Compositions and methods for treating seizure disorders in pediatric patients - Patents.com

Abstract

Disclosed herein are compositions for intranasal administration of benzodiazepines, such as diazepam, midazolam, and lorazepam, and methods of their use for treating and preventing seizures in pediatric subjects aged 2 to 5 years, compositions for rapid initiation of treatment with reduced incidence and / or severity of side effects following administration, and methods for improving patient compliance with prescribed treatment regimens.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 209,092, entitled "Methods and Compositions for Treating Seizure Disorders in Pediatric Patients," filed June 10, 2021, the entire contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] The present disclosure relates generally to compositions having a benzodiazepine and an alkyl maltoside that are suitable for intranasal administration to pediatric patients and are effective for treating seizures and seizure disorders in said pediatric patients.

[0003] Epilepsy is a major health problem affecting 50 million people worldwide, including 2.7 million Americans. The distribution of epilepsy is bimodal, with peaks in infancy / childhood and older adults. Approximately one-third of patients with epilepsy are drug-resistant, despite the approval of numerous oral chronic therapies with various mechanisms of action. Epilepsy adversely affects quality of life and increases morbidity and mortality. In the United States, between 25,000 and 50,000 people die each year from epilepsy seizures and related causes.

[0004] Epileptic seizure emergencies include acute recurrent seizures (ARS, also known as seizure clusters), defined as intermittent increases in seizure activity during stable administration of antiepileptic drugs (ASDs). Pediatric epilepsy patients are often prone to seizure clusters, especially those with severe early-onset developmental epileptic encephalopathy or epileptic encephalopathy. Seizure clusters in childhood often portend poor neurological outcome. Intravenous formulations of diazepam have been used for more than 50 years to treat seizure emergencies, including status epilepticus. Currently, VALTOCO® and DIASTAT®, a rectal gel formulation of diazepam, are used to treat ARS.

[0005] Intranasal diazepam (VALTOCO®) received marketing approval from the U.S. Food and Drug Administration (FDA) in 2020 and is indicated for the acute treatment of intermittent, atypical seizure activity (ARS) that differs from the patient's usual seizure pattern in patients with epilepsy 6 years of age and older.

[0006] DIASTAT® was approved in 1997 for rectal administration in the management of refractory epilepsy patients on a stable regimen of AEDs who require intermittent use of diazepam to suppress increased seizure activity, and is approved for use in patients aged 2 years and older. Clinical trial and post-marketing experience have demonstrated an excellent safety profile of DIASTAT®, with few reported serious adverse events. Despite the safety and efficacy of DIASTAT®, its use is limited by social and legal restrictions related to the route of administration. In addition, rectal administration of diazepam results in highly variable dosages due to inconsistent absorption and possible bowel movements, necessitating additional dosing if part of the initial dose is expelled. Due to this route of administration, the use of DIASTAT® is primarily limited to the pediatric population aged 2 to 12 years. Summary of the Invention

[0007] In one aspect, the disclosure provides a method of treating a pediatric subject having a seizure disorder, the method comprising administering to a pediatric subject between 2 and 5 years of age a composition having an effective amount of diazepam, an alkyl maltoside, and a carrier system comprising one or more natural or synthetic tocopherols or tocotrienols and one or more alcohols. The composition is administered to the nasal mucosa of the pediatric subject to treat the seizure disorder in the pediatric subject.

[0008] In another aspect, the present disclosure provides a method of treating recurrent seizures in a pediatric subject in need thereof, comprising administering to a pediatric subject between 2 and 5 years of age a composition having an effective amount of diazepam, an alkyl maltoside, and a carrier system comprising one or more natural or synthetic tocopherols or tocotrienols and one or more alcohols to the nasal mucosa of the pediatric subject during or before a seizure.

[0009] Diazepam nasal solution (Valtoco®) is approved for the acute treatment of convulsive seizures in patients with epilepsy aged 6 years and older. In a previous pharmacokinetic (PK) study, diazepam nasal solution had similar bioavailability but less interpatient variability compared to diazepam rectal gel in healthy adult volunteers. In a study of epilepsy patients aged 6-65 years, diazepam nasal solution had a similar PK profile in the interictal and ictal / periictal phases. In a long-term Phase 3 safety study of patients aged 6-65 years, diazepam nasal solution had a similar safety profile to the rectal gel.

[0010] Additionally, younger children may require out-of-hospital treatment for seizure clusters. There are limited data on the PK of diazepam in children, and no pediatric data on the rectal gel, which is approved for patients 2 years of age and older. Diazepam nasal spray is a formulation of diazepam that may be easier to use and have more predictable plasma concentrations than rectal gel in this population. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Before describing the compositions and methods, it should be understood that various aspects of the nasal benzodiazepine compositions and methods of use thereof are disclosed herein. Unless otherwise indicated, all technical and scientific terms used in this description have the meanings commonly understood by those skilled in the art. It should also be understood that the terms used in this description are for the purpose of describing specific aspects or embodiments only, and are not intended to limit the scope. The disclosed nasal compositions, methods of making them, and methods of using them are not strictly limited to the specific compositions, steps, or methods described, as these may vary to the extent recognized by those skilled in the art without departing from the advantages and benefits imparted by the compositions and methods. For the purpose of describing various aspects and embodiments of the nasal benzodiazepine compositions, methods of making them, and methods of use thereof, preferred compositions and methods are described below, although those skilled in the art will readily recognize obvious modifications and substitutions that may be made to achieve the same results by equivalent means or functions.

[0012] The compositions disclosed in this description are suitable for administration to the nasal cavity, and therefore the terms "intranasal solution", "intranasal composition" and "intranasal formulation" are used interchangeably to mean a composition suitable for administration to the nasal mucous membranes lining the nasal cavity.

[0013] As used herein, the terms "subject" and "patient" expressly include human and non-human mammalian subjects. The term "non-human mammal" as used herein extends to, but is not limited to, household pets and domesticated animals. Non-limiting examples of such animals include primates, cows, sheep, ferrets, mice, rats, pigs, camels, horses, poultry, fish, rabbits, goats, dogs and cats. As used herein, the term "child" refers to a subject between the ages of 2 and 5.

[0014] As used herein, "treat" and other grammatical forms (e.g., treat, treat) may improve the symptoms of a seizure disorder or acute seizures. Amelioration may include reducing the frequency, length, or severity of acute seizures or recurrent episodes of seizures.

[0015] In any embodiment, the methods and compositions disclosed in this description may comprise the recited steps and components. The term "comprise" as used herein is an open language and is used to indicate that the recited steps or components are included in the recited method or composition, but other elements may also be included, even if the elements are not explicitly recited. In any embodiment, the methods and compositions disclosed herein may consist essentially of the recited steps and components. As used herein, "consist essentially of" is used to refer to the steps or components included in the recited method or composition, and is used to indicate that other elements may be included, but that the other elements will not materially affect the properties of the composition or the results of the method. In any embodiment, the methods and compositions disclosed herein may consist of the recited steps and components. As used herein, "consist" is a closed language used to recite the steps or components included in the recited method or composition, meaning that no other elements are included other than the elements explicitly recited. The use of the terms comprise, comprise, or comprising can be replaced with "consisting essentially of" or "consisting of".

[0016] Surprisingly, administration of a benzodiazepine to the nasal mucosa of a pediatric subject via various intranasal compositions as disclosed herein induces a therapeutic effect in the pediatric subject substantially earlier than would be expected based on measurements of the systemic levels of the benzodiazepine. The therapeutic effect is not only experienced by the pediatric subject, but is also measured via electroencephalogram well before the systemic concentration of the benzodiazepine reaches a therapeutically relevant level (e.g., less than 2 minutes after administration). As used herein, the term "pharmacodynamic" or "PD" is used to describe the qualitative effects of an administered benzodiazepine on a pediatric subject, such as changes in EEG data, changes in seizure length or severity, changes in symptoms associated therewith, or changes associated with side effects caused by the administered benzodiazepine. The term "pharmacokinetics" or "PK" refers to the relationship between the drug and its metabolites (e.g., C max , T max ) plasma concentration, bioavailability, half-life, etc. Various aspects of the PK profile of benzodiazepines administered intranasally via the nasal compositions disclosed herein are similar to those of benzodiazepines administered intravenously (e.g., similar AUC and bioavailability, similar AUC and bioavailability) and orally (e.g., similar C max , and T max ), and many of the adverse side effects associated with intravenous, oral, and rectal administration of benzodiazepines, such as somnolence, headache, and depressive / suicidal thoughts and behaviors, are reduced. Thus, the intranasal compositions and methods of use provided herein represent a substantial improvement in the treatment of seizures and seizure disorders, both in the rapid realization of therapeutic benefit following administration and in improved patient compliance after experiencing reduced unpleasant side effects.

[0017] composition Thus, in one embodiment, the disclosure provides a composition suitable for intranasal administration (an "intranasal composition") comprising: a therapeutically effective amount of a benzodiazepine drug; from about 0.01% w / v to about 1% w / v of an alkyl maltoside; and from about 30% w / v to about 90% w / v of a natural or synthetic tocopherol, a natural or synthetic tocotrienol, or a combination thereof, and a carrier system comprising from about 10% w / v to about 70% w / v of one or more alcohols.

[0018] Benzodiazepines have the basic structure of general formula I: A compound of formula I, [ka]

[0019] Here, R, -R 15 is a substitutable chemical moiety. R1 is an optionally substituted alkyl or may form an optionally substituted heterocycle with R4 (where the heteroatom is the nitrogen (N) in the diazepine ring); R2 is a halogen (e.g., Cl, Br); R3 is an optionally substituted aryl group (e.g., 2-chloro or 2-fluorophenyl); R5 is -H or -OH; if R4 does not combine with R1 to form an optionally substituted heterocycle, R4 and R4' may form a carbonyl moiety (C=O) together with the carbon to which they are attached; R3' and R6 may combine together to form a double bond or to form an optionally substituted heterocycle fused to the diazepine ring at the atom to which they are attached. Benzodiazepines are basic compounds and therefore may form acid addition salts with pharma-ceutically acceptable acids, such as pharma-ceutically acceptable mineral acids and pharma-ceutically acceptable organic acids. As used herein, benzodiazepine means and includes any pharma- ceutically acceptable form, such as the free base form, an acid addition salt, a base addition salt, or a solvate (such as a hydrate).

[0020] Pharmaceutically acceptable mineral acids include hydrochloric acid, sulfuric acid, sulfurous acid, phosphoric acid, phosphorous acid, and other acids recognized by those of skill in the art. Pharmaceutically acceptable organic acids include acetic acid, benzoic acid, tartaric acid, citric acid, oxalic acid, maleic acid, malonic acid, 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-anosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), caproic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclic acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, geranilic ... Intisic acid, glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, hydrochloride, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid (DL), methanesulfonic acid, benzenesulfonic acid (besylic acid), naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p), undecylenic acid. The other pharma- ceutically acceptable acids may be pharma-ceutically acceptable acidic (anionic) polymers or pharma-ceutically acceptable amphoteric polymers.Those skilled in the art will recognize that other basic pharma- ceutically active ingredients may be combined with the aforementioned acids to prepare acid addition salts.

[0021] Examples of benzodiazepines that can be delivered nasally via the nasal compositions disclosed herein include, but are not limited to, alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, chlorazepam, demoxazepam, diazepam, flumazenil, flurazepam, halazepam, olanzapine, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, any pharmaceutically acceptable salt thereof, and any combination thereof.For example, a particularly useful composition can include diazepam, midazolam, lorazepam, or any pharmaceutically acceptable salt thereof. Diazepam is known chemically as 7-chloro-1,3-dihydro-1-methyl-5-phenyl-1-,4-benzodiazepin-2-one and has formula II below. A compound of formula II, [ka]

[0022] A composition for nasal administration of a benzodiazepine ("nasal composition") comprises a therapeutically effective amount of a benzodiazepine, e.g., about 1 mg to about 20 mg of benzodiazepine per volume of about 10 μL to about 200 μL. For example, a nasal composition may comprise about 5 mg / mL (0.5% w / v) to about 0.6 g / mL (60% w / v) or about 10 mg / mL to about 250 mg / mL of benzodiazepine, including benzodiazepine concentrations of about 1% w / v to about 50% w / v, about 5% w / v to about 25% w / v, or about 5% w / v to about 15% w / v. These ranges include any discreet concentration within the disclosed ranges, such as about 5% w / v, about 7.5% w / v, about 10% w / v, about 15% w / v, about 20% w / v, of benzodiazepine.

[0023] The intranasal compositions disclosed herein comprise a benzodiazepine dissolved in a carrier system comprising a natural or synthetic tocopherol, a natural or synthetic tocotrienol, or a combination thereof, and one or more alcohols.

[0024] The nasal composition may contain from about 30% w / v to about 90% w / v of natural or synthetic tocopherols, natural or synthetic tocotrienols, or combinations thereof, for example, from about 50% w / v to about 75% w / v, from about 50% w / v to about 60% w / v, from about 45% w / v to about 65% w / v, from about 45% w / v to about 85% w / v, or from about 10% w / v to about 25% w / v of natural or synthetic tocopherols, natural or synthetic tocotrienols, or combinations thereof.

[0025] Examples of suitable natural or synthetic tocopherols or tocotrienols include, but are not limited to, α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, δ-tocotrienol, tocotrienol, tocopherolane, their isomers, their esters, their analogs or derivatives, and combinations thereof. Synthetic tocopherols may be covalently bound to glycol polymers such as polyethylene glycol, such as vitamin E TPGS (vitamin E polyethylene glycol succinate). Alternatively, the nasal compositions disclosed herein are free or substantially free of such glycol-bound synthetic tocopherols. Many of the solvents for the various tocopherols and tocotrienols mentioned above are naturally occurring vitamin E compounds or vitamin E esters. Vitamin E is a type of fat-soluble methylated phenol. As used herein, vitamin E refers to natural or synthetic tocopherols, tocotrienols, their isomers, esters, or their analogs or derivatives, and combinations thereof. Vitamin E has been found to be an effective carrier of benzodiazepines and does not irritate sensitive mucous membranes. Generally, vitamin E is considered to be hydrophobic, and is therefore used in emulsion-type compositions that tend to be unstable. However, the inclusion of one or more lower alcohols in the vitamin E carrier can improve stability and provide the composition with suitability as a carrier for nasal administration of benzodiazepines.

[0026] Thus, the carrier system of the intranasal compositions disclosed herein also includes one or more alcohols at about 10% w / v to about 70% w / v. As used herein, "alcohol" is used to refer to a molecule having at least one hydroxyl functional group (OH) attached to a saturated carbon atom, including monohydric alcohols such as glycols and polyhydric alcohols. The alcohol may be a lower alcohol, including compounds having six or fewer carbon atoms, such as ethanol, propanol, butanol, pentanol, benzyl alcohol, ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, isomers thereof, or any combination thereof. The intranasal compositions may include one or more alcohols at about 10% w / v to about 70% w / v, such as one or more alcohols at about 15% w / v to about 55% w / v, or one or more alcohols at about 25% w / v to about 40% w / v, or one or more alcohols at about 30% w / v. For example, the nasal composition may comprise about 15% w / v to about 55% w / v, or about 25% w / v to about 40% w / v, or about 30% w / v of benzyl alcohol, ethanol, or a mixture thereof. In another example, the nasal composition may comprise a mixture of ethanol and benzyl alcohol. In any embodiment, the nasal composition is about 10% w / v to about 25% w / v ethanol and about 5% w / v to about 15% w / v benzyl alcohol, or about 15% w / v to about 22.5% w / v ethanol and about 7.5% w / v to about 12.5% ​​w / v benzyl alcohol, or about 10% w / v to about 25% w / v ethanol and about 7.5% w / v to about 12.5% ​​w / v benzyl alcohol, or about 17% w / v to about 20% w / v ethanol and about 10% w / v to about 12% w / v benzyl alcohol.In any embodiment, the nasal composition is about 5% w / v to about 15% w / v ethanol and about 10% w / v to about 25% w / v benzyl alcohol, or about 7.5% w / v to about 12.5% ​​w / v ethanol and about 15% w / v to about 22.5% w / v benzyl alcohol, or about 7.5% w / v to about 12.5% ​​w / v ethanol and about 10% w / v to about 25% w / v benzyl alcohol, or about 10% w / v to about 12% w / v ethanol and about 17% w / v to about 20% w / v benzyl alcohol.

[0027] Optionally, in any embodiment, the nasal composition as disclosed herein can be substantially free or free of polymerene glycols such as polyethylene glycols without reducing the therapeutic benefit of the benzodiazepine administered via the nasal composition. For example, in any embodiment, the nasal composition as disclosed herein can be substantially free or free of polymerene glycols having a molecular weight greater than about 200 g / mol. Additionally or alternatively, in any embodiment, the nasal composition as disclosed herein can be non-aqueous, with very little water, substantially no water, or completely free of water. For example, the nasal composition can be essentially or essentially composed of 1) a benzodiazepine drug; 2) one or more alkyl maltosides (e.g., DDM and / or TDM); and 3) a carrier system consisting of a) one or more natural or synthetic tocopherols or tocotrienols and b) one or more alcohols, optionally substantially free of water.

[0028] In addition to the benzodiazepine and carrier system described above, the intranasal compositions disclosed herein include from about 0.01% w / v to about 1% w / v of an alkyl maltoside, such as octyl-, nonyl-, decyl-, undecyl-, dodecyl, tridecyl, tetradecyl, pentadecyl, octadecyl α- or β-D maltoside. In any embodiment, the intranasal composition may include one or both of dodecyl maltoside (DDM) and tetradecyl maltoside (TDM). For example, in any embodiment, the intranasal composition may include from about 0.01% w / v to about 1% w / v of an alkyl maltoside, such as from about 0.05% w / v to about 0.5% w / v, or from about 0.125% w / v to about 0.5% w / v. In certain examples, the nasal composition comprises about 0.1% w / v to about 0.5% w / v dodecylmaltoside (DDM), about 0.15% w / v to about 0.3% w / v DDM, 0.18% w / v dodecylmaltoside, or about 0.25% w / v DDM.

[0029] The toxicokinetics and metabolism of alkyl glycosides such as Intravale A3 (dodecyl maltoside) have been studied in detail according to the Organization for Economic Cooperation and Development (OECD) guidelines for the testing of chemicals. Orally and nasally administered alkyl glycosides are hydrolyzed to glucose and the corresponding long-chain alcohols. No toxic metabolites are formed at any stage of the metabolic process. Dodecyl maltoside is a component (up to about 25%) of a mixture of alkyl glycosides and is the subject of a Generally Recognized as Safe (GRAS) status designation application by the US FDA Center for Food Safety and Nutrition (CFSAN) and the US Environmental Protection Agency (EPA) due to its use as a detergent or surfactant as an ingredient in compounds for food industry and agricultural applications. No oral or topical exposure limits have been established for humans in these applications.

[0030] Advantageously, it has been observed that the nasal composition as described herein does not support bacterial growth, and therefore is substantially free or free of antibacterial or other preservatives.However, the use of antibacterial agents does not eliminate the therapeutic benefits of administering benzodiazepines via the nasal composition as described herein.Therefore, in any nasal composition as disclosed herein, one or more additional preservatives, antidegradants, antibacterial agents, or antifungal agents may be included.Nasal compositions as disclosed herein may further optionally include one or more agents for enhancing appearance, taste, or odor.

[0031] How to use The present disclosure provides a method of treating a pediatric subject having a seizure disorder, the method comprising administering to a pediatric subject, the pediatric subject being between 2 and 5 years of age, a composition comprising an effective amount of a benzodiazepine (e.g., diazepam), an alkyl maltoside, and a carrier system comprising one or more natural or synthetic tocopherols or tocotrienols and one or more alcohols, the administration being to the nasal mucosa of the pediatric subject to treat the seizure disorder.

[0032] Another aspect of the present disclosure provides a method of treating recurrent seizures in a pediatric subject, the method comprising administering to a pediatric subject between 2 and 5 years of age a composition comprising an effective amount of a benzodiazepine (e.g., diazepam), an alkyl maltoside, and a carrier system comprising one or more natural or synthetic tocopherols or tocotrienols and one or more alcohols, wherein the administration is to the nasal mucosa of the pediatric subject during or prior to a seizure.

[0033] Another aspect of the disclosure provides a method of preventing seizures in a pediatric subject, the method comprising administering to a pediatric subject between 2 and 5 years of age a composition comprising an effective amount of a benzodiazepine (e.g., diazepam), an alkyl maltoside, and a carrier system comprising one or more natural or synthetic tocopherols or tocotrienols and one or more alcohols to the nasal mucosa of the pediatric subject during the prodromal or preictal phase of a seizure.

[0034] In another aspect, the disclosure provides a method for increasing the time to a second seizure in a pediatric subject suffering from recurrent seizures, the method comprising administering to the pediatric subject, age 2-5, a composition comprising an effective amount of a benzodiazepine (e.g., diazepam), an alkyl maltoside, and a carrier system comprising one or more natural or synthetic tocopherols or tocotrienols and one or more alcohols to the nasal mucosa of the pediatric subject during or before the first seizure.

[0035] Nasal compositions comprising benzodiazepines for use in the methods described herein include a carrier system comprising about 0.01% w / v to about 1% w / v of an alkyl maltoside, and about 30% w / v to about 90% w / v of a natural or synthetic tocopherol, natural or synthetic tocotrienol, or combination thereof, and about 10% w / v to about 70% w / v of one or more alcohols. These compositions provide a therapeutic benefit to a pediatric subject when administered to the intranasal mucosa of the pediatric subject. Administration of the intranasal composition may include spraying at least a portion of a therapeutically effective amount of a benzodiazepine into at least one nostril via the intranasal composition such that the intranasal composition contacts the nasal mucosa of the pediatric subject. In another example, administration of the intranasal composition may include spraying at least a portion of a therapeutically effective amount of a benzodiazepine into each nostril via the intranasal composition. In yet another example, administering the intranasal composition may include spraying a first amount of the intranasal composition into a first nostril, spraying a second amount of the intranasal composition into a second nostril, and, optionally after a preselected time delay, spraying a third amount of the intranasal composition into the first nostril. Optionally, after a preselected time delay, a fourth amount of the nasal composition can be administered into the second nostril.

[0036] Benzodiazepines can be administered via any nasal composition as disclosed herein to treat conditions, disorders, syndromes, or diseases for which administration of a benzodiazepine drug can provide therapeutic benefit.Non-limiting examples of benzodiazepines that can be administered via nasal compositions as disclosed herein for therapeutic benefit include alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, chlorazepam, demoxazepam, diazepam flumazenil, flurazepam, halazepam, olanzapine, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, pharmaceutically acceptable salts thereof, and combinations thereof.Conditions, disorders, syndromes, or diseases may be accompanied by undesirable symptoms that can be improved by administration of a benzodiazepine. In one example, a condition, disorder, syndrome, disease, or symptom thereof may be treated by administering an intranasal composition any time before or after the onset of symptoms of the condition, disorder, syndrome, or disease that may be treatable by a benzodiazepine. For example, the intranasal compositions disclosed herein that include a benzodiazepine may be used to treat conditions, disorders, syndromes, and diseases, such as seizures and seizure disorders, such as epilepsy, and symptoms associated therewith.

[0037] The intranasal compositions as disclosed herein may be used in preventing (i.e., inhibiting the onset of seizures) or treating seizures or seizure disorders, conditions, syndromes, or diseases. Thus, in one aspect, the present disclosure provides a method for administering to the nasal mucosa of a pediatric subject an effective amount of a benzodiazepine (such as diazepam, lorazepam, midazolam, etc.); about 0.01% w / v to about 1% w / v of an alkyl maltoside; and about 30% w / v to about 90% w / v of a natural or synthetic tocopherol, natural or synthetic tocotrienol, or combination thereof, and about 10% w / v to about 70% w / v of one or more alcohols. For example, the nasal compositions disclosed herein can include about 2.5 mg to about 20 mg of diazepam, about 0.01% w / v to about 1% w / v of an alkyl maltoside, about 55% w / v to about 70% w / v of a natural or synthetic tocopherol or tocotrienol, and a mixture of about 5% w / v to about 15% w / v of benzyl alcohol and about 10% w / v to about 25% w / v of ethanol. Any nasal composition as disclosed herein is suitable and can be used to treat or prevent seizures, such as epileptic seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures, atonic seizures, focal seizures, atonic seizures, and combinations thereof. Seizures that can be treated with the disclosed nasal compositions include acute seizures, acute repetitive seizures, or seizures that are part of a group of seizures.

[0038] The progression of a seizure event can be divided into phases. For example, a seizure event can be composed of one or more of a prodromal phase, a preictal phase, an ictal / periictal phase, and a postictal phase. According to the method of treating or inhibiting the onset of a seizure disclosed herein, a benzodiazepine can be administered via an intranasal composition as disclosed herein during any phase, such as the prodromal phase, the preictal phase, and the ictal / periictal, postictal, or interictal phase. In some embodiments, a benzodiazepine is administered via an intranasal composition as disclosed herein during the prodromal or preictal phase to prevent or reduce the severity or length of an impending seizure. In some embodiments, a benzodiazepine is administered via a nasal composition as disclosed herein during the preictal or ictal phase to acutely treat an active seizure. In some embodiments, an intranasal composition can be administered during the postictal phase, for example, when an intranasal composition is not available during the prodromal, preictal, or ictal phase. Such administration may serve, for example, to prevent subsequent seizures or to alleviate any residual effects from a current seizure event.

[0039] Pediatric subjects may or may not recognize the prodromal phase as feelings or sensations such as confusion, anxiety, irritability, headache, tremors, anger, and other mood disorders. The prodromal phase is generally not characterized as part of an active seizure, but may function as a warning sign to the pediatric subject of an impending seizure. Thus, in any embodiment, the intranasal composition disclosed herein may be administered during the prodromal phase to prevent the occurrence of a seizure or reduce the severity of the seizure. If or in addition to the pediatric subject does not self-recognize the prodromal phase, the pediatric subject may employ a monitoring device, such as a medical device that measures various biometric data of the pediatric subject to allow for the identification of an impending seizure and thus suggests the administration of an intranasal composition as disclosed herein before the onset of the seizure, such as that available from EMPATICA™. Thus, in another aspect, the present disclosure is administered to the nasal mucosa of a pediatric subject via a carrier system comprising an effective amount of diazepam; about 0.01% w / v to about 1% w / v of an alkyl maltoside; and about 30% w / v to about 90% w / v of a natural or synthetic tocopherol, natural or synthetic tocotrienol, or combination thereof, and about 10% w / v to about 70% w / v of one or more alcohols.

[0040] Pre-seizure (or early seizure) symptoms may also include auras and sensory disturbances, although not all pediatric patients experience these. Examples include, but are not limited to, blurred / blurred vision, flickering vision, hallucinations, ringing / buzzing sounds, strange odors, bitter / sour tastes, out-of-body sensations, nausea, numbness, tingling, dizziness, pain, convulsions, strong emotions, déjà vu, or jamais vu. Thus, in another aspect, the present disclosure provides a method for administering, for example by self-administration, to the nasal mucosa of a pediatric subject an effective amount of diazepam; about 0.01% w / v to about 1% w / v of an alkyl maltoside; and about 30% w / v to about 90% w / v of a natural or synthetic tocopherol, natural or synthetic tocotrienol, or combination thereof, and about 10% w / v to about 70% w / v of one or more alcohols.

[0041] Ictal / periictal period includes times when active seizures are experienced or measured physiologically and may include symptoms such as, but are not limited to, confusion, loss of memory, distractibility, depersonalization, jerking eye or head movements in one direction, inability to move or speak, loss of bladder and / or bowel control, pale / flushed skin, hearing loss, strange sounds, loss of vision, blurred vision, flashes of light, chewing or lip smacking, unusual physical activity, walking / running, dilated pupils, difficulty breathing, racing heart, sweating, trembling, convulsions, stiffness or numbness in arms or legs, or salivation. Thus, in another aspect, the present disclosure provides for administering to the nasal mucosa of a pediatric subject an effective amount of diazepam; about 0.01% w / v to about 1% w / v of an alkyl maltoside; and about 30% w / v to about 90% w / v of a natural or synthetic tocopherol, natural or synthetic tocotrienol, or combination thereof, and about 10% w / v to about 70% w / v of one or more alcohols.

[0042] After the ictal or postictal phase has ended, the pediatric subject experiences a recovery or postictal phase, which may last less than a minute or may last for minutes, hours, or days. Typical symptoms of the postictal phase include, but are not limited to, drowsiness, confusion, memory loss, nausea, general fatigue, body pain, difficulty finding names and words, headache, dry mouth, weakness in arms and legs, high blood pressure, fear, embarrassment, and sadness. The period from the postictal phase until the start of the next seizure is called the "interictal" phase. Thus, in another embodiment, the present disclosure provides a method for administering to the nasal mucosa of a pediatric subject an effective amount of a carrier system comprising: diazepam; about 0.01% w / v to about 1% w / v of an alkyl maltoside; and about 30% w / v to about 90% w / v of a natural or synthetic tocopherol, natural or synthetic tocotrienol, or combination thereof, and about 10% w / v to about 70% w / v of one or more alcohols.

[0043] The present disclosure also provides a method of treating a pediatric subject having Rett Syndrome, comprising administering to a pediatric subject between 2 and 5 years of age a composition comprising an effective amount of a benzodiazepine (e.g., diazepam), an alkyl maltoside, and a carrier system comprising one or more natural or synthetic tocopherols or tocotrienols and one or more alcohols to the nasal mucosa of the pediatric subject to treat Rett Syndrome.

[0044] The disclosure also provides a method of treating a pediatric subject having Lennox-Gastaut syndrome, the method comprising administering to a pediatric subject between 2 and 5 years of age a composition comprising an effective amount of a benzodiazepine (e.g., diazepam), an alkyl maltoside, and a carrier system comprising one or more natural or synthetic tocopherols or tocotrienols and one or more alcohols, the administration being administered to the nasal mucosa of the pediatric subject to treat Lennox-Gastaut syndrome.

[0045] In any embodiment, the nasal composition may include an effective amount of diazepam. As disclosed herein, the effective amount of diazepam that may be administered via the nasal composition may be about 2.5 mg to about 20 mg of diazepam, such as about 5 mg to about 15 mg of diazepam, about 5 mg to about 10 mg of diazepam, about 10 mg to about 20 mg of diazepam, or about 15 mg to about 20 mg of diazepam. In any embodiment, the effective dosage may be determined based on the weight of the pediatric subject to which the diazepam is administered. For example, a dose of about 0.25 mg / kg to about 0.60 mg / kg may be administered to any pediatric subject having a body weight (kg). For example, a suitable dosage may be administered to a pediatric subject having a body weight of about 0.27 mg / kg, about 0.35 mg / kg, about 0.40 mg / kg, about 0.50 mg / kg, or about 0.55 mg / kg. In some embodiments, a suitable dose is about 0.50 mg / kg of body weight. The diazepam comprises about 0.01% w / v to about 1% w / v of an alkyl maltoside, and about 30% w / v to about 90% w / v of a natural or synthetic tocopherol, natural or synthetic tocotrienol, or a combination thereof, and a carrier system comprising about 10% w / v to about 70% w / v, and the intranasal composition has a volume of about 10 μL to about 200 μL, about 50 μL to about 150 μL, about 75 μL to about 125 μL, about 75 μL, about 100 μL, or about 125 μL. For example, 5 mg, 7.5 mg, 10 mg, 15 mg, or 20 mg of diazepam can be administered in a volume of about 75 μL, 100 μL, or 125 μL. The dose may be administered to a single nostril or may be split between the nostrils. For example, 5 mg diazepam in 100 μL, 7.5 mg diazepam in 100 μL, 10 mg diazepam in 100 μL, or 20 mg diazepam in 100 μL may be administered to a single nostril. A 10 mg dose may also be administered to each nostril as 5 mg diazepam in 100 μL. Similarly, a 15 mg dose may be administered to each nostril as, for example, 7.5 mg diazepam in 100 μL. A 20 mg dose may be administered to each nostril as, for example, 10 mg diazepam in 100 μL.

[0046] In one embodiment, an intranasal composition administered according to any of the methods disclosed herein contains 5% w / v benzodiazepine, 56.5% w / v vitamin E, 0.25% DDM, 10.5% benzyl alcohol, and a sufficient amount of ethanol to reach a desired volume (e.g., 100 μL).

[0047] In one embodiment, an intranasal composition administered according to any of the methods disclosed herein contains 10% w / v benzodiazepine, 56.5% w / v vitamin E, 0.25% DDM, 10.5% benzyl alcohol, and a sufficient amount of ethanol to reach a desired volume (e.g., 100 μL).

[0048] In one embodiment, an intranasal composition administered according to any of the methods disclosed herein contains 20% w / v benzodiazepine, 56.5% w / v vitamin E, 0.25% DDM, 10.5% benzyl alcohol, and a sufficient amount of ethanol to reach a desired volume (e.g., 100 μL).

[0049] An effective amount of a benzodiazepine may be administered to a pediatric subject via an intranasal composition as disclosed herein, multiple times as necessary, to effectively treat or prevent attacks. In accordance with the methods disclosed herein, administration is carried out to reduce one or more of the frequency, length, and severity of recurrent attacks in the pediatric subject. Thus, in another aspect, the disclosure provides a method of preventing a seizure (i.e., inhibiting the onset of a seizure) or administering to the nasal mucosa of a pediatric subject during or prior to a seizure a carrier system comprising an effective amount of a benzodiazepine, such as diazepam; about 0.01% w / v to about 1% w / v of an alkyl maltoside; and about 30% w / v to about 90% w / v of a natural or synthetic tocopherol, natural or synthetic tocotrienol, or combination thereof, and about 10% w / v to about 70% w / v of one or more alcohols, wherein if sufficient cessation or prevention of the seizure is not achieved within 4 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 10 minutes after administration of the initial dose, one or more subsequent doses of the composition are administered to the pediatric subject. For example, a composition comprising about 5 mg to about 20 mg of diazepam, about 0.01% w / v to about 1% w / v of an alkyl maltoside; and about 30% w / v to about 90% w / v of a natural or synthetic tocopherol, natural or synthetic tocotrienol, or combination thereof, and a carrier system comprising about 10% w / v to about 70% w / v of one or more alcohols can be administered in a first dose, and upon insufficient cessation of the seizure, a second dose of the composition can be administered. The second dose can be of the same amount and strength as the first dose. Optionally, if sufficient cessation or prevention of the seizure is not achieved within 4 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 10 minutes after administration of the second dose, the method can further include administering a third dose of the composition.

[0050] Advantageously, administration of a benzodiazepine to a pediatric subject via an intranasal composition as disclosed herein may induce a therapeutic benefit in the pediatric subject substantially before a therapeutically relevant benzodiazepine concentration is achieved in the pediatric subject's plasma. For example, a maximum plasma concentration (C) of about 200 ng / mL to about 500 ng / mL may be achieved. max) has a T of about 1 hour or more, such as about 1 hour, about 1.25 hours, about 1.5 hours, or about 2 hours, after administration of a benzodiazepine via a nasal composition described herein. max Thus, the PK profile of the nasal compositions as disclosed herein appears to be similar to the oral formulations (see, e.g., Friedman et al., Clinical Pharmacology & Therapeutics, 1992;52(2):139-150, which is incorporated herein by reference in its entirety).

[0051] Several clinical trials with earlier intranasal formulations of benzodiazepines (e.g., diazepam) have been reported in the literature. In general, the absolute bioavailability of benzodiazepines administered via these formulations was low (approximately 50%). For example, Gizurarson S. and Bechgaard E; Diabetes Res Clin Pract. 1991; 12(2):71-84 (incorporated herein by reference in its entirety) reported a 2 mg dose of a 20 mg / mL solution of diazepam dissolved in 5% glycofurol in polyethylene glycol 200. The mean bioavailability of benzodiazepines was 50.4% ± 23.3%, with T max The reported time to release was 18±11 minutes. Lindhardt et al.; Br J Clin Pharmacol. 2001;52(5):521-527, incorporated herein by reference in its entirety, evaluated intranasal formulations of diazepam in polyethylene glycol 300 at doses of 4 mg and 7 mg versus 5 mg intravenously in seven healthy volunteers. The relative bioavailability of the benzodiazepine administered in the intranasal formulation was 45% and 42%, C max 99ng / mL and 170ng / mL, T maxwere 18 and 42 minutes for the 4 and 7 mg doses, respectively. Ivaturi et al.; Acta Neurol Scand. 2009; 120(5):353-357, incorporated herein by reference in its entirety, conducted a bioavailability and tolerability study of intranasal diazepam in healthy volunteers. Nasal doses of 5 and 10 mg were compared with intravenous administration of 5 mg diazepam. After administration of 5 and 10 mg, T max The median values ​​for were 20 and 30 minutes, respectively, and C max The mean values ​​for diazepam were 134.3 ± 62 ng / mL and 247.6 ± 61 ng / mL. The estimated bioavailability of diazepam was 75% for both doses.

[0052] In contrast, the absolute bioavailability of diazepam administered via intranasal compositions as disclosed herein achieves about 90% to about 110% of the bioavailability of intravenously administered diazepam. In some embodiments, a bioavailability of about 92.5% to about 107.5% of intravenously administered diazepam is achieved. In some embodiments, a bioavailability of about 96% of intravenously administered diazepam is achieved. Additionally, the mean elimination half-life of benzodiazepine following administration of the intranasal compositions described herein is significantly longer (i.e., t 1 / 2 , ~49 hours vs. 2-6 hours). This longer half-life provides a longer duration of action, lowering the risk of a second attack or the need for repeat dosing.

[0053] Thus, in some embodiments, administering a composition comprising an effective amount of diazepam, an alkyl maltoside, and a carrier system comprising one or more natural or synthetic tocopherols or tocotrienols and one or more alcohols described herein to the nasal mucosa of a pediatric subject during or before a seizure is effective to reduce clinical seizure activity in the pediatric subject for a period of at least 8 hours after said administration. In some embodiments, clinical seizure activity is reduced for a period of at least 12 hours after said administration, for a period of at least 18 hours after said administration, for a period of at least 24 hours after said administration, for a period of at least 36 hours after said administration, for a period of at least 48 hours after said administration, or for a period of >48 hours after said administration. Longer half-lives and longer durations of action are particularly useful for treating pediatric subjects experiencing seizure clusters or acute recurrent seizures.

[0054] In some embodiments, administering a composition comprising an effective amount of diazepam as described herein to the nasal mucosa of a pediatric subject during or before a seizure is effective in preventing a second seizure in the pediatric subject for a period of at least 8 hours after said administration. In some embodiments, a second seizure in the pediatric subject is prevented for a period of at least 12 hours after said administration, for a period of at least 18 hours after said administration, for a period of at least 24 hours after said administration, for a period of at least 36 hours after said administration, for a period of at least 48 hours after said administration, or for a period of >48 hours after said administration. Prevention of a second seizure is particularly beneficial for pediatric subjects experiencing seizure clusters or acute recurrent seizures.

[0055] In some embodiments, administering a composition comprising an effective amount of diazepam as described herein to the nasal mucosa of a pediatric subject during or before a seizure is effective to eliminate the need for a second administration of the composition within 24 hours of experiencing a first seizure. In some embodiments, the dose is effective to eliminate the need for a second administration of the composition within 48 hours or more of experiencing a first seizure.

[0056] Equally surprising is that the therapeutic benefit of the disclosed nasal compositions is realized in pediatric subjects prior to PK-based prediction. For example, therapeutic benefit may be realized in pediatric subjects within 10 minutes, e.g., within 5 minutes, within 1 minute, within about 30 seconds to about 4 minutes, within about 30 seconds to about 3 minutes, within about 30 seconds to about 2 minutes, or within about 30 seconds to about 1 minute, after nasal administration of a benzodiazepine via a nasal composition as disclosed herein. Examples of therapeutic benefits that may be realized in pediatric subjects include, but are not limited to, not experiencing seizures, having less severe seizures, or having shorter seizures compared to pediatric subjects receiving benzodiazepines orally or intravenously. This is particularly surprising and advantageous since the only non-IV administration route that provides a rapid effect is rectal administration (e.g., DIASTAT™), whose therapeutic effect has been reported to occur in about 5 to about 10 minutes, which is more than double the time observed using the nasal compositions disclosed herein.

[0057] Thus, in another aspect, the present disclosure provides for preventing (i.e., inhibiting the onset of) or treating seizures in a pediatric subject in need thereof by administering to the nasal mucosa of the pediatric subject an effective amount of a benzodiazepine, about 0.01% w / v to about 1% w / v of an alkyl maltoside (e.g., DDM or TDM), and about 30% w / v to about 90% w / v of a natural or synthetic tocopherol, natural or synthetic tocotrienol, or combination thereof, and about 10% w / v to about 70% w / v of one or more alcohols during or before a seizure. For example, an intranasal composition can include an effective amount of a benzodiazepine (e.g., about 5 mg to about 20 mg of diazepam), about 0.01% w / v to about 1% w / v of an alkyl maltoside, about 55% w / v to about 70% w / v of a natural or synthetic tocopherol or tocotrienol, and a mixture of about 5% w / v to about 15% w / v of benzyl alcohol and about 10% w / v to about 25% w / v of ethanol. In some embodiments, the composition includes about 5% to about 20% w / v of diazepam, about 56.5% w / v of vitamin E, about 0.25% DDM, about 510.5% benzyl alcohol, and a sufficient amount of ethanol to reach a desired volume (e.g., 100 μL). In accordance with the methods disclosed herein, administration is performed to reduce one or more of the frequency, length, and severity of recurrent seizures in a pediatric subject.

[0058] Quantitatively, the therapeutic effect on seizure activity of benzodiazepines administered via intranasal compositions as disclosed herein can be detected by monitoring beta rhythm or beta frequency by electroencephalography. Changes in beta frequency following intranasal administration of 20 mg diazepam have been observed within about 10 minutes of intranasal administration. In contrast, beta frequency following oral administration of 10 mg diazepam does not change until about 1.5 to 2 hours (see, e.g., Friedman et al., disclosed above). The discrepancy in PD and PK profiles, and more specifically, the PK profile of diazepam administered according to the methods disclosed herein, is consistent with the T of the oral dosage form. max and C maxThe observation that intranasal compositions mimicking intravenous or rectal administration, but with the bioavailability and rapid onset of therapeutic effect of intravenously or rectally administered benzodiazepines, is surprising and unexpected. Despite similar systemic drug concentrations, therapeutic benefit, as evidenced by both cessation of seizures and measurable changes in beta frequency, is achieved more rapidly using the intranasal compositions disclosed herein than with oral dosage forms. Moreover, therapeutic effect is realized in a similar time frame to intravenous administration, while avoiding high and dangerous systemic circulating concentrations.

[0059] Thus, in another aspect, the disclosure provides a method of preventing (i.e., inhibiting) the onset of an attack by administering to the nasal mucosa of a pediatric subject an effective amount of a benzodiazepine (e.g., diazepam), about 0.01% wv / to about 1% wv / of an alkyl maltoside (e.g., DDM or TDM), and about 30% wv / to about 90% wv / of a natural or synthetic tocopherol, natural or synthetic tocotrienol, or combination thereof, and about 10% w / v to about 70% w / v of one or more alcohols during or before the attack. For example, an intranasal composition can include an effective amount of a benzodiazepine (e.g., about 5 mg to about 20 mg diazepam), about 0.01% w / v to about 1% w / v alkyl maltoside, about 55% w / v to about 70% w / v natural or synthetic tocopherol or tocotrienol, and a mixture of about 5% w / v to about 15% w / v benzyl alcohol and about 10% w / v to about 25% w / v ethanol. In some embodiments, the composition includes about 5% to about 20% w / v diazepam benzodiazepine, about 56.5% w / v vitamin E, about 0.25% DDM, about 10.5% benzyl alcohol, and a sufficient amount of ethanol to reach a desired volume (e.g., 100 μL). In accordance with the methods disclosed herein, administration is performed to reduce one or more of the frequency, length, and severity of recurrent seizures in a pediatric subject. A change in beta frequency in a pediatric subject following administration of a benzodiazepine (e.g., diazepam) via an intranasal composition to the pediatric subject can occur within about 30 minutes, within about 25 minutes, within about 20 minutes, within about 15 minutes, within about 10 minutes, or within about 5 minutes following administration of the benzodiazepine.

[0060] Systemic administration of benzodiazepines is often associated with undesirable side effects, including but not limited to somnolence, euphoria, headache / migraine, suicidal thoughts and behaviors, depression, vasodilation, diarrhea, ataxia, dizziness, incoordination, rash, asthma, confusion, slurred speech, muscle weakness, memory impairment, dry mouth, constipation, and blurred vision. Therefore, pediatric subjects may be less compliant with treatment regimens because they want to avoid undesirable side effects. Furthermore, pediatric subjects may delay systemic administration in an attempt to avoid undesirable side effects.

[0061] Pediatric subjects treated with benzodiazepines via an intranasal composition are expected to experience a lower incidence and / or less severity of many of these aforementioned side effects, such as somnolence, euphoria, headache, suicidal thoughts and behaviors, depression, incoordination, rash, asthma, and vasodilation. Thus, pediatric subjects being treated using an intranasal composition as disclosed herein may be less likely to discontinue or delay use of the composition to treat seizures compared to pediatric subjects using an orally, intravenously, or rectally administered benzodiazepine composition.

[0062] Thus, in another aspect, the disclosure provides a method of preventing (i.e., inhibiting) the onset of an attack by administering to the nasal mucosa of a pediatric subject during or prior to an attack an effective amount of a benzodiazepine, about 0.01% w / v to about 1% w / v of an alkyl maltoside (e.g., DDM or TDM), and about 30% w / v to about 90% w / v of a natural or synthetic tocopherol, natural or synthetic tocotrienol, or combination thereof, and about 10% w / v to about 70% w / v of one or more alcohols, wherein the pediatric subject experiences a reduced incidence or severity of euphoria following administration. For example, the incidence or severity of euphoria may be reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, or greater than 50% in pediatric subjects compared to the euphoria experienced after rectal, intravenous, or oral administration of a therapeutically effective amount of diazepam. For example, an intranasal composition may include an effective amount of a benzodiazepine (such as about 5 mg to about 20 mg of diazepam), about 0.01% w / v to about 1% w / v of an alkyl maltoside, about 55% w / v to about 70% w / v of a natural or synthetic tocopherol or tocotrienol, and a mixture of about 5% w / v to about 15% w / v of benzyl alcohol and about 10% w / v to about 25% w / v of ethanol. In some embodiments, the composition comprises about 5% to about 20% w / v diazepam, about 56.5% w / v vitamin E, about 0.25% DDM, about 10.5% benzyl alcohol, and a sufficient amount of ethanol to reach a desired volume (e.g., 100 μL). In accordance with the methods disclosed herein, administration is performed to reduce one or more of the frequency, length, and severity of recurrent seizures in a pediatric subject, and may have the added benefit of subsequently reducing euphoria.

[0063] In another aspect, the disclosure provides a method of preventing (i.e., inhibiting) the onset of headaches, comprising administering to the nasal mucosa of a pediatric subject during or prior to an attack an effective amount of a benzodiazepine, about 0.01% w / v to about 1% w / v of an alkyl maltoside (e.g., DDM or TDM), and about 30% w / v to about 90% w / v of a natural or synthetic tocopherol, natural or synthetic tocotrienol, or combination thereof, and about 10% w / v to about 70% w / v of one or more alcohols, wherein the pediatric subject experiences a reduction in the incidence or severity of headaches following administration. For example, the incidence or severity of headaches may be reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, or greater than 50% in pediatric subjects compared to headaches experienced after rectal, intravenous, or oral administration of a therapeutically effective amount of diazepam. For example, the intranasal compositions disclosed herein include an effective amount of a benzodiazepine (e.g., about 5 mg to about 20 mg of diazepam), about 0.01% w / v to about 1% w / v of an alkyl maltoside, about 55% w / v to about 70% w / v of a natural or synthetic tocopherol or tocotrienol, and a mixture of about 5% w / v to about 15% w / v of benzyl alcohol and about 10% w / v to about 25% w / v of ethanol. In some embodiments, the composition comprises about 5% to about 20% w / v diazepam, about 56.5% w / v vitamin E, about 0.25% DDM, about 10.5% benzyl alcohol, and a sufficient amount of ethanol to reach a desired volume (e.g., 100 μL). In accordance with the methods disclosed herein, administration is performed to reduce one or more of the frequency, length, and severity of recurrent attacks in a pediatric subject, which may then have the additional benefit of reducing the severity or length of headaches.

[0064] In another aspect, the disclosure provides a method of preventing (i.e., inhibiting) the onset of, comprising administering to the nasal mucosa of a pediatric subject during or prior to a seizure an effective amount of a benzodiazepine, about 0.01% w / v to about 1% w / v of an alkyl maltoside (e.g., DDM or TDM), and about 30% w / v to about 90% w / v of a natural or synthetic tocopherol, natural or synthetic tocotrienol, or combination thereof, and about 10% w / v to about 70% w / v of one or more alcohols, wherein after administration, the pediatric subject experiences a reduction in the incidence or severity of suicidal ideation, behavior, or tendency. For example, the incidence or severity of suicidal ideation, behavior, or tendency may be reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, or more in pediatric subjects relative to suicidal ideation, behavior, or tendency experienced after rectal, intravenous, or oral administration of a therapeutically effective amount of diazepam. For example, the intranasal compositions disclosed herein include an effective amount of a benzodiazepine (e.g., about 5 mg to about 20 mg of diazepam), about 0.01% w / v to about 1% w / v of an alkyl maltoside, about 55% w / v to about 70% w / v of a natural or synthetic tocopherol or tocotrienol, and a mixture of about 5% w / v to about 15% w / v of benzyl alcohol and about 10% w / v to about 25% w / v of ethanol. In some embodiments, the composition comprises about 5% to about 20% w / v diazepam, about 56.5% w / v vitamin E, about 0.25% DDM, about 10.5% benzyl alcohol, and a sufficient amount of ethanol to reach a desired volume (e.g., 100 μL). In accordance with the methods disclosed herein, administration is performed to reduce one or more of the frequency, length, and severity of recurrent seizures in a pediatric subject, which may then have the additional benefit of reducing suicidal thoughts, behaviors, or tendencies.

[0065] In another aspect, the disclosure provides a method of preventing (i.e., inhibiting) the onset of depression, comprising administering to the nasal mucosa of a pediatric subject during or prior to an attack an effective amount of a benzodiazepine, about 0.01% w / v to about 1% w / v of an alkyl maltoside (e.g., DDM or TDM), and about 30% w / v to about 90% w / v of a natural or synthetic tocopherol, natural or synthetic tocotrienol, or combination thereof, and about 10% w / v to about 70% w / v of one or more alcohols, wherein after administration, the pediatric subject experiences a reduction in the incidence or severity of depression. For example, the incidence or severity of depression may be reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, or greater than 50% in pediatric subjects relative to depression experienced after rectal, intravenous, or oral administration of a therapeutically effective amount of diazepam. For example, the intranasal compositions disclosed herein include an effective amount of a benzodiazepine (e.g., about 5 mg to about 20 mg of diazepam), about 0.01% w / v to about 1% w / v of an alkyl maltoside, about 55% w / v to about 70% w / v of a natural or synthetic tocopherol or tocotrienol, and a mixture of about 5% w / v to about 15% w / v of benzyl alcohol and about 10% w / v to about 25% w / v of ethanol. In some embodiments, the composition comprises about 5% to about 20% w / v diazepam, about 56.5% w / v vitamin E, about 0.25% DDM, about 10.5% benzyl alcohol, and a sufficient amount of ethanol to reach a desired volume (e.g., 100 μL). In accordance with the methods disclosed herein, administration is performed to reduce one or more of the frequency, length, and severity of recurrent seizures in a pediatric subject, which may then have the additional benefit of reducing depression.

[0066] In another aspect, the disclosure provides a method of preventing (i.e., inhibiting) the onset of an attack, comprising administering to the nasal mucosa of a pediatric subject during or prior to an attack an effective amount of a benzodiazepine, about 0.01% w / v to about 1% w / v of an alkyl maltoside (e.g., DDM or TDM), and about 30% w / v to about 90% w / v of a natural or synthetic tocopherol, natural or synthetic tocotrienol, or combination thereof, and about 10% w / v to about 70% w / v of one or more alcohols, wherein after administration, the pediatric subject experiences a reduction in the incidence or severity of somnolence. For example, the incidence or severity of somnolence may be reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, or greater than 50% in pediatric subjects relative to somnolence experienced after rectal, intravenous, or oral administration of a therapeutically effective amount of diazepam. For example, the intranasal compositions disclosed herein include an effective amount of a benzodiazepine (e.g., about 5 mg to about 20 mg of diazepam), about 0.01% w / v to about 1% w / v of an alkyl maltoside, about 55% w / v to about 70% w / v of a natural or synthetic tocopherol or tocotrienol, and a mixture of about 5% w / v to about 15% w / v of benzyl alcohol and about 10% w / v to about 25% w / v of ethanol. In some embodiments, the composition comprises about 5% to about 20% w / v diazepam, about 56.5% w / v vitamin E, about 0.25% DDM, about 10.5% benzyl alcohol, and a sufficient amount of ethanol to reach a desired volume (e.g., 100 μL). In accordance with the methods disclosed herein, administration is performed to reduce one or more of the frequency, length, and severity of recurrent seizures in a pediatric subject, and may have the additional benefit of subsequently reducing somnolence.

[0067] Due to the reduced incidence of side effects, compliance of pediatric subjects with a treatment regimen using the compositions disclosed herein may be more complete compared to treatment regimens using alternative benzodiazepine compositions.Accordingly, in another aspect, the present disclosure provides a method for improving patient compliance with a prescribed treatment regimen for preventing (i.e., inhibiting the occurrence of) or treating a seizure, wherein the treatment method comprises administering to the nasal mucosa of a pediatric subject during or before a seizure an effective amount of a benzodiazepine, about 0.01% w / v to about 1% w / v of an alkyl maltoside (e.g., DDM or TDM), and about 30% w / v to about 90% w / v of a natural or synthetic tocopherol, natural or synthetic tocotrienol, or a combination thereof, and about 10% w / v to about 70% w / v of one or more alcohols. For example, an intranasal composition as disclosed herein comprises an effective amount of a benzodiazepine (e.g., about 5 mg to about 20 mg diazepam), about 0.01% w / v to about 1% w / v alkyl maltoside, about 55% w / v to about 70% w / v natural or synthetic tocopherol or tocotrienol, and a mixture of about 5% w / v to about 15% w / v benzyl alcohol and about 10% w / v to about 25% w / v ethanol. In some embodiments, the composition comprises about 5% to about 20% w / v diazepam, about 56.5% w / v vitamin E, about 0.25% DDM, about 10.5% benzyl alcohol, and a sufficient amount of ethanol to reach a desired volume (e.g., 100 μL). According to this aspect of the disclosure, administration is performed to reduce one or more of the frequency, length, and severity of recurrent seizures in a pediatric subject.

[0068] To effectively treat recurrent seizures in children, it is important to adhere to the prescribed treatment regimen. Undertreatment, mistreatment, or leaving recurrent seizures untreated, as occurs in epilepsy syndromes, can lead to neurological impairment after repeated seizure episodes. For example, evidence of progressive damage in temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) has been identified by neuroimaging and electroencephalography (see, e.g., Coan, AC, and Cendes, F.; Epilepsy & Behavior; March 2013, 26(3): pages 313-321). Pathologically, the neuronal hyperexcitability that characterizes seizures leads to massive depolarization of neurons, excessive release of glutamate, and increased intracellular calcium that causes a cascade of changes that ultimately result in cell death (see, e.g., Holmes, GL; Neurology; November 12, 2002, 59(9 Suppl.5), which is incorporated herein by reference in its entirety). The deleterious effects of recurrent attacks may be evidenced, for example, by increased cognitive impairment, increased severity, length, or frequency of attacks. However, administration of benzodiazepines via an intranasal composition as disclosed herein advantageously results in a slowing or halting of cognitive decline and / or a reduction in the severity, length, and frequency of recurrent attacks compared to the severity, length, and frequency of recurrent attacks in pediatric subjects left untreated or treated with another route of administration.

[0069] Thus, in another aspect, the present disclosure provides a carrier system comprising an effective amount of a benzodiazepine, about 0.01% w / v to about 1% w / v of an alkyl maltoside (e.g., DDM or TDM), and about 30% w / v to about 90% w / v of a natural or synthetic tocopherol, natural or synthetic tocotrienol, or combination thereof, and about 10% w / v to about 70% w / v of one or more alcohols, administered to the nasal mucosa of a pediatric subject during or before a seizure. For example, a nasal composition disclosed herein may comprise a mixture of about 5 mg to about 20 mg of diazepam, about 55% w / v to about 70% w / v of a natural or synthetic tocopherol or tocotrienol, and about 5% w / v to about 15% w / v of benzyl alcohol and about 10% w / v to about 25% w / v of ethanol. In some embodiments, the composition comprises about 5% to about 20% w / v diazepam, about 56.5% w / v vitamin E, about 0.25% DDM, about 10.5% benzyl alcohol, and a sufficient amount of ethanol to reach a desired volume (e.g., 100 μL). According to the methods disclosed herein, administration is performed to reduce one or more of the frequency, length, and severity of recurrent seizures in a pediatric subject.

[0070] Administering a benzodiazepine to a pediatric subject via an intranasal composition as disclosed herein may, in any embodiment, reduce neuronal cell loss caused by recurrent seizures in a pediatric subject that would occur in the absence of treatment or treatment with another benzodiazepine dosage form. For example, a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or greater than 20% reduction in neuronal cell loss is observed in a pediatric subject following administration of a benzodiazepine via an intranasal composition as disclosed herein, as compared to the neuronal cell loss that would occur in the absence of treatment or treatment with another benzodiazepine dosage form.

[0071] Administering a benzodiazepine via an intranasal composition as disclosed herein for the treatment of recurrent seizures can, in any embodiment, reduce or prevent cognitive impairment caused by recurrent seizures in a pediatric subject. In any embodiment, a 1% reduction, 2% reduction, 3% reduction, 4% reduction, 5% reduction, 6% reduction, 7% reduction, 8% reduction, 9% reduction, 10% reduction, 11% reduction, 12% reduction, 13% reduction, 14% reduction, 15% reduction, 16% reduction, 17% reduction, 18% reduction, 19% reduction, or more than 20% reduction in cognitive impairment is observed in a pediatric subject after administration of a benzodiazepine via an intranasal composition as disclosed herein, compared to the cognitive impairment that would occur in the absence of treatment or when treated with another benzodiazepine dosage form.

[0072] Currently available benzodiazepine dosage forms have various contraindications due to various side effects observed with administration of the dosage forms. For example, administration of diazepam is contraindicated in pediatric subjects with glaucoma (especially acute narrow-angle glaucoma and untreated open-angle glaucoma) due to the possibility of increased intraocular pressure. Due to the reduced incidence of side effects, the intranasal compositions disclosed herein can be safely and effectively administered to pediatric subjects with glaucoma to treat coexisting seizures or seizure disorders or syndromes. Thus, in another aspect, the disclosure provides a method of treating or preventing (i.e., inhibiting the onset of) attacks in a pediatric subject having glaucoma comprising administering to the nasal mucosa of the pediatric subject an effective amount of a benzodiazepine, from about 0.01% w / v to about 1% w / v of an alkyl maltoside (e.g., DDM or TDM), and from about 30% w / v to about 90% w / v of a natural or synthetic tocopherol, natural or synthetic tocotrienol, or combination thereof, and from about 10% w / v to about 70% w / v of one or more alcohols during or before the attack. For example, the intranasal compositions disclosed herein may include about 5 mg to about 20 mg of diazepam, about 55% w / v to about 70% w / v of natural or synthetic tocopherols or tocotrienols, and a mixture of about 5% w / v to about 15% w / v of benzyl alcohol and about 10% w / v to about 25% w / v of ethanol. In some embodiments, the composition includes about 5% to about 20% w / v of diazepam, about 56.5% w / v of vitamin E, about 0.25% DDM, about 10.5% benzyl alcohol, and a sufficient amount of ethanol to reach a desired volume (e.g., 100 μL). In some embodiments, the pediatric subject has narrow angle glaucoma.

[0073] Concomitant use of benzodiazepines with opioids is also contraindicated because both drugs sedate the user and depress breathing, increasing the risk of overdose and death from respiratory distress. The reduced incidence of side effects allows the intranasal compositions disclosed herein to be safely and effectively administered, in some cases, to pediatric subjects undergoing treatment involving opioid administration. Thus, in another aspect, the present disclosure provides a method of treating or preventing (i.e., inhibiting the occurrence of) seizures in a pediatric subject taking prescription opioids, comprising administering to the nasal mucosa of the pediatric subject during or before a seizure an effective amount of a benzodiazepine, about 0.01% w / v to about 1% w / v of an alkyl maltoside (e.g., DDM or TDM), and about 30% w / v to about 90% w / v of a natural or synthetic tocopherol, natural or synthetic tocotrienol, or combination thereof, and about 10% w / v to about 70% w / v of one or more alcohols. For example, an intranasal composition disclosed herein may contain about 5 mg to about 20 mg of diazepam, about 55% w / v to about 70% w / v of natural or synthetic tocopherol or tocotrienol, and a mixture of about 5% w / v to about 15% w / v of benzyl alcohol and about 10% w / v to about 25% w / v of ethanol. In some embodiments, the composition contains about 5% to about 20% w / v of diazepam, about 56.5% w / v of vitamin E, 0.25% DDM, about 10.5% benzyl alcohol, and a sufficient amount of ethanol to reach a desired volume (e.g., 100 μL).

[0074] Chronic administration of benzodiazepines to treat seizures (e.g., administration of benzodiazepines more than 5 times per month) is also contraindicated because oral, intravenous, and rectal administration of benzodiazepines tend to develop tolerance and / or dependence with repeated systemic exposure to benzodiazepines. Advantageously, the intranasal compositions disclosed herein do not induce tolerance or dependence in pediatric subjects, even when administered chronically to treat recurrent seizures, such as at least 6 times per month, 10 or more times per month, or 15 or more times per month. Thus, the intranasal compositions disclosed herein may be used to prevent or acutely treat seizures, regardless of prior administration and its timing.

[0075] Thus, in another aspect, the disclosure provides a method of preventing (i.e., inhibiting the occurrence of) or treating attacks within a series of recurrent attacks, comprising administering to the nasal mucosa of a pediatric subject during or prior to each of the recurrent attacks an effective amount of a benzodiazepine, about 0.01% w / v to about 1% w / v of an alkyl maltoside (e.g., DDM or TDM), and a carrier system comprising about 30% w / v to about 90% w / v of a natural or synthetic tocopherol, natural or synthetic tocotrienol, or combination thereof, and about 10% w / v to about 70% w / v of one or more alcohols, wherein the attacks occur 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or more times per month. For example, the intranasal compositions disclosed herein may include about 5 mg to about 20 mg of diazepam, about 55% w / v to about 70% w / v of natural or synthetic tocopherol or tocotrienol, and a mixture of about 5% w / v to about 15% w / v of benzyl alcohol and about 10% w / v to about 25% w / v of ethanol. In some embodiments, the composition includes about 5% to about 20% w / v of diazepam, about 56.5% w / v of vitamin E, about 0.25% DDM, about 10.5% benzyl alcohol, and a sufficient amount of ethanol to reach a desired volume (e.g., 100 μL). In accordance with the methods disclosed herein, administration is performed to reduce one or more of the frequency, length, and severity of recurrent seizures in a pediatric subject.

[0076] Administration of benzodiazepines by oral, intravenous, or rectal routes is also contraindicated in children aged 2-5 years due to the potential for developing tolerance and dependence. Thus, in addition to suitability for pediatric subjects aged 6 years and older, the compositions disclosed herein are also suitable for administration to younger patient populations, such as 2-5 years old. Thus, in another aspect, the disclosure provides a method of preventing (i.e., inhibiting the onset of) or treating seizures in a pediatric subject aged 2, 3, 4, 5, or older, wherein the treatment method comprises administering to the nasal mucosa of the pediatric subject during or before a seizure an effective amount of a benzodiazepine, about 0.01% w / v to about 1% w / v of an alkyl maltoside (e.g., DDM or TDM), and about 30% w / v to about 90% w / v of a natural or synthetic tocopherol, natural or synthetic tocotrienol, or combination thereof, and about 10% w / v to about 70% w / v of one or more alcohols. For example, the intranasal compositions disclosed herein may include about 5 mg to about 20 mg of diazepam, about 55% w / v to about 70% w / v of natural or synthetic tocopherol or tocotrienol, and a mixture of about 5% w / v to about 15% w / v of benzyl alcohol and about 10% w / v to about 25% w / v of ethanol. In some embodiments, the composition includes about 5% to about 20% w / v of diazepam, about 56.5% w / v of vitamin E, about 0.25% DDM, about 10.5% benzyl alcohol, and a sufficient amount of ethanol to reach a desired volume (e.g., 100 μL). In accordance with the methods disclosed herein, administration is performed to reduce one or more of the frequency, length, and severity of recurrent seizures in a pediatric subject.

[0077] Compared with other routes of administration such as oral, intravenous, or rectal, the compositions disclosed herein can be administered in a much simpler way through nasal spray. Thus, pediatric subjects themselves, especially when in the prodromal or pre-attack stage of an attack, can effectively self-administer any intranasal composition as disclosed herein to the nasal mucosa. Furthermore, caregivers do not need to be trained medical professionals to effectively administer the composition to pediatric subjects, as is required for example in intravenous administration. Thus, advantageously, the compositions disclosed herein provide an easily administrable dosage form that can be administered before or during an attack for rapid and immediate prevention or treatment of an attack, and in some cases has the ability to provide long-term benefits.

[0078] Treatment System Another aspect of the present disclosure pertains to a therapeutic system for the treatment of seizure conditions, disorders, syndromes, or diseases. The therapeutic system comprises a neurological monitoring device and an intranasal benzodiazepine composition as described herein. The neurological monitoring device may consist of a smartwatch (e.g., Embrace by EMPATICA™, Inc.), an adhesive sensor applied externally to the skin (e.g., BioStamp by MC10), an implantable detection device, an electrode patch (e.g., SPEAC system by Brain Sentinel), or any other detection device suitable for detecting changes in neurological or other physiological parameters indicative of an impending seizure. Alternatively, and / or in addition to the monitoring device, an algorithm for predicting the onset of seizure effects may also be employed or included in the therapeutic system (e.g., Dauod and Bayouimi, “Efficient Epileptic Seizure Prediction Based on Deep Learning,” IEEE Trans.Biomed.Circuits Systems 13(5):804 (2019), incorporated herein by reference in its entirety).

[0079] In accordance with this aspect of the disclosure, the intranasal benzodiazepine composition of the system includes about 5 mg to about 20 mg of diazepam, about 55% w / v to about 70% w / v of a natural or synthetic tocopherol or tocotrienol, and a mixture of about 5% w / v to about 15% w / v of benzyl alcohol and about 10% w / v to about 25% w / v of ethanol. In some embodiments, the intranasal benzodiazepine composition includes about 5%, about 10%, or about 20% w / v of a benzodiazepine, about 56.5% w / v of vitamin E, about 0.25% DDM, about 10.5% benzyl alcohol, and a sufficient amount of ethanol to reach a desired volume (e.g., 100 μL).

[0080] The therapeutic system herein constitutes a suitable therapeutic regimen for treating a seizure condition, disorder, syndrome, or disease. Pairing a monitoring device with the nasal benzodiazepine composition described herein allows a pediatric subject suffering from a seizure condition, disorder, syndrome, or disease to recognize the onset or impending onset of a seizure and administer the nasal benzodiazepine composition prior to or at the onset of a seizure to prevent the onset of a seizure or reduce the frequency, length, and / or severity of the seizure.

[0081] The therapeutic systems described herein are also suitable for use in methods to prevent injury resulting from seizures, such as falls, and to prevent ongoing or further injury to the brain in recurrent seizure syndromes. In some embodiments, the therapeutic systems described herein are employed as an alternative or adjunct therapy to chronic anti-epileptic drugs, reducing or avoiding the chronic side effects of those drugs.

[0082] Further embodiments Provided herein is embodiment A, a method of treating a pediatric subject having a seizure disorder, the method comprising: administering to a pediatric subject between 2 and 5 years of age a composition comprising: an effective amount of diazepam, an alkyl maltoside, and a carrier system comprising one or more natural or synthetic tocopherols or tocotrienols and one or more alcohols, the administration being administered to the nasal mucosa of the pediatric subject to treat the seizure disorder in the pediatric subject.

[0083] In embodiment B, the method of embodiment A, wherein the effective amount of diazepam is from about 2 mg to about 20 mg of diazepam in a volume of the composition of from about 10 μL to 200 μL.

[0084] In embodiment C, the method of embodiment B, wherein the effective amount of diazepam is from about 5 mg to about 15 mg in a volume of 100 μL to 200 μL of the composition.

[0085] In embodiment D, the method of any one of embodiments A to C, wherein the composition is provided in a pre-primed single-use dispensing device containing about 100 μL of the composition.

[0086] In embodiment E, the method of any one of embodiments A to D, wherein the administering comprises delivering about 5 mg to about 10 mg of diazepam in a volume of about 100 μL of the composition to a single nostril of the pediatric subject.

[0087] In embodiment F, the method of any one of embodiments A to D, wherein the administering comprises delivering about 7.5 mg of diazepam to each nostril of the pediatric subject in a volume of 100 μL of the composition.

[0088] In embodiment G, the method of any one of embodiments A to F, wherein the alkyl maltoside is selected from dodecyl maltoside, tetradecyl maltoside, or a combination thereof.

[0089] In embodiment H, the method of any one of embodiments A to G, wherein the composition comprises about 0.1% w / v to about 1% w / v of an alkyl maltoside.

[0090] In embodiment I, the method of any one of embodiments A through H, wherein the one or more alcohols comprises a mixture of ethanol and benzyl alcohol.

[0091] In embodiment J, the method of any one of embodiments A to I, wherein the composition comprises about 17% w / v to about 20% w / v ethanol and about 10% w / v to about 12% w / v benzyl alcohol.

[0092] In embodiment K, the method of any one of embodiments A through J, wherein the administering reduces clinical seizure activity in a pediatric subject for a period of at least 8 hours following the administering.

[0093] In embodiment L, the method of any one of embodiments A to J, wherein the administering reduces clinical seizure activity in a pediatric subject for a period of at least 24 hours following the administering.

[0094] In embodiment M, the method of any one of embodiments A through J, wherein said administering reduces clinical seizure activity in a pediatric subject for a period of at least 48 hours following said administering.

[0095] In embodiment N, the method of any one of embodiments A to J, wherein the administration prevents a second seizure in the pediatric subject for a period of at least 8 hours following the administration.

[0096] In embodiment O, the method of any one of embodiments A through J, wherein the administration prevents a second seizure in the pediatric subject for a period of at least 24 hours following the administration.

[0097] In embodiment P, the method of any one of embodiments A through J, wherein the administering prevents a second seizure in the pediatric subject for a period of at least 48 hours after the administering.

[0098] In embodiment Q, the method of any one of embodiments A through P, wherein the pediatric subject does not require a second administration of the composition within at least 24 hours of experiencing a first seizure.

[0099] In embodiment R, the method of any one of embodiments A to Q, wherein the pediatric subject has epilepsy or an epileptic disorder.

[0100] In embodiment S, the method of any one of embodiments A to R, wherein the administration is performed by a caregiver.

[0101] In embodiment T, the method of any one of embodiments A to S, wherein administration occurs during the prodromal or preictal phase of a seizure.

[0102] In embodiment U, the method of any one of embodiments A to S, wherein administration occurs during the ictal phase of a seizure.

[0103] In embodiment V, the method of any one of embodiments A-U, wherein said administration achieves a bioavailability of about 90% to about 110% of intravenously administered diazepam.

[0104] Provided herein is embodiment W, a method of treating recurrent seizures in a pediatric subject in need thereof, comprising: administering to a pediatric subject between 2 and 5 years of age a composition comprising an effective amount of diazepam, an alkyl maltoside, one or more natural or synthetic tocopherols or tocotrienols, and a carrier system comprising one or more alcohols, said administration being administered to the nasal mucosa of the pediatric subject during or before a seizure.

[0105] In embodiment X, the method of embodiment W, wherein the recurrent seizures are seizure clusters.

[0106] In embodiment Y, the method of embodiment W, wherein the recurrent seizures are acute recurrent seizures.

[0107] In embodiment Z, the method of embodiments WY, wherein the effective amount of diazepam is from about 2 mg to about 20 mg of diazepam in a volume of from about 10 μL to about 200 μL of the composition.

[0108] In embodiment AA, the method of embodiment Z, wherein the effective amount of diazepam is from about 5 mg to about 15 mg in a volume of 100 μL to 200 μL of the composition.

[0109] In embodiment BB, the method of embodiments W-AA, wherein the composition is provided in a pre-primed single-use dispensing device containing about 100 μL of the composition.

[0110] In embodiment CC, the method of embodiments W through BB, wherein said administering comprises delivering about 5 mg to about 10 mg of diazepam in a composition volume of about 100 μL to a single nostril of the pediatric subject.

[0111] In embodiment DD, the method of embodiments W to CC, wherein the administering comprises delivering about 7.5 mg of diazepam in a volume of about 100 μL of the composition to each nostril of the pediatric subject.

[0112] In embodiment EE, the method of embodiments W through DD, wherein the alkyl maltoside is selected from dodecyl maltoside, tetradecyl maltoside, or a combination thereof.

[0113] In embodiment FF, the method of embodiments W-EE, wherein the composition comprises about 0.1% w / v to about 1% w / v of an alkyl maltoside.

[0114] In embodiment GG, the method of embodiments W through FF, wherein the one or more alcohols consist of a mixture of ethanol and benzyl alcohol.

[0115] In embodiment HH, the method of embodiments W through GG, wherein the composition comprises about 17% w / v to about 20% w / v ethanol and about 10% w / v to about 12% w / v benzyl alcohol.

[0116] In embodiment II, the method of embodiments W-HH, wherein said administering reduces clinical seizure activity in a pediatric subject for a period of at least 8 hours following said administering.

[0117] In embodiment JJ, the method of embodiments W through HH, wherein said administering reduces clinical seizure activity in a pediatric subject for a period of at least 24 hours following said administering.

[0118] In embodiment KK, the method of embodiments W-HH, wherein said administering reduces clinical seizure activity in a pediatric subject for a period of at least 48 hours following said administering.

[0119] In embodiment LL, the method of embodiments W-HH, wherein said administering prevents a second seizure in the pediatric subject for a period of at least 8 hours following said administering.

[0120] In embodiment MM, the method of embodiments W through HH, wherein the administration prevents a second seizure in the pediatric subject for a period of at least 24 hours after the administration.

[0121] In embodiment NN, the method of embodiments W through HH, wherein the administration prevents a second seizure in the pediatric subject for a period of at least 48 hours after the administration.

[0122] In embodiment OO, the method of embodiments W through NN, wherein the pediatric subject does not require a second administration of the composition within at least 24 hours of experiencing a first seizure.

[0123] In embodiment PP, the method of embodiments W-OO, wherein the pediatric subject has epilepsy or an epileptic disorder.

[0124] In embodiment QQ, the method of embodiments W through PP, wherein the administration is performed by a caregiver.

[0125] In embodiment RR, the method of embodiments W through QQ, wherein administration occurs during the prodromal or preictal phase of a seizure.

[0126] In embodiment SS, the method of embodiments W through RR, wherein administration occurs during the ictal phase of a seizure.

[0127] In embodiment TT, the method of embodiments W through SS, wherein said administration achieves a bioavailability of about 90% to about 110% of the intravenously administered diazepam.

[0128] The following examples are intended to illustrate embodiments of the present disclosure, but are not intended to limit its scope in any way. EXAMPLES

[0129] Example 1: Formulations - Various non-limiting examples of intranasal compositions containing benzodiazepines as described herein are provided in Table 1 below. In any embodiment, the alkyl maltoside may be tetradecyl maltoside or dodecyl maltoside, preferably dodecyl maltoside. In any embodiment, the vitamin E may be, for example, α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, δ-tocotrienol, tocopherolane, preferably α-tocopherol. [Table 1] EXAMPLES

[0130] Example 2: An open-label, single-dose, pharmacokinetic study with safety period of VALTOCO® in pediatric patients with epilepsy

[0131] The purpose of this study is to evaluate the pharmacokinetics (PK) of diazepam (VALTOCO®) following a single intranasal dose in patients with epilepsy aged 2 to 5 years. Approximately 30 subjects aged 2 to 5 years (approximately 15 subjects aged 4 to 5 years and approximately 15 subjects aged 2 to 3 years) will be enrolled.

[0132] The primary objective of this study was to evaluate the PK of diazepam following a single intranasal dose of Valtoco in patients with epilepsy aged 2 to 5 years. The primary PK variable determining bioavailability was the peak plasma concentration (C max ) and 6-hour area under the curve (AUC (0-6) The study also evaluates the safety and tolerability of intranasal diazepam (VALTOCO®) in the study population, and the long-term safety and tolerability of intranasal repeated exposure to diazepam (VALTOCO®) in the study population.

[0133] Intranasal diazepam (VALTOCO®) is administered at the clinical site at a dose of 5 mg, 10 mg, or 15 mg depending on the subject's weight, followed by PK sampling. VALTOCO® formulations contain 0.25% dodecylmaltoside (0.025 mg / 100 μL).

[0134] All doses will be administered by trained medical professionals following instructions for use consistent with the prescribing information for diazepam (VALTOCO®). Appropriate recreation will be permitted to ensure subjects are relaxed and undistracted during study procedures. The study will consist of a screening period, a baseline period, a single-dose period, an open-label safety period, and follow-up telephone calls.

[0135] Each subject is assigned a screening number upon enrollment. After screening, a randomization number is automatically assigned by the system, and a block-permuted random sequence determines which of the following blood collection sequences will be used. A total of six blood samples for PK evaluation will be drawn from each subject at specific times according to the sequence: Sequence 1: Pre-dose, 60 min, 120 min, 180 min, 240 min, 360 min Sequence 2: Pre-dose, 15 min, 75 min, 195 min, 300 min, 360 min Sequence 3: Pre-dose, 45, 90, 150, 210, and 360 minutes

[0136] A window of ±5 minutes is permitted between 15 and 60 minutes, and ±10 minutes is permitted between 75 and 360 minutes. The actual time of collection of all blood specimens should be recorded and entered on the Case Report Form (CRF).

[0137] An initial group of approximately 15 children aged 4-5 years will be enrolled. After initial evaluation of safety and PK in the 4-5 year old group, approximately 15 additional subjects will be enrolled in the 2-3 year old group.

[0138] Subjects who discontinue for any reason pre-dose and / or before blood collection for at least 120 minutes for PK assessments may be replaced at the Sponsor's discretion. If a subject discontinues post-dose but before completion of PK assessments and is non-evaluable, the open-label portion of the safety study may be continued.

[0139] If a subject experiences a seizure after dosing (during the blood collection period), PK blood collection will be suspended for as long as the subject's medical needs require and will be resumed when clinically possible, provided the subject is not being treated with other diazepam-containing products. If a subject experiences a seizure after dosing and receives an excluded medication (e.g., intravenous, oral, or rectal diazepam), PK blood collection will be stopped, the time of diazepam administration will be recorded, and the sponsor will be notified. All other safety measures will be implemented according to the "Schedule of Study Procedures" in the clinical trial protocol.

[0140] Subjects will be discharged after completion of the 6-hour post-dose assessment if there are no signs of clinically significant sedation. For the open-label safety portion of the study, subjects will be provided with intranasal diazepam (VALTOCO®) to be used as rescue medication as needed for frequent breakthrough seizures or acute recurrent seizures (ARS) (per VALTOCO® prescribing information). Subjects and caregivers will be provided with an electronic diary to record VALTOCO® use for seizures, including date of use, time to seizure onset, time of administration, time to seizure resolution, adverse events (AEs), and dose and device errors.

[0141] Subjects will return to the site on Day 30 (± 4 days) for safety assessments and additional supplies of study drug, and on Days 90 and 180 (± 4 days) for safety assessments. Telephone contact will be made on Days 60, 120, and 150 (± 4 days) to ascertain whether AEs have occurred and to follow up on ongoing AEs. A follow-up telephone call will be made 7 days (+4 days) after the Day 180 visit to ascertain whether AEs have occurred and to follow up on ongoing AEs since the subject's last contact.

[0142] Safety assessments included AEs, physical examination, neurological examination, and nasal irritation assessment. Site personnel were trained to perform nasal irritation assessments based on a standardized scale.

[0143] The inclusion criteria for this study are as follows: · Males and females aged 2-5 years at the time of enrollment. · Written informed consent from a legal guardian to participate in this study. Subjects with a clinical diagnosis of epilepsy who, in the opinion of the investigator, require the use of benzodiazepines for seizure control. Subjects with either partial or generalized epilepsy who have been using rescue medication at least once a month for the past 3 months for motor seizures or seizures with obvious altered consciousness. No clinically significant abnormalities in medical history, physical exam, electrocardiogram (ECG) (corrected QT interval [QTcF] less than 440 milliseconds), or laboratory findings during the screening period. · Caregivers must agree to comply with all required study procedures.

[0144] The exclusion criteria were as follows: -Weight at the time of registration is less than 6kg or more than 33kg. Subjects undergoing intracranial electroencephalogram (EEG) monitoring. History of clinically significant gastrointestinal, renal, hepatic, neurological, hematological, endocrine, oncological, pulmonary, immunological, psychiatric, or cardiovascular disease, severe seasonal or nonseasonal allergies, nasal polyps or nasal abnormalities that may interfere with the administration of nasal sprays, or any other condition that the investigator determines may jeopardize the subject's safety or affect the validity of the study results. · Major trauma, major surgery or open biopsy within 30 days prior to study screening. Donation of blood or plasma within 30 days of first dose of study drug. Participation in a clinical trial within 30 days prior to the first dose of the investigational drug. Participation in an observational study (non-interventional study) is not excluded, as long as the study dates do not overlap with those of this study. ·Inadequate or difficult venous access that may compromise the quality or timing of PK samples. Treatment with phenobarbital or primidone within 30 days of the scheduled date of dosing (i.e., baseline). -If you received warfarin, dabigatran, or other blood thinners within 30 days of the scheduled date of treatment (i.e. baseline). - If you have received diazepam-containing products within 14 days of the scheduled date of dosing (i.e., baseline). Use of nasal decongestants or nasal steroids within 7 days prior to screening or during the study period.

[0145] The administration of known strong or moderate inhibitors or inducers of metabolic enzymes (e.g., CYP-P450 enzymes or MAO), including herbal medicines, within 14 days prior to the first dose of VALTOCO® or during the study period is prohibited without approval from the medical monitor.

[0146] The investigator or their designee will perform a complete physical examination including head, ears, eyes, nose, and pharynx (HEENT) and neurologic examination at Screening, and targeted physical examinations at baseline, upon discharge from the clinical research site or equivalent (i.e., EMU), and at visits at Days 30, 90, and 180. Results will be recorded on the appropriate pages of the CRF.

[0147] A medical history is taken at screening. The medical history includes demographic data (e.g., age, sex, race / ethnicity). Seizure history is also taken. The number of rescue medications used per month for the past 3 months is reported on the CRF. The average number of seizures over the past 3 months is used as the baseline. The ECG is evaluated by the investigator or cardiologist and compared to the baseline ECG. The ECG report is reviewed, signed, and dated by the investigator or cardiologist. One duplicate ECG tracing and evaluation report is printed and sent to the sponsor after subject identification for attachment to the CRF. The original ECG results are kept at the site as source documentation.

[0148] Height will be measured in centimeters at screening, baseline, days 30, 90, and 180. Weight will be measured in kilograms at screening, baseline, days 30, 90, and 180. Height and weight will be recorded on the CRF.

[0149] Standard supine (after at least 5 minutes of rest) 12-lead electrocardiograms will be performed by trained technicians at screening and three times at baseline.

[0150] Vital signs (body temperature, pulse, blood pressure) will be measured at screening, baseline (just before administration), 30 (± 5 min), 1 (± 10 min), 2 (± 15 min), 4 (± 30 min), and 6 (± 30 min) hours after administration, at discharge from the clinical research facility or equivalent facility (EMU, etc.), and at visits on Day 30, Day 90, and Day 180. Vital signs will be recorded on the CRF.

[0151] Screening also assesses for the presence of HIV antibodies, hepatitis B surface antigen (HbSAg), and hepatitis C antibodies.

[0152] The dose of intranasal diazepam (VALTOCO®) is selected according to subject weight (rounded to the nearest kg, 0.5 mg / kg per DIASTAT® label) based on the following: Spray 5 mg (50 mg / mL, 100 µL) once into the left nostril for a patient weighing 6 kg to 11 kg. For patients weighing 12 kg to 22 kg, give 10 mg (100 mg / mL, 100 μL) as one spray into the left nostril. For patients weighing 23 kg to 33 kg, give 15 mg (75 mg / mL, 100 μL x 2) as two 7.5 mg sprays, one spray into each nostril (first spray through the left nostril, then the right nostril).

[0153] To assess the safety and tolerability of diazepam nasal solution, the occurrence of AEs will be recorded and reviewed. Other safety assessments will include physical and neurological examinations of the head, ears, eyes, nose, and throat (HEENT), vital signs, laboratory tests (hematology, serum chemistry, urinalysis), and a 12-lead electrocardiogram. Recording of AEs will begin after baseline evaluations and before VALTOCO administration and will continue until follow-up. AEs will be reported spontaneously or elicited during subject questioning and testing. AE information will be elicited by indirect questioning using non-leading questions at study visits. Subjects will have a follow-up telephone call approximately 7 days (± 4 days) after the Day 180 visit to determine the occurrence of AEs and to follow up on any ongoing treatment-emergent AEs (TEAEs) since the subject's last contact.

[0154] Objective assessment of nasal irritation is assessed by trained observers after administration of the nasal formulation. Nasal irritation is also assessed before (baseline), 2 hours (±15 minutes), 4 hours (±30 minutes), 6 hours (±30 minutes) after administration of nasal diazepam (VALTOCO®), and at discharge. Mucosal erythema, mucosal edema, nasal discharge, mucosal crust, and mucosal epistaxis are assessed on separate scales before (baseline), 30 (±10) minutes, 1 (±10), 2 (±15), 4 (±30), and 6 (±30) hours after administration of nasal diazepam (VALTOCO®), and at discharge. Nasal irritation assessments are also performed at the 30th, 90th, and 180th day visits.

[0155] Safety data will be summarized and descriptive statistics will be provided for actual values ​​and changes from baseline for physical and neurological examinations including HEENT, vital signs, and clinical laboratory values ​​(serum chemistry, hematology, urinalysis). The incidence and severity of adverse events reported during the study, and their relationship to study drug, will be tabulated. TEAEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and presented by body system.

[0156] The World Health Organization Drug Dictionary (WHODD) will be used to classify reference and concomitant medications by therapeutic class and preferred term. Use of reference and concomitant medications will be summarized by number and percentage of subjects receiving each agent within each therapeutic class, by dose cohort.

[0157] Following a single dose, a total of six blood samples (3 mL each) for PK evaluation will be collected from each subject at specific times according to the assigned block-permutation-random sequence:

[0158] Blood samples for PK evaluation will be collected from each subject at specific times, for a total of six times, according to the following sequence: Sequence 1: Pre-dose, 60 min, 120 min, 180 min, 240 min, 360 min Sequence 2: Pre-dose, 15 min, 75 min, 195 min, 300 min, 360 min Sequence 3: Pre-dose, 45, 90, 150, 210, and 360 minutes

[0159] A time window of ±5 minutes is permitted between 15 and 60 minutes, and ±10 minutes between 75 and 360 minutes. The actual time of collection of all blood samples is recorded and entered on the Case Report Form (CRF).

[0160] Diazepam and desmethyldiazepam (metabolite) concentrations during the single-dose period were analyzed using a model-independent method, and C max , C max Time to max ), AUC (0-6) PK parameters such as PK, β-blockers, and β-blockers are calculated. Other PK parameters are calculated as needed. PK parameters are determined using actual sample collection times relative to administration of Valtoco®. Concentrations below the limit of quantification (BLQ) prior to the first quantifiable concentration are assigned a value of zero, and BLQ concentrations at other time points are reported as missing.

[0161] C max , AUC (0-6) Systemic exposures measured in subjects aged 2-5 years and subjects aged 6 years and older were compared using a one-sided two-way t-test. For the geometric mean ratios (GMRs) of the two parameters, confidence intervals (CIs) (90%) were constructed using log-transformed data. In addition, plasma concentration data obtained in this study were fitted to a population model previously developed for diazepam PK after Valtoco administration in pediatric (6-12 years) and adult subjects using NONMEM software (V7.3, Icon Ltd). The relationship between diazepam PK parameters and age was evaluated. The analysis additionally considered covariates that may explain the variability in exposure. Exposure parameters in the 2-5 year old population are compared with exposure in other pediatric age groups and, when possible, in adults.

[0162] Complete blood count (CBC) includes red blood cells (RBC), RBC morphology, reticulocyte count, hemoglobin, hematocrit, white blood cells (WBC) (with differential), and platelet count.Comprehensive metabolic panel includes serum alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), glucose, calcium, phosphorus, chloride, sodium, potassium, blood urea nitrogen (BUN), creatinine, total bilirubin, albumin, total protein, amylase, bicarbonate / carbon dioxide (CO2), uric acid, and lactate dehydrogenase (LDH).

[0163] Urine testing includes appearance, color, pH, specific gravity, glucose, protein, ketones, hematology, creatinine clearance, and detailed microscopic analysis. Microscopic examination is performed regardless of macroscopic results and includes the following: WBC, RBC, mould, crystal, and bacteria. Standard urinalysis is performed on the same day as blood chemistry.

[0164] Each subject will participate in the study for approximately 208 days, consisting of a 21-day screening period, a single-dose treatment period, a 180-day open-label safety period, and a follow-up telephone call 7 days after day 180.

Claims

**Claim 1**: A pharmaceutical solution for treating episodes of intermittent, stereotypical, frequent seizures that differ from the patient's normal seizure pattern in pediatric subjects having epilepsy aged 2 to 5 years, wherein the pharmaceutical solution is administered nasally to the pediatric subject, and wherein the pharmaceutical solution is a 100 μL pharmaceutical solution having a diazepam concentration of 75 mg / mL, 0.25% w / v dodecyl maltoside, and a carrier system, per spray into each nostril of the pediatric subject when the weight of the pediatric subject is 23 kg to 33 kg. The pharmaceutical solution is a pharmaceutical solution administered to the nasal mucosa of the pediatric subject for treating episodes of intermittent, stereotypical, frequent seizures that differ from the normal seizure pattern of the pediatric subject. **Claim 2**: The pharmaceutical solution according to claim 1, wherein the pharmaceutical solution is provided in a pre-primed single-use dosing device. **Claim 3**: The pharmaceutical solution according to claim 1, wherein the administration reduces the clinical seizure activity of the pediatric subject for at least 48 hours after administration. **Claim 4**: The pharmaceutical solution according to claim 1, wherein the administration prevents a second seizure in the pediatric subject for at least 8 hours after administration. **Claim 5**: The pharmaceutical solution according to claim 1, wherein the administration prevents a second seizure in the pediatric subject for at least 48 hours after administration. **Claim 6**: The pharmaceutical solution according to claim 1, wherein the pediatric subject does not require a second administration of the composition within at least 24 hours after the onset of the first seizure. **Claim 7**: The pharmaceutical solution according to claim 1, wherein the administration is performed during the prodromal or pre-seizure phase of the seizure. **Claim 8**: The pharmaceutical solution according to claim 1, wherein the administration is performed during the pre-ictal phase of the seizure. **Claim 9**: The pharmaceutical solution according to claim 1, wherein the administration achieves a bioavailability of 96% to 97% relative to an equivalent dose of intravenously administered diazepam. **Claim 10** A pharmaceutical solution according to claim 1, wherein the pharmaceutical solution is self-administered by the subject. **Claim 11** A pharmaceutical solution for treating an episode of intermittent, stereotypical, frequent seizures that is different from the normal seizure pattern of a pediatric subject having epilepsy aged 2 to 5 years, wherein the pharmaceutical solution is administered nasally to the pediatric subject, and when the weight of the pediatric subject is 6 to 11 kg, the pharmaceutical solution is a single spray into one nostril of 100 μL of a pharmaceutical solution having a diazepam concentration of 50 mg / mL, 0.25% w / v dodecyl maltoside, and a carrier system. The pharmaceutical solution is administered to the nasal mucosa of the pediatric subject to treat an episode of intermittent, stereotypical, frequent seizures that is different from the normal seizure pattern of the pediatric subject. **Claim 12** A pharmaceutical solution according to claim 11, wherein the pharmaceutical solution is provided in a pre-primed single-use dosing device. **Claim 13** A pharmaceutical solution according to claim 11, wherein the administration reduces the clinical seizure activity of the pediatric subject for at least 48 hours after administration. **Claim 14** A pharmaceutical solution according to claim 11, wherein the administration prevents a second seizure in the pediatric subject for at least 8 hours after administration. **Claim 15** A pharmaceutical solution according to claim 11, wherein the administration prevents a second seizure in the pediatric subject for at least 48 hours after administration. **Claim 16** A pharmaceutical solution according to claim 22, wherein the pediatric subject does not require a second administration of the composition within at least 24 hours after the onset of the first seizure. **Claim 17** A pharmaceutical solution according to claim 22, wherein the administration is performed during the prodromal or pre-seizure phase of the seizure. **Claim 18**: A pharmaceutical solution according to claim 22, wherein the administration is performed in the pre-ictal phase of a seizure. **Claim 19**: A pharmaceutical solution according to claim 22, wherein the administration achieves a bioavailability of 96% to 97% relative to the equivalent dose of diazepam administered intravenously. **Claim 20**: A pharmaceutical solution according to claim 22, wherein the pharmaceutical preparation is self-administered by the subject. **Claim 21**: A pharmaceutical solution for treating intermittent, stereotypical, frequent seizures that differ from the normal seizure pattern of a pediatric subject having epilepsy aged 2 to 5 years, wherein the pharmaceutical solution is administered nasally to the pediatric subject, and when the body weight of the pediatric subject is 12 kg to 22 kg, the pharmaceutical solution is a single spray into one nostril of 100 μL having a diazepam concentration of 100 mg / mL, 0.25% w / v dodecyl maltoside, and a carrier system. The pharmaceutical solution is administered to the nasal mucosa of the pediatric subject to treat episodes of intermittent, stereotypical, frequent seizures that differ from the normal seizure pattern of the pediatric subject. **Claim 22**: A pharmaceutical solution according to claim 21, wherein the pharmaceutical solution is provided in a pre-primed single-use dosing device. **Claim 23**: A pharmaceutical solution according to claim 21, wherein the administration reduces the clinical seizure activity of the pediatric subject for at least 48 hours after the administration. **Claim 24**: A pharmaceutical solution according to claim 21, wherein the administration prevents a second seizure in the pediatric subject for at least 8 hours after the administration. **Claim 25**: A pharmaceutical solution according to claim 21, wherein the administration prevents a second seizure in the pediatric subject for at least 48 hours after the administration. **Claim 26**: The pharmaceutical solution according to claim 21, wherein the pediatric subject does not require a second administration of the composition within at least 24 hours after experiencing the first seizure. **Claim 27**: The pharmaceutical solution according to claim 21, wherein the administration is carried out in the prodromal or pre-seizure phase of the seizure. **Claim 28**: The pharmaceutical solution according to claim 21, wherein the administration is carried out in the pre-ictal phase of the seizure. **Claim 29**: The pharmaceutical solution according to claim 21, wherein the administration achieves a bioavailability of 96% to 97% relative to an equivalent dose of intravenously administered diazepam. **Claim 30**: The pharmaceutical solution according to claim 21, wherein the pharmaceutical formulation is self-administered by the subject.