"9 mL^"1; at 24 hours was 320.44 x 10^"9 mL^"1; at 36 hours was 233.66 x 10^"9 mL^"1; at; at 48 hours was 199.41 x 10^"9 mL^"1; and at 72 hours was 136.80. The dose normalized concentration of doxepin dnC* of doxepin in plasma after ingestion of 2.4 mg sublingual doxepin with phosphate was: at 20 min was 157.60 x 10^"9 mL^"1; at 30 min was 301.60 x 10^"9 mL^"1; at 45 min was 432.58x 10^"9 mL^"1; at 1 hour was 598.85x 10^"9 mL^"1; at 2 hour was 683.58x 10^"9 mL^"1; at 2.5 hours (150 min) was 727.67x 10^"9 mL^"1; at 3 hours was 840.33x 10^"9 mL^"1 x 10^"9 mL^"1; at 3.3 hours (200 min) was 923.58 x 10^"9 mL^"1; at 3.67 hours (220 min) was 952.71x 10^"9 mL^"1; at 4 hours was 1012.35x 10^"9 mL^"1; at 4.33 hours (260 min) was 1030. lOx 10^"9 mL^"1; at 4.67 hours (280 min) was 1038.58x 10^"9 mL^"1; at 5 hours was 990.90x 10^"9 mL^"1; at 5.5 hours (330 min) was 1046.42x 10^"9 mL^"1; at 6 hours was 911.07x 10^"9 mL^"1; at 8 hours was 696.33x 10^"9 mL^"1; at 12 hours was 504.90x 10^"9 mL^"1; at 16 hours was 354.04x 10^"9 mL^"1; at 24 hours was 294.40x 10^"9 mL^"1; at 36 hours was 184.19x 10^"9 mL^"1; at; at 48 hours was 143.37x 10^"9 mL^"1; and at 72 hours was 88.23. For example, dnC* can be measured 5 minutes after administration, 10 minutes after administration, 15 minutes after administration, 20 minutes after administration, 30 minutes after administration, 45 minutes after administration, 1 hour after administration, 2 hours after administration, 3 hours after administration, 4 hours after

administration, 5 hours after administration, 6 hours after administration, 7 hours after administration, 8 hours after administration, 9 hours after administration, 10 hours after administration, 11 hours after administration, or 12 hours after administration. For example, a dnC* value may be about, or greater than about, 8.0 + 25% x 10^"7 mL^"1, 0.001 + 25% x 10^"6 mL^"1, 0.01 + 25% x 10^"6 mL^"1, 0.05 + 25% x 10^"6 mL^"1, 0.1 + 25% x 10^"6 mL^"1, 0.5 + 25% x 10^"6 mL^"1, 1.0 + 25% x 10^" ⁶ mL^"1, 5.0 + 25% x 10^"6 mL^"1, 10.0 + 25% x 10^"6 mL^"1, 50.0 + 25% x 10^"6 mL^"1, or 100.0 + 25% x 10^"6 mL^"1, 125.0 + 25% x 10^"6 mL^"1, 150.0 + 25% x 10^"6 mL^"1, 175.0 + 25% x 10^"6 mL^"1, 200.0 + 25% x 10^"6 mL^"1, 300.0 + 25% x 10^"6 mL^"1, 400.0 + 25% x 10^"6 mL^"1, 500.0 + 25% x 10^"6 mL^"1, 600.0 + 25% x 10^"6 mL o or 700.0 + 25% x 10^"6 mL^"1. For example, a dnC* value may be about, or greater than or equal to 50 + 25% x 10^"9 mL^"1 10 minutes after administration, greater than or equal to 125 + 25% x 10^"9 mL^"1 15 minutes after administration, greater than or equal to 150 + 25% x 10^"9 mL^"1 20 minutes after administration, greater than or equal to 300 + 25% x 10^"9 mL^"1 30 minutes after administration, greater than or equal to 450 + 25% x 10^"9 mL^"1 45 minutes after administration, greater than or equal to 600 + 25% x 10^"9 mL^"1 1 hour after administration, greater than or equal to 700 + 25% x 10^"9 mL^"1 2 hours after administration, greater than or equal to 750 + 25% x 10^"9 mL^"1 2.5 hours after administration, greater than or equal to 850 + 25% x 10^"9 mL^"1 3 hours after administration, greater than or equal to 900 + 25% x 10^"9 mL^"1 3.3 hours after administration, greater than or equal to 950 + 25% x 10^"9 mL^"1 3.7 hours after administration, greater than or equal to 1000 + 25% x 10^" ⁹ mL^"1 4 hours after administration, greater than or equal to 1050 + 25% x 10^"9 mL^"1 4.33 hours after administration, greater than or equal to 1050 + 25% x 10^"9 mL^"1 4.67 hours after administration, less than or equal to 1000 + 25% x 10^"9 mL^"1 5 hours after administration, less than or equal to 1000 + 25% x 10^"9 mL^"1 5.5 hours after administration, less than or equal to 900 + 25% x 10^"9 mL^"1 6 hours after administration, less than or equal to 700 + 25% x 10^"9 mL^"1 8 hours after administration, less than or equal to 650 + 25% x 10^"9 mL^"1 10 hours after administration, less than or equal to 500 + 25% x 10^"9 mL^"1 12 hours after administration, less than or equal to 400 + 25% x 10^"9 mL^"1 14 hours after administration, less than or equal to 350 + 25% x 10^"9 mL^"1 16 hours after administration, less than or equal to 340 + 25% x 10^"9 mL^"1 18 hours after administration, less than or equal to 320 + 25% x 10^"9 mL^"1 20 hours after administration, less than or equal to 310 + 25% x 10^"9 mL^"1 22 hours after administration, less than or equal to 300 + 25% x 10^"9 mL^"1 24 hours after administration, less than or equal to 180 + 25% x 10^"9 mL^"1 36 hours after administration, less than or equal to 140 + 25% x 10^"9 mL^"1 48 hours after administration, or less than or equal to 90 + 25% x 10^"9 mL^"1 72 hours after administration. In some embodiments, dnC* can be measured 10 hours after administration, 11 hours after administration, 12 hours after administration, 13 hours after administration, 14 hours after administration, 15 hours after

administration, 16 hours after administration, 17 hours after administration, 18 hours after administration, 19 hours after administration, 20 hours after

administration, 21 hours after administration, 22 hours after administration, 23 hours after administration, 24 hours after administration, or 36 hours after administration. For example, a dnC* value may be about, or less than about, 1.0 + 25% x 10^"9 mL^"1, 1.0 + 25% x 10^"8 mL^"1, 0.7 + 25% x 10^"7 mL^"1, 1.0 + 25% x 10^" ⁷ mL^"1, 2.0 + 25% x 10^"7 mL^"1, 3.0 + 25% x 10^"7 mL^"1, 4.0 + 25% x 10^"7 mL^"1, 5.0 + 25% x 10^"7 mL^"1, 1.0 + 25% x 10^"6 mL^"1, or 5.0 + 25% x 10^"6 mL^"1 In some embodiments, the dnC* value can relate to single dosing. In some embodiments, the dnC* value can relate to a multi-dose regimen (e.g., repeated daily

administration). In some embodiments, the plasma concentration used to calculate the dnC* may be adjusted to reflect a baseline plasma concentration (e.g., a baseline plasma level because of repeated daily administration). C_max is defined as the peak plasma concentration of a compound of the invention after administration. If a dnC* value is calculated at the time point corresponding to C_max, the value may alternatively be referred to as a dose normalized C_max or dnC_max*. In some embodiments, a dnC_max* is greater than or equal to 1.0 + 25% x 10^"6 mL^"1, greater than or equal to 1.5 + 25% x 10^"6 mL^"1, greater than or equal to 2.0 + 25% x 10^"6 mL^"1, greater than or equal to 2.5 + 25% x 10^"6 mL^"1, greater than or equal to 3.0 + 25% x 10^"6 mL^"1, greater than or equal to 3.5 + 25% x 10^"6 mL^"1, greater than or equal to 4.0 + 25% x 10^"6 mL^"1, greater than or equal to 4.5 + 25% x 10^"6 mL^"1, greater than or equal to 5.0 + 25% x 10^"6 mL^"1.

[0083] Transmucosal absorption also produces higher plasma concentrations of a compound as compared to oral administration. A plasma concentration may be an individual plasma concentration or a mean plasma concentration when observing multiple individuals. The higher plasma concentrations produced by transmucosal absorption may be determined by measuring the plasma concentration of the compound being administered or by calculating the ratio of the plasma

concentration*body mass product and the dose administered, which is the dose- and body mass-normalized plasma concentration (C) or dbmnC*, measured in kg mL^"1. The dbmnC* is calculated by determining the ratio of plasma level times body mass product to dose administered. For example, if 2.4 mg of doxepin or imipramine is administered to a 70 kg animal and the plasma level is 4.8 ng/mL at 15 minutes, the dbmnC* at 15 minutes is ((4.8 ng/mL) x (70 kg)/(2.4 mg)) = dbmnC(o.25h) * = 140.0 x 10^"6 kg mL^"1. The dbmnC* can be measured either at fixed time points or at a variable time point, e.g., the time point corresponding to C_max. For example, dbmnC* can be measured 5 minutes after administration, 10 minutes after administration, 15 minutes after administration, 30 minutes after administration, 45 minutes after administration, 1 hour after administration, 2 hours after administration, 3 hours after administration, 4 hours after

administration, 5 hours after administration, 6 hours after administration, 7 hours after administration, 8 hours after administration, 9 hours after administration, 10 hours after administration, 11 hours after administration, or 12 hours after administration. For example, a dbmnC* value may be about, or greater than about, 80.0 + 25% x 10^"7 kg mL^"1, 0.01 + 25% x 10^"6 kg mL^"1, 0.1 + 25% x 10^"6 kg mL^"1, 0.5 + 25% x 10^"6 kg mL^"1, 1.0 + 25% x 10^"6 kg mL^"1, 5.0 + 25% x 10^"6 kg mL^"1, 10.0 + 25% x 10^"6 kg mL^"1, 50.0 + 25% x 10^"6 kg mL^"1, 100.0 + 25% x 10^"6 kg mL^"1, 500.0 + 25% x 10^"6 kg mL^"1, or 1000.0 + 25% x 10^"6 kg mL^"1, 1250.0 + 25% x 10^"6 kg mL^"1, 1500.0 + 25% x 10^"6 kg mL^"1, 1750.0 + 25% x 10^"6 kg mL^"1, 2000.0 + 25% x 10^"6 kg mL^"1, 3000.0 + 25% x 10^"6 kg mL^"1, 4000.0 + 25% x 10^"6 kg mL^"1, 5000.0 + 25% x 10^"6 kg mL^"1, 6000.0 + 25% x 10^"6 kg mL o or 7000.0 + 25% x lO^ kg mL^"1. In some embodiments, dbmnC* can be measured 10 hours after administration, 11 hours after administration, 12 hours after administration, 13 hours after administration, 14 hours after administration, 15 hours after administration, 16 hours after administration, 17 hours after administration, 18 hours after administration, 19 hours after administration, 20 hours after

administration, 21 hours after administration, 22 hours after administration, 23 hours after administration, 24 hours after administration, or 36 hours after administration. For example, a dbmnC* value may be about, or less than about,

1.0 ± 25% x 10^"9 mL^"1, 1.0 + 25% x 10^"8 mL^"1, 0.7 + 25% x 10^"7 mL^"1, 1.0 + 25% x 10^"7 mL^"1, 2.0 + 25% x 10^"7 mL^"1, 3.0 + 25% x 10^"7 mL^"1, 4.0 + 25% x 10^"7 mL^" 5.0 + 25% x lO^ mL^"1, 1.0 + 25% x 10^"6 mL^"1, or 5.0 + 25% x 10^"6 mL^"1. In some embodiments, the dbmnC* value can relate to single dosing. In some embodiments, the dbmnC* value can relate to a multi-dose regimen (e.g., repeated daily administration). In some embodiments, the plasma concentration used to calculate the dbmnC* may be adjusted to reflect a baseline plasma concentration (e.g., a baseline plasma level because of repeated daily administration). C_max is defined as the peak plasma concentration of a compound of the invention after administration. If a dbmnC* value is calculated at the time point corresponding to Cmax, the value may alternatively be referred to as a dose and body mass normalized C_max or dbmnC_max*. In some embodiments, a dbmnC_max* is greater than or equal to 10.0 + 25% x 10^"6 kg mL^"1, greater than or equal to 15 + 25% x 10^"6 kg mL^"1, greater than or equal to 20 + 25% x 10^"6 kg mL^"1, greater than or equal to 25 + 25% x 10^"6 kg mL^"1, greater than or equal to 30 + 25% x 10^"6 kg mL^" \ greater than or equal to 35 + 25% x 10^"6 kg mL^"1, greater than or equal to 40 + 25% x 10^"6 kg mL^"1, greater than or equal to 45 + 25% x 10^"6 kg mL^"1, greater than or equal to 50 + 25% x 10^"6 kg mL^"1. In some embodiments, a dbmnC_max* is greater than or equal to 100.0 + 25% x 10^"6 kg mL^"1, greater than or equal to 150 + 25% x 10^"6 kg mL^"1, greater than or equal to 200 + 25% x 10^"6 kg mL^"1, greater than or equal to 250 + 25% x 10^"6 kg kg mL^"1, greater than or equal to 300 + 25% x 10^"6 mL^"1, greater than or equal to 350 + 25% x 10^"6 kg mL^"1, greater than or equal to 400 + 25% x 10^"6 kg mL^"1, greater than or equal to 450 + 25% x 10^"6 kg mL^"1, greater than or equal to 500 + 25% x 10^"6 kg mL^"1.

[0084] As described above, C_max is defined as the peak plasma concentration of a compound of the invention after administration. By administering a composition of the invention for transmucosal absorption, it is possible to obtain higher C_max values than if the composition were administered orally. In some embodiments, a composition affords a C_max of a compound greater than or equal to 10 ng/mL, greater than or equal to 11 ng/mL, greater than or equal to 12 ng/mL, greater than or equal to 13 ng/mL, greater than or equal to 14 ng/mL, greater than or equal to 15 ng/mL, greater than or equal to 16 ng/mL, greater than or equal to 17 ng/mL, greater than or equal to 18 ng/mL, greater than or equal to 19 ng/mL, greater than or equal to 20 ng/mL, greater than or equal to 21 ng/mL, greater than or equal to 22 ng/mL, greater than or equal to 23 ng/mL, greater than or equal to 24 ng/mL, greater than or equal to 25 ng/mL, greater than or equal to 26 ng/mL, greater than or equal to 27 ng/mL, greater than or equal to 28 ng/mL, greater than or equal to 29 ng/mL, greater than or equal to 30 ng/mL, greater than or equal to 31 ng/mL, greater than or equal to 32 ng/mL, greater than or equal to 33 ng/mL, greater than or equal to 34 ng/mL, greater than or equal to 35 ng/mL, greater than or equal to 36 ng/mL, greater than or equal to 37 ng/mL, greater than or equal to 38 ng/mL, greater than or equal to 39 ng/mL, greater than or equal to 40 ng/mL, greater than or equal to 50 ng/mL, greater than or equal to 60 ng/mL, greater than or equal to 70 ng/mL, greater than or equal to 80 ng/mL, greater than or equal to 90 ng/mL, greater than or equal to 100 ng/mL, greater than or equal to 120 ng/mL, greater than or equal to 140 ng/mL, greater than or equal to 160 ng/mL, greater than or equal to 180 ng/mL, or greater than or equal to 200 ng/mL.

[0085] A C_max may be measured either after administration of a first dose or after the administration of any dose of a composition of the invention. However, because the compositions and methods of the invention may be used to prolong a therapeutic regimen, plasma levels of a compound useful in the compositions and methods may not return to 0 between dosing (i.e., there may be a baseline level of a compound in circulation). Accordingly, a composition may afford a C_max that can be compared to a baseline level of the compound rather than taken as an absolute numerical value compared to a starting plasma concentration of 0 ng/mL. In some embodiments, a composition affords a C_max of a compound greater than or equal to 10 ng/mL, greater than or equal to 11 ng/mL, greater than or equal to 12 ng/mL, greater than or equal to 13 ng/mL, greater than or equal to 14 ng/mL, greater than or equal to 15 ng/mL, greater than or equal to 16 ng/mL, greater than or equal to 17 ng/mL, greater than or equal to 18 ng/mL, greater than or equal to 19 ng/mL, greater than or equal to 20 ng/mL, greater than or equal to 21 ng/mL, greater than or equal to 22 ng/mL, greater than or equal to 23 ng/mL, greater than or equal to 24 ng/mL, greater than or equal to 25 ng/mL, greater than or equal to 26 ng/mL, greater than or equal to 27 ng/mL, greater than or equal to 28 ng/mL, greater than or equal to 29 ng/mL, greater than or equal to 30 ng/mL, greater than or equal to 31 ng/mL, greater than or equal to 32 ng/mL, greater than or equal to 33 ng/mL, greater than or equal to 34 ng/mL, greater than or equal to 35 ng/mL, greater than or equal to 36 ng/mL, greater than or equal to 37 ng/mL, greater than or equal to 38 ng/mL, greater than or equal to 39 ng/mL, greater than or equal to 40 ng/mL, greater than or equal to 50 ng/mL, greater than or equal to 60 ng/mL, greater than or equal to 70 ng/mL, greater than or equal to 80 ng/mL, greater than or equal to 90 ng/mL, greater than or equal to 100 ng/mL, greater than or equal to 120 ng/mL, greater than or equal to 140 ng/mL, greater than or equal to 160 ng/mL, greater than or equal to 180 ng/mL, or greater than or equal to 200 ng/mL above a baseline level (e.g., plasma concentration) of the compound as measured immediately prior to a second administration. As used herein, "immediately prior to administration" means within 1 hour, 45 minutes, 30 minutes, 15 minutes, 10 minutes, 5 minutes, or 1 minute of administration.

[0086] As a result of the higher C_max values achieved through sublingual administration, the area under the curve (AUC) for plasma concentration of a compound over time also is greater in comparison to the AUC afforded by an oral administration. AUC can be measured between two specific time points (e.g., AUCo-8h) or over an extrapolated period of time from 0 to infinity (AUCo-∞h,

AUCo-oo or AUC_mf). AUC is typically given in units of ng hr mL^"1, so for example in the experiment on human subjects who received 5 mg immediate release doxepin tablets in Figure 1, the AUCo-∞h was determined to be 103.1 + 35.8 ng hr mL^"1 and the AUCo-i68h was 92.2 + 29.9 ng hr mL^"1. In another example, a dose of a 2.4 mg doxepin sublingual tablet with basifying agent from 0 to 0.75 h resulted in an AUCo-0.75 h of 135.6 ng hr mL^"1 in an experiment on Beagles. In the same experiment, for the sublingual tablet with basifying agent, the AUCo-∞h was 179.0 + 50.2 ng hr mL^"1 and the AUC₀-ioh was 176.6 + 49.9 ng hr mL^"1. In the Beagle experiment, for the sublingual 2.4 mg tablet lacking the basifying agent, the AUCo- 0.75 _h was 82.4 ng hr mL^"1, the AUC₀-∞h was 155.4 + 64.6 ng hr mL^"1 and the AUC₀- ioh was 151.6 + 64.0 ng hr mL^"1. In a Beagle experiment (Figures 2 and 3) for i.v. doxepin at an average dose of 1.79 mg, the AUCo-∞h was 44.9 + 4.15 ng hr mL^"1 and the AUC₀-24h was 43.5 + 3.77 ng hr mL^"1. In a Beagle experiment (Figures 2 and 3) for sublingual solution doxepin at an average dose of 1.79 mg, the AUCo-∞h was 129.1 + 36.4 ng hr mL^"1 and the AUC₀-₂4h was 126.9 + 37.1 ng hr mL^"1. By contrast, in an example from the literature, administering 2.5, 5.0 or 10 mg (10 mg in a 70 kg human being equivalent to 0.14 mg/kg in Beagles) doxepin immediate release tablets to humans resulted in AUCo-8 h of 11.1, 23.0, and 45.9 ng hr mL^"1, respectively and AUCo-∞h of 44.2, 89.5, and 178.2 ng hr mL^"1, respectively

(Winchell G.A. et al. "Doxepin pharmacokinetics, including the effects of age, gender and hepatic insufficiency", J. Clin. Pharmacol 2002 42:61). In some embodiments, for example, at a 2.4 mg dosing, the AUCo-₂omin is about 0.04 ng hr mL^"1, AUCo-30min is about 0.13 ng hr mL^"1, AUCo-45min is about 0.33 ng hr mL^"1, AUCo-ih is about 0.61 ng hr mL^"1, AUCo-₂h is about 2.10 ng hr mL^"1, AUCo-₂.5h is about 2.95 ng hr mL^"1, AUCo-3h is about 3.93 ng hr mL^"1, AUCo-3.3h is about 4.66 ng hr mL^"1, AUCo-3.7h is about 5.46 ng hr mL^"1, AUCo-4h is about 6.27 ng hr mL^"1, AUCo-4.3h is about 7.12 ng hr mL^"1, AUC₀-4.7h is about 7.99 ng hr mL^"1, AUCo-o-5h is about 8.81 ng hr mL^"1, AUCo-5.5h is about 10.06 ng hr mL^"1, AUCo-6h is about 11.27 ng hr mL^"1, AUCo-8h is about 15.11 ng hr mL^"1, AUCo-i2h is about 50.30 ng hr mL^"1, AUCo-inf is about 60.97 ng hr mL^"1. In some embodiments (with TNX-102 SL

2.8), the AUCo-20min is about 0.04 ng hr mL^"1, AUCo-30min is about 0.15 ng hr mL^"1, AUCo -45min IS about 0.39 ng hr mL^"1, AUC₀-i_h is about 0.72 ng hr mL^"1, AUC₀-₂h is about 2.45 ng hr mL^"1, AUCo-₂.5h is about 3.45 ng hr mL^"1, AUCo-3h is about 4.59 ng hr mL^"1, AUCo-3.3h is about 5.44 ng hr mL^"1, AUCo-3.7h is about 6.37 ng hr mL^"1, AUCo-4h is about 7.32 ng hr mL^"1, AUC₀-4.3h is about 8.30 ng hr mL^"1, AUC₀-4.7h is about 9.32 ng hr mL^"1, AUCo-o-5h is about 10.27 ng hr mL^"1, AUCo-5.5h is about 11.74 ng hr mL^"1, AUCo-6h is about 13.14 ng hr mL^"1, AUCo-8h is about 17.63 ng hr mL^"1, AUCo-i2h is about 58.68 ng hr mL^"1, AUCo-inf is about 71.13 ng hr mL^"1. AUC also can be compared to the dose administered to generate an AUC to dose ratio which is sometimes referred to as dose normalized AUC, or dnAUC. The dose normalized dnAUCo-∞h for the human data described above and in Figure 1 is 20.6 x 10^"6 hr mL^"1. The dose normalized AUC0-0.75 h (dnAUCo-0.75 h) for the Beagle data described above is dnAUCo-0.75 h = 135.6 6 ng hr mL^"V2.4 mg = 56.5 x 10^"6 hr mL^"1. In a Beagle experiment (Figures 2 and 3) for IV doxepin at an average dose of 1.79 mg, the dnAUCo-∞h was 25.04 x 10^"6 hr mL^"1 and the dnAUCo-24h was 24.2 x 10^"6 hr mL^"1. In a Beagle experiment (Figures 2 and 3) for sublingual doxepin in solution at an average dose of 1.79 mg, the dnAUCo-∞h was 71.95 x 10^"6 hr mL^"1 and the dnAUC₀-₂4h was 70.72 x 10^"6 hr mL^"1. The dose normalized AUCo-8 h (dnAUCo-8h) for the human data described above (from Winchell et al) is 4.4 x 10^"6 hr mL^"1, 4.6 x 10^"6 hr mL^"1 and 4.6 x 10^"6 hr mL^"1 for the 2.5, 5.0 and 10 mg doxepin doses, respectively. The dose normalized dnAUCo-∞h for the human data described above (from Winchell et al.) is 17.7 x 10^"6 hr mL^"1, 17.9 x 10^"6 hr mL^"1, and 17.8 x 10^"6 hr mL^"1 for the 2.5, 5.0 and 10 mg doxepin doses, respectively. In some embodiments, the dnAUCo-₂omin is about 0.02 + 25% x 10^"6 hr mL^"1, the dnAUC₀-30min is about 0.05 + 25% x 10^"6 hr mL^"1, the dnAUC₀-45min is about 0.15 + 25% x 10^"6 hr mL^"1, the dnAUC₀-i_h is about 0.25 + 25% x 10^"6 hr mL^"1, the dnAUC₀-_2h is about 0.90 + 25% x 10^"6 hr mL^"1, the dnAUCo-2.5h is about 1.2 + 25% x 10^"6 hr mL^"1, the dnAUC₀-₃h is about 1.6 + 25% x 10^"6 hr mL^"1, the dnAUC_{3 3h} is about 1.8 + 25% x 10^"6 hr mL^"1, dnAUC₀-₃._7h is about 2.3 + 25% x 10^"6 hr mL^"1, the dnAUC₀-_4h is about 2.6 + 25% x 10^"6 hr mL^" \ the dnAUCo-_{4 3h} is about 3.0 + 25% x 10^"6 hr mL^"1, the dnAUC₀-₄._7h is about 3.3 + 25% x 10^"6 hr mL^"1, the dnAUC₀-_5h is about 3.7 + 25% x 10^"6 hr mL^"1, the dnAUCo-5.5h is about 4.2 + 25% x 10^"6 hr mL^"1, the dnAUC₀-₆h is about 4.7 + 25% x 10^"6 hr mL^"1, the dnAUC₀-_8h is 6.3 + 25% x 10^"6 hr mL^"1, the dnAUC₀-i₂h is about 20 + 25% x 10^"6 hr mL^"1, and the dnAUC₀-_∞h is about 25 + 25% x 10^"6 hr mL^"1. In some embodiments, a dnAUCo-_8h is greater than or equal to 5 + 25% x 10^"6 hr mL^"1, greater than or equal to 6 + 25% x 10^"6 hr mL^"1, greater than or equal to 7 + 25% x 10^"6 hr mL^"1, greater than or equal to 8 + 25% x 10^"6 hr mL^"1, greater than or equal to 9 + 25% x 10^"6 hr mL^"1, greater than or equal to 10 + 25% x 10^"6 hr mL^"1, greater than or equal to 11 + 25% x 10^"6 hr mL^"1, greater than or equal to 12 + 25% x 10^"6 hr mL^"1, greater than or equal to 13 + 25% x 10^"6 hr mL^"1, greater than or equal to 14 + 25% x 10^"6 hr mL^"1, greater than or equal to 15 + 25% x 10^"6 hr mL^"1, greater than or equal to 16 + 25% x 10^"6 hr mL^"1, greater than or equal to 17 + 25% x 10^"6 hr mL^"1, greater than or equal to 18 + 25% x 10^"6 hr mL^"1, or greater than or equal to 19 + 25% x 10^"6 hr mL^"1. In some embodiments, a dnAUCo-_8h is greater than or equal to 20 + 25% x 10^"6 hr mL^"1, greater than or equal to 22 + 25% x 10^"6 hr mL^"1, greater than or equal to 24 + 25% x 10^"6 hr mL^"1, greater than or equal to 26 + 25% x 10^"6 hr mL^"1, greater than or equal to 28 + 25% x 10^"6 hr mL^"1, or greater than or equal to 30 + 25% x 10^"6 hr mL^"1. In some embodiments, a dnAUCo-_8h is greater than or equal to 40 + 25% x 10^"6 hr mL^"1, greater than or equal to 50 + 25% x 10^"6 hr mL^"1, greater than or equal to 60 + 25% x 10^"6 hr mL^"1, greater than or equal to 70 + 25% x 10^"6 hr mL^"1, greater than or equal to 80 + 25% x 10^"6 hr mL^"1, or greater than or equal to 90 + 25% x lO^ hr mL^"1. In some embodiments, a dnAUCo-_8h is greater than or equal to 100 + 25% x 10^"6 hr mL^"1, greater than or equal to 120 + 25% x 10^"6 hr mL^"1, greater than or equal to 140 + 25% x 10^"6 hr mL^"1, greater than or equal to 160 + 25% x 10^"6 hr mL^"1, greater than or equal to 180 + 25% x 10^"6 hr mL^"1, or greater than or equal to 200 + 25% x 10^"6 hr mL^"1. In some embodiments, a dnAUCo-io_h is greater than or equal to 5 + 25% x 10^"6 hr mL^"1, greater than or equal to 6 + 25% x - so lo ⁶ hr mL^"1, greater than or equal to 7 + 25% x 10^"6 hr mL^"1, greater than or equal to 8 + 25% x 10^"6 hr mL^"1, greater than or equal to 9 + 25% x 10^"6 hr mL^"1, greater than or equal to 10 + 25% x 10^"6 hr mL^"1, greater than or equal to 11 + 25% x 10^"6 hr mL^"1, greater than or equal to 12 + 25% x 10^"6 hr mL^"1, greater than or equal to 13 + 25% x 10^"6 hr mL^"1, greater than or equal to 14 + 25% x 10^"6 hr mL^" \ greater than or equal to 15 + 25% x 10^"6 hr mL^"1, greater than or equal to 16 + 25% x 10^"6 hr mL^"1, greater than or equal to 17 + 25% x 10^"6 hr mL^"1, greater than or equal to 18 + 25% x 10^"6 hr mL^"1, or greater than or equal to 19 + 25% x 10^"6 hr mL^"1. In some embodiments, a dnAUCo-ioh is greater than or equal to 20 + 25% x 10^"6 hr mL^"1, greater than or equal to 22 + 25% x 10^"6 hr mL^"1, greater than or equal to 24 + 25% x 10^"6 hr mL^"1, greater than or equal to 26 + 25% x 10^"6 hr mL^" \ greater than or equal to 28 + 25% x 10^"6 hr mL^"1, or greater than or equal to 30 + 25% x lO^ hr mL^"1. In some embodiments, a dnAUCo-ioh is greater than or equal to 40 + 25% x 10^"6 hr mL^"1, greater than or equal to 50 + 25% x 10^"6 hr mL^"1, greater than or equal to 60 + 25% x 10^"6 hr mL^"1, greater than or equal to 70 + 25% x 10^"6 hr mL^"1, greater than or equal to 80 + 25% x 10^"6 hr mL^"1, or greater than or equal to 90 + 25% x 10^"6 hr mL^"1. In some embodiments, a dnAUCo-ioh is greater than or equal to 100 + 25% x 10^"6 hr mL^"1, greater than or equal to 120 + 25% x 10^"6 hr mL^"1, greater than or equal to 140 + 25% x 10^"6 hr mL^"1, greater than or equal to 160 + 25% x 10^"6 hr mL^"1, greater than or equal to 180 + 25% x 10^"6 hr mL^"1, or greater than or equal to 200 + 25% x 10^"6 hr mL^"1. In some

embodiments, a dnAUCo-i2h is greater than or equal to 20 + 25% x 10^"6 hr mL^"1, greater than or equal to 30 + 25% x 10^"6 hr mL^"1, greater than or equal to 40 + 25% x 10^"6 hr mL^"1, greater than or equal to 50 + 25% x 10^"6 hr mL^"1, greater than or equal to 60 + 25% x 10^"6 hr mL^"1, or greater than or equal to 70 + 25% x 10^"6 hr mL^"1. In some embodiments, a dnAUCo-i2h is greater than or equal to 80 + 25% x 10^"6 hr mL^"1, greater than or equal to 90 + 25% x 10^"6 hr mL^"1, greater than or equal to 100 + 25% x 10^"6 hr mL^"1, greater than or equal to 120 + 25% x 10^"6 hr mL^"1, greater than or equal to 160 + 25% x 10^"6 hr mL^"1, or greater than or equal to 180 + 25% x lO^ hr mL^"1. In some embodiments, a dnAUCo-24h is greater than or equal to 24 + 25% x 10^"6 hr mL^"1, or greater than or equal to 25 + 25% x 10^"6 hr mL^"1, greater than or equal to 30 + 25% x 10^"6 hr mL^"1, greater than or equal to 35 + 25% x 10^~6 hr mL^"1, greater than or equal to 40 + 25% x 10^"6 hr mL^"1, greater than or equal to 50 + 25% x 10^"6 hr mL^"1, greater than or equal to 60 + 25% x 10^"6 hr mL^"1, greater than or equal to 70 + 25% x 10^"6 hr mL^"1, greater than or equal to 80 + 25% x 10^"6 hr mL^"1, or greater than or equal to 90 + 25% x 10^"6 hr mL^"1. In some embodiments, dnAUCo-24h is greater than or equal to 100 + 25% x 10^"6 hr mL^"1, greater than or equal to 110 + 25% x 10^"6 hr mL^"1, greater than or equal to 120 + 25% x 10^"6 hr mL^"1, greater than or equal to 130 + 25% x 10^"6 hr mL^"1, greater than or equal to 140 + 25% x 10^"6 hr mL^"1, or greater than or equal to 150 + 25% x lO^ hr mL^"1. In some embodiments, a dnAUCo-24h is greater than or equal to 160 + 25% x 10^"6 hr mL^"1, greater than or equal to 170 + 25% x 10^"6 hr mL^"1, greater than or equal to 180 + 25% x 10^"6 hr mL^"1, greater than or equal to 190 + 25% x 10^"6 hr mL^"1, greater than or equal to 200 + 25% x 10^"6 hr mL^"1, or greater than or equal to 210 + 25% x 10^"6 hr mL^"1. In some embodiments, a dnAUCo-24h is greater than or equal to 220 + 25% x 10^"6 hr mL^"1, greater than or equal to 240 + 25% x 10^"6 hr mL^"1, greater than or equal to 250 + 25% x 10^"6 hr mL^"1, greater than or equal to 260 + 25% x 10^"6 hr mL^"1, greater than or equal to 270 + 25% x 10^"6 hr mL^"1, or greater than or equal to 280 + 25% x 10^"6 hr mL^"1. In some embodiments, a dnAUCo-∞h is greater than or equal to 24 + 25% x 10^"6 hr mL^"1, or greater than or equal to 25 + 25% x 10^"6 hr mL^"1, greater than or equal to 30 + 25% x 10^"6 hr mL^"1, greater than or equal to 35 + 25% x 10^"6 hr mL^"1, greater than or equal to 40 + 25% x 10^"6 hr mL^"1, greater than or equal to 50 + 25% x 10^"6 hr mL^" \ greater than or equal to 60 + 25% x 10^"6 hr mL^"1, greater than or equal to 70 + 25% x 10^"6 hr mL^"1, greater than or equal to 80 + 25% x 10^"6 hr mL^"1, or greater than or equal to 90 + 25% x 10^"6 hr mL^"1. In some embodiments, dnAUCo-∞h is greater than or equal to 100 + 25% x 10^"6 hr mL^"1, greater than or equal to 110 + 25% x 10^"6 hr mL^"1, greater than or equal to 120 + 25% x 10^"6 hr mL^"1, greater than or equal to 130 + 25% x 10^"6 hr mL^"1, greater than or equal to 140 + 25% x 10^"6 hr mL^"1, or greater than or equal to 150 + 25% x 10^"6 hr mL^"1. In some embodiments, a dnAUCo-∞h is greater than or equal to 160 + 25% x 10^"6 hr mL^"1, greater than or equal to 170 + 25% x 10^"6 hr mL^"1, greater than or equal to 180 + 25% x 10^"6 hr mL^"1, greater than or equal to 190 + 25% x 10^"6 hr mL^"1, greater than or equal to 200 + 25% x 10^"6 hr mL^"1, or greater than or equal to 210 + 25% x lO^ hr mL^"1. In some embodiments, a dnAUCo-∞h is greater than or equal to 220 + 25% x 10^"6 hr mL^"1, greater than or equal to 240 + 25% x 10^"6 hr mL^"1, greater than or equal to 250 + 25% x 10^"6 hr mL^"1, greater than or equal to 260 + 25% x 10^"6 hr mL^"1, greater than or equal to 270 + 25% x 10^"6 hr mL^"1, or greater than or equal to 280 + 25% x 10^"6 hr mL^"1.

[0087] The product of AUC and body mass also can be compared to the dose administered to generate a ratio between the AUC times body mass product to dose which is herein referred to as dose- and body mass- normalized AUC, or dbmnAUC. The dose- and body mass- normalized dbmnAUCo-∞h for the human data described above and in Figure 1 is approximately, for 70 kg humans, 140.6 x 10^"6 kg hr mL^"1. The dose- and body mass- normalized AUC₀-₀.75 h (dbmnAUCo-₀.75 h) for the Beagle data described above (average body mass of Beagles was 12.5 kg) is dbmnAUCo-0.75 h = 12.5 kg x 135.6 ng hr mL^"V2.4 mg = 708 x 10^"6 kg hr mL^"1. In a Beagle experiment (Figures 2 and 3) for IV doxepin at an average dose of 1.79 mg, the dbmnAUCo-∞h was 12.5 kg x 25.04 x 10^"6 hr mL^"1 and the dbmnAUCo-24h was 314 x 10^"6 kg hr mL^"1. In a Beagle experiment (Figures 2 and 3) for sublingual doxepin in solution at an average dose of 1.79 mg, the dbmnAUCo-∞h was 12.5 kg x 71.95 x 10^"6 hr mL^"1 and the dbmnAUC₀-24h was 886 x 10^"6 kg hr mL^"1. The dbmnAUCo-8 h for the human data described above (from Winchell et al.), assuming 70 kg humans, is approximately 70 kg x 4.4 + 25% x 10^"6 hr mL^"1 = 308 + 25% x 10^"6 kg hr mL^"1, 322 + 25% x 10^"6 kg hr mL^"1 and 322 + 25% x 10^"6 kg hr mL^"1 for the 2.5, 5.0 and 10 mg doxepin doses, respectively. The dose normalized dbmnAUCo-∞h for the human data described above (from Winchell et al.) is 70 kg x 17.7 + 25% x 10^"6 hr mL^"1 = 1239 + 25% x 10^"6 kg hr mL^"1, 1253 + 25% x 10^"6 kg hr mL^"1, and 1246 + 25% x 10^"6 kg hr mL^"1 for the 2.5, 5.0 and 10 mg doxepin doses, respectively. In some embodiments, the dbmnAUCo-20min is about 1.1 + 25% x 10^"6 kg hr mL^"1, the dbmnAUCo-somin is about 3.7 + 25% x 10^"6 kg hr mL^"1, the dbmnAUC₀-45min is about 9.7 + 25% x 10^"6 kg hr mL^"1, the dbmnAUCo-ih is about 18 + 25% x 10^"6 kg hr mL^"1, the dbmnAUC₀-2h is about 62 + 25% x 10^"6 kg hr mL^"1, the dbmnAUC₀-2.₅h is about 86 + 25% x 10^"6 kg hr mL^"1, the dbmnAUCo-3h is about 115 + 25% x 10^"6 kg hr mL^"1, the dbmnAUC_{3 3h} is about 135 + 25% x 10^"6 kg hr mL^"1, dbmnAUC₀-₃.7h is about 160 + 25% x 10^"6 kg hr mL^" \ the dbmnAUCo-4h is about 180 + 25% x 10^"6 kg hr mL^"1, the dbmnAUC₀-4.3h is about 210 + 25% x 10^"6 kg hr mL^"1, the dbmnAUC₀-4.7h is about 230 + 25% x 10^"6 kg hr mL^"1, the dbmnAUCo-sh is about 260 + 25% x 10^"6 kg hr mL^"1, the dbmnAUCo-5.5h is about 290 + 25% x 10^"6 kg hr mL^"1, the dbmnAUC₀-6h is about 330 + 25% x 10^"6 kg hr mL^"1, the dbmnAUCo-sh is 440 + 25% x 10^"6 kg hr mL^"1, the dbmnAUCo-i2h is about 1500 + 25% x 10^"6 kg hr mL^"1, and the dbmnAUCo-inf is about 1800 + 25% x 10^"6 kg hr mL^"1. In some embodiments, a dbmnAUCo-8h is greater than or equal to 350 + 25% x 10^"6 kg hr mL^"1. In some embodiments, a dbmnAUCo-8h is greater than or equal to 400 + 25% x 10^"6 hr mL^"1, greater than or equal to 500 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 600 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 700 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 800 + 25% x 10^"6 kg hr mL^"1, or greater than or equal to 900 + 25% x 10^" ⁶ kg hr mL^"1. In some embodiments, a dbmnAUCo-8h is greater than or equal to 1000 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 1200 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 1400 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 1600 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 1800 + 25% x 10^"6 kg hr mL^"1, or greater than or equal to 2000 + 25% x 10^"6 kg hr mL^"1. In some embodiments, a dbmnAUCo-ioh is greater than or equal to 400 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 500 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 600 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 700 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 800 + 25% x 10^"6 kg hr mL^"1, or greater than or equal to 900 + 25% x 10^"6 kg hr mL^"1. In some embodiments, a dbmnAUCo-ioh is greater than or equal to 1000 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 1200 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 1400 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 1600 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 1800 + 25% x 10^"6 kg hr mL^"1, or greater than or equal to 2000 + 25% x 10^"6 kg hr mL^"1. In some embodiments, a dbmnAUCo-i2h is greater than or equal to 500 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 600 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 700 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 800 + 25% x 10^"6 kg hr mL^"1, or greater than or equal to 900 + 25% x 10^"6 kg hr mL^"1. In some embodiments, a dbmnAUCo-i2h is greater than or equal to 1000 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 1200 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 1400 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 1600 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 1800 + 25% x 10^"6 kg hr mL^"1, or greater than or equal to 2000 + 25% x 10^"6 kg hr mL^"1. In some embodiments, a dbmnAUCo-_24h is greater than or equal to 500 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 600 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 700 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 800 + 25% x 10^"6 kg hr mL^"1, or greater than or equal to 900 + 25% x 10^"6 kg hr mL^"1. In some embodiments, dbmnAUCo- _24h is greater than or equal to 1000 + 25% x 10^"6 kg mL^"1, greater than or equal to 1100 + 25% x 10^"6 hr mL^"1, greater than or equal to 1200 + 25% x 10^"6 kg hr mL^" \ greater than or equal to 1300 + 25% x 10^"6 kg hr mL^"1, greater than or equal to

1400 + 25% x 10^"6 kg hr mL^"1, or greater than or equal to 1500 + 25% x 10^"6 kg hr mL^"1. In some embodiments, a dbmnAUCo-_24h is greater than or equal to 1600 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 1700 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 1800 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 1900 + 25% x 10^"6 kg hr rnL^"1, greater than or equal to 2000 + 25% x 10^"6 kg hr mL^"1, or greater than or equal to 2100 + 25% x 10^"6 kg hr mL^"1. In some embodiments, a dbmnAUCo-_24h is greater than or equal to 2200 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 2400 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 2500 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 2600 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 2700 + 25% x 10^"6 kg hr mL^"1, or greater than or equal to 2800 + 25% x 10^"6 kg hr mL^"1. In some embodiments, a dnAUCo-_∞h is greater than or equal to 240 + 25% x 10^"6 kg hr mL^"1, or greater than or equal to 250 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 300 + 25% x 10^"6 kg hr mL^" \ greater than or equal to 35 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 400 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 500 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 600 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 700 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 800 + 25% x 10^"6 kg hr mL^"1, or greater than or equal to 900 + 25% x 10^"6 kg hr mL^"1. In some embodiments, dbmnAUCo-ooh is greater than or equal to 1000 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 1100 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 1200 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 1300 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 1400 + 25% x 10^"6 kg hr mL^"1, or greater than or equal to 1500 + 25% x lO^ kg hr mL^"1. In some embodiments, a dbmnAUCo-∞h is greater than or equal to 1600 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 1700 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 1800 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 1900 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 2000 + 25% x 10^"6 kg hr rnL^"1, or greater than or equal to 2100 + 25% x 10^"6 kg hr mL^"1. In some embodiments, a dbmnAUCo-∞h is greater than or equal to 2200 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 2400 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 250 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 2600 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 2700 + 25% x 10^"6 hr mL^"1, or greater than or equal to 2800 + 25% x 10^"6 kg hr mL^"1. In some embodiments, a dbmnAUCo-ooh is greater than or equal to 5000 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 10000 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 15000 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 20000 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 25000 + 25% x 10^"6 kg hr mL^"1, or greater than or equal to 30000 + 25% x 10^"6 kg hr mL^"1. In some embodiments, a dbmnAUCo-∞h is greater than or equal to 35000 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 40000 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 45000 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 50000 + 25% x 10^"6 kg hr mL^"1, greater than or equal to 55000 + 25% x 10^"6 hr mL^"1, or greater than or equal to 60000 + 25% x 10^"6 kg hr mL^"1.

[0088] In some embodiments, a composition of the invention is one that produces a bioequivalent effect to the compositions described herein.

Bioequivalence may be determined by AUC, C_max, t_max, mean absorption time, metabolite plasma concentration, mean residence time, rate constants, rate profiles, and C_max normalized to AUC. An exemplary test for bioequivalence is a confidence interval for C_max and/or AUC that is approximately 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 115%, 120%, or 125% of a given compound. [0089] In some embodiments, a method of the invention is one that produces a bioequivalent effect to the compositions described herein. Bioequivalence may be determined by AUC, C_max, t_max, mean absorption time, metabolite plasma concentration, mean residence time, rate constants, rate profiles, and C_max normalized to AUC. An exemplary test for bioequivalence is a confidence interval for Cmax and/or AUC that is approximately 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 115%, 120%, or 125% of a given compound.

[0090] In some embodiments, the methods and compositions of the invention allow an administered compound including biologically active metabolites of the compound to be removed from the plasma more quickly than if the compound was administered orally. This is beneficial because the clearance of a compound can aid in the reduction of side effects. For example, if a subject takes a sublingual composition comprising doxepin or imipramine before going to sleep, the doxepin or imipramine may be rapidly absorbed but be substantially metabolized and excreted by the time the subject wakes up, minimizing fatigue, somnolence and grogginess felt upon waking. In some embodiments, a plasma level of a compound decreases by at least 50% of the C_max by 4 hours after administration, 5 hours after administration, 6 hours after administration, 7 hours after administration, 8 hours after administration, 9 hours after administration, 10 hours after administration, 11 hours after administration, 12 hours after administration, 13 hours after

administration, 14 hours after administration, or 15 hours after administration. In some embodiments, a plasma level of a compound decreases by at least 50% of the Cmax by 4 hours after t_max, by at least 55% of the C_max by 4 hours after t_max, by at least 60% of the C_max by 4 hours after t_max, by at least 65% of the C_max by 4 hours after t_{m x}, by at least 70% of the C_max by 4 hours after t_{m x}, by at least 75% of the C_max by 4 hours after t_{m x}, by at least 80% of the C_max by 4 hours after t_{m x}, by at least 85% of the C_max by 4 hours after t_{m x}, by at least 90% of the C_max by 4 hours after t_{m x}, by at least 91% of the C_max by 4 hours after t_{m x}, by at least 92% of the C_max by 4 hours after t_{m x}, by at least 93% of the C_max by 4 hours after t_{m x}, by at least 94% of the C_max by 4 hours after t_{m x}, by at least 95% of the C_max by 4 hours after t_{m x}, by at least 96% of the C_max by 4 hours after t_{m x}, by at least 97% of the C_max by 4 hours after t_{m x}, by at least 98% of the C_max by 4 hours after t_{m x}, or by at least 99% of the C_max by 4 hours after t_{m x}. In some embodiments, a plasma level of a compound decreases by at least 50% of the C_max by 8 hours after

administration, by at least 55% of the C_max by 8 hours after administration, by at least 60% of the C_max by 8 hours after administration, by at least 65% of the C_max by 8 hours after administration, by at least 70% of the C_max by 8 hours after administration, by at least 75% of the C_max by 8 hours after administration, by at least 80% of the C_max by 8 hours after administration, by at least 85% of the C_max by 8 hours after administration, by at least 90% of the C_max by 8 hours after administration, by at least 91% of the C_max by 8 hours after administration, by at least 92% of the C_max by 8 hours after administration, by at least 93% of the C_max by 8 hours after administration, by at least 94% of the C_max by 8 hours after administration, by at least 95% of the C_max by 8 hours after administration, by at least 96% of the C_max by 8 hours after administration, by at least 97% of the C_max by 8 hours after administration, by at least 98% of the C_max by 8 hours after administration, or by at least 99% of the C_max by 8 hours after administration. In some embodiments, a plasma level of a compound decreases by at least 50% of the C_max by 4 hours after administration, by at least 55% of the C_max by 4 hours after administration, by at least 60% of the C_max by 4 hours after administration, by at least 65% of the C_max by 4 hours after administration, by at least 70% of the C_max by 4 hours after administration, by at least 75% of the C_max by 4 hours after administration, by at least 80% of the C_max by 4 hours after administration, by at least 85% of the C_max by 4 hours after administration, by at least 90% of the C_max by 4 hours after administration, by at least 91% of the C_max by 4 hours after administration, by at least 92% of the C_max by 4 hours after administration, by at least 93% of the C_max by 4 hours after administration, by at least 94% of the C_max by 4 hours after administration, by at least 95% of the C_max by 4 hours after administration, by at least 96% of the C_max by 4 hours after administration, by at least 97% of the C_max by 4 hours after administration, by at least 98% of the C_max by 4 hours after administration, or by at least 99% of the C_max by 4 hours after administration.

[0091] In some embodiments, a composition or method of the invention affords an increased C_max and a decreased t_max, in combination with increased clearance of doxepin or imipramine. For example, a composition or method of the invention may afford a C_max from about 20 to about 200 ng/mL from about 0.05 to about 2.5 hours after administration, while also affording a minimum plasma concentration from about 1 to about 5 ng/mL from about 22 to about 26 hours after

administration, wherein the composition is administered for four days or more of daily administration. In some embodiments, a composition is administered within two hours of sleep. In some embodiments, a method is for reducing the symptoms of fibromyalgia in a human patient.

[0092] In some embodiments, the methods and compositions of the invention allow a compound to be removed from the plasma more quickly than if the compound was administered orally. This is beneficial because the clearance of a compound can aid in the reduction of the accumulation of doxepin or imipramine from the body when administered by nightly dosing and in a chronic dosing schedule. The minimal concentration or Cmin may be determined by measuring the plasma concentration of the compound being administered can be measured either at fixed time points or at a variable time point, e.g., at time points after the time point corresponding to C_max, for example 23 hours after C_max. The C_mi_n can be measured after a single dose or after repeated, multiple, or chronic dosing, for example in daily dosing. For example, Cmin can be measured 3 hours after administration, 4 hours after administration, 5 hours after administration, 6 hours after administration, 7 hours after administration, 8 hours after administration, 9 hours after administration, 10 hours after administration, 11 hours after administration, or 12 hours after administration. In some embodiments, Cmin can be measured 10 hours after administration, 11 hours after administration, 12 hours after administration, 13 hours after administration, 14 hours after administration, 15 hours after administration, 16 hours after administration, 17 hours after administration, 18 hours after administration, 19 hours after administration, 20 hours after administration, 21 hours after administration, 22 hours after administration, 23 hours after administration, 24 hours after administration, or 36 hours after administration. In some embodiments, a composition affords a C_min of a compound less than or equal to 10 pg/mL, less than or equal to 11 pg/mL, less than or equal to 12 pg/mL, less than or equal to 13 pg/mL, less than or equal to 14 pg/mL, less than or equal to 15 pg/mL, less than or equal to 16 pg/mL, less than or equal to 17 pg/mL, less than or equal to 18 pg/mL, less than or equal to 19 pg/mL, less than or equal to 20 pg/mL, less than or equal to 21 pg/mL, less than or equal to 22 pg/mL, less than or equal to 23 pg/mL, less than or equal to 24 pg/mL, less than or equal to 25 pg/mL, less than or equal to 26 pg/mL, less than or equal to 27 pg/mL, less than or equal to 28 pg/mL, less than or equal to 29 pg/mL, less than or equal to 30 pg/mL, less than or equal to 31 pg/mL, less than or equal to 32 pg/mL, less than or equal to 33 pg/mL, less than or equal to 34 pg/mL, less than or equal to 35 pg/mL, less than or equal to 36 pg/mL, less than or equal to 37 pg/mL, less than or equal to 38 pg/mL, less than or equal to 39 pg/mL, less than or equal to 40 pg/mL, less than or equal to 50 pg/mL, less than or equal to 60 pg/mL, less than or equal to 70 pg/mL, less than or equal to 80 pg/mL, less than or equal to 90 pg/mL, less than or equal to 100 pg/mL, less than or equal to 120 pg/mL, less than or equal to 140 pg/mL, less than or equal to 160 pg/mL, less than or equal to 180 pg/mL, or less than or equal to 200 pg/mL. In some embodiments, a composition affords a Cmin of a compound less than or equal to 100 pg/mL, less than or equal to 110 pg/mL, less than or equal to 120 pg/mL, less than or equal to 130 pg/mL, less than or equal to 140 pg/mL, less than or equal to 150 pg/mL, less than or equal to 160 pg/mL, less than or equal to 170 pg/mL, less than or equal to 180 pg/mL, less than or equal to 190 pg/mL, less than or equal to 200 pg/mL, less than or equal to 210 pg/mL, less than or equal to 220 pg/mL, less than or equal to 230 pg/mL, less than or equal to 240 pg/mL, less than or equal to 250 pg/mL, less than or equal to 260 pg/mL, less than or equal to 270 pg/mL, less than or equal to 280 pg/mL, less than or equal to 290 pg/mL, less than or equal to 300 pg/mL, less than or equal to 310 pg/mL, less than or equal to 320 pg/mL, less than or equal to 330 pg/mL, less than or equal to 340 pg/mL, less than or equal to 350 pg/mL, less than or equal to 360 pg/mL, less than or equal to 370 pg/mL, less than or equal to 380 pg/mL, less than or equal to 390 pg/mL, less than or equal to 400 pg/mL, less than or equal to 500 pg/mL, less than or equal to 600 pg/mL, less than or equal to 700 pg/mL, less than or equal to 800 pg/mL, less than or equal to 900 pg/mL, less than or equal to 1.0 ng/mL, less than or equal to 1.20 ng/mL, less than or equal to 1.40 ng/mL, less than or equal to 1.60 ng/mL, less than or equal to 1.80 ng/mL, or less than or equal to 2.00 ng/mL. In some embodiments, a composition affords a Cmin of a compound less than or equal to 3.0 ng/mL, less than or equal to 4.0 ng/mL, less than or equal to 5.0 ng/mL, less than or equal to 6.0 ng/mL, less than or equal to 7.0 ng/mL, less than or equal to 8.0 ng/mL, or less than or equal to 10.0 ng/mL The minimal concentration at 24 hours or Cmin(24) may be determined by measuring the plasma concentration of the compound being administered approximately 24 hours after the last dose or immediately prior to the next dose. Cmin(24) is significant as a plasma value or by calculating the ratio of C_mi_n(24) and the dose administered, which is the dose-normalized minimum plasma concentration or dnC_mm(24)* . The dnC_mi_n(24)* is calculated by determining the ratio of plasma level to dose administered. For example, in a study (shown in Figure 1) in which 5.0 mg of doxepin in an immediate release tablet was administered PO, the mean C_mi_n(24) was 1.384 ng/mL at 24 hours and the

was ((1.384 ng/mL)/(5.0 mg)) = 0.27680 ng/(mg mL), or 0.27680 x 10^"6 ml^"1. In another example, in a study in which 2.4 mg of doxepin in an sublingual tablet was administered, the mean Cmin(24) was 706.55 ng/mL at 24 hours and the dnCmin(24)* was ((706.55

ng/mL)/(2.4 mg)) = 294.40 ng/(mg mL), or 0.29440 x 10^"6 mL^"1. In some embodiments, a dnC_mi_n(24)* is less than or equal to 1.0 + 25% x 10^"6 mL^"1, less than or equal to 0.9 + 25% x 10^"6 mL^"1, less than or equal to 0.8 + 25% x 10^"6 mL^"1, less than or equal to 0.7 + 25% x 10^"6 mL^"1, less than or equal to 0.6 + 25% x 10^"6 mL^" less than or equal to 0.5 + 25% x 10^"6 mL^"1, less than or equal to 0.4 + 25% x 10^"6 mL^"1, or less than or equal to 0.3 + 25% x 10^"6 mL^"1. In some embodiments, a dnCmin(24)* is less than or equal to 240 + 25% x 10^"9 mL^"1, less than or equal to 220 + 25% x 10^"9 mL^"1, less than or equal to 200 + 25% x 10^"9 mL^"1, less than or equal to 180 + 25% x 10^"9 mL^"1, less than or equal to 160 + 25% x 10^"9 mL^"1, less than or equal to 140 + 25% x 10^"9 mL^"1, less than or equal to 120 + 25% x 10^"6 mL^"1, less than or equal to 100 + 25% x 10^"6 mL^"1, less than or equal to 80 + 25% x 10^"9 mL^"1, less than or equal to 60 + 25% x 10^"9 mL^"1, less than or equal to 40 + 25% x 10^"9 mL^"1, less than or equal to 20 + 25% x 10^"9 mL^"1, or less than or equal to 10 + 25% x lO^ mL^"1. In some embodiments, an a dnC_mi_n(24)* is less than or equal to 9 + 25% x 10^"9 mL^"1, less than or equal to 9 + 25% x 10^"6 mL^"1, less than or equal to 7 + 25% x 10^"9 mL^"1, less than or equal to 6 + 25% x 10^"9 mL^"1, less than or equal to 5 + 25% x 10^"9 mL^"1, less than or equal to 4 + 25% x 10^"9 mL^"1, less than or equal to 3 + 25% x 10^~9 mL^"1, less than or equal to 2 + 25% x 10^~9 mL^"1, or less than or equal to 1 + 25% x 10^"9 mL^"1.

[0093] The dose- and body mass- normalized C_mi_n, or the dbmnC_mi_n* is calculated by determining the ratio of the product of the plasma level and body mass to dose administered. The dbmnC_mi_n* at 24 hours, or dbmnC_mi_n(24)*, may be determined by measuring the plasma concentration of the compound being administered approximately 24 hours after the last dose or immediately prior to the next dose in a daily dosing schedule, such as a bedtime dosing schedule. The dbmnC_mi_n* may be determined by measuring the plasma concentration of the compound being administered can be measured either at fixed time points, for example 24 hours after administration (C_mi_n(24)*), or at a variable time point, e.g., at time points after the time point corresponding to C_max, for example 23 hours after C_ma_x- For example, in a study (shown in Figure 1) in which 5.0 mg of doxepin in an immediate release tablet was administered PO, the mean C_mi_n(24)* was 1.384 ng/mL at 24 hours and, assuming a 70 kg human, the approximate dbmnC_mi_n(24)* was 70 kg x ((1.384 ng/mL)/(5.0 mg)) = 19.4 x 10^"6 kg mL^"1. For example, in a study in which 2.4 mg of doxepin in an sublingual tablet was administered, the mean Cmin(24) was 706.55 ng/mL at 24 hours and the dnCmin(24)* was ((706.55 ng/mL)/(2.4 mg)) = 294.40 ng/(mg mL), or 294.40 x 10^"9 mL^"1 and, assuming a 70 kg human, the approximate dbmnC_mi_n(24)* was 70 kg x ((706.55 ng/mL)/(2.4 mg)) = 20.608 x lO^"6 kg mL^"1. In some embodiments, a dbmnC_mi_n(24)* is less than or equal to 1.0 + 25% x 10^"6 kg mL^"1, less than or equal to 0.9 + 25% x 10^"6 kg mL^"1, less than or equal to 0.8 + 25% x 10^"6 kg mL^"1, less than or equal to 0.7 + 25% x 10^"6 kg mL^"1, less than or equal to 0.6 + 25% x 10^"6 kg mL^"1, less than or equal to 0.5 + 25% x 10^"6 kg mL^"1, less than or equal to 0.4 + 25% x 10^"6 kg mL^"1, or less than or equal to 0.3 + 25% x 10^"6 kg mL^"1. In some embodiments, a dbmnC_mi_n(24)* is less than or equal to 240 + 25% x 10^"9 mL^"1, less than or equal to 220 + 25% x 10^"9 kg mL^"1, less than or equal to 200 + 25% x 10^"9 kg mL^"1, less than or equal to 180 + 25% x 10^"9 kg mL^"1, less than or equal to 160 + 25% x 10^"9 kg mL^"1, less than or equal to 140 + 25% x 10^"9 kg mL^"1, less than or equal to 120 + 25% x 10^"6 kg mL^"1, less than or equal to 100 + 25% x 10^"6 kg mL^"1, less than or equal to 80 + 25% x 10^"9 kg mL^"1, less than or equal to 60 + 25% x 10^"9 kg mL^"1, less than or equal to 40 + 25% x 10^"9 kg mL^"1, less than or equal to 20 + 25% x 10^"9 kg mL^"1, or less than or equal to 10 + 25% x 10^"9 kg mL^"1. In some embodiments, an a dbmnC_mi_n(24)* is less than or equal to 9 + 25% x 10^"9 kg mL^"1, less than or equal to 9 + 25% x 10^"6 mL^"1, less than or equal to 7 + 25% x 10^"9 kg mL^"1, less than or equal to 6 + 25% x 10^"9 kg mL^"1, less than or equal to 5 + 25% x 10^"9 kg mL^"1, less than or equal to 4 + 25% x 10^"9 kg mL^"1, less than or equal to 3 + 25% x 10^"9 kg mL^"1, less than or equal to 2 + 25% x 10^"9 kg mL^"1, or less than or equal to 1 + 25% x lO^ kg mL^"1.

[0094] In some embodiments, the methods and compositions of the invention allow a compound to be absorbed into plasma without gut or hepatic metabolism which reduces the metabolism of doxepin and imipramine by p450. This is beneficial. The ratio of the plasma concentration of a metabolite to the dose of the agent administered is the dose-normalized concentration of the metabolite or dnC_met*. The ratio of the plasma concentration of N-desmethyldoxepin to the dose of doxepin administered is the dose-normalized concentration of N- desmethyldoxepin or dnC_met(desmethyldoxepin)*. The ratio of the plasma concentration of desipramine to the dose of imipramine administered is the dose- normalized concentration of desipramine or dnC_met(desipramine)*. The dnC_met* may be measured at various times after administration of the compound either after a single dose or after multiple doses. The dnC_met* can be measured either at fixed time points or at a variable time point, e.g., the time point corresponding to C_max. For example, dnC_met* can be measured 5 minutes after administration, 10 minutes after administration, 15 minutes after administration, 30 minutes after

administration, 45 minutes after administration, 1 hour after administration, 2 hours after administration, 3 hours after administration, 4 hours after

administration, 5 hours after administration, 6 hours after administration, 7 hours after administration, 10 hours after administration, 11 hours after administration, or 12 hours after administration. In some embodiments, dnC_met* can be measured 10 hours after administration, 11 hours after administration, 12 hours after

administration, 13 hours after administration, 14 hours after administration, 15 hours after administration, 16 hours after administration, 17 hours after

administration, 18 hours after administration, 19 hours after administration, 20 hours after administration, 21 hours after administration, 22 hours after

administration, 23 hours after administration, 24 hours after administration, or 36 hours after administration. The dnC_met* at 24 hours or dnC_met (24)* may be determined by measuring the plasma concentration of the compound being administered approximately 24 hours after the last dose or immediately prior to the next dose in a daily dosing schedule, such as a bedtime dosing schedule. In some embodiments, a dnC_met(24)* is less than or equal to 1.0 + 25% x 10^~6 mL^"1, less than or equal to 0.9 + 25% x 10^"6 mL^"1, less than or equal to 0.8 + 25% x 10^"6 mL^"1, less than or equal to 0.7 + 25% x 10^"6 mL^"1, less than or equal to 0.6 + 25% x 10^"6 mL^" less than or equal to 0.5 + 25% x 10^"6 mL^"1, less than or equal to 0.4 + 25% x 10^"6 mL^"1, or less than or equal to 0.3 + 25% x 10^"6 mL^"1. In some embodiments, a dnC_met(24)* is less than or equal to 240 + 25% x 10^"9 mL^"1, less than or equal to 220 + 25% x 10^"9 mL^"1, less than or equal to 200 + 25% x 10^"9 mL^"1, less than or equal to 180 + 25% x 10^"9 mL^"1, less than or equal to 160 + 25% x 10^"9 mL^"1, less than or equal to 140 + 25% x 10^"9 mL^"1, less than or equal to 120 + 25% x 10^"6 mL^"1, less than or equal to 100 + 25% x 10^"6 mL^"1, less than or equal to 80 + 25% x 10^"9 mL^"1, less than or equal to 60 + 25% x 10^"9 mL^"1, less than or equal to 40 + 25% x 10^"9 mL^"1, less than or equal to 20 + 25% x 10^"9 mL^"1, or less than or equal to 10 + 25% x lO^ mL^"1. In some embodiments, an a dnC_met(24)* is less than or equal to 9 + 25% x 10^"9 mL^"1, less than or equal to 9 + 25% x 10^"6 mL^"1, less than or equal to 7 + 25% x 10^"9 mL^"1, less than or equal to 6 + 25% x 10^"9 mL^"1, less than or equal to 5 + 25% x 10^"9 mL^"1, less than or equal to 4 + 25% x 10^"9 mL^"1, less than or equal to 3 + 25% x 10^"9 mL^"1, less than or equal to 2 + 25% x 10^"9 mL^"1, or less than or equal to 1 + 25% x 10^"9 mL^"1. [0095] The ratio of the product of the body mass and plasma concentration of N- desmethyldoxepin to the dose of doxepin administered is the dose-and body mass- normalized concentration of N-desmethyldoxepin or dbmnC_met(norcycl)*. The ratio of the product of the body mass and plasma concentration of desipramine to the dose of imipramine administered is the dose- and body mass- normalized concentration of desipramine or dbmnC_met(nortrip)*. The dbmnC_met* may be measured at various times after administration of the compound either after a single dose or after multiple doses. The dbmnC_met* can be measured either at fixed time points or at a variable time point, e.g., the time point corresponding to C_max. For example, dbmnC_met* can be measured 5 minutes after administration, 10 minutes after administration, 15 minutes after administration, 30 minutes after administration, 45 minutes after administration, 1 hour after administration, 2 hours after administration, 3 hours after administration, 4 hours after

administration, 5 hours after administration, 6 hours after administration, 7 hours after administration, 10 hours after administration, 11 hours after administration, or 12 hours after administration. In some embodiments, dbmnC_met* can be measured 10 hours after administration, 11 hours after administration, 12 hours after administration, 13 hours after administration, 14 hours after administration, 15 hours after administration, 16 hours after administration, 17 hours after

administration, 23 hours after administration, 24 hours after administration, or 36 hours after administration. The dbmnC_met* at 24 hours or dbmnC_met(24)* may be determined by measuring the plasma concentration of the compound being administered approximately 24 hours after the last dose or immediately prior to the next dose in a daily dosing schedule, such as a bedtime dosing schedule. For example, in a study in which 5.0 mg of doxepin in an immediate release tablet was administered and the mean plasma concentration of N-desmethyldoxepin was

1.227 ng/mL at 24 hours, and the average body mass of the human is estimated to be 70 kg, the dbmnC_met (24)(norcycl) * is 70 kg x ((1.227 ng/mL)/(5.0 mg)) = 17.2 x 10^"6 kg mL^"1. The dbmnC_met(24)* for multiple dosing of doxepin or imipramine is expected to be higher. In some embodiments, a dbmnC_met(24)* is less than or equal to 1.0 + 25% x 10^"6 kg mL^"1, less than or equal to 0.9 + 25% x 10^"6 kg mL^"1, less than or equal to 0.8 + 25% x 10^"6 kg mL^"1, less than or equal to 0.7 + 25% x 10^"6 kg mL^"1, less than or equal to 0.6 + 25% x 10^"6 kg mL^"1, less than or equal to 0.5 + 25% x 10^"6 kg mL^"1, less than or equal to 0.4 + 25% x 10^"6 kg mL^"1, or less than or equal to 0.3 + 25% x 10^"6 kg mL^"1. In some embodiments, a dbmnC_met(24)* is less than or equal to 240 + 25% x 10^"9 kg mL^"1, less than or equal to 220 + 25% x 10^"9 kg mL^"1, less than or equal to 200 + 25% x 10^"9 kg mL^"1, less than or equal to 180 + 25% x 10^"9 kg mL^"1, less than or equal to 160 + 25% x 10^"9 kg mL^"1, less than or equal to 140 + 25% x 10^"9 kg mL^"1, less than or equal to 120 + 25% x 10^"6 kg mL^" less than or equal to 100 + 25% x 10^"6 kg mL^"1, less than or equal to 80 + 25% x 10^"9 kg mL^"1, less than or equal to 60 + 25% x 10^"9 kg mL^"1, less than or equal to 40 + 25% x 10^"9 kg mL^"1, less than or equal to 20 + 25% x 10^"9 kg mL^"1, or less than or equal to 10 + 25% x 10^"9 kg mL^"1. In some embodiments, an a dbmnC_met(24)* is less than or equal to 9 + 25% x 10^"9 kg mL^"1, less than or equal to 9 + 25% x 10^"6 kg mL^"1, less than or equal to 7 + 25% x 10^"9 kg mL^"1, less than or equal to 6 + 25% x 10^"9 kg mL^"1, less than or equal to 5 + 25% x 10^"9 kg mL^"1, less than or equal to 4 + 25% x 10^"9 kg mL^"1, less than or equal to 3 + 25% x 10^"9 kg mL^"1, less than or equal to 2 + 25% x 10^"9 kg mL^"1, or less than or equal to 1 + 25% x lO^ kg mL^"1.

Excipients

[0096] In some embodiments, a composition of the invention is useful as a medicament. In some embodiments, the invention provides for the use of a composition of the invention in the manufacture of a medicament. In some embodiments, it may be beneficial to include one or more excipients in the compositions of the invention. One of skill in the art would appreciate that the choice of any one excipient may influence the choice of any other excipient. For example, the choice of a particular excipient may preclude the use of one or more additional excipient because the combination of excipients would produce undesirable effects. One of skill in the art would be able to empirically determine which additional excipients, if any, to include in the formulations of the invention. For example, a compound of the invention can be combined with at least one pharmaceutically acceptable carrier such as a solvent, bulking agents, binder, humectant, disintegrating agent, solution retarder, disintegrant, glidant, absorption accelerator, wetting agent, solubilizing agent, lubricant, sweetening agent, or flavorant agent. A "pharmaceutically acceptable carrier" refers to any diluent or excipient that is compatible with the other ingredients of the formulation, and which is not deleterious to the recipient. A pharmaceutically acceptable carrier can be selected on the basis of the desired route of administration, in accordance with standard pharmaceutical practices. Bulking agents

[0097] In some embodiments, it may be beneficial to include a bulking agent in the compositions of the invention. Bulking agents are commonly used in pharmaceutical compositions to provide added volume to the composition.

Bulking agents are well known in the art. Accordingly, the bulking agents described herein are not intended to constitute an exhaustive list, but are provided merely as exemplary bulking agents that may be used in the compositions and methods of the invention.

[0098] Exemplary bulking agents may include carbohydrates, sugar alcohols, amino acids, and sugar acids. Bulking agents include, but are not limited to, mono-, di-, or poly-, carbohydrates, starches, aldoses, ketoses, amino sugars, glyceraldehyde, arabinose, lyxose, pentose, ribose, xylose, galactose, glucose, hexose, idose, mannose, talose, heptose, glucose, fructose, methyl a-D- glucopyranoside, maltose, lactone, sorbose, erythrose, threose, arabinose, allose, altrose, gulose, idose, talose, erythrulose, ribulose, xylulose, psicose, tagatose, glucosamine, galactosamine, arabinans, fructans, fucans, galactans, galacturonans, glucans, mannans, xylans, inulin, levan, fucoidan, carrageenan, galactocarolose, pectins, amylose, pullulan, glycogen, amylopectin, cellulose, microcrystalline cellulose, pustulan, chitin, agarose, keratin, chondroitin, dermatan, hyaluronic acid, xanthin gum, sucrose, trehalose, dextran, lactose, alditols, inositols, sorbitol, mannitol, glycine, aldonic acids, uronic acids, aldaric acids, gluconic acid, isoascorbic acid, ascorbic acid, glucaric acid, glucuronic acid, gluconic acid, glucaric acid, galacturonic acid, mannuronic acid, neuraminic acid, pectic acids, maize starch, and alginic acid. Disintegrants

[0099] In some embodiments, it may be beneficial to include a disintegrant in the compositions of the invention. Disintegrants aid in the breakup of solid

compositions, facilitating delivery of an active pharmaceutical composition.

Disintegrants are well known in the art. Some disintegrants have been referred to as superdisintegrants because they have fast properties, and may be used as disintegrants in the context of the invention. Accordingly, the disintegrants described herein are not intended to constitute an exhaustive list, but are provided merely as exemplary disintegrants that may be used in the compositions and methods of the invention. Exemplary disintegrants include crospovidone, microcrystalline cellulose, sodium carboxymethyl cellulose, methyl cellulose, sodium starch glycolate, calcium carboxymethyl croscarmellose sodium, polyvinylpyrrolidone, lower alky 1- substituted hydroxypropyl cellulose, Indion 414, starch, pre-gelatinized starch, calcium carbonate, gums, sodium alginate, and Pearlitol Flash®. Pearlitol Flash® (Roquette) is a mannitol- maize starch disintegrant that is specifically designed for orally dispersible tablets (ODT).

Certain disintegrants have an efferverscent quality.

Glidants

[0100] In some embodiments, it may be beneficial to include a glidant in the compositions of the invention. Glidants aid in the ability of a powder to flow freely. Glidants are well known in the art. Accordingly, the glidants described herein are not intended to constitute an exhaustive list, but are provided merely as exemplary glidants that may be used in the compositions and methods of the invention. Exemplary glidants include colloidal silica (silicon dioxide), magnesium stearate, starch, talc, glycerol behenate, DL-leucine, sodium lauryl sulfate, calcium stearate, and sodium stearate.

Lubricants

[0101] In some embodiments, it may be beneficial to include a lubricant in the compositions of the invention. Lubricants help keep the components of a composition from clumping. Lubricants are well known in the art. Accordingly, the lubricants described herein are not intended to constitute an exhaustive list, but are provided merely as exemplary lubricants that may be used in the compositions and methods of the invention. Exemplary lubricants include calcium stearate, magnesium stearate, stearic acid, sodium stearyl fumarate, vegetable based fatty acids, talc, mineral oil, light mineral oil, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, safflower oil, canola oil, coconut oil and soybean oil), silica, zinc stearate, ethyl oleate, ethyl laurate.

Sweeteners

[0102] In some embodiments, it may be beneficial to include a sweetener in the compositions of the invention. Sweeteners help improve the palatability of the composition by conferring a sweet taste to the composition. Sweeteners are well known in the art. Accordingly, the sweeteners described herein are not intended to constitute an exhaustive list, but are provided merely as exemplary sweeteners that may be used in the compositions and methods of the invention. Exemplary sweeteners include, without limitation, compounds selected from the saccharide family such as the mono-, di-, tri-, poly-, and oligosaccharides; sugars such as sucrose, glucose (corn syrup), dextrose, invert sugar, fructose, maltodextrin and polydextrose; saccharin and salts thereof such as sodium and calcium salts;

cyclamic acid and salts thereof; dipeptide sweeteners; chlorinated sugar derivatives such as sucralose and dihydrochalcone; sugar alcohols such as sorbitol, sorbitol syrup, mannitol, xylitol, hexa-resorcinol, and the like, and combinations thereof. Hydrogenated starch hydrolysate, and the potassium, calcium, and sodium salts of 3,6-dihydro-6-methyl-l-l,2,3-oxathiazin-4-one-2,2-dioxide many also be used.

Flavorants [0103] In some embodiments, it may be beneficial to include a flavorant in the compositions of the invention. Flavorants help improve the palatability of the composition by conferring a more desirable taste to the composition. Flavorants are well known in the art. Accordingly, the flavorants described herein are not intended to constitute an exhaustive list, but are provided merely as exemplary flavorants that may be used in the compositions and methods of the invention. Exemplary flavorants include, without limitation, natural and/or synthetic (i.e., artificial) compounds such as peppermint, spearmint, wintergreen, menthol, cherry, strawberry, watermelon, grape, banana, peach, pineapple, apricot, pear, raspberry, lemon, grapefruit, orange, plum, apple, lime, fruit punch, passion fruit, pomegranate, chocolate (e.g., white, milk, dark), vanilla, caramel, coffee, hazelnut, cinnamon, combinations thereof, and the like.

Coloring Agents

[0104] Coloring agents can be used to color code the composition, for example, to indicate the type and dosage of the therapeutic agent therein. Coloring Agents are well known in the art. Accordingly, the coloring agents described herein are not intended to constitute an exhaustive list, but are provided merely as exemplary coloring agents that may be used in the compositions and methods of the invention. Exemplary coloring agents include, without limitation, natural and/or artificial compounds such as FD & C coloring agents, natural juice concentrates, pigments such as titanium oxide, silicon dioxide, and zinc oxide, combinations thereof, and the like.

Combination therapy

[0105] As described above, the compositions and methods of the invention may be used to treat PTSD, depression, fibromyalgia, traumatic brain injury, sleep disorder, non-restorative sleep, chronic pain, and anxiety disorder. Any of the methods of treatment described also may be combined with a psychotherapeutic intervention to improve the outcome of the treatment. Exemplary

psychotherapeutic interventions directed at either modifying traumatic memories or reducing emotional responses to traumatic memories, including psychological debriefing, cognitive behavior therapy and eye movement desensitization and reprocessing, systematic desensitization, relaxation training, biofeedback, cognitive processing therapy, stress inoculation training, assertiveness training, exposure therapy, combined stress inoculation training and exposure therapy, combined exposure therapy, and relaxation training and cognitive therapy. In each case, the goal of the intervention involves either modifying traumatic memories or reducing emotional responses to traumatic memories. The intended result is generally a improvement in the symptoms of PTSD or the reduction of occurrences of symptoms, as evidenced in terms of physiological responding, anxiety, depression, and feelings of alienation. [0106] In some embodiments of the invention, a composition is combined with a drug which may further alleviate the symptoms of PTSD, depression, fibromyalgia, traumatic brain injury, sleep disorder, non-restorative sleep, chronic pain, or anxiety disorder. The drugs include an alpha- 1 -adrenergic receptor antagonist, a beta-adrenergic antagonist, an anticonvulsant, a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, and an analgesic.

Exemplary anticonvulsants include carbamazepine, gabapentin, lamotrigine, oxcarbazepine, pregabalin, tiagabine, topiramate, and valproate. An exemplary alpha- 1 -adrenergic receptor antagonist is prazosin. Exemplary selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors include, bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, escitalopram, fluvoxamine, milnacipran, paroxetine, sertraline, trazodone, and venlafaxine. Exemplary analgesics include pregabalin, gabapentin,

acetaminophen, tramadol, and non-steroidal anti- inflammatory drugs (e.g., ibupro fen and naproxen sodium). Additional drugs that can be used in

combination with the compositions of the invention include sodium oxybate, Zolpidem, pramipexole, modafinil, temazepam, zaleplon, and armodafinil.

[0107] It is to be understood that the embodiments of the present invention which have been described are merely illustrative of some of the applications of the principles of the present invention. Numerous modifications may be made by those skilled in the art based upon the teachings presented herein without departing from the true spirit and scope of the invention.

[0108] The following examples are set forth as being representative of the present invention. These examples are not to be construed as limiting the scope of the invention as these and other equivalent embodiments will be apparent in view of the present disclosure, figures, and accompanying claims. Examples Example 1

[0109] To test the effects of the methods and compositions of the invention described herein, a protocol was designed for the administration of doxepin HC1 and imipramine HC1 in beagle dogs. The protocol is described below.

[0110] 5 non-naive female dogs are used, each dog receiving the test substance by oral administration via nasogastric tube to the stomach (NG) administration, sublingual administration (SL), and by intravenous (IV) administration. There is a "wash-out" period of at least two weeks between each type of administration. Blood samples are drawn as follows:

Session 1: oral administration

[0111] A single NG dose of 0.14 mg/kg (under a volume of 5 ml/kg and a solution concentration of 0.028 mg/mL) is administered. Blood samples are taken pre-dosing, and then at 30 min, 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours after administration (for a total of 12 blood samples per animal).

Session 2: sublingual administration

[0112] After a wash-out period of at least 2 weeks, dogs are sedated using propofol (6.5 mg/kg IV). They will be then given a single sublingual dose of 0.14 mg/kg (under a volume of 0.056 mL/kg and a solution concentration of 2.5 mg/mL). Blood samples are taken pre-dosing, and then at 10 min, 20 min, 30 min, 1, 2, 3, 4, 6, 8, 10 and 24 hours after administration (for a total of 12 blood samples per animal). After administration, animals do not have any access to water for 30 minutes.

Session 3: intravenous administration [0113] After a wash-out period of at least 2 weeks, dogs are given a single IV dose of 0.14 mg/kg (under a volume of 1 mL/kg, bolus of approximately 30 sec, and a solution concentration of 0.14 mg/mL). Blood samples are taken pre-dosing, and then at 10 min, 20 min, 30 min, 1, 2, 3, 4, 6, 8, 10 and 24 hours after administration (for a total of 12 blood samples per animal).

[0114] Blood sampling was designed to minimize animal suffering and to ensure the quality of the biological samples, and was adapted from basic procedures commonly used in studies performed in dogs. Serial blood samples (1 tube of approximately 5 mL) are collected from a jugular vein using vacuum tubes containing lithium heparin. After sealing each tube, the blood samples are manually agitated and stored on ice until centrifugation (within 30 minutes of sampling). The samples are centrifuged at 1500 g, at 4°C, for 10 minutes. The entire resultant plasma obtained from each tube is immediately transferred to suitably labeled polypropylene tubes (3 aliquots of plasma of at least 500 μΐ each), which are stored upright at approximately -80°C and protected from light until bioanalysis.

[0115] The dogs are fasted overnight before each administration, and food is given to the dogs 4 hours after each treatment. The doxepin HC1 or imipramine HC1 is dosed at 0.14 mg/kg for each of the three routes of administration (PO, sublingual, and IV). In each of the three routes, a potassium phosphate buffer (pH 7.4) is used as the vehicle.

[0116] Female beagle dogs, weighing 12 - 18 kg, obtained from HARLAN or CEDS are used in these trials. The dogs are housed in groups in a kennel with free access to food and water, under natural lighting and in a controlled ambient temperature of 18 + 3°C. During the pharmacokinetic phase, dogs are housed singly in a floor area of approximately 1 or 2 m . During this phase, the animal house is maintained under artificial lighting (12 hours) between 7:00 and 19:00 in a controlled ambient temperature of 18 + 3°C.

[0117] Sublingual administration of doxepin HC1 and of imipramine HC1 results in improved pharmacokinetic properties and bioavailability as compared to PO administration. In particular, the C_max is significantly higher when administered sublingually. The T_max also diminishes, and the bioavailability increases. Example 2

[0118] To study whether sublingual doxepin and imipramine are efficiently absorbed in humans, a solution for sublingual administration containing doxepin HCl or imipramine HCl formulations in an aqueous solution containing K₂HP0₄ at pH 7.0 - 7.4 may also be used in lieu of sublingual tablets that would introduce a disintegration factor. Sublingual administration of doxepin or imipramine in the context of the invention may take place through, inter alia, sublingual tablets or a liquid solution. As described above, with a sublingual formulation, doxepin and imipramine are expected to be more bioavailable and to provide more predictable absorption of doxepin and imipramine than oral tablets. As a result, patients may be less likely to receive too little drug to receive therapeutic effect, and yet may also be less likely to be overdosed, reducing the potential for side-effects, i.e., next-day drowsiness and/or noncompliance due to intolerance. Sublingual administration also is expected to bypass the first-pass hepatic metabolism that results in metabolites of doxepin and imipramine.

[0119] The single-center, randomized, open- label, single-dose, comparative, parallel-design pharmacokinetic study described below was appropriately designed to compare the rate and extent of absorption of doxepin HCl and imipramine sublingual formulations versus doxepin and imipramine oral formulations, respectively.

[0120] Potential subjects are screened by medical and psychiatric history and laboratory and physical examinations 2 to 30 days prior to dose administration. Baseline evaluations are conducted and subjects are randomly assigned to a formulation/treatment 1 day prior to drug administration (Day -1). The next morning, after all pre-dose assessments are completed and eligible subjects agreed to continue, subjects are randomly assigned to study medication and receive the assigned dose of test or reference drug. Subjects are required to have fasted for at least 10 hours prior to dosing and for 4 hours thereafter.

[0121] Subjects are confined from at least 10 hours before dosing until after the 72-hour discharge procedures. Subjects are required to remain seated or semi- reclined and to avoid lying down or sleeping, unless medically necessary or procedurally required, for up to 4 hours after administration of the assigned study drug. Due to the long confinement period, supervised outings are permitted during the period of confinement. No outing is allowed on the day of dosing (Day 1). [0122] Tests for thyroid- stimulating hormone (TSH), human immunodeficiency virus types 1 and 2 (HIV1 and HIV2), hepatitis B (HBsAg), and hepatitis C

(HCAb) are conducted at screening only, and urine drug screens, alcohol breath tests, and urine cotinine tests were conducted at screening and admission. Physical examinations, laboratory tests, vital signs, 12-lead electrocardiograms (ECGs), weight/body mass index (BMI), and pregnancy tests were performed at specified intervals. Monitoring for adverse events (AEs) and concomitant medications were conducted continuously. Blood and urine samples were collected at specified intervals for the measurement of levels of doxepin and imimpramine and their metabolites in plasma and urine. A post-study follow-up telephone call was scheduled 10 + 3 days after administration of the assigned study medication. For subjects who discontinued prematurely, every effort was made to complete the discharge assessments and the follow-up telephone call.

[0123] The objective of comparing the rate and extent of absorption of sublingual doxepin HC1 and imipramine HC1 solution in an aqueous solution containing K₂HPO₄ versus oral doxepin HC1 and imipramine HC1 is met through analysis of multiple plasma and urine samples collected from the subjects and by comparing those associated with the two formulations. The objective of comparing the rate and extent of absorption of sublingual doxepin HC1 and imipramine HC1 versus oral doxepin HC1 and imipramine HC1 tablets, and intravenous doxepin HC1 and imipramine HC1 in an aqueous solution containing K₂HPO₄ is met through analysis of multiple plasma and urine samples collected from the subjects and comparing those associated with these formulations or treatments. The objective of assessing the safety and tolerability of doxepin HC1 and imipramine HC1 is addressed by monitoring AEs, clinical laboratory values, vital signs, 12-lead ECGs, weight/BMI, concomitant medications, and overall well-being prior to, during, and at the close of the 4-day in- house dosing period. [0124] Before undergoing any study-related screening procedures, each potential subject provides signed informed consent. The investigator determines the potential subject's suitability for the study by interviewing the subject and by performing per-protocol screening assessments. Subjects are administered a single-dose treatment according to a block randomization scheme. Six subjects were are randomly assigned to each of the four groups, for a total enrollment of 24 subjects.

The four treatments are as follows:

Treatment A: 1 dose of 2.4 mg doxepin HCl or imipramine HCl sublingual solution (2.4 mg/mL) in aqueous solution containing K₂HP0₄, administered as 1 mL held under the tongue for 90 seconds without swallowing

Treatment B: 1 dose of 2.4 mg doxepin HCl or imipramine HCl sublingual solution (2.4 mg/mL) in aqueous solution containing K₂HP0₄, administered as 1 mL held under the tongue for 90 seconds without swallowing Treatment C: 1 dose of 5 mg doxepin HCl or imipramine HCl immediate-release tablets, swallowed with 240 mL of room-temperature water

Treatment D: 1 dose of 2.4 mg doxepin HCl or imipramine HCl in aqueous solution containing K₂HP0₄ (0.6 mg/mL), administered intravenously as a 4 mL bolus injection over 30 seconds [0125] Each subject participates for up to approximately 43 days, including an up to 30-day screening period, a 4-day in-house dosing period, and a follow-up telephone call 10 + 3 days after study drug administration.

[0126] The low-dose doxepin HCl or imipramine HCl sublingual solution 2.4 mg (2.4 mg/mL) is administered sublingually via Becton Dickinson 1 mL needle-less syringe. This sublingual solution consists of doxepin HCl or imipramine HCl dissolved in aqueous solution containing K₂HP0₄ at a concentration of 2.4 mg/mL. The solution is manufactured as two formulations that were identical except that one is provided at pH 7.4 and the other is provided at pH 3.5. The two doxepin HC1 and imipramine HCl 2.4 mg sublingual formulations are filled in single-use 3 mL vials (1.5 mL per 3 mL vial), labeled, packaged, and provided for use in the study.

[0127] For blood samples, ANOVA is performed on T_max, K_ei, and T_{½ el} and on AUCo-t, AUCo-inf, and Cmax at the alpha level of 0.05. The ratio of means

(treatments A/B, A/C, A/D, B/C, and B/D) and 90% geometric confidence interval (CI) for the ratio of means, based on least-squares means from the ANOVA of the In-transformed data, was calculated for AUCo-t, AUCo-inf, and C_max. For all analytes, the ratio of means (treatments A/B, A/C, A/D, B/C, and B/D) and 90% geometric CI for the ratio of means, based on least-squares means from the ANOVA of the In-transformed data, is calculated for Aeo-t and R_max.

[0128] As with studies in beagles, administration of sublingual doxepin HCl or of sublingual imipramine HCl improves pharmacokinetic measurements.

Claims

What is Claimed is:

1. A composition comprising doxepin, wherein the composition is suitable for transmucosal absorption.

2. A composition comprising doxepin and a basifying agent, wherein the composition is suitable for transmucosal absorption.

3. A composition comprising imipramine, wherein the composition is suitable for transmucosal absorption.

4. A composition comprising imipramine and a basifying agent, wherein the composition is suitable for transmucosal absorption.

5. The composition of any one of claims 2 and 4, wherein the basifying agent is selected from the group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate.

6. The composition of any one of claims 1-5, wherein the transmucosal absorption is oral absorption.

7. The composition of claim 6, wherein the composition is suitable for sublingual administration.

8. The composition of claim 7, wherein the composition is in a form selected from the group consisting of a sublingual tablet, a sublingual film, a sublingual powder, and a sublingual spray solution.

9. The composition of claim 6, wherein the composition is suitable for buccal administration.

10. The composition of claim 9, wherein the composition is in a form selected from the group consisting of a buccal tablet, a lozenge, a buccal powder, and a buccal spray solution.

11. The composition of any one of claims 1-5, wherein the transmucosal absorption is intranasal absorption.

12. The composition of claim 11, wherein the composition is in a form of a nasal spray solution.

13. The composition of any one of claims 1-5, wherein the transmucosal absorption is pulmonary absorption.

14. The composition of claim 13, wherein the composition is in a form selected from the group consisting of an aerosolized composition and an inhalable dry powder.

15. The composition of any one of claims 1-14, characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 0.1 + 25% x 10 -^"7 mL -^"1 15 minutes after administration.

16. The composition of any one of claims 1-15, characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 0.5 + 25% x 10 -^"7 mL -^"1 30 minutes after administration.

17. The composition of any one of claims 1-16, characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 1.5 + 25% x 10 -^"7 mL -^"1 45 minutes after administration.

18. The composition of any one of claims 1-17, characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 4.0 + 25% x 10 -^"7 mL -^"1 1 hour after administration.

19. The composition of any one of claims 1-18, characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 5.2 + 25% x 10 -^"7 mL -^"1 2 hours after administration .

20. The composition of any one of claims 1-19, characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 9.0 + 25% x 10^"6 mL^"1 3 hours after administration.

21. The composition of any one of claims 1-20, characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of less than or equal to 5.0 + 25% x 10 -^"7 mL -^"1 10 hours after administration.

22. The composition of any one of claims 1-21, characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of less than or equal to 5.0 + 25% x 10 -^"7 mL -^"1 12 hours after administration.

23. The composition of any one of claims 1-22, characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of less than or equal to 5.0 + 25% x 10 -^"7 mL -^"1 14 hours after administration.

24. The composition of any one of claims 1-23, characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of less than or equal to 5.0 + 25% x 10 -^"7 mL -^"1 16 hours after administration.

25. The composition of any one of claims 1-24, characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of less than or equal to 5.0 + 25% x 10 -^"7 mL -^"1 18 hours after administration.

26. The composition of any one of claims 1-25, characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnAUCo-20min of greater than or equal to 0.02 + 25% x 10^"6 hr mL^"1, a dnAUCo-30min of greater than or equal to 0.05 + 25% x 10^"6 hr mL^"1, a dnAUCo- 45min of greater than or equal to 0.14 + 25% x 10^"6 hr mL^"1, a dnAUCo-ih of greater than or equal to 0.26 + 25% x 10^"6 hr mL^"1, a dnAUCo-2h of greater than or equal to 0.87 + 25% x 10^"6 hr mL^"1, or a dnAUC₀-₂.5h of greater than or equal to 1.23 + 25% x 10^"6 hr mL^"1.

27. The composition of any one of claims 1-26, characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnAUCo-∞h of greater than or equal to 20 mL^"1 hr^"1.

28. The composition of any one of claims 1-27, characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC_ma_x* of greater than or equal to 1.0 + 25% x 10^"6 mL^"1.

29. The composition of any one of claims 1-28, characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a plasma concentration of 50% or less of the C_max 4 hours after administration.

30. The composition of any one of claims 1-29, characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a plasma concentration of 50% or less of the C_max 6 hours after administration.

31. The composition of any one of claims 1-30, characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a plasma concentration of 50% or less of the C_max 8 hours after administration.

32. The composition of any one of claims 1-31, characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a plasma concentration of 50% or less of the C_max 12 hours after

administration.

33. The composition of any one of claims 1-32, wherein the doxepin is present in an amount from 0.1 mg to 10 mg.

34. The composition of claim 33, wherein the doxepin is present in an amount from 0.1 mg to 5 mg.

35. The composition of claim 34, wherein the doxepin is present in an amount of about 2.4 mg.

36. The composition of claim 34, wherein the doxepin is present in an amount of less than about 2.4 mg.

37. The composition of claim 34, wherein the doxepin is present in an amount of about 4.8 mg.

38. The composition of claim 34, wherein the doxepin is present in an amount of less than about 4.8 mg.

39. The composition of any one of claims 1-38, characterized in that, when administered by transmucosal absorption, the composition affords a Cmax of doxepin greater than or equal to 10 ng/mL.

40. The composition of claim 39, characterized in that, when administered by transmucosal absorption, the composition affords a C_max of doxepin greater than or equal to 15 ng/mL.

41. The composition of claim 40, characterized in that, when administered by transmucosal absorption, the composition affords a C_max of doxepin greater than or equal to 20 ng/mL.

42. The composition of claim 41, characterized in that, when administered by transmucosal absorption, the composition affords a C_max of doxepin greater than or equal to 25 ng/mL.

43. The composition of claim 42, characterized in that, when administered by transmucosal absorption, the composition affords a Cmax Of doxepin greater than or equal to 30 ng/mL.

44. The composition of any one of claims 1-43, characterized that, when administered by transmucosal absorption, the composition affords a C_max of doxepin greater than or equal to 10 ng/mL above the baseline level of doxepin in the individual immediately prior to administration.

45. The composition of claim 44, characterized in that, when administered by transmucosal absorption, the composition affords a C_max of doxepin greater than or equal to 15 ng/mL above the baseline level of doxepin in the individual immediately prior to administration.

46. The composition of claim 45, characterized in that, when administered by transmucosal absorption, the composition affords a C_max of doxepin greater than or equal to 20 ng/mL above the baseline level of doxepin in the individual immediately prior to administration.

47. The composition of claim 46, characterized in that, when administered by transmucosal absorption, the composition affords a C_max of doxepin greater than or equal to 25 ng/mL above the baseline level of doxepin in the individual immediately prior to administration.

48. The composition of claim 47, characterized in that, when administered by transmucosal absorption, the composition affords a C_max of doxepin greater than or equal to 30 ng/mL above the baseline level of doxepin in the individual immediately prior to administration.

49. The composition of any one of claims 1-48, characterized that, when administered by transmucosal? absorption, the composition affords a t_max of doxepin of less than 4 hours.

50. The composition of claim 49, characterized in that, when administered by transmucosal? absorption, the composition affords a t_max of doxepin of less than 3 hours.

51. The composition of claim 50, characterized in that, when administered by transmucosal absorption, the composition affords a t_max of doxepin of less than 2 hours.

52. The composition of claim 51, characterized in that, when administered by transmucosal absorption, the composition affords a t_max of doxepin of less than 1 hour.

53. The composition of claim 52, characterized in that, when administered by transmucosal absorption, the composition affords a t_max of doxepin of less than 45 minutes.

54. The composition of claim 53, characterized in that, when administered by transmucosal absorption, the composition affords a t_max of doxepin of less than 30 minutes.

55. The composition of claim 54, characterized in that, when administered by transmucosal absorption, the composition affords a t_max of doxepin of less than 15 minutes.

56. The composition of any one of claims 1-55, characterized in that, when administered by transmucosal absorption, the composition affords a plasma level of doxepin that decreases by at least 50% of the C_max by 8 hours after administration.

57. The composition of claim 56, characterized in that, when administered by transmucosal absorption, the composition affords a plasma level of doxepin that decreases by at least 60% of the C_max by 8 hours after

administration.

58. The composition of claim 57, characterized in that, when administered by transmucosal absorption, the composition affords a plasma level of doxepin that decreases by at least 70% of the C_max by 8 hours after

administration.

59. The composition of claim 58, characterized in that, when administered by transmucosal absorption, the composition affords a plasma level of doxepin that decreases by at least 80% of the C_max by 8 hours after

administration.

60. The composition of claim 59, characterized in that, when administered by transmucosal absorption, the composition affords a plasma level of doxepin that decreases by at least 90% of the C_max by 8 hours after

administration.

61. The composition of claim 60, characterized in that, when administered by transmucosal absorption, the composition affords a plasma level of doxepin that decreases by at least 95% of the C_max by 8 hours after

administration.

62. A method for treating a disease or condition in an individual in need thereof comprising administering a composition of any one of claims 1-61 by transmucosal absorption.

63. The method of claim 62, wherein the disease or condition is post-traumatic stress disorder (PTSD).

64. The method of claim 63, wherein administration of the composition treats the development of PTSD following a traumatic event.

65. The method of claim 63, wherein administration of the composition treats the initiation of PTSD following a traumatic event.

66. The method of claim 63, wherein administration of the composition treats the consolidation of PTSD following a traumatic event.

67. The method of claim 63, wherein administration of the composition treats the perpetuation of PTSD following a traumatic event.

68. The method of claim 62, wherein the disease or condition is selected from the group consisting of fibromyalgia, depression, traumatic brain injury, sleep disorder, non-restorative sleep, chronic pain, muscle spasm, and anxiety disorder.

69. The method of any one of claims 62-68, wherein the basifying agent is selected from the group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate.

70. The method of any one of claims 62-69, wherein the oral absorption is sublingual absorption.

71. The method of claim 70, wherein the composition is in a form selected from the group consisting of a sublingual tablet, a sublingual film, a sublingual powder, and a sublingual spray solution.

72. The method of any one of claims 62-69, wherein the oral absorption is buccal absorption.

73. The method of claim 72, wherein the composition is selected from the group consisting of a buccal tablet, a lozenge, a buccal powder, and a buccal spray solution.

74. The method of any one of claims 62-73, wherein the transmucosal absorption is intranasal absorption.

75. The method of claim 74, wherein the composition is in a form of a nasal spray solution.

76. The method of any one of claims 62-73, wherein the transmucosal absorption is pulmonary absorption.

77. The method of claim 76, wherein the composition is in a form selected from the group consisting of an aerosolized composition and an inhalable dry powder.

78. The method of any one of claims 62-77, wherein the doxepin or imipramine has a dnC* of greater than or equal to 1.0 + 25% x 10 mL^"1 20 minutes after administration.

79. The method of any one of claims 62-78, wherein the doxepin or imipramine has a dnC* of greater than or equal to 2.5 + 25% x 10 mL^"1 30 minutes after administration.

80. The method of any one of claims 62-79, wherein the doxepin or imipramine has a dnC* of greater than or equal to 3.0 + 25% x 10 mL^"1 45 minutes after administration.

81. The method of any one of claims 62-80, wherein the doxepin or imipramine has a dnC* of greater than or equal to 4.2 + 25% x 10 mL^"1 1 hour after administration.

82. The method of any one of claims 62-81, wherein the doxepin or imipramine has a dnC* of greater than or equal to 6.0 + 25% x 10 mL^"1 2 hours after administration.

83. The method of any one of claims 62-82, wherein the doxepin or imipramine has a dnC of greater than or equal to 7.0 + 25% x 10^" mL

3 hours after administration.

84. The method of any one of claims 62-83, wherein the doxepin or imipramine has a dnC of less than or equal to 5.0 + 25% x 10^" mL -1

3.3 hours after administration.

85. The method of any one of claims 62-84, wherein the doxepin or imipramine has a dnC of less than or equal to 5.0 + 25% x 10^" mL -1

12 hours after administration.

86. The method of any one of claims 62-85, wherein the doxepin or imipramine has a dnC* of less than or equal to 5.0 + 25% x 10 -^"7 mL -^"1 14 hours after administration.

87. The method of any one of claims 62-86, wherein the doxepin or imipramine has a dnC* of less than or equal to 5.0 + 25% x 10 -^"7 mL -^"1 16 hours after administration.

88. The method of any one of claims 62-87, wherein the doxepin or imipramine has a dnC* of less than or equal to 5.0 + 25% x 10 -^"7 mL -^"1 18 hours after administration.

89. The method of any one of claims 62-88, wherein the doxepin or imipramine has a dnAUCo-20min of greater than or equal to 0.02 + 25% x 10^"6 hr mL^"1, a dnAUCo-30min of greater than or equal to 0.05 + 25% x 10^"6 hr mL^"1, a dnAUCo-45min of greater than or equal to 0.14 + 25% x 10^"6 hr mL^"1, a dnAUCo-ih of greater than or equal to 0.26 + 25% x 10^"6 hr mL^"1, a dnAUCo-2h of greater than or equal to 0.87 + 25% x 10^"6 hr mL^"1, or a dnAUCo-2.5h of greater than or equal to 1.23 + 25% x 10^"6 hr mL^"11.

90. The method of any one of claims 62-89, wherein the doxepin or imipramine has a dnAUCo-∞h of greater than or equal to 20 mL^"1 hr^"1.

91. The method of any one of claims 62-90, wherein the doxepin or imipramine has a dnC_max* of greater than or equal to 1.0 + 25% x 10^"6 mL^"1.

92. The method of any one of claims 62-91, wherein the doxepin or imipramine has a plasma concentration of 50% or less of the C_max 4 hours after administration.

93. The method of any one of claims 62-92, wherein the doxepin or imipramine has a plasma concentration of 50% or less of the C_max 6 hours after administration.

94. The method of any one of claims 62-93, wherein the doxepin or imipramine has a plasma concentration of 50% or less of the C_max 8 hours after administration.

95. The method of any one of claims 62-94, wherein the doxepin or imipramine has a plasma concentration of 50% or less of the C_max 12 hours after administration.

96. The method of any one of claims 62-95, wherein the doxepin is present in the composition in an amount from 0.1 mg to 10 mg.

97. The method of claim 96, wherein the doxepin is present in the composition in an amount from 0.1 mg to 5 mg.

98. The method of claim 97, wherein the doxepin is present in the composition in an amount of about 2.4 mg.

99. The method of claim 98, wherein the doxepin is present in an amount of less than about 2.4 mg.

100. The method of claim 99, wherein the doxepin is present in an amount of about 4.8 mg.

101. The method of claim 100, wherein the doxepin is present in an amount of less than about 4.8 mg.

102. The method of any one of claims 62-101, wherein the composition affords a C_max of doxepin greater than or equal to 10 ng/mL.

103. The method of claim 102, wherein the composition affords a Cmax of doxepin greater than or equal to 15 ng/mL.

104. The method of claim 103, wherein the composition affords a Cmax of doxepin greater than or equal to 20 ng/mL.

105. The method of claim 104, wherein the composition affords a Cmax of doxepin greater than or equal to 25 ng/mL.

106. The method of claim 105, wherein the composition affords a Cmax of doxepin greater than or equal to 30 ng/mL.

107. The method of any one of claims 62-106, wherein the composition affords a C_max of doxepin greater than or equal to 10 ng/mL above the baseline level of doxepin in the individual immediately prior to administration.

108. The method of claim 107, wherein the composition affords a Cmax of doxepin greater than or equal to 15 ng/mL above the baseline level of doxepin in the individual immediately prior to administration.

109. The method of claim 108, wherein the composition affords a Cmax of doxepin greater than or equal to 20 ng/mL above the baseline level of doxepin in the individual immediately prior to administration.

110. The method of claim 109, wherein the composition affords a Cmax of doxepin greater than or equal to 25 ng/mL above the baseline level of doxepin in the individual immediately prior to administration.

111. The method of claim 110, wherein the composition affords a Cmax of doxepin greater than or equal to 30 ng/mL above the baseline level of doxepin in the individual immediately prior to administration.

112. The method of any one of claims 62- 111, wherein the composition affords a t_max of doxepin of less than 4 hours.

113. The method of claim 112, wherein the composition affords a tmax of doxepin of less than 3 hours.

114. The method of claim 113, wherein the composition affords a tmax of doxepin of less than 2 hours.

115. The method of claim 114, wherein the composition affords a tmax of doxepin of less than 1 hour.

116. The method of claim 115, wherein the composition affords a tmax of doxepin of less than 45 minutes.

117. The method of claim 116, wherein the composition affords a tmax of doxepin of less than 30 minutes.

118. The method of claim 117, wherein the composition affords a tmax of doxepin of less than 15 minutes.

119. The method of any one of claims 62-118, wherein the composition affords a plasma level of doxepin that decreases by at least 50% of the Cmax by 8 hours after administration.

120. The method of claim 119, wherein the composition affords a plasma level of doxepin that decreases by at least 60% of the C_max by 8 hours after administration.

121. The method of claim 120, wherein the composition affords a plasma level of doxepin that decreases by at least 70% of the C_max by 8 hours after administration.

122. The method of claim 121, wherein the composition affords a plasma level of doxepin that decreases by at least 80% of the C_max by 8 hours after administration.

123. The method of claim 122, wherein the composition affords a plasma level of doxepin that decreases by at least 90% of the C_max by 8 hours after administration.

124. The method of claim 123, wherein the composition affords a plasma level of doxepin that decreases by at least 95% of the C_max by 8 hours after administration.

125. A composition comprising doxepin for transmucosal administration comprising from about 2 to about 20 mg of doxepin or a salt thereof, said formulation affording a C_max of doxepin from about 20 to about 200 ng/mL from about 0.0.05 to about 2.5 hours after administration, and a minimum doxepin plasma concentration from about 1 to about 5 ng/mL from about 22 to about 26 hours after administration, wherein the composition is administered for four days or more of daily administration.

126. A method for reducing the symptoms of fibromyalgia in a human patient, comprising administering a transmucosal dosage formulation comprising from about 2 to about 20 mg of doxepin or a salt thereof, said formulation affording a C_max of doxepin from about 20 to about 200 ng/mL from about 0.05 to about 2.5 hours after administration, and a minimum plasma concentration from about 1 to about 5 ng/mL from about 22 to about 26 hours after administration, wherein the composition is administered for four days or more of daily administration, and wherein the composition is administered within two hours of sleep.

127. A composition comprising imipramine for transmucosal administration comprising from about 2 to about 25 mg of imipramine or a salt thereof, said formulation affording a C_max of imipramine from about 20 to about 200 ng/mL from about 0.05 to about 2.5 hours after administration, and a minimum imipramine plasma concentration from about 1 to about 5 ng/mL from about 22 to about 26 hours after administration, wherein the composition is administered for four days or more of daily administration.

128. A method for reducing the symptoms of fibromyalgia in a human patient, comprising administering a transmucosal dosage formulation comprising from about 2 to about 25 mg of imipramine or a salt thereof, said formulation affording a C_max of imipramine from about 20 to about 200 ng/mL from about 0.05 to about 2.5 hours after administration, and a minimum plasma concentration from about 1 to about 5 ng/mL from about 22 to about 26 hours after administration, wherein the composition is administered for four days or more of daily administration, and wherein the composition is administered within two hours of sleep.

129. The composition of any one of claims 1-14, characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 1.0 + 25% x 10 -^"7 mL -^"1 20 minutes after administration .

130. The composition of any one of claims 1-14, characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 157.60 x 10^"9 mL^"1 20 minutes after administration.

131. The composition of any one of claims 1-14, characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of 301.60 x 10^"9 mL^"1 30 minutes after administration.

132. The composition of any one of claims 1-14, characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 432.58 x 10^"9 mL^"1 45 minutes after administration.

133. The composition of any one of claims 1-14, characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 598.85 x 10^"9 mL^"1 60 minutes after administration.

134. The composition of any one of claims 1-14, characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 683.58 x 10^"9 mL^"1 2 hours after

administration.

135. The composition of any one of claims 1-14, characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 727.67 x 10^"9 mL^"1 2.5 hours after administration.

136. The composition of any one of claims 1-14, characterized in that, when administered by transmucosal absorption, the doxepin or imipramine has a dnC* of greater than or equal to 840.33 x 10^"9 mL^"1 3 hours after administration.

137. The composition of any one of claims 1-32, wherein the doxepin is present in an amount of 2.8 mg.

138. The composition of any one of claims 1-32, wherein the doxepin is present in an amount of 5.6 mg.

139. The composition of any one of claims 1-32, wherein the doxepin is present in an amount of less than about 9 mg.

140. The method of any one of claims 62-77, wherein the doxepin or imipramine has a dnC* of greater than or equal to 157.60 x 10^"9 mL^"1 20 minutes after administration.

141. The method of any one of claims 62-77, wherein the doxepin or imipramine has a dnC* of greater than or equal to 301.60 x 10^"9 mL^"1 30 minutes after administration.

142. The method of any one of claims 62-77, wherein the doxepin or imipramine has a dnC* of greater than or equal to 432.58 x 10^"9 mL^"1 45 minutes after administration.

143. The method of any one of claims 62-77, wherein the doxepin or imipramine has a dnC* of greater than or equal to 598.85 x 10^"9 mL^"1 1 hour after administration.

144. The method of any one of claims 62-77, wherein the doxepin or imipramine has a dnC* of greater than or equal to 683.58 x 10^"9 mL^"1 2 hours after administration.

145. The method of any one of claims 62-77, wherein the doxepin or imipramine has a dnC* of greater than or equal to 6.0 + 25% x 10^" mL^"1 2.5 hours after administration.

146. The method of any one of claims 62-77, wherein the doxepin or imipramine has a dnC* of greater than or equal to 727.67 + 25% x 10^"ζ mL^"1 2.5 hours after administration.

147. The method of any one of claims 62-77, wherein the doxepin or imipramine has a dnC* of greater than or equal to 840.33 x 10^"9 mL^"1 3 hours after administration.