Centanafadine formulations and methods of making and using same

Abstract

Pharmaceutical formulations containing centanafadine (CTN) or a pharma- ceutically acceptable salt thereof and excipients, and related methods of manufacture and use, are disclosed.

Description

[Technical Field]

[0001] (Cross-reference to related applications) The benefit under 35 USC §119(e) of U.S. Provisional Application Nos. 63 / 152,826 (filed February 23, 2021) and 63 / 241,839 (filed September 8, 2021) is claimed by this application, and the disclosures therein are incorporated herein by reference.

[0002] The present invention relates broadly to pharmaceutical formulations of centanafadine and its pharmaceutically acceptable salts, as well as methods for their preparation and treatment, including the treatment and prevention of central nervous system disorders and other conditions affected by monoamine neurotransmitters. [Background technology]

[0003] (1R,5S)-1-(Naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane (centanafadine) [CAS 924012-43-1]: [ka] is an unbalanced triple reuptake inhibitor with the highest potency for the norepinephrine reuptake transporter (NET), approximately 6-fold less potent for the dopamine reuptake transporter (DAT), and approximately 14-fold less potent for the serotonin reuptake transporter (SERT). There is a need for new pharmaceutical compositions containing the free form or pharmaceutically acceptable salts of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane. Summary of the Invention

[0004] Provided herein are pharmaceutical formulations of centanafadine or a salt thereof, and methods for making and using the same. The pharmaceutical formulations can include multiple regions containing centanafadine or a pharmaceutically acceptable salt thereof, such as beads, each of which contains a core particle containing centanafadine or a salt thereof and excipients.

[0005] Also provided herein is a pharmaceutical formulation containing centanafadine or a salt thereof, which is a solid oral formulation for pediatric use.

[0006] Also provided herein is a pharmaceutical formulation containing centanafadine or a salt thereof and excipients, which has a multifaceted release profile when tested in an acidic medium for 2 hours followed by a buffered medium at pH 7.4. Also provided herein is a pharmaceutical formulation containing centanafadine or a salt thereof and excipients, which exhibits a delayed-sustained release profile in vivo.

[0007] Also provided herein is a pharmaceutical formulation comprising a plurality of beads containing centanafadine or a salt thereof, each of the plurality of beads containing a core particle containing centanafadine or a salt thereof and an excipient, at least some of the core particles containing centanafadine or a salt thereof in an amount ranging from about 70% to about 90% by weight.

[0008] Also provided herein are pharmaceutical uses and methods of treatment employing the formulations disclosed herein, or uses of the formulations disclosed herein, including administering the formulations disclosed herein to an animal subject in need of treatment, optionally a mammalian subject in need of treatment, optionally a human subject in need of treatment.

[0009] Also provided herein is a method for producing a pharmaceutical formulation containing centanafadine or a salt thereof, the method comprising mixing centanafadine or a salt thereof with a binder to form particles containing centanafadine or a salt thereof having a predetermined particle size range, and coating at least a portion of the particles. [Brief explanation of the drawings]

[0010] [Figure 1] FIG. 1 is a graph of the in vivo absorption profile of a pharmaceutical formulation containing centanafadine hydrochloride administered to a subject in Example 2. [Figure 2]FIG. 2 is a graph of the in vivo absorption profile of a pharmaceutical formulation containing centanafadine hydrochloride administered to a subject in Example 3. [Figure 3-4] 3 and 4 are graphs of the in vivo absorption profile of a pharmaceutical formulation containing centanafadine hydrochloride administered to a subject in Example 4. [Figure 5-6] FIG. 5 is a graph showing the in vitro dissolution profile of the pharmaceutical formulation containing centanafadine hydrochloride in Example 5-4, and FIG. 6 is a graph showing the in vivo absorption profile of the same. [Figure 7-8] FIG. 7 is a graph showing the in vitro dissolution profile of the pharmaceutical formulation containing centanafadine hydrochloride in Example 5-5, and FIG. 8 is a graph showing the in vivo absorption profile of the same. [Figure 9-10] 9 and 10 are graphs of the in vivo absorption profiles of pharmaceutical formulations disclosed herein, including fast-release beads, sustained-release beads, and delayed-release beads containing centanafadine hydrochloride in Examples 5-6. [Figure 11-13] 11, 12 and 13 are graphs of the dissolution release profiles of centanafadine hydrochloride pharmaceutical formulations in various media in Example 6. [Figure 14] FIG. 14 is a graph of the dissolution release profile of a centanafadine hydrochloride formulation disclosed herein coated with a copolymer derived from methacrylic acid and ethyl acrylate (1:1). [Figure 15-16] 15 and 16 are graphs of the dissolution release profiles of centanafadine hydrochloride formulations disclosed herein coated with various ammonio methacrylate copolymer dispersions. [Figure 17] FIG. 17 is a graph of the dissolution release profile of the centanafadine hydrochloride formulation of Example 10, as described in Example 11. [Figure 18] FIG. 18 shows the mean centanafadine plasma concentrations obtained from doses of the formulations in Table 17 in the first pharmacokinetic (PK) study described in Example 12. [Figure 19]FIG. 19 shows the mean centanafadine plasma concentrations obtained from doses of the formulations in Table 17 in the second PK study described in Example 12. [Figure 20] FIG. 20 shows the dissolution release profile of the coated beads in Example 13. [Figure 21] FIG. 21 shows the dissolution release profile of the coated beads in Example 14. DETAILED DESCRIPTION OF THE INVENTION

[0011] Described herein are pharmaceutical formulations and dosage forms suitable for delivering centanafadine (CTN) or its pharmaceutically acceptable salts. CTN is classified as a BSC Class I molecule and has high solubility and high permeability. As used herein, CTN should be understood to mean centanafadine, and unless otherwise expressly stated, its pharmaceutically acceptable salts are also considered in addition to or as alternatives to one or more of the CTN options in all formulations, methods, and uses described herein. For example, in all instances where CTN is referred to, the disclosure is specifically contemplated as an option for the use of centanafadine hydrochloride. One embodiment of the formulation is a core / coating structure comprising CTN in a core region and a modified release region covering (e.g., on) the core region. Additional regions are also contemplated. For example, the core region can have an intermediate region (e.g., in the form of a seal-coating layer) between the core region and the modified release region.

[0012] The formulations described herein can be measured for the appropriate CTN dose prior to administration, or the formulations can be packaged in unit dosage form (e.g., capsules, sachets, etc.) Alternatively, the formulations can be formed into unit dosage form by compression into a monolithic unit form, such as a tablet.

[0013] One type of formulation includes multiple CTN-containing regions, each of which may have one or more release characteristics selected from delayed release, sustained release, fast release, and delayed-sustained release. The regions may be physically linked or separated. For example, one type of formulation includes multiple CTN-containing beads (CTN beads), each of which may contain a core particle and an excipient. In an embodiment, the multiple CTN beads may include one or more types of beads selected from delayed release beads, sustained release beads, fast release beads, and delayed-sustained release beads.

[0014] The pharmaceutical formulation may be provided in a unit dosage form, for example, as a collection of beads disposed in a capsule shell or as a collection of beads disposed in a sachet. In another type of embodiment, a collection of granules, with or without extragranular components (e.g., extragranular disintegrants), is compressed into a tablet. Other forms will be apparent to those skilled in the art in light of the disclosure herein.

[0015] Also provided herein is a pharmaceutical formulation containing CTN and excipients, which has an in vivo absorption profile that is bimodal.

[0016] The pharmaceutical formulations disclosed herein can be designed according to the disclosures herein, for example: 1) Where appropriate, the formulation may be a pediatric formulation that allows CTN preparations to be administered to children and young adults or patients who have difficulty swallowing solid oral preparations such as tablets or pills by sprinkling them (e.g., onto other soft foods such as applesauce or jelly), swallowing them without chewing, or via an enteral feeding tube; 2) the formulation may be effective in treating one or more of the conditions described herein when administered less than twice daily (e.g., on a once daily schedule); 3) the formulation is stable when exposed to high temperatures (e.g., 40°C) and high humidity (e.g., 75% RH); 4) The formulation is suitable for commercial scale manufacturing The present invention may be designed to incorporate one or more of the following features and advantages.

[0017] As described above, the formulations of the present disclosure may contain multiple CTN beads comprising one or more types selected from fast-release beads, sustained-release beads, delayed-release beads, and delayed-sustained-release beads. The multiple CTN-containing beads may include at least one bead comprising a delayed-release or delayed-sustained-release coating, at least one bead comprising a sustained-release coating, and at least one bead that is a fast-release bead. Such formulations have been shown to exhibit advantageous pharmacokinetics suitable for administration to pediatric subjects and for once-daily administration. Without intending to be bound by any particular theory, it is believed that pharmacokinetics are affected by multiple CTN beads comprising a combination of fast-release, sustained-release, and delayed-release bead types.

[0018] The pharmaceutical formulations and methods of the present disclosure are considered to include embodiments comprising any combination of one or more of the additional optional ingredients, features, and steps further described below (including those described in the Figures and Examples), unless otherwise indicated.

[0019] In jurisdictions that prohibit the patenting of methods performed on the human body, "administering" a composition to a human subject is limited to prescribing a controlled substance that the human subject self-administers by some technique (e.g., orally, inhalation, topical application, injection, insertion, etc.). The broadest reasonable interpretation consistent with the statute or regulation defining patentable subject matter is intended. In jurisdictions that do not prohibit the patenting of methods performed on the human body, "administering" a composition includes both the method performed on the human body and the aforementioned activities.

[0020] As used herein, the term "comprising" indicates that other agents, ingredients, steps or features are potentially included in addition to those specified.

[0021] As used herein, the term sustained release is synonymous with extended release and prolonged release.A dosage form is characterized by its overall release profile, which is the profile obtained from multiple regions if present in the dosage form.A dosage form that exhibits sustained release can be characterized as sustained release even if it further comprises a fast-release region in addition to a sustained-release formulation region (e.g., beads).Similarly, a dosage form that exhibits sustained release can be characterized as sustained release dosage form even if it further comprises a delayed-release region in addition to a sustained-release formulation region (e.g., beads).

[0022] As used herein, the term "wt%" refers to the total weight of what is being described, e.g., the total weight of the entire core particle, coating, or bead, as contextually or explicitly described. Unless otherwise specified, "wt%" is intended to represent the weight% based on dry weight (e.g., for the core particle after drying). Unless otherwise specified, the terms "wt%" and "% by weight" are used interchangeably herein.

[0023] The description herein refers to beads, and while beads, such as those produced by extrusion and spheronization, may have certain advantages, such as greater uniformity and size, particles of any size and shape and particles produced by other processes, as well as monolithic dosage forms, are contemplated as alternatives.

[0024] All ranges described herein include all possible subsets of ranges and any combination of such subset ranges.Unless otherwise specified, initially, the ranges include the specified endpoints.When a range of numerical values ​​is provided, it is understood that each value between the upper and lower limits of that range, as well as other stated values ​​or intermediate values ​​within the stated range, are encompassed within the present disclosure.The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the present disclosure, subject to any specifically excluded limits within the stated ranges.When a stated range includes one or both of the limits, ranges excluding one or both of those included limits are also considered to be part of the present disclosure.

[0025] Unless otherwise specified, all references to centanafadine herein are intended to encompass pharmaceutically acceptable salts thereof, and for all references to centanafadine herein, the use of centanafadine hydrochloride is specifically contemplated as an embodiment.

[0026] Unless expressly stated otherwise, references herein to beads and their properties are intended to be construed as applying equally to a collection of beads (e.g., a plurality of such beads). Similarly, unless expressly stated otherwise, references herein to core particles and their properties are intended to be construed as applying equally to a collection of core particles (e.g., a plurality of such core particles).

[0027] Centanafadine provided herein refers to (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, and may include its pharmaceutically acceptable salts. Pharmaceutically acceptable salts are known in the art, and include physiologically acceptable salts in the dosage and dosage form to be administered, such as hydrochloride salts. As used herein, "(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane" should be understood to include crystalline and amorphous compounds, including, for example, polymorphs, solvates (including hydrates), non-solvated polymorphs (including anhydrous forms), conformational polymorphs, and amorphous forms of compounds, and mixtures thereof. The terms "crystalline form" and "polymorph" can be used interchangeably herein and refer to all crystalline forms of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, either in free form or in pharmaceutically acceptable salt form, including, for example, polymorphs, solvates (including hydrates), non-solvated polymorphs (including anhydrates), and conformational polymorphs, as well as mixtures thereof, unless a specific crystalline form is specified. In some embodiments, CTN is provided as CTN hydrochloride. In the description herein, the amount, weight percentage, or range of CTN in a pharmaceutical formulation, bead, core particle, etc., is applicable to centanafadine free base and its pharmaceutically acceptable salts, and descriptions by weight should be considered as those relating to CTN free base, or alternatively, as descriptions applicable to pharmaceutically acceptable salt forms, unless otherwise specified.

[0028] Bead formulation The pharmaceutical formulations herein include multiple CTN-containing regions, e.g., beads, particles, etc., and the CTN-containing regions may have one or more release characteristics selected from fast-release, sustained-release, delayed-release beads, and delayed-sustained-release. In the following description, CTN beads are described as an example of such a formulation type. The formulation characteristics described, e.g., the ratio of different bead types, also apply to a collection of beads disposed in a unit dosage form, e.g., a capsule.

[0029] In one type of embodiment, the plurality of beads comprises a mixture of one or more fast-release beads and one or more sustained-release beads. In some embodiments, the amount of CTN by weight can be present in a ratio of about 1:100 to about 1:1 for a collection of one or more fast-release beads to a collection of one or more sustained-release beads. In some embodiments, the amount of CTN by weight can be present in a ratio of about 1:50 to about 1:1, or about 1:20 to about 1:1, or about 1:15 to about 1:1, e.g., 1:10, for a collection of one or more fast-release beads to a collection of one or more sustained-release beads.

[0030] In one type of embodiment, the plurality of beads comprises a mixture of one or more fast-release beads and one or more delayed-release beads. In some embodiments, the amount of CTN by weight can be present in a ratio of about 1:100 to about 1:1 for a population of one or more fast-release beads to a population of one or more delayed-release beads. In some embodiments, the amount of CTN by weight can be present in a ratio of about 1:50 to about 1:1 for a population of one or more fast-release beads to a population of one or more delayed-release beads, or in a ratio of about 1:20 to about 1:1, or about 1:15 to about 1:1, e.g., 1:10.

[0031] In one type of embodiment, the plurality of beads comprises a mixture of one or more delayed release beads and one or more sustained release beads. In some embodiments, the amount of CTN by weight can be present in a ratio of one or more delayed release bead populations to one or more delayed-sustained release bead populations in the range of about 5:1 to about 1:5, about 3:1 to about 1:3, or about 2:1 to about 1:2, and also about 1.5:1 to about 1:1.5, e.g., about 1:1.

[0032] In one type of embodiment, the plurality of beads comprises a mixture of one or more fast-release beads and one or more delayed-sustained release beads. In some embodiments, the amount of CTN by weight can be present in a ratio ranging from about 1:100 to about 1:1 for a collection of one or more fast-release beads to a collection of one or more delayed-sustained release beads. In some embodiments, the amount of CTN by weight can be present in a ratio ranging from about 1:50 to about 1:1, or from about 1:20 to about 1:1, or from about 1:15 to about 1:1, e.g., in a range of 1:10, for a collection of one or more delayed-sustained release beads to a collection of one or more fast-release beads.

[0033] In one type of embodiment, the plurality of beads comprises a mixture of one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads. In some embodiments, the ratio of CTN may be present in one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads in a ratio ranging from about 0.1 to 1:1 to 20:1 to 20 parts by weight based on the weight of CTN. In some embodiments, the ratio of CTN may be present in one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads in a ratio ranging from about 0.5 to 1:5 to 20:5 to 20 parts by weight based on the weight of CTN. In some embodiments, the ratio of CTN or a pharmaceutically acceptable salt thereof may be present in one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads in a ratio ranging from about 0.7 to 1.3:3 to 6:3 to 6 parts by weight based on the weight of CTN. In some embodiments, the ratio of CTN or a pharmaceutically acceptable salt thereof in one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads can be in a range of about 0.7-1:5-15:5-15 parts by weight based on the weight of CTN. For example, the ratio of CTN or a pharmaceutically acceptable salt thereof in one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads can be 1:3.6:3.6.

[0034] In one type of embodiment, the plurality of beads comprises a mixture of one or more fast-release beads, one or more sustained-release beads, and one or more delayed-sustained-release beads. In some embodiments, the ratio of CTN in one or more fast-release beads, one or more sustained-release beads, and one or more delayed-sustained-release beads may be in a ratio ranging from about 0.1 to 1:1 to 20:1 to 20 parts by weight based on the weight of CTN. In some embodiments, the ratio of CTN or a pharmaceutically acceptable salt thereof in one or more fast-release beads, one or more sustained-release beads, and one or more delayed-sustained-release beads may be in a ratio ranging from about 0.5 to 1:5 to 20:5 to 20 parts by weight based on the weight of CTN. In some embodiments, the ratio of CTN or a pharmaceutically acceptable salt thereof may be present in one or more fast-release beads, one or more sustained-release beads, and one or more delayed-sustained-release beads in a ratio ranging from about 0.7 to 1.3:3 to 6:3 to 6 parts by weight based on the weight of CTN. In some embodiments, the ratio of CTN or a pharmaceutically acceptable salt thereof may be present in one or more fast-release beads, one or more sustained-release beads, and one or more delayed-sustained-release beads in a ratio ranging from about 0.7 to 1:5 to 15:5 to 15 parts by weight based on the weight of CTN. For example, the ratio of CTN or a pharmaceutically acceptable salt thereof may be present in one or more fast-release beads, one or more sustained-release beads, and one or more delayed-sustained-release beads in a ratio ranging from about 1:3.6:3.6 parts by weight based on the weight of CTN.

[0035] In some embodiments, the fast-release beads may be present in the formulation or dosage form in an amount ranging from about 1% to about 75% based on the total weight of the plurality of CTN beads in the formulation or dosage form. For example, the fast-release beads may be present in the formulation in an amount ranging from about 1% to about 60%, or from about 1% to about 50%, or from about 5% to about 50%, or from about 5% to about 40%, or from about 5% to about 30%, or from about 5% to about 25%, or from about 10% to about 30%, or from about 9% to about 55%, or from about 18% to about 28%, or from about 5% to about 20%, or from about 5% to about 15%, or from about 1% to about 25%, or from about 1% to about 10%, based on the total weight of the plurality of CTN beads. In some embodiments, the fast-release beads may be present in the formulation in an amount ranging from about 1% to about 50% based on the total weight of the plurality of CTN beads. In some embodiments, the fast-release beads are present in the formulation in an amount ranging from about 1% to about 25% based on the total weight of the plurality of CTN beads. In some embodiments, the fast-release beads are present in the formulation in an amount ranging from about 1% to about 10% based on the total weight of the plurality of CTN beads. In some embodiments, the fast-release beads may be present in the formulation in an amount ranging from about 9% to about 19% based on the total weight of the plurality of CTN beads, with such embodiments being particularly contemplated when the drug loading in the beads is about 40% to about 60% by weight (e.g., 50% by weight). In some embodiments, the fast-release beads may be present in the formulation in an amount ranging from about 40% to about 55% based on the total weight of the plurality of CTN beads, with such embodiments being particularly contemplated when the drug loading in the beads is about 5% to about 15% by weight (e.g., 10% by weight). In some embodiments, the fast-release beads are present in the formulation in an amount ranging from about 18% to about 28% based on the total weight of the plurality of CTN beads.

[0036] In some embodiments, the fast-release beads or bead cores may contain CTN in an amount ranging from about 5% to about 90% by weight, based on the total weight of the beads or bead cores. For example, the fast-release beads or bead cores may contain CTN in an amount ranging from about 5% to about 85% by weight, about 5% to about 80% by weight, about 5% to about 60% by weight, about 5% to about 30% by weight, about 25% to about 60% by weight, about 40% to about 60% by weight, or about 5% to about 15% by weight, based on the total weight of the beads or bead cores. In some embodiments, the fast-release beads or bead cores may contain CTN in an amount ranging from 5% to 15% by weight, based on the total weight of the beads or bead cores. In some embodiments, the fast-release beads or bead cores may contain CTN in an amount ranging from 40% to 60% by weight, based on the total weight of the fast-release beads or bead cores. In some embodiments, the release beads or bead cores may contain CTN in an amount ranging from about 70% to about 90% by weight, or from about 75% to about 80% by weight, based on the total weight of the fast-release beads or bead cores. In some embodiments, the pharmaceutical formulations herein may contain first fast-release beads or bead cores (in which the CTN is present in an amount ranging from 5% to 15% by weight, based on the total weight of the fast-release beads or bead cores) and second fast-release beads (in which the CTN is present in an amount ranging from 40% to 60% by weight, based on the total weight of the fast-release beads or bead cores). In some embodiments, the pharmaceutical formulations may contain bead cores having CTN in an amount ranging from about 70% to about 90% by weight, or from about 75% to about 80% by weight, based on the total weight of the bead cores, together with one or more coatings covering the bead cores.

[0037] In some embodiments, the sustained release beads may be present in the formulation or dosage form in an amount ranging from about 5% to about 80% based on the total weight of the plurality of CTN beads in the formulation or dosage form. For example, the sustained release beads may be present in the formulation or dosage form in an amount ranging from about 5% to about 65%, or from about 10% to about 60%, or from about 20% to about 60%, or from about 25% to about 55%, or from about 25% to about 50%, or from about 35% to about 55%, or from about 40% to about 50%, or from about 45% to about 55%, based on the total weight of the plurality of CTN beads. In some embodiments, the sustained release beads may be present in the formulation or dosage form in an amount ranging from about 5% to about 65% based on the total weight of the plurality of CTN beads. In some embodiments, the sustained release beads may be present in the formulation or dosage form in an amount ranging from about 35% to about 55%, or from about 42% to about 48%, based on the total weight of the plurality of CTN beads.

[0038] In some embodiments, the sustained release beads may contain CTN in an amount ranging from 10% to 95% by weight, based on the total weight of the sustained release beads. For example, the sustained release beads may contain CTN in an amount ranging from about 30% to about 90% by weight, about 40% to about 90% by weight, about 50% to about 90% by weight, about 50% to about 80% by weight, or about 50% to about 70% by weight, based on the total weight of the sustained release beads. In some embodiments, the sustained release beads may contain CTN in an amount ranging from 40% to 90% by weight, based on the total weight of the sustained release beads. In some embodiments, the sustained release beads may contain CTN in an amount ranging from 50% to 70% by weight, based on the total weight of the sustained release beads.

[0039] In some embodiments, the delayed-release beads may be present in the formulation or dosage form in an amount ranging from about 5% to about 80% based on the total weight of the plurality of CTN beads in the formulation or dosage form. For example, the delayed-release beads may be present in the formulation in an amount ranging from about 5% to about 65%, or from about 10% to about 70%, or from about 20% to about 60%, or from about 25% to about 55%, or from about 25% to about 50%, or from about 30% to about 55%, or from about 36% to about 46%, or from about 40% to about 50% based on the total weight of the plurality of CTN beads. In some embodiments, the delayed-release beads may be present in the formulation in an amount ranging from about 5% to about 65% based on the total weight of the plurality of CTN beads. In some embodiments, the delayed-release beads may be present in the formulation in an amount ranging from about 30% to about 55%, or from about 38% to about 44% based on the total weight of the plurality of CTN beads.

[0040] In some embodiments, the delayed-release beads may contain CTN in an amount ranging from 10% to 95% by weight, based on the total weight of the delayed-release beads. For example, the delayed-release beads may contain CTN in an amount ranging from about 30% to about 90% by weight, about 40% to about 90% by weight, about 50% to about 90% by weight, about 50% to about 85% by weight, or about 50% to about 70% by weight, based on the total weight of the delayed-release beads. In some embodiments, the delayed-release beads may contain CTN in an amount ranging from 40% to 90% by weight, based on the total weight of the delayed-release beads. In some embodiments, the delayed-release beads may contain CTN in an amount ranging from 50% to 70% by weight, based on the total weight of the delayed-release beads.

[0041] In some embodiments, the fast release beads are present in the formulation or dosage form in an amount ranging from about 1% to about 10% by weight, the sustained release beads are present in the formulation or dosage form in an amount ranging from about 45% to about 55% by weight, and the delayed release beads are present in the formulation or dosage form in an amount ranging from about 40% to about 50% by weight. In some embodiments, the fast release beads may be present in the formulation or dosage form in an amount ranging from about 4% to about 28% by weight, the sustained release beads may be present in the formulation or dosage form in an amount ranging from about 15% to about 40% by weight, and the delayed release beads may be present in the formulation or dosage form in an amount ranging from about 30% to about 65% by weight.

[0042] In some embodiments, the fast-release beads may be present in the formulation or dosage form in an amount ranging from about 11% to about 17% by weight of the formulation or dosage form, the sustained-release beads may be present in the formulation or dosage form in an amount ranging from about 42% to about 48% by weight of the formulation or dosage form, and the delayed-release beads (or delayed-sustained-release beads) may be present in the formulation or dosage form in an amount ranging from about 38% to about 44% by weight of the formulation or dosage form, wherein such embodiments are specifically contemplated where the drug loading in each bead type is about 5% to about 10% by weight, about 45% to about 55% by weight, and about 45% to about 55% by weight, respectively, based on the total weight of the beads. In some embodiments, the fast release beads may be present in the formulation or dosage form in an amount ranging from about 43% to about 49% by weight of the formulation or dosage form, the sustained release beads may be present in the formulation or dosage form in an amount ranging from about 25% to about 31% by weight of the formulation or dosage form, and the delayed release beads may be present in the formulation or dosage form in an amount ranging from about 38% to about 44% by weight of the formulation or dosage form, wherein such embodiments are specifically contemplated where the drug loading on each bead type is about 45% to about 55% by weight.

[0043] Nuclear bead preparation Each of the multiple CTN beads includes a core particle. The core particle includes CTN and an excipient. The CTN bead may consist of the core particle itself without a coating. As described further below, the CTN bead may include a core particle and one or more coatings.

[0044] In some embodiments, the core particles may be characterized by a particle size distribution. In some embodiments, at least some or all of the core particles of a plurality of CTN beads may have a core particle size (maximum diameter) of about 0.2 mm to about 2 mm, or about 0.3 mm to about 1.5 mm, or about 0.4 mm to about 1.5 mm. For example, at least some of the core particles of a plurality of CTN beads may have a core particle size of about 0.2 mm to about 2 mm, or about 0.3 mm to about 1.5 mm, or about 0.4 mm to about 1.4 mm, or about 0.4 mm to about 1.3 mm, or about 0.4 mm to about 1.2 mm, or about 0.4 mm to about 1.1 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm. In one embodiment, at least a portion of the core particles of the plurality of CTN beads have a core particle diameter of about 0.5 mm to about 0.71 mm. In one embodiment, the core particles of the plurality of CTN beads have a core particle diameter of about 0.5 mm to about 0.71 mm. The core particle diameter is selected by sieving, for example, to remove particles having a size outside the desired range. In one embodiment, the particle size distribution of the core particles can be characterized in that at least 60% by weight of the core particles have a particle diameter in the range of about 0.4 mm to about 1.5 mm. For example, the particle size distribution of the core particles may be characterized in that at least 60% by weight of the core particles have a particle size in the range of about 0.4 mm to about 1.4 mm, or about 0.4 mm to about 1.3 mm, or about 0.4 mm to about 1.2 mm, or about 0.4 mm to about 1.1 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm. In one embodiment, the particle size distribution of the core particles is characterized in that at least 60% by weight of the core particles have a particle size in the range of about 0.5 mm to about 0.71 mm. In another embodiment, the particle size distribution of the core particles is characterized in that at least 80% by weight of the core particles have a particle size in the range of about 0.4 mm to about 1.5 mm. For example, the particle size distribution of the core particles is characterized in that at least 80% by weight of the core particles have particle sizes in the range of about 0.4 mm to about 1.4 mm, or about 0.4 mm to about 1.3 mm, or about 0.4 mm to about 1.2 mm, or about 0.4 mm to about 1.1 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm.In one embodiment, the particle size distribution of the core particles is characterized by at least 80% by weight of the core particles having a particle size in the range of about 0.5 mm to about 0.71 mm. In another embodiment, the particle size distribution of the core particles is characterized by at least 90% by weight of the core particles having a particle size in the range of about 0.4 mm to about 1.5 mm. For example, the particle size distribution of the core particles is characterized by at least 90% by weight of the core particles having a particle size in the range of about 0.4 mm to about 1.4 mm, or about 0.4 mm to about 1.3 mm, or about 0.4 mm to about 1.2 mm, or about 0.4 mm to about 1.1 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm. In another embodiment, the particle size distribution of the core particles is characterized by at least 90% by weight of the core particles having a particle size in the range of about 0.5 mm to about 0.71 mm. In some embodiments, the CTN beads may have an average particle size (diameter) ranging from about 0.2 mm to about 2.8 mm. For example, the CTN beads may have an average particle size (diameter) ranging from about 0.2 mm to about 2.5 mm, or from about 0.2 mm to about 2.0 mm, or from about 0.7 mm to about 2.5 mm, or from about 0.7 mm to about 2.8 mm, or from about 0.5 mm to about 2.8 mm, or from about 0.8 mm to about 1.7 mm, or from about 0.5 mm to about 1.2 mm, or from about 0.5 mm to about 1.0 mm, or from about 0.5 mm to about 0.71 mm. In some embodiments, the CTN beads may have an average particle size (diameter) ranging from about 0.5 mm to about 0.71 mm.

[0045] The amount of CTN in the core particle can range from about 5% to about 95% by weight. In some embodiments, at least a portion of the plurality of CTN beads includes a core particle containing CTN in an amount ranging from about 5% to about 75% by weight. For example, at least a portion of the plurality of CTN beads includes a core particle containing CTN in an amount ranging from about 5% to about 70% by weight, or from about 10% to about 70% by weight, or from about 20% to about 60% by weight, or from about 30% to about 60% by weight, or from about 40% to about 60% by weight, or from about 45% to about 55% by weight. In some embodiments, at least a portion of the plurality of CTN beads includes a core particle containing CTN in an amount ranging from about 45% to about 55% by weight. In some embodiments, at least a portion of the plurality of CTN beads includes a core particle containing CTN in an amount of about 50% by weight. For example, fast-release beads include a core particle containing CTN in an amount of about 10% by weight or about 50% by weight. In some embodiments, at least a portion of the plurality of CTN beads comprises a core particle containing CTN in an amount ranging from about 25% to about 95% by weight. For example, at least a portion of the plurality of CTN beads comprises a core particle containing CTN in an amount ranging from about 25% to about 90% by weight, or from about 35% to about 90% by weight, or from about 45% to about 90% by weight, or from about 50% to about 85% by weight, or from about 60% to about 85% by weight, or from about 75% to about 85% by weight, or about 50%, about 60%, about 70%, or about 80% by weight. In some embodiments, at least a portion of the plurality of CTN beads comprises a core particle containing CTN in an amount ranging from about 75% to about 85% by weight. In some embodiments, at least a portion of the plurality of CTN beads comprises a core particle containing CTN in an amount of about 80% by weight. For example, sustained-release beads may comprise a core particle containing CTN in an amount of about 80% by weight. For example, the delayed release beads include core particles containing CTN in an amount of about 80% by weight.

[0046] The core particles disclosed herein include excipients. In some embodiments, the excipients include one or more materials selected from fillers, binders, glidants, surfactants, polymer coatings, lubricants, disintegrants, and plasticizers. In some embodiments, the excipients may include one or more materials selected from fillers, binders, glidants, surfactants, polymer coatings, and plasticizers. In some embodiments, the excipients may include fillers and binders. In some embodiments, the excipients may include binders and polymer coatings. In some embodiments, the excipients may include fillers, binders, and polymer coatings. In some embodiments, the excipients may include fillers, binders, polymer coatings, and plasticizers. In some embodiments, the pharmaceutical formulation may not include a disintegrant. In some embodiments, the dosage form containing the pharmaceutical formulation may not include a disintegrant.

[0047] Bulking agents may include, but are not limited to, lactose, sucrose, glucose, starch, microcrystalline cellulose, microfine cellulose, mannitol, sorbitol, calcium hydrogen phosphate, aluminum silicate, amorphous silica, and sodium chloride, starch, and dicalcium phosphate dihydrate. In one type of embodiment, the bulking agent is capable of absorbing water but is not water-soluble. In one type of embodiment, the bulking agent is a spheronization aid. Spheronization aids may include, for example, one or more of crospovidone, carrageenan, chitosan, pectic acid, glycerides, β-CD, cellulose derivatives, microcrystalline cellulose, powdered cellulose, polyplasdone, and polyethylene oxide. In one type of embodiment, the bulking agent includes microcrystalline cellulose.

[0048] Binders include cellulose ethers, methylcellulose, ethylcellulose, hydroxyethylcellulose, propylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose, e.g., hypromellose 2910, METHOCE TME-5 [CAS 9004-65-3] Hydroxypropyl methylcellulose HPMC (Sigma or DuPont TM Examples of binders include, but are not limited to, cellulose acetate (same as available from Pharmacy), carboxymethylcellulose, starch, pregelatinized starch, acacia, tragacanth, gelatin, polyvinylpyrrolidone (povidone, PVP), cross-linked polyvinylpyrrolidone, sodium alginate, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose. In one type of embodiment, the binder is selected from a wet binder. In one type of embodiment, the binder is selected from cellulose ethers, such as hypromellose.

[0049] The surfactant may include, but is not limited to, anionic surfactants such as sodium lauryl sulfate, sodium deoxycholate, dioctyl sodium sulfosuccinate, and sodium stearyl fumarate, nonionic surfactants such as polyoxyethylene ethers and polysorbate 80, and cationic surfactants such as quaternary ammonium compounds. In one type of embodiment, the surfactant is selected from anionic surfactants, such as sodium lauryl sulfate.

[0050] Disintegrants may include, but are not limited to, starch, cross-linked sodium carboxymethylcellulose, croscarmellose sodium, croscarmellose calcium, cross-linked polyvinylpyrrolidone, and sodium starch glycolate, low-substituted hydroxypropyl cellulose, and hydroxypropyl starch.

[0051] Glidants may include, but are not limited to, polyethylene glycol of various molecular weights, magnesium stearate, calcium stearate, calcium silicate, fumed silicon dioxide, magnesium carbonate, magnesium lauryl sulfate, aluminum stearate, stearic acid, palmitic acid, cetyl alcohol, sterols, and talc.

[0052] Lubricants may include, but are not limited to, stearic acid, magnesium stearate, calcium stearate, aluminum stearate, and siliconized talc.

[0053] In some embodiments, excipients include lactose, mannitol, corn starch, microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), polyvinylpyrrolidone, talc, polysorbate 80, glycerol monostearate, triethyl citrate, polyvinyl alcohol-polyethylene glycol graft copolymer (e.g., Kollicoat, available from Sigma), and the like. TM In some embodiments, the excipient may include one or more materials selected from cellulose acetate (IR CAS 96734-39-3) and silica. In some embodiments, the excipient may include microcrystalline cellulose and mannitol. In some embodiments, the excipient may include microcrystalline cellulose, talc, hypromellose, and polysorbate 80. In some embodiments, the excipient may include microcrystalline cellulose. In some embodiments, the core particles may include an excipient including microcrystalline cellulose.

[0054] The amount of filler in the core particles is not particularly limited. In some embodiments, the amount of filler (e.g., crystalline cellulose) can be about 10% by weight to about 90% by weight, about 10% by weight to about 75% by weight, or about 10% by weight to about 60% by weight, or at least 10% by weight, or at least 15% by weight, for example, about 20% by weight, or about 30% by weight, or about 40% by weight, or about 50% by weight.

[0055] The amount of binder in the core particles is not particularly limited. In some embodiments, the amount of binder (e.g., hypromellose and / or polyvinyl alcohol-polyethylene glycol graft copolymer) can be in the range of about 1 wt% to about 10 wt%, or about 2 wt% to about 8 wt%, or about 4 wt% to about 6 wt%, for example, about 5 wt%.

[0056] The amount of surfactant in the core particles, for example, the amount of surfactant as a processing aid, is not particularly limited. In some embodiments, the amount of surfactant (e.g., crystalline cellulose) can be in the range of about 0.1% by weight to about 1% by weight, or about 0.2% by weight to about 0.8% by weight, or about 0.4% by weight to about 0.6% by weight, for example, about 0.5% by weight.

[0057] coating One type of embodiment of the pharmaceutical formulation disclosed herein includes a plurality of beads, at least some of which are coated. In some embodiments, at least some of the beads may be uncoated. In some embodiments, the coating may be one or more coatings selected from a delayed-release coating, a sustained-release coating, and a delayed-sustained-release coating. In some embodiments, at least some of the beads may include a delayed-release coating. In some embodiments, at least some of the beads may include a sustained-release coating. In some embodiments, at least some of the beads may include a delayed-sustained-release coating.

[0058] The coating materials, e.g., polymers, disclosed herein can be delayed-release coatings. In some embodiments, the delayed-release coating dissolves in intestinal fluids at pH levels higher than that of the stomach (e.g., pH 4.5 or higher in the small intestine), thereby releasing the active agent in the small intestine or later regions without substantially releasing it in the upper gastrointestinal tract. In one type of embodiment, the enteric material begins to dissolve in aqueous solution at a pH of about 4.5 to about 5.5. In another type of embodiment, the delayed-release material rapidly dissolves in aqueous solution at a pH of about 5. In another type of embodiment, the delayed-release material rapidly dissolves in aqueous solution at a pH of about 5.5. For example, a pH-sensitive material can be selected that does not undergo significant dissolution until the dosage form is emptied from the stomach. The pH of the small intestine gradually increases from about 4.5 to about 6.5 in the duodenal bulb to about 7.2 in the distal part of the small intestine (ileum). In another type of embodiment, the delayed-release material dissolves at a pH of at least 7, or at least 7.2, or at least 7.4, for example, to target release in the distal small intestine or the large intestine. In another type of embodiment, the delayed-release material is insoluble in water or gastric fluids, but instead swells to provide a membrane through which the CTN active agent can diffuse. The insoluble polymer can also be selected to swell at a specific pH threshold, for example, a pH threshold of at least 7, or at least 7.2, or at least 7.4, for example, to target release in the distal small intestine or the large intestine.

[0059] Delayed release coating materials may include, but are not limited to, one or more of the following materials: Cross-linked polyvinylpyrrolidone; Non-crosslinked polyvinylpyrrolidone; Hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate succinate; Cellulose acetate phthalate, hydroxypropylmethyl cellulose acetate succinate, cellulose acetate trimellitate; Starch acetate phthalate; Polyvinyl acetate phthalate; Carboxymethylcellulose; methylcellulose phthalate; methylcellulose succinate; Methylcellulose phthalate succinate; Methylcellulose phthalate half ester; Ethyl cellulose succinate; Carboxymethylamide; potassium methacrylate / divinylbenzene copolymer; Polyvinyl alcohols; Polyoxyethylene glycol; Polyethylene glycol; sodium alginate; Galactomannan; Carboxypolymethylene; Sodium carboxymethyl starch; Copolymers of acrylic acid and / or methacrylic acid containing monomers selected from the following: methyl methacrylate, ethyl methacrylate, ethyl acrylate, butyl methacrylate, hexyl methacrylate, decyl methacrylate, lauryl methacrylate, phenyl methacrylate, methyl acrylate, isopropyl acrylate, isobutyl acrylate, or octadecyl acrylate, such as EUDRAGIT available from Evonik Industries (Essen, North Rhine-Westphalia, Germany). TM -L and -S series, for example, L 100-55, L 30 D-55, L 100, S 100, L 12.5, and S 12.5; Polyvinyl acetate; fat; oil; wax; fatty alcohols; Shellac; Zane; gluten; Ethyl acrylate-maleic anhydride copolymer; Maleic anhydride-vinyl methyl ether copolymer; styrene-maleic acid copolymer; 2-Ethyl-hexyl-acrylate maleic anhydride; Crotonic acid-vinyl acetate copolymer; Glutamic acid / glutamic acid ester copolymer; Carboxymethylethylcellulose glycerol monooctanoate; Polyarginine; polyethylene); polypropylene); Poly(ethylene oxide); Poly(ethylene terephthalate); Poly(vinyl isobutyl ether); poly(vinyl chloride); and Polyurethane. A combination of delayed-release coatings may also be used. In one type of embodiment, the delayed-release coating dissolves at a pH of 7.0 or higher, or 7.2 or higher, or 7.4 or higher, and is released, for example, in the large intestine. For example, the delayed-release coating may be selected from a copolymer of methacrylic acid and methyl methacrylate and a copolymer of methacrylic acid and ethyl acrylate. In some embodiments, the delayed-release coating may comprise one or more materials selected from amylose acetate phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate trimellitate, carboxymethyl ethyl cellulose, copolymerized methacrylic acid / methacrylic acid methyl ester, copolymerized methacrylic acid / methyl methacrylate, copolymerized methyl acrylate / methyl methacrylate / methacrylic acid, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, styrene-maleic acid copolymer, and styrene-vinylpyridine copolymer. In some embodiments, the delayed-release coating can include one or more materials selected from copolymers of methacrylic acid, methyl methacrylate, and methyl acrylate, and methacrylic acid-acrylate copolymers. In some embodiments, the delayed-release coating can include copolymers of methyl acrylate, methyl methacrylate, and methacrylic acid, for example, in a molar ratio of about 7:3:1 (e.g., Eudragit TM FS 30 D). Eudragit TM FS 30 D is poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid [CAS 26936-24-3] available from Evonik Industries. In another embodiment, the delayed release coating is a cationic copolymer of ethyl acrylate, methyl methacrylate, and methacrylic acid esters containing quaternary ammonium groups (e.g., Eudragit TM RL and Eudragit TM RS polymer). TM RL 30 D and Eudragit TMRS 30 D is an aqueous dispersion of a copolymer of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups, available from Evonik Industries.

[0060] In some embodiments, the delayed-release coating may also provide sustained release of CTN. In some embodiments, the delayed-release coating comprises an anionic polymer that optionally includes carboxylate moieties. FIG. 7 illustrates a copolymer of methyl acrylate, methyl methacrylate, and methacrylic acid (e.g., in a molar ratio of about 7:3:1 (e.g., Eudragit TM It has been shown that delayed-release coatings based on FS 30 D) also have sustained-release functionality. Without intending to be bound by any particular theory, it is possible that because poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) polymer is anionic and has negatively charged carboxylate moieties (ratio of carboxyl groups to ester groups is approximately 1:10), and centanafadine is a positively charged secondary amine, the polymer may affect the release rate of centanafadine from the beads through ionic interactions.

[0061] Some examples of delayed-release coatings are disclosed in U.S. Pat. No. 5,225,202, and include beeswax and glyceryl monostearate; beeswax, shellac and cellulose; cetyl alcohol, mastic and shellac, and shellac and stearic acid (U.S. Pat. No. 2,809,918); polyvinyl acetate and ethyl cellulose (U.S. Pat. No. 3,835,221); and neutral copolymers of polymethacrylic acid esters (Eudragit TM L30D) (FW Goodhart et al., Pharm. Tech., pp. 64-71, April 1984); copolymers of methacrylic acid and methacrylic acid methyl ester (Eudragit TMPolymers), or neutral copolymers of polymethacrylates containing metal stearates (Mehta et al., U.S. Pat. Nos. 4,728,512 and 4,794,001). Such coatings include mixtures of fats and fatty acids, mixtures of shellac and shellac derivatives, and mixtures of cellulose acid phthalates, including those with free carboxyl content. For a description of suitable enteric coating compositions, see Remington's Pharmaceutical Sciences, A. Osol, ed., Mack Pub. Co., Easton, Pa. (16th ed. 1980) at pages 1590-1593, and Zeitova et al. (U.S. Pat. No. 4,432,966).

[0062] The coating materials disclosed herein, such as polymers, can be sustained-release coatings. A non-limiting list of suitable sustained-release materials includes hydrophilic and / or hydrophobic materials such as gums, cellulose ethers, acrylic resins, protein-derived materials, waxes, shellac, and oils, such as hydrogenated castor oil and hydrogenated vegetable oil. However, any pharmaceutically acceptable hydrophobic or hydrophilic sustained-release material capable of providing sustained release of CTN can be used in accordance with the present invention. In some embodiments, the sustained-release coating includes one or more materials selected from alkylcelluloses such as ethylcellulose, polymers and copolymers of acrylic and methacrylic acid, and cellulose ethers, particularly hydroxyalkylcelluloses (particularly hydroxypropylmethylcellulose) and carboxyalkylcelluloses. Preferred acrylic and methacrylic acid polymers and copolymers include methyl methacrylate, methyl methacrylate copolymer, ethoxyethyl methacrylate, ethyl acrylate, trimethylammonioethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymer, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymer. In one type of embodiment, the sustained-release coating material is insoluble in water.

[0063] In some embodiments, the sustained-release coating includes one or more materials selected from alkylcelluloses such as ethylcellulose, acrylic acid polymers, methacrylic acid polymers, acrylic acid copolymers, methacrylic acid copolymers, and cellulose ether hydroxyalkylcelluloses (particularly hydroxypropylmethylcellulose), and carboxyalkylcelluloses. In some embodiments, the sustained-release coating includes one or more materials selected from hydroxyalkylcelluloses, carboxyalkylcelluloses, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylate, ethyl acrylate, trimethylammonioethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymers, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic anhydride), and glycidyl methacrylate copolymers. In some embodiments, the sustained release polymer includes one or more materials selected from poly[ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride], hydroxypropyl methylcellulose, and poly[ethyl acrylate, methyl methacrylate]. In some embodiments, the sustained release polymer includes poly[ethyl acrylate, methyl methacrylate] (e.g., Eudragit) in a molar ratio of, for example, about 2:1. TM In some embodiments, the sustained release coating includes the EUDRAGIT 30D, including RL30D, RS30D, NE 30D, and NM 30D. TM The Eudragit® 1000 series includes one or more materials selected from the -RL, -RS, -NE, and -NM series, which are available from Evonik Industries. A combination of sustained release coatings may also be used. TM NM 30D [CAS 9010-88-4] and Eudragit TMNE 30D [CAS 9010-88-2] is an aqueous dispersion of a neutral copolymer based on ethyl acrylate and ethyl methacrylate with a polymer content of about 30% available from Evonik Industries. In some embodiments, sustained release polymers include ethyl cellulose, available from, for example, DuPont TM Aquacoat available from TM It has an ECD 30D coating.

[0064] As is known in the art, one or more plasticizers can be added to the delayed-release and / or sustained-release coatings to increase flexibility and reduce brittleness. Suitable plasticizers are known in the art and include, for example, butyl citrate, triethyl citrate, diethyl phthalate, dibutyl sebacate, PEG (e.g., PEG 6000), acetyltriethyl citrate, and triacetin. In one type of embodiment, the plasticizer is triethyl citrate. Some delayed-release and / or sustained-release coatings are flexible and do not require the addition of a plasticizer, while more brittle polymers (e.g., Eudragit TM L / S type, Eudragit TM RL / RS, and Eudragit TM FS 30 D) benefits from a plasticizer, for example, in the range of 5% to 30% by weight based on the dry polymer mass, for example, about 8% to about 12% by weight of PlasACRYL available from Evonik Industries. TM At T20, an anti-adhesion system containing glycerol monostearate, triethyl citrate and polysorbate 80 at approximately 20% solids is used.

[0065] As is known in the art, one or more anti-adherents (anti-sticking agents) may be added to the enteric coating mixture to reduce film stickiness and prevent clumping. Examples of anti-adherents include talc, glyceryl monostearate, and fumed silica (e.g., AEROSIL available from Evonik Industries).TM 200), precipitated silica (e.g., SIPERNAT TM PQ), and magnesium stearate. The anti-blocking agent can be used in any suitable amount, for example, in the range of about 10% to 100% by weight based on the dry polymer weight, or about 1% to about 30% by weight, or about 10% to about 50% by weight, or about 10% to about 30% by weight, or about 15% to about 30% by weight. For example, in one embodiment, the amount of talc is in the range of 15% to about 30% by weight based on the dry polymer weight. In another embodiment, the amount of talc is in the range of 1% to about 10% by weight based on the dry polymer weight.

[0066] As is known in the art, one or more surfactants may also be added to the delayed-release and / or sustained-release coatings to improve substrate wetting and / or stabilize the suspension. Surfactants include polysorbate 80, sorbitan monooleate, sodium dodecyl sulfate, and the like.

[0067] The delayed-release coating and / or sustained-release coating can be formed by any suitable process. Coating processes include, for example, pan coating, fluidized-bed coating, and dry coating (e.g., heat-dried coating and electrostatic dry coating). Solvent-based pan coating and fluidized-bed coating are well-established processes. In liquid coating, the enteric material and optional excipients (e.g., pigments, plasticizers, and / or anti-blocking agents) are mixed in an organic solvent or water to form a solution or dispersion. The coating solution or dispersion is sprayed onto the solid dosage form in a pan coater or fluidized-bed dryer and dried with hot air. For example, in the Wurster fluidized-bed coating process, the coating fluid is sprayed from the bottom of the fluidized-bed apparatus; in an alternative, the coating fluid is applied by top spray, and in another alternative, by tangential spray.

[0068] The amount of delayed-release coating applied is an amount sufficient to achieve the desired release profile. For example, in some embodiments, the amount of delayed-release coating is determined according to the United States Pharmacopoeia (USP) by not releasing 10.0% by weight of the drug after 2 hours in 0.1 N HCl. <711> In another embodiment, the formulation is sufficient to meet the requirements of USP 43-NF 38 2S. In another embodiment, the formulation is sufficient to meet the requirements of USP 43-NF 37 2S. <711> and is sufficient to release at least 80% of the active substance.

[0069] In one type of embodiment, the median amount of delayed-release coating disposed on the core particle is at least 10 wt% of the total weight of the CTN beads. In some embodiments, the median amount of delayed-release coating disposed on the core particle is in the range of about 10 wt% to about 50 wt%, or about 10 wt% to about 40 wt%, or about 10 wt% to about 30 wt%, or about 20 wt%, or about 12 wt% to about 50 wt%, or about 12 wt% to about 35 wt%, based on the total weight of the CTN beads. In some embodiments, the median amount of delayed-release coating disposed on the core particle is in the range of about 15 wt% to about 45 wt%, based on the total weight of the CTN beads.

[0070] In one type of embodiment, the median amount of sustained release coating disposed on the core particle is at least 5% by weight, based on the total weight of the coated CTN beads. In some embodiments, the median amount of sustained release coating disposed on the core particle ranges from about 5% to about 50% by weight, or from about 7.5% to about 45% by weight, or from about 10% to about 40% by weight, or from about 15% by weight, or from about 5% to about 40% by weight, or from 15% to about 40% by weight, or from about 20% to about 40% by weight, based on the total weight of the coated CTN beads. In some embodiments, the median amount of sustained release coating disposed on the core particle is from about 20% to about 40% by weight, based on the total weight of the coated CTN beads.

[0071] In another embodiment, the median amount of sustained release coating disposed on the core particle is at least 5% by weight gain, based on the total weight of the uncoated CTN beads. In some embodiments, the median amount of sustained release coating disposed on the core particle is in the range of about 5% to about 60% by weight, or about 15% to about 60% by weight, or about 20% to about 50% by weight, or about 5% to about 40% by weight, or 15% to about 40% by weight, or about 20% to about 40% by weight, based on the total weight of the uncoated CTN beads. In some embodiments, the median amount of sustained release coating disposed on the core particle is about 20% to about 40% by weight, based on the total weight of the uncoated CTN beads.

[0072] Additional lubricants (glidants, anti-adherents) may be added to the coated beads in powder form. Anti-adherents include, for example, talc, glyceryl monostearate, fumed silica (e.g., AEROSIL TM 200), and precipitated silica (e.g., SIPERNAT TM For example, talc powder can be added to the coated beads in an amount of, for example, 0.1% to about 3% by weight, based on the total weight of the beads.

[0073] Additionally, the coatings disclosed herein may further include a pore-forming agent. The CTN release rate through the release coating material may be low and may be increased by adding a pore-forming agent to the coating. Pore-forming agents are often hydrophilic polymers that dissolve in water and / or gastric juices and form pores in the coating layer. The amount and type of pore-forming material affect the release profile and can be selected to achieve a desired release profile. In some embodiments, the pore-forming agent may include one or more materials selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, poloxamer 188, polyvinylpyrrolidone, D-mannitol, methylcellulose, polyvinyl alcohol-polyethylene glycol graft copolymer, and saccharides. In some embodiments, the pore-forming agent may include one or more materials selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyvinylpyrrolidone. In some embodiments, the pore-forming agent includes hydroxypropyl methylcellulose. In some embodiments, the pore-forming agent does not include polyvinylpyrrolidone. In some embodiments, the pore-forming agent does not include polyvinylpyrrolidone when the release coating includes ethylcellulose. The pore-forming agent can be present in the release coating in an amount of about 5% by weight or more, or about 10% by weight or more, or about 13% by weight or more, or about 15% by weight or more, or in a range of about 5% to about 20% by weight based on the total weight of the coating. In some embodiments, the pore-forming agent is present in an amount of about 15% by weight, or less than 50% by weight, or less than 20% by weight based on the total weight of the coating, and in a range of about 1% to about 16% by weight, or about 1% to about 12% by weight based on the total weight of the coating.

[0074] It is also contemplated herein that at least a portion of the total number of beads may include a coating (e.g., a seal coating) containing only a soluble polymer that does not affect the release of CTN from the formulation. In some embodiments, the seal coating may include hydroxypropyl methylcellulose. In some embodiments, the core beads may be coated with a seal coating before other coatings. In some embodiments, at least a portion of the core particles are seal coated.

[0075] In some embodiments, the pharmaceutical preparation may include a plurality of CTN beads enclosed in one or more containers, such as a container selected from a capsule, a sachet, and a stick pack. In some embodiments, the pharmaceutical preparation includes a plurality of CTN beads enclosed in a capsule. Soft capsules and hard capsules are known. In one embodiment, the capsule is a hard capsule, such as a gelatin capsule or a vegetable-derived hard capsule.

[0076] Thus, for example, one type of embodiment combining various of the above features includes a pharmaceutical formulation containing a plurality of CTN beads, the beads including a core particle containing CTN and a filler (optionally, crystalline cellulose and / or mannitol), the core particle characterized by a particle size (maximum diameter) distribution ranging from about 0.2 mm to about 1.5 mm, or from about 0.3 mm to about 1.2 mm, or from about 0.5 mm to about 0.85 mm, and the core particle may include a selective coating covering the core particle, and the plurality of CTN beads include fast-release beads, sustained-release beads, and delayed-release beads.

[0077] A unit dosage form containing the CTN formulation disclosed herein may contain a suitable amount of CTN. For example, the amount of CTN in the unit dosage form may range from 1 mg to 1800 mg, for example, 10 mg to 1800 mg, for example, 25 mg to 1800 mg, for example, 10 mg to 1600 mg, for example, 10 mg to 1200 mg, for example, 50 mg to 490 mg, for example, 50 mg to 250 mg, for example, 50 mg to 1200 mg, for example, 50 mg to 1000 mg, for example, 75 mg to 1000 mg, for example, 75 mg to 800 mg, for example, 75 mg to 500 mg, for example, 100 mg to 750 mg, for example, 100 mg to 500 mg, for example, 100 mg to 400 mg, for example, 100 mg to 300 mg, for example, 100 mg to 200 mg.

[0078] Functional properties As described above, pharmaceutical formulations or dosage forms can be advantageously designed to have one or more pharmacokinetic characteristics, e.g., characteristics in humans. Pharmaceutical formulations herein can be characterized by the amount of CTN released in vitro over a predetermined time period. In embodiments where the pharmaceutical formulation contains fast-release beads, at least 90% of the CTN or a salt thereof is released from the fast-release beads in a range of 0 to 2 hours. In embodiments where the pharmaceutical formulation contains sustained-release beads, at least 90% of the CTN is released from the sustained-release beads in a range of 2 to 6 hours. In embodiments where the pharmaceutical formulation contains delayed-release beads, at least 90% of the CTN or a salt thereof is released from the delayed-release beads in a range of 4 to 14 hours. In embodiments where the pharmaceutical formulation contains delayed-sustained-release beads, at least 90% of the CTN or a salt thereof is released from the delayed-sustained-release beads in a range of 4 to 14 hours.

[0079] In some embodiments, the formulation or dosage form may be characterized in vivo and / or in vitro by one or more release profiles selected from fast release, sustained release, delayed release, and delayed-sustained release. In some embodiments, the formulation, e.g., a pediatric formulation, may optionally have a multi-phase release profile when tested in an acidic medium for 2 hours followed by a buffered medium at pH 7.4. For example, see USP <711> The release profile obtained by testing in accordance with the method described above using Apparatus 1 (basket) in 1000 mL of 0.1 N hydrochloric acid at 37° C.±0.5° C. and 100 rpm for 2 hours, followed by testing in 1000 mL of pH 7.4 phosphate buffer at 37° C.±0.5° C. and 100 rpm for 16 hours using Apparatus 1 (basket) may have a multi-phase release profile, optionally at least a two-phase release profile, and optionally at least a three-phase release profile. Such a profile may optionally be characterized by about 22% to about 45% CTN release at 3 hours, optionally about 40% to about 65% CTN release at 8 hours, optionally about 65% to about 95% CTN release at 12 hours, and optionally at such release rates at all three time points. In another type of embodiment, such a profile can be identified with about 24% to 48% CTN release at 3 hours, and optionally at least 66% CTN release at 6 hours, and optionally at least 86% CTN release at 10 hours, and optionally at such release rates at all three time points. Further optionally, the release profile can be identified with 49% to 73% release at 4 hours.

[0080] The pharmaceutical formulations herein may optionally be characterized as exhibiting a bimodal in vivo absorption profile. In some embodiments, a pharmaceutical formulation having a bimodal in vivo absorption profile comprises a first centanafadine plasma C max In some embodiments, the first centanafadine plasma C is represented by a plurality of CTN beads at a time ranging from 0 to 4.5 hours, or from about 0.5 hours to about 2 hours, or from about 3.5 hours to about 4.5 hours. maxis in the range of about 320 ng / mL to about 420 ng / mL, or about 325 ng / mL to about 390 ng / mL. In some embodiments, the pharmaceutical formulation having a bimodal in vivo absorption profile comprises a second centanafadine plasma C max In some embodiments, the second centanafadine plasma C is displayed by a plurality of CTN beads at a time ranging from about 6 hours to 10 hours, or from about 7 hours to 9 hours, or from about 7.5 to about 8.5 hours. max In some embodiments, the in vivo absorption profile is in the range of about 450 ng / mL to about 550 ng / mL, or about 470 ng / mL to about 530 ng / mL. max and second centanafadine plasma C max and the first centanafadine plasma C max and second centanafadine plasma C max is divided into a time range of 1.5 to 8.5 hours, or about 2 hours to about 6 hours, or about 3 hours to about 5 hours.

[0081] The pharmaceutical formulations and uses thereof described herein may be designed to exhibit one or more of the following pharmacokinetic profile characteristics:

[0082] The formulations provide a subject with a relatively rapid increase in centanafadine plasma concentration, approaching or reaching therapeutic concentrations in a relatively short time. Thus, for example, the formulations may provide an adult subject with a 1-hour post-dose (C) of at least 150 ng / mL, or at least 200 ng / mL, or at least 250 ng / mL, or at least 280 ng / mL. 1h ) or in the range of about 180 ng / mL to about 610 ng / mL, or about 200 ng / mL to about 590 ng / mL, or about 220 ng / mL to about 540 ng / mL, or about 245 ng / mL to about 490 ng / mL at 1 hour (C 1h ) to provide centanafadine plasma concentrations, and in some cases such exposure may be achieved at a dosage strength in the range of about 145 mg to about 185 mg CTN, for example, 164.4 mg CTN.

[0083] The formulation has a 1-hour dose (AUC 0.001) in the range of at least 30 ng·h / mL, or at least 40 ng·h / mL, or at least 100 ng·h / mL, or at least 200 ng·h / mL, or from about 30 ng·h / mL to about 500 ng·h / mL, or from about 32 ng·h / mL to about 480 ng·h / mL, or from about 36 ng·h / mL to about 440 ng·h / mL, or from about 40 ng·h / mL to about 400 ng·h / mL. 0-1h ) provides a cumulative CTN plasma exposure in an adult subject, and in some cases such exposure can be achieved at doses ranging from about 145 mg to about 185 mg of CTN, for example, 164.4 mg of CTN.

[0084] The formulations can maintain plasma concentrations of CTN in an adult subject within the therapeutic range for extended periods of time to achieve sustained efficacy. Thus, for example, the formulations can provide post-administration CTN plasma concentrations that are maintained within a range of at least 200 ng / mL, or at least 250 ng / mL, or at least 280 ng / mL, or at least 300 ng / mL, or at least 1000 ng / mL, or at least 1500 ng / mL, or from about 150 ng / mL to about 4125 ng / mL, or from about 160 ng / mL to about 3960 ng / mL, or from about 180 ng / mL to about 3630 ng / mL, or from about 200 ng / mL to about 3300 ng / mL over a 2-8 hour period following administration. Optionally, such plasma concentrations can be achieved with an administration dose of CTN in the range of about 145 mg to about 185 mg, e.g., 164.4 mg.

[0085] The formulation or its use is intended to assess the cumulative CTN plasma exposure (AUC0- 8h) in the range of at least 1275 ng·h / mL, or at least 1530 ng·h / mL, or at least 1700 ng·h / mL, or at least 2500 ng·h / mL, or from about 1275 ng·h / mL to about 6250 ng·h / mL, or from about 1275 ng·h / mL to about 6250 ng·h / mL, or from about 1275 ng·h / mL to about 6250 ng·h / mL, or from about 1360 ng·h / mL to about 6000 ng·h / mL, or from about 1530 ng·h / mL to about 5500 ng·h / mL, or from about 1700 ng·h / mL to about 5000 ng·h / mL, and optionally such exposure can be achieved with an amount of CTN administered in the range of about 145 mg to about 185 mg, e.g., 164.4 mg of CTN. The formulations may provide a cumulative plasma exposure (AUC2- 8h ) can be provided in a range of at least 1050 ng·h / mL, or at least 1120 ng·h / mL, or at least 1330 ng·h / mL, or at least 2000 ng·h / mL, or at least 2500 ng·h / mL, or from about 1050 ng·h / mL to about 5250 ng·h / mL, or from about 1120 ng·h / mL to about 5040 ng·h / mL, or from about 1260 ng·h / mL to about 4620 ng·h / mL, or from about 1330 ng·h / mL to about 4410 ng·h / mL, or from about 1400 ng·h / mL to about 4200 ng·h / mL; optionally, such exposure can be achieved with an amount of CTN administered in the range of about 145 mg to about 185 mg, e.g., 164.4 mg of CTN.

[0086] The pharmaceutical preparation or its use is not intended to limit the plasma concentration (C 12h ) can be at least 95 ng / mL, or at least 160 ng / mL, or at least 230 ng / mL, or at least 360 ng / mL, or in the range of about 95 ng / mL to about 450 ng / mL, or about 100 ng / mL to about 435 ng / mL, or about 110 ng / mL to about 400 ng / mL, or about 30 ng / mL to about 360 ng / mL, and optionally such plasma concentrations can be achieved with an amount of CTN administered in the range of about 145 mg to about 185 mg, e.g., 164.4 mg of CTN.

[0087] The pharmaceutical formulation or use thereof can provide an adult subject with a plasma concentration of CTN that declines relatively rapidly after 12 hours post-dose, and promote a relatively low plasma concentration of CTN at 16 hours post-dose and up until the next dose. Thus, for example, the ratio of the plasma concentration at 16 hours post-dose to the plasma concentration at 12 hours post-dose (C 16h / C 12h ) can be less than 1, or 0.75 or less, or 0.5 or less, or 0.3 or less, or in the range of about 0.5 to 0.1, and optionally such ratios can be achieved with doses ranging from about 145 mg to about 185 mg of CTN, e.g., 164.4 mg of CTN.

[0088] The pharmaceutical formulations or uses thereof can provide plasma concentrations of CTN in an adult subject 16 hours after administration of less than 375 ng / mL, or less than 300 ng / mL, or less than 250 ng / mL, or less than 230 ng / mL, or less than 200 ng / mL, or less than 100 ng / mL, or in the range of about 60 ng / mL to about 375 ng / mL, or about 64 ng / mL to about 300 ng / mL, or about 76 ng / mL to about 250 ng / mL, or about 80 ng / mL to about 300 ng / mL. In some cases, such exposures can be achieved with doses of CTN in the range of about 145 mg to about 185 mg, e.g., 164.4 mg. For example, the plasma concentration can be relatively low at a time point to facilitate repeated administration once daily without CTN accumulation. In another embodiment, the plasma concentration can be relatively low at a time point to avoid one or more adverse effects, such as insomnia in the subject, when administration is performed in the morning.

[0089] The pharmaceutical formulation or its use is intended to assess the cumulative CTN plasma exposure (AUC0- 24h) can be in the range of at least 2400 ng·h / mL, or at least 2880 ng·h / mL, or at least 3200 ng·h / mL, or at least 5000 ng·h / mL, or at least 7100 ng·h / mL, or about 2400 ng·h / mL to about 12500 ng·h / mL, or about 2560 ng·h / mL to about 12000 ng·h / mL, or about 2880 ng·h / mL to about 11000 ng·h / mL, or about 3040 ng·h / mL to about 10500 ng·h / mL, or about 3200 ng·h / mL to about 10000 ng·h / mL, or about 7000 ng·h / mL to about 10000 ng·h / mL. The pharmaceutical formulation or its use can be used in adult subjects to measure the cumulative CTN plasma exposure (AUC0- 48h ) can be at least 2400 ng·h / mL, or 2880 ng·h / mL, or 3200 ng·h / mL, 5000 ng·h / mL, or 7100 ng·h / mL, or in the range of about 2400 ng·h / mL to about 12500 ng·h / mL, or about 2560 ng·h / mL to about 12000 ng·h / mL, or about 2880 ng·h / mL to about 11000 ng·h / mL, or about 3040 ng·h / mL to about 10500 ng·h / mL, or about 3200 ng·h / mL to about 10000 ng·h / mL, or about 7000 ng·h / mL to about 10000 ng·h / mL, optionally with an amount of CTN in the range of about 145 mg to about 185 mg, e.g., 164.4 mg of CTN.

[0090] The pharmaceutical formulation or its use is intended to assess the cumulative CTN plasma exposure (AUC0- inf) can be at least 2400 ng·h / mL, or 2880 ng·h / mL, or 3200 ng·h / mL, 5000 ng·h / mL, or 7100 ng·h / mL, or in the range of about 2400 ng·h / mL to about 12500 ng·h / mL, or about 2560 ng·h / mL to about 12000 ng·h / mL, or about 2880 ng·h / mL to about 11000 ng·h / mL, or about 3040 ng·h / mL to about 10500 ng·h / mL, or about 3200 ng·h / mL to about 10000 ng·h / mL, or about 7000 ng·h / mL to about 10000 ng·h / mL, optionally with an amount of CTN in the range of about 145 mg to about 185 mg, e.g., 164.4 mg of CTN.

[0091] The pharmaceutical formulation or its use provides an adult subject with a maximum CTN plasma concentration (t max ) can be provided.

[0092] The pharmaceutical formulations disclosed herein can be identified by the release mechanism of the active pharmaceutical ingredient (API), e.g., centanafadine hydrochloride. In some embodiments, one or more of the plurality of CTN beads have a release mechanism including one or more of dissolution, diffusion, erosion, permeation, partitioning, swelling, and targeting. In some embodiments, one or more of the plurality of CTN beads have a diffusive release mechanism. In some embodiments, one or more of the plurality of CTN beads have a porous matrix that leads to a diffusive release mechanism. In some embodiments, one or more of the plurality of CTN beads have a pH-driven diffusive release mechanism. In some embodiments, one or more of the plurality of CTN beads have a combination of a pH-driven elution release mechanism and a diffusive release mechanism. In some embodiments, as partially disclosed above, delayed-release beads have a combination of a pH-driven elution release mechanism and a diffusive release mechanism. As used herein, the term "porous matrix" refers to an insoluble frame comprising a matrix of pores. In some embodiments, at least a portion of the plurality of beads comprises a porous matrix. In some embodiments, sustained-release beads contain a porous matrix.

[0093] Pediatric formulations Also contemplated herein is a pharmaceutical formulation comprising CTN or a pharmaceutically acceptable salt thereof, wherein the formulation is a solid oral formulation suitable for pediatric use. In some embodiments, the solid oral formulation suitable for pediatric use is selected from one or more types, including beads, orodispersible tablets, orodispersible films, mini-tablets, chewable tablets, and soft chews. In some embodiments, the solid oral formulation suitable for pediatric use includes beads, such as a plurality of CTN beads as disclosed herein.

[0094] In some embodiments, a solid oral formulation suitable for pediatric use may be characterized by one or more release profiles selected from fast release, sustained release, delayed release, and delayed-sustained release in vivo and / or in vitro. In some embodiments, a solid oral formulation suitable for pediatric use may have a multi-phase release profile when tested in an acidic medium for 2 hours followed by testing in a buffered medium at pH 7.4. For example, see USP <711> The release profile obtained by testing in accordance with the method described above using Apparatus 1 (basket) in 1000 mL of 0.1 N hydrochloric acid at 37°C ± 0.5°C and 100 rpm for 2 hours, followed by testing in 1000 mL of pH 7.4 phosphate buffer at 37°C ± 0.5°C and 100 rpm for 16 hours using Apparatus 1 (basket) may have a multi-stage release profile, optionally at least a two-stage release profile, and optionally at least a three-stage release profile. Such a profile may be characterized by, optionally, about 22% to about 45% CTN release at 3 hours, further optionally about 40% to about 65% CTN release at 8 hours, further optionally about 65% to about 95% CTN release at 12 hours, and further optionally by release at such release rates at all three time points. In another embodiment, such a profile may be identified as about 24% to 48% CTN release at 3 hours, and optionally at least 66% CTN release at 6 hours, and optionally at least 86% CTN release at 10 hours, and optionally at such release rates at all three time points. Further, optionally, a release profile may be identified as 49% to 73% release at 4 hours.

[0095] In some embodiments, a solid oral formulation suitable for pediatric use includes a plurality of centanafadine (CTN) beads disclosed herein, each of the plurality of CTN beads including a core particle comprising CTN or a pharmaceutically acceptable salt thereof and an excipient. In some embodiments, the solid oral formulation suitable for pediatric use has a median bead size (diameter) ranging from about 0.2 mm to about 2.8 mm, or from about 0.2 mm to about 2.5 mm, or from about 0.2 mm to about 2.0 mm, or from about 0.7 mm to about 2.5 mm, or from about 0.7 mm to about 2.8 mm, or from about 0.5 mm to about 2.8 mm, or from about 0.8 mm to about 1.7 mm, or from about 0.5 mm to about 1.2 mm, or from about 0.5 mm to about 1.0 mm.

[0096] Delayed-sustained release profile Also contemplated herein is a pharmaceutical formulation or dosage form comprising the CTN and excipients, wherein the formulation exhibits a delayed-sustained release profile in vivo.

[0097] In one type of embodiment, the formulation may be a solid oral formulation and / or a semi-solid oral formulation disclosed herein. In embodiments, the formulation may comprise a core and a coating disposed over the core. In some embodiments, the formulation may comprise a core and a coating disposed on the core. In some embodiments, the coating may be identified by a pH-dependent dissolution trigger. In some embodiments, the coating disposed over the core begins to dissolve at a pH of at least 7, optionally in the range of about 7 to about 8, and optionally in the range of about 7.2 to about 7.6. In some embodiments, the coating begins to dissolve at a pH of about 7.2 to about 7.6. In some embodiments, the coating begins to dissolve at a pH of about 7.4. In some embodiments, the coating may comprise an anionic polymer. In some embodiments, the coating may comprise a methacrylic acid polymer. In some embodiments, the coating comprises one or more polymers selected from copolymerized methacrylic acid / methacrylic acid methyl ester, copolymerized methacrylic acid / methyl methacrylate, and copolymerized methyl acrylate / methyl methacrylate / methacrylic acid. In some embodiments, the one or more polymers are selected from copolymers of methacrylic acid, methyl methacrylate, and methyl acrylate, and methacrylic acid-acrylate copolymers. In some embodiments, the coating includes a copolymer of methyl acrylate, methyl methacrylate, and methacrylic acid (e.g., in a molar ratio of about 7:3:1), such as Eudragit TM FS 30 D. In some embodiments, the delayed release coating may also provide sustained release of CTN. In some embodiments, the delayed release coating comprises an anionic polymer, optionally containing carboxylate moieties. FIG. 7 illustrates a copolymer of methyl acrylate, methyl methacrylate, and methacrylic acid (e.g., in a molar ratio of about 7:3:1 (e.g., Eudragit TMIt has been shown that delayed-release coatings based on FS 30 D) also have sustained-release functionality. Without intending to be bound by any particular theory, it is possible that because poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) polymers are anionic and have negatively charged carboxylate moieties (ratio of carboxyl groups to ester groups is approximately 1:10), and centanafadine is a positively charged secondary amine, the polymer may affect the release rate of centanafadine from the beads through ionic interactions. In embodiments that include a fast-release region (e.g., beads), a sustained-release region (e.g., beads), and a third region (e.g., beads) having a delayed-release aspect, the delayed-release region or beads may lack or substantially lack a sustained-release aspect. This type of embodiment can be designed so that the excretion phase after CTN administration is not excessively prolonged, and as described above, for example, the CTN plasma concentration 12 hours after administration is less than 250 ng / mL, or 220 ng / mL or less, or 200 ng / mL or less, or 180 ng / mL or less.

[0098] Manufacturing method The CTN-containing region or core particle can be prepared by any suitable process. In one embodiment, the core particle is formed by granulating a mixture of CTN and excipients, milling the resulting granules to the desired particle size range, and optionally sieving the resulting granules to the selected particle size range. The core particle can be formed by extrusion and spheronization of the CTN and excipient mixture. Granulation processes can include, for example, fluidized-bed granulation, wet granulation, hot-melt granulation, and spray congealing. Other processes include slugging and roller compaction. As known in the art, the mixture to be granulated can be first dry-blended. The dry-blended dry ingredients can be mixed with water before extrusion. In another embodiment, inert seeds, such as nonpareil seeds or spherical microcrystalline cellulose seeds, can be coated with a mixture containing CTN and a binder to form a coated region containing CTN on the inert seeds. The wet beads obtained from the spheronizer can be dried to the desired moisture content in a fluidized-bed processor and optionally heat-set. At the end of the drying and curing process, the beads can be blended with an antiblocking agent, if desired, to improve handling, by fluidizing the antiblocking agent in the same air stream, optionally at ambient temperature.

[0099] Specifically contemplated methods include a method for preparing a pharmaceutical formulation containing CTN, which includes blending CTN with a binder and disposing a coating on at least a portion of the particles to produce particles containing CTN having a specified particle size range. In some embodiments, blending includes extrusion. In some embodiments, blending can further include post-extrusion spheronization. The desired bead size before drying can be determined by the selection of an extruder screen and spheronization equipment. In embodiments, the CTN particles can be dried after spheronization. For example, this process can include wetting a powder mixture of CTN and excipients, forming an extrudate by extrusion, crushing the extrudate into round particles by spheronization, and drying the finished particles. An anti-blocking agent can be applied to the particles.

[0100] It has been found that extrusion and spheronization of a mixture of CTN and excipients can produce desirable core particles having the core particle size distribution described herein and one or more other desirable properties. In some embodiments, extrusion and spheronization of a mixture of centanafadine or a pharmaceutically acceptable salt thereof and an excipient disclosed herein can provide a high drug loading (e.g., 80% by weight based on the total weight of the core particle) at a low total core particle weight. Thus, the overall "footprint" of the drug is reduced because the amount of added excipients that do not have the desired pharmacological effect on the subject is reduced. In some embodiments, extrusion and spheronization of a mixture of centanafadine or a pharmaceutically acceptable salt thereof and an excipient disclosed herein can provide an easy way to change the particle size distribution with the same amount of API and excipients by using different extrusion screens. In some embodiments, extrusion and spheronization of a mixture of centanafadine or a pharmaceutically acceptable salt thereof and an excipient disclosed herein can provide uniform dissolution of the pharmaceutical agent due to the uniformity of the coating weight gain disposed on the core particle. In certain embodiments, a pediatric formulation can be provided by extrusion and spheronization of a mixture of centanafadine or a pharmaceutically acceptable salt thereof disclosed herein and excipients.

[0101] As discussed above in connection with the description of the core particles, the method can include a step of sorting (e.g., sieving) the core particles prior to coating to maintain the particles within a predetermined size range, e.g., from about 0.2 mm to about 2.8 mm, or from about 0.2 mm to about 2.5 mm, or from about 0.2 mm to about 1.7 mm, or from about 0.5 mm to about 0.71 mm, or any of the ranges discussed above in connection with the core particles.

[0102] The following optional features can be used individually or in combination with one or more of them in the extrusion and spheronization process: Water can be used as a granulating agent. Microcrystalline cellulose can be used in the core particles as a spheronization aid. Low-substituted hydroxypropyl cellulose is also known as a spheronization aid.

[0103] In embodiments, the method can further include coating the dried core particles. In some embodiments, the coating can be applied using a fluidized bed processor. In some embodiments, the required amount of coating dispersion / solution is sprayed using a Wurster process with a controlled set of process parameters.

[0104] The beads and / or filled capsules can be stored with a desiccant.The beads and / or filled capsules can be stored with an oxygen scavenger.

[0105] Coating processes, such as seal coating, can be carried out using a fluidized bed processor. Seal coating is optional. In this description, generally, when beads are coated, the uncoated portion of the bead is referred to as the bead core, although the uncoated bead core can also be considered the bead itself. In the examples described below, 80% by weight active CTN bead cores were seal coated before subsequently coating with the SR and DR coatings, while 10% and 50% by weight active CTN beads were not coated in these examples. Using a Wurster process with a controlled set of process parameters, the desired amount of coating dispersion / solution can be sprayed, and the coated beads can then be dried to the desired moisture content and heat-cured, if necessary. The seal coating polymer can be selected from any material that does not substantially affect the release characteristics of the active substance from the beads and preferably provides a smooth outer surface to the bead core after coating. Examples of suitable materials include hydrophilic polymers, such as hydrophilic cellulose ethers, e.g., hydroxypropylmethylcellulose and hydroxypropylcellulose. Other polymers include polyvinylpyrrolidone and polyethylene glycols (PEGs), particularly polyethylene glycol 20000.

[0106] Application of sustained-release and delayed-release coatings can be accomplished using a fluidized bed processor, for example, by weight gain to the desired coating weight. In such a process, the required amount of coating dispersion / solution is sprayed using a Wurster process with a controlled set of process parameters. The coated beads are then dried to the desired moisture content and, if necessary, heat cured.

[0107] Depending on the desired product strength, one or more regions or amounts of formulation types, for example, an immediate-release region (e.g., 10% or 50% beads), along with an SR and / or DR region (e.g., SR-coated beads and DR-coated beads), can be packaged by encapsulating them into a suitable capsule shell using a multi-bead filling and encapsulation machine. In one type of embodiment, multiple CTN beads can be encapsulated within a capsule shell. In some embodiments, an automated encapsulation machine is used to encapsulate multiple CTN beads into a capsule shell. In some embodiments, the encapsulation process includes sequentially filling one or more bead types selected from fast-release beads, sustained-release beads, and delayed-release beads, as desired, with appropriate fill weight control. After the bead components are filled, the capsule is closed at the desired capsule height.

[0108] For example, one embodiment of a method involving various combinations of the above parameters includes a method for preparing a pharmaceutical dosage form comprising CTN beads, which includes forming a wet mass comprising CTN and excipients, optionally microcrystalline cellulose, extruding and spheronizing the wet mass comprising CTN and excipients to form core particles, screening the core particles to a target particle size range (optionally 0.7 mm to 2.5 mm), coating the optionally screened core particles with a polymer to form beads comprising the core particles and a release membrane thereon, and screening the bead particles to a target particle size range (optionally 0.7 mm to 2.5 mm).

[0109] Treatment method / use Also provided herein are methods of treatment using a formulation or dosage form described herein, or uses of a formulation or dosage form described herein, comprising administering an effective amount of a formulation or dosage form described herein to an animal subject in need of treatment. In some embodiments, the animal subject is a mammalian subject in need of treatment. In some embodiments, the mammalian subject is a human in need of treatment. The formulation or dosage form may be administered with one or more additional psychotherapeutic agents. The one or more additional psychotherapeutic agents may be administered separately or incorporated into a formulation or dosage form described herein. The one or more additional psychotherapeutic agents may be administered simultaneously with CTN or at a different frequency or administration schedule.

[0110] The formulation or dosage form can be administered to an animal, e.g., a mammalian subject, e.g., a human patient, to inhibit norepinephrine reuptake, and / or dopamine reuptake, and / or serotonin reuptake. The formulation or dosage form can be administered to an animal, e.g., a mammalian subject, e.g., a human patient, to treat or prevent one or more symptoms of a disorder that is alleviated by inhibiting norepinephrine reuptake, and / or dopamine reuptake, and / or serotonin reuptake. In some embodiments, "treatment" or "treating" refers to the improvement of one or more symptoms of a disorder, whereby the symptoms are alleviated by inhibiting the reuptake of dopamine and / or norepinephrine and / or serotonin. In other embodiments, "treatment" or "treating" refers to the improvement of at least one measurable physical parameter associated with the disorder. In yet another embodiment, "treatment" or "treating" refers to inhibiting or reducing the progression or severity of a disorder (or one or more symptoms) that is alleviated by inhibiting dopamine and / or norepinephrine and / or serotonin reuptake, as determined, for example, based on physical, physiological, and / or psychological parameters. The formulations or dosage forms described herein can be used to delay the onset of a disorder (or one or more symptoms) by inhibiting norepinephrine and / or dopamine and / or serotonin reuptake, as appropriate.

[0111] An "effective amount," "therapeutic amount," "therapeutically effective amount," or "effective dose" of a formulation or dosage form described herein, and / or an additional psychotherapeutic agent used herein, refers to an effective amount or dose of an active compound described herein sufficient to elicit a desired pharmacological or therapeutic effect in a subject, e.g., a human subject. In the case of ADHD or substance abuse treatments, these terms often refer to a significant reduction in the occurrence, frequency, or severity of one or more symptoms of a particular disorder, including any combination of neurological and / or psychiatric symptoms, diseases, or conditions associated with or caused by the disorder in question.

[0112] The formulations or dosage forms herein can be administered in amounts based on the subject's body weight or can be labeled for administration. The formulations or dosage forms herein can be administered in amounts of CTN or a pharmaceutically acceptable salt thereof (e.g., an HCl salt) in the range of 0.5 mg / kg to 20 mg / kg per day, e.g., 1 mg / kg to 15 mg / kg per day, e.g., 1 mg / kg to 10 mg / kg per day, e.g., 2 mg / kg to 20 mg / kg per day, e.g., 2 mg / kg to 10 mg / kg per day, e.g., 3 mg / kg to 15 mg / kg per day, or about 1.5 mg / kg per day. Embodiments can include about 1.43 mg / kg to 5.71 mg / kg per day, about 2.86 mg / kg to 5.71 mg / kg per day, about 1.5 mg / kg to about 6 mg / kg per day, or about 3 mg / kg to 6 mg / kg per day. If necessary, administration can be in divided doses. In another embodiment, the formulations or dosage forms described herein can contain CTN or a pharmaceutically acceptable salt thereof (e.g., the HCl salt) in an amount ranging from about 10 to about 25 mg, or about 30 to about 50 mg, or about 25 to about 150 mg, or about 50 to about 100 mg, or about 100 to about 250 mg, or about 250 to about 500 mg, administered (or labeled for administration) once, twice, three, or four times daily. Doses of about 50 to 75 mg, about 100 to 200 mg, about 250 to 400 mg, or about 400 to 600 mg can be administered or labeled for administration once or twice daily. Doses of about 100 to 300 mg can be administered or labeled for administration once daily. A dose of approximately 100-300 mg can be administered or labeled for administration once daily in the morning. A dose of approximately 40-330 mg can be administered or labeled for administration once daily in the morning. A dose of approximately 40-330 mg can be administered or labeled for administration once daily in the morning. Specific dosage amounts include 41.1 mg, 82.2 mg, 123.3 mg, 164.4 mg, 246.6 mg, and 328.8 mg.

[0113] Subjects weighing less than 20 kg can start with a CTN dose of 41.1 mg per day. Subjects weighing between 20 kg and less than 35 kg can start with a CTN dose of 82.2 mg per day. Subjects weighing between 35 kg and less than 50 kg can start with a dose of 123.3 mg per day. Subjects weighing more than 50 kg can start with a dose of 164.4 mg. Dosages can be increased by 25%, 50%, 75%, or 100% of the initial dose. For example, a subject receiving an initial dose of 164.4 mg / day can receive an increase of 41.1 mg for a subsequent progression dose of 205.5 mg / day, unless further dose increases are made. In another embodiment, the increase can be 82.2 mg. In another embodiment, the increase can be 123.3 mg / day, or in another embodiment, 164.4 mg / day.

[0114] The formulations or dosage forms described herein can be used to treat a variety of conditions, including, for example, attention-deficit / hyperactivity disorder (ADHD), major depressive disorder, smoking and nicotine dependence, and binge eating disorders.

[0115] ADHD is characterized by symptoms of difficulty concentrating and paying attention, difficulty controlling behavior, impulsivity, disruption, and hyperactivity (overactivity). ADHD is diagnosed in both adults and children based on the criteria set forth in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (2000), Text Revision (DSM-IV-TR), American Psychiatric Association, Washington, DC. The DSM-IV-TR criteria describe three subtypes of ADHD: attention-deficit hyperactivity disorder (ADD), primarily hyperactive-impulsive subtype; attention-deficit hyperactivity disorder (ADD), primarily inattentive subtype (also known as attention-deficit disorder or ADD); and attention-deficit hyperactivity disorder (ADD), combined subtype. In the predominantly inattentive type, individuals may have six or more of the following disruptive, age-inappropriate symptoms: difficulty paying attention to details, difficulty maintaining attention on tasks, difficulty following instructions, difficulty planning activities, difficulty following conversations, being easily distracted, and forgetting daily routines. In the predominantly hyperactive-impulsive type, individuals may have six or more of the following disruptive, age-inappropriate symptoms: frequent fidgeting, inappropriate running around, inability to play quietly or enjoy leisure activities, excessive chattering, evasiveness, difficulty waiting their turn, and interrupting others. In the combined type, both inattentive and hyperactive-impulsive behaviors may be present. (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane or its pharmaceutically acceptable salts are effective in treating all subtypes of ADHD, both in adults and children. (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof is also effective in treating ADHD-related disorders, such as attention-deficit / hyperactivity disorder (not otherwise specified (NOS)), conduct disorder, oppositional defiant disorder, and disruptive behavior disorder (not otherwise specified (NOS)).

[0116] The formulations or dosage forms described herein can be used to treat autism spectrum disorder in patients with fragile X-associated disorder. As used herein, "autism spectrum disorder" includes autistic disorder (classic autism), Asperger's disorder (Asperger's syndrome), pervasive developmental disorder not otherwise specified (PDD-NOS), Rett's disorder (Rett's syndrome), and childhood disintegrative disorder (CDD).

[0117] The formulations or dosage forms described herein can be used to treat fragile X-associated disorders. Fragile X-associated disorders are a family of genetic conditions that can affect individuals in different ways. Three fragile X-associated disorders are fragile X syndrome (FXS), fragile X-associated tremor / ataxia syndrome (FXTAS), and fragile X-associated primary ovarian insufficiency (FXPOI). All of these conditions are caused by changes in the fragile X mental retardation 1 (FMR1) gene, which is located on the X chromosome.

[0118] The formulations or dosage forms described herein can be used to treat binge eating disorder. Binge eating disorder involves recurrent episodes of binge eating. Binge eating episodes can include eating more food in a discrete period of time (e.g., within any two-hour period) than most people would eat in a similar time and under similar circumstances, and a feeling of being unable to control eating during the episode (e.g., feeling unable to stop eating, unable to control what or how much to eat). Binge eating episodes can include three (or more) of the following: eating much faster than usual, eating until you feel uncomfortable and full, eating large amounts of food without feeling hungry, eating alone because you are embarrassed about the amount of food you are eating, feeling disgusted with yourself, feeling depressed, or experiencing strong guilt after binge eating. Binge eating disorder can also include significant distress related to the binge eating. On average, binge eating can occur at least once a week for three months. Binge eating is not associated with repeated inappropriate compensatory behaviors (e.g., purging).

[0119] The formulations, dosage forms, and related methods described herein can be used to treat or prevent one or more symptoms of a CNS disorder that is alleviated by inhibiting dopamine reuptake, and / or norepinephrine reuptake, and / or serotonin reuptake in a mammalian, e.g., human, subject. In some embodiments, "treatment" or "treating" can refer to the improvement of one or more symptoms of a CNS disorder, where the symptoms are alleviated by inhibiting dopamine and / or norepinephrine and / or serotonin reuptake. In other embodiments, "treatment" or "treating" can refer to the improvement of at least one measurable physical parameter associated with a CNS disorder. In yet other embodiments, "treatment" or "treating" can refer to inhibiting or reducing the progression or severity of a CNS disorder (or one or more symptoms thereof) that is alleviated by inhibiting dopamine and / or norepinephrine and / or serotonin reuptake, for example, as identified based on physical, physiological, and / or psychological parameters. In a further embodiment, "treatment" or "treating" refers to delaying the onset of a CNS disorder (or one or more symptoms thereof) that is alleviated by inhibiting dopamine and / or norepinephrine and / or serotonin reuptake.

[0120] The formulations, dosage forms, and related methods described herein can be used in mammalian, e.g., human, patients as prophylactic or preventative treatments for CNS disorders (one or more symptoms thereof) that are alleviated by inhibiting the reuptake of dopamine and / or norepinephrine and / or serotonin. As used herein, "prevention" and "preventing" refer to a reduction in the risk or likelihood that a subject will acquire a CNS disorder or one or more symptoms thereof, where the risk or likelihood in the subject is reduced by inhibiting dopamine and / or norepinephrine and / or serotonin reuptake. Alternatively, prevention can refer to a reduction in the risk of recurrence of a CNS disorder or its symptoms in a subject once the subject has been treated and returned to a normal state or has been relieved from the subject's CNS disorder. The formulations, dosage forms, and related methods described herein can be used as a measure of prophylaxis in a subject. Subjects suitable for prophylactic treatment in this context may have a genetic predisposition to a CNS disorder suitable for treatment by inhibiting the reuptake of dopamine, and / or serotonin, and / or norepinephrine, such as a family history of a biochemical imbalance in the brain, a non-genetic predisposition to a disorder that is alleviated by inhibiting the reuptake of dopamine and / or norepinephrine and / or serotonin, etc.

[0121] The formulations, dosage forms, and related methods described herein can be used to treat or prevent endogenous disorders that are alleviated by inhibiting dopamine and / or norepinephrine and / or serotonin reuptake, including, but not limited to, attention deficit disorder, depression, anxiety, obesity, Parkinson's disease, tic disorders, and addictive disorders.

[0122] Disorders alleviated by inhibiting the reuptake of dopamine and / or norepinephrine and / or serotonin are not limited to the specific disorders described herein, and it is understood or readily ascertained that the formulations, dosage forms, and related methods described herein provide effective therapeutic agents for the treatment and / or prevention of a wide range of additional CNS disorders and related conditions. For example, the formulations, dosage forms, and related methods described herein may provide promising candidates for the treatment and / or prevention of attention deficit hyperactivity disorder and related conditions, as well as forms and symptoms of alcohol abuse, drug abuse, obsessive-compulsive disorder, learning disabilities, reading comprehension disorders, gambling addiction, manic symptoms, phobias, panic attacks, oppositional defiant disorder, conduct disorders, academic problems at school, smoking, abnormal sexual behavior, schizophrenic behavior, somatization, depression, sleep disorders, generalized anxiety disorder, stuttering, and tic disorders (see, e.g., U.S. Pat. No. 6,132,724). These and other symptoms, regardless of the underlying CNS disorder, are potential therapeutic targets for formulations, dosage forms, and related methods that mediate therapeutic effects by inhibiting the reuptake of dopamine and / or norepinephrine and / or serotonin. Additional CNS disorders contemplated for treatment using the formulations, dosage forms, and related methods described herein are described, for example, in the "Quick Reference to Diagnostic Criteria from DSM-IV" (Diagnostic and Statistical Manual of Mental Disorders, 4th ed., The American Psychiatric Association, Washington, DC, 1994). These target disorders for treatment and / or prevention according to the present invention include, but are not limited to, attention-deficit / hyperactivity disorder, predominantly inattentive type; attention-deficit / hyperactivity disorder, predominantly hyperactive-impulsive type; attention-deficit / hyperactivity disorder, combined type; attention-deficit / hyperactivity disorder (not otherwise specified (NOS)); conduct disorder; oppositional defiant disorder; and disruptive behavior disorder (not otherwise specified (NOS)).

[0123] Depressive disorders suitable for treatment and / or prevention using the formulations, dosage forms, and related methods described herein include, but are not limited to, major depressive disorder, recurrent, dysthymic disorder, depressive disorder not otherwise specified (NOS), and major depressive disorder, single episode.

[0124] Addiction disorders suitable for treatment and / or prevention using the formulations, dosage forms, and related methods described herein include, but are not limited to, eating disorders, impulse control disorders, alcohol-related disorders, nicotine-related disorders, amphetamine-related disorders, cannabis-related disorders, cocaine-related disorders, hallucinogen use disorders, inhalant-related disorders, and opioid-related disorders, all of which are further subclassified as listed below.

[0125] Eating disorders include, but are not limited to, bulimia nervosa, non-purgative type; bulimia nervosa, purgative type; and eating disorder (not otherwise specified (NOS)).

[0126] Impulse control disorders include, but are not limited to, intermittent explosive disorder, kleptomania, pyromania, problem gambling, trichotillomania, and impulse control disorder (not otherwise specified (NOS)).

[0127] Alcohol-related disorders include, but are not limited to, alcohol-induced psychotic disorder with delusions, alcohol abuse, alcohol intoxication, alcohol withdrawal, alcoholic delirium, alcohol-withdrawal delirium, alcohol-induced persistent dementia, alcohol-induced persistent amnesic disorder, alcohol dependence, alcohol-induced psychotic disorder with hallucinations, alcohol-induced mood disorder, alcohol-induced anxiety disorder, alcohol-induced sexual dysfunction, alcohol-induced sleep disorder, alcohol-related disorder (not otherwise specified (NOS)), alcohol intoxication, and alcohol withdrawal.

[0128] Nicotine-related disorders include, but are not limited to, nicotine dependence, nicotine withdrawal, and nicotine-related disorder (not otherwise specified (NOS)).

[0129] Amphetamine-related disorders include, but are not limited to, amphetamine dependence, amphetamine abuse, amphetamine intoxication, amphetamine withdrawal, amphetamine-intoxicated delirium, amphetamine-induced psychotic disorder with delusions, amphetamine-induced psychotic disorder with hallucinations, amphetamine-induced mood disorder, amphetamine-induced anxiety disorder, amphetamine-induced sexual dysfunction, amphetamine-induced sleep disorder, amphetamine-related disorder (not otherwise specified (NOS)), amphetamine intoxication, and amphetamine withdrawal.

[0130] Cannabis-related disorders include, but are not limited to, cannabis dependence, cannabis abuse, cannabis intoxication, cannabis-induced delirium, cannabis-induced psychotic disorder with delusions, cannabis-induced psychotic disorder with hallucinations, cannabis-induced anxiety disorder, cannabis-related disorder (not otherwise specified (NOS)), and cannabis addiction.

[0131] Cocaine-related disorders include, but are not limited to, cocaine dependence, cocaine abuse, cocaine intoxication, cocaine withdrawal, cocaine-induced delirium, cocaine-induced psychotic disorder with delusions, cocaine-induced psychotic disorder with hallucinations, cocaine-induced mood disorder, cocaine-induced anxiety disorder, cocaine-induced sexual dysfunction, cocaine-induced sleep disorder, cocaine-related disorder (not otherwise specified (NOS)), cocaine intoxication, and cocaine withdrawal.

[0132] Hallucinogen use disorders include, but are not limited to, hallucinogen dependence, hallucinogen abuse, hallucinogen intoxication, hallucinogen withdrawal, hallucinogen intoxication delirium, hallucinogen-induced psychotic disorder with delusions, hallucinogen-induced psychotic disorder with hallucinations, hallucinogen-induced mood disorder, hallucinogen-induced anxiety disorder, hallucinogen-induced sexual dysfunction, hallucinogen-induced sleep disorder, hallucinogen-related disorder (not otherwise specified (NOS)), hallucinogen intoxication, and hallucinogen-persisting perception disorder (flashback).

[0133] Inhalant-related disorders include, but are not limited to, inhalant dependence, inhalant abuse, inhalant poisoning, inhalant poisoning delirium, inhalant-induced psychotic disorder with delusions, inhalant-induced psychotic disorder with hallucinations, inhalant-induced anxiety disorder, inhalant-related disorder (not otherwise specified (NOS)), and inhalant poisoning.

[0134] Opioid-related disorders include, but are not limited to, opioid dependence, opioid abuse, opioid addiction, opioid intoxication delirium, opioid-induced psychotic disorder with delusions, opioid-induced psychotic disorder with hallucinations, opioid-induced anxiety disorder, opioid-related disorder (not otherwise specified (NOS)), opioid intoxication, and opioid withdrawal.

[0135] Tic disorders include, but are not limited to, Tourette's syndrome, chronic motor or vocal tic disorder, transient tic disorder, tic disorder (not otherwise specified (NOS)), stuttering, autistic disorder, and somatization disorder.

[0136] Thus, by virtue of their multiple reuptake inhibitory activity, the formulations, dosage forms and associated methods described herein are useful for a wide range of veterinary and human medical applications, particularly for the treatment and / or prevention of a wide range of CNS disorders and / or associated conditions that are alleviated by inhibiting the reuptake of dopamine and / or norepinephrine and / or serotonin.

[0137] It is understood or easily ascertained that the disorders that can be alleviated by using the formulations or dosage forms described herein are not limited to the specific disorders described herein, and provide effective drugs for treating and / or preventing a wide range of other disorders and related symptoms.For example, the formulations or dosage forms described herein provide promising candidates for treating and / or preventing cognitive disorders, bipolar disorder, anorexia nervosa, bulimia nervosa, cyclothymic disorder, chronic fatigue syndrome, chronic or acute stress, learning disabilities, reading comprehension disorders, gambling addiction, manic symptoms, phobias, panic attacks, academic problems at school, smoking, abnormal sexual behavior, schizophrenic behavior, sleep disorders, stuttering, fibromyalgia and other somatoform disorders (such as somatization disorder, conversion disorder, pain disorder, hypochondriasis, body dysmorphic disorder, undifferentiated somatoform disorder, somatoform NOS), incontinence (i.e., stress urinary incontinence, true stress urinary incontinence and mixed urinary incontinence), inhalation disorders, mania, migraine, peripheral neuropathy. The formulations or dosage forms described herein can be used to treat or prevent any one of the disorders or indications described in U.S. Pat. Nos. 8,461,196, 9,839,627, or U.S. Patent Application Publication Nos. 2018 / 0008575A and 2014 / 0206740A, the contents of each of which are incorporated herein by reference.

[0138] Various aspects of the pharmaceutical formulations, methods of treatment and uses are described using the following enumerated aspects.

[0139] Aspect A A1. A pharmaceutical formulation comprising a plurality of centanafadine (CTN) beads, each of the plurality of CTN beads comprising a core particle containing CTN or a pharmaceutically acceptable salt thereof and an excipient.

[0140] A2. The pharmaceutical formulation of A1, wherein at least a portion of the plurality of beads are coated.

[0141] A3. The pharmaceutical formulation of any of A1-A2, wherein at least a portion of the plurality of beads are uncoated.

[0142] A4. The pharmaceutical formulation of A2, wherein the coating is one or more coatings selected from a delayed release coating, a sustained release coating, and a delayed-sustained release coating.

[0143] A5.The coating is one or more materials selected from amylose acetate phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate trimellitate, carboxymethyl ethyl cellulose, copolymerized methacrylic acid / methacrylic acid methyl ester, copolymerized methacrylic acid / methyl methacrylate, copolymerized methyl acrylate / methyl methacrylate / methacrylic acid, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, styrene-maleic acid copolymer, and styrene-vinylpyridine copolymer; optionally, one or more materials selected from copolymers of methacrylic acid, methyl methacrylate, and methyl acrylate, and methacrylic acid-acrylate copolymers; and Optionally, a copolymer of methacrylic acid, methyl methacrylate, and methyl acrylate. 2. The pharmaceutical formulation of A4, wherein the delayed release coating comprises:

[0144] A6. Any of the pharmaceutical formulations of A1 to A5 comprising a delayed-release coating, wherein the median amount of the delayed-release coating disposed on the core particles is at least 10% by weight of the total weight of the CTN beads, or in the range of about 12% to about 50% by weight, or about 12% to about 35% by weight, or about 15% to about 45% by weight based on the total weight of the CTN beads; or in the range of about 10% to about 50% by weight, or about 10% to about 40% by weight, or about 10% to about 30% by weight, or about 20% by weight based on the total weight of the CTN beads.

[0145] A7. Any of the pharmaceutical formulations of A1 to A6 comprising a sustained release coating, wherein the sustained release coating is: one or more materials selected from alkyl celluloses, acrylic acid polymers, methacrylic acid polymers, acrylic acid copolymers, methacrylic acid copolymers, and cellulose ethers; optionally, one or more materials selected from hydroxyalkyl cellulose, carboxyalkyl cellulose, ethyl cellulose, methyl methacrylate, methyl methacrylate copolymer, ethoxyethyl methacrylate, ethyl acrylate, trimethylammonioethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, aqueous dispersion of neutral copolymer based on ethyl acrylate and methacrylate with a polymer content of about 30% [CAS 9010-88-4], poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymer, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic anhydride), and glycidyl methacrylate copolymer; optionally, one or more materials selected from poly[ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride], hydroxypropyl methylcellulose, and poly[ethyl acrylate, methyl methacrylate]; Optionally, a pharmaceutical formulation comprising poly[ethyl acrylate, methyl methacrylate].

[0146] A8. Any of the pharmaceutical formulations of A1 to A7 comprising a sustained release coating, wherein the median amount of the sustained release coating disposed on the core particle is at least 5% by weight of the total weight of the core particle, or in the range of about 5% to about 60% by weight, or about 15% to about 60% by weight, or about 20% to about 50% by weight of the total weight of the core particle; or in the range of about 5% to about 50% by weight, or about 7.5% to about 45% by weight, or about 10% to about 40% by weight, or about 15% by weight; or in the range of about 5% to about 40% by weight, about 15% to about 40% by weight, or about 20% to about 40% by weight of the total weight of the core particle.

[0147] A9. Any of the pharmaceutical formulations of A1 to A8 comprising a coating, wherein the coating further comprises a pore-forming agent.

[0148] A10. The pore-forming agent is one or more materials selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, poloxamer 188, polyvinylpyrrolidone, D-mannitol, methylcellulose, polyvinyl alcohol-polyethylene glycol graft copolymer, and saccharides; optionally, one or more materials selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyvinylpyrrolidone; A pharmaceutical formulation of A9 optionally containing hydroxypropyl methylcellulose.

[0149] A11. The pore former is based on the total weight of the coating. or in an amount ranging from about 5% by weight or more, or about 10% by weight or more, or from about 5% by weight to about 20% by weight, in some cases 15% by weight; or The pharmaceutical formulation of A9, present in the coating in an amount ranging from less than 50% by weight, or less than 20% by weight, or from about 1% to about 16% by weight, or from about 1% to about 12% by weight.

[0150] A12. Any of the pharmaceutical formulations A1 to A11, wherein the core particles are specified by a particle size distribution, and at least a portion of the core particles of the multiple beads have a core particle size (maximum diameter) of about 0.2 mm to about 2 mm, or about 0.3 mm to about 1.5 mm, 0.4 mm to about 1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm.

[0151] A13. The particle size distribution of the core particles is At least 60% by weight of core particles have a particle size (maximum diameter) in the range of about 0.4 mm to about 1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm; In some cases, at least 80% by weight of core particles have a particle size (maximum diameter) in the range of about 0.4 mm to about 1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm; In some cases, at least 90% by weight of the core particles have a particle size (maximum diameter) in the range of about 0.4 mm to about 1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm; In some cases, at least 99% by weight of the core particles have a particle size (maximum diameter) in the range of about 0.4 mm to about 1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm. A12 pharmaceutical preparation identified by

[0152] A14. Any of the pharmaceutical formulations of A1 to A13, wherein the plurality of CTN beads have an average particle size (diameter) in the range of about 0.2 mm to about 2.8 mm, or about 0.2 mm to about 2.5 mm, or about 0.2 mm to about 2.0 mm, or about 0.7 mm to about 2.5 mm, or about 0.7 mm to about 2.8 mm, or about 0.5 mm to about 2.8 mm, or about 0.8 mm to about 1.7 mm, or about 0.5 mm to about 1.2 mm, or about 0.5 mm to about 1.0 mm, or about 0.5 mm to about 0.71 mm.

[0153] A15. The pharmaceutical formulation of any of A1 to A14, wherein the plurality of CTN beads comprises one or more types selected from fast-release beads, sustained-release beads, delayed-release beads, and delayed-sustained-release beads.

[0154] A16. The pharmaceutical formulation of any of A1-A15, wherein the plurality of beads comprises a mixture of one or more fast-release beads and one or more sustained-release beads.

[0155] A17. A pharmaceutical formulation of A16, wherein the ratio of CTN or a pharmaceutically acceptable salt thereof is present in one or more fast-release beads and one or more sustained-release beads in a ratio ranging from about 1:100 to about 1:1 parts by weight, based on the weight of CTN.

[0156] A18. The pharmaceutical formulation of any of A1-A17, wherein the plurality of beads comprises a mixture of one or more fast-release beads and one or more delayed-release beads.

[0157] A19. A pharmaceutical formulation of A18, wherein the ratio of CTN or a pharmaceutically acceptable salt thereof is present in one or more fast-release beads and one or more delayed-release beads in a ratio ranging from about 1:100 to about 1:1 parts by weight, based on the weight of CTN.

[0158] A20. The pharmaceutical formulation of any of A1-A19, wherein the plurality of beads comprises a mixture of one or more delayed release beads and one or more sustained release beads.

[0159] A21. A pharmaceutical formulation of A20, wherein the ratio of CTN or a pharmaceutically acceptable salt thereof is present in one or more sustained-release beads and one or more delayed-release beads in a ratio ranging from about 5:10 to about 1:5 parts by weight, based on the weight of CTN.

[0160] A22. The pharmaceutical formulation of any of A1-A21, wherein the plurality of beads comprises a mixture of one or more fast-release beads and one or more delayed-sustained-release beads.

[0161] A23. A pharmaceutical formulation of A22, wherein the ratio of CTN or a pharmaceutically acceptable salt thereof is present in one or more fast-release beads and one or more delayed-sustained-release beads in a ratio ranging from about 1:100 to about 1:1 parts by weight, based on the weight of CTN.

[0162] A24. The pharmaceutical formulation of any of A1-A23, wherein the plurality of beads comprises a mixture of one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads.

[0163] A25. The ratio of CTN or a pharmaceutically acceptable salt thereof in one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads is in the range of about 0.1-1:1-20:1-20 parts by weight based on the total weight of CTN or a salt thereof; optionally in a ratio ranging from about 0.5-1:5-20:5-20 parts by weight based on the total weight of CTN or a salt thereof; optionally in a ratio ranging from about 0.7-13:3-6:3-6 parts by weight based on the total weight of CTN or a salt thereof; and optionally in a ratio ranging from about 0.7-1:5-15:5-15 parts by weight based on the total weight of CTN or a salt thereof; A pharmaceutical formulation of A24 exists.

[0164] A26. Any of the pharmaceutical formulations of A1-A25, wherein the plurality of beads comprises a mixture of one or more fast-release beads, one or more sustained-release beads, and one or more delayed-sustained-release beads.

[0165] A27. The ratio of CTN or a pharmaceutically acceptable salt thereof in one or more fast-release beads, one or more sustained-release beads, and one or more delayed-sustained-release beads is in the range of about 0.1-1:1-20:1-20 parts by weight based on the total weight of CTN or a salt thereof; optionally in a ratio ranging from about 0.5-1:5-20:5-20 parts by weight based on the total weight of CTN or a salt thereof; optionally in a ratio ranging from about 0.7-13:3-6:3-6 parts by weight based on the total weight of CTN or a salt thereof; and optionally in a ratio ranging from about 0.7-1:5-15:5-15 parts by weight based on the total weight of CTN or a salt thereof; A pharmaceutical formulation of A26 exists.

[0166] A28. Any of the pharmaceutical formulations of A1 to A27, wherein the rapid-release beads are uncoated.

[0167] A29. Rapid-release beads in the formulation in an amount ranging from about 1% to about 75% based on the total weight of the plurality of CTN beads; optionally, in the range of about 40% to about 50% based on the total weight of the plurality of CTN beads, when the drug incorporated in the fast-release beads is about 5% to about 15% by weight; optionally, in the range of about 1% to about 50%, based on the total weight of the plurality of CTN beads; optionally, in the range of about 1% to about 25%, based on the total weight of the plurality of CTN beads; optionally, in the range of about 1% to about 10%, based on the total weight of the plurality of CTN beads; Optionally, in the range of about 9% to about 19% based on the total weight of the plurality of CTN beads when the drug incorporated in the rapid-release beads is about 40% to about 50% by weight; and Optionally, in the range of about 18% to about 28% based on the total weight of the plurality of CTN beads. Any of the pharmaceutical preparations A1 to A28 exists.

[0168] A30. Contains sustained release beads, The sustained-release beads range from about 5% to 80% based on the total weight of the plurality of CTN beads in the formulation; optionally, in the range of about 23% to about 33%, based on the total weight of the plurality of CTN beads; optionally, in the range of about 5% to about 65%, based on the total weight of the plurality of CTN beads; optionally, in the range of about 40% to about 50% based on the total weight of the plurality of CTN beads; Optionally, in the range of about 35% to about 55% based on the total weight of the plurality of CTN beads. A pharmaceutical formulation of any of A1 to A29, wherein the pharmaceutical formulation is present in an amount of

[0169] A31. Contains delayed release beads, The delayed-release beads range from about 5% to 80% based on the total weight of the CTN beads in the formulation; optionally, in the range of about 21% to about 31%, based on the total weight of the plurality of CTN beads; optionally, in the range of about 5% to about 65%, based on the total weight of the plurality of CTN beads; optionally, in the range of about 36% to about 46%, based on the total weight of the plurality of CTN beads; Optionally, in the range of about 30% to about 55% based on the total weight of the plurality of CTN beads. A pharmaceutical formulation of any of A1 to A30, wherein the pharmaceutical formulation is present in an amount of

[0170] A32. Contains sustained-release beads, USP <711> Any of the pharmaceutical formulations of A1 to A31, wherein at least 90% of CTN or a salt thereof is released from the sustained-release beads in 1000 mL of deionized water at 37°C ± 0.5°C and 100 rpm in accordance with the test method described above, using Apparatus 1 (basket), within a range of 2 to 6 hours.

[0171] A33. Contains delayed release beads, USP <711> According to the method described above, at 37°C ± 0.5°C, 100 rpm, using Apparatus 1 (basket), first test in 1000 mL of 0.1 N HCl solution for 2 hours, and then test in 1000 mL of unbuffered deionized water for the remaining time, and at least 90% of CTN or a salt thereof is released from the delayed-release beads within a range of 4 to 14 hours, or USP <711> According to the test, using Apparatus 1 (basket), at 37°C ± 0.5°C, 100 rpm, first test in 1000 mL of 0.1 N HCl solution for 2 hours, then test in 1000 mL of pH 7.4 phosphate buffer solution for the remaining time, and at least 90% of CTN or its salt is released from the delayed-release beads within a range of 4 to 14 hours. A pharmaceutical preparation according to any one of A1 to A32.

[0172] A34. Delayed-sustained release beads, USP <711> and (iii) at least 90% of the CTN or a salt thereof is released from the delayed-sustained-release beads in a range of 4 to 14 hours, using Apparatus 1 (basket) at 37°C ± 0.5°C, 100 rpm, first in 1000 mL of 0.1 N HCl solution for 2 hours, and then in 1000 mL of unbuffered deionized water for the remaining time. USP <711> According to the test, using Apparatus 1 (basket), at 37°C ± 0.5°C, 100 rpm, first in 1000 mL of 0.1 N HCl solution for 2 hours, then in 1000 mL of pH 7.4 phosphate buffer solution for the remaining time, at least 90% of CTN or its salt is released from the delayed-sustained-release beads within a range of 4 to 14 hours. A pharmaceutical preparation according to any one of A1 to A33.

[0173] A35. Contains rapid-release beads, USP <711> Any of the pharmaceutical formulations A1 to A34, wherein at least 90% of CTN or a salt thereof is released from the fast-release beads in 1000 mL of deionized water at 37°C ± 0.5°C and 100 rpm in the range of 0 to 2 hours when tested using Apparatus 1 (basket) according to the method described above.

[0174] A36. Contains a mixture of fast-release beads, sustained-release beads, and delayed-release beads, USP <711> In accordance with the method described above, using Apparatus 1 (basket), at 37°C ± 0.5°C, 100 rpm, first in 1000 mL of 0.1 N HCl solution for 2 hours, and then in 1000 mL of unbuffered deionized water for the remaining time, at least 40% of CTN or its salt is released from the mixture of beads within 3 to 5 hours, at least 90% of CTN or its salt is released from the mixture of beads within 12 to 14 hours, or USP <711> According to the method described above, the test is carried out using Apparatus 1 (basket) at 37°C ± 0.5°C, 100 rpm, first with 1000 mL of 0.1 N HCl solution for 2 hours, and then with 1000 mL of pH 7.4 phosphate buffer solution for the remaining time, and at least 40% of the CTN or its salt is released from the bead mixture within 3 to 5 hours, and at least 90% of the CTN or its salt is released from the bead mixture within 12 to 14 hours. A pharmaceutical preparation according to any one of A1 to A35.

[0175] A37. Contains a mixture of fast-release beads, sustained-release beads, and delayed-release beads, USP <711> According to the above, using the apparatus 1 (basket), the test was carried out in 1000 mL of 0.1 N hydrochloric acid at 37°C ± 0.5°C and 100 rpm for 2 hours, and then using the apparatus 1 (basket), the test was carried out in 1000 mL of pH 7.4 phosphate buffer at 37°C ± 0.5°C and 100 rpm for 12 hours, and the release profile was (a) about 22% to about 45% release of CTN at 3 hours, and further optionally about 40% to about 65% release of CTN at 8 hours, and further optionally about 65% to about 95% release of CTN at 12 hours, and further optionally these percentages of release at all three of these time points; and / or (b) about 24% to 48% release of CTN at 3 hours, further optionally at least 66% release of CTN at 6 hours, further optionally at least 86% release of CTN at 10 hours, and further optionally these release percentages at all three time points, and still further optionally 49% to 73% release at 4 hours; Any of the pharmaceutical formulations A1 to A35, characterized in that:

[0176] A38. Contains fast-release beads CTN or a salt thereof is in the range of 5 wt% to 80 wt% in the fast-release beads based on the total weight of the fast-release beads; optionally in the range of 5% to 60% by weight based on the total weight of the fast-release beads; optionally in the range of 5% to 15% by weight based on the total weight of the fast-release beads; Optionally, in the range of 40% to 60% by weight based on the total weight of the fast-release beads is present in an amount of, and Optionally, the CTN or salt thereof is present in a first fast-release bead in an amount ranging from 5% to 15% by weight based on the total weight of the fast-release bead, and the CTN or salt thereof is present in a second fast-release bead in an amount ranging from 40% to 60% by weight based on the total weight of the fast-release bead. A pharmaceutical preparation according to any one of A1 to A37.

[0177] A39. Contains sustained release beads CTN or a salt thereof is in the range of 10% by weight to 95% by weight in the sustained-release beads, based on the total weight of the sustained-release beads; optionally in the range of 40% to 90% by weight, based on the total weight of the sustained release beads; Optionally, in the range of 50% to 70% by weight based on the total weight of the sustained release beads. A pharmaceutical formulation of any of A1 to A38, wherein the pharmaceutical formulation is present in an amount of

[0178] A40. Contains delayed release beads, CTN or a salt thereof is in the range of 10% by weight to 95% by weight in the delayed-release beads, based on the total weight of the delayed-release beads; optionally in the range of 40% to 90% by weight based on the total weight of the delayed release beads; Optionally, in the range of 50% to 70% by weight based on the total weight of the delayed release beads. A pharmaceutical formulation of any of A1 to A39, wherein the pharmaceutical formulation is present in an amount of

[0179] A41. A pharmaceutical formulation of any of A1-A40, characterized in that it exhibits a multimodal, optionally bimodal, in vivo absorption profile.

[0180] A42. The in vivo absorption profile of the first C max A pharmaceutical formulation according to any one of A1 to A41, comprising:

[0181] A43. The in vivo yield profile of the second C is in the range of about 6 hours to 10 hours, or about 7 hours to 9 hours, or about 7.5 to about 8.5 hours. max A pharmaceutical formulation according to any one of A1 to A42, comprising:

[0182] A44. The first C shown by the formulation in adult humans max having a mean plasma level in the range of about 250 ng / mL to about 420 ng / mL, or about 320 ng / mL to about 420 ng / mL, or about 325 ng / mL to about 390 ng / mL.

[0183] A45. Second C shown by the formulation in human adults max Any of the pharmaceutical formulations A42 to A44, wherein the pharmaceutical formulation has a mean plasma level in the range of about 450 ng / mL to about 550 ng / mL, or about 470 ng / mL to about 530 ng / mL.

[0184] A46. In vivo absorption profile is the first C max and the second C maxand the first C max and the second C max The pharmaceutical formulation of any of A1 to A45, wherein the time difference between the first and second doses is in the range of 1.5 to 8.5 hours, or about 2 to about 6 hours, or about 3 to about 5 hours.

[0185] A47. The pharmaceutical formulation of any of A1-A46, wherein one or more of the plurality of CTN beads has a release mechanism comprising one or more of dissolution, diffusion, erosion, osmosis, partitioning, swelling, and targeting.

[0186] A48. The pharmaceutical formulation of any of A1 to A47, wherein one or more of the plurality of CTN beads has a diffusion release mechanism.

[0187] A49. The pharmaceutical formulation of any of A1 to A48, wherein one or more of the plurality of CTN beads has a pH-dependent dissolution release mechanism.

[0188] A50. The pharmaceutical formulation of any of A1-A49, wherein one or more of the plurality of CTN beads has a combination of a pH-dependent dissolution release mechanism and a diffusion release mechanism.

[0189] A51. The pharmaceutical formulation of any of A1-A50, wherein one or more of the plurality of CTN beads comprises a porous matrix containing CTN.

[0190] A52. The pharmaceutical formulation of any of A1 to A51, wherein a plurality of CTN beads are packaged in one or more containers selected from capsules, sachets, and stick packs, optionally in capsules.

[0191] A53. A pharmaceutical formulation according to any of A1 to A52, wherein the CTN is present as a salt, optionally as the hydrochloride salt.

[0192] A54. The excipient is one or more materials selected from fillers, binders, glidants, surfactants, polymer coatings, and plasticizers; optionally a combination of fillers and binders; Optionally, a combination of a binder and a polymer coating; Optionally, a combination of fillers, binders, and polymer coatings; Optionally, a combination of fillers, binders, polymer coatings, and plasticizers A pharmaceutical formulation according to any one of A1 to A53, comprising:

[0193] A55. The pharmaceutical formulation of any of A1-A54, wherein the excipient comprises one or more materials selected from lactose, mannitol, corn starch, microcrystalline cellulose, hydroxypropyl cellulose, hypromellose, polyvinylpyrrolidone, talc, polysorbate 80, glycerol monostearate, triethyl citrate, polyvinyl alcohol-polyethylene glycol graft copolymer, and silica.

[0194] A56. A pharmaceutical formulation according to any one of A1 to A55, wherein the formulation does not contain a disintegrant.

[0195] Aspect B B1. A pharmaceutical formulation containing CTN or a pharmaceutically acceptable salt thereof, wherein the formulation is a solid oral formulation suitable for pediatric use.

[0196] B2. The pharmaceutical formulation of B1, wherein the solid oral dosage form suitable for pediatric use is selected from one or more types, optionally beads, including beads, orodispersible tablets, orodispersible films, minitablets, chewable tablets, and soft chews.

[0197] B3. The pharmaceutical formulation of B1 or B2, wherein the solid oral dosage form suitable for pediatric use is characterized by one or more release profiles selected from fast release, sustained release, delayed release, and delayed-sustained release in vivo and / or in vitro.

[0198] B4. Any of the pharmaceutical formulations of B1 to B3, wherein the solid oral formulation suitable for pediatric use contains a plurality of centanafadine (CTN) beads, each of the plurality of CTN beads containing a core particle comprising CTN or a pharmaceutically acceptable salt thereof and an excipient.

[0199] B5. The pharmaceutical formulation of B4, wherein at least a portion of the plurality of beads are coated.

[0200] B6. The pharmaceutical formulation of any of B4-B5, wherein at least a portion of the plurality of beads are uncoated.

[0201] B7. The pharmaceutical formulation of B6, wherein the coating is one or more coatings selected from a delayed release coating, a sustained release coating, and a delayed-sustained release coating.

[0202] B8. Coating, one or more materials selected from amylose acetate phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate trimellitate, carboxymethyl ethyl cellulose, copolymerized methacrylic acid / methacrylic acid methyl ester, copolymerized methacrylic acid / methyl methacrylate, copolymerized methyl acrylate / methyl methacrylate / methacrylic acid, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, styrene-maleic acid copolymer, and styrene-vinylpyridine copolymer; optionally, one or more materials selected from copolymers of methacrylic acid, methyl methacrylate, and methyl acrylate, and methacrylic acid-acrylate copolymers; and Optionally, a copolymer of methacrylic acid, methyl methacrylate, and methyl acrylate. 10. A pharmaceutical formulation of B7, wherein the delayed release coating comprises:

[0203] B9. Any of the pharmaceutical formulations of B4 to B8 comprising a delayed-release coating, wherein the median amount of the delayed-release coating disposed on the core particles is at least 10% by weight of the total weight of the CTN beads, or in the range of about 12% to about 50% by weight, or about 12% to about 35% by weight, based on the total weight of the CTN beads.

[0204] B10. A pharmaceutical formulation according to any one of B4 to B9, comprising a sustained release coating, wherein the sustained release coating is one or more materials selected from alkyl celluloses, acrylic acid polymers, methacrylic acid polymers, acrylic acid copolymers, methacrylic acid copolymers, and cellulose ethers; optionally, one or more materials selected from hydroxyalkyl cellulose, carboxyalkyl cellulose, methyl methacrylate, methyl methacrylate copolymer, ethoxyethyl methacrylate, ethyl acrylate, trimethylammonioethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymer, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic anhydride), and glycidyl methacrylate copolymer; optionally, one or more materials selected from poly[ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride], hydroxypropyl methylcellulose, and poly[ethyl acrylate, methyl methacrylate]; Optionally, a pharmaceutical formulation comprising poly[ethyl acrylate, methyl methacrylate].

[0205] B11. A pharmaceutical formulation according to any one of B4 to B10, comprising a sustained release coating, wherein the median amount of the sustained release coating disposed on the core particle is at least 5% by weight of the total weight of the core particle, or in the range of about 5% to about 60% by weight, or about 15% to about 60% by weight, or about 20% to about 50% by weight of the total weight of the core particle.

[0206] B12. A pharmaceutical formulation according to any one of B4 to B11, comprising a coating, wherein the coating further comprises a pore-forming agent.

[0207] B13. The pore-forming agent is one or more materials selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, poloxamer 188, polyvinylpyrrolidone, D-mannitol, methylcellulose, polyvinyl alcohol-polyethylene glycol graft copolymer, and saccharides; optionally, one or more materials selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyvinylpyrrolidone; A pharmaceutical formulation of B12, optionally containing hydroxypropyl methylcellulose.

[0208] B14. The pharmaceutical formulation of B12, wherein the pore-forming agent is present in the coating in an amount of about 5% by weight or more, or about 10% by weight or more, or in the range of about 5% to about 20% by weight, optionally in an amount of 15% by weight.

[0209] B15. A pharmaceutical formulation according to any one of B4 to B14, wherein the core particles are specified by a particle size distribution, and at least a portion of the core particles of the plurality of beads have a core particle size (maximum diameter) of about 0.2 mm to about 2 mm, or about 0.3 mm to about 1.5 mm, 0.4 mm to about 1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm.

[0210] B16. The particle size distribution of the core particles At least 60% by weight of core particles have a particle size (maximum diameter) in the range of about 0.4 mm to about 1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm; In some cases, at least 80% by weight of core particles have a particle size (maximum diameter) in the range of about 0.4 mm to about 1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm; In some cases, at least 90% by weight of the core particles have a particle size (maximum diameter) in the range of about 0.4 mm to about 1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm; In some cases, at least 99% by weight of the core particles have a particle size (maximum diameter) in the range of about 0.4 mm to about 1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm. A pharmaceutical preparation of B15 identified as

[0211] B17. A pharmaceutical formulation according to any one of B4 to B16, wherein the plurality of CTN beads have an average particle size (diameter) in the range of about 0.2 mm to about 2.8 mm, or about 0.2 mm to about 2.5 mm, or about 0.2 mm to about 2.0 mm, or about 0.7 mm to about 2.5 mm, or about 0.7 mm to about 2.8 mm, or about 0.5 mm to about 2.8 mm, or about 0.8 mm to about 1.7 mm, or about 0.5 mm to about 1.2 mm, or about 0.5 mm to about 1.0 mm, or about 0.5 mm to about 0.71 mm.

[0212] B18. The pharmaceutical formulation of any of B4-B17, wherein the plurality of CTN beads comprises one or more types selected from fast-release beads, sustained-release beads, delayed-release beads, and delayed-sustained-release beads.

[0213] B19. The pharmaceutical formulation of any of B4-B18, wherein the plurality of beads comprises a mixture of one or more fast-release beads and one or more sustained-release beads.

[0214] B20. The pharmaceutical formulation of B19, wherein the ratio of CTN or a pharmaceutically acceptable salt thereof is present in one or more fast-release beads and one or more sustained-release beads in a ratio ranging from about 1:100 to about 1:1 parts by weight, based on the weight of CTN.

[0215] B21. The pharmaceutical formulation of any of B4-B20, wherein the plurality of beads comprises a mixture of one or more fast-release beads and one or more delayed-release beads.

[0216] B22. The pharmaceutical formulation of B21, wherein the ratio of CTN or a pharmaceutically acceptable salt thereof is present in one or more fast-release beads and one or more delayed-release beads in a ratio ranging from about 1:100 to about 1:1 parts by weight, based on the weight of CTN.

[0217] B23. The pharmaceutical formulation of any of B4-B22, wherein the plurality of beads comprises a mixture of one or more delayed release beads and one or more sustained release beads.

[0218] B24. The pharmaceutical formulation of B23, wherein the ratio of CTN or a pharmaceutically acceptable salt thereof is present in the one or more sustained release beads and the one or more delayed release beads in a ratio ranging from about 5:10 to about 1:5 parts by weight based on the weight of CTN.

[0219] B25. The pharmaceutical formulation of any of B4-B24, wherein the plurality of beads comprises a mixture of one or more fast-release beads and one or more delayed-sustained release beads.

[0220] B26. The pharmaceutical formulation of B25, wherein the ratio of CTN or a pharmaceutically acceptable salt thereof is present in one or more fast-release beads and one or more delayed-sustained-release beads in a ratio ranging from about 1:100 to about 1:1 parts by weight, based on the weight of CTN.

[0221] B27. The pharmaceutical formulation of any of B4-B26, wherein the plurality of beads comprises a mixture of one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads.

[0222] B28. The ratio of CTN or a pharmaceutically acceptable salt thereof in one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads is in the range of about 0.1-1:1-20:1-20 parts by weight based on the total weight of CTN or a salt thereof; optionally in a ratio ranging from about 0.5-1:5-20:5-20 parts by weight based on the total weight of CTN or a salt thereof; optionally in a ratio ranging from about 0.7-13:3-6:3-6 parts by weight based on the total weight of CTN or a salt thereof; and optionally in a ratio ranging from about 0.7-1:5-15:5-15 parts by weight based on the total weight of CTN or a salt thereof; There exists a pharmaceutical formulation of B27.

[0223] B29. The pharmaceutical formulation of any of B4-B28, wherein the plurality of beads comprises a mixture of one or more fast-release beads, one or more sustained-release beads, and one or more delayed-sustained-release beads.

[0224] B30. The ratio of CTN or a pharmaceutically acceptable salt thereof in one or more fast-release beads, one or more sustained-release beads, and one or more delayed-sustained-release beads is in the range of about 0.1-1:1-20:1-20 parts by weight based on the total weight of CTN or a salt thereof; optionally in a ratio ranging from about 0.5-1:5-20:5-20 parts by weight based on the total weight of CTN or a salt thereof; optionally in a ratio ranging from about 0.7-13:3-6:3-6 parts by weight based on the total weight of CTN or a salt thereof; and optionally in a ratio ranging from about 0.7-1:5-15:5-15 parts by weight based on the total weight of CTN or a salt thereof; A pharmaceutical formulation of B29 exists.

[0225] B31. A pharmaceutical formulation of any of B4 to B30, wherein the rapid-release beads are uncoated.

[0226] B32. The fast-release beads are in the range of about 1% to about 75% based on the total weight of the plurality of CTN beads in the formulation; optionally, in the range of about 40% to about 50% based on the total weight of the plurality of CTN beads, when the drug incorporated in the fast-release beads is about 5% to about 15% by weight; optionally, in the range of about 1% to about 50% based on the total weight of the plurality of CTN beads; optionally, in the range of about 1% to about 25% based on the total weight of the plurality of CTN beads; optionally, in the range of about 1% to about 10% based on the total weight of the plurality of CTN beads; In some cases, the range is about 9% to about 19% based on the total weight of the plurality of CTN beads, when the drug incorporated into the rapid-release beads is about 40% to about 50% by weight or about 40% to about 55% by weight; and Optionally, in the range of about 18% to about 28% based on the total weight of the plurality of CTN beads. The pharmaceutical formulation of any one of B4 to B31, wherein the amount of

[0227] B33. Contains sustained release beads, The sustained-release beads range from about 5% to 80% based on the total weight of the plurality of CTN beads in the formulation; optionally, in the range of about 23% to about 33%, based on the total weight of the plurality of CTN beads; optionally, in the range of about 5% to about 65%, based on the total weight of the plurality of CTN beads; optionally, in the range of about 40% to about 50% based on the total weight of the plurality of CTN beads; Optionally, in the range of about 35% to about 55% based on the total weight of the plurality of CTN beads. A pharmaceutical formulation of any one of B4 to B32, wherein B4 to B32 are present in an amount of

[0228] B34. Contains delayed release beads, The delayed-release beads range from about 5% to 80% based on the total weight of the CTN beads in the formulation; optionally, in the range of about 21% to about 31%, based on the total weight of the plurality of CTN beads; optionally, in the range of about 5% to about 65%, based on the total weight of the plurality of CTN beads; optionally, in the range of about 36% to about 46%, based on the total weight of the plurality of CTN beads; Optionally, in the range of about 30% to about 55% based on the total weight of the plurality of CTN beads. A pharmaceutical formulation of any one of B4 to B33, wherein the amount of B4 to B33 is

[0229] B35. Contains sustained-release beads, USP <711> Any of B4 to B34 pharmaceutical formulations, which are tested in accordance with the above using Apparatus 1 (basket) in 1000 mL of deionized water at 37°C ± 0.5°C and 100 rpm, and which release at least 90% of CTN or a salt thereof from the sustained-release beads within a range of 2 to 6 hours.

[0230] B36. Contains delayed release beads, USP <711> According to the method described above, at 37°C ± 0.5°C, 100 rpm, using Apparatus 1 (basket), first test in 1000 mL of 0.1 N HCl solution for 2 hours, and then test in 1000 mL of unbuffered deionized water for the remaining time, and at least 90% of CTN or a salt thereof is released from the delayed-release beads within a range of 4 to 14 hours, or USP <711> According to the test, using Apparatus 1 (basket), at 37°C ± 0.5°C, 100 rpm, first test in 1000 mL of 0.1 N HCl solution for 2 hours, then test in 1000 mL of pH 7.4 phosphate buffer solution for the remaining time, and at least 90% of CTN or its salt is released from the delayed-release beads within a range of 4 to 14 hours. Any of pharmaceutical preparations B4 to B35.

[0231] B37. Delayed-sustained release beads, USP <711> and (iii) at least 90% of the CTN or a salt thereof is released from the delayed-sustained-release beads in a range of 4 to 14 hours, using Apparatus 1 (basket) at 37°C ± 0.5°C, 100 rpm, first in 1000 mL of 0.1 N HCl solution for 2 hours, and then in 1000 mL of unbuffered deionized water for the remaining time. USP <711> According to the test, using Apparatus 1 (basket), at 37°C ± 0.5°C, 100 rpm, first in 1000 mL of 0.1 N HCl solution for 2 hours, then in 1000 mL of pH 7.4 phosphate buffer solution for the remaining time, at least 90% of CTN or its salt is released from the delayed-sustained-release beads within a range of 4 to 14 hours. Any of the pharmaceutical preparations B4 to B36.

[0232] B38. Contains fast-release beads, USP <711> Any of the pharmaceutical formulations B4 to B37, which are tested in accordance with the above method using Apparatus 1 (basket) in 1000 mL of deionized water at 37°C ± 0.5°C and 100 rpm, and at least 90% of CTN or a salt thereof is released from the fast-release beads within a range of 0 to 2 hours.

[0233] B39. A mixture of fast-release beads, sustained-release beads, and delayed-release beads, USP <711> In accordance with the method described above, using Apparatus 1 (basket), at 37°C ± 0.5°C, 100 rpm, first in 1000 mL of 0.1 N HCl solution for 2 hours, and then in 1000 mL of unbuffered deionized water for the remaining time, at least 40% of CTN or its salt is released from the mixture of beads within 3 to 5 hours, at least 90% of CTN or its salt is released from the mixture of beads within 12 to 14 hours, or USP <711> According to the method described above, the test is carried out using Apparatus 1 (basket) at 37°C ± 0.5°C, 100 rpm, first with 1000 mL of 0.1 N HCl solution for 2 hours, and then with 1000 mL of pH 7.4 phosphate buffer solution for the remaining time, and at least 40% of the CTN or its salt is released from the bead mixture within 3 to 5 hours, and at least 90% of the CTN or its salt is released from the bead mixture within 12 to 14 hours. Any of the pharmaceutical preparations B4 to B38.

[0234] B40. A mixture of fast-release beads, sustained-release beads, and delayed-release beads, USP <711> According to the above, using the apparatus 1 (basket), the test was carried out in 1000 mL of 0.1 N hydrochloric acid at 37°C ± 0.5°C and 100 rpm for 2 hours, and then using the apparatus 1 (basket), the test was carried out in 1000 mL of pH 7.4 phosphate buffer at 37°C ± 0.5°C and 100 rpm for 12 hours, and the release profile was (a) about 22% to about 45% release of CTN at 3 hours, and further optionally about 40% to about 65% release of CTN at 8 hours, and further optionally about 65% to about 95% release of CTN at 12 hours, and further optionally these percentages of release at all three of these time points; and / or (b) about 24% to 48% release of CTN at 3 hours, further optionally at least 66% release of CTN at 6 hours, further optionally at least 86% release of CTN at 10 hours, and further optionally these release percentages at all three time points, and still further optionally 49% to 73% release at 4 hours; Any of the pharmaceutical preparations B1 to B39, characterized in that:

[0235] B41. Contains fast-release beads, CTN or a salt thereof is in the range of 5 wt% to 80 wt% in the fast-release beads based on the total weight of the fast-release beads; optionally in the range of 5% to 60% by weight based on the total weight of the fast-release beads; optionally in the range of 5% to 15% by weight based on the total weight of the fast-release beads; Optionally, in the range of 40% to 60% by weight based on the total weight of the fast-release beads is present in an amount of, and Optionally, the CTN or salt thereof is present in a first fast-release bead in an amount ranging from 5% to 15% by weight based on the total weight of the fast-release bead, and the CTN or salt thereof is present in a second fast-release bead in an amount ranging from 40% to 60% by weight based on the total weight of the fast-release bead. Any of pharmaceutical preparations B4 to B40.

[0236] B42. Contains sustained release beads, CTN or a salt thereof is in the range of 10% by weight to 95% by weight in the sustained-release beads, based on the total weight of the sustained-release beads; optionally in the range of 40% to 90% by weight, based on the total weight of the sustained release beads; Optionally, in the range of 50% to 70% by weight based on the total weight of the sustained release beads. The pharmaceutical formulation of any one of B4 to B41, wherein the amount of

[0237] B43. Contains delayed release beads, CTN or a salt thereof is in the range of 10% by weight to 95% by weight in the delayed-release beads, based on the total weight of the delayed-release beads; optionally in the range of 40% to 90% by weight based on the total weight of the delayed release beads; Optionally, in the range of 50% to 70% by weight based on the total weight of the delayed release beads. A pharmaceutical formulation of any one of B4 to B42, wherein the amount of B4 to B42 is

[0238] B44. A pharmaceutical formulation of any of B4-B43, characterized in that it exhibits a multimodal, optionally bimodal, in vivo absorption profile.

[0239] B45. The first C max The pharmaceutical preparation according to any one of B4 to B44, comprising:

[0240] B46. The in vivo yield profile of the second C is in the range of about 6 hours to 10 hours, or about 7 hours to 9 hours, or about 7.5 to about 8.5 hours. max Any of the pharmaceutical preparations B4 to B45, having the following structure:

[0241] B47. First C shown from formulation in human adults max A pharmaceutical formulation of B45 or B46 having a mean plasma level in the range of about 250 ng / mL to about 420 ng / mL, or about 320 ng / mL to about 420 ng / mL, or about 325 ng / mL to about 390 ng / mL.

[0242] B48. Second C shown from formulation in human adults max any of the pharmaceutical formulations B45 to B47, having a mean plasma level in the range of about 450 ng / mL to about 550 ng / mL, or about 470 ng / mL to about 530 ng / mL.

[0243] B49. In vivo absorption profile is the first C max and the second C max and the first C max and the second C max The pharmaceutical formulation of any one of B4 to B48, wherein the time difference is in the range of 1.5 to 8.5 hours, or about 2 hours to about 6 hours, or about 3 hours to about 5 hours.

[0244] B50. The pharmaceutical formulation of any of B4-B49, wherein one or more of the plurality of CTN beads has a release mechanism comprising one or more of dissolution, diffusion, erosion, osmosis, partitioning, swelling, and targeting.

[0245] B51. The pharmaceutical formulation of any of B4-B50, wherein one or more of the plurality of CTN beads has a diffusional release mechanism.

[0246] B52. The pharmaceutical formulation of any of B4 to B51, wherein one or more of the plurality of CTN beads has a pH-dependent elution release mechanism.

[0247] B53. The pharmaceutical formulation of any of B4-B52, wherein one or more of the plurality of CTN beads has a combination of a pH-driven dissolution release mechanism and a diffusion release mechanism.

[0248] B54. The pharmaceutical formulation of any of B4-B53, wherein one or more of the plurality of CTN beads comprises a porous matrix containing CTN.

[0249] B55. The pharmaceutical formulation of any of B4-B54, wherein a plurality of CTN beads are packaged in one or more containers selected from capsules, sachets, and stick packs, optionally in capsules.

[0250] B56. A pharmaceutical formulation of any of B4 to B55, wherein the CTN is present as a salt, optionally as the hydrochloride salt.

[0251] B57. The excipient is one or more materials selected from fillers, binders, glidants, surfactants, polymer coatings, and plasticizers; optionally a combination of fillers and binders; Optionally, a combination of a binder and a polymer coating; Optionally, a combination of fillers, binders, and polymer coatings; Optionally, a combination of fillers, binders, polymer coatings, and plasticizers Any of the pharmaceutical preparations B4 to B56, comprising:

[0252] B58. The pharmaceutical formulation of any of B4-B56, wherein the excipient comprises one or more materials selected from lactose, mannitol, corn starch, microcrystalline cellulose, hydroxypropyl cellulose, hypromellose, polyvinylpyrrolidone, talc, polysorbate 80, glycerol monostearate, triethyl citrate, polyvinyl alcohol-polyethylene glycol graft copolymer, and silica.

[0253] B59. A pharmaceutical formulation according to any one of B4 to B57, wherein the formulation does not contain a disintegrant. Aspect C

[0254] C1. A pharmaceutical formulation comprising centanafadine (CTN) or a pharmaceutically acceptable salt thereof, and an excipient, wherein the pharmaceutical formulation has a multi-phase release profile, optionally at least a two-phase release profile, optionally at least a three-phase release profile, when tested in an acidic medium for 2 hours, followed by a buffered medium at pH 7.4; (a) optionally identified as releasing about 22% to about 45% CTN release at 3 hours, optionally about 40% to about 65% CTN release at 8 hours, optionally about 65% to about 95% CTN release at 12 hours, and optionally at such release rates at all three time points; or (b) optionally identified by about 24%-48% CTN release at 3 hours, further optionally at least 66% CTN release at 6 hours, further optionally at least 86% CTN release at 10 hours, and further optionally at such release rates at all three time points; Further optionally, the release profile may be specified as 49% to 73% release at 4 hours.

[0255] C2. The pharmaceutical formulation of C1, wherein the formulation is a solid oral formulation and / or a semi-solid oral formulation.

[0256] C3. The pharmaceutical formulation of C1 or C2, wherein the formulation is a solid oral formulation suitable for pediatric use.

[0257] C4. The pharmaceutical formulation of any of C1-C3, wherein the solid oral dosage form comprises one or more forms selected from powders, beads, orodispersible tablets, orodispersible films, minitablets, chewable tablets, and soft chews; optionally selected from powders and beads; and optionally beads.

[0258] C5. The pharmaceutical formulation of any of C1 to C4, wherein the formulation is a solid oral formulation suitable for adult use.

[0259] C6. The pharmaceutical formulation of C5, wherein the solid oral dosage form is selected from tablets, capsules, sachets, powders, beads, and lozenges; optionally selected from tablets, capsules, beads, and powders; and optionally comprising one or more forms selected from capsules and beads.

[0260] C7. Any of the pharmaceutical formulations of C1 to C6, wherein the solid oral formulation comprises a plurality of centanafadine (CTN) beads, each of the plurality of CTN beads comprising a core particle containing CTN or a pharmaceutically acceptable salt thereof and an excipient.

[0261] It is specifically contemplated that embodiments C1-C7 may include, as further optional features, each of the following embodiments B1-B58 individually and in combination.

[0262] B1. A pharmaceutical formulation according to any one of C1 to C7, which comprises CTN or a pharmaceutically acceptable salt thereof, and which is a solid oral formulation suitable for pediatric use.

[0263] B2. The pharmaceutical formulation of B1, wherein the solid oral dosage form suitable for pediatric use is selected from one or more types, optionally beads, including beads, orodispersible tablets, orodispersible films, minitablets, chewable tablets, and soft chews.

[0264] B3. The pharmaceutical formulation of B1 or B2, wherein the solid oral dosage form suitable for pediatric use is characterized by one or more release profiles selected from fast release, sustained release, delayed release, and delayed-sustained release in vivo and / or in vitro.

[0265] B4. Any of the pharmaceutical formulations of B1 to B3, wherein the solid oral formulation suitable for pediatric use contains a plurality of centanafadine (CTN) beads, each of the plurality of CTN beads containing a core particle comprising CTN or a pharmaceutically acceptable salt thereof and an excipient.

[0266] B5. The pharmaceutical formulation of B4, wherein at least a portion of the plurality of beads are coated.

[0267] B6. The pharmaceutical formulation of any of B4-B5, wherein at least a portion of the plurality of beads are uncoated.

[0268] B7. The pharmaceutical formulation of B6, wherein the coating is one or more coatings selected from a delayed release coating, a sustained release coating, and a delayed-sustained release coating.

[0269] B8. Coating, one or more materials selected from amylose acetate phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate trimellitate, carboxymethyl ethyl cellulose, copolymerized methacrylic acid / methacrylic acid methyl ester, copolymerized methacrylic acid / methyl methacrylate, copolymerized methyl acrylate / methyl methacrylate / methacrylic acid, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, styrene-maleic acid copolymer, and styrene-vinylpyridine copolymer; optionally, one or more materials selected from copolymers of methacrylic acid, methyl methacrylate, and methyl acrylate, and methacrylic acid-acrylate copolymers; and Optionally, a copolymer of methacrylic acid, methyl methacrylate, and methyl acrylate. 10. A pharmaceutical formulation of B7, wherein the delayed release coating comprises:

[0270] B9. Any of the pharmaceutical formulations of B4 to B8 comprising a delayed-release coating, wherein the median amount of the delayed-release coating disposed on the core particles is at least 10% by weight of the total weight of the CTN beads, or in the range of about 12% to about 50% by weight, or about 12% to about 35% by weight, based on the total weight of the CTN beads.

[0271] B10. A pharmaceutical formulation according to any one of B4 to B9, comprising a sustained release coating, wherein the sustained release coating is one or more materials selected from alkyl celluloses, acrylic acid polymers, methacrylic acid polymers, acrylic acid copolymers, methacrylic acid copolymers, and cellulose ethers; optionally, one or more materials selected from hydroxyalkyl cellulose, carboxyalkyl cellulose, methyl methacrylate, methyl methacrylate copolymer, ethoxyethyl methacrylate, ethyl acrylate, trimethylammonioethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymer, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic anhydride), and glycidyl methacrylate copolymer; optionally, one or more materials selected from poly[ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride], hydroxypropyl methylcellulose, and poly[ethyl acrylate, methyl methacrylate]; Optionally, a pharmaceutical formulation comprising poly[ethyl acrylate, methyl methacrylate].

[0272] B11. A pharmaceutical formulation according to any one of B4 to B10, comprising a sustained release coating, wherein the median amount of the sustained release coating disposed on the core particle is at least 5% by weight of the total weight of the core particle, or in the range of about 5% to about 60% by weight, or about 15% to about 60% by weight, or about 20% to about 50% by weight of the total weight of the core particle.

[0273] B12. A pharmaceutical formulation according to any one of B4 to B11, comprising a coating, wherein the coating further comprises a pore-forming agent.

[0274] B13. The pore-forming agent is one or more materials selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, poloxamer 188, polyvinylpyrrolidone, D-mannitol, methylcellulose, polyvinyl alcohol-polyethylene glycol graft copolymer, and saccharides; optionally, one or more materials selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyvinylpyrrolidone; A pharmaceutical formulation of B12, optionally containing hydroxypropyl methylcellulose.

[0275] B14. The pharmaceutical formulation of B12, wherein the pore-forming agent is present in the coating in an amount of about 5% by weight or more, or about 10% by weight or more, or in the range of about 5% to about 20% by weight, optionally in an amount of 15% by weight.

[0276] B15. A pharmaceutical formulation according to any one of B4 to B14, wherein the core particles are specified by a particle size distribution, and at least a portion of the core particles of the plurality of beads have a core particle size (maximum diameter) of about 0.2 mm to about 2 mm, or about 0.3 mm to about 1.5 mm, 0.4 mm to about 1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm.

[0277] B16. The particle size distribution of the core particles At least 60% by weight of core particles have a particle size (maximum diameter) in the range of about 0.4 mm to about 1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm; In some cases, at least 80% by weight of core particles have a particle size (maximum diameter) in the range of about 0.4 mm to about 1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm; In some cases, at least 90% by weight of the core particles have a particle size (maximum diameter) in the range of about 0.4 mm to about 1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm; In some cases, at least 99% by weight of the core particles have a particle size (maximum diameter) in the range of about 0.4 mm to about 1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm. A pharmaceutical preparation of B15 identified as

[0278] B17. A pharmaceutical formulation according to any one of B4 to B16, wherein the plurality of CTN beads have an average particle size (diameter) in the range of about 0.2 mm to about 2.8 mm, or about 0.2 mm to about 2.5 mm, or about 0.2 mm to about 2.0 mm, or about 0.7 mm to about 2.5 mm, or about 0.7 mm to about 2.8 mm, or about 0.5 mm to about 2.8 mm, or about 0.8 mm to about 1.7 mm, or about 0.5 mm to about 1.2 mm, or about 0.5 mm to about 1.0 mm, or about 0.5 mm to about 0.71 mm.

[0279] B18. The pharmaceutical formulation of any of B4-B17, wherein the plurality of CTN beads comprises one or more types selected from fast-release beads, sustained-release beads, delayed-release beads, and delayed-sustained-release beads.

[0280] B19. The pharmaceutical formulation of any of B4-B18, wherein the plurality of beads comprises a mixture of one or more fast-release beads and one or more sustained-release beads.

[0281] B20. The pharmaceutical formulation of B19, wherein the ratio of CTN or a pharmaceutically acceptable salt thereof is present in one or more fast-release beads and one or more sustained-release beads in a ratio ranging from about 1:100 to about 1:1 parts by weight, based on the weight of CTN.

[0282] B21. The pharmaceutical formulation of any of B4-B20, wherein the plurality of beads comprises a mixture of one or more fast-release beads and one or more delayed-release beads.

[0283] B22. The pharmaceutical formulation of B21, wherein the ratio of CTN or a pharmaceutically acceptable salt thereof is present in one or more fast-release beads and one or more delayed-release beads in a ratio ranging from about 1:100 to about 1:1 parts by weight, based on the weight of CTN.

[0284] B23. The pharmaceutical formulation of any of B4-B22, wherein the plurality of beads comprises a mixture of one or more delayed release beads and one or more sustained release beads.

[0285] B24. The pharmaceutical formulation of B23, wherein the ratio of CTN or a pharmaceutically acceptable salt thereof is present in the one or more sustained release beads and the one or more delayed release beads in a ratio ranging from about 5:10 to about 1:5 parts by weight based on the weight of CTN.

[0286] B25. The pharmaceutical formulation of any of B4-B24, wherein the plurality of beads comprises a mixture of one or more fast-release beads and one or more delayed-sustained release beads.

[0287] B26. The pharmaceutical formulation of B25, wherein the ratio of CTN or a pharmaceutically acceptable salt thereof is present in one or more fast-release beads and one or more delayed-sustained-release beads in a ratio ranging from about 1:100 to about 1:1 parts by weight, based on the weight of CTN.

[0288] B27. The pharmaceutical formulation of any of B4-B26, wherein the plurality of beads comprises a mixture of one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads.

[0289] B28. The ratio of CTN or a pharmaceutically acceptable salt thereof in one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads is in the range of about 0.1-1:1-20:1-20 parts by weight based on the total weight of CTN or a salt thereof; optionally in a ratio ranging from about 0.5-1:5-20:5-20 parts by weight based on the total weight of CTN or a salt thereof; optionally in a ratio ranging from about 0.7-13:3-6:3-6 parts by weight based on the total weight of CTN or a salt thereof; and optionally in a ratio ranging from about 0.7-1:5-15:5-15 parts by weight based on the total weight of CTN or a salt thereof; There exists a pharmaceutical formulation of B27.

[0290] B29. The pharmaceutical formulation of any of B4-B28, wherein the plurality of beads comprises a mixture of one or more fast-release beads, one or more sustained-release beads, and one or more delayed-sustained-release beads.

[0291] B30. The ratio of CTN or a pharmaceutically acceptable salt thereof in one or more fast-release beads, one or more sustained-release beads, and one or more delayed-sustained-release beads is in the range of about 0.1-1:1-20:1-20 parts by weight based on the total weight of CTN or a salt thereof; optionally in a ratio ranging from about 0.5-1:5-20:5-20 parts by weight based on the total weight of CTN or a salt thereof; optionally in a ratio ranging from about 0.7-13:3-6:3-6 parts by weight based on the total weight of CTN or a salt thereof; and optionally in a ratio ranging from about 0.7-1:5-15:5-15 parts by weight based on the total weight of CTN or a salt thereof; A pharmaceutical formulation of B29 exists.

[0292] B31. A pharmaceutical formulation of any of B4 to B30, wherein the rapid-release beads are uncoated.

[0293] B32. The fast-release beads are in the range of about 1% to about 75% based on the total weight of the plurality of CTN beads in the formulation; optionally, in the range of about 40% to about 50% based on the total weight of the plurality of CTN beads, when the drug incorporated in the fast-release beads is about 5% to about 15% by weight; optionally, in the range of about 1% to about 50% based on the total weight of the plurality of CTN beads; optionally, in the range of about 1% to about 25% based on the total weight of the plurality of CTN beads; optionally, in the range of about 1% to about 10% based on the total weight of the plurality of CTN beads; Optionally, in the range of about 9% to about 19% based on the total weight of the plurality of CTN beads when the drug incorporated into the rapid-release beads is about 40% to about 55% by weight; and Optionally, in the range of about 18% to about 28% based on the total weight of the plurality of CTN beads. The pharmaceutical formulation of any one of B4 to B31, wherein the amount of

[0294] B33. Contains sustained release beads, The sustained-release beads range from about 5% to 80% based on the total weight of the plurality of CTN beads in the formulation; optionally, in the range of about 23% to about 33%, based on the total weight of the plurality of CTN beads; optionally, in the range of about 5% to about 65%, based on the total weight of the plurality of CTN beads; optionally, in the range of about 40% to about 55%, based on the total weight of the plurality of CTN beads; Optionally, in the range of about 35% to about 55% based on the total weight of the plurality of CTN beads. A pharmaceutical formulation of any one of B4 to B32, wherein B4 to B32 are present in an amount of

[0295] B34. Contains delayed release beads, The delayed-release beads range from about 5% to 80% based on the total weight of the CTN beads in the formulation; optionally, in the range of about 21% to about 31%, based on the total weight of the plurality of CTN beads; optionally, in the range of about 5% to about 65%, based on the total weight of the plurality of CTN beads; optionally, in the range of about 36% to about 46%, based on the total weight of the plurality of CTN beads; Optionally, in the range of about 30% to about 55% based on the total weight of the plurality of CTN beads. A pharmaceutical formulation of any one of B4 to B33, wherein the amount of B4 to B33 is

[0296] B35. Contains sustained-release beads, USP <711> Any of B4 to B34 pharmaceutical formulations, which are tested in accordance with the above using Apparatus 1 (basket) in 1000 mL of deionized water at 37°C ± 0.5°C and 100 rpm, and which release at least 90% of CTN or a salt thereof from the sustained-release beads within a range of 2 to 6 hours.

[0297] B36. Contains delayed release beads, USP <711> According to the method described above, at 37°C ± 0.5°C, 100 rpm, using Apparatus 1 (basket), first test in 1000 mL of 0.1 N HCl solution for 2 hours, and then test in 1000 mL of unbuffered deionized water for the remaining time, and at least 90% of CTN or a salt thereof is released from the delayed-release beads within a range of 4 to 14 hours, or USP <711> According to the test, using Apparatus 1 (basket), at 37°C ± 0.5°C, 100 rpm, first test in 1000 mL of 0.1 N HCl solution for 2 hours, then test in 1000 mL of pH 7.4 phosphate buffer solution for the remaining time, and at least 90% of CTN or its salt is released from the delayed-release beads within a range of 4 to 14 hours. Any of pharmaceutical preparations B4 to B35.

[0298] B37. Delayed-sustained release beads, USP <711> and (iii) at least 90% of the CTN or a salt thereof is released from the delayed-sustained-release beads in a range of 4 to 14 hours, using Apparatus 1 (basket) at 37°C ± 0.5°C, 100 rpm, first in 1000 mL of 0.1 N HCl solution for 2 hours, and then in 1000 mL of unbuffered deionized water for the remaining time. USP <711> According to the test, using Apparatus 1 (basket), at 37°C ± 0.5°C, 100 rpm, first in 1000 mL of 0.1 N HCl solution for 2 hours, then in 1000 mL of pH 7.4 phosphate buffer solution for the remaining time, at least 90% of CTN or its salt is released from the delayed-sustained-release beads within a range of 4 to 14 hours. Any of the pharmaceutical preparations B4 to B36.

[0299] B38. Contains fast-release beads, USP <711> Any of the pharmaceutical formulations B4 to B37, which are tested in accordance with the above method using Apparatus 1 (basket) in 1000 mL of deionized water at 37°C ± 0.5°C and 100 rpm, and at least 90% of CTN or a salt thereof is released from the fast-release beads within a range of 0 to 2 hours.

[0300] B39. A mixture of fast-release beads, sustained-release beads, and delayed-release beads, USP <711> In accordance with the method described above, using Apparatus 1 (basket), at 37°C ± 0.5°C, 100 rpm, first in 1000 mL of 0.1 N HCl solution for 2 hours, and then in 1000 mL of unbuffered deionized water for the remaining time, at least 40% of CTN or its salt is released from the mixture of beads within 3 to 5 hours, at least 90% of CTN or its salt is released from the mixture of beads within 12 to 14 hours, or USP <711> According to the method described above, the test is carried out using Apparatus 1 (basket) at 37°C ± 0.5°C, 100 rpm, first with 1000 mL of 0.1 N HCl solution for 2 hours, and then with 1000 mL of pH 7.4 phosphate buffer solution for the remaining time, and at least 40% of the CTN or its salt is released from the bead mixture within 3 to 5 hours, and at least 90% of the CTN or its salt is released from the bead mixture within 12 to 14 hours. Any of the pharmaceutical preparations B4 to B38.

[0301] B40. Contains fast-release beads, CTN or a salt thereof is in the range of 5 wt% to 80 wt% in the fast-release beads based on the total weight of the fast-release beads; optionally in the range of 5% to 60% by weight based on the total weight of the fast-release beads; optionally in the range of 5% to 15% by weight based on the total weight of the fast-release beads; Optionally, in the range of 40% to 60% by weight based on the total weight of the fast-release beads is present in an amount of, and Optionally, the CTN or salt thereof is present in a first fast-release bead in an amount ranging from 5% to 15% by weight based on the total weight of the fast-release bead, and the CTN or salt thereof is present in a second fast-release bead in an amount ranging from 40% to 60% by weight based on the total weight of the fast-release bead. Any of the pharmaceutical preparations B4 to B39.

[0302] B41. Contains sustained release beads, CTN or a salt thereof is in the range of 10% by weight to 95% by weight in the sustained-release beads, based on the total weight of the sustained-release beads; optionally in the range of 40% to 90% by weight, based on the total weight of the sustained release beads; Optionally, in the range of 50% to 70% by weight based on the total weight of the sustained release beads. A pharmaceutical formulation of any one of B4 to B40, wherein the amount of

[0303] B42. Contains delayed release beads, CTN or a salt thereof is in the range of 10% by weight to 95% by weight in the delayed-release beads, based on the total weight of the delayed-release beads; optionally in the range of 40% to 90% by weight based on the total weight of the delayed release beads; Optionally, in the range of 50% to 70% by weight based on the total weight of the delayed release beads. The pharmaceutical formulation of any one of B4 to B41, wherein the amount of

[0304] B43. A pharmaceutical formulation of any of B4-B42, characterized in that it exhibits a multimodal, optionally bimodal, in vivo absorption profile.

[0305] B44. The first C max A pharmaceutical preparation according to any one of B4 to B43, comprising:

[0306] B45. The in vivo yield profile of the second C is in the range of about 6 hours to 10 hours, or about 7 hours to 9 hours, or about 7.5 to about 8.5 hours. max The pharmaceutical preparation according to any one of B4 to B44, comprising:

[0307] B46. The first C shown from the formulation in human adults max A pharmaceutical formulation of B44 or B45 having a mean plasma level in the range of about 250 ng / mL to about 420 ng / mL, or about 320 ng / mL to about 420 ng / mL, or about 325 ng / mL to about 390 ng / mL.

[0308] B47. Second C shown from formulation in human adults max any of the pharmaceutical formulations of B44 to B46, having a mean plasma level in the range of about 450 ng / mL to about 550 ng / mL, or about 470 ng / mL to about 530 ng / mL.

[0309] B48. In vivo absorption profile is first C max and the second C maxand the first C max and the second C max The pharmaceutical formulation of any one of B4 to B47, wherein the time difference is in the range of 1.5 to 8.5 hours, or about 2 hours to about 6 hours, or about 3 hours to about 5 hours.

[0310] B49. The pharmaceutical formulation of any of B4-B48, wherein one or more of the plurality of CTN beads has a release mechanism comprising one or more of dissolution, diffusion, erosion, osmosis, partitioning, swelling, and targeting.

[0311] B50. The pharmaceutical formulation of any of B4-B49, wherein one or more of the plurality of CTN beads has a diffusional release mechanism.

[0312] B51. The pharmaceutical formulation of any of B4 to B50, wherein one or more of the plurality of CTN beads has a pH-dependent elution release mechanism.

[0313] B52. The pharmaceutical formulation of any of B4-B51, wherein one or more of the plurality of CTN beads has a combination of a pH-driven dissolution release mechanism and a diffusion release mechanism.

[0314] B53. The pharmaceutical formulation of any of B4-B52, wherein one or more of the plurality of CTN beads comprises a porous matrix containing CTN.

[0315] B54. The pharmaceutical formulation of any of B4-B53, wherein a plurality of CTN beads are packaged in one or more containers selected from capsules, sachets, and stick packs, optionally in capsules.

[0316] B55. A pharmaceutical formulation of any of B4-B54, wherein the CTN is present as a salt, optionally as the hydrochloride salt.

[0317] B56. The excipient is one or more materials selected from fillers, binders, glidants, surfactants, polymer coatings, and plasticizers; optionally a combination of fillers and binders; Optionally, a combination of a binder and a polymer coating; Optionally, a combination of fillers, binders, and polymer coatings; Optionally, a combination of fillers, binders, polymer coatings, and plasticizers A pharmaceutical preparation according to any one of B4 to B55, comprising:

[0318] B57. The pharmaceutical formulation of any of B4-B56, wherein the excipient comprises one or more materials selected from lactose, mannitol, corn starch, microcrystalline cellulose, hydroxypropyl cellulose, hypromellose, polyvinylpyrrolidone, talc, polysorbate 80, glycerol monostearate, triethyl citrate, polyvinyl alcohol-polyethylene glycol graft copolymer, and silica.

[0319] B58. A pharmaceutical formulation according to any one of B4 to B56, wherein the formulation does not contain a disintegrant.

[0320] Aspect D D1. A pharmaceutical formulation comprising centanafadine (CTN) or a pharmaceutically acceptable salt thereof, and excipients, wherein the pharmaceutical formulation has a multimodal, optionally bimodal, in vivo absorption profile.

[0321] D2. A pharmaceutical formulation of D1, wherein the CTN plasma concentration 16 hours after administration is less than 300 ng / mL, or less than 250 ng / mL, or less than 230 ng / mL.

[0322] It is specifically contemplated that embodiments D1-D2 may include, as further optional features, each of the following embodiments B1-B58, and C1-C7, individually and in combination.

[0323] C1. A pharmaceutical formulation of D1 or D2 containing centanafadine (CTN) or a pharmaceutically acceptable salt thereof, and an excipient, wherein the pharmaceutical formulation has a multi-phase release profile, optionally at least a two-phase release profile, optionally at least a three-phase release profile, when tested in an acidic medium for 2 hours, followed by a buffered medium at pH 7.4; (a) optionally identified as releasing about 22% to about 45% CTN release at 3 hours, optionally about 40% to about 65% CTN release at 8 hours, optionally about 65% to about 95% CTN release at 12 hours, and optionally at such release rates at all three time points; or (b) optionally identified by about 24%-48% CTN release at 3 hours, further optionally at least 66% CTN release at 6 hours, further optionally at least 86% CTN release at 10 hours, and further optionally at such release rates at all three time points; Further optionally, the release profile may be specified as 49% to 73% release at 4 hours.

[0324] C2. The pharmaceutical formulation of C1, wherein the formulation is a solid oral formulation and / or a semi-solid oral formulation.

[0325] C3. The pharmaceutical formulation of C1 or C2, wherein the formulation is a solid oral formulation suitable for pediatric use.

[0326] C4. The pharmaceutical formulation of any of C1-C3, wherein the solid oral dosage form comprises one or more forms selected from powders, beads, orodispersible tablets, orodispersible films, minitablets, chewable tablets, and soft chews; optionally selected from powders and beads; and optionally beads.

[0327] C5. The pharmaceutical formulation of any of C1 to C4, wherein the formulation is a solid oral formulation suitable for adult use.

[0328] C6. The pharmaceutical formulation of C5, wherein the solid oral dosage form is selected from tablets, capsules, sachets, powders, beads, and lozenges; optionally selected from tablets, capsules, beads, and powders; and optionally comprising one or more forms selected from capsules and beads.

[0329] C7. Any of the pharmaceutical formulations of C1 to C6, wherein the solid oral formulation comprises a plurality of centanafadine (CTN) beads, each of the plurality of CTN beads comprising a core particle containing CTN or a pharmaceutically acceptable salt thereof and an excipient.

[0330] B1. A pharmaceutical formulation of any of C1 to C7, or D1 or D2, comprising CTN or a pharmaceutically acceptable salt thereof, wherein the formulation is a solid oral formulation suitable for pediatric use.

[0331] B2. The pharmaceutical formulation of B1, wherein the solid oral dosage form suitable for pediatric use is selected from one or more types, optionally beads, including beads, orodispersible tablets, orodispersible films, minitablets, chewable tablets, and soft chews.

[0332] B3. The pharmaceutical formulation of B1 or B2, wherein the solid oral dosage form suitable for pediatric use is characterized by one or more release profiles selected from fast release, sustained release, delayed release, and delayed-sustained release in vivo and / or in vitro.

[0333] B4. Any of the pharmaceutical formulations of B1 to B3, wherein the solid oral formulation suitable for pediatric use contains a plurality of centanafadine (CTN) beads, each of the plurality of CTN beads containing a core particle comprising CTN or a pharmaceutically acceptable salt thereof and an excipient.

[0334] B5. The pharmaceutical formulation of B4, wherein at least a portion of the plurality of beads are coated.

[0335] B6. The pharmaceutical formulation of any of B4-B5, wherein at least a portion of the plurality of beads are uncoated.

[0336] B7. The pharmaceutical formulation of B6, wherein the coating is one or more coatings selected from a delayed release coating, a sustained release coating, and a delayed-sustained release coating.

[0337] B8. Coating, one or more materials selected from amylose acetate phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate trimellitate, carboxymethyl ethyl cellulose, copolymerized methacrylic acid / methacrylic acid methyl ester, copolymerized methacrylic acid / methyl methacrylate, copolymerized methyl acrylate / methyl methacrylate / methacrylic acid, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, styrene-maleic acid copolymer, and styrene-vinylpyridine copolymer; optionally, one or more materials selected from copolymers of methacrylic acid, methyl methacrylate, and methyl acrylate, and methacrylic acid-acrylate copolymers; and Optionally, a copolymer of methacrylic acid, methyl methacrylate, and methyl acrylate. 10. A pharmaceutical formulation of B7, wherein the delayed release coating comprises:

[0338] B9. Any of the pharmaceutical formulations of B4 to B8 comprising a delayed-release coating, wherein the median amount of the delayed-release coating disposed on the core particles is at least 10% by weight of the total weight of the CTN beads, or in the range of about 12% to about 50% by weight, or about 12% to about 35% by weight, based on the total weight of the CTN beads.

[0339] B10. A pharmaceutical formulation according to any one of B4 to B9, comprising a sustained release coating, wherein the sustained release coating is one or more materials selected from alkyl celluloses, acrylic acid polymers, methacrylic acid polymers, acrylic acid copolymers, methacrylic acid copolymers, and cellulose ethers; optionally, one or more materials selected from hydroxyalkyl cellulose, carboxyalkyl cellulose, methyl methacrylate, methyl methacrylate copolymer, ethoxyethyl methacrylate, ethyl acrylate, trimethylammonioethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymer, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic anhydride), and glycidyl methacrylate copolymer; optionally, one or more materials selected from poly[ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride], hydroxypropyl methylcellulose, and poly[ethyl acrylate, methyl methacrylate]; Optionally, a pharmaceutical formulation comprising poly[ethyl acrylate, methyl methacrylate].

[0340] B11. A pharmaceutical formulation according to any one of B4 to B10, comprising a sustained release coating, wherein the median amount of the sustained release coating disposed on the core particle is at least 5% by weight of the total weight of the core particle, or in the range of about 5% to about 60% by weight, or about 15% to about 60% by weight, or about 20% to about 50% by weight of the total weight of the core particle.

[0341] B12. A pharmaceutical formulation according to any one of B4 to B11, comprising a coating, wherein the coating further comprises a pore-forming agent.

[0342] B13. The pore-forming agent is one or more materials selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, poloxamer 188, polyvinylpyrrolidone, D-mannitol, methylcellulose, polyvinyl alcohol-polyethylene glycol graft copolymer, and saccharides; optionally, one or more materials selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyvinylpyrrolidone; A pharmaceutical formulation of B12, optionally containing hydroxypropyl methylcellulose.

[0343] B14. The pharmaceutical formulation of B12, wherein the pore-forming agent is present in the coating in an amount of about 5% by weight or more, or about 10% by weight or more, or in the range of about 5% to about 20% by weight, optionally in an amount of 15% by weight.

[0344] B15. A pharmaceutical formulation according to any one of B4 to B14, wherein the core particles are specified by a particle size distribution, and at least a portion of the core particles of the plurality of beads have a core particle size (maximum diameter) of about 0.2 mm to about 2 mm, or about 0.3 mm to about 1.5 mm, 0.4 mm to about 1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm.

[0345] B16. The particle size distribution of the core particles At least 60% by weight of core particles have a particle size (maximum diameter) in the range of about 0.4 mm to about 1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm; In some cases, at least 80% by weight of core particles have a particle size (maximum diameter) in the range of about 0.4 mm to about 1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm; In some cases, at least 90% by weight of the core particles have a particle size (maximum diameter) in the range of about 0.4 mm to about 1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm; In some cases, at least 99% by weight of the core particles have a particle size (maximum diameter) in the range of about 0.4 mm to about 1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm. A pharmaceutical preparation of B15 identified as

[0346] B17. A pharmaceutical formulation according to any one of B4 to B16, wherein the plurality of CTN beads have an average particle size (diameter) in the range of about 0.2 mm to about 2.8 mm, or about 0.2 mm to about 2.5 mm, or about 0.2 mm to about 2.0 mm, or about 0.7 mm to about 2.5 mm, or about 0.7 mm to about 2.8 mm, or about 0.5 mm to about 2.8 mm, or about 0.8 mm to about 1.7 mm, or about 0.5 mm to about 1.2 mm, or about 0.5 mm to about 1.0 mm, or about 0.5 mm to about 0.71 mm.

[0347] B18. The pharmaceutical formulation of any of B4-B17, wherein the plurality of CTN beads comprises one or more types selected from fast-release beads, sustained-release beads, delayed-release beads, and delayed-sustained-release beads.

[0348] B19. The pharmaceutical formulation of any of B4-B18, wherein the plurality of beads comprises a mixture of one or more fast-release beads and one or more sustained-release beads.

[0349] B20. The pharmaceutical formulation of B19, wherein the ratio of CTN or a pharmaceutically acceptable salt thereof is present in one or more fast-release beads and one or more sustained-release beads in a ratio ranging from about 1:100 to about 1:1 parts by weight, based on the weight of CTN.

[0350] B21. The pharmaceutical formulation of any of B4-B20, wherein the plurality of beads comprises a mixture of one or more fast-release beads and one or more delayed-release beads.

[0351] B22. The pharmaceutical formulation of B21, wherein the ratio of CTN or a pharmaceutically acceptable salt thereof is present in one or more fast-release beads and one or more delayed-release beads in a ratio ranging from about 1:100 to about 1:1 parts by weight, based on the weight of CTN.

[0352] B23. The pharmaceutical formulation of any of B4-B22, wherein the plurality of beads comprises a mixture of one or more delayed release beads and one or more sustained release beads.

[0353] B24. The pharmaceutical formulation of B23, wherein the ratio of CTN or a pharmaceutically acceptable salt thereof is present in the one or more sustained release beads and the one or more delayed release beads in a ratio ranging from about 5:10 to about 1:5 parts by weight based on the weight of CTN.

[0354] B25. The pharmaceutical formulation of any of B4-B24, wherein the plurality of beads comprises a mixture of one or more fast-release beads and one or more delayed-sustained release beads.

[0355] B26. The pharmaceutical formulation of B25, wherein the ratio of CTN or a pharmaceutically acceptable salt thereof is present in one or more fast-release beads and one or more delayed-sustained-release beads in a ratio ranging from about 1:100 to about 1:1 parts by weight, based on the weight of CTN.

[0356] B27. The pharmaceutical formulation of any of B4-B26, wherein the plurality of beads comprises a mixture of one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads.

[0357] B28. The ratio of CTN or a pharmaceutically acceptable salt thereof in one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads is in the range of about 0.1-1:1-20:1-20 parts by weight based on the total weight of CTN or a salt thereof; optionally in a ratio ranging from about 0.5-1:5-20:5-20 parts by weight based on the total weight of CTN or a salt thereof; optionally in a ratio ranging from about 0.7-13:3-6:3-6 parts by weight based on the total weight of CTN or a salt thereof; and optionally in a ratio ranging from about 0.7-1:5-15:5-15 parts by weight based on the total weight of CTN or a salt thereof; There exists a pharmaceutical formulation of B27.

[0358] B29. The pharmaceutical formulation of any of B4-B28, wherein the plurality of beads comprises a mixture of one or more fast-release beads, one or more sustained-release beads, and one or more delayed-sustained-release beads.

[0359] B30. The ratio of CTN or a pharmaceutically acceptable salt thereof in one or more fast-release beads, one or more sustained-release beads, and one or more delayed-sustained-release beads is in the range of about 0.1-1:1-20:1-20 parts by weight based on the total weight of CTN or a salt thereof; optionally in a ratio ranging from about 0.5-1:5-20:5-20 parts by weight based on the total weight of CTN or a salt thereof; optionally in a ratio ranging from about 0.7-13:3-6:3-6 parts by weight based on the total weight of CTN or a salt thereof; and optionally in a ratio ranging from about 0.7-1:5-15:5-15 parts by weight based on the total weight of CTN or a salt thereof; A pharmaceutical formulation of B29 exists.

[0360] B31. A pharmaceutical formulation of any of B4 to B30, wherein the rapid-release beads are uncoated.

[0361] B32. The fast-release beads are in the range of about 1% to about 75% based on the total weight of the plurality of CTN beads in the formulation; optionally, in the range of about 40% to about 55% based on the total weight of the plurality of CTN beads, when the drug incorporated in the fast-release beads is about 5% to about 15% by weight; optionally, in the range of about 1% to about 50% based on the total weight of the plurality of CTN beads; optionally, in the range of about 1% to about 25% based on the total weight of the plurality of CTN beads; optionally, in the range of about 1% to about 10% based on the total weight of the plurality of CTN beads; Optionally, in the range of about 9% to about 19% based on the total weight of the plurality of CTN beads when the drug incorporated into the rapid-release beads is about 40% to about 55% by weight; and Optionally, in the range of about 18% to about 28% based on the total weight of the plurality of CTN beads. The pharmaceutical formulation of any one of B4 to B31, wherein the amount of

[0362] B33. Contains sustained release beads, The sustained-release beads range from about 5% to 80% based on the total weight of the plurality of CTN beads in the formulation; optionally, in the range of about 23% to about 33%, based on the total weight of the plurality of CTN beads; optionally, in the range of about 5% to about 65%, based on the total weight of the plurality of CTN beads; optionally, in the range of about 40% to about 55%, based on the total weight of the plurality of CTN beads; Optionally, in the range of about 35% to about 55% based on the total weight of the plurality of CTN beads. A pharmaceutical formulation of any one of B4 to B32, wherein B4 to B32 are present in an amount of

[0363] B34. Contains delayed release beads, The delayed-release beads range from about 5% to 80% based on the total weight of the CTN beads in the formulation; optionally, in the range of about 21% to about 31%, based on the total weight of the plurality of CTN beads; optionally, in the range of about 5% to about 65%, based on the total weight of the plurality of CTN beads; optionally, in the range of about 36% to about 46%, based on the total weight of the plurality of CTN beads; Optionally, in the range of about 30% to about 55% based on the total weight of the plurality of CTN beads. A pharmaceutical formulation of any one of B4 to B33, wherein the amount of B4 to B33 is

[0364] B35. Contains sustained-release beads, USP <711> Any of B4 to B34 pharmaceutical formulations, which are tested in accordance with the above using Apparatus 1 (basket) in 1000 mL of deionized water at 37°C ± 0.5°C and 100 rpm, and which release at least 90% of CTN or a salt thereof from the sustained-release beads within a range of 2 to 6 hours.

[0365] B36. Contains delayed release beads, USP <711> According to the method described above, at 37°C ± 0.5°C, 100 rpm, using Apparatus 1 (basket), first test in 1000 mL of 0.1 N HCl solution for 2 hours, and then test in 1000 mL of unbuffered deionized water for the remaining time, and at least 90% of CTN or a salt thereof is released from the delayed-release beads within a range of 4 to 14 hours, or USP <711> According to the test, using Apparatus 1 (basket), at 37°C ± 0.5°C, 100 rpm, first test in 1000 mL of 0.1 N HCl solution for 2 hours, then test in 1000 mL of pH 7.4 phosphate buffer solution for the remaining time, and at least 90% of CTN or its salt is released from the delayed-release beads within a range of 4 to 14 hours. Any of pharmaceutical preparations B4 to B35.

[0366] B37. Delayed-sustained release beads, USP <711> and (iii) at least 90% of the CTN or a salt thereof is released from the delayed-sustained-release beads in a range of 4 to 14 hours, using Apparatus 1 (basket) at 37°C ± 0.5°C, 100 rpm, first in 1000 mL of 0.1 N HCl solution for 2 hours, and then in 1000 mL of unbuffered deionized water for the remaining time. USP <711> According to the test, using Apparatus 1 (basket), at 37°C ± 0.5°C, 100 rpm, first in 1000 mL of 0.1 N HCl solution for 2 hours, then in 1000 mL of pH 7.4 phosphate buffer solution for the remaining time, at least 90% of CTN or its salt is released from the delayed-sustained-release beads within a range of 4 to 14 hours. Any of the pharmaceutical preparations B4 to B36.

[0367] B38. Contains fast-release beads, USP <711> Any of the pharmaceutical formulations B4 to B37, which are tested in accordance with the above method using Apparatus 1 (basket) in 1000 mL of deionized water at 37°C ± 0.5°C and 100 rpm, and at least 90% of CTN or a salt thereof is released from the fast-release beads within a range of 0 to 2 hours.

[0368] B39. A mixture of fast-release beads, sustained-release beads, and delayed-release beads, USP <711> In accordance with the method described above, using Apparatus 1 (basket), at 37°C ± 0.5°C, 100 rpm, first in 1000 mL of 0.1 N HCl solution for 2 hours, and then in 1000 mL of unbuffered deionized water for the remaining time, at least 40% of CTN or its salt is released from the mixture of beads within 3 to 5 hours, at least 90% of CTN or its salt is released from the mixture of beads within 12 to 14 hours, or USP <711> According to the method described above, the test is carried out using Apparatus 1 (basket) at 37°C ± 0.5°C, 100 rpm, first with 1000 mL of 0.1 N HCl solution for 2 hours, and then with 1000 mL of pH 7.4 phosphate buffer solution for the remaining time, and at least 40% of the CTN or its salt is released from the bead mixture within 3 to 5 hours, and at least 90% of the CTN or its salt is released from the bead mixture within 12 to 14 hours. Any of the pharmaceutical preparations B4 to B38.

[0369] B40. Contains fast-release beads, CTN or a salt thereof is in the range of 5 wt% to 80 wt% in the fast-release beads based on the total weight of the fast-release beads; optionally in the range of 5% to 60% by weight based on the total weight of the fast-release beads; optionally in the range of 5% to 15% by weight based on the total weight of the fast-release beads; Optionally, in the range of 40% to 60% by weight based on the total weight of the fast-release beads is present in an amount of, and Optionally, the CTN or salt thereof is present in a first fast-release bead in an amount ranging from 5% to 15% by weight based on the total weight of the fast-release bead, and the CTN or salt thereof is present in a second fast-release bead in an amount ranging from 40% to 60% by weight based on the total weight of the fast-release bead. Any of the pharmaceutical preparations B4 to B39.

[0370] B41. Contains sustained release beads, CTN or a salt thereof is in the range of 10% by weight to 95% by weight in the sustained-release beads, based on the total weight of the sustained-release beads; optionally in the range of 40% to 90% by weight, based on the total weight of the sustained release beads; Optionally, in the range of 50% to 70% by weight based on the total weight of the sustained release beads. A pharmaceutical formulation of any one of B4 to B40, wherein the amount of

[0371] B42. Contains delayed release beads, CTN or a salt thereof is in the range of 10% by weight to 95% by weight in the delayed-release beads, based on the total weight of the delayed-release beads; optionally in the range of 40% to 90% by weight based on the total weight of the delayed release beads; Optionally, in the range of 50% to 70% by weight based on the total weight of the delayed release beads. The pharmaceutical formulation of any one of B4 to B41, wherein the amount of

[0372] B43. A pharmaceutical formulation of any of B4-B42, characterized in that it exhibits a multimodal, optionally bimodal, in vivo absorption profile.

[0373] B44. The first C max A pharmaceutical preparation according to any one of B4 to B43, comprising:

[0374] B45. The in vivo yield profile of the second C is in the range of about 6 hours to 10 hours, or about 7 hours to 9 hours, or about 7.5 to about 8.5 hours. max The pharmaceutical preparation according to any one of B4 to B44, comprising:

[0375] B46. The first C shown from the formulation in human adults max A pharmaceutical formulation of B44 or B45 having a mean plasma level in the range of about 250 ng / mL to about 420 ng / mL, or about 320 ng / mL to about 420 ng / mL, or about 325 ng / mL to about 390 ng / mL.

[0376] B47. Second C shown from formulation in human adults max any of the pharmaceutical formulations of B44 to B46, having a mean plasma level in the range of about 450 ng / mL to about 550 ng / mL, or about 470 ng / mL to about 530 ng / mL.

[0377] B48. In vivo absorption profile is first C max and the second C max and the first C max and the second C max The pharmaceutical formulation of any one of B4 to B47, wherein the time difference is in the range of 1.5 to 8.5 hours, or about 2 hours to about 6 hours, or about 3 hours to about 5 hours.

[0378] B49. The pharmaceutical formulation of any of B4-B48, wherein one or more of the plurality of CTN beads has a release mechanism comprising one or more of dissolution, diffusion, erosion, osmosis, partitioning, swelling, and targeting.

[0379] B50. The pharmaceutical formulation of any of B4-B49, wherein one or more of the plurality of CTN beads has a diffusional release mechanism.

[0380] B51. The pharmaceutical formulation of any of B4 to B50, wherein one or more of the plurality of CTN beads has a pH-dependent elution release mechanism.

[0381] B52. The pharmaceutical formulation of any of B4-B51, wherein one or more of the plurality of CTN beads has a combination of a pH-driven dissolution release mechanism and a diffusion release mechanism.

[0382] B53. The pharmaceutical formulation of any of B4-B52, wherein one or more of the plurality of CTN beads comprises a porous matrix containing CTN.

[0383] B54. The pharmaceutical formulation of any of B4-B53, wherein a plurality of CTN beads are packaged in one or more containers selected from capsules, sachets, and stick packs, optionally in capsules.

[0384] B55. A pharmaceutical formulation of any of B4-B54, wherein the CTN is present as a salt, optionally as the hydrochloride salt.

[0385] B56. The excipient is one or more materials selected from fillers, binders, glidants, surfactants, polymer coatings, and plasticizers; optionally a combination of fillers and binders; Optionally, a combination of a binder and a polymer coating; Optionally, a combination of fillers, binders, and polymer coatings; Optionally, a combination of fillers, binders, polymer coatings, and plasticizers A pharmaceutical preparation according to any one of B4 to B55, comprising:

[0386] B57. The pharmaceutical formulation of any of B4-B55, wherein the excipient comprises one or more materials selected from lactose, mannitol, corn starch, microcrystalline cellulose, hydroxypropyl cellulose, hypromellose, polyvinylpyrrolidone, talc, polysorbate 80, glycerol monostearate, triethyl citrate, polyvinyl alcohol-polyethylene glycol graft copolymer, and silica.

[0387] B58. A pharmaceutical formulation according to any one of B4 to B56, wherein the formulation does not contain a disintegrant.

[0388] Aspect E E1. A pharmaceutical formulation comprising centanafadine (CTN) or a pharmaceutically acceptable salt thereof, and excipients, wherein the formulation exhibits a delayed-sustained release profile in vivo.

[0389] E2. The pharmaceutical formulation of E1, wherein the formulation is a solid oral formulation and / or a semi-solid oral formulation.

[0390] E3. The pharmaceutical formulation of E1 or E2, wherein the formulation comprises a core and a coating disposed over the core.

[0391] E4. The pharmaceutical formulation of E3, wherein a coating disposed over said core has a pH-dependent elution trigger.

[0392] E5. The pharmaceutical formulation of E4, wherein the coating disposed over the core begins to dissolve at a pH of at least 7, optionally in the range of about 7 to about 8, optionally in the range of about 7.2 to about 7.6.

[0393] E6. Any of the pharmaceutical formulations of E3-E5, wherein the coating comprises a methacrylic acid polymer.

[0394] E7. The coating is one or more polymers selected from copolymerized methacrylic acid / methacrylic acid methyl ester, copolymerized methacrylic acid / methyl methacrylate, copolymerized methyl acrylate / methyl methacrylate / methacrylic acid; optionally one or more polymers selected from copolymers of methacrylic acid, methyl methacrylate, and methyl acrylate, and methacrylic acid-acrylate copolymers; Optionally, a copolymer of methacrylic acid, methyl methacrylate, and methyl acrylate 1. A pharmaceutical formulation of E6 comprising:

[0395] It is specifically contemplated that embodiments E1-E7 may include, as further optional features, each of embodiments B1-B58, C1-C7, and D1-D2 individually and in combination.

[0396] D1. A pharmaceutical formulation of any of E1 to E7 containing centanafadine (CTN) or a pharmaceutically acceptable salt thereof, and an excipient, wherein the pharmaceutical formulation has a multimodal, optionally bimodal, in vivo absorption profile.

[0397] D2. A pharmaceutical formulation of D1, wherein the CTN plasma concentration 16 hours after administration is less than 300 ng / mL, or less than 250 ng / mL, or less than 230 ng / mL.

[0398] C1. A pharmaceutical formulation of any of E1 to E7, or D1 or D2, containing centanafadine (CTN) or a pharmaceutically acceptable salt thereof, and an excipient, wherein the pharmaceutical formulation has a multi-phase release profile, optionally at least a two-phase release profile, optionally at least a three-phase release profile, when tested in an acidic medium for 2 hours followed by a buffered medium at pH 7.4; (a) optionally identified as releasing about 22% to about 45% CTN release at 3 hours, optionally about 40% to about 65% CTN release at 8 hours, optionally about 65% to about 95% CTN release at 12 hours, and optionally at such release rates at all three time points; or (b) optionally identified by about 24%-48% CTN release at 3 hours, further optionally at least 66% CTN release at 6 hours, further optionally at least 86% CTN release at 10 hours, and further optionally at such release rates at all three time points; Further optionally, the release profile may be specified as 49% to 73% release at 4 hours.

[0399] C2. The pharmaceutical formulation of C1, wherein the formulation is a solid oral formulation and / or a semi-solid oral formulation.

[0400] C3. The pharmaceutical formulation of C1 or C2, wherein the formulation is a solid oral formulation suitable for pediatric use.

[0401] C4. The pharmaceutical formulation of any of C1-C3, wherein the solid oral dosage form comprises one or more forms selected from powders, beads, orodispersible tablets, orodispersible films, minitablets, chewable tablets, and soft chews; optionally selected from powders and beads; and optionally beads.

[0402] C5. The pharmaceutical formulation of any of C1 to C4, wherein the formulation is a solid oral formulation suitable for adult use.

[0403] C6. The pharmaceutical formulation of C5, wherein the solid oral dosage form is selected from tablets, capsules, sachets, powders, beads, and lozenges; optionally selected from tablets, capsules, beads, and powders; and optionally comprising one or more forms selected from capsules and beads.

[0404] C7. Any of the pharmaceutical formulations of C1 to C6, wherein the solid oral formulation comprises a plurality of centanafadine (CTN) beads, each of the plurality of CTN beads comprising a core particle containing CTN or a pharmaceutically acceptable salt thereof and an excipient.

[0405] B1. A pharmaceutical formulation of any one of C1 to C7, D1 or D2, or E1 to E7, comprising CTN or a pharmaceutically acceptable salt thereof, wherein the formulation is a solid oral formulation suitable for pediatric use.

[0406] B2. The pharmaceutical formulation of B1, wherein the solid oral dosage form suitable for pediatric use is selected from one or more types, optionally beads, including beads, orodispersible tablets, orodispersible films, minitablets, chewable tablets, and soft chews.

[0407] B3. The pharmaceutical formulation of either B1 or B2, wherein the solid oral dosage form suitable for pediatric use is characterized by one or more release profiles selected from fast release, sustained release, delayed release, and delayed-sustained release in vivo and / or in vitro.

[0408] B4. Any of the pharmaceutical formulations of B1 to B3, wherein the solid oral formulation suitable for pediatric use contains a plurality of centanafadine (CTN) beads, each of the plurality of CTN beads containing a core particle comprising CTN or a pharmaceutically acceptable salt thereof and an excipient.

[0409] B5. The pharmaceutical formulation of B4, wherein at least a portion of the plurality of beads are coated.

[0410] B6. The pharmaceutical formulation of any of B4-B5, wherein at least a portion of the plurality of beads are uncoated.

[0411] B7. The pharmaceutical formulation of B6, wherein the coating is one or more coatings selected from a delayed release coating, a sustained release coating, and a delayed-sustained release coating.

[0412] B8. Coating, one or more materials selected from amylose acetate phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate trimellitate, carboxymethyl ethyl cellulose, copolymerized methacrylic acid / methacrylic acid methyl ester, copolymerized methacrylic acid / methyl methacrylate, copolymerized methyl acrylate / methyl methacrylate / methacrylic acid, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, styrene-maleic acid copolymer, and styrene-vinylpyridine copolymer; optionally, one or more materials selected from copolymers of methacrylic acid, methyl methacrylate, and methyl acrylate, and methacrylic acid-acrylate copolymers; and Optionally, a copolymer of methacrylic acid, methyl methacrylate, and methyl acrylate. 10. A pharmaceutical formulation of B7, wherein the delayed release coating comprises:

[0413] B9. Any of the pharmaceutical formulations of B4 to B8 comprising a delayed-release coating, wherein the median amount of the delayed-release coating disposed on the core particles is at least 10% by weight of the total weight of the CTN beads, or in the range of about 12% to about 50% by weight, or about 12% to about 35% by weight, based on the total weight of the CTN beads.

[0414] B10. A pharmaceutical formulation according to any one of B4 to B9, comprising a sustained release coating, wherein the sustained release coating is one or more materials selected from alkyl celluloses, acrylic acid polymers, methacrylic acid polymers, acrylic acid copolymers, methacrylic acid copolymers, and cellulose ethers; optionally, one or more materials selected from hydroxyalkyl cellulose, carboxyalkyl cellulose, methyl methacrylate, methyl methacrylate copolymer, ethoxyethyl methacrylate, ethyl acrylate, trimethylammonioethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymer, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic anhydride), and glycidyl methacrylate copolymer; optionally, one or more materials selected from poly[ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride], hydroxypropyl methylcellulose, and poly[ethyl acrylate, methyl methacrylate]; Optionally, a pharmaceutical formulation comprising poly[ethyl acrylate, methyl methacrylate].

[0415] B11. A pharmaceutical formulation according to any one of B4 to B10, comprising a sustained release coating, wherein the median amount of the sustained release coating disposed on the core particle is at least 5% by weight of the total weight of the core particle, or in the range of about 5% to about 60% by weight, or about 15% to about 60% by weight, or about 20% to about 50% by weight of the total weight of the core particle.

[0416] B12. A pharmaceutical formulation according to any one of B4 to B11, comprising a coating, wherein the coating further comprises a pore-forming agent.

[0417] B13. The pore-forming agent is one or more materials selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, poloxamer 188, polyvinylpyrrolidone, D-mannitol, methylcellulose, polyvinyl alcohol-polyethylene glycol graft copolymer, and saccharides; optionally, one or more materials selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyvinylpyrrolidone; A pharmaceutical formulation of B12, optionally containing hydroxypropyl methylcellulose.

[0418] B14. The pharmaceutical formulation of B12, wherein the pore-forming agent is present in the coating in an amount of about 5% by weight or more, or about 10% by weight or more, or in the range of about 5% to about 20% by weight, optionally in an amount of 15% by weight.

[0419] B15. A pharmaceutical formulation according to any one of B4 to B14, wherein the core particles are specified by a particle size distribution, and at least a portion of the core particles of the plurality of beads have a core particle size (maximum diameter) of about 0.2 mm to about 2 mm, or about 0.3 mm to about 1.5 mm, 0.4 mm to about 1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm.

[0420] B16. The particle size distribution of the core particles At least 60% by weight of core particles have a particle size (maximum diameter) in the range of about 0.4 mm to about 1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm; In some cases, at least 80% by weight of core particles have a particle size (maximum diameter) in the range of about 0.4 mm to about 1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm; In some cases, at least 90% by weight of the core particles have a particle size (maximum diameter) in the range of about 0.4 mm to about 1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm; In some cases, at least 99% by weight of the core particles have a particle size (maximum diameter) in the range of about 0.4 mm to about 1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm. A pharmaceutical preparation of B15 identified as

[0421] B17. A pharmaceutical formulation according to any one of B4 to B16, wherein the plurality of CTN beads have an average particle size (diameter) in the range of about 0.2 mm to about 2.8 mm, or about 0.2 mm to about 2.5 mm, or about 0.2 mm to about 2.0 mm, or about 0.7 mm to about 2.5 mm, or about 0.7 mm to about 2.8 mm, or about 0.5 mm to about 2.8 mm, or about 0.8 mm to about 1.7 mm, or about 0.5 mm to about 1.2 mm, or about 0.5 mm to about 1.0 mm, or about 0.5 mm to about 0.71 mm.

[0422] B18. The pharmaceutical formulation of any of B4-B17, wherein the plurality of CTN beads comprises one or more types selected from fast-release beads, sustained-release beads, delayed-release beads, and delayed-sustained-release beads.

[0423] B19. The pharmaceutical formulation of any of B4-B18, wherein the plurality of beads comprises a mixture of one or more fast-release beads and one or more sustained-release beads.

[0424] B20. The pharmaceutical formulation of B19, wherein the ratio of CTN or a pharmaceutically acceptable salt thereof is present in one or more fast-release beads and one or more sustained-release beads in a ratio ranging from about 1:100 to about 1:1 parts by weight, based on the weight of CTN.

[0425] B21. The pharmaceutical formulation of any of B4-B20, wherein the plurality of beads comprises a mixture of one or more fast-release beads and one or more delayed-release beads.

[0426] B22. The pharmaceutical formulation of B21, wherein the ratio of CTN or a pharmaceutically acceptable salt thereof is present in one or more fast-release beads and one or more delayed-release beads in a ratio ranging from about 1:100 to about 1:1 parts by weight, based on the weight of CTN.

[0427] B23. The pharmaceutical formulation of any of B4-B22, wherein the plurality of beads comprises a mixture of one or more delayed release beads and one or more sustained release beads.

[0428] B24. The pharmaceutical formulation of B23, wherein the ratio of CTN or a pharmaceutically acceptable salt thereof is present in the one or more sustained release beads and the one or more delayed release beads in a ratio ranging from about 5:10 to about 1:5 parts by weight based on the weight of CTN.

[0429] B25. The pharmaceutical formulation of any of B4-B24, wherein the plurality of beads comprises a mixture of one or more fast-release beads and one or more delayed-sustained release beads.

[0430] B26. The pharmaceutical formulation of B25, wherein the ratio of CTN or a pharmaceutically acceptable salt thereof is present in one or more fast-release beads and one or more delayed-sustained-release beads in a ratio ranging from about 1:100 to about 1:1 parts by weight, based on the weight of CTN.

[0431] B27. The pharmaceutical formulation of any of B4-B26, wherein the plurality of beads comprises a mixture of one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads.

[0432] B28. The ratio of CTN or a pharmaceutically acceptable salt thereof in one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads is in the range of about 0.1-1:1-20:1-20 parts by weight based on the total weight of CTN or a salt thereof; optionally in a ratio ranging from about 0.5-1:5-20:5-20 parts by weight based on the total weight of CTN or a salt thereof; optionally in a ratio ranging from about 0.7-13:3-6:3-6 parts by weight based on the total weight of CTN or a salt thereof; and optionally in a ratio ranging from about 0.7-1:5-15:5-15 parts by weight based on the total weight of CTN or a salt thereof; There exists a pharmaceutical formulation of B27.

[0433] B29. The pharmaceutical formulation of any of B4-B28, wherein the plurality of beads comprises a mixture of one or more fast-release beads, one or more sustained-release beads, and one or more delayed-sustained-release beads.

[0434] B30. The ratio of CTN or a pharmaceutically acceptable salt thereof in one or more fast-release beads, one or more sustained-release beads, and one or more delayed-sustained-release beads is in the range of about 0.1-1:1-20:1-20 parts by weight based on the total weight of CTN or a salt thereof; optionally in a ratio ranging from about 0.5-1:5-20:5-20 parts by weight based on the total weight of CTN or a salt thereof; optionally in a ratio ranging from about 0.7-13:3-6:3-6 parts by weight based on the total weight of CTN or a salt thereof; and optionally in a ratio ranging from about 0.7-1:5-15:5-15 parts by weight based on the total weight of CTN or a salt thereof; A pharmaceutical formulation of B29 exists.

[0435] B31. A pharmaceutical formulation of any of B4 to B30, wherein the rapid-release beads are uncoated.

[0436] B32. The fast-release beads are in the range of about 1% to about 75% based on the total weight of the plurality of CTN beads in the formulation; optionally, in the range of about 40% to about 55% based on the total weight of the plurality of CTN beads, when the drug incorporated in the fast-release beads is about 5% to about 15% by weight; optionally, in the range of about 1% to about 50% based on the total weight of the plurality of CTN beads; optionally, in the range of about 1% to about 25% based on the total weight of the plurality of CTN beads; optionally, in the range of about 1% to about 10% based on the total weight of the plurality of CTN beads; Optionally, in the range of about 9% to about 19% based on the total weight of the plurality of CTN beads when the drug incorporated into the rapid-release beads is about 40% to about 55% by weight; and Optionally, in the range of about 18% to about 28% based on the total weight of the plurality of CTN beads. The pharmaceutical formulation of any one of B4 to B31, wherein the amount of

[0437] B33. Contains sustained release beads, The sustained-release beads range from about 5% to 80% based on the total weight of the plurality of CTN beads in the formulation; optionally, in the range of about 23% to about 33%, based on the total weight of the plurality of CTN beads; optionally, in the range of about 5% to about 65%, based on the total weight of the plurality of CTN beads; optionally, in the range of about 40% to about 55%, based on the total weight of the plurality of CTN beads; Optionally, in the range of about 35% to about 55% based on the total weight of the plurality of CTN beads. A pharmaceutical formulation of any one of B4 to B32, wherein B4 to B32 are present in an amount of

[0438] B34. Contains delayed release beads, The delayed-release beads range from about 5% to 80% based on the total weight of the CTN beads in the formulation; optionally, in the range of about 21% to about 31%, based on the total weight of the plurality of CTN beads; optionally, in the range of about 5% to about 65%, based on the total weight of the plurality of CTN beads; optionally, in the range of about 36% to about 46%, based on the total weight of the plurality of CTN beads; Optionally, in the range of about 30% to about 55% based on the total weight of the plurality of CTN beads. A pharmaceutical formulation of any one of B4 to B33, wherein the amount of B4 to B33 is

[0439] B35. Contains sustained-release beads, USP <711> Any of B4 to B34 pharmaceutical formulations, which are tested in accordance with the above using Apparatus 1 (basket) in 1000 mL of deionized water at 37°C ± 0.5°C and 100 rpm, and which release at least 90% of CTN or a salt thereof from the sustained-release beads within a range of 2 to 6 hours.

[0440] B36. Contains delayed release beads, USP <711> According to the method described above, at 37°C ± 0.5°C, 100 rpm, using Apparatus 1 (basket), first test in 1000 mL of 0.1 N HCl solution for 2 hours, and then test in 1000 mL of unbuffered deionized water for the remaining time, and at least 90% of CTN or a salt thereof is released from the delayed-release beads within a range of 4 to 14 hours, or USP <711> According to the test, using Apparatus 1 (basket), at 37°C ± 0.5°C, 100 rpm, first test in 1000 mL of 0.1 N HCl solution for 2 hours, then test in 1000 mL of pH 7.4 phosphate buffer solution for the remaining time, and at least 90% of CTN or its salt is released from the delayed-release beads within a range of 4 to 14 hours. Any of pharmaceutical preparations B4 to B35.

[0441] B37. Delayed-sustained release beads, USP <711> and (iii) at least 90% of the CTN or a salt thereof is released from the delayed-sustained-release beads in a range of 4 to 14 hours, using Apparatus 1 (basket) at 37°C ± 0.5°C, 100 rpm, first in 1000 mL of 0.1 N HCl solution for 2 hours, and then in 1000 mL of unbuffered deionized water for the remaining time. USP <711> According to the test, using Apparatus 1 (basket), at 37°C ± 0.5°C, 100 rpm, first in 1000 mL of 0.1 N HCl solution for 2 hours, then in 1000 mL of pH 7.4 phosphate buffer solution for the remaining time, at least 90% of CTN or its salt is released from the delayed-sustained-release beads within a range of 4 to 14 hours. Any of the pharmaceutical preparations B4 to B36.

[0442] B38. Contains fast-release beads, USP <711> Any of the pharmaceutical formulations B4 to B37, which are tested in accordance with the above method using Apparatus 1 (basket) in 1000 mL of deionized water at 37°C ± 0.5°C and 100 rpm, and at least 90% of CTN or a salt thereof is released from the fast-release beads within a range of 0 to 2 hours.

[0443] B39. A mixture of fast-release beads, sustained-release beads, and delayed-release beads, USP <711> In accordance with the method described above, using Apparatus 1 (basket), at 37°C ± 0.5°C, 100 rpm, first in 1000 mL of 0.1 N HCl solution for 2 hours, and then in 1000 mL of unbuffered deionized water for the remaining time, at least 40% of CTN or its salt is released from the mixture of beads within 3 to 5 hours, at least 90% of CTN or its salt is released from the mixture of beads within 12 to 14 hours, or USP <711> According to the method described above, the test is carried out using Apparatus 1 (basket) at 37°C ± 0.5°C, 100 rpm, first with 1000 mL of 0.1 N HCl solution for 2 hours, and then with 1000 mL of pH 7.4 phosphate buffer solution for the remaining time, and at least 40% of the CTN or its salt is released from the bead mixture within 3 to 5 hours, and at least 90% of the CTN or its salt is released from the bead mixture within 12 to 14 hours. Any of the pharmaceutical preparations B4 to B38.

[0444] B40. Contains fast-release beads, CTN or a salt thereof is in the range of 5 wt% to 80 wt% in the fast-release beads based on the total weight of the fast-release beads; optionally in the range of 5% to 60% by weight based on the total weight of the fast-release beads; optionally in the range of 5% to 15% by weight based on the total weight of the fast-release beads; Optionally, in the range of 40% to 60% by weight based on the total weight of the fast-release beads is present in an amount of, and Optionally, the CTN or salt thereof is present in a first fast-release bead in an amount ranging from 5% to 15% by weight based on the total weight of the fast-release bead, and the CTN or salt thereof is present in a second fast-release bead in an amount ranging from 40% to 60% by weight based on the total weight of the fast-release bead. Any of the pharmaceutical preparations B4 to B39.

[0445] B41. Contains sustained release beads, CTN or a salt thereof is in the range of 10% by weight to 95% by weight in the sustained-release beads, based on the total weight of the sustained-release beads; optionally in the range of 40% to 90% by weight, based on the total weight of the sustained release beads; Optionally, in the range of 50% to 70% by weight based on the total weight of the sustained release beads. A pharmaceutical formulation of any one of B4 to B40, wherein the amount of

[0446] B42. Contains delayed release beads, CTN or a salt thereof is in the range of 10% by weight to 95% by weight in the delayed-release beads, based on the total weight of the delayed-release beads; optionally in the range of 40% to 90% by weight based on the total weight of the delayed release beads; Optionally, in the range of 50% to 70% by weight based on the total weight of the delayed release beads. The pharmaceutical formulation of any one of B4 to B41, wherein the amount of

[0447] B43. A pharmaceutical formulation of any of B4-B42, characterized in that it exhibits a multimodal, optionally bimodal, in vivo absorption profile.

[0448] B44. The first C max A pharmaceutical preparation according to any one of B4 to B43, comprising:

[0449] B45. The in vivo yield profile of the second C is in the range of about 6 hours to 10 hours, or about 7 hours to 9 hours, or about 7.5 to about 8.5 hours. max The pharmaceutical preparation according to any one of B4 to B44, comprising:

[0450] B46. The first C shown from the formulation in human adults max A pharmaceutical formulation of B44 or B45 having a mean plasma level in the range of about 250 ng / mL to about 420 ng / mL, or about 320 ng / mL to about 420 ng / mL, or about 325 ng / mL to about 390 ng / mL.

[0451] B47. Second C shown from formulation in human adults max any of the pharmaceutical formulations of B44 to B46, having a mean plasma level in the range of about 450 ng / mL to about 550 ng / mL, or about 470 ng / mL to about 530 ng / mL.

[0452] B48. In vivo absorption profile is first C max and the second C max and the first C max and the second C max The pharmaceutical formulation of any one of B4 to B47, wherein the time difference is in the range of 1.5 to 8.5 hours, or about 2 hours to about 6 hours, or about 3 hours to about 5 hours.

[0453] B49. The pharmaceutical formulation of any of B4-B48, wherein one or more of the plurality of CTN beads has a release mechanism comprising one or more of dissolution, diffusion, erosion, osmosis, partitioning, swelling, and targeting.

[0454] B50. The pharmaceutical formulation of any of B4-B49, wherein one or more of the plurality of CTN beads has a diffusional release mechanism.

[0455] B51. The pharmaceutical formulation of any of B4 to B50, wherein one or more of the plurality of CTN beads has a pH-dependent elution release mechanism.

[0456] B52. The pharmaceutical formulation of any of B4-B51, wherein one or more of the plurality of CTN beads has a combination of a pH-driven dissolution release mechanism and a diffusion release mechanism.

[0457] B53. The pharmaceutical formulation of any of B4-B52, wherein one or more of the plurality of CTN beads comprises a porous matrix containing CTN.

[0458] B54. The pharmaceutical formulation of any of B4-B53, wherein a plurality of CTN beads are packaged in one or more containers selected from capsules, sachets, and stick packs, optionally in capsules.

[0459] B55. A pharmaceutical formulation of any of B4-B54, wherein the CTN is present as a salt, optionally as the hydrochloride salt.

[0460] B56. The excipient is one or more materials selected from fillers, binders, glidants, surfactants, polymer coatings, and plasticizers; optionally a combination of fillers and binders; Optionally, a combination of a binder and a polymer coating; Optionally, a combination of fillers, binders, and polymer coatings; Optionally, a combination of fillers, binders, polymer coatings, and plasticizers A pharmaceutical preparation according to any one of B4 to B55, comprising:

[0461] B57. The pharmaceutical formulation of any of B4-B55, wherein the excipient comprises one or more materials selected from lactose, mannitol, corn starch, microcrystalline cellulose, hydroxypropyl cellulose, hypromellose, polyvinylpyrrolidone, talc, polysorbate 80, glycerol monostearate, triethyl citrate, polyvinyl alcohol-polyethylene glycol graft copolymer, and silica.

[0462] B58. A pharmaceutical formulation according to any one of B4 to B56, wherein the formulation does not contain a disintegrant.

[0463] Aspect F F1. A pharmaceutical formulation containing a plurality of centanafadine (CTN) beads, each of the plurality of CTN beads comprising a core particle containing CTN or a pharmaceutically acceptable salt thereof and an excipient, wherein at least a portion of the core particles comprise CTN or a pharmaceutically acceptable salt thereof in an amount ranging from about 70% by weight to about 90% by weight.

[0464] It is specifically contemplated that embodiment F1 may include, as further optional features, each of embodiments B1-B58, C1-C7, D1-D2, and E1-E7 individually and in combination.

[0465] E1. The pharmaceutical formulation of F1, comprising centanafadine (CTN) or a pharmaceutically acceptable salt thereof, and excipients, wherein the formulation exhibits a delayed-sustained release profile in vivo.

[0466] E2. The pharmaceutical formulation of E1, wherein the formulation is a solid oral formulation and / or a semi-solid oral formulation.

[0467] E3. The pharmaceutical formulation of E1 or E2, wherein the formulation comprises a core and a coating disposed over the core.

[0468] E4. The pharmaceutical formulation of E3, wherein a coating disposed over said core has a pH-dependent elution trigger.

[0469] E5. The pharmaceutical formulation of E4, wherein the coating disposed over the core begins to dissolve at a pH of at least 7, optionally in the range of about 7 to about 8, optionally in the range of about 7.2 to about 7.6.

[0470] E6. Any of the pharmaceutical formulations of E3-E5, wherein the coating comprises a methacrylic acid polymer.

[0471] E7. The coating is one or more polymers selected from copolymerized methacrylic acid / methacrylic acid methyl ester, copolymerized methacrylic acid / methyl methacrylate, copolymerized methyl acrylate / methyl methacrylate / methacrylic acid; optionally one or more polymers selected from copolymers of methacrylic acid, methyl methacrylate, and methyl acrylate, and methacrylic acid-acrylate copolymers; Optionally, a copolymer of methacrylic acid, methyl methacrylate, and methyl acrylate 1. A pharmaceutical formulation of E6 comprising:

[0472] D1. A pharmaceutical formulation of any of E1-E7 or F1 containing centanafadine (CTN) or a pharmaceutically acceptable salt thereof, and an excipient, wherein the pharmaceutical formulation has a multimodal, optionally bimodal, in vivo absorption profile.

[0473] D2. A pharmaceutical formulation of D1, wherein the CTN plasma concentration 16 hours after administration is less than 300 ng / mL, or less than 250 ng / mL, or less than 230 ng / mL.

[0474] C1. A pharmaceutical formulation of any of E1 to E7, or D1 or D2 or F1, containing centanafadine (CTN) or a pharmaceutically acceptable salt thereof, and an excipient, wherein the pharmaceutical formulation has a multi-phase release profile, optionally at least a two-phase release profile, optionally at least a three-phase release profile, when tested in an acidic medium for 2 hours followed by a buffered medium at pH 7.4; (a) optionally identified as releasing about 22% to about 45% CTN release at 3 hours, optionally about 40% to about 65% CTN release at 8 hours, optionally about 65% to about 95% CTN release at 12 hours, and optionally at such release rates at all three time points; or (b) optionally identified by about 24%-48% CTN release at 3 hours, further optionally at least 66% CTN release at 6 hours, further optionally at least 86% CTN release at 10 hours, and further optionally at such release rates at all three time points; Further optionally, the release profile may be specified as 49% to 73% release at 4 hours.

[0475] C2. The pharmaceutical formulation of C1, wherein the formulation is a solid oral formulation and / or a semi-solid oral formulation.

[0476] C3. The pharmaceutical formulation of C1 or C2, wherein the formulation is a solid oral formulation suitable for pediatric use.

[0477] C4. The pharmaceutical formulation of any of C1-C3, wherein the solid oral dosage form comprises one or more forms selected from powders, beads, orodispersible tablets, orodispersible films, minitablets, chewable tablets, and soft chews; optionally selected from powders and beads; and optionally beads.

[0478] C5. The pharmaceutical formulation of any of C1 to C4, wherein the formulation is a solid oral formulation suitable for adult use.

[0479] C6. The pharmaceutical formulation of C5, wherein the solid oral dosage form is selected from tablets, capsules, sachets, powders, beads, and lozenges; optionally selected from tablets, capsules, beads, and powders; and optionally comprising one or more forms selected from capsules and beads.

[0480] C7. Any of the pharmaceutical formulations of C1 to C6, wherein the solid oral formulation comprises a plurality of centanafadine (CTN) beads, each of the plurality of CTN beads comprising a core particle containing CTN or a pharmaceutically acceptable salt thereof and an excipient.

[0481] B1. A pharmaceutical formulation of any of C1 to C7, or D1 or D2, or E1 to E7, or F1, comprising CTN or a pharmaceutically acceptable salt thereof, wherein the formulation is a solid oral formulation suitable for pediatric use.

[0482] B2. The pharmaceutical formulation of B1, wherein the solid oral dosage form suitable for pediatric use is selected from one or more types, optionally beads, including beads, orodispersible tablets, orodispersible films, minitablets, chewable tablets, and soft chews.

[0483] B3. The pharmaceutical formulation of either B1 or B2, wherein the solid oral dosage form suitable for pediatric use is characterized by one or more release profiles selected from fast release, sustained release, delayed release, and delayed-sustained release in vivo and / or in vitro.

[0484] B4. Any of the pharmaceutical formulations of B1 to B3, wherein the solid oral formulation suitable for pediatric use contains a plurality of centanafadine (CTN) beads, each of the plurality of CTN beads containing a core particle comprising CTN or a pharmaceutically acceptable salt thereof and an excipient.

[0485] B5. The pharmaceutical formulation of B4, wherein at least a portion of the plurality of beads are coated.

[0486] B6. The pharmaceutical formulation of any of B4-B5, wherein at least a portion of the plurality of beads are uncoated.

[0487] B7. The pharmaceutical formulation of B6, wherein the coating is one or more coatings selected from a delayed release coating, a sustained release coating, and a delayed-sustained release coating.

[0488] B8. Coating, one or more materials selected from amylose acetate phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate trimellitate, carboxymethyl ethyl cellulose, copolymerized methacrylic acid / methacrylic acid methyl ester, copolymerized methacrylic acid / methyl methacrylate, copolymerized methyl acrylate / methyl methacrylate / methacrylic acid, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, styrene-maleic acid copolymer, and styrene-vinylpyridine copolymer; optionally, one or more materials selected from copolymers of methacrylic acid, methyl methacrylate, and methyl acrylate, and methacrylic acid-acrylate copolymers; and Optionally, a copolymer of methacrylic acid, methyl methacrylate, and methyl acrylate. 10. A pharmaceutical formulation of B7, wherein the delayed release coating comprises:

[0489] B9. Any of the pharmaceutical formulations of B4 to B8 comprising a delayed-release coating, wherein the median amount of the delayed-release coating disposed on the core particles is at least 10% by weight of the total weight of the CTN beads, or in the range of about 12% to about 50% by weight, or about 12% to about 35% by weight, based on the total weight of the CTN beads.

[0490] B10. A pharmaceutical formulation according to any one of B4 to B9, comprising a sustained release coating, wherein the sustained release coating is one or more materials selected from alkyl celluloses, acrylic acid polymers, methacrylic acid polymers, acrylic acid copolymers, methacrylic acid copolymers, and cellulose ethers; optionally, one or more materials selected from hydroxyalkyl cellulose, carboxyalkyl cellulose, methyl methacrylate, methyl methacrylate copolymer, ethoxyethyl methacrylate, ethyl acrylate, trimethylammonioethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymer, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic anhydride), and glycidyl methacrylate copolymer; optionally, one or more materials selected from poly[ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride], hydroxypropyl methylcellulose, and poly[ethyl acrylate, methyl methacrylate]; Optionally, a pharmaceutical formulation comprising poly[ethyl acrylate, methyl methacrylate].

[0491] B11. A pharmaceutical formulation according to any one of B4 to B10, comprising a sustained release coating, wherein the median amount of the sustained release coating disposed on the core particle is at least 5% by weight of the total weight of the core particle, or in the range of about 5% to about 60% by weight, or about 15% to about 60% by weight, or about 20% to about 50% by weight of the total weight of the core particle.

[0492] B12. A pharmaceutical formulation according to any one of B4 to B11, comprising a coating, wherein the coating further comprises a pore-forming agent.

[0493] B13. The pore-forming agent is one or more materials selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, poloxamer 188, polyvinylpyrrolidone, D-mannitol, methylcellulose, polyvinyl alcohol-polyethylene glycol graft copolymer, and saccharides; optionally, one or more materials selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyvinylpyrrolidone; A pharmaceutical formulation of B12, optionally containing hydroxypropyl methylcellulose.

[0494] B14. The pharmaceutical formulation of B12, wherein the pore-forming agent is present in the coating in an amount of about 5% by weight or more, or about 10% by weight or more, or in the range of about 5% to about 20% by weight, optionally in an amount of 15% by weight.

[0495] B15. A pharmaceutical formulation according to any one of B4 to B14, wherein the core particles are specified by a particle size distribution, and at least a portion of the core particles of the plurality of beads have a core particle size (maximum diameter) of about 0.2 mm to about 2 mm, or about 0.3 mm to about 1.5 mm, 0.4 mm to about 1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm.

[0496] B16. The particle size distribution of the core particles At least 60% by weight of core particles have a particle size (maximum diameter) in the range of about 0.4 mm to about 1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm; In some cases, at least 80% by weight of core particles have a particle size (maximum diameter) in the range of about 0.4 mm to about 1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm; In some cases, at least 90% by weight of the core particles have a particle size (maximum diameter) in the range of about 0.4 mm to about 1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm; In some cases, at least 99% by weight of the core particles have a particle size (maximum diameter) in the range of about 0.4 mm to about 1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm. A pharmaceutical preparation of B15 identified as

[0497] B17. A pharmaceutical formulation according to any one of B4 to B16, wherein the plurality of CTN beads have an average particle size (diameter) in the range of about 0.2 mm to about 2.8 mm, or about 0.2 mm to about 2.5 mm, or about 0.2 mm to about 2.0 mm, or about 0.7 mm to about 2.5 mm, or about 0.7 mm to about 2.8 mm, or about 0.5 mm to about 2.8 mm, or about 0.8 mm to about 1.7 mm, or about 0.5 mm to about 1.2 mm, or about 0.5 mm to about 1.0 mm, or about 0.5 mm to about 0.71 mm.

[0498] B18. The pharmaceutical formulation of any of B4-B17, wherein the plurality of CTN beads comprises one or more types selected from fast-release beads, sustained-release beads, delayed-release beads, and delayed-sustained-release beads.

[0499] B19. The pharmaceutical formulation of any of B4-B18, wherein the plurality of beads comprises a mixture of one or more fast-release beads and one or more sustained-release beads.

[0500] B20. The pharmaceutical formulation of B19, wherein the ratio of CTN or a pharmaceutically acceptable salt thereof is present in one or more fast-release beads and one or more sustained-release beads in a ratio ranging from about 1:100 to about 1:1 parts by weight, based on the weight of CTN.

[0501] B21. The pharmaceutical formulation of any of B4-B20, wherein the plurality of beads comprises a mixture of one or more fast-release beads and one or more delayed-release beads.

[0502] B22. The pharmaceutical formulation of B21, wherein the ratio of CTN or a pharmaceutically acceptable salt thereof is present in one or more fast-release beads and one or more delayed-release beads in a ratio ranging from about 1:100 to about 1:1 parts by weight, based on the weight of CTN.

[0503] B23. The pharmaceutical formulation of any of B4-B22, wherein the plurality of beads comprises a mixture of one or more delayed release beads and one or more sustained release beads.

[0504] B24. The pharmaceutical formulation of B23, wherein the ratio of CTN or a pharmaceutically acceptable salt thereof is present in the one or more sustained release beads and the one or more delayed release beads in a ratio ranging from about 5:10 to about 1:5 parts by weight based on the weight of CTN.

[0505] B25. The pharmaceutical formulation of any of B4-B24, wherein the plurality of beads comprises a mixture of one or more fast-release beads and one or more delayed-sustained release beads.

[0506] B26. The pharmaceutical formulation of B25, wherein the ratio of CTN or a pharmaceutically acceptable salt thereof is present in one or more fast-release beads and one or more delayed-sustained-release beads in a ratio ranging from about 1:100 to about 1:1 parts by weight, based on the weight of CTN.

[0507] B27. The pharmaceutical formulation of any of B4-B26, wherein the plurality of beads comprises a mixture of one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads.

[0508] B28. The ratio of CTN or a pharmaceutically acceptable salt thereof in one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads is in the range of about 0.1-1:1-20:1-20 parts by weight based on the total weight of CTN or a salt thereof; optionally in a ratio ranging from about 0.5-1:5-20:5-20 parts by weight based on the total weight of CTN or a salt thereof; optionally in a ratio ranging from about 0.7-13:3-6:3-6 parts by weight based on the total weight of CTN or a salt thereof; and optionally in a ratio ranging from about 0.7-1:5-15:5-15 parts by weight based on the total weight of CTN or a salt thereof; There exists a pharmaceutical formulation of B27.

[0509] B29. The pharmaceutical formulation of any of B4-B28, wherein the plurality of beads comprises a mixture of one or more fast-release beads, one or more sustained-release beads, and one or more delayed-sustained-release beads.

[0510] B30. The ratio of CTN or a pharmaceutically acceptable salt thereof in one or more fast-release beads, one or more sustained-release beads, and one or more delayed-sustained-release beads is in the range of about 0.1-1:1-20:1-20 parts by weight based on the total weight of CTN or a salt thereof; optionally in a ratio ranging from about 0.5-1:5-20:5-20 parts by weight based on the total weight of CTN or a salt thereof; optionally in a ratio ranging from about 0.7-13:3-6:3-6 parts by weight based on the total weight of CTN or a salt thereof; and optionally in a ratio ranging from about 0.7-1:5-15:5-15 parts by weight based on the total weight of CTN or a salt thereof; A pharmaceutical formulation of B29 exists.

[0511] B31. A pharmaceutical formulation of any of B4 to B30, wherein the rapid-release beads are uncoated.

[0512] B32. The fast-release beads are in the range of about 1% to about 75% based on the total weight of the plurality of CTN beads in the formulation; optionally, in the range of about 40% to about 55% based on the total weight of the plurality of CTN beads, when the drug incorporated in the fast-release beads is about 5% to about 15% by weight; optionally, in the range of about 1% to about 50% based on the total weight of the plurality of CTN beads; optionally, in the range of about 1% to about 25% based on the total weight of the plurality of CTN beads; optionally, in the range of about 1% to about 10% based on the total weight of the plurality of CTN beads; Optionally, in the range of about 9% to about 19% based on the total weight of the plurality of CTN beads when the drug incorporated into the rapid-release beads is about 40% to about 55% by weight; and Optionally, in the range of about 18% to about 28% based on the total weight of the plurality of CTN beads. The pharmaceutical formulation of any one of B4 to B31, wherein the amount of

[0513] B33. Contains sustained release beads, The sustained-release beads range from about 5% to 80% based on the total weight of the plurality of CTN beads in the formulation; optionally, in the range of about 23% to about 33%, based on the total weight of the plurality of CTN beads; optionally, in the range of about 5% to about 65%, based on the total weight of the plurality of CTN beads; optionally, in the range of about 40% to about 55%, based on the total weight of the plurality of CTN beads; Optionally, in the range of about 35% to about 55% based on the total weight of the plurality of CTN beads. A pharmaceutical formulation of any one of B4 to B32, wherein B4 to B32 are present in an amount of

[0514] B34. Contains delayed release beads, The delayed-release beads range from about 5% to 80% based on the total weight of the CTN beads in the formulation; optionally, in the range of about 21% to about 31%, based on the total weight of the plurality of CTN beads; optionally, in the range of about 5% to about 65%, based on the total weight of the plurality of CTN beads; optionally, in the range of about 36% to about 46%, based on the total weight of the plurality of CTN beads; Optionally, in the range of about 30% to about 55% based on the total weight of the plurality of CTN beads. A pharmaceutical formulation of any one of B4 to B33, wherein the amount of B4 to B33 is

[0515] B35. Contains sustained-release beads, USP <711> Any of B4 to B34 pharmaceutical formulations, which are tested in accordance with the above using Apparatus 1 (basket) in 1000 mL of deionized water at 37°C ± 0.5°C and 100 rpm, and which release at least 90% of CTN or a salt thereof from the sustained-release beads within a range of 2 to 6 hours.

[0516] B36. Contains delayed release beads, USP <711> According to the method described above, at 37°C ± 0.5°C, 100 rpm, using Apparatus 1 (basket), first test in 1000 mL of 0.1 N HCl solution for 2 hours, and then test in 1000 mL of unbuffered deionized water for the remaining time, and at least 90% of CTN or a salt thereof is released from the delayed-release beads within a range of 4 to 14 hours, or USP <711> According to the test, using Apparatus 1 (basket), at 37°C ± 0.5°C, 100 rpm, first test in 1000 mL of 0.1 N HCl solution for 2 hours, then test in 1000 mL of pH 7.4 phosphate buffer solution for the remaining time, and at least 90% of CTN or its salt is released from the delayed-release beads within a range of 4 to 14 hours. Any of pharmaceutical preparations B4 to B35.

[0517] B37. Delayed-sustained release beads, USP <711> and (iii) at least 90% of the CTN or a salt thereof is released from the delayed-sustained-release beads in a range of 4 to 14 hours, using Apparatus 1 (basket) at 37°C ± 0.5°C, 100 rpm, first in 1000 mL of 0.1 N HCl solution for 2 hours, and then in 1000 mL of unbuffered deionized water for the remaining time. USP <711> According to the test, using Apparatus 1 (basket), at 37°C ± 0.5°C, 100 rpm, first in 1000 mL of 0.1 N HCl solution for 2 hours, then in 1000 mL of pH 7.4 phosphate buffer solution for the remaining time, at least 90% of CTN or its salt is released from the delayed-sustained-release beads within a range of 4 to 14 hours. Any of the pharmaceutical preparations B4 to B36.

[0518] B38. Contains fast-release beads, USP <711> Any of the pharmaceutical formulations B4 to B37, which are tested in accordance with the above method using Apparatus 1 (basket) in 1000 mL of deionized water at 37°C ± 0.5°C and 100 rpm, and at least 90% of CTN or a salt thereof is released from the fast-release beads within a range of 0 to 2 hours.

[0519] B39. A mixture of fast-release beads, sustained-release beads, and delayed-release beads, USP <711> In accordance with the method described above, using Apparatus 1 (basket), at 37°C ± 0.5°C, 100 rpm, first in 1000 mL of 0.1 N HCl solution for 2 hours, and then in 1000 mL of unbuffered deionized water for the remaining time, at least 40% of CTN or its salt is released from the mixture of beads within 3 to 5 hours, at least 90% of CTN or its salt is released from the mixture of beads within 12 to 14 hours, or USP <711> According to the method described above, the test is carried out using Apparatus 1 (basket) at 37°C ± 0.5°C, 100 rpm, first with 1000 mL of 0.1 N HCl solution for 2 hours, and then with 1000 mL of pH 7.4 phosphate buffer solution for the remaining time, and at least 40% of the CTN or its salt is released from the bead mixture within 3 to 5 hours, and at least 90% of the CTN or its salt is released from the bead mixture within 12 to 14 hours. Any of the pharmaceutical preparations B4 to B38.

[0520] B40. Contains fast-release beads, CTN or a salt thereof is in the range of 5 wt% to 80 wt% in the fast-release beads based on the total weight of the fast-release beads; optionally in the range of 5% to 60% by weight based on the total weight of the fast-release beads; optionally in the range of 5% to 15% by weight based on the total weight of the fast-release beads; Optionally, in the range of 40% to 60% by weight based on the total weight of the fast-release beads is present in an amount of, and Optionally, the CTN or salt thereof is present in a first fast-release bead in an amount ranging from 5% to 15% by weight based on the total weight of the fast-release bead, and the CTN or salt thereof is present in a second fast-release bead in an amount ranging from 40% to 60% by weight based on the total weight of the fast-release bead. Any of the pharmaceutical preparations B4 to B39.

[0521] B41. Contains sustained release beads, CTN or a salt thereof is in the range of 10% by weight to 95% by weight in the sustained-release beads, based on the total weight of the sustained-release beads; optionally in the range of 40% to 90% by weight, based on the total weight of the sustained release beads; Optionally, in the range of 50% to 70% by weight based on the total weight of the sustained release beads. A pharmaceutical formulation of any one of B4 to B40, wherein the amount of

[0522] B42. Contains delayed release beads, CTN or a salt thereof is in the range of 10% by weight to 95% by weight in the delayed-release beads, based on the total weight of the delayed-release beads; optionally in the range of 40% to 90% by weight based on the total weight of the delayed release beads; Optionally, in the range of 50% to 70% by weight based on the total weight of the delayed release beads. The pharmaceutical formulation of any one of B4 to B41, wherein the amount of

[0523] B43. A pharmaceutical formulation of any of B4-B42, characterized in that it exhibits a multimodal, optionally bimodal, in vivo absorption profile.

[0524] B44. The first C max A pharmaceutical preparation according to any one of B4 to B43, comprising:

[0525] B45. The in vivo yield profile of the second C is in the range of about 6 hours to 10 hours, or about 7 hours to 9 hours, or about 7.5 to about 8.5 hours. max The pharmaceutical preparation according to any one of B4 to B44, comprising:

[0526] B46. The first C shown from the formulation in human adults max A pharmaceutical formulation of B44 or B45 having a mean plasma level in the range of about 250 ng / mL to about 420 ng / mL, or about 320 ng / mL to about 420 ng / mL, or about 325 ng / mL to about 390 ng / mL.

[0527] B47. Second C shown from formulation in human adults max any of the pharmaceutical formulations of B44 to B46, having a mean plasma level in the range of about 450 ng / mL to about 550 ng / mL, or about 470 ng / mL to about 530 ng / mL.

[0528] B48. In vivo absorption profile is first C max and the second C max and the first C max and the second C max The pharmaceutical formulation of any one of B4 to B47, wherein the time difference is in the range of 1.5 to 8.5 hours, or about 2 hours to about 6 hours, or about 3 hours to about 5 hours.

[0529] B49. The pharmaceutical formulation of any of B4-B48, wherein one or more of the plurality of CTN beads has a release mechanism comprising one or more of dissolution, diffusion, erosion, osmosis, partitioning, swelling, and targeting.

[0530] B50. The pharmaceutical formulation of any of B4-B49, wherein one or more of the plurality of CTN beads has a diffusional release mechanism.

[0531] B51. The pharmaceutical formulation of any of B4 to B50, wherein one or more of the plurality of CTN beads has a pH-dependent elution release mechanism.

[0532] B52. The pharmaceutical formulation of any of B4-B51, wherein one or more of the plurality of CTN beads has a combination of a pH-driven dissolution release mechanism and a diffusion release mechanism.

[0533] B53. The pharmaceutical formulation of any of B4-B52, wherein one or more of the plurality of CTN beads comprises a porous matrix containing CTN.

[0534] B54. The pharmaceutical formulation of any of B4-B53, wherein a plurality of CTN beads are packaged in one or more containers selected from capsules, sachets, and stick packs, optionally in capsules.

[0535] B55. A pharmaceutical formulation of any of B4-B54, wherein the CTN is present as a salt, optionally as the hydrochloride salt.

[0536] B56. The excipient is one or more materials selected from fillers, binders, glidants, surfactants, polymer coatings, and plasticizers; optionally a combination of fillers and binders; Optionally, a combination of a binder and a polymer coating; Optionally, a combination of fillers, binders, and polymer coatings; Optionally, a combination of fillers, binders, polymer coatings, and plasticizers A pharmaceutical preparation according to any one of B4 to B55, comprising:

[0537] B57. The pharmaceutical formulation of any of B4-B55, wherein the excipient comprises one or more materials selected from lactose, mannitol, corn starch, microcrystalline cellulose, hydroxypropyl cellulose, hypromellose, polyvinylpyrrolidone, talc, polysorbate 80, glycerol monostearate, triethyl citrate, polyvinyl alcohol-polyethylene glycol graft copolymer, and silica.

[0538] B58. A pharmaceutical formulation according to any one of B4 to B57, wherein the formulation does not contain a disintegrant.

[0539] Aspect G G1. A method of treatment using a formulation according to any of the above aspects, or use of a formulation according to any of the above aspects, comprising administering a formulation according to any of the above aspects to an animal subject in need of treatment, optionally a mammalian subject in need of treatment, optionally a human in need of treatment.

[0540] G2. The method of treatment of G1, wherein the subject in need of treatment is a subject in need of modulation of plasma levels of centanafadine or a pharmaceutically acceptable salt thereof.

[0541] G3. The method of treating G1 or G2, wherein the administration is for treating or preventing one or more symptoms of a disorder alleviated by inhibiting the reuptake of one or more of norepinephrine, dopamine, or serotonin.

[0542] G4. Any of the treatment methods G1 to G3, where the subject requiring treatment is attention-deficit / hyperactivity disorder (ADHD).

[0543] G5. Treatment method for G4, where ADHD is primarily of the inattentive type.

[0544] G6. Treatment method for G4, where ADHD is primarily a hyperactive-impulsive subtype.

[0545] G7. Treatment method for G4, who has multiple types of ADHD.

[0546] G8. Any of the treatment methods G1 to G7, in which the subject requiring treatment has autism spectrum disorder and fragile X-associated disorder.

[0547] G9. Any of the treatment methods G1 to G8, in which the subject requiring treatment has fragile X-associated disorder.

[0548] G10. The method of treating G9, wherein the fragile X-associated disorder is fragile X syndrome (FXS).

[0549] G11. The method of treating G9, wherein the fragile X-associated disorder is fragile X-associated tremor / ataxia syndrome (FXTAS).

[0550] G12. The method of treating G9, wherein the fragile X-associated disorder is fragile X-associated primary ovarian insufficiency (FXPOI).

[0551] G13. Any of the treatment methods G1 to G12, in which the subject requiring treatment has binge eating disorder.

[0552] G14. Treatment method for G13, where the binge eating disorder involves 1 to 3 binge eating episodes per week, or 4 to 7 binge eating episodes per week, or 8 to 13 binge eating episodes per week, or 14 or more binge eating episodes per week.

[0553] G15. Any of the treatment methods G1 to G14, administered on a schedule of twice daily or less.

[0554] G16. A method of treatment for G19, wherein administration is on a once-daily schedule.

[0555] G17. The drug product or dosage form is 0.5mg / kg to 20mg / kg per day 1mg / kg to 15mg / kg per day, depending on the case In some cases, 1 mg / kg to 10 mg / kg per day, 2mg / kg to 20mg / kg per day, depending on the case 2mg / kg to 10mg / kg per day, depending on the case 3mg / kg to 15mg / kg per day in some cases The treatment method according to any one of G1 to G16, wherein the amount of the compound administered is in the range of

[0556] G18. The formulation is administered once, twice, three times, or four times daily. Approximately 10mg to approximately 25mg, In some cases, about 30 mg to about 50 mg In some cases, about 25 mg to about 150 mg, In some cases, about 50 mg to about 100 mg, In some cases, about 100 mg to about 250 mg, Approximately 250 to 500 mg depending on the case A treatment method according to any one of G1 to G17, wherein the amount of the compound administered is in the range of

[0557] G19. The formulation is administered once or twice daily. Approximately 50mg~75mg, In some cases, about 100mg to 200mg In some cases, approximately 250 mg to 400 mg Approximately 400mg to 600mg depending on the case A method of treating G18, wherein the compound is administered in an amount ranging from 0.01 to 0.01.

[0558] G20. A method of treating G19, wherein the formulation is administered in an amount ranging from about 100 mg to 300 mg once daily.

[0559] G21. Any of the methods of treatment G1-G20, wherein administration includes mixing the formulation with a soft food prior to administration, and optionally the soft food includes one or more foods selected from applesauce, yogurt, pudding, and jelly.

[0560] G22. Any of the treatment methods G1 to G21 in which administration is via an enteral feeding tube.

[0561] G23. Any of the treatment methods G1 to G22, wherein the formulation is administered to a subject in a fasting state.

[0562] G24. During one dosing interval, a maximum centanafadine plasma concentration (C) in the range of at least 200 ng / mL, or at least 250 ng / mL, or at least 300 ng / mL, or at least 340 ng / mL, or from about 250 ng / mL to about 1500 ng / mL, or from about 310 ng / mL to about 1300 ng / mL, or from about 325 to about 1250 ng / mL, or from about 340 ng / mL to about 1190 ng / mL, or from about 400 ng / mL to about 850 ng / mL is achieved. max) is administered to an adult subject as one of the treatment methods G1 to G23.

[0563] G25. One hour after administration (C 1h ), any of the treatment methods G1 to G24, which provides the subject with a centanafadine plasma concentration in the range of at least 150 ng / mL, or at least 200 ng / mL, or at least 250 ng / mL, or at least 280 ng / mL, or from about 180 ng / mL to about 610 ng / mL, or from about 200 ng / mL to about 590 ng / mL, or from about 220 ng / mL to about 540 ng / mL, or from about 245 ng / mL to about 490 ng / mL.

[0564] G26. 12 hours after administration (C 12h ), or any of the treatment methods G1 to G25, which provides an adult subject with a centanafadine plasma concentration in the range of at least 95 ng / mL, or at least 160 ng / mL, or at least 230 ng / mL, or at least 360 ng / mL, or from about 95 ng / mL to about 450 ng / mL, or from about 100 ng / mL to about 435 ng / mL, or from about 110 ng / mL to about 400 ng / mL, or from about 30 ng / mL to about 360 ng / mL, or from about 150 ng / mL to about 300 ng / mL.

[0565] G27. 16 hours after administration (C 16h ), or less than 300 ng / mL, or less than 250 ng / mL, or less than 230 ng / mL, or less than 200 ng / mL, or less than 100 ng / mL, or about 95 ng / mL to about 450 ng / mL, or about 100 ng / mL to about 300 ng / mL, or about 110 ng / mL to about 250 ng / mL, or about 30 ng / mL to about 250 ng / mL, or about 60 ng / mL to about 150 ng / mL.

[0566] G28. Any of the methods of treatment G1-G27, providing an adult subject with a post-administration centanafadine plasma concentration that remains at least 75 ng / mL, or at least 200 ng / mL, or at least 250 ng / mL, or at least 280 ng / mL, or from about 75 ng / mL to about 1500 ng / mL, or from about 200 ng / mL to about 1440 ng / mL, or from about 230 ng / mL to about 1320 ng / mL, or from about 250 ng / mL to about 1260 ng / mL over a period of 2 to 8 hours after administration.

[0567] G29. One hour after administration (AUC 0-1h ), any of the treatment methods G1 to G28, which provides an adult subject with a cumulative centanafadine plasma exposure in the range of at least 30 ng·h / mL, or at least 40 ng·h / mL, or at least 100 ng·h / mL, or at least 200 ng·h / mL, or about 30 ng·h / mL to about 500 ng·h / mL, or about 32 ng·h / mL to about 480 ng·h / mL, or about 36 ng·h / mL to about 440 ng·h / mL, or about 40 ng·h / mL to about 400 ng·h / mL, or about 350 ng·h / mL to about 450 ng·h / mL.

[0568] G30. Over the period 0 to 8 hours after administration (AUC 0-8h ), or any of the treatment methods G1 to G29, providing an adult subject with a cumulative centanafadine plasma exposure in the range of at least 1275 ng·h / mL, or at least 1530 ng·h / mL, or at least 1700 ng·h / mL, or at least 2500 ng·h / mL, or about 1275 ng·h / mL to about 6250 ng·h / mL, or about 1275 ng·h / mL to about 6250 ng·h / mL, or about 1360 ng·h / mL to about 6000 ng·h / mL, or about 1530 ng·h / mL to about 5500 ng·h / mL, or about 1700 ng·h / mL to about 5000 ng·h / mL, or about 2100 ng·h / mL to about 4100 ng·h / mL.

[0569] G31. Over the period 2 to 8 hours after administration (AUC 2-8h), or at least 1050 ng·h / mL, or at least 1120 ng·h / mL, or at least 1330 ng·h / mL, or at least 2000 ng·h / mL, or at least 2500 ng·h / mL, or in the range of about 1050 ng·h / mL to about 5250 ng·h / mL, or about 1120 ng·h / mL to about 5040 ng·h / mL, or about 1260 ng·h / mL to about 4620 ng·h / mL, or about 1330 ng·h / mL to about 4410 ng·h / mL, or about 1400 ng·h / mL to about 4200 ng·h / mL, or about 1700 ng·h / mL to about 3500 ng·h / mL.

[0570] G32. 24 hours after administration (AUC 0-24h ), at least 2400 ng·h / mL, or at least 2880 ng·h / mL, or at least 3200 ng·h / mL, or at least 5000 ng·h / mL, or at least 7100 ng·h / mL, or about 2400 ng·h / mL to about 12500 ng·h / mL, or about 2560 ng·h / mL to about 12000 ng·h / mL, or about 2880 ng·h / mL to about Any of the treatment methods G1 to G31, providing an adult subject with a cumulative centanafadine plasma exposure in the range of 11,000 ng·h / mL, or about 3,040 ng·h / mL to about 10,500 ng·h / mL, or about 3,200 ng·h / mL to about 10,000 ng·h / mL, or about 7,000 ng·h / mL to about 10,000 ng·h / mL, or about 4,000 ng·h / mL to about 6,000 ng·h / mL.

[0571] G33. 48 hours after administration (AUC 0-48h), or any of the treatment methods G1 to G32, providing an adult subject with a cumulative centanafadine plasma exposure in the range of at least 2400 ng·h / mL, or at least 2880 ng·h / mL, or at least 3200 ng·h / mL, at least 5000 ng·h / mL, or at least 7100 ng·h / mL, or from about 2400 ng·h / mL to about 12500 ng·h / mL, or from about 2560 ng·h / mL to about 12000 ng·h / mL, or from about 2880 ng·h / mL to about 11000 ng·h / mL, or from about 3040 ng·h / mL to about 10500 ng·h / mL, or from about 3200 ng·h / mL to about 10000 ng·h / mL, or from about 7000 ng·h / mL to about 10000 ng·h / mL.

[0572] G34. Post-administration period (AUC 0-inf ), or any of the treatment methods G1 to G33, providing an adult subject with a cumulative centanafadine plasma exposure in the range of at least 2400 ng·h / mL, or at least 2880 ng·h / mL, or at least 3200 ng·h / mL, at least 5000 ng·h / mL, or at least 7100 ng·h / mL, or from about 2400 ng·h / mL to about 12500 ng·h / mL, or from about 2560 ng·h / mL to about 12000 ng·h / mL, or from about 2880 ng·h / mL to about 11000 ng·h / mL, or from about 3040 ng·h / mL to about 10500 ng·h / mL, or from about 3200 ng·h / mL to about 10000 ng·h / mL, or from about 7000 ng·h / mL to about 10000 ng·h / mL.

[0573] G35. The method of treatment of any of G1-G34, wherein administering comprises administering a CTN dose of 164.4 mg of CTN per day.

[0574] G36. Within a dosing interval, a maximum centanafadine plasma concentration (C) in the range of at least about 525 ng / mL, or at least about 560 ng / mL, or at least about 700 ng / mL, or at least about 1000 ng / mL, or at least about 1600 ng / mL, or from about 525 ng / mL to about 4000 ng / mL, or from about 560 ng / mL to about 3840 ng / mL, or from about 630 ng / mL to about 3520 ng / mL, or from about 6650 ng / mL to about 700 ng / mL, or about 3200 ng / mL is achieved. max ) is administered to an adult subject as one of the treatment methods G1 to G23.

[0575] G37. At 1 hour after administration (C 1h ), or a method of treatment of any of G1 to G23 or G36, which provides an adult subject with a centanafadine plasma concentration of at least 225 ng / mL, or at least 250 ng / mL, or at least 285 ng / mL, or at least 300 ng / mL, or in the range of about 225 ng / mL to about 1375 ng / mL, or about 240 ng / mL to about 1320 ng / mL, or about 285 ng / mL to about 1155 ng / mL, or about 300 ng / mL to about 1100 ng / mL.

[0576] G38. At 12 hours after administration (C 12h ), a method of treatment of any of G1 to G23 or any of G36 to G37, which provides an adult subject with a centanafadine plasma concentration in the range of at least 190 ng / mL, or at least 225 ng / mL, or at least 250 ng / mL, or at least 400 ng / mL, or from about 190 ng / mL to about 1250 ng / mL, or from about 200 ng / mL to about 1200 ng / mL, or from about 225 ng / mL to about 1100 ng / mL, or from about 250 ng / mL to about 1000 ng / mL.

[0577] G39. At 16 hours after administration (C 16h), or less than 375 ng / mL, or less than 300 ng / mL, or less than 250 ng / mL, or less than 230 ng / mL, or less than 200 ng / mL, or less than 100 ng / mL, or in the range of about 60 ng / mL to about 375 ng / mL, or about 64 ng / mL to about 300 ng / mL, or about 76 ng / mL to about 250 ng / mL, or about 80 ng / mL to about 300 ng / mL.

[0578] G40. A method of treatment of any of G1 to G23 or any of G36 to G39, providing an adult subject with a post-administration centanafadine plasma concentration that is maintained in the range of at least 200 ng / mL, or at least 250 ng / mL, or at least 280 ng / mL, or at least 300 ng / mL, or at least 1000 ng / mL, or at least 1500 ng / mL, or about 150 ng / mL to about 4125 ng / mL, or about 160 ng / mL to about 3960 ng / mL, or about 180 ng / mL to about 3630 ng / mL, or about 200 ng / mL to about 3300 ng / mL for 2 to 8 hours after administration.

[0579] G41. 1 hour after administration (AUC 0-1h ), or any of G1-G23 or any of G36-G40, providing an adult subject with a cumulative centanafadine plasma exposure in the range of at least 60 ng·h / mL, or at least 80 ng·h / mL, or at least 200 ng·h / mL, or at least 300 ng·h / mL, or about 60 ng·h / mL to about 750 ng·h / mL, or about 64 ng·h / mL to about 720 ng·h / mL, or about 72 ng·h / mL to about 660 ng·h / mL, or about 80 ng·h / mL to about 600 ng·h / mL.

[0580] G42. Over the period 0 to 8 hours after administration (AUC 0-8h), or any of G1-G23 or any of G36-G41, providing an adult subject with a cumulative centanafadine plasma exposure of at least 2250 ng·h / mL, or at least 3000 ng·h / mL, or at least 5000 ng·h / mL, or at least 6000 ng·h / mL, or in the range of about 2250 ng·h / mL to about 13750 ng·h / mL, or about 2400 ng·h / mL to about 13200 ng·h / mL, or about 72700 ng·h / mL to about 12100 ng·h / mL, or about 3000 ng·h / mL to about 11000 ng·h / mL.

[0581] G43. Over the period 2 to 8 hours after administration (AUC 2-8h ), a method of treatment of any of G1-G23 or any of G36-G42, which provides an adult subject with a cumulative centanafadine plasma exposure in the range of at least 1875 ng·h / mL, or at least 2500 ng·h / mL, or at least 3000 ng·h / mL, or at least 4000 ng·h / mL, or at least 5000 ng·h / mL, or from about 1875 ng·h / mL to about 11250 ng·h / mL, or from about 2000 ng·h / mL to about 10800 ng·h / mL, or from about 2250 ng·h / mL to about 9900 ng·h / mL, or from about 2375 ng·h / mL to about 9450 ng·h / mL, or from about 2500 ng·h / mL to about 9000 ng·h / mL.

[0582] G44. 24 hours after administration (AUC 0-24h), or any of G1-G23 or any of G36-G43, providing an adult subject with a cumulative centanafadine plasma exposure in the range of at least 10,950 ng·h / mL, or at least 11,680 ng·h / mL, or at least 14,600 ng·h / mL, or at least 16,000 ng·h / mL, or at least 19,000 ng·h / mL, or from about 10,950 ng·h / mL to about 30,000 ng·h / mL, or from about 11,680 ng·h / mL to about 28,800 ng·h / mL, or from about 13,140 ng·h / mL to about 26,400 ng·h / mL, or from about 13,870 ng·h / mL to about 25,200 ng·h / mL, or from about 14,600 ng·h / mL to about 24,000 ng·h / mL.

[0583] G45. Post-administration period (AUC 0-inf ), or a cumulative centanafadine plasma exposure in an adult subject of at least 10,950 ng·h / mL, or at least 11,680 ng·h / mL, or at least 14,600 ng·h / mL, or at least 16,000 ng·h / mL, or at least 19,000 ng·h / mL, or from about 10,950 ng·h / mL to about 30,000 ng·h / mL, or from about 11,680 ng·h / mL to about 28,800 ng·h / mL, or from about 13,140 ng·h / mL to about 26,400 ng·h / mL, or from about 13,870 ng·h / mL to about 25,200 ng·h / mL, or from about 14,600 ng·h / mL to about 25,000 ng·h / mL.

[0584] G46. A method of treatment of any of G1-G19, any of G21-G23, or any of G36-G45, wherein the administration comprises administering a CTN dose of 328.8 mg of CTN daily.

[0585] G47. The ratio of centanafadine plasma concentration at 16 hours post-dose to centanafadine plasma concentration at 12 hours post-dose (C 16h / C 12hany of the treatment methods G1 to G47, in which an adult subject is provided with a ratio of 0.75 or less, 0.5 or less, 0.3 or less, or in the range of about 0.66 to about 0.25, or about 0.5 to about 0.1.

[0586] G48. Administration of centanafadine results in a maximum plasma concentration (t max Any of the treatment methods G1 to G47, in which an adult subject is given a time period in the range of about 1.5 hours to about 11 hours, or about 2.25 hours to about 10 hours, or about 2.7 hours to about 8.8 hours, or about 3 hours to about 8 hours, or about 4 hours to about 6 hours to achieve the desired effect.

[0587] Aspect H H1. A method for producing a pharmaceutical formulation containing centanafadine (CTN) or a pharmaceutically acceptable salt thereof, comprising combining CTN or a pharmaceutically acceptable salt thereof with a binder to form particles containing CTN or a pharmaceutically acceptable salt thereof having a predetermined particle size range, and disposing a coating over at least a portion of the particles.

[0588] H2. Manufacturing method H1, wherein the blending includes extrusion, and optionally the blending further includes spheronization after extrusion.

[0589] H3. The manufacturing method according to any one of H1 to H2, wherein the average particle size is in the range of about 0.2 mm to about 2 mm, 0.4 mm to about 1.5 mm, about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm.

[0590] Aspect I I1. Within the dosing interval, a maximum CTN plasma concentration (C) in the range of at least 200 ng / mL, or at least 250 ng / mL, or at least 300 ng / mL, or at least 340 ng / mL, or from about 250 ng / mL to about 1500 ng / mL, or from about 310 ng / mL to about 1300 ng / mL, or from about 325 to about 1250 ng / mL, or from about 340 ng / mL to about 1190 ng / mL. max) to an adult subject.

[0591] I2. At 1 hour after administration (C 1h ), a pharmaceutical formulation of I1 that provides an adult subject with a CTN plasma concentration in the range of at least 150 ng / mL, or at least 200 ng / mL, or at least 250 ng / mL, or at least 280 ng / mL, or from about 180 ng / mL to about 610 ng / mL, or from about 200 ng / mL to about 590 ng / mL, or from about 220 ng / mL to about 540 ng / mL, or from about 245 ng / mL to about 490 ng / mL.

[0592] I3. At 12 hours after administration (C 12h ), or at least 95 ng / mL, or at least 160 ng / mL, or at least 230 ng / mL, or at least 360 ng / mL, or about 95 ng / mL to about 450 ng / mL, or about 100 ng / mL to about 435 ng / mL, or about 110 ng / mL to about 400 ng / mL, or about 30 ng / mL to about 360 ng / mL.

[0593] I4. At 16 hours after administration (C 16h ), or less than 300 ng / mL, or less than 250 ng / mL, or less than 230 ng / mL, or less than 200 ng / mL, or less than 100 ng / mL, or about 95 ng / mL to about 450 ng / mL, or about 100 ng / mL to about 300 ng / mL, or about 110 ng / mL to about 250 ng / mL, or about 30 ng / mL to about 250 ng / mL.

[0594] I5. Any of the pharmaceutical formulations I1 to I4, which provides an adult subject with a post-administration CTN plasma concentration that is maintained in the range of at least 75 ng / mL, or at least 200 ng / mL, or at least 250 ng / mL, or at least 280 ng / mL, or about 75 ng / mL to about 1500 ng / mL, or about 200 ng / mL to about 1440 ng / mL, or about 230 ng / mL to about 1320 ng / mL, or about 250 ng / mL to about 1260 ng / mL for 2 to 8 hours after administration.

[0595] I6. At 1 hour after administration (AUC 0-1h ), any of the pharmaceutical formulations I1-I5, which provides an adult subject with a cumulative CTN plasma exposure in the range of at least 30 ng·h / mL, or at least 40 ng·h / mL, or at least 100 ng·h / mL, or at least 200 ng·h / mL, or from about 30 ng·h / mL to about 500 ng·h / mL, or from about 32 ng·h / mL to about 480 ng·h / mL, or from about 36 ng·h / mL to about 440 ng·h / mL, or from about 40 ng·h / mL to about 400 ng·h / mL.

[0596] I7. Over the period 0 to 8 hours after administration (AUC 0-8h ), any of the pharmaceutical formulations I1-I6, which provides an adult subject with a cumulative CTN plasma exposure in the range of at least 1275 ng·h / mL, or at least 1530 ng·h / mL, or at least 1700 ng·h / mL, or at least 2500 ng·h / mL, or from about 1275 ng·h / mL to about 6250 ng·h / mL, or from about 1275 ng·h / mL to about 6250 ng·h / mL, or from about 1360 ng·h / mL to about 6000 ng·h / mL, or from about 1530 ng·h / mL to about 5500 ng·h / mL, or from about 1700 ng·h / mL to about 5000 ng·h / mL.

[0597] I8. Over the period 2 to 8 hours after administration (AUC 2-8h), or any of the pharmaceutical formulations I1-I7, providing an adult subject with a cumulative CTN plasma exposure in the range of at least 1050 ng·h / mL, or at least 1120 ng·h / mL, or at least 1330 ng·h / mL, or at least 2000 ng·h / mL, or at least 2500 ng·h / mL, or from about 1050 ng·h / mL to about 5250 ng·h / mL, or from about 1120 ng·h / mL to about 5040 ng·h / mL, or from about 1260 ng·h / mL to about 4620 ng·h / mL, or from about 1330 ng·h / mL to about 4410 ng·h / mL, or from about 1400 ng·h / mL to about 4200 ng·h / mL.

[0598] 19. 24 hours after administration (AUC 0-24h ), or any of the pharmaceutical formulations I1-I8, which provides an adult subject with a cumulative CTN plasma exposure in the range of at least 2400 ng·h / mL, or at least 2880 ng·h / mL, or at least 3200 ng·h / mL, or at least 5000 ng·h / mL, or at least 7100 ng·h / mL, or from about 2400 ng·h / mL to about 12500 ng·h / mL, or from about 2560 ng·h / mL to about 12000 ng·h / mL, or from about 2880 ng·h / mL to about 11000 ng·h / mL, or from about 3040 ng·h / mL to about 10500 ng·h / mL, or from about 3200 ng·h / mL to about 10000 ng·h / mL, or from about 7000 ng·h / mL to about 10000 ng·h / mL.

[0599] I10. 24 hours after administration (AUC 0-48h), or any of the pharmaceutical formulations I1-I9, providing an adult subject with a cumulative CTN plasma exposure in the range of at least 2400 ng·h / mL, or 2880 ng·h / mL, or 3200 ng·h / mL, 5000 ng·h / mL, or 7100 ng·h / mL, or from about 2400 ng·h / mL to about 12500 ng·h / mL, or from about 2560 ng·h / mL to about 12000 ng·h / mL, or from about 2880 ng·h / mL to about 11000 ng·h / mL, or from about 3040 ng·h / mL to about 10500 ng·h / mL, or from about 3200 ng·h / mL to about 10000 ng·h / mL, or from about 7000 ng·h / mL to about 10000 ng·h / mL.

[0600] I11. 24 hours after administration (AUC 0-inf ), any of the pharmaceutical formulations I1 to I10, which provides an adult subject with a cumulative CTN plasma exposure in the range of at least 2400 ng·h / mL, or 2880 ng·h / mL, or 3200 ng·h / mL, 5000 ng·h / mL, or 7100 ng·h / mL, or from about 2400 ng·h / mL to about 12500 ng·h / mL, or from about 2560 ng·h / mL to about 12000 ng·h / mL, or from about 2880 ng·h / mL to about 11000 ng·h / mL, or from about 3040 ng·h / mL to about 10500 ng·h / mL, or from about 3200 ng·h / mL to about 10000 ng·h / mL, or from about 7000 ng·h / mL to about 10000 ng·h / mL.

[0601] I12. The pharmaceutical formulation of any of I1-I11, wherein the formulation comprises CTN or a pharmaceutically acceptable salt thereof in an amount ranging from about 145 mg to about 185 mg of CTN, or in an amount of 164.4 mg.

[0602] I13. Within a dosing interval, a maximum CTN plasma concentration (C) in the range of at least about 525 ng / mL, or at least about 560 ng / mL, or at least about 700 ng / mL, or at least about 1000 ng / mL, or at least about 1600 ng / mL, or from about 525 ng / mL to about 4000 ng / mL, or from about 560 ng / mL to about 3840 ng / mL, or from about 630 ng / mL to about 3520 ng / mL, or from about 6650 ng / mL to about 700 ng / mL, or about 3200 ng / mL. max ) to an adult subject.

[0603] I14. At 1 hour after administration (C 1h ), a pharmaceutical formulation of I13 that provides an adult ...

Claims

1. A pharmaceutical formulation containing multiple centanafadine (CTN) regions, each of the multiple CTN regions containing a core region containing CTN or a pharmaceutically acceptable salt thereof and excipients, the multiple CTN regions including a fast-release region, a sustained-release region, and a delayed-release region; the sustained release region comprises a sustained release coating and the delayed release region comprises a delayed release coating; the sustained-release coating comprises one or more materials selected from alkyl celluloses, acrylic acid polymers, methacrylic acid polymers, acrylic acid copolymers, methacrylic acid copolymers, cellulose ethers, hydroxyalkyl celluloses, and carboxyalkyl celluloses; the sustained release coating is present in an amount ranging from 5% to 50% by weight based on the total weight of the sustained release region; the delayed-release coating comprises one or more materials selected from amylose acetate phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate trimellitate, carboxymethyl ethyl cellulose, copolymerized methacrylic acid / methacrylic acid methyl ester, copolymerized methacrylic acid / methyl methacrylate, copolymerized methyl acrylate / methyl methacrylate / methacrylic acid, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, styrene-maleic acid copolymer, and styrene-vinylpyridine copolymer; the delayed release coating is present in an amount ranging from 10% to 50% by weight based on the total weight of the delayed release region; the excipients comprise one or more materials selected from fillers, binders, glidants, surfactants, polymer coatings, and plasticizers; CTN or a pharmaceutically acceptable salt thereof is present in each of the fast-release region, the sustained-release region, and the delayed-release region in a ratio ranging from about 0.1 to 1:1 to 20:1 to 20 parts by weight based on the weight of CTN or a pharmaceutically acceptable salt thereof, A pharmaceutical preparation administered on a once-daily schedule.

2. 10. The pharmaceutical formulation of claim 1, wherein the rapid-release region comprises CTN or a pharmaceutically acceptable salt thereof in an amount ranging from about 5% to about 15% by weight based on the weight of the region.

3. 10. The pharmaceutical formulation of claim 1, wherein the rapid-release region comprises CTN or a pharmaceutically acceptable salt thereof in an amount ranging from about 40% to about 60% by weight based on the weight of the region.

4. A pharmaceutical formulation of any of claims 1 to 3, wherein the core region included in the sustained release region contains CTN or a pharmaceutically acceptable salt thereof in an amount ranging from about 70% by weight to about 90% by weight based on the total weight of the core region.

5. A pharmaceutical formulation of any of claims 1 to 4, wherein the core region contained in the delayed release region contains CTN or a pharmaceutically acceptable salt thereof in an amount ranging from about 70% by weight to about 90% by weight based on the total weight of the core region.

6. 6. The pharmaceutical formulation of any one of claims 1 to 5, wherein the sustained-release coating comprises one or more materials selected from alkylcelluloses, acrylic acid polymers, methacrylic acid polymers, acrylic acid copolymers, methacrylic acid copolymers, and cellulose ethers.

7. 6. The pharmaceutical formulation of any of claims 1 to 5, wherein the sustained release coating comprises a copolymer of ethyl acrylate and methyl methacrylate.

8. 8. The pharmaceutical formulation of any of claims 1 to 7, wherein the sustained release coating further comprises a pore-forming agent.

9. 9. The pharmaceutical formulation of claim 8, wherein the pore-forming agent comprises one or more materials selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, poloxamer 188, polyvinylpyrrolidone, D-mannitol, methylcellulose, polyvinyl alcohol-polyethylene glycol graft copolymer, and saccharides.

10. 10. The pharmaceutical formulation of any of claims 1 to 9, wherein the delayed-release region comprises a coating comprising poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid).

11. The pharmaceutical formulation of any one of claims 1 to 10, wherein the multiple CTN domains are physically associated. 。

12. 12. The pharmaceutical formulation of any of claims 1 to 11, wherein CTN is present as a pharmaceutically acceptable salt or as the hydrochloride salt.

13. 13. The pharmaceutical formulation of any one of claims 1 to 12, wherein CTN or a pharmaceutically acceptable salt thereof is present in each of the fast-release region, the sustained-release region, and the delayed-release region in a ratio ranging from about 0.5 to 1:5 to 20:5 to 20 parts by weight based on the weight of CTN or a pharmaceutically acceptable salt thereof, respectively.

14. 13. The pharmaceutical formulation of any one of claims 1 to 12, wherein CTN or a pharmaceutically acceptable salt thereof is present in each of the fast-release region, the sustained-release region, and the delayed-release region in a ratio ranging from about 0.7 to 1.3:3 to 6:3 to 6 parts by weight based on the weight of CTN or a pharmaceutically acceptable salt thereof, respectively.

15. 13. The pharmaceutical formulation of any one of claims 1 to 12, wherein CTN or a pharmaceutically acceptable salt thereof is present in each of the fast-release region, the sustained-release region, and the delayed-release region in a ratio ranging from about 0.7 to 1:5 to 15:5 to 15 parts by weight based on the weight of CTN or a pharmaceutically acceptable salt thereof, respectively.

16. 13. The pharmaceutical formulation of any one of claims 1 to 12, wherein CTN or a pharmaceutically acceptable salt thereof is present in each of the fast-release region, the sustained-release region, and the delayed-release region in a ratio ranging from about 1:3.6:3.6 parts by weight based on the weight of CTN or a pharmaceutically acceptable salt thereof, respectively.

17. 17. The pharmaceutical formulation of any one of claims 1 to 16, which is in the form of an orodispersible tablet, an orodispersible film, a mini-tablet, a chewable tablet, or a soft chew.

18. 18. The pharmaceutical formulation of any of claims 1 to 17, wherein CTN is present as the hydrochloride salt.

19. 19. The pharmaceutical formulation of any of claims 1 to 18, wherein the excipient comprises one or more materials selected from lactose, mannitol, corn starch, microcrystalline cellulose, hydroxypropyl cellulose, hypromellose, polyvinylpyrrolidone, talc, polysorbate 80, glycerol monostearate, triethyl citrate, polyvinyl alcohol-polyethylene glycol graft copolymer, and silica.

20. 20. The pharmaceutical formulation of any one of claims 1 to 19, wherein the formulation is tested according to USP <711> using Apparatus 1 (basket) at 37°C ± 0.5°C, 100 rpm, first with 1000 mL of 0.1 N HCl solution for 2 hours, and then with 1000 mL of pH 7.4 aqueous buffer solution for the remaining time at 37°C ± 0.5°C, 100 rpm, and the formulation releases at least 40% of the CTN or pharmaceutically acceptable salt thereof from the formulation within 3 to 5 hours, and at least 90% of the CTN or pharmaceutically acceptable salt thereof from the formulation within 12 to 14 hours.

21. 20. The pharmaceutical formulation of any of claims 1 to 19, wherein the pharmaceutical formulation is tested according to USP <711> using Apparatus 1 (basket) in 1000 mL of 0.1 N hydrochloric acid at 37°C ± 0.5°C and 100 rpm for 2 hours, followed by Apparatus 1 (basket) in 1000 mL of pH 7.4 phosphate buffer at 37°C ± 0.5°C and 100 rpm for 12 hours, and the release profile is characterized by a release of about 24% to 48% of CTN or a pharmaceutically acceptable salt thereof at 3 hours.

22. 10. The pharmaceutical formulation of claim 1, wherein the formulation contains CTN or a pharmaceutically acceptable salt thereof in an amount ranging from 10 mg to 490 mg.

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