Methods and products for treating subjects with autism spectrum disorders

Abstract

This invention relates to a method and product for treating individuals diagnosed with autism spectrum disorder, intellectual disability, anxiety disorder, mood disorder, social interaction disorder, irritability, aggression, self-harm, hyperactivity, attention deficit, fragile X syndrome, or neuroinflammation. It involves administering a tablet, liquid, or solid ODT, ODF, or SMEDDS containing ticagrelor or ticagrelor salt, or in combination with a second agent, of ticagrelor or ticagrelor salt. The second agent may include magnesium-containing compounds, zinc-containing compounds, lysine or lysine salts, arginine or arginine salts, lecithin, or combinations thereof. The ODT, ODF, or SMEDDS releases >50% of the ticagrelor or its pharmaceutically acceptable salt and >50% of the second agent within 15 minutes.

Description

[Technical Field]

[0001] This invention relates to methods and materials for treating individuals suffering from autism spectrum disorder and related disorders. [Previous Technology]

[0002] Autism or pan-autistic disorder (ASD) is a complex neurodevelopmental disorder characterized by persistent difficulties in social interaction and communication, as well as restricted interests and repetitive behaviors. ASD is usually diagnosed during the first three years of life and presents with characteristic symptoms or behavioral traits (core symptoms). The diagnosis of ASD now includes several conditions that were previously diagnosed separately: autism disorder, pervasive developmental disorder unclassified (PDD-NOS), and Asperger syndrome. All of these conditions are now covered within the diagnostic criteria for pan-autistic disorder as defined in the American Psychiatric Association's Diagnostic & Statistical Manual of Mental Disorders, Fifth Edition (DSM-V).

[0003] Autism can manifest as challenges in communication, behavior, and social interaction, ranging in severity from mild to severe. Because autism is a broad-spectrum disorder, two individuals with autism may exhibit very different behaviors, developmental levels, and health or support needs. Behaviors observed in children and adults with autism may include difficulty interacting with others or lack of interest in people, extreme sensitivity to certain sounds, smells, or lights, repetitive behavioral patterns, narrow obsessive interests, avoidance of eye contact, difficulty adapting to routine changes, and difficulty expressing their needs. Despite progress in early diagnosis and behavioral intervention, there are currently no FDA-approved medications specifically targeting the core symptoms of ASD (social communication deficits and strict adherence to routines and repetitive behaviors). The primary approaches to autism treatment are behavioral therapy and educational intervention. The pharmaceutical industry has repeatedly failed in developing effective treatments for autism, with a series of product failures in recent years, including oxytocin, arbaclofen, memantine, and mavoglurant. A clinical trial of balovaptan (RG7314), a breakthrough marker vasopressin 1a receptor antagonist, to improve social communication in autistic individuals was recently discontinued due to ineffectiveness.

[0004] Multiple studies have reported that abnormal immune function, including inflammation, cytokine dysregulation, and anti-brain autoantibodies, can significantly affect the development of pan-autism disorder. Some individuals may not show outward signs of infection but may actually have a subclinical (or asymptomatic) infection (Lintas et al. Association of autism with polyomavirus infection in postmortem brains. J Neurovirol. 2010 Mar;16(2):141-9).

[0005] There has been a long-standing but unmet demand for pharmaceutical products that treat autism spectrum disorder and the core symptoms of autism. [Summary of the Invention]

[0006] This invention includes products and methods for treating individuals suffering from autism spectrum disorder and related disorders who exhibit social interaction impairment, anxiety, irritability, aggression, temper tantrums, rapid mood swings, self-harming behavior (SIB), hyperactivity, and inattention. In some embodiments, this invention includes administering to an individual a combination of ticagrelor and a pharmaceutically acceptable salt thereof. Ticagrelor is also known as (1S,2S,3R,5S)-3-[7-[[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-1,2-cyclopentanediol]. This invention also includes enantiomers of ticagrelor or pharmaceutically acceptable salts thereof. For example, one enantiomer of ticagrelor is (1R,2R,3S,5R)-3-(7-(((1S,2R)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol. Unless otherwise stated, the term ticagrelor should be interpreted broadly to include its enantiomers.

[0007] In one embodiment, the present invention includes a method for treating an individual diagnosed with autism spectrum disorder, intellectual disability, epilepsy, anxiety disorder, mood disorder, social interaction disorder, irritability, aggression, self-harming behavior, hyperactivity, inattention, fragile X syndrome, or other neuroinflammatory disorders, by administering to the individual alone ticagrelor, its enantiomer, or a medically acceptable salt thereof, or in combination with a second agent at a weight ratio of 1:0.1 to 1:50.

[0008] In one embodiment, the present invention includes an orally disintegrating tablet (ODT) or orally dissolving film (ODF) containing ticagrelor, an enantiomer, or a pharmaceutically acceptable salt thereof, and a second dose. The ODT and ODF of the present invention are solid oral dosage forms. Those skilled in the art will readily recognize that ODT or ODF are different from other oral dosage forms (e.g., chewable tablets or tablets swallowed whole with liquid) and have different pharmaceutical properties, manufacturing techniques, and regulatory requirements. ODT and ODF have specific efficacy characteristics, including rapid oral disintegration in saliva, allowing ingestion of such products without chewing or drinking liquid.

[0009] In one embodiment, the present invention includes administering to an individual, in the form of an orally disintegrating tablet (ODT), a combination of ticagrelor, an enantiomer, or a pharmaceutically acceptable salt thereof, in combination with a second dose.

[0010] In one embodiment, the present invention includes administering to an individual, in the form of an oral dissolving film (ODF), a combination of ticagrelor, an enantiomer, or a pharmaceutically acceptable salt thereof, in combination with a second dose.

[0011] In one embodiment, the present invention includes administering ticagrelor, an enantiomer or a pharmaceutically acceptable salt thereof to an individual in the form of drops, for example from a microemulsion drug delivery system (SMEDDS), or in combination with a second dose of ticagrelor, an enantiomer or a pharmaceutically acceptable salt thereof.

[0012] In one embodiment, the invention comprises administering to an individual a combination of ticagrelor, an enantiomer, or a pharmaceutically acceptable salt thereof, and a magnesium salt. In another embodiment, the invention comprises administering to an individual a combination of ticagrelor, an enantiomer, or a pharmaceutically acceptable salt thereof, and a zinc salt.

[0013] In one embodiment, the present invention comprises administering to an individual a combination of ticagrelor, an enantiomer, or a pharmaceutically acceptable salt thereof, and lysine. In one embodiment, the present invention comprises administering to an individual a combination of ticagrelor, or a pharmaceutically acceptable salt thereof, and lecithin. In one embodiment, the present invention comprises administering to an individual a combination of ticagrelor, or a pharmaceutically acceptable salt thereof, and lysine and lecithin. In one embodiment, the present invention comprises administering to an individual a combination of ticagrelor, or a pharmaceutically acceptable salt thereof, and lysine and magnesium salt. In one embodiment, the present invention comprises administering to an individual a combination of ticagrelor, or a pharmaceutically acceptable salt thereof, and lysine and zinc salt. In one embodiment, the present invention comprises administering to an individual a combination of ticagrelor, or a pharmaceutically acceptable salt thereof, and an arginine-containing compound.

[0014] In one formulation, the weight of ticagrelor in the ODT, ODF, or SMEDDS of the present invention is less than the weight in conventional ticagrelor products, for example, less than 90 mg, less than 60 mg, less than 40 mg, less than 35 mg, less than 30 mg, or less than 10 mg. In one formulation, the weight of ticagrelor administered daily according to the method of the present invention is less than the weight of conventional ticagrelor therapy, for example, less than 90 mg / day, less than 60 mg / day, less than 40 mg / day, less than 30 mg / day, less than 20 mg / day, less than 10 mg / day, or less than 0.25-0.5 mg / kg body weight, and administered two to four times daily as needed. In some formulations, only one ODT, ODF, or SMEDDS of the present invention is administered daily.

[0015] In one embodiment, the present invention includes administering to an individual a combination of ticagrelor or a pharmaceutically acceptable salt thereof with another component, such as an acid chelated with magnesium or zinc, including but not limited to citric acid, ascorbic acid, threonic acid, tartaric acid, malic acid, fumaric acid, caprylic acid, gluconic acid, succinic acid, lactic acid, glyceric acid and / or α-hydroxy-carboxylic acid.

[0016] In one state, an individual has been diagnosed with autism spectrum disorder.

[0017] In one phenotype, the individual has intellectual disability, epilepsy, anxiety disorder, mood disorder, social interaction disorder, irritability, aggression, self-harming behavior, hyperactivity, and / or inattention. In another phenotype, the individual has fragile X syndrome.

[0018] In a sample, the individual is an infant, child or adolescent, in which case the amount of tegagra to be administered is calculated based on body weight, for example 0.01-3 mg / kg, once or three times daily.

[0019] In one case, an individual has been diagnosed with elevated plasma TNFα or inflammatory interferon as markers of neuroinflammation. Further features and characteristics of the subject matter of this invention, as well as the methods of operation, the function and combination of related structural elements, and the economics of manufacture, will become more apparent upon consideration of the following description and the appended claims, all of which form part of this specification.

[0020] In one embodiment, the present invention includes administering ticagrelor or a medically acceptable salt thereof to an individual suffering from autism spectrum disorder, intellectual disability, epilepsy, anxiety disorder, mood disorder, social interaction disorder, irritability, aggression, self-harming behavior, hyperactivity and / or inattention, fragile X syndrome, or diagnosed with elevated plasma TNFα or inflammatory interstitial hormones as markers of neuroinflammation.

[0021] In another formulation, ticagrelor and the second agent shall be contained in a self-microemulsifying delivery system (SMEDDS) to increase the water solubility and bioavailability of ticagrelor. For example, in some formulations, the ticagrelor formulation has a solubility at 25°C at at least twice that of ticagrelor in Brilinta® (a commercially available product).

[0022] The present invention addresses the need for improved ticagrelor formulations, particularly low-dose formulations that can rapidly and safely deliver ticagrelor to the brains of individuals with autism spectrum disorder and related disorders.

Implementation Method

[0024] Although the subject matter of the present invention may be implemented in many forms, the following description is only intended to disclose some of these forms as specific examples of the subject matter covered by the present invention. Therefore, the subject matter of the present invention is not intended to be limited to the forms or embodiments described herein.

[0025] Unless the context clearly specifies otherwise, the singular forms “a / an” and “the” include a plural of indicators.

[0026] As used herein and fully understood in this art, the term "treatment" means a means of obtaining a beneficial or desired outcome, including clinical outcomes. Beneficial or desired clinical outcomes may include, but are not limited to, relief or improvement of one or more symptoms or conditions, reduction of disease severity, stabilization (i.e., no worsening) of the disease state, delay or slowing of disease progression, improvement or mitigation of the disease state, reduction of disease relapse, and remission (whether partial or complete), whether detectable or undetectable. "Treatment" may also mean extended survival compared to expected survival without treatment. In addition to being used as a treatment method, the methods described herein may be applied to the prevention or treatment of disease.

[0027] Concentration, quantity, and other numerical data may be presented or expressed in range format herein. It should be understood that this range format is used only for convenience and brevity, and therefore should be interpreted flexibly to include not only the values ​​explicitly stated as the limits of the range, but also all individual values ​​or subranges covered within that range, as if each value and subrange were explicitly stated. For example, the numerical range "about 0.01 to 2.0" should be interpreted to include not only the explicitly stated values ​​of about 0.01 to about 2.0, but also the individual values ​​and subranges within the specified range. Thus, included in this numerical range are individual values ​​such as 0.5, 0.7, and 1.5, and subranges such as 0.5 to 1.7, 0.7 to 1.5, and 1.0 to 1.5, etc. Furthermore, this interpretation should apply regardless of the breadth of the range or the characteristics described. Additionally, it should be noted that unless otherwise specified, all percentages are by weight.

[0028] In understanding the scope of this invention, the terms "comprising" or "including" and their derivatives as used herein are intended to be open-ended terms specifying the presence of stated features, elements, components, groups, integers and / or steps but excluding the presence of other unstated features, elements, components, groups, integers and / or steps. The foregoing also applies to words with similar meanings, such as the terms "comprising," "having," and their derivatives. The term "comprising" and its derivatives as used herein are intended to be closed-ended terms specifying the presence of stated features, elements, components, groups, integers and / or steps but excluding the presence of other unstated features, elements, components, groups, integers and / or steps. The term "substantially composed of" as used herein is intended to specify the presence of stated features, elements, components, groups, integers and / or steps, as well as those that do not significantly affect one or more of the basic and novel features of the features, elements, components, groups, integers and / or steps. It should be understood that references to any of these transitional terms (i.e., "comprising," "consisting of," or "substantially constitute") provide direct support for replacing any of the other transitional terms not specifically used. For example, changing the term from "comprising" to "substantially constitutes" would be directly supported by this definition.

[0029] As used herein, the term "about" is used to provide flexibility for the endpoints of a numerical range by specifying that a given value may be "slightly above" or "slightly below" an endpoint. The degree of this flexibility may be determined by a particular variable and will be judged based on experience and the relevant descriptions herein, to the knowledge of those skilled in the art. For example, in one state, the degree of flexibility may be within about ±10% of the numerical value. In another state, the degree of flexibility may be within about ±5% of the numerical value. In yet another state, the degree of flexibility may be within about ±2%, ±1%, or ±0.05% of the numerical value.

[0030] Generally, the term "or" in this document includes "and / or".

[0031] As used herein, for convenience, multiple compounds, elements, or steps may be presented in a common list. However, such lists should be interpreted as if each member of the list were individually identified as a separate and unique member. Therefore, in the absence of any indication to the contrary, an individual member of this list should not be interpreted as substantially equivalent to any other member of the same list simply because of its presentation in the common group.

[0032] Furthermore, certain compositions, elements, excipients, ingredients, barriers, symptoms, properties, steps, or similar elements may be discussed in the context of a particular embodiment or pattern or in a separate paragraph or section of the invention. It should be understood that this is for convenience and brevity only, and any such disclosure is equally applicable to and intended to be combined with any other embodiment or pattern found anywhere in the invention and the claims, which form part of this application and the claimed invention at the filing date. For example, a list of method steps, active agents, kits, or compositions described in relation to ODT, ODF, or SMEDDS or a method of treating an individual is intended and indeed found to directly support embodiments relating to compositions, formulations, ODT, ODF, SMEDDS, and methods described in any other part of the invention, even if those method steps, active agents, kits, or compositions are not restated in the context or section of that embodiment or pattern.

[0033] The compositions of the present invention may be administered in any suitable dosage form and route of administration, including but not limited to oral, non-enteric (including subcutaneous, intramuscular, intravenous, transdermal, subepidermal, and intradermal), mucosal, by inhalation spray, topical, rectal, patch or micropatch, nasal, buccal, vaginal, or via implantable reservoir. In some embodiments, the provided compounds or compositions may be administered intravenously and / or intraperitoneally. Suitable dosage forms include, but are not limited to, liquid, gel, semi-liquid (e.g., liquid containing some solids, such as viscous liquids), semi-solid (solid containing some liquids), and / or solid forms. By way of example only, tablets, capsules, food forms, chewable forms, non-chewable forms, slow-release or sustained-release forms, non-slow-release or non-sustained-release forms (e.g., immediate-release forms), and / or the like may be used. Pharmaceutically acceptable compositions can be prepared, for example, by dissolving or dispersing the compounds of the present invention in a liquid excipient, such as water, physiological saline, dextran aqueous solution, glycerol or ethanol, or as SMEDDS. The compositions may also contain other pharmaceutical agents, adjuvants, carriers and excipients, such as wetting agents or emulsifiers and pH buffers.

[0034] Preferably, the composition is administered orally, intranasally, buccally, or sublingually. In some embodiments, the method includes administering a pharmaceutically acceptable composition in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. When an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and a suspending agent. Certain sweeteners, flavoring agents, or coloring agents may also be added if desired. In some embodiments, the provided oral formulation is formulated for immediate or sustained / delayed release. In some embodiments, the composition is suitable for buccal or sublingual administration, including tablets, lozenges, and tablets. The provided compound may also be in microencapsulated form.

[0035] The pharmaceutically acceptable compositions of the present invention can also be administered via nasal aerosol or inhaler.

[0036] In some embodiments, the pharmaceutically acceptable composition of the present invention is formulated for intraperitoneal administration.

[0037] This invention provides an ODT containing ticagrelor, an enantiomer, or a pharmaceutically acceptable salt thereof, and a second agent. In some formulations, the second agent may be a magnesium salt, a zinc salt, lysine, lecithin, or a combination thereof. In some formulations, the ODT may further include another component, including but not limited to citric acid, ascorbic acid, caprylic acid, threonic acid, tartaric acid, malic acid, fumaric acid, gluconic acid, succinic acid, lactic acid, glyceric acid, α-hydroxy-carboxylic acid, amino acids, and their magnesium or zinc salts.

[0038] The present invention also provides an ODF containing ticagrelor, an enantiomer, or a pharmaceutically acceptable salt thereof, and a second agent. In some forms, the second agent may be a magnesium-containing compound, a zinc-containing compound, a lysine (e.g., L-lysine) or a lysine salt (e.g., lysine HCl), lecithin, or a combination thereof. In some forms, the ODF may further comprise another component, including but not limited to hydrochloric acid, pyrophosphate, taurine, sulfuric acid, acetic acid, caprylic acid, carbonic acid, citric acid, ascorbic acid, threonic acid, tartaric acid, malic acid, fumaric acid, gluconic acid, succinic acid, lactic acid, glyceric acid, glyceraldehyde, α-hydroxy-carboxylic acid, amino acids, and their magnesium or zinc salts.

[0039] In some formulations, the ODT or ODF contains 5 mg to 200 mg of ticagrelor, its enantiomer, or a pharmaceutically acceptable salt thereof. In some formulations, the ODT or ODF contains 1 mg to 90 mg of ticagrelor, its enantiomer, or a pharmaceutically acceptable salt thereof. In some formulations, the ODT or ODF contains 4 mg to 60 mg of ticagrelor, its enantiomer, or a pharmaceutically acceptable salt thereof. In some formulations, the ODT or ODF contains 4 mg to 50 mg of ticagrelor, its enantiomer, or a pharmaceutically acceptable salt thereof. In some formulations, the ODT or ODF contains 5 mg to 50 mg of ticagrelor, its enantiomer, or a pharmaceutically acceptable salt thereof. In some formulations, the ODT or ODF contains 5 mg to 40 mg of ticagrelor, its enantiomer, or a pharmaceutically acceptable salt thereof. In some formulations, ODT or ODF contains 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, or 65 mg of ticagrelor, an enantiomer, or a pharmaceutically acceptable salt thereof.

[0040] In some samples, ODT or ODF contains 1 mg to 300 mg of the second dose. In some samples, ODT or ODF contains 2 mg to 250 mg of the second dose. In some samples, ODT or ODF contains 3 mg to 225 mg of the second dose. In some samples, ODT or ODF contains 4 mg to 200 mg of the second dose. In some samples, ODT or ODF contains 5 mg to 175 mg of the second dose. In some samples, ODT or ODF contains 5 mg to 160 mg of the second dose. In some samples, ODT or ODF contains 6 mg to 150 mg of the second dose. In some samples, ODT or ODF contains 7 mg to 140 mg of the second dose. In some samples, ODT or ODF contains 8 mg to 130 mg of the second dose. In some samples, ODT or ODF contains 9 mg to 120 mg of the second dose. In some formulations, ODT or ODF contains 10 mg to 110 mg of a second dose. In some formulations, ODT or ODF contains 15 mg to 100 mg of a second dose. In some formulations, ODT or ODF contains 20 mg to 80 mg of a second dose. In some formulations, ODT or ODF contains 25 mg to 75 mg of a second dose. In some formulations, ODT or ODF contains 30 mg to 60 mg of a second dose. In some formulations, ODT or ODF contains 35 mg to 55 mg of a second dose. In some formulations, ODT or ODF contains 40 mg to 50 mg of a second dose. In some formulations, ODT or ODF may contain 2 mg to 160 mg of lysine. In some formulations, the second dose is between 10% and 50% by weight of the total weight of ODT or ODF.

[0041] In some formulations, the ODT or ODF contains ticagrelor or a pharmaceutically acceptable salt thereof in a ratio of 1:0.1 to 1:100 with the second dose. In some formulations, the ODT or ODF contains ticagrelor or a pharmaceutically acceptable salt thereof in a ratio of 1:0.3 to 1:80 with the second dose. In some formulations, the ODT or ODF contains ticagrelor or a pharmaceutically acceptable salt thereof in a ratio of 1:0.5 to 1:70 with the second dose. In some formulations, the ODT or ODF contains ticagrelor or a pharmaceutically acceptable salt thereof in a ratio of 1:0.8 to 1:60 with the second dose. In some formulations, the ODT or ODF contains ticagrelor or a pharmaceutically acceptable salt thereof in a ratio of 1:1 to 1:50 with the second dose. In some formulations, the ODT or ODF contains ticagrelor or a pharmaceutically acceptable salt thereof in a ratio of 1:1 to 1:40 with the second dose. In some formulations, the ODT or ODF contains ticagrelor or a pharmaceutically acceptable salt thereof in a ratio of 1:1 to 1:30 with the second dose. In some formulations, the ODT or ODF contains ticagrelor or a pharmaceutically acceptable salt thereof in a ratio of 1:1 to 1:20 with the second dose. In some formulations, the ODT or ODF contains ticagrelor or a pharmaceutically acceptable salt thereof in a ratio of 1:1 to 1:10 with the second dose. In some formulations, the ODT or ODF contains ticagrelor or a pharmaceutically acceptable salt thereof in a ratio of 1:1 to 1:9 with the second dose. In some formulations, the ODT or ODF contains ticagrelor or a pharmaceutically acceptable salt thereof in a ratio of 1:1 to 1:8 with the second dose. In some formulations, the ODT or ODF contains ticagrelor or a pharmaceutically acceptable salt thereof in a ratio of 1:1 to 1:7 with the second dose. In some formulations, the ODT or ODF contains ticagrelor or a pharmaceutically acceptable salt thereof in a ratio of 1:1 to 1:6 with the second dose. In some formulations, the ODT or ODF contains ticagrelor or a pharmaceutically acceptable salt thereof in a ratio of 1:1 to 1:5 with the second dose. In some formulations, the ODT or ODF contains ticagrelor or a pharmaceutically acceptable salt thereof in a ratio of 1:1 to 1:4 with the second dose. In some formulations, the ODT or ODF contains ticagrelor or a pharmaceutically acceptable salt thereof in a ratio of 1:1 to 1:3 with the second dose. In some formulations, the ODT or ODF contains ticagrelor or a pharmaceutically acceptable salt thereof in a ratio of 1:1 to 1:2 with the second dose. In some formulations, ODT or ODF may contain ticagrelor or a pharmaceutically acceptable salt thereof in a ratio of 1:0.1 to 1:10, 1:0.4, 1:2 or 1:4 to lysine.

[0042] In some samples, ODT or ODF contains lysine or lysine salt as a second agent. In some samples, ODT or ODF contains lecithin as a second agent. In some samples, ODT or ODF contains a combination of lysine and lecithin as a second agent.

[0043] In some formulations, the ODT or ODF contains ticagrelor or an acid addition salt of ticagrelor in the form of a free base. In some formulations, the acid addition salt of ticagrelor is any pharmaceutically acceptable acid addition salt. In some formulations, the acid addition salt of ticagrelor includes, for example, ticagrelor hydrochloride, ticagrelor tartrate, ticagrelor threonate, ticagrelor glycerate, ticagrelor citrate, or ticagrelor fumarate.

[0044] In some samples, the ODT or ODF contains one or more magnesium salts or magnesium compounds or zinc salts or zinc compounds. In some samples, the ODT or ODF contains a complex of bromide, iodide, or magnesium or zinc compound with hydrochloric acid, pyrophosphate, taurine, sulfuric acid, acetic acid, carbonic acid, citric acid, ascorbic acid, threonic acid, tartaric acid, malic acid, fumaric acid, gluconic acid, succinic acid, lactic acid, glyceric acid, glyceraldehyde, α-hydroxy-carboxylic acid, amino acid, and their magnesium or zinc salts. In some samples, the second agent or salt is not a compound containing a threonate (e.g., not magnesium threonate). In some samples, the second agent or salt is not a compound containing a stearate (e.g., not magnesium stearate).

[0045] ODTs are typically produced in single-unit form or multi-unit systems, in which multiple particles, each containing an active ingredient, are compressed into a single dosage form. Conventional methods used to manufacture ODTs can result in tablets that are soft, brittle, and unsuitable for packaging in typical blister packs or bottles. Therefore, designing ODTs as multi-unit systems that remain stable and have acceptable fragility during manufacturing and storage remains a challenge.

[0046] Pharmaceutical compositions may be in the form of orally disintegrating tablets (ODTs), such as compressed ODTs. As used herein, the term "orally disintegrating tablet" means a tablet that substantially disintegrates in the oral cavity of an individual in need within a short period of time after administration. Disintegration may be measured in vitro using, for example, the USP <701> disintegration test, which is incorporated herein by reference. Alternatively, "orally disintegrating tablet" may mean a tablet that, upon administration to the buccal cavity of an individual, loses its structural integrity upon contact with the mucous membranes of the tongue, cheek, and / or oral cavity. Orally disintegrating tablets are typically placed on the tongue (or administered lingually), where they stimulate saliva production and promote the disintegration of the composition. In some forms, ODTs may contain one or more groups of particles, beads, pellets, or powders containing one or more of the active ingredients and / or excipients described herein.

[0047] The pharmaceutical composition of the present invention may be in the form of ODF. The ODF of the present invention dissolves in the oral cavity of a human individual within about 1 second to about 60 seconds, for example, within 5 to 50 seconds, 10 to 40 seconds, or 15 to 30 seconds. The ODF of the present invention has high flexibility, wettability, and is non-irritating to the oral mucosa.

[0048] The ODF according to the present invention may contain a plurality of layers. Each layer of the ODF may contain one or more active ingredients. In some embodiments, one or more polymers, buffers or acids may be provided in one or more layers of the ODF of the present invention.

[0049] The ODF according to the present invention may have a thickness of 0.01 to 10 mils. The ODF according to the present invention may have a thickness of 10 to 200 micrometers.

[0050] The ODF according to the present invention may have regions with different dissolution rates. The ODF according to the present invention may contain polymers, including but not limited to ethyl cellulose, hydroxypropyl ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, acrylic polymers, vinyl acetate, sulfonated sodium polyester, carboxylated acrylic acid, trimethylpentanediol / adipic acid / glycerol crosslinked polymers, polyglycerol-2-diisostearate / IPDI copolymers, carboxylated vinyl acetate copolymers, vinylpyrrolidone / vinyl acetate / alkylamino acrylate terpolymers, vinylpyrrolidone / vinyl acetate copolymers, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate, poly(ethyl acrylate methacrylate) copolymers, shellac, and hydroxypropyl succinate. Methylcellulose, poly(methyl vinyl ether / maleic acid) monoethyl ester, poly(methyl vinyl ether / maleic acid) n-butyl ester, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), pullulan, carboxymethyl cellulose (CMC), pectin, starch, polyvinyl acetate (PVA), polyvinylpyrrolidone (PVP), polyvinyl alcohol-polyethylene glycol graft copolymer, sodium propylparaben, sodium methylparaben, crospovidone, crospovidone carboxymethyl cellulose, polyvinylpyrrolidone, sodium alginate, polyalkylene glycol, polyoxyethylene, polyethylene glycol (PEG), gum arabic, tragacanth gum, guar gum, acacia gum Gum, arabic gum, polyacrylic acid, methyl methacrylate copolymers, carboxyvinyl polymers, polymers of acrylic acid and C10-C30 alkyl acrylates crosslinked with allyl neopentyl terephthalol, starch, microcrystalline cellulose, amylose, high amylose, hydroxypropylated high amylose, dextrin, pectin, chitin, polyglucosamine, levulin, elisan, collagen, gelatin, corn protein, gluten, soy protein isolate, sodium stearyl fumarate, whey protein isolate, casein, plasticizers, sweeteners and flavorings, colorants, salivary stimulants and thickeners. The polymeric materials are present in amounts ranging from about 0.1% to about 99%, for example, from about 10% to about 90%, from about 20% to about 80%, from about 30% to about 70%, or from about 40% to about 65%. The molecular weight of the polymeric material can range from about 1,000 to 900,000, and more specifically from about 5,000 to 600,000, 7,000 to 400,000, 10,000 to 200,000, 12,000 to 100,000, or 15,000 to 80,000. ODT or ODF may also contain one or more solvents. Solvents include, but are not limited to, organic or inorganic solvents, polar organic solvents, non-polar organic solvents, water, alcohols, dichloromethane, or sugar alcohols.In some formulations, sugar alcohols may include allicin, arabinitol, dextrose, aspartame, erythritol, galactitol, ethylene glycol, glycerol, idotitol, isomaltitol, lactitol, maltitol, mannitol, sorbitol, threitol, xylitol, and combinations thereof. Plasticizers may include, but are not limited to, benzoyl benzoate, chlorobutanol, dibutyl sebacate, diethyl phthalate, glycerol, polyethylene glycol, propylene glycol, sorbitol, triacetin, and triethyl citrate. Other ingredients that may be selected, depending on the circumstances, may include flavor modifiers, such as flavoring agents, sweeteners, and masking agents; coloring agents; polyethylene glycols, such as polyethylene glycol, propylene glycol, and glycerol; chelating agents to prevent oxidation, such as ethylenediaminetetraacetic acid (EDTA); fillers, such as sorbitol, mannitol, sucralose, lactitol, erythritol, maltitol, lactose, sucrose, xylitol, silicon dioxide, glucose binders, glucose, fructose, saccharin, and their various salts, such as sodium salts; dipeptide sweeteners, such as aspartame; dihydrochalcone compounds, glycyrrhizin, stevia (stevioside), chlorinated derivatives of sucrose, such as sucralose, sugar alcohols, sugars, and trehalose; and emulsifiers, such as surface and release modifiers, including but not limited to castor oil, cetyl alcohol, and hydrogenated vegetable oils. Sweeteners may include, but are not limited to, soluble saccharin salts (e.g., sodium and calcium salts); free acid form of saccharin; saccharin salts; aspartame; and potassium, calcium, sodium, and ammonium salts of 3,4-dihydro-6-methyl-1,2,3-thiazolyl-4-one-2,2-dioxide.

[0051] Pharmaceutical compositions may be administered orally to them in the form of SMEDDS to increase the bioavailability of poorly water-soluble drugs or pharmaceutical compositions. SMEDDS formulations typically comprise emulsions containing oil or lipid materials, surfactants, and hydrophilic co-surfactants. Poorly water-soluble drugs or pharmaceuticals are emulsified in self-microemulsifying excipient formulations, thereby increasing the in vivo bioavailability of the drug or pharmaceutical formulation. Additionally, poorly water-soluble drugs, such as ticagrelor, may be processed according to the present invention and may subsequently be used in combination with other drugs and / or pharmaceutical ingredients, which may or may not have poor water solubility.

[0052] The SMEDDS pharmaceutical compositions of the present invention can be formulated for oral administration of ticagrelor, for example, in the form of emulsions, aqueous or oily suspensions, filled hard or soft capsules or syrups (50-300 mg ticagrelor / ml) or prepared powders or granules, sugar-coated tablets, tablets or lozenges. Pharmaceutically acceptable carriers or additives used to formulate formulations (such as tablets and capsules) include binders such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch or sweet potato starch; and lubricants such as magnesium stearate, calcium stearate, sodium stearate fumarate.

[0053] The oil phase of the self-microemulsion formulation includes one or more compounds containing lipids or glycerides, such as caprylic / capric glycerides, but may also include other suitable oil phase compounds, such as polyoxyglycerides, isopropyl myristate, isopropyl palmitate, triglycerides, propylene glycol derivatives and monooleate.

[0054] Suitable surfactants or emulsifiers used in the self-microemulsion formulations of the present invention include polyoxyethylene castor oil derivatives, octylhexyl polyethylene glycol glycerol esters, sorbitol derivatives, polyoxyethylene alkyl ethers, polyoxyethylene sorbitol fatty acids, polyoxyethylene-polyoxypropylene copolymers, and other suitable surfactants, such as long alkyl chain sulfonates / sulfates (e.g., sodium dodecylbenzenesulfonate, sodium lauryl sulfate, and dialkyl sulfosuccinate), quaternary ammonium salts, fatty alcohols (e.g., lauryl alcohol, cetyl alcohol, and sterols), glycerides, fatty acid esters, and their polyoxyethylene derivatives.

[0055] A co-surfactant suitable for use with the self-emulsifying excipient formulation of the present invention may contain one or more of the following groups: tetraethylene glycol, propylene glycol, diethylene glycol monoethyl ether and polyethylene glycol, and alcohols with intermediate chain lengths, such as hexanol, pentanol and octanol, which are known to reduce the oil / water interface and allow for spontaneous formulation of emulsions.

[0056] A method for manufacturing a drug delivery system for increasing the bioavailability of a drug and / or pharmaceutical ingredient or formulation by emulsifying a drug with the self-microemulsifying excipient formulation of the present invention includes the step of dissolving ticagrelor and additional ingredients in a mixture of surfactant, co-surfactant and oil. The emulsion may then be added to a suitable dosage form, such as droplets, soft or hard-filled gelatin capsules, and cooled.

[0057] The relative proportions of surfactants and co-surfactants in the self-microemulsifying formulations of the present invention can affect the solubilization and dissolution properties of the formulations. In some formulations, the emulsion composition may contain about 10% to 50% by weight of oil, 5% to 80% by weight of surfactant, and 5% to 80% by weight of co-surfactant, based on the total weight of the emulsion composition and the self-emulsifying drug delivery system. The self-emulsifying drug delivery system is characterized by containing an emulsion composition and ticagrelor in a weight ratio of 15:1 to 3:1.

[0058] The solid formulations of the present invention are palatable, for example, having acceptable sensory characteristics, such as a pleasant taste and mouthfeel, to maintain patient compliance or adherence to the dosing regimen, while also providing the disclosed pharmacokinetic and bioavailability characteristics to deliver the desired therapeutic effect. Masking components can inhibit or delay drug release and reduce drug solubility, thereby providing unacceptable pharmacokinetic properties. Conversely, formulation components that promote rapid release can result in unpleasant taste or mouthfeel characteristics. Therefore, acceptable solid ODT or ODF formulations must balance these conflicting characteristics to provide a palatable (e.g., masking), rapidly disintegrating composition with acceptable pharmacokinetics.

[0059] In some embodiments, the oral dosage form of the present invention may contain at least one of the following: hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, carrageenan, polyethylene glycol, polyvinyl alcohol, or mixtures or combinations thereof. The ODT may contain a core, a base coat, and / or a coating.

[0060] In some formulations, the active ingredient is encapsulated in, for example, a matrix, layer, polymer, gel-forming region, and / or gel. Stabilization can be provided such that, after the oral disintegrating tablets have been stored under accelerated storage conditions at 40°C and 75% relative humidity for 1–3 months, the impurity content measured is below the necessary pharmaceutically acceptable specification, thus making them suitable for commercial use.

[0061] In some embodiments, ODT has been produced by mixing ticagrelor or a pharmaceutically acceptable salt thereof with a second active agent in a liquid solution or suspension, filling the mixture into a mold, and freeze-drying. In some samples, the ODT or ODF of the present invention is aseptically produced. In some samples, the ODT or ODF of the present invention is terminally sterilized.

[0062] In some embodiments, the ODT may be coated. In some embodiments, the enteric coating applied to the core comprises one or more of the following: hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose succinate (HPMCAS), polyvinyl acetate phthalate, cellulose benzotriester acetate, cellulose phthalate (CAP), shellac, polymethacrylic acid, polymethyl methacrylate, polyethyl methacrylate, polyethyl acrylate, or mixtures or combinations thereof, each possibility representing a separate example. In various embodiments, the plurality of cores are further coated with a base coat as a base layer of the enteric coating and / or a coating comprising a reverse enteric polymer as an outer layer of the enteric coating. Each possibility represents a separate example. In a particular embodiment, the base coat applied to the core comprises one or more of the following: hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, or mixtures or combinations thereof, each possibility representing a separate example.

[0063] In some embodiments, the ODT of the present invention includes a water-soluble polymer, a combination of two or more water-soluble polymers, or a combination of a water-soluble polymer and a water-insoluble or poorly soluble polymer. Water-soluble polymers that can be used in the oral dissolving formulations of the present invention include, but are not limited to, cellulose derivatives, synthetic polymers such as polyacrylates, and natural gums. For example, water-soluble polymers used in the oral dissolving formulations of the present invention may include, but are not limited to, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, cellulose acetate phthalate, cellulose acetate butyrate, amylose, polydextrose, casein, pullulan, gelatin, pectin, agar, carrageenan, tragacanth gum, guar gum, gum arabic, gum arabic, polyethylene glycol, polyethylene oxide, polyvinylpyrrolidone, polyvinyl alcohol, cyclodextrin, carboxyvinyl polymers, sodium alginate, polyacrylic acid, methyl methacrylate, or mixtures thereof.

[0064] In a particular embodiment, the concentration of the water-soluble polymer in the formulation may be from about 20% to about 90% (by weight), or from about 40% to about 80% (by weight). The above polymers can be used to coat the ODT. The coating can act as a taste-masking barrier (i.e., on the drug particles contained within the ODT) and can also protect the components from atmospheric degradation and improve appearance. Where this coating can delay disintegration, a rapid disintegrant can also be included in the composition. Disintegrants such as dried starch, sodium alginate, lactose, sodium bicarbonate, calcium carbonate, polyvinylpyrrolidone, microcrystalline cellulose, and the like are known to be used in the core of tablets or granulated mixtures of swallowable tablet formulations. Such elements can be used in combination with polymer coatings to promote disintegration. Additionally, any of the disintegrants known to those skilled in the art can be used to improve the disintegration of the ODT and the dissolution of ticagrelor and the second agent when coated with the polymer.

[0065] The compressed ODT may include a disintegrant, for example, in an amount of about 2% to about 25% by weight of the total tablets. In some embodiments, the ODT may contain one or more additional excipients. Such excipients may be selected from the group consisting of: binders, fillers, diluents, surfactants, lubricants, plasticizers, anti-sticking agents, alkaline substances, tension enhancers, wetting agents, buffering substances, preservatives, flavoring agents, opacifiers, colorants, antioxidants, or mixtures or combinations thereof, in an amount not exceeding about 50% by weight of the total tablets.

[0066] The excipient may be a distribution agent, such as colloidal SiO2, fumed silica, diatomaceous earth, kaolin, talc and / or magnesium aluminum trisilicate.

[0067] Suitable examples of lubricants include, but are not limited to, talc, sodium stearate, calcium stearate, magnesium stearate, zinc stearate, glyceryl dodecanoate, and glyceryl monostearate. Preferred lubricants for the compositions of the present invention are sodium stearate or magnesium stearate, or combinations thereof. In some formulations, one or more lubricants may be included in an amount from about 0.1% to 5% by weight of the solid formulation of the present invention.

[0068] The foaming compound selected as appropriate includes compounds that release gas. For example, the gas may be released by a chemical reaction between a soluble acid source, an alkali metal bicarbonate, or other carbonate source and water and / or saliva in the oral cavity. The gas produced by such a chemical reaction may be carbon dioxide. The acid source may be any acid safe for human consumption and may include edible acids such as citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, and similar acids. The carbonate source includes dry solid carbonates and bicarbonates, such as sodium carbonate, sodium bicarbonate, magnesium carbonate, calcium carbonate, and the like. A preferred foaming combination of the present invention is citric acid (anhydrous) / sodium bicarbonate. In some formulations, one or more foaming compounds may be included in an amount of about 1% to 30% by weight of the solid dosage form of the present invention.

[0069] In some embodiments, the oral dissolving formulation according to the present invention may include surfactants, including but not limited to sodium docusate, polyoxyethylene ether, poloxamer, polysorbate (Tween), glyceryl monostearate, polyoxyethylene stearate, sodium lauryl sulfate, sorbitol ester, and combinations thereof. If present, the formulation may include about 0.1% to about 10%, for example, about 1% to about 5% (by weight) of surfactant. In some embodiments, the surfactant may be included in a coating. In some other embodiments, the surfactant may be used as a compressibility enhancer. Those skilled in the art will understand, with the aid of the present invention, that other components may be included to enhance one or more properties of the formulation. For example, the oral dissolving formulation according to the present invention may include disintegrants, defoamers, antioxidants, buffers, or colorants.

[0070] In some embodiments, the anti-adhesion agent or lubricant of the present invention may include talc, magnesium silicate, colloidal silica, amorphous silica, and calcium silicate. In some embodiments, the anti-adhesion agent and lubricant compound may be used in an amount of about 0.1% to 5% by weight.

[0071] In some embodiments, the oral dissolving formulations of the present invention may contain an emulsifier as an excipient. As used herein, an emulsifier includes both a solubilizer and a wetting agent. Suitable emulsifiers include, but are not limited to, polyvinyl alcohol, sorbitan ester, cyclodextrin, methyl benzoate, glyceryl monostearate, polyoxyethylene alkyl ethers, polyoxyethylene stearate, poloxamer, polyoxyethylene castor oil derivatives (Cremophor), hydrogenated vegetable oil, bile salts, polysorbate, ethanol, or combinations thereof. Emulsifiers can improve compressibility during the wet granulation process in the manufacturing process.

[0072] In some embodiments, the orally disintegrating formulations or SMEDDS of the present invention may contain sweeteners or flavorings. Generally, any natural or synthetic flavorings or sweeteners known in this art can be used in the orally disintegrating or dissolving formulations of the present invention. For example, sweeteners or flavorings include, but are not limited to, essential oils, water-soluble extracts, sugars, monosaccharides, oligosaccharides, aldoses, ketoses, dextrose, maltose, lactose, glucose, fructose, sucrose, mannitol, xylitol, D-sorbitol, erythritol, pentitol, hexitol, maltitol, acetylsulfamate, acetoxin, glycyrrhizin, sucralose, aspartame, saccharin, sodium saccharin, sodium saccharin, eugenol formate flavorings, and combinations thereof.

[0073] A disintegrant or "disintegrating agent" that can be used in the compositions of the present invention can be defined as any material capable of accelerating the disintegration / dispersion of the compositions of the present invention to a measurable degree. Thus, a disintegrant can provide an in vitro disintegration time of about 30 seconds or less, as measured according to, for example, the standard United States Pharmacopeia (USP) disintegration test method (see FDA Industry Guidance: Orally Disintegrating Tablets; December 2008). This can be achieved, for example, by a material that can swell, wick, and / or deform when placed in contact with water and / or mucus (e.g., saliva), thereby causing the tablet formulation to disintegrate upon such wetting. Suitable disintegrants (as defined, for example, in Rowe et al., Handbook of Pharmaceutical Excipients, 6th edition, (2009)) include cellulose derivatives such as hydroxypropyl cellulose (HPC), low-substituted HPC, methylcellulose, ethyl hydroxyethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, microcrystalline cellulose, and modified cellulose gum; starch derivatives such as moderately cross-linked starch, modified starch, hydroxypropyl starch, and pregelatinized starch; and other disintegrants such as calcium alginate, sodium alginate, alginate, polyglucosamine, colloidal silica, sodium docusate, guar gum, magnesium aluminum silicate, potassium pluckleate, and polyvinylpyrrolidone. Combinations of two or more disintegrants may be used. Disintegrants include so-called "hyperdisintegrants" (as defined, for example, in Mohanachandran et al., International Journal of Pharmaceutical Sciences Review and Research, 6, 105 (2011)), such as croscarmellose, sodium glycolate starch, calcium silicate, and croscarmellose sodium. Combinations of two or more hyperdisintegrants may be used. In the compositions of the present invention, disintegrants may also be combined with hyperdisintegrants. The disintegrants and / or hyperdisintegrants are preferably used in amounts between 0.5% and 15% by weight (e.g., total) of the total weight of the composition, such as 1% to 8% by weight, such as about 2% to about 7% by weight (e.g., about 5% by weight, such as about 4% by weight).

[0074] In some embodiments, the oral disintegrating formulation of the present invention may contain a weak acid or particles of a weak acid buffer-forming material. The weak acid buffer-forming material comprises, when provided in the compositions of the present invention, a material that provides a weak acid buffering system when the compositions are dissolved in water and / or saliva (e.g., at the site of administration of the compositions of the present invention), such that a pH between about 4.0 and about 6.5 (e.g., about 6.25) is provided, and is present in sufficient quantity to allow the pH to be maintained within this range for an appropriate duration (e.g., about 30 seconds, such as about 1 minute) to about 3 minutes (e.g., about 2 minutes, such as about 1.5 minutes) to promote, in particular, the dissolution of ticagrelor and the second agent, and / or subsequent absorption of ticagrelor and the second agent through the oral mucosa. Weakly acidic materials include weak acids that are safe for human consumption, such as food acids, such as malic acid, fumaric acid, adipic acid, caprylic acid, succinic acid, lactic acid, acetic acid, oxalic acid, maleic acid, ammonium chloride, preferably tartaric acid, and even better citric acid, or combinations of such acids.

[0075] The particle size of the weakly acidic material or the weakly acidic buffer forming material is in the range of about 1 pm to about 10,000 pm. The suitable amount of the weakly acidic material that can maintain the pH within the aforementioned range after oral administration, as described above, is in the range of at least about 1% to about 10% by weight of the total formulation. The suitable total amount of the weakly acidic buffer forming material that can maintain the pH within the aforementioned range after oral administration, as described above, is in the range of at least about 1% to about 15% by weight of the total formulation.

[0076] In various embodiments, the orally disintegrating tablets have a hardness of about 20 N to about 100 N and a brittleness of 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, or 0.2% or lower. In other embodiments, the ODT substantially disintegrates in the oral cavity of the individual in need within about 20, 15, 10, 5, 1, or 0.5 minutes after administration. Disintegration can be measured in vitro using, for example, the USP <701> disintegration test.

[0077] In some samples, using a standard dissolution test, ODT or ODF or SMEDDS releases at least 75%, at least 80%, at least 85%, at least 90%, at least 92%, at least 93%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of ticagrelor or its pharmaceutically acceptable salt within 5, 10, 15, or 20 minutes. For example, dissolution can be measured using a dissolution device USP 2 (paddle) with a suitable dissolution medium, such as water at pH 7.0, phosphate buffer (50 mM) at pH 6.8, or simulated human saliva at pH 6.8. The volume can be 500 mL. The temperature can be 37.0 ± 0.5°C. The speed can be 50 rpm. The total dissolution time can be sampled at 5, 10, 15, 20, 30, 60, 120, 360, 480, 720, and 960 minutes.

[0078] In some samples, using a standard dissolution test, ODT or ODF or SMEDDS release at least 75%, at least 80%, at least 85%, at least 90%, at least 92%, at least 93%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of magnesium or zinc compounds or salts within 5, 10, 15, or 20 minutes.

[0079] In some samples, ODT or ODF or SMEDDS uses a simulated saliva fluid with a pH of about 6.8 to release at least 75%, at least 80%, at least 85%, at least 90%, at least 92%, at least 93%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of magnesium or zinc compounds or salts within 5, 10, 15, or 20 minutes.

[0080] In some formulations, approximately 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95% or higher of the maximum concentration of ticagrelor and approximately 50% or higher of the maximum concentration of the second active agent are absorbed in vivo into the plasma of a human individual within 1 hour after administration. In some formulations, approximately 70, 75, 80, 85% or higher of the maximum concentration of ticagrelor and approximately 70% or higher of the maximum concentration of the second active agent are absorbed in vivo into the circulating plasma of a human individual within 6 hours after administration. In some formulations, approximately 80, 85, 90, 95% or higher of the maximum concentration of ticagrelor and approximately 80% or higher of the maximum concentration of the second active agent are absorbed in vivo into the circulating plasma of a human individual within 8 hours after administration. In some formulations, the ODT or ODF of the present invention delivers a therapeutically effective amount of ticagrelor to the brain of an individual within 1 hour of oral ingestion.

[0081] In some formulations, at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60% or more of ticagrelor and / or a second agent in ODT or ODF or SMEDDS are absorbed via the oral mucosa (e.g., sublingual, supralingual or buccal).

[0082] This invention provides an ODT, ODF, or SMEDDS having structural and physical properties suitable for minimizing hepatic and gastrointestinal metabolism, delivering a more consistent dose to the brain, and avoiding the cardiac effects of ticagrelor. Therefore, this invention provides a method of transmucosal administration. This invention provides an ODT, ODF, or SMEDDS having physical properties that allow the active compound to be rapidly absorbed and directly enter the bloodstream. Therefore, the ODT and ODF or SMEDDS of this invention enable rapid delivery of the drug to the individual's brain, rather than via gastric breakdown and hepatic metabolism.

[0083] In some samples, ODT or ODF or SMEDDS have a water absorption rate of at least 40%, 50%, 55%, 60%, 65%, 70% or higher. In some samples, ODT or ODF has a wetting time of 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 or 65 seconds.

[0084] In some samples, the ODT or ODF has a tensile strength of 4, 4.5, 5, 5.5, 6, or 6.5 N / cm² or higher. In some samples, the ODT or ODF has a porosity of 15, 20, 25, 30, 35, 40, 45, or 50% or higher.

[0085] In some samples, ODT has a hardness of 30, 35, 40, 45, 50, 55, 60 N or higher. In some samples, ODT has a thickness of 0.5, 1, 1.5, 2, 2.5 or 3 mm. In some samples, ODT or ODF has a total tablet weight of 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 mg.

[0086] To provide such physical properties, the ODT and ODF of the present invention contain a combination of components that maximize the solubility of ticagrelor in the oral cavity. Although compounds such as magnesium, zinc, lysine, and lecithin can reduce the solubility of ticagrelor, the structure and composition of the ODT and ODF provided by the present invention provide high solubility of ticagrelor and a satisfactory good taste and mouthfeel to maintain patient compliance or adherence to the dosing regimen, while also providing the disclosed pharmacokinetic and bioavailability characteristics to provide the desired therapeutic effect. In some forms, the ODT or ODF has a pH of 5.5 to 7 when dissolved in human oral cavity, deionized water, or simulated human saliva, such as 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7.0.

[0087] In some embodiments, the present invention includes the use or method of treating an individual suffering from autism spectrum disorder, intellectual disability, epilepsy, anxiety disorder, mood disorder, social interaction disorder, irritability, aggression, self-harming behavior, hyperactivity, attention deficit, or fragile X syndrome by administering, alone or in combination with a second agent of the present invention, ticagrelor according to the present invention, its enantiomers, or a pharmaceutically acceptable salt thereof. Ticagrelor, its enantiomers, or a pharmaceutically acceptable salt thereof may be co-administered with the second agent. Co-administration may include any suitable manner of administering ticagrelor, its enantiomers, or a pharmaceutically acceptable salt thereof together with the second agent. In some cases, the compound is present in the same dosage form or administered simultaneously with the first and second dosage forms. In some cases, the first dosage form is administered after the second dosage form, or the second dosage form is administered after the first dosage form. In some cases, the first and second dosage forms are administered in an alternating order. In some embodiments, the invention includes the use or method of treating individuals with autism spectrum disorder, intellectual disability, epilepsy, anxiety disorder, mood disorder, social interaction disorder, irritability, aggression, self-harming behavior, hyperactivity, attention deficit, or fragile X syndrome by administering the ODT, ODF, or SMEDDS of the invention. In one embodiment, the daily weight of ticagrelor administered according to the method of the invention is lower than that of conventional ticagrelor therapy, for example, lower than 180 mg / day, lower than 120 mg / day, lower than 100 mg / day, lower than 90 mg / day, lower than 80 mg / day, lower than 60 mg / day, lower than 40 mg / day, lower than 30 mg / day, lower than 20 mg / day, or lower than 10 mg / day. In some embodiments, the invention includes a method of co-administering ticagrelor and acetylsalicylic acid. In some formulations, co-administration involved 5 mg to 300 mg, 10 to 280 mg, 20 to 260 mg, 30 to 250 mg, 40 to 200 mg, 50 to 180 mg, 60 to 160 mg, 70 to 150 mg, 80 to 140 mg, 90 to 130 mg, 75 to 100 mg, or less than 100 mg of acetylsalicylic acid.

[0088] In some cases, the method of the present invention will reduce behavioral problems on the Abnormal Behavior Checklist (ABC-C). The ABC-C is a comprehensive behavioral checklist used to measure the effectiveness of medication and other treatments in individuals with developmental disorders. It consists of five subscales, including irritability, lethargy, inappropriate speech, hyperactivity, and repetitive speech and behavior, based on 58 items describing various behavioral problems.

[0089] In some cases, the method of the present invention will reduce behavioral problems on the Clinical Global Impression Scale (CGI). The CGI is used by research psychiatrists to assess overall clinical condition relative to a baseline using the same scale as CGI-S. The research psychiatrists will evaluate improvement relative to baseline. The CGI consists of a 7-point subjective scale that assesses symptoms. On this scale, 1, 2, and 3 represent normal, some symptoms present, and mild behavior, respectively. 4 represents moderate behavior. 5, 6, and 7 represent significant, severe, and most severe behavior, respectively.

[0090] In some cases, the method of the present invention will reduce behavioral problems on the Revised Scale of Overt Aggressive Behavior (IBR-MOAS). The IBR-MOAS is a questionnaire that includes five types of aggression (verbal aggression against oneself and others, physical aggression against objects, and physical aggression against oneself and others), each with four severity levels. Only the portion assessing the five types of aggression will be used for repeated assessment: verbal aggression against others, verbal aggression against oneself, physical aggression against others, physical aggression against objects, and physical aggression against oneself. The frequency of each item is as follows: 0 = Never (never occurred); 1 = Rarely (approximately once a year to once a month on average); 2 = Sometimes (approximately several times a month to several times a week on average); 3 = Frequently (approximately once a day to several times a day on average); and U (occurred but not in the past year).

[0091] In some cases, the method of the present invention will reduce behavioral problems in the Questionnaire-Analog-Based Functional Assessment (QABF). The QABF is an indirect assessment of behavioral functioning in individuals with developmental disabilities. It contains 25 items. The QABF generates five categories of behavioral functioning: attention-seeking, avoidance needs, bodily functions, tangible and non-social functions (i.e., sensory or automatic maintenance). Each question is scored using frequency descriptors such as never, rarely, sometimes, and often. If a specific function scores 4 or higher, that function is recognized.

[0092] In certain formulations, specific dosing regimens involve administering the pharmaceutical composition to achieve or maintain ticagrelor plasma concentrations in the range of approximately 50-1000 ng / mL, 100-800 ng / mL, approximately 120-700 ng / mL, approximately 140-600 ng / mL, approximately 160-520 ng / mL, approximately 180-500 ng / mL, approximately 200-480 ng / mL, approximately 220-460 ng / mL, approximately 240-420 ng / mL, approximately 260-400 ng / mL, or approximately 500 ng / mL, approximately 530 ng / mL, approximately 560 ng / mL, approximately 580 ng / mL, approximately 600 ng / mL, or approximately 620 ng / mL. In some formulations, the dosage is intended to achieve plasma concentrations of 1-1000 ng / mL within 2 hours after administration. In some samples, ticagrelor or its pharmaceutically acceptable salts maintained a ticagrelor plasma concentration of approximately 50–300 ng / mL for at least 1, 2, 3, 4, 5, or 6 hours. In other samples, ticagrelor or its pharmaceutically acceptable salts maintained a ticagrelor plasma concentration of approximately 30–50 ng / mL for at least 1, 2, 3, 4, 5, or 6 hours.

[0093] The oral dose of ticagrelor for humans aged 18 years and older is 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg, for example, 60 to 180 mg of ticagrelor, for example, once or twice daily. In some cases, the dosing regimen may be increased at weekly intervals based on response.

[0094] For humans aged 18 years and under, the dosage may be 0.1-3 mg / kg body weight, once, twice, three or four times daily.

[0095] A method for safely delivering the combination of the present invention to an individual may include measuring the individual's electrocardiogram, pulse, and blood pressure before, during, and / or after administration. Additionally, a method for safely delivering the combination of the present invention to an individual may include measuring liver enzyme levels while continuing administration of the combination. In some cases, if liver enzyme levels are abnormal, for example due to a transient increase in transaminases, steps may be taken to protect the kidneys, liver, intestines, or heart. In some cases, the method further includes a preliminary step of measuring the individual's liver enzyme levels before administration. This can be used to establish baseline liver enzyme levels. The method may also include measuring liver enzyme levels at specified time intervals after the start of the administration step. In some embodiments, the individual's liver enzyme levels may be monitored at 4-hour intervals, 6-hour intervals, 8-hour intervals, 12-hour intervals, 24-hour intervals, etc. Alternatively, the content can be tested at approximately 12 hours, approximately 24 hours, approximately 36 hours, approximately 48 hours, approximately 60 hours, approximately 72 hours, approximately 84 hours, approximately 96 hours, approximately 108 hours, approximately 120 hours, approximately 132 hours, approximately 154 hours, approximately 168 hours, on the day of individual discharge, or in combination thereof.

[0096] Example 1: Element quantity Ticargul (mg) 10 Gelatin (mg) 40 Mannitol (mg) 20 Magnesium tartrate (mg) 10 Purified water Sufficient volume up to 250 µl 1) Dissolve gelatin and other ingredients in purified water while stirring at 200 to 500 rpm. 2) Make up the final volume of the solution with purified water. 3) Mix the solution again for 15 minutes while stirring at 200 to 500 rpm. 4) Add the solution to the cavities of the pre-formed blister pack (preferably using a dispensing pipette). 5) Freeze the filled blister packs at a temperature range of -20°C to -110°C. 6) Freeze-dry the blister packs in a lyophilizer. 7) Place the blister pack containing the dried lyophilized material onto the stamping carrier mesh of the blister packer to convey the blister pack through the sealing stage of the packer. 8) Seal the blister pack with a cap foil and stamp it into the final blister pack.

[0097] Example 2: Element quantity Ticargul (mg) 10 Gelatin (mg) 40 Mannitol (mg) 20 Sodium methylparaben (mg) 10 Sodium propylparaben (mg) 10 Zinc glycerate (mg) 5 Aspartame (mg) 2 Purified water Sufficient volume up to 250 µl 1) Dissolve gelatin and other ingredients in purified water while stirring at 200 to 500 rpm. 2) Make up the final volume of the solution with purified water. 3) Mix the solution again for 15 minutes while stirring at 200 to 500 rpm. 4) Add the solution to the cavities of the pre-formed blister pack (preferably using a dispensing pipette). 5) Freeze the filled blister packs at a temperature range of -20°C to -110°C. 6) Freeze-dry the blister packs in a lyophilizer. 7) Place the blister pack containing the dried lyophilized material onto the stamping carrier mesh of the blister packer to convey the blister pack through the sealing stage of the packer. 8) Seal the blister pack with a cap foil and stamp it into the final blister pack.

[0098] Example 3: Element Weight (mg) Ticagre 10 Avicel® PH 102 50 Spray-dried lactose 110 Sodium glycolate starch 4 Cross-linked polyvinylpyrrolidone 4 Cross-linked carboxymethyl cellulose sodium 4 L-lysine 10 talc 10 Aspartame 10 The ingredients in the formulation are mixed and compressed using a single-stroke tablet press into tablets, each with a diameter of 5 mm and a thickness of 2 to 3 mm, and a hardness between 3 and 5 kg. The fully blended composition is then compressed into ordinary tablets.

[0099] Example 4: Element Weight (mg) Ticagre 10 Avicel® PH 102 50 Spray-dried lactose 100 Sodium glycolate starch 4 Cross-linked polyvinylpyrrolidone 4 Cross-linked carboxymethyl cellulose sodium 4 Magnesium glycerate 10 Lecithin 10 talc 10 Aspartame 10

[0100] The components in the formulation are mixed and compressed by a single-stroke tablet press into tablets, each having a diameter of 5 mm and a thickness of 2 to 3 mm, with a hardness between 3 and 5 kg. The fully blended composition is then compressed into ordinary tablets.

[0101] Example 5: Element quantity Ticargul (mg) 70 Prucalan (mg) 400 Propylene glycol (ml) 0.25 Polyvinylpyrrolidone (mg) 100 Citric acid (mg) 200 Magnesium tartrate (mg) 40 Purified water (ml) 20

[0102] Accurately weigh ticagrelor and pullulan and dissolve them in distilled water. Mix the solution thoroughly, then add the plasticizer and superdisintegrant. Pour the resulting homogenized solution into a Piper dish (6 cm in diameter) and dry in an oven at 600°C for 24 hours. Carefully remove the film from the Piper dish and cut it to the desired size (2 × 2 cm²).

[0103] Example 6: Element quantity Ticargul (mg) 70 Prucalan (mg) 400 Propylene glycol (ml) 0.25 Polyvinylpyrrolidone (mg) 100 Citric acid (mg) 200 Zinc sulfate (mg) 40 Purified water (ml) 20

[0104] Accurately weigh ticagrelor and pullulan and dissolve them in distilled water. Mix the solution thoroughly, then add the plasticizer and superdisintegrant. Pour the resulting homogenized solution into a Piper dish (6 cm in diameter) and dry in an oven at 600°C for 24 hours. Carefully remove the film from the Piper dish and cut it to the desired size (2 × 2 cm²).

[0105] Example 7: Element quantity Ticargul (mg) 70 Pectin (mg) 200 Mannitol (mg) 100 Carbopol (mg) 300 Citric acid (mg) 100 L-Lysine (mg) 40 Purified water (ml) Sufficient volume up to 250 µl

[0106] Accurately weigh ticagrelor and pullulan and dissolve them in distilled water. Mix the solution thoroughly, then add the plasticizer and superdisintegrant. Pour the resulting homogenized solution into a Piper dish (6 cm in diameter) and dry in an oven at 600°C for 24 hours. Carefully remove the film from the Piper dish and cut it to the desired size (2 × 2 cm²).

[0107] Example 8: Element quantity Ticargul (mg) 70 Prucalan (mg) 400 Propylene glycol (ml) 0.25 Polyvinylpyrrolidone (mg) 100 Citric acid (mg) 200 L-Lysine (mg) 30 Lecithin (mg) 100 Purified water (ml) 20

[0108] Accurately weigh ticagrelor and pullulan and dissolve them in distilled water. Mix the solution thoroughly, then add the plasticizer and superdisintegrant. Pour the resulting homogenized solution into a Piper dish (6 cm in diameter) and dry in an oven at 600°C for 24 hours. Carefully remove the film from the Piper dish and cut it to the desired size (2 × 2 cm²).

[0109] Example 9: ODT T1 to T11 further illustrate the state of the present invention: T1 T2 T3 T4 T5 T6 Active materials Ticargul free base or in combination with (1) X X X X X X Magnesium salts with (2) X X Zinc salts with (2) X X X L-Lysine / L-arginine X X excipient Acid(3) X X X X gelatin X X X X Mannitol X X X X Sodium p-hydroxybenzoate X X Sodium p-hydroxybenzoate X X Avicel® PH 102 X X Spray-dried lactose X X Sodium glycolate starch X X Cross-linked polyvinylpyrrolidone X X Cross-linked carboxymethyl cellulose sodium X X talc X X Taste-making agents Aspartame X X X X Lecithin X X T7 T8 T9 T10 T11 Active materials Ticargul free base or in combination with (1) X X X X X Magnesium salts with (2) X X X Zinc salts with (2) X X L-Lysine / L-arginine X X excipient Acid(3) X X X gelatin X X X X Mannitol X X X X Sodium p-hydroxybenzoate X Sodium p-hydroxybenzoate X Avicel® PH 102 X Spray-dried lactose X Sodium glycolate starch X Cross-linked polyvinylpyrrolidone X Cross-linked carboxymethyl cellulose sodium X talc X Taste-making agents Aspartame X X Lecithin X (1) In combination with the following: hydrochloric acid, pyrophosphate, taurine, sulfuric acid, acetic acid, carbonic acid, citric acid, ascorbic acid, threonine, tartaric acid, malic acid, fumaric acid, gluconic acid, succinic acid, lactic acid, glyceric acid, glyceraldehyde, or α-hydroxy-carboxylic acid. (2) Salt forms: sulfate, acetate, threonate, tartrate, glycerate, citrate, caprylate, chloride, sulfate, lactate, carbonate, malate, taurine, gluconic acid, succinate, or pyrophosphate. (3) Acids: tartaric acid, glyceric acid, threonine, caprylic acid, or gluconic acid. The relative amounts of the ODT components are consistent with the above-mentioned forms.

[0110] Example 10: ODF F1 to F11 further illustrate the state of the present invention: F1 F2 F3 F4 F5 F6 Active materials Ticargul free base or in combination with (1) X X X X X X Magnesium salts with (2) X X Zinc salts with (2) X X X L-Lysine / L-arginine X X excipient Acid(3) X X X X Pruland X X X Propylene glycol X X X Polyvinylpyrrolidone X X X Purified water X X X X X X pectin X X X Mannitol X X X Kapop X X X Taste-making agents Aspartame X X X X Lecithin X X X F7 F8 F9 F10 F11 Active materials Ticargul free base or in combination with (1) X X X X X Magnesium salts with (2) X X X Zinc salts with (2) X X L-Lysine / L-arginine X excipient Acid(3) X X Pruland X X X Propylene glycol X X X Polyvinylpyrrolidone X X X Purified water X X X X X pectin X X Mannitol X X Kapop X X Taste-making agents Aspartame X X X Lecithin X X (1) In combination with the following: hydrochloric acid, pyrophosphate, taurine, sulfuric acid, acetic acid, caprylic acid, carbonic acid, citric acid, ascorbic acid, threonine, tartaric acid, malic acid, fumaric acid, gluconic acid, succinic acid, lactic acid, glyceric acid, glyceraldehyde, or α-hydroxy-carboxylic acid. (2) Salt forms: sulfate, acetate, threonate, tartrate, glycerate, caprylate, citrate, chloride, sulfate, lactate, carbonate, malate, taurine, gluconic acid, succinate, or pyrophosphate. Acids: tartaric acid, glyceric acid, threonine, caprylic acid, or gluconic acid. The relative amounts of the ODF components are consistent with the above-mentioned forms.

[0111] Example 11:

[0112] A self-microemulsifying formulation (total weight: 800 mg), modified from (Na et al., Strategic approach to developing a self-microemulsifying drug delivery system to enhance antiplatelet activity and bioavailability of ticagrelor. Int J Nanomedicine. 2019 Feb 15;14:1193-1212; CN104971042A; and KR102007731B1 (each of which is incorporated herein by reference in its entirety)), was prepared by means of a mixture of oils (Capmul MCM; 45.0 w / w%), a surfactant (Cremophor EL; 38 w / w%), and a co-surfactant (Transcutol P; 17 w / w%). The mixture was gently stirred to prepare a homogeneous solution, followed by the addition of 100 mg ticagrelor and 100 mg zinc octanoate and mixing to prepare a homogeneous formulation. Each drop of the mixture contains 5 mg ticagrelor and 5 mg zinc octanoate. Element Dosage (mg) Ticargul (mg) 100 Zinc caprylate (mg) 100 Capmul MCM (mg) 360 Cremophor EL (mg) 304 Transcutol P (mg) 136

[0113] Example 12: SMEDDS S1 to S11 further illustrate the state of the present invention: S1 S2 S3 S4 S5 S6 Active materials Ticargul free base or in combination with (1) X X X X X X Magnesium salts with (2) X X Zinc salts with (2) X X X L-Lysine / L-arginine X X excipient bitter X X X X Decanoic acid X X X glyceryl monooctyldecanoate X X X Polyoxyethylated castor oil X X X Polyoxyethylene dehydrated sorbitol fatty acids X X X X X X Diethylene glycol monoethyl ether X X X X Tetraethylene glycol X X X X Taste-making agents Aspartame X X X X Lecithin X X X S7 S8 S9 S10 S11 Active materials Ticargul free base or in combination with (1) X X X X X Magnesium salts with (2) X X X Zinc salts with (2) X X L-Lysine / L-arginine X excipient bitter X X Decanoic acid X X X glyceryl monooctyldecanoate X X X Polyoxyethylated castor oil X X X Polyoxyethylene dehydrated sorbitol fatty acids X X X X X Diethylene glycol monoethyl ether X X Tetraethylene glycol X X Taste-making agents Aspartame X X X Lecithin X X

[0114] Example 13: In vivo experiment: - Valproic acid (VPA) model of autism

[0115] Exposure to valproic acid (VPA) during pregnancy has been shown to increase the risk of autism in children. Furthermore, rodents exposed to this drug prenatally exhibit behavioral phenotypic features of human autism. This model is more representative of many cases of idiopathic autism of environmental / epigenetic origin than transgenic models carrying a single autism-related gene mutation. The VPA model is an environmentally triggered model with strong constructivity and clinical validity. The VPA-induced rodent model is a recognized, well-established, and widely used animal model in this technology for testing the hypothetical efficacy of pharmacological agents on behavioral and social elements in human autism spectrum disorder.

[0116] C57BL / 6J mice were acquired and mated at 7-8 weeks of age, and pregnancy was confirmed by the presence of a vaginal plug on embryonic day 0 (E0). At E12.5, pregnant females received a single intraperitoneal injection of sodium valproate (VPA, 500 mg / kg) dissolved in saline (SAL). Control females received only an equal volume of SAL. The date of birth was recorded as P0 (postpartum day 0). Offspring were weaned at P21 (postpartum day 21), and male offspring were housed in groups of 4-5. Experiments were conducted on the male offspring. Mice were housed in a temperature- and humidity-controlled environment with free access to food and water. Animals were kept under a 12-hour light / dark cycle, with lights turned on at 8:00 AM.

[0117] Male offspring of VPA-treated mice were divided into four groups (n=8-9 / group): VPA-mediator + 50 μg ZnSO4, VPA-ticagrelor (0.3 mg / kg) + 50 μg ZnSO4, VPA-ticagrelor (10 mg / kg) + 50 μg ZnSO4, and VPA-ticagrelor (30 mg / kg) + 50 μg ZnSO4. Male offspring of SAL-treated mice were divided into two groups (n=10 / group): SAL-mediator and SAL-ticagrelor (30 mg / kg) + 50 μg ZnSO4. From week 6 to week 8 of age, mice received three weekly injections of saline (5 µl / g ip) or ticagrelor (ip). A three-compartment test was performed 24 hours after the last injection.

[0118] Behavioral Analysis - Three-Compartment Test

[0119] The three-compartment test assesses cognition in a rodent model of CNS disease by assessing general social competence and attention to social novelties. This test measures social competence by comparing the time spent alone in the same but empty room with the tendency to spend time with another mouse.

[0120] The device is an acrylic box (length: 62 cm, width: 41 cm, height: 30.5 cm) divided into three chambers. A 5 cm × 5 cm opening was made in the partition to allow mice to freely explore the three chambers. First, the mouse was placed in the central chamber and allowed to acclimatize for 5 minutes. After the acclimatization period, the test mouse was moved to a holding cage and the bedding was redistributed. Then, a novel mouse sealed in a small cage was placed in one side chamber (social area), and an empty small cage was placed in another side chamber as a novelty object (non-social area). First, the mouse was placed in the central chamber and allowed to freely explore each chamber for 10 minutes, and the time spent in each of the three areas (social, central, and non-social areas) was recorded.

[0121] Statistical Analysis: Data were statistically analyzed using one-way or two-way RM analysis (SigmaStat 3.1). Post-hoc comparisons were performed using the Tukey HSD method. If the data were not normally distributed, a Kruskal-Wallis one-way rank-variable analysis was performed, followed by Dunn's method. All data are expressed as mean ± SEM. The significance level was set at p < 0.05.

[0122] Results: One-way variable analysis of time spent in the social area showed significant differences among the six groups (F(5, 48) = 5.201, p < 0.001). Post-hoc comparisons showed that the VPA-mediator group had significantly less time spent in the social area compared to the SAL-mediator group (p < 0.05) (Figure 1, left). Compared to the VPA-mediator group, both the VPA-ticagrelor (10 mg / kg) and VPA-ticagrelor (30) groups showed significantly more time spent in the social area (p < 0.01 and p < 0.001, respectively). There was no significant difference in time spent in the social area between the SAL-mediator group and the SAL-ticagrelor (30) group (p > 0.05).

[0123] One-way variable analysis of the time consumed in the central region showed significant differences among the six groups (F(5, 48) = 3.821, p < 0.01). Post-hoc comparisons showed that VPA-ticagrelor (30) significantly reduced the time consumed in the central region compared with the VPA-mediator group (p < 0.05) (Figure 1, middle plot).

[0124] One-way variable analysis of time spent in non-social areas showed significant differences among the six groups (F(5, 48) = 5.230, p < 0.001). Post-hoc comparisons showed that the VPA-mediator group had a significantly increased time spent in non-social areas compared to the SAL-mediator group (p < 0.01) (Figure 1, right panel). Compared to the VPA-mediator group, both the VPA-ticagrelor (10 mg / kg) and VPA-ticagrelor (30 mg / kg) groups had significantly reduced time spent in non-social areas (both, p < 0.01). There was no significant difference in time spent in non-social areas between the SAL-mediator group and the SAL-ticagrelor (30 mg / kg) group (p > 0.05).

[0125] Conclusion: Weekly, three-times administration of ticagrelor and zinc salts reduced social deficits, an autism-related symptom, observed in C57BL / 6J mice exposed to VPA in utero. Damage was observed in the VPA group compared to the control group in the 3-compartment test. In contrast, the ticagrelor treatment groups at doses of 10 and 30 mg / kg showed a significant increase in the time spent near the cage stimulating the "social" area. The data suggest that the postnatal effects of ticagrelor in relevant autism animal models indicate an improvement in social deficits in autistic patients.

[0126] Any of the above-mentioned regimens or their similar variants may be described in various documents related to pharmaceutical products. Such documents may include, but are not limited to, protocols, statistical analysis plans, investigator manuals, clinical guidelines, drug guides, risk assessment and mitigation plans, prescribing information, and other documents that may be related to pharmaceutical products. After special consideration, such documents may be physically packaged together with an ODT or ODF pharmaceutical product according to the present invention into a kit, which may be beneficial or required by regulatory authorities.

[0127] Although the subject matter of the present invention has been described and illustrated in considerable detail with reference to certain illustrative embodiments, including various combinations and sub-combinations of features, those skilled in the art will readily appreciate other embodiments and their variations and modifications as encompassed within the scope of the present invention. In addition, the description of such embodiments, combinations, and sub-combinations is not intended to convey that the claimed subject matter requires features or combinations of features other than those expressly recited therein in the claims. Accordingly, the scope of the present invention is intended to include all modifications and variations that fall within the spirit and scope of the following appended claims.

Brief Description of the Drawings

[0023] Figure 1 shows the results of a three-chamber test of the time spent by mice treated with SAL vehicle, SAL ticagrelor (30 mg / kg), VPA vehicle, VPA ticagrelor (0.3 mg / kg), VPA ticagrelor (10 mg / kg), and VPA ticagrelor (30 mg / kg) in the social area, central area, or non-social area. The bars from left to right in Figure 1 are in the same order as the labels from top to bottom in the legend, i.e., SAL vehicle is the leftmost bar, and VPA ticagrelor (30 mg / kg) is the rightmost bar.

Claims

1. Use of a combination of ticagrelor, its enantiomer or a pharmaceutically acceptable salt thereof, and a second agent in a weight ratio of 1:0.1 to 1:50, for the preparation of a medicament for the treatment of individuals diagnosed with autism spectrum disorder, intellectual disability, epilepsy, anxiety disorder, mood disorder, social interaction disorder, irritability, aggression, self-harm, hyperactivity, attention deficit, fragile X syndrome, or diagnosed with elevated TNFα or elevated inflammatory cytokine markers of neuroinflammation, wherein the second agent is selected from the group consisting of: magnesium-containing compounds, zinc-containing compounds, L-lysine or a salt thereof, L-arginine or a salt thereof, lecithin or a combination thereof.

2. As claimed in claim 1, wherein the combination is administered orally, non-enterally, intranasally, buccally, sublingually, or via mucosal route.

3. As claimed in claim 1, wherein the combination is administered as a liquid composition or in capsules.

4. As requested in claim 1, wherein the combination is administered in the form of a solid ODT, ODF, or self-microemulsifying drug delivery system (SMEDDS).

5. As claimed in claim 1, wherein the combination is administered in the form of SMEDDS comprising ticagrelor, its enantiomer or a pharmaceutically acceptable salt thereof, the second agent, and excipients, wherein when tested for dissolution in 500 mL of deionized water at 37.0 ± 0.5 °C using a United States Pharmacopeia apparatus 2 with a paddle at 50 rpm, the SMEDDS releases at least 75% of the ticagrelor, its enantiomer or a pharmaceutically acceptable salt thereof, and at least 75% of the second agent within 15 minutes.

6. As claimed in claim 4 or claim 5, wherein the SMEDDS has in vivo absorption properties such that approximately 50% of the maximum concentration of ticagrelor and approximately 50% of the maximum concentration of the second agent are absorbed into the plasma of a healthy human within 1 hour of ingestion; or such that approximately 80% of the maximum concentration of ticagrelor and approximately 80% of the maximum concentration of the second agent are absorbed into the plasma of a healthy human within 8 hours of ingestion.

7. As claimed in claim 4 or claim 5, wherein the SMEDDS contains 1 mg to 90 mg of ticagrelor and about 5 mg to 200 mg of the second dose.

8. As claimed in claim 4 or claim 5, wherein the SMEDDS contains 1 mg to 60 mg of ticagrelor and about 5 mg to 200 mg of the second dose.

9. As claimed in claim 4 or claim 5, wherein the SMEDDS is administered orally as an emulsion, aqueous suspension or oil suspension.

10. As used in claim 4 or claim 5, wherein the ratio of ticagrelor, its enantiomer or its pharmaceutically acceptable salt to the L-lysine in the SMEDDS is 1:0.4 to 1:20; or the ratio of ticagrelor, its enantiomer or its pharmaceutically acceptable salt to the magnesium-containing compound in the SMEDDS is 1:1 to 1:10; or the ratio of ticagrelor, its enantiomer or its pharmaceutically acceptable salt to the zinc-containing compound in the SMEDDS is 1:5 to 1:

50.

11. For any of the uses of claims 1 to 5, wherein the combination is formulated with a mixture of a magnesium compound or zinc compound and hydrochloric acid, pyrophosphate, taurine, sulfuric acid, acetic acid, carbonic acid, citric acid, caprylic acid, capric acid, ascorbic acid, threonic acid, tartaric acid, malic acid, fumaric acid, gluconic acid, succinic acid, lactic acid, glyceric acid, glyceraldehyde, α-hydroxy-carboxylic acid, or combinations thereof, in a ratio of 1:0.1 to 1:

50.

12. The use as claimed in any of claims 1 to 5, wherein the ticagrelor is a free base ticagrelor or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is ticagrelor hydrochloride, ticagrelor tartrate, ticagrelor threonate, ticagrelor glycerate, ticagrelor octanoate, ticagrelor citrate, or ticagrelor transbutenediazone.

13. For any of the uses described in claims 1 to 5, wherein the ticagrelor, its enantiomer or its pharmaceutically acceptable salt is administered at a dose of less than 60, 40, 30 or 20 mg / day.

14. As claimed in claim 1, wherein the second agent is a magnesium ion-containing compound.

15. As claimed in claim 14, wherein the magnesium-containing compound is a magnesium bromide, iodide, sulfate, acetate, threonate, tartrate, glycerol, citrate, caprylate, chloride, lactate, carbonate, malate, taurine, gluconate, succinate, or pyrophosphate.

16. The use of any of claims 1 to 5, wherein the second agent is a zinc ion compound.

17. As claimed in claim 16, wherein the zinc ion-containing compound is a bromide, iodide, or a complex of zinc ions with hydrochloric acid, pyrophosphate, taurine, sulfuric acid, acetic acid, carbonic acid, citric acid, caprylic acid, capric acid, ascorbic acid, threonic acid, tartaric acid, malic acid, fumaric acid, gluconic acid, succinic acid, lactic acid, glyceric acid, glyceraldehyde, or α-hydroxy-carboxylic acid.

18. The use of any of claims 1 to 5, wherein the second agent is L-lysine or a salt thereof.

19. The use of any of claims 1 to 5, wherein the second agent is L-arginine or a salt thereof.

20. The use of any of claims 1 to 5, wherein the second agent is lecithin.

21. The use of any of claims 1 to 5, wherein the second agent is not a stearate-containing compound, or wherein the second agent is not a threonate-containing compound.

22. The use of any of the claims 1 to 5, wherein the drug provides a therapeutically effective dose of ticagrelor within 1 hour of administration of the combination.

23. For any of the uses of claims 1 to 5, wherein the individual has been diagnosed with autism spectrum disorder.

24. For any of the uses of claims 1 to 5, wherein the individual is diagnosed with intellectual disability, epilepsy, anxiety disorder, mood disorder, social interaction disorder, irritability, aggression, self-harming behavior, hyperactivity, attention deficit, fragile X syndrome, elevated TNFα, or elevated inflammatory cytokine markers of neuroinflammation.

25. Use of ticagrelor, its enantiomer or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating an individual diagnosed with intellectual disability, irritability, aggression, self-harm, hyperactivity, inattention, fragile X syndrome or diagnosed with elevated TNFα or elevated inflammatory cytokine markers of neuroinflammation, wherein the ticagrelor, its enantiomer or a pharmaceutically acceptable salt thereof is administered to the individual, or wherein a combination of the ticagrelor, its enantiomer or a pharmaceutically acceptable salt thereof and a second agent in a weight ratio of 1:0.1 to 1:50 is administered to the individual, wherein the second agent is selected from the group consisting of: magnesium-containing compounds, zinc-containing compounds, L-lysine or a salt thereof, L-arginine or a salt thereof, lecithin or a combination thereof.

26. As requested in claim 2, wherein the combination is administered intravenously.

27. As requested in claim 2, wherein the combination is administered subcutaneously.

28. As claimed in claim 12, wherein the free base ticagrelor, ticagrelor hydrochloride, ticagrelor tartrate, ticagrelor threonate, ticagrelor glycerol, ticagrelor octanoate, ticagrelor citrate, or ticagrelor transbutenediarate is in a racemic form, or wherein the free base ticagrelor, ticagrelor hydrochloride, ticagrelor tartrate, ticagrelor threonate, or ticagrelor glycerol is in a racemic form. The ticagrelor citrate, the ticagrelor octanoate, or the ticagrelor transbutenedioate contains at least 95% enantiomeric purity of (1S,2S,3R,5S)-3-[7-[[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-1,2-cyclopentanediol.

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