Pharmaceutical Compositions Comprising Zolmitriptan

Abstract

Provided herein are oral compositions comprising zolmitriptan and methods of use thereof, for example, for treating symptoms of autism spectrum disorder and for treating aggression in patients with dementia.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 306,377, filed February 3, 2022, and U.S. Provisional Patent Application No. 63 / 165,938, filed March 25, 2021, the disclosures of which are hereby incorporated by reference in their entireties for all purposes.

[0002] Field of the Disclosure

[0002] The present disclosure relates to pharmaceutical compositions of zolmitriptan and uses thereof. [Background technology]

[0003] Background of the Disclosure

[0003] Zolmitriptan is a triptan whose molecular targets are the serotonin (5-HT) 1B receptors expressed in intracranial arteries and the 5-HT 1D receptors located in the peripheral trigeminal sensory nerve endings in the meninges and the central endings in the brainstem sensory nuclei. The chemical name of zolmitriptan is (4S)-4-[[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl]-1,3-oxazolidin-2-one, and its structural formula is shown below. [ka]

[0004]

[0004] Zolmitriptan is sold in the United States and other markets as ZOMIG® for the treatment of headaches, including migraines.

[0005]

[0005] Zolmitriptan can be used to treat symptoms associated with autism spectrum disorder (ASD). ASD patients often exhibit sensory processing abnormalities and may have aversions to the color, taste, smell, and / or texture of food or medicine. Therefore, maintaining medication adherence in ASD patients can be a challenge. Summary of the Invention [Problem to be solved by the invention]

[0006] Thus, there is a need for pharmaceutical compositions of zolmitriptan that provide therapeutic efficacy when administered once daily, twice daily, or three times daily. [Means for solving the problem]

[0007] Summary of the Disclosure In one aspect, the disclosure provides a pharmaceutical composition comprising zolmitriptan or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a pharmaceutical composition that provides a therapeutically effective plasma zolmitriptan level when administered on a once-daily or twice-daily basis.

[0008]

[0008] In some embodiments, the composition contains zolmitriptan in an amount of about 7.5 mg to about 150 mg. In some embodiments, the composition contains zolmitriptan in an amount of about 60 mg to about 120 mg. In some embodiments, the pharmaceutical composition contains about 7.5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, or about 150 mg of zolmitriptan.

[0009]

[0009] In some embodiments, the present disclosure provides a composition for treating symptoms of autism spectrum disorder, comprising about 7.5 mg to about 150 mg of zolmitriptan, or a pharma- ceutically acceptable salt thereof, wherein administration of the composition provides a therapeutically effective plasma concentration of zolmitriptan for at least about 12 hours.

[0010] In some embodiments, the present disclosure provides a composition for treating a symptom of an autism spectrum disorder, comprising zolmitriptan, or a pharma- ceutically acceptable salt thereof, wherein oral administration of the composition provides an AUC 0-24h,ssis provided over a period of about 12 to 24 hours to treat symptoms of autism spectrum disorder.

[0011] In some embodiments, the present disclosure provides a composition for treating a symptom of an autism spectrum disorder, the composition comprising zolmitriptan or a pharma- ceutically acceptable salt thereof, wherein injection of the composition provides an AUC 0-24h,ss is provided for a period of about one day to about one month to treat the symptoms of autism spectrum disorder.

[0012]

[0012] In some embodiments, the present disclosure provides a method for treating a symptom of an autism spectrum disorder, comprising administering a pharmaceutical composition to a patient in need thereof, wherein the pharmaceutical composition comprises from about 2 mg to about 150 mg of zolmitriptan, or a pharma- ceutically acceptable salt thereof, and wherein the administration provides a therapeutically effective plasma concentration for at least about 12 hours.

[0013]

[0013] In some embodiments, the present disclosure provides a composition for treating aggression in a patient with dementia (e.g., an Alzheimer's disease patient), comprising about 7.5 mg to about 150 mg of zolmitriptan, or a pharma- ceutically acceptable salt thereof, wherein administration of the composition provides a therapeutically effective plasma concentration of zolmitriptan for at least about 12 hours.

[0014] In some embodiments, the present disclosure provides a composition for treating aggression in a patient with dementia (e.g., an Alzheimer's disease patient), comprising zolmitriptan, or a pharma- ceutically acceptable salt thereof, wherein oral administration of the composition provides an AUC 0-24h,ss is provided over a period of about 12 to 24 hours to treat symptoms of autism spectrum disorder.

[0015] In some embodiments, the present disclosure provides a composition for treating aggression in a patient with dementia (e.g., an Alzheimer's disease patient), comprising zolmitriptan or a pharma- ceutically acceptable salt thereof, wherein injection of the composition provides an AUC 0-24h,ss is provided for a period of about one day to about one month to treat the symptoms of autism spectrum disorder.

[0016]

[0016] In some embodiments, the present disclosure provides a method for treating aggression in a patient with dementia (e.g., an Alzheimer's disease patient), comprising administering a pharmaceutical composition to a patient in need thereof, wherein the pharmaceutical composition comprises from about 2 mg to about 150 mg of zolmitriptan, or a pharma- ceutically acceptable salt thereof, and wherein the administration provides a therapeutically effective plasma concentration for at least about 12 hours. [Brief description of the drawings]

[0017] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1]

[0017] Figure 1 shows the aggression latency (seconds) of adult male CD-1 mice from a crossover resident-intruder (RI) study in which resident CD-1 mice were treated with vehicle control, 10 mg / kg zolmitriptan, or 0.03 mg / kg risperidone. Aggression latency was measured over a 5-minute period in a crossover design. Data are presented as the mean ± standard error of the mean. [Diagram 2]

[0018] 1 shows social index in a valproic acid (VPA)-induced autism spectrum disorder c57 / Bl6 mouse model in mice treated with vehicle control or 10 mg / kg zolmitriptan. [Diagram 3]

[0019] 1 shows the mean CSF levels of zolmitriptan and its metabolite N-desmethylzolmitriptan (NDMZ) following oral administration of 5 mg, 10 mg, 20 mg, and 30 mg doses to human subjects. [Figure 4]

[0020] 1 shows the zolmitriptan dissolution profiles of extended release tablets (15 mg ER zolmitriptan) and immediate release / extended release 25 mg (10 mg IR zolmitriptan / 15 mg ER zolmitriptan) bilayer tablets. [Diagram 5]

[0021] Figure 1 shows the zolmitriptan dissolution profile of 12 mg (3 mg IR / 9 mg ER) and 24 mg (6 mg IR / 18 mg ER) zolmitriptan immediate / extended release oral bilayer tablets (n=6). [Figure 6]

[0022] FIG. 1 shows a schematic of the study design for the study described in Example 10. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] definition

[0023] The term "about", when placed immediately before a numerical value, means a range (e.g., ±10% from that value). For example, unless otherwise indicated in the context of this disclosure or inconsistent with such an interpretation, "about 50" can mean 45 to 55, "about 25,000" can mean 22,500 to 27,500, etc. For example, in a list of numerical values ​​such as "about 49, about 50, about 55, ...", "about 50" means a range that extends to less than half of one or more intervals between the preceding and following values, for example, a range greater than 50.5 and less than 52.5. Furthermore, the phrase "less than about (a value)" or "greater than about (a value)" should be understood in light of the definition of the term "about" provided herein. Similarly, the term "about," when placed before a series of numerical values ​​or a range of values ​​(e.g., "about 10, 20, 30" or "about 10 to 30"), refers to every value in that series, or to each of the endpoints of that range.

[0019]

[0024] Throughout this disclosure, various patents, patent applications, and publications are referenced. The disclosures of these patents, patent applications, and publications are incorporated by reference in their entireties into this disclosure for all purposes in order to more fully describe the state of the art as known to those skilled in the art as of the date of this disclosure. In the event of a conflict between the cited patents, patent applications, and publications and this disclosure, the present disclosure shall control.

[0020]

[0025] For convenience, certain terms used in the specification, examples, and claims are collected here. Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0021]

[0026] The terms "administer", "administering" or "administration" as used herein refer to either administering a compound or a pharma- ceutically acceptable salt or ester of the compound, or a composition comprising a compound or a pharma- ceutically acceptable salt or ester of the compound, directly to a patient.

[0022]

[0027] The term "carrier" as used herein includes carriers, excipients, and diluents, that is, means a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a pharmaceutical agent from one organ or part of the body to another.

[0023]

[0028] The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0024]

[0029] The terms "effective amount" and "therapeutically effective amount" are used interchangeably in this disclosure and refer to an amount of a compound, or a salt, solvate or ester thereof, that is capable of achieving the intended result when administered to a patient. For example, in some embodiments, an effective amount of zolmitriptan is the amount required to reduce at least one symptom of ASD in a patient. The actual amount, including "effective amount" or "therapeutically effective amount", will vary depending on a number of conditions, including but not limited to the severity of the disorder, the size and health of the patient, and the route of administration. A skilled physician can easily determine the appropriate amount using methods known in the medical arts.

[0025]

[0030] The phrase "pharmacologically acceptable" as used herein refers to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit-risk ratio.

[0026]

[0031] The term "salts" as used herein includes pharma- ceutically acceptable salts commonly used to form addition salts of free bases. The nature of the salt is not critical, provided it is pharma- ceutically acceptable. The term "salts" also includes solvates of the addition salts, such as hydrates, as well as polymorphs of the addition salts. Suitable pharma- ceutically acceptable acid addition salts can be prepared from inorganic acids or from organic acids.

[0027]

[0032] The term "pharmaceutically acceptable salt" includes salts obtained by reacting an active compound, which functions as a base, with an inorganic or organic acid to form a salt, such as, for example, 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, Included are those obtained by forming salts of glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid, (-L) malonic acid, mandelic acid (DL), methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p), and undecylenic acid. Those skilled in the art will further recognize that acid addition salts can be prepared by any of a number of known methods by reacting the compounds with the appropriate inorganic or organic acid.

[0028]

[0033] The term "treating" as used herein with reference to a patient refers to improving at least one symptom of the patient's disorder. Treating can be improving the disorder or making it at least partially better.

[0029]

[0034] The term "therapeutic effect" as used herein refers to the desired or beneficial effect provided by the method and / or composition.For example, in some embodiments, a method for treating autism spectrum disorder provides a therapeutic effect when the method improves at least one symptom of ASD in a patient (e.g., improves irritability or increases sociality associated with ASD).In some embodiments, a method for treating aggression in a dementia patient (e.g., an Alzheimer's disease patient) provides a therapeutic effect when the method improves at least one symptom of aggression in the patient.

[0030] Detailed Description of the Disclosure

[0035] The present disclosure provides a pharmaceutical composition comprising zolmitriptan or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition provides therapeutically effective plasma levels when administered on a once-daily, twice-daily, or three-times-daily basis. In some embodiments, the pharmaceutical composition achieves similar therapeutic efficacy as the reference drug product (ZOMIG®), but has an improved safety profile.

[0031] Zolmitriptan

[0036] Zolmitriptan as used in the present method may form part of a pharmaceutical composition by combining zolmitriptan, or a pharma- ceutically acceptable salt thereof, with a pharma- ceutically acceptable carrier. In addition, the present composition may include an additive selected from the group consisting of an adjuvant, an excipient, a diluent, a release modifier, and a stabilizer.

[0032]

[0037] Zolmitriptan is a triptan. Triptans belong to the serotonin receptor subtype-selective class of drugs. Triptans inhibit the 5-HT receptor subtypes that belong to the serotonin (5-HT) system. 1B , 5-HT 1D , and 5-HT 1F Triptans have selective activity against the 5-HT receptors in arterial smooth muscle. 1BThe effect of triptans on the regulation of cerebral blood flow is mediated by their action on the peripheral nociceptors. Triptan-induced vasoconstriction leads to a dose-dependent increase in blood flow velocity in the middle and large cerebral vessels. Triptans are believed to inhibit abnormal activation of peripheral nociceptors. Triptans are presumed to reduce plasma protein extravasation (PPE) by inhibiting nociceptor activation and preventing peripheral release of vasoactive peptides, including substance P and calcitonin gene-related peptide (CGRP). Triptan binding sites are also present in the central nervous system. Thus, it is possible that triptans exert effects on the central nervous system. As of the time of this disclosure, triptans are FDA approved for the treatment of migraine headaches.

[0033]

[0038] The serotonergic system has been implicated in the pathophysiology of autism since abnormalities in blood 5-HT levels were identified as the first biomarker of the disorder over 50 years ago (Schain et al. J Pediatr. 1961 Mar;58:315-20). The main source of 5-HT in the brain originates in the midbrain dorsal raphe nucleus (DRN) and projects widely across the cortex, amygdala, and hypothalamus to other subcortical structures related to emotional processing and social behavior. Dense serotonergic projections from the DRN innervate the nucleus accumbens (NAc), a well-conserved basal forebrain structure that acts as an integrator of motivational signals that precede the selection of behavioral actions (Kravitz et al. Physiology (Bethesda). 2012 Jun;27(3):167-77.). In the context of social interactions, reward processing in the NAc is thought to govern the choice between social approach versus social avoidance behaviors (Pfaff. Trends Neurosci. 2019 Jul;42(7):448-457.). Evidence from preclinical studies supports a critical role for 5-HT signaling in social behavior and social reward (Kane et al. PLoS One. 2012;7(11):e48975.;Challis et al. J Neurosci. 2013 Aug 28;33(35):13978-88, 13988a.;Li et al. Nat Commun. 2016 Jan 28;7:10503.). Furthermore, abnormal reward processing in the NAc has been observed in fMRI imaging studies of children with ASD (Clements et al. JAMA Psychiatry. 2018 Aug 1;75(8):797-808. doi: 10.1001 / jamapsychiatry.2018.1100.).

[0034]

[0039] In the human brain, 5-HT1B is highly expressed in the NAc (Garcia-Alloza et al. Neuropsychologia. 2005;43(3):442-9.;Varnas et al. Hum Brain Mapp. 2004 Jul;22(3):246-60.;Varnas et al. Synapse. 56: 21-8.). It is an inhibitory G protein-coupled receptor localized to axon terminals and acts to suppress neurotransmitter release (Sari. Neurosci Biobehav Rev. 2004 Oct;28(6):565-82.). As an autoreceptor, 5-HT1B inhibits the release of 5-HT, but it also plays an important role as a heteroreceptor that inhibits the release of other neurotransmitters, including glutamate, GABA, dopamine, and acetylcholine (Boscher et al. (1994) Neuroscience 58:167-182.). According to the present disclosure, the 5-HT1B agonistic properties of the triptans described herein modulate the behavioral symptoms of ASD.

[0035]

[0040] The synthesis of zolmitriptan is described in U.S. Patent No. 9,006,453, which is hereby incorporated by reference in its entirety for all purposes. The synthesis of optically pure zolmitriptan is described in U.S. Patent Application Publication No. 2005 / 105792, which is hereby incorporated by reference in its entirety for all purposes.

[0036]

[0041] In some embodiments, the zolmitriptan used in the compositions and methods of the present disclosure is a pharma- ceutically acceptable salt of zolmitriptan. In some embodiments, the pharma- ceutically acceptable salt of zolmitriptan used in the formulations and methods of the present disclosure is selected from the group consisting of oxalate, camphorsulfonate, sulfonate, hydrobromide, hydrochloride, hydrogen sulfate, mesylate, succinate, and tartrate.

[0037] Pharmaceutical Compositions

[0042] In one aspect, the disclosure provides a pharmaceutical composition comprising zolmitriptan.

[0038]

[0043] In some embodiments, the disclosure provides pharmaceutical compositions that provide a therapeutic effect for treating one or more symptoms associated with ASD when administered on a once-daily, twice-daily, or three-times-daily basis.

[0039]

[0044] In some embodiments, the disclosure provides pharmaceutical compositions that provide therapeutic efficacy for treating aggression in patients with dementia (e.g., Alzheimer's disease patients) when administered on a once-daily, twice-daily, or three-times-daily basis.

[0040]

[0045] In some embodiments, the pharmaceutical compositions provided herein are administered to a subject in a fasted state. In some embodiments, the pharmaceutical compositions are administered to a subject in a postprandial state.

[0041]

[0046] In some embodiments, the pharmaceutical compositions described herein contain zolmitriptan in an amount of about 1 mg to about 200 mg, for example, about 1 mg, about 3 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12 mg, about 20 mg, about 24 mg, about 30 mg, about 36 mg, about 40 mg, about 48 mg, about 50 mg, about 60 mg, about 70 mg, about 72 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg (including all values ​​and subranges therebetween). In some embodiments, the pharmaceutical compositions described herein contain zolmitriptan in an amount of about 50 mg to about 200 mg. In some embodiments, the pharmaceutical compositions described herein contain about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, or about 200 mg of zolmitriptan. In some embodiments, the pharmaceutical compositions described herein contain zolmitriptan or a pharma- ceutically acceptable salt thereof in an amount of about 7.5 mg to about 50 mg. In some embodiments, the pharmaceutical compositions described herein contain zolmitriptan or a pharma- ceutically acceptable salt thereof in an amount of about 10 mg to about 30 mg. In some embodiments, the pharmaceutical compositions described herein contain about 12 mg, about 24 mg, about 36 mg, or about 48 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof. In embodiments, the pharmaceutical compositions described herein contain about 12 mg, about 24 mg, about 36 mg, about 48, or about 72 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof.

[0042]

[0047] In some embodiments, the pharmaceutical composition releases zolmitriptan in two or more pulses, for example, 2, 3, 4, 5, 6, 7, 8, 9, and 10 or more pulses. The timing of the pulses can be modified to release the drug in a desired area of ​​the gastrointestinal tract. For example, in some embodiments, the pharmaceutical compositions described herein are formulated to release one or more pulses in the stomach and one or more pulses in the intestine.

[0043]

[0048] In some embodiments, the pharmaceutical compositions described herein comprise (i) an immediate release component and (ii) a delayed release component, each of which accounts for a portion of the total amount of zolmitriptan in the pharmaceutical composition.

[0044]

[0049] In some embodiments, the pharmaceutical compositions described herein comprise (i) an immediate release component and (ii) an extended release component, each of which accounts for a portion of the total amount of zolmitriptan in the pharmaceutical composition.

[0045]

[0050] In some embodiments, the ratio of zolmitriptan in the immediate release component compared to the zolmitriptan in the delayed or sustained release component ranges from about 1:99 to about 99:1, e.g., about 1:99, about 5:95, about 10:90, about 15:85, about 20:80, about 25:75, about 30:70, about 35:65, about 40:60, about 45:55, about 50:50, about 55:45, about 60:40, about 65:35, about 70:30, about 75:25, about 80:20, about 85:15, about 90:10, about 95:5, and about 99:1, including all values ​​and sub-ranges therebetween. In some embodiments, the ratio of zolmitriptan in the immediate release component compared to zolmitriptan in the delayed or sustained release component is about 25:75. In some embodiments, the immediate release component comprises about 75% or less of the total amount of zolmitriptan in the pharmaceutical composition (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, and about 74%, including all values ​​and subranges therebetween), and the delayed or sustained release component comprises about 25% or more of the total amount of zolmitriptan in the pharmaceutical composition (e.g., about 25%, about 20%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, and about 99%, including all values ​​and subranges therebetween). In some embodiments, the immediate release component comprises about 20%-40% by weight of the total zolmitriptan in the composition, including about 20%, about 25%, about 30%, about 35%-40% by weight of the total zolmitriptan in the composition, including all values ​​and subranges therebetween. In some embodiments, the sustained release component comprises about 60%-80% by weight of the total zolmitriptan in the composition, including about 60%, about 65%, about 70%, about 75%-80% by weight of the total zolmitriptan in the composition, including all values ​​and subranges therebetween. In some embodiments, the immediate release component comprises about 25% of the total zolmitriptan in the composition and the sustained release component comprises about 75% of the total zolmitriptan in the composition.

[0046]

[0051] In some embodiments, the immediate release component comprises about 1 mg to about 20 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof, including about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg to about 20 mg (including all values ​​and subranges therebetween). In some embodiments, the immediate release component comprises about 1 mg to about 10 mg, or about 3 mg to about 10 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof. In some embodiments, the immediate release component comprises about 3 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof. In some embodiments, the immediate release component comprises about 6 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof.

[0047]

[0052] In some embodiments, the sustained release component is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, g, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, and about 50 mg, including all values ​​and subranges therebetween. In some embodiments, the sustained release component comprises about 5 mg to about 25 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof. In some embodiments, the sustained release component comprises about 9 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof. In some embodiments, the sustained release component comprises about 18 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof.

[0048]

[0053] In some embodiments, the immediate release component is about 0.01% w / w, about 0.02% w / w, about 0.03% w / w, about 0.04% w / w, about 0.05% w / w, about 0.06% w / w, about 0.07% w / w, about 0.08% w / w, about 0.09% w / w, 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 1.5%, about 2% w / w, about 2.5% w / w, About 0.01-10% w / w of zolmitriptan or a pharma- ceutically acceptable salt thereof, based on the total weight of the composition (e.g., bilayer tablet), including about 3% w / w, about 3.5% w / w, about 4% w / w, about 4.5% w / w, about 5% w / w, about 5.5% w / w, about 6% w / w, about 6.5% w / w, about 7% w / w, about 7.5% w / w, about 8% w / w, about 8.5% w / w, about 9% w / w, about 9.5% w / w, and about 10% w / w of zolmitriptan or a pharma- ceutically acceptable salt thereof (including all values ​​and sub-ranges therebetween). In some embodiments, the immediate release component comprises about 0.01-5% w / w, or about 0.1-2.5% w / w of zolmitriptan or a pharma- ceutically acceptable salt thereof, based on the total weight of the composition.In some embodiments, the sustained release component is about 0.05% w / w, about 0.06% w / w, about 0.07% w / w, about 0.08% w / w, about 0.09% w / w, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 1.5%, about 2% w / w, about 2.5% w / w, about 3% w / w, about 3.5% w / w, about 4% w / w, about 4.5% w / w, about 5% w / w, about 5.5% w / w, About 0.05 to 20% w / w of zolmitriptan or a pharma- ceutically acceptable salt thereof, based on the total weight of the composition (e.g., bilayer tablet), including about 6% w / w, about 6.5% w / w, about 7% w / w, about 7.5% w / w, about 8% w / w, about 8.5% w / w, about 9% w / w, about 9.5% w / w, about 11% w / w, about 12% w / w, about 13% w / w, about 14% w / w, about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, and about 20% w / w (including all values ​​and subranges therebetween). In some embodiments, the sustained release component comprises about 1-10% w / w, or 0.05-5% w / w, or 0.01-2.5% w / w of zolmitriptan or a pharma- ceutically acceptable salt thereof, based on the total weight of the composition.

[0049]

[0054] Non-limiting examples of suitable immediate release components include one or more immediate release components incorporated as part or parts of a dosage form that can be in the form of a tablet, liquid composition (e.g., suspensions and emulsions), capsule, elixir, syrup, drug-containing beads and particles, etc. In some embodiments, the immediate release component can be placed over the delayed or sustained release component, or the immediate release component can be separate from the delayed or sustained release component. For example, the immediate release component can be in the form of an osmotic delivery system or a coating that can be placed over a capsule, or immediate release beads can be combined with delayed or sustained release beads in a capsule or tablet. In other embodiments, the immediate release component can be provided as a layer of a bilayer or multilayer tablet. In some embodiments, the immediate release component is provided as a layer of a bilayer tablet. The delayed release component can be any formulation that substantially prevents release of a portion (e.g., about 25-99%) of the total amount of zolmitriptan in the pharmaceutical composition for at least 30 minutes. Non-limiting examples of suitable delayed release components include one or more delayed release components incorporated as part or parts of a drug-containing tablet, particle, bead, etc., coated with a delayed release polymer, a delayed release matrix containing zolmitriptan, and an osmotic pump containing zolmitriptan.

[0050]

[0055] In some embodiments, the compositions comprise one or more immediate release components in combination with one or more sustained release components, where the sustained release components release zolmitriptan over an extended period of time.

[0051]

[0056] In some embodiments, the composition is a multiparticulate formulation. In some embodiments, the composition is a gastrorentive tablet.

[0052]

[0057] In some embodiments, the sustained release component is a gastrorentive layer. In some embodiments, the composition is retained in the stomach for at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, or at least about 12 hours after oral administration. In some embodiments, the composition is retained in the stomach for at least about 2 hours after oral administration. In some embodiments, the composition is retained in the stomach for at least about 8 hours after oral administration.

[0053]

[0058] The present disclosure provides enumerated embodiments that disclose compositions and methods for treating symptoms of autism spectrum disorder. The compositions and methods described herein are also suitable for treating other conditions characterized by aggression (e.g., aggression in dementia patients, such as Alzheimer's disease patients). Thus, the enumerated embodiments described herein for compositions and treatment of symptoms of autism spectrum disorder are equally applicable to treating conditions characterized by aggression (e.g., aggression in dementia patients, such as Alzheimer's disease patients).

[0054]

[0059] In some embodiments, provided herein is an oral composition for treating symptoms of an autism spectrum disorder, the composition comprising about 7.5 mg to about 90 mg of zolmitriptan, or a pharma- ceutically acceptable salt thereof, wherein oral administration of the composition provides a therapeutically effective plasma concentration of zolmitriptan for at least 8 hours.

[0055]

[0060] In some embodiments, provided herein is an oral composition for treating aggression in a patient with dementia, the composition comprising about 7.5 mg to about 90 mg of zolmitriptan, or a pharma- ceutically acceptable salt thereof, wherein oral administration of the composition provides a therapeutically effective plasma concentration of zolmitriptan for at least 8 hours.

[0056]

[0061] In some embodiments, provided herein is an oral composition for treating aggression in a patient with Alzheimer's disease, the composition comprising about 7.5 mg to about 90 mg of zolmitriptan, or a pharma- ceutically acceptable salt thereof, wherein oral administration of the composition provides a therapeutically effective plasma concentration of zolmitriptan for at least 8 hours.

[0057]

[0062] In some embodiments, the pharmaceutical compositions of the present disclosure exhibit a zolmitriptan release profile when dissolution tested in 900 mL of 0.1 N HCl (or suitable vehicle) at about 37° C. using United States Pharmacopeia Apparatus II (paddle method, 50 rpm) that corresponds substantially to the following pattern: Approximately 20% to 40% of the total zolmitriptan is released after approximately 15 minutes; Approximately 40% to 75% of the total zolmitriptan is released after about 4 hours; and Approximately 75% to 90% of the total zolmitriptan is released after approximately 8 hours.

[0058]

[0063] In some embodiments, dissolution is tested under simulated fasting conditions. In some embodiments, dissolution is tested under simulated post-prandial conditions.

[0059]

[0064] In some embodiments, when the dissolution of the pharmaceutical compositions provided herein is tested using United States Pharmacopeia Apparatus II (paddle method, 50 rpm) in 900 mL of 0.1 N HCl (or suitable vehicle) at about 37° C., about 5% to 40% of the total zolmitriptan is released after about 15 minutes, including about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, and about 40% of the total zolmitriptan is released after about 15 minutes (including all values ​​and subranges therebetween).

[0060]

[0065] In some embodiments, when the dissolution of the pharmaceutical compositions provided herein is tested using United States Pharmacopeia Apparatus II (paddle method, 50 rpm) in 900 mL of 0.1 N HCl (or suitable vehicle) at about 37° C., about 40%-75% of the total zolmitriptan is released after about 4 hours, including about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, and about 75% of the total zolmitriptan is released after about 4 hours (including all values ​​and subranges therebetween).

[0061]

[0066] In some embodiments, when dissolution of the pharmaceutical compositions provided herein is tested using United States Pharmacopoeia Apparatus II (paddle method, 50 rpm) in 900 mL of 0.1 N HCl (or suitable vehicle) at about 37° C., about 75%-90% of the total zolmitriptan is released after about 8 hours, including about 75%, about 80%, about 85%, and about 90% (including all values ​​and subranges therebetween). In some embodiments, about 85% of the total zolmitriptan is released within 9-10 hours. In some embodiments, dissolution is tested under simulated postprandial conditions.

[0062]

[0067] In embodiments, the pharmaceutical compositions thus provide therapeutically effective plasma concentrations over an extended period of time, typically between about 6 and 24 hours (e.g., about 8 hours, or about 12 hours, or about 16 hours), to treat symptoms of autism spectrum disorder in a human.

[0063]

[0068] In embodiments, the pharmaceutical compositions thus provide therapeutically effective plasma concentrations over an extended period of time, typically at least about 6 to 24 hours (e.g., at least about 8 hours, at least about 12 hours, or at least about 16 hours), to treat symptoms of autism spectrum disorder in a human.

[0064]

[0069] In embodiments, the pharmaceutical compositions thus provide therapeutically effective plasma concentrations over an extended period of time, typically between about 6 and 24 hours (e.g., about 8 hours, or about 12 hours, or about 16 hours) to treat aggression in patients with dementia (e.g., Alzheimer's disease patients).

[0065]

[0070] In embodiments, the pharmaceutical compositions thus provide therapeutically effective plasma concentrations over an extended period of time, typically at least about 6-24 hours (e.g., at least about 8 hours, at least about 12 hours, or at least about 16 hours), to treat aggression in patients with dementia (e.g., Alzheimer's disease patients).

[0066]

[0071] In some embodiments, pharmaceutical compositions of the present disclosure that include one or more immediate release and / or delayed or sustained release components include at least one pharma- ceutically acceptable carrier, diluent, and / or excipient, including, without limitation, any auxiliary agent, carrier, excipient, flow agent, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier.

[0067]

[0072] In some embodiments, the sustained release component is a gastroretentive layer, which comprises zolmitriptan or a pharma- ceutically acceptable salt thereof, a drug release modifier, and, optionally, one or more excipients described herein, such as a lubricant, and a binder and / or diluent, and other excipients. In some embodiments, the gastroretentive layer comprises one or more drug release modifiers, including any swellable, erodible hydrophilic polymer disclosed herein, such as a water-swellable polymer (e.g., polyethylene oxide). In some embodiments, the gastroretentive layer comprises a drug release modifier (e.g., a water-swellable polymer) in about 15% to about 75% w / w of the total composition (e.g., bilayer tablet), including about 15% w / w, about 20% w / w, about 25% w / w, about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, about 50% w / w, about 55% w / w, about 60% w / w, about 65% w / w, about 70% w / w, and about 75% w / w (including all values ​​and subranges therebetween) of the total composition. In some embodiments, the gastroretentive layer comprises a drug release modifier (e.g., a water-swellable polymer such as polyethylene oxide) in about 35-55% w / w of the total composition (e.g., bilayer tablet). Suitable lubricants for the gastroretentive layer include any of the lubricants listed herein, such as stearic acid and stearates, e.g., magnesium stearate. In some embodiments, the gastroretentive layer comprises, for example, about 0.05% w / w, about 0.06% w / w, about 0.07% w / w, about 0.08% w / w, about 0.09% w / w, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w based on the total weight of the composition (e.g., bilayer tablet). and 0.05-5% w / w of lubricant, including about 0.5% w / w, about 1.0% w / w, about 1.5% w / w, about 2.0% w / w, about 2.5% w / w, about 3.0% w / w, about 3.5% w / w, about 4.0% w / w, about 4.5% w / w, and about 5% w / w, including all values ​​and subranges therebetween. Suitable binders for the gastroretentive layer include any of the binders listed herein, including microcrystalline cellulose, such as Avicel™ PH101, or Ceolus™ KG802.The amount of binder in the gastroretentive layer may be in the range of about 10 to about 50% w / w, including, for example, about 10% w / w, about 15% w / w, about 20% w / w, about 25% w / w, about 30% w / w, about 35% w / w, about 40% w / w, and about 45% w / w (including all values ​​and subranges therebetween), based on the total weight of the composition (e.g., a bilayer tablet).

[0068]

[0073] In some embodiments, suitable pharma- ceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions. Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, aqueous and non-aqueous solutions. Pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents suitable for use herein include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers suitable for use herein include, but are not limited to, water, ethanol, alcoholic / aqueous solutions, glycerol, emulsions or suspensions, including saline and buffered media.

[0069]

[0074] Liquid carriers suitable for use herein include, but are not limited to, water (partially containing an additive, such as a cellulose derivative, preferably sodium carboxymethylcellulose solution), alcohols (including monohydric and polyhydric alcohols, such as glycols) and their derivatives, and oils (e.g., fractionated coconut oil and peanut oil).

[0070]

[0075] The liquid carrier suitable for use in the present application can be used to prepare solutions, suspensions, emulsions, syrups, elixirs, and compounds under pressure.In some embodiments, the active ingredient is dissolved or suspended in a pharma-ceutically acceptable liquid carrier, such as water, an organic solvent, a mixture of both, or a pharma-ceutically acceptable oil or fat.In some embodiments, the liquid carrier contains other suitable pharmaceutical additives, such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavorings, suspending agents, thickeners, colorings, viscosity regulators, stabilizers, or osmotic pressure regulators.

[0071]

[0076] Suitable solid carriers for use herein include, but are not limited to, inert materials such as lactose, starch, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, mannitol, etc. The solid carrier may further include one or more substances that act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, flow agents, compression aids, binders, or tablet disintegrants; it may also be an encapsulating material. In powders, the carrier may be a finely divided solid in admixture with the finely divided active compound. In tablets, the active compound is mixed with a carrier having the necessary compression properties in suitable proportions and compressed into the desired shape and size. Powders and tablets may contain up to 99% of the active compound. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidone, low melting waxes, and ion exchange resins. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with binders (e.g., povidone, gelatin, hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethylcellulose), surface active agents or dispersants. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may be optionally coated or scored and formulated to provide delayed or controlled release of the active ingredient therein, for example using hydroxypropylmethylcellulose in various proportions to provide the desired release profile. The tablets may be optionally provided with an enteric coating to provide release in intestinal sites other than the stomach.

[0072]

[0077] Carriers suitable for use herein may be mixed using conventional techniques known in the art, as appropriate, with disintegrants, diluents, granulating agents, lubricants, binders, etc. The carriers may also be sterilized using methods that do not adversely react with the compounds, as generally known in the art.

[0073]

[0078] Diluents may be added to the formulations described herein. Diluents increase the bulkiness of solid pharmaceutical compositions and / or combinations, which may make it easier for patients and caregivers to handle pharmaceutical dosage forms containing the compositions and / or combinations. In various embodiments, diluents for solid compositions include, for example, microcrystalline cellulose (e.g., AVICEL), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., EUDRAGIT®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc, and / or mixtures of any of the foregoing. Specific examples of microcrystalline cellulose include those sold under the trademark Avicel (FMC Corp., Philadelphia, Pa.), e.g., Avicel™ pH101, Avicel™ pH102, and Avicel™ pH112; lactose includes lactose monohydrate, lactose anhydrous, and Pharmatose DCL21; dibasic calcium phosphate includes Emcompress.

[0074]

[0079] Lubricants are used to facilitate tablet manufacture, promoting powder flow and preventing particle capping (i.e., particle breakage) when pressure is released. Useful lubricants are magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, talc, colloidal silicon dioxide such as Aerosil™ 200, mineral oil (in PEG), hydrogenated vegetable oil (e.g., composed of hydrogenated and refined triglycerides of stearic and palmitic acids), and combinations thereof.

[0075]

[0080] Binders are used to give tablets cohesive qualities and thus ensure that the tablet or tablet layer remains intact after compression.Suitable binder materials include, but are not limited to, starch (including cornstarch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose and lactose), polyethylene glycol, polyvinyl alcohol, wax, and natural and synthetic gums, such as sodium acacia alginate, polyvinylpyrrolidone, cellulose-based polymers (including hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, microcrystalline cellulose, ethylcellulose, hydroxyethylcellulose, etc.), and Veegum, and combinations thereof.Examples of polyvinylpyrrolidone include povidone, copovidone and crospovidone.

[0076]

[0081] Fillers include, for example, materials such as silicon dioxide, titanium dioxide, alumina, talc, kaolin, powdered cellulose, microcrystalline cellulose, urea, sodium chloride, and saccharides, or combinations thereof. Any suitable saccharide may be used in the compositions of the present disclosure. As used herein, "saccharides" used in the present invention include sugar alcohols, monosaccharides, disaccharides, and oligosaccharides. Exemplary sugar alcohols include, but are not limited to, xylitol, mannitol, sorbitol, erythritol, lactitol, pentitol, and hexitol. Exemplary monosaccharides include, but are not limited to, glucose, fructose, aldose, and ketose. Exemplary disaccharides include, but are not limited to, sucrose, isomalt, lactose, trehalose, and maltose. Exemplary oligosaccharides include, but are not limited to, fructooligosaccharides, inulin, galactooligosaccharides, and mannan oligosaccharides. In some embodiments, the saccharide is sorbitol, mannitol, or xylitol. In some embodiments, the saccharide is sorbitol. In some embodiments, the saccharide is sucrose.

[0077]

[0082] Disintegrants are used to facilitate tablet disintegration, thereby increasing the erosion rate relative to the dissolution rate, and are generally starches, clays, celluloses, algins, gums, or crosslinked polymers (e.g., crosslinked polyvinylpyrrolidone).Other non-limiting examples of suitable disintegrants include, for example, lightly crosslinked polyvinylpyrrolidone, corn starch, potato starch, maize starch and modified starches, croscarmellose sodium, crospovidone, sodium starch glycolate, and combinations and mixtures thereof.

[0078]

[0083] The pharmaceutical formulations of the present disclosure may be prepared by methods known to those skilled in the art, such as mixing, dissolving, granulating, dragee-forming, elutriating, emulsifying, encapsulating, entrapping, or lyophilizing processes. As mentioned above, the zolmitriptan compositions of the present disclosure may include one or more pharma- ceutically acceptable carriers, such as excipients and adjuvants, that facilitate processing of the active molecules into preparations for pharmaceutical use.

[0079]

[0084] In some embodiments, the pharmaceutical composition of the present disclosure is prepared into an oral formulation. For oral administration, the compound can be easily formulated by combining the active compound with a pharma- ceutically acceptable carrier known in the art. Such carriers allow zolmitriptan to be formulated as a tablet, pill, dragee, capsule, liquid, gel, syrup, slurry, suspension, etc., for oral ingestion by a subject. Pharmaceutical compositions for oral use may be obtained as solid excipients, and optionally the resulting mixture may be milled, and the mixture of granules may be processed to obtain tablets or dragee cores, after adding suitable auxiliary agents, if necessary. Such oral pharmaceutical compositions may also be prepared by milling or melt extrusion. Suitable excipients may be any of those disclosed herein, in particular fillers such as sugars including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP) preparations. Disintegrants may also be used, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts such as sodium alginate. Wetting agents such as sodium dodecyl sulfate may be added.

[0080]

[0085] In some embodiments, zolmitriptan is combined with excipients to form a core (i.e., active core) containing zolmitriptan. In some embodiments, the active core comprises inert particles such as sugar spheres having an appropriate average particle size. In one embodiment, the inert core may be sugar spheres, cellulose spheres, spherical silicon dioxide beads, buffer crystals or encapsulated buffer crystals, such as calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid, etc. Buffer crystals are useful for altering the microenvironment. Alternatively, according to other embodiments, drug-containing microgranules or pellets may be prepared by rotary granulation, high shear granulation and extrusion-spheronization or compression of the drug (as mini-tablets, e.g., with a diameter of about 2 mm or more), polymeric binder and optionally filler / diluent.

[0081]

[0086] In some embodiments, the dragee cores may be provided with a suitable coating. For this purpose, concentrated sugar solutions are used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0082]

[0087] In some embodiments of the present disclosure, the pharmaceutical composition is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.). In some such embodiments, the pharmaceutical composition includes a carrier and is formulated in an aqueous solution, such as water or a physiologically compatible buffer, for example, Hank's solution, Ringer's solution, or physiological saline buffer. In some embodiments, other ingredients (e.g., ingredients that aid in solubility or act as preservatives) are included. In some embodiments, an injectable suspension is prepared using appropriate liquid carriers, suspending agents, and the like. Certain injectable pharmaceutical compositions are provided in unit dosage form, for example, in ampoules or multi-dose containers. Certain injectable pharmaceutical compositions are suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending agents, stabilizing agents, and / or dispersing agents. Certain solvents suitable for use in injectable pharmaceutical compositions include, but are not limited to, lipophilic solvents, such as vegetable oils (e.g., sesame oil, etc.), and fatty oils, synthetic fatty acid esters, such as ethyl oleate or triglycerides. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, such suspensions may also contain suitable stabilizers or agents which increase the solubility of the pharmaceutical agents to allow for the preparation of highly concentrated solutions.

[0083]

[0088] Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as a solution in 1,3-butanediol, or may be prepared as lyophilized powders. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic saline. In addition, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any bland fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may also be used in the preparation of injectable solutions. Preparations for intravenous administration may include a solution in a sterile isotonic aqueous buffer. If necessary, the preparation may also include a solubilizing agent and a local anesthetic to ease pain at the site of the injection. Generally, these ingredients are either supplied separately or mixed together in a unit dosage form, for example, as a dry lyophilized powder or waterless concentrate in a hermetically sealed container indicating the quantity of active agent, such as an ampoule or sachet. Where the compound is to be administered by infusion, the compound in the formulation may be dispensed with an infusion bottle containing sterile pharmaceutical grade water, saline or dextrose / water. Where the compound is administered by injection, an ampoule of sterile water for injection or saline may be provided so that the ingredients may be mixed prior to administration.

[0084]

[0089] Suitable formulations further include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, bactericidal antibiotics and solutes that render the formulation isotonic with the body fluids of the intended recipient; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickening agents. Liposomal suspensions containing tissue-targeting liposomes may also be present in suitable formulations.

[0085]

[0090] Parenteral administration of the formulations of the present invention includes intravenous, subcutaneous and intramuscular administration of the pharmaceutical compositions described herein. Preparations for parenteral administration include sterile dry soluble preparations ready to be combined with a solvent immediately before use, including sterile solutions ready to be injected, tablets for subcutaneous injection, sterile suspensions ready to be injected, sterile dry insoluble preparations ready to be combined with a vehicle immediately before use, and sterile emulsions. These solutions may be either aqueous or non-aqueous. Pharmaceutically acceptable carriers used in parenteral preparations include aqueous media, non-aqueous media, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, thickening agents, emulsifying agents, metal ion sequestering or chelating agents, and other pharmaceutically acceptable substances. Liposomal suspensions are also suitable as pharmaceutically acceptable carriers.

[0086]

[0091] In some embodiments of the present disclosure, the pharmaceutical composition is formulated as a depot preparation. Such depot preparations are typically longer acting than non-depot preparations. In some embodiments, such preparations are administered parenterally (e.g., by injection or implantation). For example, subcutaneous or intramuscular depot injection of a sterile solution containing zolmitriptan is an effective mode of administration. In some embodiments, the depot preparation is prepared using a suitable polymer or hydrophobic material (e.g., an emulsion in an acceptable oil) or ion exchange resin, or as a poorly soluble derivative, e.g., as a poorly soluble salt. Thus, for example, zolmitriptan may be formulated with a suitable polymer or hydrophobic material (e.g., an emulsion in an acceptable oil) or ion exchange resin, or as a poorly soluble derivative, e.g., as a poorly soluble salt. In some embodiments, the depot preparation provides a 1-day, 7-day, or 30-day depot release profile. In some embodiments, such preparations are administered on a daily, weekly, or monthly injection schedule.

[0087]

[0092] The concentration of the pharma- ceutically active compound can be adjusted so that the injection provides an effective amount to produce the desired pharmacological effect. The exact dose depends on the age, weight and condition of the patient or animal, as is known in the art. In some embodiments, the unit-dose parenteral preparation is packaged in an ampoule or a syringe with a needle. All preparations for parenteral administration must be sterile, as is known and practiced in the art. Illustratively, intravenous or intraarterial infusion of a sterile aqueous solution containing zolmitriptan is an effective mode of administration.

[0088]

[0093] Delayed Release Components

[0094] In some embodiments, the pharmaceutical compositions described herein comprise one or more immediate release components and one or more delayed release components. In some embodiments, the delayed release component comprises one or more delayed release components (e.g., 2, 3, 4, 5, 6, 7, 8, 9, and 10 or more), each of which may provide a different release profile. In some embodiments, the delayed release portion is a gastrorentive layer. In some embodiments, each delayed release component is formulated to release zolmitriptan in a pulse that occurs after a desired delay, with a first delayed release component releasing zolmitriptan in a pulse and a second delayed release component providing a sustained release, or both delayed release components providing a sustained release of zolmitriptan.

[0089]

[0095] As used herein, "delayed release" refers to a pharmaceutical formulation in which the active ingredient (e.g., zolmitriptan) contained in the delayed release component is not substantially released (meaning that no more than about 5-10% is released) for a period of time after oral administration. In some embodiments, the delayed release is such that the active ingredient is not substantially released for at least 30 minutes, e.g., 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 65 minutes, 70 minutes, 75 minutes, 80 minutes, 85 minutes, 90 minutes, 95 minutes, 100 minutes, 105 minutes, 110 minutes, 115 minutes, 120 minutes, or more, after oral administration. Delayed release also includes formulations in which no portion of the active ingredient (e.g., zolmitriptan) is released from the formulation for a certain period of time.

[0090]

[0096] In some embodiments, the delayed release component can prevent at least about 40% (e.g., about 40% to about 60%) of the total amount of zolmitriptan present in the pharmaceutical formulation from being substantially released for at least about 30 minutes, e.g., 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 65 minutes, 70 minutes, 75 minutes, 80 minutes, 85 minutes, 90 minutes, 95 minutes, 100 minutes, 105 minutes, 110 minutes, 115 minutes, 120 minutes, or more, after oral administration.

[0091]

[0097] In some embodiments, substantially complete release (e.g., at least about 90-95%) of zolmitriptan from the delayed release component is achieved while the pharmaceutical composition is in the acidic environment of the stomach. Thus, in some embodiments, substantially complete release of zolmitriptan from the delayed release component is achieved before the pharmaceutical composition reaches the less acidic environment of the intestine.

[0092]

[0098] In some embodiments, the delayed release component is suitably formulated to provide a pulsed release of zolmitriptan in the acidic environment of the stomach, occurring at least 30 minutes after oral administration (e.g., about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, or about 120 minutes or more).

[0093]

[0099] In some embodiments, the delayed release component is suitably formulated (e.g., as a sustained release formulation) to slowly release zolmitriptan over a period of time, where the initial release of zolmitriptan from the delayed release component occurs at least 30 minutes after oral administration and continues for about 30 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, or more. In certain other embodiments, the initial release of zolmitriptan from the delayed release component occurs at least 30 minutes after oral administration and continues for a period of time ranging from about 0.5 hours to about 4 hours, e.g., about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, and about 3.5 hours, including all values ​​and subranges therebetween.

[0094]

[0100] In some embodiments, the delayed release component is suitably formulated (e.g., as a sustained release formulation) to slowly release zolmitriptan over a period of time, where the initial release of zolmitriptan from the delayed release component occurs at least 30 minutes after oral administration and continues for at least about 30 minutes, at least about 1 hour, at least about 1.5 hours, at least about 2 hours, at least about 2.5 hours, at least about 3 hours, at least about 3.5 hours, at least about 4 hours, at least about 4.5 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, or at least about 10 hours or more.

[0095]

[0101] In some embodiments, the delayed release component comprises two or more delayed release components, in some embodiments, a first delayed release component is suitably formulated to release a first portion of zolmitriptan in the acidic environment of the stomach, and a second delayed release component is suitably formulated to release a second portion of zolmitriptan in the less acidic environment of the lower intestine. The ratio of zolmitriptan released in the stomach compared to the release in the lower intestine may range from about 99:1 to about 1:99, e.g., about 95:1, about 90:10, about 85:1, about 80:1, about 75:1, about 70:1, about 65:1, about 60:1, about 55:1, about 50:1, about 45:1, about 40:1, about 35:1, about 30:1, about 25:1, about 20:1, about 15:1, about 10:1, and about 5:1, including all values ​​and subranges therebetween. In some embodiments, the ratio of zolmitriptan released in the stomach compared to the release in the lower intestine ranges from about 70:30 to about 40:60, e.g., about 60:40 to about 50:50. The relative amount of zolmitriptan released in the stomach and lower intestine can be selected to reduce maximum plasma zolmitriptan levels relative to the reference listed formulation and achieve an AUC that is 80-125% of that of the reference listed formulation. In some embodiments, delayed release is achieved by suitably coating the drug-containing component with one or more suitable delayed release polymers (also referred to as controlled release or rate-limiting polymers) or by embedding the drug in a matrix that includes one or more suitable delayed release polymers. Suitable delayed release polymers include pharma- ceutically acceptable water-insoluble polymers (also referred to as hydrophobic polymers), pharma-ceutically acceptable water-soluble polymers (also referred to as hydrophilic polymers), pharma-ceutically acceptable gastric-soluble polymers, pharma-ceutically acceptable enteric polymers, and combinations thereof.

[0096]

[0102] In some embodiments, non-limiting examples of pharma- ceutically acceptable water-soluble polymers include N-vinylpyrrolidone, homopolymers and copolymers of N-vinyllactams, including homopolymers and copolymers of polyvinylpyrrolidone (PVP), copolymers of N-vinylpyrrolidone with vinyl acetate or vinyl propionate, cellulose esters and cellulose ethers, particularly methylcellulose and ethylcellulose, hydroxyalkylcelluloses, particularly hydroxypropylcellulose, hydroxyalkylalkylcelluloses, and hydroxypropylmethylcellulose, cellulose phthalate, cellulose succinate, cellulose butyrate, or cellulose trimellitate, particularly cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose succinate, and hydroxypropylmethylcellulose acetate succinate. cellulose; polymeric polyalkylene oxides and copolymers of ethylene oxide and propylene oxide, such as polyethylene oxide and polypropylene oxide, polyacrylates and polymethacrylates, such as methacrylic acid / ethyl acrylate copolymer, methacrylic acid / methyl methacrylate copolymer, butyl methacrylate / 2-dimethylaminoethyl methacrylate copolymer, poly(hydroxyalkyl acrylates), poly(hydroxyalkyl methacrylates), polyacrylamides, vinyl acetate polymers, such as copolymers of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate (also referred to as partially saponified "polyvinyl alcohol"), polyvinyl alcohol, polyethylene glycol oligosaccharides and polysaccharides, such as carrageenan, galactomannan, and xanthan gum, or mixtures of one or more thereof.

[0097]

[0103] Non-limiting examples of gastrosoluble polymers include maltrin, aminoalkyl methacrylate copolymers available under the trade name EUDRAGIT® (type E100 or EPO), polyvinyl acetal diethylaminoacetate, e.g., AEA® available from Sankyo Co., Ltd., Tokyo, Japan, and the like.

[0098]

[0104] Non-limiting examples of enteric polymers include cellulose acetate phthalate (CAP), cellulose acetate succinate, methylcellulose phthalate, hydroxymethylethylcellulose phthalate, hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), polyvinyl alcohol phthalate, polyvinylbutyrate phthalate, polyvinyl acetal phthalate (PVAP), vinyl acetate / maleic anhydride copolymer, vinyl butyl ether / maleic anhydride copolymer, styrene / maleic acid monoester copolymer, acetamide copolymer, styrene / maleic acid monoester ... Examples include methyl acrylate / methacrylic acid copolymer, styrene / acrylic acid copolymer, methyl acrylate / methacrylic acid / octyl acrylate copolymer, methacrylic acid / methyl methacrylate copolymer, cellulose acetate hexahydrophthalate, hydroxypropyl methylcellulose hexahydrophthalate, hydroxypropyl methylcellulose phthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate trimellitate, cellulose acetate butyrate, cellulose acetate propionate, methacrylic acid / methacrylic acid polymer (acid value 300-330 and also known as EUDRAGIT L), methacrylic acid-methyl methacrylate copolymer, ethyl methacrylate-methyl methacrylate-chlorotrimethylammonium ethyl methacrylate copolymer, and the like, and combinations comprising one or more of the foregoing enteric polymers. Other examples include natural resins such as shellac, sandarac, copal collophorium, and the like, and combinations comprising one or more of the foregoing polymers. Yet other examples of enteric polymers include synthetic resins bearing carboxyl groups. The term "enteric polymer" as used herein is defined to mean a polymeric material that is substantially insoluble and / or substantially stable under acidic conditions of a pH of less than about 5, and is substantially soluble or degradable under conditions exhibiting a pH of about 5 or higher, when used in enteric coating formulations.

[0099]

[0105] Non-limiting examples of hydrophilic polymers include hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose, methylcellulose, polyethylene oxide, sodium carboxymethylcellulose, and the like, or combinations thereof.

[0100]

[0106] In some embodiments, the delayed release coating comprises about 40 wt% to about 95 wt% (e.g., about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90% (including all values ​​and subranges therebetween)) of any of the pharma- ceutically acceptable polymers listed above, based on the total weight of the polymer coating, and about 5 wt% to about 60 wt% of a plasticizer (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55% (including all values ​​and subranges therebetween). The relative proportions of the components, particularly the ratio of enteric polymer to plasticizer, can be varied according to methods known to those skilled in the art of pharmaceutical formulation.

[0101] sustained release component

[0107] In some embodiments, the pharmaceutical compositions described herein include one or more immediate release components and one or more sustained release components, where the sustained release components release zolmitriptan over an extended period of time, which is longer than the immediate release components as described herein, such that the total amount of active agent in the sustained release components is released over a period of between about 1 and 24 hours, such as about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours, including all ranges therebetween. When combined into a pharmaceutical composition, the combination of immediate release and sustained release components in the pharmaceutical composition releases less than about 75% of the total zolmitriptan dose within about 30 minutes, e.g., as measured using the dissolution test described herein. In some embodiments, such pharmaceutical compositions release about 74%, about 73%, about 72%, about 71%, about 70%, about 69%, about 68%, about 67%, about 66%, about 65%, about 64%, about 63%, about 62%, about 61%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, and about 5% or less of the total zolmitriptan dose within about 30 minutes, e.g., as measured using the dissolution test described herein. Advantageously, such pharmaceutical compositions provide equivalent therapeutic efficacy while providing reduced maximum exposure levels compared to the reference listed formulation (i.e., ZOMIG) as described herein.

[0102]

[0108] In some embodiments, the sustained release component comprises one or more sustained release components (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more), each of which may provide a different release profile. In some embodiments, the sustained release portion is a gastroretentive layer.

[0103]

[0109] In some embodiments, the sustained release component is prepared by embedding the drug in a matrix comprising one or more suitable sustained release polymers (such as a water-swellable polymer for gastroretentive formulations).

[0104]

[0110] In some embodiments, the sustained release component is a gastroretentive composition. Such compositions have a long residence time in the stomach, thereby resulting in delayed gastric emptying of zolmitriptan. Examples include floating drug delivery systems, also known as hydrodynamically balanced systems, swelling and expanding systems, shape-changing systems, high-density systems, and other gastric emptying delayed systems (U.S. Patent No. 9,000,046, incorporated herein by reference in its entirety). Gastric retentive compositions may also be formulated with bioadhesives (e.g., mucoadhesives), particle diameters that substantially prevent drug-containing particles from passing through the stomach to the lower intestine, and floating drug delivery systems. In some embodiments, the bioadhesive is selected from the group consisting of polycarbophil, lectins, carbopol, chitosan, carboxymethylcellulose (CMC), pectin, gliadin, polyethylene glycol, tragacanth, sodium alginate, cholestyramine, polyacrylic acid, and sucralfate (see Madal, UK, et al. "Gastro-retentive drug delivery systems and their in vivo success: A recent update" Asian J. of Pharm. Sci. 2016, 11, 575-584; and Sharma, AR; et al. "Gastroretentive Drug Delivery System: An Approach to Enhance Gastric Retention for Prolonged Drug Release" International J. of Pharm. Sci. and Res. 2014, 5, 1095-1106, each of which is incorporated by reference in its entirety).

[0105]

[0111] In some embodiments, the sustained release component is a gastroretentive composition having zolmitriptan in a water-swellable polymer matrix. Suitable water-swellable polymers for use herein are those that swell indefinitely in size when in contact with water. Such polymers may also slowly erode over time. Examples of such polymers include polyalkylene oxides, such as polyethylene glycols, particularly high molecular weight polyethylene glycols; cellulose polymers and derivatives thereof, including but not limited to hydroxyalkylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, microcrystalline cellulose; polysaccharides and derivatives thereof; chitosan; poly(vinyl alcohol); xanthan gum; maleic anhydride copolymers; poly(vinylpyrrolidone); starch and starch-based polymers; maltodextrins; poly(2-ethyl-2-oxazoline); poly(ethyleneimine); polyurethanes; hydrogels; crosslinked polyacrylic acid; and combinations or blends of any of the foregoing.

[0106]

[0112] Further examples are copolymers, including block copolymers and graft polymers. Specific examples of copolymers are PLURONIC® and TECTONIC®, which are polyethylene oxide-polypropylene oxide block copolymers available from BASF Corporation, Chemicals Div., Wyandotte, Mich., USA. A further example is hydrolyzed starch polyacrylonitrile graft copolymer, commonly known as "Super Slurper", available from Illinois Corn Growers Association, Bloomington, Ill., USA.

[0107]

[0113] In some embodiments, the swellable, erodible hydrophilic polymers suitable for forming the gastroretentive portion of the dosage forms described herein are poly(ethylene oxide), hydroxypropyl methylcellulose, and combinations of poly(ethylene oxide) and hydroxypropyl methylcellulose. Poly(ethylene oxide) is used herein to refer to linear polymers of unsubstituted ethylene oxide. The molecular weight of the poly(ethylene oxide) polymers can range from about 9×105 Daltons to about 8×106 Daltons. Exemplary molecular weight poly(ethylene oxide) polymers include about 9×105 Daltons (e.g., SENTRY™ POLYOX™ WSR 1105). In some embodiments, wetting, swelling and erosion rates can be modified by changing the molecular weight Polyox™.

[0108]

[0114] In some embodiments, the water-swellable polymer is selected from the group consisting of polyalkylene oxides, cellulose polymers and derivatives thereof, polysaccharides and derivatives thereof, chitosan, poly(vinyl alcohol), xanthan gum, maleic anhydride copolymers, poly(vinylpyrrolidone), starch and starch-based polymers; maltodextrin, poly(2-ethyl-2-oxazoline), poly(ethyleneimine), polyurethanes, hydrogels, crosslinked polyacrylic acid, and combinations thereof.

[0109]

[0115] In some embodiments, the water-swellable polymer is selected from the group consisting of high molecular weight polyethylene oxide, hydroxyalkyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, and microcrystalline cellulose.

[0110]

[0116] In some embodiments, the water-swellable polymer is polyethylene oxide.

[0111]

[0117] In some embodiments, the composition comprises about 15% to about 75% (by weight) of a water-swellable polymer, including about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70% to about 75% (including all values ​​and subranges therebetween). In some embodiments, the composition comprises about 35-55% of a water-swellable polymer by weight. In some embodiments, the water-swellable polymer is polyethylene oxide. In some embodiments, the composition comprises about 35-55% of a polyethylene oxide by weight. In some embodiments, sustained release is achieved by appropriately coating the drug-containing component with one or more suitable sustained release polymers (also referred to as rate-limiting polymers). Suitable sustained release polymers include, for example, pharma-ceutically acceptable water-insoluble polymers (also referred to as hydrophobic polymers) and pharma-ceutically acceptable water-swellable polymers.

[0112]

[0118] In some embodiments, the sustained release portion comprises a drug-containing particle coated with a sustained release coating. In some embodiments, the multiparticulate formulation.

[0113]

[0119] Non-limiting examples of pharma- ceutically acceptable water-insoluble polymers include acrylic polymers, methacrylic acid polymers, acrylic copolymers, such as methacrylic acid-ethyl acrylate copolymers available under the trade name EUDRAGIT® (Types L, RL, RS, and NE30D), and their respective esters, zein, waxes, shellac, and hydrogenated vegetable oils, cellulose derivatives, such as ethyl cellulose, cellulose acetate, cellulose acetate butyrate, and the like.

[0114]

[0120] In some embodiments, the sustained release coating comprises about 40 wt% to about 95 wt% (e.g., about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90% (including all values ​​and subranges therebetween)) of any of the pharma- ceutically acceptable polymers listed above, based on the total weight of the polymer coating, and about 5 wt% to about 60 wt% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55% (including all values ​​and subranges therebetween)) of a plasticizer.

[0115]

[0121] Osmotic Release System

[0122] In some embodiments, the delayed release is an osmotic system. The osmotic system is a core with a semipermeable outer membrane and one or more openings. The semipermeable membrane is impermeable to zolmitriptan but allows water to enter the osmotic system from the outside by osmosis. As the core passes through the body, water is absorbed through the semipermeable membrane by osmosis, and the resulting osmotic pressure is used to force the active drug through the core's opening or openings. The total amount and rate of zolmitriptan release can be controlled by appropriately selecting the thickness and porosity of the semipermeable membrane, the composition of the core, and the number and size of the opening or openings. Information regarding the formulation aspects, dosage forms, and preparation processes are described, for example, in the following documents: Santus, G., Baker, RW, “Osmotic drug delivery: a review of the patent literature”, Journal of Controlled Release 35 (1995), 1-21; Verma, RK, Mishra, B., Garg, S., “Osmotically controlled oral drug delivery”, Drug Development and Industrial Pharmacy 26 (2000), 695-708; Verma, RK, Krishna, DM, Garg, S., “Formulation aspects in the development of osmotically controlled oral drug delivery systems”, Journal of Controlled Release 79 (2002), 7-27; Verma, RK, Arora, S., Garg, S., “Osmotic Pumps in drug delivery”, Critical Reviews in Therapeutic Drug Carrier Systems 21 (2004), 477-520 Malaterre, V., Ogorka, J., Loggia, N., Gurny, R., “Oral osmotically driven systems: 30 years of development and clinical use”, European Journal of Pharmaceutics and Biopharmaceutics 73 (2009), 311-323; and U.S. Patent No. 4,327,725, U.S. Patent No. 4,765,989; each of which is incorporated herein by reference in its entirety for all purposes.

[0116]

[0123] Both single chamber systems (basic osmotic pump) and two chamber systems (push-pull systems) are suitable for the delayed release components described herein.

[0117]

[0124] In some embodiments, the shell of the osmotic delivery system comprises either a semipermeable membrane, single chamber system or a two chamber system. Non-limiting examples of shell materials include cellulose acetate or a mixture of cellulose acetate and polyethylene glycol.

[0118]

[0125] In some embodiments, the shell may be coated with a coating, such as a photoprotective and / or color coating. Suitable materials for this purpose are, for example, polymers such as polyvinyl alcohol, hydroxypropyl cellulose and / or hydroxypropyl methylcellulose, where appropriate in combination with suitable plasticizers, such as polyethylene glycol or polypropylene glycol, and pigments, such as titanium dioxide or iron oxide.

[0119]

[0126] In some embodiments, the core in the osmotic single chamber system comprises (i) 2-30 wt. % zolmitriptan; (ii) 20-50 wt. % xanthan, and (iii) 10-30 wt. % vinylpyrrolidone-vinyl acetate copolymer, where the difference from 100% is formed, where appropriate, by one or more additional components selected from the group of further hydrophilic swellable polymers, osmotically active additives and pharma- ceutically acceptable excipients.

[0120]

[0127] In some embodiments, the core of the osmotic single chamber system comprises a hydrophilic water-swellable polymer, such as xanthan. Xanthan is an anionic heteropolysaccharide, available, for example, under the trade name Rhodigel® (manufacturer Rhodia). In some embodiments, the hydrophilic water-swellable polymer is present in an amount of about 20 to about 50% (e.g., about 25%, about 30%, about 35%, about 40%, about 45% (including all values ​​and subranges therebetween)) based on the total weight of the core components.

[0121]

[0128] Another component of the core may be a vinylpyrrolidone-vinyl acetate copolymer. This copolymer is known in the art and can be made in any desired monomer mix ratio. A non-limiting example of such a copolymer is Kollidon® VA64 (manufacturer BASF). It generally has a weight average molecular weight (Mw) of about 45,000 to about 70,000, as determined by light scattering measurements. In some embodiments, the amount of vinylpyrrolidone-vinyl acetate copolymer in the core is about 10% to about 30% (e.g., about 15%, about 20%, about 25% (including all values ​​and subranges therebetween)) based on the total weight of the core components.

[0122]

[0129] In some embodiments, a hydrophilic swellable polymer is present in the core. Non-limiting examples of hydrophilic swellable polymers include, for example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, sodium carboxymethyl starch, polyacrylic acid and its salts.

[0123]

[0130] In some embodiments, the osmotic release system comprises a water-swellable substance.Suitable water-swellable substances include compounds that can expand when exposed to aqueous solutions such as gastrointestinal fluid.One or more water-swellable substances can be present together in the core material.Alternatively, one or more water-swellable substances can be included in a swelling layer that is applied on the core material.

[0124]

[0131] Suitable water-swellable substances include, for example, low-substituted hydroxypropylcellulose, such as L-HPC; cross-linked polyvinylpyrrolidone (PVP-XL), such as Kollidon® CL and Poly-plasdone® XL; cross-linked sodium carboxymethylcellulose, such as Ac-di-sol, Primellose®; sodium starch glycolate, such as Primojel®; sodium carboxymethylcellulose, such as Nym-cel ZSBlO®; sodium carboxymethyl starch, such as Explotab®; ion exchange resins, such as Dowex® or Amber-lite®; microcrystalline cellulose, such as Avicel®; starch and pregelatinized starch, such as Starch 1500®, Sepistab ST200®; formalin-casein, such as Plas-Vita®, and mixtures thereof.

[0125]

[0132] In some embodiments, the osmotic pump composition includes one or more osmotically active additives in the core, such as water-soluble pharmaceutically acceptable substances, such as water-soluble excipients described in the Pharmacopoeia or in "Remington Pharmaceutical Science," (1985) 17th ed. Edited by Alfonso R. Gennaro. Mack Publishing Co., Easton, PA., which is incorporated by reference in its entirety for all purposes. In some embodiments, the osmotically active additives are selected from water-soluble salts of inorganic or organic acids or non-ionic organic substances with high water solubility, such as carbohydrates, particularly sugars, sugar alcohols, or amino acids. In some embodiments, the osmotically active additives are selected from inorganic salts, such as chlorides, sulfates, carbonates, and bicarbonates of alkali or alkaline earth metals, such as lithium, sodium, potassium, magnesium, calcium, and the like, as well as phosphates, hydrogen phosphates, or dihydrogen phosphates, acetates, succinates, benzoates, citrates, or ascorbates thereof. In some embodiments, the osmotically active additive is selected from pentoses such as arabinose, ribose or xylose, hexoses such as glucose, fructose, galactose or mannose, disaccharides such as sucrose, maltose or lactose, or trisaccharides such as raffinose. Water-soluble amino acids include glycine, leucine, alanine or methionine. According to the invention, sodium chloride is particularly preferably used. In some embodiments, the osmotically active additive is present in an amount of 10-30% based on the total weight of the core component.

[0126]

[0133] In some embodiments, the core of the osmotic pump composition core comprises a buffer substance (such as sodium bicarbonate), a binder (such as hydroxypropyl cellulose), hydroxypropyl methylcellulose and / or polyvinylpyrrolidone, a lubricant (such as magnesium stearate), a wetting agent (such as sodium lauryl sulfate) and / or a flow regulator (such as colloidal silicon dioxide).

[0127]

[0134] The disclosure further relates to a method for producing an osmotic single-chamber system, in which the components of the core are mixed together and, where appropriate, subjected to wet or dry granulation and subsequent tabletting, and the core thus produced is coated with a shell and then, where appropriate, coated with a photoprotective and / or colour coating and provided with one or more orifices.

[0128]

[0135] In an osmotic two-chamber system, the core consists of two layers, one active ingredient layer and one osmotic layer. This type of osmotic two-chamber system is described, for example, in U.S. Pat. No. 4,612,008, the disclosure of which is incorporated herein by reference.

[0129]

[0136] The osmotically active additives used in the core of the osmotic two-chamber system may be the same as those for the single-chamber system described above.

[0130]

[0137] The pharma- ceutically acceptable excipients used in the core of the osmotic two-chamber system may be the same as those in the single-chamber system described above. In some embodiments, binders (such as hydroxypropylcellulose), hydroxypropylmethylcellulose and / or polyvinylpyrrolidone, lubricants (such as magnesium stearate), wetting agents (such as sodium lauryl sulfate) and / or flow regulators (such as colloidal silicon dioxide), and coloring pigments (such as iron oxide) are used in one of the two layers to distinguish the active ingredient layer from the osmotic layer.

[0131]

[0138] matrix

[0139] In some embodiments, the delayed release component is a matrix. As used herein, the term "matrix" refers to a composition in which a drug is embedded or dispersed in a water-soluble, water-insoluble, or hydrophilic polymer, or a lipophilic material, to achieve delayed release of the drug. The drug release mechanism generally involves drug diffusion through a viscous gel layer or tortuous channels; and / or drug dissolution due to the gradual erosion or degradation of one or more polymers. In some embodiments, the matrix comprises a swellable / erodible polymer, such as a hydrophilic polymer that forms a high viscosity gel in contact with water. In some embodiments, the matrix comprises a water-insoluble polymer or a lipophilic polymer.

[0132]

[0140] In some embodiments, the matrix is ​​prepared using coated tablets or granules with one or more hydrophilic polymers (e.g., hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene oxide), one or more lipophilic materials (e.g., carnauba wax, hydrogenated castor oil, hydrogenated rapeseed oil, polyglycerol fatty acid esters), and / or one or more delayed release polymers (e.g., cellulose polymers such as ethyl cellulose; acrylic acid copolymers such as aminoalkyl methacrylate copolymer RS ​​[Eudragit RS (trade name, Degussa Co.)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE (trade name, Degussa Co.)]).

[0133]

[0141] In some embodiments, the delayed release component is a matrix comprising one or more hydrophilic polymers. As used herein, hydrophilic polymer refers to a polymer that becomes a hydrogel by absorbing water and allows the diffusion of zolmitriptan contained in the matrix to its exterior, thereby controlling the release of zolmitriptan.

[0134]

[0142] In some embodiments, the viscosity of the hydrophilic polymer is, for example, from about 1 mPa·s to about 200,000 mPa·s, or from about 4 mPa·s to about 120,000 mPa·s, or from about 4 mPa·s to about 5,000 mPa·s, when measured using a Brookfield viscometer in a 2 wt % aqueous solution at 20° C. The release duration of zolmitriptan from the matrix can be modified by appropriately selecting the viscosity of the hydrophilic polymer.

[0135]

[0143] Non-limiting examples of suitable hydrophilic polymers include hydroxypropyl cellulose (HPC), such as HPC-SSL (trade name, manufactured by Nippon Soda Co., Ltd., viscosity at 20° C. in a 2% by weight aqueous solution: 2.0 to 2.9 mPa·s), HPC-SL (trade name, manufactured by Nippon Soda Co., Ltd., viscosity at 20° C. in a 2% by weight aqueous solution: 3.0 to 5.9 mPa·s), HPC-L (trade name, manufactured by Nippon Soda Co., Ltd., viscosity at 20° C. in a 2% by weight aqueous solution: 6.0 to 10.0 mPa·s), HPC-M (trade name, manufactured by Nippon Soda Co., Ltd., viscosity at 20° C. in a 2% by weight aqueous solution: 150 to 400 mPa·s), HPC-H (trade name, manufactured by Nippon Soda Co., Ltd., viscosity at 20° C. in a 2% by weight aqueous solution: 1000 to 4000 mPa·s); hydroxypropyl methylcellulose, such as Metolose SB-4 (trade name, manufacturer: Shin-Etsu Chemical Co., Ltd.; viscosity at 20°C in a 2% by weight aqueous solution: approximately 4 mPa·s), TC-5RW (trade name, manufacturer: Shin-Etsu Chemical Co., Ltd.; viscosity at 20°C in a 2% by weight aqueous solution: approximately 6 mPa·s), TC-5S (trade name, manufacturer: Shin-Etsu Chemical Co., Ltd.; viscosity at 20°C in a 2% by weight aqueous solution: approximately 15 mPa·s), Metolose 60SH-50 (trade name, manufacturer: Shin-Etsu Chemical Co., Ltd.; viscosity at 20°C in a 2% by weight aqueous solution: approximately 50 mPa·s), Metolose 65SH-50 (trade name, manufacturer: Shin-Etsu Chemical Co., Ltd.; viscosity at 20°C in a 2% by weight aqueous solution: approximately 50 mPa·s), Metolose 90SH-100 (trade name, manufacturer: Shin-Etsu Chemical Co., Ltd.; viscosity at 20°C in a 2% by weight aqueous solution: approximately 100 mPa·s), Metolose 90SH-100SR (trade name, manufacturer: Shin-Etsu Chemical Co., Ltd., viscosity at 20°C in a 2% by weight aqueous solution: approximately 100 mPa·s), Metolose 65SH-400 (trade name, manufacturer: Shin-Etsu Chemical Co., Ltd., viscosity at 20°C in a 2% by weight aqueous solution: approximately 400 mPa·s), Metolose 90SH-400 (trade name, manufacturer: Shin-Etsu Chemical Co., Ltd., viscosity at 20°C in a 2% by weight aqueous solution: approximately 400 mPa·s), Metolose 65SH-1500 (trade name, manufacturer: Shin-Etsu Chemical Co., Ltd., viscosity at 20°C in a 2% by weight aqueous solution: approximately 1500 mPa·s), Metolose60SH-4000 (trade name, manufacturer: Shin-Etsu Chemical Co., Ltd.; viscosity at 20°C in a 2% by weight aqueous solution: approximately 4000 mPa·s), Metolose 65SH-4000 (trade name, manufacturer: Shin-Etsu Chemical Co., Ltd.; viscosity at 20°C in a 2% by weight aqueous solution: approximately 4000 mPa·s), Metolose 90SH-4000 (trade name, manufacturer: Shin-Etsu Chemical Co., Ltd.; viscosity at 20°C in a 2% by weight aqueous solution: approximately 4000 mPa·s), Metolose 90SH-4000SR (trade name, manufacturer: Shin-Etsu Chemical Co., Ltd.; viscosity at 20°C in a 2% by weight aqueous solution: approximately 4000 mPa·s), Metolose 90SH-30000 (trade name, manufacturer: Shin-Etsu Chemical Co., Ltd.; viscosity at 20°C in a 2% by weight aqueous solution: approximately 30000 mPa·s), Metolose 90SH-100000 (trade name, manufacturer Shin-Etsu Chemical Co., Ltd., viscosity at 20° C. in a 2% by weight aqueous solution: about 100,000 mPa·s), Metolose 90SH-100000SR (trade name, manufacturer Shin-Etsu Chemical Co., Ltd., viscosity at 20° C. in a 2% by weight aqueous solution: about 100,000 mPa·s); methylcellulose, for example, Metolose SM15 (trade name, manufacturer Shin-Etsu Chemical Co., Ltd., viscosity: about 15 mPa·s, in a 2% by weight aqueous solution at 20° C.), Metolose SM25 (trade name, manufacturer Shin-Etsu Chemical Co., Ltd., viscosity at 20° C. in a 2% by weight aqueous solution: about 25 mPa·s), Metolose SM100 (trade name, manufacturer Shin-Etsu Chemical Co., Ltd., viscosity at 20° C. in a 2% by weight aqueous solution: about 100 mPa·s), Metolose SM400 (trade name, manufacturer: Shin-Etsu Chemical Co., Ltd.; viscosity at 20°C in a 2% by weight aqueous solution: about 400 mPa·s), Metolose SM1500 (trade name, manufacturer: Shin-Etsu Chemical Co., Ltd.; viscosity at 20°C in a 2% by weight aqueous solution: about 1500 mPa·s), Metolose SM4000 (trade name, manufacturer: Shin-Etsu Chemical Co., Ltd.; viscosity at 20°C in a 2% by weight aqueous solution: about 4000 mPa·s), Metolose SM8000 (trade name, manufacturer: Shin-Etsu Chemical Co., Ltd.; viscosity at 20°C in a 2% by weight aqueous solution: about 8000 mPa·s); polyethylene oxide, for example, WSR N-12K (trade name, manufacturer: Union Carbide Co.; viscosity at 20°C in a 2% by weight aqueous solution: 400-800 mPa·s), WSR N-60K (trade name, manufacturer: Union% by weight at 25° C.: 2000-4000 mPa·s), WSR 301 (trade name, manufacturer Union Carbide Co., viscosity at 25° C. in a 1% by weight solution: 1500-4500 mPa·s), WSR Coagulant (trade name, manufacturer Union Carbide Co., viscosity at 25° C. in a 1% by weight solution: 4500-7500 mPa·s), WSR 303 (trade name, manufacturer Union Carbide Co., viscosity at 25° C. in a 1% by weight solution: 7500-10000 mPa·s), WSR 308 (trade name, manufacturer Union Carbide Co., viscosity at 25° C. in a 1% by weight solution: 10000-15000 mPa·s); sodium carboxymethylcellulose, e.g. Sunrose Examples of suitable polyolefin copolymers include F-150MC (trade name, manufacturer: Nippon Paper Industries Co., Ltd.; viscosity at 25°C in a 1% by weight aqueous solution: 1200 to 1800 mPa·s), Sunrose F-300MC (trade name, manufacturer: Nippon Paper Industries Co., Ltd.; viscosity at 25°C in a 1% by weight aqueous solution: 2500 to 3000 mPa·s), Sunrose F-1000MC (trade name, manufacturer: Nippon Paper Industries Co., Ltd.; viscosity at 25°C in a 1% by weight aqueous solution: 8000 to 12000 mPa·s), and combinations thereof.

[0136]

[0144] In some embodiments, the hydrophilic matrix further comprises a pH-dependent polymer. The release duration of zolmitriptan from the matrix can be modified by appropriately selecting the amount of pH-dependent polymer.

[0137]

[0145] The term "pH-dependent" refers to a polymer that releases zolmitriptan at a certain pH. Non-limiting examples of suitable pH-dependent polymers include hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, carboxymethylethylcellulose, methyl methacrylate-methacrylic acid copolymer, methacrylic acid-ethyl acrylate copolymer, ethyl acrylate-methyl methacrylate-trimethylammonium ethyl chloride copolymer, methyl methacrylate-ethyl acrylate copolymer, methacrylic acid-methyl acrylate-methyl methacrylate copolymer, hydroxypropylcellulose acetate succinate, polyvinyl acetate phthalate, and the like, and combinations thereof.

[0138]

[0146] Suitable pharma- ceutically acceptable carriers for matrix formulations include various organic or inorganic carrier substances, such as excipients, lubricants, binders, disintegrants, etc. Furthermore, pharma- ceutically acceptable additives such as antioxidants, colorants, sweeteners, etc. may be used.

[0139]

[0147] Non-limiting examples of suitable excipients include lactose, D-mannitol, D-sorbitol, starch, dextrin of starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethylcellulose, gum arabic, dextrin, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminometasilicate, and the like.

[0140]

[0148] Non-limiting examples of suitable lubricants include magnesium stearate, calcium stearate, talc, colloidal silica, and the like.

[0141]

[0149] Non-limiting examples of suitable binders include starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, refined sugar, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and the like.

[0142]

[0150] Non-limiting examples of suitable disintegrants include lactose, refined sugar, starch, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl starch, light anhydrous silicic acid, low-substituted hydroxypropylcellulose, and the like.

[0143]

[0151] Non-limiting examples of suitable disinfectants include paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like.

[0144]

[0152] Non-limiting examples of suitable antioxidants include bisulfate, ascorbate, and the like.

[0145]

[0153] Non-limiting examples of suitable coloring agents include water-soluble edible coal-tar dyes (e.g., food dyes such as Food Red No. 2 and No. 3, Food Yellow No. 4 and No. 5, and Food Blue No. 1 and No. 2), water-insoluble lake dyes (e.g., aluminum salts of the water-soluble edible coal-tar dyes mentioned above), and natural dyes (e.g., β-carotene, chlorophyll, red iron oxide, and yellow ferric oxide).

[0146]

[0154] Non-limiting examples of suitable sweeteners include sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia, and the like.

[0147]

[0155] Delayed release tablets

[0156] In some embodiments, the delayed release component is a delayed release tablet comprising a core and one or more coatings. In some embodiments, the core comprises zolmitriptan and any of the excipients described herein, such as a lubricant, and a binder and / or filler, and a flow agent and other excipients. The one or more coatings may be, for example, a semipermeable coating that provides delayed or sustained release of the drug. In some embodiments, the coating comprises a water-insoluble polymer, a plasticizer, and a water-soluble polymer (such as those described herein). In some embodiments, the water-insoluble polymer is selected from cellulose ethers (such as ethyl cellulose), cellulose esters (such as cellulose acetate), polyvinyl alcohol, and the like. Optionally, other excipients may also be present in the coating, such as acrylic acid derivatives (such as EUDRAGIT), dyes, and the like. When multiple coatings are used, they may be the same or different.

[0148]

[0157] The relative proportions of the components, particularly the ratio of water-insoluble polymer to water-soluble polymer, can vary depending on the release profile to be achieved (wherein a greater delay in release is achieved by using a greater amount of water-insoluble polymer). In some embodiments, the ratio of water-insoluble polymer to water-soluble polymer ranges from about 99:1 to about 1:1, e.g., about 95:1, about 90:10, about 85:1, about 80:1, about 75:1, about 70:1, about 65:1, about 60:1, about 55:1, about 50:1, about 45:1, about 40:1, about 35:1, about 30:1, about 25:1, about 20:1, about 15:1, about 10:1, and about 5:1, including all values ​​and subranges therebetween.

[0149]

[0158] Mini Tablets

[0159] In some embodiments, the delayed release component is formulated to remain in the stomach for an appropriate amount of time to release zolmitriptan in the acidic stomach environment and have a dosage unit size sufficient to avoid migration to the lower intestine.

[0150]

[0160] In some embodiments, the pharmaceutical composition comprises a plurality of mini-tablets (also known as "mini-tabs"), the mini-tablets being about 5 mm or less in diameter. In other embodiments, the mini-tablets comprise zolmitriptan in a matrix of one or more polymers, or optionally coated with a delayed release polymer. In some embodiments, the matrix polymer is one or a combination of hydrophilic polymers described herein. In some embodiments, the pharmaceutical composition comprises a plurality of enteric coated mini-tablets.

[0151]

[0161] In some embodiments, the mini-tablets further comprise a filler, a lubricant, and / or a flow agent. For example, in some embodiments, the mini-tablets comprise, based on the total weight of the composition, 5-50% zolmitriptan, 20-50% matrix polymer, 20-50% filler, 0.1-5% lubricant, and 0.1-5% flow agent. In some embodiments, the matrix polymer is hypromellose (also known as hydroxypropyl methylcellulose or "HPMC"), the filler is microcrystalline cellulose, the lubricant is magnesium stearate, and the flow agent is colloidal silicon dioxide.

[0152]

[0162] In some embodiments, the pharmaceutical compositions disclosed herein include a plurality of mini-tablets, for example, in the range of 2 to 30 mini-tablets, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, and 29 mini-tablets, including all values ​​and subranges therebetween. In some embodiments, the mini-tablets are in a capsule or sachet for oral administration. In some embodiments, the capsule is a hard gelatin or hydroxypropylmethylcellulose (HPMC) capsule. In some embodiments, the capsule includes an overfill of a powdered material, such as microcrystalline cellulose. In some embodiments, the capsule contains 2 to 30 mini-tablets, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, and 29 mini-tablets (including all values ​​and sub-ranges therebetween).

[0153]

[0163] In some embodiments, the mini-tablets are about 5 mm or less in diameter, e.g., about 4.5 mm or less, about 4 mm or less, about 3.5 mm or less, about 3.0 mm or less, about 2.5 mm or less, or about 2 mm. In some embodiments, the mini-tablets are in the range of about 2 mm to about 5 mm in diameter, including about 2.5 mm, about 2.6 mm, about 2.7 mm, about 2.8 mm, about 2.9 mm, about 3.0 mm, about 3.1 mm, about 3.2 mm, about 3.3 mm, about 3.4 mm, about 3.5 mm, about 3.6 mm, about 3.7 mm, about 3.8 mm, about 3.9 mm, about 4.0 mm, about 4.1 mm, about 4.2 mm, about 4.3 mm, about 4.4 mm, about 4.5 mm, about 4.6 mm, about 4.7 mm, about 4.8 mm, and about 4.9 mm (including all values ​​and subranges therebetween). Minitablets can be of any shape convenient to one of skill in the art, for example, spherical or cylindrical, hi one embodiment, the minitablets are round and convex (known in the art as "round standard convex").

[0154]

[0164] In some embodiments, the mini-tablets are formulated to modify the release of zolmitriptan, for example by coating the mini-tablets with a polymer disclosed herein. In other embodiments, zolmitriptan is embedded or dispersed in a matrix polymer that is formulated as a mini-tablet. In some embodiments, the mini-tablets further comprise a filler, a lubricant, or a flow agent (one or more such components may be utilized), or a combination thereof.

[0155]

[0165] Suitable matrix polymers include hydrophilic water-soluble polymers, such as any of the hydrophilic polymers listed herein, including hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene oxide, sodium carboxymethylcellulose, and in some embodiments, the hydrophilic water-soluble polymer is a high molecular weight polymer (i.e., 100,000-800,000 Daltons), such as hydroxypropylmethylcellulose polymer (also known as HPMC or hypromellose) sold under the trademark Methocel™, e.g., Methocel™ K100M, Methocel™ K15M, or Methocel™ K4M, preferably Methocel™ K15M. In some embodiments, the matrix-containing mini-tablets comprise about 20 to about 60 wt. % of the matrix polymer, e.g., about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, or about 55% (including all values ​​and subranges therebetween).

[0156]

[0166] Suitable fillers for the mini-tablets include any of the fillers listed herein, including microcrystalline cellulose, such as Avicel™ PH 101. The amount of filler in the mini-tablets can range from about 20 to about 50% filler, for example, about 25%, about 30%, about 35%, about 40%, and about 45% (including all values ​​and subranges therebetween).

[0157]

[0167] Suitable glidants for the mini-tablets include any of the glidants listed herein, such as colloidal silicon dioxide and talc. In some embodiments, the mini-tablets comprise about 0.1 to about 5 wt% of the glidant, for example, about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, about 2.5, about 3.0, about 3.5, about 4.0, or about 4.5 wt%, based on the total weight of the composition, including all values ​​and subranges therebetween.

[0158]

[0168] Suitable lubricants for the mini-tablets include any of the lubricants listed herein, such as stearic acid and stearate salts, e.g., magnesium stearate. In some embodiments, the mini-tablets comprise 0.1-5% lubricant, for example, about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, about 2.5, about 3.0, about 3.5, about 4.0, or about 4.5%, including all values ​​and sub-ranges therebetween, based on the total weight of the composition.

[0159]

[0169] The mini-tablets may be uncoated or may be coated with one or more coating layers. In some embodiments, the mini-tablets have at least a partial enteric coating. In some embodiments, the enteric coating comprises a pH-dependent polymer, such as a copolymer of methacrylic acid and a methacrylic acid ester, such as a methacrylic acid copolymer, for example Eudragit, for example Eudragit L30D55, which exhibits dissolution above pH 5.5. Other Eudragit polymers include Eudragit L100-55 (dissolves above pH 5.5), Eudragit L100 (dissolves above pH 6.0) and Eudragit S100 (dissolves above pH 7.0). In some embodiments, the enteric coating comprises 5-10% based on the total weight (dry polymer weight) of the composition. The enteric coating may be prepared by spraying an enteric polymer onto the core mini-tablets described above.

[0160]

[0170] The enteric coating may further comprise a plasticizer such as acetyl triethyl citrate or triethyl citrate, e.g., triethyl citrate (Citroflex). In some embodiments, the pharmaceutical compositions disclosed herein comprise about 0.1 to about 5% of a plasticizer, e.g., about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, about 2.5, about 3.0, about 3.5, about 4.0, or about 4.5%, including all values ​​and subranges therebetween, based on the total weight of the composition.

[0161]

[0171] In some embodiments, the enteric coating further comprises a fluidizing agent to remove adhesion during the film coating process, such as talc, kaolin, or glycerol monostearate, e.g., glycerol monostearate (Imwitor 900K). In some embodiments, the fluidizing agent comprises about 0.1 to about 5 wt%, e.g., about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, about 2.5, about 3.0, about 3.5, about 4.0, or about 4.5%, based on the total weight of the composition, including all values ​​and subranges therebetween.

[0162]

[0172] In some embodiments, the enteric coating further comprises a surfactant to provide a uniform film mix, such as sodium lauryl sulfate, polyethylene glycol, or a polysorbate, e.g., polysorbate 80 (Crillet 4HP). In some embodiments, the surfactant comprises about 0.1 to about 5 wt%, about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, about 2.5, about 3.0, about 3.5, about 4.0, or about 4.5% (including all values ​​and subranges therebetween) based on the total weight of the composition.

[0163]

[0173] The mini-tablets may further comprise one or more pharma- ceutically acceptable excipients, if desired. Suitable pharma-ceutically acceptable excipients may include colors, flavors (such as menthol), sweeteners (such as mannitol), preservatives, stabilizers, antioxidants, and any other excipients known to those skilled in the art.

[0164]

[0174] Timed Pulse Emission

[0175] In some embodiments, the delayed release component is formulated to release zolmitriptan in a pulse at least 30 minutes after oral administration. The timed pulsatile release systems described herein have the ability to provide an immediate release pulse of zolmitriptan after a predetermined delay time or at one or more specific sites to improve drug absorption.

[0165]

[0176] In some embodiments, the timed pulsatile release system comprises a membrane surrounding an active core, the membrane comprising a swelling agent (e.g., low-substituted hydroxypropyl cellulose, crospovidone, cross-linked carboxymethyl cellulose, sodium starch glycolate), e.g., as disclosed in U.S. Pat. No. 4,871,549, which is incorporated by reference herein in its entirety.

[0166]

[0177] In other embodiments, the timed pulsatile release system comprises a core material (such as a polysaccharide or cross-linked protein and a disintegrant that swells upon exposure to bodily fluids or water) and a hard membrane surrounding the core that comprises hydrophobic and hydrophilic polymers that rapidly ruptures to release the active as the core swells, e.g., as disclosed in U.S. Pat. No. 6,531,152, which is incorporated herein by reference in its entirety.

[0167]

[0178] In some embodiments, the timed pulsatile release component comprises an inner barrier coating and an outer lag-time (i.e. delayed release) coating. In some embodiments, the inner barrier coating comprises a water-insoluble polymer in combination with a water-soluble / pore-forming polymer. In some embodiments, the outer lag-time coating comprises a water-insoluble polymer in combination with an enteric polymer.

[0168]

[0179] Non-limiting examples of water insoluble polymers suitable for the inner barrier coating include ethyl cellulose, polyvinyl acetate (e.g., Kollicoat SR#30D from BASF), cellulose acetate, cellulose acetate butyrate, neutral copolymers based on ethyl acrylate and methyl methacrylate, copolymers of acrylic and methacrylic acid esters containing quaternary ammonium groups, such as Eudragit NE, RS and RS30D, RL or RL30D.

[0169]

[0180] Non-limiting examples of water soluble / pore forming polymers suitable for the inner barrier coating include polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, and mixtures thereof.

[0170]

[0181] In some embodiments, the ratio of water insoluble polymer to water soluble / pore forming polymer for the inner barrier is from about 99:1 to about 1:99, including about 90:10, about 80:20, about 70:30, about 60:40, about 50:50, about 40:60, about 30:70, about 20:80, about 10:90 (including all values ​​and subranges therebetween).

[0171]

[0182] In some embodiments, the inner barrier coating comprises from about 1 wt% to about 20 wt%, including about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, and about 19 wt%, including all values ​​and sub-ranges therebetween.

[0172]

[0183] Non-limiting examples of enteric polymers suitable for the outer lag time coating include esters of cellulose and its derivatives (cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate), polyvinyl acetate phthalate, pH-sensitive methacrylic acid-methyl methacrylate copolymers and shellac. These polymers may be used as dry powders or as aqueous dispersions. Some commercially available materials that may be used are methacrylic acid copolymers sold under the trademarks Eudragit (L100, S100, L30D) manufactured by Rohm Pharma, Cellacefate (cellulose acetate phthalate) from Eastman Chemical Co., Aquateric (cellulose acetate phthalate aqueous dispersion) from FMC Corp. and Aqoat (hydroxypropylmethylcellulose acetate succinate aqueous dispersion) from Shin Etsu KK.

[0173]

[0184] In some embodiments, the outer lag time membrane comprises a plasticized mixture of a water insoluble polymer and an enteric polymer, where the water insoluble polymer and the enteric polymer may be present in a weight ratio ranging from about 10:1 to about 1:2, typically from about 3:1 to about 1:1, including about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, and about 1:1 (including all values ​​and subranges therebetween). In other embodiments, the water insoluble polymer comprises from about 10% to about 99%, including about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% (including all values ​​and subranges therebetween) of the plasticized mixture of water insoluble polymer and enteric polymer. The total weight of the rag coating can vary from about 30% to about 60% by weight, including about 35%, about 40%, about 45%, about 50%, and about 55% (including all values ​​and subranges therebetween) based on the total weight of the coated beads.

[0174]

[0185] Both the enteric polymer and the water-insoluble polymer used to form the outer lag time coating may be plasticized. Representative examples of plasticizers that may be used to plasticize the outer lag time coating include triacetin, tributyl citrate, triethyl citrate, acetyl tri-n-butyl citrate, diethyl phthalate, castor oil, dibutyl sebacate, acetylated monoglycerides, acetylated diglycerides, and the like, or mixtures thereof. When present, the plasticizer comprises about 3% to 30 wt.% of the polymer wt, such as about 5%, about 10%, about 15%, about 20%, about 25%, including all values ​​and subranges therebetween. The type of plasticizer and its content will depend on the polymer(s) and the nature of the coating system (e.g., aqueous or solvent based, solution or dispersion based, and total solids).

[0175]

[0186] The amounts and ratios of components in the inner barrier coating and the outer lag time coating can be modified to provide a desired release time, for example, within about 1 hour, within about 2 hours, or within about 3 hours, etc. Additionally, the time pulsed release system may be formulated as particles having a diameter of at least 2 mm (e.g., as mini-tablets as described above having a diameter of about 2 mm to about 5 mm) to provide sufficient residence time in the stomach.

[0176]

[0187] For examples of timed pulsed release systems, see, for example, U.S. Pat. No. 4,871,549, U.S. Pat. No. 6,531,152, U.S. Pat. No. 6,287,599, U.S. Pat. No. 6,627,223, U.S. Pat. No. 6,663,888, U.S. Pat. No. 9,161,918, and U.S. Pat. No. 9,161,919 (each of which is incorporated by reference in its entirety herein).

[0177]

[0188] Softgel capsules

[0189] In some embodiments, the delayed release component is formulated as a softgel capsule. Softgel capsules are known in the art and can be prepared from gelatin and its derivatives. In some embodiments, the softgel capsule is formulated to dissolve at the acidic pH of the stomach.

[0178]

[0190] In some embodiments, the softgel capsules are filled with a pharma- ceutically acceptable liquid that contains drug particles dissolved or suspended therein.

[0179]

[0191] Non-limiting examples of suitable pharma- ceutically acceptable liquids include oils or polyols, such as glycerin and its homologous polyhydric alcohols, and its esters, and polycarbonates or syrups; waxes that are liquid at room temperature, such as Labrafac Lipophile, Labrafil M1944CS, Labrasol, Transcutol, Peceol, and Plurol, manufactured by Gatefosse, Elmsford, NY, USA; triethyl citrate, acetyl triethyl citrate, tri-n-butyl citrate, or acetyl tri-n-butyl citrate, manufactured by Morflex, Greensboro, NC, USA; glyceryl triacetate; or other liquids that do not solubilize gelatin. Mixtures of these can also be used. In some embodiments, the pharma-ceutically acceptable liquid is vegetable oil or mineral oil. In some embodiments, the vegetable oil is selected from the group consisting of castor oil, coconut oil, peanut oil, palm kernel oil, canola oil, avocado oil, evening primrose oil, rice bran oil, borage oil, sunflower oil, soybean oil, palm oil, corn oil, and safflower oil, and mixtures thereof.

[0180]

[0192] Depot formulation

[0193] In some embodiments, the delayed release component comprises an injectable lipid-based liquid in which zolmitriptan is dissolved, which naturally forms a controlled release liquid crystal gel matrix in an aqueous environment (e.g., after it is subcutaneously injected into a patient in need thereof). Without being bound by any theory, such lipid solutions are transformed in situ into liquid crystal gels upon contact with fluids at the injection site, which effectively encapsulate zolmitriptan. In the depot formulations of the present disclosure, zolmitriptan is slowly released as the liquid crystal matrix degrades in an aqueous environment (e.g., tissue or body fluid). Injectable lipid-based liquid depot formulations are described in U.S. Pat. Nos. 8,236,292, 8,097,239, and 9,585,959, the contents of which are hereby incorporated by reference in their entireties.

[0181]

[0194] The release rate of zolmitriptan from the depot can be controlled over hours, days, or weeks, depending on the composition, by using methods known to those skilled in the art, for example, as described in U.S. Patent No. 8,236,292 and U.S. Patent No. 9,585,959. In some embodiments, suitable lipid-based liquids include suitable neutral lipids, and / or amphipathic lipids and / or polar lipids, or combinations thereof. In some embodiments, suitable lipid-based liquids include neutral diacyl lipids and / or phospholipids, such as those described in U.S. Patent No. 8,097,239 and U.S. Patent No. 9,585,959. In some embodiments, such preparations are administered subcutaneously (e.g., injected by syringe). In some embodiments of the present disclosure, the depot formulation uses FluidCrystal® injection depot, e.g., as described in U.S. Patent Nos. 8,236,292, 8,097,239, and 9,585,959, the contents of which are hereby incorporated by reference in their entireties. Thus, in some embodiments, the depot formulation is a FluidCrystal® sustained release formulation of zolmitriptan.

[0182]

[0195] In some embodiments, the delayed release component comprises an injectable aqueous suspension of multivesicular liposomes (MVL). Injectable aqueous suspensions of MVL are described in U.S. Pat. Nos. 5,723,147, 5,766,627, 5,891,467, 5,997,899, 6,793,938, and 9,585,838, the contents of which are hereby incorporated by reference in their entirety. Pharmaceutical compositions comprising MVL for parenteral administration may be obtained, for example, by a double emulsion process to form a water-in-oil-in-water emulsion. The liposomal particles are generally in the diameter size range of 10-30 μm. In some embodiments, the multivesicular liposomes comprise neutral lipids and amphipathic lipids. In some embodiments, the multivesicular liposomes comprise phospholipids, cholesterol, and triglycerides. In some embodiments, phospholipids such as dioleylphosphatidylcholine are the major component of the lipid bilayer membrane. In some embodiments, the lipid bilayer membrane includes a charged phospholipid (dipalmitoylphosphatidylglycerol) that helps prevent liposome aggregation by charge repulsion. In some embodiments, cholesterol is used, for example, to provide mechanical stability of the lipid bilayer membrane. For parenteral administration, the drug substance can be formulated with MVL to provide a carrier matrix of microscopic spherical lipid-based particles composed of multiple honeycomb-like, centralless, internal aqueous cavities containing encapsulated zolmitriptan. In some embodiments, each cavity is separated from the adjacent cavity by a lipid membrane. After injection, such preparations release zolmitriptan over an extended period of time, for example, due to erosion and / or reorganization of the lipid membrane. The release rate of zolmitriptan from the MVL can be controlled using methods known to those skilled in the art and described, for example, in U.S. Patent No. 5,723,147, U.S. Patent No. 5,766,627, U.S. Patent No. 5,891,467, U.S. Patent No. 6,793,938, and U.S. Patent No. 9,585,838. In some embodiments, such compositions provide, for example, an immediate release dose followed by sustained delivery depending on the composition.In some embodiments, such preparations are administered intravenously, subcutaneously, intramuscularly, or intrathecally (e.g., injected by a pen system or by a syringe (e.g., using a 25G needle or larger so that the structural integrity of the liposomes is maintained)). Illustratively, systemic delivery by releasing zolmitriptan into the bloodstream via the interstitial space is an effective mode of administration. In some embodiments of the present disclosure, the depot formulation is prepared using the DepoFoam® technology platform, e.g., as described in U.S. Pat. Nos. 5,723,147, 5,766,627, 5,891,467, 5,997,899, 6,793,938, and 9,585,838. Thus, in some embodiments, the depot formulation is a zolmitriptan MVL injectable suspension.

[0183]

[0196] In some embodiments, the delayed release component comprises an injectable hydrogel depot. Hydrogel depots are described, for example, in U.S. Pat. No. 8,084,045, U.S. Reissue Patent No. RE46686, U.S. Pat. No. 7,659,365, and U.S. Pat. No. 8,206,744, the contents of which are hereby incorporated by reference in their entirety. For parenteral administration, suitable hydrogel compositions include those that include an amphiphilic polymer that allows for non-covalent entrapment of zolmitriptan and spontaneous formation of a colloidal suspension of stable nanoparticles (e.g., 10-50 nm) in water (e.g., under isotonic conditions). In some embodiments, the polymer is any polymer described herein or in U.S. Pat. No. 8,084,045, U.S. Reissue Patent No. RE46686, U.S. Pat. No. 7,659,365, and U.S. Pat. No. 8,206,744. In some embodiments, the polymer is a water-soluble biodegradable amphiphilic copolymer. Without being bound by any theory, the sustained drug release is based on reversible drug interaction with the hydrophobic nano-domain. In some embodiments, the parenteral hydrogel depot injection provides modification of the release rate of zolmitriptan. The hydrogel depot preparation can be obtained, for example, from self-assembling polyamino acid nanoparticles made of a poly-Glu backbone grafted with hydrophobic α-tocopherol molecules, using methods known to those skilled in the art, for example, as described in U.S. Pat. No. 8,084,045 and U.S. Pat. No. RE46686E1. In some embodiments, the hydrogel depot injection is administered subcutaneously. In some embodiments of the present disclosure, the depot formulation is prepared using the Medusa® Platform technology platform, for example, as described in the following figures and in U.S. Pat. No. 8,084,045, U.S. Pat. No. RE46686E1, U.S. Pat. No. 7,659,365, and U.S. Pat. No. 8,206,744, the contents of which are hereby incorporated by reference in their entirety. Thus, in some embodiments, the depot formulation is an injectable hydrogel sustained release formulation of zolmitriptan.

[0184]

[0197] In some embodiments, the delayed release component comprises a polymer depot system. Injectable polymer depots are described, for example, in U.S. Pat. No. 10,300,019, U.S. Pat. No. 8,674,033, and U.S. Pat. No. 8,481,651, the contents of which are hereby incorporated by reference in their entirety. Such preparations can be obtained by using suitable monomers to form a biodegradable polymer matrix in which zolmitriptan is entrapped. Exemplary monomers are described in U.S. Pat. No. 10,300,019, U.S. Pat. No. 8,674,033, and U.S. Pat. No. 8,481,651. Upon rehydration, the polymer swells and zolmitriptan is released by diffusion. The release time can be adjusted from hours to days to up to months by methods known to those skilled in the art, for example, as described in U.S. Pat. No. 10,300,019, U.S. Pat. No. 8,674,033, and U.S. Pat. No. 8,481,651. In some embodiments, the polymer matrix comprises poly(lactic acid) (PLA) and / or poly(lactic-co-glycolic acid) (PLGA), or multi-block copolymers composed of lactide, glycolide, ε-caprolactone, and polyethylene glycol building blocks. In some embodiments, the polymer matrix maintains a near neutral pH. In some embodiments, the block copolymer is represented by: [ka] In some embodiments of the present disclosure, the depot formulation is prepared using the SynBiosys® Platform technology platform, e.g., as described in U.S. Patent No. 10,300,019, U.S. Patent No. 8,674,033, and U.S. Patent No. 8,481,651. Thus, in some embodiments, the depot formulation is a polymeric sustained release depot formulation of zolmitriptan.

[0185]

[0198] In some embodiments, the delayed release component comprises a phospholipid depot composition. Injectable phospholipid depots are described in U.S. Pat. No. 9,517,202, the contents of which are hereby incorporated by reference in their entirety. In some embodiments, suitable phospholipids may be formulated with zolmitriptan to provide a formulation that gels in situ upon parenteral injection. In some embodiments, such formulations may also be used as suspensions for microspheres. In some embodiments, the gel may be substantially homogeneous or monophasic. Exemplary phospholipid compositions are described in U.S. Pat. No. 9,517,202 and may include 20-80%, 25-70%, or 30-60% by weight of phospholipid, such as 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% by weight of phospholipid or phospholipid mixture (including all values ​​and subranges therebetween). In some embodiments, the phospholipid is a non-liposomal phospholipid. In some embodiments, the phospholipid depot formulation is prepared to provide a customizable release profile over days or weeks depending on the composition, by methods known to those skilled in the art and described in U.S. Pat. No. 9,517,202. In some embodiments, the depot formulation is administered parenterally (e.g., by subcutaneous or intramuscular injection, or by injection or infusion into a living tissue, blood vessel, or cavity). In some embodiments of the present disclosure, the depot formulation is prepared using, for example, the PG Depot™ injectable depot described in U.S. Pat. No. 9,517,202. Thus, in some embodiments, the depot formulation is a phospholipid depot sustained release formulation of zolmitriptan.

[0186]

[0199] Administration and Dosing

[0200] The present disclosure provides a method for treating symptoms associated with autism by administering to a patient in need thereof an effective amount of a zolmitriptan composition of the present disclosure.

[0187]

[0201] The present disclosure provides a method for treating aggression in a patient with dementia by administering to a patient in need thereof an effective amount of a zolmitriptan composition of the present disclosure.

[0188]

[0203] The present disclosure provides a method for treating aggression in an Alzheimer's disease patient by administering to a patient in need thereof an effective amount of a zolmitriptan composition of the present disclosure.

[0189]

[0204] In one aspect, the disclosure provides a method of treatment by administering (such as by oral administration) an effective amount of a zolmitriptan composition of the disclosure to a patient in need thereof, the effective amount depending on the condition being treated, being an amount sufficient to eliminate or significantly reduce at least one symptom of the condition or to alleviate those symptoms (e.g., a symptom of autism spectrum disorder, or aggression in patients with dementia, such as those with Alzheimer's disease).

[0190]

[0205] The enumerated embodiments below disclose methods for treating symptoms of AD. These enumerated methods are also suitable for treating other conditions characterized by aggression (e.g., aggression in patients with dementia, such as Alzheimer's disease patients). The enumerated embodiments (e.g., doses, PK parameters, and administration) described herein for treating symptoms of autism spectrum disorder equally apply to treating conditions characterized by aggression (e.g., aggression in patients with Alzheimer's disease). Thus, the present disclosure contemplates embodiments for treating aggression in patients with dementia, such as Alzheimer's disease patients, using the following doses, PK parameters, and administration.

[0191]

[0206] According to some embodiments of the present disclosure, administration of the zolmitriptan composition of the present disclosure provides a statistically significant therapeutic effect. In one embodiment, the statistically significant therapeutic effect is determined based on one or more specifications or standards provided by one or more regulatory authorities in the United States, e.g., the FDA, or other countries. In another embodiment, the statistically significant therapeutic effect is determined based on results obtained from a clinical trial setup and / or procedure approved by the regulatory authority.

[0192]

[0207] In some embodiments, the statistically significant therapeutic effect is determined based on a patient population of at least 20, 50, 60, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or 2000 patients. In some embodiments, the statistically significant therapeutic effect is determined based on data obtained from a randomized double-blind clinical trial set-up. In some embodiments, the statistically significant therapeutic effect is determined based on data with a p-value of about 0.05, 0.04, 0.03, 0.02, or 0.01 or less. In some embodiments, the statistically significant therapeutic effect is determined based on data with a confidence interval of 95%, 96%, 97%, 98%, or 99% or more.

[0193]

[0208] In some embodiments, a statistically significant therapeutic effect is determined by a randomized, double-blind clinical trial of patients treated with zolmitriptan or a pharma- ceutically acceptable salt thereof, and optionally in combination with standard of care. The method of determining the therapeutic effect will depend on the condition being treated.

[0194]

[0209] Generally, statistical analysis may include any suitable method approved by a regulatory agency, such as the FDA, in the United States or Europe or any other country. In some embodiments, statistical analysis includes non-stratified analysis, log-rank analysis, such as Kaplan-Meier, Jacobson-Truax, Gulliken-Lord-Novick, Edwards-Nunnally, Hageman-Arrindel, and hierarchical linear model building (HLM), and Cox regression analysis.

[0195]

[0210] In accordance with the present disclosure, the compositions of the present disclosure are administered on a once-daily, twice-daily, or three-times-daily basis to provide effective relief of the symptoms of the condition being treated (e.g., symptoms of autism spectrum disorder or aggression in patients with dementia, such as those with Alzheimer's disease).

[0196]

[0211] In some embodiments, the dose provided herein refers to the amount of zolmitriptan administered per day to treat symptoms of autism spectrum disorder.In some embodiments, the dose provided herein refers to the amount of zolmitriptan administered per day to treat aggression in patients with dementia.In some embodiments, the dose provided herein refers to the amount of zolmitriptan administered per day to treat aggression in patients with Alzheimer's disease. In some embodiments, the total daily dose of zolmitriptan is about 7.5 mg, about 10 mg, about 12 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, and about 150 mg. In some embodiments, the daily dose of zolmitriptan is about 12 mg, about 24 mg, about 36 mg, or about 48 mg. In some embodiments, the daily dose of zolmitriptan is about 12 mg, about 24 mg, about 36 mg, about 48 mg, or about 72 mg.

[0197]

[0212] In some embodiments, the total daily dose of zolmitriptan is from about 7.5 mg to about 150 mg, including about 7.5 mg, 10 mg, about 12 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, and about 150 mg (including all ranges therebetween). In some embodiments, the total daily dose of zolmitriptan is about 60 mg to about 120 mg, including about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, and about 120 mg (including all ranges therebetween). In some embodiments, the total daily dose of zolmitriptan is about 7.5 mg to about 90 mg. In some embodiments, the total daily dose of zolmitriptan is about 7.5 mg to about 50 mg. In some embodiments, the total daily dose of zolmitriptan is about 10 mg to about 30 mg. In embodiments, the total daily dose of zolmitriptan is about 12 mg to about 72 mg. In embodiments, the total daily dose of zolmitriptan is about 24 mg to about 72 mg. In embodiments, the total daily dose of zolmitriptan is from about 48 mg to about 72 mg.

[0198]

[0213] In some embodiments, the total daily dose of zolmitriptan is at least about 2.5 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 5 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 7.5 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 10 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 12 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 15 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 20 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 24 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 25 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 30 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 35 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 40 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 45 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 48 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 50 mg per day for treating symptoms of autism spectrum disorder.In some embodiments, the total daily dose of zolmitriptan is at least about 55 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 60 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 65 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 70 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 72 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 75 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 80 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 85 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 90 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 95 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 100 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 105 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 110 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 115 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 120 mg per day for treating symptoms of autism spectrum disorder.In some embodiments, the total daily dose of zolmitriptan is at least about 125 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 130 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 135 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 140 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 145 mg per day for treating symptoms of autism spectrum disorder. In some embodiments, the total daily dose of zolmitriptan is at least about 150 mg per day for treating symptoms of autism spectrum disorder.

[0199]

[0214] In some embodiments, the total daily dose of zolmitriptan is about 12 mg per day for treating symptoms of ASD. In some embodiments, the total daily dose of zolmitriptan is about 24 mg per day for treating symptoms of ASD. In some embodiments, the total daily dose of zolmitriptan is about 36 mg per day for treating symptoms of ASD. In some embodiments, the total daily dose of zolmitriptan is about 48 mg per day for treating symptoms of ASD. In some embodiments, the total daily dose of zolmitriptan is about 60 mg per day for treating symptoms of ASD. In some embodiments, the total daily dose of zolmitriptan is about 65 mg per day for treating symptoms of ASD. In some embodiments, the total daily dose of zolmitriptan is about 70 mg per day for treating symptoms of ASD. In some embodiments, the total daily dose of zolmitriptan is about 72 mg per day for treating symptoms of ASD. In some embodiments, the total daily dose of zolmitriptan is about 75 mg per day for treating symptoms of ASD. In some embodiments, the total daily dose of zolmitriptan is about 80 mg per day for treating symptoms of ASD. In some embodiments, the total daily dose of zolmitriptan is about 85 mg per day for treating symptoms of ASD. In some embodiments, the total daily dose of zolmitriptan is about 90 mg per day for treating symptoms of ASD. In some embodiments, the total daily dose of zolmitriptan is about 95 mg per day for treating symptoms of ASD. In some embodiments, the total daily dose of zolmitriptan is about 100 mg per day for treating symptoms of ASD. In some embodiments, the total daily dose of zolmitriptan is about 105 mg per day for treating symptoms of ASD. In some embodiments, the total daily dose of zolmitriptan is about 110 mg per day for treating symptoms of ASD. In some embodiments, the total daily dose of zolmitriptan is about 115 mg per day for treating symptoms of ASD. In some embodiments, the total daily dose of zolmitriptan is about 120 mg per day for treating symptoms of ASD.

[0200]

[0215] In some embodiments, about 12 mg of zolmitriptan once a day (or twice a day or three times a day) is selected for treating symptoms of ASD. In some embodiments, about 24 mg of zolmitriptan once a day (or twice a day or three times a day) is selected for treating symptoms of ASD. In some embodiments, about 36 mg of zolmitriptan once a day (or twice a day or three times a day) is selected for treating symptoms of ASD. In some embodiments, about 48 mg of zolmitriptan once a day (or twice a day or three times a day) is selected for treating symptoms of ASD. In some embodiments, about 60 mg of zolmitriptan once a day (or twice a day or three times a day) is selected for treating symptoms of ASD. In some embodiments, about 65 mg of zolmitriptan once a day (or twice a day or three times a day) is selected for treating symptoms of ASD. In some embodiments, about 70 mg of zolmitriptan once a day (or twice a day or three times a day) is selected for treating symptoms of ASD. In some embodiments, about 72 mg of zolmitriptan once a day (or twice a day or three times a day) is selected for treating symptoms of ASD. In some embodiments, about 75 mg of zolmitriptan once a day (or twice a day or three times a day) is selected for treating symptoms of ASD. In some embodiments, about 80 mg of zolmitriptan once a day (or twice a day or three times a day) is selected for treating symptoms of ASD. In some embodiments, about 85 mg of zolmitriptan once a day (or twice a day or three times a day) is selected for treating symptoms of ASD. In some embodiments, about 90 mg of zolmitriptan once a day (or twice a day or three times a day) is selected for treating symptoms of ASD. In some embodiments, about 95 mg of zolmitriptan once a day (or twice a day or three times a day) is selected for treating symptoms of ASD. In some embodiments, about 100 mg of zolmitriptan once a day (or twice a day or three times a day) is selected for treating symptoms of ASD. In some embodiments, about 105 mg of zolmitriptan once a day (or twice a day or three times a day) is selected for treating symptoms of ASD.In some embodiments, about 110 mg of zolmitriptan once a day (or twice a day or three times a day) is selected for treating symptoms of ASD. In some embodiments, about 115 mg of zolmitriptan once a day (or twice a day or three times a day) is selected for treating symptoms of ASD. In some embodiments, about 120 mg of zolmitriptan once a day (or twice a day or three times a day) is selected for treating symptoms of ASD.

[0201]

[0216] In some embodiments, zolmitriptan or a pharma- ceutically acceptable salt thereof is administered on a once-daily or twice-daily or three-times-daily basis for at least one day, e.g., about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 12 days, about 13 days, and about 14 days.

[0202]

[0217] In some embodiments, zolmitriptan or a pharma- ceutically acceptable salt thereof is administered on a once-daily or twice-daily basis for at least one week, e.g., about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, about eight weeks, about nine weeks, about ten weeks, about twelve weeks, about eighteen weeks, about twenty-four weeks, and about fifty weeks.

[0203]

[0218] In some embodiments, zolmitriptan or a pharma- ceutically acceptable salt thereof is administered on a once-daily or twice-daily basis for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 12 weeks, at least about 16 weeks, at least about 18 weeks, at least about 24 weeks, and at least about 50 weeks.

[0204]

[0219] In some embodiments, at least about 7.5 mg or about 7.5 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof is administered on a once-day or twice-day basis for at least one week. In some embodiments, at least about 12 mg or about 12 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof is administered on a once-day or twice-day basis for at least one week. In some embodiments, at least about 24 mg or about 24 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof is administered on a once-day or twice-day basis for at least one week. In some embodiments, at least about 36 mg or about 36 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof is administered on a once-day or twice-day basis for at least one week. In some embodiments, at least about 48 mg or about 48 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof is administered on a once-day or twice-day basis for at least one week. In some embodiments, at least about 60 mg or about 60 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof is administered on a once-day or twice-day basis for at least one week. In some embodiments, at least about 65 mg or about 65 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof is administered on a once-day or twice-day basis for at least one week. In some embodiments, at least about 70 mg or about 70 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof is administered on a once-day or twice-day basis for at least one week. In some embodiments, at least about 72 mg or about 72 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof is administered on a once-day or twice-day basis for at least one week. In some embodiments, at least about 75 mg or about 75 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof is administered on a once-day or twice-day basis for at least one week. In some embodiments, at least about 80 mg or about 80 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof is administered on a once-daily basis for at least one week, hi some embodiments, at least about 85 mg or about 85 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof is administered on a once-daily basis for at least one week.In some embodiments, at least about 90 mg or about 90 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof is administered on a once-daily basis for at least one week. In some embodiments, at least about 95 mg or about 95 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof is administered on a once-daily basis for at least one week. In some embodiments, at least about 100 mg or about 100 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof is administered on a once-daily basis for at least one week. In some embodiments, at least about 105 mg or about 105 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof is administered on a once-daily basis for at least one week. In some embodiments, at least about 110 mg or about 110 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof is administered on a once-daily basis for at least one week. In some embodiments, at least about 115 mg or about 115 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof is administered on a once-daily basis for at least one week. In some embodiments, at least about 120 mg or about 120 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof is administered on a once-daily basis for at least one week. In some embodiments, at least about 125 mg or about 125 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof is administered on a once-daily or twice-daily basis for at least one week. In some embodiments, at least about 130 mg or about 130 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof is administered on a once-daily basis for at least one week. In some embodiments, at least about 135 mg or about 135 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof is administered on a once-daily basis for at least one week. In some embodiments, at least about 140 mg or about 140 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof is administered on a once-daily basis for at least one week, hi some embodiments, at least about 145 mg or about 145 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof is administered on a once-daily basis for at least one week.In some embodiments, at least about 150 mg or about 150 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof is administered on a once-per-day basis for at least one week.

[0205]

[0220] In some embodiments, the methods described herein further comprise titrating the dose of zolmitriptan, or a pharma- ceutically acceptable salt thereof, to a maximum safe and effective dose for at least about one week (a titration period). In some embodiments, the titration period is about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days to about 14 days (including all values ​​and subranges therebetween). In some embodiments, the titration period is at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days, at least about 8 days, at least about 9 days, at least about 10 days, at least about 11 days, at least about 12 days, at least about 13 days, or at least about 14 days. In an embodiment, titration comprises increasing the daily dose of zolmitriptan. In embodiments, the dose adjustment comprises increasing the daily dose of zolmitriptan by about 5 mg to about 20 mg, including about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, including all values ​​and subranges therebetween. In embodiments, the dose adjustment comprises increasing the daily dose of zolmitriptan by about 12 mg per day.

[0206]

[0221] In embodiments of the methods described herein, the method further comprises titrating the dose of zolmitriptan downward. In embodiments, the titration comprises decreasing the daily dose of zolmitriptan by about 5 mg to about 20 mg, including about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg (including all values ​​and subranges therebetween). In embodiments, the titration comprises decreasing the daily dose of zolmitriptan by about 12 mg per day.

[0207]

[0222] In embodiments, the methods described herein include titrating the dose of zolmitriptan to a therapeutically effective dose, and administering the therapeutically effective dose for about 1 day to about 20 weeks or more, including about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks or more (including all values ​​and subranges therebetween).

[0208]

[0223] In embodiments, the methods described herein include titrating the dose of zolmitriptan to a therapeutically effective dose, and administering the therapeutically effective dose for at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 13 weeks, at least about 14 weeks, at least about 15 weeks, at least about 16 weeks, at least about 17 weeks, at least about 18 weeks, at least about 19 weeks, or at least about 20 weeks or more.

[0209]

[0224] In embodiments, the methods described herein include titrating the dose of zolmitriptan to a maximum safe and effective dose, and administering the maximum safe and effective dose for about 1 day to about 20 weeks or more, including about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about or about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, or about 20 weeks or more (including all values ​​and subranges therebetween).

[0210]

[0225] In embodiments, the methods described herein include titrating the dose of zolmitriptan to a maximum safe and effective dose, and administering the maximum safe and effective dose for at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 13 weeks, at least about 14 weeks, at least about 15 weeks, at least about 16 weeks, at least about 17 weeks, at least about 18 weeks, at least about 19 weeks, or at least about 20 weeks or more.

[0211]

[0226] In an embodiment of the disclosed method, the zolmitriptan composition is administered to a patient in need thereof (e.g., a patient with autism spectrum disorder (ASD) or a patient with Alzheimer's disease accompanied by aggression) as an initial daily dose of about 12 mg zolmitriptan, and then the zolmitriptan dose is titrated to a therapeutically effective dose. In an embodiment, the maximum daily dose is about 72 mg or less of zolmitriptan.

[0212]

[0227] In an embodiment of the disclosed method, the zolmitriptan composition is administered to a patient in need thereof (e.g., a patient with autism spectrum disorder (ASD) or a patient with Alzheimer's disease accompanied by aggression) as an initial daily dose of at least about 12 mg zolmitriptan, and then the zolmitriptan dose is titrated up to a therapeutically effective dose. In an embodiment, the maximum daily dose is no more than about 72 mg zolmitriptan.

[0213]

[0228] In an embodiment of the disclosed method, the zolmitriptan composition is administered to a patient in need thereof (e.g., a patient with autism spectrum disorder (ASD) or a patient with Alzheimer's disease accompanied by aggression) as an initial daily dose of about 12 mg zolmitriptan, and then the dose of zolmitriptan is titrated up to the maximum safe and effective dose. In an embodiment, the maximum daily dose is about 72 mg or less of zolmitriptan.

[0214]

[0229] In an embodiment of the disclosed method, the zolmitriptan composition is administered to a patient in need thereof (e.g., a patient with autism spectrum disorder (ASD) or a patient with Alzheimer's disease accompanied by aggression) as an initial daily dose of at least about 12 mg zolmitriptan, and then the dose of zolmitriptan is titrated up to a maximum safe and effective dose. In an embodiment, the maximum daily dose is no more than about 72 mg zolmitriptan.

[0215]

[0230] In some embodiments, the present disclosure provides zolmitriptan compositions that are characterized based on the pharmacokinetic (or PK) parameters observed after oral administration of the compositions to a patient in need thereof. However, the applicant contemplates that the same PK parameters achieved after oral administration of zolmitriptan may be achieved using other drug administration routes, such as parenteral routes, including, but not limited to, intravenous, intramuscular, intranasal, and transdermal. The PK parameters described herein may be achieved using any of the sustained release compositions described herein.

[0216]

[0231] In some embodiments, the pharmaceutical compositions provided herein provide plasma zolmitriptan levels that correlate with one or more statistically significant therapeutic effects over an extended period of time, typically at least about 4 hours, at least about 6 hours, at least about 8 hours, at least about 10 hours, at least about 12 hours, at least about 14 hours, at least about 16 hours, at least about 18 hours, at least about 20 hours, at least about 22 hours, or at least about 24 hours, to treat symptoms of autism spectrum disorder in humans. In some embodiments, the pharmaceutical compositions provided herein provide plasma zolmitriptan levels that correlate with one or more statistically significant therapeutic effects over a period of about 4 to 24 hours, including between about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours to about 24 hours, including all values ​​and subranges therebetween. In some embodiments, the plasma levels are steady state plasma levels. In some embodiments, when orally administered to a patient in need thereof, the compositions of the present disclosure provide a therapeutically effective plasma zolmitriptan concentration for about 8 hours, about 10 hours, about 12 hours, or about 16 hours after a single dose of the composition. In some embodiments, when orally administered to a patient in need thereof, the compositions of the present disclosure provide a therapeutically effective plasma zolmitriptan concentration for about 10 hours, about 12 hours, or about 16 hours after a single dose of the composition. In some embodiments, when orally administered to a patient in need thereof, the compositions of the present disclosure provide a therapeutically effective plasma zolmitriptan concentration for at least about 8 hours, at least about 10 hours, at least about 12 hours, or at least about 16 hours after a single dose of the composition.

[0217]

[0232] In some embodiments, the compositions provide steady state plasma zolmitriptan levels that correlate with one or more statistically significant therapeutic effects when administered on a once-daily, twice-daily, or three-times-daily basis. In some embodiments, when orally administered to a patient in need thereof, the compositions provide steady state plasma zolmitriptan levels that provide a statistically significant effect for at least about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 1 day, about 2 days, about 3 days, about 4 days, about For at least about 12 hours, including 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, and about 31 days. Methods of measuring a statistically significant effect will depend on the condition under treatment and are known to those of skill in the art.

[0218]

[0233] In some embodiments, the zolmitriptan compositions of the present disclosure have an average molecular weight of about 3 ng / mL, about 5 ng / mL, about 10 ng / mL, about 11 ng / mL, about 12 ng / mL, about 13 ng / mL, about 14 ng / mL, about 15 ng / mL, about 16 ng / mL, about 17 ng / mL, about 18 ng / mL, about 19 ng / mL, about 20 ng / mL, about 21 ng / mL, about 22 ng / mL, about 23 ng / mL, about 24 ng / mL, about 25 ng / mL, about 26 ng / mL, about 27 ng / mL, about 28 ng / mL, about 29 ng / mL, about 30 ng / mL, about 31 ng / mL, about 32 ng / mL, about 33 ng / mL, about 34 ng / mL, about 35 ng / mL, about 36 ng / mL, about 37 ng / mL, about 38 ng / mL, about 39 ng / mL, about 40 ng / mL, about 41 ng / mL, about 42 ng / mL, about 43 ng / mL, about 44 ng / mL, about 45 ng / mL, about 46 ng / mL, about 47 ng / mL, about 48 ng / mL, about 49 ng / mL, about 50 ng / mL, about 51 ng / mL, about 52 ng / mL, about 53 ng / mL, about 54 ng / mL, about 55 ng / mL, about 56 ng / mL, about 57 ng / mL, about 58 ng / mL, about 59 ng / mL, about 60 ng / mL, about 61 ng / mL, about 62 ng / mL, approximately 24ng / mL, approximately 25ng / mL, approximately 26ng / mL, approximately 27ng / mL, approximately 28ng / mL, approximately 29ng / mL, approximately 30ng / mL, approximately 31ng / mL, approximately 32ng / mL, approximately 33ng / mL, approximately 34ng / mL, approximately 3 5ng / mL, approximately 36ng / mL, approximately 37ng / mL, approximately 37ng / mL, approximately 38ng / mL, approximately 29ng / mL, approximately 40ng / mL, approximately 41ng / mL, approximately 42ng / mL, approximately 43ng / mL, approximately 44ng / mL, approximately 45ng / mL, Approximately 46ng / mL, approximately 47ng / mL, approximately 48ng / mL, approximately 49ng / mL, approximately 50ng / mL, approximately 51ng / mL, approximately 52ng / mL, approximately 53ng / mL, approximately 54ng / mL, approximately 55ng / mL, approximately 56ng / mL, approximately 57ng / mL, approximately 58ng / mL, approximately 59ng / mL, approximately 60ng / mL, approximately 61ng / mL, approximately 62ng / mL, approximately 63ng / mL, approximately 64ng / mL, approximately 65ng / mL, approximately 66ng / mL, approximately 67ng / mL, approximately 68ng / mL, approximately 69n In some embodiments, the zolmitriptan compositions of the present disclosure provide therapeutically effective steady state plasma zolmitriptan levels in the range of about 3 ng / mL to about 85 ng / mL, including about 70 ng / mL, about 71 ng / mL, about 72 ng / mL, about 73 ng / mL, about 74 ng / mL, about 75 ng / mL, about 76 ng / mL, about 77 ng / mL, about 78 ng / mL, about 80 ng / mL, about 81 ng / mL, about 82 ng / mL, about 83 ng / mL, about 84 ng / mL, and about 85 ng / mL (including all ranges therebetween). In some embodiments, the zolmitriptan compositions of the present disclosure provide therapeutically effective steady state plasma zolmitriptan levels in the range of about 3 ng / mL to 85 ng / mL when orally administered to a patient in need thereof on a once-daily, twice-daily, or three-times-daily basis.

[0219]

[0234] In some embodiments, when orally administered to a patient in need thereof, the compositions of the present disclosure provide plasma concentrations of at least about 8-15 ng / mL for an extended period of time, including providing at least about 8 ng / mL, at least about 9 ng / mL, at least about 10 ng / mL, at least about 11 ng / mL, at least about 12 ng / mL, at least about 13 ng / mL, at least about 14 ng / mL to at least about 15 ng / mL (including all values ​​and subranges therebetween), typically for at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, or at least about 12 hours after administration of a single dose of the composition. In some embodiments, when orally administered to a patient in need thereof, the compositions of the present disclosure provide plasma concentrations of at least about 10 ng / mL for at least about 8 hours.

[0220]

[0235] In an embodiment of the method, administration of about 24 mg zolmitriptan composition of the present disclosure provides plasma levels of about 10 ng / mL to about 25 ng / mL, including about 10 ng / mL, about 11 ng / mL, about 12 ng / mL, about 13 ng / mL, about 14 ng / mL, about 15 ng / mL, about 16 ng / mL, about 17 ng / mL, about 17 ng / mL, about 18 ng / mL, about 19 ng / mL, about 20 ng / mL, about 21 ng / mL, about 22 ng / mL, about 23 ng / mL, about 24 ng / mL to about 25 ng / mL (including all values ​​and subranges therebetween). In an embodiment of the method, administration of about 48 mg zolmitriptan provides plasma levels of about 25 ng / mL to about 60 ng / mL. In an embodiment of the method, administration of about 48 mg of zolmitriptan provides a plasma level of about 25 ng / mL to about 50 ng / mL. In an embodiment of the method, administration of about 48 mg of the zolmitriptan composition of the present disclosure provides a plasma level of about 25 ng / mL to about 45 ng / mL, including about 25 ng / mL, about 26 ng / mL, about 27 ng / mL, about 28 ng / mL, about 29 ng / mL, about 30 ng / mL, about 31 ng / mL, about 32 ng / mL, about 33 ng / mL, about 33 ng / mL, about 34 ng / mL, about 35 ng / mL, about 36 ng / mL, about 37 ng / mL, about 38 ng / mL, about 39 ng / mL, about 40 ng / mL, about 41 ng / mL, about 42 ng / mL, about 43 ng / mL, about 44 ng / mL, about 45 ng / mL (including all values ​​and partial ranges therebetween). In an embodiment of the method, administration of about 72 mg zolmitriptan composition of the present disclosure provides a plasma level of about 40 ng / mL to about 65 ng / mL, including about 40 ng / mL, about 41 ng / mL, about 42 ng / mL, about 43 ng / mL, about 44 ng / mL, about 45 ng / mL, about 46 ng / mL, about 47 ng / mL, about 48 ng / mL, about 49 ng / mL, about 50 ng / mL, about 51 ng / mL, about 52 ng / mL, about 53 ng / mL, about 54 ng / mL, about 55 ng / mL, about 56 ng / mL, about 57 ng / mL, about 58 ng / mL, about 59 ng / mL to about 60 ng / mL (including all values ​​and subranges therebetween).

[0221]

[0236] In some embodiments, the zolmitriptan compositions of the present disclosure have an average molecular weight of about 1 ng / mL, about 2 ng / mL, about 3 ng / mL, about 5 ng / mL, about 10 ng / mL, about 11 ng / mL, about 12 ng / mL, about 13 ng / mL, about 14 ng / mL, about 15 ng / mL, about 16 ng / mL, about 17 ng / mL, about 18 ng / mL, about 19 ng / mL, about 20 ng / mL, about 21 ng / mL, about 22 ng / mL, about 23 ng / mL, about 24 ng / mL, about 25 ng / mL, about 26 ng / mL, about 27 ng / mL, about 28 ng / mL, about 29 ng / mL, about 30 ng / mL, about 31 ng / mL, about 32 ng / mL, about 33 ng / mL, about 34 ng / mL, about 35 ng / mL, about 36 ng / mL, about 37 ng / mL, about 38 ng / mL, about 39 ng / mL, about 40 ng / mL, about 41 ng / mL, about 42 ng / mL, about 43 ng / mL, about 44 ng / mL, about 45 ng / mL, about 46 ng / mL, about 47 ng / mL, about 48 ng / mL, about 49 ng / mL, about 50 ng / mL, about 51 ng / mL, about 52 ng / mL, about 53 ng / mL, about 54 ng / mL, about 55 ng / mL, about 56 ng / mL, about 57 ng / mL, about 58 ng / mL, about 59 ng / mL, about 60 ng / mL ng / mL, approximately 26ng / mL, approximately 27ng / mL, approximately 28ng / mL, approximately 29ng / mL, approximately 30ng / mL, approximately 31ng / mL, approximately 32ng / mL, approximately 33ng / mL, approximately 34ng / mL, approximately 35ng / mL, approximately 36ng / mL, approximately 37ng / mL, approximately 37ng / mL , about 38ng / mL, about 29ng / mL, about 40ng / mL, about 41ng / mL, about 42ng / mL, about 43ng / mL, about 44ng / mL, about 45ng / mL, about 46ng / mL, about 47ng / mL, about 48ng / mL, about 49ng / mL, about 50ng / mL, about 51n g / mL, approximately 52ng / mL, approximately 53ng / mL, approximately 54ng / mL, approximately 55ng / mL, approximately 56ng / mL, approximately 57ng / mL, approximately 58ng / mL, approximately 59ng / mL, approximately 60ng / mL, approximately 61ng / mL, approximately 62ng / mL, approximately 63ng / mL, approximately 64ng / mL , about 65ng / mL, about 66ng / mL, about 67ng / mL, about 68ng / mL, about 69ng / mL, about 70ng / mL, about 71ng / mL, about 72ng / mL, about 73ng / mL, about 74ng / mL, about 75ng / mL, about 76ng / mL, about 77ng / mL, about 78n ng / mL, about 80 ng / mL, about 81 ng / mL, about 82 ng / mL, about 83 ng / mL, about 84 ng / mL, about 85 ng / mL, about 86 ng / mL, about 87 ng / mL, about 88 ng / mL, about 89 ng / mL, about 90 ng / mL, about 91 ng / mL, about 92 ng / mL, about 93 ng / mL, about 94 ng / mL, about 95 ng / mL, about 96 ng / mL, about 97 ng / mL, about 98 ng / mL, about 99 ng / mL, and about 100 ng / mL (including all ranges therebetween), in the range of about 1 ng / mL to about 100 ng / mL (e.g.,In embodiments, the zolmitriptan compositions of the present disclosure provide plasma levels ranging from about 40 ng / mL to about 60 ng / mL when orally administered to a patient in need thereof on a once-daily, twice-daily, or three-times-daily basis. In embodiments, the zolmitriptan compositions of the present disclosure provide plasma levels ranging from about 40 ng / mL to about 50 ng / mL when orally administered to a patient in need thereof on a once-daily, twice-daily, or three-times-daily basis.

[0222]

[0237] In some embodiments, therapeutically effective steady state plasma zolmitriptan levels are provided by administering one or more compositions of the present disclosure to provide a daily dose of between about 7.5 mg and 150 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof. In some embodiments, therapeutically effective steady state plasma zolmitriptan levels are provided by administering once a day a composition of the present disclosure containing between about 7.5 mg and about 90 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof. In some embodiments, therapeutically effective steady state plasma zolmitriptan levels are provided by administering once a day a composition of the present disclosure containing between about 12 mg and about 72 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof. In some embodiments, therapeutically effective steady state plasma zolmitriptan levels are provided by administering once a day a composition of the present disclosure containing between about 7.5 mg and about 50 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof. In some embodiments, therapeutically effective steady state plasma zolmitriptan levels are provided by administering a composition of the present disclosure containing between about 2.5 mg and about 50 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof once a day. In some embodiments, therapeutically effective steady state plasma zolmitriptan levels are provided by administering a composition of the present disclosure containing between about 2.5 mg and about 50 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof twice a day. In some embodiments, therapeutically effective steady state plasma zolmitriptan levels are provided by administering a composition of the present disclosure containing between about 2.5 mg and about 50 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof three times a day. In some embodiments, therapeutically effective steady state plasma zolmitriptan levels are provided by administering a composition of the present disclosure containing between about 10 mg and about 30 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof once a day.

[0223]

[0238] In some embodiments, administration of the composition results in a CSF level of zolmitriptan that correlates with one or more statistically significant therapeutic effects. In some embodiments, the therapeutically effective CSF level of zolmitriptan provided by the methods of the present disclosure is about 0.05 ng / mL, about 0.075 ng / mL, about 0.1 ng / mL, about 0.125 ng / mL, about 0.15 ng / mL, about 0.175 ng / mL, about 0.2 ng / mL, about 0.25 ng / mL, about 0.3 ng / mL, about 0.35 ng / mL, about 0.4 ng / mL, about 0.45 ng / mL, about 0.5 ng / mL, about 0.55 ng / mL, about 0.6 ng / mL, about 0.65 ng / mL, about 0.7 ng / mL, about 0.75 ng / mL, about 0.8 ng / mL, about 0.85 ng / mL, about 0.9 ng / mL, about 0.1 ng / mL, about 0.2 ng / mL, about 0.2 ng / mL, about 0.3 ng / mL, about 0.4 ng / mL, about 0.5 ng / mL, about 0.5 The range is from about 0.05ng / mL to about 2ng / mL (including all values ​​and ranges therebetween), including about 0.95ng / mL, about 1ng / mL, about 1.1ng / mL, about 1.15ng / mL, about 1.2ng / mL, about 1.25ng / mL, about 1.3ng / mL, about 1.35ng / mL, about 1.4ng / mL, about 1.45ng / mL, about 1.5ng / mL, about 1.55ng / mL, about 1.6ng / mL, about 1.65ng / mL, about 1.7ng / mL, about 1.75ng / mL, about 1.8ng / mL, about 1.85ng / mL, about 1.9ng / mL, about 1.95ng / mL, and about 2ng / mL. In some embodiments, the therapeutically effective CSF levels of zolmitriptan provided by the methods of the present disclosure range from about 0.078 ng / mL to about 1.24 ng / mL. In some embodiments, the therapeutically effective CSF levels of zolmitriptan provided by the methods of the present disclosure range from about 0.103 ng / mL to about 0.93 ng / mL.

[0224]

[0239] In some embodiments, the compositions have a mean steady-state AUC that correlates with one or more statistically significant therapeutic effects when administered on a once-daily, twice-daily, or three-times-daily basis. 0-24h In some embodiments, the compositions provide zolmitriptan levels (expressed in ng·hr / mL) that provide a statistically significant effect on mean steady-state AUC 0-24hzolmitriptan levels at about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days after oral administration to a patient in need thereof For at least about 1 hour, including about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, and about 31 days or more (including all values ​​and ranges therebetween). In an embodiment, the composition provides a mean steady state AUC 0-24hzolmitriptan levels for at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, at least about 12 hours, at least about 13 hours, at least about 14 hours, at least about 15 hours, at least about 16 hours, at least about 17 hours, at least about 18 hours, at least about 19 hours, at least about 20 hours, at least about 21 hours, at least about 22 hours, at least about 23 hours, at least about 24 hours, at least about 1 day, at least about 2 days, at least about 3 days after oral administration to a patient in need thereof , at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days, at least about 8 days, at least about 9 days, at least about 10 days, at least about 11 days, at least about 12 days, at least about 13 days, at least about 14 days, at least about 15 days, at least about 16 days, at least about 17 days, at least about 18 days, at least about 19 days, at least about 20 days, at least about 21 days, at least about 22 days, at least about 23 days, at least about 24 days, at least about 25 days, at least about 26 days, at least about 27 days, at least about 28 days, at least about 29 days, at least about 30 days, or at least about 31 days or more. In some embodiments, the compositions provide a statistically significant effect on mean steady state AUC 0-24h The zolmitriptan levels are provided for at least about 12 hours after oral administration to a patient in need thereof.

[0225]

[0240] In some embodiments, the composition provides a statistically significant effect on mean steady state AUC 0-24hProvides zolmitriptan levels for about or at least about 1 to 24 hours, including about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, and about 24 hours after administration to a patient in need thereof. In some embodiments, the compositions provide a statistically significant effect on mean steady-state AUC 0-24h In some embodiments, the compositions provide zolmitriptan levels that provide a statistically significant effect for about 12 to about 24 hours after administration to a patient in need thereof. 0-24h Provides zolmitriptan levels for at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, at least about 12 hours, at least about 13 hours, at least about 14 hours, at least about 15 hours, at least about 16 hours, at least about 17 hours, at least about 18 hours, at least about 19 hours, at least about 20 hours, at least about 21 hours, at least about 22 hours, at least about 23 hours, or at least about 24 hours. In some embodiments, the compositions provide a statistically significant effect of a mean steady-state AUC 0-24h Zolmitriptan levels are provided for about 1 day to about 1 month, including at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, and about 5 weeks after administration to a patient in need thereof.

[0226]

[0241] In some embodiments, the therapeutically effective mean steady-state AUC provided by the zolmitriptan compositions of the present disclosure0-24h Zolmitriptan levels range from about 15ng·hr / mL to about 1150ng·hr / mL, including about 15ng·hr / mL, 20ng·hr / mL, 25ng·hr / mL, 30ng·hr / mL, 35ng·hr / mL, 40ng·hr / mL, 50ng·hr / mL, 100ng·hr / mL, 150ng·hr / mL, 200ng·hr / mL, 250ng·hr / mL, 300ng·hr / mL, about 400ng·hr / mL, about 500ng·hr / mL, about 600ng·hr / mL, about 700ng·hr / mL, about 800ng·hr / mL, about 900ng·hr / mL, about 1000ng·hr / mL, about 1100ng·hr / mL, and about 1150ng·hr / mL (including all ranges and values ​​therebetween). In some embodiments, the therapeutically effective mean steady-state AUC provided by the zolmitriptan compositions of the present disclosure 0-24h Zolmitriptan levels range from about 40 ng·hr / mL to about 110 ng·hr / mL, including about 40 ng·hr / mL, about 50 ng·hr / mL, about 60 ng·hr / mL, about 70 ng·hr / mL, about 80 ng·hr / mL, about 90 ng·hr / mL, about 100 ng·hr / mL, and about 110 ng·hr / mL (including all ranges and values ​​therebetween). In some embodiments, the therapeutically effective mean steady-state AUC 0-24h Zolmitriptan levels range from about 150 ng·hr / mL to about 450 ng·hr / mL, including about 150 ng·hr / mL, about 175 ng·hr / mL, about 200 ng·hr / mL, about 225 ng·hr / mL, about 250 ng·hr / mL, about 275 ng·hr / mL, about 300 ng·hr / mL, about 325 ng·hr / mL, about 350 ng·hr / mL, about 375 ng·hr / mL, about 400 ng·hr / mL, about 425 ng·hr / mL, and about 450 ng·hr / mL (including all ranges and values ​​therebetween). In some embodiments, the therapeutically effective mean steady-state AUC 0-24hZolmitriptan levels range from about 600ng·hr / mL to about 1150ng·hr / mL, including about 600ng·hr / mL, about 650ng·hr / mL, about 700ng·hr / mL, about 750ng·hr / mL, about 800ng·hr / mL, about 850ng·hr / mL, about 900ng·hr / mL, about 950ng·hr / mL, about 1000ng·hr / mL, about 1050ng·hr / mL, about 1100ng·hr / mL, and about 1150ng·hr / mL (including all ranges and values ​​therebetween).

[0227]

[0242] In some embodiments, the composition provides a concentration of about 20 ng·h / mL, about 30 ng·h / mL, about 40 ng·h / mL, about 50 ng·h / mL, about 60 ng·h / mL, about 70 ng·h / mL, about 80 ng·h / mL, about 90 ng·h / mL, about 100 ng·h / mL, about 110 ng·h / mL, about 120 ng·h / mL, about 130 ng·h / mL, about 140 ng·h / mL, about 150 ng·h / mL, about 160 ng·h / mL, about 170 ng·h / mL, about 180 ng·h / mL, about 190 ng·h / mL, about 200 ng·h / mL, Approx. 210ng h / mL, approx. 220 ng h / mL, approx. 230 ng h / mL, approx. 240 ng h / mL, approx. 250 ng h / mL, approx. 260 ng h / mL, approx. 270 ng h / mL, approx. 280 ng h / mL, approx. 290 ng h / mL, approx. 300 ng h / mL, approx. 310 ng h / mL, approximately 320 ng h / mL, approximately 330 ng h / mL, approximately 340 ng h / mL, approximately 350 ng h / mL, approximately 360 ng h / mL, approximately 370 ng h / mL, approximately 380 ng h / mL, approximately 390 ng h / mL, approximately 400 ng h / mL, approximately 410 ng h / mL / mL, approx. 420ng h / mL, approx. 430ng h / mL, approx. 440 ng h / mL, approx. 450 ng h / mL, approx. 460 ng h / mL, approx. 470 ng h / mL, approx. 480 ng h / mL, approx. 490 ng h / mL, approx. 500 ng h / mL, approx. 510 ng h / mL, Approx. 520ng h / mL, approx. 530 ng h / mL, approx. 540 ng h / mL, approx. 550 ng h / mL, approx. 560 ng h / mL, approx. 570 ng h / mL, approx. 580 ng h / mL, approx. 590 ng h / mL, approx. 600 ng h / mL, approx. 610 ng h / mL, approx. 620 ng h / mL, approximately 630 ng h / mL, approximately 640 ng h / mL, approximately 650 ng h / mL, approximately 660 ng h / mL, approximately 670 ng h / mL, approximately 680 ng h / mL, approximately 690 ng h / mL, approximately 700 ng h / mL, approximately 710 ng h / mL, approximately 720 ng H / mL / mL, approx. 730ng h / mL, approx. 740 ng h / mL, approx. 750 ng h / mL, approx. 760 ng h / mL, approx. 770 ng h / mL, approx. 780 ng h / mL, approx. 790 ng h / mL, approx. 800 ng h / mL, approx. 810 ng h / mL, approx.Approx. 830ng h / mL, approx. 840 ng h / mL, approx. 850 ng h / mL, approx. 860 ng h / mL, approx. 870 ng h / mL, approx. 890 ng h / mL, approx. 900 ng h / mL, approx. 910 ng h / mL, approx. 920 ng h / mL, approx. 930 ng h / mL, approx. 940 ng h / m L, approx. 950ng h / mL, approx. 960 ng h / mL, approx. 970 ng h / mL, approx. 980 ng h / mL, approx. 990 ng h / mL, approx. 1000 ng h / mL, approx. 1010 ng h / mL, approx. 1020 ng h / mL, approx. 1030 ng h / mL, approx. 1040 ng h / mL, approx. 10 AUC from about 20ng·h / mL to about 1200ng·h / mL, including 50ng·h / mL, about 1060ng·h / mL, about 1070ng·h / mL, about 1080ng·h / mL, about 1090ng·h / mL, about 1100ng·h / mL, about 1110ng·h / mL, about 1120ng·h / mL, about 1130ng·h / mL, about 1140ng·h / mL, about 1150ng·h / mL, about 1160ng·h / mL, about 1170ng·h / mL, about 1180ng·h / mL, about 1190ng·h / mL, and about 1200ng·h / mL (including all values ​​and partial ranges therebetween); 0-24h (expressed in ng·hr / mL). In some embodiments, the compositions provide an AUC of about 20 ng·h / mL to about 500 ng·h / mL after a single administration of the composition. 0-24h In some embodiments, the composition provides an AUC of about 80 ng·h / mL to about 750 ng·h / mL after a single administration of the composition. 0-24h In some embodiments, the composition provides an AUC of about 50 ng·h / mL to about 250 ng·h / mL after a single administration of the composition. 0-24h In some embodiments, the composition provides an AUC of about 40 ng·h / mL to about 300 ng·h / mL, or about 150 ng·h / mL to about 250 ng·h / mL, or about 50 ng·h / mL to about 150 ng·h / mL after a single administration of the composition. 0-24h In embodiments, the composition provides an AUC of about 20 ng·h / mL to about 500 ng·h / mL after a single administration of the composition. 0-24h(expressed in ng·hr / mL). In an embodiment, the composition is administered in a fed state. In an embodiment, the composition is administered in a fasted state.

[0228]

[0243] In some embodiments, the therapeutically effective mean steady state AUC 0-24h Zolmitriptan levels are provided by administering one or more compositions of the present disclosure to provide a daily dose of between about 7.5 mg and about 150 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof. In some further embodiments, the therapeutically effective mean steady-state AUC 0-24h Zolmitriptan levels are provided by administering a composition of the present disclosure containing between about 7.5 mg and about 150 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof once daily. In other further embodiments, the therapeutically effective mean steady-state AUC 0-24h Zolmitriptan levels are provided by administering twice daily a composition of the present disclosure containing between about 3.75 mg and about 75 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof. In other further embodiments, the therapeutically effective mean steady-state AUC 0-24h Zolmitriptan levels are provided by administering a composition of the present disclosure containing between about 2.5 mg and about 50 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof three times daily.

[0229]

[0244] In some embodiments, the composition provides a concentration of about 20 ng·h / mL, about 30 ng·h / mL, about 40 ng·h / mL, about 50 ng·h / mL, about 60 ng·h / mL, about 70 ng·h / mL, about 80 ng·h / mL, about 90 ng·h / mL, about 100 ng·h / mL, about 110 ng·h / mL, about 120 ng·h / mL, about 130 ng·h / mL, about 140 ng·h / mL, about 150 ng·h / mL, about 160 ng·h / mL, about 170 ng·h / mL, about 180 ng·h / mL, about 190 ng·h / mL, about 200 ng·h / mL, Approx. 210ng h / mL, approx. 220 ng h / mL, approx. 230 ng h / mL, approx. 240 ng h / mL, approx. 250 ng h / mL, approx. 260 ng h / mL, approx. 270 ng h / mL, approx. 280 ng h / mL, approx. 290 ng h / mL, approx. 300 ng h / mL, approx. 310 ng h / mL, approximately 320 ng h / mL, approximately 330 ng h / mL, approximately 340 ng h / mL, approximately 350 ng h / mL, approximately 360 ng h / mL, approximately 370 ng h / mL, approximately 380 ng h / mL, approximately 390 ng h / mL, approximately 400 ng h / mL, approximately 410 ng h / mL / mL, approximately 420ng h / mL, approximately 430ng h / mL, approximately 440ng h / mL, approximately 450ng h / mL, approximately 460 ng h / mL, approximately 470 ng h / mL, approximately 480 ng h / mL, approximately 490 ng h / mL, approximately 500 ng h / mL, approximately 510 ng h / mL, Approx. 520ng h / mL, approx. 530 ng h / mL, approx. 540 ng h / mL, approx. 550 ng h / mL, approx. 560 ng h / mL, approx. 570 ng h / mL, approx. 580 ng h / mL, approx. 590 ng h / mL, approx. 600 ng h / mL, approx. 610 ng h / mL, approx. 620 ng h / mL, approximately 630 ng h / mL, approximately 640 ng h / mL, approximately 650 ng h / mL, approximately 660 ng h / mL, approximately 670 ng h / mL, approximately 680 ng h / mL, approximately 690 ng h / mL, approximately 700 ng h / mL, approximately 710 ng h / mL, approximately 720 ng h / mL / mL, approximately 730ng h / mL, approximately 740ng h / mL, approximately 750ng h / mL, approximately 760ng h / mL, approximately 770 ng h / mL, approximately 780 ng h / mL, approximately 790 ng h / mL, approximately 800 ng h / mL, approximately 810 ng h / mL, approximately 820 ng h / mL,Approx. 830ng h / mL, approx. 840 ng h / mL, approx. 850 ng h / mL, approx. 860 ng h / mL, approx. 870 ng h / mL, approx. 880 ng h / mL, approx. 890 ng h / mL, approx. 900 ng h / mL, approx. 940ng·h / mL, approximately 950ng·h / mL, approximately 960ng·h / mL, approximately 970ng·h / mL, approximately 980ng·h / mL, approximately 990ng·h / mL, approximately 1000ng·h / mL, approximately 1010ng·h / mL, approximately 1020ng·h / mL, approximately 1030ng·h / mL, approximately 1040ng·h / an AUC of about 20 ng·h / mL to about 1200 ng·h / mL, including about 1050 ng·h / mL, about 1060 ng·h / mL, about 1070 ng·h / mL, about 1080 ng·h / mL, about 1090 ng·h / mL, about 1100 ng·h / mL, about 1110 ng·h / mL, about 1120 ng·h / mL, about 1130 ng·h / mL, about 1140 ng·h / mL, about 1150 ng·h / mL, about 1160 ng·h / mL, about 1170 ng·h / mL, about 1180 ng·h / mL, and about 1190 ng·h / mL to about 1200 ng·h / mL (including all values ​​and partial ranges therebetween); last (expressed in ng·hr / mL). In some embodiments, the compositions provide an AUC of about 50 ng·h / mL to about 250 ng·h / mL after a single administration of the composition. last In some embodiments, the composition provides an AUC of about 40 ng·h / mL to about 300 ng·h / mL, or about 150 ng·h / mL to about 250 ng·h / mL, or about 50 ng·h / mL to about 150 ng·h / mL after a single administration of the composition. last In embodiments, the composition provides an AUC of about 20 ng·h / mL to about 500 ng·h / mL after a single administration of the composition. last (expressed in ng·hr / mL). In an embodiment, the composition is administered in a fed state. In an embodiment, the composition is administered in a fasted state.

[0230]

[0245] In some embodiments, the compositions provide steady state plasma Cmax zolmitriptan levels that correlate with one or more statistically significant therapeutic effects when administered on a once-daily, twice-daily, or three-times-daily basis. In some embodiments, the therapeutically effective steady state plasma Cmax zolmitriptan levels provided by the zolmitriptan compositions of the present disclosure are about 0.5 ng / mL, about 1 ng / mL, about 1.5 ng / mL, about 2 ng / mL, about 2.5 ng / mL, about 3 ng / mL, 4 ng / mL, 5 ng / mL, 6 ng / mL, 7 ng / mL, 8 ng / mL, 9 ng / mL, about 10 ng / mL, about 15 ng / mL, about 20 ng / mL, about 25 ng / mL, about 30 ng / mL, about 35 ng / mL, about 40 ng / mL, about 45 ng / mL, about 50 ng / mL, about 55 ng / mL, about 60 ng / mL The range is from about 0.05 ng / mL to about 100 ng / mL, including about 65 ng / mL, about 70 ng / mL, about 75 ng / mL, about 80 ng / mL, about 85 ng / mL, about 90 ng / mL, about 95 ng / ml, and about 100 ng / mL (including all values ​​and ranges therebetween). In some embodiments, the therapeutically effective steady state plasma Cmax zolmitriptan levels provided by the zolmitriptan compositions of the present disclosure range from about 3 ng / mL to about 85 ng / mL. In an embodiment, the composition is administered in a prandial state. In an embodiment, the composition is administered in a fasted state.

[0231]

[0246] In some embodiments, the composition provides a concentration of about 1 ng / mL, about 2 ng / mL, about 3 ng / mL, about 4 ng / mL, about 5 ng / mL, about 6 ng / mL, about 7 ng / mL, about 8 ng / mL, about 9 ng / mL, about 10 ng / mL, about 11 ng / mL, about 12 ng / mL, about 13 ng / mL, about 14 ng / mL, about 15 ng / mL, about 16 ng / mL, about 17 ng / mL, about 18 ng / mL, about 19 ng / mL, about 20 ng / mL, about 21 ng / mL, about 22 ng / mL, about 23 ng / mL, about 24 ng / mL, about 25 ng / mL, or about 26 ng / mL after a single administration of the composition. L, about 26ng / mL, about 27ng / mL, about 28ng / mL, about 29ng / mL, about 30ng / mL, about 31ng / mL, about 32ng / mL, about 33ng / mL, about 34ng / mL, about 35ng / mL, about 36ng / mL, about 37ng / mL, about 38ng / mL, about 39ng / mL, approximately 40ng / mL, 41ng / mL, approximately 42ng / mL, approximately 43ng / mL, approximately 44ng / mL, approximately 45ng / mL, approximately 46ng / mL, approximately 47ng / mL, approximately 48ng / mL, approximately 49ng / mL, approximately 50ng / mL, approximately 51ng / mL, approximately 52ng / mL, approximately 53ng / mL, approximately 54ng / mL, approximately 55ng / mL, approximately 56ng / mL, approximately 57ng / mL, approximately 58ng / mL, approximately 59ng / mL, approximately 60ng / mL, approximately 61ng / mL, approximately 62ng / mL, approximately 63ng / mL, approximately 64ng / mL, approximately 65ng / mL, Approximately 66ng / mL, approximately 67ng / mL, approximately 68ng / mL, approximately 69ng / mL, approximately 70ng / mL, approximately 71ng / mL, approximately 72ng / mL, approximately 73ng / mL, approximately 74ng / mL, approximately 75ng / mL, approximately 76ng / mL, approximately 77ng / mL, approximately 78ng / mL, approximately 79n C of about 1 ng / mL to about 100 ng / mL, including about 80 ng / mL, about 81 ng / mL, about 82 ng / mL, about 83 ng / mL, about 84 ng / mL, about 85 ng / mL, about 86 ng / mL, about 87 ng / mL, about 88 ng / mL, about 89 ng / mL, about 90 ng / mL, about 91 ng / mL, about 92 ng / mL, about 93 ng / mL, about 94 ng / mL, about 95 ng / mL, about 96 ng / mL, about 97 ng / mL, about 98 ng / mL, about 99 ng / mL to about 100 ng / mL (including all values ​​and partial ranges therebetween). maxIn some embodiments, the composition has a C of about 1 ng / mL to about 80 ng / mL. max In some embodiments, the composition provides a C of about 3 ng / mL to about 30 ng / mL after a single administration of the composition. max In embodiments, the composition provides a C of about 5 ng / mL to about 60 ng / mL after a single administration of the composition. max In an embodiment, the composition is administered in a fed state. In an embodiment, the composition is administered in a fasted state.

[0232]

[0247] In some embodiments, therapeutically effective steady state plasma Cmax zolmitriptan levels are provided by administering one or more compositions of the present disclosure to provide a daily dose of between about 7.5 mg and about 150 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof. In some further embodiments, therapeutically effective steady state plasma Cmax zolmitriptan levels are provided by administering a composition of the present disclosure containing between about 7.5 mg and about 150 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof once a day. In other further embodiments, therapeutically effective steady state plasma Cmax zolmitriptan levels are provided by administering a composition of the present disclosure containing between about 3.75 mg and 75 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof twice a day. In other further embodiments, therapeutically effective steady state plasma Cmax zolmitriptan levels are provided by administering a composition of the present disclosure containing between about 2.5 mg and 50 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof three times a day. In some embodiments, a therapeutically effective steady state plasma Cmax zolmitriptan level is provided by administering one or more compositions of the present disclosure to provide a daily dose of about 12 mg to about 78 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof, including about 12 mg, about 24 mg, about 36 mg, about 48 mg to about 72 mg, including all values ​​and subranges therebetween.

[0233]

[0248] In some embodiments, the compositions provide a t of about 1 hour to about 24 hours, including about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours to about 24 hours (including all values ​​and subranges therebetween) after a single administration of the composition. 1 / 2 In some embodiments, the composition provides a t of about 5 hours to about 18 hours after a single administration of the composition. 1 / 2 In some embodiments, the composition has a plasma half-life (t) of about 8.5 hours to about 15 hours after a single administration of the composition. 1 / 2 ) is provided.

[0234]

[0249] In some embodiments, the composition provides a Tmax of about 1 hour to about 10 hours, including about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours to about 10 hours (including all values ​​and subranges therebetween) after a single administration of the composition, In some embodiments, the composition provides a Tmax of about 2 hours to about 5 hours after a single administration of the composition.

[0235]

[0250] A suitable pharmaceutical composition of the present disclosure can be administered to a subject by any clinically acceptable route of administration of the composition. The method of administering the composition depends, in part, on the cause and / or site. Those skilled in the art will recognize the advantages of certain routes of administration. The method includes administering an effective amount of an agent or compound (or a composition comprising an agent or compound), e.g., an amount effective to alleviate, ameliorate, or prevent, in whole or in part, the symptoms of the condition to be treated, e.g., symptoms associated with autism spectrum disorder, to achieve a desired biological response. In various aspects, the route of administration is systemic, e.g., oral, or by injection. In some embodiments, zolmitriptan, or a pharma- ceutically acceptable salt thereof, is administered orally, intranasally, transdermally, intrapulmonary, by inhalation, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, intraportally, or parenterally. In some embodiments, zolmitriptan is administered orally. In some embodiments, zolmitriptan is administered parenterally.

[0236] How to Treat the Symptoms of ASD

[0251] In some embodiments, the present disclosure provides a method for treating symptoms associated with autism spectrum disorder (ASD), comprising administering a zolmitriptan composition of the present disclosure. In some embodiments, the method comprises administering a zolmitriptan composition of the present disclosure as the only composition used to treat symptoms of ASD. In some embodiments, the method uses a zolmitriptan composition of the present disclosure in combination with one or more active ingredients used to treat symptoms of ASD. In some embodiments, the zolmitriptan composition of the present disclosure is administered in combination with additional active ingredients used to treat ASD, e.g., co-formulated or administered separately.

[0237]

[0252] Non-limiting examples of ASD symptoms include irritability, communication difficulties, social interaction difficulties, obsessive-compulsive interests, repetitive behaviors, inappropriate social interactions, poor eye contact, compulsive behaviors, impulsivity, repetitive movements, self-harm, repetitive words or actions, learning disabilities, delayed speech, intense interest in a limited number of things, problems paying attention, lack of awareness of other people's feelings, depression, anxiety, voice changes, sensitivity to sounds, and tics.In some embodiments, the patient in need of treatment shows a substantial reduction in the irritability associated with ASD compared to before the treatment.In some embodiments, the patient in need of treatment shows a substantial improvement in sociality compared to before the treatment.

[0238]

[0253] In some embodiments, the present disclosure provides a method for treating a symptom of ASD, comprising administering an effective amount of a zolmitriptan composition of the present disclosure. In some embodiments, the zolmitriptan composition is administered as a monotherapy. In some embodiments, the zolmitriptan composition is administered as an adjunct to a patient's existing therapy (e.g., current standard of care). In some embodiments, the zolmitriptan composition is administered as an adjunct to risperidone. In some embodiments, the zolmitriptan composition is administered as an adjunct to aripiprazole.

[0239]

[0254] In an embodiment, the present disclosure provides a method for treating irritability associated with autism, comprising administering an effective amount of a zolmitriptan composition of the present disclosure. In an embodiment, the present disclosure provides a method for treating autism-associated aggression, comprising administering an effective amount of a zolmitriptan composition of the present disclosure. In an embodiment, the present disclosure provides a method for treating autism-associated lethargy, comprising administering an effective amount of a zolmitriptan composition of the present disclosure. In an embodiment, the present disclosure provides a method for treating autism-associated social deficits, comprising administering an effective amount of a zolmitriptan composition of the present disclosure to improve socialization. In an embodiment, the present disclosure provides a method for reducing social deficits associated with autism, comprising administering an effective amount of a zolmitriptan composition of the present disclosure or a pharma- ceutically acceptable salt thereof.

[0240]

[0255] In some embodiments, following the treatment, the patient experiences a substantial reduction in symptoms of ASD as characterized by improvement on the Vineland Adaptive Behavior Scales, ADOS-2, CGI-C Social Deficits subscale, Aberrant Behavior Checklist, Autism Treatment Evaluation Checklist (ATEC), Social Responsiveness Scale, 2nd Edition (SRS-2), or any combination thereof.

[0241]

[0256] In embodiments, after said treatment, the patient experiences improvement in ASD symptoms as characterized by an improvement in the Autism Behavior Inventory (ABI)-Social Communication Domain Score compared to before treatment.

[0242]

[0257] The ABI-Social Communication Domain Score is a 62-item questionnaire to report on the behavior of subjects (ages: 3 years to adulthood) diagnosed with ASD. The tool is suitable for completion by parents or care / study partners of individuals with ASD. Each item assesses either the quality (never to need help) or frequency (never to very often) of a particular behavior. The Social Communication Domain Score is the sum of the Social Communication Domain scores divided by the number of items in this domain.

[0243]

[0258] In embodiments, after said treatment, the patient experiences an improvement in symptoms associated with ASD characterized by about a 20% improvement, about a 25% improvement, about a 30% improvement, about a 35% improvement, about a 40% improvement, about a 45% improvement, about a 50% improvement, about a 55% improvement, about a 60% improvement, about a 65% improvement, about a 70% improvement, about a 80% improvement, about a 90% improvement, or about a 95% improvement in ABI-Social Communication Domain score compared to before treatment.

[0244]

[0259] In some embodiments, after said treatment, the patient experiences an improvement in symptoms associated with ASD characterized by at least about a 20% improvement, at least about a 25% improvement, at least about a 30% improvement, at least about a 35% improvement, at least about a 40% improvement, at least about a 45% improvement, at least about a 50% improvement, at least about a 55% improvement, at least about a 60% improvement, at least about a 65% improvement, at least about a 70% improvement, at least about a 80% improvement, at least about a 90% improvement, or at least about a 95% improvement in ABI-Social Communication Domain score compared to before treatment.

[0245]

[0260] In embodiments, after said treatment, the patient experiences improvement in ASD symptoms as characterized by improvement as measured by Clinician Global Impression of Improvement (CGI-I) score compared to pre-treatment.

[0246]

[0261] The CGI-I score is a single-item instrument based on a 7-point scale used to capture the investigator's global impression of the response. The investigator or designee rates the observed improvement from 1 to 7 (1=very much improved; 2=very much improved; 3=slightly improved; 4=no change; 5=slightly worse; 6=very much worse; 7=very much worse).

[0247]

[0262] In embodiments, after said treatment, the patient exhibits improvement in symptoms associated with ASD compared to before treatment, with a post-treatment CGI-I score of about 1, about 2, about 3, about 4, or about 5. In embodiments, after said treatment, the patient exhibits improvement in symptoms associated with ASD, with a CGI-I score of about 1, about 2, or about 3. In embodiments, after said treatment, the patient exhibits improvement in symptoms associated with ASD, with a CGI-I score of about 1 or 2.

[0248]

[0263] In some embodiments, after said treatment, the patient experiences improvement in symptoms associated with ASD, as characterized by improvement in Autism Behavior Inventory-Clinician (ABI-C) scores compared to before treatment.

[0249]

[0264] The ABI-Clinician (ABI-C) captures the clinician's assessment of the behavior of individuals with ASD during the week prior to their assessment. It includes 14 items reflecting core and relevant autism behavior domains: social communication, restricted behaviors, mood and anxiety, self-regulation, and challenging behaviors. Each item is rated on a 7-point scale ranging from 1 (not at all; no symptoms observed) to 7 (very severe; consistently interfering with functioning or adjustment).

[0250]

[0265] In some embodiments, the patient experiences an improvement in symptoms characterized by about a 20% improvement, about a 25% improvement, about a 30% improvement, about a 35% improvement, about a 40% improvement, about a 45% improvement, about a 50% improvement, about a 55% improvement, about a 60% improvement, about a 65% improvement, about a 70% improvement, about a 80% improvement, about a 90% improvement, or about a 95% improvement in ABI-C score compared to before treatment.

[0251]

[0266] In some embodiments, the patient experiences an improvement in symptoms characterized by at least about a 20% improvement, at least about a 25% improvement, at least about a 30% improvement, at least about a 35% improvement, at least about a 40% improvement, at least about a 45% improvement, at least about a 50% improvement, at least about a 55% improvement, at least about a 60% improvement, at least about a 65% improvement, at least about a 70% improvement, at least about a 80% improvement, at least about a 90% improvement, or at least about a 95% improvement in ABI-C score compared to pre-treatment.

[0252]

[0267] In some embodiments, after said treatment, the patient experiences improvement in ASD symptoms as characterized by improvement as measured by ABI repetitive / restricted behaviors domain score compared to before treatment.

[0253]

[0268] Each item in the ABI-Repetitive / Restricted Behaviors domain is scored according to frequency (0 = never to 3 = very often). The domain score is the sum of all domain item scores divided by the number of items in this domain.

[0254]

[0269] In some embodiments, after said treatment, the patient experiences improvement in symptoms of ASD, as characterized by improvement according to ABI Challenging Behavior Domain score compared to before treatment.

[0255]

[0270] Each item in the ABI-Challenging Behaviors domain is scored by frequency (0 = never to 3 = very often). The domain score is the sum of all domain item scores divided by the number of items in this domain.

[0256]

[0271] In some embodiments, after said treatment, the patient experiences improvement in ASD symptoms as characterized by improvement in ABI-Short Form (ABI-S) scores compared to before treatment.

[0257]

[0272] The ABI-S is a 24-item shortened version of the ABI that includes items from each of the five domains. The domain score for each domain is calculated as the sum of the scores of all domain items divided by the number of items in this domain.

[0258]

[0273] In some embodiments, after said treatment, the patient experiences improvement in symptoms of ASD as characterized by improvement in ABC-Social Withdrawal (ABC-SW) subscale scores compared to before treatment.

[0259]

[0274] The ABC-SW subscale consists of 16 items from the ABC-2 that are scored from 0 (no problem) to 3 (severe problem).

[0260]

[0275] In some embodiments, after the treatment, the patient experiences improvement in ASD symptoms as characterized by an improvement in the Vineland-3 (Domain Level Version) score: sum of communication, socialization, and maladaptive behavior domains compared to before the treatment.

[0261]

[0276] The Vineland-3 Domain-Level Version includes five domains. Responses to each item are scored from 0 (never) to 2 (always).

[0262]

[0277] The Vineland Adaptive Behavior Scales (VABS), Third Edition, is a standardized measure of adaptive behavior used to assess an individual's personal and social skills from birth to adulthood. Individuals may be assessed on the VABS scale by either a teacher or a caregiver. According to the VABS, individuals are assigned a VABS Adaptive Behavior Composite Score, which measures the individual's functionality compared to others of their age. Individuals are also assigned domain scores in communication, daily living skills, socialization, and motor skills, which assess the strengths and weaknesses of the individual's adaptive behavior. Individuals are given a score of 20-140 for each of the domain scores and the VABS Adaptive Behavior Composite Score. A score of 20-70 represents a low level of adaptation. A score of 71-85 represents a moderately poor level of adaptation. A score of 86-114 represents a moderately adequate level of adaptation. A score of 115-129 represents a moderately high level of adaptation. A score of 130-140 indicates a high level of adaptation.

[0263]

[0278] In some embodiments, after the treatment, the patient experiences a reduction in symptoms associated with ASD characterized by at least a 1 point increase in the VABS Adaptive Behavior Composite score compared to before the treatment. In some embodiments, the increase in the VABS Adaptive Behavior score is about 1 point, about 2 points, about 3 points, about 4 points, about 5 points, about 6 points, about 7 points, about 8 points, about 9 points, about 10 points, about 11 points, about 12 points, about 13 points, about 14 points, about 15 points, about 16 points, about 17 points, about 18 points, about 19 points, about 20 points, about 21 points, about 22 points, about 23 points, about 24 points, about 25 points, about 26 points, about 27 points, about 28 points, about 29 points, about 30 points, about 31 points, about 32 points, about 33 points, about 34 points, about 35 points, about 36 points, about 37 points, about 38 points, about 39 points, about 40 points, about 41 points, about 42 points, about 43 points, about 44 points, about 45 points, about 46 points, about 47 points, about 48 points, about 49 points, about 50 points, about 51 points, about 52 points, about 53 points, about 54 points, about 55 points, about 56 points, about 57 points, about 58 points, about 59 points, about 60 points, about 61 points, about 62 points, about 63 points, about 64 points, about 65 points, about 66 points, about 67 points, about 68 points, about 69 points, about 70 points, about 71 points, about 72 points, about 73 points, about 74 points, about 75 points, about 76 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 points.

[0264]

[0279] In some embodiments, the increase in the VABS Adaptive Behavior Composite score is at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, or at least about 60% compared to before said treatment.

[0265]

[0280] In some embodiments, after said treatment, the patient exhibits increased socialization as characterized by an increase in the VABS Adaptive Behavior Socialization Domain score compared to before said treatment. In some embodiments, the increase in the VABS Adaptive Behavior Socialization Domain score compared to before said treatment is about 1 point, about 2 points, about 3 points, about 4 points, about 5 points, about 6 points, about 7 points, about 8 points, about 9 points, about 10 points, about 11 points, about 12 points, about 13 points, about 14 points, about 15 points, about 16 points, about 17 points, about 18 points, about 19 points, about 20 points, about 21 points, about 22 points, about 23 points, about 24 points, about 25 points, about 26 points, about 27 points, about 28 points, about 29 points, about 30 points, about 31 points, about 32 points, or about 33 points. , about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, or about 70 points.

[0266]

[0281] In some embodiments, the increase in the VABS Adaptive Behavior Socialization domain score is at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, or at least about 60% compared to before said treatment. In some embodiments, the patient experiences at least a 10% improvement in the VABS Socialization domain score after treatment. In some embodiments, the patient experiences at least a 35% improvement in the VABS Socialization domain score after treatment.

[0267]

[0282] In some embodiments, after said treatment, the patient experiences improved communication as characterized by an increase in the VABS Adaptive Behavior Communication Domain score compared to before treatment. In some embodiments, the increase in the VABS Adaptive Behavior Communication Domain is about 1 point, about 2 points, about 3 points, about 4 points, about 5 points, about 6 points, about 7 points, about 8 points, about 9 points, about 10 points, about 11 points, about 12 points, about 13 points, about 14 points, about 15 points, about 16 points, about 17 points, about 18 points, about 19 points, about 20 points, about 21 points, about 22 points, about 23 points, about 24 points, about 25 points, about 26 points, about 27 points, about 28 points, about 29 points, about 30 points, about 31 points, about 32 points, or about 33 points compared to before treatment. , about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, or about 70 points.

[0268]

[0283] In some embodiments, the increase in the VABS Adaptive Behavior Communication Domain score compared to before said treatment is at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, or at least about 60%.

[0269]

[0284] The Autism Diagnostic Observation Schedule, 2nd Edition (ADOS-2) is an instrument that allows for accurate assessment and diagnosis of ASD across all ages, developmental levels, and language skills. The ADOS-2 is a clinician-administered observational assessment that includes two behavioral domains: social-emotional (SA) and restricted repetitive behaviors (RRB). Individuals are administered one of five ADOS-2 modules, selected based on the individual's expressive language level and chronological age. The toddler module is for children aged 12-30 months who do not use consistent phrased speech. Module 1 is for children aged 31 months and older who do not use consistent phrased speech. Module 2 is for children of any age who use phrased speech but are not fluent in speech. Module 3 is for children and adolescents who are fluent in speech. Module 4 is for later adolescents and adults who are fluent in speech. Individuals are assigned an ADOS-2 composite total score ranging from 1 to 10. Individuals with ASD are characterized by an ADOS-2 composite total score of 6 to 10.

[0270]

[0285] In some embodiments, the patient experiences a reduction in symptoms associated with ASD associated with at least a 1 point decrease in the ADOS-2 composite total score compared to before said treatment, in some embodiments, the patient experiences an improvement in symptoms of ASD characterized by a decrease of at least 1 point, at least 2 points, at least 3 points, at least 4 points, or at least 5 points on the ADOS-2 composite total score compared to before said treatment.

[0271]

[0286] In some embodiments, the patient experiences improvement in symptoms of ASD characterized by at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 25%, or at least about 30%, or at least about 35%, or at least about 40%, or at least about 45%, or at least about 50%, or at least about 55%, or at least about 60%, or at least about 65%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90% improvement in ADOS-2 composite score compared to before said treatment.

[0272]

[0287] In some embodiments, the patient experiences a reduction in symptoms associated with ASD, characterized by a decrease in ADOS-2 Module 4 social-emotional score of at least 1 point compared to before the treatment. In some embodiments, the decrease in ADOS-2 Module 4 social-emotional score correlates with improved sociality. In some embodiments, the improvement in sociality is characterized by a decrease in social-emotional score of at least 1 point, or at least 2 points, or at least 3 points, or at least 4 points, or at least 5 points, or at least 6 points on the ADOS-2 Module 4 compared to before the treatment.

[0273]

[0288] In some embodiments, improved sociality is characterized by at least a 10%, or at least a 15%, or at least a 20%, or at least a 25%, or at least a 30%, or at least a 35%, or at least a 40%, or at least a 45%, or at least a 50%, or at least a 55% decrease in the Social Emotional scale on the ADOS-2 Module 4 compared to before said treatment. In some embodiments, the patient exhibits improved sociality characterized by at least a 10% decrease in Social Interactions score on the Autism Diagnostic Observation Schedule Module 4 compared to before said treatment.

[0274]

[0289] The Clinical Global Impression-Severity (CGI-S) scale is used by clinicians to rate the severity of symptoms in individuals with ASD. Individuals are assigned a score from 1 to 7, with a score of 1 corresponding to a normal individual. A score of 7 corresponds to an individual with ASD.

[0275]

[0290] In some embodiments, after said treatment, the patient experiences a reduction in symptoms associated with ASD, characterized by at least a 1 point decrease in CGI-S score compared to before said treatment, hi some embodiments, the patient experiences at least a 1 point, or at least 2 point, or at least 3 point, or at least 4 point, or at least 5 point decrease on the CGI-S scale compared to before said treatment.

[0276]

[0291] In some embodiments, the patient experiences at least a 5%, or at least a 10%, or at least a 15%, or at least a 20%, or at least a 25%, or at least a 30%, or at least a 35%, or at least a 40%, or at least a 45%, or at least a 50%, or at least a 55%, or at least a 60%, or at least a 65%, or at least a 70%, or at least a 75%, or at least a 80%, or at least a 85%, or at least a 90% reduction in the CGI-S scale compared to before said treatment.

[0277]

[0292] The Clinical Global Impression-Severity (CGI-C) scale is used by clinicians to assess symptom change in individuals with ASD. Individuals are assigned a score from 1 (much improved) to 7 (much worse).

[0278]

[0293] In some embodiments, after said treatment, the patient experiences a reduction in symptoms associated with ASD, characterized by at least a one point decrease on the CGI-C scale. In some embodiments, after said treatment, the patient experiences an improvement in irritability, characterized by a CGI-C score of 1 or less, 2 or less, 3 or less, or 4 or less. In some embodiments, after said treatment, the patient experiences an improvement in irritability, characterized by a Clinical Global Impression-Change (CGI-C) score of 3 or less. In some embodiments, after said treatment, the patient experiences an improvement in sociality, characterized by a CGI-C score of 1 or less, 2 or less, 3 or less, or 4 or less. In some embodiments, after said treatment, the patient experiences an improvement in sociality, characterized by a CGI-C score of 3 or less.

[0279]

[0294] The Autism Behavior Inventory (ABI) Social Deficits subscale is a scale used to assess change in core and associated symptoms of ASD. Individuals are administered the ABI-Full (93 items) or ABI-Short (36 items) scale. For each item on the scale, individuals are given a score from 0 to 6, where 0 is no symptoms and 6 is maximum symptoms. Individuals who score 0 do not exhibit symptoms. Individuals assigned a score of 6 exhibit severe ASD symptoms.

[0280]

[0295] In some embodiments, the patient experiences improvement in symptoms characterized by a decrease in the ABI score of at least 1 point. In some embodiments, the patient experiences improvement in symptoms characterized by a decrease in the ABI score of at least 1 point, or at least 2 points, or at least 3 points, or at least 4 points compared to before said treatment.

[0281]

[0296] In some embodiments, the patient experiences improvement in symptoms characterized by a reduction in ABI score of at least 5%, or at least 10%, or at least 15%, or at least 20%, or at least 25%, or at least 30%, or at least 35%, or at least 40%, or at least 45%, or at least 50%, or at least 55%, or at least 60%, or at least 65%, or at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90%, or at least 95% compared to before said treatment.

[0282]

[0297] The Childhood Autism Rating Scale (CARS) is used to identify children aged 2 years and older who have ASD. The CARS consists of 14 domains that assess behaviors associated with ASD, with a 15th domain assessing the overall impression of autism. Each domain is scored on a scale ranging from 1 to 4; higher scores are associated with higher levels of impairment. Total scores can range from a low of 15 to a high of 60; a score below 30 indicates that the individual does not fall within the autism spectrum, a score of 30 to 36.5 indicates mild to moderate autism, and a score of 37 to 60 indicates severe autism.

[0283]

[0298] In some embodiments, after said treatment, the patient experiences a reduction in symptoms associated with ASD, characterized by a reduction in the CARS total score of about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, or about 30 points compared to before said treatment.

[0284]

[0299] In some embodiments, after said treatment, the patient experiences a reduction in symptoms associated with ASD, characterized by a reduction in CARS total score of at least 5%, or at least 10%, or at least 15%, or at least 20%, or at least 25%, or at least 30%, or at least 35%, or at least 40%, or at least 45%, or at least 50%, or at least 55%, or at least 60%, or at least 65%, or at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90%, or at least 95% compared to before said treatment.

[0285]

[0300] The Interpersonal Responsiveness Scale, Second Edition (SRS-2) is utilized to obtain an efficient quantitative measure of various dimensions of interpersonal behavior, communication, and repetitive / stereotypic behaviors associated with ASD. According to the SRS-2, individuals are assigned a proxy total t-score based on the SRS-2. Individuals are assigned a proxy t-score that reflects the sum of their responses to the 65 Interpersonal Responsiveness Scale questions, which is an index of social skill severity across the entire autism spectrum. Individuals who score a proxy t-score higher than 76 receive a severe ASD clinical diagnosis. When an individual is assigned a proxy t-score between 66 and 75, it is associated with a moderate impairment in reciprocal social behavior that leads to substantial impairment in everyday social interactions that are clinically significant. When an individual is assigned a proxy t-score between 60 and 65, the individual exhibits mild to moderate impairment in social interaction. If a patient exhibits a proxy t-score of 59 or less, the patient exhibits normal social interaction.

[0286]

[0301] In some embodiments, prior to administering the zolmitriptan composition to a patient in need thereof, the patient in need thereof exhibits a proxy-reported sum t-score of 66 or greater.

[0287]

[0302] In some embodiments, the patient experiences improvement in symptoms characterized by a reduction in proxy version total t-score of at least 1 point, or at least 2 points, or at least 3 points, or at least 4 points, or at least 5 points, or at least 6 points, or at least 7 points, or at least 8 points, or at least 9 points, or at least 10 points, or at least 11 points, or at least 12 points, or at least 13 points, or at least 14 points, or at least 15 points, or at least 16 points, or at least 17 points, or at least 18 points, or at least 20 points, or at least 21 points, or at least 22 points, or at least 23 points, or at least 24 points, or at least 25 points compared to before said treatment. In some embodiments, the patient experiences improvement in symptoms characterized by a reduction in the proxy version of the SRS-2 total t-score of at least 5%, or at least 10%, or at least 15%, or at least 20%, or at least 25%, or at least 30%, or at least 35%, or at least 40%, or at least 45%, or at least 50%, or at least 55%, or at least 60%, or at least 65%, or at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90%, or at least 95% compared to before said treatment.

[0288]

[0303] The Interpersonal Responsiveness Scale for Adults (SRS-A) is a tool to assess interpersonal responsiveness in adults. The SRS-A includes 65 items that are scored from 0 to 3. If an individual scores 0, the individual does not have the condition. If an individual scores 3, the individual has severe symptoms. An SRS-A total score of 67 indicates that an individual has ASD. The maximum possible SRS-A total score is 195.

[0289]

[0304] In some embodiments, after the treatment, the patient exhibits a reduction in symptoms associated with ASD characterized by about a 5%, about a 10%, about a 15%, about a 20%, about a 25%, about a 30%, about a 35%, about a 40%, about a 45%, about a 50%, about a 55%, about a 60%, about a 65%, about a 70% reduction in SRS-A score compared to before the treatment. In some embodiments, after the treatment, the patient exhibits a reduction in symptoms associated with ASD characterized by at least a 10% reduction in SRS-A score compared to before the treatment.

[0290]

[0305] In some embodiments, improvement in sociality is associated with about a 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or about 50% reduction in SRS-A score compared to before said treatment.

[0291]

[0306] The Aberrant Behavior Checklist (ABC) is a behavioral rating scale used to rate individuals on five subscales: (1) irritability, agitation, and crying; (2) lethargy and withdrawal; (3) stereotypic behaviors; (4) hyperactivity and noncompliance; and (5) inappropriate speech. An individual can be assessed on the ABC by any adult who knows the individual well. The ABC contains a 58-item questionnaire used to rate the five subscales. Each item on the 58-item questionnaire is rated from 0 to 3. A score of 0 means the symptom is absent. A score of 3 means the individual has a high severity of the symptom. The items within each subscale are added together to arrive at a subscale score. Possible subscale scores on the ABC range from 0 to 48, with higher subscores indicating behavioral disturbance.

[0292]

[0307] In some embodiments, after said treatment, the patient exhibits a reduction in symptoms associated with ASD, characterized by at least a one point decrease in the ABC Irritability, Agitation, and Crying (ABC-I) subscore. In some embodiments, after said treatment, the patient exhibits a reduction in irritability, characterized by a decrease in the ABC-I Communication domain score, compared to before treatment.

[0293]

[0308] In some embodiments, the patient presents with an ABC-I score of 18 or greater prior to treatment.

[0294]

[0309] In some embodiments, after said treatment, the patient experiences a reduction in irritability characterized by a decrease in ABC-I domain score of about 2, about 4, about 6, about 8, about 10, about 15, about 20, about 25, or about 30 points compared to before said treatment. In some embodiments, the decrease in ABC-I domain score is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% compared to before said treatment. In some embodiments, the reduction in ABC-I domain score compared to before treatment is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or about at least 95%.

[0295]

[0310] In an embodiment, following said treatment, the patient experiences a reduction in irritability characterized by a 25% reduction on the Irritability subscale, and wherein the patient is rated as greatly improved or very greatly improved (i.e., 2 or 1, respectively) on the CGI Improvement Scale.

[0296]

[0311] In some embodiments, after said treatment, the patient exhibits a reduction in symptoms associated with ASD, characterized by at least a one point reduction in the ABC-Amotivation and Withdrawal (ABC-LSW) subscore compared to before said treatment. In some embodiments, after said treatment, the patient exhibits a reduction in amotivation and withdrawal, characterized by a reduction in the ABC-LSW Communication domain score compared to before said treatment.

[0297]

[0312] In some embodiments, the reduction in the ABC-LSW Communication Domain score is about 2 points, about 4 points, about 6 points, about 8 points, about 10 points, about 15 points, about 20 points, about 25 points, or about 30 points compared to before said treatment.

[0298]

[0313] In some embodiments, the reduction in the ABC-LSW Communication Domain score is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% compared to before said treatment.

[0299]

[0314] The Social Communication Questionnaire is a tool used by physicians to screen individuals with ASD. An individual's caregiver rates the individual on a scale of 0 to 39 for verbal individuals or 0 to 33 for non-verbal individuals. Individuals with ASD are characterized by a Social Communication Questionnaire score above 15.

[0300]

[0315] In some embodiments, after said treatment, the patient experiences a reduction in symptoms associated with ASD characterized by at least a 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% decrease in Social Communication Questionnaire scale compared to before said treatment.

[0301]

[0316] The Pervasive Developmental Disorders Behavior Inventory (PDDBI) is utilized to determine the effectiveness of ASD treatments. The PDDBI assesses both problem behaviors and appropriate social, language, and learning / memory skills. The PDDBI is divided into two behavioral dimensions: (a) approach-avoidance problems, which assess maladaptive behaviors, and (b) receptive / expressive social communication skills, which assess social communication skills. The approach-avoidance problems dimension is subdivided into behavioral domains including sensory / perceptual approach behaviors, ritualistic behaviors / resistance to change (RITUAL), social pragmatic problems (SOCPP), semantic / pragmatic problems (SEMPP), arousal control problems (AROUSE), specific fears (FEARS), and aggression (AGG) domains. The receptive / expressive social communication skills (REXSCA), which assesses social communication skills, is subdivided into behavioral domains including social approach behaviors (SOCAPP), expressive language (EXPRESS), and learning, memory, and receptive language (LMRL) domains. Individuals receive a T-score for each domain and a composite score that is the sum of the scores for each domain. Individuals with ASD are assigned a T-score above 50.

[0302]

[0317] In some embodiments, the Pervasive Developmental Disorder Behavior Inventory (PDDBI) is utilized to characterize the reduction in symptoms associated with ASD provided by the methods of the present disclosure. In some embodiments, the patient exhibits a T-score greater than 50 prior to the treatment. In some embodiments, after the treatment, the patient exhibits a reduction in symptoms associated with ASD characterized by a decrease in PDDBI of about 5%, or about 10%, or about 15%, or about 20%, or about 25%, or about 30%, or about 35%, or about 40%, or about 45%, or about 50%, or about 55%, or about 60%, or about 65%, or about 70%, or about 75%, or about 80%, or about 85%, or about 90%, or about 95% compared to before the treatment.

[0303]

[0318] The ATEC is a measure utilized to determine the effectiveness of ASD treatments. The ATEC is a one-page form designed to be completed by a parent, teacher, or caregiver. The ATEC consists of four subtests: Speech / Language Communication, Social, Sensory / Cognitive Awareness, and Health / Physical / Behavior. Individuals are assigned a Speech / Language Communication subtest rating of 0-28. Individuals are assigned a Social subtest rating of 0-40. Individuals are assigned a Sensory / Cognitive Awareness subtest rating of 0-36. Individuals are assigned a Health / Physical / Behavior subtest rating of 0-75. The individual subsets are summed and an individual can receive a maximum score of 180 points.

[0304]

[0319] In some embodiments, after the treatment, the patient experiences a reduction in symptoms associated with ASD, characterized by a decrease in mean ATEC score compared to before the treatment. In some embodiments, after the treatment, the patient experiences an improvement in speech / language communication, characterized by a decrease in speech / language communication subtest rating compared to before the treatment. In some embodiments, after the treatment, the patient experiences an improvement in sociality, characterized by a decrease in social subtest rating compared to before the treatment. In some embodiments, after the treatment, the patient experiences an improvement in sensory / cognitive awareness, characterized by a decrease in sensory / cognitive awareness subtest rating compared to before the treatment. In some embodiments, after the treatment, the patient experiences an improvement in health / physical / behavior, characterized by a decrease in health / physical / behavior rating compared to before the treatment.

[0305]

[0320] In some embodiments, the patient exhibits a decrease of at least 1 point, or about 2 points, or about 3 points, or about 4 points, or about 5 points, or about 6 points, or about 7 points, or about 8 points, or about 9 points, or about 10 points, or about 11 points, or about 12 points, or about 13 points, or about 14 points, or about 15 points, or about 16 points, or about 17 points, or about 18 points, or about 19 points, or about 20 points on the social subsection of the ATEC compared to before said treatment. In some embodiments, the patient exhibits a decrease of at least 1 point on the social subsection of the ATEC compared to before said treatment.

[0306]

[0321] In some embodiments, the patient exhibits at least a 5%, or at least a 10%, or at least a 15%, or at least a 20%, or at least a 25%, or at least a 30%, or at least a 35%, or at least a 40%, or at least a 50% decrease on the social subsection of the ATEC compared to before said treatment, hi some embodiments, the patient exhibits at least a 10% decrease on the social subsection of the ATEC compared to before said treatment.

[0307]

[0322] Objective / performance-based assessments are utilized to measure the reduction in symptoms associated with ASD after administering a therapeutically effective amount of a triptan to a patient in need thereof. In some embodiments, the objective / performance-based assessments are selected from the group consisting of social stimuli eye tracking, the Parental Engagement Inventory (JERI), and Noldus Ethovision analysis. In some embodiments, social stimuli eye tracking is utilized to characterize the reduction in symptoms associated with ASD provided by the methods of the present disclosure. ASD patients exhibit significantly shorter eye contact when compared to peers without ASD. ASD patients have more difficulty finding and processing relevant social information when stimuli are presented more quickly.

[0308]

[0323] PCIT provides a training method designed to help adults improve their parenting and language skills, and to help children learn how to better control their emotions. In some embodiments, the parent-child interaction task (PCIT) is used to improve relationships between caregivers and ASD patients. In some embodiments, PCIT helps reduce child behavior problems and improve communication and interaction skills among family members. In some embodiments, children who participate in CPT develop higher self-esteem, become less angry and frustrated, show improved social, organizational, and play skills, feel more secure and calm, and communicate more effectively.

[0309]

[0324] The Joint Engagement Ranking Inventory (JERI) is a tool used to measure early intervention goals for developmental disorders and delays, including ASD. The JERI is an 18-item inventory developed to measure relevant intervention goals, including disengagement, object engagement, joint engagement, stereotyped and restricted repetitive behaviors, attention to caregiver, initiating communication, expressive language level and use, scaffolding, following, caregiver affect, fluency, and connection, and sharing habitual and ritualistic behaviors. Individuals assessed on the JERI scale score a score from 1 to 7 for each item on the JERI inventory. A score of 7 is assigned to individuals with most joint engagement. Individuals with no episodes of joint engagement are assigned a score of 1 on an item. Lower scores on the JERI scale correlate with ASD.

[0310]

[0325] In some embodiments, a reduction in symptoms of ASD is associated with a lower JERI score compared to before treatment with the disclosed methods. In some embodiments, after the treatment, the patient experiences a reduction in symptoms associated with ASD, characterized by a lower JERI score compared to before treatment. In some embodiments, the JERI score is reduced by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, or about 70% compared to before treatment.

[0311]

[0326] The Ohio State University Autism Rating Scale (OARS-5) measures persistent social interaction impairments, restricted interests / activities and repetitive behaviors, and levels of social, academic, and community support (Hollway, JA, Arnold, LE, & Aman, MG (2017, September). OSU Autism Rating Scale - DSM-5 (OARS-5).). The OARS-5 was developed to provide three summary scores: (A) an autism symptom count (OARS-5 total score) based on a clinical interview; (b) a weighted mean severity score derived from the clinical interview based on the severity of autism symptoms; and (c) a disability index ranging from 0 to 9 based on the level of support needed due to severity. The OARS-5 total score is equal to the OARS-5 social deficit subscale score + the OARS-5 restricted interest pattern subscale score.

[0312]

[0327] The OARS-5 includes the following subscales:

[0328] Section A: persistent social interaction impairment across multiple settings (OARS-5 social deficits subscale scores);

[0329] Section B: Restricted interests / activities and repetitive behavior patterns (OARS-5 Restricted Interest Patterns subscale scores) and

[0330] Section C: Level of support for Sections A (social interaction / communication) and B (restricted repetitive behaviors).

[0313]

[0331] In some embodiments, after the treatment, the patient experiences a reduction in symptoms associated with ASD, characterized by a decrease in OARS-5 total score compared to before the treatment. In some embodiments, after the treatment, the patient experiences a reduction in symptoms associated with ASD, characterized by a decrease in OARS-5 total score of about 1 point, about 2 points, about 3 points, or about 4 points, about 5 points, about 6 points, about 7 points, about 8 points, about 9 points, or about 10 points compared to before the treatment.

[0314]

[0332] In some embodiments, after the treatment, the patient experiences a reduction in symptoms associated with ASD, characterized by a decrease in OARS-5 social deficit subscale score compared to before the treatment. In some embodiments, after the treatment, the patient experiences a reduction in symptoms associated with ASD, characterized by a decrease in OARS-5 social deficit subscale score of about 1 point, about 2 points, about 3 points, or about 4 points, about 5 points, about 6 points, about 7 points, about 8 points, or about 9 points compared to before the treatment.

[0315]

[0333] In some embodiments, after the treatment, the patient exhibits a reduction in symptoms associated with ASD, as characterized by a decrease in the Ohio State University Autism Clinical Global Impression (OSU Autism CGI) total score compared to before the treatment. The OSU Autism CGI-S total score is equal to the OSU Autism CGI-Severity Scale (OSU Autism CGI-S) score + the OSU Autism CGI-Improvement Scale (OSU Autism CGI-I) score.

[0316]

[0334] In some embodiments, after the treatment, the patient experiences a reduction in symptoms associated with ASD, characterized by a decrease in the OSU Autism CGI total score of about 1 point, about 2 points, about 3 points, or about 4 points, about 5 points, about 6 points, or about 7 points compared to before the treatment.

[0317]

[0335] In some embodiments, after the treatment, the patient experiences a reduction in symptoms associated with ASD, characterized by a decrease in the Ohio State University Autism Clinical Global Impression-Improvement (OSU Autism CGI-I) score compared to before the treatment. In some embodiments, after the treatment, the patient experiences a reduction in symptoms associated with ASD, characterized by a decrease of about 1, about 2, about 3, or about 4, about 5, about 6, or about 7 points on the OSU Autism CGI-I compared to before the treatment.

[0318]

[0336] In some embodiments, after the treatment, the patient exhibits a reduction in symptoms associated with ASD, characterized by a decrease in the Ohio State University Autism Clinical Global Impression-Severity Scale (OSU Autism CGI-S) score compared to before the treatment. In some embodiments, after the treatment, the patient exhibits a reduction in symptoms associated with ASD, characterized by a decrease of about 1, about 2, about 3, or about 4, about 5, about 6, or about 7 points on the OSU Autism CGI-S compared to before the treatment.

[0319]

[0337] Patient population

[0338] In some embodiments, the present disclosure provides a method of treating a symptom of ASD, comprising administering to a patient in need thereof an effective amount of a zolmitriptan composition of the present disclosure.

[0320]

[0339] In an embodiment, the patient is an adolescent or adult with autism spectrum disorder (ASD). In an embodiment, the patient is at least 12 years old. In an embodiment, the patient is between 12 and 45 years old.

[0321]

[0340] In some embodiments, a patient in need thereof is a patient diagnosed with ASD according to DSM-5 diagnostic criteria.

[0322]

[0341] In some embodiments, prior to treatment according to the methods of the present disclosure, an ASD patient in need thereof has a full-scale IQ score of 70 or greater on the Weschsler Abbreviated Scale of Intelligence (WASI®)-II.

[0323]

[0342] In some embodiments, the present disclosure provides a method for treating the symptoms associated with ASD that are refractory to existing ASD treatments.In some embodiments, the symptoms associated with ASD are refractory to aripiprazole treatment.In some embodiments, the symptoms associated with ASD are refractory to risperidone treatment.

[0324]

[0343] In some embodiments, the ASD patient to be treated exhibits atypical sensory processing. Sensory processing refers to the ability to register, process, and organize sensory information and to execute appropriate responses to environmental demands, which manifests as hyper- or hypo-sensitivity to stimuli. A patient in need with atypical sensory processing may have aversion to the color, taste, smell, and / or texture of food or medicine. In some embodiments, atypical sensory processing manifests in a patient in need as non-compliance with prescribed medication. In some embodiments, the ASD patient to be treated refuses to swallow prescribed medication. In some embodiments, the prescribed medication is a liquid formulation or a pill.

[0325]

[0344] In some embodiments, the ASD patient to be treated is an infant. In some embodiments, the ASD patient to be treated is a child. In some embodiments, the ASD patient to be treated is an adolescent. In some embodiments, the ASD patient to be treated is an adult. In some embodiments, the ASD patient to be treated is an elderly patient. EXAMPLES

[0326] Working Example

[0345] The present disclosure is further illustrated by reference to the following examples, however, it is noted that these examples, like the embodiments described above, are illustrative and should not be construed as limiting the scope of the invention in any way.

[0327] Example 1. Pharmacokinetic simulation of zolmitriptan administration

[0346] Steady-state simulations of zolmitriptan human plasma concentration-time data for various dosing regimens were performed using nonparametric superposition. Nonparametric superposition pharmacokinetic profiles were derived from median plasma zolmitriptan concentrations following a single oral dose of 2.5 mg to healthy male volunteers as described in Seaber et al., The absolute bioavailability and effect of food on the pharmacokinetics of zolmitriptan in healthy volunteers., Br J Clin Pharmacol. 1998 Nov;46(5):433-9 (Seaber). Steady-state simulated concentration-time data were analyzed using noncompartmental methods to determine C max,ss and AUC 0-24h,ss It was decided 。 Pharmacokinetic parameters and nonparametric superposition were calculated using Phoenix WinNonlin version 8.1 (Certara Inc., Princeton, NJ, USA).

[0328]

[0347] Nonparametric superposition techniques are used to predict drug concentrations after multiple doses at steady state and are based on noncompartmental results describing single dose data. The predictions are based on accumulation ratios derived from terminal elimination rate constants. The basic assumptions of nonparametric superposition for a drug are that the mean total body clearance is constant, the rate and magnitude of absorption are the same for each dose, linear pharmacokinetics apply, and the kinetics of the drug after a single dose do not change after subsequent doses.

[0329]

[0348] The human pharmacokinetic profile of zolmitriptan was derived from previously reported median plasma concentrations following a single oral dose of 2.5 mg in healthy male volunteers (Seaber, 1998).

[0330] [Table 1]

[0331]

[0349] The following table shows simulated steady-state human plasma pharmacokinetic parameters of zolmitriptan following QD, BID and TID oral dosing regimens.

[0332] [Table 2]

[0333] Example 2. In vivo evaluation of zolmitriptan in a mouse model of aggression

[0350] The rodent resident-intruder assay (RI) was used to monitor aggressive behavior in terms of behavioral patterns exhibited in establishing and defending territories (Miczek et al., 1984). Correspondingly, the RI assay has been used preclinically to study the effects of drugs on rodent aggression (Miczek et al., 2001). RI assays typically rely on the interpretation and scoring of aggressive (resident animal) behavioral patterns and may also include analysis of defensive (intruder animal) behavioral patterns as well.

[0334]

[0351] Using the CD-1-C57BL / 6 combination, the effect of zolmitriptan (10 mg / kg) on ​​aggressive behavior was determined in CD-1 mice using a rodent RI assay. Risperidone (0.3 mg / kg) was used as a control compound. Aggression time was measured over a 5-minute period in a crossover design.

[0335]

[0352] Zolmitriptan administered at 3 and 10 mg / kg (ip) produced Cmax values ​​of 5.40 ng / ml and 34.42 ng / ml, respectively, in the CSF of adult male CD-1 mice. N-desmethylzolmitriptan ("NDMZ", the primary metabolite of zolmitriptan found in humans) was below the lower limit of quantification in male CD-1 mice administered at 3 and 10 mg / kg (ip).

[0336]

[0353] Results: As shown in FIG. 1 (and Table 2 below), CD-1 mice administered zolmitriptan at 10 mg / kg showed a significant reduction in attack time (seconds) compared to risperidone (0.03 mg / kg) and vehicle controls.

[0337] [Table 3]

[0338] Example 3. In vivo evaluation of zolmitriptan in an ASD mouse model

[0354] We investigated the effect of zolmitriptan in a mouse model of valproic acid-induced autism spectrum disorder (Nicolini C et al., 2018 Exp. Neurol., 2018, 217-227;Bey AL, and Jiang J. H, Current Protocols in Pharmacology, 01 Sep 2014, 66:5.66.1-26). Specifically, sociality was determined in male C57 / Bl6 mice pre-exposed to valproic acid (VPA) by ip delivery of 500mg / kg to pregnant mothers at day 13 post-fertilization embryos.

[0339]

[0355] In this study, zolmitriptan was dissolved in 10% (2-hydroxypropyl)-β-cyclodextrin in saline and administered intraperitoneally (i.p.), and 15 min later mice were placed in the test chamber. Behavioral recordings were measured using an automated video tracking system (Noldus EthoVision v14) and analyzed and graphed using GraphPad Prism software v8. Sociality was assessed over a 10-min period in a three-chamber social interaction assay. The time spent (in seconds) in the empty interaction zone (EIZ) and the social interaction zone (SIZ) in front of young novel C57 / BL6 mice was used to calculate the sociality score for individual mice. The SIZ / EIZ ratio was used to calculate the sociality index. The social interaction preference was calculated using (SIZ) / (SIZ+EIZ)×100. Simultaneous recordings of up to four arenas were performed for this social interaction assay. Paired and unpaired t-tests were used as statistical tests.

[0340]

[0356] Zolmitriptan administered at 10 mg / kg (ip) produced a Cmax value (15 min post-dose) of 17.83 ng / ml in the CSF of adult male c57 / Bl6 mice (i.e., the Tg2576 background strain and the strain used for VPA treatment). NDMZ was below the lower limit of quantification in the CSF of male c57 / Bl6 mice administered at 10 mg / kg (ip).

[0341]

[0357] As shown in Figure 2, administration of zolmitriptan at 10 mg / kg (ip) increased the social index in adult male C57 / Bl6 mice pre-exposed to valproic acid (VPA). The improvement in sociality in zolmitriptan-treated mice was statistically significant compared to the vehicle-treated group.

[0342] Example 4. Clinical Trials

[0358] A study was conducted to evaluate the safety, tolerability, and pharmacokinetic response after multiple ascending doses of oral zolmitriptan in healthy adult volunteers.

[0343]

[0359] Zolmitriptan 2.5 mg or placebo tablets were administered three times daily (TID) during the titration period, the 7-day treatment period, and the titration period. The dosing regimens are shown in Table 3.

[0344] [Table 4]

[0345]

[0360] A lumbar puncture was performed for each subject to determine the concentration of zolmitriptan in the CSF. CSF samples were collected on treatment day 5 for cohort 1, treatment day 7 for cohorts 2 and 3, and treatment day 8 for cohorts 4 and 5. CSF collection was 2 hours (± 30 minutes) after the morning dose. CSF concentrations were measured using a validated bioanalytical method.

[0346]

[0361] Results: CSF levels measured in humans are in a ratio of zolmitriptan:NDMZ=1.0:0.75, as shown in Figure 5. Overall, zolmitriptan was safe and well tolerated in all cohorts.

[0347] Example 5. Dosage Test

[0362] Human PK studies correlating oral zolmitriptan dose administration with CSF concentrations (Example 4, i.e., mg of zolmitriptan administered with CSF Cmax achieved), effective CSF concentrations determined from the valproic acid ASD mouse model (Example 3), and species-specific binding assay data (human and mouse) were used to estimate an effective human dose for treating ASD symptoms with zolmitriptan.

[0348]

[0363] Specifically, the 5-HT1b receptor occupancy and efficacy models measured the potency of zolmitriptan and NDMZ at the 5-HT1b receptor and the ratio of zolmitriptan:NDMZ in human CSF. The 5-HT1b receptor efficacy model was used to predict the level of 5-HT1b activation (i.e. efficacy) by both zolmitriptan and NDMZ based on the concentration of zolmitriptan in the CSF. This allowed the calculation of the target zolmitriptan dose range required to achieve effective CSF exposure in humans.

[0349] 35S-GTPγS binding assay

[0364] In this study, we measured the affinity of zolmitriptan and its active metabolite NDMZ for rat and human 5-HT1B receptors by performing in vitro binding assays.

[0350]

[0365] Zolmitriptan was tested in duplicate in an SPA-based 35S-GTPγS binding assay in cells expressing human 5-HT1b (h5-HT1b) or rat recombinant 5-HT1b (r5-HT1b) receptors at 10 concentrations. EC50 values ​​are shown in Table 4.

[0351] [Table 5]

[0352]

[0366] Zolmitriptan exhibits a lower apparent affinity (i.e., EC50) at rat 5-HT1b receptors than at human 5-HT1b receptors, with the species difference being 8.3-fold for zolmitriptan.

[0353]

[0367] The mouse and rat orthologues of 5-HT1b are 98% identical. They differ by only two amino acids, both of which are conservative changes and are outside the agonist binding pocket (i.e., mouse / rat E152D in intracellular loop 1 and mouse / rat M192V in extracellular loop 2).

[0354]

[0368] Based on this data, the CSF levels required for zolmitriptan to have a therapeutic effect in humans are approximately 8.3-fold lower than the CSF levels required for a comparable activity in mice.

[0355]

[0369] Assuming that the CSF values ​​reflect the free drug concentrations in the brain, the estimated effective Cmax CSF value can be expressed as follows:

[0356]

[0370] CD-1 (mouse aggression model, Example 2); 3 mg / Kg (ip); CSF Cmax=18.8 nM or EC36 (36% activity in GTPgS).

[0357]

[0371] c57 / Bl6 (ASD mouse model, Example 3); 10 mg / Kg (ip); CSF Cmax=62 nM EC65 (65% activity in GTPgS).

[0358] Radioligand binding competition assay

[0372] The affinity of zolmitriptan and NDMZ (the active metabolite of zolmitriptan in humans) to the human 5-HT1B receptor was determined in duplicate using 10 concentrations of 3H-5-CT and a radioligand binding competition assay with recombinant human 5-HT1B receptors. The affinity of the test compounds to the h5-HT1b receptor is shown in Table 5. From the IC50 values, Ki values ​​were calculated using the Cheng-Prusoff equation.

[0359] [Table 6]

[0360] 5-HT1b Receptor Occupancy and Efficacy Model

[0373] Using classical receptor theory, receptor occupancy when considering two ligands (i.e., entities) can be predicted using the following relationship:

[0361]

[0373] Total occupancy = (% occupancy by A) + {[100% - (% occupancy by A)] x (% occupancy by B)}, where both A and B are considered to be constant concentrations.

[0362]

[0374] Given that the ratio of zolmitriptan:NDMZ in humans is 1.0:0.75 in human CSF (FIG. 3), and that the potency of NDMZ is 2.83-fold higher than zolmitriptan, a model for 5-HT1b occupancy was constructed using the % total occupancy formula above as a basis. This model was transformed to predict the level of 5-HT1b activation (i.e., efficacy) by both zolmitriptan and NDMZ based on zolmitriptan concentration in CSF by substituting efficacy for occupancy as predicted by Clark's formula {efficacy=[L] / ([L]+Ki);[L]=ligand concentration} for both zolmitriptan and NDMZ:

[0363]

[0376] % Total Effectiveness = {[zolmitriptan] / ([zolmitriptan]+Ki,Z)}+(100-{[zolmitriptan] / ([zolmitriptan]+Ki,Z)}×{[NDMZ] / ([NDMZ]+Ki,N)}

[0364]

[0377] Using the measured EC50 value of zolmitriptan in the GTPgS assay, the 2.83-fold higher affinity of NMDZ for the human 5-HT1b receptor, and the measured relationship of zolmitriptan:NDMZ=1.0:0.75, the % total efficacy was calculated for a range of zolmitriptan concentrations, and the resulting % total efficacy predictions were fitted with a logistic equation:

[0365]

[0378] % Total Efficacy = 100 / (1 + 10^((LogEC50-[zolmitriptan]))) and Log EC50 is calculated as -8.963. The predicted concentration of zolmitriptan in human CSF that would produce 50% efficacy of 5-HT1b by zolmitriptan and NDMZ (i.e., EC50) is 1.09 nM or 0.31 ng / ml.

[0366]

[0379] The concentration of zolmitriptan required to achieve 50% total efficacy is 3.7-fold the zolmitriptan EC50 due to the combined effects of potent metabolites.

[0367]

[0380] Zolmitriptan Human Dose Ranges Across a range of 5-HT1b activity, as shown in Table 6, doses necessary to achieve the predicted effective CSF concentration range in humans are determined.

[0368] [Table 7]

[0369] Example 6. Preparation of Zolmitriptan Tablets

[0381] Zolmitriptan bulk drug was ground in a jet mill to produce a finely divided dry bulk powder.

[0370]

[0382] Immediate release layer blend formulation: Micronized zolmitriptan and the excipients disclosed in the table below were weighed, sieved and blended. Micronized zolmitriptan, anhydrous lactose (such as Duralac® H), microcrystalline cellulose (such as Avicel® PH102), sodium starch glycolate (such as Explotab), colloidal silicon dioxide (such as Cab-O-Sil® M5P), and magnesium stearate (such as Hyqual® vegetable) were mixed and blended in a diffusion blender. After unloading from the blender, the blend was stored in a polyethylene bag in a HDPE pail at room temperature for subsequent tableting operations.

[0371]

[0383] Sustained release layer blend formulation: Micronized zolmitriptan, polyethylene oxide (such as Polyox™ WSR-303 LEO) and other excipients disclosed in the table below were weighed, sieved and blended. Micronized zolmitriptan, polyethylene oxide (such as Polyox™ WSR-303 LEO), microcrystalline cellulose (such as Ceolus™ KG-802), and magnesium stearate (such as Hyqual® vegetable) were mixed and blended in a diffusion blender. After unloading from the blender, the blend was stored in a polyethylene bag in a HDPE pail at room temperature for subsequent tableting operations.

[0372]

[0384] Tableting: The ER and IR layer blends were compressed using a bilayer tablet press to produce tablets.

[0373] [Table 8]

[0374] [Table 9]

[0375] Example 7. Dissolution measurements

[0385] Dissolution studies were performed as described in Table 9 and evaluated using a Pion Rainbow dissolution monitoring system. The Pion was set to collect spectra for quantification every 5 minutes for the first hour, then every 20 minutes for the next 17 hours.

[0376] [Table 10]

[0377]

[0386] Figure 4 provides a comparison of the dissolution profiles of a 15 mg zolmitriptan extended release tablet and a 25 mg zolmitriptan immediate / extended release oral bilayer tablet (10 mg IR zolmitriptan / 15 mg ER zolmitriptan). As shown in Figure 4, there is nearly complete zolmitriptan release from the IR layer by the 5 minute time point. The release of zolmitriptan remaining in the ER layer of the bilayer tablet corresponded to the profile of the ER layer only tablet.

[0378]

[0387] The dissolution curves for the 12 mg (3 mg IR / 9 mg ER) and 24 mg (6 mg IR / 18 mg ER) zolmitriptan IR / ER oral bilayer tablets described in Example 6 are shown in FIG.

[0379] Example 8. Pharmacokinetic simulation of zolmitriptan IR / ER oral bilayer tablets under fasting and fed conditions

[0388] Physiologically based pharmacokinetic (PBPK) modeling and simulation was applied to facilitate the development of zolmitriptan bilayer tablet formulations that combine immediate release (IR) and extended release (ER) gastroretentive components. The PK profiles of zolmitriptan 12 mg (3 mg IR / 9 mg ER) and 24 mg (6 mg IR / 18 mg ER) tablets when administered orally once daily (QD) were predicted using the refined PBPK GP9.7 model and in vitro dissolution data (USP Apparatus 2, 50 RPM, 900 mL 01N HCl) as input. Gastric retention times (GRT) of 2 and 8 hours were specified for fasted conditions and after small and large meals, respectively. The predictions under different meal conditions are compared in Table 10 below.

[0380] [Table 11]

[0381] Example 9. Open-label, crossover comparative bioavailability pharmacokinetic study

[0389] This study was an open-label, crossover, comparative bioavailability and pharmacokinetic study evaluating the zolmitriptan bilayer immediate / extended release gastroretentive 24 mg oral tablet formulation (6 mg immediate / 18 mg extended) described in Example 6 under fasting and fed conditions in a total of 12 healthy adult volunteer subjects. All subjects were discharged on day 6 as residents of the study facility and were followed up by telephone on days 11 and 18. The dosing regimen included the following: Day 1: Zolmitriptan immediate release 20 mg in the morning under fasting conditions Day 2: Zolmitriptan bilayer immediate-release / extended-release gastroretentive 24 mg oral tablet (6 mg IR / 18 mg ER) in the morning under fasting conditions Day 4: Zolmitriptan bilayer immediate-release / extended-release gastroretentive 24 mg oral tablet (6 mg IR / 18 mg ER) in the morning under postprandial conditions

[0382]

[0390] All subjects completed the study, and no subjects discontinued study treatment due to adverse events.

[0383]

[0391] A summary of the preliminary pharmacokinetic parameters of the 12 study subjects for zolmitriptan immediate release administered in the fasted state on day 1, zolmitriptan bilayer tablet administered 24 mg in the fasted state on day 2, and zolmitriptan bilayer immediate / extended release gastroretentive 24 mg oral tablet administered in the fed state on day 4 is presented in Table 11.

[0384] [Table 12]

[0385]

[0392] The plasma concentrations of zolmitriptan are summarized in Table 12.

[0386] [Table 13]

[0387] [Table 14]

[0388] Example 10. Multicenter, randomized, double-blind, placebo-controlled study

[0394] The study is a Phase 2, multicenter, randomized, double-blind, placebo-controlled study that will enroll approximately 150 adolescent and adult subjects with ASD. The primary objective of the study will determine the efficacy of a zolmitriptan bilayered immediate-release (IR) / extended-release (ER, gastroretentive) oral tablet formulation compared to placebo for treating care / study partner-reported social-communication deficits in individuals with ASD. Subjects will be randomized to study treatment in a 1:1 ratio of zolmitriptan bilayered immediate-release (IR) / extended-release (ER, gastroretentive) oral tablet formulation:placebo.

[0389]

[0395] Dose / Administration: Zolmitriptan bilayer immediate release (IR) / extended release (ER, gastroretentive) oral tablet formulation is taken orally once daily in the morning with a meal and is provided in two dosage strengths: 12 mg tablet (3 mg IR / 9 mg ER) and 24 mg tablet (6 mg IR / 18 mg ER). The dose level in this study is 12 mg (provided as one 12 mg tablet).

[0390]

[0396] The study design is shown in Figure 6. Treatment will begin with once-daily administration of zolmitriptan bilayered immediate-release (IR) / extended-release (ER, gastroretentive) oral tablet formulation or placebo for 2 weeks, followed by a 9-12 day titration period until the maximum tolerated dose (based on subject's body weight) is reached. For example, dose escalation will occur every 3 days as follows: from 12 mg (starting dose), 24 mg, 48 mg, 72 mg, or matching placebo until (but not exceeding) a target dose of either 48 mg (if screening weight 55 kg or less or female taking oral contraceptives) or 72 mg (if screening weight >55 kg and female not taking oral contraceptives). If the escalating dose is not tolerated, the subject may be tapered to the last tolerated dose, if 24 mg or 48 mg.

[0391]

[0397] The highest dose tolerated during titration will become the maintenance dose (MD) for that subject, who will remain on that dose for 12 weeks and then be titrated down. An independent DSMC will monitor the progress of the study to ensure that the safety of the study subjects is not compromised.

[0392]

[0398] The zolmitriptan bilayer immediate-release (IR) / extended-release (ER, gastroretentive) oral tablet formulation is taken orally once daily for up to 16 weeks and is provided in two dosage strengths as tablets: 12 mg (3 mg IR / 9 mg ER) and 24 mg tablets (6 mg IR / 18 mg ER). The dose levels in this study are 12 mg (provided as one 12 mg tablet), 24 mg (one 24 mg tablet), 48 mg (two 24 mg tablets), and 72 mg (three 24 mg tablets).

[0393]

[0399] Primary outcome measures:

[0400] Change from baseline in Autism Behavior Inventory (ABI)-Social Communication Domain Score [Time Frame: From baseline up to Day 110]

[0401] Changes from baseline in the ABI-Social Communication Domain score will be reported. The ABI is a 62-item questionnaire to report on the behavior of subjects (ages: 3 years to adulthood) diagnosed with ASD. The tool is suitable for completion by a parent or care / study partner of the person with ASD. Each item assesses either the quality (never to need help) or frequency (never to very often) of a particular behavior. The Social Communication Domain score is the sum of the Social Communication Domain scores divided by the number of items in this domain.

[0394]

[0402] Secondary outcome measures:

[0403] Change from baseline in Clinician Global Impression of Improvement (CGI-I) [Time frame: Day 110]

[0404] The CGI-I score is a single-item instrument based on a 7-point scale that is routinely used in clinical trials to capture the investigator's global impression of response. The investigator or designee rates the observed improvement from 1 (much better) to 7 (much worse).

[0395]

[0405] Change from baseline in Autism Behavior Inventory-Clinician (ABI-C) scores [Time frame: from baseline up to day 110]

[0406] The ABI-Clinician (ABI-C) captures the clinician's assessment of the behavior of individuals with ASD during the week prior to their assessment. It includes 14 items reflecting core and relevant autism behavior domains: social communication, restricted behaviors, mood and anxiety, self-regulation, and challenging behaviors. Each item is rated on a 7-point scale ranging from 1 (not at all; no symptoms observed) to 7 (very severe; consistently interfering with functioning or adjustment).

[0396]

[0407] Change from baseline in Aberrant Behavior Checklist 2-Irritability (ABC-I) subscale scores [Time frame: from baseline up to day 110]

[0408] The ABC is a parent or care / study partner reported behavioural assessment of 5 domains and 58 items rated on a scale from 0 (no problem) to 3 (severe problem). The irritability domain consists of 15 items.

[0397]

[0409] Change from baseline in Clinician Global Impression of Severity (CGI-S) score [Time frame: from baseline up to Day 110]

[0410] The CGI-S is a global assessment of the assessor's impression of the severity of the participant's illness, rated on a scale from 1 (normal, not ill at all) to 7 (extremely ill, at the highest level).

[0398]

[0411] Change from baseline in ABI Repetitive / Restrictive Behavior Domain score [Time frame: from baseline up to day 110]

[0412] Each item in the ABI-Repetitive / Restricted Behaviors domain is scored by frequency (0 = never to 3 = very often). The domain score is the sum of all domain item scores divided by the number of items in this domain.

[0399]

[0413] Change from baseline in ABI Mood and Anxiety Domain scores [Time frame: from baseline up to Day 110]

[0414] Each item in the ABI-Mood and Anxiety domain is scored by frequency (0=never to 3=very often). The domain score is the sum of all domain item scores divided by the number of items in this domain.

[0400]

[0415] Change from baseline in ABI Challenging Behavior Domain score [Time frame: from baseline up to day 110]

[0416] Each item in the ABI-Challenging Behaviors domain is scored by frequency (0 = never to 3 = very often). The domain score is the sum of all domain item scores divided by the number of items in this domain.

[0401]

[0417] Change from baseline in ABI Self-regulation Domain score [Time frame: from baseline up to day 110]

[0418] Each item in the ABI-Self-Control domain is scored by frequency (0 = never to 3 = very often). The domain score is the sum of all domain item scores divided by the number of items in this domain.

[0402]

[0419] Change from baseline in ABI-Short Form (ABI-S) score [Time frame: from baseline up to day 110]

[0420] The ABI-S is a 24-item shortened version of the ABI that includes items from each of the five domains. The domain score for each domain is calculated as the sum of the scores of all domain items divided by the number of items in this domain.

[0403]

[0421] Change from baseline in ABC-Social Withdrawal (ABC-SW) subscale scores [Time frame: from baseline up to day 110]

[0422] The ABC-SW subscale consists of 16 items from the ABC-2 that are scored from 0 (no problem) to 3 (severe problem).

[0404]

[0423] Change from baseline in Social Responsiveness Scale 2 (SRS-2) score [Time frame: from baseline up to day 110]

[0424] The SRS-2 consists of 65 items across five subscales, with responses ranging from 1 (not true) to 4 (almost always true).

[0405]

[0425] Vineland-3 (Domain-Level Version) Score: Change from baseline in Communication, Socialization, and Maladaptive Behavior domains combined [Time Frame: From baseline up to Day 110]

[0426] The Vineland-3 Domain-Level Version includes five domains. Responses to each item are scored from 0 (never) to 2 (always).

[0406]

[0427] Eligibility Criteria

[0428] 12 to 45 years old (children and adults)

[0429] Inclusion Criteria:

[0430] Age at screening: 12-45 years

[0431] Body Mass Index (BMI) 18kg / m 2 More than 34kg / m 2 below

[0432] Have a designated care / study partner who can provide reliable reporting of symptoms

[0433] Participants were to have a diagnosis of autism spectrum disorder (ASD) based on the American Psychiatric Association (APA 2013) Diagnostic and Statistical Manual, 5th ed (DSM-5) and / or the World Health Organization (WHO) International Classification of Diseases External 10th Revision, 2nd ed (ICD-10, WHO 2004) with a confirmed diagnosis on the Autism Diagnostic Observation Scale (ADOS, Lord 1999; or ADOS-2, Lord 2012) or Autism Diagnostic Interview-Revised (ADI-R, Lord 1994) administered within the past 3 years, or the ADOS-2 administered at screening. Full scale IQ (or equivalent) score of 70 or greater.

[0407]

[0434] The Aberrant Behavior Checklist 2-Social Withdrawal (ABC-SW) subscale score at screening is 11 or greater.

[0408]

[0435] Stable psychotropic and adjunctive medications for the 4 weeks prior to screening.

[0409]

[0436] Patients must be able to swallow the investigational product.

[0410]

[0437] Sexually active male subjects and female subjects of childbearing potential must practice effective contraception from screening through 30 days after their last study drug dose. Effective contraception is the use of two methods of contraception defined as the use of condoms (male and / or female), hormonal contraception (female), or an intrauterine device (IUD). This does not apply to subjects who have been surgically sterilized by bilateral tubal ligation, bilateral oophorectomy, or hysterectomy; or who practice abstinence while they are study subjects in this study; or who are in a same-sex relationship.

[0411]

[0438] Exclusion criteria:

[0439] Have Rett syndrome or childhood disintegrative disorder

[0440] Participating in any other study within 60 days prior to screening and receiving any other investigational drug (except COVID-19 vaccination) or device

[0441] History of epilepsy not currently adequately controlled or seizures in the 6 months prior to screening

[0442] History of suicidal thoughts or behavior in the past 12 months or answer "yes" to questions 4 and / or 5 of the C-SSRS

[0443] Systolic blood pressure ≥ 160mmHg or diastolic blood pressure ≥ 100, or a history of uncontrolled or severe hypertension

[0444] If female, pregnant or breastfeeding

[0445] Within 2 weeks (or within 5 half-lives, whichever is longer) of single-blind baseline (Visit 2), have taken any of the following: Selective serotonin reuptake inhibitors (SSRIs) Serotonin-norepinephrine reuptake inhibitors (SNRIs) Tricyclic antidepressants (TCAs) Any monoamine oxidase type A (MAO-A) inhibitor Another 5-HT1 agonist or antagonist (e.g., risperidone), partial agonist / antagonist (e.g., aripiprazole) Any ergotamine-containing or ergot-based drug (e.g., dihydroergotamine or methysergide), including St. John's wort

[0446] Currently taking cimetidine and unable to discontinue use of cimetidine during screening and until the end of the study

[0447] Diagnosis or history of coronary artery disease, coronary spasm, Prinzmetal angina, Wolff-Parkinson-White syndrome, peripheral vascular disease, stroke, transient ischemic attack, ischemic bowel disease, or other significant cardiac or cerebrovascular disease3

[0448] Diagnosis or history of migraine with or without aura, including basilar and / or hemiplegic migraine

[0449] History of galactose intolerance (i.e., Lapp lactase deficiency or glucose-galactose malabsorption)

[0450] Participating in any other study within 60 days prior to screening, receiving any other investigational drug (except COVID-19 vaccination) or device, or participating in a non-drug study that, in the opinion of the investigator, would interfere with the interpretation of the assessments in this study

[0451] History of suicidal ideation or behavior in the past 12 months or answer "yes" to C-SSRS questions 4 and / or 5 (currently or in the past 6 months) at Screening or the single-blind Baseline (Visit 2) assessment, and / or at significant risk for suicidal behavior in the investigator's opinion

[0452] Screening or single-blind baseline (Visit 2) systolic blood pressure ≥ 140mmHg (for adults) or > 135mmHg (for adolescents), or diastolic blood pressure ≥ 90mmHg (for adults) or > 85mmHg (for adolescents), or a history of poorly controlled or severe hypertension. For subjects with automated or manual blood pressure in the less severe abnormal ranges (SBP 140-159mmHg, DBP 90-99mmHg for adults and SBP 135-140mmHg, DBP 85-89mmHg for adolescents), no absolute exclusion is required under this protocol, but the medical monitor may request further data (following guidelines) to accurately determine the subject's blood pressure status when determining eligibility. In such cases, subjects may be eligible to participate if either hypertension is excluded or the cause can be identified and appropriately treated, and the medical monitor reviews and gives permission to do so.

[0412]

[0453] Clinically significant ECG abnormalities at screening or single-blind baseline (Visit 2) in the investigator's clinical judgment

[0454] One of the following laboratory test results at screening: a. Platelets ≤ 75,000 / mm3 b. Neutrophils, absolute value, ≤ 1000 / mm3 c. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2x upper limit of normal and / or total bilirubin > 1x upper limit of normal Creatinine ≥ 2 mg / dL and / or eGFR < 60 mL / min / 1.73 m2 (adults) or < 75 mL / min / 1.73 m2 (adolescents) e. Free thyroxine (T4) abnormalities

[0455] Laboratory tests may be repeated during screening at the discretion of the medical monitor.

[0413]

[0456] History of alcohol use or substance use disorder (per DSM-5 criteria) within 12 months of screening, or positive drug of abuse screen at screening (unless consistent with prescription for a current medical condition).

[0414]

[0457] Screening positive for human immunodeficiency virus antibody, hepatitis B surface antigen, or hepatitis C virus antibody at screening

[0458] If female, pregnant or breastfeeding

[0459] A diagnosis or history consistent with schizophrenia, bipolar disorder, or other medical or psychiatric condition that, in the opinion of the investigator or medical monitor, may place the subject at high risk for safety / tolerability problems and / or may preclude the subject from providing voluntary consent and / or may confound the interpretation of the primary outcome measures of the study.

[0460] Unwilling or unable to comply with the study protocol for any reason (including inability to swallow the investigational product).

[0415]

[0461] Have significant visual, hearing, or motor impairments that may prevent participation in completing the main evaluation.

[0416]

[0462] The investigator or medical monitor determines that the individual is unsuitable for the study for any reason.

[0417] Embodiments: 1. An oral composition for treating symptoms of aggression in a patient with autism spectrum disorder or Alzheimer's disease, the composition comprising from about 7.5 mg to about 90 mg of zolmitriptan, or a pharma- ceutically acceptable salt thereof, and wherein oral administration of the composition provides a therapeutically effective plasma concentration of zolmitriptan for at least 8 hours.

[0418] 1a. An oral composition for treating symptoms of aggression in a dementia patient, the composition comprising from about 7.5 mg to about 90 mg of zolmitriptan, or a pharma- ceutically acceptable salt thereof, and wherein oral administration of the composition provides a therapeutically effective plasma concentration of zolmitriptan for at least 8 hours.

[0419] 2. The composition according to claim 1 or 1a, comprising from about 10 mg to about 30 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof.

[0420] 3. The composition according to claim 1 or 2, comprising an immediate release portion and a sustained release portion.

[0421] 4. The composition of claim 3, wherein the immediate release portion contains about 20% to 40% by weight of the total zolmitriptan in the composition.

[0422] 5. The composition according to claim 3 or 4, wherein the sustained release portion contains about 60% to 80% by weight of the total zolmitriptan in the composition.

[0423] 6. The composition according to any one of claims 3 to 5, wherein the immediate release portion contains about 25% of the total zolmitriptan in the composition and the sustained release portion contains about 75% of the total zolmitriptan in the composition.

[0424] 7. The composition according to any one of claims 3 to 6, wherein the immediate release portion comprises from about 1 mg to about 10 mg of zolmitriptan.

[0425] 8. The composition of claim 7, wherein the immediate release portion comprises about 3 mg of zolmitriptan.

[0426] 9. The composition of claim 7, wherein the immediate release portion comprises about 6 mg of zolmitriptan.

[0427] 10. The composition according to any one of claims 3 to 9, wherein the sustained release portion comprises from about 5 mg to about 25 mg of zolmitriptan.

[0428] 11. The composition of claim 10, wherein the sustained release portion comprises 9 mg of zolmitriptan.

[0429] 12. The composition of claim 10, wherein the sustained release portion comprises about 18 mg of zolmitriptan.

[0430] 13. Oral administration of the composition results in a C of about 3 ng / mL to about 30 ng / mL after a single dose of the composition. max The composition according to any one of claims 1 to 12, wherein

[0431] 14. The composition of any one of claims 1 to 13, wherein oral administration of the composition provides a plasma concentration of at least about 10 ng / mL for at least 8 hours after a single dose of the composition.

[0432] 15. Oral administration of the composition results in an AUC of about 40 ng·h / mL to about 300 ng·h / mL after a single dose of the composition. 0-24h The composition according to any one of claims 1 to 14, wherein

[0433] 16. Oral administration of the composition results in an AUC of about 50 ng·h / mL to about 250 ng·h / mL after a single dose of the composition. 0-24h The composition according to any one of claims 1 to 15, wherein

[0434] 17. Oral administration of the composition results in an AUC of about 150 ng·h / mL to about 250 ng·h / mL after a single dose of the composition. 0-24h The composition according to any one of claims 1 to 15, wherein

[0435] 18. Oral Administration of the Composition AUC of about 50 ng·h / mL to about 150 ng·h / mL after a single dose of the composition 0-24h The composition according to any one of claims 1 to 15.

[0436] 19. The composition of any one of claims 1 to 18, wherein oral administration of the composition provides a therapeutically effective plasma zolmitriptan concentration for about 12 hours after a single dose of the composition.

[0437] 20. The composition of any one of claims 1 to 19, wherein oral administration of the composition provides a therapeutically effective plasma zolmitriptan concentration for about 18 hours after a single dose of the composition.

[0438] 21. Oral Administration of the Composition The composition of any one of claims 1 to 20, wherein a therapeutically effective plasma zolmitriptan concentration is achieved for about 24 hours after a single dose of the composition.

[0439] 22. The composition according to any one of claims 1 to 21, which is a multiparticulate formulation.

[0440] 23. The composition of any one of claims 3 to 21, wherein the sustained release portion comprises a drug-containing particle coated with a sustained release coating.

[0441] 24. The composition of any one of claims 1 to 21, which is a gastrorentive tablet.

[0442] 25. The composition of any one of claims 3 to 21, wherein the sustained release portion is a gastrorentive layer.

[0443] 26. The composition of claim 25, wherein the gastroretentive layer comprises a water-swellable polymer.

[0444] 27. The composition of claim 25, wherein the water-swellable polymer is selected from the group consisting of polyalkylene oxides, cellulose polymers and derivatives thereof, polysaccharides and derivatives thereof, chitosan, poly(vinyl alcohol), xanthan gum, maleic anhydride copolymers, poly(vinylpyrrolidone), starch and starch-based polymers; maltodextrin, poly(2-ethyl-2-oxazoline), poly(ethyleneimine), polyurethanes, hydrogels, crosslinked polyacrylic acid, and combinations thereof.

[0445] 28. The composition of claim 25, wherein the water-swellable polymer is selected from the group consisting of high molecular weight polyethylene oxide, hydroxyalkyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, and microcrystalline cellulose.

[0446] 29. The composition of claim 28, wherein the water-swellable polymer is polyethylene oxide.

[0447] 30. The composition according to any one of claims 26 to 29, comprising about 35 to 55% by weight of polyethylene oxide.

[0448] 31. The composition of any one of claims 24 to 30, which is retained in the stomach for at least 2 hours after oral administration.

[0449] 32. The composition of any one of claims 24 to 31, which is retained in the stomach for at least 8 hours after oral administration.

[0450] 33. An oral composition of zolmitriptan, or a pharma- ceutically acceptable salt thereof, for the treatment of symptoms of autism spectrum disorder (or aggression in Alzheimer's disease patients), providing a modified release profile, When dissolution tested in 900 mL of 0.1 N HCl at 37° C. using the USP Apparatus II (paddle method, 50 rpm), the zolmitriptan release profile corresponds substantially to the following pattern: Approximately 20% to 40% of the total zolmitriptan is released after approximately 15 minutes; Approximately 40% to 75% of the total zolmitriptan is released after 4 hours; and A composition in which about 75%-90% of the total zolmitriptan is released after 8 hours.

[0451] 34. The composition of claim 33, wherein about 85% of the total zolmitriptan is released within 9 to 10 hours.

[0452] 35. The composition according to claim 33 or 34, comprising from about 10 mg to about 30 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof.

[0453] 36. The composition of any one of claims 33 to 35, comprising an immediate release portion and a sustained release portion.

[0454] 37. The composition of claim 36, wherein the immediate release portion contains about 20% to 40% by weight of the total zolmitriptan in the composition.

[0455] 38. The composition of claim 36 or 37, wherein the sustained release portion contains about 60% to 80% by weight of the total zolmitriptan in the composition.

[0456] 39. The composition of any one of claims 36 to 38, wherein the immediate release portion comprises from about 1 mg to about 10 mg of zolmitriptan.

[0457] 40. The composition of any one of claims 36 to 39, wherein the sustained release portion comprises from about 5 mg to about 25 mg of zolmitriptan.

[0458] 41. Oral administration of the composition results in a C of about 3 ng / mL to about 30 ng / mL after a single dose of the composition. max The composition according to any one of claims 33 to 40, wherein

[0459] 42. Oral administration of the composition results in an AUC of about 40 ng·h / mL to about 300 ng·h / mL after a single dose of the composition. 0-24h The composition according to any one of claims 33 to 40, wherein

[0460] 43. The composition of any one of claims 33 to 42, which is a gastroretentive tablet.

[0461] 44. The composition of any one of claims 33 to 43, wherein the sustained release portion is a gastrorentive layer.

[0462] 45. The composition of claim 44, wherein the gastroretentive layer comprises a water-swellable polymer.

[0463] 46. ​​The composition of claim 45, wherein the water-swellable polymer is selected from the group consisting of polyalkylene oxides, cellulose polymers and derivatives thereof, polysaccharides and derivatives thereof, chitosan, poly(vinyl alcohol), xanthan gum, maleic anhydride copolymers, poly(vinylpyrrolidone), starch and starch-based polymers; maltodextrin, poly(2-ethyl-2-oxazoline), poly(ethyleneimine), polyurethanes, hydrogels, crosslinked polyacrylic acid, and combinations thereof.

[0464] 47. The composition of claim 45, wherein the water-swellable polymer is selected from the group consisting of high molecular weight polyethylene oxide, hydroxyalkyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, and microcrystalline cellulose.

[0465] 48. The composition of claim 45, wherein the water-swellable polymer is polyethylene oxide.

[0466] 49. The composition of any one of claims 46 to 48, comprising about 35 to 55% by weight of polyethylene oxide.

[0467] 50. The composition of any one of claims 33 to 49, wherein oral administration of the composition provides a therapeutically effective plasma zolmitriptan concentration for about 12 hours after a single dose of the composition.

[0468] 51. The composition according to any one of claims 33 to 42, which is a multiparticulate formulation.

[0469] 52. The composition of any one of claims 33 to 42, wherein the sustained release portion comprises a drug-containing particle coated with a sustained release coating.

[0470] 53. A composition for treating symptoms of autism spectrum disorder, comprising zolmitriptan or a pharma- ceutical acceptable salt thereof, wherein oral administration of the composition produces an AUC of about 40 ng·h / mL to about 300 ng·h / mL. 0-24h wherein the composition is provided to treat a symptom of an autism spectrum disorder.

[0471] 54. Oral administration of the composition results in an AUC of about 40 ng·h / mL to about 110 ng·h / mL after a single dose of the composition. 0-24h The composition of claim 53, wherein

[0472] 55. Oral administration of the composition results in an AUC of about 150 ng·h / mL to about 450 ng·h / mL after a single dose of the composition. 0-24h,ss The composition of claim 53, wherein

[0473] 56. The composition of any one of claims 53 to 55, wherein oral administration of the composition provides a therapeutically effective plasma zolmitriptan concentration for about 12 hours after a single dose of the composition.

[0474] 57. A method for treating a symptom of an autism spectrum disorder, comprising orally administering to a patient in need thereof a pharmaceutical composition of the composition of any one of claims 1-56.

[0475] 58. A composition for treating aggression in a patient with Alzheimer's disease, the composition comprising zolmitriptan or a pharma- ceutical acceptable salt thereof, wherein oral administration of the composition provides an AUC 0-24h is provided to treat aggression in a patient.

[0476] 59. Oral administration of the composition results in an AUC of about 40 ng·h / mL to about 110 ng·h / mL after a single dose of the composition. 0-24h 59. The composition of claim 58, wherein

[0477] 60. Oral administration of the composition results in an AUC of about 150 ng·h / mL to about 450 ng·h / mL after a single dose of the composition. 0-24h,ss 59. The composition of claim 58, wherein

[0478] 61. The composition of any one of claims 58 to 60, wherein oral administration of the composition provides a therapeutically effective plasma zolmitriptan concentration for about 12 hours after a single dose of the composition.

[0479] 62. A method for treating aggression in a patient with Alzheimer's disease, comprising orally administering to a patient in need thereof a pharmaceutical composition of the composition of any one of claims 1-56.

[0480] 63. A composition for treating aggression in a dementia patient, comprising zolmitriptan or a pharma- ceutical acceptable salt thereof, and having an AUC of about 40 ng·h / mL to about 300 ng·h / mL upon oral administration of the composition. 0-24h is provided to treat aggression in a patient.

[0481] 64. Oral administration of the composition results in an AUC of about 40 ng·h / mL to about 110 ng·h / mL after a single dose of the composition. 0-24h The composition of claim 63, wherein

[0482] 65. Oral administration of the composition results in an AUC of about 150 ng·h / mL to about 450 ng·h / mL after a single dose of the composition. 0-24h,ss The composition of claim 63, wherein

[0483] 66. The composition of any one of claims 63 to 65, wherein oral administration of the composition provides a therapeutically effective plasma zolmitriptan concentration for about 12 hours after a single dose of the composition.

[0484] 67. A method for treating aggression in a dementia patient, comprising orally administering to a patient in need thereof a pharmaceutical composition of the composition of any one of claims 1-56.

[0485] Incorporation by Reference

[0463] All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated by reference in their entirety for all purposes. However, reference to any references, articles, publications, patents, patent publications, and patent applications cited herein is not, and should not be construed as, an admission or any form of suggestion that they constitute prior art or form part of the common general knowledge in any country in the world.

Claims

1. 1. An oral composition for treating symptoms of an autism spectrum disorder, the composition comprising from about 1 mg to about 200 mg of zolmitriptan, or a pharma- ceutically acceptable salt thereof, wherein oral administration of the composition provides a therapeutically effective plasma concentration of zolmitriptan for at least 8 hours.

2. 10. The composition of claim 1, comprising about 10 mg to about 30 mg, about 7.5 mg to about 150 mg, about 7.5 mg to about 90 mg, or about 24 mg to about 72 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof.

3. The composition of claim 1 or 2, comprising an immediate release portion and a sustained release portion.

4. The composition of claim 3, wherein the immediate release portion comprises about 20% to 40% by weight of the total zolmitriptan in the composition.

5. The composition of claim 3 or 4, wherein the sustained release portion comprises about 60% to 80% by weight of the total zolmitriptan in the composition.

6. The composition of any one of claims 3 to 5, wherein the immediate release portion contains about 25% of the total zolmitriptan in the composition and the sustained release portion contains about 75% of the total zolmitriptan in the composition.

7. The composition of any one of claims 3 to 6, wherein the immediate release portion comprises from about 1 mg to about 20 mg, or from about 1 mg to about 10 mg of zolmitriptan.

8. The composition of claim 7, wherein the immediate release portion comprises about 3 mg of zolmitriptan.

9. The composition of claim 7, wherein the immediate release portion comprises about 6 mg of zolmitriptan.

10. The composition of any one of claims 3 to 9, wherein the sustained release portion comprises from about 1 mg to about 50 mg, or from about 5 mg to about 25 mg of zolmitriptan.

11. The composition of claim 10, wherein the sustained release portion comprises 9 mg of zolmitriptan.

12. The composition of claim 10, wherein the sustained release portion comprises about 18 mg of zolmitriptan.

13. Oral administration of the composition results in a C of about 3 ng / mL to about 30 ng / mL after a single dose of the composition. ｍａｘ The composition according to any one of claims 1 to 12, wherein

14. The composition of any one of claims 1 to 13, wherein oral administration of the composition provides a plasma concentration of at least about 10 ng / mL for at least 8 hours after a single dose of the composition.

15. Oral administration of the composition provides an AUC of about 40 ng·h / mL to about 300 ng·h / mL after a single dose of the composition. ０－２４ｈ The composition according to any one of claims 1 to 14, wherein

16. Oral administration of the composition provides an AUC of about 50 ng·h / mL to about 250 ng·h / mL after a single dose of the composition. ０－２４ｈ The composition according to any one of claims 1 to 15, wherein

17. Oral administration of the composition provides an AUC of about 150 ng·h / mL to about 250 ng·h / mL after a single dose of the composition. ０－２４ｈ The composition according to any one of claims 1 to 15, wherein

18. Oral administration of the composition. AUC of about 50 ng·h / mL to about 150 ng·h / mL after a single dose of the composition. ０－２４ｈ The composition according to any one of claims 1 to 15.

19. The composition of any one of claims 1 to 18, wherein oral administration of the composition provides a therapeutically effective plasma zolmitriptan concentration for about 12 hours after a single dose of the composition.

20. The composition of any one of claims 1 to 19, wherein oral administration of the composition provides a therapeutically effective plasma zolmitriptan concentration for about 18 hours after a single dose of the composition.

21. Oral Administration of the Composition The composition of any one of claims 1 to 20, wherein a therapeutically effective plasma zolmitriptan concentration is achieved for about 24 hours after a single administration of the composition.

22. A composition according to any one of claims 1 to 21 which is a multiparticulate formulation.

23. The composition of any one of claims 3 to 21, wherein the sustained release portion comprises a drug-containing particle coated with a sustained release coating.

24. The composition of any one of claims 1 to 21, which is a gastrorentive tablet.

25. The composition of any one of claims 3 to 21, wherein the sustained release portion is a gastrorentive layer.

26. 26. The composition of claim 25, wherein the gastroretentive layer comprises a water-swellable polymer.

27. 26. The composition of claim 25, wherein the water-swellable polymer is selected from the group consisting of polyalkylene oxides, cellulose polymers and derivatives thereof, polysaccharides and derivatives thereof, chitosan, poly(vinyl alcohol), xanthan gum, maleic anhydride copolymers, poly(vinylpyrrolidone), starch and starch-based polymers; maltodextrin, poly(2-ethyl-2-oxazoline), poly(ethyleneimine), polyurethanes, hydrogels, crosslinked polyacrylic acid, and combinations thereof.

28. 26. The composition of claim 25, wherein the water-swellable polymer is selected from the group consisting of high molecular weight polyethylene oxide, hydroxyalkyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, and microcrystalline cellulose.

29. 30. The composition of claim 28, wherein the water-swellable polymer is polyethylene oxide.

30. 30. The composition of any one of claims 26 to 29, comprising about 35 to 55% by weight of polyethylene oxide.

31. The composition according to any one of claims 24 to 30, which is retained in the stomach for at least 2 hours after oral administration.

32. The composition according to any one of claims 24 to 31, which is retained in the stomach for at least 8 hours after oral administration.

33. 1. An oral composition of zolmitriptan, or a pharma- ceutically acceptable salt thereof, for the treatment of symptoms of autism spectrum disorder, which provides a modified release profile, comprising: The composition, when dissolution tested in 900 mL of 0.1 N HCl at 37° C. using USP Apparatus II (paddle method, 50 rpm), exhibits a zolmitriptan release profile substantially corresponding to the following pattern: About 20% to 40% of the total zolmitriptan is released after about 15 minutes; Approximately 40% to 75% of the total zolmitriptan is released after 4 hours; and A composition in which about 75% to 90% of the total zolmitriptan is released after 8 hours.

34. The composition of claim 33, wherein about 85% of the total zolmitriptan is released within 9 to 10 hours.

35. The composition of claim 33 or 34, comprising about 1 mg to about 200 mg, about 7.5 mg to about 150 mg, about 7.5 mg to about 90 mg, or about 24 mg to about 72 mg, or about 10 mg to about 30 mg of zolmitriptan or a pharma- ceutically acceptable salt thereof.

36. The composition of any one of claims 33 to 35, comprising an immediate release portion and a sustained release portion.

37. 37. The composition of claim 36, wherein the immediate release portion comprises about 20% to 40% by weight of the total zolmitriptan in the composition.

38. The composition of claim 36 or 37, wherein the sustained release portion comprises about 60% to 80% by weight of the total zolmitriptan in the composition.

39. The composition of any one of claims 36 to 38, wherein the immediate release portion comprises from about 1 mg to about 20 mg, or from about 1 mg to about 10 mg of zolmitriptan.

40. 40. The composition of any one of claims 36-39, wherein the sustained release portion comprises from about 1 mg to about 50 mg, or from about 5 mg to about 25 mg of zolmitriptan.

41. Oral administration of the composition results in a C of about 3 ng / mL to about 30 ng / mL after a single dose of the composition. ｍａｘ The composition according to any one of claims 33 to 40, wherein

42. Oral administration of the composition provides an AUC of about 40 ng·h / mL to about 300 ng·h / mL after a single dose of the composition. ０－２４ｈ The composition according to any one of claims 33 to 40, wherein

43. The composition of any one of claims 33 to 42, which is a gastroretentive tablet.

44. The composition of any one of claims 33 to 43, wherein the sustained release portion is a gastrorentive layer.

45. 45. The composition of claim 44, wherein the gastroretentive layer comprises a water-swellable polymer.

46. 46. ​​The composition of claim 45, wherein the water-swellable polymer is selected from the group consisting of polyalkylene oxides, cellulose polymers and derivatives thereof, polysaccharides and derivatives thereof, chitosan, poly(vinyl alcohol), xanthan gum, maleic anhydride copolymers, poly(vinylpyrrolidone), starch and starch-based polymers; maltodextrin, poly(2-ethyl-2-oxazoline), poly(ethyleneimine), polyurethanes, hydrogels, crosslinked polyacrylic acid, and combinations thereof.

47. 46. ​​The composition of claim 45, wherein the water-swellable polymer is selected from the group consisting of high molecular weight polyethylene oxide, hydroxyalkyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, and microcrystalline cellulose.

48. 46. ​​The composition of claim 45, wherein the water-swellable polymer is polyethylene oxide.

49. The composition of any one of claims 46 to 48, comprising about 35 to 55% by weight of polyethylene oxide.

50. 50. The composition of any one of claims 33 to 49, wherein oral administration of the composition provides a therapeutically effective plasma zolmitriptan concentration for about 12 hours after a single dose of the composition.

51. A composition according to any one of claims 33 to 42 which is a multiparticulate formulation.

52. The composition of any one of claims 33 to 42, wherein the sustained release portion comprises a drug-containing particle coated with a sustained release coating.

53. 1. A composition for treating symptoms of an autism spectrum disorder, the composition comprising zolmitriptan, or a pharma- ceutical acceptable salt thereof, wherein oral administration of the composition provides an AUC of about 40 ng·h / mL to about 300 ng·h / mL. ０－２４ｈ wherein the composition is provided to treat a symptom of an autism spectrum disorder.

54. Oral administration of the composition provides an AUC of about 40 ng·h / mL to about 110 ng·h / mL after a single dose of the composition. ０－２４ｈ The composition of claim 53, wherein

55. Oral administration of the composition provides an AUC of about 150 ng·h / mL to about 450 ng·h / mL after a single dose of the composition. ０－２４ｈ，ｓｓ The composition of claim 53, wherein

56. 56. The composition of any one of claims 53 to 55, wherein oral administration of the composition provides a therapeutically effective plasma zolmitriptan concentration for about 12 hours after a single dose of the composition.

57. 57. A method for treating a symptom of an autism spectrum disorder comprising orally administering to a patient in need thereof a pharmaceutical composition of the composition of any one of claims 1-56.

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