Compounds, compositions, and methods of use thereof

Abstract

The present disclosure provides pharmaceutical compositions and methods for the treatment of a sleep disorder such as insomnia, by inducing, extending, or consolidating sleep. The compositions comprise mirtazapine, or a salt or derivative thereof, optionally in combination with and gabapentin, or a salt or derivative thereof, at relatively low doses of each such that the combination provides useful therapeutic benefit while avoiding unwanted side effects associated with treatment using alternative pharmaceutical agents.

Description

Attorney Docket No. 130371-860830COMPOUNDS, COMPOSITIONS, AND METHODS OF USE THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application Serial No. 63 / 709,327, filed October 11, 2024, the entire disclosure of which is incorporated by reference.BACKGROUNDField

[0002] The present disclosure relates to novel compositions and methods for treating insomnia that avoid common unwanted side effects of existing treatments for insomnia.Background

[0003] Approximately one out of every seven individuals in the United States experiences chronic sleep disorders, and only a fraction are estimated to get the recommended duration of seven to eight hours of sleep per night. The economic and social impact of sleep deprivation is significant, including costs associated with decreased productivity and increased accidents in various industries. Excessive sleepiness not only reduces quality of life but also contributes to illness and death, primarily through its involvement in accidents related to transportation and work. Sleepiness negatively affects activities like driving, employment, career advancement, education, leisure activities, and personal relationships.

[0004] Sleep disorders, also known as sleep disturbances, encompass a range of conditions that affect the quality, duration, and timing of sleep. These disorders can disrupt a person’s ability to fall asleep, stay asleep, or achieve restorative sleep. There are numerous types of sleeping disorders, including sleep apnea, restless leg syndrome, narcolepsy, circadian rhythm disorders, parasomnias, sleep-related movement disorders, and insomnia.

[0005] Insomnia is a sleep disorder that affects a significant proportion of the population, characterized by persistent difficulty falling asleep, staying asleep, waking up earlier than desired, or experiencing non-restorative sleep. Individuals with insomnia often struggle with initiating or maintaining sleep, significantly impacting their overall quality of life. Common symptoms of insomnia include trouble falling asleep at bedtime, waking up frequently during the night, waking1106466116.3Attorney Docket No. 130371-860830 up too early in the morning, feeling unrested upon awakening, daytime fatigue, irritability, difficulty concentrating, and cognitive impairment. Insomnia can be acute, which lasts for a brief period of time (e.g., 2-14 days), or chronic, persisting for at least three nights a week for three months or longer. Insomnia can be caused by stress, anxiety, depression and other psychiatric disorders, chronic pain, medication side-effects, endocrine and other medical disorders, caffeine or alcohol consumption, illicit drug use, work-shift changes, and disruptions in the sleep environment. Insomnia often causes complications such as chronic fatigue, higher risk of stroke, heart attack, irritability, substance abuse, depression, infections, obesity, and diabetes.

[0006] Insomnia can refer to a state of sleep loss as well as a disorder of hyperarousal, which often remains present day and night. Physiological and psychological factors that may contribute to the onset of insomnia include stressful events, thyroid conditions, anxious or depressed personality traits, age-related sleep homeostasis, perimenopause and menopause, underlying sleep disorders including circadian disruption, other medical problems, including side-effects of medications, and environmentally-related sleeplessness. Insomnia may also co-exist with other medical problems (e.g., asthma, arthritis with pain), neurological disorders (e g., Parkinson’s and Alzheimer’s diseases), psychiatric disorders (e.g., anxiety or depression), or sleep disorders (e.g., sleep apnea, restless legs). Chronic insomnia may impair occupational performance, quality of life, and health.

[0007] Treatment options for sleeping disorders such as insomnia include non-pharmacological approaches, such as practicing good sleep hygiene (establishing a consistent sleep routine, creating a comfortable sleep environment, avoiding stimulating activities before bed), undergoing cognitive-behavioral therapy, or utilizing relaxation techniques (e.g., meditation, deep breathing exercises). Medications, such as sedative-hypnotics, anti-depressants, or melatonin agonists, are also prescribed for insomnia. While several sleeping disorder medications have been developed, these medications have variable levels of efficacy and safety, often being accompanied by significant side effects. For example, insomnia medications can cause side-effects including daytime drowsiness, dizziness, impaired coordination, memory problems, hallucinations, confusion, a “hangover” feeling, and / or dangerous behaviors such as sleepwalking. These side effects can negatively impact cognitive function, performance at work or school, and overall daily functioning. Additionally, some medications used to treat insomnia can lead to dependency and tolerance over time. Thus, the body may become reliant and chemically dependent on the2106466116.3Attorney Docket No. 130371-860830 medication to fall asleep, and over time higher doses may be needed to achieve the same sleepinducing effect. The occurrence of side effects often results in patients’ non-compliance with a prescribed drug regimen.

[0008] A need thus remains for improved medical treatments for treating chronic insomnia, while reducing dependency and tolerance and minimizing side effects to facilitate a smoother and safer withdrawal process, minimizing or eliminating morning sedation that occurs with many insomnia therapies, and / or maintaining long-term efficacy and patient compliance.SUMMARY OF THE INVENTION

[0009] Among various aspects provided herein are compositions and methods of treating a sleep disorder, e.g., insomnia, and methods of inducing, extending or consolidating sleep. The compositions and methods described herein are surprisingly therapeutically effective for treating insomnia, while resulting in minimal or no daytime drowsiness. Compositions described herein can be administered to a subject for an extended period of time without causing dependence, addiction, or withdrawal symptoms. As described further herein below, at least one of the pharmaceutically active ingredients used in the disclosed compositions and methods may be administered at a surprisingly low dose.

[0010] In one aspect, a composition as disclosed herein may comprise more than one active ingredient where each active ingredient is independently administered at its approved dose, lower than its approved dose, or higher than its approved dose. In some aspects, a composition as disclosed herein comprises more than one active ingredient wherein each active ingredient is independently administered at a dose lower than its approved dose. A composition may be provided in a single dosage form. In some aspects, a composition as disclosed herein is a fixed- dose combination of at least two active pharmaceutical ingredients.

[0011] In some aspects, the present disclosure provides a single dosage form, comprising mirtazapine, or a salt or a derivative thereof, and gabapentin, or a salt or a derivative thereof. In some aspects, the present disclosure provides a single dosage form comprising mirtazapine and gabapentin. In some aspects, the present disclosure provides a single dosage form comprising mirtazapine and gabapentin and one or more pharmaceutically acceptable excipients in a pharmaceutical composition. In some aspects, the present disclosure provides a method of treating a sleep disorder, inducing, extending or consolidating sleep, comprising administering to a subject3106466116.3Attorney Docket No. 130371-860830 in need thereof a single dosage form as described herein. In some aspects, the present disclosure provides a method of treating a sleep disorder, inducing extending or consolidating sleep, comprising administering to a subject in need thereof a first agent selected from the group consisting of: an anti -histamine (e.g., histamine Hl receptor antagonist / inverse agonist), an anti- serotonergic [e.g., 5-HT2 (5-hydroxytryptamine subtype 2) receptor antagonist / inverse agonist] and an alpha-blocker (e.g., alpha-2 adrenergic receptor antagonist); and a second agent which is a voltage gated calcium-channel modulator.INCORPORATION BY REFERENCE

[0012] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.DETAILED DESCRIPTIONOverview

[0013] Among various aspects, provided herein are compositions and methods of treating a sleep disorder, e.g., insomnia and methods of inducing, extending or consolidating sleep. The compositions and methods described herein are surprisingly therapeutically effective for treating insomnia, while resulting in minimal or no day-time drowsiness. Compositions described herein can be administered to a subject for an extended period of time without causing dependence, addiction, or withdrawal symptoms. It is believed that the disclosed compositions are absorbed by the body of a subject more rapidly than existing sleep disorder medications. At least one of the active pharmaceutical ingredients used in the disclosed compositions and methods is administered at a dose significantly lower than the dose approved for marketing by the governing regulatory agency. A composition as disclosed herein may comprise more than one active ingredient where each active ingredient is independently administered at its approved dose, lower than its approved dose, or higher than its approved dose. In some aspects, a composition as disclosed herein comprises more than one active ingredient wherein each active ingredient is independently administered at a dose lower than its approved dose. A composition may be provided in a single dosage form. In some aspects, a provided composition is a fixed-dose combination.4106466116.3Attorney Docket No. 130371-860830

[0014] As such, provided herein are methods, compositions, dosages and dosage forms that are surprisingly effective for treating a sleep disorder in a subject in need thereof, while avoiding serious unwanted side effects of other drugs and known higher doses.Definitions

[0015] The following definitions supplement those in the art and are directed to the current application and are not to be imputed to any related or unrelated case, e g., to any commonly owned patent or application. Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present disclosure, the preferred materials and methods are described herein. Accordingly, the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise.

[0016] In this application, the use of “or” means “and / or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting.

[0017] Reference in the specification to “some aspects,” “an aspect,” “one aspect” or “other aspects” means that a particular feature, structure, or characteristic described in connection with an aspect of the disclosure is included in at least some aspects, but not necessarily all aspects.

[0018] As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open- ended and do not exclude additional, unrecited elements or method steps. It is contemplated that any aspect discussed in this specification can be implemented with respect to any method or composition of the invention, and vice versa. Furthermore, compositions of the invention can be used to achieve methods of the invention. At the same time, it should be understood that the present disclosure encompasses compositions and methods that consist of disclosed elements and exclude additional, unrecited elements or steps. For example, one aspect of the present disclosure encompasses compositions in which the active pharmaceutical ingredients consist essentially of or5106466116.3Attorney Docket No. 130371-860830 consist of mirtazapine and gabapentin as disclosed herein, without any additional active pharmaceutical ingredient, but mirtazapine and gabapentin may be combined with pharmaceutically acceptable inactive ingredients such as one or more excipients. Methods may include administration of any such composition to a subject in need, and may be limited to administering mirtazapine and gabapentin as the only active pharmaceutical ingredients.

[0019] The term “about” in relation to a reference numerical value and its grammatical equivalents as used herein can include the numerical value itself and a range of values plus or minus 10% from that numerical value. For example, the amount “about 10” includes 10 and any amounts from 9 to 11. For example, the term “about” in relation to a reference numerical value can also include a range of values plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from that value.

[0020] Ranges: throughout this disclosure, various aspects may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. As another example, a range such as 95-99% identity, includes something with 95%, 96%, 97%, 98% or 99% identity, and includes subranges such as 96-99%, 96-98%, 96-97%.

[0021] The compounds disclosed herein, in some aspects, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H, 11C,13C and / or14C. In one particular aspect, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997 (the disclosures of which are incorporated herein by reference in their entirety). As described in the disclosures of U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0022] Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium6106466116.3Attorney Docket No. 130371-860830 or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0023] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as deuterium (2H), tritium (3H), iodine-125 (123I) or carbon-14 (14C). Isotopic substitution with2H,nC,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,33C1,37C1,79Br,81Br, and / or125I are all contemplated. In some aspects, isotopic substitution with18F is contemplated. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0024] In certain aspects, the compounds disclosed herein have some or all of the ’H atoms replaced with2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art

[0025] In one aspect, the compounds disclosed herein contain one deuterium atom. In another aspect, the compounds disclosed herein contain two deuterium atoms. In another aspect, the compounds disclosed herein contain three deuterium atoms. In another aspect, the compounds disclosed herein contain four deuterium atoms. In another aspect, the compounds disclosed herein contain five deuterium atoms. In another aspect, the compounds disclosed herein contain six deuterium atoms. In another aspect, the compounds disclosed herein contain more than six deuterium atoms. In another aspect, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeablehydrogen atoms. In one aspect, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.

[0026] “Pharmaceutically acceptable salt” includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the mirtazapine and / or gabapentin compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0027] “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise7106466116.3Attorney Docket No. 130371-860830 undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bi sulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66: 1-19 (1997)). Acid addition salts of basic compounds are, In some aspects, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0028] “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared by addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, In some aspects, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,8106466116.3Attorney Docket No. 130371-860830 dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, V-dibenzyl ethylenedi amine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N- methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0029] “Pharmaceutically acceptable solvate” refers to a composition of matter that is the solvent addition form. In some aspects, solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein exist in either unsolvated or solvated forms.

[0030] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[0031] As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and / or a prophylactic benefit. By “therapeutic benefit” is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, In some aspects, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.

[0032] As used herein, “bedtime” can refer to the time of day that the subject gets into bed (or other location) with the intention to fall asleep (e.g., conventionally referred to as “going to bed”). Bedtime can refer to a particular time on a clock (e.g., 9:00 pm, 10:00 pm, 11 :00 pm, 12:00 am (midnight), or any specific in which the subject wishes to be asleep), a daily time (e.g., dusk, sunset, twilight, or a period of time before or after the daily time (such as 1 hour after sunset) or a9106466116.3Attorney Docket No. 130371-860830 period of time following a daily event (e.g., 2 hours after a last meal or 12 hours after waking). A subject or person with insomnia may actually fall asleep after their intended bedtime.

[0033] As used herein, “latency to sleep,” “latency to sleep onset,” or “sleep latency” are interchangeable and refer to the time it takes a subject to fall asleep after bedtime.

[0034] As used herein, “last meal” can refer to the subject’s final consumption and / or ingestion of a substantial amount of food prior to bedtime. Last meal can be distinguished from dessert or snack (e g., what is conventionally understood as a late-night snack or a midnight snack) where the food is consumed after completion of the last meal, and is ingested for taste rather than to alleviate hunger pangs.Compositions

[0035] The present disclosure provides compositions. Compositions provided herein can comprise a small molecule, or a combination of small molecules. Provided herein are single dosage forms, comprising mirtazapine, or a salt or a derivative thereof, and gabapentin, or a salt or a derivative thereof. In some aspects, a derivative is a metabolite. In some aspects, a metabolite of mirtazapine is 8-hydroxy metabolite of mirtazapine. In some aspects, a metabolite of mirtazapine is a N-desmethyl or a N-oxide metabolite of mirtazapine. In some aspects, derivatives of mirtazapine can include tetracyclic piperazino-azepines that can have additional heteroatoms (e.g., N, O, or S) within the tetracyclic core and / or replace one or more hydrogens with another moiety, such as, for example, a halogen, hydroxyl, Ci-Ce alkyl, or an additional bond within the tetracyclic core. In some aspects, derivatives of mirtazapine can include, but are not limited to, mianserin, setiptiline, or aptazapine.

[0036] In some aspects, the single dosage form comprises an anti-histamine (histamine Hl receptor antagonist / inverse agonist), an anti serotonergic [e.g., 5-HT2 (5-hydroxytryptamine subtype 2) receptor antagonist / inverse agonist] or an alpha-blocker (e.g., alpha-2 adrenergic receptor antagonist). In some aspects, the single dosage form comprises an alpha-blocker (alpha- 2 adrenergic receptor antagonist). In some aspects, the single dosage form comprises mirtazapine, or a salt thereof. In some aspects, the single dosage form comprises mirtazapine. Mirtazapine is an atypical antidepressant and is used primarily for the treatment of a major depressive disorder. Mirtazapine is in a group of tetracyclic antidepressants (TeCA). Specifically, mirtazapine is a tetracyclic piperazino-azepine antidepressant agent. It was initially approved to treat major10106466116.3Attorney Docket No. 130371-860830 depressive disorder (MDD) in the Netherlands in 1994 and received FDA approval in 1997 to treat MDD. Mirtazapine inhibits the central presynaptic alpha-2-adrenergic receptors, which increases release of serotonin and norepinephrine. Conventional daily doses of mirtazapine include 7.5 mg and more.Mirtazapine

[0037] As used herein, and unless otherwise indicated, mirtazapine can include all stereoisomers of the drug, including (R)-(-)-mirtazapine and (S)-(+)-mirtazapine (also known as esmirtazapine) as well as their combination (e.g., ‘mirtazapine’). In some aspects, mirtazapine can be esmirtazapine.

[0038] In some aspects, mirtazapine, or salts or derivatives thereof, is present in the single dosage form in an amount from about 0.5 mg to about 4.5 mg, about 0.5 mg to about 5.0 mg, about 0.5 mg to about 5.5 mg, about 0.5 mg to about 6.0 mg, about 6.5 mg to about 7.0 mg, about 1.0 mg to about 1.5 mg, about 1.0 mg to about 2.0 mg, about 1.0 mg to about 2.5 mg, about 1.0 mg to about 3.0 mg, about 1.0 mg to about 3.5 mg, about 1.0 mg to about 4.0 mg, about 1.0 mg to about4.5 mg, about 1.5 mg to about 4.5 mg, about 2.0 mg to about 4.5 mg, about 2.5 mg to about 4.5 mg, about 3.0 mg to about 4.5 mg, about 3.5 mg to about 4.5 mg, or about 4.0 mg to about 4.5 mg. In some aspects, mirtazapine, or salts or derivatives thereof, is present in the single dosage form in an amount from about 1 mg to about 4.5 mg. In some aspects, mirtazapine, or salts or derivatives thereof, is present in the single dosage form in an amount from about 1.5 mg to about 1.5 mg, about 1.5 mg to about 2.0 mg, about 1.5 mg to about 2.5 mg, about 1.5 mg to about 3.0 mg, about1.5 mg to about 3.5 mg, about 2.0 mg to about 3.5 mg, about 2.5 mg to about 3.5 mg, or about 3.0 mg to about 3.5 mg. In some aspects, mirtazapine, or salts or derivatives thereof, is present in the single dosage form in an amount from about 1.5 mg to about 3.5 mg. In some aspects, mirtazapine, or salts or derivatives thereof, is present in the single dosage form in an amount from about 2.0 mg to about 3.0 mg, or about 2.5 mg to about 3.0 mg. In some aspects, mirtazapine, or a salt of derivative thereof, is present in the single dosage form in an amount from about 2 mg to about 3 mg.11106466116.3Attorney Docket No. 130371-860830

[0039] In some aspects, the single dosage form comprises from about 1.6 mg to about 1.7 mg, about 1.6 mg to about 1.8 mg, about 1.6 mg to about 1.9 mg, about 1.6 mg to about 2.0 mg, about 1.6 mg to about 2.1 mg, about 1.6 mg to about 2.2 mg, about 1.6 mg to about 2.3 mg, about 1.6 mg to about 2.4 mg, about 1.6 mg to about 2.5 mg, about 1.6 mg to about 2.6 mg, about 1.6 mg to about 2.7 mg, about 1.6 mg to about 2.8 mg, about 1.6 mg to about 2.9 mg, about 1.6 mg to about 3.0 mg, about 1.6 mg to about 3.1 mg, about 1.6 mg to about 3.2 mg, about 1.7 mg to about 3.2 mg, about 1.8 mg to about 3.2 mg, about 1.9 mg to about 3.2 mg, about 2.0 mg to about 3.2 mg, about 2.1 mg to about 3.2 mg, about 2.2 mg to about 3.2 mg, about 2.3 mg to about 3.2 mg, about 2.4 mg to about 3.2 mg, about 2.5 mg to about 3.2 mg, about 2.6 mg to about 3.2 mg, about 2.7 mg to about 3.2 mg, about 2.8 mg to about 3.2 mg, about 2.9 mg to about 3.2 mg, about 3.0 mg to about 3.2 mg, or about 3.1 mg to about 3.2 mg mirtazapine, or a salt or derivative thereof. In some aspects, the single dosage form comprises from about 1.6 mg to about 7.4 mg mirtazapine, or a salt or derivative thereof. In some aspects, the single dosage form comprises from about 0.5 mg to about 4.5 mg mirtazapine, or a salt or derivative thereof. In some aspects, the single dosage form comprises about 0.5 mg, about 1 .0 mg, about 1 .5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, or about 7.0 mg mirtazapine, or a salt or derivative thereof. Single dosage forms comprising less than 5.0 mg mirtazapine, or a salt or derivative thereof, can be termed “very low dose” or “VLD.”

[0040] In some aspects, the single dosage form comprises about 0.5 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 15 mg, about 30 mg, about 45 mg, about 50 mg, about 80 mg, about 90 mg, or about 100 mg mirtazapine, or a salt or derivative thereof. In some aspects, the single dosage form comprises from about 5 mg to about 10 mg, about 10 mg to about 20 mg, about 20 mg to about 30 mg, about 30 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 90 mg mirtazapine, or a salt or derivative thereof.

[0041] In some aspects, the single dosage form comprises a membrane-stabilizing compound. In some aspects, the single dosage form comprises a mood-stabilizing compound. In some aspects, the single dosage form comprises a non-myo-relaxing hypnotic compound. In some aspects, the single dosage form comprises a voltage gated calcium-channel modulator. In some aspects, the12106466116.3Attorney Docket No. 130371-860830 single dosage form comprises gabapentin, or a salt or derivative thereof. In some aspects, the single dosage form comprises gabapentin. Gabapentin belongs to a class of medications called anticonvulsants. Gabapentin is a calcium channel / y-aminobutyric acid-modulating medication used to treat postherpetic neuralgia in adults and epilepsy. Conventional daily doses of gabapentin include 300-2400 mg / day and more.Gabapentin

[0042] As used herein, and unless otherwise indicated, gabapentin can include all stereoisomers and isomeric chair forms of the drug.

[0043] In some aspects, the gabapentin, or a salt or derivative thereof, can be included in the same single dose form that includes mirtazapine, or a salt or derivative thereof. In some aspects, irrespective of whether the gabapentin, or salt or derivative thereof, is co-formulated with mirtazapine, the gabapentin, or salt or derivative thereof

[0044] In some aspects, gabapentin, or a salt or derivative thereof, is present in the single dosage form in an amount from about 10 mg to about 15 mg, about 10 mg to about 20 mg, about 10 mg to about 25 mg, about 10 mg to about 30 mg, about 10 mg to about 35 mg, about 10 mg to about 40 mg, about 10 mg to about 45 mg, about 10 mg to about 50 mg, about 10 mg to about 55 mg, about 10 mg to about 60 mg, about 10 mg to about 65 mg, about 10 mg to about 70 mg, about 10 mg to about 75 mg, about 10 mg to about 80 mg, about 10 mg to about 85 mg, about 10 mg to about 90 mg, about 10 mg to about 95 mg, about 10 mg to about 100 mg, about 10 mg to about 105 mg, about 10 mg to about 110 mg, about 10 mg to about 115 mg, about 10 mg to about 120 mg, about 10 mg to about 125 mg, about 10 mg to about 130 mg, about 10 mg to about 135 mg, about 10 mg to about 140 mg, about 10 mg to about 145 mg, about 10 mg to about 150 mg, about 10 mg to about 155 mg, about 10 mg to about 160 mg, about 10 mg to about 165 mg, about 10 mg to about 170 mg, about 10 mg to about 175 mg, about 10 mg to about 180 mg, about 10 mg to about 185 mg, about 10 mg to about 190 mg, about 10 mg to about 195 mg, about 10 mg to about 200 mg, about 10 mg to about 225 mg, about 10 mg to about 250 mg, about 10 mg to about 275 mg, about 10 mg to about 300 mg, about 10 mg to about 325 mg, about 10 mg to about 350 mg, about 10 mg to about 375 mg, about 10 mg to about 400 mg, about 50 mg to about 100 mg, about13106466116.3Attorney Docket No. 130371-86083050 mg to about 105 mg, about 50 mg to about 110 mg, about 50 mg to about 115 mg, about 50 mg to about 120 mg, about 50 mg to about 125 mg, about 50 mg to about 130 mg, about 50 mg to about 135 mg, about 50 mg to about 140 mg, about 50 mg to about 145 mg, about 50 mg to about 150 mg, about 50 mg to about 155 mg, about 50 mg to about 160 mg, about 50 mg to about 165 mg, about 50 mg to about 170 mg, about 50 mg to about 175 mg, about 50 mg to about 180 mg, about 50 mg to about 185 mg, about 50 mg to about 190 mg, about 50 mg to about 195 mg, about 50 mg to about 200 mg, about 50 mg to about 225 mg, about 50 mg to about 250 mg, about 50 mg to about 275 mg, about 50 mg to about 300 mg, about 50 mg to about 325 mg, about 50 mg to about 350 mg, about 50 mg to about 375 mg, about 50 mg to about 400 mg, about 15 mg to about 200 mg, about 20 mg to about 200 mg, about 25 mg to about 200 mg, about 30 mg to about 200 mg, about 35 mg to about 200 mg, about 40 mg to about 200 mg, about 45 mg to about 200 mg, about 50 mg to about 200 mg, about 55 mg to about 200 mg, about 60 mg to about 200 mg, about65 mg to about 200 mg, about 70 mg to about 200 mg, about 75 mg to about 200 mg, about 80 mg to about 200 mg, about 85 mg to about 200 mg, about 90 mg to about 200 mg, about 95 mg to about 200 mg, about 100 mg to about 200 mg, about 105 mg to about 200 mg, about 110 mg to about 200 mg, about 115 mg to about 200 mg, about 120 mg to about 200 mg, about 125 mg to about 200 mg, about 130 mg to about 200 mg, about 135 mg to about 200 mg, about 140 mg to about 200 mg, about 145 mg to about 200 mg, about 150 mg to about 200 mg, about 155 mg to about 200 mg, about 160 mg to about 200 mg, about 165 mg to about 200 mg, about 170 mg to about 200 mg, about 175 mg to about 200 mg, about 180 mg to about 200 mg, about 185 mg to about 200 mg, about 190 mg to about 200 mg, or about 195 mg to about 200 mg. In some aspects, gabapentin, or a salt or derivative thereof, is present in the single dosage form in an amount from about 10 mg to 200 mg. In some aspects, gabapentin, or a salt or derivative thereof, is present in the single dosage form in an amount from about 50 mg to 200 mg. In some aspects, gabapentin, or a salt or derivative thereof, is present in the single dosage form in an amount from about 50 mg to about 55 mg, about 50 mg to about 60 mg, about 50 mg to about 65 mg, about 50 mg to about 70 mg, about 50 mg to about 75 mg, about 50 mg to about 80 mg, about 50 mg to about 85 mg, about 50 mg to about 90 mg, about 50 mg to about 95 mg, or about 50 mg to about 100 mg, about 55 mg to about 100 mg, about 60 mg to about 100 mg, about 65 mg to about 100 mg, about 70 mg to about 100 mg, about 75 mg to about 100 mg, about 80 mg to about 100 mg, about 85 mg to about 100 mg, about 90 mg to about 100 mg, or about 95 mg to about 100 mg. In some aspects,14106466116.3Attorney Docket No. 130371-860830 gabapentin, or a salt or derivative thereof, is present in the single dosage form in an amount from about 50 mg to 100 mg. In some aspects, gabapentin, or a salt or derivative thereof, is present in the single dosage form in an amount from about 10 mg to about 400 mg. In some aspects, gabapentin, or a salt or derivative thereof, is present in the single dosage form in an amount from about 50 mg to about 275 mg.

[0045] In some aspects, the single dosage form comprises from about 90 mg to about 95 mg, about 90 mg to about 100 mg, about 90 mg to about 105 mg, about 90 mg to about 110 mg, about 90 mg to about 115 mg, about 90 mg to about 120 mg, about 90 mg to about 125 mg, about 90 mg to about 130 mg, about 90 mg to about 135 mg, about 90 mg to about 140 mg, about 90 mg to about 145 mg, about 90 mg to about 150 mg, about 90 mg to about 155 mg, about 90 mg to about 160 mg, about 90 mg to about 165 mg, about 90 mg to about 170 mg, about 90 mg to about 175 mg, about 90 mg to about 180 mg, about 95 mg to about 180 mg, about 100 mg to about 180 mg, about 105 mg to about 180 mg, about 110 mg to about 180 mg, about 115 mg to about 180 mg, about 120 mg to about 180 mg, about 125 mg to about 180 mg, about 130 mg to about 180 mg, about 135 mg to about 180 mg, about 140 mg to about 180 mg, about 145 mg to about 180 mg, about 150 mg to about 180 mg, about 155 mg to about 180 mg, about 160 mg to about 180 mg, about 165 mg to about 180 mg, about 170 mg to about 180 mg, or about 175 mg to about 180 mg gabapentin, or a salt or derivative thereof.

[0046] In some aspects, the single dosage form comprises about 100 mg, about 120 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg or about 1000 mg gabapentin, or a salt or derivative thereof. In some aspects, the single dosage form comprises from about 300 mg to about 400 mg, about 400 mg to about 450 mg, about 450 mg to about 500 mg, about 500 mg to about 600 mg, about 600 mg to about 700 mg, about 700 mg to about 800 mg, or about 800 mg to about 900 mg, or about 900 mg to about 1000 mg gabapentin, or a salt or derivative thereof.

[0047] In some aspects, the single dosage form comprises mirtazapine, or a salt or derivative thereof, and gabapentin, or a salt or derivative thereof. In some aspects, the single dosage form comprises mirtazapine and gabapentin. In some aspects, the single dosage form comprises from about 1.6 mg to about 1.7 mg, about 1.6 mg to about 1.8 mg, about 1.6 mg to about 1.9 mg, about 1.6 mg to about 2.0 mg, about 1.6 mg to about 2.1 mg, about 1.6 mg to about 2.2 mg, about 1.615106466116.3Attorney Docket No. 130371-860830 mg to about 2.3 mg, about 1.6 mg to about 2.4 mg, about 1.6 mg to about 2.5 mg, about 1.6 mg to about 2.6 mg, about 1.6 mg to about 2.7 mg, about 1.6 mg to about 2.8 mg, about 1.6 mg to about 2.9 mg, about 1.6 mg to about 3.0 mg, about 1.6 mg to about 3.1 mg, about 1.6 mg to about 3.2 mg, about 1.7 mg to about 3.2 mg, about 1.8 mg to about 3.2 mg, about 1.9 mg to about 3.2 mg, about 2.0 mg to about 3.2 mg, about 2.1 mg to about 3.2 mg, about 2.2 mg to about 3.2 mg, about 2.3 mg to about 3.2 mg, about 2.4 mg to about 3.2 mg, about 2.5 mg to about 3.2 mg, about 2.6 mg to about 3.2 mg, about 2.7 mg to about 3.2 mg, about 2.8 mg to about 3.2 mg, about 2.9 mg to about 3.2 mg, about 3.0 mg to about 3.2 mg, about 3.1 mg to about 3.2 mg, about 5 mg to about 10 mg, about 10 mg to about 20 mg, about 20 mg to about 30 mg, about 30 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 90 mg mirtazapine, or a salt or derivative thereof, and from about 90 mg to about 95 mg, about 90 mg to about 100 mg, about 90 mg to about 105 mg, about 90 mg to about 110 mg, about 90 mg to about 115 mg, about 90 mg to about 120 mg, about 90 mg to about 125 mg, about 90 mg to about 130 mg, about 90 mg to about 135 mg, about 90 mg to about 140 mg, about 90 mg to about 145 mg, about 90 mg to about 150 mg, about 90 mg to about 155 mg, about 90 mg to about 160 mg, about 90 mg to about 165 mg, about 90 mg to about 170 mg, about 90 mg to about 175 mg, about 90 mg to about 180 mg, about 95 mg to about 180 mg, about 100 mg to about 180 mg, about 105 mg to about 180 mg, about 110 mg to about 180 mg, about 115 mg to about 180 mg, about 120 mg to about 180 mg, about 125 mg to about 180 mg, about 130 mg to about 180 mg, about 135 mg to about 180 mg, about 140 mg to about 180 mg, about 145 mg to about 180 mg, about 150 mg to about 180 mg, about 155 mg to about 180 mg, about 160 mg to about 180 mg, about 165 mg to about 180 mg, about 170 mg to about 180 mg, about 175 mg to about 180 mg, about 300 mg, about 400 mg, about 450 mg, about500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg or about 1000 mg gabapentin, or a salt or derivative thereof. In some aspects, the single dosage form comprises from about 300 mg to about 400 mg, about 400 mg to about 450 mg, about 450 mg to about 500 mg, about 500 mg to about 600 mg, about 600 mg to about 700 mg, about 700 mg to about 800 mg, or about 800 mg to about 900 mg, or about 900 mg to about 1000 mg gabapentin, or a salt or derivative thereof. In some aspects, the single dosage form comprises from about 1.6 mg to about 3.2 mg mirtazapine and from about 90 mg to about 180 mg gabapentin. In some aspects, the single dosage form comprises from about 1.0 mg to about 4.5 mg mirtazapine and from about 100 mg to about 400 mg gabapentin. In some aspects, the single dosage form comprises about 1.0 mg, about 1.5 mg,16106466116.3Attorney Docket No. 130371-860830 about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, or about 4.5 mg mirtazapine, or a salt or derivative thereof and about 100 mg, about 120 mg, about 200 mg, about 300 mg, or about 400 mg gabapentin, or a salt or derivative thereof.

[0048] In some aspects, the single dosage form comprises from about 1.0 mg to about 7.0 mg mirtazapine, or a salt or derivative thereof, and gabapentin, or a salt or derivative thereof. In some aspects, the single dosage form can include about 1 mg, about 1.5 mg, about 2 mg, about 3 mg, about 3.5, about 4 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, or about 7.0 mg mirtazapine, or a salt or derivative thereof. In some aspects the mirtazapine, or a salt or derivative thereof, can be esmirtazapine. In some aspects, the single dosage form can include between about 100 mg and about 400 mg gabapentin, or a salt or derivative thereof. In some aspects, the single dosage form can include about 100 mg, about 120 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, or about 400 mg gabapentin, or a salt or derivative thereof.

[0049] In some aspects, the single dosage form is formulated for oral administration. In some aspects, the single dosage form is formulated for oral mucosal administration. In some aspects, the single dosage form is formulated as a tablet or capsule. In some aspects, the single dosage form further comprises one or more pharmaceutically acceptable excipients. In some aspects, the pharmaceutically acceptable excipients can include, but are not limited to, diluents, lubricants, sweeteners, preservatives, glidants, bulking agents, and / or antioxidants. In some aspects, the pharmaceutically acceptable excipients, can include, but are not limited to, microcrystalline cellulose, methyl cellulose, hydroxypropyl methyl cellulose, povidone, crospovidone, polyethylene glycol (PEG), sodium starch glycolate, mannitol, lactose, magnesium stearate, dicalcium phosphate, croscarmellose sodium, poloxamer, Carbopol, colloidal silicon dioxide, gelatin, sodium lauryl sulfate, sorbitol, chitosan, starch, propylene glycol, and / or citric acid. In some cases, provided herein are pharmaceutical compositions. In some cases, provided herein are pharmaceutical composition comprises (i) the single dosage form disclosed herein; and (ii) a pharmaceutically acceptable carrier and / or excipient. In some aspects, the pharmaceutical composition can include: i) a single dosage form that includes mirtazapine, or a salt or derivative thereof, in an amount of between about 1.0 mg and about 4.5 mg and gabapentin, or a salt or derivative thereof, and ii) a pharmaceutically acceptable carrier and / or excipient. In some aspects,17106466116.3Attorney Docket No. 130371-860830 the pharmaceutical composition is formulated for oral administration, intravenous injection, subcutaneous injection, intrathecal administration, topical administration, inhalation, or nasal administration. In some aspects, the pharmaceutical composition can be formulated for oral administration. In some aspects, the pharmaceutical composition is a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, a buccal film, an oral film, a sublingual tablet, a dissolvable tablet, a granule, a powder, a solid lipid nanoparticle, an ointment, a lotion, an eye drop, an ear drop, or an oral mucosal formulation.

[0050] In some aspects, the pharmaceutical composition further include an additional therapeutic agent. In some aspects, the additional therapeutic agent can include L-theanine, melatonin, magnesium, zinc, glycine, valerian, cannabis, tryptophan, hops (Humulus lupulus), y- aminobutyric acid (GABA), kava (Piper methysticum), German chamomile (Matricaria chamomilla), tart cherry (Primus cerasus), lavender (Lavandula angustifolia) purple passionflower (Passiflora incarnata) and combinations thereof.

[0051] In some aspects, there is provided a kit that includes mirtazapine, or a salt or derivative thereof, gabapentin, or a salt or derivative thereof, and optionally instructions for use. In some aspects, the kit can include one or more doses of mirtazapine, or a salt or derivative thereof, and one or more doses of gabapentin, or a salt or derivative thereof. In some aspects, the mirtazapine, or a salt or derivative thereof, and the gabapentin, or a salt or derivative thereof, can be combined and formulated in a single dosage form. In some aspects, the mirtazapine, or a salt or derivative thereof, and the gabapentin, or a salt or derivative thereof, can be separately formulated or provided and administered to the subject in distinct dosage forms. A kit can include multiple dosage forms, including dosage forms that include mirtazapine, or a salt or derivative thereof, and dosage forms that include gabapentin, or a salt or derivative thereof. In alternate aspects, the kit can include multiple dosage forms that each include a mirtazapine, or a salt or derivative thereof, and gabapentin, or a salt or derivative thereof. The optional instructions may be provided as printed matter or can be provided in an electronic medium, for example as a Word document of PDF fde.Methods of Treatment

[0052] Provided herein are methods of treating a sleep disorder or inducing, extending or consolidating sleep, comprising administering to a subject in need thereof a single dosage form as18106466116.3Attorney Docket No. 130371-860830 described herein. In some aspects, the present disclosure provides a method of treating a sleep disorder. In some aspects, the present disclosure provides a method of inducing sleep. In some aspects, the present disclosure provides a method of extending sleep. In some aspects, the present disclosure provides a method of consolidating sleep. Treatment of sleep disorders with mirtazapine, or a salt or derivative thereof, alone or in combination gabapentin, or a salt or derivative thereof, described below can reduce insomnia and improve sleep in an effective and sustainable manner with minimal or reduced adverse effects (e.g., undesired weight gain).

[0053] In some aspects, the method for treating a sleep disorder with a single dosage form that includes mirtazapine, or a salt or derivative thereof, and gabapentin, or a salt or derivative thereof, wherein the mirtazapine, or salt or derivative thereof, is present in an amount of from about 1.0 mg to about 4.5 mg. In an alternate aspect, the method for treating a sleep disorder with pharmaceutical composition that includes a single dosage form that includes mirtazapine, or a salt or derivative thereof, and gabapentin, or a salt or derivative thereof, wherein the mirtazapine, or salt or derivative thereof, is present in an amount of from about 1.0 mg to about 4.5 mg and a pharmaceutically acceptable carrier and / or excipient, wherein the pharmaceutical composition is formulated for oral administration, intravenous injection, subcutaneous injection, intrathecal administration, topical administration, inhalation, or nasal administration.

[0054] Provided herein are methods of treating a sleep disorder or inducing, extending or consolidating sleep, comprising administering to a subject a first agent which is selected from the group of an antihistamine (e.g., histamine Hl receptor antagonist / inverse agonist), an anti- serotonergic [e.g., 5-HT2 (5-hydroxytryptamine subtype 2) receptor antagonist / inverse agonist], and an alpha-blocker (e.g., alpha-2 adrenergic receptor antagonist); and a second agent which is a voltage gated calcium-channel modulator. In some aspects, the first agent is mirtazapine, or a salt or derivative thereof. In some aspects, the voltage gated calcium-channel modulator is gabapentin, or a salt or derivative thereof.

[0055] In some aspects, the first agent acts predominantly through one mechanistic pathway at a given dosage as described herein. In some aspects, the first agent acts predominantly as an Hl receptor antagonist / inverse agonist at a given dosage as described herein. In some aspects, the first agent is mirtazapine and acts predominantly as an Hl receptor antagonist / inverse agonist at a given dosage as described herein. In some aspects, the first agent is mirtazapine, or a salt or derivative thereof, and acts exclusively as an Hl receptor antagonist / inverse agonist at a given dosage as19106466116.3Attorney Docket No. 130371-860830 described herein. In some aspects, the first agent is mirtazapine, or a salt or derivative thereof, and acts predominantly as an Hl receptor antagonist / inverse agonist when administered to a subject at an amount from about 1.6 mg to about 7.4 mg. In some aspects, the first agent is mirtazapine, or a salt or derivative thereof, and acts exclusively as an Hl receptor antagonist / inverse agonist when administered to a subject at an amount from about 1.6 mg to about 7.4 mg.

[0056] In some aspects, the first agent, e.g., an alpha-2 adrenergic receptor antagonist (such as mirtazapine or a salt or derivative thereof) and a voltage gated calcium-channel modulator (such as gabapentin or a salt or derivative thereof) are administered in a chronic treatment regimen. In some aspects, the first agent and voltage gated calcium-channel modulator are independently administered chronically for at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 6 weeks, at least 2 months, at least 3 months, at least 6 months, or at least one year.

[0057] In some aspects, chronic treatment regimen comprises administering the first agent and voltage gated calcium-channel modulator at least once daily, at least twice daily, at least three times daily, at least four times daily, at least five times daily, at least six times daily, or more. In some aspects, chronic treatment regimen comprises administering the first agent and voltage gated calcium-channel modulator at most once daily, at most twice daily, at most three times daily, at most four times daily, at most five times daily, or at most six times daily. In some aspects, chronic treatment regimen comprises administering the first agent and voltage gated calcium-channel modulator daily.

[0058] The present disclosure encompasses a method for treating a sleep disorder comprising administering to a subject in need thereof a VLD of mirtazapine, or a salt or derivative thereof. In various aspects, the VLD of mirtazapine or a salt or derivative thereof is 1.0 mg to 4.5 mg, or about 1.0 mg to about 4.5 mg. The amount of mirtazapine, or a salt or derivative thereof may be selected for example from 1 mg, 1.5 mg, 2 mg, 3 mg, 3.5 mg, 4 mg and 4.5 mg, or about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, or about 4 mg. In other aspects, the method can further include co-admini strati on of gabapentin, or a salt or derivative thereof to the subject. In some aspects, the amount of gabapentin or salt or derivative thereof is any amount selected from 50 mg to 400 mg, or any amount of about 50 mg to about 400 mg gabapentin. In some aspects, the amount of gabapentin or salt or derivative thereof is any amount selected from 50 mg to 275 mg, or any amount of about 50 mg to about 275 mg gabapentin. The amount of gabapentin or salt or derivative thereof may selected for example from 100 mg, 120 mg, 125 mg,20106466116.3Attorney Docket No. 130371-860830150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, or 400 mg, or about 100 mg, about 120 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, or about 400 mg.

[0059] In various aspects, the gabapentin can be co-administered in a single dosage form that also contains the mirtazapine, or separately. In some aspects, the mirtazapine can be coadministered simultaneously with the gabapentin, or within a time period of several hours up to minutes before, or within minutes up to several hours after gabapentin administration. In some aspects, the gabapentin can be administered within 5 minutes, within 10 minutes, within 15 minutes, within 30 minutes, within 45 minutes, within 1 hour, within 2 hours, within 3 hours, within 4 hours or within 5 hours before or after the administration of mirtazapine, or a salt or derivative thereof to the subject; or administered within about 5 minutes, within about 10 minutes, within about 15 minutes, within about 30 minutes, within about 45 minutes, within about 1 hour, within about 2 hours, within about 3 hours, within about 4 hours or within about 5 hours before or after the administration of mirtazapine, or a salt or derivative thereof.

[0060] In some aspects, the first agent (e.g., mirtazapine, or a salt or derivative thereof) and voltage gated calcium-channel modulator (e.g., gabapentin, or a salt or derivative thereof) are administered once daily prior to bedtime. In some aspects, the first agent and voltage gated calcium-channel modulator are administered once daily after a last meal. In some aspects, the first agent and voltage gated calcium-channel modulator are administered once daily prior to bedtime and after a last meal. In some aspects, the first agent and voltage gated calcium-channel modulator are administered from about 5 minutes (mins) to about 15 mins, about 5 mins to about 30 mins, about 5 mins to about 45 mins, about 5 mins to about 1 hour, about 5 mins to about 1 hour and 15 mins, about 5 mins to about 1 hour and 30 mins, about 5 mins to about 1 hour and 45 mins, about 5 mins to about 2 hours, about 15 mins to about 2 hours, about 30 mins to about 2 hours, about 45 mins to about 2 hours, about 1 hour to about 2 hours, about 1 hour 15 mins to about 2 hours, about 1 hour 30 mins to about 2 hours, or about 1 hour 45 mins to about 2 hours prior to bedtime. In some aspects, the first agent and voltage gated calcium-channel modulator are administered from about 5 mins to about 2 hours prior to bedtime. In some aspects, the mirtazapine, or a salt or derivative thereof, and, optionally, the gabapentin, or a salt or derivative thereof, is administered at a time that is about 5 mins to about 2 hours prior to the subject’s bedtime.21106466116.3Attorney Docket No. 130371-860830

[0061] In some aspects, the first agent (e.g., mirtazapine, or a salt or derivative thereof) and voltage gated calcium-channel modulator (e.g., gabapentin, or a salt or derivative thereof) are administered from about 5 minutes (mins) to about 15 mins, about 5 mins to about 30 mins, about 5 mins to about 45 mins, about 5 mins to about 1 hour, about 5 mins to about 1 hour and 15 mins, about 5 mins to about 1 hour and 30 mins, about 5 mins to about 1 hour and 45 mins, about 5 mins to about 2 hours, about 5 mins to about 2 hours and 15 mins, about 5 mins to about 2 hours and 30 mins, about 5 mins to about 2 hours and 45 mins, about 5 mins to about 3 hours, about 5 mins to about 3 hours and 15 mins, about 5 mins to about 3 hours and 30 mins, about 5 mins to about 3 hours and 45 mins, about 5 mins to about 4 hours, about 5 mins to about 4 hours and 15 mins, about 5 mins to about 2 hours and 30 mins, about 5 mins to about 4 hours and 45 mins, about 5 mins to about 5 hours, about 15 mins to about 5 hours, about 30 mins to about 5 hours, about 45 mins to about 5 hours, about 1 hour to about 5 hours, about 1 hour and 15 mins to about 5 hours, about 1 hour and 30 mins to about 5 hours, about 1 hour and 45 mins to about 5 hours, about 2 hours to about 5 hours, about 2 hours and 15 mins to about 5 hours, about 2 hours and 30 mins to about 5 hours, about 2 hours and 45 mins to about 5 hours, about 3 hours to about 5 hours, about 3 hours and 15 mins to about 5 hours, about 3 hours and 30 mins to about 5 hours, about 3 hours and 45 mins to about 5 hours, about 4 hours to about 5 hours, about 4 hours and 15 mins to about 5 hours, about 4 hours and 30 mins to about 5 hours, or about 4 hours and 45 mins to about 5 hours after a last meal. In some aspects, the first agent and voltage gated calcium-channel modulator are administered from about 5 mins to about 5 hours after a last meal. In some aspects, the mirtazapine, or a salt or derivative thereof, and, optionally, the gabapentin, or a salt or derivative thereof, is or are administered at a time that is about 5 mins to about 5 hours after a subject’s last meal.

[0062] In some aspects, the first agent and voltage gated calcium-channel modulator are administered from about 5 mins to about 15 mins, about 5 minutes (mins) to about 30 mins, about 5 mins to about 45 mins, about 5 mins to about 1 hour, about 5 mins to about 1 hour and 15 mins, about 5 mins to about 1 hour and 30 mins, about 5 mins to about 1 hour and 45 mins, about 5 mins to about 2 hours, about 15 mins to about 2 hours, about 30 mins to about 2 hours, about 45 mins to about 2 hours, about 1 hour to about 2 hours, about 1 hour 15 mins to about 2 hours, about 1 hour 30 mins to about 2 hours, or about 1 hour 45 mins to about 2 hours prior to bedtime and about 5 minutes (mins) to about 15 mins, about 5 mins to about 30 mins, about 5 mins to about 45 mins, about 5 mins to about 1 hour, about 5 mins to about 1 hour and 15 mins, about 5 mins to about 122106466116.3Attorney Docket No. 130371-860830 hour and 30 mins, about 5 mins to about 1 hour and 45 mins, about 5 mins to about 2 hours, about 5 mins to about 2 hours and 15 mins, about 5 mins to about 2 hours and 30 mins, about 5 mins to about 2 hours and 45 mins, about 5 mins to about 3 hours, about 5 mins to about 3 hours and 15 mins, about 5 mins to about 3 hours and 30 mins, about 5 mins to about 3 hours and 45 mins, about 5 mins to about 4 hours, about 5 mins to about 4 hours and 15 mins, about 5 mins to about 2 hours and 30 mins, about 5 mins to about 4 hours and 45 mins, about 5 mins to about 5 hours, about 15 mins to about 5 hours, about 30 mins to about 5 hours, about 45 mins to about 5 hours, about 1 hour to about 5 hours, about 1 hour and 15 mins to about 5 hours, about 1 hour and 30 mins to about 5 hours, about 1 hour and 45 mins to about 5 hours, about 2 hours to about 5 hours, about 2 hours and 15 mins to about 5 hours, about 2 hours and 30 mins to about 5 hours, about 2 hours and 45 mins to about 5 hours, about 3 hours to about 5 hours, about 3 hours and 15 mins to about 5 hours, about 3 hours and 30 mins to about 5 hours, about 3 hours and 45 mins to about 5 hours, about 4 hours to about 5 hours, about 4 hours and 15 mins to about 5 hours, about 4 hours and 30 mins to about 5 hours, or about 4 hours and 45 mins to about 5 hours after a last meal.

[0063] In some aspects, the first agent and voltage gated calcium-channel modulator are administered about 5 minutes (mins), about 10 mins, about 15 mins, about 20 mins, about 25 mins, about 30 mins, about 35 mins, about 40 mins, about 45 mins, about 50 mins, about 55 mins, or about 60 mins prior to bedtime. In some aspects, the first agent and voltage gated calcium-channel modulator are administered about 20 mins prior to bedtime.

[0064] In some aspects, the chronic treatment regimen does not cause, or causes minimal, or is not associated with significant increases in daytime drowsiness, confusion, memory problems, difficulty in moving, impaired focus, headache, constipation, dizziness, nausea, decreased appetite, heartburn, nightmares, or xerostomia relative to pretreatment. In some aspects, daytime drowsiness impairs vigilant. In some aspects, daytime drowsiness is measured by psychomotor vigilance test.

[0065] In some aspects, a method as described herein comprises a chronic treatment regimen. In some aspects, the method comprises administering mirtazapine, or a salt or derivative thereof, including a very low dose, in an amount from about 0.5 mg to about 4.0 mg, about 1.0 mg to about 1.5 mg, about 1.0 mg to about 2.0 mg, about 1.0 mg to about 2.5 mg, about 1.0 mg to about 3.0 mg, about 1.0 mg to about 3.5 mg, about 1.0 mg to about 4.0 mg, about 1.0 mg to about 4.5 mg, about 1.5 mg to about 4.5 mg, about 2.0 mg to about 4.5 mg, about 2.5 mg to about 4.5 mg, about 3.0 mg to about 4.5 mg, about 3.5 mg to about 4.5 mg, or about 4.0 mg to about 4.5 mg. In some23106466116.3Attorney Docket No. 130371-860830 aspects, the method comprises administering mirtazapine, or a salt or derivative thereof, in an amount from about 1 mg to about 4.5 mg. In some aspects, the method comprises administering mirtazapine, or a salt or derivative thereof, in an amount from about 1.5 mg to about 1.5 mg, about1.5 mg to about 2.0 mg, about 1.5 mg to about 2.5 mg, about 1.5 mg to about 3.0 mg, about 1.5 mg to about 3.5 mg, about 2.0 mg to about 3.5 mg, about 2.5 mg to about 3.5 mg, or about 3.0 mg to about 3.5 mg. In some aspects, the method comprises administering mirtazapine, or a salt or derivative thereof, in an amount from about 1.5 mg to about 3.5 mg. In some aspects, the method comprises administering mirtazapine, or a salt or derivative thereof, in an amount from about 2.0 mg to about 3.0 mg, or about 2.5 mg to about 3.0 mg. In some aspects, the method comprises administering mirtazapine, or a salt or derivative thereof, in an amount from about 2 mg to about 3 mg. In some aspects, the method comprises administering mirtazapine, or a salt or derivative thereof, in an amount from about 3 mg to about 5 mg. In some aspects, the method comprises administering mirtazapine, or a salt or derivative thereof, in an amount from about 3 mg to about3.5 mg. In some aspects, the method comprises administering mirtazapine, or a salt or derivative thereof, in an amount from about 3.5 mg to about 4.0 mg. In some aspects, the method comprises administering mirtazapine, or a salt or derivative thereof, in an amount from about 4.0 mg to about4.5 mg. In some aspects, the method comprises administering mirtazapine, or a salt or derivative thereof, in an amount from about 4.5 mg to about 5.0 mg. In some aspects, the method comprises administering mirtazapine, or a salt or derivative thereof, in an amount from about 1.0 mg to about4.5 mg.

[0066] In some aspects, mirtazapine, or a salt or derivative thereof, is administered in an amount of about 5 mg, about 15 mg, about 30 mg, about 45 mg, about 50 mg, about 80 mg, about 90 mg, or about 100 mg mirtazapine, or a salt or derivative thereof. In some aspects, mirtazapine, or a salt or derivative thereof, is administered in an amount from about 5 mg to about 10 mg, about 10 mg to about 20 mg, about 20 mg to about 30 mg, about 30 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 90 mg.

[0067] In some aspects, the gabapentin, or a salt or derivative thereof, is administered in an amount from about 10 mg to about 15 mg, about 10 mg to about 20 mg, about 10 mg to about 25 mg, about 10 mg to about 30 mg, about 10 mg to about 35 mg, about 10 mg to about 40 mg, about 10 mg to about 45 mg, about 10 mg to about 50 mg, about 10 mg to about 55 mg, about 10 mg to about 60 mg, about 10 mg to about 65 mg, about 10 mg to about 70 mg, about 10 mg to about 7524106466116.3Attorney Docket No. 130371-860830 mg, about 10 mg to about 80 mg, about 10 mg to about 85 mg, about 10 mg to about 90 mg, about10 mg to about 95 mg, about 10 mg to about 100 mg, about 10 mg to about 105 mg, about 10 mg to about 110 mg, about 10 mg to about 115 mg, about 10 mg to about 120 mg, about 10 mg to about 125 mg, about 10 mg to about 130 mg, about 10 mg to about 135 mg, about 10 mg to about 140 mg, about 10 mg to about 145 mg, about 10 mg to about 150 mg, about 10 mg to about 155 mg, about 10 mg to about 160 mg, about 10 mg to about 165 mg, about 10 mg to about 170 mg, about 10 mg to about 175 mg, about 10 mg to about 180 mg, about 10 mg to about 185 mg, about 10 mg to about 190 mg, about 10 mg to about 195 mg, about 10 mg to about 200 mg, about 15 mg to about 200 mg, about 20 mg to about 200 mg, about 25 mg to about 200 mg, about 30 mg to about 200 mg, about 35 mg to about 200 mg, about 40 mg to about 200 mg, about 45 mg to about200 mg, about 50 mg to about 200 mg, about 55 mg to about 200 mg, about 60 mg to about 200 mg, about 65 mg to about 200 mg, about 70 mg to about 200 mg, about 75 mg to about 200 mg, about 80 mg to about 200 mg, about 85 mg to about 200 mg, about 90 mg to about 200 mg, about 90 mg to about 180 mg, about 95 mg to about 200 mg, about 100 mg to about 200 mg, about 105 mg to about 200 mg, about 1 10 mg to about 200 mg, about 1 15 mg to about 200 mg, about 120 mg to about 200 mg, about 125 mg to about 200 mg, about 130 mg to about 200 mg, about 135 mg to about 200 mg, about 140 mg to about 200 mg, about 145 mg to about 200 mg, about 150 mg to about 200 mg, about 155 mg to about 200 mg, about 160 mg to about 200 mg, about 165 mg to about 200 mg, about 170 mg to about 200 mg, about 175 mg to about 200 mg, about 180 mg to about 200 mg, about 185 mg to about 200 mg, about 190 mg to about 200 mg, or about 195 mg to about 200 mg. In some aspects, the gabapentin, or a salt or derivative thereof, is administered in an amount from about 10 mg to about 200 mg. In some aspects, gabapentin, or a salt or derivative thereof, is administered in an amount from about 50 mg to about 200 mg. In some aspects, the gabapentin, or a salt or derivative thereof, is administered in an amount from about 100 mg to about 400 mg. In some aspects, the gabapentin, or a salt or derivative thereof, is administered in an amount of about 100 mg, about 120 mg, about 300 mg or about 400 mg.

[0068] In some aspects, the gabapentin, or a salt or derivative thereof, is administered in an amount from about 50 mg to about 55 mg, about 50 mg to about 60 mg, about 50 mg to about 65 mg, about 50 mg to about 70 mg, about 50 mg to about 75 mg, about 50 mg to about 80 mg, about 50 mg to about 85 mg, about 50 mg to about 90 mg, about 50 mg to about 95 mg, or about 50 mg to about 100 mg, about 55 mg to about 100 mg, about 60 mg to about 100 mg, about 65 mg to25106466116.3Attorney Docket No. 130371-860830 about 100 mg, about 70 mg to about 100 mg, about 75 mg to about 100 mg, about 80 mg to about 100 mg, about 85 mg to about 100 mg, about 90 mg to about 100 mg, or about 95 mg to about 100 mg. In some aspects, gabapentin, or a salt or derivative thereof, is administered in an amount from about 50 mg to about 100 mg.

[0069] In some aspects, gabapentin, or a salt or derivative thereof, is administered in an amount of about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg or about 1000 mg. In some aspects, gabapentin, or a salt or derivative thereof, is administered in an amount from about 300 mg to about 400 mg, about 400 mg to about 450 mg, about 450 mg to about 500 mg, about 500 mg to about 600 mg, about 600 mg to about 700 mg, about 700 mg to about 800 mg, or about 800 mg to about 900 mg, or about 900 mg to about 1000 mg.

[0070] In some aspects, the administration of the first agent (e.g., mirtazapine, or a salt or derivative thereof) and the administration of voltage gated calcium-channel modulator (e.g., gabapentin, or a salt or derivative thereof) is separated by about 0 mins to about 2-hours, about 5 minutes (mins) to about 15 mins, about 5 mins to about 30 mins, about 5 mins to about 45 mins, about 5 mins to about 1 hour, about 5 mins to about 1 hour and 15 mins, about 5 mins to about 1 hour and 30 mins, about 5 mins to about 1 hour and 45 mins, about 5 mins to about 2 hours, about 15 mins to about 2 hours, about 30 mins to about 2 hours, about 45 mins to about 2 hours, about 1 hour to about 2 hours, about 1 hour 15 mins to about 2 hours, about 1 hour 30 mins to about 2 hours, or about 1 hour 45 mins to about 2 hours. In some aspects, the administration of the first agent and the administration of voltage gated calcium-channel modulator are separated by about 0 mins to about 2 hours.

[0071] In some aspects, the first agent and voltage gated calcium-channel modulator are administered together.

[0072] In some aspects, the method provides decreased latency to sleep onset, increased sleep efficiency, increased sleep duration, decreased number of nocturnal awakenings, improved sleep quality, improved daytime alertness, reduction in waking time after sleep onset, or any combinations thereof in the subject relative to a timepoint prior to administration.

[0073] In some aspects, the method provides decreased latency to sleep onset, increased sleep efficiency, increased sleep duration, decreased number of nocturnal awakenings, or improved sleep quality, improved daytime alertness, reduction in waking time after sleep onset, or any26106466116.3Attorney Docket No. 130371-860830 combinations thereof in the subject after administration of the single dosage form for 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or 2 months relative to a timepoint prior to administration.

[0074] In some aspects, latency to sleep onset of the subject decreased by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% relative to a timepoint prior to administration as measured by a method known in the art.

[0075] In some aspects, sleep efficiency of the subject increased by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 500%, or 1000% relative to a timepoint prior to administration as measured by percentage of total time in bed actually spent in sleep in a method known in the art. For example, In some aspects, sleep efficiency is measured in a polysomnography study. In some aspects, sleep efficiency is measured in an actigraphy study. In some aspects, sleep efficiency is measured in Pittsburgh Sleep Quality Index (PSQ1), Athens Insomnia Scale (AIS), Insomnia Severity Index (ISI), Mini-Sleep Questionnaire (MSQ), Jenkins Sleep Scale (JSS), Leeds Sleep Evaluation Questionnaire (LSEQ), or SLEEP-50 Questionnaire.

[0076] In some aspects, sleep duration of the subject increased by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 500%, or 1000% relative to a timepoint prior to administration as measured by a method known in the art, e.g., Pittsburgh Sleep Quality Index (PSQI), Athens Insomnia Scale (AIS), Insomnia Severity Index (ISI), Mini-Sleep Questionnaire (MSQ), Jenkins Sleep Scale (JSS), Leeds Sleep Evaluation Questionnaire (LSEQ), or SLEEP-50 Questionnaire.

[0077] In some aspects, the number of nocturnal awakenings of the subject decreased by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% relative to a timepoint prior to administration as measured by a method known in the art, e.g., Pittsburgh Sleep Quality Index (PSQI), Athens Insomnia Scale (AIS), Insomnia Severity Index (ISI), Mini-Sleep Questionnaire (MSQ), Jenkins Sleep Scale (JSS), Leeds Sleep Evaluation Questionnaire (LSEQ), SLEEP-50 Questionnaire, or Epworth Sleepiness Scale (ESS).

[0078] In some aspects, the number of waking after sleep onset (WASO) in a subject decreased by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% relative to a timepoint prior to administration.27106466116.3Attorney Docket No. 130371-860830

[0079] In some aspects, the daytime alertness in a subject is increased by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% relative to a timepoint prior to administration.

[0080] In some aspects, the waking time after sleep onset is decreased by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% relative to a timepoint prior to administration.

[0081] In some aspects, sleep quality of the subject increased by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 500%, or 1000% relative to a timepoint prior to administration as measured by a method known in the art, e.g., Pittsburgh Sleep Quality Index (PSQI), Athens Insomnia Scale (AIS), Insomnia Severity Index (ISI), Mini-Sleep Questionnaire (MSQ), Jenkins Sleep Scale (JSS), Leeds Sleep Evaluation Questionnaire (LSEQ), SLEEP-50 Questionnaire, or Epworth Sleepiness Scale (ESS).

[0082] In some aspects, the sleep disorder is sleep apnea, restless leg syndrome, narcolepsy, circadian rhythm disorders, parasomnias, sleep-related movement disorders, and / or insomnia. In some aspects, the sleep disorder is insomnia. In some aspects, the sleep disorder is acute insomnia, transient insomnia, chronic insomnia, initial (e.g., sleep onset) insomnia, middle (e.g., maintenance) insomnia, late (e.g., early morning waking) insomnia, idiopathic insomnia, inadequate sleep hygiene insomnia, insomnia not otherwise specified (NOS), comorbid insomnia, and / or a combination thereof. In some aspects, the various insomnias can coexist or co-present In some aspects, the methods described herein can treat or ameliorate symptoms of insomnia, including, but not limited to, trouble falling asleep at bedtime, waking up frequently during the night, waking up too early in the morning, feeling unrested upon awakening, daytime fatigue, irritability, difficulty concentrating, and / or cognitive impairment.EXAMPLES

[0083] The following examples are included to demonstrate various aspects of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent techniques discovered by the inventor to function well in the practice of the present disclosure, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many28106466116.3Attorney Docket No. 130371-860830 changes can be made in the specific aspects which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the present disclosure.

[0084] EXAMPLE 1 - Very Low Dose Mirtazapine Treats Chronic Insomnia

[0085] Patients with chronic insomnia having inadequate response or undesirable side-effects to FDA approved medications to treat insomnia were prescribed a compounded liquid formulation of VLD mirtazapine (0.2 to 3.75 mg doses taken 30 min prior to bedtime), often in conjunction with gabapentin. Thirty-nine patients (18 men, 21 women), ages 31 to 87 years old (mean age 60.2), with severe chronic insomnia who had failed at least one FDA approved insomnia medications were treated. The failure of medications approved to treat insomnia resulted from lack of efficacy and / or adverse effects (e.g., daytime sedation, tolerance). Patients were monitored and followed clinically for an average of 11 months (6 months to 4 years) after initiation of VLD mirtazapine alone or with gabapentin. Demographics and clinical characteristics of these patients are shown in Table 1. Results are summarized below, separated in single medication or combination therapies.

[0086] Table 1: Demographics and baseline characteristics of patients29106466116.3Attorney Docket No. 130371-860830

[0087] Legend: M = mirtazapine; G = gabapentin; BZD = benzodiazepine; SII = sleep initiation insomnia; SMI = sleep maintenance insomnia; EMA = early morning awakening; PLMS = periodic limb movement in sleep; OSA = obstructive sleep apnea; APAP = auto positive airway pressure; standard* = including Z drugs, doxepin, BZD, DORAs; J = subject that was misdiagnosed with insomnia instead of severe deep sleep phase syndrome (DSPS).30106466116.3Attorney Docket No. 130371-860830

[0088] Single use -Mirtazapine (n=26; Cases 1-26): Twenty-six patients with chronic insomnia were treated with VLD (0.5 to 4 mg) mirtazapine of as single new agent taken approximately 30 minutes before bedtime. Twenty (77%) patients successfully tapered and discontinued Z drugs (e.g., eszopiclone (Lunesta™), zaleplon (Sonata™), zolpidem (Ambien™)) and benzodiazepines, of whom four reported improved memory and cognition (one patient had taken Z drugs for 21 years), one reported underlying anxiety disorder and had their mirtazapine dose increased to 15 mg over several weeks with marked reduction in anxiety and continued sleep benefits, and another patient reported constipation after 2 weeks, which later resolved and the patient asked to resume VLD mirtazapine after a 3 month gap, without recurrence of constipation. Three patients (11.5%) discontinued the VLD mirtazapine - two due to taste in the compounded formulation (after 1 and 3 doses); and one due to weight gain (3-4 mg doses). Two patients (7.7%) failed to show improved sleep on VLD mirtazapine; both were chronically treated with zolpidem. One patient (3.8%; Case 27) could not be assessed due to inability to pay for medication from a compounding pharmacy.

[0089] Combination use (n=12; Cases 28-39): Twelve patients with chronic insomnia received VLD (0.5 to 3.75 mg) mirtazapine and in combination with gabapentin (50 to 400 mg) nightly with significant improvement in sleep duration and quality. Nine (75%) had successfully tapered and discontinued benzodiazepines (n=5), Z drugs (n=3), and amitriptyline (n=l).

[0090] Another patient (Case 28) failed to respond to VLD mirtazapine but was incorrectly diagnosed with chronic insomnia, as the sleep onset difficulty due to severe delayed sleep phase syndrome and improved with measures to improve circadian regulation.

[0091] Side-effects'. Four of 38 (10.5%) patients discontinued VLD mirtazapine alone or with gabapentin therapy. Weight gain of 2-5 pounds occurred in 5 patients on doses >3 mg: one discontinued mirtazapine, the other 4 lowered the dose to <3 mg with sustained efficacy and without further weight gain. Intolerance to taste of the compounded liquid formulation led 2 patients to discontinue treatment before efficacy could be assessed. One patient treated with mirtazapine 1.875 - 3.75 mg had improved sleep duration and quality but developed constipation and discontinued the medication after 5 weeks.

[0092] Reduction of concomitant insomnia medications'. Over 70% of patients discontinued benzodiazepines or Z drugs after successful treatment with VDL mirtazapine alone or with gabapentin. These prospectively-followed patients continued with improved sleep without sideeffects.31106466116.3Attorney Docket No. 130371-860830

[0093] The following examples are included to demonstrate aspects of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent techniques discovered by the inventor to function well in the practice of the present disclosure, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific aspects which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the present disclosure.

[0094] VLD mirtazapine, alone or in combination with gabapentin, was effective and well tolerated by most patients. VLD mirtazapine improved symptoms of chronic insomnia in patients who had failed FDA-approved as well as over-the-counter medications to treat insomnia, had intolerable side-effects, or desired to stop taking these medications. The benefit of VLD mirtazapine alone or with gabapentin was sustained during an average follow-up of 11 months. Over 70% of patients safely tapered and discontinued benzodiazepines and Z drugs in this group. One barrier to using VLD mirtazapine was sourcing the medication at doses not available in commercial pharmacies, which required compounding pharmacies to prepare the VLD formulations. This impacted some patients due to lack of access to a compounding pharmacy, lack of insurance coverage for compounding pharmacy medications, and unpleasant taste of compounded liquid.

[0095] Twelve patients tolerated VLD mirtazapine but did not enjoy clinically significant improvement in insomnia symptoms. In these individuals, low dose (50 to 400 mg) gabapentin was combined with VLD mirtazapine, which led to a marked improvement in sleep quality and duration based on subjective reports. In addition, 77% of these patients tapered and discontinue other medications used to treat insomnia, including Z drugs and benzodiazepines. The combination of VLD mirtazapine and low-dose gabapentin was well tolerated by all 12 patients.

[0096] These observations support the use of VLD mirtazapine alone or with low-dose gabapentin to treat chronic insomnia. Additional efficacy was found when combined with low dose gabapentin, which was often added when either VLD mirtazapine or gabapentin alone did not result in significant clinical improvement in insomnia symptoms.

[0097] EXAMPLE 2 - Very Low Dose Mirtazapine Improves Sleep Quality

[0098] Objective metrics of sleep quality were assessed in one of the above listed subjects with insomnia that received a combination of very low dose mirtazapine and gabapentin. This subject32106466116.3Attorney Docket No. 130371-860830 was evaluated at baseline while on the Z drug, and after changing insomnia treatment to compounded 1.2 mg mirtazapine and 130 mg gabapentin before bedtime. The baseline sleep quality data was acquired while using a Z drug prior to sleep and evaluated using Polysomnography (PSG) - PSG recording consists of four-channel electroencephalogram, bilateral electrooculogram, submental and anterior tibialis electromyogram, two lead electrocardiogram, rib cage and abdominal movement by inductive plethysmography, body position, pulse oximetry, and nasal pressure respiratory flow monitoring. Scoring of the data including sleep stages and respiratory events was performed manually by a registered and licensed sleep polysomnographic technologist.

[0099] The at home treatment nights were acquired after replacing the bedtime medication from the Z-drug to the combination of VLD mirtazapine and gabapentin. Objective sleep quality was evaluated using a portable at home sleep monitoring device called Somfit® that allows for brain activity monitoring and sleep stage scoring. The Somfit® device is a non-invasive, FDA-approved wearable device used for home-based sleep monitoring device manufactured by Compumedics Limited. It attaches to the forehead to collect physiological data, including brain activity, oxygen saturation, heart rate, and motion, to provide a comprehensive sleep analysis using a non-invasive patch. This diagnostic device is intended for use by clinicians to monitor sleep in a home setting, transmitting the collected data via Bluetooth to a mobile app, which then sends it to a cloud-based system for remote data analysis and interpretation. The Somfit® sleep monitoring device has been validated against PSG and found to have an equal level of accuracy and precision.

[0100] Table 2: Sleep Quality at baseline (using Z-drug) and following Very Low Dose Mirtazapine and Gabapentin on 3 separate nights33106466116.3Attorney Docket No. 130371-860830

[0101] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0102] All terms are intended to be understood as they would be understood by a person skilled in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure pertains. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise.

[0103] While certain aspects of the present disclosure have been shown and described in detail herein, it will be obvious to those skilled in the art that these aspects are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the different aspects of the invention as described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.34106466116.3

Claims

Attorney Docket No. 130371-860830CLAIMSWhat is claimed is:

1. A method for treating a sleep disorder comprising administering to a subj ect in need thereof an amount of about 1.0 mg to about 7.0 mg mirtazapine, or a salt or derivative thereof.

2. The method of claim 1, wherein the amount of mirtazapine, or a salt or derivative thereof, is selected from about 1 mg, about 1.5 mg, about 2 mg, about 3 mg, about 3.5, or about 4 mg.

3. The method of claim 1 or claim 2, further comprising co-administering to the subject an amount of gabapentin, or a salt or derivative thereof.

4. The method of claim 3, wherein the amount of gabapentin, or a salt or derivative thereof, is about 50 mg to about 275 mg.

5. The method of any claim 3 or claim 4, wherein the amount of gabapentin, or a salt or derivative thereof, is selected from about 50 mg, about 100 mg, about 120 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, and about 275 mg.

6. The method of any one of claims 1 to 5, wherein the sleep disorder is selected from the group consisting of sleep apnea, restless leg syndrome, narcolepsy, circadian rhythm disorders, parasomnias, sleep-related movement disorders, and insomnia.

7. The method of any one of claims 1 to 6, wherein the sleep disorder is insomnia.

8. The method of any one of claims 1 to 7, wherein the sleep disorder is selected from the group consisting of acute insomnia, transient insomnia, chronic insomnia, initial insomnia, middle insomnia, late insomnia, idiopathic insomnia, inadequate sleep hygiene insomnia, comorbid insomnia, and insomnia not otherwise specified (NOS).

9. The method of any one of claims 3 to 8, wherein the mirtazapine and gabapentin are administered at a time that is about 5 minutes to about 2 hours prior to bedtime for the subject.

10. The method of any one of claims 3 to 9, wherein the mirtazapine and gabapentin are administered at a time that is about 5 minutes to about 5 hours after a last meal for the subject.35106466116.3Attorney Docket No. 130371-86083011. A single dosage form comprising: mirtazapine, or a salt or derivative thereof in an amount of about 1.0 mg to about 7.0 mg; and gabapentin, or a salt or derivative thereof.

12. The single dosage form of claim 11, wherein the mirtazapine, or salt or derivative thereof is present in an amount selected from about 1 mg, about 1.5 mg, about 2 mg, about 3 mg, about 3.5, and about 4 mg.

13. The single dosage form of any one of Claims 11 or 12, wherein the mirtazapine is esmirtazapine.

14. The single dosage form of any one of claims 11 to 13, wherein the gabapentin, or a salt or derivative thereof, is present in an amount of about 50 mg to about 275 mg.

15. The single dosage form of claim 14, wherein the gabapentin, or a salt or derivative thereof, is present in an amount selected from about 50 mg, about 100 mg, about 120 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, and about 275 mg.

16. A pharmaceutical composition comprising: i) mirtazapine, or a salt or derivative thereof in an amount of about 1.0 mg to about 7.0 mg; (ii) gabapentin, or a salt or derivative thereof, in an amount of about 50 mg to about 275 mg; and iii) a pharmaceutically acceptable carrier and / or excipient.

17. The pharmaceutical composition of claim 16, formulated for oral administration, intravenous injection, subcutaneous injection, intrathecal administration, topical administration, inhalation, or nasal administration.

18. The pharmaceutical composition of claim 16, wherein the pharmaceutical composition is formulated for oral administration.

19. The pharmaceutical composition of claim 16 or claim 17, wherein the pharmaceutical composition is in a form selected from the group consisting of tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a36106466116.3Attorney Docket No. 130371-860830 suspension, a solution, an emulsion, a buccal film, an oral film, a sublingual tablet, a dissolvable tablet, a granule, a powder, a solid lipid nanoparticle, an ointment, a lotion, an eye drop, an ear drop, or an oral mucosal formulation.

20. The pharmaceutical composition of any one of claims 16 to 18, further comprising an additional therapeutic agent.

21. A method for treating a sleep disorder comprising administering to a subj ect in need thereof the single dosage form of any one of claims 11 to 15 or the pharmaceutical composition of any one of claims 16 to 19.

22. Use of the single dosage form of any one of claims 11 to 15, or the pharmaceutical composition of any one of claims 16 to 19 for the treatment of insomnia.37106466116.3