Pharmaceutical compositions and methods for acute and subacute treatment of traumatic brain injury

Abstract

This invention relates to pharmaceutical compositions, including compositions adapted for intranasal administration, comprising an active ingredient, including dexmedetomidine, pomalidomide, a selective phosphodiesterase type 4 inhibitor such as roflumilast, or combinations thereof, useful in the treatment of traumatic brain injury (TBI), including to prevent or reduce the neurological sequalae of TBI.

Description

[0001] DOCKET NO.: 267181.000202 PATENT

[0002] PHARMACEUTICAL COMPOSITIONS AND METHODS FOR ACUTE AND SUBACUTE TREATMENT OF TRAUMATIC BRAIN INJURY

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims the benefit of priority of US Provisional Patent Application Serial No.

[0005] 63 / 733,051, filed on December 12, 2024, entitled “PHARMACEUTICAL COMPOSITIONS AND METHODS FOR ACUTE AND SUBACUTE TREATMENT OF TRAUMATIC BRAIN INJURY,” the entire contents of which is hereby incorporated by reference herein.

[0006] FIELD OF THE INVENTION

[0007] This invention relates to compositions useful in the treatment of traumatic brain injury (TBI), including to prevent or reduce the neurological and behavioral sequalae of TBI, including Post Traumatic Stress Disorder (PTSD) and Post-concussion Syndrome (PCS). Such compositions comprise active therapeutic compounds, including dexmedetomidine, pomalidomide, or combinations thereof.

[0008] BACKGROUND OF THE INVENTION

[0009] There are an estimated 50 million new cases of traumatic brain injury (TBI) worldwide each year and it has been predicted that TBI will remain the most important cause of disability from neurological disease, from about two to three times higher than the disability from Alzheimer’s disease. Treatment costs associated with TBI are estimated at around $400 billion annually, without taking into account the costs of rehabilitation and other impacts such as loss in economic productivity and reduction in quality of life.

[0010] A 2008 Institute of Medicine report concluded that TBIs are consistently associated with neurocognitive deficits. Epidemiological evidence of repetitive head injury has established TBI as an independent risk factor for the development of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer’s disease.

[0011] TBI has been linked to subsequent neurocognitive effects in a range of groups, including military service members, athletes, assault victims, and victims of vehicle accidents, workplace accidents, and falls. The majority (80%) of military related TBIs result from blast and / or impact concussion. TBI in older veterans was associated with a 60% increase in the risk of developing dementia over 9 years. Neurology 2014, 83(4), 312-319. Among military veterans, TBI is associated with 56% increased risk of Parkinson’s Disease. Neurology 2018, 90(20), e1771–e1779. TBI in veterans is also associated with higher risk of developing ALS. TBI is increasingly recognized not only as an acute mechanical insult but as a catalyst for DOCKET NO.: 267181.000202 PATENT

[0012] long-lasting neurobiological cascades that predispose individuals to neuropsychiatric disorders. Among these, post-traumatic stress disorder (PTSD) shows striking comorbidity with mild and moderate TBI. While it has been historically considered a response to psychological trauma, PTSD also occurs at high rates among individuals with mild to moderate TBI. This includes military personnel, athletes, and survivors of accidents or interpersonal violence.

[0013] For decades, clinical assumptions suggested that the amnesia and altered consciousness that accompany TBI might “protect” against PTSD. Research over the past 15-20 years contradicts this view, showing consistently elevated rates of PTSD following TBI.

[0014] Nevertheless, clinical guidance remains vague, and frontline providers often lack clear evidence-based pathways to manage PTSD in the context of TBI. Pharmacotherapies face several barriers as Many PTSD medications (e.g., SSRIs) have only modest efficacy.

[0015] Emerging evidence suggests that this association of TBI and neuropsychiatric disorders is not simply psychological or circumstantial but reflects shared molecular and network-level mechanisms. TBI promotes tau hyperphosphorylation, misfolding, and accumulation. This altered tau, particularly in its oligomeric or truncated forms, disrupts microtubule stability and impairs neuronal connectivity across prefrontal, hippocampal, and amygdala circuits, regions which are central to fear processing and emotional regulation. Such tau-mediated network vulnerability may amplify susceptibility to pathological fear learning, a core feature of PTSD.

[0016] In parallel, blood-brain barrier (BBB) disruption following TBI enables peripheral cytokines, immune cells, and stress mediators to enter the central nervous system. This breach fuels sustained neuroinflammation, perturbs synaptic plasticity, and alters limbic-prefrontal communication. This BBB-compromised environment further potentiates tau pathology, creating a feedforward loop in which misfolded tau and inflammatory signaling reinforce one another. Notably, BBB leakage in hippocampal and medial prefrontal regions aligns with functional impairments associated with deficient contextual memory and reduced top-down regulation of threat responses, which are two hallmarks of PTSD.

[0017] A third convergent mechanism involves noradrenergic dysregulation. TBI acutely activates the locus coeruleus and induces prolonged elevations in central norepinephrine (NE). This heightened noradrenergic tone enhances amygdala excitability and strengthens fear memory consolidation while impairing extinction learning. DOCKET NO.: 267181.000202 PATENT

[0018] Elevated norepinephrine also exacerbates BBB permeability and promotes tau phosphorylation, linking the three pathological domains of tauopathy, barrier dysfunction, and stress hyperreactivity into a unified framework for therapeutic intervention. TBI sets off a cascade of tau misfolding, BBB compromise, and noradrenergic hyperactivation that collectively increase vulnerability to PTSD. Traumatic events trigger massive norepinephrine release in the amygdala, hippocampus, and prefrontal cortex, which enhance long-term potentiation (LTP) that stabilizes long-term memory traces.

[0019] In contrast, when a drug blocks norepinephrine signaling during the consolidation window (typically the first few hours after trauma), it prevents the neurochemical events needed to stabilize the traumatic memory.

[0020] Recognizing TBI not only as a structural injury but as a molecular initiator of stress-sensitive neurocircuit dysregulation can guide the development of therapeutics targeting early BBB stabilization, and noradrenergic modulation.

[0021] Another common condition associated with TBI is Post-concussion Syndrome (PCS). PCS manifests more quickly after TBI than PTSD and is believed to contribute to the development of PTSD. In PCS, symptoms from a concussion last longer than expected, typically weeks to months, and occasionally a year or more after the initial injury. PCS is best understood as a disorder of brain network dysfunction and altered neurophysiology, rather than ongoing structural brain damage.

[0022] Symptoms of PCS usually fall into four major categories: Cognitive, Physical, Emotional, and Sleep-related. Cognitive symptoms may include brain fog, poor concentration, memory problems, and slowed speed of mental processing. Physical symptoms may include headache, dizziness, sensitivity to light or noise, fatigue, nausea, and visual disturbance. Emotional / psychological symptoms may include anxiety, irritability, depression, and mood swings. Sleep-related symptoms may include insomnia, excessive sleepiness, and disrupted sleep cycles.

[0023] Treatment for PCS is symptom-targeted and multidisciplinary, often including headache management (migraine-type therapies), vestibular therapy for dizziness, cognitive rehabilitation, sleep optimization, and treatment of anxiety / depression. Currently, there is no single therapeutic for the treatment of PCS.

[0024] Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative tauopathy most evident in populations exposed to repetitive head impacts (RHIs), such as contact sport athletes Autopsy studies of former professional players show CTE in up to 99% of cases, DOCKET NO.: 267181.000202 PATENT

[0025] with severity escalating with years of exposure. Symptoms often include subtle cognitive deficits, mood disturbances, and behavioral changes. Chronic and sustained activation of microglia, and associated inflammatory signaling, appear to play a major role in the progression of CTE and may persist for years (even decades) after an initial TBI, leading to a milieu of neuroinflammation, oxidative stress, cytokine / chemokine release, and possibly primed glia. Studies of human postmortem CTE brain tissue have shown increased densities of activated microglia that correlate with phosphorylated tau (p-tau) pathology.

[0026] Given the strong connection between TBI and the subsequent development of serious neurological sequalae, there is an extraordinarily significant unmet need for acute point of care therapeutics that can be administered immediately after or soon after a TBI event. There is a need for such therapies that can be administered in a timely and safe manner in settings where TBIs frequently occur, and ideally by non-medical personnel in cases where individuals with medical training are not available.

[0027] SUMMARY OF THE INVENTION

[0028] Provided herein are pharmaceutical compositions and methods for treating TBI in the prehospital phase, (i.e., point of care at the scene of the incident and during transport to hospital) to reduce or prevent the neurological sequalae of TBI, including PTSD, PCS and CTE.

[0029] Provided herein are pharmaceutical compositions that can be administered during the prehospital period following TBI, and during the initial hours of hospitalization, on an acute or subacute basis to prevent or reduce the neurological and neuropsychiatric sequalae of TBI. The pharmaceutical compositions of the invention are suitable for use as point of care therapeutics for administration in adverse or field environments, as well as administration in hospital settings. In some aspects of the invention, the compositions utilize intranasal delivery to rapidly deliver drugs to the brain. The compositions provide novel treatment options for TBI, including their use for soldiers and others experiencing blast injuries, athletes experiencing head impacts, and victims of industrial, vehicular, and other accidents.

[0030] The present invention provides methods and compositions for preventing or reducing the risk and severity of PTSD in subjects who have sustained a traumatic brain injury (TBI) by administering intranasal dexmedetomidine in the acute phase (and ideally within 12-24 hours) after injury. Dexmedetomidine is unusual among sedatives in TBI patients because it does not cause clinically significant respiratory depression at therapeutic doses applied in a way similar to the administration of opioids or propofol. “Prevention" means reducing the incidence, delaying the onset, or reducing the severity of PTSD, and even more optimally DOCKET NO.: 267181.000202 PATENT

[0031] within the first hour post injury. This may include clinician-diagnosed PTSD (e.g., utilizing DSM-5 or ICD-11 criteria) at 1 to 12 months post-injury.

[0032] In aspects of the present invention, methods and compositions are provided for preventing or reducing the risk and severity of PCS in subjects who have sustained a traumatic brain injury (TBI) by administering intranasal dexmedetomidine after diagnosis of PCS. This treatment is administered upon diagnosis, generally within the period of one day up to one week in order to achieve maximum benefit after injury, this could translate to faster resolution of cognitive / emotional symptoms via reduced "sickness behavior" and sleep modulation -dexmedetomidine promotes natural sleep architecture, potentially aiding insomnia and irritability seen in 50-70% of PCS cases.

[0033] Current deficiencies in the acute and chronic management of TBI

[0034] Currently, there is no consensus for the use of pharmacologic agents as a standard treatment of TBI and its frequent neuropsychiatric sequalae. Agitation and confusion are common symptoms after mild to moderate TBI and in acute settings may hinder the ability to perform lifesaving supportive care for instance in the battlefield.

[0035] Propofol and ketamine are commonly utilized in acute management of patients with traumatic brain injury (TBI) to address agitation. However, when either of these agents are employed, they can dramatically influence cerebral physiology, thermodynamics, and potential longterm neuropsychological outcomes. For instance, propofol is a potent vasodilator that reduces cerebral blood flow (CBF). TBI patients often have unstable autoregulation, so even mild hypotension can be dangerous. Conversely, ketamine increases blood pressure where central sympathetic tone potentially increases ICP. In loss-of-autoregulation states ketamine can also cause behavioral disturbances including hallucination and agitation. In TBI patients this may worsen agitation or delirium and contribute to long-term psychological disturbances. Some studies have suggested an increased incidence of unpleasant recall or nightmares in the ICU. An additional deficiency of TBI treatment relates to the high co-morbidity and risk of developing PTSD after TBI. In a systematic review and meta-analysis that was conducted in 7 databases, PTSD after TBI was more frequently observed in military samples than in civilians (37% vs 16%) and were 4X times more inclined to have a diagnosis of PTSD after TBI than when there was no TBI. J Head Trauma Rehabil 2020 Jan / Feb;35(1):E21-E35. Currently, there is a gap in the pharmacological management of PTSD after TBI to address this risk. This lack of treatment results in a widespread toll on the mental health of TBI DOCKET NO.: 267181.000202 PATENT

[0036] patient populations. The present invention is designed to address this gap and provides viable management options for these patients.

[0037] Clonidine and other alpha-2 adrenergic receptor agonists have been widely used to treat the long-term effects of PTSD, such as insomnia and nightmares. However, these therapies have drawbacks in terms of adverse effects and lack of overall efficacy. After TBI, patients commonly develop paroxysmal sympathetic hyperactivity (PSH), characterized by surges of norepinephrine, hypertension, tachycardia, agitation, and heightened fear / stress encoding. Clonidine, which is normally associated as a blood pressure medication, may decreases norepinephrine tone but has significant limitations in TBI patients who exhibit cardiovascular instability with blood pressure drops that may lower cerebral perfusion pressure in an already compromised neurovascular system.

[0038] In the present invention, an alternative therapeutic is employed. This therapeutic compound, dexmedetomidine, has an extensive history of safe and effective use for conscious sedation that dampens central sympathetic outflow, attenuates norepinephrine (NE)-driven hyperactivation and symptomatically reduces agitation.

[0039] While dexmedetomidine and clonidine are both central a2-adrenergic agonists, their clinical effects, especially after traumatic brain injury (TBI), are not equivalent. Dexmedetomidine is ~8 times more selective for a2 over al receptors than clonidine, and highly favors the a2A subtype, which is the receptor most involved in traumatic memory encoding, a major contributor to PTSD. J Psychiatry Neurosci 2010 Jul;35(4):221-8. Unlike Dexmedetomidine, clonidine's oral / transdermal routes yield a delayed onset (45+ min) and variable CNS bioavailability (-30-40%), missing the acute post-TBI window for PTSD. Its impairment is common in TBI, and exacerbating hypotension or bradycardia.

[0040] Provided herein are pharmaceutical compositions that can be administered on an acute or subacute basis to prevent or reduce the neurological sequalae of TBI. These compositions are ideally suited as point of care therapeutics in adverse or field environments. In some aspects of the invention, the compositions utilize intranasal or through aerosol delivery to rapidly deliver drugs to the brain. The compositions provide novel treatment options for TBI, including soldiers and other experiencing blast injuries, athletes experiencing head impacts, and victims of industrial, vehicular, and other accidents.

[0041] Provided herein are pharmaceutical compositions of the present invention where dexmedetomidine, or 4-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, with molecular formula C₁₃H₁₆N₂, is formulated for intranasal delivery to reduce heightened sympathetic DOCKET NO.: 267181.000202 PATENT

[0042] activity as a point of care therapy for TBI. Nasal formulations are described to enable effective transport of the drug across the blood brain barrier, thereby providing a more easily delivered therapy under field conditions, as well as an alternative therapy in cases where IV access is not readily available. These nasal formulations further provide an alternative to oral therapy in situations which frequently occur with TBI, when the patient may be experiencing significant impairment in the level of consciousness.

[0043] Dexmedetomidine is a highly selective a2-adrenergic receptor agonist that reduces central sympathetic outflow, norepinephrine release, and excitotoxicity while promoting hemodynamic stability. Its neuroprotective pharmacology is well-substantiated in both in vitro and in vivo models, with effects manifesting through interconnected pathways that address core drivers of neuronal damage: Clinically, it is used as a sedative in ICU settings with observed neuroprotective benefits (e.g., lower delirium rates). In total, 77 randomized trials (n = 11,997) compared dexmedetomidine to other sedatives, finding that dexmedetomidine reduced the risk of delirium, the duration of mechanical ventilation, and ICU length of stay. Intensive Care Med 2022 Jul;48(7):811-840.

[0044] In another aspect of the invention, formulations of pomalidomide [CC-4047; (A< S’)-4-amino-2- (2, 6-dioxo-piperidin-3-yl)-isoindoline-l, 3-dione] are provided for the treatment of TBI. These formulations include nasal, oral or IV and can also be utilized in subacute settings or longer-term chronic treatment.

[0045] In some aspects of the invention, formulations of dexmedetomidine are delivered by means of an aqueous nasal spray device. In other aspects, the therapeutics may be formulated for delivery in a dry powder nasal spray device. In other aspects on the invention, the therapeutics may be formulated as aqueous solutions that are delivered into the nose via droplets from an ampule. In another aspect of the invention, the therapeutics may be formulated as a gel for delivery by means of a nasal swab applicator. In another aspect of the invention, the therapeutics may be formulated for delivery via nebulizer.

[0046] In other aspects of the invention, methods are disclosed for use of the therapeutic formulations to treat TBI in acute and subacute settings. In one aspect of the invention, dexmedetomidine is used in an acute setting for treatment of a TBI patient immediately after the event, In one aspect of the invention, dexmedetomidine is used in an acute setting for treatment of a TBI patient with the period up to 12 to 24 hours after the event. In one aspect of the invention, dexmedetomidine is used on a subacute basis for treatment of a TBI patient over a period of time between one day up to seven days after the event. In an additional DOCKET NO.: 267181.000202 PATENT

[0047] aspect of the invention, dexmedetomidine is used for the treatment of post concussive syndrome within 30 days after the event. In one aspect of the invention, pomalidomide is used in a subacute setting to treat patients having previously experienced TBI. In one aspect of the invention, dexmedetomidine and pomalidomide therapies are combined to treat TBI patients during the subacute phase of the disease by addressing overlapping disease mechanisms.

[0048] BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Fig. 1 shows an algorithm for the acute treatment of TBI.

[0050] DETAILED DESCRIPTION OF THE INVENTION

[0051] Currently, no FDA approved pharmacological therapy is available for immediate treatment of traumatic brain injury' (TBI) to prevent or reduce the likelihood of neurological and psychiatric sequalae such as PTSD. TBI pathophysiology can be split into acute, sub-acute and chronic phases, occurring within 3-24 hours, 1 day - 3 weeks and from 3 weeks of the trauma, respectively. Single time-point measurements are unable to capture the dynamically changing state of the patient in different phases of the injury. In TBI, normal neurometabolic coupling is disrupted, resulting in a state in which neuronal energy demand and the supply oxygen and glucose are mismatched due to disruption of autoregulatory mechanisms, where the coupling between cerebral metabolic requirement (CMRO2) and cerebral blood flow (CBF) is lost, intracranial hypertension leads to brain hypoperfusion, without any proportional reduction in CMRO2.

[0052] Both traumatic TBI and PTSD are strongly linked to dysregulation of the brain’s norepinephrine (NE) system, that ultimately converge on heightened noradrenergic tone, increased arousal, and difficulty modulating stress responses. TBI triggers excessive NE release, prolonged sympathetic activation, and disrupted autonomic regulation. This contributes to agitation, sleep disturbances, impaired attention, and heightened stress responsivity. TBI-related dysautonomia and PTSD-related hyperarousal both involve increased sympathetic output.

[0053] Management of TBI

[0054] In acute management (emergency & early post-injury), of TBI. a computed tomography (CT) head scan is typically performed to evaluate for intracranial bleeding, contusion, or skull fracture. Monitoring and observation for neurologic deterioration is recommended (4-24 hours depending on severity and risk factors). Symptom management includes pain control. DOCKET NO.: 267181.000202 PATENT

[0055] Patients with continued symptoms after concussive injury (>4-6 weeks), are considered to have post-concussion syndrome (PCS). Common aspects of PCS include anxiety, depression, and irritability, which are PTSD-like symptoms.

[0056] Currently, there is no consensus for the use of pharmacologic agents as a standard treatment of PTSD. A large meta-analysis of 115 randomized controlled trials (RCTs) found that certain drugs (mostly fluoxetine, paroxetine, sertraline, venlafaxine and the antipsychotic quetiapine) produced only a small reduction in overall PTSD symptom severity compared to placebo with minimal effect size. A high dropout rate highlighted issues of

[0057] tolerability / adherence among patients receiving pharmacotherapy, suggesting that although SSRIs are used as first-line therapy, they are suboptimal.

[0058] A further concern is the high risk of suicide in patients with PTSD. Large-scale epidemiological studies and meta-analyses show that PTSD is associated with a substantially elevated risk of suicidal behavior and suicide death: suicide rates were about 6.74 times higher for women with PTSD and 3.96 times higher for men with PTSD. Among military veterans, those with PTSD have increased overall mortality and particularly elevated suicide mortality: one survey found a standardized mortality ratio (SMR) for suicide of ~ 2.52 compared with the general population.

[0059] In one aspect of the present invention, acute administration of dexmedetomidine is employed in a therapeutic window. Therapeutic window is defined as the optimal time in which a therapeutic intervention is most likely to ameliorate the pathological processes of a specific condition. For instance, in the case of patients who exhibit symptoms of a stroke, the therapeutic window was initially set at three hours from onset, but with further developments the window is now within six hours to reduce what is referred to as the ischemic penumbra. In a similar manner, research has shown that the encoding of traumatic memories can be inhibited up to a set period of time after TBI.

[0060] The advantages of intranasal dexmedetomidine as utilized in the present invention include therapeutic action within this acute time window. Its rapid intranasal delivery to the CNS enables intervention during the critical "golden hour" post-TBI, when noradrenergic surges drive both secondary injury and PTSD memory encoding. This contrasts with oral clonidine or guanfacine, which have delayed peak effects. Treatment to prevent PTSD that is proximal to TBI is analogous to the rapid treatment of heart attack and stroke to prevent irreversible damage from those events. DOCKET NO.: 267181.000202 PATENT

[0061] The advantages of intranasal dexmedetomidine further include enhanced selectivity and safety. Dexmedetomidine is eight times (8x) more a2-selective than clonidine, reducing peripheral side effects while amplifying central sympatholysis and neuroprotection.

[0062] Table 1 provides a summary of these advantages.

[0063] Table 1: Rationale for IN Dexmedetomidine in TBI mediated PTSD Prevention and Treatment

[0064] Aspect Intranasal Dexmedetomidine

[0065] High (1620:1 ratio), minimizing peripheral al -mediated side effects like a2:al Selectivity

[0066] vasoconstriction.

[0067] Administration & Intranasal: Rapid absorption (Tmax <30 min), 30-50% bioavailability; no Bioavailability IV access needed, ideal for pre-hospital / ED use in TBI.

[0068] Ultra-rapid onset for acute intervention; short half-life (~2 hours) allows Onset & Duration

[0069] precise titration without accumulation in unstable TBI patients.

[0070] Neuroprotective studies show lower PTSD incidence post-craniotomy and improved GCS Effects in TBI scores.

[0071] PTSD-Specific

[0072] Emerging: Reduces postoperative PTSD incidence

[0073] Outcomes

[0074] Minimal respiratory depression; bradycardia / hypotension dose-dependent Side Effect Profile

[0075] and transient; lower delirium risk vs. GABAergics.

[0076]

[0077] As a further advantage, intranasal dexmedetomidine provides sedation-analgesia without respiratory compromise, which is critical for non-intubated TBI patients. This is in stark comparison to the use of propofol and ketamine in patients with traumatic brain injury (TBI). whereas, when either of these agents are employed, they can dramatically influence cerebral physiology, thermodynamics, and long-term neuropsychological outcomes. For instance.

[0078] Propofol is a potent vasodilator that reduces cerebral blood flow (CBF). TBI patients often have unstable autoregulation, so even mild hypotension can be dangerous. Conversely, ketamine increases blood pressure where central sympathetic tone potentially increases ICP. In loss-of-autoregulation states, ketamine can also cause behavioral disturbances including hallucination and agitation. In TBI patients, this may worsen agitation or delirium and contribute to long-term psychological disturbances. Some studies have suggested an increased incidence of delirium in the ICU. A 2021 cohort-study found that ketamine was DOCKET NO.: 267181.000202 PATENT

[0079] independently associated with incident ICU delirium: Crit Care Explor 2021 Sep 28;3(10):e0544.

[0080] Therapeutic formulations

[0081] There is a high unmet need to develop novel therapeutics for TBI that can be administered “in the field’’ or at a time proximal to the TBI event. For a therapeutic agent, or group of agents, to treat TBI they must readily cross the blood-brain barrier and avoid off target effects. The vast majority of potentially effective neurotherapeutics fail to reach clinical trials due to their poor bioavailability, poor aqueous solubility, limited permeability through biological membranes, and hepatic first-pass metabolism.

[0082] The blood-brain barrier is the bottleneck in brain drug development and is the single most important factor limiting the future growth of neurotherapeutics. In addition, in an effective therapeutic the active ingredients must have rapid onset in the setting of TBI to be effective and able to cross.

[0083] Nasal formulations, such as the aerosol sprays described herein, are preferred over oral delivery in order to assist in transport of the drug across the blood-brain barrier (BBB) in a rapid onset manner. Importantly, these formulations also provide an alternative for drug administration in situations where IV access is not readily available.

[0084] In aspects of the invention, formulations of dexmedetomidine are provided for intranasal administration. Dexmedetomidine is a highly selective alpha-2 adrenergic receptor agonist currently approved for sedation during mechanical ventilation, first approved by the FDA in 1999 in ICU settings.

[0085]

[0086] Dexmedetomidine

[0087] Dexmedetomidine is a highly selective a2-adrenergic receptor agonist that reduces central sympathetic outflow, norepinephrine release, and excitotoxicity while promoting hemodynamic stability. Its neuroprotective pharmacology is well-substantiated in both in vitro and in vivo models, with effects manifesting through interconnected pathways that address core drivers of neuronal damage. DOCKET NO.: 267181.000202 PATENT

[0088] The primary effects of dexmedetomidine involve the coupling of a2-adrenergic receptors to downregulate norepinephrine after TBI, which may reduce cerebral edema and elevated intracranial pressure.

[0089] Formulations for Intranasal Delivery

[0090] In one aspect of the present invention, dexmedetomidine is formulated for convenient administration via a nasal spray, which supports a rapid onset of action with potentially higher brain concentrations than other methods of delivery.

[0091] Pharmaceutical formulations and treatment methods of the present invention utilize characteristics of the nasal route in order to achieve delivery to the target sites in the brain of levels of drug necessary to obtain a therapeutic effect. There is a direct anatomic pathway between the olfactory / trigeminal neuroepithelium of the nasal mucosa and the brain, allowing for more targeted delivery to specific regions, e.g., the olfactory region in the nasal cavity, while achieving less off-target drug loss. Low polar surface area (PSA 58 Å2) compounds are prone to clearance or decomposition by nasal enzymes and can be expected to have a short absorption window before being cleared to the throat and swallowed. Conversely, hydrophilic drugs are very soluble in mucus, leading to high clearance, while extremely hydrophobic agents may fail to reach the nasal cavity. Thus, the composition must present with moderate hydrophilic properties to minimize hydrophobic interactions that maintain the ability to be dissolved in aqueous media.

[0092] The targeting of drug deposition and subsequent absorption within the nasal cavity is affected by the geometry of the spray plume as influenced by drug formulation and device mechanics. Droplet size also affects deposition, with droplets > 10 μm retained in the nasal cavity.

[0093] Narrower plume angles have been associated with better deposition in the olfactory regions of the cavity, while wider angles result in more deposition on more anterior portions of the nasal cavity.

[0094] Minimizing off-target deposition is also important so as to avoid loss of dose through leaking out of the nostrils.

[0095] In the present invention, the mean dose of dexmedetomidine can range from 0.2 to 5 pg / kg based upon PK and PD subject variability. The determination of dosing can be made simply by monitoring of blood pressure, where systolic BP readings < 80 or >180 mm Hg in adverse situations or field settings may be contraindicated. In certain embodiments, dexmedetomidine is administered in a fixed dose of about 20 to 500 pg. In certain embodiments, dexmedetomidine is administered in a fixed dose of about 20 to 200 pg. In certain DOCKET NO.: 267181.000202 PATENT

[0096] embodiments, dexmedetomidine is administered in a fixed dose of about 50 to 200 μg. In certain embodiments, dexmedetomidine is administered in a fixed dose of about 100 to 200 μg. In certain embodiments, dexmedetomidine is administered in a fixed dose of about 100, 105, 110, 115, 120. 125, 130, 135, 140, 145, 150, 155, 160, 165. 170, 175, 180, 185, 190, 195, or 200 ug. In certain embodiments, dexmedetomidine is administered in a fixed dose of about 100, 150, or 200 pg. In certain embodiments, dexmedetomidine is administered in a fixed dose of about 100 pg. In certain embodiments, dexmedetomidine is administered in a fixed dose of about 150 pg. In certain embodiments, dexmedetomidine is administered in a fixed dose of about 200 pg.

[0097] The use of dexmedetomidine has a superior effect in comparison to current analgesic agents used in adverse situations such as ketamine or benzodiazepines that may reduce cognition in already compromised mental status changes in TBI. Although initially approved for intravenous use, for up to 24 hours, in the adult intensive care unit population only, applications of dexmedetomidine in clinical practice have been widened over the past few years. This broadened application stems from the recognition that dexmedetomidine appears to be useful in multiple off-label applications such as pediatric sedation.

[0098] Table 2 describes the advantages of dexmedetomidine for TBI treatment.

[0099] Table 2: Advantages of dexmedetomidine in TBI treatment

[0100] Benefit Explanation

[0101] | ICP Reduces cerebral metabolic rate (CMRO2) without vasodilation Preserves CPP Minimal effect on systemic BP (at low-moderate doses) Neurologic assessment Light sedation —> easier wake-up for exams

[0102] | delirium Lower incidence vs. benzodiazepines

[0103]

[0104] In another aspect of the invention, pharmaceutical compositions of pomalidomide and associated methods of treatment of TBI in subacute and chronic phases of injury are provided. Formulations for intranasal administration of pomalidomide for the treatment of TBI are provided to serve as an alternative to oral formulations on an acute basis in patients experiencing significant impairments in the level of consciousness.

[0105] Pomalidomide is a Food and Drug Administration (FDA) -approved immunomodulatory drug clinically used in treating multiple myeloma that belongs to a class of immunomodulatory DOCKET NO.: 267181.000202 PATENT

[0106] compounds that also includes thalidomide and lenalidomide, under clinical development for the treatment of myelofibrosis, as well as for the treatment of systemic sclerosis.

[0107]

[0108] Pomalidomide

[0109] Pomalidomide is classified as an immunomodulatory imide drug related to thalidomide that is devoid of the teratogenic effects associated with thalidomide. It has a wide range of biological effects, including reduced TNF-a production, decreased or destabilized COX-2 expression, and NF-KB inhibition.

[0110] Thalidomide and related analogs target ubiquitin E3 ligase substrate adapter cereblon (CRBN) mimicking a naturally occurring degron: thereby inducing CRBN-dependent ubiquitination and degradation. Nature 2022, 610, 775–782. The ubiquitin-proteasome system (UPS) plays a cardinal role in maintaining intracellular protein homeostasis by eliminating misfolded, damaged, and worn-out proteins, starting with ubiquitin activation by enzyme E3 ubiquitin ligase promotes the transfer of ubiquitin onto a lysine which serve as a signal for protein degradation via the 26S proteasome.

[0111] Due in part to its low molecular weight, pomalidomide readily crosses the blood brain barrier. Pomalidomide is also particularly attractive because it displays a TNF-α inhibitory activity of up to 50,000-fold greater than thalidomide and it has a favorable BBB permeability.

[0112] Mechanistically, TGF-P binds to a serine / threonine kinase type II receptor and activates phosphorylation. R-Smads form a complex and then translocate into the nucleus. In the nucleus, the heteromeric Smad complex then regulates transcription mitogen-activated protein kinases (MAPKs), phosphatidylinositol 3-kinase-AKT (PI-3K / AKT), NF-KB, the small GTPases Rac / Cdc42 and RhoA in a context-dependent manner. Pomalidomide reduces DOCKET NO.: 267181.000202 PATENT

[0113] ischemic brain injury in rodents and may reduce the consequences of TBI Cell Transplant. Cell Transplant. 2024, 33, 1-17.

[0114] PK / PD

[0115] The pharmacokinetics and pharmacodynamics of novel formulations of pomalidomide can be determined via measurements of absorption of pomalidomide through carbon labeling [14C]. Oral suspension pomalidomide absorption is rapid with a plasma half-life between 8.2–12.0 h.

[0116] Pomalidomide is a racemic mixture of the S-enantiomer (CC-5083) and the R-enantiomer (CC-6016). When orally administered, pomalidomide is eliminated predominantly through renal excretion (~73.0% of the administered dose), with a low fraction of the dose excreted in urine as unchanged drug. Pomalidomide has a low oral bioavailability mainly due to its poor solubility in water and does not cross the blood brain barrier, limiting its potential anti¬ inflammatory effects for brain disorders such as TBI. While pomalidomide is commonly administered as a single oral dose of 2-4 mg, in the present invention doses of 1 mg or less may be sufficient for patients through non-oral routes of administration. In certain embodiments, pomalidomide is administered in a fixed dose of about 0.10 to 4.00 mg. In certain embodiments, pomalidomide is administered in a fixed dose of about 0.10 to 2.00 mg. In certain embodiments, pomalidomide is administered in a fixed dose of about 0.10 to 1.00 mg. In certain embodiments, pomalidomide is administered in a fixed dose of about 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, or 1.00 mg. In certain embodiments, pomalidomide is administered in a fixed dose of about 0.10, 0.25, 0.50, 0.75, or 1.00 mg. In certain embodiments, pomalidomide is administered in a fixed dose of about 0.25 mg. In certain embodiments, pomalidomide is administered in a fixed dose of about 0.50 mg. In certain embodiments, pomalidomide is administered in a fixed dose of about 1.00 mg.

[0117] Formulations

[0118] Dosing levels required to achieve therapeutic effect, when utilizing the intranasal route of the present invention, are substantially lower than dose levels found in products utilizing other delivery routes. Table 3 contains information on the dosing levels of active ingredients typically used in IV administration, as well as anticipated dosing levels for various embodiments of the invention. The intranasal routes provide significantly lower dosing. Should nano formulation be utilized in the intranasal formulations, these doses may be further reduced. DOCKET NO.: 267181.000202 PATENT

[0119] Table 3: Relative Dosing Levels by Route of Delivery (daily dose)

[0120] API IV Intranasal Dexmedetomidine 0.2 to 5 ug / kg <= 0.2 to 5 ug / kg Pomalidomide n / a 4 mg

[0121]

[0122] Formulation of Pharmaceutical Compositions

[0123] In the present invention, various pharmaceutical compositions and nasal delivery systems are conceived of and optimized to enhance solubility and stability for the APIs, while certain excipients may also act as functionally active ingredients. An aerosol spray comprised of a saline solution containing oxygenated nanobubbles, for example, may exert a range of beneficial physiologic and pharmacologic effects that include tissue oxygenation as a treatment for patients with hypoxemic respiratory failure.

[0124] Active ingredients in some embodiments of the invention may not be highly soluble, and this characteristic must be addressed if they are to be successfully delivered via the intranasal route. In one aspect of the present invention, excipients are introduced to increase solubility and absorption.

[0125] In another aspect of the present invention, intranasal delivery of dexmedetomidine or pomalidomide is enhanced by means of increasing the binding of the API to the olfactory neuroepithelium, a form of molecular “hitch hiking” across biological membranes for drug delivery. This may be achieved by co-formulation with cyclodextrins a-l,4-linked D-glucopyranose units consisting of six to eight glucopyranose units. In certain embodiments, this excipient is dimethyl-beta-cyclodextrin (DIMEB). The ratio between the active pharmaceutical ingredient (API) and DIMEB can be in any integer ratio from 1:1 to 1:10.000. The choice of excipients in the design of a pharmaceutical formulation is generally made based on their function, as well as chemical compatibility with the drug substance. Typical drug-excipient formulations influence environmental conditions (microenvironmental pH, temperature, water content, and / or water activity (RH), and oxygen).

[0126] Synthetic permeation enhancers such as Poloxamer 407, Poloxamer 188, and hydroxypropyl methylcellulose (HPMC) can be employed for gel preparation, augmentation nasal absorption, and reduction of mucus viscosity, which may also allow prolonged delivery and half-life of the active API. In situ gels composed of 15% Poloxamer 407, 12% Poloxamer 188, and 1% HPMC are exemplary. DOCKET NO.: 267181.000202 PATENT

[0127] Beta cyclodextrins are GRAS (generally regarded as safe) and are cited in the FDA’ s list of Inactive Pharmaceuticals. These are preferred absorption enhancers for nasal drug formulations.

[0128] Allergy Asthma Immunol Res. 2019, 11(3), 306-319. The most common cyclodextrin excipients are 2-hydroxypropyl-beta-cyclodextrin Beta hydroxy-cy clodextrin which improve solubility but are only weak P-gp inhibitor to improve nasal-brain delivery. AAPS J. 2021, 23(5), 106. Alternatively, methylated P-cyclodextrins, in particular (2, 6-di-O-methyl)-P-cyclodextrin (DM-p-CD), is chosen as a preferred excipient to increase nose brain delivery selectively.

[0129] In a preferred embodiment of the invention, cyclodextrins are utilized as excipients that have putative beneficial effects beyond enhanced solubility. These benefits include promotion of autophagy, inhibition of the p-glycoprotein (MDR inhibition), and facilitation of transit of the API across the blood-brain barrier.

[0130] Cyclodextrins are cyclic oligosaccharides consisting of (a-l,4-linked) D-glucopyranose units: a-CD, -CD and y-CD, consisting of six, seven, and eight glucopyranose units, respectively. Cyclodextrins consist of a hydrophilic shell and a hydrophobic cavity, where poorly water-soluble drugs can become more soluble. The hydroxyl groups of cyclodextrins are responsible for the hydrophilic character that improves solubility of compounds commonly used in drug development.

[0131] In a preferred, but non-limiting, embodiment of the present invention, dimethyl-beta-cyclodextrin (DIMEB) is used as an excipient. Limitations of other excipients are overcome by DIMEB. It can be shown that dimethyl-beta-cyclodextrin (DIMEB) can inhibit P-gp level in the apical membranes of brainstem monolayers. Unlike all other excipients used in drug delivery', DIMEB is distinguished by its ability to inhibit P-gp and increase the deposition of an active API into affected brain areas.

[0132] Intranasal (IN) administration for nose-to-brain transport volume for each nostril is limited (<200 pL). Particle size is a pivotal requirement (<200 nm). The API must be protected from enzymatic degradation with formulations with pH values compatible with the nasal mucosa. Description of aqueous formulations

[0133] As used herein, the term “aerosol” refers to suspension in the air. In particular, aerosol refers to the partidization or atomization of a formulation of the invention and its suspension in the air. According to the present invention, an aerosol formulation is a formulation comprising an API. such as dexmedetomidine or pomalidomide, for nasal inhalation. DOCKET NO.: 267181.000202 PATENT

[0134] As used herein, the term “inhaler” refers to a device for nasal administration of a drug, e.g., in solution, powder and the like delivery via handheld devices, such as plastic spray bottles commonly used to administer decongestants.

[0135] As used herein, the term “dispersant” refers to an agent that assists aerosol! zation in mucosal tissue. In a specific aspect of the invention, the dispersant can be a mucosal penetration enhancer. Preferably, the dispersant is pharmaceutically acceptable. " Pharmaceutically acceptable" refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0136] Table 4 below provides active ingredient compounds for use in the invention. The active ingredients may take various compound forms, including various salt(s), derivative(s), metabolite(s), and / or prodrug(s).

[0137] Table 4: Active Ingredients

[0138] Ingredient Current Route of Administration / Indication Dexmedetomidine IV

[0139] Pomalidomide Oral

[0140]

[0141] Table 5 illustrates excipients for intranasal formulation of the pharmaceutical compositions of the present invention.

[0142] Table 5: Excipients for Intranasal Formulation

[0143] Category of Excipients Excipients

[0144] Preservatives Benzalkonium chloride, Phenylethyl alcohol, Sorbic acid, Potassium sorbate, Parabens (e.g., methylparaben, propylparaben), EDTA, Ethyl alcohol, Propylene glycol, Chlorobutanol, Fatty acids (lauric, myristic, palmitic, stearic, erucic, and oleic)

[0145] Suspension Agents and Stabilizers DIMEB, Hydroxypropyl methylcellulose (HPMC),

[0146] Polyvinyl alcohol (PVA), Carboxymethylcellulose (CMC), Xanthan gum, Sodium hyaluronate, Sodium caprate, Sodium chloride (for isotonicity), Sodium citrate, Potassium chloride, Calcium chloride

[0147]

[0148] DOCKET NO.: 267181.000202 PATENT

[0149] Wetting Agents and Surfactants Glycerin, Propylene glycol. Polysorbates (e.g.,

[0150] Polysorbate 20, Polysorbate 80), Sodium lauryl sulfate (SLS), Sorbitol, Parabens (e.g., methylparaben, propylparaben)

[0151] Osmolarity Adjusters and Mannitol, Sorbitol, Trehlose, Maltose, Lecithin, Emulsifiers Glyceryl stearate

[0152] pH Adjusters Citric acid, Sodium hydroxide, Lactic acid, Sodium phosphate, Sodium citrate

[0153] Permeation Enhancers Chitosan, Poloxamer 407, Poloxamer 188, HMPC,

[0154] Tween 80, Transcutol® P, Peppermint Mucoadhesives Alginate, Cellulose derivatives (e.g., HMPC,

[0155] hydroxypropyl cellulose (HPC), methylcellulose (MC), carboxymethyl cellulose (CMC), ethylcellulose, microcrystalline cellulose (MCC)), Polyacrylates (e.g., Carbopol 97 IP, Carbopol 934P, Carbopol 981P), Starch (e.g., degradable starch microspheres), Chitosan

[0156] Taste Masking Agents Peppermint, Vanilla

[0157]

[0158] In a preferred embodiment, the active ingredient, such as dexmedetomidine or pomalidomide, is co-formulated with dimethyl-beta-cyclodextrin on average between 1-10% weight of formulation as CD microspheres, sodium chloride and sodium citrate to maintain pH compatible with nasal mucosal tissue (6-6.5), methylparaben 0.1%, glycerin as an emulsifier, and alginate or chitosan as a mucoadhesive polymer. Physical requirements for the spray include spray patterns between 3-7 cm, 0.05 mg / 1 cc of API, droplet size distribution between 10-120 μm, and osmolality 300-700 mOsm / kg.

[0159] Tables 6 and 7 through 9 provide illustrative examples of formulations of the invention and dose ranges for active and inactive ingredients.

[0160] Table 6: Example Formulations

[0161] Suspension Wetting Osmolarity PH Mucoadhesive API Preservatives Agent Agent Adjuster Adjuster

[0162] / Stabilizers

[0163] Dexmedetomidine NaCl, DIMEB Methyl Mannitol Citric Alginate hydrochloride Palmitic acid paraben acid

[0164]

[0165] DOCKET NO.: 267181.000202 PATENT

[0166] Dexmedetomidine NaCl, DIMEB Methyl Glycerin Citric Chitosan hydrochloride Palmitic acid paraben acid Dexmedetomidine NaCl, 2-hydroxy Methyl Treholose Citric Alginate, hydrochloride Oleic acid propyl-beta- paraben acid Chitosan cyclodextrin

[0167] Pomalidomide NaCl, DIMEB Methyl Mannitol Citric Alginate Palmitic acid paraben acid Pomalidomide NaCl, DIMEB Methyl Glycerin Citric Chitosan Palmitic acid paraben acid Pomalidomide NaCl, 2-hydroxy Methyl Treholose Citric Alginate,

[0168] Oleic acid propyl-beta- paraben acid Chitosan cyclodextrin

[0169]

[0170] Table 7: Example active and inactive ingredient formulation dose ranges Dexmedetomidine hydrochloride 20-500 mcg

[0171] Beta cyclodextrin 1-10%

[0172] Chitosan: 1-5%

[0173] Mannitol: 1-5%

[0174] NaCl: 0.9%

[0175] Sodium Citrate: 0.5-1%

[0176] Methylparaben

[0177] API / Excipient Ratio: 1:1 to 1:10,000

[0178]

[0179] Table 8: Example active and inactive ingredient formulation dose ranges Pomalidomide 0.10 to 4.00 mg

[0180] Beta cyclodextrin 1-10%

[0181] Alginate 1-5%

[0182] Mannitol: 1-5%

[0183] NaCl: 0.9%

[0184] Sodium Citrate: 0.5-1%

[0185] Methylparaben

[0186] API / Excipient Ratio: 1:1 to 1:10,000

[0187]

[0188] DOCKET NO.: 267181.000202 PATENT

[0189] Table 9: Example active and inactive ingredient formulation dose ranges Pomalidomide 0.10 to 4.00 mg

[0190] Beta cyclodextrin 1-10%

[0191] Chitosan: 1-5%

[0192] Mannitol: 1-5%

[0193] NaCl: 0.9%

[0194] Sodium Citrate: 0.5-1%

[0195] Methylparaben

[0196] API / Excipient Ratio: 1:1 to 1:10,000

[0197]

[0198] The example formulations provided in tables 6-9 allow for a variety of beta cyclodextrins to be employed. Preferred beta cyclodextrins include dimethyl-beta-cyclodextrin and 2- hydroxypropyl-beta-cyclodextrin.

[0199] The formulation is further refined with the addition of β-CDs derivatives (2-hydroxypropyl-β-CD and methyl-β-CD) to increase nasal compatibility by solubilizing lipophilic drugs and constantly supplying the dissolved drug molecules to the surface of the nasal epithelium. Intranasal Delivery Devices

[0200] In one aspect of the invention, intranasal devices are contemplated for delivery of dexmedetomidine and / or pomalidomide.

[0201] In one aspect of the invention, a unit dose of the medication is contained in a single use vial or ampule. The vial is opened by removal of the vial head and the medication is poured directly into one of the patient’s nostrils. Single use ampules can be made from plastic or glass, and sized to contain varying volumes of medication, as is well known in the art.

[0202] In aspects of the invention, a nasal spray device is used to deliver an aqueous formulation to the nasal cavity, utilizing devices such as the VP3 and VP7 Multi-dose Spray or UniDose systems manufactured by Aptar Pharma, the SP270+ and SP370+ pumps or UniSpray devices manufactured by Nemera, or the soft nasal spray device manufactured by Resyca BV. https: / / aptar.com / wp-content / uploads / 2020 / 07 / Brochure-Nasal-spray-pump-Vp3.pdf. https: / / aptar.com / products / pharmaceutical / vp3-technology -platform / , https: / / aptar.com / wp-content / uploads / 2020 / 07 / Brochure-nasal-spray -pump- Vp7.pdf. https: / / www.nemera.net / products / ear-nose-throat / multidose-pumps / sp270-sp370 / .

[0203] In another aspect of the invention, a prefilled syringe fitted with a nozzle that produces a mist can be used to deliver an aqueous formulation to the nasal cavity. DOCKET NO.: 267181.000202 PATENT

[0204] In another aspect of the invention, the medication is formulated as a dry powder and delivered by a dry powder nasal spray device, such as the Unidose systems of Aptar Pharma. These devices are representative of nasal administration devices and intra nasal delivery devices which may be utilized.

[0205] In other aspect of the invention, a nasal applicator swab, carrying the therapeutic formulated as a gel is used to deliver the pharmaceutical compositions of the invention.

[0206] Packaging

[0207] In one aspect of the invention, a package is provided containing multiple medicationcontaining ampoules. In one aspect of the invention, a package is provided containing multiple single or bi-dose nasal spray devices. This packaging facilitates use by first responders, such as EMT, or military corpsmen, during a mass casualty event.

[0208] In one aspect of the invention, a package is provided containing multiple medicationcontaining nasal swabs. The package can have individual compartments (e.g., blisters) for each swab. This packaging facilitates use by first responders, such as EMT, or military corpsmen, during a mass casualty event.

[0209] Methods of Treatment

[0210] Additional aspects of the invention involve the utilization of therapeutic formulations disclosed herein to treat TBI patients in timeframes both proximal to time of TBI event (e.g., immediately after or within 24 hours) and during a period of weeks to months after the event. In one aspect of the invention, one of the formulations of dexmedetomidine disclosed herein is used at the time of TBI or within 24 hours immediately following the injury. According to this method, a patient suffering a TBI will be given dexmedetomidine by intranasal administration. This administration may be from ampule or vial, from a nasal spray device, a nasal swab, or a nebulizer with a mask that enables nasal delivery of aerosolized drug. The frequency of dosing of dexmedetomidine can be determined on a personalized basis by the healthcare provider. In certain embodiments, dexmedetomidine is administered once per day. In certain embodiments, dexmedetomidine is administered twice per day. In certain embodiments, dexmedetomidine is administered three times per day. In certain embodiments, dexmedetomidine is administered four times per day.

[0211] In circumstances where a professional healthcare provider is not present, the intranasal dexmedetomidine administration can follow an established guideline by emergency personnel such as EMT or other first responders at the point of care. DOCKET NO.: 267181.000202 PATENT

[0212] In one aspect of the invention, one of the formulations of dexmedetomidine disclosed herein is administered to a patient that has experienced a TBI. This administration may be by means of any of the intranasal forms and devices disclosed herein. In this subacute setting, dexmedetomidine is administered over a select period of time from onset of injury. A non¬ limiting example of an administration regime is a twice daily intranasal administration of 200 μg of dexmedetomidine given over a period of up to three weeks.

[0213] In one aspect of the invention, one of the formulations of pomalidomide disclosed herein is administered to a patient that has experienced a TBI. This administration may be from an oral form or by any of the intranasal forms and devices disclosed herein. A non-limiting example of an administration regime is a twice daily intranasal administration of 3 mg of pomalidomide given over a period of up to three weeks. In another example, the dosing and frequency of pomalidomide can be determined by the periodic assessment of select biomarkers, such as TGF-β levels, TBI biomarkers such as TGF-β levels change over time, therefore it is critical to reliably identify appropriate time windows for an intervention as the injury evolves. Prognostic biomarkers that reliably predict outcomes and recovery windows to assess neurodegenerative change and guide decisions for return to play or duty are also important.

[0214] Treatment Algorithms

[0215] In some aspects of the invention, protocols or algorithms are provided for administration of dexmedetomidine. These protocols may be used by medics and other military personnel, sports team staff, EMTs and other first responders, and medical personnel. Fig. 1 provides one embodiment of such as protocol elucidated in the form of a simple flow chart.

[0216] Referring to Fig. 1. for a patient with mild to moderate TBI, the patient is evaluated for potential contraindications including prolonged loss of consciousness (LOC), seizure at onset of traumatic event, hemodynamical instability with BP systolic > 180 or less than 80 mm Hg, heart rate less than 50, focal neurological deficits, and / or facial trauma. Next, dexmedetomidine is administered intranasally at doses between 25 mcg - 100 mcg.

[0217] Monitoring is continued for BP and assessment of mental status. If no response, repeat dose after 10 minutes.

[0218] Exemplary Treatment Protocols

[0219] Example 1 - Emergency Department / Pre-hospital Adult patient (70 kg) with moderate TBI (GCS 13) after motor vehicle collision: DOCKET NO.: 267181.000202 PATENT

[0220] • 70 μg (1.0 μg / kg) intranasal dexmedetomidine (e.g., two 70 μg sprays, one per nostril) administered by EMS or upon ED arrival.

[0221] • Optional repeat dose of 70 - 100 μg at 6 - 12 hours if persistent agitation or sympathetic hyperactivity.

[0222] Example 2 – Battlefield / Combat Casualty Care Soldier with blast-related mild TBI and psychological trauma:

[0223] • 180 μg intranasal dexmedetomidine administered by medic within 1 hour of injury, repeated once at 8 hours if patient remains conscious and hemodynamically stable. Example 3 - Outpatient Visit: Adult patient (70 kg) with moderate TBI (GCS 13) after motor vehicle collision three weeks prior to visit, and experiencing symptoms of PCS, including headaches, anxiety, restless sleep, nausea, and subjective balance loss. Neurological exam is normal and brain imaging is negative for signs of intracranial or extracranial bleeding:

[0224] • 180 μg intranasal dexmedetomidine BID for a period of ten days.

Claims

DOCKET NO.: 267181.000202 PATENTCLAIMS1. A method of treatment of a traumatic brain injury comprising administering intranasally to a human in need thereof a composition comprising a compound selected from the group consisting of dexmedetomidine and pomalidomide, or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 wherein the compound is dexmedetomidine or a pharmaceutically acceptable salt thereof.

3. The method according to claim 2 wherein the compound is dexmedetomidine hydrochloride.

4. The method according to claim 1 wherein the compound is pomalidomide.

5. The method according to claim 2 or claim 3 wherein the composition further comprises a second compound which is pomalidomide.

6. The method according to claim 2 or claim 3 wherein the compound is administered at a dose of about 20 to 500 μg.

7. The method according to claim 6 wherein the compound is administered at a dose of about 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200 μg.

8. The method according to claim 4 wherein the compound is administered at a dose of about 0.10 to 4.00 mg.

9. The method according to claim 9 wherein the compound is administered at a dose of about 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.

65. 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, or 1.00 mg.

10. The method according to any one of claims 1 -9 wherein the composition is administered once per day.

11. The method according to any one of claims 1-9 'wherein the composition is administered twice per day.

12. The method according to any one of claims 1-11 wherein the composition is administered to a single nostril.

13. The method according to any one of claims 1-11 wherein the composition is administered to each nostril.

14. The method according to any one of claims 1-13 wherein the composition further comprises a cyclodextrin.DOCKET NO.: 267181.000202 PATENT15. The method according to claim 14 wherein the cyclodextrin is dimethyl-beta- cyclodextrin.

16. The method according to claim 14 wherein the cyclodextrin is 2-hydroxypropyl-beta- cyclodextrin.

17. The method according to any one of claims 1-16 wherein the composition further comprises a mucoadhesive.

18. The method according to claim 17 wherein the mucoadhesive is alginate.

19. The method according to claim 17 wherein the mucoadhesive is chitosan.

20. The method according to any one of claims 1-19 wherein the composition further comprises mannitol.

21. The method according to any one of claims 1-20 wherein the composition further comprises methyl paraben.

22. The method according to any one of claims 1-21 wherein the composition is delivered by means of an aqueous nasal spray device.

23. The method according to any one of claims 1-21 wherein the composition is delivered by means of drops from an ampule.

24. The method according to any one of claims 1-21 wherein the composition is formulated as a gel for delivery by means of a nasal swab applicator.

25. The method according to any one of claims 1-24 wherein the composition is administered within 24 hours of the incident causing the traumatic brain injury.

26. The method according to any one of claims 1-24 wherein the composition is administered within 30 days of the incident causing the traumatic brain injury.

27. The method according to claim 26 wherein the human has been diagnosed with Post-concussion Syndrome,28. A method of treatment of a traumatic brain injury comprising following the steps of the algorithm described in Fig. 1.

29. A pharmaceutical composition comprising a compound selected from the group consisting of dexmedetomidine and pomalidomide, or a pharmaceutically acceptable salt thereof for intranasal use in the treatment of traumatic brain injury.

30. Use of a pharmaceutical composition comprising a compound selected from the group consisting of dexmedetomidine and pomalidomide, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for intranasal use in the treatment of traumatic brain injury.DOCKET NO.: 267181.000202 PATENT31. The pharmaceutical composition according to claim 29 or use according to claim 30 wherein the compound is dexmedetomidine or a pharmaceutically acceptable salt thereof.

32. The pharmaceutical composition or use according to claim 31 wherein the compound is dexmedetomidine hydrochloride.

33. The pharmaceutical composition according to claim 29 or use according to claim 30 wherein the compound is pomalidomide.

34. The pharmaceutical composition or use according to claim 31 or claim 32 wherein the composition further comprises a second compound which is pomalidomide.

35. The pharmaceutical composition or use according to claim 31 or claim 32 wherein the compound is administered at a dose of about 20 to 500 pg.

36. The pharmaceutical composition or use according to claim 35 wherein the compound is administered at a dose of about 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200 μg.

37. The pharmaceutical composition or use according to claim 33 wherein the compound is administered at a dose of about 0.10 to 4.00 mg.

38. The pharmaceutical composition or use according to claim 37 wherein the compound is administered at a dose of about 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, or 1.00 mg.

39. The pharmaceutical composition or use according to any one of claims 29-38 wherein the composition is administered once per day.

40. The pharmaceutical composition or use according to any one of claims 29-38 wherein the composition is administered twice per day.

41. The pharmaceutical composition or use according to any one of claims 29-40 wherein the composition is administered to a single nostril.

42. The pharmaceutical composition or use according to any one of claims 29-40 wherein the composition is administered to each nostril.

43. The pharmaceutical composition or use according to any one of claims 29-42 wherein the composition further comprises a cyclodextrin.

44. The pharmaceutical composition or use according to claim 43 wherein the cyclodextrin is dimethyl-beta-cyclodextrin.

45. The pharmaceutical composition or use according to claim 43 wherein the cyclodextrin is 2-hydroxypropyl-beta-cyclodextrin.DOCKET NO.: 267181.000202 PATENT46. The pharmaceutical composition or use according to any one of claims 29-45 wherein the composition further comprises a mucoadhesive.

47. The pharmaceutical composition or use according to claim 46 wherein the mucoadhesive is alginate.

48. The pharmaceutical composition or use according to claim 46 wherein the mucoadhesive is chitosan.

49. The pharmaceutical composition or use according to any one of claims 29-48 wherein the composition further comprises mannitol.

50. The pharmaceutical composition or use according to any one of claims 29-49 wherein the composition further comprises methyl paraben.

51. The pharmaceutical composition or use according to any one of claims 29-50 wherein the composition is delivered by means of an aqueous nasal spray device.

52. The pharmaceutical composition or use according to any one of claims 29-50 wherein the composition is delivered by means of drops from an ampule.

53. The pharmaceutical composition or use according to any one of claims 29-50 wherein the composition is formulated as a gel for delivery by means of a nasal swab applicator.

54. The pharmaceutical composition or use according to any one of claims 29-53 wherein the composition is administered within 24 hours of the incident causing the traumatic brain injury.

55. The pharmaceutical composition or use according to any one of claims 29-53 wherein the composition is administered within 30 days of the incident causing the traumatic brain injury.

56. The pharmaceutical composition or use according to claim 55 wherein the composition is administered after a diagnosis of Post-concussion Syndrome.

Images