Compositions and methods for transmucosal absorption

Abstract

To provide an improved method and composition for wound healing, comprising a composition for transmucosal absorption of a therapeutic compound, specifically cyclobenzaprine or amitriptyline, wherein the composition contains a basicizing agent in addition to the therapeutic agent. [Solution] The composition and method have many remarkable pharmacokinetic benefits over oral administration. A method for treating fibromyalgia in human subjects is also provided. In some embodiments, the present invention provides a composition comprising cyclobenzaprine suitable for transmucosal absorption. In some embodiments, the present invention provides a composition comprising cyclobenzaprine and a basicizing agent suitable for transmucosal absorption.

Description

[Technical Field]

[0001] Cross-references to other applications This application claims priority from U.S. Provisional Patent Application No. 61 / 660,593 filed on 15 June 2012, U.S. Provisional Patent Application No. 61 / 667,774 filed on 3 July 2012, U.S. Provisional Patent Application No. 61 / 725,402 filed on 12 November 2012, and U.S. Provisional Patent Application No. 61 / 792,900 filed on 15 March 2013. The disclosures of these applications are incorporated herein by reference in their entirety. [Background technology]

[0002] Background of the Invention Cyclobenzapurine, or 3-(5H-dibenzo[a,d]cycloheptene-5-ylidene)-N,N-dimethyl-1-propanamine, was initially approved by the U.S. Food and Drug Administration in 1977 for the treatment of acute muscle spasms of topical origin. (Katz, W. et al., Clinical Therapeutics Vol. 10: pp. 216-228 (1988)). Amitriptyline, or 3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-ylidene)-N,N-dimethyl-1-propanamine, was initially approved by the U.S. Food and Drug Administration for the treatment of depression. Subsequent studies have shown that cyclobenzaprine is effective in treating fibromyalgia syndrome, post-traumatic stress disorder (PTSD), traumatic brain injury (TBI), generalized anxiety disorder, and depression. Furthermore, the practical applications of cyclobenzaprine as a sleep quality enhancer, a sleep deepener, or a sleep disruptor have been investigated. However, while FDA-approved treatments address pain and mood, there are currently no FDA-approved treatments that address sleep disruption and fatigue associated with fibromyalgia syndrome. Treatment with cyclobenzaprine may be particularly useful in treating sleep disruption caused, exacerbated, or associated with fibromyalgia syndrome, chronic fatigue, chronic fatigue syndrome, sleep disorders, psychogenic pain disorders, chronic pain syndrome (type II), drug use, autoimmune diseases, stress or anxiety, or diseases caused or exacerbated by sleep disruption, and in treating the symptoms of such diseases. See, for example, U.S. Patent Nos. 6,395,788 and 6,358,944, which are incorporated herein by reference. Despite its broad therapeutic utility, cyclobenzaprine is slowly absorbed into the bloodstream after oral administration and should be taken approximately 1-2 hours before the desired effect is needed. Even when a more rapid effect is desired, patients must wait for the effect to occur, which is undesirable for use as a sleep aid and undesirable for patients with muscle spasms seeking relief. For one thing, because oral cyclobenzaprine has a slow onset of action, desperate fibromyalgia patients may try to manage fibromyalgia-related non-recovering sleep by using prescription sedatives or hypnotics, which are ineffective in addressing fibromyalgia-related sleep quality problems and may become habit-forming. Despite its broad therapeutic utility, cyclobenzaprine often causes fatigue, drowsiness, a feeling of being drowsy, or cognitive impairment in individuals, which is undesirable during normal periods of wakefulness. Furthermore, cyclobenzaprine has not been shown to provide benefits during long-term administration and is therefore recommended for short-term use only. One reason is that cyclobenzaprine is not used in long-term treatment, so desperate fibromyalgia patients may try to manage fibromyalgia-related pain by using opioid analgesics, which are ineffective in treating fibromyalgia pain and can be habit-forming. Studies using various formulations of cyclobenzaprine have concluded that slow and delayed absorption of cyclobenzaprine after oral administration is an undesirable characteristic for a bedtime medication designed to target the brain during sleep with once-daily treatment. Therefore, an improved cyclobenzaprine formulation is desirable. [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] U.S. Patent No. 6,395,788 [Patent Document 2] U.S. Patent No. 6,358,944 [Overview of the Initiative] [Means for solving the problem]

[0004] Summary of the Invention In some embodiments, the present invention provides a composition comprising cyclobenzaprine suitable for transmucosal absorption. In some embodiments, the present invention provides a composition comprising cyclobenzaprine and a basicizing agent suitable for transmucosal absorption.

[0005] In some embodiments, the present invention provides a composition comprising amitriptyline suitable for transmucosal absorption. In some embodiments, the present invention provides a composition comprising amitriptyline and a basicizing agent suitable for transmucosal absorption.

[0006] In certain embodiments, the basicizing 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.

[0007] In certain embodiments, 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 sublingual tablets, sublingual films, sublingual powders, and sublingual spray solutions.

[0008] In certain embodiments, the composition is suitable for oral administration. In further embodiments, the composition is in a form selected from the group consisting of oral tablets, lozenges, oral tablets, and oral spray solutions.

[0009] In certain embodiments, the transmucosal absorption is nasal absorption. In further embodiments, the composition is in the 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.

[0010] In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline has 50 ± 25% × 10 -9 mL -1 or more of dnC * characterized in that. In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline has 125 ± 25% × 10 -9 mL -1 or more of dnC * characterized in that. In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline has 150 ± 25% × 10 -9 mL -1 or more of dnC * characterized in that. In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline has 300 ± 25% × 10 -9 mL -1 or more of dnC * characterized in that. In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline has 450 ± 25% × 10 -9 mL -1 or more of dnC * characterized in that. In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline has 600 ± 25% × 10 -9 mL -1 or more of dnC *The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 700±25%×10 2 hours after administration. -9 mL -1 The above dnC * The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 750±25%×10 2.5 hours (150 minutes) after administration. -9 mL -1 The above dnC * The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 850 ± 25% × 10¹⁶ 3 hours after administration. -9 mL -1 The above dnC * The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, cyclobenzaprine or amitriptyline is found to be 900±25%×10 3.3 hours (200 minutes) after administration. -9 mL -1 The above dnC * The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, cyclobenzaprine or amitriptyline is found to be present at 950 ± 25% × 10⁻¹⁰ 3.7 hours (220 minutes) after administration. -9 mL -1 The above dnC * The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 1000±25%×10 4 hours after administration. -9 mL -1 The above dnC * The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, cyclobenzaprine or amitriptyline is found to be present at 1000±25%×10 4.33 hours (260 minutes) after administration. -9 mL -1 The above dnC *The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 1050 ± 25% × 10 4.67 hours (280 minutes) after administration. -9 mL -1 The above dnC * The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 1000±25%×10 5 hours after administration. -9 mL -1 The above dnC * The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 1000±25%×10 5.5 hours after administration. -9 mL -1 The above dnC * The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 900 ± 25% × 10⁻¹⁰ 6 hours after administration. -9 mL -1 The above dnC * The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 700±25%×10 8 hours after administration. -9 mL -1 The above dnC * The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 650 ± 25% × 10 times 10 hours after administration. -9 mL -1 The following dnC * The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 500±25%×10 12 hours after administration. -9 mL -1 The following dnC *The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 500±25%×10 14 hours after administration. -9 mL -1 The following dnC * The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 350 ± 25% × 10¹⁶ hours after administration. -9 mL -1 The following dnC * The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 350 ± 25% × 10¹⁶ hours after administration. -9 mL -1 The following dnC * The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 300±25%×10 20 hours after administration. -9 mL -1 The following dnC * The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 300±25%×10 22 hours after administration. -9 mL -1 The following dnC * The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 300±25%×10 24 hours after administration. -9 mL -1 The following dnC * The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 200 ± 25% × 10¹⁶ hours after administration. -9 mL -1 The following dnC *Characterized by having. In some embodiments, when the composition is administered by trans mucosal absorption, cyclobenzaprine or amitriptyline is 150 ± 25% × 10 -9 mL -1 The following dnC * Characterized by having. In some embodiments, when the composition is administered by trans mucosal absorption, cyclobenzaprine or amitriptyline is 100 ± 25% × 10 -9 mL -1 The following dnC * Characterized by having. In some embodiments, when the composition is administered by trans mucosal absorption, cyclobenzaprine or amitriptyline is 2.0 ± 25% × 10 -9 mL -1 The above dnC * Characterized by having. In some embodiments, when the composition is administered by trans mucosal absorption, cyclobenzaprine or amitriptyline is 2.0 ± 25% × 10 -9 mL -1 The above dnC * Characterized by having. In some embodiments, when the composition is administered by trans mucosal absorption, cyclobenzaprine or amitriptyline is 2.0 ± 25% × 10 -9 mL -1 The above dnC * Characterized by having. In some embodiments, when the composition is administered by trans mucosal absorption, cyclobenzaprine or amitriptyline is 2.0 ± 25% × 10 -9 mL -1 The above dnC * Characterized by having. In some embodiments, when the composition is administered by trans mucosal absorption, cyclobenzaprine or amitriptyline is 2.0 ± 25% × 10 -9 mL -1 The above dnC *The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 5.0 ± 25% × 10⁻¹⁰ 8 hours after administration. -7 mL -1 The following dnC * The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 5.0 ± 25% × 10 10 hours after administration. -7 mL -1 The following dnC * The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 5.0 ± 25% × 10¹⁶ 12 hours after administration. -7 mL -1 The following dnC * The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 5.0 ± 25% × 10¹⁶ hours after administration. -7 mL -1 The following dnC * The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 5.0 ± 25% × 10¹⁶ hours after administration. -7 mL -1 The following dnC * The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 5.0 ± 25% × 10¹⁶ hours after administration. -7 mL -1 The following dnC * The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 5.0 ± 25% × 10¹⁶ 20 hours after administration. -7 mL -1 The following dnC *The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 5.0 ± 25% × 10¹⁶ 22 hours after administration. -7 mL -1 The following dnC * The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 5.0 ± 25% × 10⁻¹⁶ 24 hours after administration. -7 mL -1 The following dnC * It is characterized by having the following features.

[0011] In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 5±25% × 10 -6 mL -1 • dnAUC of hr or more 0-8h The composition is characterized by having cyclobenzaprine or amitriptyline when administered via mucosal absorption. -6 mL -1 • dnAUC of hr or more 0-∞h The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, the composition contains cyclobenzaprine or amitriptyline at a concentration of 1.0 ± 25% × 10 -6 mL -1 The above dnC max * The composition is characterized by having cyclobenzaprine or amitriptyline when administered via mucosal absorption at 37±25% ng·hr·L -1 The above partial AUC 0-20min , 128±25%ng·hr·L -1 The above AUC 0-30min , 333±25%ng·hr·L -1 The above AUC 0-45min , 614±25%ng·hr·L -1 The above AUC 0-1h , 2098±25%ng·hr·L -1 The above AUC0-2h , 2955±25%ng·hr·L -1 The above AUC 0-2.5h , 3931±25%ng·hr·L -1 The above AUC 0-3h The composition is characterized by having cyclobenzaprine or amitriptyline when administered via mucosal absorption at a concentration of 23±25% ng·hr·L. -1 The above partial AUC 0-20min , 86±25%ng·hr·L -1 The above AUC 0-30min , 223±25%ng·hr·L -1 The above AUC 0-45min , 405±25%ng·hr·L -1 The above AUC 0-1h , 1478±25%ng·hr·L -1 The above AUC 0-2h , 2167±25%ng·hr·L -1 The above AUC 0-2.5h It is characterized by having dnAUC. In some embodiments, 0-20min This is approximately 0.02 ± 25% × 10 -6 hr·mL -1 And dnAUC 0-30min This is approximately 0.05 ± 25% × 10 -6 hr·mL -1 And dnAUC 0-45min This is approximately 0.15 ± 25% × 10 -6 hr·mL -1 And dnAUC 0-1h This is approximately 0.25 ± 25% × 10 -6 hr·mL -1 And dnAUC 0-2h This is approximately 0.9 ± 25% × 10 -6 hr·mL -1 And dnAUC 0-2.5h This is approximately 1.2 ± 25% × 10 -6 hr·mL -1 And dnAUC 0-3h This is approximately 1.5 ± 25% × 10 -6 hr·mL -1 And dnAUC 3.3h This is approximately 1.8 ± 25% × 10 -6 hr·mL-1 And dnAUC 0-3.7h It is approximately 2.3 ± 25% × 10 -6 hr·mL -1 And dnAUC 0-4h This is approximately 2.6 ± 25% × 10 -6 hr·mL -1 And dnAUC 0-4.3h This is approximately 3.0 ± 25% × 10 -6 hr·mL -1 And dnAUC 0-4.7h This is approximately 3.3 ± 25% × 10 -6 hr·mL -1 And dnAUC 0-5h This is approximately 3.7 ± 25% × 10 -6 hr·mL -1 And dnAUC 0-5.5h This is approximately 4.2 ± 25% × 10 -6 hr·mL -1 And dnAUC 0-6h This is approximately 4.7 ± 25% × 10 -6 hr·mL -1 And dnAUC 0-8h is 6.30±25%×10 -6 hr·mL -1 And dnAUC 0-12h This is approximately 20±25% × 10 -6 hr·mL -1 And dnAUC 0-∞h It is approximately 25±25% × 10 -6 hr·mL -1 That is the case.

[0012] In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 1.0 ± 25% × 10 -6 kg·hr·mL -1 The above dbmnAUC 0-20min The composition is characterized by having cyclobenzaprine or amitriptyline when administered via mucosal absorption. -6 kg·hr·mL -1 The above dbmnAUC 0-30minThe composition is characterized by having cyclobenzaprine or amitriptyline when administered via mucosal absorption. -6 kg·hr·mL -1 The above dbmnAUC 0-45min The composition is characterized by having cyclobenzaprine or amitriptyline when administered via mucosal absorption. -6 kg·hr·mL -1 The above dbmnAUC 0-1h The composition is characterized by having cyclobenzaprine or amitriptyline when administered via mucosal absorption. -6 kg·hr·mL -1 The above dbmnAUC 0-2h The composition is characterized by having cyclobenzaprine or amitriptyline when administered via mucosal absorption. -6 kg·hr·mL -1 The above dbmnAUC 0-2.5h The composition is characterized by having cyclobenzaprine or amitriptyline when administered via mucosal absorption. -6 kg·hr·mL -1 The above dbmnAUC 0-3h The composition is characterized by having cyclobenzaprine or amitriptyline when administered via mucosal absorption. -6 kg·hr·mL -1 The above dbmnAUC 3.3h The composition is characterized by having the following characteristics when administered via mucosal absorption: cyclobenzaprine or amitriptyline is present at 160±25% × 10 -6 kg·hr·mL -1 The above dbmnAUC 0-3.7hThe composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, the composition contains cyclobenzaprine or amitriptyline at 180±25%×10 -6 kg·hr·mL -1 The above dbmnAUC 0-4h The composition is characterized by having the following properties: In some embodiments, when administered by transmucosal absorption, the composition contains cyclobenzaprine or amitriptyline at 210±25%×10 -6 kg·hr·mL -1 The above dbmnAUC 0-4.3h The composition is characterized by having cyclobenzaprine or amitriptyline when administered via mucosal absorption. -6 kg·hr·mL -1 The above dbmnAUC 0-4.7h The composition is characterized by having the following characteristics when administered via mucosal absorption: cyclobenzaprine or amitriptyline is present at 250±25% × 10 -6 kg·hr·mL -1 The above dbmnAUC 0-5h The composition is characterized by having cyclobenzaprine or amitriptyline when administered via mucosal absorption. -6 kg·hr·mL -1 The above dbmnAUC 0-5.5h The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, the composition contains cyclobenzaprine or amitriptyline at 330±25%×10 -6 kg·hr·mL -1 The above dbmnAUC 0-6h The composition is characterized by having the following characteristics: In some embodiments, when administered by transmucosal absorption, the composition contains cyclobenzaprine or amitriptyline at 440±25%×10 -6 kg·hr·mL -1 dbmnAUC 0-8hThe composition is characterized by having the following properties: In some embodiments, when administered by transmucosal absorption, the composition contains cyclobenzaprine or amitriptyline at 1500±25%×10 -6 kg·hr·mL -1 The above dbmnAUC 0-12h The composition is characterized by having the following properties: In some embodiments, when administered by transmucosal absorption, the composition contains cyclobenzaprine or amitriptyline at 1800±25%×10 -6 kg·hr·mL -1 The above dbmnAUC 0-Inf It is characterized by having the following features.

[0013] In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline is absorbed 8 hours after administration. max The composition is characterized by having a plasma concentration of 50% or less of the present value. In some embodiments, when administered by transmucosal absorption, the composition contains cyclobenzaprine or amitriptyline 12 hours after administration. max It is characterized by having a plasma concentration of 50% or less of the above.

[0014] In some embodiments, cyclobenzaprine is present in the composition of the present invention in an amount of 0.1 mg to 10 mg, for example, 0.1 mg to 5 mg. In certain embodiments, cyclobenzaprine 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, cyclobenzaprine 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, cyclobenzaprine is present in an amount of about 4.5 mg, less than about 5 mg, about 9 mg, or less than about 10 mg.

[0015] In some embodiments, when administered by transmucosal absorption, the composition contains 10 ng / mL or more of cyclobenzaprine C maxIt is characterized by providing the following when administered by transmucosal absorption: 15 ng / mL or more, 20 ng / mL or more, 25 ng / mL or more, or 30 ng / mL or more of cyclobenzaprine C max It is characterized by providing the following. In some embodiments, when administered by transmucosal absorption, the composition provides 2.5 ng / mL or more, 3 ng / mL or more, 4 ng / mL or more, and 10 ng / mL or more of cyclobenzaprine C max It is characterized by providing the following. In some embodiments, when administered by transmucosal absorption, the composition provides 2.74 ng / mL or more, 3.20 ng / mL or more, 5.13 ng / mL or more, or 10.27 ng / mL or more of cyclobenzaprine C max It is characterized by bringing about [something].

[0016] In some embodiments, when administered via mucosal absorption, the composition provides a cyclobenzaprine C content that is 10 ng / mL or higher, 15 ng / mL or higher, 20 ng / mL or higher, 25 ng / mL or higher, or 30 ng / mL or higher than the baseline level of cyclobenzaprine in the individual immediately prior to administration. max It is characterized by providing the following. In some embodiments relating to long-term administration of continuous repeated once-daily doses, the composition, when administered by transmucosal absorption, provides a cyclobenzaprine C level that is 10 ng / mL or higher, 15 ng / mL or higher, 20 ng / mL or higher, 25 ng / mL or higher, or 30 ng / mL or higher than the baseline level of cyclobenzaprine in the individual immediately before administration. max The composition is characterized by providing the following: In some embodiments, when administered by transmucosal absorption, the C of cyclobenzaprine exceeds the baseline level of cyclobenzaprine in the individual immediately before administration by 2.74 ng / ml or more, 3.20 ng / ml or more, 5.13 ng / ml or more, or 10.27 ng / ml or more. maxIt is characterized by providing the following. In some embodiments relating to long-term administration of continuous repeated once-daily doses, the composition, when administered by transmucosal absorption, provides a cyclobenzaprine C level that is 10 ng / ml or higher, 15 ng / ml or higher, 20 ng / ml or higher, 25 ng / ml or higher, or 30 ng / ml or higher than the baseline level of cyclobenzaprine in the individual immediately before administration. max It is characterized by bringing about [something].

[0017] In some embodiments, when administered by transmucosal absorption, the composition has a cyclobenzaprine t of less than 4.70 hours. max It is characterized by bringing about [something].

[0018] In some embodiments, when the composition is administered by transmucosal absorption, C is released within 8 hours of administration. max This is characterized by resulting in plasma levels of cyclobenzaprine that are reduced by at least 50%, at least 60%, at least 70%, and at least 80%.

[0019] In some embodiments, the present invention provides a method for treating a disease or condition in an individual requiring such treatment, comprising the step of administering a composition 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 onset of PTSD after a traumatic event, the initiation of PTSD after a traumatic event, the exacerbation of PTSD after a traumatic event, or the persistence of PTSD after a traumatic event. In certain embodiments, the disease or condition is selected from the group consisting of fibromyalgia, depression, traumatic brain injury, sleep disorders, non-recovering sleep, chronic pain, muscle spasms, acute pain, and anxiety disorders.

[0020] In some embodiments, the basicizing agent useful in the method of the present 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.

[0021] In some embodiments, oral absorption in the method of the present invention is sublingual absorption. In certain embodiments, the composition is in a form selected from the group consisting of sublingual tablets, sublingual films, sublingual powders, and sublingual spray solutions.

[0022] In some embodiments, oral absorption in the method of the present invention is intraoral absorption. In certain embodiments, the composition is selected from the group consisting of oral tablets, lozenges, oral tablets, and oral spray solutions.

[0023] In some embodiments, the transmucosal absorption useful in the method of the present invention is intranasal absorption. In certain embodiments, the composition is in the form of a nasal spray solution.

[0024] In some embodiments, the transmucosal absorption useful in the method of the present invention is transpulmonary absorption. In certain embodiments, the composition is in a form selected from the group consisting of aerosolized compositions and inhalable dry powders.

[0025] In some embodiments, the present invention provides cyclobenzaprine or amitriptyline, which delivers 8.0 ± 25% × 10¹⁶ doses 15 minutes after administration. -7 mL -1 The above results were obtained 30 minutes after administration, at a rate of 1.0 ± 25% × 10 -6 mL -1 The above results were obtained 45 minutes after administration, at a rate of 1.0 ± 25% × 10 -6 mL -1 The above results were obtained 1.0 ± 25% × 10 times 1 hour after administration. -6mL -1 The above results were obtained 2 hours after administration at 1.0 ± 25% × 10 -6 mL -1 The above, or 1.0 × mL 3 hours after administration. -1 The above dnC * The present invention provides a method having the following characteristics: In some embodiments, the present invention provides cyclobenzaprine or amitriptyline at 5.0 ± 25% × 10 8 hours after administration. -7 mL -1 The following dnC * The present invention provides a method having cyclobenzaprine or amitriptyline at 5.0 ± 25% × 10 10 hours after administration. -7 mL -1 The following dnC * The present invention provides a method having the following characteristics: In some embodiments, the present invention provides cyclobenzaprine or amitriptyline at 5.0 ± 25% × 10¹⁶ 12 hours after administration. -7 mL -1 The following dnC * The present invention provides a method having the following characteristics: In some embodiments, the present invention provides cyclobenzaprine or amitriptyline at 5.0 ± 25% × 10¹⁶ hours after administration. -7 mL -1 The following dnC * The present invention provides a method having cyclobenzaprine or amitriptyline 16 hours after administration 5.0 ± 25% × 10 -7 mL -1 The following dnC * The present invention provides a method having the following characteristics: In some embodiments, the present invention provides cyclobenzaprine or amitriptyline at 5.0 ± 25% × 10¹⁶ hours after administration. -7 mL -1 The following dnC * The present invention provides a method having cyclobenzaprine or amitriptyline at 5.0 ± 25% × 10 20 hours after administration. -7 mL -1 The following dnC *The present invention provides a method having the following characteristics: In some embodiments, the present invention provides cyclobenzaprine or amitriptyline at 5.0 ± 25% × 10 22 hours after administration. -7 mL -1 The following dnC * The present invention provides a method having the following characteristics: In some embodiments, the present invention provides cyclobenzaprine or amitriptyline at 5.0 ± 25% × 10 24 hours after administration. -7 mL -1 The following dnC * The present invention provides a method having cyclobenzaprine or amitriptyline administered 50±25%×10 minutes after administration. -9 mL -1 The above dnC * The present invention provides a method having cyclobenzaprine or amitriptyline 20 minutes after administration 150 ± 25% × 10 -9 mL -1 The above dnC * The present invention provides a method having the following characteristics: In some embodiments, the present invention provides a method in which cyclobenzaprine or amitriptyline is administered 30 minutes after administration and yields 300 ± 25% × 10 -9 mL -1 The above dnC * The present invention provides a method having cyclobenzaprine or amitriptyline 450 ± 25% × 10 after administration. -9 mL -1 The above dnC * The present invention provides a method having the following characteristics: In some embodiments, the present invention provides a method in which cyclobenzaprine or amitriptyline is administered at a rate of 600 ± 25% × 10¹⁶ hours after administration. -9 mL -1 The above dnC * The present invention provides a method having the following characteristics: In some embodiments, the present invention provides a method in which cyclobenzaprine or amitriptyline is administered at a rate of 700 ± 25% × 10⁻¹⁶ 2 hours after administration. -9 mL -1 The above dnC * The present invention provides a method having the following characteristics: In some embodiments, the present invention provides a method in which cyclobenzaprine or amitriptyline is administered 2.5 hours later and yields 750 ± 25% × 10-9 mL -1 The above dnC * The present invention provides a method having the following characteristics: In some embodiments, the present invention provides a method in which cyclobenzaprine or amitriptyline is administered 3 hours after administration and yields 850 ± 25% × 10 -9 mL -1 The above dnC * The present invention provides a method having the following characteristics: In some embodiments, the present invention provides a method in which cyclobenzaprine or amitriptyline is administered 3.3 hours later and yields 900 ± 25% × 10 -9 mL -1 The above dnC * The present invention provides a method having the following characteristics: In some embodiments, the present invention provides a method in which cyclobenzaprine or amitriptyline is administered 3.7 hours later and yields 950 ± 25% × 10 -9 mL -1 The above dnC * The present invention provides a method having the following characteristics: In some embodiments, the present invention provides a method in which cyclobenzaprine or amitriptyline is administered 4 hours after administration and yields 1000 ± 25% × 10 -9 mL -1 The above dnC * The present invention provides a method having cyclobenzaprine or amitriptyline 4.33 hours after administration 1050 ± 25% × 10 -9 mL -1 The above dnC * The present invention provides a method having the following characteristics: In some embodiments, the present invention provides cyclobenzaprine or amitriptyline at 4.67 hours after administration, resulting in 1050 ± 25% × 10 -9 mL -1 The following dnC * The present invention provides a method having the following characteristics: In some embodiments, the present invention provides a method in which cyclobenzaprine or amitriptyline is administered 5 hours after administration and yields 1000 ± 25% × 10 -9 mL -1 The following dnC * The present invention provides a method having the following characteristics: In some embodiments, the present invention provides a method in which cyclobenzaprine or amitriptyline is administered 5.5 hours later and yields 1000 ± 25% × 10 -9 mL -1 The following dnC *The present invention provides a method having the following characteristics: In some embodiments, the present invention provides a method in which cyclobenzaprine or amitriptyline is administered 6 hours after administration and yields 900 ± 25% × 10 -9 mL -1 The following dnC * The present invention provides a method having the following characteristics: In some embodiments, the present invention provides a method in which cyclobenzaprine or amitriptyline is administered 8 hours after administration and yields 700 ± 25% × 10 -9 mL -1 The following dnC * The present invention provides a method having the following characteristics: In some embodiments, the present invention provides a method in which cyclobenzaprine or amitriptyline is administered 12 hours after administration and yields 500 ± 25% × 10 -9 mL -1 The following dnC * The present invention provides a method having cyclobenzaprine or amitriptyline 16 hours after administration at 350 ± 25% × 10 -9 mL -1 The following dnC * The present invention provides a method having the following characteristics: In some embodiments, the present invention provides a method in which cyclobenzaprine or amitriptyline is administered 24 hours after administration and yields 300 ± 25% × 10 -9 mL -1 The following dnC * The present invention provides a method having cyclobenzaprine or amitriptyline 36 hours after administration at 180 ± 25% × 10 -9 mL -1 The following dnC * The present invention provides a method having cyclobenzaprine or amitriptyline 48 hours after administration at 140 ± 25% × 10 -9 mL -1 The following dnC * The present invention provides a method having cyclobenzaprine or amitriptyline 72 hours after administration at a rate of 90 ± 25% × 10 -9 mL -1 The following dnC * A method for holding is provided.

[0026] In some embodiments, the present invention provides cyclobenzaprine or amitriptyline in 5 mL -1 • dnAUC of hr or more 0-8h The present invention provides a method having cyclobenzaprine or amitriptyline in 20 mL -1 • dnAUC of hr or more 0-∞h In some embodiments, the present invention provides cyclobenzaprine or amitriptyline in a concentration of 1.0 ± 25% × 10 -6 mL -1 The above dnC max * The present invention provides a method having cyclobenzaprine or amitriptyline in 6.3±25% × 10 -6 hr·mL -1 The above dnAUC 0-8h The present invention provides a method having the following characteristics: In some embodiments, cyclobenzaprine or amitriptyline is 25±25% × 10 -6 hr·mL -1 The above dnAUC 0-∞h The present invention has cyclobenzaprine or amitriptyline, which is 1.1±25% × 10 -6 mL -1 The above dnC max * A method for holding is provided.

[0027] In some embodiments, the present invention provides a solution in which cyclobenzaprine or amitriptyline is administered 4 hours after C max Less than 50% of the total, and 6 hours after administration, C max Less than 50% of the total, and 8 hours after administration, C max Less than 50% of the total, or 12 hours after administration, C max The present invention provides a method having a plasma concentration of 50% or less of the specified value.

[0028] In some embodiments, the present invention provides a method for cyclobenzaprine to be present in a composition in an amount of 0.1 mg to 10 mg. In certain embodiments, cyclobenzaprine is present in a composition in an amount of 0.1 mg to 5 mg, for example, about 2.4 mg, less than about 2.4 mg, about 4.8 mg, or less than about 4.8 mg, or about 2.8 mg, less than about 2.8 mg, about 5.6 mg, or less than about 5.6 mg, about 9.0 mg, or less than 10 mg.

[0029] In some embodiments, the present invention relates to a composition containing cyclobenzaprine C10 ng / mL or more, 15 ng / mL or more, 20 ng / mL or more, 25 ng / mL or more, 30 ng / mL or more, 40 ng / mL or more, 50 ng / mL or more, 60 ng / mL or more, 70 ng / mL or more, 80 ng / mL or more, 90 ng / mL or more, 100 ng / mL or more, 120 ng / mL or more, 140 ng / mL or more, 150 ng / mL or more, 160 ng / mL or more, 170 ng / mL or more, 180 ng / mL or more, 190 ng / mL or more, 200 ng / mL or more, 220 ng / mL or more, 240 ng / mL or more, 260 ng / mL or more, or 280 ng / mL or more. max The present invention provides a method for achieving the following: In some embodiments, the present invention provides a composition containing 2.74 ng / ml or more, 3.20 ng / ml or more, 5.13 ng / ml or more, 10.27 ng / ml or more, 2 ng / ml or more, and 3 ng / ml or more of cyclobenzaprine C max It provides a way to bring about this.

[0030] In some embodiments, the present invention provides a composition that raises the baseline level of cyclobenzaprine in an individual immediately before administration by 10 ng / mL or more, 15 ng / mL or more, 20 ng / mL or more, 25 ng / mL or more, 30 ng / mL or more, 40 ng / mL or more, 50 ng / mL or more, 60 ng / mL or more, 70 ng / mL or more, 80 ng / mL or more, 90 ng / mL or more, or 100 ng / mL. Cyclobenzapurine C10 is above g / mL, above 120 ng / mL above baseline, above 140 ng / mL above baseline, above 150 ng / mL above baseline, above 160 ng / mL above baseline, above 170 ng / mL above baseline, above 180 ng / mL above baseline, above 190 ng / mL above baseline, above 200 ng / mL above baseline, above 220 ng / mL above baseline, above 240 ng / mL above baseline, above 260 ng / mL above baseline, or above 280 ng / mL above baseline. maxThe present invention provides a method to bring about the following. In some embodiments relating to continuous, repeated, once-daily long-term administration, the present invention provides a composition that brings the baseline level of cyclobenzaprine in the individual immediately before administration to 10 ng / mL or more, 15 ng / mL or more, 20 ng / mL or more, 25 ng / mL or more, 30 ng / mL or more, 40 ng / mL or more, 50 ng / mL or more, 60 ng / mL or more, 70 ng / mL or more, 80 ng / mL or more, 90 ng / mL or more, Cyclobenzapurine C is present if the C levels are 100 ng / mL or more above the baseline level, 120 ng / mL or more above the baseline level, 140 ng / mL or more above the baseline level, 150 ng / mL or more above the baseline level, 160 ng / mL or more above the baseline level, 170 ng / mL or more above the baseline level, 180 ng / mL or more above the baseline level, 190 ng / mL or more above the baseline level, 200 ng / mL or more above the baseline level, 220 ng / mL or more above the baseline level, 240 ng / mL or more above the baseline level, 260 ng / mL or more above the baseline level, or 280 ng / mL or more above the baseline level. max The present invention provides a method for bringing about the following: In some embodiments, the present invention provides a composition in which the C of cyclobenzaprine is 2.74 ng / ml or more above the baseline level, 3.20 ng / ml or more above the baseline level, 5.13 ng / ml or more above the baseline level, 10.27 ng / ml or more above the baseline level, 2 ng / ml or more above the baseline level, 3 ng / ml or more above the baseline level, 10 ng / ml, 15 ng / ml or more above the baseline level, 20 ng / ml or more above the baseline level, 25 ng / ml or more above the baseline level, 30 ng / ml or more above the baseline level, and 40 ng / ml or more above the baseline level. maxIt provides a way to bring about this.

[0031] In some embodiments, the present invention relates to a composition containing cyclobenzaprine t max It provides a way to bring about this.

[0032] In some embodiments, the present invention provides a composition that reaches C 8 hours after administration. max At least 50% of C by 8 hours after administration max At least 60% of C by 8 hours after administration max At least 70% of C by 8 hours after administration max At least 80% of C by 8 hours after administration max At least 90% of, or by 8 hours after administration, C max This provides a method that results in a reduction of at least 95% in plasma levels of cyclobenzaprine.

[0033] In some embodiments, the present invention relates to a composition for transmucosal administration comprising cyclobenzaprine, comprising about 2 to about 20 mg of cyclobenzaprine or a salt thereof, wherein the formulation delivers about 20 to about 200 ng / mL of cyclobenzaprine about 0.05 to about 2.5 hours after administration. max The present invention provides a composition administered once daily for four days or more, which yields a minimum cyclobenzaprine plasma concentration of about 1 to about 5 ng / mL about 22 to about 26 hours after administration. In some embodiments, the present invention provides a cyclobenzaprine-containing composition for transmucosal administration comprising about 2 to about 20 mg of cyclobenzaprine or a salt thereof, wherein the formulation yields a cyclobenzaprine concentration of about 1.0 ng / ml to about 30.0 ng / ml about 2 to about 5.0 hours after administration. max The present invention provides a composition administered once daily for four days or more, within two hours prior to sleep, which yields a minimum plasma concentration of approximately 1 to 5 ng / ml approximately 22 to 26 hours after administration.

[0034] In some embodiments, the present invention relates to a composition for transmucosal administration comprising cyclobenzaprine or a salt thereof, comprising about 2 to about 20 mg, wherein the formulation exhibits about 100 ± 25% × 10⁻¹⁰ 22 to about 26 hours after administration. -9 mL -1 ~Approx. 1000±25%×10 -9 mL -1 dnC of cyclobenzaprine min(24) * The present invention provides a composition that is administered once daily for four days or more, within two hours prior to sleep. In some embodiments, the present invention provides a cyclobenzaprine-containing composition for transmucosal administration, comprising about 2 to about 20 mg of cyclobenzaprine or a salt thereof, wherein the formulation delivers 300±25% × 10¹⁰ 24 hours or 22 to about 26 hours after administration. -9 mL -1 The following cyclobenzaprine dnC min(24) * (resulting in average C after 24 hours) min(24) Calculated using 706.55 pg / mL, dnC min(24) * This is ((706.55 pg / mL) / (2.4 mg)) = 294.40 pg / (mg·mL), or 300 ± 25% × 10 -9 mL -1 The present invention provides a composition that is administered once a day for four days or more, within two hours before sleep.

[0035] In some embodiments, the present invention provides a method for reducing the symptoms of fibromyalgia in a human patient, comprising the step of administering a transmucosal formulation containing about 2 to about 20 mg of cyclobenzaprine or a salt thereof, wherein the formulation contains about 20 to about 200 ng / mL of cyclobenzaprine about 0.05 to about 2.5 hours after administration. max The present invention provides a method in which the composition is administered once daily for four days or more, within two hours prior to sleep, yielding a minimum plasma concentration of approximately 1 to 5 ng / mL approximately 22 to 26 hours after administration.

[0036] In some embodiments, the present invention provides a method for reducing the symptoms of fibromyalgia in a human patient, comprising the step of administering a transmucosal formulation containing about 2.4 mg of cyclobenzaprine or a salt thereof, wherein in a single-dose study, about 2.74 μg·mL of the formulation was obtained about 4.70 hours after administration. -1 C of cyclobenzaprine max , and approximately 706.55 ng·mL about 24 hours after administration -1 The present invention provides a method for achieving the minimum plasma concentration of the composition, which is administered once daily for at least four days, within two hours prior to sleep.

[0037] In some embodiments, the present invention relates to a method for reducing the symptoms of PTSD in a human patient, comprising the step of administering a transmucosal formulation containing about 2 to about 20 mg of cyclobenzaprine or a salt thereof, wherein the formulation contains about 1.0 ng / ml to about 30.0 ng / ml of cyclobenzaprine approximately 2 to about 5.0 hours after administration. max The present invention provides a method in which the composition is administered once daily for four days or more, within two hours prior to sleep, yielding a minimum plasma concentration of approximately 1 to 5 ng / ml approximately 22 to 26 hours after administration.

[0038] In some embodiments, the present invention relates to a method for reducing symptoms of muscle spasms and acute painful musculoskeletal conditions, including localized pain and limited range of motion, in a human patient, comprising the step of administering a transmucosal formulation containing about 2 to about 20 mg of cyclobenzaprine or a salt thereof, wherein the formulation contains about 1.0 ng / ml to about 30.0 ng / ml of cyclobenzaprine at about 2 to about 5.0 hours after administration. max It provides a way to bring about this.

[0039] In some embodiments, the present invention relates to a composition for transmucosal administration comprising amitriptyline, comprising about 2 to about 25 mg of amitriptyline or a salt thereof, wherein the formulation provides about 20 to about 200 ng / mL of amitriptyline about 0.05 to about 2.5 hours after administration. max, and yield a minimum amitriptyline plasma concentration of about 1 to about 5 ng / mL about 22 to about 26 hours after administration, and the composition is administered once daily for four days or more. In some embodiments, the present invention provides a composition for transmucosal administration comprising about 2 to about 25 mg of amitriptyline or a salt thereof, wherein the formulation yields a minimum amitriptyline plasma concentration of about 20 to about 200 ng / mL about 0.05 to about 5 hours after administration. max The composition provides a minimum amitriptyline plasma concentration of approximately 1 to 5 ng / mL approximately 22 to 26 hours after administration, and is administered once daily for four days or more. In embodiments of the present invention, for example, the following items are provided. (Item 1) A composition containing cyclobenzaprine that is suitable for transmucosal absorption. (Item 2) A composition containing cyclobenzaprine and a basicizing agent, suitable for transmucosal absorption. (Item 3) A composition containing amitriptyline that is suitable for transmucosal absorption. (Item 4) A composition containing amitriptyline and a basicizing agent, suitable for transmucosal absorption. (Item 5) The composition according to any one of items 2 and 4, wherein the basicizing 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. (Item 6) The composition according to any one of items 1 to 5, wherein the transmucosal absorption is oral absorption. (Item 7) The composition described in item 6, suitable for sublingual administration. (Item 8) The composition according to item 7, which is in a form selected from the group consisting of sublingual tablets, sublingual films, sublingual powders, and sublingual spray solutions. (Item 9) A composition as described in item 6, suitable for oral administration. (Item 10) The composition according to item 9, which is in a form selected from the group consisting of oral tablets, lozenges, oral tablets, and oral spray solutions. (Item 11) The composition according to any one of items 1 to 5, wherein the transmucosal absorption is intranasal absorption. (Item 12) The composition according to item 11, which is in the form of a nasal spray solution. (Item 13) The composition according to any one of items 1 to 5, wherein the transmucosal absorption is transpulmonary absorption. (Item 14) The composition according to item 13, which is a form of composition selected from the group consisting of aerosolized compositions and inhalable dry powders. (Item 15) When administered via transmucosal absorption, cyclobenzaprine or amitriptyline is absorbed at a concentration of 0.1 ± 25% × 10¹⁶ after 15 minutes of administration. -7 mL -1 The above dnC * A composition according to any one of items 1 to 14, characterized by having the following: (Item 16) When administered via mucosal absorption, cyclobenzaprine or amitriptyline is absorbed at a concentration of 0.5 ± 25% × 10¹⁶ after 30 minutes of administration. -7 mL -1 The above dnC * A composition according to any one of items 1 to 15, characterized by having the following: (Item 17) When administered via mucosal absorption, cyclobenzaprine or amitriptyline is absorbed at a concentration of 1.5 ± 25% × 10¹⁰ 45 minutes after administration. -7 mL -1 The above dnC * A composition according to any one of items 1 to 16, characterized by having the following: (Item 18) When administered via mucosal absorption, cyclobenzaprine or amitriptyline is found to be present at 4.0 ± 25% × 10¹⁶ times 1 hour after administration. -7 mL -1 The above dnC * A composition according to any one of items 1 to 17, characterized by having the following: (Item 19) When administered via mucosal absorption, cyclobenzaprine or amitriptyline is absorbed at a concentration of 5.2 ± 25% × 10¹⁶ 2 hours after administration. -7 mL -1 The above dnC * A composition according to any one of items 1 to 18, characterized by having the following: (Item 20) When administered via mucosal absorption, cyclobenzaprine or amitriptyline is found to be present at 9.0 ± 25% × 10⁻¹⁰ 3 hours after administration. -6 mL -1 The above dnC * A composition according to any one of items 1 to 19, characterized by having the following: (Item 21) When administered via mucosal absorption, cyclobenzaprine or amitriptyline is found to be present at 5.0 ± 25% × 10¹⁰ times 10 hours after administration. -7 mL -1 The following dnC * A composition according to any one of items 1 to 20, characterized by having the following: (Item 22) When administered via mucosal absorption, cyclobenzaprine or amitriptyline is found to be present at 5.0 ± 25% × 10¹⁶ times 12 hours after administration. -7 mL -1 The following dnC * A composition according to any one of items 1 to 21, characterized by having the following: (Item 23) When administered via mucosal absorption, cyclobenzaprine or amitriptyline is found to be present at 5.0 ± 25% × 10¹⁶ times 14 hours after administration. -7 mL -1 The following dnC *A composition according to any one of items 1 to 22, characterized by having the following: (Item 24) When administered via mucosal absorption, cyclobenzaprine or amitriptyline is found to be present at 5.0 ± 25% × 10¹⁶ hours after administration. -7 mL -1 The following dnC * A composition according to any one of items 1 to 23, characterized by having the following: (Item 25) When administered via mucosal absorption, cyclobenzaprine or amitriptyline is found to be present at 5.0 ± 25% × 10¹⁶ times 18 hours after administration. -7 mL -1 The following dnC * A composition according to any one of items 1 to 24, characterized by having the following: (Item 26) When administered via transmucosal absorption, the cyclobenzaprine or amitriptyline is 0.02±25%×10 -6 hr·mL -1 The above dnAUC 0-20min , 0.05±25%×10 -6 hr·mL -1 The above dnAUC 0-30min , 0.14±25%×10 -6 hr·mL -1 The above dnAUC 0-45min , 0.26±25%×10 -6 hr·mL -1 The above dnAUC 0-1h , 0.87±25%×10 -6 hr·mL -1 The above dnAUC 0-2h , or 1.23±25%×10 -6 hr·mL -1 The above dnAUC 0-2.5h A composition according to any one of items 1 to 25, characterized by having the following: (Item 27) When administered via mucosal absorption, the cyclobenzaprine or amitriptyline is 20 mL -1 · hr -1 The above dnAUC 0-∞hA composition according to any one of items 1 to 26, characterized by having the following: (Item 28) When administered via mucosal absorption, the cyclobenzaprine or amitriptyline is 1.0 ± 25% × 10 -6 mL -1 The above dnC max * A composition according to any one of items 1 to 27, characterized by having the following: (Item 29) When administered via mucosal absorption, the cyclobenzaprine or amitriptyline reacts with the C 4 hours after administration. max A composition according to any one of items 1 to 28, characterized by having a plasma concentration of 50% or less. (Item 30) When administered via transmucosal absorption, the cyclobenzaprine or amitriptyline reacts with the C 6 hours after administration. max A composition according to any one of items 1 to 29, characterized by having a plasma concentration of 50% or less. (Item 31) When administered via mucosal absorption, the cyclobenzaprine or amitriptyline reacts with the C 8 hours after administration. max A composition according to any one of items 1 to 30, characterized by having a plasma concentration of 50% or less. (Item 32) When administered via mucosal absorption, cyclobenzaprine or amitriptyline is absorbed 12 hours after administration. max A composition according to any one of items 1 to 31, characterized by having a plasma concentration of 50% or less. (Item 33) The composition according to any one of items 1 to 32, wherein the cyclobenzaprine is present in an amount of 0.1 mg to 10 mg. (Item 34) The composition according to item 33, wherein the cyclobenzaprine is present in an amount of 0.1 mg to 5 mg. (Item 35) The composition described in item 34, wherein the cyclobenzaprine is present in an amount of approximately 2.4 mg. (Item 36) The composition according to item 34, wherein the cyclobenzaprine is present in an amount of less than approximately 2.4 mg. (Item 37) The composition described in item 34, wherein the cyclobenzaprine is present in an amount of approximately 4.8 mg. (Item 38) The composition according to item 34, wherein the cyclobenzaprine is present in an amount of less than approximately 4.8 mg. (Item 39) When administered via mucosal absorption, cyclobenzaprine C10 ng / mL or higher max A composition according to any one of items 1 to 38, characterized by providing a result. (Item 40) When administered via mucosal absorption, cyclobenzaprine C15 ng / mL or higher max The composition according to item 39, characterized by providing the following: (Item 41) When administered via mucosal absorption, cyclobenzaprine C20 ng / mL or higher max The composition according to item 40, characterized by producing (Item 42) When administered via mucosal absorption, cyclobenzaprine C25 ng / mL or higher max The composition according to item 41, characterized by producing the following. (Item 43) When administered via mucosal absorption, cyclobenzaprine C30 ng / mL or higher max The composition according to item 42, characterized by producing (Item 44) When administered via mucosal absorption, the C of cyclobenzaprine in the individual immediately prior to administration exceeds the baseline level of cyclobenzaprine by 10 ng / mL or more. max A composition according to any one of items 1 to 43, characterized by providing a result. (Item 45) When administered via mucosal absorption, the C of cyclobenzaprine in the individual immediately prior to administration exceeds the baseline level by 15 ng / mL or more. max The composition according to item 44, characterized by producing (Item 46) When administered via mucosal absorption, the C of cyclobenzaprine in the individual immediately prior to administration exceeds the baseline level of cyclobenzaprine by 20 ng / mL or more. max The composition according to item 45, characterized by producing (Item 47) When administered via mucosal absorption, the C of cyclobenzaprine in the individual immediately prior to administration exceeds the baseline level of cyclobenzaprine by 25 ng / mL or more. max The composition according to item 46, characterized by producing the following. (Item 48) When administered via mucosal absorption, the C of cyclobenzaprine in the individual immediately before administration exceeds the baseline level of cyclobenzaprine by 30 ng / mL or more. max The composition according to item 47, characterized by producing the following. (Item 49) When administered via mucosal absorption, cyclobenzaprine t max A composition according to any one of items 1 to 48, characterized by providing a result. (Item 50) When administered via mucosal absorption, cyclobenzaprine t max The composition according to item 49, characterized by producing (Item 51) When administered via mucosal absorption, cyclobenzaprine t max The composition according to item 50, characterized by providing the following: (Item 52) When administered via mucosal absorption, cyclobenzaprine t max The composition according to item 51, characterized by producing the following. (Item 53) When administered via mucosal absorption, cyclobenzaprine t max The composition according to item 52, characterized by producing the following. (Item 54) When administered via mucosal absorption, cyclobenzaprine t max The composition according to item 53, characterized by producing (Item 55) When administered via mucosal absorption, cyclobenzaprine t max The composition according to item 54, characterized by producing the following. (Item 56) When administered via mucosal absorption, the above C max The composition according to any one of items 1 to 55, characterized by resulting in a plasma level of cyclobenzaprine that is reduced by at least 50%. (Item 57) When administered via mucosal absorption, the above C max The composition according to item 56, characterized by resulting in a plasma level of cyclobenzaprine that is reduced by at least 60%. (Item 58) When administered via mucosal absorption, the above C max The composition according to item 57, characterized by resulting in a plasma level of cyclobenzaprine that is reduced by at least 70%. (Item 59) When administered via mucosal absorption, the above C max The composition according to item 58, characterized by resulting in a plasma level of cyclobenzaprine that is reduced by at least 80%. (Item 60) When administered via mucosal absorption, the above C max The composition according to item 59, characterized by resulting in a plasma level of cyclobenzaprine that is reduced by at least 90%. (Item 61) When administered via mucosal absorption, the above Cmax The composition according to item 60, characterized by resulting in a plasma level of cyclobenzaprine that is reduced by at least 95%. (Item 62) A method for treating a disease or condition in an individual requiring treatment of a disease or condition, comprising the step of administering a composition described in any one of items 1 to 61 by transmucosal absorption. (Item 63) The method according to item 62, wherein the disease or condition is post-traumatic stress disorder (PTSD). (Item 64) The method according to item 63, wherein the administration of the composition treats the onset of PTSD following a traumatic event. (Item 65) The method according to item 63, wherein the administration of the composition treats the onset of PTSD following a traumatic event. (Item 66) The method according to item 63, wherein administration of the composition treats the exacerbation of PTSD following a traumatic event. (Item 67) The method according to item 63, wherein the administration of the composition treats the persistence of PTSD following a traumatic event. (Item 68) The method according to item 62, wherein the disease or condition is selected from the group consisting of fibromyalgia, depression, traumatic brain injury, sleep disorders, unrecoverable sleep, chronic pain, muscle spasms, and anxiety disorders. (Item 69) The method according to any one of items 62 to 68, wherein the basicizing 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. (Item 70) The method according to any one of items 62 to 69, wherein the oral absorption is sublingual absorption. (Item 71) The method according to item 70, wherein the composition is a composition selected from the group consisting of sublingual tablets, sublingual films, sublingual powders, and sublingual spray solutions. (Item 72) The method according to any one of items 62 to 69, wherein the oral absorption is oral absorption. (Item 73) The method according to item 72, wherein the composition is selected from the group consisting of oral tablets, lozenges, oral tablets, and oral spray solutions. (Item 74) The method according to any one of items 62 to 73, wherein the transmucosal absorption is intranasal absorption. (Item 75) The method according to item 74, wherein the composition is in the form of a nasal spray solution. (Item 76) The method according to any one of items 62 to 73, wherein the transmucosal absorption is transpulmonary absorption. (Item 77) The method according to item 76, wherein the composition is a form of composition selected from the group consisting of aerosolized compositions and inhalable dry powders. (Item 78) The cyclobenzaprine or amitriptyline was found to be present at 1.0 ± 25% × 10¹⁰ 20 minutes after administration. -7 mL -1 The above dnC * The method according to any one of items 62 to 77, having the characteristics of: (Item 79) The cyclobenzaprine or amitriptyline was found to be 2.5±25% × 10¹⁶ after 30 minutes of administration. -7 mL -1 The above dnC * The method according to any one of items 62 to 78, having the characteristics of: (Item 80) The cyclobenzaprine or amitriptyline was found to be 3.0±25%×10 after 45 minutes of administration. -7 mL -1 The above dnC * The method according to any one of items 62 to 79, having the characteristics of: (Item 81) The cyclobenzaprine or amitriptyline was found to produce 4.2 ± 25% × 10¹⁶ of cyclobenzaprine or amitriptyline 1 hour after administration. -7 mL -1 The above dnC * The method according to any one of items 62 to 80, having the characteristics of: (Item 82) The cyclobenzaprine or amitriptyline was found to produce 6.0 ± 25% × 10¹⁶ of cyclobenzaprine or amitriptyline 2 hours after administration. -7 mL -1 The above dnC * The method according to any one of items 62 to 81, having the characteristics of: (Item 83) The cyclobenzaprine or amitriptyline was found to produce 7.0 ± 25% × 10¹⁶ of cyclobenzaprine or amitriptyline 3 hours after administration. -7 mL -1 The above dnC * The method according to any one of items 62 to 82, having the characteristics of: (Item 84) The cyclobenzaprine or amitriptyline was found to be present at 8.0 ± 25% × 10¹⁶ 3.3 hours after administration. -7 mL -1 The above dnC * The method according to any one of items 62 to 83, having the characteristics of: (Item 85) The cyclobenzaprine or amitriptyline was found to be present at 5.0 ± 25% × 10¹⁶ 12 hours after administration. -7 mL -1 The following dnC * The method according to any one of items 62 to 84, having the characteristics of: (Item 86) The cyclobenzaprine or amitriptyline was found to be 5.0 ± 25% × 10¹⁶ at 14 hours after administration. -7 mL -1 The following dnC * The method according to any one of items 62 to 85, having the characteristics of: (Item 87) The cyclobenzaprine or amitriptyline was found to be 5.0 ± 25% × 10¹⁶ at 16 hours after administration. -7 mL -1 The following dnC *The method according to any one of items 62 to 86, having the characteristics of: (Item 88) The cyclobenzaprine or amitriptyline was found to be 5.0 ± 25% × 10¹⁶ at 18 hours after administration. -7 mL -1 The following dnC * The method according to any one of items 62 to 87, having the characteristics of: (Item 89) The cyclobenzaprine or amitriptyline is 0.02±25% × 10 -6 hr·mL -1 The above dnAUC 0-20min , 0.05±25%×10 -6 hr·mL -1 The above dnAUC 0-30min , 0.14±25%×10 -6 hr·mL -1 The above dnAUC 0-45min , 0.26±25%×10 -6 hr·mL -1 The above dnAUC 0-1h , 0.87±25%×10 -6 hr·mL -1 The above dnAUC 0-2h , or 1.23±25%×10 -6 hr·mL -11 The above dnAUC 0-2.5h The method according to any one of items 62 to 88, having the characteristics of: (Item 90) The cyclobenzaprine or amitriptyline is 20 mL -1 · hr -1 The above dnAUC 0-∞h The method according to any one of items 62 to 89, having the characteristics of: (Item 91) The cyclobenzaprine or amitriptyline is 1.0±25% × 10 -6 mL -1 The above dnC max * The method according to any one of items 62 to 90, having the characteristics of: (Item 92) The cyclobenzaprine or amitriptyline was administered 4 hours after the C max The method according to any one of items 62 to 91, having a plasma concentration of 50% or less. (Item 93) The cyclobenzaprine or amitriptyline is administered 6 hours after the C max The method according to any one of items 62 to 92, having a plasma concentration of 50% or less. (Item 94) The cyclobenzaprine or amitriptyline mentioned above was administered 8 hours after the C max The method according to any one of items 62 to 93, having a plasma concentration of 50% or less. (Item 95) The cyclobenzaprine or amitriptyline was administered 12 hours after the C max The method according to any one of items 62 to 94, having a plasma concentration of 50% or less. (Item 96) The method according to any one of items 62 to 95, wherein the cyclobenzaprine is present in the composition in an amount of 0.1 mg to 10 mg. (Item 97) The method according to item 96, wherein the cyclobenzaprine is present in the composition in an amount of 0.1 mg to 5 mg. (Item 98) The method according to item 97, wherein the cyclobenzaprine is present in the composition in an amount of about 2.4 mg. (Item 99) The method according to item 98, wherein the cyclobenzaprine is present in an amount of less than approximately 2.4 mg. (Item 100) The method according to item 99, wherein the cyclobenzaprine is present in an amount of approximately 4.8 mg. (Item 101) The method according to item 100, wherein the cyclobenzaprine is present in an amount of less than approximately 4.8 mg. (Item 102) The composition contains 10 ng / mL or more of cyclobenzaprine C maxThe method described in any one of items 62 to 101, which results in the occurrence of the method described in any one of items 62 to 101. (Item 103) The composition contains 15 ng / mL or more of cyclobenzaprine C max The method described in item 102 brings about the result. (Item 104) The composition contains 20 ng / mL or more of cyclobenzaprine C max The method described in item 103 brings about the following result. (Item 105) The composition contains 25 ng / mL or more of cyclobenzaprine C max The method described in item 104 brings about the result. (Item 106) The composition contains 30 ng / mL or more of cyclobenzaprine C max The method described in item 105 brings about the result. (Item 107) The composition contains cyclobenzaprine at a concentration of 10 ng / mL or more above the baseline level of cyclobenzaprine in the individual immediately before administration. max The method described in any one of items 62 to 106, which results in... (Item 108) The composition contains cyclobenzaprine C at a concentration that is 15 ng / mL or more higher than the baseline level of cyclobenzaprine in the individual immediately before administration. max The method described in item 107 brings about the result. (Item 109) The composition contains cyclobenzaprine at a concentration of 20 ng / mL or more above the baseline level of cyclobenzaprine in the individual immediately before administration. max The method described in item 108 brings about the result. (Item 110) The composition contains cyclobenzaprine C2 at a concentration that is 25 ng / mL or more higher than the baseline level of cyclobenzaprine in the individual immediately before administration. max The method described in item 109 brings about the result. (Item 111) The composition contains cyclobenzaprine C at a concentration that is 30 ng / mL or more higher than the baseline level of cyclobenzaprine in the individual immediately before administration. max The method described in item 110 brings about the following: (Item 112) The above composition contains cyclobenzaprine for less than 4 hours max The method described in any one of items 62 to 111, which results in... (Item 113) The aforementioned composition contains cyclobenzaprine for less than 3 hours. max The method described in item 112 brings about the result. (Item 114) The above composition contains cyclobenzaprine for less than 2 hours max The method described in item 113 brings about the following: (Item 115) The above composition contains cyclobenzaprine for less than 1 hour. max The method described in item 114 brings about the following: (Item 116) The composition contains cyclobenzaprine with a time of less than 45 minutes. max The method described in item 115 brings about the following: (Item 117) The aforementioned composition contains cyclobenzaprine for less than 30 minutes. max The method described in item 116, which brings about the result. (Item 118) The above composition contains cyclobenzaprine with a time of less than 15 minutes. max The method described in item 117, which brings about the result. (Item 119) The composition is absorbed by the time 8 hours after administration. max The method described in any one of items 62 to 118, which results in a plasma level of cyclobenzaprine that is reduced by at least 50%. (Item 120) The composition is absorbed by the time 8 hours after administration. max The method described in item 119 results in a reduction of at least 60% in plasma levels of cyclobenzaprine. (Item 121) The composition is absorbed by the time 8 hours after administration. max The method described in item 120 results in a plasma level of cyclobenzaprine that is reduced by at least 70%. (Item 122) The composition is absorbed by the time 8 hours after administration. max The method described in item 121 results in a reduction of at least 80% in plasma levels of cyclobenzaprine. (Item 123) The composition is absorbed by the time 8 hours after administration. max The method described in item 122 results in a reduction of at least 90% in plasma levels of cyclobenzaprine. (Item 124) The composition is absorbed by the time 8 hours after administration. max The method described in item 123 results in a reduction of at least 95% in plasma levels of cyclobenzaprine. (Item 125) A composition for transmucosal administration containing cyclobenzaprine, comprising approximately 2 to approximately 20 mg of cyclobenzaprine or a salt thereof, wherein the formulation contains approximately 20 to approximately 200 ng / mL of cyclobenzaprine approximately 0.0.05 to approximately 2.5 hours after administration. max a composition that yields a minimum cyclobenzaprine plasma concentration of about 1 to about 5 ng / mL about 22 to about 26 hours after administration, and is administered once daily for four days or more. (Item 126) A method for reducing the symptoms of fibromyalgia in a human patient, comprising the step of administering a transmucosal administration preparation containing about 2 to about 20 mg of cyclobenzaprine or a salt thereof, wherein the preparation contains about 20 to about 200 ng / mL of cyclobenzaprine approximately 0.05 to about 2.5 hours after administration. max a method comprising administering the composition once daily for four days or more, and giving rise to a minimum plasma concentration of approximately 1 to 5 ng / mL approximately 22 to 26 hours after administration, and administering within two hours prior to sleep. (Item 127) A composition for transmucosal administration containing amitriptyline, comprising approximately 2 to approximately 25 mg of amitriptyline or a salt thereof, wherein the formulation provides approximately 20 to approximately 200 ng / mL of amitriptyline C approximately 0.05 to approximately 2.5 hours after administration. max a composition that yields a minimum amitriptyline plasma concentration of about 1 to about 5 ng / mL about 22 to about 26 hours after administration, and is administered once daily for four days or more. (Item 128) A method for reducing the symptoms of fibromyalgia in a human patient, comprising the step of administering a transmucosal preparation containing about 2 to about 25 mg of amitriptyline or a salt thereof, wherein the preparation contains about 20 to about 200 ng / mL of amitriptyline about 0.05 to about 2.5 hours after administration. max a method comprising administering the composition once daily for four days or more, and giving rise to a minimum plasma concentration of approximately 1 to 5 ng / mL approximately 22 to 26 hours after administration, and administering within two hours prior to sleep. (Item 129) When administered via mucosal absorption, cyclobenzaprine or amitriptyline is absorbed at a concentration of 1.0 ± 25% × 10¹⁶ after 20 minutes of administration. -7 mL -1 The above dnC * A composition according to any one of items 1 to 14, characterized by having the following: (Item 130) When administered via mucosal absorption, cyclobenzaprine or amitriptyline is absorbed at a dose of 157.60 × 10⁶ minutes after administration. -9 mL -1 The above dnC * A composition according to any one of items 1 to 14, characterized by having the following: (Item 131) When administered via transmucosal absorption, cyclobenzaprine or amitriptyline is absorbed at a concentration of 2.5 ± 25% × 10¹⁶ after 30 minutes of administration. -7 dnC * A composition according to any one of items 1 to 14, characterized by having the following: (Item 132) When administered via transmucosal absorption, cyclobenzaprine or amitriptyline is absorbed at a concentration of 3.0 ± 25% × 10¹⁶ after 45 minutes of administration. -7 mL -1 The above dnC * A composition according to any one of items 1 to 14, characterized by having the following: (Item 133) When administered via mucosal absorption, cyclobenzaprine or amitriptyline is absorbed at a concentration of 4.2 ± 25% × 10¹⁶ after 60 minutes of administration. -7 mL -1 The above dnC * A composition according to any one of items 1 to 14, characterized by having the following: (Item 134) When administered via mucosal absorption, cyclobenzaprine or amitriptyline is found to be present at 6.0 ± 25% × 10¹⁶ times 2 hours after administration. -7 mL -1 The above dnC * A composition according to any one of items 1 to 14, characterized by having the following: (Item 135) When administered via transmucosal absorption, cyclobenzaprine or amitriptyline is absorbed at a concentration of 6.5 ± 25% × 10¹⁶ 2.5 hours after administration. -7 mL -1 The above dnC * A composition according to any one of items 1 to 14, characterized by having the following: (Item 136) When administered via transmucosal absorption, cyclobenzaprine or amitriptyline is found to be present at 7.0 ± 25% × 10⁻¹⁰ 3 hours after administration. -7 mL -1 The above dnC * A composition according to any one of items 1 to 14, characterized by having the following: (Item 137) The composition according to any one of items 1 to 32, wherein the cyclobenzaprine is present in an amount of 2.8 mg. (Item 138) The composition according to any one of items 1 to 32, wherein the cyclobenzaprine is present in an amount of 5.6 mg. (Item 139) The composition according to any one of items 1 to 32, wherein the cyclobenzaprine is present in an amount of less than approximately 9 mg. (Item 140) The cyclobenzaprine or amitriptyline was found to be present at 1.0 ± 25% × 10¹⁰ 20 minutes after administration. -7 mL -1 The above dnC * The method according to any one of items 62 to 77, having the characteristics of: (Item 141) The cyclobenzaprine or amitriptyline was found to be 2.5±25% × 10¹⁶ after 30 minutes of administration. -7 The above dnC * The method according to any one of items 62 to 77, having the characteristics of: (Item 142) The cyclobenzaprine or amitriptyline was found to be 3.0±25%×10 after 45 minutes of administration. -7 The above dnC * The method according to any one of items 62 to 77, having the characteristics of: (Item 143) The cyclobenzaprine or amitriptyline was found to produce 4.2 ± 25% × 10¹⁶ of cyclobenzaprine or amitriptyline 1 hour after administration. -7 The above dnC * The method according to any one of items 62 to 77, having the characteristics of: (Item 144) The cyclobenzaprine or amitriptyline was found to produce 6.0 ± 25% × 10¹⁶ of cyclobenzaprine or amitriptyline 2 hours after administration. -7 mL -1 The above dnC * The method according to any one of items 62 to 77, having the characteristics of: (Item 145) The cyclobenzaprine or amitriptyline was found to contain 6.5 ± 25% × 10¹⁶ of cyclobenzaprine or amitriptyline 2.5 hours after administration. -7 mL -1 The above dnC * The method according to any one of items 62 to 77, having the characteristics of: (Item 146) The cyclobenzaprine or amitriptyline was found to have a concentration of 727.67 ± 25% × 10¹⁶ after 2.5 hours of administration. -9 mL -1 The above dnC * The method according to any one of items 62 to 77, having the characteristics of: (Item 147) The cyclobenzaprine or amitriptyline was found to produce 7.0 ± 25% × 10¹⁶ of cyclobenzaprine or amitriptyline 3 hours after administration. -7 mL -1 The above dnC * The method according to any one of items 62 to 77, having the characteristics of: (Item 148) When administered via mucosal absorption, cyclobenzaprine C2 is present at concentrations of 2 ng / mL or higher. max A composition according to any one of items 1 to 38, characterized by providing a result. (Item 149) When administered via mucosal absorption, the C of cyclobenzaprine in the individual immediately before administration exceeds the baseline level of cyclobenzaprine by 2 ng / mL or more. max A composition according to any one of items 1 to 43, characterized by providing a result.

[0040] In some embodiments, the present invention provides a method for reducing the symptoms of fibromyalgia in a human patient, comprising the step of administering a transmucosal formulation containing about 2 to about 25 mg of amitriptyline or a salt thereof, wherein the formulation contains about 20 to about 200 ng / mL of amitriptyline about 0.05 to about 2.5 hours after administration. max The present invention provides a method for administering a composition once daily for four days or more, within two hours prior to sleep, which yields a minimum plasma concentration of about 1 to about 5 ng / mL about 22 to about 26 hours after administration. In some embodiments, the present invention provides a method for reducing the symptoms of fibromyalgia in a human patient, comprising the step of administering a transmucosal formulation containing about 7.5 to about 50 mg of amitriptyline or a salt thereof, wherein the formulation yields a minimum plasma concentration of about 3 to about 90 ng / mL of amitriptyline about 2 to about 5 hours after administration. maxThe present invention provides a method in which the composition is administered once daily for four days or more, yielding a minimum amitriptyline plasma concentration of approximately 3 to 15 ng / ml about 22 to 26 hours after administration. Some embodiments of the present invention are as follows: 1. A composition containing cyclobenzaprine that is suitable for transmucosal absorption. 2. A composition containing cyclobenzaprine and a basicizing agent, suitable for transmucosal absorption. 3. A composition containing amitriptyline that is suitable for transmucosal absorption. 4. A composition containing amitriptyline and a basicizing agent that is suitable for transmucosal absorption. 5. The composition according to any one of Embodiments 2 and 4, wherein the basicizing 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 according to any one of Embodiments 1 to 5, wherein the transmucosal absorption is oral absorption. 7. The composition according to Embodiment 6, which is suitable for sublingual administration. 8. The composition according to Embodiment 7, which is in a form selected from the group consisting of sublingual tablets, sublingual films, sublingual powders, and sublingual spray solutions. 9. The composition according to Embodiment 6, which is suitable for oral administration. 10. The composition according to Embodiment 9, which is in a form selected from the group consisting of oral tablets, lozenges, oral tablets, and oral spray solutions. 11. The composition according to any one of Embodiments 1 to 5, wherein the transmucosal absorption is intranasal absorption. 12. The composition according to Embodiment 11, which is in the form of a nasal spray solution. 13. The composition according to any one of Embodiments 1 to 5, wherein the transmucosal absorption is transpulmonary absorption. 14. The composition according to Embodiment 13, which is a form of composition selected from the group consisting of aerosolized compositions and inhalable dry powders. 15. When administered by transmucosal absorption, cyclobenzaprine or amitriptyline is absorbed at 0.1 ± 25% × 10¹⁶ minutes after administration. -7 mL -1 The above dnC * A composition according to any one of embodiments 1 to 14, characterized by having the following: 16. When administered by transmucosal absorption, cyclobenzaprine or amitriptyline is absorbed at 0.5 ± 25% × 10¹⁶ minutes after administration. -7 mL -1 The above dnC * A composition according to any one of embodiments 1 to 15, characterized by having the following: 17. When administered by transmucosal absorption, cyclobenzaprine or amitriptyline is absorbed at a concentration of 1.5 ± 25% × 10¹⁰ 45 minutes after administration. -7 mL -1 The above dnC * A composition according to any one of embodiments 1 to 16, characterized by having the following: 18. When administered by transmucosal absorption, cyclobenzaprine or amitriptyline is absorbed at a concentration of 4.0 ± 25% × 10¹⁶ 1 hour after administration. -7 mL -1 The above dnC * A composition according to any one of embodiments 1 to 17, characterized by having the following: 19. When administered by transmucosal absorption, cyclobenzaprine or amitriptyline is absorbed at a concentration of 5.2 ± 25% × 10¹⁶ 2 hours after administration. -7 mL -1 The above dnC * A composition according to any one of embodiments 1 to 18, characterized by having the following: 20. When administered by transmucosal absorption, cyclobenzaprine or amitriptyline is absorbed at a concentration of 9.0 ± 25% × 10¹⁶ 3 hours after administration. -6 mL -1 The above dnC *A composition according to any one of embodiments 1 to 19, characterized by having the following: 21. When administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 5.0 ± 25% × 10¹⁰ hours after administration. -7 mL -1 The following dnC * A composition according to any one of embodiments 1 to 20, characterized by having the following: 22. When administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 5.0 ± 25% × 10¹⁶ hours after administration. -7 mL -1 The following dnC * A composition according to any one of embodiments 1 to 21, characterized by having the following: 23. When administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 5.0 ± 25% × 10¹⁶ hours after administration. -7 mL -1 The following dnC * A composition according to any one of embodiments 1 to 22, characterized by having the following: 24. When administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 5.0 ± 25% × 10¹⁶ hours after administration. -7 mL -1 The following dnC * A composition according to any one of embodiments 1 to 23, characterized by having the following: 25. When administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 5.0 ± 25% × 10¹⁶ hours after administration. -7 mL -1 The following dnC * A composition according to any one of embodiments 1 to 24, characterized by having the following: 26. When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 0.02±25%×10 -6 hr·mL -1 The above dnAUC 0-20min , 0.05±25%×10 -6 hr·mL -1The above dnAUC 0-30min , 0.14±25%×10 -6 hr·mL -1 The above dnAUC 0-45min , 0.26±25%×10 -6 hr·mL -1 The above dnAUC 0-1h , 0.87±25%×10 -6 hr·mL -1 The above dnAUC 0-2h , or 1.23±25%×10 -6 hr·mL -1 The above dnAUC 0-2.5h A composition according to any one of embodiments 1 to 25, characterized by having the following: 27. When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 20 mL -1 · hr -1 The above dnAUC 0-∞h A composition according to any one of embodiments 1 to 26, characterized by having the following: 28. When administered via transmucosal absorption, the cyclobenzaprine or amitriptyline is 1.0 ± 25% × 10 -6 mL -1 The above dnC max * A composition according to any one of embodiments 1 to 27, characterized by having the following: 29. When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is absorbed 4 hours after administration. max The composition according to any one of Embodiments 1 to 28, characterized by having a plasma concentration of 50% or less. 30. When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is absorbed 6 hours after administration. max The composition according to any one of Embodiments 1 to 29, characterized by having a plasma concentration of 50% or less. 31. When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline reacts with the C 8 hours after administration. maxThe composition according to any one of Embodiments 1 to 30, characterized by having a plasma concentration of 50% or less. 32. When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is absorbed 12 hours after administration. max The composition according to any one of Embodiments 1 to 31, characterized by having a plasma concentration of 50% or less. 33. The composition according to any one of Embodiments 1 to 32, wherein the cyclobenzaprine is present in an amount of 0.1 mg to 10 mg. 34. The composition according to Embodiment 33, wherein the cyclobenzaprine is present in an amount of 0.1 mg to 5 mg. 35. The composition according to Embodiment 34, wherein the cyclobenzaprine is present in an amount of approximately 2.4 mg. 36. The composition according to Embodiment 34, wherein the cyclobenzaprine is present in an amount of less than approximately 2.4 mg. 37. The composition according to Embodiment 34, wherein the cyclobenzaprine is present in an amount of approximately 4.8 mg. 38. The composition according to Embodiment 34, wherein the cyclobenzaprine is present in an amount of less than approximately 4.8 mg. 39. When administered via mucosal absorption, cyclobenzaprine at concentrations of 10 ng / mL or higher may be present. max A composition according to any one of embodiments 1 to 38, characterized by providing a result. 40. When administered via mucosal absorption, cyclobenzaprine C15 ng / mL or higher max The composition according to embodiment 39, characterized by providing a result. 41. When administered via mucosal absorption, cyclobenzaprine at concentrations of 20 ng / mL or higher may be present. max The composition according to embodiment 40, characterized by providing a result. 42. When administered via mucosal absorption, cyclobenzaprine C25 ng / mL or higher max The composition according to embodiment 41, characterized by providing a result. 43. When administered via mucosal absorption, cyclobenzaprine C30 ng / mL or higher maxThe composition according to embodiment 42, characterized by providing a result. 44. When administered via mucosal absorption, the C of cyclobenzaprine in the individual immediately before administration exceeds the baseline level of cyclobenzaprine by 10 ng / mL or more. max A composition according to any one of embodiments 1 to 43, characterized by providing a result. 45. When administered via mucosal absorption, the C of cyclobenzaprine in the individual immediately before administration exceeds the baseline level by 15 ng / mL or more. max The composition according to embodiment 44, characterized by providing a result. 46. ​​When administered via mucosal absorption, the C of cyclobenzaprine in the individual immediately before administration exceeds the baseline level by 20 ng / mL or more. max The composition according to embodiment 45, characterized by providing a result. 47. When administered via mucosal absorption, the C of cyclobenzaprine in the individual immediately before administration exceeds the baseline level by 25 ng / mL or more. max The composition according to embodiment 46, characterized by providing a result. 48. When administered via mucosal absorption, the C of cyclobenzaprine in the individual immediately before administration exceeds the baseline level by 30 ng / mL or more. max The composition according to embodiment 47, characterized by providing the following: 49. When administered via mucosal absorption, cyclobenzaprine t max A composition according to any one of embodiments 1 to 48, characterized by providing a result. 50. When administered via mucosal absorption, cyclobenzaprine t max The composition according to embodiment 49, characterized by providing the following: 51. When administered via mucosal absorption, cyclobenzaprine t max The composition according to embodiment 50, characterized by providing a result. 52. When administered via mucosal absorption, cyclobenzaprine t max The composition according to embodiment 51, characterized by providing a result. 53. When administered via mucosal absorption, cyclobenzaprine t max The composition according to embodiment 52, characterized by providing a result. 54. When administered via mucosal absorption, cyclobenzaprine t max The composition according to embodiment 53, characterized by providing a result. 55. When administered via mucosal absorption, cyclobenzaprine t max The composition according to embodiment 54, characterized by providing a result. 56. When administered by transmucosal absorption, the above C max The composition according to any one of Embodiments 1 to 55, characterized by resulting in a plasma level of cyclobenzaprine that is reduced by at least 50%. 57. When administered by transmucosal absorption, the above C max The composition according to embodiment 56, characterized by resulting in a plasma level of cyclobenzaprine that is reduced by at least 60%. 58. When administered by transmucosal absorption, the above C max The composition according to Embodiment 57, characterized by resulting in a plasma level of cyclobenzaprine that is reduced by at least 70%. 59. When administered by transmucosal absorption, the above C max The composition according to Embodiment 58, characterized by resulting in a plasma level of cyclobenzaprine that is reduced by at least 80%. 60. When administered by transmucosal absorption, the above C max The composition according to Embodiment 59, characterized by resulting in a plasma level of cyclobenzaprine that is reduced by at least 90%. 61. When administered by transmucosal absorption, the above C maxThe composition according to Embodiment 60, characterized by resulting in a plasma level of cyclobenzaprine that is reduced by at least 95%. 62. A method for treating a disease or condition in an individual requiring treatment of a disease or condition, comprising the step of administering a composition according to any one of Embodiments 1 to 61 by transmucosal absorption. 63. The method according to Embodiment 62, wherein the disease or condition is post-traumatic stress disorder (PTSD). 64. The method according to Embodiment 63, wherein the administration of the composition treats the onset of PTSD following a traumatic event. 65. The method according to Embodiment 63, wherein the administration of the composition treats the onset of PTSD following a traumatic event. 66. The method according to Embodiment 63, wherein administration of the composition treats the exacerbation of PTSD following a traumatic event. 67. The method according to Embodiment 63, wherein the administration of the composition treats the persistence of PTSD following a traumatic event. 68. The method according to Embodiment 62, wherein the disease or condition is selected from the group consisting of fibromyalgia, depression, traumatic brain injury, sleep disorders, non-recovering sleep, chronic pain, muscle spasms, and anxiety disorders. 69. The method according to any one of embodiments 62 to 68, wherein the basicizing 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 according to any one of embodiments 62 to 69, wherein the oral absorption is sublingual absorption. 71. The method according to Embodiment 70, wherein the composition is a composition selected from the group consisting of sublingual tablets, sublingual films, sublingual powders, and sublingual spray solutions. 72. The method according to any one of embodiments 62 to 69, wherein the oral absorption is intraoral absorption. 73. The method according to Embodiment 72, wherein the composition is selected from the group consisting of oral tablets, lozenges, oral tablets, and oral spray solutions. 74. The method according to any one of embodiments 62 to 73, wherein the transmucosal absorption is intranasal absorption. 75. The method according to Embodiment 74, wherein the composition is in the form of a nasal spray solution. 76. The method according to any one of embodiments 62 to 73, wherein the transmucosal absorption is transpulmonary absorption. 77. The method according to Embodiment 76, wherein the composition is a composition selected from the group consisting of aerosolized compositions and inhalable dry powders. 78. The cyclobenzaprine or amitriptyline was found to be 1.0 ± 25% × 10¹⁶ after 20 minutes of administration. -7 mL -1 The above dnC * The method according to any one of embodiments 62 to 77, having the following characteristics: 79. The cyclobenzaprine or amitriptyline was found to be 2.5 ± 25% × 10¹⁶ after 30 minutes of administration. -7 mL -1 The above dnC * The method according to any one of embodiments 62 to 78, having the following characteristics: 80. The cyclobenzaprine or amitriptyline was found to be 3.0 ± 25% × 10¹⁶ after 45 minutes of administration. -7 mL -1 The above dnC * The method according to any one of embodiments 62 to 79, having the following characteristics: 81. The cyclobenzaprine or amitriptyline was found to be 4.2 ± 25% × 10¹⁶ at 1 hour after administration. -7 mL -1 The above dnC * The method according to any one of embodiments 62 to 80, having the following characteristics: 82. The cyclobenzaprine or amitriptyline was found to be 6.0 ± 25% × 10¹⁶ at 2 hours after administration. -7 mL -1 The above dnC * The method according to any one of embodiments 62 to 81, comprising: 83. The cyclobenzaprine or amitriptyline was found to be 7.0 ± 25% × 10 times 3 hours after administration. -7 mL -1 The above dnC * The method according to any one of embodiments 62 to 82, having the characteristics of the method. 84. The cyclobenzaprine or amitriptyline was found to be 8.0 ± 25% × 10¹⁶ after 3.3 hours of administration. -7 mL -1 The above dnC * The method according to any one of embodiments 62 to 83, having the following characteristics: 85. The cyclobenzaprine or amitriptyline was found to be 5.0 ± 25% × 10¹⁶ at 12 hours after administration. -7 mL -1 The following dnC * The method according to any one of embodiments 62 to 84, having the following characteristics: 86. The cyclobenzaprine or amitriptyline was found to be 5.0 ± 25% × 10¹⁶ at 14 hours after administration. -7 mL -1 The following dnC * The method according to any one of embodiments 62 to 85, having the following characteristics: 87. The cyclobenzaprine or amitriptyline was found to be 5.0 ± 25% × 10¹⁶ at 16 hours after administration. -7 mL -1 The following dnC * The method according to any one of embodiments 62 to 86, comprising: 88. The cyclobenzaprine or amitriptyline was found to be 5.0 ± 25% × 10¹⁶ at 18 hours after administration. -7 mL -1 The following dnC * The method according to any one of embodiments 62 to 87, having the following characteristics: 89. The cyclobenzaprine or amitriptyline is 0.02±25% × 10 -6 hr·mL -1 The above dnAUC 0-20min , 0.05±25%×10 -6 hr·mL -1 The above dnAUC 0-30min , 0.14±25%×10 -6hr·mL -1 The above dnAUC 0-45min , 0.26±25%×10 -6 hr·mL -1 The above dnAUC 0-1h , 0.87±25%×10 -6 hr·mL -1 The above dnAUC 0-2h , or 1.23±25%×10 -6 hr·mL -11 The above dnAUC 0-2.5h The method according to any one of embodiments 62 to 88, having the characteristics of: 90. The cyclobenzaprine or amitriptyline is divided into 20 mL -1 · hr -1 The above dnAUC 0-∞h The method according to any one of embodiments 62 to 89, having the following characteristics: 91. The cyclobenzaprine or amitriptyline is 1.0±25% × 10 -6 mL -1 The above dnC max * The method according to any one of embodiments 62 to 90, having the following characteristics: 92. The cyclobenzaprine or amitriptyline is administered four hours after the C max The method according to any one of embodiments 62 to 91, having a plasma concentration of 50% or less. 93. The cyclobenzaprine or amitriptyline is administered 6 hours after the C max The method according to any one of embodiments 62 to 92, having a plasma concentration of 50% or less. 94. The cyclobenzaprine or amitriptyline is administered 8 hours after the C max The method according to any one of embodiments 62 to 93, having a plasma concentration of 50% or less. 95. The cyclobenzaprine or amitriptyline is administered 12 hours after the C max The method according to any one of embodiments 62 to 94, having a plasma concentration of 50% or less. 96. The method according to any one of Embodiments 62 to 95, wherein the cyclobenzaprine is present in the composition in an amount of 0.1 mg to 10 mg. 97. The method according to Embodiment 96, wherein the cyclobenzaprine is present in the composition in an amount of 0.1 mg to 5 mg. 98. The method according to Embodiment 97, wherein the cyclobenzaprine is present in the composition in an amount of about 2.4 mg. 99. The method according to Embodiment 98, wherein the cyclobenzaprine is present in an amount of less than approximately 2.4 mg. 100. The method according to Embodiment 99, wherein the cyclobenzaprine is present in an amount of approximately 4.8 mg. 101. The method according to Embodiment 100, wherein the cyclobenzaprine is present in an amount of less than approximately 4.8 mg. 102. The composition contains 10 ng / mL or more of cyclobenzaprine C max The method according to any one of embodiments 62 to 101, which brings about the following: 103. The composition contains 15 ng / mL or more of cyclobenzaprine C max The method according to embodiment 102, which brings about the following. 104. The composition contains 20 ng / mL or more of cyclobenzaprine C max The method according to embodiment 103, which brings about the following. 105. The composition contains 25 ng / mL or more of cyclobenzaprine C max The method according to embodiment 104, which brings about the following. 106. The composition contains 30 ng / mL or more of cyclobenzaprine C max The method according to embodiment 105, which brings about the following. 107. The composition contains cyclobenzaprine at a concentration of 10 ng / mL or more above the baseline level of cyclobenzaprine in the individual immediately before administration. max The method according to any one of embodiments 62 to 106, which brings about the following: 108. The composition contains cyclobenzaprine at a concentration of 15 ng / mL or more above the baseline level of cyclobenzaprine in the individual immediately before administration. maxThe method according to embodiment 107, which brings about the following. 109. The composition contains cyclobenzaprine at a concentration of 20 ng / mL or more above the baseline level of cyclobenzaprine in the individual immediately before administration. max The method according to embodiment 108, which brings about the following. 110. The composition contains cyclobenzaprine at a concentration of 25 ng / mL or more above the baseline level of cyclobenzaprine in the individual immediately before administration. max The method according to embodiment 109, which brings about the following. 111. The composition contains cyclobenzaprine C at a concentration 30 ng / mL or more above the baseline level of cyclobenzaprine in the individual immediately before administration. max The method according to embodiment 110, which brings about the following. 112. The composition contains less than 4 hours of cyclobenzaprine t max The method according to any one embodiment 62 to 111, which brings about the result of the method according to any one embodiment 62 to 111. 113. The composition contains less than 3 hours of cyclobenzaprine t max The method according to embodiment 112, which brings about the following. 114. The composition contains less than 2 hours of cyclobenzaprine t max The method according to embodiment 113, which brings about the following. 115. The composition contains less than 1 hour of cyclobenzaprine t max The method according to embodiment 114, which brings about the following. 116. The composition contains less than 45 minutes of cyclobenzaprine t max The method according to embodiment 115, which brings about the following. 117. The composition contains less than 30 minutes of cyclobenzaprine t max The method according to embodiment 116, which brings about the following. 118. The composition contains less than 15 minutes of cyclobenzaprine t max The method according to embodiment 117, which brings about the following. 119. The composition contains the C by 8 hours after administration. max The method according to any one of embodiments 62 to 118, which results in a plasma level of cyclobenzaprine that is reduced by at least 50%. 120. The composition contains the C by 8 hours after administration. max The method according to embodiment 119, which results in a plasma level of cyclobenzaprine that is reduced by at least 60%. 121. The composition contains the C by 8 hours after administration. max The method according to embodiment 120, which results in a plasma level of cyclobenzaprine that is reduced by at least 70%. 122. The composition contains the C by 8 hours after administration. max The method according to embodiment 121, which results in a plasma level of cyclobenzaprine that is reduced by at least 80%. 123. The composition contains the C by 8 hours after administration. max The method according to embodiment 122, which results in a plasma level of cyclobenzaprine that is reduced by at least 90%. 124. The composition contains the C by 8 hours after administration. max The method according to embodiment 123, which results in a plasma level of cyclobenzaprine that is reduced by at least 95%. 125. A composition for transmucosal administration containing cyclobenzaprine, comprising approximately 2 to approximately 20 mg of cyclobenzaprine or a salt thereof, wherein the formulation contains approximately 20 to approximately 200 ng / mL of cyclobenzaprine approximately 0.0.05 to approximately 2.5 hours after administration. max a composition that yields a minimum cyclobenzaprine plasma concentration of about 1 to about 5 ng / mL about 22 to about 26 hours after administration, and is administered once daily for four days or more. 126. A method for reducing the symptoms of fibromyalgia in a human patient, comprising the step of administering a transmucosal administration preparation containing about 2 to about 20 mg of cyclobenzaprine or a salt thereof, wherein the preparation contains about 20 to about 200 ng / mL of cyclobenzaprine approximately 0.05 to about 2.5 hours after administration. max a method comprising administering the composition once daily for four days or more, and giving rise to a minimum plasma concentration of approximately 1 to 5 ng / mL approximately 22 to 26 hours after administration, and administering within two hours prior to sleep. 127. A composition for transmucosal administration containing amitriptyline, comprising approximately 2 to approximately 25 mg of amitriptyline or a salt thereof, wherein the formulation provides approximately 20 to approximately 200 ng / mL of amitriptyline approximately 0.05 to approximately 2.5 hours after administration. max a composition that yields a minimum amitriptyline plasma concentration of about 1 to about 5 ng / mL about 22 to about 26 hours after administration, and is administered once daily for four days or more. 128. A method for reducing the symptoms of fibromyalgia in a human patient, comprising the step of administering a transmucosal preparation containing about 2 to about 25 mg of amitriptyline or a salt thereof, wherein the preparation contains about 20 to about 200 ng / mL of amitriptyline about 0.05 to about 2.5 hours after administration. max a method comprising administering the composition once daily for four days or more, and giving rise to a minimum plasma concentration of approximately 1 to 5 ng / mL approximately 22 to 26 hours after administration, and administering within two hours prior to sleep. 129. When administered by transmucosal absorption, cyclobenzaprine or amitriptyline is absorbed at a concentration of 1.0 ± 25% × 10¹⁰ 20 minutes after administration. -7 mL -1 The above dnC * A composition according to any one of embodiments 1 to 14, characterized by having the following: 130. When administered by transmucosal absorption, cyclobenzaprine or amitriptyline is present at 157.60 × 10⁻¹⁴ 20 minutes after administration. -9 mL -1 The above dnC * A composition according to any one of embodiments 1 to 14, characterized by having the following: 131. When administered by transmucosal absorption, cyclobenzaprine or amitriptyline is absorbed at 2.5 ± 25% × 10¹⁰ minutes after administration. -7 dnC * A composition according to any one of embodiments 1 to 14, characterized by having the following: 132. When administered by transmucosal absorption, cyclobenzaprine or amitriptyline is absorbed at 3.0 ± 25% × 10¹⁶ minutes after administration. -7 mL -1The above dnC * A composition according to any one of embodiments 1 to 14, characterized by having the following: 133. When administered by transmucosal absorption, cyclobenzaprine or amitriptyline is absorbed at 4.2 ± 25% × 10¹⁶ minutes after administration. -7 mL -1 The above dnC * A composition according to any one of embodiments 1 to 14, characterized by having the following: 134. When administered by transmucosal absorption, cyclobenzaprine or amitriptyline is absorbed at a concentration of 6.0 ± 25% × 10¹⁶ 2 hours after administration. -7 mL -1 The above dnC * A composition according to any one of embodiments 1 to 14, characterized by having the following: 135. When administered by transmucosal absorption, cyclobenzaprine or amitriptyline is absorbed at a concentration of 6.5 ± 25% × 10¹⁶ 2.5 hours after administration. -7 mL -1 The above dnC * A composition according to any one of embodiments 1 to 14, characterized by having the following: 136. When administered by transmucosal absorption, cyclobenzaprine or amitriptyline is absorbed at a concentration of 7.0 ± 25% × 10¹⁶ 3 hours after administration. -7 mL -1 The above dnC * A composition according to any one of embodiments 1 to 14, characterized by having the following: 137. The composition according to any one of Embodiments 1 to 32, wherein the cyclobenzaprine is present in an amount of 2.8 mg. 138. The composition according to any one of Embodiments 1 to 32, wherein the cyclobenzaprine is present in an amount of 5.6 mg. 139. The composition according to any one of Embodiments 1 to 32, wherein the cyclobenzaprine is present in an amount of less than about 9 mg. 140. The cyclobenzaprine or amitriptyline was found to be 1.0 ± 25% × 10¹⁶ after 20 minutes of administration. -7 mL -1 The above dnC *The method according to any one of embodiments 62 to 77, having the following characteristics: 141. The cyclobenzaprine or amitriptyline was found to be 2.5 ± 25% × 10¹⁶ after 30 minutes of administration. -7 The above dnC * The method according to any one of embodiments 62 to 77, having the following characteristics: 142. The cyclobenzaprine or amitriptyline was found to be 3.0 ± 25% × 10¹⁶ after 45 minutes of administration. -7 The above dnC * The method according to any one of embodiments 62 to 77, having the following characteristics: 143. The cyclobenzaprine or amitriptyline was found to be 4.2 ± 25% × 10¹⁶ at 1 hour after administration. -7 The above dnC * The method according to any one of embodiments 62 to 77, having the following characteristics: 144. The cyclobenzaprine or amitriptyline was found to be 6.0 ± 25% × 10 times 2 hours after administration. -7 mL -1 The above dnC * The method according to any one of embodiments 62 to 77, having the following characteristics: 145. The cyclobenzaprine or amitriptyline was found to be 6.5 ± 25% × 10¹⁶ after 2.5 hours of administration. -7 mL -1 The above dnC * The method according to any one of embodiments 62 to 77, having the following characteristics: 146. The cyclobenzaprine or amitriptyline was found to be 727.67±25%×10 at 2.5 hours after administration. -9 mL -1 The above dnC * The method according to any one of embodiments 62 to 77, having the following characteristics: 147. The cyclobenzaprine or amitriptyline was found to be 7.0 ± 25% × 10 times 3 hours after administration. -7 mL -1 The above dnC * The method according to any one of embodiments 62 to 77, having the following characteristics: 148. When administered via mucosal absorption, cyclobenzaprine C2 is present at concentrations of 2 ng / mL or higher. maxA composition according to any one of embodiments 1 to 38, characterized by providing a result. 149. When administered via mucosal absorption, the C of cyclobenzaprine in the individual immediately before administration exceeds the baseline level by 2 ng / mL or more. max A composition according to any one of embodiments 1 to 43, characterized by providing a result. [Brief explanation of the drawing]

[0041] [Figure 1a] Figure 1a shows line graphs of mean plasma cyclobenzaprine concentration ± standard deviation and mean plasma norcyclobenzaprine concentration ± standard deviation in 10 healthy human subjects after oral (PO) administration of 5 mg cyclobenzaprine HCl immediate-release tablets in a fasted state.

[0042] [Figure 1b] Figure 1b is a logarithmic graph of the mean plasma cyclobenzaprine concentration ± standard deviation and the mean plasma norcyclobenzaprine concentration ± standard deviation in 10 healthy human subjects who underwent PO treatment with 5 mg of cyclobenzaprine HCl immediate-release tablets while fasted.

[0043] [Figure 2] Figure 2 is a line graph showing the mean cyclobenzaprine concentration ± standard deviation over time in the plasma of female beagle dogs. Cyclobenzapurine was administered orally (PO) via nasogastric (NG) tube, sublingually, or intravenously (IV).

[0044] [Figure 3] Figure 3 is a semi-logarithmic graph of the mean cyclobenzaprine concentration ± standard deviation over time in the plasma of female beagle dogs. Cyclobenzapurine was administered orally (PO) via NG tube, sublingually, or intravenously.

[0045] [Figure 4]Figure 4 is a graph of the mean cyclobenzaprine concentration-time profile ± standard deviation after intravenous administration of cyclobenzaprine HCl in the plasma of female beagle dogs. The mean values ​​(IV study) for dogs treated with propofol preanesthetic and dogs that were not treated are compared with the mean values ​​for dogs based on IV data in Figure 2.

[0046] [Figure 5] Figure 5 is a graph of the mean cyclobenzaprine concentration-time profile ± standard deviation after sublingual administration of cyclobenzaprine HCl in the plasma of female beagle dogs. The mean (sublingual study) of dogs treated with propofol preanesthetic and untreated dogs is compared with the mean of dogs based on sublingual data in Figure 2.

[0047] [Figure 6] Figure 6 is a line graph showing the mean cyclobenzaprine concentration ± standard deviation over time in the plasma of female beagle dogs. Cyclobenzapurine was administered sublingually in the form of tablets containing the basicizing agent K2HPO4 or tablets lacking the basicizing agent K2HPO4.

[0048] [Figure 7] Figure 7 is a logarithmic graph of the mean cyclobenzaprine concentration ± standard deviation over time in the plasma of female beagle dogs. Cyclobenzapurine was administered sublingually in the form of tablets with or without the basicizing agent K2HPO4.

[0049] [Figure 8] Figure 8 is a table showing the once-daily evaluations conducted throughout the course of a study in which cyclobenzaprine HCl was administered to humans.

[0050] [Figure 9] Figure 9 is a table showing hourly evaluations performed in humans after PO administration during a study of 5 mg cyclobenzaprine HCl immediate-release tablets.

[0051] [Figure 10]Figure 10 is a graph showing the cyclobenzaprine plasma concentration-time profiles 0–1 hours after administration of sublingual (SL, subject 7 only), oral (PO, group mean), and intravenous (IV, group mean) doses of cyclobenzaprine.

[0052] [Figure 11] Figure 11 is a graph showing the cyclobenzaprine plasma concentration-time profiles 0–24 hours after administration of sublingual (subject 7 only), oral (group average), and intravenous (group average) doses of cyclobenzaprine.

[0053] [Figure 12] Figure 12 is a graph showing the mean cyclobenzaprine plasma concentration-time profiles 0 to 24 hours after administration of cyclobenzaprine sublingually at pH 7.1 (mean for all subjects except subjects 7 and 10), at pH 3.5 (mean for all subjects except subject 4), and orally (group mean).

[0054] [Figure 13] Figure 13 is a graph showing the norcyclobenzaprine plasma concentration-time profiles 0–24 hours after administration of sublingual (subject 7 only), oral (group average), and intravenous (group average) doses of cyclobenzaprine.

[0055] [Figure 14a] Figure 14 is a graph showing the plasma concentrations of cyclobenzaprine 0 to 2 hours after administration of sublingual cyclobenzaprine 2.4 mg (Figure 14a) and 4.8 mg (Figure 14b), as well as oral cyclobenzaprine 5 mg. [Figure 14b] Figure 14 is a graph showing the plasma concentrations of cyclobenzaprine 0 to 2 hours after administration of sublingual cyclobenzaprine 2.4 mg (Figure 14a) and 4.8 mg (Figure 14b), as well as oral cyclobenzaprine 5 mg.

[0056] [Figure 15]Figure 15 is a graph showing the plasma concentrations of cyclobenzaprine 0 to 8 hours after administration of sublingual cyclobenzaprine 4.8 mg and oral cyclobenzaprine 5 mg.

[0057] [Figure 16] Figure 16 is a graph showing the plasma concentrations of cyclobenzaprine 0 to 8 hours after administration of sublingual cyclobenzaprine 2.4 mg and 4.8 mg.

[0058] [Figure 17a] Figure 17 is a graph showing the plasma concentrations of cyclobenzaprine 0–2 hours (Figure 17a) and 0–8 hours (Figure 17b) after administration of 2.4 mg of sublingual cyclobenzaprine with or without phosphate. [Figure 17b] Figure 17 is a graph showing the plasma concentrations of cyclobenzaprine 0–2 hours (Figure 17a) and 0–8 hours (Figure 17b) after administration of 2.4 mg of sublingual cyclobenzaprine with or without phosphate.

[0059] [Figure 18a] Figure 18 is a graph showing the equilibrium binding studies of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) to serotonin (5-HT1A, Figure 18a; 5-HT2A, Figure 18b; 5-HT2B, Figure 18c; 5-HT2C, Figure 18d), histamine H1 (H1) (Figure 18e), adrenergic α1A (α1A) (Figure 18f), muscarinic M1 (M1) (Figure 18g), and dopamine D1 (D1) (Figure 18h) receptors expressed in the human central nervous system. [Figure 18b] Figure 18 is a graph showing the equilibrium binding studies of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) to serotonin (5-HT1A, Figure 18a; 5-HT2A, Figure 18b; 5-HT2B, Figure 18c; 5-HT2C, Figure 18d), histamine H1 (H1) (Figure 18e), adrenergic α1A (α1A) (Figure 18f), muscarinic M1 (M1) (Figure 18g), and dopamine D1 (D1) (Figure 18h) receptors expressed in the human central nervous system. [Figure 18c] Figure 18 is a graph showing the equilibrium binding studies of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) to serotonin (5-HT1A, Figure 18a; 5-HT2A, Figure 18b; 5-HT2B, Figure 18c; 5-HT2C, Figure 18d), histamine H1 (H1) (Figure 18e), adrenergic α1A (α1A) (Figure 18f), muscarinic M1 (M1) (Figure 18g), and dopamine D1 (D1) (Figure 18h) receptors expressed in the human central nervous system. [Figure 18d] Figure 18 is a graph showing the equilibrium binding studies of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) to serotonin (5-HT1A, Figure 18a; 5-HT2A, Figure 18b; 5-HT2B, Figure 18c; 5-HT2C, Figure 18d), histamine H1 (H1) (Figure 18e), adrenergic α1A (α1A) (Figure 18f), muscarinic M1 (M1) (Figure 18g), and dopamine D1 (D1) (Figure 18h) receptors expressed in the human central nervous system. [Figure 18e] Figure 18 is a graph showing the equilibrium binding studies of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) to serotonin (5-HT1A, Figure 18a; 5-HT2A, Figure 18b; 5-HT2B, Figure 18c; 5-HT2C, Figure 18d), histamine H1 (H1) (Figure 18e), adrenergic α1A (α1A) (Figure 18f), muscarinic M1 (M1) (Figure 18g), and dopamine D1 (D1) (Figure 18h) receptors expressed in the human central nervous system. [Figure 18f] Figure 18 is a graph showing the equilibrium binding studies of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) to serotonin (5-HT1A, Figure 18a; 5-HT2A, Figure 18b; 5-HT2B, Figure 18c; 5-HT2C, Figure 18d), histamine H1 (H1) (Figure 18e), adrenergic α1A (α1A) (Figure 18f), muscarinic M1 (M1) (Figure 18g), and dopamine D1 (D1) (Figure 18h) receptors expressed in the human central nervous system. [Figure 18g]Figure 18 is a graph showing the equilibrium binding studies of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) to serotonin (5-HT1A, Figure 18a; 5-HT2A, Figure 18b; 5-HT2B, Figure 18c; 5-HT2C, Figure 18d), histamine H1 (H1) (Figure 18e), adrenergic α1A (α1A) (Figure 18f), muscarinic M1 (M1) (Figure 18g), and dopamine D1 (D1) (Figure 18h) receptors expressed in the human central nervous system. [Figure 18h] Figure 18 is a graph showing the equilibrium binding studies of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) to serotonin (5-HT1A, Figure 18a; 5-HT2A, Figure 18b; 5-HT2B, Figure 18c; 5-HT2C, Figure 18d), histamine H1 (H1) (Figure 18e), adrenergic α1A (α1A) (Figure 18f), muscarinic M1 (M1) (Figure 18g), and dopamine D1 (D1) (Figure 18h) receptors expressed in the human central nervous system.

[0060] [Figure 19] Figure 19 is a graph showing the equilibrium binding study of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) to norepinephrine (NE), 5-HT, and dopamine (D) transporters expressed in the human central nervous system.

[0061] [Figure 20a] Figure 20 is a graph showing the study of G protein-dependent signaling of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) to serotonin (5-HT1A, Figure 20a; 5-HT2A, Figure 20b; 5-HT2B, Figure 20c; 5-HT2C, Figure 20d), histamine H1 (H1) (Figure 20e), adrenergic α1A (α1A) (Figure 20f), muscarinic M1 (M1) (Figure 20g), and dopamine D1 (D1) (Figure 20h) receptors expressed in the human central nervous system. [Figure 20b]Figure 20 is a graph showing the study of G protein-dependent signaling of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) to serotonin (5-HT1A, Figure 20a; 5-HT2A, Figure 20b; 5-HT2B, Figure 20c; 5-HT2C, Figure 20d), histamine H1 (H1) (Figure 20e), adrenergic α1A (α1A) (Figure 20f), muscarinic M1 (M1) (Figure 20g), and dopamine D1 (D1) (Figure 20h) receptors expressed in the human central nervous system. [Figure 20c] Figure 20 is a graph showing the study of G protein-dependent signaling of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) to serotonin (5-HT1A, Figure 20a; 5-HT2A, Figure 20b; 5-HT2B, Figure 20c; 5-HT2C, Figure 20d), histamine H1 (H1) (Figure 20e), adrenergic α1A (α1A) (Figure 20f), muscarinic M1 (M1) (Figure 20g), and dopamine D1 (D1) (Figure 20h) receptors expressed in the human central nervous system. [Figure 20d] Figure 20 is a graph showing the study of G protein-dependent signaling of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) to serotonin (5-HT1A, Figure 20a; 5-HT2A, Figure 20b; 5-HT2B, Figure 20c; 5-HT2C, Figure 20d), histamine H1 (H1) (Figure 20e), adrenergic α1A (α1A) (Figure 20f), muscarinic M1 (M1) (Figure 20g), and dopamine D1 (D1) (Figure 20h) receptors expressed in the human central nervous system. [Figure 20e] Figure 20 is a graph showing the study of G protein-dependent signaling of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) to serotonin (5-HT1A, Figure 20a; 5-HT2A, Figure 20b; 5-HT2B, Figure 20c; 5-HT2C, Figure 20d), histamine H1 (H1) (Figure 20e), adrenergic α1A (α1A) (Figure 20f), muscarinic M1 (M1) (Figure 20g), and dopamine D1 (D1) (Figure 20h) receptors expressed in the human central nervous system. [Figure 20f]Figure 20 is a graph showing the study of G protein-dependent signaling of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) to serotonin (5-HT1A, Figure 20a; 5-HT2A, Figure 20b; 5-HT2B, Figure 20c; 5-HT2C, Figure 20d), histamine H1 (H1) (Figure 20e), adrenergic α1A (α1A) (Figure 20f), muscarinic M1 (M1) (Figure 20g), and dopamine D1 (D1) (Figure 20h) receptors expressed in the human central nervous system. [Figure 20g] Figure 20 is a graph showing the study of G protein-dependent signaling of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) to serotonin (5-HT1A, Figure 20a; 5-HT2A, Figure 20b; 5-HT2B, Figure 20c; 5-HT2C, Figure 20d), histamine H1 (H1) (Figure 20e), adrenergic α1A (α1A) (Figure 20f), muscarinic M1 (M1) (Figure 20g), and dopamine D1 (D1) (Figure 20h) receptors expressed in the human central nervous system. [Figure 20h] Figure 20 is a graph showing the study of G protein-dependent signaling of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) to serotonin (5-HT1A, Figure 20a; 5-HT2A, Figure 20b; 5-HT2B, Figure 20c; 5-HT2C, Figure 20d), histamine H1 (H1) (Figure 20e), adrenergic α1A (α1A) (Figure 20f), muscarinic M1 (M1) (Figure 20g), and dopamine D1 (D1) (Figure 20h) receptors expressed in the human central nervous system.

[0062] [Figure 21a] Figure 21 is a graph showing the study of G protein-independent signaling of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) to serotonin (5-HT2A) (Figure 21d), histamine H1 (H1) (Figure 21a), adrenergic α1B (α1A) (Figure 21b), and muscarinic M1 (M1) (Figure 21c) receptors expressed in the human central nervous system. [Figure 21b]Figure 21 is a graph showing the study of G protein-independent signaling of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) to serotonin (5-HT2A) (Figure 21d), histamine H1 (H1) (Figure 21a), adrenergic α1B (α1A) (Figure 21b), and muscarinic M1 (M1) (Figure 21c) receptors expressed in the human central nervous system. [Figure 21c] Figure 21 is a graph showing the study of G protein-independent signaling of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) to serotonin (5-HT2A) (Figure 21d), histamine H1 (H1) (Figure 21a), adrenergic α1B (α1A) (Figure 21b), and muscarinic M1 (M1) (Figure 21c) receptors expressed in the human central nervous system. [Figure 21d] Figure 21 is a graph showing the study of G protein-independent signaling of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) to serotonin (5-HT2A) (Figure 21d), histamine H1 (H1) (Figure 21a), adrenergic α1B (α1A) (Figure 21b), and muscarinic M1 (M1) (Figure 21c) receptors expressed in the human central nervous system. [Modes for carrying out the invention]

[0063] Detailed description of the invention Unless otherwise defined herein, the scientific and technical terms used herein have meanings commonly understood by those skilled in the art. In general, the nomenclature and techniques used herein in relation to pharmacology, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, genetics, and protein and nucleic acid chemistry are well known and commonly used in the art.

[0064] Unless otherwise specified, the methods and techniques of the present invention are generally carried out in accordance with the conventional methods described in various general and more specific references well known in the art and referenced and discussed herein.

[0065] The chemical terms used herein are used in accordance with the common usage in the art, as exemplified by "The McGraw-Hill Dictionary of Chemical Terms," ​​Parker S., Ed., McGraw-Hill, San Francisco, CA (1985).

[0066] All other publications, patent documents, and published patent application documents referenced herein are incorporated specifically by reference herein. Any inconsistencies, including specific definitions, shall be governed by this specification.

[0067] Throughout this specification, variations of the term “comprise,” “comprises,” or “comprising” shall be understood to imply that they include the integers (or components) or groups of integers (or components) described herein, and do not exclude any other integers (or components) or groups of integers (or components).

[0068] The singular forms "a," "an," and "the" include plural nouns unless otherwise specified.

[0069] The term "includes" is used to mean "includes but not limited to." "Includes" and "includes but not limited to" are used interchangeably.

[0070] The terms "patient," "subject," or "individual" are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, e.g., humans, primates, domesticated animals (including cattle, pigs, etc.), pet animals (e.g., dogs, cats, etc.), and rodents (e.g., mice and rats).

[0071] "To treat" a condition or patient means to take steps to obtain a beneficial or desired outcome, including a clinical outcome. A beneficial or desired clinical outcome includes, but is not limited to, the reduction or relief of one or more symptoms associated with the disease or condition described herein.

[0072] "Administering" a substance, compound, or drug to a subject, or "administering" them, can be carried out using one of the various methods known to those skilled in the art. For example, a compound or drug may be administered sublingually or intranasally, by inhalation into the lungs, or rectally. Administration may also be carried out, for example, once, multiple times, and / or over one or more periods. In some embodiments, 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 person, and / or prepares a prescription for the drug for the patient, shall be considered to have administered the drug to the patient.

[0073] This invention provides compositions for transmucosal absorption and methods for administering compounds for transmucosal absorption. The compositions and methods offer many remarkable pharmacokinetic advantages compared to oral administration of compounds, which primarily involve absorption of the compounds in the stomach, small intestine, and colon.

[0074] Each embodiment described herein can be used individually or in combination with any other embodiment described herein. compound

[0075] Compounds useful in embodiments of the present invention include cyclobenzaprine and amitriptyline. In some embodiments, the compounds are micronized. In alternative embodiments, the compounds are not micronized. In some embodiments, the compounds may exist in isoform form of one or more crystals.

[0076] As used herein, "cyclobenzaprine" includes cyclobenzaprine and pharmaceutically acceptable salts of cyclobenzaprine (e.g., cyclobenzaprine HCl). In some embodiments, cyclobenzaprine may be modified by covalent addition of lysine or by binding with albumin.

[0077] As used herein, "amitriptyline" includes amitriptyline and pharmaceutically acceptable salts of amitriptyline (e.g., amitriptyline HCl). In some embodiments, amitriptyline may be modified by covalent addition of lysine or by binding with albumin. dose

[0078] The "therapeutic dose" of a drug or medication is the amount of the drug or medication administered to a subject that, when given, produces the desired therapeutic effect, for example, by reducing the symptoms of fibromyalgia or post-traumatic stress disorder (PTSD), or by treating the onset of fibromyalgia or post-traumatic stress disorder (PTSD). Complete therapeutic effect may not necessarily occur with a single dose, but may only occur after a series of doses. Generally, treatment with cyclobenzaprine can be administered indefinitely to alleviate the target symptoms, and the frequency of administration can be changed as needed. Therefore, the therapeutic dose can be administered in one or more doses. The exact effective dose required for a subject will depend, for example, on the subject's size, health and age, the nature and degree of cognitive impairment, the treatment or combination of treatments chosen for administration, and the method of administration. Those skilled in the art can easily determine the effective dose for a given situation using routine experimental methods. Generally, the therapeutically effective doses of cyclobenzaprine or amitriptyline administered to a patient are 0.1 mg to 20.0 mg, 0.1 mg to 5.0 mg, 0.1 mg to 4.0 mg, 0.1 to 3.0 mg, 1 to 50 mg, or 1 to 75 mg. In some embodiments, the therapeutically effective dose is approximately 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 The dosages are 0.1 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, the therapeutically effective dose is approximately 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, amitriptyline is present in the composition of the present invention in an amount of 1 mg to 25 mg, for example, 1 mg to 10 mg. In certain embodiments, amitriptyline is present in amounts of about 8 mg, less than about 16 mg, about 16 mg, or less than about 24 mg. Administration

[0079] The appropriate method for administering a substance, compound, or drug to a subject will depend, for example, on the subject's age, whether the subject is active or inactive at the time of administration, whether the subject is experiencing symptoms of a disease or condition at the time of administration, the severity of the symptoms, and the chemical and biological properties of the compound or drug (e.g., solubility, digestibility, bioavailability, stability, and toxicity). In some embodiments, the compound is administered for transmucosal absorption. The absorption characteristics of the compounds of the present invention by transmucosal delivery cannot be predicted without experimental methods. The suitability of the compounds of the present invention for transmucosal absorption is a remarkable feature. Transmucosal absorption can occur through any mucous membrane. Exemplary mucous membranes include the oral mucosa (e.g., buccal and sublingual mucosa), nasal mucosa, rectal mucosa, and pulmonary mucosa. In some embodiments, the composition is suitable for transmucosal absorption. In some embodiments, the composition is formulated for transmucosal absorption.

[0080] Methods for administering compositions for transmucosal absorption are well known in the art. For example, compositions can be administered for oral absorption by oral tablets, lozenges, oral tablets, and oral spray solutions. Compositions can be administered for sublingual absorption by sublingual tablets, sublingual films, liquids, sublingual powders, and sublingual spray solutions. Compositions can be administered for intranasal absorption by nasal sprays. Compositions can be administered for transpulmonary absorption by aerosolized compositions or inhalable dry powders. When administered by spray or aerosolized composition, compositions can be prepared as solutions using physiological saline, may use benzyl alcohol or other suitable preservatives, or may contain absorption promoters, carbon fluoride, and / or other solubilizers or dispersants to enhance bioavailability.

[0081] Dosage and administration regimens may be determined by those skilled in the art as needed for the subject being treated. Those skilled in the art may consider factors such as the subject's age or weight, the severity of the disease or condition being treated, and the subject's response to the treatment. The compositions of the present invention may be administered, for example, as needed or on a once-daily basis. In some embodiments, the compositions may be administered immediately before or several hours before sleep. Administration before sleep may be beneficial by providing a therapeutic effect before the onset of symptoms of the disease or condition being treated. Administration may be carried out over a variety of periods. For example, an administration regimen may continue for one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, twelve weeks, or longer. In some embodiments, an administration regimen may continue for one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, twelve months, or longer. Use for treatment

[0082] The compounds of the present invention can be used to treat or prevent the onset of fibromyalgia syndrome, also known as connective tissue inflammation (e.g., Moldofsky et al., J Rheumatol). See Volume 38 (No. 12): pp. 2653-2663 (2011) and Thomas, J Rheumatol Volume 38 (No. 12): pp. 2499-2500 (2011). Fibromyalgia is a chronic, non-inflammatory rheumatic disorder. The American College of Rheumatology (ACR) published classification criteria for fibromyalgia in 1990 (Wolfe, F. et al., Arthritis). (and Rheumatism, Vol. 33: pp. 160-172 (1990)). Subsequently, a revised version of the ACR criteria was published (Wolfe et al., J Rheumatol, Vol. 38 (No. 6): pp. 1113-1122 (2011)). Diagnostic criteria were published by the international network of working groups called the “Outcome Measures in Rheumatology” clinical trial or OMERACT (Mease P et al., J Rheumatol, 2009; Vol. 36 (No. 10): pp. 2318-2329). Fibromyalgia is traditionally characterized by stiffness or diffusing pain, throbbing pain, burning pain in the muscles, sleep disturbance, or fatigue. Pain is generally widespread but is generally localized to specific “tender points” that can produce widespread pain and muscle spasms upon touch. Other symptoms include mental and emotional disturbances, such as difficulty concentrating and irritability; neuropsychiatric symptoms, such as depression and anxiety; joint swelling; headaches; and numbness. Fibromyalgia is associated with cognitive impairment, including restless sleep, fatigue, drowsiness, reflux, mental fogginess, and difficulty multitasking. Fibromyalgia is also often accompanied by sleep disturbances, fatigue, unrecoverable sleep, anxiety, and depression. The compositions and methods of the present invention can be used to treat any one of the previously identified conditions and any combination thereof.

[0083] According to one physician, fibromyalgia can be further classified into two categories: primary fibromyalgia or secondary-associated fibromyalgia. Generally, primary fibromyalgia can be considered fibromyalgia that occurs in the absence of another serious condition, while secondary-associated fibromyalgia can be considered fibromyalgia that occurs in the presence of another serious medical disorder, which may be caused by or simply associated with the patient's fibromyalgia. Secondary or associated fibromyalgia may include fibromyalgia in patients with classic or limited rheumatoid arthritis, osteoarthritis of the knee or hand, lower back pain syndrome, cervical pain syndrome, cancer pain syndrome, temporomandibular joint disorder, migraine, menopause, post-traumatic stress disorder, and interstitial cystitis or painful bladder syndrome (or a combination thereof).

[0084] Furthermore, the compounds of the present invention can be used to treat or prevent the onset (initiation, exacerbation, or perpetuation) of PTSD symptoms following a traumatic event. A traumatic event is defined as a direct personal experience involving actual death or serious injury or the threat thereof, or another threat to an individual's physical integrity, or witnessing an event involving the death, injury, or threat to the physical integrity of another person; or knowing of an unexpected or violent death, serious harm, or threat of death or injury experienced by a family member or other close relative. Directly experienced traumatic events include, but are not limited to, combat, violent personal attacks (sexual attacks, physical assaults, robbery, street robbery), experiences of kidnapping, experiences of being taken hostage, terrorist attacks, torture, imprisonment as a prisoner of war or in a concentration camp, natural or man-made disasters, serious car accidents, or a diagnosis of a life-threatening illness. For children, sexual traumatic events may include developmentally inappropriate sexual experiences that do not involve actual violence or injury or the threat thereof. Eyewitness events include, but are not limited to, witnessing a violent attack, an accident, war, or disaster resulting in serious injury or unnatural death of another person, or unexpectedly witnessing a corpse or part of a corpse. Events experienced by others that become known may include, but are not limited to, a violent personal attack, a serious accident, or serious injury experienced by a family member or close friend, learning of the unexpected sudden death of a family member or close friend, or learning that one's child has a life-threatening illness. Distress may be particularly severe or long-lasting, especially if the stressor is the work of another person (e.g., torture or rape). The onset of PTSD symptoms typically occurs immediately after the traumatic event, but PTSD symptoms can also appear during the traumatic event and gradually become more severe. One theory about how PTSD develops is that there is a type of “learning” or reinforcement process in which memories of the trauma become deeply ingrained in the mind. As these memories become more strongly fixed (a process called reinforcement), symptoms such as flashbacks and nightmares become more severe and frequent. Intervening during this critical period can prevent a patient from developing full-blown PTSD.The intensification of PTSD symptoms typically occurs in the weeks and months following a traumatic event. A person's memory of the traumatic event becomes more vivid and clear, and this memory is re-experienced with increasing frequency as either flashbacks or nightmares. During this period, hyperarousal and avoidance behaviors may gradually become more severe, interfering with daily life. Persistence of PTSD symptoms occurs when the memory of the trauma is reinforced, and the re-experiencing symptoms (flashbacks and nightmares) and hyperarousal become persistent, remaining at a level that functionally impairs the patient's daily life.

[0085] The compositions and methods of the present invention can be used at various time intervals to treat different phases of PTSD development after a traumatic event. For example, to treat the initial phase of PTSD, it may be necessary to administer the compositions of the present invention shortly after the traumatic event, for example, within one week, within two weeks, within three weeks, or within four weeks or thereafter. In contrast, when treating the reinforcement phase of PTSD, those skilled in the art may administer the compositions of the present invention some time after the traumatic event, some time during the onset of symptoms, for example, within one month, within two months, or within three months or thereafter. The permanence phase of PTSD can be treated with the compositions of the present invention administered three months or more after the traumatic event, for example, within three months, within four months, within five months or thereafter. As a result of treatment in the initial, reinforcement, or permanence phase, PTSD symptoms are alleviated or eliminated.

[0086] The compositions and methods of the present invention can also be used to treat traumatic brain injury (TBI), which is associated with sleep disorders, sleep disturbances, fatigue, unrecoverable sleep, anxiety, and depression. The compositions and methods of the present invention can also be used, in combination with or independently, to treat any of the aforementioned conditions.

[0087] The compositions and methods of the present invention can also be used to treat chronic traumatic encephalopathy (CTE), which is associated with sleep disorders, sleep disturbances, fatigue, unrecoverable sleep, anxiety, and depression. The compositions and methods of the present invention can also be used, in combination with or independently, to treat any of the aforementioned conditions.

[0088] The compositions and methods of the present invention can be used to treat sleep disorders or sleep disturbances. “Sleep disorders” can be any one of the four main categories of sleep dysfunction (see also DSM-IV, pp. 551–607; The International Classification of Sleep Disorders: (ICSD) Diagnostic and Coding Manual, 1990, American Sleep Disorders Association). One category, primary sleep disorders, includes sleep disorders not resulting from another mental disorder, substance, or general medical condition. These sleep disorders include, but are not limited to, primary insomnia, primary hypersomnia, narcolepsy, circadian rhythm sleep disorders, nightmare disorders, night terror disorders, sleepwalking disorders, REM sleep behavior disorders, sleep paralysis, day-night reversal, and other related disorders; substance-induced sleep disorders; and sleep disorders resulting from a general medical condition. Non-recovering sleep, which is primary insomnia, is described by DSM-IV-TR as a type of primary insomnia in which the main problem is not feeling fresh or refreshed upon waking. The second category includes sleep disorders caused by substances, including pharmaceuticals and abused drugs. The third category includes sleep disturbances resulting from the effects of common medical conditions on the sleep / wake system. The fourth category of sleep disorders includes sleep disorders resulting from identifiable mental disorders, such as mood or anxiety disorders. The fifth category of sleep disorders includes sleep disorders described as non-recovering sleep. One definition of non-recovering sleep is described in the DSM-IV-TR as a certain type of primary insomnia (A1.3), in which the main problem is not feeling refreshed or not refreshed upon waking. The symptoms of each category of sleep disorders are well known in the art. "Sleep disturbance" can be a dysfunction in refreshing sleep. Such clinical diagnoses can be made based on the patient's own account of feeling tired upon waking or the patient's reports of poor quality sleep.Such disturbances of quality sleep can be described as shallow sleep or frequent awakenings, which may be related to an increase in Cyclic Alternating Pattern (CAP) A2 or A3 rate or cycle duration, or an increase in normalized CAP A2+A3 determined by CAP(A2+A3) / CAP(A1+A2+A3) in non-REM sleep (see, e.g., Moldofsky et al., J Rheumatol 38(12): pp. 2653-2663 (2011) and Thomas, J Rheumatol 38(12): pp. 2499-2500 (2011)), alpha rhythm contamination in non-REM sleep, or the absence of delta waves in deeper sleep where physical recovery occurs. Such “sleep disturbances” may or may not escalate to the level of “sleep impairment” as defined in DSM-IV, but these sleep disturbances may share one or more common symptoms. The symptoms of sleep disturbance are well known in the art. Known symptoms include feelings of drowsiness or confusion, fatigue, exhaustion, and difficulty concentrating during waking hours.Sleep-related conditions that can be treated with the methods and compositions of the present invention include sleep disorders (e.g., endogenous sleep disorders, e.g., sleep state misperception, psychopsychological insomnia, idiopathic insomnia, obstructive sleep apnea syndrome, central sleep apnea syndrome, central alveolar hypoventilation syndrome, restless legs syndrome, and periodic limb movement disorder; exogenous sleep disorders, e.g., environmental sleep disorders, adaptive sleep disorders, limit-setting sleep disorders, stimulant-dependent sleep disorders, alcohol-dependent sleep disorders, toxin-induced sleep disorders, sleep-onset disorders, hypnotic-dependent sleep disorders, and inappropriate sleep disorders) Sleep hygiene disorders, altitude insomnia, sleep deprivation syndrome, nocturnal eating syndrome, and nocturnal drinking syndrome; as well as circadian rhythm sleep disorders (e.g., 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., wakefulness disorders, e.g., sleepwalking, confusional awakenings, as well as night terrors and sleep-wake transition disorders, e.g., rhythmic disorders, sleep talking and sleep starts, as well as nocturnal leg cramps), and sleep disorders associated with medical or psychiatric conditions or disorders. Basicizing agent

[0089] The compositions of the present invention may contain a basicizing agent in addition to the compounds useful in the compositions of the present invention. As used herein, “basicizing agent” refers to an agent useful in the compositions and methods of the present invention that raises the pH of a solution containing a compound (e.g., cyclobenzaprine HCl or amitriptyline HCl) (e.g., 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, NaH2PO4), disodium hydrogen phosphate (disodium phosphate, dibasic sodium phosphate, Na2HPO4), trisodium phosphate (Na3PO4), bicarbonates or carbonates, dipotassium citrate, tripotassium citrate, disodium citrate, trisodium citrate, borates, hydroxides, silicates, nitrates, dissolved ammonia, conjugated bases of several organic acids (including bicarbonates), and sulfides, which increase the local pH of liquids near mucosal surfaces). The target solution is a layer of aqueous material covering the mucous membrane. Therefore, the basicizing agent is sometimes a component (and excipient) in the tablet, and while the basicizing agent exerts its effect while the tablet is dispersed in the mucosal material, a portion of the formulation remains dissolved in the mucosal material for a certain period after the tablet has dissolved. Surprisingly, the pharmacokinetic properties of the composition are improved by adding a basicizing agent to the composition of the present invention. This is exemplified by cyclobenzaprine HCl as a specific compound useful in the methods and compositions of the present invention. A basicizing agent that has a specific effect on cyclobenzaprine HCl is dipotassium hydrogen phosphate (K2HPO4). Another basicizing agent that has a specific effect on cyclobenzaprine HCl is potassium dihydrogen phosphate (KH2PO4). Another basicizing agent that has a specific effect on cyclobenzaprine HCl is disodium hydrogen phosphate (Na2HPO4). Another basicizing agent that has a specific effect on cyclobenzaprine HCl is tripotassium citrate. Another basicizing agent that has a specific effect on cyclobenzaprine HCl is trisodium citrate.In some embodiments, amitriptylin HCl is a specific compound useful in the methods and compositions of the present invention. A basicizing agent that has a particular effect on amitriptylin HCl is K2HPO4. Another basicizing agent that has a particular effect on amitriptylin HCl is Na2HPO4. Another basicizing agent that has a particular effect on amitriptylin HCl is KH2PO4. Another basicizing agent that has a particular effect on amitriptylin HCl is tripotassium citrate. Another basicizing agent that has a particular effect on amitriptylin HCl is trisodium citrate.

[0090] Cyclobenzapurine HCl has an amine group acid dissociation constant (or pKa) of approximately 8.5 at 25°C, which indicates that 50% of the compound is ionized or protonated at pH 8.5 (50% is unionized or free base). (ML Cotton, GRB Down, Anal Profiles Drug) (Subs. Vol. 17, pp. 41-72 (1988)). The pH of cyclobenzaprine HCl aqueous solutions at concentrations of 10 gm / 100 mL (0.32 mol) to 30 gm / 100 mL (0.96 mol) is approximately 3.1 to 3.3, which provides a state in which almost all of the cyclobenzaprine is ionized and becomes soluble. Therefore, those skilled in the art who possess this knowledge can take care to maintain the cyclobenzaprine at a low pH to maximize its solubility. However, ionized cyclobenzaprine may not be optimally absorbed through the mucosal surface due to its charge. This problem can be solved by combining cyclobenzaprine with a basicizing agent. In fact, the inventors have found that combining cyclobenzaprine HCl with a basicizing agent such as dipotassium hydrogen phosphate (K2HPO4) or potassium dihydrogen phosphate (KH2PO4) improves the pharmacokinetic properties of compositions for transmucosal absorption containing cyclobenzaprine. In experiments using oral and intravenous solutions containing cyclobenzaprine and a basicizing agent, the pH was adjusted to approximately pH 7.1 to pH 7.4. In experiments using tablet formulations containing cyclobenzaprine and a basicizing agent, the addition of the basicizing agent resulted in a higher pH when the tablets were dissolved in water. Furthermore, combining cyclobenzaprine with a basicizing agent enhanced the uptake of cyclobenzaprine via mucosal absorption. It is likely that the concentration of free cyclobenzaprine base increases compared to ionized cyclobenzaprine, causing a 2.5 mg / ml cyclobenzaprine HCl solution at pH 7.4 containing K2HPO4 or KH2PO4 to approach its saturation point, where cyclobenzaprine is extracted from the solution or becomes insoluble. Therefore, the effect of basicizing agents such as K2HPO4 or KH2PO4 on the mucosal pharmacokinetic properties of compositions containing cyclobenzaprine is significant.While not adhering to any particular theory, basicizing agents can increase the pH of the local microenvironment on the mucous membrane, allowing more cyclobenzaprine to be deionized or become a free base on the mucosal surface. This helps cyclobenzaprine enter the bloodstream via the mucous membrane, thereby offsetting any decrease in cyclobenzaprine solubility resulting from the action of basicizing agents in the solution near the mucous membrane. While not adhering to any particular theory, basicizing agents can create a transition state involving the hydration of free bases, resulting in the formation of free bases in situ near the mucosal surface and their passage through the mucous membrane.

[0091] A useful basicizing agent in the compositions and methods of the present invention may be any agent that increases the pH of a compound-containing solution and is useful in the methods and compositions of the present invention. Exemplary basicizing 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, NaH2PO4), disodium hydrogen phosphate (disodium phosphate, dibasic sodium phosphate, Na2HPO4), trisodium phosphate (Na3PO4), 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, the compositions of the present invention have a molar ratio of the compound (e.g., cyclobenzaprine or amitriptyline) to the basicizing 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 cyclobenzaprine HCl (2.4 mg, MW 275.387) to K2HPO4 (1.05 mg, MW 174.2) is 0.69. Metabolism of cyclobenzaprine and amitriptyline

[0092] Cyclobenzapurine is rapidly distributed from the vascular structure after intravenous (IV) bolus administration to humans (Hucker et al., J Clin Pharmacol Vol. 17: pp. 719-727 (1977), Hucker et al., Drug Metab Dispos Vol. 6: pp. 659-672 (1978), Till et al., Annu Rev Pharmacol Toxicol Vol. 40: pp. 581-616 (2000), and Winchell et al., J Clin Pharmacol Vol. 42: pp. 61-69 (2002)). The amount of cyclobenzaprine in plasma within 3-30 minutes is compared to the theoretical initial concentration (C) of each infusion dose. init ) is less than 5%, and C is relatively high at the 3-minute mark. init This occurred. Overall, this information indicates that cyclobenzaprine is rapidly distributed from plasma. Since more than 95% of the injected cyclobenzaprine is eliminated from plasma before the first time point in any of the four studies listed above, these studies do not provide information on the phase 1 half-life of IV cyclobenzaprine distributed from plasma, and only establish that the upper limit of the phase 1 half-life is clearly less than 3-5 minutes.

[0093] Amitriptyline is structurally related to cyclobenzaprine but chemically differs from it due to the absence of a C10-C11 double bond in the central cycloheptyl ring. However, this change in chemical structure can affect the drug's action on normal or pathological tissues, as well as its absorption, disposal, metabolism, and excretion. Amitriptyline and its demethylated metabolite, nortriptyline, are the active ingredients in the tricyclic antidepressants (TCAs) Elavil® and Pamelor®, respectively. Amitriptyline, like cyclobenzaprine, is rapidly distributed from plasma. The pharmacokinetics of intravenous administration of cyclobenzaprine or amitriptyline, or amitriptyline alone, can be described by a two-compartment model containing a plasma "central" compartment and a "peripheral" compartment.

[0094] Neither cyclobenzaprine nor amitriptyline were useful for long-term treatment of fibromyalgia in any of the formulations tested; for example, currently available formulations were not effective for 6 months of treatment (Carette, S. Arthritis Rheum. 1994, January; Vol. 37 (No. 1): pp. 32-40). Cyclobenzaprine was not effective for treating fibromyalgia in a 12-week study (Bennett et al., Arthritis Rheum. Vol. 31: pp. 1535-1542 (1988)). In general, cyclobenzaprine is not recommended for long-term use. The inventors assumed that the side effects of fatigue, drowsiness, and a feeling of drowsiness outweighed the therapeutic effects of cyclobenzaprine or amitriptyline, but no known method was known to shorten the plasma half-life of either cyclobenzaprine or amitriptyline. Furthermore, the inventors have shown for the first time that the ineffectiveness of cyclobenzaprine may be due to its metabolism by the liver. It is known that amitriptyline is metabolized to nortriptyline, and a delay in the plasma half-life of nortriptyline has been reported (Bhatt, Biomed Chromatogr vol. 24 (no. 11): pp. 1247-1254 (2010)), but the mechanism by which nortriptyline accumulation can reduce the efficiency of amitriptyline during sleep as a long-term treatment was not understood.

[0095] Cyclobenzapurine is extensively metabolized and, in humans, is mainly excreted by the kidney as N+-glucuronide conjugates. Glucuronidation of the aliphatic tertiary amine group in the molecule produces quaternary ammonium-linked glucuronide metabolites (i.e., N+-glucuronide) (Hucker et al., Drug Metab Dispos Vol. 6: pp. 659-672 (1978), Hawes, Drug Metab Dispos Vol. 26: pp. 830-837 (1998)). Amitriptyline has recently been studied in more detail than cyclobenzaprine, and the enzyme UDP-glucuronosyl-transferase (UGT) UGT2B10 has been found to be a high-affinity component (Zhou et al., Drug Metab Dispos Vol. 38: pp. 863-870 (2010)). However, UGT1A4 is a low-affinity enzyme for glucuronidation in human liver microsomes (HLM) (Breyer-Pfaff et al., Drug Metab Dispos Vol. 25: pp. 340-345 (1997), Nakajima et al., Drug Metab Dispos Vol. 30: pp. 636-642 (2002)). Similarly, cyclobenzaprine is also metabolized to cyclobenzaprine-N+-glucuronide by UGT2B10, but it is highly likely that it is not metabolized to the same extent by UGT1A4.

[0096] Furthermore, cyclobenzaprine is N-demethylated to 3-(5H-dibenzo[a,d]cycloheptene-5-ylidene)-N-methyl-1-propanamine (norcyclobenzaprine) mainly by the liver enzymes P450 3A4 and 1A2 (Wong et al., J Anal Toxicol 19: pp. 218-224 (1995)). Amitriptyline is similarly converted to nortriptyline through P450-mediated N-demethylation. Nortriptyline resulted in significant percentage plasma amitriptyline and nortriptyline content in subjects who received amitriptyline as a single dose or over the long term, whereas norcyclobenzaprine has not been measured in human plasma except in cases of overdose (Hucker et al., Drug Metab Dispos Vol. 6: pp. 659-672 (1978), Wong et al., J Anal Toxicol Vol. 19: pp. 218-224 (1995)).

[0097] To date, several studies have been conducted and published showing that cyclobenzaprine, amitriptyline, and nortriptyline bind to various receptors in the central nervous system and peripheral tissues. The inventors have conducted a systematic analysis of the binding affinity of these molecules (cyclobenzaprine, amitriptyline, and nortriptyline) and norcyclobenzaprine (which had not been studied at all prior to the inventors' knowledge), and have determined the K2 binding affinity of these molecules to various receptors. iwas determined. The binding of cyclobenzaprine, norcyclobenzaprine, amitriptyline and nortriptyline to receptors was studied by the following methods: adrenergic alpha-2A (Langin et al., Eur J Pharmacol 167:95-104 (1989)), -2B and -2C receptors (Devedjian et al., Eur J Pharmacol 252:43-49 (1994)), histamine H1 receptor (Smit et al., Brit. J. Pharmacol 117:1071-1080 (1996)), muscarinic M1 and M2 receptors (Dorje et al., J Pharmacol Exp Ther 256:727-733 (1991)), and 5-HT1A (Mulheron et al., J<00035​​​​​​​​​​​​​​​​=0.44 μM and 1.22 μM) and alpha - 2A (IC 50 =4.3 μM and 6.4 μM) is a functional antagonist. In contrast, both cyclobenzaprine and norcyclobenzaprine are functional agonists for 5HT1a (EC 50 =5.3 μM and 3.2 μM). The antagonist activity of cyclobenzaprine against 5HT2b is consistent with the lack of relevance to heart valve pathology. Antagonists of 5HT2a and H - 1 are known to have effects on sleep and sleep maintenance. Adrenergic antagonists can have effects on autonomic dysfunction.

[0098] Without being bound by any theory, the inventors hypothesize that the main activity of cyclobenzaprine regarding its effects on fibromyalgia, PTSD, TBI, and sleep disruption is binding to 5 - HT2a. Plasma cyclobenzaprine and norcyclobenzaprine were measured over 168 hours in 10 fasted healthy subjects who received 5 mg of oral (PO) immediate - release cyclobenzaprine HCl. The oral bioavailability of cyclobenzaprine was similar to published results (C max =4.12 ng·mL -1 、t max =3.5 hours, AUC 0-∞ =103.1 ng·hr·mL -1 ), but plasma norcyclobenzaprine was unexpectedly high and persistent (C max =1.27 ng·mL -1 、t max =24.0 hours, AUC 0-∞ =169.5 ng·hr·mL -1 ). The inventors calculated the half - life of norcyclobenzaprine in human plasma for the first time after oral ingestion of a 5 mg cyclobenzaprine HCl immediate - release tablet (72.8 hours), which is significantly longer than the half - life of cyclobenzaprine (31.0 hours) in the same study.

[0099] Without adhering to any particular theory, the inventors hypothesize that the efficiency of long-term cyclobenzaprine treatment, with bedtime or once-daily use, where the therapeutic goal is to dynamically change cyclobenzaprine levels throughout the day, is impaired by the accumulation of norcyclobenzaprine. The accumulation of biologically active norcyclobenzaprine may affect the response to cyclobenzaprine treatment in long-term bedtime dosing regimens. Without adhering to any particular theory, the inventors hypothesize that long-term occupancy of 5-HT2A and other receptors allows for the adaptation of various mechanisms that control the flexibility of neuronal signaling and responsiveness. The inventors hypothesize that norcyclobenzaprine, with a K2 of 13.2 nM relative to 5-HT2A, i It contains cyclobenzaprine with a K content of 5.1 nM relative to 5HT2A. i We found that norcyclobenzaprine has a binding ratio of 16 nM to 5-HT2A, which indicates that nortriptyline competes with cyclobenzaprine for binding to 5-HT2A. Similarly, nortriptyline has a binding ratio of 16 nM to 5-HT2A. i It has amitriptyline at a concentration of 2.5 nM relative to 5-HT2A. iThis indicates that nortriptyline competes with amitriptyline for binding to 5-HT2A. Cyclobenzaprine and amitriptyline are 5-HT2A conjugates with higher binding affinity than norcyclobenzaprine and nortriptyline, but the concentrations of norcyclobenzaprine and nortriptyline are significantly higher, especially with continuous administration on a once-daily schedule, due to their longer half-lives and accumulation. By administering cyclobenzaprine or amitriptyline for transmucosal absorption, cyclobenzaprine or amitriptyline avoid first-pass metabolism in the liver, thereby reducing or eliminating the formation of norcyclobenzaprine or nortriptyline by p450 metabolism in the intestine and liver, respectively. Therefore, cyclobenzaprine and amitriptyline can be effectively administered over longer treatment regimens than currently available, without the accumulation of demethylated metabolites. While not adhering to any particular theory, the inventors hypothesize that the long half-lives of norcyclobenzaprine and nortriptyline are due to the instability of norcyclobenzaprine-N+-glucuronide and nortriptyline (observed by the inventors in attempts to synthesize norcyclobenzaprine-N+-glucuronide), possibly because human enzymes, including UDP-glucuronosyl-transferase (UGT) UGT2B10 and UGT1A4, are unable to form -N+-glucuronide metabolites that can be excreted by the kidneys. Since norcyclobenzaprine has not been measured in animal plasma after therapeutic administration, and the long half-life of norcyclobenzaprine is not previously known, and since norcyclobenzaprine is known not to bind to 5-HT2A or other receptors in the CNS and peripheral tissues, the benefit of transmucosal administration, which reduces norcyclobenzaprine and increases the potential therapeutic potential of cyclobenzaprine, was surprising and novel. In contrast, it is well known that nortriptyline has a long half-life after ingestion of either amitriptyline or nortriptyline, and the long half-life of nortriptyline in plasma and at the site of action appears to be an advantage in the treatment of depression and major depressive disorder. Table 1: Binding affinity of cyclobenzaprine, norcyclobenzaprine, amitriptyline, and nortriptyline to various receptors [Table 1] Pharmacokinetic properties

[0100] Transmucosal absorption of compounds useful in the compositions and methods of the present invention offers several beneficial effects on the pharmacokinetic properties of the compounds, in addition to the advantage of avoiding the formation of norcyclobenzaprine. Transmucosal delivery allows the compounds of the present invention to be absorbed more rapidly than when administered orally, resulting in a shorter time to reach therapeutic concentrations of cyclobenzaprine or amitriptyline in plasma. In some embodiments, the compositions of the present invention can achieve therapeutic concentrations of cyclobenzaprine or amitriptyline in plasma in 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 present invention can achieve high concentrations of cyclobenzaprine or amitriptyline in plasma within 3.3 hours, within 3 hours, within 2.5 hours, within 2 hours, within 1 hour, within 45 minutes, within 30 minutes, or within 20 minutes compared to oral administration. In some embodiments, the compositions of the present invention yield high AUCs of cyclobenzaprine or amitriptyline in plasma at 0-3.3 hours, 0-3 hours, 0-2.5 hours, 0-2 hours, 0-1 hour, 0-45 minutes, 0-30 minutes, or 0-20 minutes compared to oral administration. In some embodiments, the compositions of the present invention yield high dose-normalized concentrations (dnC) of cyclobenzaprine or amitriptyline in plasma compared to oral administration. * ) is obtained within 3.3 hours, 3 hours, 2.5 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, or 20 minutes. In some embodiments, the compositions of the present invention provide a higher dose-normalized AUC (dnAUC) of cyclobenzaprine or amitriptyline in plasma compared to oral administration. *) is obtained at 0-3.3 hours, 0-3 hours, 0-2.5 hours, 0-2 hours, 0-1 hour, 0-45 minutes, 0-30 minutes, or 0-20 minutes. By transmucosal delivery, the compounds of the present invention are absorbed more rapidly than when administered orally, resulting in the maximum concentration or t max The time to reach the target is shortened. In some embodiments, the compositions of the present invention have a time 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 for cyclobenzaprine or amitriptyline t max In some embodiments, the compositions of the present invention provide cyclobenzaprine or amitriptyline for 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. max It brings about.

[0101] Furthermore, transmucosal absorption yields higher plasma concentrations of compounds compared to oral administration. Plasma concentration can be the individual plasma concentration when observing multiple individuals, or the mean plasma concentration. The higher plasma concentration obtained by transmucosal absorption can be determined by measuring the plasma concentration of the administered compound, or by calculating the ratio of plasma concentration to the administered dose, which is known as dose-normalized plasma concentration (C) or dnC. * and mL -1 Measured at dnC. * This is calculated by determining the ratio of plasma level to administered dose. For example, if cyclobenzaprine or amitriptyline 2.4 mg is administered and the plasma level is 2.4 ng / mL at 3 hours, then dnC at 3 hours is calculated. * ((2.4 ng / mL) / (2.4 mg)) = 1.0 × 10 -6 mL -1 dnC * This can be either a fixed point in time or a variable point in time, for example, C maxIt can be measured at the time corresponding thereto. The dose-normalized concentration of cyclobenzaprine in plasma after ingestion of 5 mg of immediate-release cyclobenzaprine, i.e., the dnC of cyclobenzaprine * is 〈0.00〉 at 20 minutes and 〈1.95×10 -9 mL -1 〉 at 45 minutes and 〈19.31×10 -9 mL -1 〉 at 1 hour and 〈50.00×10 -9 mL -1 〉 at 2 hours and 〈378.65×10 -9 mL -1 〉 at 2.5 hours (150 minutes) and 〈510.94×10 -9 mL -1 〉 at 3 hours and 〈625.29×10 -9 mL -1 ×10 -9 mL -1 〉 at 3.3 hours (200 minutes) and 〈698.49×10 -9 mL -1 〉 at 3.67 hours (220 minutes) and 〈818.31×10 -9 mL -1 〉 at 4 hours and 〈848.33×10 -9 mL -1 〉 at 4.33 hours (260 minutes) and 〈968.09×10 -9 mL -1 〉 at 4.67 hours (280 minutes) and 〈933.95×10 -9 mL -1 〉 at 5 hours and 〈932.86×10 -9 mL -1 〉 at 5.5 hours (330 minutes) and 〈920.94×10 -9 mL -1 〉 at 6 hours and 〈953.40×10 -9 mL -1 〉 at 8 hours and 〈801.23×10 -9 mL -1 〉 at 12 hours and 〈516.73×10 -9 mL -1 〉 at 16 hours and 〈347.39×10 -9 mL-1 Therefore, in 24 hours, 320.44 × 10 -9 mL -1 Therefore, over 36 hours, 233.66 × 10 -9 mL -1 Therefore, in 48 hours, 199.41 × 10 -9 mL -1 The value was 136.80 after 72 hours. This represents the dose-normalized plasma concentration of cyclobenzaprine, i.e., dnC of cyclobenzaprine, after sublingual ingestion of 2.4 mg of cyclobenzaprine and phosphate. * In 20 minutes, 157.60 × 10 -9 mL -1 And, in 30 minutes, 301.60 × 10 -9 mL -1 And, in 45 minutes, 432.58 × 10 -9 mL -1 Therefore, in one hour, 598.85 × 10 -9 mL -1 Therefore, over 2 hours, 683.58 × 10 -9 mL -1 Therefore, in 2.5 hours (150 minutes), 727.67 × 10 -9 mL -1 Therefore, over 3 hours, 840.33 × 10 -9 mL -1 ×10 -9 mL -1 Therefore, in 3.3 hours (200 minutes), 923.58 × 10 -9 mL -1 Therefore, in 3.67 hours (220 minutes), 952.71 × 10 -9 mL -1 Therefore, in 4 hours, 10¹² × 10¹² -9 mL -1 Therefore, in 4.33 hours (260 minutes), 1030.10 × 10 -9 mL -1 Therefore, in 4.67 hours (280 minutes), 1038.58 × 10 -9 mL -1 Therefore, in 5 hours, 990.90 × 10 -9 mL -1 Therefore, in 5.5 hours (330 minutes), 1046.42 × 10-9 mL -1 Therefore, over 6 hours, 911.07 × 10 -9 mL -1 Therefore, over 8 hours, 696.33 × 10 -9 mL -1 Therefore, in 12 hours, 504.90 × 10 -9 mL -1 Therefore, over 16 hours, 354.04 × 10 -9 mL -1 Therefore, in 24 hours, 294.40 × 10 -9 mL -1 Therefore, over 36 hours, 184.19 × 10 -9 mL -1 Therefore, over 48 hours, 143.37 × 10 -9 mL -1 It was 88.23 over 72 hours. For example, dnC * This can be measured 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours after administration. For example, dnC * The value is approximately 8.0 ± 25% × 10 -7 mL -1 , about 0.001±25%×10 -6 mL -1 , about 0.01±25%×10 -6 mL -1 , about 0.05±25%×10 -6 mL -1 , about 0.1±25%×10 -6 mL -1 , about 0.5±25%×10 -6 mL -1 , about 1.0±25%×10 -6 mL -1 , about 5.0±25%×10 -6 mL -1 , about 10.0±25%×10 -6 mL -1 , approx. 50.0±25%×10 -6 mL -1, or approximately 100.0 ± 25% × 10 -6 mL -1 , about 125.0±25%×10 -6 mL -1 , about 150.0±25%×10 -6 mL -1 , about 175.0±25%×10 -6 mL -1 , about 200.0±25%×10 -6 mL -1 , about 300.0±25%×10 -6 mL -1 , about 400.0±25%×10 -6 mL -1 , about 500.0±25%×10 -6 mL -1 , about 600.0±25%×10 -6 mL -1 , or approximately 700.0 ± 25% × 10 -6 mL -1 It may be, or it may exceed these values. For example, dnC * The value is approximately 50 ± 25% × 10 minutes after administration. -9 mL -1 In summary, approximately 125 ± 25% × 10 times was observed 15 minutes after administration. -9 mL -1 In summary, approximately 150 ± 25% × 10 20 minutes after administration. -9 mL -1 In summary, approximately 300 ± 25% × 10 30 minutes after administration. -9 mL -1 In summary, approximately 450 ± 25% × 10 after administration. -9 mL -1 In summary, approximately 600 ± 25% × 10¹⁰ was observed 1 hour after administration. -9 mL -1 In summary, approximately 700 ± 25% × 10 times was observed 2 hours after administration. -9 mL -1 In summary, approximately 750 ± 25% × 10 times was observed 2.5 hours after administration. -9 mL -1 In summary, approximately 850 ± 25% × 10 times was observed 3 hours after administration. -9 mL -1 In summary, approximately 900 ± 25% × 10 times was observed 3.3 hours after administration. -9 mL -1 In summary, approximately 950 ± 25% × 10¹⁰ was observed 3.7 hours after administration.-9 mL -1 In summary, approximately 1000 ± 25% × 10 times was observed 4 hours after administration. -9 mL -1 In summary, approximately 1050 ± 25% × 10 was observed 4.33 hours after administration. -9 mL -1 In summary, approximately 1050 ± 25% × 10¹⁰ was observed 4.67 hours after administration. -9 mL -1 In summary, approximately 1000 ± 25% × 10 times was observed 5 hours after administration. -9 mL -1 Below, approximately 1000 ± 25% × 10 times 5.5 hours after administration. -9 mL -1 Below, approximately 900 ± 25% × 10 times 6 hours after administration. -9 mL -1 Below, approximately 700 ± 25% × 10 times 8 hours after administration. -9 mL -1 Below, approximately 650 ± 25% × 10 times after administration. -9 mL -1 Below, approximately 500 ± 25% × 10 12 hours after administration. -9 mL -1 Below, approximately 400 ± 25% × 10 times 14 hours after administration. -9 mL -1 Below, approximately 350 ± 25% × 10 times 16 hours after administration. -9 mL -1 Below, approximately 340 ± 25% × 10 times 18 hours after administration. -9 mL -1 Below, approximately 320 ± 25% × 10 times 20 hours after administration. -9 mL -1 Below, approximately 310 ± 25% × 10 times 22 hours after administration. -9 mL -1 Below, approximately 300 ± 25% × 10 24 hours after administration. -9 mL -1 Below, approximately 180 ± 25% × 10 times 36 hours after administration. -9 mL -1 Below, approximately 140 ± 25% × 10 times 48 hours after administration. -9 mL -1 The following, or approximately 90±25% × 10 times 72 hours after administration. -9 mL -1 The following may also apply. In some embodiments, dnC *This can be measured 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or 36 hours after administration. For example, dnC * The value is approximately 1.0 ± 25% × 10 -9 mL -1 , about 1.0±25%×10 -8 mL -1 , about 0.7±25%×10 -7 mL -1 , about 1.0±25%×10 -7 mL -1 , about 2.0±25%×10 -7 mL -1 , about 3.0±25%×10 -7 mL -1 , about 4.0±25%×10 -7 mL -1 , about 5.0±25%×10 -7 mL -1 , about 1.0±25%×10 -6 mL -1 , or approximately 5.0 ± 25% × 10 -6 mL -1 It may be or may be less than these values. In some embodiments, dnC * The values ​​may relate to a single dose. In some embodiments, dnC * The values ​​may relate to multi-dose regimens (e.g., consecutive doses once daily). In some embodiments, dnC * The plasma concentration used to calculate this can be adjusted to reflect the baseline plasma concentration (e.g., baseline plasma level from a single daily dose). max This is defined as the peak plasma concentration of the compound of the present invention after administration. Alternatively, dnC * The value is C max Calculated at the corresponding point in time. In this case, dose normalization C max or dnCmax * It can also be called dnC. max * is 1.0±25%×10 -6 mL -1 The above is 1.5±25%×10 -6 mL -1 The above is 2.0±25%×10 -6 mL -1 The above is 2.5±25%×10 -6 mL -1 The above is 3.0±25%×10 -6 mL -1 The above is 3.5±25%×10 -6 mL -1 The above is 4.0±25%×10 -6 mL -1 The above is 4.5±25%×10 -6 mL -1 The above is 5.0±25%×10 -6 mL -1 That's all.

[0102] Furthermore, transmucosal absorption yields higher plasma concentrations of compounds compared to oral administration. Plasma concentration can be the individual plasma concentration when observing multiple individuals or the average plasma concentration. The higher plasma concentration obtained by transmucosal absorption can be determined by measuring the plasma concentration of the administered compound, or by measuring the plasma concentration of the administered compound. * This can be determined by calculating the ratio of the body mass product to the administered dose, which is the dose- and body mass-normalized plasma concentration (C) or dbmnC. * It is, kg·mL -1 Measured at dbmnC * This is calculated by determining the ratio of the product of plasma level × body mass to the administered dose. For example, if cyclobenzaprine or amitriptyline 2.4 mg is administered to a 70 kg animal and the plasma level is 4.8 ng / mL at 15 minutes, then the dbmnC at 15 minutes is... * ((4.8 ng / mL) × (70 kg) / (2.4 mg)) = dbmnC (0.25h) * = 140.0 × 10 -6 kg·mL-1 dbmnC * This can be either a fixed point in time or a variable point in time, for example, C max It can be measured at the corresponding point in time. For example, dbmnC * This can be measured 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours after administration. For example, dbmnC * The value is approximately 80.0 ± 25% × 10 -7 kg·mL -1 , about 0.01±25%×10 -6 kg·mL -1 , about 0.1±25%×10 -6 kg·mL -1 , about 0.5±25%×10 -6 kg·mL -1 , about 1.0±25%×10 -6 kg·mL -1 , about 5.0±25%×10 -6 kg·mL -1 , about 10.0±25%×10 -6 kg·mL -1 , approx. 50.0±25%×10 -6 kg·mL -1 , about 100.0±25%×10 -6 kg·mL -1 , about 500.0±25%×10 -6 kg·mL -1 , or approximately 1000.0 ± 25% × 10 -6 kg·mL -1 , about 1250.0±25%×10 -6 kg·mL -1 , about 1500.0±25%×10 -6 kg·mL -1 , about 1750.0±25%×10 -6 kg·mL -1 , about 2000.0±25%×10 -6 kg·mL -1 , about 3000.0±25%×10 -6 kg·mL-1 , about 4000.0±25%×10 -6 kg·mL -1 , about 5000.0±25%×10 -6 kg·mL -1 , about 6000.0±25%×10 -6 kg·mL -1 , or approximately 7000.0 ± 25% × 10 -6 kg·mL -1 It may be, or it may exceed these values. In some embodiments, dbmnC * This can be measured 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or 36 hours after administration. For example, dbmnC * The value is approximately 1.0 ± 25% × 10 -9 mL -1 , about 1.0±25%×10 -8 mL -1 , about 0.7±25%×10 -7 mL -1 , about 1.0±25%×10 -7 mL -1 , about 2.0±25%×10 -7 mL -1 , about 3.0±25%×10 -7 mL -1 , about 4.0±25%×10 -7 mL -1 , about 5.0±25%×10 -7 mL -1 , about 1.0±25%×10 -6 mL -1 , or approximately 5.0 ± 25% × 10 -6 mL -1 It may be or may be less than these values. In some embodiments, dbmnC * The values ​​may relate to a single dose. In some embodiments, dbmnC * The values ​​may relate to multi-dose regimens (e.g., once daily consecutive doses). In some embodiments, dbmnC* The plasma concentration used to calculate this can be adjusted to reflect the baseline plasma concentration (e.g., baseline plasma level from a single daily dose). max This is defined as the peak plasma concentration of the compound of the present invention after administration. Alternatively, dbmnC * The value is C max When calculated at the corresponding time point, the dose and body mass normalization C max or dbmnC max * It can also be called dbmnC. max * is 10.0±25%×10 -6 kg·mL -1 The above is 15±25%×10 -6 kg·mL -1 The above is 20±25%×10 -6 kg·mL -1 The above is 25±25%×10 -6 kg·mL -1 The above is 30±25%×10 -6 kg·mL -1 The above is 35±25%×10 -6 kg·mL -1 The above is 40±25%×10 -6 kg·mL -1 The above is 45±25%×10 -6 kg·mL -1 The above is 50±25%×10 -6 kg·mL -1 That concludes the explanation. In some embodiments, dbmnC max * is 100.0±25%×10 -6 kg·mL -1 The above is 150±25%×10 -6 kg·mL -1 The above is 200±25%×10 -6 kg·mL -1 The above is 250±25%×10 -6 kg·kg·mL -1 The above is 300±25%×10 -6 mL -1 The above is 350±25%×10 -6 kg·mL-1 The above is 400±25%×10 -6 kg·mL -1 The above is 450±25%×10 -6 kg·mL -1 The above is 500±25%×10 -6 kg·mL -1 That's all.

[0103] As mentioned above, C max C is defined as the peak plasma concentration of the compound of the present invention after administration. By administering the composition of the present invention for transmucosal absorption, a higher C concentration is achieved compared to when the composition is administered orally. max It is possible to obtain values ​​of 10 ng / mL or more, 11 ng / mL or more, 12 ng / mL or more, 13 ng / mL or more, 14 ng / mL or more, 15 ng / mL or more, 16 ng / mL or more, 17 ng / mL or more, 18 ng / mL or more, 19 ng / mL or more, 20 ng / mL or more, 21 ng / mL or more, 22 ng / mL or more, 23 ng / mL or more, 24 ng / mL or more, 25 ng / mL or more, 26 ng / mL or more, 27 ng / mL or more, 28 ng / mL or more, 29 ng / mL or more, and 30 ng / mL or more. Above, C of compounds with a C content of 31 ng / mL or higher, 32 ng / mL or higher, 33 ng / mL or higher, 34 ng / mL or higher, 35 ng / mL or higher, 36 ng / mL or higher, 37 ng / mL or higher, 38 ng / mL or higher, 39 ng / mL or higher, 40 ng / mL or higher, 50 ng / mL or higher, 60 ng / mL or higher, 70 ng / mL or higher, 80 ng / mL or higher, 90 ng / mL or higher, 100 ng / mL or higher, 120 ng / mL or higher, 140 ng / mL or higher, 160 ng / mL or higher, 180 ng / mL or higher, or 200 ng / mL or higher. max It brings about.

[0104] C maxThis can be measured after administering either the initial dose or any dose of the composition of the present invention. However, since the compositions and methods of the present invention can be used to extend a treatment regimen, the plasma levels of compounds useful in the compositions and methods will not return to zero between doses (i.e., baseline levels of the compounds may exist in the blood circulation). Therefore, the compositions are not considered absolute values ​​compared to a starting plasma concentration of 0 ng / mL, but rather C levels that can be compared to the baseline level of the compounds. max In some embodiments, the composition can bring about baseline levels (e.g., plasma concentrations) of the compound measured immediately before the second administration, which are 10 ng / mL or higher, 11 ng / mL or higher, 12 ng / mL or higher, 13 ng / mL or higher, 14 ng / mL or higher, 15 ng / mL or higher, 16 ng / mL or higher, 17 ng / mL or higher, 18 ng / mL or higher, 19 ng / mL or higher, 20 ng / mL or higher, 21 ng / mL or higher, 22 ng / mL or higher, 23 ng / mL or higher, 24 ng / mL or higher, 25 ng / mL or higher, 26 ng / mL or higher, 27 ng / mL or higher, 28 ng / mL or higher, and 2 Compounds with a C content exceeding 9 ng / mL, 30 ng / mL, 31 ng / mL, 32 ng / mL, 33 ng / mL, 34 ng / mL, 35 ng / mL, 36 ng / mL, 37 ng / mL, 38 ng / mL, 39 ng / mL, 40 ng / mL, 50 ng / mL, 60 ng / mL, 70 ng / mL, 80 ng / mL, 90 ng / mL, 100 ng / mL, 120 ng / mL, 140 ng / mL, 160 ng / mL, 180 ng / mL, or 200 ng / mL or more max This results in the following. As used herein, “immediately before administration” means within 1 hour, 45 minutes, 30 minutes, 15 minutes, 10 minutes, 5 minutes, or 1 minute prior to administration.

[0105] Higher C achieved through sublingual administration max As a result of the values, the area under the curve (AUC) of the plasma concentration of the compound is also larger over time compared to the AUC obtained by oral administration. The AUC is between two specific time points (e.g., AUC 0-8h) or over the extrapolation period from 0 to infinity (AUC 0-∞h AUC 0-∞ or AUC inf ) can be measured. AUC is typically ng·hr·mL -1 It is expressed in units of AUC, and therefore, for example, in the experiment in Figure 1 with human subjects administered 5 mg of immediate-release cyclobenzaprine tablets, AUC 0-∞h The value is 103.1 ± 35.8 ng·hr·mL -1 It was determined that AUC 0-168h The value is 92.2 ± 29.9 ng·hr·mL -1 As another example, in experiments with beagles, administration of 2.4 mg of cyclobenzaprine sublingual tablets with a basicizing agent resulted in 135.6 ng·hr·mL in 0-0.75 hours. -1 AUC 0-0.75h The following was obtained. In the same experiment, the AUC of sublingual tablets containing a basicizing agent was obtained. 0-∞h The value is 179.0 ± 50.2 ng·hr·mL -1 And, AUC 0-10h The value is 176.6 ± 49.9 ng·hr·mL -1 In the Beagle experiment on a 2.4 mg sublingual tablet lacking a basicizing agent, the AUC was 0-0.75h is 82.4 ng·hr·mL -1 And, AUC 0-∞h The value is 155.4 ± 64.6 ng·hr·mL -1 And, AUC 0-10h The value is 151.6 ± 64.0 ng·hr·mL -1 In the Beagle experiment (Figures 2 and 3) for an average dose of 1.79 mg of iv-cyclobenzaprine, the AUC was 0-∞h The value is 44.9 ± 4.15 ng·hr·mL -1 And, AUC 0-24h The value is 43.5 ± 3.77 ng·hr·mL -1 In the Beagle experiment (Figures 2 and 3) for sublingual cyclobenzaprine at an average dose of 1.79 mg, the AUC was 0-∞h The value is 129.1 ± 36.4 ng·hr·mL -1 And, AUC 0-24h The value is 126.9 ± 37.1 ng·hr·mL -1In contrast, literature studies have shown that when cyclobenzaprine immediate-release tablets at doses of 2.5, 5.0, or 10 mg (10 mg in a 70 kg human is equivalent to 0.14 mg / kg in a beagle) are administered to humans, the levels are 11.1, 23.0, and 45.9 ng·hr·mL, respectively. -1 AUC 0-8h The results were 44.2, 89.5, and 178.2 ng·hr·mL, respectively. -1 AUC 0-∞h This was obtained (Winchell GA et al., "Cyclobenzaprine pharmacokinetics, including the effects of age, gender and hepatic insufficiency," J. Clin. Pharmacol 2002, Vol. 42: p. 61). In some embodiments, for example, at a dose of 2.4 mg, AUC 0-20min Approximately 0.04 ng·hr·mL -1 And, AUC 0-30min Approximately 0.13 ng·hr·mL -1 And, AUC 0-45min Approximately 0.33 ng·hr·mL -1 And, AUC 0-1h Approximately 0.61 ng·hr·mL -1 And, AUC 0-2h Approximately 2.10 ng·hr·mL -1 And, AUC 0-2.5h Approximately 2.95 ng·hr·mL -1 And, AUC 0-3h Approximately 3.93 ng·hr·mL -1 And, AUC 0-3.3h Approximately 4.66 ng·hr·mL -1 And, AUC 0-3.7h Approximately 5.46 ng·hr·mL -1 And, AUC 0-4h Approximately 6.27 ng·hr·mL -1 And, AUC 0-4.3h Approximately 7.12 ng·hr·mL -1 And, AUC 0-4.7h Approximately 7.99 ng·hr·mL -1 And, AUC 0-0-5h Approximately 8.81 ng·hr·mL-1 And, AUC 0-5.5h Approximately 10.06 ng·hr·mL -1 And, AUC 0-6h Approximately 11.27 ng·hr·mL -1 And, AUC 0-8h Approximately 15.11 ng·hr·mL -1 And, AUC 0-12h Approximately 50.30 ng·hr·mL -1 And, AUC 0-Inf Approximately 60.97 ng·hr·mL -1 In some embodiments (using TNX-102 SL 2.8), AUC 0-20min Approximately 0.04 ng·hr·mL -1 And, AUC 0-30min Approximately 0.15 ng·hr·mL -1 And, AUC 0-45min Approximately 0.39 ng·hr·mL -1 And, AUC 0-1h Approximately 0.72 ng·hr·mL -1 And, AUC 0-2h Approximately 2.45 ng·hr·mL -1 And, AUC 0-2.5h Approximately 3.45 ng·hr·mL -1 And, AUC 0-3h Approximately 4.59 ng·hr·mL -1 And, AUC 0-3.3h Approximately 5.44 ng·hr·mL -1 And, AUC 0-3.7h Approximately 6.37 ng·hr·mL -1 And, AUC 0-4h Approximately 7.32 ng·hr·mL -1 And, AUC 0-4.3h Approximately 8.30 ng·hr·mL -1 And, AUC 0-4.7h Approximately 9.32 ng·hr·mL -1 And, AUC 0-0-5h Approximately 10.27 ng·hr·mL -1 And, AUC 0-5.5h Approximately 11.74 ng·hr·mL -1 And, AUC 0-6h Approximately 13.14 ng·hr·mL -1 And, AUC0-8h Approximately 17.63 ng·hr·mL -1 And, AUC 0-12h Approximately 58.68 ng·hr·mL -1 And, AUC 0-Inf Approximately 71.13 ng·hr·mL -1 Furthermore, by comparing the AUC to the administered dose, a ratio of AUC to dose can be generated, which is sometimes called dose-normalized AUC or dnAUC. The dose-normalized dnAUC for the human data in Figure 1 above. 0-∞h is 20.6 × 10 -6 hr·mL -1 This is the dose-normalized AUC for the aforementioned Beagle data. 0-0.75h (dnAUC 0-0.75h ) is dnAUC 0-0.75h = 135.6 6 ng·hr·mL -1 / 2.4mg = 56.5 × 10 -6 hr·mL -1 In the Beagle experiment (Figures 2 and 3) for an average dose of 1.79 mg of IV cyclobenzaprine, dnAUC was observed. 0-∞h is 25.04 × 10 -6 hr·mL -1 And dnAUC 0-24h is 24.2 × 10 -6 hr·mL -1 In the Beagle experiment (Figures 2 and 3) for a sublingual cyclobenzaprine solution with an average dose of 1.79 mg, dnAUC was observed. 0-∞h is 71.95 × 10 -6 hr·mL -1 And dnAUC 0-24h is 70.72 × 10 -6 hr·mL -1 This was the case. The dose-normalized AUC for the aforementioned human data (by Winchell et al.) 0-8h (dnAUC 0-8h ) corresponds to 4.4 × 10 for cyclobenzaprine doses of 2.5, 5.0, and 10 mg, respectively. -6 hr·mL -1 , 4.6×10 -6 hr·mL -1 and 4.6 × 10 -6 hr·mL -1This is the dose-normalized dnAUC for the aforementioned human data (by Winchell et al.). 0-∞h This is 17.7 × 10 for cyclobenzaprine doses of 2.5, 5.0, and 10 mg, respectively. -6 hr·mL -1 , 17.9×10 -6 hr·mL -1 and 17.8×10 -6 hr·mL -1 In some embodiments, dnAUC 0-20min Approximately 0.02 ± 25% × 10 -6 hr·mL -1 And dnAUC 0-30min Approximately 0.05 ± 25% × 10 -6 hr·mL -1 And dnAUC 0-45min Approximately 0.15 ± 25% × 10 -6 hr·mL -1 And dnAUC 0-1h Approximately 0.25 ± 25% × 10 -6 hr·mL -1 And dnAUC 0-2h Approximately 0.90 ± 25% × 10 -6 hr·mL -1 And dnAUC 0-2.5h Approximately 1.2 ± 25% × 10 -6 hr·mL -1 And dnAUC 0-3h Approximately 1.6 ± 25% × 10 -6 hr·mL -1 And dnAUC 3.3h Approximately 1.8 ± 25% × 10 -6 hr·mL -1 And dnAUC 0-3.7h Approximately 2.3 ± 25% × 10 -6 hr·mL -1 And dnAUC 0-4h Approximately 2.6 ± 25% × 10 -6 hr·mL -1 And dnAUC 0-4.3h Approximately 3.0 ± 25% × 10 -6 hr·mL -1 And dnAUC 0-4.7h Approximately 3.3 ± 25% × 10 -6 hr·mL-1 And dnAUC 0-5h Approximately 3.7 ± 25% × 10 -6 hr·mL -1 And dnAUC 0-5.5h Approximately 4.2 ± 25% × 10 -6 hr·mL -1 And dnAUC 0-6h Approximately 4.7 ± 25% × 10 -6 hr·mL -1 And dnAUC 0-8h is 6.3±25%×10 -6 hr·mL -1 And dnAUC 0-12h Approximately 20±25% × 10 -6 hr·mL -1 And dnAUC 0-∞h Approximately 25 ± 25% × 10 -6 hr·mL -1 In some embodiments, dnAUC 0-8h is 5±25%×10 -6 hr·mL -1 The above is 6±25%×10 -6 hr·mL -1 The above is 7±25%×10 -6 hr·mL -1 The above is 8±25%×10 -6 hr·mL -1 The above is 9±25%×10 -6 hr·mL -1 The above is 10±25%×10 -6 hr·mL -1 The above is 11±25%×10 -6 hr·mL -1 The above is 12±25%×10 -6 hr·mL -1 The above is 13±25%×10 -6 hr·mL -1 The above is 14±25%×10 -6 hr·mL -1 The above is 15±25%×10 -6 hr·mL -1 The above is 16±25%×10 -6 hr·mL -1 The above is 17±25%×10 -6 hr·mL -1The above is 18±25%×10 -6 hr·mL -1 The above, or 19±25%×10 -6 hr·mL -1 That concludes the explanation. In some embodiments, dnAUC 0-8h is 20±25%×10 -6 hr·mL -1 The above is 22±25%×10 -6 hr·mL -1 The above is 24±25%×10 -6 hr·mL -1 The above is 26±25%×10 -6 hr·mL -1 The above is 28±25%×10 -6 hr·mL -1 The above, or 30±25%×10 -6 hr·mL -1 That concludes the explanation. In some embodiments, dnAUC 0-8h is 40±25%×10 -6 hr·mL -1 The above is 50±25%×10 -6 hr·mL -1 The above is 60±25%×10 -6 hr·mL -1 The above is 70±25%×10 -6 hr·mL -1 The above is 80±25%×10 -6 hr·mL -1 The above, or 90±25% × 10 -6 hr·mL -1 That concludes the explanation. In some embodiments, dnAUC 0-8h is 100±25%×10 -6 hr·mL -1 The above is 120±25%×10 -6 hr·mL -1 The above is 140±25%×10 -6 hr·mL -1 The above is 160±25%×10 -6 hr·mL -1 The above is 180±25%×10 -6 hr·mL -1 The above, or 200±25%×10 -6 hr·mL -1That concludes the explanation. In some embodiments, dnAUC 0-10h is 5±25%×10 -6 hr·mL -1 The above is 6±25%×10 -6 hr·mL -1 The above is 7±25%×10 -6 hr·mL -1 The above is 8±25%×10 -6 hr·mL -1 The above is 9±25%×10 -6 hr·mL -1 The above is 10±25%×10 -6 hr·mL -1 The above is 11±25%×10 -6 hr·mL -1 The above is 12±25%×10 -6 hr·mL -1 The above is 13±25%×10 -6 hr·mL -1 The above is 14±25%×10 -6 hr·mL -1 The above is 15±25%×10 -6 hr·mL -1 The above is 16±25%×10 -6 hr·mL -1 The above is 17±25%×10 -6 hr·mL -1 The above is 18±25%×10 -6 hr·mL -1 The above, or 19±25%×10 -6 hr·mL -1 That concludes the explanation. In some embodiments, dnAUC 0-10h is 20±25%×10 -6 hr·mL -1 The above is 22±25%×10 -6 hr·mL -1 The above is 24±25%×10 -6 hr·mL -1 The above is 26±25%×10 -6 hr·mL -1 The above is 28±25%×10 -6 hr·mL -1 The above, or 30±25%×10 -6 hr·mL -1 That concludes the explanation. In some embodiments, dnAUC0-10h is 40±25%×10 -6 hr·mL -1 The above is 50±25%×10 -6 hr·mL -1 The above is 60±25%×10 -6 hr·mL -1 The above is 70±25%×10 -6 hr·mL -1 The above is 80±25%×10 -6 hr·mL -1 The above, or 90±25% × 10 -6 hr·mL -1 That concludes the explanation. In some embodiments, dnAUC 0-10h is 100±25%×10 -6 hr·mL -1 The above is 120±25%×10 -6 hr·mL -1 The above is 140±25%×10 -6 hr·mL -1 The above is 160±25%×10 -6 hr·mL -1 The above is 180±25%×10 -6 hr·mL -1 The above, or 200±25%×10 -6 hr·mL -1 That concludes the explanation. In some embodiments, dnAUC 0-12h is 20±25%×10 -6 hr·mL -1 The above is 30±25%×10 -6 hr·mL -1 The above is 40±25%×10 -6 hr·mL -1 The above is 50±25%×10 -6 hr·mL -1 The above is 60±25%×10 -6 hr·mL -1 The above, or 70±25% × 10 -6 hr·mL -1 That concludes the explanation. In some embodiments, dnAUC 0-12h is 80±25%×10 -6 hr·mL -1 The above is 90±25%×10 -6 hr·mL -1The above is 100±25%×10 -6 hr·mL -1 The above is 120±25%×10 -6 hr·mL -1 The above is 160±25%×10 -6 hr·mL -1 The above, or 180±25%×10 -6 hr·mL -1 That concludes the explanation. In some embodiments, dnAUC 0-24h is 24±25%×10 -6 hr·mL -1 The above, or 25±25%×10 -6 hr·mL -1 The above is 30±25%×10 -6 hr·mL -1 The above is 35±25%×10 -6 hr·mL -1 The above is 40±25%×10 -6 hr·mL -1 The above is 50±25%×10 -6 hr·mL -1 The above is 60±25%×10 -6 hr·mL -1 The above is 70±25%×10 -6 hr·mL -1 The above is 80±25%×10 -6 hr·mL -1 The above, or 90±25% × 10 -6 hr·mL -1 That concludes the explanation. In some embodiments, dnAUC 0-24h is 100±25%×10 -6 hr·mL -1 The above is 110±25%×10 -6 hr·mL -1 The above is 120±25%×10 -6 hr·mL -1 The above is 130±25%×10 -6 hr·mL -1 The above is 140±25%×10 -6 hr·mL -1 The above, or 150±25%×10 -6 hr·mL -1 That concludes the explanation. In some embodiments, dnAUC 0-24h is 160±25%×10-6 hr·mL -1 The above is 170±25%×10 -6 hr·mL -1 The above is 180±25%×10 -6 hr·mL -1 The above is 190±25%×10 -6 hr·mL -1 The above is 200±25%×10 -6 hr·mL -1 The above, or 210±25%×10 -6 hr·mL -1 That concludes the explanation. In some embodiments, dnAUC 0-24h is 220±25%×10 -6 hr·mL -1 The above is 240±25%×10 -6 hr·mL -1 The above is 250±25%×10 -6 hr·mL -1 The above is 260±25%×10 -6 hr·mL -1 The above is 270±25%×10 -6 hr·mL -1 The above, or 280±25%×10 -6 hr·mL -1 That concludes the explanation. In some embodiments, dnAUC 0-∞h is 24±25%×10 -6 hr·mL -1 The above, or 25±25%×10 -6 hr·mL -1 The above is 30±25%×10 -6 hr·mL -1 The above is 35±25%×10 -6 hr·mL -1 The above is 40±25%×10 -6 hr·mL -1 The above is 50±25%×10 -6 hr·mL -1 The above is 60±25%×10 -6 hr·mL -1 The above is 70±25%×10 -6 hr·mL -1 The above is 80±25%×10 -6 hr·mL -1 The above, or 90±25% × 10-6 hr·mL -1 That concludes the explanation. In some embodiments, dnAUC 0-∞h is 100±25%×10 -6 hr·mL -1 The above is 110±25%×10 -6 hr·mL -1 The above is 120±25%×10 -6 hr·mL -1 The above is 130±25%×10 -6 hr·mL -1 The above is 140±25%×10 -6 hr·mL -1 The above, or 150±25%×10 -6 hr·mL -1 That concludes the explanation. In some embodiments, dnAUC 0-∞h is 160±25%×10 -6 hr·mL -1 The above is 170±25%×10 -6 hr·mL -1 The above is 180±25%×10 -6 hr·mL -1 The above is 190±25%×10 -6 hr·mL -1 The above is 200±25%×10 -6 hr·mL -1 The above, or 210±25%×10 -6 hr·mL -1 That concludes the explanation. In some embodiments, dnAUC 0-∞h is 220±25%×10 -6 hr·mL -1 The above is 240±25%×10 -6 hr·mL -1 The above is 250±25%×10 -6 hr·mL -1 The above is 260±25%×10 -6 hr·mL -1 The above is 270±25%×10 -6 hr·mL -1 The above, or 280±25%×10 -6 hr·mL -1 That's all.

[0106] Furthermore, by comparing the product of AUC and body mass with the administered dose, a ratio of the product of AUC × body mass to the dose can be generated, which is referred to herein as dose- and body mass-normalized AUC or dbmnAUC. Dose- and body mass-normalized dbmnAUC for the human data in Figure 1 above. 0-∞h For a 70kg person, this is approximately 140.6 × 10 -6 kg·hr·mL -1 This is the dose- and body mass-normalized AUC for the aforementioned Beagle data. 0-0.75h (dbmnAUC 0-0.75h (The average body mass of a Beagle was 12.5 kg) is dbmnAUC 0-0.75h = 12.5 kg × 135.6 ng·hr·mL -1 / 2.4mg = 708 × 10 -6 kg·hr·mL -1 In the Beagle experiment (Figures 2 and 3) for an average dose of 1.79 mg of IV cyclobenzaprine, dbmnAUC 0-∞h 12.5kg × 25.04 × 10 -6 hr·mL -1 And dbmnAUC 0-24h is 314×10 -6 kg·hr·mL -1 In the Beagle experiment (Figures 2 and 3) with an average dose of 1.79 mg of sublingual cyclobenzaprine solution, dbmnAUC was found to be... 0-∞h 12.5kg × 71.95 × 10 -6 hr·mL -1 And dbmnAUC 0-24h is 886×10 -6 kg·hr·mL -1 The dbmnAUC for the aforementioned human data (by Winchell et al.) assuming a 70kg person was the case. 0-8h For cyclobenzaprine doses of 2.5, 5.0, and 10 mg, the calculation is approximately 70 kg × 4.4 ± 25% × 10 -6 hr·mL -1 = 308 ± 25% × 10 -6 kg·hr·mL -1 , 322±25%×10 -6 kg·hr·mL-1 and 322±25%×10 -6 kg·hr·mL -1 This is the dose-normalized dbmnAUC for the aforementioned human data (by Winchell et al.). 0-∞h For cyclobenzaprine doses of 2.5, 5.0, and 10 mg, the formula is 70 kg × 17.7 ± 25% × 10 -6 hr·mL -1 = 1239 ± 25% × 10 -6 kg·hr·mL -1 , 1253±25%×10 -6 kg·hr·mL -1 , and 1246±25%×10 -6 kg·hr·mL -1 In some embodiments, dbmnAUC 0-20min Approximately 1.1 ± 25% × 10 -6 kg·hr·mL -1 And dbmnAUC 0-30min Approximately 3.7 ± 25% × 10 -6 kg·hr·mL -1 And dbmnAUC 0-45min It is approximately 9.7 ± 25% × 10 -6 kg·hr·mL -1 And dbmnAUC 0-1h Approximately 18±25% × 10 -6 kg·hr·mL -1 And dbmnAUC 0-2h Approximately 62 ± 25% × 10 -6 kg·hr·mL -1 And dbmnAUC 0-2.5h Approximately 86±25% × 10 -6 kg·hr·mL -1 And dbmnAUC 0-3h Approximately 115 ± 25% × 10 -6 kg·hr·mL -1 And dbmnAUC 3.3h Approximately 135 ± 25% × 10 -6 kg·hr·mL -1 And dbmnAUC 0-3.7h Approximately 160 ± 25% × 10 -6 kg·hr·mL -1 And dbmnAUC 0-4hApproximately 180 ± 25% × 10 -6 kg·hr·mL -1 And dbmnAUC 0-4.3h Approximately 210 ± 25% × 10 -6 kg·hr·mL -1 And dbmnAUC 0-4.7h Approximately 230 ± 25% × 10 -6 kg·hr·mL -1 And dbmnAUC 0-5h Approximately 260 ± 25% × 10 -6 kg·hr·mL -1 And dbmnAUC 0-5.5h Approximately 290 ± 25% × 10 -6 kg·hr·mL -1 And dbmnAUC 0-6h Approximately 330 ± 25% × 10 -6 kg·hr·mL -1 And dbmnAUC 0-8h is 440±25%×10 -6 kg·hr·mL -1 And dbmnAUC 0-12h Approximately 1500 ± 25% × 10 -6 kg·hr·mL -1 And dbmnAUC 0-Inf Approximately 1800 ± 25% × 10 -6 kg·hr·mL -1 In some embodiments, dbmnAUC 0-8h is 350±25%×10 -6 kg·hr·mL -1 That concludes the explanation. In some embodiments, dbmnAUC 0-8h is 400±25%×10 -6 hr·mL -1 The above is 500±25%×10 -6 kg·hr·mL -1 The above is 600±25%×10 -6 kg·hr·mL -1 The above is 700±25%×10 -6 kg·hr·mL -1 The above is 800±25%×10 -6 kg·hr·mL -1 The above, or 900±25%×10 -6 kg·hr·mL-1 That concludes the explanation. In some embodiments, dbmnAUC 0-8h is 1000±25%×10 -6 kg·hr·mL -1 The above is 1200±25%×10 -6 kg·hr·mL -1 The above is 1400±25%×10 -6 kg·hr·mL -1 The above is 1600±25%×10 -6 kg·hr·mL -1 The above is 1800±25%×10 -6 kg·hr·mL -1 The above, or 2000±25%×10 -6 kg·hr·mL -1 That concludes the explanation. In some embodiments, dbmnAUC 0-10h is 400±25%×10 -6 kg·hr·mL -1 The above is 500±25%×10 -6 kg·hr·mL -1 The above is 600±25%×10 -6 kg·hr·mL -1 The above is 700±25%×10 -6 kg·hr·mL -1 The above is 800±25%×10 -6 kg·hr·mL -1 The above, or 900±25%×10 -6 kg·hr·mL -1 That concludes the explanation. In some embodiments, dbmnAUC 0-10h is 1000±25%×10 -6 kg·hr·mL -1 The above is 1200±25%×10 -6 kg·hr·mL -1 The above is 1400±25%×10 -6 kg·hr·mL -1 The above is 1600±25%×10 -6 kg·hr·mL -1 The above is 1800±25%×10 -6 kg·hr·mL -1 The above, or 2000±25%×10 -6 kg·hr·mL -1That concludes the explanation. In some embodiments, dbmnAUC 0-12h is 500±25%×10 -6 kg·hr·mL -1 The above is 600±25%×10 -6 kg·hr·mL -1 The above is 700±25%×10 -6 kg·hr·mL -1 The above is 800±25%×10 -6 kg·hr·mL -1 The above, or 900±25%×10 -6 kg·hr·mL -1 That concludes the explanation. In some embodiments, dbmnAUC 0-12h is 1000±25%×10 -6 kg·hr·mL -1 The above is 1200±25%×10 -6 kg·hr·mL -1 The above is 1400±25%×10 -6 kg·hr·mL -1 The above is 1600±25%×10 -6 kg·hr·mL -1 The above is 1800±25%×10 -6 kg·hr·mL -1 The above, or 2000±25%×10 -6 kg·hr·mL -1 That concludes the explanation. In some embodiments, dbmnAUC 0-24h is 500±25%×10 -6 kg·hr·mL -1 The above is 600±25%×10 -6 kg·hr·mL -1 The above is 700±25%×10 -6 kg·hr·mL -1 The above is 800±25%×10 -6 kg·hr·mL -1 The above, or 900±25%×10 -6 kg·hr·mL -1 That concludes the explanation. In some embodiments, dbmnAUC 0-24h is 1000±25%×10 -6 kg·mL -1 The above is 1100±25%×10 -6 hr·mL-1 The above is 1200±25%×10 -6 kg·hr·mL -1 The above is 1300±25%×10 -6 kg·hr·mL -1 The above is 1400±25%×10 -6 kg·hr·mL -1 The above, or 1500±25%×10 -6 kg·hr·mL -1 That concludes the explanation. In some embodiments, dbmnAUC 0-24h is 1600±25%×10 -6 kg·hr·mL -1 The above is 1700±25%×10 -6 kg·hr·mL -1 The above is 1800±25%×10 -6 kg·hr·mL -1 The above is 1900±25%×10 -6 kg·hr·mL -1 The above is 2000±25%×10 -6 kg·hr·mL -1 The above, or 2100±25%×10 -6 kg·hr·mL -1 That concludes the explanation. In some embodiments, dbmnAUC 0-24h is 2200±25%×10 -6 kg·hr·mL -1 The above is 2400±25%×10 -6 kg·hr·mL -1 The above is 2500±25%×10 -6 kg·hr·mL -1 The above is 2600±25%×10 -6 kg·hr·mL -1 The above is 2700±25%×10 -6 kg·hr·mL -1 The above, or 2800±25%×10 -6 kg·hr·mL -1 That concludes the explanation. In some embodiments, dnAUC 0-∞h is 240±25%×10 -6 kg·hr·mL -1 The above, or 250±25%×10 -6 kg·hr·mL -1The above is 300±25%×10 -6 kg·hr·mL -1 The above is 35±25%×10 -6 kg·hr·mL -1 The above is 400±25%×10 -6 kg·hr·mL -1 The above is 500±25%×10 -6 kg·hr·mL -1 The above is 600±25%×10 -6 kg·hr·mL -1 The above is 700±25%×10 -6 kg·hr·mL -1 The above is 800±25%×10 -6 kg·hr·mL -1 The above, or 900±25%×10 -6 kg·hr·mL -1 That concludes the explanation. In some embodiments, dbmnAUC 0-∞h is 1000±25%×10 -6 kg·hr·mL -1 The above is 1100±25%×10 -6 kg·hr·mL -1 The above is 1200±25%×10 -6 kg·hr·mL -1 The above is 1300±25%×10 -6 kg·hr·mL -1 The above is 1400±25%×10 -6 kg·hr·mL -1 The above, or 1500±25%×10 -6 kg·hr·mL -1 That concludes the explanation. In some embodiments, dbmnAUC 0-∞h is 1600±25%×10 -6 kg·hr·mL -1 The above is 1700±25%×10 -6 kg·hr·mL -1 The above is 1800±25%×10 -6 kg·hr·mL -1 The above is 1900±25%×10 -6 kg·hr·mL -1The above is 2000±25%×10 -6 kg·hr·mL -1 The above, or 2100±25%×10 -6 kg·hr·mL -1 That concludes the explanation. In some embodiments, dbmnAUC 0-∞h is 2200±25%×10 -6 kg·hr·mL -1 The above is 2400±25%×10 -6 kg·hr·mL -1 The above is 250±25%×10 -6 kg·hr·mL -1 The above is 2600±25%×10 -6 kg·hr·mL -1 The above is 2700±25%×10 -6 hr·mL -1 The above, or 2800±25%×10 -6 kg·hr·mL -1 That concludes the explanation. In some embodiments, dbmnAUC 0-∞h is 5000±25%×10 -6 kg·hr·mL -1 The above is 10000±25%×10 -6 kg·hr·mL -1 The above is 15000±25%×10 -6 kg·hr·mL -1 The above is 20000±25%×10 -6 kg·hr·mL -1 The above is 25000±25%×10 -6 kg·hr·mL -1 The above, or 30000±25%×10 -6 kg·hr·mL -1 That concludes the explanation. In some embodiments, dbmnAUC 0-∞h is 35000±25%×10 -6 kg·hr·mL -1 The above is 40000±25%×10 -6 kg·hr·mL -1 The above is 45000±25%×10 -6 kg·hr·mL -1 The above is 50000±25%×10 -6 kg·hr·mL -1The above is 55000±25%×10 -6 hr·mL -1 The above, or 60000±25%×10 -6 kg·hr·mL -1 That's all.

[0107] In some embodiments, the compositions of the present invention are compositions that provide the effect of bioequivalence to the compositions described herein. Bioequivalence is measured by AUC, C max t max , mean absorption time, metabolite plasma concentration, mean residence time, rate constant, rate profile, and C normalized to AUC max This can be determined by. Exemplary bioequivalence tests are C max The AUC and / or confidence intervals for a given compound, which are 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%.

[0108] In some embodiments, the method of the present invention is a method for providing the bioequivalence effect to the compositions described herein. Bioequivalence is determined by AUC, C max t max , mean absorption time, metabolite plasma concentration, mean residence time, rate constant, rate profile, and C normalized to AUC max This can be determined by. Exemplary bioequivalence tests are C max The AUC and / or confidence intervals for a given compound, which are 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%.

[0109] In some embodiments, the methods and compositions of the present invention result in the rapid removal of administered compounds, including their biologically active metabolites, from the plasma more quickly than when administered orally. This is beneficial because the clearance of the compound can help reduce side effects. For example, if a subject ingests a sublingual composition containing cyclobenzaprine or amitriptyline before sleep, the cyclobenzaprine or amitriptyline is rapidly absorbed but substantially metabolized and excreted by the time the subject wakes up, thus minimizing fatigue, drowsiness, and grogginess felt upon waking. In some embodiments, plasma levels of the compound are elevated by 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 hours after administration. max It decreases by at least 50%. In some embodiments, the plasma level of the compound is t max C max at least 50% of, t max C max at least 55% of, t max C max at least 60% of, t max C max at least 65% of, t max C max at least 70% of, t max C max at least 75% of, t max C max at least 80% of, t max C max at least 85% of, t max C max at least 90% of, t max C max at least 91% of, t max C max at least 92%, t max C maxat least 93% of, t max C max at least 94% of, t max C max at least 95% of, t max C max at least 96% of, t max C max at least 97% of, t max C max at least 98% of, or t max C max At least 99% of it is reduced. In some embodiments, the plasma level of the compound is reduced by 8 hours after administration. max At least 50% of C by 8 hours after administration max At least 55% of C by 8 hours after administration max At least 60% of C by 8 hours after administration max At least 65% of C by 8 hours after administration max At least 70% of C by 8 hours after administration max At least 75% of C by 8 hours after administration max At least 80% of C by 8 hours after administration max At least 85% of C by 8 hours after administration max At least 90% of C by 8 hours after administration max At least 91% of C max At least 92% of C max At least 93% of C max At least 94% of C max At least 95% of C max At least 96% of C max At least 97% of C max At least 98% of, or by 8 hours after administration, C max At least 99% of it is reduced. In some embodiments, the plasma level of the compound is reduced by 4 hours after administration. maxAt least 50% of C by 4 hours after administration max At least 55% of C by 4 hours after administration max At least 60% of C by 4 hours after administration max At least 65% of C by 4 hours after administration max At least 70% of C by 4 hours after administration max At least 75% of C by 4 hours after administration max At least 80% of C by 4 hours after administration max At least 85% of C by 4 hours after administration max At least 90% of C max At least 91% of C max At least 92% of C max At least 93% of C max At least 94% of C max At least 95% of C max At least 96% of C max At least 97% of C max At least 98% of or up to 4 hours after administration max At least 99% will decrease.

[0110] In some embodiments, the compositions or methods of the present invention provide high C content for cyclobenzaprine or amitriptyline. max and low t max However, this is achieved in combination with high clearance. For example, by the composition or method of the present invention administered once daily for four days or more, approximately 20 to approximately 200 ng / mL of C is obtained approximately 0.05 to approximately 2.5 hours after administration. max Simultaneously, a minimum plasma concentration of approximately 1 to 5 ng / mL can be obtained approximately 22 to 26 hours after administration. In some embodiments, the composition is administered within 2 hours prior to sleep. In some embodiments, the method is for reducing the symptoms of fibromyalgia in human patients.

[0111] In some embodiments, the methods and compositions of the present invention allow the compound to be removed from plasma more rapidly than when administered orally. This is beneficial because the clearance of the compound may help reduce the accumulation of cyclobenzaprine or amitriptyline in the body when administered on a long-term dosing schedule by nightly administration. Minimum concentration or C min This can be determined by measuring the plasma concentration of the administered compound, which can be either a fixed time point or a variable time point, for example, C max A point in time after the corresponding point in time, for example, C max It can be measured 23 hours later. min This can be measured after a single dose, or after a series of multiple doses, or after a long-term administration such as once-daily doses. For example, C min This can be measured 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours after administration. In some embodiments, C minThis can be measured 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or 36 hours after administration. In some embodiments, the compositions contain 10 pg / mL or less, 11 pg / mL or less, 12 pg / mL or less, 13 pg / mL or less, 14 pg / mL or less, 15 pg / mL or less, 16 pg / mL or less, 17 pg / mL or less, 18 pg / mL or less, 19 pg / mL or less, 20 pg / mL or less, 21 pg / mL or less, 22 pg / mL or less, 23 pg / mL or less, 24 pg / mL or less, 25 pg / mL or less, 26 pg / mL or less, 27 pg / mL or less, 28 pg / mL or less, 29 pg / mL or less, and 30 pg / mL or less. Below, C of compounds with a C content of 31 pg / mL or less, 32 pg / mL or less, 33 pg / mL or less, 34 pg / mL or less, 35 pg / mL or less, 36 pg / mL or less, 37 pg / mL or less, 38 pg / mL or less, 39 pg / mL or less, 40 pg / mL or less, 50 pg / mL or less, 60 pg / mL or less, 70 pg / mL or less, 80 pg / mL or less, 90 pg / mL or less, 100 pg / mL or less, 120 pg / mL or less, 140 pg / mL or less, 160 pg / mL or less, 180 pg / mL or less, or 200 pg / mL or less. minIn some embodiments, the composition yields 100 pg / mL or less, 110 pg / mL or less, 120 pg / mL or less, 130 pg / mL or less, 140 pg / mL or less, 150 pg / mL or less, 160 pg / mL or less, 170 pg / mL or less, 180 pg / mL or less, 190 pg / mL or less, 200 pg / mL or less, 210 pg / mL or less, 220 pg / mL or less, 230 pg / mL or less, 240 pg / mL or less, 250 pg / mL or less, 260 pg / mL or less, 270 pg / mL or less, 280 pg / mL or less, 290 pg / mL or less, and 300 pg / mL or less. Below, C of compounds with a C content of 310 pg / mL or less, 320 pg / mL or less, 330 pg / mL or less, 340 pg / mL or less, 350 pg / mL or less, 360 pg / mL or less, 370 pg / mL or less, 380 pg / mL or less, 390 pg / mL or less, 400 pg / mL or less, 500 pg / mL or less, 600 pg / mL or less, 700 pg / mL or less, 800 pg / mL or less, 900 pg / mL or less, 1.0 ng / mL or less, 1.20 ng / mL or less, 1.40 ng / mL or less, 1.60 ng / mL or less, 1.80 ng / mL or less, or 2.00 ng / mL or less. min This results in the following: In some embodiments, the composition contains a compound with a concentration of 3.0 ng / mL or less, 4.0 ng / mL or less, 5.0 ng / mL or less, 6.0 ng / mL or less, 7.0 ng / mL or less, 8.0 ng / mL or less, or 10.0 ng / mL or less. min This results in the minimum concentration or C in 24 hours. min(24) This can be determined by measuring the plasma concentration of the administered compound approximately 24 hours after the most recent dose or immediately before the next dose. min(24) is expressed as a plasma value, or C min(24) This can be made significant by calculating the ratio of the administered dose to the dose-normalized minimum plasma concentration or dnC. min(24) * dnC min(24) * This is calculated by determining the ratio of plasma levels to the administered dose. For example, in a study in which 5.0 mg of cyclobenzaprine immediate-release tablets were administered as a PO (shown in Figure 1), the mean C min(24) The level was 1.384 ng / mL over 24 hours, and dnCmin(24) * This is ((1.384 ng / mL) / (5.0 mg)) = 0.27680 ng / (mg·mL), or 0.27680 × 10 -6 ml -1 In another example, a study in which 2.4 mg of cyclobenzaprine sublingual tablets were administered showed an average C min(24) The concentration was 706.55 ng / mL over 24 hours, and dnC min(24) * This is ((706.55 ng / mL) / (2.4 mg)) = 294.40 ng / (mg·mL) or 0.29440 × 10 -6 mL -1 In some embodiments, dnC min(24) * is 1.0±25%×10 -6 mL -1 Below, 0.9±25%×10 -6 mL -1 Below, 0.8±25%×10 -6 mL -1 Below, 0.7±25% × 10 -6 mL -1 Below, 0.6±25% × 10 -6 mL -1 Below, 0.5±25% × 10 -6 mL -1 Below, 0.4±25% × 10 -6 mL -1 The following, or 0.3±25%×10 -6 mL -1 The following applies to some embodiments, dnC min(24) * is 240±25%×10 -9 mL -1 Below, 220±25%×10 -9 mL -1 Below, 200±25%×10 -9 mL -1 Below, 180±25%×10 -9 mL -1 Below, 160±25%×10 -9 mL -1 Below, 140±25%×10 -9 mL -1 Below, 120±25%×10 -6 mL-1 Below, 100±25%×10 -6 mL -1 Below, 80±25% × 10 -9 mL -1 Below, 60±25% × 10 -9 mL -1 Below, 40±25% × 10 -9 mL -1 Below, 20±25% × 10 -9 mL -1 The following, or 10±25%×10 -9 mL -1 The following applies to some embodiments, dnC min(24) * is 9±25%×10 -9 mL -1 Below, 9±25% × 10 -6 mL -1 Below, 7±25% × 10 -9 mL -1 Below, 6±25% × 10 -9 mL -1 Below, 5±25% × 10 -9 mL -1 Below, 4±25% × 10 -9 mL -1 Below, 3±25% × 10 -9 mL -1 Below, 2±25% × 10 -9 mL -1 The following, or 1±25%×10 -9 mL -1 The following applies:

[0112] Dose- and body mass-normalized C min or dbmnC min * This is calculated by determining the ratio of the product of plasma levels and body mass to the administered dose. dbmnC over 24 hours min * or dbmnC min(24) * This can be determined by measuring the plasma concentration of the compound administered on a once-daily dosing schedule, for example, a bedtime dosing schedule, approximately 24 hours after the most recent dose or immediately before the next dose. dbmnC min *This can be determined by measuring the plasma concentration of the administered compound, which can be determined at a certain point in time, for example, 24 hours after administration (C min(24) * ), or at a variable time, for example C max A point in time after the corresponding point in time, for example, C max It can be measured 23 hours later. For example, in a study in which 5.0 mg of cyclobenzaprine immediate-release tablets were administered as a pre-oxidation dose (shown in Figure 1), the average C min(24) * The value over 24 hours is 1.384 ng / mL, and assuming a 70kg person, the approximate value is dbmnC min(24) * 70kg × ((1.384ng / mL) / (5.0mg)) = 19.4 × 10 -6 kg·mL -1 For example, in a study in which 2.4 mg of cyclobenzaprine sublingual tablets were administered, the average C min(24) The concentration was 706.55 ng / mL over 24 hours, and dnC min(24) * This is ((706.55 ng / mL) / (2.4 mg)) = 294.40 ng / (mg·mL) or 294.40 × 10 -9 mL -1 Therefore, assuming a 70kg person, the approximate dbmnC min(24) * 70kg × ((706.55ng / mL) / (2.4mg)) = 20.608 × 10 -6 kg·mL -1 In some embodiments, dbmnC min(24) * is 1.0±25%×10 -6 kg·mL -1 Below, 0.9±25%×10 -6 kg·mL -1 Below, 0.8±25%×10 -6 kg·mL -1 Below, 0.7±25% × 10 -6 kg·mL -1 Below, 0.6±25% × 10 -6 kg·mL -1 Below, 0.5±25% × 10 -6 kg·mL -1Below, 0.4±25% × 10 -6 kg·mL -1 The following, or 0.3±25%×10 -6 kg·mL -1 The following applies to some embodiments, dbmnC min(24) * is 240±25%×10 -9 mL -1 Below, 220±25%×10 -9 kg·mL -1 Below, 200±25%×10 -9 kg·mL -1 Below, 180±25%×10 -9 kg·mL -1 Below, 160±25%×10 -9 kg·mL -1 Below, 140±25%×10 -9 kg·mL -1 Below, 120±25%×10 -6 kg·mL -1 Below, 100±25%×10 -6 kg·mL -1 Below, 80±25% × 10 -9 kg·mL -1 Below, 60±25% × 10 -9 kg·mL -1 Below, 40±25% × 10 -9 kg·mL -1 Below, 20±25% × 10 -9 kg·mL -1 The following, or 10±25%×10 -9 kg·mL -1 The following applies to some embodiments, dbmnC min(24) * is 9±25%×10 -9 kg·mL -1 Below, 9±25% × 10 -6 mL -1 Below, 7±25% × 10 -9 kg·mL -1 Below, 6±25% × 10 -9 kg·mL -1 Below, 5±25% × 10 -9 kg·mL -1 Below, 4±25% × 10 -9 kg·mL -1Below, 3±25% × 10 -9 kg·mL -1 Below, 2±25% × 10 -9 kg·mL -1 The following, or 1±25%×10 -9 kg·mL -1 The following applies:

[0113] In some embodiments, the methods and compositions of the present invention allow compounds to be absorbed into plasma without intestinal or hepatic metabolism, thereby reducing the degree of p450 demethylation. This is beneficial because p450 demethylation converts cyclobenzaprine to norcyclobenzaprine, which has a long half-life, and amitriptyline to nortriptyline, which also has a long half-life. The reduced concentrations of the secondary amine metabolites norcyclobenzaprine and nortriptyline are beneficial because the tertiary amines cyclobenzaprine and nortriptyline are more rapidly eliminated from the plasma and body, and compound clearance may help reduce the accumulation of compounds (drugs and metabolites) that act on the body when administered on a long-term dosing schedule by nightly administration. The ratio of the plasma concentration of the metabolite to the dose of the administered drug is the dose-normalized concentration or dnC of the metabolite. met * The ratio of the plasma concentration of norcyclobenzaprine to the dose of cyclobenzaprine administered is the dose-normalized concentration of norcyclobenzaprine or dnC met (Norcyclo) * The ratio of the plasma concentration of nortriptyline to the dose of amitriptyline administered is the dose-normalized concentration of nortriptyline or dnC met (Nortrip) * dnC met * This can be measured at various time points after the compound is administered, either after a single dose or after multiple doses. dnC met * This can be either a fixed point in time or a variable point in time, for example, C max It can be measured at the corresponding point in time. For example, dnC met *This can be measured 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 10 hours, 11 hours, or 12 hours after administration. In some embodiments, dnC met * This can be measured 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or 36 hours after administration. dnC over 24 hours met * or dnC met(24) * This can be determined by measuring the plasma concentration of the compound administered on a once-daily dosing schedule, for example, a bedtime dosing schedule, approximately 24 hours after the most recent dose or immediately before the next dose. For example, in a study where 5.0 mg of cyclobenzaprine immediate-release tablets were administered and the mean plasma concentration of norcyclobenzaprine over 24 hours was 1.227 ng / mL, dnC met(24) (Norcyclo) * This is ((1.227 ng / mL) / (5.0 mg)) = 0.245 ng / (mL mg) or 0.245 × 10 -6 mL -1 This is the case. dnC regarding multiple doses of cyclobenzaprine or amitriptyline. met(24) * It is predicted to be higher. In some embodiments, dnC met(24) * is 1.0±25%×10 -6 mL -1 Below, 0.9±25%×10 -6 mL -1 Below, 0.8±25%×10 -6 mL -1 Below, 0.7±25% × 10 -6 mL -1 Below, 0.6±25% × 10 -6 mL-1 Below, 0.5±25% × 10 -6 mL -1 Below, 0.4±25% × 10 -6 mL -1 The following, or 0.3±25%×10 -6 mL -1 The following applies to some embodiments, dnC met(24) * is 240±25%×10 -9 mL -1 Below, 220±25%×10 -9 mL -1 Below, 200±25%×10 -9 mL -1 Below, 180±25%×10 -9 mL -1 Below, 160±25%×10 -9 mL -1 Below, 140±25%×10 -9 mL -1 Below, 120±25%×10 -6 mL -1 Below, 100±25%×10 -6 mL -1 Below, 80±25% × 10 -9 mL -1 Below, 60±25% × 10 -9 mL -1 Below, 40±25% × 10 -9 mL -1 Below, 20±25% × 10 -9 mL -1 The following, or 10±25%×10 -9 mL -1 The following applies to some embodiments, dnC met(24) * is 9±25%×10 -9 mL -1 Below, 9±25% × 10 -6 mL -1 Below, 7±25% × 10 -9 mL -1 Below, 6±25% × 10 -9 mL -1 Below, 5±25% × 10 -9 mL -1 Below, 4±25% × 10 -9 mL -1Below, 3±25% × 10 -9 mL -1 Below, 2±25% × 10 -9 mL -1 The following, or 1±25%×10 -9 mL -1 The following applies:

[0114] The ratio of the product of the body mass and plasma concentrations of norcyclobenzaprine to the dose of cyclobenzaprine administered is the dose- and body mass-normalized concentration (dbmnC) of norcyclobenzaprine. met (Norcyclo) * The ratio of the product of the body mass and plasma concentration of nortriptyline to the dose of amitriptyline administered is the dose- and body mass-normalized concentration or dbmnC of nortriptyline. met (Nortrip) * dbmnC met * This can be measured at various time points after the compound is administered, either after a single dose or after multiple doses. dbmnC met * This can be either a fixed point in time or a variable point in time, for example, C max It can be measured at the corresponding point in time. For example, dbmnC met * This can be measured 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 10 hours, 11 hours, or 12 hours after administration. In some embodiments, dbmnC met * This can be measured 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or 36 hours after administration. dbmnC over 24 hours met * or dbmnCmet(24) * This can be determined by measuring the plasma concentration of the compound administered on a once-daily dosing schedule, for example, a bedtime dosing schedule, approximately 24 hours after the most recent dose or immediately before the next dose. For example, in a study where 5.0 mg of cyclobenzaprine immediate-release tablets were administered and the mean plasma concentration of norcyclobenzaprine over 24 hours was 1.227 ng / mL, assuming a mean human body mass of 70 kg, dbmnC met(24) (Norcyclo) * 70kg × ((1.227ng / mL) / (5.0mg)) = 17.2 × 10 -6 kg·mL -1 This is the case with dbmnC regarding multiple doses of cyclobenzaprine or amitriptyline. met(24) * It is predicted to be higher. In some embodiments, dbmnC met(24) * is 1.0±25%×10 -6 kg·mL -1 Below, 0.9±25%×10 -6 kg·mL -1 Below, 0.8±25%×10 -6 kg·mL -1 Below, 0.7±25% × 10 -6 kg·mL -1 Below, 0.6±25% × 10 -6 kg·mL -1 Below, 0.5±25% × 10 -6 kg·mL -1 Below, 0.4±25% × 10 -6 kg·mL -1 The following, or 0.3±25%×10 -6 kg·mL -1 The following applies to some embodiments, dbmnC met(24) * is 240±25%×10 -9 kg·mL -1 Below, 220±25%×10 -9 kg·mL -1 Below, 200±25%×10 -9 kg·mL -1 Below, 180±25%×10 -9kg·mL -1 Below, 160±25%×10 -9 kg·mL -1 Below, 140±25%×10 -9 kg·mL -1 Below, 120±25%×10 -6 kg·mL -1 Below, 100±25%×10 -6 kg·mL -1 Below, 80±25% × 10 -9 kg·mL -1 Below, 60±25% × 10 -9 kg·mL -1 Below, 40±25% × 10 -9 kg·mL -1 Below, 20±25% × 10 -9 kg·mL -1 The following, or 10±25%×10 -9 kg·mL -1 The following applies to some embodiments, dbmnC met(24) * is 9±25%×10 -9 kg·mL -1 Below, 9±25% × 10 -6 kg·mL -1 Below, 7±25% × 10 -9 kg·mL -1 Below, 6±25% × 10 -9 kg·mL -1 Below, 5±25% × 10 -9 kg·mL -1 Below, 4±25% × 10 -9 kg·mL -1 Below, 3±25% × 10 -9 kg·mL -1 Below, 2±25% × 10 -9 kg·mL -1 The following, or 1±25%×10 -9 kg·mL -1 The following applies: Excipients

[0115] In some embodiments, the compositions of the present invention are useful as pharmaceuticals. In some embodiments, the present invention provides the use of the compositions of the present invention in the manufacture of pharmaceuticals. In some embodiments, it may be beneficial to include one or more excipients in the compositions of the present invention. Those skilled in the art will understand that the selection of any one excipient may affect the selection of any other excipients. For example, selecting a particular excipient may prevent the use of one or more additional excipients, as certain combinations of excipients may produce undesirable effects. Those skilled in the art will be able to empirically determine which additional excipients, if any, should be included in the formulation of the present invention. For example, the compounds of the present invention can be combined with at least one pharmaceutically acceptable carrier, such as a solvent, bulking agent, binder, humectant, disintegrant, dissolution retarder, disintegrant, flow enhancer, absorption enhancer, wetting agent, solubilizer, lubricant, sweetener, or flavoring agent. "pharmaceutically acceptable carrier" refers to any diluent or excipient that is compatible with the other components of the formulation and is not harmful to the recipient. A pharmaceutically acceptable carrier can be selected based on the desired route of administration, in accordance with standard pharmaceutical regulations. Bulking agent

[0116] In some embodiments, it may be beneficial to include a bulking agent in the composition of the present invention. Bulking agents are commonly used in pharmaceutical compositions to increase the volume of the composition. Bulking agents are well known in the art. Therefore, the bulking agents described herein do not constitute a comprehensive list, but are provided merely as illustrative bulking agents that may be used in the compositions and methods of the present invention.

[0117] Exemplary bulking agents may include carbohydrates, sugar alcohols, amino acids, and sugar acids. Bulking agents include monosaccharides, disaccharides, or polysaccharides, starch, 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, growth, idose, talose, erythrolose, ribulose, xylulose, psicose, tagatose, glucosamine, galactosamine, arabinan, fructan, fucane, galactan, galacturonan, glucan, mannan, xylan, inulin, levan, fucoidan, carrageenan, This list includes, but is not limited to, galactocarolose, pectin, amylose, pullulan, glycogen, amylopectin, cellulose, microcrystalline cellulose, pustulan, chitin, agarose, keratin, chondroitin, dermatan, hyaluronic acid, xanthan gum, sucrose, trehalose, dextran, lactose, algitol, inositol, sorbitol, mannitol, glycine, aldonic acid, uronic acid, aldalic acid, gluconic acid, isoascorbic acid, ascorbic acid, glucaric acid, glucuronic acid, gluconic acid, glucaric acid, galacturonic acid, mannuronic acid, neuraminic acid, pectinic acid, corn starch, and alginic acid. Disintegrant

[0118] In some embodiments, it may be beneficial to include a disintegrant in the composition of the present invention. Disintegrants help to break down solid compositions and facilitate the delivery of active pharmaceutical compositions. Disintegrants are well known in the art. Some disintegrants, having rapid properties, are called superdisintegrants and can be used as disintegrants in the context of the present invention. Therefore, the disintegrants described herein do not constitute a comprehensive list, but are provided merely as exemplary disintegrants that can be used in the compositions and methods of the present invention. Exemplary disintegrants include crospovidone, microcrystalline cellulose, sodium carboxymethylcellulose, methylcellulose, sodium starch glycolate, calcium carboxymethyl croscarmellose sodium, polyvinylpyrrolidone, lower alkyl-substituted hydroxypropylcellulose, Indion 414, starch, pregelatinized starch, calcium carbonate, gum, sodium alginate, and Pearlitol Flash®. Pearlitol Flash® (Roquette) is a mannitol-corn starch disintegrant specifically designed for oral dispersible tablets (ODTs). Certain disintegrants have foaming properties. Flow accelerator

[0119] In some embodiments, it may be beneficial to include a flow promoter in the composition of the present invention. The flow promoter helps the powder to flow freely. Flow promoters are well known in the art. Therefore, the flow promoters described herein do not constitute a comprehensive list, but are provided merely as exemplary flow promoters that can be used in the compositions and methods of the present invention. Exemplary flow promoters include colloidal silica (silicon dioxide), magnesium stearate, starch, talc, glycerol behenate, DL-leucine, sodium lauryl sulfate, calcium stearate, and sodium stearate. lubricant

[0120] In some embodiments, it may be beneficial to include a lubricant in the composition of the present invention. The lubricant helps to prevent the components of the composition from agglomerating. Lubricants are well known in the art. Therefore, the lubricants described herein do not constitute a comprehensive list, but are provided merely as illustrative lubricants that may be used in the compositions and methods of the present invention. Exemplary lubricants include calcium stearate, magnesium stearate, stearic acid, sodium stearyl fumarate, vegetable-based fatty acids, talc, mineral oil, diesel fuel, hydrogenated vegetable oils (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, and ethyl laurate. Sweetener

[0121] In some embodiments, it may be beneficial to include a sweetener in the composition of the present invention. Sweeteners help to improve the mouthfeel of the composition by imparting sweetness to it. Sweeteners are well known in the art. Therefore, the sweeteners described herein do not constitute a comprehensive list, but are provided merely as exemplary sweeteners that can be used in the compositions and methods of the present invention. Exemplary sweeteners include, but are not limited to, compounds selected from the saccharide family, e.g., monosaccharides, disaccharides, trisaccharides, polysaccharides and oligosaccharides; sugars, e.g., sucrose, glucose (corn syrup), dextrose, invert sugar, fructose, maltodextrin and polydextrose; saccharin and its salts, e.g., sodium and calcium salts; cyclamic acid and its salts; dipeptide sweeteners; chlorinated sugar derivatives, e.g., sucralose and dihydrochalcone; sugar alcohols, e.g., sorbitol, sorbitol syrup, mannitol, xylitol, hexa-resorcinol, etc., and combinations thereof. Hydrolyzed starch hydrolysates, as well as potassium, calcium, and sodium salts of 3,6-dihydro-6-methyl-1-1,2,3-oxathiadin-4-one-2,2-dioxide, may be used. Flavoring

[0122] In some embodiments, it may be beneficial to include flavoring agents in the compositions of the present invention. Flavoring agents help improve the mouthfeel of the compositions by imparting a more desirable taste to them. Flavoring agents are well known in the art. Therefore, the flavoring agents described herein do not constitute a comprehensive list, but are provided merely as illustrative flavoring agents that may be used in the compositions and methods of the present invention. Exemplary flavoring agents include, but are not limited to, 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, and combinations thereof. Coloring agents

[0123] Colorants can be used to color-code compositions, for example, to indicate the type and dosage of therapeutic agents in a composition. Colorants are well known in the art. Therefore, the colorants described herein do not constitute a comprehensive list, but are provided merely as illustrative colorants that can be used in the compositions and methods of the present invention. Exemplary colorants include, but are not limited to, natural and / or synthetic compounds, such as FD&C colorants, natural fruit juice concentrates, pigments, such as titanium dioxide, silicon dioxide, and zinc oxide, and combinations thereof. Combination therapy

[0124] As described above, the compositions and methods of the present invention can be used to treat PTSD, depression, fibromyalgia, traumatic brain injury, sleep disorders, non-recovering sleep, chronic pain, and anxiety disorders. Any of the treatment methods described may be combined with psychotherapeutic interventions to improve treatment outcomes. Exemplary psychotherapeutic interventions include psychological debriefing, cognitive behavioral therapy, and eye movement desensitization and reprocessing, systematic desensitization, relaxation training, biofeedback, cognitive processing therapy, stress immunization training, assertiveness training, exposure therapy, a combination of stress immunization training and exposure therapy, a combination of exposure therapy and relaxation training, and cognitive therapy, all aimed at modifying traumatic memories or reducing emotional responses to traumatic memories. In each case, the goal of the intervention includes either modifying traumatic memories or reducing emotional responses to traumatic memories. The expected results are generally improvement or reduction of PTSD symptoms, as is evident with respect to physiological responses, anxiety, depression, and feelings of alienation.

[0125] In some embodiments of the present invention, the composition is combined with a drug that can further alleviate symptoms of PTSD, depression, fibromyalgia, traumatic brain injury, sleep disorders, non-recovering sleep, chronic pain, or anxiety disorders. The drugs include alpha-1-adrenergic receptor antagonists, beta-adrenergic antagonists, anticonvulsants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and analgesics. Exemplary anticonvulsants include carbamazepine, gabapentin, lamotrigine, oxycarbazepine, pregabalin, thiagabine, topiramate, and valproate. An exemplary alpha-1-adrenergic receptor antagonist is prazosin. Examples of selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors include bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, escitalopram, fluvoxamine, milnacipran, paroxetine, sertraline, trazodone, and venlafaxine. Examples of analgesics include pregabalin, gabapentin, acetaminophen, tramadol, and nonsteroidal anti-inflammatory drugs (e.g., ibuprofen and naproxen sodium). Additional drugs that can be used in combination with the compositions of the present invention include sodium oxybate, zolpidem, pramipexole, modafinil, temazepam, zaleplon, and almodafinil.

[0126] It should be understood that the embodiments of the present invention described herein are merely illustrative of some of the applications of the principles of the present invention. Those skilled in the art can make numerous modifications based on the teachings presented herein without departing from the spirit and scope of the invention.

[0127] The following embodiments are described as representative of the present invention. These embodiments and other equivalent embodiments will become apparent from the present disclosure, the figures, and the appended claims, and therefore should not be construed as limiting the scope of the present invention. [Examples]

[0128] (Example 1) To study the metabolism of cyclobenzaprine, immediate-release cyclobenzaprine HCl (bioequivalent to Watson, Flexeril 5 mg) was administered orally to 10 healthy human subjects in the form of 5 mg tablets. Plasma concentrations of cyclobenzaprine and norcyclobenzaprine were measured at 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3 hours 20 minutes, 3 hours 40 minutes, 4 hours, 4 hours 20 minutes, 4 hours 40 minutes, 5 hours, 5.5 hours, 6 hours, 8 hours, 12 hours, 16 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, 96 hours, and 168 hours (1 week) (Table 2, Figures 1a and 1b). High-performance liquid chromatography (HCM) chromatography was also developed and validated to determine cyclobenzaprine and norcyclobenzaprine in human EDTA K3 plasma. The conditions used were as follows: Mobile phase A (MPA) and autosampler rinse solution No. 1: Milli-Q type water / methanol (40 / 60), ammonium formate 5 mM, formic acid 0.1% (0.1:100) Mobile phase B (MPB) and autosampler rinsing solution No. 2: Methanol (100%) buffer solution: Trizma® base 500 mM, pH 11.0 Dissolving solution: Milli-Q type water / methanol (50 / 50) Solvent delivery module: Hewlett Packard Series 1100, Agilent (Montreal, Canada) Chromatography mode: reversed phase Homogeneous solvent / gradient mode: gradient Timetable program: [ka] Flow rate of mobile phase A: 1,000 mL / min Back pressure: 130 bar (approximately) CTC PAL (HTC-XT) * (Stator cleaning station) Injection macro: Sample Pickup Needle immersion for cleaning 1 Sample injection Valve purification with solvent 2 Post-purification with solvent 2 Valve purification with solvent 1 Post-purification with solvent 1 (Stator cleaning) Autosampler method: Void volume (mL): 3 Valve purification time with solvent 2 (seconds): 2 Pre-purification volume (mL): 0 Post-purification time with solvent 2 (seconds): 2 Rear volume (mL): 0 Valve purification time with solvent 1 (seconds): 3 Packing rate (μL / sec): 5 Post-purification time with solvent 1 (seconds): 3 Pull-up delay (milliseconds): 3000 Stator cleaning: 1 Injection into LC VLV1 Stator cleaning delay (seconds): 120 Injection rate (mL / sec): 5 Stator washing time with solvent 2 (sec): 5 Pre-injection delay (milliseconds): 500 Stator washing time with solvent 1 (seconds): 5 Post-infusion delay (milliseconds): 500; Method syringe (μL): 100 Needle gap valve purification (mm): 3 Note: Solvent 1 corresponds to autosampler rinse solution number 1, and solvent 2 corresponds to autosampler rinse solution number 2. Therefore, valve cleaning, post-cleaning, and stator cleaning are performed first with methanol and last with mobile phase A. Autosampler loop: 100 μL, stainless steel Injection volume: 20 μL Injection temperature: room temperature Pre-column filter: Supelco Filter 0.5μm Column: Supplier / Manufacturer ACE Brand / Model: ACE 3 C18 Length x Width (mm): 30 x 4.6 Particle size (μm) Column temperature: Room temperature Retention time (retention time may vary between implementations. Retention time was obtained without double injection (e.g., cohesive)): Cyclobenzaprine: 1.05 minutes Norcyclobenzaprine: 1.16 minutes Internal standard A: 1.05 minutes Internal standard B: 1.15 minutes Autosampler execution time: 3.50 minutes (Time saver on) Acquisition time: 3.50 minutes Detector parameters Source: TurboIonSpray Division ratio: Not applicable Ionization mode: positive API 5000 (can be modified to optimize chromatography conditions, sensitivity, or reproducibility) Auxiliary gas pressure (GS2): 70 psi Nebulizer gas pressure (GS1): 50 psi Curtain gas pressure: 45 psi CAD gas: 4 Interface heater (Ihe): On TurboIonSpray temperature: 450℃ Ion spray voltage (ISV): 1800 State file parameters: DP=70;EP=10; (Cyclobenzaprine) CE=55; CXP=12 State file parameters: DP=65;EP=10; (Norcyclobenzaprine) CE=48; CXP=12 State file parameters: DP=70;EP=10; (Internal standard A)CE=55;CXP=12 State file parameters: DP=65;EP=10; (Internal standard B)CE=48;CXP=12 Mass acquisition parameters: Analyte: MRM; Residence time = 150 milliseconds; Pause time = 5 milliseconds IS:MRM dwell time = 90 milliseconds; pause time = 5 milliseconds Cyclobenzapurine 276.4 (registered trademark) 215.2 amu Norcyclobenzaprine 262.4 (registered trademark) 215.2 amu Internal standard A279.2(registered trademark)215.1amu Internal standard B265.4(registered trademark)215.2amu Integration parameters (which can be varied to optimize the peak integral) [ka] Calibration parameters Peak characteristics: Area Calibration equation: y = mx + b Calibrated regression: Linear Weighting factor: 1 / C2 Determinant: r2

[0129] Cyclobenzaprine and norcyclobenzaprine were extracted from a constant volume of 0.200 mL of human EDTA K3 plasma using an automated liquid-liquid extraction procedure, and then injected into a liquid chromatograph equipped with a tandem mass spectrometry detector. Quantification was performed based on the peak area ratio of the analytes and their stable labeled internal standards. Weighted (1 / C2) linear regression was performed to determine the concentrations of the analytes. All regressions and figures presented in this validation report were created using MDS Sciex Analyst version 1.4.2 and Thermo Electron Corporation Watson LIMS software, version 7.0.0.01b. The results of the method validation were acceptable, demonstrating that this method is suitable for determining cyclobenzaprine and norcyclobenzaprine in human EDTA K3 plasma in the ranges of 50–10000 pg / mL for cyclobenzaprine and 5–1000 pg / mL for norcyclobenzaprine. Cyclobenzapurine and norcyclobenzaprine were measured in plasma. Equilibrium receptor binding assays were performed in cell lines expressing recombinant human receptors to determine the endogenous potency of cyclobenzaprine and norcyclobenzaprine against human serotonin 5-HT1a, 5-HT2a, 5-HT2b, 5-HT2c, 5-HT5a, and 5-HT6 receptors, adrenergic α-1A, adrenergic α-2(A, B, C), histamine H1, and muscarinic M1 and M2 receptors. Selected receptors were analyzed by ligand-induced intracellular calcium mobilization.

[0130] The amount of norcyclobenzaprine in the plasma was unexpectedly high, and this finding suggests that the method used by the inventors is an improvement over methods in the literature that did not detect norcyclobenzaprine. Furthermore, the half-life of norcyclobenzaprine was unexpectedly long. max This is approximately 3.5 hours (AUC 0-∞h = 103.1 ± 35.8 ng·hr·mL -1 It was calculated that the t of norcyclobenzaprine is ) maxThis is approximately 24.0 hours (AUC 0-∞h = 169.5 ± 94.3 ng·hr·mL -1 It was calculated that cyclobenzaprine and norcyclobenzaprine have high affinity binding (K) to the following receptors in vitro. Furthermore, the ratio of cyclobenzaprine to norcyclobenzaprine decreased more rapidly than expected, reaching a ratio of 1.1:1 within 24 hours and decreasing to 1:2 by 72 hours (Table 3). This is supported by the fact that the half-life of norcyclobenzaprine was calculated to be approximately 73 hours (72.75 ± 27.71 hours), which is surprisingly long compared to approximately 31 hours (30.95 ± 7.18 hours) for cyclobenzaprine. These data indicate that norcyclobenzaprine remains in the system for a long time even after most of the cyclobenzaprine has been eliminated. Cyclobenzapurine and norcyclobenzaprine exhibit high affinity binding (K) to the following receptors in vitro. i ) exhibited: 5-HT2a (5.2 and 13 nM) and 5-HT2c (5.2 and 43 nM), adrenergic α-1A (5.6 and 34 nM), α-2B (K i =21 and 150 nM) and α-2C(K i =21 and 48 nM); H1 (1.3 nM and 5.6 nM); M1 (7.9 nM and 30 nM). Functionally, norcyclobenzaprine becomes an antagonist to 5-HT2a by Ca+ recruitment (IC). 50 (=92nM). Cyclobenzapurine is a functional antagonist to 5-HT2B (IC 50 (=100nM), which is consistent with the lack of association with any cardiac valve pathology. Cyclobenzaprine and norcyclobenzaprine are associated with 5-HT2c (IC2). 50 =0.44μM and 1.22μM) and α-2A(IC 50 It is a functional antagonist to (4.3 μM and 6.4 μM). In contrast, both CBP and nCBP have been shown to be functional agonists against 5-HT1a (EC). 50 (=5.3 μM and 3.2 μM). Table 2: Plasma concentrations of cyclobenzaprine and norcyclobenzaprine [Table 2] Table 3: Cyclobenzapurine:Norcyclobenzaprine ratio [Table 3] (Example 2)

[0131] To ensure the accuracy of data collected from in vivo studies, it was crucial to first develop in vitro analytical methods for assaying the active pharmaceutical ingredients usable in the compositions and methods of the present invention. Therefore, an LC-MS / MS analytical method for assaying cyclobenzaprine in beagle dogs was developed as described below.

[0132] The reagents were prepared as follows: Methanol / UHQ water 20 / 80v / v and 0.1% formic acid: 20 mL of methanol (VWR) was mixed with 80 mL of UHQ water (ADME) and 0.1 mL of formic acid (Merck). Carbonate buffer solution (Na2CO3 0.1M / NaHCO3 0.1M 50 / 50v / v (pH 9.8)): 2.65g of Na2CO3 was diluted with 250mL of UHQ water to produce 0.1M Na2CO3. 2.1g of NaHCO3 was diluted with 250mL of UHQ water to produce 0.1M NaHCO3. The final solution was prepared by mixing 250mL of 0.1M Na2CO3 and 250mL of 0.1M NaHCO3.

[0133] Chromatographic peak areas were obtained and integrated using Analyst® 1.5.1 (Applied Biosystems) software. Watson® 7.2.0.03 (Thermo Electro Corporation) software was used for concentration calculation, data analysis, concentration data storage, and statistical calculations. Excel® (2003) (Microsoft) was used for statistical calculations related to carryover.

[0134] Labeled cyclobenzaprine ([13 C, 2 [H3]cyclobenzaprine HCl (Alsachim) was used as the internal standard (IS) for the cyclobenzaprine HCl (Alsachim) reference sample. Cyclobenzaprine and IS standard solutions were dissolved in appropriate volumes of solvent in dark flasks, taking into account their respective correction factors, and then prepared according to Tables 4 and 5. The solutions were vortex-mixed and sonicated as needed until dissolution was complete. Table 4: Standard solution [Table 4] These solutions were prepared, divided into fixed volumes, stored at -20°C ± 5°C, and each fixed volume was discarded after use. Table 5: Diluted cyclobenzaprine solution [Table 5] Table 6: Diluted internal standard solutions [Table 6]

[0135] In a polypropylene microcentrifuge tube, 20 μl of an appropriate diluted solution of cyclobenzaprine was added to 200 μl of lithium heparin beagle dog plasma (also referred to herein as blank canine plasma), which had been pre-centrifuged at 3500 rpm for approximately 5 minutes at 0-9°C, as follows: Table 7: Preparation of calibration standards [Table 7] Table 8: Preparation of blanks and double blanks [Table 8] Table 9: Preparation of quality control samples [Table 9] Calibration standards and quality control samples were prepared daily.

[0136] The extraction procedure was carried out as follows: 0.25 μg / mL [ 13 C, 2 For H3 cyclobenzaprine, 20 μl of methanol was added to 200 μl of canine plasma. 200 μl of carbonate buffer was added to this solution and vortex-mixed for 10 seconds. Then, 1000 μl of hexane was added to the solution and mixed at 180 rpm for 10 minutes, followed by centrifugation at 3500 rpm at 0-9°C for 5 minutes. The organic phase was transferred to a polypropylene tube and dried under a nitrogen stream at 40°C. 200 μl of methanol / water (20 / 80, v / v) and 0.1% formic acid were added to the dried residue, then sonicated for approximately 5 minutes and vortex-mixed for 10 seconds. Next, the mixture was transferred to a polypropylene plate, centrifuged at 3500 rpm at 0-9°C for 5 minutes, stored at 0-9°C, and then injected into the LC-MS / MS system. Chromatography was then performed using the parameters shown below. Table 10: Chromatography parameters [Table 10] Table 11: Auto Sampler Parameters [Table 11] Table 12: Pump Parameters [Table 12] Table 13: Other parameters [Table 13] Table 14: Cyclobenzapurine and [ 13 C, 2 Comparison of HPLC parameters of [H3]cyclobenzaprine [Table 14] Table 15: Acquired parameters [Table 15] Table 16: Adjustment conditions for tandem mass spectrometers [Table 16]

[0137] The data collected during the HPLC method are shown in the table below. In particular, these data show that there was no carryover of cyclobenzaprine in the continuous procedure, when comparing the peak area of ​​cyclobenzaprine with the blank sample (Table 17). These data also show that the blank sample [ 13 C, 2 Comparing the area of ​​[H3]cyclobenzaprine HCl with the internal standard area, carryover is evident even with only the first test. However, at 0.1% interference, the degree of carryover is negligible (Table 18). Table 17: Comparison of cyclobenzaprine area in blank samples injected after lower limit of quantification (LLOQ) and upper limit of quantification (ULOQ) samples. [Table 17] Table 18: [ of S0SI sample 13 C, 2 Comparison of the area of ​​[H3]cyclobenzaprine HCl and the internal standard area of ​​a blank sample injected after the ULOQ sample. [Table 18] Table 19: Back-calculated canine plasma cyclobenzaprine concentration (ng / mL) and regression parameters [Table 19] Table 20: Intra-rate (repeatability), precision, and deviation of cyclobenzaprine assays in canine plasma. [Table 20] Table 21: Inter-operation (reproducibility), precision, and deviation of cyclobenzaprine assays in canine plasma. [Table 21] (Example 3)

[0138] The aforementioned LC-MS / MS analytical method was validated for concentration-response relationships and intra- and inter-labor accuracy of deviations, using a ±25% tolerance (excluding the limit of quantification (LLOQ) set at a ±30% tolerance). As previously stated, cyclobenzaprine HCl and internal standard (IS) [ 13 C, 2 [H3]Cyclobenzaprine HCl was used.

[0139] To validate the LC-MS / MS method, the target LLOQ was set to 0.1 ng / mL. Therefore, the upper limit of quantification (ULOQ) corresponds to a maximum of 500 times the LLOQ, i.e., 50 ng / mL. This method required a 200 μl volume of lithium heparin-treated plasma sample, and extraction was performed using liquid-liquid extraction with hexane. The extract was injected using an AP14000® (Applied Biosystems) column for HPLC and MS / MS detection. No data was excluded from the calculations. The accuracy of this method was estimated using the difference between the observed mean concentration and the nominal concentration. The precision of this method was estimated using the coefficient of variation.

[0140] Blank dog plasma was spiked with cyclobenzaprine HCl at four concentrations: LLOQ, 3×LLOQ, 0.5×ULOQ, and 0.8×ULOQ. Concentration-response relationships were determined from calibration standards ranging from LLOQ to ULOQ using two different implementations. At least eight non-zero calibration points, prepared on the same day as the analysis, were used for each calibration curve. One blank dog plasma sample that was not spiked (S0) and two that were spiked using only internal standards (S0SI) were analyzed for each calibration curve. Weighting factors were determined during qualification according to the results of the calibration curve regression fit. The simplest model that adequately described the concentration-response relationship was used.

[0141] The target tolerance included a 75% deviation of the calibration standard, with the deviation ranging from ±30.00% of the nominal value for LLOQ concentration levels and ±25.00% of the nominal value for other concentration levels. The deviation % was measured as ((Cmeas-Cn) / Cn)×100 (where Cmeas is the measured or inversely calculated concentration and Cn is the nominal concentration). The calibration curve included the lowest and highest levels, and the calibration standard was excluded from the final calibration curve only if its inversely calculated deviation was not within ±25.00% of the nominal value (except for LLOQ and ULOQ). Using this method for each S0 and S0SI sample, the interference of cyclobenzaprine-specific multiple reaction monitoring (MRM) traces on cyclobenzaprine retention time should be less than 30.00% of the cyclobenzaprine peak area of ​​the LLOQ calibration standard, and for each S0 sample, the interference of internal standard-specific MRM traces on internal standard retention time should be less than 2.00% of the internal standard peak area of ​​the S0SI. If these criteria are not met, a verification study should be conducted on unused QC samples of 3×LLOQ to assess the potential impact on the measured concentration of cyclobenzaprine and to draw conclusions regarding the qualification to perform the analysis. An overview of the criteria or practice, including the analytical batch, is shown in Table 22 below. Table 22: Acceptance Criteria [Table 22]

[0142] The intra- and inter-implementation precision and deviation of the assay methods were tested in canine plasma using two different implementations for each concentration level. For each concentration, QC samples were extracted in sets of six within the same implementation. Precision % was measured as (standard deviation / C-mean) × 100. All QC results were used for precision and mean deviation calculations, unless any were rejected due to defined analytical problems. Precision was calculated for each concentration to meet the acceptance criteria, and the values ​​should be <25.00% except for LLOQ, where <30.00% is acceptable (calculated with n=6 for each repeatable test and n=12 for the reproducibility test). Mean deviation was also calculated, and the values ​​should be within ±30.00% for LLOQ and within ±25.00% for other acceptable concentrations (calculated with n=6 for each repeatable test and n=12 for the reproducibility test).

[0143] Each S0 sample was injected three times immediately after the last higher calibration standard (ULOQ) on at least one calibration curve. MRM chromatograms were examined for the presence of peaks at the retention times of cyclobenzaprine and IS, and the area of ​​all peaks was measured. To meet the acceptance criteria, the peak area obtained at the cyclobenzaprine retention time of the cyclobenzaprine-specific MRM trace for each S0 should be less than 30.00% of the peak area obtained for cyclobenzaprine at the first calibration standard (LLOQ). The peak area obtained at the internal standard retention time of the internal standard-specific MRM trace for each S0 should be less than 2.00% of the peak area obtained for the internal standard of S0SI.

[0144] Cyclobenzapurine concentration was directly calculated using Watson® 7.2.0.03 from the peak area obtained after automatic integration of the chromatogram using Analyst® 1.5.1. The concentration of the QC sample was calculated by interpolation using a weighted calibration curve prepared under the same conditions and evaluated daily after automatic integration. If the concentration result was acceptable, it was expressed in "ng / mL". Statistics (mean, SD, precision, and deviation) were calculated using Watson® 7.2.0.03, excluding carryover calculated using Excel®. (Example 4)

[0145] To study the effects of the composition and method of the present invention, a protocol was developed to estimate the unchanged plasma concentration level of cyclobenzaprine after a single oral, sublingual, or intravenous administration of cyclobenzaprine hydrochloride to female beagle dogs. This protocol was designed as outlined in Table 23.

[0146] In the in vivo protocol, cyclobenzaprine HCl is tested using the analytical method described above within a calibration range of 0.1–50 ng / mL. This method requires a 200 μl volume of lithium heparin-treated plasma sample. Extraction is performed by liquid-liquid extraction using hexane, and the extract is injected using an AP14000® (Applied Biosystems) column for HPLC and MS / MS detection. Table 23: In vivo study design [Table 23]

[0147] To check the quality of the method during the biological sample assay, unused QC samples are prepared in duplicate at concentration levels of 3×LLOQ, 0.5×ULOQ, and 0.8×ULOQ. Each assay series consists of one sample of unspiked lithium heparin-treated blank beagle dog plasma (S0), two samples of lithium heparin-treated blank beagle dog plasma spiked only with internal standards (S0SI), eight calibration standards, a minimum of six quality control (QC) samples that double-cover three different concentrations of cyclobenzaprine distributed throughout the series, and the biological sample to be assayed.

[0148] The calibration curve should be validated using the following criteria: the 75% deviation of the calibration standard should be ±25.00% of the nominal value and ±30.00% for LLOQ; the lowest and highest levels must be included in the calibration curve; the calibration standard should be excluded from the final calibration curve if the backcalculated concentration is not ±25.00% of the nominal value. Additional investigations should be conducted as needed using the following criteria: for each S0SI, any potential interference in the retention time of cyclobenzaprine should be less than 30.00% of the cyclobenzaprine peak area of ​​the LLOQ calibration standard. If these criteria are not met, investigations should be conducted on pre-administration and 3×LLOQ QC samples to assess the potential impact on the measured concentration of cyclobenzaprine and therefore on the validation of the analytical implementation.

[0149] A series is considered validated if at least 67% of the QC samples have a deviation range of ±25.00% of the nominal concentration. Furthermore, any rejected QC sample should not correspond to the last QC sample analyzed in the series. Therefore, only the concentrations measured among the validated QC samples are considered validated. If dilution is necessary, the diluted QC is added to validate the dilution procedure. The diluted concentration is validated if at least one of the two QCs has a deviation range of ±25.00% of the nominal concentration.

[0150] Sample concentrations are calculated directly from the chromatogram using Watson® 7.2.0.03 after automatic integration by Analyst® 1.5.1, and expressed as ng / mL. Mean plasma concentrations are calculated using individual concentrations (where possible, i.e., n≧2) and expressed using the corresponding standard deviation and coefficient of variation (where possible, i.e., n≧3) (using CV(%) = (SD / mean) × 100). Individual plasma concentrations are tabled for each dog and for each scheduled sampling time. Concentrations below LLOQ are designated as "BLQ". All BLQ concentrations are replaced with 0 for the calculation of descriptive statistics of the concentration.

[0151] Pharmacokinetic analysis is performed using KINETICA® (version 4.3 (Thermo Electron Corporation)). An independent model (non-compartmental analysis) is used. All BLQ values ​​in the absorption phase are replaced with 0 before calculating pharmacokinetic variables, except for BLQ values ​​between evaluable concentrations that are treated as missing values. Final BLQ values ​​are ignored. The following pharmacokinetic parameters are calculated: C max (ng / mL): Maximum observed plasma concentration (for oral and sublingual administration). T max (h): Time from administration until the peak plasma concentration is measured (for oral and sublingual administration). AUC t (ng / (mL×h)): Area under the plasma concentration-time curve from administration to the final concentration observed at time t, as measured by the trapezoidal rule. AUC inf (ng / mL × h): Area under the plasma concentration-time curve from administration to infinity, extrapolated from the final phase. This is AUC. 0-∞ It can also be expressed as follows. %AUC extra :(AUC inf -AUC t / AUC inf The extrapolated AUC percentage, calculated as ) × 100. T 1 / 2 * (h):ln2 / Kel This is the calculated emission half-life. K el * (1 / h): Estimated by linear regression of the logarithm of the final concentration as a function of time using Kinetica® software. Cl and Cl / F * (L / h):Dose / AUC inf This is the apparent plasma clearance that is calculated. V d and V d / F * (L):Cl / K el The apparent distribution volume is calculated as follows. Absolute bioavailability F%(%) = ((AUC by extravascular administration) / AUC by IV administration) × 100. * These parameters are %AUC extra It is calculated only when the percentage is less than 20% and the emission phase contains three time points. (Example 5)

[0152] To test the effects of the methods and compositions of the present invention described herein, a protocol for administering cyclobenzaprine HCl to beagle dogs was designed. This protocol is described below.

[0153] Five treated female dogs will be used, and each dog will be administered the test substance via sublingual (SL) oral administration through a nasogastric tube (NG) into the stomach, and intravenous (IV) administration. A wash-out period of at least two weeks will be observed between each type of administration. Blood samples will be collected as follows: Session 1: Oral administration

[0154] A single dose of NG 0.14 mg / kg (under 5 ml / kg volume and 0.028 mg / mL solution concentration) is administered. Blood samples are collected before administration, and then at 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, and 24 hours after administration (a total of 12 blood samples per animal). Session 2: Sublingual administration

[0155] After a washout period of at least two weeks, sedate the dogs with propofol (6.5 mg / kg IV). Then administer 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). Collect blood samples before administration, and then at 10, 20, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 24 hours after administration (a total of 12 blood samples per animal). Do not give the animals water for 30 minutes after administration. Session 3: Intravenous administration

[0156] After a washout period of at least two weeks, administer a single IV dose of 0.14 mg / kg to dogs (under a volume of 1 mL / kg, a bolus of approximately 30 seconds, and a solution concentration of 0.14 mg / mL). Collect blood samples before administration, and then at 10, 20, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 24 hours after administration (a total of 12 blood samples per animal).

[0157] Blood sampling was designed to minimize animal discomfort and ensure the quality of the biological sample, following basic procedures commonly used in studies conducted in dogs. Serial blood samples (one tube of approximately 5 mL) were collected from the jugular vein using a vacuum tube containing lithium heparin. After sealing each tube, the blood samples were manually stirred and stored on ice until centrifugation (within 30 minutes of sampling). The samples were centrifuged at 1500 g at 4°C for 10 minutes. The resulting total plasma from each tube was immediately transferred to appropriately labeled polypropylene tubes (three constant volumes of at least 500 μl each of plasma), stored upright at approximately -80°C, and protected from light until bioanalysis.

[0158] After fasting the dogs overnight, administer each treatment, and feed the dogs 4 hours after each treatment. Cyclobenzaprine HCl is administered at a dose of 0.14 mg / kg for each of the three routes of administration (PO, sublingual, and IV). Potassium phosphate buffer (pH 7.4) is used as the vehicle for each of the three routes.

[0159] Female beagle dogs weighing 12-18 kg, obtained from HARLAN or CEDS, will be used in these studies. The dogs will be housed in groups in kennels with free access to food and water under natural light and a controlled ambient temperature of 18±3°C. During the pharmacokinetic phase, the dogs will be kept in a kennel approximately 1 m 2 or 2m 2 The animals are kept individually in a designated floor area. During this period, the animal enclosure is maintained at a controlled ambient temperature of 18±3℃ under artificial light from 7:00 to 19:00 (12 hours). (Example 6)

[0160] The solubility of cyclobenzaprine HCl was tested in both purified water (Table 24) and an aqueous solution containing monobasic potassium phosphate (KH2PO4) and NaOH to adjust the solution to pH 7.4. The (KH2PO4) solution was prepared according to the current USP (USP34) (Table 25). Briefly, 50 mL of 0.2 M monobasic potassium phosphate (KH2PO4) was mixed with 39.1 mL of 0.2 M NaOH, and water was added to make a final solution of 200 mL. During the test, the change in pH of the solution was also measured with each addition. The test was performed with 100 mL of sample, and 5 g of cyclobenzaprine HCl was added to an initial fixed amount of 10 g each time. Each pH value was measured only after the added amount of cyclobenzaprine HCl had completely dissolved. The measured values ​​are recorded in the table below. The solubility data for cyclobenzaprine HCl reported in the literature (30 g per 100 g of water) was consistent with that obtained using an aqueous KH2PO4 solution (pH 7.4) as the solvent. Table 24: Dissolution in purified water (volume = 100 mL) [Table 24] Table 25: Dissolution in phosphate buffer solution pH 7.4 (volume = 100 mL) [Table 25]

[0161] According to the protocol for the aforementioned preclinical studies, the solution administered via the sublingual route had to be at a concentration of 2.5 mg / mL (as previously stated, solvent: KH2PO4 aqueous solution, pH 7.4). The volume of cyclobenzaprine HCl solution administered was 0.056 mL / kg. After reviewing the available literature and anticipating the collection of data after the establishment of a preliminary formulation, the inventors assumed an average body weight of 10 kg per dog. Therefore, the amount of cyclobenzaprine HCl solution administered sublingually was 0.56 mL, corresponding to 1.4 mg of cyclobenzaprine HCl.

[0162] To simulate the ambient pH under the tongue of animals, artificial saliva was prepared by considering the standard procedure in available literature (e.g., see UNI EN 12868:2002), with some modifications. Briefly, 4.2 g of sodium bicarbonate, 500 mg of sodium chloride, 200 g of potassium carbonate, and 30 mg of sodium nitrite were dissolved in 900 mL of purified water while stirring with a magnetic stirrer. The final pH of the solution was approximately pH 8 to pH 9, which was then acidified to approximately pH 5.5 using lactic acid.

[0163] To account for the different volumes of saliva that may be present under the tongue of animals, 0.56 mL of cyclobenzaprine HCl solution (solvent: H2O; basicizing agent: KH2PO4 aqueous solution, pH 7.4, as described above), equivalent to the dose administered to dogs, was added to 1 mL, 3 mL, and 5 mL of saliva, and the pH values ​​were measured as shown in Table 26. Instead of cyclobenzaprine HCl alone, formulations without a basicizing agent were added to the saliva, and the same pH measurements were performed (Table 24). Table 26: pH measurement of cyclobenzaprine HCl solution in artificial saliva [Table 26] Table 27: pH measurement of cyclobenzaprine HCl tablets in artificial saliva (control: lacking basicizing agent) [Table 27]

[0164] As mentioned above, K2HPO4 was added to the tablet formulation to increase the sublingual pH after tablet administration to pH 7.4, which is as close as possible to the pH value of the KH2PO4 aqueous solution. The amount was determined by performing a pH test on a solution obtained by dissolving the formulation tablet lacking the K2HPO4 basicizing agent in artificial saliva. By adding 1.05 mg of K2HPO4 to the control formulation (lacking the K2HPO4 basicizing agent), the results shown in Table 28 were obtained. Table 28: pH measurement of cyclobenzaprine HCl tablets (containing a basicizing agent) in artificial saliva [Table 28] (Example 7)

[0165] An exemplary composition formulated for sublingual administration is a sublingual tablet designed to disintegrate rapidly under the tongue. To develop this type of composition, the pharmacokinetic (galenic) properties of cyclobenzaprine HCl were studied. Soluble testing confirmed that slightly basic media (e.g., aqueous KH2PO4 solution, pH 7.4, as previously mentioned) are suitable solvents for cyclobenzaprine HCl.

[0166] The sublingual dosage form specification is not defined by the pharmacopoeia; therefore, to obtain tablets referred to as orally dispersible forms with a disintegration time conforming to USP specifications (disintegrating in less than 30 seconds), preliminary stockings of excipients were selected. This specification is one target of the formulation, but not a mandatory one. Based on this characteristic, disintegrants (crospovidone) and a very tasty disintegrant (Pearlitol Flash) were selected. Based on the aforementioned characteristics of the KH2PO4 aqueous solution, pH 7.4, stoichiometric ratios of K2HPO4 were introduced as a basicizing agent into one of the preliminary formulations. Furthermore, formulations lacking a basicizing agent were also produced. For each formulation method, batches of cyclobenzaprine HCl obtained from two different suppliers were tested with the aim of selecting the best batch for further testing. In both cases, the final mixture was obtained by dry mixing and adding a lubricant only in the final mixing step. Due to the low concentration of the active ingredient, a gradual dilution method was applied.

[0167] The tableting phase was performed using a GP1 tablet press equipped with a 4 mm punch. The choice of punch was considered in relation to the administration method, as it affects both the diameter and shape of the tablet to suit sublingual and transmucosal absorption. The final mixture and corresponding tablets were tested for all the standard parameters recorded below. Two formulations containing K2HPO4 as a basicizing agent were prepared as described in Table 35. These formulations differed only in the use of cyclobenzaprine HCl from different suppliers. The analytical results for each formulation are summarized in Table 36. Table 35: Cyclobenzapurine HCl preparations containing a basicizing agent [Table 35] Table 36: Analysis results of cyclobenzaprine HCl preparations containing basicizing agents [Table 36] *Preliminary analysis conditions were applied to these preliminary trials; TBD: Undetermined

[0168] Preparations lacking the K2HPO4 basicizing agent were manufactured as shown in Table 37 below. The analytical results of these preparations are shown in Table 38. Table 37: Cyclobenzaprine HCl preparations lacking basicizing agents [Table 37] Table 38: Analysis results of cyclobenzaprine HCl preparations containing basicizing agents [Table 38] *Preliminary analysis conditions were applied to these preliminary trials; TBD: Undetermined

[0169] Based on the distribution, assay, and content uniformity results, both formulations were identified as suitable. (Example 8)

[0170] To evaluate the stability of the aforementioned formulations, prototypes A, B, C, and D were maintained under stress conditions at 50°C for 30 days. The results are shown in Tables 39 and 40 below, respectively. Cyclobenzaprine HCl without excipients, obtained from each manufacturer, was also tested over a 15-day period as shown in Table 41. In summary, the formulations were stable, especially when considering high-stress storage conditions. The differences between formulations containing the K2HPO4 basicizing agent and those lacking the K2HPO4 basicizing agent were minimal. Table 39: Cyclobenzapurine HCl preparation containing a basicizing agent, 30 days at 50°C [Table 39] *Data obtained from samples stored at room temperature Table 40: Cyclobenzapurine HCl preparation without basicizing agent, 30 days at 50°C [Table 40] *Data obtained from samples stored at room temperature Table 41: Cyclobenzapurine HCl active ingredient obtained from two manufacturers [Table 41] *Data obtained from samples stored at room temperature

[0171] As previously stated, the micronized cyclobenzaprine HCl supplied by Dipharma and the unmicronized cyclobenzaprine HCl supplied by Sifavitor are equivalent in terms of their drug discovery activity and properties. To confirm this conclusion, a further clinical trial was designed using unmicronized cyclobenzaprine HCl supplied by Dipharma in both formulations (one containing a K2HPO4 basicizing agent and one without). This formulation was prepared to compare the same characteristics of unmicronized cyclobenzaprine HCl supplied by two different manufacturers (Table 42). The formulations were then analyzed and compared with the aforementioned formulations, as shown in Table 43. Table 42: Unparticulated cyclobenzaprine HCl preparation (contains a basicizing agent) [Table 42] Table 43: Analysis of non-microparticle cyclobenzaprine HCl preparation (containing K2HPO4 basicizing agent) [Table 43]

[0172] The aforementioned control cyclobenzaprine HCl formulation (lacking a basicizing agent) was replicated by substituting microparticle cyclobenzaprine HCl with unmicroparticle cyclobenzaprine HCl (Table 44). Next, the formulations were analyzed as shown in Table 45 and compared with the aforementioned formulation lacking the K2HPO4 basicizing agent. Table 44: Unparticulated cyclobenzaprine HCl preparation (lacking a basicizing agent) [Table 44] Table 45: Analysis of non-micronized cyclobenzaprine HCl preparations (control: lacking basicizing agent) [Table 45]

[0173] In summary, the Dipharma batch of non-micronized cyclobenzaprine HCl demonstrated good distribution and performance for the tested formulations (e.g., particularly short disintegration time for tablet form). The Dipharma batch of micronized cyclobenzaprine HCl demonstrated good distribution and performance for the tested formulations, except for some electrostatic phenomena typical of micronized powders. The Sifavitor batch of non-micronized cyclobenzaprine HCl demonstrated good distribution and performance for the tested formulations. All analytical results recorded in Example 8 and referring to previously recorded formulations were obtained by performing the analysis under the following conditions. Assay Analytical equipment: HPLC JASCO equipped with automatic sampler AS-1555, pump PU-1580, and detector UV-2075Plus. Analysis column: ALLTIMA C 18 5 μm 150 × 4.6 mm or equivalent Mobile phase: 49.8% water 25% methanol 25% acetonitrile 0.2% methanesulfonic acid The mobile phase was corrected to pH 3.60 ± 0.10 with diethylamine. Flow rate: 1.5ml / min Wavelength: 240nm Injection volume: 10 μl Temperature: 25℃ Acquisition time: 8 minutes Solvent: 50% methanol 50% phosphate buffer: (Dissolve 6.80 g / l potassium dihydrogen phosphate and 1.57 g / l sodium hydroxide in water, and correct the pH to 7.40 ± 0.10 with 1N sodium hydroxide as needed.) Cyclobenzapurine retention time: Approximately 5.0 minutes Preparation of product standard: Weigh approximately 20 mg of cyclobenzaprine HCl as the reference (or action) standard and place it in a 50 mL flask. Add 40 mL of solvent, sonicate for 5 minutes, and dilute with solvent to the specified volume. Transfer 2.5 mL of this solution to a 10 mL flask and dilute with solvent to the specified volume (cyclobenzaprine HCl concentration = approximately 100 μg / mL). Sample preparation (powder): Weigh approximately 160 mg of cyclobenzaprine HCl powder into a 100 mL flask, add 70 mL of solvent, stir with a magnetic stirrer for 10 minutes, sonicate for 5 minutes, and dilute with solvent to the specified volume. Filter through a syringe filter with a 0.45 μm hydrophilic PVDF membrane and then inject. The concentration of cyclobenzaprine HCl is 100 μg / mL. Sample preparation (tablets): Weigh 10 cyclobenzaprine HCl tablets and place them in a 100 mL flask. Add 80 mL of solvent, stir with a magnetic stirrer for 10 minutes, sonicate for 5 minutes, and dilute with solvent to the specified volume. Transfer 4 mL to a 10 mL flask and dilute with solvent to the specified volume. Filter through a syringe filter with a 0.45 μm hydrophilic PVDF membrane and inject. [The concentration of cyclobenzaprine HCl is 100 μg / mL]. purity Analytical equipment: HPLC JASCO equipped with automatic sampler AS-1555, pump PU-1580, and detector UV-2075Plus. Analysis column: ALLTIMA C 18 5 μm 150 × 4.6 mm or equivalent Mobile phase: 59.8% water 20% methanol 20% acetonitrile 0.2% methanesulfonic acid The mobile phase was corrected to pH 3.60 ± 0.10 with diethylamine. Flow rate: 2.0ml / min Wavelength: 240nm Injection volume: 20 μl Temperature: 25℃ Acquisition time: 60 minutes Solvent: methanol Holding time: Approximately 12.0 minutes Retention time of the substance in question: Dibenzosverenone (impurity 1): Approximately 56.0 minutes Carbinol (Impure 2): Approximately 6.0 minutes Amitriptyline (impurity 4): Approximately 15.0 minutes Preparation of relevant substance standards (for known and unknown impurities): Weigh approximately 10 mg of cyclobenzaprine HCl reference (or action) standard and approximately 10 mg of cyclobenzaprine HCl impurity 1, 2, and 4 reference (or action) standards into a 100 mL flask, add 80 mL of methanol, sonicate for 10 minutes, and dilute with methanol to the specified volume. Transfer 1.0 mL of this solution to a 100 mL flask and dilute it with solvent to the specified volume. The impurity concentration is 1 μg / mL, which corresponds to 0.1%. Sample preparation: Accurately weigh four cyclobenzaprine HCl tablets and place them in a 10 mL flask. Add 5 mL of solvent, sonicate for 10 minutes, and dilute with solvent to the specified volume. Filter through a syringe filter with a 0.45 μm hydrophilic PVDF membrane and inject. The concentration of cyclobenzaprine HCl is approximately 1000 μg / mL.

[0174] Starting with all the data collected in the formulation setup, further batches of formulations with and without basicizing agents were manufactured. As the final step in drug development, large test batches were manufactured according to the formulations recorded in Tables 46 and 47. Table 46: Cyclobenzapurine HCl preparations containing a basicizing agent [Table 46] Table 47: Cyclobenzaprine HCl preparations lacking basicizing agents [Table 47]

[0175] Starting with a cyclobenzaprine HCl formulation containing a basicizing agent, additional formulations were prepared. These were then coated using a coating mixture also containing a basicizing agent, as shown in Table 48. Table 48: Cyclobenzaprine HCl preparations containing a basicizing agent (coated preparations) [Table 48]

[0176] Table 49 records the time 0 data obtained from stability studies using large test batches of different packaging materials. Table 49: Stability study, data at time 0. [Table 49]

[0177] To study the stress-dependent stability of batches lacking basicizing agents, samples were stored at 40°C and 50°C and analyzed after 1, 2, 3, and 4 weeks. Data at week 1 were recorded in Table 50. Table 50: Stability study, week 1, without basicizing agent [Table 50]

[0178] All analyses performed, starting with large test batches, were conducted according to the following optimized and validated conditions. purity Analytical equipment: HPLC JASCO equipped with automatic samplers AS-2055 and PU-2080, and a Diode Array MD 2010 Plus detector. Analytical column: SYMMETRY C18 5μm 250×4.6mm or equivalent Mobile phase: 25% methanol, 25% acetonitrile, 50% butylamine buffer / CH3COOH (10 ml of 99.5% butylamine is added to 950 ml of water, pH is corrected to 6.20 ± 0.10 with glacial acetic acid, and then diluted to 1 L by volume with water). Flow rate: 1.5mL / min Wavelength: 239nm Injection volume: 10 μl Temperature: 28℃ Acquisition time: 35 minutes Solvent: Mobile phase Retention time: Impurity A (carbinol) approx. 6', Impurity B (amitriptyline) approx. 14', Impurity C (dibenzosverenone) approx. 29', Cyclobenzapurine HCl approx. 11'

[0179] Preparation of relevant reference materials (for known and unknown impurities): Weigh approximately 10 mg of cyclobenzaprine HCl reference (or action) standard and approximately 10 mg of cyclobenzaprine HCl impurity A, B, and C reference (or action) standards into a 100 mL flask, add 5 mL of acetonitrile, then add 75 mL of solvent, sonicate for 5 minutes, and dilute with solvent to the specified volume. Transfer 1.0 mL of this solution to a 50 mL flask and dilute it with the solvent to the specified volume to achieve a final impurity concentration of 2 μg / mL. LOQ level: Transfer the last 1.0 mL of solution to a 10 mL flask and dilute with solvent to the specified volume to bring the impurity concentration to 0.2 μg / mL. Sample preparation: Accurately weigh 10 cyclobenzaprine HCl tablets and place them in a 25 mL flask (or 20 cyclobenzaprine HCl tablets in a 50 mL flask). Add 20 mL (or 40 mL) of solvent, sonicate for 5 minutes, and dilute with solvent to the specified volume. Filter through a syringe filter with a 0.45 μm hydrophilic PVDF membrane and then inject. The concentration of cyclobenzaprine HCl is approximately 1000 μg / mL. Assay Analytical equipment: HPLC JASCO equipped with automatic sampler AS-1555, pump PU-1580, and detector UV-2075Plus. Analysis column: ALLTIMA C 18 5 μm 150 × 4.6 mm or equivalent Mobile phase: 49.8% water 25% methanol 25% acetonitrile 0.2% methanesulfonic acid The mobile phase was corrected to pH 3.60 ± 0.10 with diethylamine. Flow rate: 1.5ml / min Wavelength: 240nm Injection volume: 10 μl Temperature: 25℃ Acquisition time: 8 minutes Solvent: 50% methanol 50% phosphate buffer (dissolve 6.80 g / l potassium dihydrogen phosphate and 1.57 g / l sodium hydroxide in water, and correct the pH to 7.40 ± 0.10 with 1N sodium hydroxide as needed). Cyclobenzapurine retention time: Approximately 5.0 minutes Preparation of product standard: Weigh approximately 20 mg of cyclobenzaprine HCl as the reference (or action) standard and place it in a 50 mL flask. Add 40 mL of solvent, sonicate for 5 minutes, and dilute with solvent to the specified volume. Transfer 2.5 mL of this solution to a 10 mL flask and dilute with solvent to the specified volume to equalize the concentration of cyclobenzaprine HCl to approximately 100 μg / mL. Sample preparation (powder): Weigh approximately 160 mg of cyclobenzaprine HCl powder into a 100 mL flask, add 70 mL of solvent, stir with a magnetic stirrer for 10 minutes, sonicate for 5 minutes, and dilute with solvent to the specified volume. To obtain a cyclobenzaprine HCl concentration of 100 μg / mL, filter the solution through a syringe filter with a 0.45 μm hydrophilic PVDF membrane and then inject. Sample preparation (tablets): Weigh 10 cyclobenzaprine HCl tablets and place them in a 100 mL flask. Add 80 mL of solvent, stir with a magnetic stirrer for 10 minutes, sonicate for 5 minutes, and dilute with solvent to the specified volume. Transfer 4 mL to a 10 mL flask and dilute with solvent to the specified volume. To obtain a cyclobenzaprine HCl concentration of 100 μg / mL, filter the solution through a syringe filter with a 0.45 μm hydrophilic PVDF membrane and then inject. (Example 9)

[0180] As mentioned in Example 4, a study was designed to evaluate the effects of the composition and method of the present invention. Beagle dogs were used in the study, and cyclobenzaprine HCl was administered orally, sublingually, or intravenously. Pharmacokinetic parameters were then calculated. The outline of the study design is as follows: Test substance: Cyclobenzapurine hydrochloride Route of administration: Oral (PO), sublingual, and intravenous (IV) Breed: Beagle Sex: Female Matrix: Plasma Vehicle: Adjust the pH of the KH2PO4 aqueous solution to 7.4 with NaOH. Dosage: 0.14 mg / kg (equivalent to approximately 10 mg for a 70 kg person) Formulation concentrations: PO: 0.028 mg / mL; Sublingual: 2.5 mg / mL; IV: 0.14 mg / mL Administration volume: PO: 5 mL / kg; Sublingual: 0.056 mL / kg; IV: 1 mL / kg

[0181] For all three administration routes, blood was collected in a fasted state. For PO administration, blood was collected at 0 hours (before administration) and at 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, and 24 hours after administration. For sublingual and IV administration, blood was collected before administration and at 10 minutes, 20 minutes, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 24 hours after administration. Analysis of cyclobenzaprine was performed substantially as described above. Briefly, this method involved liquid-liquid extraction using hexane. The extract was injected using an "Onyx monolithic Phenomenex C18 100×3.0 mm" column with API4000® (Applied Biosystems) for HPLC and MS / MS detection. This method was linear for cyclobenzaprine in canine plasma from 0.1 ng / mL to 50 ng / mL. Quality control samples were prepared in canine plasma at concentrations of 0.3, 25, and 40 ng / mL for cyclobenzaprine. The results obtained from the analysis of the quality control samples were within the acceptable limits defined in the protocol, thus verifying the concentrations measured in the plasma samples.

[0182] Intravenous (IV) administration of cyclobenzaprine HCl solution containing a basicizing agent yielded a remarkably dynamic range in the plasma concentration-time profile, while the bioavailability of cyclobenzaprine administered via nasogastric tube was remarkably low. In previous Beagle experiments, 2 mg / kg of cyclobenzaprine was administered to Beagles (6.7-8.2 kg) with radiolabeling (Hucker, 1978, Drug Metabolism). (and Disposition, Vol. 6 (No. 6): p. 659). The dose is expressed as free base and therefore must be adjusted by MW 275 g / mol of free base and MW 312 g / mol of HCl salt. Thus, 1.76 mg / kg of cyclobenzaprine HCl was administered. Cyclobenzaprine was administered intravenously (IV) by saline solution or orally (PO) by gelatin capsule. In Hucker's study, the plasma level of cyclobenzaprine was measured by radioactive equivalent. 14 Plasma levels were measured by recovering 14C-labeled cyclobenzaprine, and therefore the plasma levels were "equivalents" to a specific value (μg / ml) of cyclobenzaprine. Using this method, beagles orally administered 1.76 mg / kg of cyclobenzaprine HCl had plasma levels of 0.72 μg / ml [equivalent] (at 0.5 hours), 1.14 μg / ml [equivalent] (at 1 hour), 1.46 μg / ml [equivalent] (at 2 hours), 0.92 μg / ml [equivalent] (at 4 hours), 0.58 μg / ml [equivalent] (at 6 hours), and 0.10 μg / ml [equivalent] (at 24 hours). Dogs administered 2 mg / kg of cyclobenzaprine intravenously in physiological saline had plasma levels of 0.43 μg / ml [equivalent] (0.5 hours), 0.53 μg / ml [equivalent] (1 hour), 0.60 μg / ml [equivalent] (2 hours), 0.55 μg / ml [equivalent] (4 hours), 0.45 μg / ml [equivalent] (6 hours), and 0.12 μg / ml [equivalent] (24 hours). In our beagle study, the dose was 0.14 mg / kg, which is approximately 1 / 12.6 of the dose in Hucker's study. For the sole purpose of comparing the pharmacokinetic profiles of Hucker's study and our study, Hucker's data were adjusted to be equivalent to a dose of 0.14 mg / kg of cyclobenzaprine HCl, assuming dose proportionality. These are shown in Table 51. Table 51: Comparison of pharmacokinetics [Table 51]

[0183] By comparison, it was found that the PO bioavailability of Hucker administered via gelatin capsules, adjusted for dose and dose-proportionality compared to our study, was considerably higher than that of oral cyclobenzaprine solution administered via nasogastric tube (NG) (peaking at 0.41 ng / ml at 1 hour) (peaking at 115.9 ng / ml at 2 hours). The profile of cyclobenzaprine administered IV by Hucker was relatively flat from 0.5 hours to 6 hours, and when adjusted for dose and dose-proportionality compared to our study, it changed from 34.1 ng / ml at 0.5 hours to 47.6 ng / ml (at 2 hours) and then to 35.7 ng / ml, while our profile was dynamic during that period, decreasing from 52.3 ng / ml to 3.4 ng / ml. Hucker did not measure plasma levels at 0.167 hours or 0.33 hours, but our study shows that these values ​​represent peak plasma levels and exhibit a more dynamic range. Hucker did not study sublingual administration.

[0184] Surprisingly, sublingual administration of cyclobenzaprine HCl resulted in improved pharmacokinetic properties and bioavailability compared to PO administration (Table 52, Figures 2 and 3; individual PO, sublingual (SL), and IV data: Tables 53-56). In particular, cyclobenzaprine C max The levels were significantly higher when administered sublingually, ranging from approximately 0.48 ng / mL (PO) to approximately 137 ng / mL (SL). max The time required decreased from 1 hour to 10 minutes, and bioavailability increased from approximately 3.8% to 292%. Bioavailability for IV administration was considered 100%, as with standard practice. The inventors believe that the possible explanation for sublingual bioavailability is that of true IV administration. max This can be explained by the fact that the IV measurement was performed after the value was supposed to be recorded. Nevertheless, the bioavailability of PO versus sublingual administration is almost 77 times higher. Table 52: Mean ± SD plasma pharmacokinetic parameters [Table 52] * median ** Cl and Vd are Cl / F and Vd / F in the PO and sublingual pathways, respectively. NA: Not applicable Table 53: Cyclobenzapurine plasma concentration (ng / mL) measured after oral administration of cyclobenzaprine HCl [Table 53] Table 54: Cyclobenzapurine plasma concentration (ng / mL) measured after sublingual administration of cyclobenzaprine HCl [Table 54] BLQ: Less than the limit of quantification (0.1 ng / mL) Italics: Out of range (50 ng / mL): Value given for index purposes Table 55: Cyclobenzapurine plasma concentration (ng / mL) measured after IV administration of cyclobenzaprine HCl [Table 55] BLQ: Less than the limit of quantification (0.1 ng / mL) Table 56: Cyclobenzaprine pharmacokinetic parameters after administration of cyclobenzaprine HCl [Table 56] * Cl and Vd are Cl / F and Vd / F in the PO and sublingual pathways, respectively. Italics: %AUCextra>20%: Value given for the index NC: Not calculated NA: Not applicable

[0185] To further investigate the causes of the sublingual bioavailability measured at over 100%, several additional hypotheses were proposed. These hypotheses included analytical interaction between propofol (used as an anesthetic via the sublingual route) and cyclobenzaprine, binding of cyclobenzaprine to the device used for administration, and in vivo enzymatic competition between propofol and cyclobenzaprine in the liver.

[0186] To address the hypothesis of in vivo enzymatic competition between propofol and cyclobenzaprine in the liver, four dogs were treated with or without propofol, either sublingually or intravenously, as follows: one dog was treated intravenously without propofol preanesthetic, one dog was treated intravenously after propofol preanesthetic, one dog was treated sublingually without propofol preanesthetic, and one dog was treated sublingually after propofol preanesthetic. Samples were collected from each dog before and after (where possible) propofol administration, and 5, 10, and 20 minutes after administration. Figures 4 and 5 show the mean cyclobenzaprine concentration-time profiles after intravenous and sublingual administ...

Claims

[Claim 1] Absorption via mucous membrane.

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