CN117750957A

CN117750957A - Pharmaceutical composition comprising zolmitriptan

Info

Publication number: CN117750957A
Application number: CN202280036813.9A
Authority: CN
Inventors: M·伍德; J·莉莉
Original assignee: Map Light Therapy Co ltd
Current assignee: Map Light Therapy Co ltd
Priority date: 2021-03-25
Filing date: 2022-03-24
Publication date: 2024-03-22

Abstract

Provided herein are oral compositions comprising zolmitriptan, and methods of using the same, for example, to treat symptoms of autism spectrum disorders, as well as to treat aggression in patients suffering from dementia.

Description

Pharmaceutical composition comprising zolmitriptan

Cross Reference to Related Applications

The present application claims priority from U.S. provisional application number 63/306,377 filed on 3 months 2 and 2021, U.S. provisional application number 63/165,938 filed on 25 months 3, and the disclosure of that application is hereby incorporated by reference in its entirety for all purposes.

Technical Field

The present disclosure relates to pharmaceutical compositions of zolmitriptan and uses thereof.

Background

Zolmitriptan is a triptan drug (triptan) whose molecular targets are serotonin (5-HT) 1B receptors expressed in intracranial arteries and 5-HT 1D receptors located in the meninges and central terminal ends (central terminal) of peripheral, three-way sensory nerve endings in the brain stem sensory nucleus. 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.

Zolmitriptan asAre sold in the united states and other markets for the treatment of headaches such as migraine.

Zolmitriptan can be used to treat symptoms associated with Autism Spectrum Disorder (ASD). ASD patients often exhibit abnormal sensory processing and may be aversive to the color, taste, smell and/or texture of foods or drugs. Thus, maintaining drug compliance in ASD patients can be challenging.

Thus, there is a need for a pharmaceutical composition of zolmitriptan that provides therapeutic effectiveness when administered once, twice or three times a day.

Disclosure of Invention

In one aspect, the present disclosure provides a pharmaceutical composition comprising zolmitriptan or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides pharmaceutical compositions that provide therapeutically effective plasma levels of zolmitriptan when administered on a once-a-day or twice-a-day basis.

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

In some embodiments, the present disclosure provides a composition for treating symptoms of autism spectrum disorder, wherein the composition comprises from about 7.5mg to about 150mg of zolmitriptan or a pharmaceutically acceptable salt thereof, wherein administration of the composition provides a therapeutically effective plasma concentration of zolmitriptan for a period of at least about 12 hours.

In some embodiments, the present disclosure provides a composition for treating symptoms of autism spectrum disorder, wherein the composition comprises zolmitriptan or a pharmaceutically acceptable salt thereof, wherein oral administration of the composition provides an AUC of about 10 ng-h/mL to about 1150 ng-h/mL over a period of about 12-24h _0-24h,ss To treat symptoms of the autism spectrum disorder.

In some embodiments, the present disclosure provides a composition for treating symptoms of autism spectrum disorder, wherein the composition comprises zolmitriptan or a pharmaceutically acceptable salt thereof, wherein injection of the composition provides an AUC of about 10 ng-h/mL to about 1150 ng-h/mL over a period of about 1 day to about 1 month _0-24h,ss To treat symptoms of the autism spectrum disorder.

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

In some embodiments, the present disclosure provides a composition for treating aggressiveness in a patient suffering from dementia (e.g., an alzheimer's patient), wherein the composition comprises about 7.5mg to about 150mg of zolmitriptan or a pharmaceutically acceptable salt thereof, wherein administration of the composition provides a therapeutically effective plasma concentration of zolmitriptan for a period of at least about 12 hours.

In some embodiments, the present disclosure provides a composition for treating aggressiveness in a patient suffering from dementia (e.g., an alzheimer's patient), wherein the composition comprises zolmitriptan or a pharmaceutically acceptable salt thereof, wherein oral administration of the composition provides an AUC of about 10 ng-h/mL to about 1150 ng-h/mL over a period of about 12-24h _0-24h,ss To treat symptoms of the autism spectrum disorder.

In some embodiments, the present disclosure provides a composition for treating aggressiveness in a patient suffering from dementia (e.g., an alzheimer's patient), wherein the composition comprises zolmitriptan or a pharmaceutically acceptable salt thereof, wherein injection of the composition provides an AUC of about 10 ng-h/mL to about 1150 ng-h/mL over a period of about 1 day to about 1 month _0-24h,ss To treat symptoms of the autism spectrum disorder.

In some embodiments, the present disclosure provides a method of treating aggressiveness in a patient suffering from dementia (e.g., an alzheimer's patient), the method comprising administering to a patient in need thereof a pharmaceutical composition, wherein the pharmaceutical composition comprises about 2mg to about 150mg of zolmitriptan or a pharmaceutically acceptable salt thereof, wherein the administration provides a therapeutically effective plasma concentration for a period of at least about 12 hours.

Drawings

FIG. 1 shows the challenge time (seconds) of adult male CD-1 mice from a cross-resident-intruder (RI) study, where resident CD-1 mice were treated with vehicle control, 10mg/kg zolmitriptan, or 0.03mg/kg risperidone. As a crossover design, attack time was measured over a 5min period. Data are expressed as mean ± standard error of mean.

Figure 2 shows social ability index in a c57/Bl6 mouse model of valproic acid (VPA) -induced autism spectrum disorder in mice treated with vehicle control or 10mg/kg zolmitriptan.

Figure 3 shows the average CSF levels of zolmitriptan and its metabolite N-desmethylzolmitriptan (NDMZ) following oral administration of 5mg, 10mg, 20mg and 30mg doses to human subjects.

Figure 4 shows the zolmitriptan dissolution profile for a time release tablet (15 mg ER zolmitriptan) and a normal release/time release 25mg (10 mg IR zolmitriptan/15 mg ER zolmitriptan) bilayer tablet.

Fig. 5 shows the zolmitriptan dissolution profile for a 12mg (3 mg IR/9mg ER) and 24mg (6 mg IR/18mg ER) constant/delayed release oral bilayer tablet (n=6) of zolmitriptan.

Fig. 6 shows a study design schematic of the study described in example 10.

Definition of the definition

The term "about" when immediately preceding a numerical value means a range (e.g., plus or minus 10% of the value). For example, "about 50" may mean 45 to 55, "about 25,000" may mean 22,500 to 27,500, etc., unless the context of the present disclosure indicates otherwise, or the context is inconsistent with such interpretation. For example, in a list of values such as "about 49, about 50, about 55, … …," about 50 "means a range extending less than half way to one or more intervals between a previous value and a subsequent value, e.g., greater than 49.5 to less than 50.5. Furthermore, the phrase "less than about" value or "greater than about" value should be understood in view of the definition of the term "about" provided herein. Similarly, the term "about" when preceding a series of values or ranges of values (e.g., "about 10, 20, 30" or "about 10-30"), refers to all values in the series or endpoints of the range, respectively.

Throughout this disclosure, a number of patents, patent applications, and publications are referenced. The disclosures of these patents, patent applications, and publications are incorporated herein by reference in their entirety for all purposes to more fully describe the state of the art to which those skilled in the art have become aware by the date of this disclosure. In the event of any inconsistency between the cited patents, patent applications and publications and the present disclosure, the present disclosure will prevail.

For convenience, certain terms employed in the specification, examples and claims are collected here. Unless defined otherwise, 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.

The term "administering" or "administering" as used herein refers to administering a compound or a pharmaceutically acceptable salt or ester of the compound, or a composition comprising the compound or a pharmaceutically acceptable salt or ester of the compound, directly to a patient.

The term "carrier" as used herein encompasses carriers, excipients and diluents, which means materials, compositions or vehicles, such as liquid or solid fillers, diluents, excipients, solvents or encapsulating materials, that participate in carrying or transporting an agent from one organ or portion of the body to another organ or portion of the body.

The term "disorder" is used in this disclosure to mean the term disease, condition, or disorder, or may be used interchangeably with the term unless indicated otherwise.

The terms "effective amount" and "therapeutically effective amount" are used interchangeably throughout this disclosure and refer to an amount of a compound or salt, solvate or ester thereof that is capable of exhibiting the desired result when administered to a patient. For example, in some embodiments, an effective amount of zolmitriptan is an amount that is required to alleviate at least one symptom of ASD in a patient. The actual amount, including an "effective amount" or "therapeutically effective amount" will depend on a variety of conditions including, but not limited to, the severity of the disorder, the patient's body type and health, and the route of administration. The appropriate amount can be readily determined by a skilled practitioner using methods known in the medical arts.

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

The term "salt" as used herein includes pharmaceutically acceptable salts commonly used to form addition salts of the free base. The nature of the salt is not critical provided that it is pharmaceutically acceptable. The term "salt" also includes solvates of addition salts (such as hydrates) and polymorphs of addition salts. Suitable pharmaceutically acceptable acid addition salts may be prepared from inorganic acids or from organic acids.

The term "pharmaceutically acceptable salts" includes pharmaceutically acceptable salts obtained by reacting an active compound acting as a base with an inorganic or organic acid to form a salt, for example, the salts of the following acids: 1-hydroxy-2-naphthoic acid, 2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutarate, 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 (+), caproic acid (capric acid), caproic acid (caproic acid), caproic acid (caprylic 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, glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphate, 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 (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 appreciate that acid addition salts may be prepared via any of a number of known methods by reacting a compound with an appropriate inorganic or organic acid.

The term "treating" as used herein with respect to a patient refers to ameliorating at least one symptom of a disorder in the patient. Treatment may ameliorate or at least partially ameliorate the disorder.

The term "therapeutic effect" as used herein refers to a desired or beneficial effect provided by the method and/or the 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, such as improving irritability or increasing social ability associated with ASD. In some embodiments, a method for treating aggressiveness in a dementia patient (e.g., an Alzheimer's patient) provides when the method improves at least one symptom of aggressiveness in the patient in a therapeutically active patient.

Detailed Description

The present disclosure provides pharmaceutical compositions comprising zolmitriptan or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition provides therapeutically effective plasma levels when administered on a once-a-day, twice-a-day, or three-a-day basis. In some embodiments, the pharmaceutical composition achieves a list of products with reference to the list Similar therapeutic efficacy, but with improved safety profile.

Zolmitriptan

Zolmitriptan as employed in the methods of the invention may form part of a pharmaceutical composition by combining zolmitriptan or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier. In addition, the composition may comprise additives selected from adjuvants, excipients, diluents, release modifiers and stabilizers.

Zolmitriptan is a type of triptan drug. Triptans belong to the class of serotonin receptor subtype selective drugs. Triptan pair 5-HT belonging to the serotonin (5-HT) system _1B 、5-HT _1D And 5-HT _1F The receptor has selective activity. Triptans exhibit vasoconstrictor properties, which are defined by 5-HT in arterial smooth muscle _1B Is mediated by the action of (2). Vasoconstriction by triptans leads to a dose-dependent increase in blood flow velocity in blood vessels in the brain. It is believed that triptans inhibit peripheral nociceptionAbnormal activation of the receptor. It is speculated that triptans reduce Plasma Protein Extravasation (PPE) by inhibiting nociceptors activation and preventing peripheral release of vasoactive peptides including substance P and Calcitonin Gene Related Peptide (CGRP). Triptan binding sites are also found in the central nervous system. Thus, triptans may exhibit an effect on the central nervous system. At the time of this disclosure, triptans have been FDA approved for the treatment of migraine.

Since the discovery of abnormal blood 5-HT levels over 50 years ago as the first biomarker of the disorder, the serotonin system has been implicated in the pathophysiology of autism (Schain et al J Pediatr.1961, 3 months; 58:315-20). The main source of 5-HT in the brain derives from the midbrain dorsal style nucleus (DRN), which projects widely on the cortex, amygdala, hypothalamus, and to other subcortical structures associated with emotional processing and social behavior. Dense serotonin from DRN can project dominant nucleus accumbens (NAc), a preserved basal forebrain structure, which acts as an integrator of motivation signals prior to selective behavioral actions (Kravitz et al Physiology (Bethesda), 2012, month 6; 27 (3): 167-77.). In the context of social interactions, NAc rewards processing is believed to control the selection of social ways and social avoidance behavior (Pfaff. Trends neurosci.2019, month 7; 42 (7): 448-457). Evidence from preclinical studies supports a key role for 5-HT signaling in social behavior and social rewards (Kane et al PLoS one.2012;7 (11): e48975.; challis et al JNEurosci.2013, 8 th, 33 (35): 13978-88,13988a.; li et al Nat Commun.2016, 1 th, 28 th; 7:10503.). Furthermore, exception handling in NAc winning was observed in fMRI imaging studies for children with ASD (Clements et al JAMA Psychiary.2018, month 1; 75 (8): 797-808.Doi: 10.1001/jamapsychiary.2018.1100.).

In the human Brain, 5-HT1B is highly expressed in NAc (Garcia-Alloza et al Neuropresymologia 2005;43 (3): 442-9; varnas et al Hum Brain map 2004, 7 months; 22 (3): 246-60; varnas et al Synase. 56:21-8.). It is an inhibitory G-protein coupled receptor located at the tip of axons that functions to inhibit neurotransmitter release (Sari. Neurosci Biobehav Rev.2004, month 10; 28 (6): 565-82.). As an autoreceptor, 5-HT1B inhibits 5-HT release, but it also plays an important role as a foreign receptor to inhibit the release of other neurotransmitters including glutamate, GABA, dopamine and acetylcholine. (Boscher et al (1994) Neuroscience 58:167-182.). According to the present disclosure, 5-HT1B agonism of the triptans described herein modulates behavioral symptoms of ASD.

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 International publication No. 2005/105792, which is hereby incorporated by reference in its entirety for all purposes.

In some embodiments, the zolmitriptan used in the compositions and methods of the present disclosure is a pharmaceutically acceptable salt of zolmitriptan. In some embodiments, the pharmaceutically acceptable salt of zolmitriptan used in the formulations and methods of the present disclosure is selected from oxalate, camphorsulfonate, sulfonate, hydrobromide, hydrochloride, hydrosulfate, mesylate, succinate, and tartrate.

Pharmaceutical composition

In one aspect, the present disclosure provides a pharmaceutical composition comprising zolmitriptan.

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

In some embodiments, the present disclosure provides pharmaceutical compositions that, when administered on a once-daily, twice-daily, or three-daily basis, provide a therapeutic effect of treating aggressiveness in patients with dementia (e.g., alzheimer's patients).

In some embodiments, the pharmaceutical compositions provided herein are administered to a subject in a fasted state. In some embodiments, the pharmaceutical composition is administered to a subject in a fed state.

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

In some embodiments, the pharmaceutical composition releases zolmitriptan in two or more pulses (e.g., two, three, four, five, six, seven, eight, nine, and ten or more pulses). The timing of the pulses may be modified to release the drug in a desired region 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.

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

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

In some embodiments, the ratio of the constant release component to the zolmitriptan in the delayed release or extended release component is in the range: 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 subranges therebetween. In some embodiments, the ratio of the constant release component to the zolmitriptan in the delayed release or extended release component is about 25:75. In some embodiments, the constant release component comprises up to about 75% (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) of the total amount of zolmitriptan in the pharmaceutical composition, and the delayed release or extended release component comprises about 25% or more (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) of the total amount of zolmitan in the pharmaceutical composition. In some embodiments, the constant release component comprises about 20% -40% by weight of the total zolmitriptan in the composition, including about 20%, about 25%, about 30%, about 35%, to about 40% by weight of the total zolmitriptan in the composition (including all values and subranges therebetween). In some embodiments, the extended release component comprises about 60% -80% by weight of the total zolmitriptan in the composition, including about 60%, about 65%, about 70%, about 75%, to about 80% (including all values and subranges therebetween) by weight of the total zolmitriptan in the composition. In some embodiments, the constant release component comprises about 25% of the total zolmitriptan in the composition and the extended release component comprises about 75% of the total zolmitriptan in the composition.

In some embodiments, the constant release component comprises about 1mg to about 20mg of zolmitriptan or a pharmaceutically acceptable salt thereof, including about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg, about 19mg, to about 20mg, including all values and subranges therebetween. In some embodiments, the constant release component comprises about 1mg to about 10mg or about 3mg to about 10mg of zolmitriptan or a pharmaceutically acceptable salt thereof. In some embodiments, the constant release component comprises about 3mg of zolmitriptan or a pharmaceutically acceptable salt thereof. In some embodiments, the constant release component comprises about 6mg of zolmitriptan or a pharmaceutically acceptable salt thereof.

In some embodiments, the delayed release component comprises about 1mg to about 50mg of zolmitriptan or a pharmaceutically acceptable salt thereof, including about 1mg, about 2mg, about 3mg, about 4mg, 5mg, about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg, about 19mg, about 20mg, about 21mg, about 22mg, about 23mg, about 24mg, about 25mg, about 26mg, about 27mg, about 28mg, about 29mg, about 30mg, about 31mg, about 32mg, about 33mg, about 34mg, about 35mg, about 36mg, about 37mg, about 38mg, about 39mg, about 40mg, about 41mg, about 42mg, about 43mg, about 44mg, about 45mg, about 46mg, about 47mg, about 48mg, about 49mg, and about 50mg, including all subranges therebetween. In some embodiments, the delayed release component comprises about 5mg to about 25mg of zolmitriptan or a pharmaceutically acceptable salt thereof. In some embodiments, the delayed release component comprises about 9mg of zolmitriptan or a pharmaceutically acceptable salt thereof. In some embodiments, the delayed release component comprises about 18mg of zolmitriptan or a pharmaceutically acceptable salt thereof.

In some embodiments, the constant release component comprises about 0.01% to 10% w/w of zolmitriptan or a pharmaceutically acceptable salt thereof, based on the total weight of the composition (e.g., bilayer tablet), including 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 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 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 pharmaceutically acceptable salt thereof, including all values and subranges therebetween. In some embodiments, the constant release component comprises about 0.01% to 5% w/w or about 0.1% to 2.5% w/w of zolmitriptan or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In some embodiments, the extended release component comprises about 0.05% to 20% w/w of zolmitriptan or a pharmaceutically acceptable salt thereof, based on the total weight of the composition (e.g., bilayer tablet), 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% w/w, about 2% w/w, about 2.5% w/w, about 3% w/w, about 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, 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 delayed release component comprises about 1% to 10% w/w, or 0.05% to 5% w/w, or 0.01% to 2.5% w/w of zolmitriptan or a pharmaceutically acceptable salt thereof, based on the total weight of the composition.

Non-limiting examples of suitable common release components include one or more common release components incorporated as part or multiple parts of a dosage form, which may be in the form of tablets, liquid compositions (e.g., suspensions and emulsions), capsules, elixirs, syrups, drug-containing beads and granules and the like. In some embodiments, the constant release component may be disposed over the delayed release or delayed release component, or the constant release component may be different from the delayed release or delayed release component. For example, the constant release component may be in the form of a coating that may be disposed on an osmotic delivery system or capsule, or the constant release beads may be combined with delayed release beads or time release beads in a capsule or tablet. In other embodiments, the normally released component may be provided as a bilayer or as one layer of a multilayer tablet. In some embodiments, the release-modifying component is provided as a layer of a bilayer tablet. The delayed release component may be any formulation that prevents release of a portion (e.g., about 25% -99%) of the total amount of zolmitriptan in the pharmaceutical composition for substantially at least 30 minutes. Non-limiting examples of suitable delayed release components include one or more delayed release components incorporated as part or multiple parts of a drug-containing tablet, granule, bead, etc., the one or more delayed release components being coated with a delayed release polymer; a delayed release matrix comprising zolmitriptan; and an osmotic pump comprising zolmitriptan.

In some embodiments, the composition comprises one or more constant release components in combination with one or more delayed release components, wherein the delayed release components release zolmitriptan over an extended period of time.

In some embodiments, the composition is a multiparticulate formulation. In some embodiments, the composition is a gastroretentive tablet.

In some embodiments, the time-release component is a gastric retentive layer. In some embodiments, the composition remains in the stomach after oral administration for at least about 1h, at least about 2h, at least about 3h, at least about 4h, at least about 5h, at least about 6h, at least about 7h, at least about 8h, at least about 9h, at least about 10h, at least about 11h, or at least about 12h. In some embodiments, the composition remains in the stomach for at least about 2 hours after oral administration. In some embodiments, the composition remains in the stomach for at least about 8 hours after oral administration.

The present disclosure provides the exemplified embodiments that disclose compositions and methods for treating symptoms of autism spectrum disorders. The compositions and methods described herein are also suitable for treating other conditions characterized by aggressiveness (e.g., aggressiveness in dementia patients such as Alzheimer's patients). Thus, the embodiments recited herein with respect to the compositions and treatment of symptoms of autism spectrum disorders are equally applicable to the treatment of conditions characterized by aggressiveness (e.g., aggressiveness in dementia patients such as Alzheimer's patients).

In some embodiments, provided herein is an oral composition for treating symptoms of autism spectrum disorder, wherein the composition comprises from about 7.5mg to about 90mg of zolmitriptan or a pharmaceutically acceptable salt thereof, and oral administration of the composition provides a therapeutically effective plasma concentration of zolmitriptan for a period of at least 8 hours.

In some embodiments, provided herein is an oral composition for treating aggressiveness in a patient suffering from dementia, wherein the composition comprises about 7.5mg to about 90mg of zolmitriptan or a pharmaceutically acceptable salt thereof, and oral administration of the composition provides a therapeutically effective plasma concentration of zolmitriptan for a period of at least 8 hours.

In some embodiments, provided herein is an oral composition for treating aggressiveness in a patient suffering from alzheimer's disease, wherein the composition comprises about 7.5mg to about 90mg of zolmitriptan or a pharmaceutically acceptable salt thereof, and oral administration of the composition provides a therapeutically effective plasma concentration of zolmitriptan for a period of at least 8 hours.

In some embodiments, the pharmaceutical compositions of the present disclosure exhibit substantial dissolution when tested in 900mL of 0.1N HCl (or suitable medium) at about 37 ℃ using usp apparatus II (paddle, at 50 rpm)

Zolmitriptan release profile corresponding to the following pattern:

about 20% -40% of the total zolmitriptan released after about 15 minutes;

about 40% -75% of total zolmitriptan is released after about 4 hours; and is also provided with

About 75% -90% of the total zolmitriptan is released after about 8 hours.

In some embodiments, the dissolution is tested in a simulated fasted state. In some embodiments, the dissolution is tested in a simulated fed state.

In some embodiments, when the pharmaceutical compositions provided herein are tested for dissolution in 900mL of 0.1N HCl (or a suitable medium) at about 37 ℃ using usp apparatus II (paddles, at 50 rpm), about 5% -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.

In some embodiments, when the pharmaceutical compositions provided herein are tested for dissolution in 900mL of 0.1N HCl (or a suitable medium) at about 37 ℃ using usp apparatus II (paddles, at 50 rpm), 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.

In some embodiments, when the pharmaceutical compositions provided herein are tested for dissolution in 900mL of 0.1N HCl (or a suitable medium) at about 37 ℃ using usp apparatus II (paddles, at 50 rpm), about 75% -90%, including about 75%, about 80%, about 85% and about 90%, including all values and subranges therebetween, of total zolmitriptan is released after about 8 hours. In some embodiments, about 85% of the total zolmitriptan is released over 9-10 hours. In some embodiments, the dissolution is tested in a simulated fed state.

In embodiments, the pharmaceutical composition thus provides a therapeutically effective plasma concentration over an extended period of time (typically over a period of about 6-24 hours (e.g., about 8 hours, or about 12 hours, or about 16 hours)) to treat symptoms of autism spectrum disorder in a human.

In embodiments, the pharmaceutical composition thus provides a therapeutically effective plasma concentration over an extended period of time (typically over a period of 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 symptoms of autism spectrum disorder in a human.

In embodiments, the pharmaceutical composition thus provides a therapeutically effective plasma concentration over an extended period of time (typically over a period of about 6-24 hours (e.g., about 8 hours, or about 12 hours, or about 16 hours)) to treat aggressiveness in patients with dementia (e.g., alzheimer's patients).

In embodiments, the pharmaceutical composition thus provides a therapeutically effective plasma concentration over an extended period of time, typically over a period of 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 aggressiveness in patients suffering from dementia (e.g., alzheimer's patients).

In some embodiments, the pharmaceutical compositions of the present disclosure (including one or more constant release components and/or delayed release or extended release components) comprise at least one pharmaceutically acceptable carrier, diluent, and/or excipient. Pharmaceutically acceptable carriers, diluents or excipients include, but are not limited to, any adjuvants, carriers, excipients, glidants, sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.

In some embodiments, the extended release component is a gastric retentive layer, and the gastric retentive layer comprises zolmitriptan or a pharmaceutically acceptable salt thereof, a drug release modifier, and optionally one or more excipients described herein (such as lubricants and binders and/or diluents) and other excipients. In some embodiments, the gastric retentive 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 gastric retentive layer comprises from about 15% to about 75% w/w of the total composition (e.g., bilayer tablet) of a drug release modifier (e.g., a water swellable polymer), including from 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 of the total composition, including all values and subranges therebetween. In some embodiments, the gastric retentive layer comprises about 35% -55% w/w of the drug release modifier (e.g., a water swellable polymer such as polyethylene oxide) of the total composition (e.g., bilayer tablet). Suitable lubricants for the gastric retentive layer include any of the lubricants listed herein, such as stearic acid and stearates, for example magnesium stearate. In some embodiments, the gastric-retention layer comprises 0.05% to 5% w/w lubricant, including, 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, 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, based on the total weight of the composition (e.g., bilayer tablet). Suitable binders for the gastric retentive layer include any of the binders listed herein, including microcrystalline cellulose, such as Avicel ^TM PH101 or Ceolus ^TM KG802. The amount of binder in the gastroretentive layer can 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., bilayer tablet).

In some embodiments, suitable pharmaceutically 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 can be aqueous or nonaqueous solutions, suspensions, and emulsions. Examples of nonaqueous 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). Suitable aqueous carriers for use herein include, but are not limited to, water, ethanol, alcohol/water solutions, glycerol, emulsions or suspensions, including saline and buffered media.

Suitable liquid carriers for use herein include, but are not limited to, water (partially containing additives such as cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, such as glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil).

Liquid carriers suitable for use herein can be used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compounds. In some embodiments, the active ingredient is dissolved or suspended in a pharmaceutically acceptable liquid carrier, such as water, an organic solvent, a mixture of both, or a pharmaceutically acceptable oil or fat. In some embodiments, the liquid carrier contains other suitable pharmaceutical additives, such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmotically adjusted agents.

Solid carriers suitable for use herein include, but are not limited to, inactive substances such as lactose, starch, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like. The solid carrier may further comprise one or more substances acting as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; 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 characteristics in a suitable ratio and compacted in the shape and size desired. Powders and tablets may contain up to 99% of the active compound. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidone, low melting waxes and ion exchange resins. Tablets may be manufactured by compression or moulding, optionally together with one or more auxiliary ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropyl methylcellulose), lubricant, inert diluent, preservative, disintegrant (e.g. sodium starch glycolate, crospovidone, croscarmellose sodium) surfactant or dispersing agent. 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 optionally be coated or scored and may be formulated in various ratios so as to provide a desired release profile using, for example, hydroxypropyl methylcellulose in order to provide delayed or controlled release of the active ingredient therein. The tablets may optionally be provided with an enteric coating to provide release in the portion of the intestinal tract other than the stomach.

Carriers suitable for use in the present application may be admixed with disintegrants, diluents, granulating agents, lubricants, binders and the like as desired using conventional techniques known in the art. The carrier may also be sterilized using methods that do not adversely react with the compound, as is generally known in the art.

Diluents may be added to the formulations described herein. Diluents increase the volume of the solid pharmaceutical compositions and/or combinations and can produce pharmaceutical dosage forms containing the compositions and/or combinations that are easier for patients and caregivers to handle. In various embodiments, diluents for the solid compositions include, for example, microcrystalline cellulose (e.g., AVICEL), fine cellulose (microfine cellulose), lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, amylolytic sugar mixtures (dextran), dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g.,) 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 trade mark Avicel (FMC corp., philadelphia, pa), e.g., avicel ^TM pH101、Avicel ^TM pH102 and Avicel ^TM pH112; lactose includes lactose monohydrate, lactose anhydrous, and Pharmatose DCL21; the dibasic calcium phosphate includes Emcompress.

Lubricants are used to aid in tablet manufacture, promote powder flow and prevent particle capping (i.e., particle breakage) when pressure is relieved. Useful lubricants are magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, talc, colloidal silicon dioxide (such as Aerosil ^TM 200 Mineral oil (in PEG), hydrogenated vegetable oil (e.g., composed of hydrogenated and refined stearic and palmitic triglycerides), combinations thereof.

Binders are used to impart cohesive properties to the tablet and thus ensure that the tablet or tablet layer remains intact after compression. Suitable binder materials include, but are not limited to, starches (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose, and lactose), polyethylene glycols, polyvinyl alcohol, waxes, and natural and synthetic gums (e.g., sodium alginate gum arabic), polyvinylpyrrolidone, cellulosic polymers (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, ethylcellulose, hydroxyethylcellulose, and the like), and magnesium aluminum silicate (Veegum), and combinations thereof. Examples of polyvinylpyrrolidone include povidone, copovidone, and crospovidone.

Fillers include, for example, materials such as: silica, titania, alumina, talc, kaolin, powdered cellulose, microcrystalline cellulose, urea, sodium chloride, and sugars or combinations thereof. Any suitable sugar may be used in the compositions of the present disclosure. As used herein, "sugar" for the purposes of the present invention includes sugar alcohols, monosaccharides, disaccharides and oligosaccharides. Exemplary sugar alcohols include, but are not limited to, xylitol, mannitol, sorbitol, erythritol, lactitol, pentitols, and hexitols. Exemplary monosaccharides include, but are not limited to, glucose, fructose, aldoses, and ketoses. 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 mannooligosaccharides. In some embodiments, the sugar is sorbitol, mannitol, or xylitol. In some embodiments, the sugar is sorbitol. In some embodiments, the sugar is sucrose.

Disintegrants are used to aid in the disintegration of the tablet, thereby increasing the erosion rate relative to the dissolution rate, and are typically starches, clays, celluloses, algins, gums or cross-linked polymers (e.g., cross-linked polyvinylpyrrolidone). Other non-limiting examples of suitable disintegrants include, for example, lightly crosslinked polyvinylpyrrolidone, corn starch (corn starch), potato starch, maize starch (main starch) and modified starch, crosslinked sodium carboxymethyl cellulose, crosslinked povidone, sodium starch glycolate, and combinations and mixtures thereof.

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-making, levigating, emulsifying, encapsulating, embedding (entering), or lyophilizing processes. As mentioned above, the zolmitriptan compositions of the present disclosure may include one or more pharmaceutically acceptable carriers (such as excipients and adjuvants) that facilitate processing of the active molecule into a formulation for pharmaceutical use.

In some embodiments, the pharmaceutical compositions of the present disclosure are prepared in oral formulations. For oral administration, the compounds may be readily formulated by combining the active compounds with pharmaceutically acceptable carriers known in the art. Such carriers enable the formulation of zolmitriptan into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject. Pharmaceutical compositions for oral use may be obtained as solid excipients, optionally grinding the resulting mixture, and processing the mixture of granules (if desired after adding suitable adjuvants) to obtain tablets or dragee cores. Such oral pharmaceutical compositions may also be prepared by milling or melt extrusion. Suitable excipients may be any of those disclosed herein and are specifically fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose formulations such as cornstarch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl-cellulose, hydroxypropyl-methyl-cellulose, sodium carboxymethyl-cellulose and/or polyvinylpyrrolidone (PVP) formulations. In addition, disintegrants such as crosslinked polyvinylpyrrolidone, agar or alginic acid or a salt thereof (such as sodium alginate) may be used. Wetting agents such as sodium lauryl sulfate and the like may be added.

In some embodiments, the zolmitriptan is combined with an excipient to form a core comprising zolmitriptan (i.e., the active core). In some embodiments, the active core comprises inert particles (such as sugar spheres) having a suitable average particle size. In one embodiment, the inert core may be sugar spheres, cellulose spheres, spherical silica beads, buffer crystals or encapsulated buffer crystals, such as calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid, and the like. Buffer crystals can be used to alter the microenvironment. Alternatively, according to other embodiments, the drug-containing microgranules or pellets can be prepared by rotary granulation, high shear granulation and extrusion-spheronization or compression of the drug (as microtablets, e.g., having a diameter of about 2mm or greater), a polymeric binder, and optionally a filler/diluent.

In some embodiments, dragee cores can be provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbomer gels, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablet or dragee coating for identifying or characterizing different combinations of active compound doses.

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 comprises a carrier and is formulated in an aqueous solution (such as water) or a physiologically compatible buffer (such as hanks solution, ringer's solution, or physiological saline buffer). In some embodiments, other ingredients (e.g., ingredients that aid in dissolution or act as preservatives) are included. In some embodiments, injectable suspensions are prepared using suitable liquid carriers, suspending agents and the like. Some injectable pharmaceutical compositions are presented in unit dosage form, for example, in ampoules or in multi-dose containers. Some injectable pharmaceutical compositions are suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Some solvents suitable for use in pharmaceutical compositions for injection include, but are not limited to, lipophilic solvents and fatty oils, such as vegetable oils (e.g., sesame oil, etc.); fatty acid esters such as ethyl oleate or triglycerides are synthesized. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, such suspensions may also contain suitable stabilizers or agents that increase the solubility of the agent to allow for the preparation of high concentration solutions.

The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, such as a solution in 1, 3-butanediol, or as a lyophilized powder. Acceptable vehicles and solvents that may be employed include water, ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils may be conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids (such as oleic acid) find use in the preparation of injectables. Formulations for intravenous administration may comprise solutions in sterile isotonic aqueous buffers. If desired, the formulation may also contain solubilizing agents and local anesthetics to relieve pain at the injection site. Typically, the ingredients are provided separately or mixed together in unit dosage form, for example as a dry lyophilized powder or anhydrous concentrate in a hermetically sealed container, such as an ampoule or sachet indicating the active dose. Where the compound is to be administered by infusion, it may be dispensed in a formulation with an infusion bottle containing sterile pharmaceutical grade water, saline or dextrose/water. In the case of administration of the compounds by injection, an ampoule of sterile water for injection or saline may be provided so that the ingredients may be mixed prior to administration.

Suitable formulations further include aqueous sterile injection solutions and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, bacteriocidal antibiotics, and solutes that render the formulation isotonic with the body fluids of the intended recipient; and aqueous sterile suspensions and non-aqueous sterile suspensions that may contain suspending agents and thickening agents. The liposome suspension containing tissue-targeting liposomes can be present in a suitable formulation.

Parenteral administration of the formulations of the present invention includes intravenous, subcutaneous, and intramuscular administration of the pharmaceutical compositions described herein. Formulations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products ready for combination with a solvent immediately prior to use (including subcutaneous injection tablets ready for injection, sterile suspensions), sterile dry insoluble products ready for combination with a vehicle immediately prior to use, and sterile emulsions. The solution may be aqueous or non-aqueous. Pharmaceutically acceptable carriers for parenteral formulations include aqueous vehicles, non-aqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, thickening agents, emulsifying agents, chelating agents (sequestering agent) or chelating agents (chelating agents) and other pharmaceutically acceptable substances. Liposomal suspensions are also suitable as pharmaceutically acceptable carriers.

In some embodiments of the present disclosure, the pharmaceutical composition is formulated as a depot (depot) formulation. Such depot formulations typically act longer than non-depot formulations. In some embodiments, such formulations are administered parenterally (e.g., by injection or implantation). For example, subcutaneous or intramuscular depot injection of sterile solutions containing zolmitriptan is an effective mode of administration. In some embodiments, the depot formulation is prepared using a suitable polymeric or hydrophobic material (e.g., an emulsion in an acceptable oil) or ion exchange resin, or is prepared 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. a poorly soluble salt). In some embodiments, the depot formulation provides a depot release profile of 1 day, 7 days, or 30 days. In some embodiments, such formulations are administered on a once-a-day, once-a-week, or once-a-month injection schedule.

The concentration of the pharmaceutically active compound may be adjusted so that the injection provides an effective amount to produce the desired pharmacological effect. The exact dosage will depend on the age, weight and condition of the patient or animal, as is known in the art. In some embodiments, the unit dose parenteral formulation is packaged in an ampoule or a syringe with a needle. As known and practiced in the art, all formulations for parenteral administration must be sterile. Illustratively, intravenous or intra-arterial infusion of sterile aqueous solutions containing zolmitriptan is an effective mode of administration.

Delayed release component

In some embodiments, the pharmaceutical compositions described herein comprise one or more normal 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., two, three, four, five, six, seven, eight, nine, and ten or more), each of which may provide a different release profile. In some embodiments, the delayed release portion is a gastric retentive layer. In some embodiments, each delayed release component is formulated to occur after a desired delay to pulse the release of zolmitriptan, the first delayed release component to pulse the release of zolmitriptan and the second delayed release component to provide delayed release, or both delayed release components to provide delayed release of zolmitriptan.

As used herein, "delayed release" refers to a pharmaceutical formulation that substantially prevents release (meaning release of no more than about 5% -10%) of an active (e.g., zolmitriptan) contained in the delayed-release component for a defined period of time after oral administration. In some embodiments, the delayed release substantially prevents release of the active 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 encompasses formulations wherein a portion of the active (e.g., zolmitriptan) is not released from the formulation for a specific period of time.

In some embodiments, the delayed release component may substantially prevent release of at least about 40% (e.g., about 40% to about 60%) of the total amount of zolmitriptan in the pharmaceutical formulation 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.

In some embodiments, substantially complete release (e.g., at least about 90% -95%) of the zolmitriptan from the delayed release component is achieved when 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 relatively low acidic environment of the intestine.

In some embodiments, the delayed release component is suitably formulated to provide pulsatile release of zolmitriptan in the acidic environment of the stomach that occurs at least 30 minutes (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) after oral administration.

In some embodiments, the delayed release component is suitably formulated (e.g., as a delayed release formulation) to slowly release the zolmitriptan over a period of time, wherein initial release of the zolmitriptan from the delayed release component occurs at least 30 minutes after oral administration and extends 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, initial release of the zolmitriptan from the delayed release component occurs at least 30 minutes after oral administration and occurs for an amount 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).

In some embodiments, the delayed release component is suitably formulated (e.g., as a delayed release formulation) to slowly release the zolmitriptan over a period of time, wherein initial release of the zolmitriptan from the delayed release component occurs at least 30 minutes and extends 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 after oral administration.

In some embodiments, the delayed release component comprises two or more delayed release components. In some embodiments, the first delayed-release component is suitably formulated to release a first portion of zolmitriptan in the acidic environment of the stomach and the second delayed-release component is suitably formulated to release a second portion of zolmitriptan in the lower acidic environment of the lower intestine. The ratio of zolmitriptan released in the stomach compared to the lower intestine may be in the range: 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 as compared to the lower intestine is in the range of about 70:30 to about 40:60 (e.g., about 60:40 to about 50:50). The relative amounts of zolmitriptan released in the stomach and in the lower intestine can be selected to reduce the maximum plasma level of zolmitriptan and to reach an AUC of 80% -125% of the AUC of the listed reference products. 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 polymers or rate control polymers) or embedding the drug in a matrix comprising one or more suitable delayed release polymers. Suitable delayed release polymers include pharmaceutically acceptable water insoluble polymers (also referred to as hydrophobic polymers), pharmaceutically acceptable water soluble polymers (also referred to as hydrophilic polymers), pharmaceutically acceptable gastric soluble polymers, pharmaceutically acceptable enteric polymers, and combinations thereof.

In some embodiments, non-limiting examples of pharmaceutically acceptable water-soluble polymers include homopolymers and copolymers of N-vinyl lactam, including homopolymers and copolymers of N-vinyl pyrrolidone (e.g., polyvinylpyrrolidone (PVP), copolymers of N-vinyl pyrrolidone and vinyl acetate or propionate); cellulose esters and cellulose ethers, in particular methylcellulose and ethylcellulose, hydroxyalkyl celluloses (in particular hydroxypropyl cellulose, hydroxyalkyl alkylcellulose and hydroxypropyl methylcellulose), cellulose phthalates, succinates, butyrates or trimellitates (in particular cellulose acetate phthalate, hydroxypropyl methylcellulose succinate and hydroxypropyl methylcellulose acetate succinate); high molecular weight polyalkylene oxides such as polyethylene oxide and polypropylene oxide, and copolymers of ethylene oxide and propylene oxide; polyacrylates and polymethacrylates such as methacrylic acid/ethyl acrylate copolymer, methacrylic acid/methyl methacrylate copolymer, butyl methacrylate/2-dimethylaminoethyl methacrylate copolymer, poly (hydroxyalkyl acrylate), poly (hydroxyalkyl methacrylate); an acrylamide; vinyl acetate polymers such as copolymers of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate (also known as partially saponified "polyvinyl alcohol"); polyvinyl alcohol; polyethylene glycol oligosaccharides and polysaccharides such as carrageenan, galactomannan and xanthan gum; or a mixture of one or more thereof.

Non-limiting examples of stomach-soluble polymers include polymers according to trade nameMaltrin (an aminoalkyl methacrylate copolymer), polyvinyl acetal diethylaminoacetate (e.g., available from Tokyo Sankyo Company Limited, japan)>) Etc.

Non-limiting examples of enteric polymers include Cellulose Acetate Phthalate (CAP), cellulose acetate succinate, methyl cellulose phthalate, hydroxyethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), polyvinyl alcohol phthalate, polyvinyl butyrate phthalate, polyvinyl acetate phthalate (PVAP), copolymers of vinyl acetate/maleic anhydride, copolymers of vinyl butyl ether/maleic anhydride, copolymers of styrene/maleic acid monoesters, copolymers of methyl acrylate/methacrylic acid, copolymers of styrene/acrylic acid, copolymers of methyl acrylate/methacrylic acid/octyl acrylate, copolymers of methacrylic acid/methyl methacrylate, cellulose acetate hexahydrophthalate, hydroxypropyl methyl cellulose phthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate trimellitate, cellulose acetate butyrate, cellulose acetate propionate, methacrylic acid/methacrylic acid, copolymers of styrene/maleic acid monoesters, copolymers of methacrylic acid/methacrylic acid, and the like, and the copolymers of methacrylic acid, EUT-methyl acrylate, the acid value of which are also referred to as methacrylic acid-co-methyl methacrylate, methacrylic acid-co-polymers of (GIL-methyl methacrylate, vinyl acetate-co-methyl acrylate, vinyl methacrylate-co-methyl methacrylate, etc.), and combinations comprising one or more of the foregoing enteric polymers. Other examples include natural resins such as shellac, mountain damasc, copal (copal collophorium) and combinations comprising one or more of the foregoing polymers. Still other examples of enteric polymers include synthetic resins with 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 at a pH of less than about 5 when used in an enteric coating formulation, and that is substantially soluble or decomposable under conditions exhibiting a pH of about 5 or greater.

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

In some embodiments, the delayed release coating comprises about 40wt% to about 95wt% of any of the pharmaceutically acceptable polymers listed above (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) and about 5wt% to about 60wt% 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) based on the total weight of the polymer coating. The relative proportions of the ingredients (notably the ratio of enteric polymer to plasticizer) can vary according to methods known to those skilled in the art of pharmaceutical formulation.

Delayed release component

In some embodiments, the pharmaceutical compositions described herein comprise one or more constant release components and one or more delayed release components, wherein the delayed release components release zolmitriptan over an extended period of time. The extended period of time is longer than the period of time for which the components are normally released as described herein, such that the total amount of active agent in the time-release component is released over a period of time of about 1 to 24 hours, for example, over 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 there between. When combined in a pharmaceutical composition, the combination of the normal release component and the delayed release component in the pharmaceutical composition releases less than about 75% of the total dose of zolmitriptan in about 30 minutes, for example, 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 dose of zolmitriptan in about 30 minutes, e.g., as measured using the dissolution test described herein. Advantageously, such pharmaceutical compositions achieve equivalent therapeutic efficacy with reduced maximum exposure levels compared to the listed reference products (i.e., ZOMIG) as described herein.

In some embodiments, the delayed release component comprises one or more delayed release components (e.g., two, three, four, five, six, seven, eight, nine, and ten or more), each of which may provide a different release profile. In some embodiments, the time-release portion is a gastric retentive layer.

In some embodiments, the delayed release component is prepared by embedding the drug in a matrix comprising one or more suitable delayed release polymers, such as water swellable polymers for gastric retention formulations.

In some embodiments, the time-release component is a gastric retentive composition. Such compositions have an extended residence time in the stomach, which provides delayed gastric emptying of zolmitriptan. Examples include floating drug delivery systems (floating drug delivery system) (also known as hydrodynamic balance systems), swelling and expansion systems, reshaping systems (modified-shape systems), high density systems, and other delayed gastric emptying systems (U.S. patent No. 9,000,046, incorporated herein by reference in its entirety). The gastroretentive composition can also be formulated with bioadhesives (e.g., mucoadhesives), particle sizes that substantially prevent passage of drug-containing particles 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 (polycarbophil), lectin, carbomer (carbopol), chitosan, carboxymethylcellulose (CMC), pectin, prolamin, polyethylene glycol, tragacanth, sodium alginate, cholestyramine, polyacrylic acid, and sucralfate (see Madal, U.K. et al, "gateway-retentive drug delivery systems and their in vivo success: A direct update" Asian J.of pharmaceutical. Sci.2016,11,575-584; and Shaema, A.R. et al "Gastroretentive Drug Delivery System: an Approach to Enhance Gastric Retention for Prolonged Drug Release" International J.of pharmaceutical. Sci.and Res.2014,5,1095-1106, each of which is incorporated herein by reference in its entirety).

In some embodiments, the extended release component is a gastric retentive component having zolmitriptan in a water swellable polymer matrix. Suitable water-swellable polymers for use herein are polymers that swell in an unlimited size manner upon contact with water. Such polymers may also gradually 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, hydroxyalkyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, microcrystalline cellulose; polysaccharide and derivatives thereof; a chitosan; poly (vinyl alcohol); xanthan gum; maleic anhydride copolymers; poly (vinyl pyrrolidone); starch and starch-based polymers; maltodextrin; poly (2-ethyl-2-oxazoline); poly (ethyleneimine); polyurethane; a hydrogel; crosslinking polyacrylic acid; and combinations or blends of any of the foregoing.

Further examples are copolymers, including block copolymers and graft polymers. Specific examples of copolymers areAnd->Which is a polyethylene oxide-polypropylene oxide block copolymer available from BASF Corporation, chemicals div, huai Enduo tex, michigan, usa. Further examples are hydrolyzed starch polyacrylonitrile graft copolymers, commonly known as "Super slupper" and available from Illinois Corn Growers Association, brimton, il.

In some embodiments, swellable erodible hydrophilic polymers suitable for forming the gastric retentive portion of the dosage form 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) polymer may range from about 9 x 105 daltons to about 8 x 106 daltons. Exemplary molecular weight poly (ethylene oxide) polymers include about 9 x 105 daltons (e.g., SENTRY ^TM POLYOX ^TM WSR 1105). In some embodiments, the rates of wetting, swelling, and erosion may be varied by varying the molecular weight Polyox ^TM To be modified.

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

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 methyl cellulose, carboxymethyl cellulose, and microcrystalline cellulose.

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

In some embodiments, the composition comprises from 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% by weight of the water-swellable polymer. In some embodiments, the water-swellable polymer is polyethylene oxide. In some embodiments, the composition comprises about 35% -55% by weight polyethylene oxide. In some embodiments, the extended release is achieved by suitably coating the drug-containing component with one or more suitable extended release polymers (also referred to as rate controlling polymers). Suitable time release polymers include, for example, pharmaceutically acceptable water insoluble polymers (also referred to as hydrophobic polymers) and pharmaceutically acceptable water swellable polymers.

In some embodiments, the extended release portion comprises drug-containing particles coated with an extended release coating. In some embodiments, multiparticulate formulations.

Non-limiting examples of pharmaceutically acceptable water insoluble polymers include acrylic acid polymers, methacrylic acid polymers, acrylic acid copolymers (such as according to the trade name(types L, RL, RS and NE 30D) and their corresponding esters, zein, waxes, shellac and hydrogenated vegetable oils, cellulose derivatives (such as ethylcellulose, cellulose acetate butyrate, and the like). />

In some embodiments, the delayed release coating comprises about 40wt% to about 95wt% of any of the pharmaceutically acceptable polymers listed above (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) and about 5wt% to about 60wt% 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) based on the total weight of the polymer coating.

Osmotic delivery system

In some embodiments, the delayed release is an osmotic system. The osmotic system is a core having a semi-permeable outer membrane and one or more openings. The semi-permeable 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 via osmosis and the osmotic pressure generated is used to push the active drug through one or more openings in the core. The release and release rate of total zolmitriptan can be controlled by appropriate choice of the thickness and porosity of the semipermeable membrane, the composition of the core, and the number and size of openings. Formulation aspects, administration forms and information about the preparation method are described, for example, in the following publications:

Santus,G.,Baker,R.W.,“Osmotic drug delivery:a review of the patent literature”,Journal of Controlled Release 35(1995),1-21；

Verma,R.K.,Mishra,B.,Garg,S.,“Osmotically controlled oral drug delivery”,Drug Development and Industrial Pharmacy 26(2000),695-708；

Verma,R.K.,Krishna,D.M.,Garg,S.,“Formulation aspects in the development of osmotically controlled oral drug delivery systems”,Journal of Controlled Release 79(2002),7-27；

Verma,R.K.,Arora,S.,Garg,S.,“Osmotic Pumps in drug delivery”,Critical Reviews in Therapeutic Drug Carrier Systems 21(2004),477-520

Malatere, 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. Pat. nos. 4,327,725, 4,765,989;

each of which is incorporated by reference herein in its entirety for all purposes.

Both single-chamber systems (primary osmotic pumps) and two-chamber systems (push-pull systems) are suitable for use with the delayed release components described herein.

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

In some embodiments, a coating (e.g., a photoprotective and/or colored coating) may be applied to the shell. Materials suitable for this purpose are, for example, polymers such as polyvinyl alcohol, hydroxypropyl cellulose and/or hydroxypropyl methylcellulose, in combination, where appropriate, with suitable plasticizers such as, for example, polyethylene glycol or polypropylene glycol, and pigments such as, for example, titanium dioxide or iron oxides.

In some embodiments, the core in the osmotic single compartment system comprises: (i) 2 to 30wt% of zolmitriptan; (ii) 20 to 50wt% xanthan gum, and (iii) 10 to 30wt% vinylpyrrolidone-vinyl acetate copolymer, wherein the difference from 100% is formed, where appropriate, by one or more additional ingredients selected from the group consisting of additional hydrophilic swellable polymers, osmotically active additives, and pharmaceutically acceptable excipients.

In some embodiments, the core of the osmotic single-compartment system comprises a hydrophilic water-swellable polymer, such as xanthan gum. Xanthan gum is e.g. according to nameCommercially available anionic heteropolysaccharides (produced by 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 mass of the core component.

The other component of the core may be a vinylpyrrolidone-vinyl acetate copolymer. The copolymers are known in the artAnd may be produced with any desired monomer mixing ratio. Non-limiting examples of such copolymers areVA64 (manufactured by BASF). The weight average molecular weight (Mw) is typically from about 45 to about 70,000 as determined by light scattering measurements. In some embodiments, the amount of vinylpyrrolidone-vinyl acetate copolymer in the core is from about 10% to about 30% (e.g., about 15%, about 20%, about 25%, including all values and subranges therebetween) based on the total mass of the core ingredients.

In some embodiments, the hydrophilic swellable polymer is present in the core. Non-limiting examples of hydrophilic swellable polymers include, for example, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, sodium carboxymethyl starch, polyacrylic acid, and salts thereof.

In some embodiments, the osmotic delivery system comprises a water swellable substance. Suitable water-swellable substances include compounds that are capable of swelling when they are exposed to aqueous solutions, such as gastrointestinal fluids. One or more water-swellable substances may be present together in the core material. Alternatively, one or more water-swellable substances may be included in a swelling layer applied to the core material.

Suitable water-swellable substances include, for example, low-substituted hydroxypropyl celluloses, e.g., L-HPC; crosslinked polyvinylpyrrolidone (PVP-XL), for example,CL and->XL; croscarmellose sodium, e.g. Ac-di-sol,/i>Sodium starch glycolate, e.g.)>Sodium carboxymethylcellulose, e.g. Nym-celSodium carboxymethyl starch, e.g.)>Ion exchange resins, e.g.)>Or->Microcrystalline cellulose, e.g. jersey>Starches and pregelatinized starches, e.g. Starch->Sepistab/>Formalin-casein, e.g. for example>And mixtures thereof.

In some embodiments, the osmotic pump composition comprises one or more osmotically active additives in the core, for example, pharmaceutically acceptable water-soluble substances such as pharmacopoeia or "Remington Pharmaceutical Science," (1985) edition 17 edit Alfonso r.gennaro.mack Publishing co., water-soluble excipients described in easton, pa, which are incorporated herein by reference in their entirety for all purposes. In some embodiments, the osmotically active additive is selected from water soluble salts of inorganic or organic acids or non-ionic organics with high solubility in water (such as, for example, sugars, especially sugars, sugar alcohols, or amino acids). In some embodiments, the osmotically active additive is selected from inorganic salts such as chlorides, sulfates, carbonates and bicarbonates of alkali metals or alkaline earth metals (such as lithium, sodium, potassium, magnesium, calcium), and phosphates, hydrogen phosphate or dihydrogen phosphate, 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). The water-soluble amino acid includes glycine, leucine, alanine or methionine. Sodium chloride is particularly preferably used according to the invention. In some embodiments, the osmotically active additive is present in an amount of 10% to 30% based on the total mass of the core component.

In some embodiments, the core of the osmotic pump composition 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).

The disclosure further relates to a method for producing a osmotic single-chamber system, in which the components of the core are mixed together, where appropriate subjected to wet granulation or dry granulation, and subsequently tableted, and the core produced in this way is coated with a shell, which is then covered with a photoprotective and/or coloured coating where appropriate, and the coating is provided with one or more apertures.

In a osmotic two-compartment system, the core is composed of two layers, an active ingredient layer and an osmotic layer. Osmotic two-compartment systems of this type are described, for example, in U.S. Pat. No. 4,612,008, the disclosure of which is incorporated herein by reference.

The osmotically active additives used in the core of the osmotic two-compartment system may be the same as in the case of the single-compartment system described above.

The pharmaceutically acceptable excipients used in the core of the osmotic two-compartment system may be the same as in the case of the single compartment system described above. In some embodiments, 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 modifier (such as colloidal silicon dioxide), and a colored pigment (such as iron oxide) in one of the two layers is used to distinguish between the active ingredient layer and the osmotic layer.

Substrate

In some embodiments, the delayed release component is a matrix. As used herein, the term "matrix" means a composition in which a drug is entrapped or dispersed in a water-soluble, water-insoluble or hydrophilic polymer or lipophilic material in order to achieve delayed release of the drug. The mechanism of drug release typically involves diffusion of the drug through a tacky gel layer or tortuous path; and/or drug dissolution via progressive 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 upon contact with water. In some embodiments, the matrix comprises a water insoluble polymer or a lipophilic polymer.

In some embodiments, the matrix is prepared using one or more hydrophilic polymers (e.g., hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene oxide), one or more lipophilic materials (e.g., carnauba wax, hardened castor oil, hardened canola oil, polyglycerol fatty acid esters), and/or coated tablets or granules with one or more delayed release polymers (e.g., cellulose polymers such as ethylcellulose; acrylic 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.) ]).

In some embodiments, the delayed release component is a matrix comprising one or more hydrophilic polymers. In this context, hydrophilic polymer means a polymer which can control the release of zolmitriptan by absorbing water into a hydrogel and allow the diffusion of zolmitriptan contained in a matrix out of the matrix.

In some embodiments, the hydrophilic polymer has a viscosity of, for example, about 1 mPa-s to about 200000 mPa-s, or about 4 mPa-s to about 120000 mPa-s, or about 4 mPa-s to about 5000 mPa-s, as measured in a 2% by weight aqueous solution at 20 ℃ using a brookfield viscometer (Brookfield viscometer). The duration of the release of zolmitriptan from the matrix can be modified by appropriate choice of the viscosity of the hydrophilic polymer.

Non-limiting examples of suitable hydrophilic polymers include hydroxypropyl cellulose (HPC) such as HPC-SSL (trade name, manufactured by NIPPON SODA CO. Viscosity of 2% by weight aqueous solution at 20 ℃ C.: 2.0-2.9 mPas), HPC-SL (trade name, manufactured by NIPPON SODA CO. Viscosity of 2% by weight aqueous solution at 20 ℃ C.: 3.0-5.9 mPas), HPC-L (trade name, manufactured by NIPPON SODA CO. Viscosity of 2% by weight aqueous solution at 20 ℃ C.: 6.0-10.0 mPas), HPC-M (trade name, manufactured by NIPPON SODA CO. Viscosity of 2% by weight aqueous solution at 20 ℃ C.: 150-400 mPas), HPC-H (trade name, manufactured by NIPPON SOCO. Viscosity of 2% by weight aqueous solution at 20 ℃ C.: 1000-4000 mPas); hydroxypropyl methylcellulose, such as Metolose SB-4 (trade name, manufactured by Shin-Etsu Chemical CO., viscosity of a 2% by weight aqueous solution at 20 ℃): about 4mPa S), TC-5RW (trade name, manufactured by Shin-Etsu Chemical co., viscosity of 2% by weight aqueous solution at 20 ℃); about 6mPa S), TC-5S (trade name, manufactured by Shin-Etsu Chemical co. The viscosity of a 2% by weight aqueous solution at 20 c: about 15mPa S), metaose 60SH-50 (trade name, manufactured by Shin-Etsu Chemical co. The viscosity of a 2% by weight aqueous solution at 20 c: about 50mPa S), metaose 65SH-50 (trade name, manufactured by Shin-Etsu Chemical co. The viscosity of a 2% by weight aqueous solution at 20 c: about 50mPa S), metaose 90SH-100 (trade name, manufactured by Shin-Etsu Chemical co. The viscosity of a 2% by weight aqueous solution at 20 c: about 100mPa S), metaose 90SH-100SR (trade name, manufactured by Shin-Etsu Chemical co. The viscosity of a 2% by weight aqueous solution at 20 c: about 100mPa S c: about 100 c), metaose 90SH-100S (manufactured by weight aqueous solution at 20 c: about 400 c, manufactured by means of a 2% by weight aqueous solution at 20 c: about 400 c, manufactured by means of a 400 c: about 400 c, manufactured by metaose Chemical co. The viscosity of a 2% by weight aqueous solution at 20 c: about 400 c, manufactured by means of a 2 c: about 400 c, by weight aqueous solution at 20 c: about 400 c, by means of a 2% aqueous solution at the viscosity of a 2 c, viscosity of 2% by weight aqueous solution at 20 ℃): about 1500 mPa-s), metolose 60SH-4000 (trade name, manufactured by Shin-Etsu Chemical co., viscosity of a 2% by weight aqueous solution at 20 ℃): about 4000 mPa-s), metalose 65SH-4000 (trade name, manufactured by Shin-Etsu Chemical co., viscosity of 2% by weight aqueous solution at 20 ℃): about 4000 mPa-s), metalose 90SH-4000 (trade name, manufactured by Shin-Etsu chemical co., viscosity of 2% by weight aqueous solution at 20 ℃): about 4000 mPa-s), metalose 90SH-4000SR (trade name, manufactured by Shin-Etsu Chemical co., viscosity of 2% by weight aqueous solution at 20 ℃): about 4000 mPa-s), metalose 90SH-30000 (trade name, manufactured by Shin-Etsu Chemical co., viscosity of 2% by weight aqueous solution at 20 ℃): about 30000 mPa-s), meta 90SH-100000 (trade name, manufactured by Shin-Etsu Chemical co., viscosity of 2% by weight aqueous solution at 20 ℃): about 100000 mpa.s), meta 90SH-100000SR (trade name, manufactured by Shin-Etsu Chemical co., viscosity of 2% by weight aqueous solution at 20 ℃): about 100000 mpa.s); methylcellulose such as Metolose SM15 (trade name, manufactured by Shin-Etsu Chemical CO.; viscosity: about 15 mPas, 2% by weight aqueous solution, 20 ℃ C.), metolose SM25 (trade name, manufactured by Shin-Etsu Chemical CO.; viscosity: about 25 mPas, 2% by weight aqueous solution at 20 ℃ C.), metolose SM100 (trade name, manufactured by Shin-Etsu Chemical CO.; viscosity: about 100 mPas, 2% by weight aqueous solution at 20 ℃ C.), metolose SM400 (trade name, manufactured by Shin-Etsu CO.; viscosity: about 400 mPas, 2% by weight aqueous solution at 20 ℃ C.), metolose 1500 (trade name, manufactured by Shin-Etsu Chemical CO.; viscosity: about 1500 mPas, manufactured by Shin-Etsu Chemical CO.; viscosity: about 8000% by weight aqueous solution at 20 ℃ C.), and viscosity: about 8000 mPas, manufactured by means of water solution at 20 ℃ C.; SM: about 8000% by weight aqueous solution at 20 ℃ C.; etsu Chemical CO.; SM 400; polyethylene oxide such as WSR N-12K (trade name, manufactured by Union Carbide Co., viscosity of 2% by weight at 20 ℃ C.: 400-800 mPas), WSR N-60K (trade name, manufactured by Union Carbide Co., viscosity of 2% by weight at 20 ℃ C.: 2000-4000 mPas), WSR 301 (trade name, manufactured by Union Carbide Co., viscosity of 1% by weight at 25 ℃ C.: 1500-4500 mPas), WSR Coagulont (trade name, manufactured by Union Carbide Co., viscosity of 1% by weight at 25 ℃ C.: 0-7500 mPas), WSR 303 (trade name, manufactured by Union Carbide Co., viscosity of 1% by weight at 25 ℃ C.: 7500-10000 mPas), WSR 308 (trade name, manufactured by Union Carbide Co., viscosity of 1% by weight at 25 ℃ C.: 1% by weight in water at 15000 mPas); sodium carboxymethyl cellulose such as Sunrose F-150MC (trade name, manufactured by Nippon Paper Industries Co., viscosity of 1% by weight aqueous solution at 25 ℃ C.: 1200-1800 mPa.s), sunrose F-300MC (trade name, manufactured by Nippon Paper Industries Co., viscosity of 1% by weight aqueous solution at 25 ℃ C.: 2500-3000 mPa.s), sunrose F-1000MC (trade name, manufactured by Nippon Paper Industries Co., viscosity of 1% by weight aqueous solution at 25 ℃ C.: 8000-12000 mPa.s); etc., or a combination thereof.

In some embodiments, the hydrophilic matrix further comprises a pH dependent polymer. The duration of the release of zolmitriptan from the matrix can be modified by appropriate selection of the amount of pH dependent polymer.

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

Pharmaceutically acceptable carriers suitable for matrix formulations include a variety of organic or inorganic carrier materials (e.g., excipients, lubricants, binders, disintegrants, etc.). In addition, pharmaceutically acceptable additives such as antioxidants, colorants, sweeteners, and the like may be used.

Non-limiting examples of suitable excipients include lactose, D-mannitol, D-sorbitol, starch, dextrin, crystalline cellulose, low substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, gum arabic, dextrin, pullulan, light silicic anhydride, synthetic aluminum silicate, magnesium aluminum metasilicate, and the like.

Non-limiting examples of suitable lubricants include magnesium stearate, calcium stearate, talc, colloidal silicon dioxide and the like.

Non-limiting examples of suitable binders include starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, white sugar, D-mannitol, trehalose, dextrin, pullulan, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, and the like.

Non-limiting examples of suitable disintegrants include lactose, white sugar, starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, light silicic anhydride, low substituted hydroxypropyl cellulose, and the like.

Non-limiting examples of suitable preservatives include parabens, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like.

Non-limiting examples of suitable antioxidants include bisulfate salts, ascorbate salts, and the like.

Non-limiting examples of suitable colorants include water-soluble edible tar pigments (e.g., edible pigments such as edible red nos. 2 and 3, edible yellow nos. 4 and 5, edible blue nos. 1 and 2, etc.), water-insoluble lake pigments (e.g., aluminum salts of the above-described water-soluble edible tar pigments), natural pigments (e.g., beta-carotene, chlorophyll, red lead (collothar), yellow ferric oxide), and the like.

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

Delayed release tablet

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 lubricants and binders and/or fillers, and glidants and other excipients. The one or more coatings may be, for example, semi-permeable coatings to achieve delayed or extended 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. Other excipients may also optionally be present in the coating, such as, for example, acrylic acid derivatives (such as EUDRAGIT), pigments, and the like. If multiple coatings are used, they may be the same or different.

The relative proportions of the ingredients (notably the ratio of water insoluble polymer to water soluble polymer) may vary depending on the release profile to be obtained (where a greater delayed release is typically obtained with a greater amount of water insoluble polymer). In some embodiments, the ratio of water insoluble polymer to water soluble polymer is in the range of 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.

Micro-tablet

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

In some embodiments, the pharmaceutical composition comprises a plurality of microtablets (also referred to as "mini-tablets") having a diameter of less than or equal to about 5 mm. In other embodiments, the minitablets comprise zolmitriptan in a matrix of one or more polymers, or the minitablets are optionally coated with a delayed release polymer. In some embodiments, the matrix polymer is one or a combination of the hydrophilic polymers described herein. In some embodiments, the pharmaceutical composition comprises a plurality of enteric coated microtablets.

In some embodiments, the microtablets further comprise a filler, a lubricant, and/or a glidant. For example, in some embodiments, the microtablets comprise 5% to 50% zolmitriptan, 20% to 50% matrix polymer, 20% to 50% filler, 0.1% to 5% lubricant, and 0.1% to 5% glidant, based on the total weight of the composition. 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 glidant is colloidal silicon dioxide.

In some embodiments, the pharmaceutical compositions disclosed herein comprise a plurality of microtablets, e.g., in the range of 2 to 30 microtablets, e.g., 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 microtablets, including all values and subranges therebetween. In some embodiments, the minitablets are contained in capsules or sachets for oral administration. In some embodiments, the capsule is a hard gelatin or hydroxypropyl methylcellulose (HPMC) capsule. In some embodiments, the capsule contains a particulate overflow (particulate overfill) (such as microcrystalline cellulose). In some embodiments, the capsule comprises 2 to 30 microtablets, e.g., 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 microtablets, including all values and subranges therebetween.

In some embodiments, the microtablets have a diameter less than or equal to 5mm, e.g., about 4.5mm or less, about 4mm or less, about 3.5mm or less, about 3.0mm or less, about 2.5mm or less, or about 2mm. In some embodiments, the microtablets have a diameter in the range of about 2mm to about 5mm, including about 2.5mm, about 2.6mm, about 2.7mm, about 2.8mm, about 2.9mm, about 3.0mm, about 3.1mm, about 3.2mm, about 3.3mm, about 3.4mm, about 3.5mm, about 3.6mm, about 3.7mm, about 3.8mm, about 3.9mm, about 4.0mm, about 4.1mm, about 4.2mm, about 4.3mm, about 4.4mm, about 4.5mm, about 4.6mm, about 4.7mm, about 4.8mm, and about 4.9mm, including all values and subranges therebetween. The microtablets can have any shape (e.g., spherical or cylindrical) convenient to the skilled artisan. In one embodiment, the microtablets are round and convex (referred to in the art as "round standard convexities").

In some embodiments, the minitablets are formulated to modify the release of zolmitriptan, e.g., by coating the minitablets with a polymer as disclosed herein. In other embodiments, the zolmitriptan is embedded or dispersed in a matrix polymer, which is formulated as a minitablet. In some embodiments, the microtablets further comprise a filler, lubricant, or glidant (one or more such components may be utilized) or a combination thereof.

Suitable matrix polymers include hydrophilic water-soluble polymers, such as any of the hydrophilic polymers listed herein, including hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene oxide, sodium carboxymethyl cellulose, in some embodiments, the hydrophilic water-soluble polymer is a high molecular weight polymer (i.e., 100,000 to 800,000 daltons), such as hydroxypropyl methylcellulose polymer (also known as HPMC or hydroxypropyl methylcellulose), according to a method such as Methocel ^TM (e.g. Methocel) ^TM K100M、Methocel ^TM K15M or Methocel ^TM K4M, suitably Methocel ^TM K15M). In some embodiments, the matrix-containing microtablets comprise from about 20 to about 60wt% 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.

Fillers suitable for use in the microchip include any of the fillers listed herein, including microcrystalline cellulose, such as Avicel ^TM PH101. The amount of filler in the microtablets 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.

Glidants suitable for microtablets include any of the glidants listed herein, such as colloidal silicon dioxide and talc. In some embodiments, the microtablets comprise about 0.1 to about 5wt% glidant, e.g., about 0.5%, about 1.0%, about 1.5%, about 2.0%, about 2.5%, about 3.0%, about 3.5%, about 4.0%, or about 4.5wt%, based on the total weight of the composition, including all values and subranges therebetween.

Suitable lubricants for the microtablets include any of the lubricants listed herein, such as stearic acid and stearates, for example magnesium stearate. In some embodiments, the microtablets comprise from 0.1% to 5% lubricant, based on the total weight of the composition, e.g., about 0.5%, about 1.0%, about 1.5%, about 2.0%, about 2.5%, about 3.0%, about 3.5%, about 4.0%, or about 4.5%, including all values and subranges therebetween.

The microtablets may be uncoated or coated with one or more coating layers. In some embodiments, the minitablets are at least partially enteric coated. In some embodiments, the enteric coating comprises a pH-dependent polymer, e.g., a copolymer of methacrylic acid and methacrylate ester, such as a methacrylic acid copolymer, e.g., eudragit L30D55 having a dissolution greater than pH 5.5. Other Eudragit polymers include: eudragit L100-55 (greater than pH 5.5 dissolution), eudragit L100 (greater than pH 6.0 dissolution), and Eudragit S100 (greater than pH 7.0 dissolution). In some embodiments, the enteric coating comprises 5% to 10% based on the total weight of the composition (dry polymer weight). The enteric coating may be produced by spraying an enteric polymer on top of the core micro-tablets described above.

The enteric coating may further comprise a plasticizer, such as acetyl triethyl citrate or triethyl citrate, such as triethyl citrate (Citroflex). In some embodiments, the pharmaceutical compositions disclosed herein comprise about 0.1% to about 5% plasticizer, e.g., about 0.5%, about 1.0%, about 1.5%, about 2.0%, 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.

In some embodiments, the enteric coating further comprises a glidant to eliminate blocking during the film coating process, such as talc, kaolin, or glyceryl monostearate, for example glyceryl monostearate (Imwitor 900K). In some embodiments, the glidant comprises about 0.1 to about 5wt%, e.g., about 0.5%, about 1.0%, about 1.5%, about 2.0%, 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.

In some embodiments, the enteric coating further comprises a surfactant to provide a homogeneous film mixture, such as sodium lauryl sulfate, polyethylene glycol, or Polysorbate, e.g., polysorbate 80 (Crillet 4 HP). In some embodiments, the surfactant comprises about 0.1 to about 5wt%, including about 0.5%, about 1.0%, about 1.5%, about 2.0%, 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.

The microtablets may (if desired) further comprise one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients may include colorants, flavors (such as menthol), sweeteners (such as mannitol), preservatives, stabilizers, antioxidants, and any other excipient known to those skilled in the art.

Timed pulse release

In some embodiments, the delayed release component is formulated to pulse release of zolmitriptan at least 30 minutes after oral administration. The timed pulse release system described herein is capable of providing one or more pulses of adjuvant Qu Tanchang release after a predetermined delay time or at a specific site to improve drug absorption.

In some embodiments, the timed pulse release system comprises a membrane surrounding an active core, wherein the membrane comprises a swelling agent (e.g., low substituted hydroxypropyl cellulose, crospovidone, croscarmellose, sodium starch glycolate), e.g., as disclosed in U.S. patent No. 4,871,549, which is incorporated herein by reference in its entirety.

In other embodiments, the timed pulse release system comprises a core material (such as a polysaccharide or cross-linked protein and a disintegrant that swells upon exposure to body fluids or water) and a rigid membrane surrounding the core, the rigid membrane comprising a hydrophobic and hydrophilic polymer that rapidly breaks upon swelling of the core to release the active, e.g., as disclosed in U.S. patent No. 6,531,152, which is incorporated herein by reference in its entirety.

In some embodiments, the timed pulse release component comprises an inner barrier coating and an outer time-lapse (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 time-lapse coating comprises a water-insoluble polymer in combination with an enteric polymer.

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

Non-limiting examples of water-soluble/pore-forming polymers suitable for the inner barrier coating include polyvinylpyrrolidone, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, and mixtures thereof.

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.

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

Non-limiting examples of enteric polymers suitable for the outer time-lapse coating include cellulose esters and derivatives thereof (cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate), polyvinyl acetate phthalate, pH-sensitive methacrylic acid-methyl methacrylate copolymers, and shellac. These polymers can be used as dry powders or as aqueous dispersions. Some commercially available materials that can be used are methacrylic acid copolymers sold under the trade name Eudragit (L100, S100, L30D), cellacerate from Eastman chemical co, aquaic from FMC corp, aquaic acetate, and aquaat from Shin Etsu k.k.

In some embodiments, the external time-lag film comprises a plasticized mixture of a water-insoluble polymer and an enteric polymer, wherein the water-insoluble polymer and the enteric polymer may be present in a weight ratio ranging from about 10:1 to about 1:2, 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, and typically about 3:1 to about 1:1. In other embodiments, the water-insoluble polymer comprises from about 10% to about 99% of a plasticized mixture of the water-insoluble polymer and the enteric 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%, 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. The total weight of the time-lapse coated 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 bead.

Both the enteric polymer and the water insoluble polymer used to form the outer time-lapse coating may be plasticized. Representative examples of plasticizers that may be used in plasticizing the outer time-lapse coating include glyceryl triacetate, 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. Plasticizers, when present, constitute from about 3% to 30% by weight of the polymer, 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 depend on the nature of the polymer(s) and the coating system (e.g., aqueous or solvent based, solution or dispersion based, and total solids).

The amounts and ratios of the components in the inner barrier coating and the outer lag 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. In addition, the time-pulse delivery system may be formulated as particles having a diameter of at least 2mm (e.g., microtablets having a diameter of about 2mm to about 5 mm) to provide adequate residence time in the stomach.

Examples of timed pulse release systems can be found, for example, in U.S. patent No. 4,871,549, U.S. patent No. 6,531,152, U.S. patent No. 6,287,599, U.S. patent No. 6,627,223, U.S. patent No. 6,663,888, U.S. patent No. 9,161,918, and U.S. patent No. 9,161,919, each of which is incorporated by reference herein in its entirety.

Soft gel capsule

In some embodiments, the delayed release component is formulated as a soft gel capsule. Soft gel capsules are known in the art and can be prepared from gelatin and derivatives thereof. In some embodiments, the soft gel capsule is formulated to dissolve at the acidic pH of the stomach.

In some embodiments, the soft gel capsule is filled with a pharmaceutically acceptable liquid comprising drug particles dissolved or suspended therein.

Non-limiting examples of suitable pharmaceutically acceptable liquids include: oils or polyols (such as glycerol and its homologous polyols and their 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 of emmsford (Elmsford) of new york, usa; triethyl citrate, acetyl triethyl citrate, tri-n-butyl citrate, or acetyl tri-n-butyl citrate manufactured by Morflex of Greensboro, north Carolina, U.S.A.; glyceryl triacetate; or other liquid that does not dissolve gelatin. Mixtures of these may also be used. In some embodiments, the pharmaceutically acceptable liquid is a vegetable oil or a mineral oil. In some embodiments, the vegetable oil is selected from 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.

Reservoir formulations

In some embodiments, the delayed release component comprises an injectable lipid-based liquid with dissolved zolmitriptan that spontaneously forms a controlled release liquid crystal gel matrix in an aqueous environment (e.g., after subcutaneous injection thereof into a patient in need thereof). Without being bound by any theory, such lipid solutions transform in situ upon contact with a fluid at the injection site into a liquid crystal gel that effectively encapsulates the zolmitriptan. In the reservoir formulations of the present disclosure, zolmitriptan is slowly released as the liquid crystalline matrix degrades in an aqueous environment (e.g., interstitial fluid or body fluid). Injectable lipid-based liquid depot formulations are described in U.S. patent No. 8,236,292, U.S. patent No. 8,097,239, and U.S. patent No. 9,585,959, the contents of which are hereby incorporated by reference in their entirety.

The rate of release of zolmitriptan from the reservoir can be controlled over a period of hours, days or weeks (depending on the composition) by using methods known to those skilled in the art and described for example in us patent No. 8,236,292 and us patent No. 9,585,959. In some embodiments, suitable lipid-based liquids comprise suitable neutral lipids and/or amphiphilic lipids and/or polar lipids or combinations thereof. In some embodiments, suitable lipid-based liquids comprise 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 formulations are administered subcutaneously (e.g., by syringe injection). In some embodiments of the present disclosure, the reservoir formulation uses are described, for example, in U.S. patent No. 8,236,292, U.S. patent No. 8,097,239, and U.S. patent No. 9,585,959 The reservoir is injected, the contents of which are hereby incorporated by reference in their entirety. Thus, in some embodiments, the depot formulation is +.>Delayed release formulations.

In some embodiments, the delayed release component comprises an injectable aqueous suspension of polycystic liposomes (MVL). Injectable aqueous suspensions of MVL are described 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. 5,997,899, U.S. patent No. 6,793,938, and U.S. patent No. 9,585,838, the contents of which are incorporated herein by reference in their entirety. MVL-containing medicament for parenteral administrationThe composition may be obtained, for example, by forming a water-in-oil-in-water emulsion by a double emulsion process. The liposome particles are typically in the size range of 10-30 μm diameter. In some embodiments, the multivesicular liposomes comprise neutral lipids and amphiphilic lipids. In some embodiments, the multivesicular liposomes comprise phospholipids, cholesterol, and triglycerides. In some embodiments, a phospholipid (such as dioleoyl phosphatidylcholine) forms the major component of the lipid bilayer membrane. In some embodiments, charged phospholipids (dipalmitoyl phosphatidylglycerol) are included in the lipid bilayer membrane to help prevent aggregation of the liposomes by charge repulsion. In some embodiments, cholesterol is used, for example, to provide mechanical stabilization of the lipid bilayer membrane. For parenteral administration, the drug substance may be formulated with MVL to provide a carrier matrix of tiny, spherical, lipid-based particles composed of a honeycomb structure containing a number of non-concentric internal aqueous compartments of encapsulated zolmitriptan. In some embodiments, each chamber is separated from an adjacent chamber by a lipid membrane. Such formulations release zolmitriptan over an extended period of time after injection due to, for example, erosion and/or reorganization of the lipid membrane. The rate of release of zolmitriptan from MVL can be controlled using methods known to those skilled in the art and described in, for example, the following documents: U.S. patent No. 5,723,147, U.S. patent No. 5,766,627, U.S. patent No. 5,891,467, U.S. 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 formulations are administered intravenously, subcutaneously, intramuscularly, or intrathecally (e.g., by pen-type series (pen system) or by injection through a syringe (using, for example, a 25G gauge needle or larger to maintain the structural integrity of the liposome). Illustratively, systemic delivery by releasing zolmitriptan into the blood stream via the interstitial space is an effective mode of administration. In some embodiments of the present disclosure, use is made of, for example, those described 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. 5,997,899, U.S. patent nos. 6,793,938, and U.S. patent No. 9,585,838 The technical platform prepares a depot formulation. Thus, in some embodiments, the depot formulation is an injectable suspension of zolmitriptan MVL.

In some embodiments, the delayed release component comprises an injectable hydrogel depot. Hydrogel reservoirs are described, for example, in U.S. patent No. 8,084,045, U.S. reissue patent No. RE46686, U.S. patent No. 7,659,365, and U.S. patent No. 8,206,744, the contents of which are hereby incorporated by reference in their entirety. For parenteral administration, suitable hydrogel compositions include those comprising amphiphilic polymers that allow non-covalent capture 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 of the polymers described herein or in U.S. patent No. 8,084,045, U.S. reissue patent No. RE46686, U.S.7,659,365, and U.S. patent No. 8,206,744. In some embodiments, the polymer is a water-soluble biodegradable amphiphilic copolymer. Without being bound by any theory, sustained drug release is based on reversible drug interactions with hydrophobic nano-domains. In some embodiments, the parenteral hydrogel depot injection provides a modified release rate of zolmitriptan. Hydrogel depot formulations can be obtained from self-assembled polyamino acid nanoparticles made of a poly-Glu backbone grafted with hydrophobic alpha-tocopherol molecules, for example using methods known to those skilled in the art and described, for example, in U.S. Pat. No. 8,084,045 and U.S. reissue patent No. RE46686E 1. In some embodiments, the hydrogel depot injection is administered subcutaneously. In some embodiments of the present disclosure, the use of a depot formulation is described, for example, in the following figures and in U.S. patent No. 8,084,045, U.S. reissue patent No. RE46686E1, U.S.7,659,365, and U.S. patent No. 8,206,744 Platform technology Platform, prepared by the Platform technology Platform,the contents of that patent are hereby incorporated by reference in their entirety. Thus, in some embodiments, the depot formulation is an injectable hydrogel delayed release formulation of zolmitriptan.

In some embodiments, the delayed release component comprises a polymer depot system. Injectable polymer reservoirs are described, for example, in U.S. patent No. 10,300,019, U.S. patent No. 8,674,033, and U.S. patent No. 8,481,651, the contents of which are hereby incorporated by reference in their entirety. Such formulations may be obtained by forming a biodegradable polymer matrix in which zolmitriptan is embedded using suitable monomers. Exemplary monomers are described in U.S. patent No. 10,300,019, U.S. patent No. 8,674,033, and U.S. patent No. 8,481,651. Upon rehydration, the polymer swells and releases zolmitriptan by diffusion. The release time may be adjusted by methods known to those skilled in the art and described, for example, in U.S. patent No. 10,300,019, U.S. patent No. 8,674,033 and U.S. patent No. 8,481,651 for a period of time ranging from hours to days and up to months. In some embodiments, the polymer matrix comprises poly (lactic acid) (PLA) and/or poly (lactic-co-glycolic acid) (PLGA) or a multi-block copolymer composed of the building blocks lactide, glycolide, epsilon-caprolactone, and polyethylene glycol. In some embodiments, a near neutral pH is maintained in the polymer matrix. In some embodiments, the block copolymer is represented by:

In some embodiments of the present disclosure, the use is described in, for example, U.S. patent No. 10,300,019, U.S. patent No. 8,674,033, and U.S. patent No. 8,481,651Platform technology Platform preparation of depot formulations. Thus, in some embodiments, the depot formulation is a polymeric extended release depot formulation of zolmitriptan.

In some embodiments of the present invention, in some embodiments,the delayed release component comprises a phospholipid depot composition. An injectable phospholipid depot is described in U.S. patent No. 9,517,202, the contents of which are hereby incorporated by reference in their entirety. In some embodiments, a suitable phospholipid may be formulated with zolmitriptan to provide a formulation that gels in situ following parenteral injection. In some embodiments, such formulations may also be used as suspending agents for microspheres. In some embodiments, the gel may be substantially homogeneous or single phase. Exemplary phospholipid compositions are described in U.S. patent No. 9,517,202 and may comprise 20% -80% by weight, 25% to 70% by weight, or 30% to 60% by weight of a phospholipid, such as 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60% by weight of a phospholipid or a mixture of phospholipids, including all values and subranges therebetween. In some embodiments, the phospholipid is a non-liposomal phospholipid. In some embodiments, the phospholipid depot formulation is adjusted by methods known to those skilled in the art and described in U.S. patent No. 9,517,202 to provide a customizable release profile over days or weeks depending on composition. In some embodiments, the depot formulation is administered parenterally (e.g., by subcutaneous or intramuscular injection or by injection or instillation into body tissue, blood vessels, or cavities). In some embodiments of the present disclosure, PG Depot described in, for example, U.S. Pat. No. 9,517,202 is used ^TM An injectable depot preparation depot formulation. Thus, in some embodiments, the depot formulation is a phospholipid depot delayed release formulation of zolmitriptan.

Administration and administration

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

The present disclosure provides methods of treating aggressiveness in a patient suffering from dementia by administering an effective amount of the zolmitriptan composition of the present disclosure to a patient in need thereof.

The present disclosure provides methods of treating aggressiveness in alzheimer's patients by administering to a patient in need thereof an effective amount of the zolmitriptan composition of the present disclosure.

In one aspect, the present disclosure provides a method of treatment by administering (such as by oral administration) an effective amount of an zolmitriptan composition of the present disclosure to a patient in need thereof. An effective amount depends on the condition being treated and is an amount sufficient to eliminate or significantly alleviate at least one symptom of the condition or to alleviate the symptoms (e.g., symptoms of autism spectrum disorder, or aggression in patients suffering from dementia, such as Alzheimer's disease).

The embodiments listed below disclose methods for treating symptoms of AD. The methods recited are also suitable for treating other conditions characterized by aggressiveness (e.g., aggressiveness in patients with dementia such as Alzheimer's disease). The enumerated embodiments (e.g., dosages, PK parameters, and administration) described herein for treating symptoms of autism spectrum disorders are equally applicable to treating conditions characterized by aggressiveness (e.g., aggressiveness in alzheimer's patients). Thus, the present disclosure contemplates embodiments wherein the following doses, PK parameters, and aggressiveness are administered for treating a patient suffering from dementia (such as an alzheimer's patient).

According to some embodiments of the present disclosure, administration of the zolmitriptan compositions 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 criteria or guidelines provided by one or more regulatory authorities in the united states (e.g., FDA) or other countries. In another embodiment, the statistically significant therapeutic effect is determined based on results obtained from clinical trial settings and/or procedures approved by a regulatory agency.

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. In some embodiments, the statistically significant therapeutic effect is determined based on data obtained from a randomized and double-blind clinical trial setting. In some embodiments, the statistically significant therapeutic effect is determined based on data having a p-value less than or equal to about 0.05, 0.04, 0.03, 0.02, or 0.01. In some embodiments, the statistically significant therapeutic effect is determined based on data having a confidence interval greater than or equal to 95%, 96%, 97%, 98%, or 99%.

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

In general, statistical analysis may include any suitable method allowed by regulatory authorities in the united states (e.g., FDA) or europe or any other country. In some embodiments, statistical analysis includes non-hierarchical analysis, log rank analysis (e.g., from Kaplan-Meier, jacobson-Truax, gulliken-Lord-Novick, edwards-Nunnally, hageman-Arrindel and multilayer linear modeling (HLM)), and Cox regression analysis.

According to the present disclosure, the compositions of the present disclosure are administered on a once-a-day, twice-a-day, or three-a-day basis to provide effective relief of the symptoms of the condition being treated (e.g., symptoms of autism spectrum disorder or aggression in patients suffering from dementia, such as Alzheimer's disease patients).

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

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

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

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

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

In some embodiments, zolmitriptan or a pharmaceutically acceptable salt thereof is administered on a once-a-day or twice-a-day or three-a-day 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.

In some embodiments, zolmitriptan or a pharmaceutically acceptable salt thereof is administered on a once-a-day or twice-a-day basis for at least one week, e.g., about one 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 12 weeks, about 18 weeks, about 24 weeks, and about 50 weeks.

In some embodiments, zolmitriptan or a pharmaceutically acceptable salt thereof is administered on a once-a-day or twice-a-day basis for at least about one 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.

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

In some embodiments, the methods described herein further comprise the steps of: the dose of zolmitriptan (the step-up period) or a pharmaceutically acceptable salt thereof is step-up to a maximum safe and effective dose for at least about one week. In some embodiments, the gradual adjustment 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 gradual adjustment 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 embodiments, the step-wise adjustment comprises increasing the daily dose of zolmitriptan. In embodiments, stepwise adjustment comprises increasing the daily dose of zolmitriptan by about 5mg to about 20mg, including about 5mg, about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg, about 19mg, about 20mg, including all values and subranges therebetween. In embodiments, the step-wise adjustment comprises increasing the daily dose of zolmitriptan by about 12mg per day.

In embodiments of the methods described herein, further comprising the step of gradually down-regulating the dose of zolmitriptan. In embodiments, stepwise adjustment comprises reducing the daily dose of zolmitriptan by about 5mg to about 20mg, including about 5mg, about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg, about 19mg, about 20mg, including all values and subranges therebetween. In embodiments, the stepwise adjustment comprises a daily reduction of the daily dose of zolmitriptan by about 12mg.

In embodiments, the methods described herein comprise stepwise adjusting 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.

In embodiments, the methods described herein comprise stepwise adjusting 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.

In embodiments, the methods described herein comprise stepwise adjusting 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 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, or about 20 weeks or more, including all values and subranges therebetween.

In embodiments, the methods described herein comprise stepwise adjusting 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.

In embodiments of the methods of the present disclosure, an zolmitriptan composition is administered to a patient in need thereof (e.g., a patient suffering from Autism Spectrum Disorder (ASD) or an aggressive alzheimer's patient) at an initial daily dose of about 12mg zolmitriptan, and then the zolmitriptan dose is adjusted stepwise to a therapeutically effective dose. In embodiments, the maximum daily dose is no greater than about 72mg of zolmitriptan.

In embodiments of the methods of the present disclosure, an zolmitriptan composition is administered to a patient in need thereof (e.g., a patient suffering from Autism Spectrum Disorder (ASD) or an aggressive alzheimer's patient) at an initial daily dose of at least about 12mg zolmitriptan, and then the zolmitriptan dose is adjusted stepwise to a therapeutically effective dose. In embodiments, the maximum daily dose is no greater than about 72mg of zolmitriptan.

In embodiments of the methods of the present disclosure, an zolmitriptan composition is administered to a patient in need thereof (e.g., a patient suffering from Autism Spectrum Disorder (ASD) or an aggressive alzheimer's patient) at an initial daily dose of about 12mg zolmitriptan, and then the zolmitriptan dose is adjusted stepwise to a maximum safe and effective dose. In embodiments, the maximum daily dose is no greater than about 72mg of zolmitriptan.

In embodiments of the methods of the present disclosure, an zolmitriptan composition is administered to a patient in need thereof (e.g., a patient suffering from Autism Spectrum Disorder (ASD) or an aggressive alzheimer's patient) at an initial daily dose of at least about 12mg zolmitriptan, and then the zolmitriptan dose is adjusted stepwise to a maximum safe and effective dose. In embodiments, the maximum daily dose is no greater than about 72mg of zolmitriptan.

In some embodiments, the present disclosure provides zolmitriptan compositions characterized based on pharmacokinetic (or PK) parameters observed after oral administration of the composition to a patient in need thereof. However, applicants contemplate that the same PK parameters achieved following 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 time-release compositions described herein.

In some embodiments, the pharmaceutical compositions provided herein provide a plasma level of zolmitriptan that is correlated with one or more statistically significant therapeutic effects over an extended period of time, typically over a period of 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 a human. In some embodiments, the pharmaceutical compositions provided herein provide a plasma level of zolmitriptan that is correlated with one or more statistically significant therapeutic effects over a period of about 4-24 hours (including over a period of 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 level is a steady state plasma level. In some embodiments, the compositions of the present disclosure provide a therapeutically effective plasma concentration of zolmitriptan for about 8 hours, about 10 hours, about 12 hours, or about 16 hours after a single administration of the composition when orally administered to a patient in need thereof. In some embodiments, the compositions of the present disclosure provide a therapeutically effective plasma concentration of zolmitriptan for about 10 hours, about 12 hours, or about 16 hours after a single administration of the composition when orally administered to a patient in need thereof. In some embodiments, the compositions of the present disclosure provide a therapeutically effective plasma concentration of zolmitriptan 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 administration of the composition when orally administered to a patient in need thereof.

In some embodiments, the compositions of the invention provide steady-state plasma levels of zolmitriptan that are correlated with one or more statistically significant therapeutic effects when administered on a once-a-day, twice-a-day, or three-a-day basis. In some embodiments, the steady state plasma level of zolmitriptan provided by the compositions of the invention provides a statistically significant effect after oral administration for at least about 12 hours, including 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 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, when orally administered to a patient in need thereof. Methods of measuring statistically significant effects will depend on the condition being treated and are known to those skilled in the art.

In some embodiments, the zolmitriptan compositions of the present disclosure provide a therapeutically effective steady state plasma level of zolmitriptan in the range of about 3ng/mL to about 85ng/mL when orally administered to a patient on a once-a-day, twice-a-day, or three-a-day basis, including about 3, about 5, 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, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about about 38, about 29, 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 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 78ng/mL, about 80ng/mL, about 81ng/mL, about 82ng/mL, about 83ng/mL, about 84ng/mL, and about 85ng/mL, including all ranges subsumed therein. In some embodiments, the zolmitriptan compositions of the present disclosure provide a therapeutically effective steady state plasma level of zolmitriptan in the range of about 3ng/ml to 85ng/ml when orally administered to a patient in need thereof on a once-a-day, twice-a-day, or three-a-day basis.

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

In embodiments of the methods of the invention, plasma levels of about 10ng/mL to about 25ng/mL, including about 10ng/mL, about 11ng/mL, about 12ng/mL, about 13ng/mL, about 14ng/mL, about 15ng/mL, about 16ng/mL, about 17ng/mL, about 18ng/mL, about 19ng/mL, about 20ng/mL, about 21ng/mL, about 22ng/mL, about 23ng/mL, about 24ng/mL to about 25ng/mL, including all values and subranges therebetween, are provided by administering about 24mg of the zolmitriptan composition of the present disclosure. In an embodiment of the method of the invention, a plasma level of about 25ng/mL to about 60ng/mL is provided by administering about 48mg of zolmitriptan. In an embodiment of the method of the invention, a plasma level of about 25ng/mL to about 50ng/mL is provided by administering about 48mg of zolmitriptan. In embodiments of the methods of the invention, a plasma level of about 25ng/mL to about 45ng/mL, including about 25ng/mL, about 26ng/mL, about 27g/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, about 40ng/mL, about 41ng/mL, about 42ng/mL, about 43ng/mL, about 44ng/mL, about 45ng/mL, including all values and subranges therebetween, is provided by administering about 48mg of an zolmitriptan composition of the present disclosure. In embodiments of the methods of the invention, a plasma level of about 40ng/mL to about 65ng/mL, including 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 51ng/mL, about 52ng/mL, about 53ng/mL, about 54ng/mL, about 55ng/mL, about 56ng/mL, about 57ng/mL, about 58ng/mL, about 59ng/mL, to about 60ng/mL, including all values and subranges therebetween, is provided by administering about 72mg of an zolmitriptan composition of the present disclosure.

In some embodiments, the zolmitriptan compositions of the present disclosure provide plasma levels (e.g., after a single dose of the zolmitriptan composition) in the range of about 1ng/mL to about 100ng/mL when administered orally to a patient in need thereof on a once-a-day, twice-a-day, or three-a-day basis, including about 1ng/mL, about 2ng/mL, about 3ng/mL, about 5ng/mL, about 10ng/mL, about 11ng/mL, about 12ng/mL, about 13ng/mL, about 14ng/mL, about 15ng/mL, about 16ng/mL, about 17ng/mL, about 18ng/mL, about 19ng/mL, about 20ng/mL, about 21ng/mL, about 22ng/mL, about 23ng/mL, about 24ng/mL, about 25ng/mL, 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 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 51ng/mL, about 52ng/mL, about 53ng/mL, about 54ng/mL, about 55ng/mL, about 56ng/mL, about 57ng/mL, about 58ng/mL, about 59ng/mL, about 60ng/mL, about 61ng/mL, about 62ng/mL, about 63ng/mL, about 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 78ng/mL, about 80ng/mL, about 81ng/mL, about 82ng/mL, about 83ng/mL, about 84ng/mL, about 85ng/mL, about 86ng/mL, about 87ng/mL, about 88ng/mL, about 89ng/mL, about 90ng/mL, about 91ng/mL, about 92ng/mL, about 93ng/mL, about 94ng/mL, about 95ng/mL, about 96ng/mL, about 97ng/mL, about 98ng/mL, about 99ng/mL, and about 100ng/mL, including all values therebetween. In embodiments, the zolmitriptan compositions of the present disclosure provide plasma levels ranging from about 40ng/mL to about 60ng/mL when orally administered to a patient in need thereof on a once-a-day, twice-a-day, or three-a-day basis. In embodiments, the zolmitriptan compositions of the present disclosure provide plasma levels ranging from about 40ng/mL to about 50ng/mL when orally administered to a patient in need thereof on a once-a-day, twice-a-day, or three-a-day basis.

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

In some embodiments, administration of a composition of the present disclosure provides CSF levels of zolmitriptan that are correlated 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 ranges from about 0.05ng/mL to about 2ng/mL, including about 0.05ng/mL, about 0.075ng/mL, about 0.1ng/mL, about 0.125ng/mL, about 0.15ng/mL, about 0.175ng/mL, about 0.2ng/mL, about 0.25ng/mL, about 0.3ng/mL, about 0.35ng/mL, about 0.4ng/mL, about 0.45ng/mL, about 0.5ng/mL, about 0.55ng/mL, about 0.6ng/mL, about 0.65ng/mL, about 0.7ng/mL, about 0.75ng/mL, about 0.8ng/mL, about 0.85ng/mL, about 0.9ng/mL, about 0.95ng/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 1.95ng/mL, about 1.5ng/mL, about 1.1.3 ng/mL, about 1.3ng/mL, about 1.1.1.3 ng, about 1.1.3 ng, and about 1.3ng, about 1.1.3 ng, and about 1.1.1.3 ng. In some embodiments, the therapeutically effective CSF level of zolmitriptan provided by the methods of the present disclosure ranges from about 0.078ng/mL to about 1.24ng/mL. In some embodiments, the therapeutically effective CSF level of zolmitriptan provided by the methods of the present disclosure ranges from about 0.103ng/mL to about 0.93ng/mL.

In some embodiments, the compositions of the invention provide an average steady state AUC of zolmitriptan when administered on a once-a-day, twice-a-day, or three-a-day basis _0-24h Levels (expressed in ng h/mL) are correlated with one or more statistically significant therapeutic effects. In some embodiments, the compositions of the invention provide an average steady-state AUC of zolmitriptan _0-24h Levels provide statistically significant effects after oral administration to a patient in need thereof for at least about 1 hour, 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, about 24 hours, 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 9 days, about 30 days, about 31 days, and more, including all ranges therebetween. In embodiments, the compositions of the invention provide an average steady-state AUC of zolmitriptan _0-24h The level provides a statistically significant effect upon oral administration to a patient in need thereof 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, toAt 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, 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 or more. In some embodiments, the compositions of the invention provide an average steady-state AUC of zolmitriptan _0-24h Levels provide a statistically significant effect of at least about 12 hours after oral administration to a patient in need thereof.

In some embodiments, the compositions of the invention provide an average steady-state AUC of zolmitriptan _0-24h Levels provide statistically significant effects upon administration to a patient in need thereof for a period of time of about or at least about 1-24 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. In some embodiments, the compositions of the invention provide an average steady-state AUC of zolmitriptan _0-24h Levels provide a statistically significant effect upon administration to a patient in need thereof for a period of about 12 hours to about 24 hours. In some embodiments, the compositions of the invention provide an average steady-state AUC of zolmitriptan _0-24h The level provides a statistically significant effect 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, to A time period of 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 of the invention provide an average steady-state AUC of zolmitriptan _0-24h The level provides a statistically significant effect upon administration to a patient in need thereof for a period of time ranging from 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.

In some embodiments, the therapeutically effective zolmitriptan mean steady state AUC provided by the zolmitriptan compositions of the present disclosure _0-24h Levels range from about 15ng h/mL to about 1150ng h/mL, including about 15ng h/mL, 20ng h/mL, 25ng h/mL, 30ng h/mL, 35ng h/mL, 40ng h/mL, 50ng h/mL, 100ng h/mL, 150ng h/mL, 200ng h/mL, 250ng h/mL, 300ng h/mL, about 400ng h/mL, about 500ng h/mL, about 600ng h/mL, about 700ng h/mL, about 800ng h/mL, about 1000ng h/mL, about 1100ng h/mL, and about 115 ng h/mL, including all ranges and values therebetween. In some embodiments, the therapeutically effective zolmitriptan mean steady state AUC provided by the zolmitriptan compositions of the present disclosure _0-24h Levels range from about 40ng h/mL to about 110ng h/mL, including about 40ng h/mL, about 50ng h/mL, about 60ng h/mL, about 70ng h/mL, about 80ng h/mL, about 90ng h/mL, about 100ng h/mL, and about 110ng h/mL, including all ranges and values therebetween. In some embodiments, the therapeutically effective zolmitriptan mean steady state AUC provided by the zolmitriptan compositions of the present disclosure _0-24h Levels range from about 150ng h/mL to about450ng h/mL, including about 150ng h/mL, about 175ng h/mL, about 200ng h/mL, about 225ng h/mL, about 250ng h/mL, about 275ng h/mL, about 300ng h/mL, about 325ng h/mL, about 350ng h/mL, about 375ng h/mL, about 400ng h/mL, about 425ng h/mL, and about 450ng h/mL, including all ranges and values therebetween. In some embodiments, the therapeutically effective zolmitriptan mean steady state AUC provided by the zolmitriptan compositions of the present disclosure _0-24h Levels range from about 600ng h/mL to about 1150ng h/mL, including about 600ng h/mL, about 650ng h/mL, about 700ng h/mL, about 750ng h/mL, about 800ng h/mL, about 850ng h/mL, about 900ng h/mL, about 950ng h/mL, about 1000ng h/mL, about 1050ng h/mL, about 1100ng h/mL, and about 1100ng h/mL, including all ranges and values therebetween.

In some embodiments, the compositions provide an AUC after a single administration of the compositions of the present invention _0-24h (expressed in ng h/mL) from about 20ng h/mL to about 1200ng h/mL, including about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230, about 240, about 250, about 270, about 280, about 260 about 290ng h/mL, about 300ng h/mL, about 310ng h/mL, about 320ng h/mL, about 330ng h/mL, about 340ng h/mL, about 350ng h/mL, about 360ng h/mL, about 370ng h/mL, about 380ng h/mL, about 390ng h/mL, about 400ng h/mL, about 410ng h/mL, about 420ng h/mL, about 430ng h/mL, about 440ng h/mL, about 450ng h/mL, about 460ng h/mL, about 470ng h/mL, about 480ng h/mL, about 490ng h/mL, about 500ng h/mL, about 510ng h/mL, about 520ng h/mL, about 530ng h/mL, about 540ng h/mL, about, about 550ng h/mL, about 560ng h/mL, about 570ng h/mL, about 580ng h/mL, about 590ng h/mL, about 600ng h/mL, about 610ng h/mL, about 620ng h/mL, about 630ng h/mL, about 640ng h/mL, about 650ng h/mL, about 660ng h/mL, about 670ng h/mL, about 680ng h/mL, about 690ng h/mL, About 700ng h/mL, about 710ng h/mL, about 720ng h/mL, about 730ng h/mL, about 740ng h/mL, about 750ng h/mL, about 760ng h/mL, about 770ng h/mL, about 780ng h/mL, about 790ng h/mL, about 800ng h/mL, about 810ng h/mL, about 820ng h/mL, about 830ng h/mL, about 840ng h/mL, about 850ng h/mL, about 860ng h/mL, about 870ng h/mL, about 890ng h/mL, about 900ng h/mL, about 910ng h/mL, about 920ng h/mL, about 930ng h/mL, about 940ng h/mL, about 950ng h/mL, about 960ng h/mL about 970ng h/mL, about 980ng h/mL, about 990ng h/mL, about 1000ng h/mL, about 1010ng h/mL, about 1020ng h/mL, about 1030ng h/mL, about 1040ng h/mL, about 1050ng 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 118 ng h/mL, about 0ng h/mL, about 1200ng h/mL, including all values and subranges therebetween. In some embodiments, the compositions provide an AUC after a single administration of the compositions of the present invention _0-24h From about 20ng h/mL to about 500ng h/mL. In some embodiments, the compositions provide an AUC after a single administration of the compositions of the present invention _0-24h From about 80 ng.h/mL to about 750 ng.h/mL. In some embodiments, the compositions provide an AUC after a single administration of the compositions of the present invention _0-24h From about 50ng h/mL to about 250ng h/mL. In some embodiments, the compositions provide an AUC after a single administration of the compositions of the present invention _0-24h From about 40 ng.h/mL to about 300 ng.h/mL, or from about 150 ng.h/mL to about 250 ng.h/mL, or from about 50 ng.h/mL to about 150 ng.h/mL. In embodiments, the compositions provide an AUC after a single administration of the compositions of the present invention _0-24h (expressed in ng h/mL) is from about 20ng h/mL to about 500ng h/mL. In embodiments, the compositions of the present invention are administered in a fed state. In embodiments, the composition is administered in a fasted state.

In some embodiments, the compositions of the present disclosure are used to provide between about 7.5mg and about 150mg of zolmitriptan or a pharmaceutically acceptable thereof by administering one or more compositionsDaily dosage of salts of (a) to provide a therapeutically effective mean steady-state AUC of zolmitriptan _0-24h Horizontal. In some further embodiments, a therapeutically effective mean steady-state AUC of zolmitriptan is provided by administering a composition of the present disclosure containing between about 7.5mg and about 150mg of zolmitriptan or a pharmaceutically acceptable salt thereof once a day _0-24h Horizontal. In yet other embodiments, a therapeutically effective mean steady-state AUC of zolmitriptan is provided by administering a composition of the present disclosure containing between about 3.75mg and about 75mg of zolmitriptan or a pharmaceutically acceptable salt thereof twice a day _0-24h Horizontal. In yet other embodiments, a therapeutically effective mean steady-state AUC of zolmitriptan is provided by administering a composition of the present disclosure containing between about 2.5mg and about 50mg of zolmitriptan or a pharmaceutically acceptable salt thereof three times a day _0-24h Horizontal.

In some embodiments, the compositions provide an AUC after a single administration of the compositions of the present invention _Finally (expressed in ng.h/mL) is from about 20 ng.h/mL to about 1200 ng.h/mL, including about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230, about 240, about 250, about 270, about 280, about 260 about 290ng h/mL, about 300ng h/mL, about 310ng h/mL, about 320ng h/mL, about 330ng h/mL, about 340ng h/mL, about 350ng h/mL, about 360ng h/mL, about 370ng h/mL, about 380ng h/mL, about 390ng h/mL, about 400ng h/mL, about 410ng h/mL, about 420ng h/mL, about 430ng h/mL, about 440ng h/mL, about 450ng h/mL, about 460ng h/mL, about 470ng h/mL, about 480ng h/mL, about 490ng h/mL, about 500ng h/mL, about 510ng h/mL, about 520ng h/mL, about 530ng h/mL, about 540ng h/mL, about, about 550ng h/mL, about 560ng h/mL, about 570ng h/mL, about 580ng h/mL, about 590ng h/mL, about 600ng h/mL, about 610ng h/mL, about 620 ng h/mL About 630ng h/mL, about 640ng h/mL, about 650ng h/mL, about 660ng h/mL, about 670ng h/mL, about 680ng h/mL, about 690ng h/mL, about 700ng h/mL, about 710ng h/mL, about 720ng h/mL, about 730ng h/mL, about 740ng h/mL, about 750ng h/mL, about 760ng h/mL, about 770ng h/mL, about 780ng h/mL, about 790ng h/mL, about 800ng h/mL, about 810ng h/mL, about 820ng h/mL, about 830ng h/mL, about 840ng h/mL, about 850ng h/mL, about 860ng h/mL, about 880ng h/mL, about 890ng h/mL, about 900ng h/mL about 910, about 920, about 930, about 940, about 950, about 960, about 970, about 980, about 990, about 1000, about 1160, about 1170, about 1180, about 1110, about 1190ng h/mL to about 1200ng h/mL, including all values and subranges therebetween. In some embodiments, the compositions provide an AUC after a single administration of the compositions of the present invention _Finally From about 50ng h/mL to about 250ng h/mL. In some embodiments, the compositions provide an AUC after a single administration of the compositions of the present invention _Finally From about 40 ng.h/mL to about 300 ng.h/mL, or from about 150 ng.h/mL to about 250 ng.h/mL, or from about 50 ng.h/mL to about 150 ng.h/mL. In embodiments, the compositions provide an AUC after a single administration of the compositions of the present invention _Finally (expressed in ng h/mL) is from about 20ng h/mL to about 500ng h/mL. In embodiments, the compositions of the present invention are administered in a fed state. In embodiments, the composition is administered in a fasted state.

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

In some embodiments, the composition provides C after a single administration of the composition of the present invention _max From about 1ng/mL to about 100ng/mL, including about 1ng/mL, about 2ng/mL, about 3ng/mL, about 4ng/mL, about 5ng/mL, about 6ng/mL, about 7ng/mL, about 8ng/mL, about 9ng/mL, about 10ng/mL, about 11ng/mL, about 12ng/mL, about 13ng/mL, about 14ng/mL, about 15ng/mL, about 16ng/mL, about 17ng/mL, about 18ng/mL, about 19ng/mL, about 20ng/mL, about 21ng/mL, about 22ng/mL, about 23ng/mL, about 24ng/mL, about 25ng/mL, 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 about 37ng/mL, about 38ng/mL, about 39ng/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 51ng/mL, about 52ng/mL, about 53ng/mL, about 54ng/mL, about 55ng/mL, about 56ng/mL, about 57ng/mL, about 58ng/mL, about 59ng/mL, about 60ng/mL, about 61ng/mL, about 62ng/mL, about 63ng/mL, about 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 78ng/mL, about 79ng/mL, about 80ng/mL, about 81ng/mL, about 82ng/mL, about 83ng/mL, about 84n g/mL, about 85ng/mL, about 86ng/mL, about 87ng/mL, about 88ng/mL, about 89ng/mL, about 90ng/mL, about 91ng/mL, about 92ng/mL, about 93ng/mL, about 94ng/mL, about 95ng/mL, about 96ng/mL, about 97ng/mL, about 98ng/mL, about 99ng/mL to about 100ng/mL, including all values and subranges therebetween. In some embodiments, the compositions of the present invention provide C _max From about 1ng/mL to about 80ng/mL. In some embodiments, the composition provides C after a single administration of the composition of the present invention _max From about 3ng/mL to about 30ng/mL. In embodiments, the composition provides C after a single administration of the composition of the present invention _max From about 5ng/mL to about 60ng/mL. In embodiments, the compositions of the present invention are administered in a fed state. In embodiments, the composition is administered in a fasted state.

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

In some embodiments, the composition provides t after a single administration of the composition of the present invention _1/2 From 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. In some embodiments, the composition provides t after a single administration of the composition of the present invention _1/2 From about 5 hours to about 18 hours. In some embodiments, the compositions of the invention provide a plasma half-life (t _1/2 ) From about 8.5 hours to about 15 hours.

In some embodiments, the compositions provide a Tmax of from about 1 hour to about 10 hours, including from 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 compositions of the present invention. In some embodiments, the compositions of the present invention provide a Tmax of about 2 hours to about 5 hours after a single administration of the composition.

Suitable pharmaceutical compositions of the present disclosure may be administered to a subject according to any clinically acceptable route of administration of the composition. The manner in which the composition is administered depends in part on the etiology and/or site. Those skilled in the art will recognize the advantages of certain routes of administration. The method comprises administering an effective amount of the agent or compound (or a composition comprising the agent or compound) to achieve a desired biological response, e.g., an amount effective to alleviate, ameliorate, or prevent, in whole or in part, symptoms of the disorder to be treated (e.g., symptoms associated with autism spectrum disorder). In various aspects, the route of administration is systemic, e.g., oral or by injection. In some embodiments, zolmitriptan or a pharmaceutically acceptable salt thereof is administered orally, nasally, transdermally, pulmonary, inhaled, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, or parenterally. In some embodiments, zolmitriptan is administered orally. In some embodiments, the zolmitriptan is administered parenterally.

Methods of treating ASD symptoms

In some embodiments, the present disclosure provides methods of treating symptoms associated with Autism Spectrum Disorder (ASD), comprising administering an zolmitriptan composition of the present disclosure. In some embodiments, the methods of the invention comprise administering the zolmitriptan compositions of the present disclosure as the sole composition for treating symptoms of ASD. In some embodiments, the methods of the present invention use the zolmitriptan compositions of the present disclosure in combination with one or more active ingredients for treating ASD symptoms. In some embodiments, the zolmitriptan compositions of the present disclosure are administered in combination (e.g., co-formulated or administered alone) with additional active ingredients for treating ASD.

Non-limiting examples of ASD symptoms include irritability, difficulty in communication, difficulty in social interaction, compulsive interests, repetitive behaviors, improper social interactions, poor eye contact, compulsive behaviors, impulses, repetitive movements, self-disability, sustained speech or motion repetition, learning disabilities, speech retardation, strong interest in a limited number of things, attention problems, lack of cognition of emotion to others, depression, anxiety, voice changes, sensitivity to sound, and tics. In some embodiments, the patient in need thereof experiences a significant reduction in irritability associated with ASD as compared to prior to the treatment. In some embodiments, the patient in need thereof experiences a significant improvement in social ability as compared to prior to the treatment.

In some embodiments, the present disclosure provides methods of treating symptoms of ASD comprising administering an effective amount of an zolmitriptan composition of the present disclosure. In some embodiments, the zolmitriptan composition is administered as monotherapy. In some embodiments, the zolmitriptan composition is administered as an adjunct to the 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.

In embodiments, the present disclosure provides methods of treating an irritability associated with autism comprising administering an effective amount of an zolmitriptan composition of the present disclosure. In embodiments, the present disclosure provides methods of treating aggression associated with autism comprising administering an effective amount of an zolmitriptan composition of the present disclosure. In embodiments, the present disclosure provides methods of treating non-refined harvest (lethargy) associated with autism comprising administering an effective amount of an zolmitriptan composition of the present disclosure. In embodiments, the present disclosure provides methods of treating social ability symptoms associated with autism comprising administering an effective amount of an zolmitriptan composition of the present disclosure to improve social contact. In embodiments, the present disclosure provides methods of reducing social defects associated with autism comprising administering an effective amount of an zolmitriptan composition of the present disclosure, or a pharmaceutically acceptable salt thereof.

In some embodiments, the patient experiences a significant reduction in ASD symptoms after the treatment characterized by an improvement according to Wen Lan adapted behavior scale (Vineland Adaptive Behavior Scales), ADOS-2, CGI-C social deficit score scale, abnormal behavior checkup, autism treatment assessment checkup (Autism Treatment Evaluation Checklist) (ATEC), social response scale (Social Responsiveness Scale), version 2 (SRS-2), or any combination thereof.

In embodiments, the patient experiences an improvement in ASD symptoms after the treatment as compared to before the treatment, characterized by an improvement in social communication area score (Autism Behavior Inventory (ABI) -Social Communication Domain Score) according to an autism behavior questionnaire (ABI).

The ABI-social communication area score is a 62 project questionnaire for reporting the behavior of subjects diagnosed with ASD (age: 3 years-adult). The tool is suitable for being done by a parent or care/learning partner of a person suffering from an ASD. Each item evaluates the quality (from no help at all to no help) or frequency (less often) of a particular action. The social communication domain score is the sum of the scores in the social communication domain divided by the number of items in the domain.

In embodiments, the patient experiences an improvement in ASD-related symptoms after the treatment compared to before the treatment, characterized by about 20% improvement, about 25% improvement, about 30% improvement, about 35% improvement, about 40% improvement, about 45% improvement, about 50% improvement, about 55% improvement, about 60% improvement, about 65% improvement, about 70% improvement, about 80% improvement, about 90% improvement, or about 95% improvement in the ABI-social communication area score compared to before the treatment.

In some embodiments, the patient experiences an improvement in ASD-related symptoms after the treatment as compared to before the treatment, characterized by at least about 20% improvement, at least about 25% improvement, at least about 30% improvement, at least about 35% improvement, at least about 40% improvement, at least about 45% improvement, at least about 50% improvement, at least about 55% improvement, at least about 60% improvement, at least about 65% improvement, at least about 70% improvement, at least about 80% improvement, at least about 90% improvement, or at least about 95% improvement in the ABI-social communication area score as compared to before the treatment.

In embodiments, the patient experiences an improvement in ASD symptoms after the treatment compared to before the treatment, characterized by an improvement in impression (Clinician Global Impression of Improvement) (CGI-I) score according to the clinician overall improvement.

The CGI-I score is a single item tool based on a 7-score scale for capturing the overall impression of the response by the researcher. The observed improvement was rated 1-7 by the investigator or the designated person (1=improvement was very large; 2=improvement was large; 3=improvement was small; 4=no change; 5=small deterioration; 6=much worse; 7=very bad).

In embodiments, the patient experiences an improvement in symptoms associated with ASD after the treatment as compared to before the treatment, and has a CGI-I score of about 1, about 2, about 3, about 4, or about 5 after the treatment. In embodiments, the patient experiences an improvement in symptoms associated with ASD after the treatment and has a CGI-I score of about 1, about 2, or about 3. In embodiments, the patient experiences an improvement in symptoms associated with ASD after the treatment and has a CGI-I score of about 1 or 2.

In some embodiments, the patient experiences an improvement in symptoms associated with ASD after the treatment characterized by an improvement in the autism behavior questionnaire-clinician (ABI-C) score as compared to before the treatment.

The ABI-clinician (ABI-C) captures the clinician ratings of the behavior of people with ASD occurring within the previous week of evaluation. It contains 14 projects reflecting the core and related autism behavioral domains: social communication, restrictive behavior, mood and anxiety, self-regulation, and challenging behavior. Each item was rated on a 7-point scale from 1 point (no; asymptomatic presentation) to 7 points (very severe; continuous interference function or adaptation).

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

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

In some embodiments, the patient experiences an improvement in ASD symptoms after the treatment characterized by an improvement in the domain score according to ABI repetition/restriction behavior compared to before the treatment.

Each item in the ABI repeat/limit behavior domain is rated by frequency (0=less than 3=very frequent). The domain score is the sum of all domain item scores divided by the number of items in the domain.

In some embodiments, the patient experiences an improvement in ASD symptoms after the treatment characterized by an improvement in the area of behavioural score according to ABI challenge compared to before the treatment.

Each item on the ABI challenge behavior domain was rated by frequency (0=less than 3=very frequent). The domain score is the sum of all domain item scores divided by the number of items in the domain.

In some embodiments, the patient experiences an improvement in ASD symptoms after the treatment, characterized by an improvement in accordance with an ABI-short form (ABI-S) score, as compared to before the treatment.

ABI-S is a 24-item shorthand version of ABI, containing items from each of five fields. The domain score for each domain is calculated as: the sum of all domain item scores divided by the number of items in the domain.

In some embodiments, the patient experiences an improvement in ASD symptoms after the treatment characterized by an improvement in score according to the ABC-social withdrawal (ABC-SW) component as compared to before the treatment.

The ABC-SW components table consists of 16 entries for ABC-2 rated from 0 (no problem) to 3 (problem is severe).

In some embodiments, the patient experiences an improvement in ASD symptoms after the treatment characterized by a score according to Wen Lan-3 (domain level version) compared to before the treatment: improvement in the sum of the areas of communication, socialization and maladaptive behaviour.

Wen Lan-3 Domain level version contains 5 domains. The response of each item is rated from 0 (never) to 2 (normally).

Wen Lan adaptive behavior scale (VABS) third edition is a standardized measure of adaptive behavior for evaluating individuals' personal and social skills from birth to adult. Individuals may be evaluated by a teacher or carer on the VABS scale. According to the VABS, an individual is assigned a VABS-adapted behavioral composite score that measures the individual's function compared to other individuals of his or her age. Individuals are also assigned domain scores in terms of communication, daily life skills, socialization, and motor skills to assess the strong and weak terms of the individual's adaptive behavior. For each of the domain scores and the VABS adapted behavioral composite score, the individual gets a score of 20 to 140. A score of 20 to 70 represents a low fitness level. Scores of 71 to 85 represent moderately low fitness levels. The scores of 86 to 114 represent moderately appropriate fitness levels. Scores of 115 to 129 represent moderately high fitness levels. Scores of 130 to 140 represent high fitness levels.

In some embodiments, after the treatment, the patient experiences a reduction in symptoms associated with ASD, characterized by an increase in the VABS adaptation behavioral composite score of at least one score compared to before the treatment. In some embodiments, the therapeutic agent, as compared to prior to the treatment, the VABS adaptation score increases by about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, about 10 minutes, about 11 minutes, about 12 minutes, about 13 minutes, about 14 minutes, about 15 minutes, about 16 minutes, about 17 minutes, about 18 minutes, about 19 minutes, about 20 minutes, about 21 minutes, about 22 minutes, about 23 minutes, about 24 minutes, about 25 minutes, about 26 minutes, about 27 minutes, about 28 minutes, about 29 minutes, about 30 minutes, about 31 minutes, about 32 minutes, about 33 minutes, about 34 minutes, about about 35 minutes, about 36 minutes, about 37 minutes, about 38 minutes, about 39 minutes, about 40 minutes, about 41 minutes, about 42 minutes, about 43 minutes, about 44 minutes, about 45 minutes, about 46 minutes, about 47 minutes, about 48 minutes, about 49 minutes, about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, or about 70 minutes.

In some embodiments, the VABS adaptation behavioral composite score is increased by 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% as compared to before the treatment.

In some embodiments, after the treatment, the patient experiences an increase in social ability characterized by an increase in the VABS-adapted behavioral socialization area score compared to before the treatment. In some embodiments, the therapeutic agent, as compared to prior to the treatment, the VABS adaptation behavior socialization domain score increases by about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, about 10 minutes, about 11 minutes, about 12 minutes, about 13 minutes, about 14 minutes, about 15 minutes, about 16 minutes, about 17 minutes, about 18 minutes, about 19 minutes, about 20 minutes, about 21 minutes, about 22 minutes, about 23 minutes, about 24 minutes, about 25 minutes, about 26 minutes, about 27 minutes, about 28 minutes, about 29 minutes, about 30 minutes, about 31 minutes, about 32 minutes, about 33 minutes, about 34 minutes, about about 35 minutes, about 36 minutes, about 37 minutes, about 38 minutes, about 39 minutes, about 40 minutes, about 41 minutes, about 42 minutes, about 43 minutes, about 44 minutes, about 45 minutes, about 46 minutes, about 47 minutes, about 48 minutes, about 49 minutes, about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, or about 70 minutes.

In some embodiments, the VABS adaptation behavioural socialization area score is increased by 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 the treatment. In some embodiments, the patient experiences at least a 10% improvement in the socialization area score of the VABS after treatment. In some embodiments, the patient experiences at least a 35% improvement in the socialization area score of the VABS after treatment.

In some embodiments, after the treatment, the patient experiences an improvement in communication characterized by an increased VABS adaptive behavioral communication domain score compared to before the treatment. In some embodiments, the therapeutic agent, as compared to prior to treatment, the VABS adaptive behavior communication field increases by about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, about 10 minutes, about 11 minutes, about 12 minutes, about 13 minutes, about 14 minutes, about 15 minutes, about 16 minutes, about 17 minutes, about 18 minutes, about 19 minutes, about 20 minutes, about 21 minutes, about 22 minutes, about 23 minutes, about 24 minutes, about 25 minutes, about 26 minutes, about 27 minutes, about 28 minutes, about 29 minutes, about 30 minutes, about 31 minutes, about 32 minutes, about 33 minutes, about 34 minutes, about about 35 minutes, about 36 minutes, about 37 minutes, about 38 minutes, about 39 minutes, about 40 minutes, about 41 minutes, about 42 minutes, about 43 minutes, about 44 minutes, about 45 minutes, about 46 minutes, about 47 minutes, about 48 minutes, about 49 minutes, about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, or about 70 minutes.

In some embodiments, the VABS adaptation behavioral communication field score is increased by 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 the treatment.

Autism diagnostic viewing schedule (Autism Diagnostic Observation Schedule) second edition (ADOS-2) is a tool that allows for accurate assessment and diagnosis of ASD across age, development level and language skills. ADOS-2 is a clinician-managed observational assessment that includes two areas of behavior: social impact (SA) and Restricted and Repetitive Behaviors (RRB). One of five ADOS-2 modules is administered to the individual, the module being selected based on the individual's expressive language level and chronological age. The infant module is for children between 12 and 30 months of age who cannot consistently use the phrase speech. Module 1 is for children 31 months and more who cannot consistently use the phrase speech. Module 2 is for children of any age who use the phrases to speak but who are verbally disfavored. The module 3 is for verbally fluent children and teenagers of low years. The module 4 is for verbally fluent older teenagers and adults. Individuals were assigned an ADOS-2 composite total score ranging from 1 to 10. Individuals with ASD are characterized by an ADOS-2 composite overall score of between 6 and 10.

In some embodiments, the patient experiences a reduction in ASD-related symptoms associated with a reduction in the aggregate score of ADOS-2 by at least one score as compared to prior to the treatment. In some embodiments, the patient experiences an improvement in ASD symptoms, characterized by a reduction in the aggregate score of ADOS-2 of at least 1 score, at least 2 scores, at least 3 scores, at least 4 scores, or at least 5 scores as compared to prior to said treatment.

In some embodiments, the patient experiences an improvement in ASD symptoms, characterized by an ADOS-2 composite score that is improved 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% compared to prior to said treatment.

In some embodiments, the patient experiences a reduction in symptoms associated with ASD, characterized by a reduction in ADOS-2 module 4 social impact score of at least one score compared to prior to the treatment. In some embodiments, the decrease in the ADOS-2 module 4 social impact score is related to an improvement in social ability. In some embodiments, the improvement in social ability is characterized by a reduction in social impact score by ADOS-2 module 4 of at least 1 score, or at least 2 score, or at least 3 score, or at least 4 score, or at least 5 score, or at least 6 score, as compared to prior to the treatment.

In some embodiments, the improvement in social ability is characterized by a reduction in the social impact scale of ADOS-2 module 4 of 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% compared to before the treatment. In some embodiments, the patient experiences an improvement in social ability characterized by a reduction in social reciprocity score of module 4 of at least 10% as compared to before the treatment as compared to before the diagnosis of autism.

Clinicians utilize the clinical global impression-severity (CGI-S) scale to assess the severity of symptoms in ASD patients. Individuals were assigned scores of 1 to 7. Score 1 represents normal patient. Score 7 represents the score of patients with ASD.

In some embodiments, after the treatment, the patient experiences a reduction in symptoms associated with ASD, characterized by a reduction in CGI-S score of at least one score compared to before the treatment. In some embodiments, the patient experiences a reduction in CGI-S scale of at least 1 score, or at least 2 scores, or at least 3 scores, or at least 4 scores, or at least 5 scores, as compared to prior to said treatment.

In some embodiments, the patient experiences a reduction in CGI-S scale 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% compared to prior to said treatment.

Clinicians utilize the clinical global impression-severity (CGI-C) scale to evaluate changes in symptoms in ASD patients. Individuals were assigned scores ranging from 1 (very much improved) to 7 (very poor).

In some embodiments, after the treatment, the patient experiences a reduction in symptoms associated with ASD, characterized by a reduction in CGI-C scale of at least one fraction. In some embodiments, the patient experiences an improvement in irritability, characterized by a CGI-C score of 1, 2, 3, or 4 after the treatment. In some embodiments, the improvement in patient irritability is characterized by a clinical global impression-change (CGI-C) score of 3 or less after the treatment. In some embodiments, the patient experiences an improvement in social ability characterized by a CGI-C score of 1, 2, 3, or 4 after the treatment. In some embodiments, the patient experiences an improvement in social ability characterized by a CGI-C score of 3 or less after the treatment.

Autism behavior questionnaire (ABI) social deficit score table is a measure used to evaluate changes in the core and related symptoms of ASD. The individuals were administered either an ABI full version (93 item) scale or an ABI plain version (36 item) scale. Individuals were scored from 0 to 6 per item on the scale, with 0 being the absence of symptoms and 6 being the maximum symptoms. Individuals who received a score of 0 exhibited no symptoms. Individuals assigned 6 points experience severe ASD symptoms.

In some embodiments, the patient experiences an improvement in symptoms, characterized by a decrease in ABI score of at least one score. In some embodiments, the patient experiences an improvement in symptoms, characterized by a decrease in ABI score of at least 1 score, or at least 2 scores, or at least 3 scores, or at least 4 scores, as compared to prior to said treatment.

In some embodiments, the patient experiences an improvement in symptoms, characterized in that the ABI score is reduced by 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 prior to said treatment.

Children two years old and older with ASD were identified using the childhood autism rating scale (childhood autism rating scale) (CARS). CARS consists of 14 areas of evaluation of ASD-related behavior and 15 th area of evaluation of general impressions of autism. Each field is scored by a scale ranging from one to four; higher scores are associated with higher levels of disorder. The total score may range from a low score of 15 to a high score of 60; scores below 30 indicate that the individual is in a non-autistic range, scores between 30 and 36.5 indicate mild to moderate autism, and scores of 37 to 60 indicate severe autism.

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

In some embodiments, following the treatment, the patient experiences a reduction in symptoms associated with ASD, characterized in that the total CARS score is reduced by 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 prior to the treatment.

An effective quantitative measure of various dimensions of interpersonal behavior, communication, and repeat/plate behavior associated with ASD was obtained using social reaction scale version 2 (SRS-2). According to SRS-2, individuals are assigned a surrogate version total t-score based on SRS-2. Individuals were assigned a surrogate t score that reflects the sum of responses to 65 social response scale questions, which served as an index of the severity of social skills on autism spectrum. Individuals who obtain a surrogate version t score of greater than 76 get a severe clinical diagnosis of ASD. If an individual is assigned a proxy t score between 66 and 75, this is associated with a moderate lack of reciprocal social behavior that is clinically significant and results in significant interference with daily social interactions. If an individual is assigned a proxy t score between 60 and 65, the individual exhibits mild to moderate deficits in social interactions. If the patient exhibits a proxy version t score of 59 or less, the patient exhibits normal social interactions.

In some embodiments, the patient in need exhibits a proxy version total t-score of ≡66 prior to administration of the zolmitriptan composition to the patient in need thereof.

In some embodiments, the patient experiences an improvement in symptoms, characterized in that the proxy total t-score is reduced by at least one, or at least two, or at least three, or at least four, or at least five, or at least six, or at least seven, or at least eight, or at least nine, or at least ten, or at least eleven, or at least ten, or at least thirteen, or at least fourteen, or at least fifteen, or at least sixteen, or at least seventeen, or at least eighteen, or at least twenty-four, or at least twenty-five, as compared to prior to the treatment. In some embodiments, the patient experiences an improvement in symptoms, characterized in that the surrogate version total t-score of SRS-2 is reduced by 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.

The adult social response scale (SRS-se:Sup>A) is se:Sup>A tool to evaluate social responses in adults. SRS-A contains 65 items, which are scored from 0 to 3. If the individual gets a score of 0, the individual has no symptoms. If the individual gets a score of 3, the individual has severe symptoms. An SRS-A total score of 67 indicates that the individual has ASD. The maximum SRS-A total score is 195.

In some embodiments, after the treatment, the patient exhibits se:Sup>A reduction in symptoms associated with ASD, characterized by se:Sup>A reduction in SRS-se:Sup>A score of 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% compared to before the treatment. In some embodiments, after the treatment, the patient exhibits se:Sup>A reduction in symptoms associated with ASD, characterized by se:Sup>A reduction in SRS-se:Sup>A score of at least 10% compared to before the treatment.

In some embodiments, the improvement in social ability is associated with se:Sup>A reduction in SRS-se:Sup>A score of about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or about 50% compared to before the treatment.

An Abnormal Behavior Checklist (ABC) is a behavior rating scale for rating individuals with five component tables: (1) irritability, irritation and crying, (2) insensitivity, social withdrawal, (3) clapping behavior, (4) hyperactivity and non-compliance, and (5) speech inadequacy. Individuals can be evaluated by ABC by any adult who is well known to the individual. ABC contains a 58-item questionnaire, which is used to evaluate five component tables. Each item in the 58-item questionnaire was rated from 0 to 3. A score of 0 means that symptoms are absent. Score 3 means that the individual experienced a highly severe symptom. Items within each score table are added to obtain a score table score. The possible component table scores by ABC range from 0 to 48, with higher score scores indicating behavioral disorders.

In some embodiments, following the treatment, the patient experiences a reduction in symptoms associated with ASD, characterized by a decrease in ABC irritability and crying (ABC-I) score of at least one score. In some embodiments, the patient experiences a decrease in irritability after the treatment, characterized by a decrease in ABC-I communication domain score as compared to before the treatment.

In some embodiments, the patient exhibits an ABC-I score of.gtoreq.18 prior to treatment.

In some embodiments, the patient experiences a decrease in irritability after the treatment, characterized by a decrease in ABC-I domain score of 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 as compared to before the treatment. In some embodiments, the ABC-I field score is reduced by 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% as compared to before the treatment. In some embodiments, the score is reduced in the ABC-I domain by 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% compared to before the treatment.

In embodiments, the patient experiences a decrease in irritability after said treatment, characterized by a 25% decrease in the irritability score scale, and wherein the patient is rated as having a large improvement or a very large improvement (i.e., 2 or 1, respectively) on the CGI improvement scale.

In some embodiments, after the treatment, the patient experiences a reduction in symptoms associated with ASD, characterized by an ABC-insensitivity and social withdrawal (ABC-LSW) score decrease by at least a fraction as compared to before the treatment. In some embodiments, after the treatment, the patient experiences a reduction in fecundity and social withdrawal, characterized by a reduced ABC-LSW communication domain score as compared to before the treatment.

In some embodiments, the ABC-LSW communication domain score is reduced by 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 as compared to before the treatment.

In some embodiments, the ABC-LSW communication domain score is reduced by 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% as compared to before the treatment.

Social communication questionnaires are tools that doctors use to screen patients with ASD. Individual caregivers rate individuals speaking on a scale of 0 to 39 points or individuals not speaking on a scale of 0 to 33 points. Individuals with ASD are characterized by social communication questionnaires exceeding 15 points.

In some embodiments, following the treatment, the patient experiences a reduction in symptoms associated with ASD, characterized by a reduction in social communication questionnaire scale of at least 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% compared to prior to the treatment.

The therapeutic efficacy of ASD was evaluated using the pervasive developmental disorder behavioural questionnaire (PDDBI). PDDBI evaluates both problem behavior and appropriate social, linguistic and learning/memory skills. PDDBI is divided into two behavior dimensions: (a) approach-withdrawal problems, assessing maladaptive behaviour; and (b) admitting/expressing social communication capabilities, evaluating the social communication capabilities. The approach-collapse problem dimension is further divided into behavioral domains including sensory/perceptual approach behavior, RITUAL/resistance constraint (RITUAL), social speech problem (socp), semantic/speech problem (semp), arousal adjustment problem (arose), specific Fear (FEARS), and Aggression (AGG) domains. Admission of assessing social communication capabilities/expressing social communication capabilities (REXSCA) is further divided into behavioral domains, including social proximity behavior (SOCAPP), expressive language (EXPRESS), and Learning Memory and Receptive Language (LMRL) domains. The individual gets a T score and a composite score for each domain, the composite score being the sum of the scores for each domain. Individuals with ASD are assigned a T score of greater than 50.

In some embodiments, the reduction in ASD-related symptoms provided by the methods of the present disclosure is characterized using a pervasive developmental disorder behavior questionnaire (pervasive developmental disorder behavior inventory) (PDDBI). In some embodiments, the patient exhibits a T score of greater than 50 prior to the treatment. In some embodiments, after the treatment, the patient experiences a reduction in symptoms associated with ASD, characterized by a reduction 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.

ATEC is a scale used to evaluate the efficacy of ASD treatment. ATEC is a page of form intended to be completed by a parent, teacher, or caretaker. ATEC consists of four sub-tests: speech/language communication, social ability, sensory/cognitive awareness, and health/body/behavior. Individuals were assigned speech/language communication subtest ratings of 0 to 28. Individuals were rated by social ability subtest assigned 0 to 40. Individuals were rated by sensory/cognitive consciousness subtest assigned 0 to 36. Individuals were rated by a health/body/behavioral sub-test assigned 0 to 75. The individual subsets are summed and the individual may get a maximum score of 180 points.

In some embodiments, after the treatment, the patient experiences a reduction in symptoms associated with ASD, characterized by a reduced average 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 reduced speech/language communication subtest assessment compared to before the treatment. In some embodiments, after the treatment, the patient experiences an improvement in social ability characterized by a reduced social ability 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 reduced sensory/cognitive awareness subtest assessment compared to before the treatment. In some embodiments, after the treatment, the patient experiences an improvement in health/body/behavior characterized by a reduced health/body/behavior assessment compared to before the treatment.

In some embodiments, the patient exhibits a decrease in the social capacity partition of ATEC by at least 1 minute, or about 2 minutes, or about 3 minutes, or about 4 minutes, or about 5 minutes, or about 6 minutes, or about 7 minutes, or about 8 minutes, or about 9 minutes, or about 10 minutes, or about 11 minutes, or about 12 minutes, or about 13 minutes, or about 14 minutes, or about 15 minutes, or about 16 minutes, or about 17 minutes, or about 18 minutes, or about 19 minutes, or about 20 minutes, as compared to prior to the treatment. In some embodiments, the patient exhibits a decrease in social capacity partition of ATEC by at least 1 point compared to before the treatment.

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 in the social capacity partition of ATEC compared to prior to said treatment. In some embodiments, the patient exhibits at least a 10% decrease in social capacity partition of ATEC compared to prior to the treatment.

The reduction of symptoms associated with ASD after administration of a therapeutically effective amount of a triptan to a patient in need thereof is measured using a goal/performance-based assessment. In some embodiments, the objective/performance-based assessment is selected from eye gaze tracking (eye tracking) of social stimuli, parental participation assessment questionnaires (JERI), and Noldus Ethovision analysis. In some embodiments, eye gaze tracking of social stimuli is utilized to characterize the reduction of ASD-related symptoms provided by the methods of the present disclosure. Patients with ASD exhibit significantly shorter fixation duration (eye contact) to the eyes than the same age without ASD. The more difficult it is to locate and process relevant social information for a patient with an ASD, the faster the stimulus will be presented.

PCIT provides a training method that aims to help adults improve their nurturing and linguistic skills, and to help children learn how to better control emotion. In some embodiments, parent-child interaction tasks (PCIT) are utilized to improve the relationship between caregivers and patients with ASD. In some embodiments, PCIT helps reduce child behavior problems and improve communication and interactive skills within the home. In some embodiments, children participating in CPT develop greater self-esteem, experience less anger and depression, see improvements in social, organizational, and play skills, feel safer and calmer, and communicate more effectively.

The joint participation ranking questionnaire (Joint Engagement Ranking Inventory, JERI) is a tool for measuring early intervention targets for developmental disorders and retardation, such as ASD. JERI is the development of 18-item questionnaires for measuring related intervention objectives such as no participation, objective participation, co-participation, inscription, restriction and repetition, attention to careers, onset of communication, expressive language level and use, disfigurement, follow-up, career influence, fluency and communication, and shared practices and ceremonies. Individuals rated on the JERI scale receive 1 to 7 points on each item in the JERI questionnaire. A score of 7 is assigned to the individual with the most common participation. A score of 1 for an item is assigned to individuals who do not have a common participation event. The lower JERI scale correlates to ASD.

In some embodiments, the reduction in ASD symptoms is associated with a reduction in score in JERI as compared to prior to treatment by the methods of the present disclosure. In some embodiments, after the treatment, the patient experiences a reduction in symptoms associated with ASD, characterized by a reduced JERI score compared to before the 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% as compared to before treatment.

The ohio state university autism rating scale (Ohio State University Autism Rating Scale) (OARS-5) measures persistent barriers to social interactions, restricted interests/activities and behavioral repetition and support levels from society, schools and communities (holway, j.a., arnold, l.e., and Aman, m.g. (9 months 2017), OSU Autism Rating Scale-DSM-5 (OARS-5). OARS-5 was developed to provide three types of aggregate scores: (A) Autism symptom count (OARS-5 total score) based on clinical interview; (b) Weighted average severity score from clinical interviews based on severity of autism symptoms; and (c) an obstacle index ranging from 0 to 9 based on the level of support required due to severity. The total score of OARS-5 is equal to the score of the OARS-5 social defect score+the score of the OARS-5 limited interest pattern score.

OARS-5 included the following component scale:

part A: persistent barriers to social interaction across multiple environments (OARS-5 social deficit component score);

part B: restricted interest/activity and repetitive behavior patterns (OARS-5 restricted interest pattern score)

Part C: support levels for part a (social interactions/communications) and part B (restricted and repetitive behaviors).

In some embodiments, after the treatment, the patient experiences a reduction in symptoms associated with ASD, characterized by a reduction in total fraction of oar-5 compared to before the treatment. In some embodiments, after the treatment, the patient experiences a reduction in symptoms associated with ASD, characterized by a reduction in total score of oar-5 of about 1 minute, about 2 minutes, about 3 minutes, or about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, or about 10 minutes, as compared to before the treatment.

In some embodiments, after the treatment, the patient experiences a reduction in symptoms associated with ASD, characterized by a reduced score for the oar-5 social deficit 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 reduction in the number of components of the social deficit in oar-5 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, as compared to before the treatment.

In some embodiments, after the treatment, the patient experiences a reduction in symptoms associated with ASD characterized by a reduction in the total score of ohio university autism clinical overall impression (OSU autism CGI) 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 + OSU autism CGI-improvement scale (OSU autism CGI-I) score.

In some embodiments, after the treatment, the patient experiences a reduction in symptoms associated with ASD, characterized by a reduction in the total OSU autism CGI score of about 1 minute, about 2 minutes, about 3 minutes, or about 4 minutes, about 5 minutes, about 6 minutes, or about 7 minutes as compared to before the treatment.

In some embodiments, after the treatment, the patient experiences a reduction in symptoms associated with ASD characterized by a reduction in the ohio state university autism clinical global impression-improvement scale (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 reduction in OSU autism CGI-I of about 1 minute, about 2 minutes, about 3 minutes, or about 4 minutes, about 5 minutes, about 6 minutes, or about 7 minutes as compared to before the treatment.

In some embodiments, after the treatment, the patient experiences a reduction in symptoms associated with ASD characterized by a reduction 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 experiences a reduction in symptoms associated with ASD, characterized by a reduction in OSU autism CGI-S of about 1 minute, about 2 minutes, about 3 minutes, or about 4 minutes, about 5 minutes, about 6 minutes, or about 7 minutes as compared to before the treatment.

Patient population

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

In embodiments, the patient is an adolescent or adult suffering from Autism Spectrum Disorder (ASD). In embodiments, the patient is at least 12 years old. In embodiments, the patient is 12-45 years old.

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

In some embodiments, prior to treatment according to the methods of the present disclosure, an ASD patient in need thereof has a simple Welch intellectual Meter (Weschsler Abbreviated Scale of Intelligence) of > 70 -full-scale table IQ score of II. />

In some embodiments, the present disclosure provides methods of treating existing ASD-treatment refractory ASD-related symptoms. In some embodiments, the symptom associated with ASD is refractory to treatment with aripiprazole. In some embodiments, the symptom associated with ASD is refractory to treatment with risperidone.

In some embodiments, the ASD patient treated exhibits atypical sensory processing. Sensory processing refers to the ability to record, process and organize sensory information and respond appropriately to environmental demands, which is manifested as hypersensitivity or hyposensitivity to stimuli. Patients in need of atypical sensory treatments may be aversive to the color, taste, smell and/or texture of foods or drugs. In some embodiments, the atypical sensory treatment appears to be non-compliant with dosing in a patient in need thereof. In some embodiments, the ASD patient treated refuses to swallow the drug. In some embodiments, the medicament is a liquid formulation or a pill.

In some embodiments, the ASD patient treated is an infant. In some embodiments, the ASD patient treated is a child. In some embodiments, the ASD patient treated is adolescent. In some embodiments, the ASD patient treated is an adult. In some embodiments, the ASD patient treated is an elderly patient.

Examples

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

Example 1 simulation of the administration of zolmitriptan

Steady state simulations of zolmitriptan human plasma concentration time data with various dosing regimens were performed using non-parametric overlap. Non-parametric overlapping pharmacokinetic profiles were derived from median plasma zolmitriptan concentrations after a single oral 2.5mg dose to male healthy volunteers, described in Seaber et al The absolute bioavailability and effect of food on the pharmacokinetics of zolmitriptan in healthy volumers, br J Clin pharmacol 1998, month 11; 46 433-9 (Seaber). Analysis of steady state analog concentration-time data using non-compartmental method to determine C _max,ss And AUC _0-24h,ss . Pharmacokinetic parameters and non-parametric overlap were calculated using version Phoenix WinNonlin 8.1.1 (Certara Corp., prins Stoken, N.J.).

The non-parametric overlap method is used to predict drug concentration after multiple dosing at steady state and is based on non-compartmental results describing single dose data. The prediction is based on a cumulative ratio derived from the terminal elimination rate constant. The basic assumption of non-parametric overlap of drugs is that the average systemic clearance is constant, the rate and extent of absorption is the same for each dose, linear pharmacokinetics apply and the pharmacokinetics of the drug after a single dose does not change after subsequent doses.

The human pharmacokinetic profile of zolmitriptan was derived from the median plasma concentrations reported after a single oral 2.5mg dose to male healthy volunteers (Seaber, 1998).

^a : from Seaber,1998

C _max : maximum observed concentration

T _max : time of maximum concentration

AUC _Finally : area under the concentration-time curve from time zero to time at which the concentration was last measurable

AUC _inf : area under concentration-time curve from time zero to infinity

T _1/2 : terminal half-life

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

Table 1.

QD: once a day dosage

BID: twice daily dose (12 hours apart)

TID: three times a day (8 hours apart)

AUC _0-24h,ss : area under concentration-time curve at steady state from time zero to 24 hours

C _max,ss : maximum concentration observed at steady state

Example 2 in vivo evaluation of zolmitriptan in a aggressive mouse model

Rodent occupant-intruder assays (RI) have been used to monitor aggressive behavior related to patterns of behavior exhibited when establishing and safeguarding grounds (Miczek et al, 1984). Accordingly, RI assays have been used preclinically to study the effect of drugs on rodent challenge (Miczek et al, 2001). RI determination typically relies on interpretation and scoring of offensive (living animal) behavioral patterns, and may also include analysis of defensive (invading animal) behavioral patterns.

The effect of zolmitriptan (10 mg/kg) on CD-1 mouse aggression was evaluated using a rodent RI assay using the CD-1-C57BL/6 combination. Risperidone (0.3 mg/kg) was used as a comparative compound. As a crossover design, attack time was measured over a 5min period.

Zolmitriptan administered at 3 and 10mg/kg (i.p.) produced Cmax values of 5.40ng/mL and 34.42ng/mL, respectively, in CSF of adult male CD-1 mice. N-desmethylzolmitriptan ("NDMZ", which is the major metabolite of zolmitriptan found in humans), was below the lower limit of quantitation in male CD-1 mice dosed at 3 and 10mg/kg (i.p.).

Results: as shown in FIG. 1 (and Table 2 below), CD-1 mice administered 10mg/kg of zolmitriptan showed a greater decrease in challenge time(s) compared to risperidone (0.03 mg/kg) and vehicle control.

Table 2.

Treatment of	N	Attack time(s)	SEM	Attack latency(s)	SEM
						Vehicle body	25	32.65	4.219	4.705	1.524
Risperidone 0.03mg/kg	25	21.58 ^*	3.123	12.98	4.18
						Zolmitriptan 10mg/kg	25	18.46 ^***	3.028	13.54	5.520

Example 3 in vivo evaluation of zolmitriptan in a mouse model of ASD

The role of zolmitriptan in a mouse model of valproic acid induced autism spectrum disorder was studied (Nicolin C et al, 2018exp. Neurol.,2018,217-227; bey A.L. And Jiang J.H, current Protocols in Pharmacology, 9, 01, 66:5.66.1-26). Specifically, social ability was previously assessed in male c57/Bl6 mice exposed to valproic acid (VPA) via intraperitoneal delivery of 500mg/kg to their pregnant mothers on embryo day 13.

In this study, zolmitriptan was dissolved in a physiological saline solution of 10% (2-hydroxypropyl) - β -cyclodextrin and administered intraperitoneally (i.p.). Mice were placed in the test chamber 15 minutes ago. Behavioral recordings were measured using an automated video tracking system (Noldus EthoVision v 14) and analyzed and plotted using GraphPad Prism software v 8. Social ability was assessed in a 3-room social interaction assay over a period of 10 min. The social ability score of each mouse was calculated using the time (seconds) spent in the Social Interaction Zone (SIZ) in front of the young new C57/BL6 compared to the Empty Interaction Zone (EIZ). Social ability index was calculated using the SIZ/EIZ ratio. Social interaction preferences were calculated using (SIZ)/(siz+ EIZ) 100. Simultaneous recording of up to 4 arenas was done for the social interaction assay. Paired and unpaired T-tests were used as statistical tests.

Zolmitriptan administered at 10mg/kg (i.p.) produced a Cmax value of 17.83ng/ml (15 min after administration) in CSF of adult male c57/Bl6 mice (i.e., tg2576 background strain and strain for VPA treatment). NDMZ was below the lower limit of quantitation in CSF of male c57/Bl6 mice dosed at 10mg/kg (i.p.).

As shown in fig. 2, zolmitriptan administered at 10mg/kg (i.p.) increased social ability index in adult male c57/Bl6 mice previously exposed to valproic acid (VPA). The improvement in social ability of zolmitriptan treated mice compared to vehicle treated groups was statistically significant.

Example 4 clinical trials

Safety, tolerability and pharmacokinetic response of oral zolmitriptan after multiple escalating doses were studied in adult healthy volunteer subjects.

Zolmitriptan 2.5 mg/tablet or placebo tablet is administered 3 times daily (TID) for a gradual up-regulation period, a 7 day treatment period and a gradual down-regulation period. The dosage regimen is depicted in table 3.

TABLE 3 Table 3

Lumbar puncture was performed on each subject to determine the concentration of zolmitriptan in CSF. CSF samples were collected on treatment day 5 of cohort 1, and on treatment day 7 of cohorts 2 and 3, and on treatment day 8 of cohorts 4 and 5. CSF was collected 2 hours (+/-30 minutes) after the morning dose. CSF concentration was measured using validated bioanalytical methods.

Results: as shown in fig. 3, CSF levels measured in humans were present at a ratio of zolmitriptan to ndmz=1.0:0.75. Overall, zolmitriptan was safe and well tolerated in all queues.

EXAMPLE 5 dose Studies

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

Specifically, 5-HT1b receptor occupancy and efficacy models measure the efficacy of zolmitriptan and NMDZ at the 5-HT1b receptor and the ratio of zolmitriptan to NDMZ in human CSF. The level of activation (i.e., efficacy) of 5-HT1b by both zolmitriptan and NDMZ is predicted based on the concentration of zolmitriptan in CSF using a 5-HT1b receptor efficacy model. The range required to achieve effective CSF exposure in humans was calculated from this target zolmitriptan dose.

35S-GTPγS binding assay

In this study, an in vitro binding assay was performed to measure the affinity of zolmitriptan and its active metabolite NDMZ for rat and human 5-HT1B receptors.

Zolmitriptan was tested in duplicate at ten concentrations in SPA-based 35S-GTPγS binding assays in cells expressing the human 5-HT1b (h 5-HT1 b) receptor or the rat recombinant 5-HT1b (r 5-HT1 b) receptor. EC50 values are shown in table 4.

TABLE 4 functional assay

Triptan medicine	h5-HT1b EC50(nM)	r5-HT1b EC50(nM)
			Zolmitriptan	4	33

Zolmitriptan exhibits lower apparent affinity (i.e., EC 50) at the rat 5-HT1b receptor than the human 5-HT1b receptor. In the case of zolmitriptan, the difference between species is 8.3 times.

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

Based on this data, the CSF level required for zolmitriptan to provide therapeutic effect in humans was about 8.3 times lower than that required to provide similar activity in mice.

Assuming that CSF values reflect the free concentration of drug in the brain, the estimated effective Cmax CSF values can be expressed as:

CD-1 (mouse challenge model, example 2); 3mg/Kg (i.p.); CSF cmax=18.8 nM or EC36 (36% activity in GTPgS).

c57/Bl6 (ASD mouse model, example 3); 10mg/Kg (i.p.); CSF cmax=62 nm ec65 (65% activity in GTPgS).

Radioligand binding competition assay

The affinity of zolmitriptan and NDMZ (an active metabolite of zolmitriptan in humans) for human 5-HT1B receptors was evaluated in duplicate at ten concentrations using a radioligand binding competition assay with 3H-5-CT and recombinant human 5-HT1B receptors. The affinities of the test compounds for the h5-HT1b receptor are shown in Table 5. Ki values were derived from IC50 values using the Cheng-Prusoff equation.

TABLE 5 binding assay

Test compounds	Ki(nM)
		Zolmitriptan	3.34
NDMZ	1.18

5-HT1b receptor occupancy and efficacy model

Using classical receptor theory, the following relationship can be used to predict receptor occupancy when two ligands (i.e., entities) are considered:

when considering the fixed concentrations of both a and B, the total occupancy% = (occupancy% of a) + { [100% - (occupancy% of a) ] x (occupancy% of B) }.

Whereas the ratio of zolmitriptan to NDMZ in human was 1.0:0.75 in human CSF (fig. 3) and NDMZ was 2.83 times more potent than zolmitriptan, a 5-HT1b occupancy model was constructed using the above total% occupancy formula as the basis. By using both zolmitriptan and NDMZ as by Clark equation { efficacy= [ L ]/([ L ] +ki); efficacy predicted [ L ] = ligand concentration } substitution occupancy the model was converted to predict the level of activation of 5-HT1b (i.e., efficacy) by both zolmitriptan and NDMZ based on the concentration of zolmitriptan in CSF:

total% = { [ zolmitriptan ]/([ zolmitriptan ] +ki, Z) } + with respect to the total efficacy

(100- { [ zolmitriptan ]/([ zolmitriptan ] +ki, Z) } x { [ NDMZ ]/([ NDMZ ] +ki, N) }

Using the EC50 value of zolmitriptan measured in the GTPgS assay, the affinity of NMDZ 2.83 times that of human 5-HT1b receptor, and the measured relationship of zolmitriptan: ndmz=1.0:0.75, the total% efficacy of a series of zolmitriptan concentrations was calculated and the resulting predicted total% efficacy was fitted with a logistic equation:

total efficacy% = 100/(1+10 ((LogEC 50- [ zolmitriptan ]))) and Log EC50 is calculated as-8.963. The concentration of zolmitriptan in human CSF (i.e., EC 50) predicted to induce 50% efficacy of 5-HT1b by zolmitriptan and NDMZ was 1.09nM or 0.31ng/ml.

Due to the combined action of potent metabolites, the concentration of zolmitriptan required to achieve 50% of the total potency is 3.7 times the EC50 of zolmitriptan.

Dose range of zolmitriptan human the dose required to reach the predicted effective CSF concentration range in humans appears within the 5-HT1b activity range shown in table 6.

Table 6.

Activity(s)	Zolmitriptan [ CSF ]]	Zolmitriptan human dose (mg)
			EC20-EC80	0.078-1.24ng/ml	1.25-35
EC25-EC75	0.103-0.93ng/ml	1.7-30
			EC30-EC70	0.135-0.713ng/ml	2.25-20
EC35-EC65	0.167-0.577ng/ml	3-15
			EC40-EC60	0.207-0.465ng/ml	5-12.5

EXAMPLE 6 manufacture of zolmitriptan tablets

Jet milling the zolmitriptan drug substance to produce a micronized drug substance dry powder.

Compounding of the normal release layer blend: the micronized zolmitriptan and excipients disclosed in the table below were weighed and sieved for blending. Micronizing zolmitriptan, anhydrous lactose (such asH) Microcrystalline cellulose (such as +.>PH 102), sodium starch glycolate (such as Explotab), colloidal silicon dioxide (such as +.>M5P) and magnesium stearate (such asVegetable Source) is mixed and blended in a diffusion blender. The blend was discharged and stored at room temperature in polyethylene bags in HDPE drums for subsequent tabletting operations.

Compounding of the delayed release layer blend: micronizing zolmitriptan, polyethylene oxide (such as Polyox) ^TM WSR-303 LEO) and other excipients disclosed in the table below were weighed and sieved for blending. Micronizing zolmitriptan, polyethylene oxide (such as Polyox) ^TM WSR-303 LEO), microcrystalline cellulose (such as Ceollus ^TM KG-802) and magnesium stearate (such asVegetable Source) is mixed and blended in a diffusion blender. The blend was discharged and stored at room temperature in polyethylene bags in HDPE drums for subsequent tabletting operations.

Tabletting: the ER layer blend and the IR layer blend were compressed using a bilayer tablet press to manufacture tablets.

TABLE 7 Zollatriptan 3mg IR/9mg ER oral tablet

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TABLE 8 zolmitriptan 6mg IR/18mg ER oral tablet

EXAMPLE 7 dissolution measurement

The dissolution test was performed as described in table 9 and evaluated using the Pion Rainbow dissolution monitoring system. Pion is set to collect spectra for quantification every 5 minutes during the first hour and then every 20 minutes during the next 17 hours.

TABLE 9 dissolution test conditions

Fig. 4 provides a comparison of dissolution profiles of 15mg zolmitriptan extended release tablet and 25mg zolmitriptan constant release/extended release oral bilayer tablet (10 mg IR zolmitriptan/15 mg ER zolmitriptan). As shown in fig. 4, almost complete zolmitriptan release from the IR layer was observed through the 5 minute time point. The zolmitriptan release remaining in the ER layer of the bilayer tablet matches the profile of the ER layer-only tablet.

The dissolution profile of 12mg (3 mg IR/9mg ER) and 24mg (6 mg IR/18mg ER) of zolmitriptan IR/ER oral bilayer tablet described in example 6 is shown in FIG. 5.

Example 8 simulated pharmacokinetics of zolmitriptan IR/ER oral bilayer tablet under fasted and fed conditions

Physiological-based pharmacokinetic (PBPK) modeling and simulation was applied to facilitate development of zolmitriptan bilayer tablet formulations (combination of constant release (IR) and delayed release (ER) gastric retentive components). PK profiles of 12mg (3 mg IR/9mg ER) and 24mg (6 mg IR/18mg ER) tablets of zolmitriptan after once daily (QD) oral administration were predicted using the refined PBPK GP 9.7 model and in vitro dissolution data (USP apparatus 2, 50RPM,900mL 01N HCl) as inputs. Gastric Retention Times (GRT) were 2 hours and 8 hours for fasted and fed light meal and fed heavy meal conditions, respectively. The predictions for the different meal conditions are compared in table 10 below.

Table 10 predicted pharmacokinetics of zolmitriptan 12mg (3 mg IR/9mg ER) and 24mg (6 mg IR/18mg ER) oral tablets under fasted and fed conditions.

Example 9 open label cross-over relative bioavailability pharmacokinetic Studies

This study was an open-label cross-over relative bioavailability pharmacokinetic study that evaluated the zolmitriptan bilayer sustained/delayed release gastric retention 24mg oral tablet formulation described in example 6 (6 mg sustained/18 mg delayed release) under fasted and fed conditions in a total of 12 healthy adult volunteer subjects. All subjects were resident at the study site until discharge on day 6 and telephone follow-up on days 11 and 18. The dosing regimen included:

Day 1: in the morning under fasted conditions, zolmitriptan is constantly released at 20mg

Day 2: in the morning under fasted conditions, zolmitriptan double-layer constant/delayed release gastric stasis 24mg oral tablet (6 mg IR/18mg ER)

Day 4: in the morning under fed conditions, zolmitriptan double-layer constant/delayed release gastric stasis 24mg oral tablet (6 mg IR/18mg ER)

All subjects completed the study and no subjects discontinued study treatment due to adverse events.

Table 11 presents a summary of the preliminary pharmacokinetic parameters of 12 study subjects, with zolmitriptan being administered on day 1 in a fasted state, zolmitriptan bilayer tablet on day 2-24 mg in a fasted state, and zolmitriptan bilayer sustained/delayed release gastric retention 24mg oral tablet on day 4-in a fed state.

Table 11: summary of pharmacokinetics data study

The plasma concentrations of zolmitriptan are summarized in table 12.

Table 12: plasma concentration after 24mg zolmitriptan bilayer tablet administration

TABLE 13.24 study of blood serotonin level in Zymatriptan bilayer tablet

Example 10 multicenter, randomized, double-blind, placebo-controlled study

This study was a phase 2, multicentric, randomized, double blind, placebo-controlled study that will recruit approximately 150 adolescent and adult subjects with ASD. The main objective of the study will be to evaluate the efficacy of the zolmitriptan bilayer sustained release (IR)/delayed release (ER, gastric retention) oral tablet formulation compared to placebo in treating social communication deficits reported by nursing/learning partners in patients with ASD. Subjects were randomized to study treatment at a 1:1 ratio of zolmitriptan bilayer sustained release (IR)/delayed release (ER, gastric retention) oral tablet formulation to placebo.

Dose/administration: the zolmitriptan bilayer sustained release (IR)/delayed release (ER, gastroretentive) oral tablet formulation was orally taken with food once daily in the morning and provided as a tablet at two dosage strengths of 12mg (3 mg IR/9mg ER) and 24mg tablet (6 mg IR/18mg ER). The dose level for this study was 12mg (provided as one 12 mg).

The study design is shown in fig. 6. Treatment will begin with once daily dosing of zolmitriptan bi-layer constant release (IR)/delayed release (ER, gastric retention) oral tablet formulation or placebo for 2 weeks followed by a stepwise dosing phase of 9-12 days until the maximum allowable tolerated dose (based on subject body weight) is reached. For example, dose escalation will occur every 3 days as follows: 12mg (initial dose), 24mg, 48mg, 72mg, or matched placebo to achieve the target dose (no more than) 48mg (if weight is screened.ltoreq.55 kg or if the female is taking oral contraceptives) or 72mg (if weight is screened >55kg and the female is not taking oral contraceptives). If an ascending dose cannot be tolerated, if the dose is 24mg or 48mg, the subject may be reduced to the last tolerated dose.

The maximum dose tolerated during the stepwise adjustment of the dose will become the Maintenance Dose (MD) for that subject, and the subject will hold that dose for 12 weeks, then stepwise down-regulate. The independent DSMC will monitor the progress of the test and ensure that the safety of the test subjects is not compromised.

The zolmitriptan bilayer sustained release (IR)/delayed release (ER, gastric retention) oral tablet formulation was orally taken once daily for up to 16 weeks and provided as a tablet at two dose strengths of 12mg (3 mg IR/9mg ER) and 24mg tablet (6 mg IR/18mg ER). The dose levels for this study were 12mg (provided as one 12mg tablet), 24mg (one 24mg tablet), 48mg (two 24mg tablets) and 72mg (three 24mg tablets).

Primary outcome measure:

autism behavior questionnaire (ABI) -change from baseline in social communication domain score [ time frame: baseline up to day 110

Changes in ABI-social communication area scores from baseline will be reported. ABI is a 62-item questionnaire for reporting the behavior of subjects diagnosed with ASD (age: 3 years-adult). The tool is suitable for being done by a parent or care/learning partner of a person suffering from an ASD. Each item evaluates the quality (from no help at all to no help) or frequency (less often) of a particular action. The social communication domain score is the sum of the scores in the social communication domain divided by the number of items in the domain.

Secondary outcome measure:

the clinician generally improves the change from baseline in the impression (CGI-I) [ time frame: day 110 ]

The CGI-I score is a single item tool based on the 7-score scale routinely used in clinical trials to capture the overall impression of the response by the investigator. The observed improvement was rated from 1 (very large improvement) to 7 (very poor) by the investigator or the designated personnel.

Changes from baseline in autism behavior questionnaire-clinician (ABI-C) scores [ time range: baseline up to day 110

Abnormal behavior checklist changes from baseline in 2-irritability (ABC-I) component table scores [ time frame: baseline up to day 110

ABC is a behavioral assessment of a parent or care/learning partner report, with five fields and 58 projects, each of which is rated on a scale of 0 (no question) to 3 (the question is severe). The field of irritability consists of 15 items.

Changes from baseline in clinician global impression-severity (CGI-S) score [ time frame: baseline up to day 110

CGI-S is an overall assessment of the impression of the severity of a clinician 'S assessor of a participant' S illness. It was rated on a scale of 1 (normal, no disease at all) to 7 (most severely diseased).

Changes from baseline in ABI repeat/limit behavioural domain scores [ time frame: baseline up to day 110

Changes from baseline in ABI mood and anxiety domain scores [ time frame: baseline up to day 110

Each item in the ABI-mood and anxiety areas was rated on a frequent basis (0=less than 3=very frequent). The domain score is the sum of all domain item scores divided by the number of items in the domain.

Changes from baseline in ABI challenge behavioral field scores [ time frame: baseline up to day 110

Changes from baseline in ABI self-regulatory domain scores [ time range: baseline up to day 110

Every item in the ABI self-regulating domain is rated by frequency (0=less than 3=very frequent). The domain score is the sum of all domain item scores divided by the number of items in the domain.

Changes from baseline in ABI-short form (ABI-S) scores [ time range: baseline up to day 110

Changes from baseline in ABC-social withdrawal (ABC-SW) component table scores [ time range: baseline up to day 110

Changes from baseline in social response table 2 (SRS-2) score [ time horizon: baseline up to day 110

SRS-2 consists of 65 items across 5 component tables. The reaction ranges from 1 (incorrect) to 4 (almost always correct).

Wen Lan-3 (domain level version) score: changes from baseline in the sum of communication, socialization, and maladaptive behavioral areas [ time frame: baseline up to day 110

Qualification criteria

12 to 45 years (children, adults)

Inclusion criteria:

12 to 45 years of screening

Body Mass Index (BMI) 18 to 34kg/m2, including end point values

With a specified care/learning partner, symptoms can be reported reliably

Diagnosis of Autism Spectrum Disorder (ASD) is carried out according to american society for psychiatry (American Psychiatric Association) (APA 2013) diagnosis and statistics manual (Diagnostic and Statistical Manual) 5 th edition (DSM-5) and/or World Health Organization (WHO) international disease classification external 10th Revision (World Health Organization (WHO) International Classification of Diseases External th Revision) 2 nd edition (ICD-10, WHO 2004), and has been confirmed by autism diagnosis observation scale (Autism Diagnostic Observation Scale) (ADOS, lord 1999; or ADOS-2, lord 2012) or autism diagnosis interview Revision (Autism Diagnostic Interview-Revised) (ADI-R, lord 1994) obtained in the previous 3 years or ADOS-2 performed at screening. The total IQ (or equivalent) is more than or equal to 70 minutes.

Abnormal behavior check table 2-social withdrawal (ABC-SW) component table score at screening is not less than 11.

The psychoactive drugs and adjuvant therapy were stable 4 weeks before screening.

It is necessary to be able to swallow the study drug.

Sexually active male and female subjects with fertility potential must practice effective contraception 30 days from screening time to their final dose of study drug. Effective contraception is the use of 2 contraceptive methods, defined as the use of condoms (male and/or female types), hormonal contraception (female) or intrauterine devices (IUDs). This is not applicable to subjects who are surgically sterilized by bilateral tubal ligation, bilateral ovariectomy or hysterectomy; or subjects practicing abstinence as study subjects in the present study; or subjects in a homosexual relationship.

Exclusion criteria:

with Leider syndrome or childhood disintegration disorder (Child Disintegrative Disorder)

Any additional study was enrolled and any additional study drug (except for covd-19 vaccination) or device was received within 60 days prior to screening

There is currently no history of adequately controlled seizures, or screening for any seizures within the first 6 months

A history of suicidal ideation or behavior over the past 12 months, or positive responses to C-SSRS questions 4 and/or 5

Systolic pressure of 160mmHg or greater than 100, or diastolic pressure of 100, or a clinical history of uncontrolled or severe hypertension

If female, pregnant or lactating

Within 2 weeks (or 5 half-lives, whichever is longer) of a single blind baseline (visit 2), any of the following were taken:

selective Serotonin Reuptake Inhibitors (SSRI)

Serotonin-norepinephrine reuptake inhibitors (SNRI)

Tricyclic antidepressants (TCA)

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 ergotamine-type drug (e.g., dihydroergotamine or Mexicergot), including St John's wort

Cimetidine was being administered and was not discontinued during screening and at the end of the study

With diagnosis or clinical history of coronary artery disease, coronary vasospasm, prins et al's angina, wolff-Parkinson-White syndrome, peripheral vascular disease, stroke, transient ischemic attacks, ischemic bowel disease or other important heart or cerebral vascular disease 3

Diagnostic or clinical history indicates migraine with or without aura, including basal migraine and/or hemiplegic migraine

There was a history of galactose intolerance (i.e., lapp lactase deficiency or glucose-galactose malabsorption)

Any additional study was administered within 60 days prior to screening and any additional study drug (except covd-19 vaccination) or device was received, or no drug study was being considered by the participating investigator to interfere with the interpretation of the assessment of the study

A history of suicidal ideation or behavior in the past 12 months, or positive responses to C-SSRS questions 4 and/or 5 (current or last 6 months) at screening or single blind baseline (visit 2) evaluation, and/or a significant risk of suicidal behavior perceived by the investigator

Has a clinical history of screened or single blind baseline (visit 2) systolic blood pressure of 140mmHg (if adult) or >135mmHg (if adolescent), or diastolic blood pressure of 90mmHg (if adult) or >85mmHg (if adolescent), or uncontrolled or severe hypertension. For subjects with automatic or manual blood pressure in the milder abnormal range (SBP 140-15mmHg, DBP 90-99mmHg for adults; SBP 135-140mmHg, DBP 85-89mmHg for teenagers), the regimen does not require absolute exclusion, but the medical monitor (medical monitor) will need further data (according to guidelines) to accurately determine the subject's blood pressure status in order to determine eligibility. In these cases, if hypertension is excluded or the cause is identified and adequate treatment is available, the subject may be eligible to participate if the medical inspector has reviewed and granted permission to do so.

Clinically significant ECG abnormalities at screening or single blind baseline (visit 2) at the discretion of the investigator

With one of the following screening laboratory results: a. platelets less than or equal to 75,000/mm3

b. Neutrophils, absolute, less than or equal to 1000/mm3

c. Alanine Aminotransferase (ALT) or aspartate Aminotransferase (AST) 2 times the upper normal limit and/or total bilirubin 1 times the upper normal limit

d. Creatinine is not less than 2mg/dL and/or eGFR <60mL/min/1.73m2 (adult) or <75mL/min/1.73m2 (teenager)

e. Free thyroxine (T4) abnormality

The repetition of laboratory tests may be at the discretion of the medical inspector during screening.

There was a history of alcohol use or substance use disorder (according to the DSM-5 guidelines) within 12 months of screening, or drug abuse screening positive (unless consistent with current medical condition prescriptions) at the time of screening.

Screening positive of human immunodeficiency virus antibody, hepatitis B surface antigen or hepatitis C virus antibody

If female, pregnant or lactating

A diagnostic or clinical history consistent with schizophrenia, bipolar disorder or other medical or psychiatric conditions that researchers or medical inspectors consider to be at increased risk of safety/tolerability problems in subjects and/or to prevent voluntary consent from being obtained and/or to confuse interpretation of major outcome measures in the study

Study regimens (including inability to swallow study products) were unwilling or unable to adhere for any reason.

Significant visual, auditory or movement impairment can prevent participation in the completion of critical evaluations.

For any reason, it is judged by the researcher or medical inspector to be unsuitable for research.

Embodiments are described below:

1. an oral composition for treating symptoms of autism spectrum disorder or aggressiveness in alzheimer's disease patients, wherein the composition comprises about 7.5mg to about 90mg of zolmitriptan or a pharmaceutically acceptable salt thereof, and oral administration of the composition provides a therapeutically effective plasma concentration of zolmitriptan for a period of at least 8 hours.

An oral composition for treating aggressive symptoms in a patient suffering from dementia, wherein the composition comprises from about 7.5mg to about 90mg of zolmitriptan or a pharmaceutically acceptable salt thereof, and oral administration of the composition provides a therapeutically effective plasma concentration of zolmitriptan for a period of at least 8 hours.

2. The composition of claims 1-1a, wherein the composition comprises about 10mg to about 30mg zolmitriptan or a pharmaceutically acceptable salt thereof.

3. The composition of any one of claims 1-2, wherein the composition comprises an ordinary release portion and a delayed release portion.

4. The composition of claim 3, wherein the constant release fraction comprises about 20% -40% by weight of total zolmitriptan in the composition.

5. The composition according to any one of claims 3-4, wherein the extended release portion comprises about 60% -80% by weight of total zolmitriptan in the composition.

6. The composition of any one of claims 3-5, wherein the constant release fraction comprises about 25% of the total zolmitriptan in the composition and the extended release fraction comprises about 75% of the total zolmitriptan in the composition.

7. The composition of any one of claims 3-6, wherein the constant release fraction comprises about 1mg to about 10mg of zolmitriptan.

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

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

10. The composition of any one of claims 3-9, wherein the extended release portion comprises about 5mg to about 25mg of zolmitriptan.

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

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

13. The composition of any one of claims 1-12, wherein oral administration of the composition provides about 3ng/mL to about 30ng/mL of C after a single administration of the composition _max 。

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

15. The composition of any one of claims 1-14, wherein oral administration of the composition provides an AUC of about 40 ng-h/mL to about 300 ng-h/mL after a single administration of the composition _0-24h 。

16. The composition of any one of claims 1-15, wherein oral administration of 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 。

17. The composition of any one of claims 1-15, wherein oral administration of the composition provides an AUC of about 150 ng-h/mL to about 250 ng-h/mL after a single administration of the composition _0-24h 。

18. The composition of any one of claims 1-15, wherein oral administration of the composition provides an AUC of about 50 ng-h/mL to about 150 ng-h/mL after a single administration of the composition _0-24h 。

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

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

21. The composition of any one of claims 1-20, wherein oral administration of the composition provides a therapeutically effective plasma concentration of zolmitriptan for a period of about 24 hours after a single administration of the composition.

22. The composition of any one of claims 1-21, wherein the composition is a multiparticulate formulation.

23. The composition of claims 3-21, wherein the extended release portion comprises drug-containing particles coated with an extended release coating.

24. The composition of any one of claims 1-21, wherein the composition is a gastroretentive tablet.

25. The composition of any one of claims 3-21, wherein the time-release moiety is a gastric retentive layer.

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

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

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 methyl cellulose, carboxymethyl cellulose, and microcrystalline cellulose.

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

30. The composition of any one of claims 26-29, wherein the composition comprises about 35% -55% by weight polyethylene oxide.

31. The composition of any one of claims 24-30, wherein the composition remains gastric for at least 2 hours after oral administration.

32. The composition of any one of claims 24-31, wherein the composition remains gastric for at least 8 hours after oral administration.

33. An oral composition of zolmitriptan or a pharmaceutically acceptable salt thereof for use in the treatment of symptoms of autism spectrum disorders (or aggression in Alzheimer's patients), the oral composition providing a modified release profile,

wherein the composition exhibits an zolmitriptan release profile that substantially corresponds to the following pattern when tested for dissolution in 900mL of 0.1N HCl at 37 ℃ using usp apparatus II (paddle at 50 rpm):

about 20% -40% of the total zolmitriptan released after about 15 minutes;

about 40% -75% of total zolmitriptan released after 4 hours; and is also provided with

About 75% -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 over 9-10 hours.

35. The composition of any one of claims 33-34, wherein the composition comprises about 10mg to about 30mg of zolmitriptan or a pharmaceutically acceptable salt thereof.

36. The composition of any one of claims 33-35, wherein the composition comprises an ordinary release portion and a delayed release portion.

37. The composition of claim 36, wherein the constant release fraction comprises about 20% -40% by weight of total zolmitriptan in the composition.

38. The composition of any one of claims 36-37, wherein the extended release portion comprises about 60% -80% by weight of total zolmitriptan in the composition.

39. The composition of any one of claims 36-38, wherein the constant release fraction comprises about 1mg to about 10mg of zolmitriptan.

40. The composition of any one of claims 36-39, wherein the extended release portion comprises about 5mg to about 25mg of zolmitriptan.

41. The composition of any one of claims 33-40, wherein oral administration of the composition provides about 3ng/mL to about 30ng/mL of C after a single administration of the composition _max 。

42. The composition of any one of claims 33-40, wherein oral administration of the composition provides an AUC of about 40 ng-h/mL to about 300 ng-h/mL after a single administration of the composition _0-24h 。

43. The composition of any one of claims 33-42, wherein the composition is a gastroretentive tablet.

44. The composition of any one of claims 33-43, wherein the time-release moiety is a gastric retentive layer.

45. The composition according to claim 44, wherein the gastric retentive layer comprises a water swellable polymer.

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

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

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

49. The composition of any one of claims 46-48, wherein the composition comprises about 35% -55% by weight polyethylene oxide.

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

51. The composition of any one of claims 33-42, wherein the composition is a multiparticulate formulation.

52. The composition of claims 33-42, wherein the extended release portion comprises drug-containing particles coated with an extended release coating.

53. A composition for treating symptoms of autism spectrum disorder, wherein the composition comprises zolmitriptan or a pharmaceutically 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 To treat symptoms of autism spectrum disorder.

54. The composition of claim 53, wherein oral administration of the composition provides an AUC of about 40 ng-h/mL to about 110 ng-h/mL after a single administration of the composition _0-24h 。

55. The composition of claim 53, wherein oral administration of the composition provides an AUC of about 150 ng-h/mL to about 450 ng-h/mL after a single administration of the composition _0-24h,ss 。

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

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

58. A composition for treating aggression in a patient suffering from alzheimer's disease, wherein the composition comprises zolmitriptan or a pharmaceutically 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 To treat aggressiveness of the patient.

59. The composition of claim 58, wherein oral administration of the composition provides an AUC of about 40 ng-h/mL to about 110 ng-h/mL after a single administration of the composition _0-24h 。

60. The composition of claim 58, wherein oral administration of the composition provides an AUC of about 150 ng-h/mL to about 450 ng-h/mL after a single administration of the composition _0-24h,ss 。

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

62. A method of treating aggressiveness in a patient suffering from alzheimer's disease, said method comprising orally administering to a patient in need thereof a pharmaceutical composition of the composition of any of claims 1-56.

63. A composition for treating aggressiveness in a patient suffering from dementia, wherein the composition comprises zolmitriptan or a pharmaceutically 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 To treat aggressiveness of the patient.

64. The composition of claim 63, wherein oral administration of the composition provides an AUC of about 40 ng-h/mL to about 110 ng-h/mL after a single administration of the composition _0-24h 。

65. The composition of claim 63, wherein oral administration of the composition provides an AUC of about 150 ng-h/mL to about 450 ng-h/mL after a single administration of the composition _0-24h,ss 。

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

67. A method of treating aggressiveness in a patient suffering from dementia, the method comprising orally administering to a patient in need thereof a pharmaceutical composition of the composition of any one of claims 1-56.

Incorporated by reference

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

Claims

1. An oral composition for treating symptoms of autism spectrum disorder, wherein the composition comprises about 7.5mg to about 90mg of zolmitriptan or a pharmaceutically acceptable salt thereof, and oral administration of the composition provides a therapeutically effective plasma concentration of zolmitriptan for a period of at least 8 hours.

2. The composition of claim 1, wherein the composition comprises about 10mg to about 30mg zolmitriptan or a pharmaceutically acceptable salt thereof.

33. An oral composition of zolmitriptan or a pharmaceutically acceptable salt thereof for use in the treatment of symptoms of autism spectrum disorder, the oral composition providing a modified release profile,

about 20% -40% of the total zolmitriptan released after about 15 minutes;

About 75% -90% of the total zolmitriptan is released after 8 hours.

54. The composition of claim 53, wherein oral administration of the composition provides about 40 ng-h/mL to about 110 after a single administration of the compositionAUC of ng.h/mL _0-24h 。