Flumazenil for treating post-traumatic stress disorder and anxiety

Abstract

There is disclosed a method for treating post-traumatic stress disorder (PTSD) or treating anxiety comprising administering flumazenil. The flumazenil may be administered non-orally and / or at least daily. The non-oral route of administration may be subcutaneous, buccal, sublingual, nasal, transdermal, intravenous, intramuscular injection, or rectal. The present disclosure further provides a flumazenil dosage form comprising (a) a buccal flumazenil lozenge formulation; (b) a flumazenil dissolving sublingual strip formulation; (c) a subcutaneous injection dosage form of an aqueous solution of flumazenil; or (d) a rectal suppository formulation, wherein each flumazenil dosage form is capable of systemically delivering from about 0.1 mg to about 3 mg of flumazenil. There is further disclosed a chronic (at least one week or longer) treatment regimen of flumazenil to reach the brain of a patient having anxiety or PTSD, comprising administering a daily non-oral dose of flumazenil.

Description

Disease-Modifying Method for Treating Post-Traumatic Stress Disorder and Anxiety Cross-Reference to Related Applications

[0001] This application claims the benefit of priority of US Provisional Application No.63 / 598,650, filed on November 14, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0002] In a first aspect, the present disclosure provides a disease-modifying method for treating post-traumatic stress disorder (PTSD) and for treating anxiety comprising an initial chronic (meaning at least one week or longer) course of treatment comprising individual self- administering a daily non-oral (upper GI tract) dose of flumazenil wherein the non-oral route of administration is selected from the group consisting of subcutaneous, buccal, sublingual, nasal, transdermal, intravenous, intramuscular injection, or rectal dose of flumazenil (i.e., routes of administration that reach the brain via systemic circulation while avoiding a portal circulation first pass effect), once or up to four times each day, at from about 0.1 mg to about 3 mg flumazenil per dose, wherein each dose of flumazenil is administered at least one hour apart. More specifically, the disease modifying method for treating PTSD and anxiety disorders comprises administering chronically up to four doses of flumazenil per day via injection, including subcutaneous administration, intramuscular administration intraperitoneal administration, and / or intravenous administration, by injecting an aqueous saline solution of flumazenil, buccal administration with a lozenge or, sublingual dissolving strip, or nasally via a nasal spray, or transdermal via a skin permeation patch, or rectally via a suppository, for a chronic treatment with flumazenil. Preferably, the injection administration is subcutaneous. Preferably, the daily dose administered is from about 0.1 mg to about 3 mg of flumazenil. The present disclosure further provides a flumazenil dosage form comprising (a) a buccal flumazenil lozenge formulation; (b) a flumazenil dissolving sublingual strip formulation; (c) a subcutaneous injection dosage form of an aqueous solution of flumazenil; or (d) a rectal suppository formulation, wherein each flumazenil dosage form is capable of systemically delivering from about 0.1 mg to about 3 mg of flumazenil.

[0003] In a second aspect of the present disclosure, the present disclosure provides a chronic (at least one week or longer) treatment regimen of flumazenil to reach the brain of a patient having anxiety or PTSD, comprising individual self-administering a daily non-oral dose of flumazenil wherein the non-oral route of administration is selected from the group consisting of subcutaneous, buccal, sublingual, nasal, transdermal, intravenous, intramuscular injection, or rectal dose of flumazenil, once or up to four times each day, at from about 0.1 mgto about 3 mg flumazenil per dose, wherein each dose of flumazenil is administered at least one hour apart. Preferably, the dosing of flumazenil occurs during hours from awake time until no more than 10 hours later. Preferably, the administration of each daily dose of flumazenil is by a means for dosing selected from the group consisting of subcutaneous, intramuscular, intraperitoneal, nasal, buccal, sublingual, rectal, inhalation, and combinations thereof. Background Flumazenil

[0004] Flumazenil Injection, USP is a benzodiazepine receptor antagonist. Chemically, flumazenil is ethyl 8- fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a](1,4) benzodiazepine-3-carboxylate. Flumazenil has an imidazobenzodiazepine structure, a calculated molecular weight of 303.3, and the following structural formula:

[0005] Flumazenil is a white to off-white crystalline compound with an octanol: buffer partition coefficient of 14 to 1 at pH 7.4. It is insoluble in water but slightly soluble in acidic aqueous solutions. Flumazenil injection is available as a sterile parenteral dosage form for intravenous administration. Each mL contains 0.1 mg of flumazenil compounded with 1.8 mg of methylparaben, 0.2 mg of propylparaben, 0.9% sodium chloride, 0.01% edetate disodium, and 0.01% acetic acid; the pH is adjusted to approximately 4 with hydrochloric acid and / or, if necessary, sodium hydroxide.

[0006] Flumazenil is an imidazobenzodiazepine having high affinity for the GABAA benzodiazepine-receptor complex, the specific binding site of benzodiazepines. As flumazenil is a competitive inhibitor of benzodiazepines, it is used for reversing benzodiazepine-induced sedation and anesthesia following therapeutic or diagnostic procedures (WO 2009 / 114740). Flumazenil is also known to reverse the effect of non-benzodiazepine drugs, such as the imidazopyridine hypnotic zolpidem (Patat et al., Clin. Pharmacol. Ther., 1994, 56(4):430-6). Flumazenil antagonizes the central effects of zolpidem, an imidazopyridine hypnotic) (Bond, CNS Drugs, 9(1): 41-57, 1998). Flumazenil was also considered for treating hepatic encephalopathy (Als-Nielsen B et al., Cochrane Database of Systematic Reviews Issue 2. Art.No.: CD002798. DOI: 10.1002 / 14651858.CD002798.pub2, 2004). The therapeutic effects were achieved by intravenous administration of flumazenil in a liquid formulation. A liquid formulation of flumazenil (Romazicon®) for intravenous (iv) administration is currently approved for reversing the sedative effects of benzodiazepines. Therefore, current usage of flumazenil is sporadic, that is, on specific occasions as needed to treat medical conditions, not on a daily basis, and not in a self-administered manner. Moreover, iv flumazenil is rapidly metabolized (ROMAZICON® package insert). It should be noted that flumazenil is a drug that is only administered by physicians, available only for injection and is not available in any kind of dosage form that an individual can administer to themselves or take on their own, even with a prescription.

[0007] Flumazenil is currently used as a treatment to reverse the effects of benzodiazepine sedatives. It is a competitive antagonist that binds to the benzodiazepine site on the gamma-aminobutyric acid (GABA) receptor complex. Flumazenil’s current FDA- approved clinical uses are reversal agents for benzodiazepine overdose and postoperative sedation from benzodiazepine anesthetics.

[0008] Flumazenil has been investigated for use to “push the body back to normal ranges” such as in U.S. Patent 10,376,524 a method for treating hypersomnia (idiopathic or amphetamine resistant). Further, in US2012 / 0295893 are more treatment methods for excessive sleepiness during waking hours or sleep apnea in further attempts to push the body back to normal. And US Patent 6,689,816 goes in a different direction to treat PTSD and an anxiety disorder with an agent that increases GABA-A neurotransmission and decreases NMDA-glutamate neurotransmission because flumazenil (2 mg administered iv) “does not have anxiogenic effect in patients with PTSD.” In other words, iv flumazenil administration (2 mg as a bolus) did not improve PTSD but it also did not exacerbate PTSD attacks as well. Randall et al. (“Effects of benzodiazepine antagonist flumazenil in PTSD” Biol. Psychiatry 38:319-324, 1995) teaches that flumazenil did not overtly make the PTSD measurably worse. The supposition in Randall et al. was that flumazenil would make things worse given that it blocks GABA, but apparently it did not appear to notably exacerbate the underlying disorder. Flumazenil (iv administration) also induced panic attacks. Therefore, 2 mg iv administration of flumazenil, in an attempt to push the body back to normal ranges, failed to achieve its desired therapeutically beneficial result. Accordingly, there is a need to better utilize flumazenil in ways to not consider pushing the body back to normal and to create a flumazenil dosage form for self administration. Anxiety and PTSD

[0009] Anxiety disorder is a family of diseases characterized by abnormal (pathologic) fear and / or anxiety. The family of anxiety disorders includes generalized anxiety disorders, panic disorder, post-traumatic stress disorder (“PTSD”), phobias, and obsessive-compulsive disorder (“OCD”). Among these, PTSD is an anxiety disorder that often occurs following the experience or witnessing of a life-threatening or integrity-threatening event. It is characterized by the presence of three components: re-experiencing, avoidance, and arousal. Re-experiencing refers to the vivid sense of reliving the traumatic event emotionally (fear and panic), cognitively (imagery) and physiologically (tachycardia, sweating). Re-experiencing leads to avoidance. Nevertheless, as re-experiencing occurs rather unexpectedly, avoidance generalizes and the subject will avoid stimuli related to the trauma and stimuli not related to the trauma. Finally, arousal describes a constellation of symptoms such as insomnia, hypervigilance, and difficulty concentrating.

[0010] The current medications for anxiety and anxiety related disorders include selective serotonin reuptake inhibitor (SSRI), anxiolytic, antidepressant, sedative, and nerve pain medication. SSRI’s increase the amount of serotonin left in the synaptic clefts by inhibiting the transporter or serotonin. They have little interaction with other neurotransmitters. It is thought that a dysregulated serotonergic system attributes to the pathogenesis of anxiety. Some anxiolytics can reduce anxiety by stimulating both dopamine and serotonin receptors and benzodiazepines (in specific) can increase the action of GABA neurotransmitters. However, benzodiazepines are highly addictive and prescribed with hesitation due to the liability of abuse. Other medications also pose complications due to the off-target activity and interference on daily tasks. Anxiety is the fear response created from the hyperactive amygdala. In the amygdala nuclei there are several areas: basolateral amygdala groups, lateral nuclei, and basomedial nuclei.

[0011] The communication from these areas results in communication to other areas of the brain such as the following: lateral hypothalamus, dorsal vagal nerve, parabrachial nerve, basal forebrain, retic. pontis caudalis, central gray area, and paraventricular nerve. The communications to these areas may result in elevated heart rate, elevated blood pressure, bradycardia, ulcers, panting, respiratory distress, arousal, vigilance, attention, increased startle response, freezing / social interaction, and corticosteroid release. The activity of these brain regions is result of the activity of neurotransmitters. It is anticipated that the dysregulation in emotional processing is a result of the decreased inhibitory signaling by GABA, or a dysregulated GABAergic system. A primary function of gamma-aminobutyric acid’s (GABA) role as a neurotransmitter is to provide a calming effect as well as a sense of protection.Having a decreased level of GABA can be consequential to aberrations in a startle / panic response.

[0012] PTSD symptoms generally occur at night. These symptoms are greatly disabling and may lead to increased risk for unemployment and suicide. The lifetime prevalence of PTSD is estimated to be as high as about 1 in 12 people. This makes PTSD the fourth most prevalent mental illness in young adults after depression, drug dependence and phobia. Moreover, in the US, the problem is particularly important given the large population of war veterans. A study from the Veterans Administration (VA) revealed a lifetime prevalence of full PTSD of 30.9% among male veterans and 26% for female veterans, and the prevalence of partial PTSD revealed was 22.5% and 21.2% for male and female veterans, respectively.

[0013] Posttraumatic stress disorder is an immediate or delayed response to a catastrophic event, characterized by the following features: “re-experiencing the trauma, psychic numbing or avoidance of stimuli associated with the trauma, and increased arousal. Re-experiencing phenomena include intrusive memories, flashbacks, nightmares, and psychological or physiological distress in response to trauma reminders. Intrusive memories are spontaneous, unwanted, distressing recollections of the traumatic event. Repeated nightmares contain themes of the trauma or a highly accurate and detailed re-creation of the actual event(s). Flashbacks are dissociative states in which components of the event are relived, and the person feels as if he or she is experiencing the event for a few seconds for as long as days. Reactivity to trauma-related stimuli can involve intense emotional distress or physical symptoms similar to those of a panic attack, when the patient is exposed to sights, sounds, smells or events that were present during the traumatic event. Avoidance may include thoughts, feelings, situations or activities that are reminders of the trauma.

[0014] Current anxiety and PTSD treatments address the symptoms but not the underlying disease, and include benzodiazepines (high addiction and abuse potential), SSRI’s (selective serotonin reuptake inhibitors), and anticonvulsants (need time to "kick in", very variable results, many side effects including weight gain and increased suicide risk). The current therapy for PTSD includes a cognitive-behavioral arm consisting of exposure therapy and relaxation techniques, as well as a pharmacological arm consisting mainly of antidepressant SSRI medication such as paroxetine (Paxil®). Therefore, the mainstays for treatment are cognitive behavioral therapy, cognitive processing therapy, and prolonged exposure therapy. Therefore, there is a need in medicine for improved PTSD treatments to not just look at symptoms, but also address the underlying disease.

[0015] In a single arm open label study, reduced GABAAbenzodiazepine receptor binding was found with iv flumazenil during PET scans given to 9 male PTSD veterans and 7male veterans without PTSD (Geuze et al., “Reduced GABAAbenzodiazepine receptor binding in veterans with post-traumatic stress disorder.” Mol Psychiatry.13, 74–83, 2008). In a study of 6 PTSD patients and six age-matched controls, one acute dose of flumazenil (2 mg in 20 ml or matched saline placebo was given iv over 1 min. VAS ratings were made for the peak during the first 5 min and at 5, 15, 30, and 45 min. No subjects experienced panic. The study showed that acute, single dose iv Flumazenil was not panicogenic, but the baseline panic scores were higher. But anxiety stemmed from the experiment in general (Coupland et al., “A pilot controlled study of the effects of flumazenil in posttraumatic stress disorder” Biol Psychiatry.1997 May 1;41(9):988-90.).

[0016] The role of GABA in the pathophysiology of PTSD has not been settled. Benzodiazepines may relieve anxiety associated with PTSD. However, they usually do not do much for the specific symptoms of the disorder. In a study of trauma survivors, early administration of high-potency benzodiazepines following the trauma did not prevent the development of PTSD, even though it did reduce physiological arousal, e.g. resting heart rate (Gelpin et al. J. Clin. Psychiatry, 57:390-4, September 1996). Moreover, an acute single dose flumazenil did not produce an increase in anxiety of PTSD symptoms in patients with PTSD (Randall et al.: Biol. Psych.38(5):319-24, 1995). Therefore, prior studies teach only single acute doses of flumazenil. Dysregulated GABAergic system has been identified in patients with anxiety disorders and PTSD (Lu et al., Neural Plast.2017; 2017:5715816). Moreover,downregulation and reduced GABA receptor binding in patients with PTSD compared tocontrol has been found (Geuze et al., Mol Psychiatry.2008 Jan;13(1):74-83). Summary

[0017] In accordance with the description, the present disclosure aims to meet the needs for treating post-traumatic stress disorder and anxiety and / or provide other benefits. Accordingly, the embodiments described herein are provided, which include, but are not limited to, the following.

[0018] Embodiment 1 is a method for treating post-traumatic stress disorder (PTSD) comprising administering flumazenil to a subject in need thereof periodically for at least one week.

[0019] Embodiment 2 is a method for treating anxiety comprising administering flumazenil to a subject in need thereof periodically for at least one week.

[0020] Embodiment 2.1 is a method for treating PTSD and anxiety comprising administering flumazenil to a subject in need thereof periodically for at least one week.

[0021] Embodiment 3 is the method of any one of the preceding embodiments, wherein the flumazenil is administered at least daily for at least one week.

[0022] Embodiment 4 is the method of any one of the preceding embodiments, wherein the flumazenil is administered one to four times a day.

[0023] Embodiment 5 is the method of any one of the preceding embodiments, wherein the flumazenil is administered once a day.

[0024] Embodiment 6 is the method of embodiments 1-4, wherein the flumazenil is administered at least twice a day at least one hour apart.

[0025] Embodiment 7 is the method of any one of the preceding embodiments, wherein the flumazenil is administered by a route that avoids a portal circulation first pass effect.

[0026] Embodiment 8 is the method of any one of the preceding embodiments, wherein the flumazenil is administered non-orally.

[0027] Embodiment 9 is the method of embodiment 8, wherein the non-oral dose is administered by a subcutaneous, buccal, sublingual, nasal, transdermal, intravenous, intramuscular injection, or rectal route.

[0028] Embodiment 10 is the method of embodiment 8, wherein the non-oral dose is via injection, subcutaneous injection, intramuscular injection intraperitoneal injection, intravenous injection, by injecting an aqueous saline solution of flumazenil, buccal administration with a lozenge, a sublingual dissolving strip, a nasal spray, transdermally via a skin permeation patch, or rectally via a suppository.

[0029] Embodiment 11 is the method of embodiment 10, wherein the injection is subcutaneous.

[0030] Embodiment 12 is the method of any one of the preceding embodiments, wherein the subject self-administers the flumazenil.

[0031] Embodiment 13 is the method of any one of the preceding embodiments, wherein the flumazenil is administered at a dose from about 0.1 mg to about 3.0 mg.

[0032] Embodiment 14 is the method of any one of the preceding embodiments, wherein an initial dose of about 0.2 mg to about 3.0 mg of flumazenil is administered to the subject.

[0033] Embodiment 15 is the method of embodiment 14, wherein for each day during which flumazenil is administered to the subject, a first dose of about 0.2 mg to about 3.0 mg of flumazenil is administered, and optionally a second, third, and / or fourth dose, each of from about 0.1 mg to about 3.0 mg of flumazenil, is administered.

[0034] Embodiment 16 is the method of embodiments 1-12, wherein the flumazenil is administered at a total daily dose of about 0.1 mg to about 3.0 mg.

[0035] Embodiment 17 is a disease-modifying method for treating post-traumatic stress disorder (PTSD) and for treating anxiety comprising an initial chronic course of treatmentcomprising individual self-administering a daily non-oral dose of flumazenil wherein the non- oral route of administration is selected from the group consisting of subcutaneous, buccal, sublingual, nasal, transdermal, intravenous, intramuscular injection, or rectal dose of flumazenil, once or up to four times each day, at from about 0.1 mg to about 3 mg flumazenil per dose, wherein each dose of flumazenil is administered at least one hour apart.

[0036] Embodiment 18 is the method of embodiment 17, wherein the initial dose given each day for a chronic administration regimen is from 0.2 mg to 3.0 mg flumazenil.

[0037] Embodiment 19 is the method of embodiment 17, wherein the injection administration is subcutaneous.

[0038] Embodiment 20 is the method of embodiment 17, wherein each first dose is from 0.2 mg to 3 mg of flumazenil and each optional second through fourth dose is from 0.1 mg to 3.0 mg of flumazenil.

[0039] Embodiment 21 is the method of embodiment 17, wherein the daily dose administered is from about 0.1 mg to about 3 mg of flumazenil.

[0040] Embodiment 22 is a flumazenil dosage form comprising (a) a buccal flumazenil lozenge formulation; (b) a flumazenil dissolving sublingual strip formulation; (c) a subcutaneous injection dosage form of an aqueous solution of flumazenil; or (d) a rectal suppository formulation, wherein each flumazenil dosage form is capable of systemically delivering from about 0.1 mg to about 3 mg of flumazenil.

[0041] Embodiment 23 is a chronic treatment regimen of flumazenil to a patient having anxiety or PTSD, comprising individual self-administering a daily non-oral dose of flumazenil wherein the non-oral route of administration is selected from the group consisting of subcutaneous, buccal, sublingual, nasal, transdermal, intravenous, intramuscular injection, and rectal dose of flumazenil, once or up to four times each day, at from about 0.1 mg to about 3 mg flumazenil per dose, wherein each dose of flumazenil is administered at least one hour apart.

[0042] Embodiment 24 is the chronic treatment regimen of flumazenil to a patient having anxiety or PTSD of embodiment 23, wherein the dosing of flumazenil occurs during hours from awake time until no more than 10 hours later.

[0043] Embodiment 25 is the chronic treatment regimen of flumazenil to a patient having anxiety or PTSD of embodiment 23, wherein, the route of administration of each daily dose of flumazenil is by a means for dosing selected from the group consisting of subcutaneous, intramuscular, intraperitoneal, nasal, buccal, sublingual, rectal, or inhalation, and combinations thereof.

[0044] Additional objects and advantages will be set forth in part in the description which follows, and in part will be understood from the description, or may be learned by practice. The objects and advantages will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.

[0045] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the claims.

[0046] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate one (several) embodiment(s) and together with the description, serve to explain the principles described herein. Brief Description of the Figures

[0047] FIGs.1A and 1B show an open field test measuring time spent in the center in seconds (Wolf-200 is flumazenil) comparing vehicle / vehicle controls (left bar) to vehicle / diazepam (middle bar) positive anxiety control to flumazenil treatment (right bar) for both pre-flumazenil open field test (FIG.1A) and post-flumazenil open field test (FIG.1B), according to an exemplary embodiment. In this behavioral measure, the treatment with flumazenil returned the anxiety mice (from diazepam) to normal (vehicle / vehicle controls). This shows again the large improvement in the time spent in the center of the arena produced by flumazenil in this predictive model.

[0048] FIG.2A (pre-flumazenil) compares the test results of vehicle control (the top line) and diazepam positive control (the lower line).

[0049] FIG.2B shows vehicle / vehicle control in the top line, diazepam / flumazenil (Wolf 200) in the middle line and diazepam / vehicle in the bottom line, according to an exemplary embodiment. This shows again the large improvement in startle reflex produced by flumazenil in this predictive model. There is a reversal in the effects of diazepam. It is possible the change in the diazepam group is a result of a “freeze” behavior found in PTSD populations. Detailed Description

[0050] In general, the present disclosure provides method of using and administering flumazenil to elicit a homeostatic response to an external challenge, rather than trying to treat the body to push things back to normal ranges. In other words, the present disclosure uses flumazenil to intentionally and transiently “push away” from normal ranges in order to elicit the body’s compensatory homeostatic response to “push back to normal”. More specifically, without being bound by theory, and from a mechanism of action standpoint, the present disclosure uses flumazenil administration and its pharmacokinetics to transiently antagonize GABA-A receptors to elicit an upregulation in expression of those GABA-A receptors (i.e.,having the body compensate rather than direct treatment by flumazenil, which did not work) by longer term and repeated or continuous administration of flumazenil rather than shorter term episodic administration of this short half-life agent to increase GABA receptor expression by blocking GABA receptors to augment new GABA receptor expression.

[0051] Further, non-immediate formulations of flumazenil are impractical for the currently approved uses of flumazenil, including for reversal of benzodiazapine overdose. And flumazenil is not orally bioavailable due to extensive first pass effect to the liver. The present disclosure is based on chronic and repeated brain exposure to flumazenil by a variety of dosage forms to reach the brain and avoid first pass metabolism, to induce the adaptive changes. The preferred means for dosage administration to the brain are oral / buccal via dissolving strip or lozenge, nasal spray, rectal, transdermal via a skin patch, and various routes of injection (iv, sc, im and ip). The adaptive changes (increased GABA and NPY activity) are what convey the clinical efficacy and benefit, and were not observed in prior flumazenil studies that were based on acute short term single administration.

[0052] The concept disclosed herein, and without being bound by theory, is that repeated brain exposure to flumazenil induces adaptive changes. The adaptive changes (presumably increased GABA and NPY activity) are what convey the clinical efficacy and benefit. Therefore, without being bound by theory, the present disclosure provides an episodicsystemic dose of flumazenil, which has a short one hour systemic half-life, to induce GABAreceptor expression. Moreover, serum half-life of flumazenil is short, but once it engages target in the brain, it is "sticky" and likely stays bound to the receptor far longer than represented by serum half-life. Also, it is the repeated challenge to the homeostatic response due to chronic daily (1-4 times per day) that is needed to elicit the disclosed disease-altering treatments. The repeated daily dosing is what distinguishes the present disclosure from prior art studies with flumazenil. Without being bound by theory, the therapeutic benefit achieved by the disclosed chronic dosing schedule is realized after the flumazenil dosing is completed and circulating flumazenil is cleared systemically. Stated otherwise, flumazenil administered according to the disclosed chronic dosing regimen works to treat anxiety and PTSD not when it is "on board", but because of the changes it induces within the brain. If you treat with flumazenil for a chronic time period, once off flumazenil, the benefit remains after discontinuing flumazenil. With regard to dosing flumazenil (1-4 doses per day) occurs within 10 hours after wakening, the rationale of daytime dosing is that for most PTSD patients, symptoms and signs are more tolerable during the day, and the condition is worse at night. The presumption behind this recommended dosing is that despite the findings of Randall et al, supra (which found flumazenil didn't make PTSD overtly worse), flumazenil might incrementally exacerbatePTSD, and taking flumazenil when symptoms are more tolerable (while awake during the day) is preferable as the safest and easiest method. Definitions

[0053] “Bioavailability" is the degree to which the pharmaceutically active agent becomes available to the target tissue after the agent's introduction into the body. Enhancement of the bioavailability of a pharmaceutically active agent can provide a more efficient and effective treatment for patients because, for a given dose, more of the pharmaceutically active agent will be available at the targeted tissue sites.

[0054] “Buccal” means any form of oral cavity systemic delivery of flumazenil, such as sublingual or a lozenge that is dissolved in the mouth but absorbed by diffusion through the oral mucosa in the oral cavity but not continuing to the intestines.

[0055] “Chronic” or other forms of chronic mean a duration of daily dosing longer than one week, preferably from 1-4 weeks, as tolerated, before discontinuing the daily flumazenil regimen.

[0056] “Or” is used in the inclusive sense (equivalent to “and / or”) unless the context requires otherwise.

[0057] As used herein, ranges and amounts can be expressed as “about” a particular value or range. About also includes the exact amount. Hence “about 5 mg” means “about 5 mg” and also “5 mg.” Generally, the term “about” includes an amount that would be expected to be within experimental error, such as for example, within 15%, 10%, or 5%. Neuropeptide Y Biomarker

[0058] Neuropeptide Y (NPY) is a 36 amino-acid neuropeptide that is involved in various physiological and homeostatic processes in both the central and peripheral nervous systems. It is secreted alongside other neurotransmitters such as GABA and glutamate. Neuropeptide Y has been identified as being synthesized in GABAergic neurons and to act as a neurotransmitter during cellular communication. Neuropeptide Y is considered to be an anxiolytic endogenous peptide and its levels can be modulated by stress. NPY has connections to the HPA axis and is believed to be necessary for stress modulation (Reichmann F, Holzer P (2016) Neuropeptides 55: 99–109). Conversely, higher levels of NPY may be associated with resilience against and recovery from posttraumatic stress disorder (Yehuda et al.2006 Biological Psychiatry.59 (7): 660–3) and with dampening the fear response, allowing individuals to perform better under extreme stress. Sublingual Dissolving Film

[0059] For sublingual administration, the flumazenil film / lozenge is placed under the tongue wherein dissolved active flumazenil reaches directly into the blood stream / systemiccirculation through the ventral surface of the tongue and floor of the mouth. The reticulated vein lies underneath the oral mucosa. Flumazenil is rapidly absorbed and transported through the facial, internal jugular and brachiocephalic veins and drained into systemic circulation. The sublingual route usually produces both a faster onset of action and improved AUC (area under curve) than orally ingested forms, because flumazenil is absorbed through sublingual blood vessels and bypasses hepatic first-pass metabolic processes. The main mechanism for the absorption of flumazenil into oral mucosa is via passive diffusion into the lipoidal membrane. For sublingual formulations, a small volume of saliva is usually sufficient for disintegration in the oral cavity. The absorption of flumazenil through the sublingual route is 3 to 10 times greater than oral route and can be controlled to delay release. Peak blood levels of most products administered sublingually are achieved within 10 to 15 minutes, which is generally much faster than when those same drugs are ingested orally. Sublingual absorption is efficient. The percent of each dose absorbed is generally higher than that achieved by means of oral ingestion.

[0060] In one embodiment, the present disclosure provides a pharmaceutical sublingual film of flumazenil comprising 0.5 to 5 mg of flumazenil and pharmaceutically acceptable excipients with a diffusion flux of about 75-110μg / cm2 / min. The pharmaceutical sublingual film of flumazenil comprising 2-4 mg of flumazenil and pharmaceutically acceptable excipients with a diffusion flux of about 30-65μg / cm2 / min. Preferably, the pharmaceutical sublingual film of flumazenil comprises 3 mg of flumazenil and pharmaceutically acceptable excipients with a diffusion flux of about 10-30μg / cm2 / min.

[0061] In another embodiment, the present disclosure provides a pharmaceutical sublingual film of flumazenil comprising flumazenil or pharmaceutically acceptable salts thereof as an active ingredient, and water-soluble polymeric components. The pharmaceutical sublingual film further optionally comprises of other pharmaceutically acceptable excipients selected from muco-adhesive agents, plasticizers, surfactants / non-ionic solubilizers, flavors, sweeteners and color additives. The "water soluble polymeric components" ranges about 5% to 75% w / w of the total weight of pharmaceutical sublingual film of flumazenil, preferably about 35% to 75% w / w of the total weight of pharmaceutical sublingual film of flumazenil and more preferably about 40% to 70% w / w of the total weight of pharmaceutical sublingual film.

[0062] In another embodiment, the water-soluble polymeric components comprise polyethylene oxide, hydrophilic cellulosic polymer (HPMC) and maltodextrin. In another embodiment, polyethylene oxide is present in the sublingual film from about 0% to 20% by weight of the water-soluble polymeric components, preferably about 1% to 15% by weight of the water soluble polymeric components and more preferably about 10% to 15% by weight ofthe water soluble polymeric components. In a further embodiment, hydroxypropylmethyl cellulose is present in the sublingual film from about 30% to 90% by weight of the water soluble polymeric components, preferably about 40% to 90% by weight of water soluble polymeric components, and more preferably about 70% to 85% by weight of the water soluble water soluble polymeric components. In another embodiment, maltodextrin is present in the sublingual film ranges about 0% to 60% by weight of water soluble polymeric components, preferably about 1% to 30% by weight of water soluble polymeric components and more preferably about 5% to 15% by weight of the water soluble polymeric components.

[0063] The present disclosure provides a pharmaceutical sublingual film of flumazenil comprising flumazenil or pharmaceutically acceptable salts thereof as an active ingredient and pharmaceutically acceptable excipients delivering flumazenil dosage with a diffusion flux about 50-600μ / αη2within five minutes through the biological mucosal membranes equivalent to human oral mucosa. Preferably, the pharmaceutical sublingual film of flumazenil delivers target flux amounts with dosage amount as low as 2 mg / unit.

[0064] The "water soluble polymer" may be a partially water soluble polymer or predominantly water soluble polymer, water swellable polymer or a combination of water soluble and water swellable polymer. The polymers may include cellulose or cellulose derivatives. Suitable examples of water soluble polymer include, but are not limited to, polyethylene oxide, pullulan, hydroxypropylmethyl cellulose (HPMC), Hydroxypropyl cellulose (HPC), carboxymethyl cellulose, polyvinyl alcohol, Water-swellable polysaccharides such as starch, starch derivatives such as polymers of dextrose like maltodextrin, carrageenan, xanthan gum, locus bean gum, acacia gum, chitosan, alginates, hyaluronic acid, pectin and combinations thereof. Most preferred water soluble polymers are cellulosic polymers, maltodextrin, polyethylene oxide, and combinations thereof. The cellulosic polymers used in combination with polyethylene oxide and maltodextrin are selected from the group consisting of hydroxy propyl cellulose (HPC) and hydroxypropylmethyl cellulose (HPMC). The polyethylene oxide polymer in combination with a hydrophilic cellulosic polymer and maltodextrin achieves muco-adhesive, flexible, strong films.

[0065] "Water soluble polymeric components" desirably range from about 5% to 75%w / w of the total weight of pharmaceutical sublingual film of flumazenil, preferably about 35% to 75%w / w of the total weight of pharmaceutical sublingual film of flumazenil and more preferably about 40% to 70% w / w of the total weight of pharmaceutical sublingual film.

[0066] Polyethylene oxide, when present in the sublingual film, ranges about 0% to 20% by weight of the water soluble polymeric components, preferably about 1% to 15% byweight of the water soluble polymeric components and more preferably about 10% to 15% by weight of the water soluble polymeric components.

[0067] A plasticizer may be incorporated to impart flexibility, enhance elasticity and decrease brittleness. Preferred plasticizers include triacetine, citrate derivatives (such as triethyl, tributyl, acetyl tributyl, acetyl triethyl, trioctyl, acetyl trioctyl, trihexyl citrate, etc.), dibutyl sebacate, glycerol, polyethylene glycol, propylene glycol or combinations thereof. Plasticizer desirably ranges about 0% to 20% w / w of the total sublingual film, preferably about 2% to 15% w / w of the total sublingual film and more preferably about 3% to 12% w / w of the total sublingual film.

[0068] A muco-adhesive polymer for adhesion to mucosal membranes is often added, wherein the muco-adhesive polymer is selected from the group consisting of chitosan, hyaluronate, alginate, gelatin, collagen, poly(acrylic acid), poly(methacrylic acid), poly(L- lysine), poly(ethylene imine), poly(ethylene oxide), poly, (2-hydroxyethyl methacrylate), and salts or copolymers thereof.

[0069] The pharmaceutical sublingual film incorporates at least one flavor, chosen from natural and synthetic flavoring liquids. An illustrative list of such agents includes volatile oils, synthetic flavor oils, flavoring aromatics, oils, liquids, oleoresins or extracts derived from plants, leaves, flowers, fruits, stems and combinations thereof. A non-limiting representative list of examples includes mint oils, cocoa, and citrus oils such as lemon, orange, grape, lime and grapefruit and fruit essences including apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, apricot or other fruit flavors.

[0070] The pharmaceutical sublingual film incorporates at least one sweetener, chosen from the following non-limiting list: glucose (corn syrup), dextrose, invert sugar, fructose, and combinations thereof; saccharin and its various salts such as the sodium salt; dipeptide sweeteners such as aspartame; dihydrochalcone compounds, glycyrrhizin; Stevia Rebaudiana (Stevioside); chloro derivatives of sucrose such as sucralose; sugar alcohols such as sorbitol, mannitol, xylitol, and the like. Also contemplated are hydrogenated starch hydrolysates and the synthetic sweetener 3,6-dihydro-6-methyl-l-l-l,2,3-oxathiazin-4-one-2,2-dioxide, particularly the potassium salt (acesulfame-K), and sodium and calcium salts thereof.

[0071] The pharmaceutical sublingual film incorporates at least one diluent which is selected from the group consisting of mannitol, microcrystalline cellulose (MCC), lactose, and combinations thereof. Mannitol is preferred. The pharmaceutical sublingual film incorporates at least one surfactant / non ionic solubilizer selected from the group consisting of poloxamer, polyoxyl hydrogenated castor oil, glyceryl polyethylene glycol oxystearates, fatty acid glyceryl polyglyceryl esters, polyglyceryl esters, and combinations thereof. A coloring agent (e.g.,dyes) may be added. Suitable dyes for use in pharmaceutical compositions include, for example, natural dyes such as annatto extract, anthocyanins, beta-carotene, beta APO 8, carotenal, black currant, burnt sugar, canthaxanthin, caramel, carbo medicinals, carmine, carmine blue, carminic acid, carrot, chlorophyll, chlorophyllin, cochineal extract, copper- chlorophyll, copper-chlorophyllin, curcumin, curcumin / CU-chloro, elderberry, grape, hibiscus, lutein, mixed carotenoids, paprika, riboflavin, titanium dioxide, turmeric, natural colors, aronia / redfruit, beet juice colors, paprika extract, paprika oleoresin; or artificial dyes such as allura red, brilliant blue FCF, amaranth, carmoisine, fast red E, erythrosine, green S, patent blue V, ponceau 4R, quinoline yellow, red 2G, sunset yellow, FD&C yellow and tartrazine.

[0072] Sublingual films of flumazenil 5 mg, 3 mg & 2 mg composition: Table 1 First example of flumazenil formulations:

[0073] Process for Preparation: 1. Dispersion of flumazenil in purified water and ethanol. 2. Addition of Maltodextrin to step 1 and stirring for 3-5 minutes. 3. Addition of Polyethylene oxide to step 2 and stirring for 3-5 minutes. 4. Addition of Sucralose to step 3 and stirring for 3-5 minutes. 5. Addition of Mannitol to step 4 and stirring for 3-5 minutes. 6. Addition of Hydroxypropylmethyl cellulose, polyethylene glycol / glycerol and peppermint supreme to step 5 and stirring for 5-10 minutes to form slurry. 7. The slurry of step 6 was layered on polyethylene sheet and dried for 10-20 minutes at 90 °C to obtain the sublingual films.

[0074] The following approximate drug flux characteristics are anticipated for the foregoing formulations: Table 2

[0075] Additional examples of flumazenil sublingual film formulations: Table 3 Second example of flumazenil formulations:Table 4 Third example of flumazenil formulations:Lozenge

[0076] Flumazenil lozenges can be based on powder compression or based on hard caramels. For compressed lozenges, sugar substitutes, particularly isomalt, sorbitol or polydextrose may be used, for hard sweet base fructose and / or glucose syrup may be used, as sugar-free alternative sugar substitutes, particularly sugar alcohols, preferably maltitol or isomaltitol, may be used. Variable amounts of sweeteners (e.g. aspartame, acesulfame, cyclamate, saccharin or xylitol) may be added. Other excipients and active substances are incorporated in the matrix and the lozenges are produced by the known production methods.

[0077] In the case of compressed powder mixtures, the excipients are weighed in accordance with the recipe and mixed with the matrix. In the case of liquid excipients or active substances, these may be added by means of a further granulating step. Then powder orgranules are compressed to form lozenges. The excipients or active substances may be compressed jointly or separately, as selected, in one or more layers (1-, 2- or 3-layered tablets).

[0078] In the case of hard caramels the raw materials are mixed according to the recipe and mixed into the heated hard caramel base. Heat-sensitive excipients and / or active substances, particularly, mucilaginous drugs, preferably Icelandic moss, astringent active substances, preferably alum. optionally flavorings and optionally colorings, optionally stabilizers, particularly tartaric acid or citric acid are added in another step shortly before the final mixing and formation of the lozenges. Using these methods, sugar-free lozenges containing different amounts of astringent and mucilaginous drugs are produced, for example, as illustrated in the following Tables: Table 5 Flumazenil lozenge A

[0079] The one layer lozenge can be produced by powder compression. Table 6 Flumazenil lozenge B based on hard caramel containing 5 mg alum and 80 mg Islandic moss extract.

[0080] The one layer lozenge can be produced by powder compression. Flumazenil Suppository

[0081] In another embodiment, the present disclosure provides a flumazenil suppository comprising an adult dose of from about 0.1 mg to about 3 mg of flumazenil, preferably from about 0.1 mg to about 1 mg of flumazenil and most preferably from about 0.3 mg to about 0.5 mg of flumazenil. The suppository dosage form comprises an oleaginous base, flumazenil, a lubricant and a thickening agent, and optionally absorption enhancers. Examples of an oleaginous base are selected from the group consisting of erucic acid, beeswax, glycerin, hard fat, hydrophobic hydroxypropyl methyl cellulose (HPMC) having a long chain alkylgroup into which a small amount of a long chain alkyloxyhydroxypropoxyl group has been introduced to impart a hydrophobic property to the HPMC. The long chain alkyl group, as a part of the alkyloxyhydroxypropyl group, refers to a straight or branched chain alkyl group having 6 to 26 carbon atoms, and specific examples are a stearyl group, a palmityl group, a myristyl group and a lauryl group. The most preferred long chain alkyloxyhydroxypropoxyl group in such hydrophobic hydroxypropyl methylcellulose is a stearyloxyhydroxypropoxyl group. Preferred are hydrophobic hydroxypropyl methylcelluloses having a viscosity of 70 - 250 mm2 / s (determined with Ubbelohde viscometer, at 25°C, 0.5 W / W%, a mixture of water and isopropanol (6:4 W / W)). When the viscosity is less than 70 mm2 / s, the retainability of the suppository may be insufficient, and when the viscosity exceeds 250 mm2 / s, it may be difficult to formulate the hydrophobic hydroxypropyl methylcellulose into a preparation.

[0082] Examples of lubricants are selected from the group consisting of magnesium stearate, stearic acid, vegetable oil, glycerin, mineral oil, PEG4000, PEG6000, Sodium Lauryl Sulfate (SLS), glyceryl palmitostearate, glyceryl behenate, sodium benzoate, and sodium stearyl fumarate.

[0083] A suppository formulation contains from about 0.5% w / w to about 10% w / w of a thickening agent wherein examples of thickening agents are hydroxyethlcellulose or methylcellulose.

[0084] In some embodiments, the suppository formulations comprise about 0.01% (w / w) to about 1.0% (w / w) of one or more preservatives or in amounts of about 0.02% (w / w) to about 0.05% (w / w). Examples of preservatives include, but are not limited to, EDTA, propylparaben and methylparaben.

[0085] In some embodiments, the suppository formulations comprise about 0.1% to about 15% (w / w) of one or more lubricants, preferably from about 1.0% (w / w) to about 10% (w / w) of one or more lubricants. In other embodiments, the formulations comprise about 0.1% (w / w) to about 1.0% (w / w) of one or more lubricants. Examples of lubricants include, but are not limited to, magnesium stearate, stearic acid, vegetable oil, glycerin, mineral oil, PEG4000, PEG6000, Sodium Lauryl Sulfate (SLS), glyceryl palmitostearate, glyceryl behenate, sodium benzoate, and sodium stearyl fumarate. In some embodiments, the formulations comprise about 0.1% (w / w) to about 10% (w / w) of one or more humectants. Exemplary humectants include, but are not limited to, sorbitol, glycerin, and propylene glycol.

[0086] Pharmaceutical formulations suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used. The suppositories may beconveniently formed by admixture of the active ingredient with the softened or melted carrier(s) followed by chilling and shaping in molds. Example 1

[0087] This example provides the results of an in vivo rat behavioral study as a model for PTSD and anxiety. Without being bound by theory, benzodiazepines provide only short term, symptom treatment for PTSD by lowering GABA receptor expression in relevant parts of the brain. More specifically, when benzodiazepines bind to the benzodiazepine site on a GABAAreceptor, it causes an opening of the chloride pore to allow an influx of chloride to enter the neuron. This results in a hyper polarization and inhibition of the neuron. But that creates a need to withdraw from benzodiazepines wherein the individual can become hyper- anxious and much more excitable. Flumazenil is an antagonist to the benzodiazepine-binding site and acts by altering GABAAreceptor expression.

[0088] This study examined the diazepine antagonist flumazenil, having a toxicology profile in mice and rats: intraperitoneal (IP) administration: rat LD50 = 1360 mg / kg, mouse LD50 = 4000 mg / kg. Flumazenil was administered to mice at a dose of 10 mg / kg (IP) every 12 hours for two weeks. Male CD1 (Crl:CD1(ICR)) mice were treated with diazepam (15 mg / kg per day, divided into two 7.5 mg / kg injections per day, 12 hr apart) for 3 weeks. Diazepam was administered in an aqueous vehicle (15% cremaphor in saline) and injected IP in a volume of 0.1 ml / g body weight. Injection sites were alternated between left (morning) and right (evening). A control group received vehicle only. Mice were weighed daily in order to calculate injection volumes as well as to monitor health. The mice showed signs of sedation, but not too sleepy to maintain normal functioning (eating and drinking). Typically doses of 20 mg / kg diazepam given in a single injection are required for sleep lasting 1-2 hours depending on the mouse strain. In addition, tolerance to the sedative effects often develops such that mice sometimes showed reduced acute signs of intoxication over the course of diazepam injections.

[0089] One week following the cessation of diazepam / vehicle injections, the mice were subjected to a behavioral test battery consisting of tests, such as elevated plus maze, open field, digging, social interaction, tail suspension, forced swim, acoustic startle. Testing was limited to a one week window to capture the early abstinence phase. Therefore, the mice were subjected each day to a different test related to anxiety-like behavior in the order listed above. Half of the control mice (vehicle for diazepam – vehicle for Flumazenil) were subjected to this first round of behavioral testing and were tested with all of the other mice at the second time point (see below) in order to control for any effect of repeated testing in these protocols (i.e. to compare the results of the 2ndtests between mice having had the first set and those only experiencing the 2ndset).

[0090] Following this protracted withdrawal testing in which we observed signs of anxiety-like behavior, we initiated treatment with Flumazenil or vehicle (10% DMSO in physiological saline). Flumazenil was administered twice per day (every 12 hr) IP at a dose of 10 mg / kg for 2 weeks. Again, mice were weighed daily in order to calculate injection volumes and as a form of health monitoring. Injection sites were alternated as with diazepam / vehicle.

[0091] Following flumazenil treatment, the mice were tested in the same behavioral battery over a period of 1 week. In summary: (a) 3 weeks diazepam (or vehicle control); (b) 1 week behavioral testing; (c) 2 weeks flumazenil (or vehicle) treatment; and (d) 1 week behavioral testing.

[0092] The testing results showed in FIGs.1A and 1B an open field test measuring time spent in the center in seconds (Wolf-200 is flumazenil) comparing vehicle / vehicle controls (left bar) to vehicle / diazepam (middle bar) positive anxiety control to flumazenil treatment (right bar) for both pre-flumazenil open field test (FIG.1A) and post-flumazenil open field test (FIG.1B). In this behavioral measure, the treatment with flumazenil returned the anxiety mice (from diazepam) to normal (vehicle / vehicle controls). This shows again the large improvement in the time spent in the center of the arena produced by flumazenil in this predictive model.

[0093] The testing results showed in FIGs.2A and 2B is an acoustic startle reflex measured according to volume (dB) of sound and Vmax in the Y axis for degree of startle. A common presentation of PTSD / Anxiety is hyperarousal and hyperactivity. This behavioral assessment is relevant to this disorder as it can measure hypervigilance. Typically, a stressed or dysregulated mouse would have an increased startle response. There was an increase with flumazenil which suggests that there are anxiolytic effects and a decrease in the diazepam group. In FIG.2A (pre-flumazenil) compares the test results of vehicle control (the top line) and diazepam positive control (the lower line). FIG.2B shows vehicle / vehicle control in the top line, diazepam / flumazenil (Wolf 200) in the middle line and diazepam / vehicle in the bottom line. This shows again the large improvement in startle reflex produced by flumazenil in this predictive model. There is a reversal in the effects of diazepam. It is possible the change in the diazepam group is a result of a “freeze” behavior found in PTSD populations.

Claims

We claim:

1. A method for treating post-traumatic stress disorder (PTSD) comprising administering flumazenil to a subject in need thereof periodically for at least one week.

2. A method for treating anxiety comprising administering flumazenil to a subject in need thereof periodically for at least one week.

3. The method of any one of the preceding claims, wherein the flumazenil is administered at least daily for at least one week.

4. The method of any one of the preceding claims, wherein the flumazenil is administered one to four times a day.

5. The method of any one of the preceding claims, wherein the flumazenil is administered once a day.

6. The method of claims 1-4, wherein the flumazenil is administered at least twice a day at least one hour apart.

7. The method of any one of the preceding claims, wherein the flumazenil is administered by a route that avoids a portal circulation first pass effect.

8. The method of any one of the preceding claims, wherein the flumazenil is administered non-orally.

9. The method of claim 8, wherein the non-oral dose is administered by a subcutaneous, buccal, sublingual, nasal, transdermal, intravenous, intramuscular injection, or rectal route.

10. The method of claim 8, wherein the non-oral dose is via injection, subcutaneous injection, intramuscular injection intraperitoneal injection, intravenous injection, by injecting an aqueous saline solution of flumazenil, buccal administration with a lozenge, a sublingual dissolving strip, a nasal spray, transdermally via a skin permeation patch, or rectally via a suppository.

11. The method of claim 10, wherein the injection is subcutaneous.

12. The method of any one of the preceding claims, wherein the subject self- administers the flumazenil.

13. The method of any one of the preceding claims, wherein the flumazenil is administered at a dose from about 0.1 mg to about 3.0 mg.

14. The method of any one of the preceding claims, wherein an initial dose of about 0.2 mg to about 3.0 mg of flumazenil is administered to the subject.

15. The method of claim 14, wherein for each day during which flumazenil is administered to the subject, a first dose of about 0.2 mg to about 3.0 mg of flumazenil isadministered, and optionally a second, third, and / or fourth dose, each of from about 0.1 mg to about 3.0 mg of flumazenil, is administered.

16. The method of any one of claims 1-12, wherein the flumazenil is administered at a total daily dose of about 0.1 mg to about 3.0 mg.

17. A disease-modifying method for treating post-traumatic stress disorder (PTSD) and for treating anxiety comprising an initial chronic course of treatment comprising individual self-administering a daily non-oral dose of flumazenil wherein the non-oral route of administration is selected from the group consisting of subcutaneous, buccal, sublingual, nasal, transdermal, intravenous, intramuscular injection, or rectal dose of flumazenil, once or up to four times each day, at from about 0.1 mg to about 3 mg flumazenil per dose, wherein each dose of flumazenil is administered at least one hour apart.

18. The method of claim 17, wherein the initial dose given each day for a chronic administration regimen is from 0.2 mg to 3.0 mg flumazenil.

19. The method of claim 17, wherein the injection administration is subcutaneous.

20. The method of claim 17, wherein each first dose is from 0.2 mg to 3 mg of flumazenil and each optional second through fourth dose is from 0.1 mg to 3.0 mg of flumazenil.

21. The method of claim 17, wherein the daily dose administered is from about 0.1 mg to about 3 mg of flumazenil.

22. A flumazenil dosage form comprising (a) a buccal flumazenil lozenge formulation; (b) a flumazenil dissolving sublingual strip formulation; (c) a subcutaneous injection dosage form of an aqueous solution of flumazenil; or (d) a rectal suppository formulation, wherein each flumazenil dosage form is capable of systemically delivering from about 0.1 mg to about 3 mg of flumazenil.

23. A chronic treatment regimen of flumazenil to a patient having anxiety or PTSD, comprising individual self-administering a daily non-oral dose of flumazenil wherein the non- oral route of administration is selected from the group consisting of subcutaneous, buccal, sublingual, nasal, transdermal, intravenous, intramuscular injection, and rectal dose of flumazenil, once or up to four times each day, at from about 0.1 mg to about 3 mg flumazenil per dose, wherein each dose of flumazenil is administered at least one hour apart.

24. The chronic treatment regimen of flumazenil to a patient having anxiety or PTSD of claim 23, wherein the dosing of flumazenil occurs during hours from awake time until no more than 10 hours later.

25. The chronic treatment regimen of flumazenil to a patient having anxiety or PTSD of claim 23, wherein, the route of administration of each daily dose of flumazenil is by ameans for dosing selected from the group consisting of subcutaneous, intramuscular, intraperitoneal, nasal, buccal, sublingual, rectal, or inhalation, and combinations thereof.

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