1-(Naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane for the treatment of major depressive disorder

Abstract

The present disclosure relates generally to methods of treating central nervous system disorders using (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane (i.e., centanafadine) or a pharmaceutically acceptable salt thereof. More specifically, the present disclosure relates to the treatment of conditions affected by monoamine neurotransmitters.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) The benefit under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application No. 63 / 403,624, filed September 2, 2022, is hereby claimed, the disclosure of which is incorporated herein by reference. (Disclosure Areas) The present invention relates generally to methods of treating central nervous system disorders using (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane (i.e., centanafadine) or a pharmaceutically acceptable salt thereof. More specifically, the present invention relates to the treatment of conditions affected by monoamine neurotransmitters. [Background technology]

[0002] Major depressive disorder has a profound impact on overall functioning and is the leading cause of disability worldwide in terms of total years lost due to disability. 2010 data showed that depression-related expenditures in the United States exceeded $210 billion, costing employers $102 billion in absenteeism, absences, and disability, and $99 billion in direct medical costs. Improving treatment outcomes related to major depression is crucial.

[0003] The American Psychiatric Association recommends that healthcare professionals select a variety of treatments during the acute phase of a major depressive episode (MDE) with the goal of achieving remission and returning patients to their pre-MDE level of functioning. Currently available options include antidepressant therapy (ADT), depression-focused psychotherapy (e.g., cognitive behavioral therapy), combined ADT and psychotherapy, or other somatic therapies (e.g., electroconvulsive therapy, transcranial magnetic stimulation). Clinical characteristics (e.g., symptom severity, presence of comorbid illnesses and psychosocial stressors) and other factors (e.g., patient preference, previous treatment experience) influence clinicians' initial treatment choices. For most patient populations, when ADT is indicated and psychotherapy is an available and practical option, combining ADT and psychotherapy often produces the most rapid and sustained response. Combination therapy appears to significantly improve depressive symptoms, improve quality of life, and increase compliance with treatment.

[0004] Even among those receiving medication, there is still an unmet need. Currently, readily available and prescribed oral therapies take several weeks to be effective. The need for rapid treatment is well recognized and has led to approval. Everyday depressed patients still experience significant impairment while waiting for the full effects of treatment.

[0005] Furthermore, some patients are refractory to or resistant to existing ADT treatments and may not respond to one antidepressant monotherapy or, in some cases, combinations of antidepressants. Therefore, new approaches to treating major depressive disorder remain needed. Summary of the Invention [Problem to be solved by the invention]

[0006] The present invention provides a method of treating major depressive disorder, comprising administering to a human patient in need of treatment a therapeutically effective amount of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof. [Means for solving the problem]

[0007] In a further aspect, the present invention provides a method for treating major depressive disorder, comprising administering to a human patient in need of treatment a therapeutically effective amount of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, in combination with one or more antidepressants, optionally selected from selective serotonin reuptake inhibitors (SSRIs) and / or serotonin-norepinephrine reuptake inhibitors (SNRIs).

[0008] In a further aspect, the present invention provides a method for treating major depressive disorder, comprising administering to a human patient in need of treatment a therapeutically effective amount of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, in combination with a selective serotonin reuptake inhibitor (SSRI).

[0009] The present invention provides a method for treating major depressive disorder (MDD), comprising administering a therapeutically effective amount of centanafadine (CTN) or a pharmaceutically acceptable salt thereof to a human patient in need of treatment to effectively treat major depressive disorder (MDD), wherein centanafadine is suitably administered in a sustained-release formulation comprising a plurality of CTN beads, each of the plurality of CTN beads comprising a core granule containing CTN or a pharmaceutically acceptable salt thereof and an excipient, and the plurality of CTN beads comprises a mixture of one or more rapid-release (IR) beads, one or more sustained-release (SR) beads, and one or more delayed-release (DR) beads.

[0010] Centanafadine is a molecule with inhibitory activity at norepinephrine (NE), dopamine (DA), and serotonin (5-HT)-reuptake transporters and has been shown to be generally safe and well-tolerated with a low incidence of adverse events (AEs).

[0011] The present invention provides a method for treating major depressive disorder, comprising administering centanafadine sustained-release capsules as monotherapy to a patient in need of treatment.The present invention provides a method for treating major depressive disorder, comprising administering centanafadine sustained-release capsules as an adjunct to a selective serotonin reuptake inhibitor to a patient in need of treatment.

[0012] The present invention provides a method for alleviating the symptoms of major depressive disorder, comprising administering centanafadine sustained-release capsules as monotherapy to a patient in need of treatment.The present invention provides a method for alleviating the symptoms of major depressive disorder, comprising administering centanafadine sustained-release capsules as an adjunct to a selective serotonin reuptake inhibitor to a patient in need of treatment.

[0013] The present invention also provides a method for treating major depressive disorder, comprising administering to a patient in need thereof: a) a therapeutically effective amount of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane (CTN) or a pharmaceutically acceptable salt thereof; and b) one or more antidepressants selected from selective serotonin reuptake inhibitors (SSRIs), wherein the SSRI is selected from fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine, vilazodone, venlafaxine, desvenlafaxine, dapoxetine, vortioxetine, venlafaxine, and duloxetine; and The CTN is optionally administered in a sustained-release formulation comprising a plurality of CTN beads, wherein each of the plurality of CTN beads comprises a core granule containing CTN or a pharmaceutically acceptable salt thereof and excipients, and the plurality of CTN beads comprises a mixture of one or more rapid-release (IR) beads, one or more sustained-release (SR) beads, and one or more delayed-release (DR) beads; Methods of treatment are provided.

[0014] The present invention also provides a method for treating major depressive disorder, comprising administering to a patient in need of treatment a) a therapeutically effective amount of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane (CTN) or a pharmaceutically acceptable salt thereof, and b) one or more antidepressants selected from serotonin-norepinephrine reuptake inhibitors (SNRIs), wherein the CTN is administered in a sustained-release formulation comprising a plurality of CTN beads, each of which contains a core granule containing CTN or a pharmaceutically acceptable salt thereof and an excipient, and the plurality of CTN beads includes a mixture of one or more rapid-release (IR) beads, one or more sustained-release (SR) beads, and one or more delayed-release (DR) beads.

[0015] Methods for treating major depressive disorder (MDD) can include administering to a patient in need of treatment (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane (CTN) or a pharmaceutically acceptable salt thereof in combination with other antidepressants, including, but not limited to, benzodiazepines, anxiolytics, noradrenergic-specific serotonergic antidepressants (NaSSAs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs).

[0016] The present invention further provides (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof for use in the methods disclosed herein.

[0017] For the compositions, methods, and uses described herein, it is contemplated that any feature, including but not limited to components, compositional ranges thereof, substituents, conditions, and steps, may be selected from the various aspects, embodiments, and examples described herein.

[0018] Further aspects and advantages will become apparent to those skilled in the art upon review of the following detailed description in conjunction with the drawings. While the compositions, methods, and uses described herein are susceptible to embodiment in a variety of forms, the following description includes specific embodiments, with the understanding that the disclosure is illustrative and is not intended to limit the invention to the specific embodiments described herein. DETAILED DESCRIPTION OF THE INVENTION

[0019] This specification describes the use of centanafadine (CTN) or its pharmaceutically acceptable salts for the treatment of central nervous system disorders. CTN is classified as a BSC class I molecule with high solubility and permeability. In this specification, CTN should be understood to refer to centanafadine, but unless expressly stated otherwise, its pharmaceutically acceptable salts are also considered in addition to or as one or more substitutes for CTN in all methods, uses, and formulations described herein. Centanafadine [CAS 924012-43-1] is also known chemically as (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane or (+)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, and has the following structure: [ka] It is an unbalanced triple reuptake inhibitor with the strongest potency against the norepinephrine reuptake transporter (NET), six times less potency against the dopamine reuptake transporter (DAT), and fourteen times less potency against the serotonin reuptake transporter (SERT).

[0020] The present invention provides methods for treating major depressive disorder, comprising administering a therapeutically effective amount of centanafadine or a pharmaceutically acceptable salt thereof, where the centanafadine is optionally administered in a sustained-release formulation comprising a plurality of beads, as described herein. In some forms, the present invention provides centanafadine or a pharmaceutically acceptable salt thereof for use in the disclosed methods.

[0021] As used herein, the terms "centanafadine," "(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane," "(+)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane," and "CTN" are used interchangeably. As used herein, the term "centanafadine" includes less than 5, 3, 2, 1, 0.5, or 0.2% by weight of "(1S,5R)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane," as appropriate, based on 100% total weight of the compound.

[0022] The terms "(1S,5R)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane" and "(-)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane" are used interchangeably herein to refer to the (-)-enantiomer of CTN.

[0023] In some embodiments described herein involving administering centanafadine or a pharmaceutically acceptable salt thereof, the centanafadine may contain different amounts of other stereoisomers.

[0024] In any embodiment involving administering CTN or a pharmaceutically acceptable salt thereof, it is contemplated that the CTN is substantially free of (1S,5R)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane.

[0025] As used herein, "substantially free of (1S,5R)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane" or "substantially free of the corresponding (-) enantiomer" means that there is at least more (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane than the corresponding (-) enantiomer. "Substantially free of the corresponding (-) enantiomer" means, optionally, containing 5% w / w or less of the corresponding (-) enantiomer in free or pharmaceutically acceptable salt form, optionally containing 3% w / w or less of the corresponding (-) enantiomer in free or pharmaceutically acceptable salt form, optionally containing 2% w / w or less of the corresponding (-) enantiomer in free or pharmaceutically acceptable salt form, optionally containing 1% w / w or less of the corresponding (-) enantiomer in free or pharmaceutically acceptable salt form, optionally containing 0.5% w / w or less of the corresponding (-) enantiomer in free or pharmaceutically acceptable salt form, optionally containing 0.2% w / w or less of the corresponding (-) enantiomer in free or pharmaceutically acceptable salt form.

[0026] As used herein, any aspect or embodiment including "(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane" is contemplated to include or use the compound in any form, for example, as a free base or a pharmaceutically acceptable salt form, such as a pharmaceutically acceptable acid addition salt.

[0027] The term "pharmaceutically acceptable" generally means biologically or pharmacologically compatible for in vivo use in animals or humans, and, as appropriate, approved by a federal or state regulatory agency or listed in the United States Pharmacopoeia or other generally recognized pharmacopeia for use in animals, and particularly humans.

[0028] Pharmaceutically acceptable salts are known in the art and include salts that are physiologically acceptable in the dosages and forms in which they are administered. CTN is provided as CTN hydrochloride.

[0029] Any aspect or embodiment comprising "(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane" as used herein is also contemplated to include or use the compound in crystalline or amorphous form, including polymorphs, solvates (including hydrates), non-solvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compound, as well as mixtures thereof. "Crystalline form" and "polymorph" are used interchangeably herein and are meant to encompass all crystalline forms of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or 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 referenced.

[0030] As used herein, amounts, weight percentages, or ranges of CTN in pharmaceutical formulations (e.g., tablets, capsules, beads, core granules, etc.) and in any method or use disclosed herein are applicable not only to the CTN free base but also to its pharmaceutically acceptable salts, and therefore descriptions by weight should be considered as relating to the CTN free base, unless otherwise specified, and alternatively as descriptions applicable to the pharmaceutically acceptable salt forms. In each description, CTN as the hydrochloride salt is specifically envisioned.

[0031] The crystalline and amorphous forms of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane can be used in any combination, or in a form that is substantially free of one or more of the other crystalline forms, or free of the amorphous form.

[0032] As used herein, "substantially free of other polymorphic forms" means that the crystalline material contains no more than 20% other crystalline forms, optionally no more than 10% w / w other crystalline forms, optionally no more than 5% w / w other crystalline forms, or no more than 2% w / w other crystalline forms, optionally no more than 1% w / w other crystalline forms.

[0033] (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane can be provided or used in the form of a prodrug. Prodrugs are considered to be covalently bonded carriers that release the active parent drug in vivo.

[0034] (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane can be synthesized as described in U.S. Pat. No. 8,461,196, International Publication No. WO2007 / 016155, International Publication No. WO2013 / 019271, International Publication No. WO2021 / 075494, or Japanese Patent No. 2019147794A, each of which is incorporated herein by reference in its entirety.

[0035] As used herein, the term "escitalopram," whose chemical name is (S)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile, is the S-enantiomer of citalopram. Escitalopram is a selective serotonin reuptake inhibitor. The term "escitalopram" also includes polymorphs, hydrates, solvates, and amorphous forms of escitalopram and its pharmaceutically acceptable salts. Escitalopram oxalate is currently marketed in the United States under the name Lexapro for the treatment of major depressive disorder and generalized anxiety disorder. TM It is sold as.

[0036] As used herein, the term "patient" includes human or non-human (i.e., animal) patients. In some embodiments, patient includes both humans and non-humans. In some embodiments, patient refers to a non-human. In other embodiments, patient refers to a human.

[0037] As used herein, "therapeutically effective amount" or "therapeutic dose" refers to an amount effective to produce therapeutic effects, including, when administered to a human or non-human patient, any one or more of the following: prevention of symptoms, amelioration of symptoms, and delay of the onset of symptoms. Depressive symptoms include low mood, decreased interest in activities, psychomotor slowness or agitation, appetite changes, poor concentration or indecisiveness, excessive feelings of guilt or worthlessness, and suicidal ideation, and can occur in the context of depression, bipolar disorder, mood disorders due to general medical conditions, substance-induced mood disorders, and other unspecified mood disorders, and can also be present in association with various other mental disorders, including, but not limited to, psychotic disorders, cognitive disorders, eating disorders, anxiety disorders, and personality disorders.

[0038] The specific dosage of a substance administered to achieve a therapeutic effect will, of course, depend on the particular circumstances surrounding the case, such as the specific substance administered, the route of administration, the condition being treated, and the individual being treated.

[0039] As used herein, the term "improvement of depressive symptoms" refers to a gradual decrease in one or more depressive symptoms selected from avoidance, isolation, social withdrawal, anxiety, and suicidality, and an increase in engagement in previously enjoyed activities and activities shown to improve mood.

[0040] The term "palliative" as used herein means to make less severe, lessen, alleviate, relieve, ease, or make manageable.

[0041] The term "alleviate" as used here means to make less severe, lessen, alleviate, ease, or make manageable.

[0042] As used herein, the term "concurrently" means that the compounds are administered "at the same time," at the same time, or in the same composition. In embodiments, the compounds can be administered simultaneously. In embodiments, the compounds can be administered in the same composition.

[0043] As used herein, the term "sequential" means that the compounds are administered in a particular order or sequence.

[0044] In one embodiment, centanafadine and escitalopram can be administered simultaneously or in a single oral dosage form containing both active ingredients.In another related embodiment, centanafadine and escitalopram can be administered simultaneously or in two or more oral dosage forms containing one or both active ingredients.Optionally, the single dosage form or separate dosage forms are a once-daily regimen, that is, administering each dosage form once a day is sufficient to treat the desired CNS disorder.In yet another embodiment, centanafadine and escitalopram can be administered sequentially.

[0045] In yet another embodiment, centanafadine and escitalopram may be administered at different times of the day, for example, centanafadine may be administered in the morning and escitalopram may be administered in the evening. In yet another embodiment, centanafadine and escitalopram may be administered with food. In yet another embodiment, centanafadine and escitalopram may be administered without food. In yet another embodiment, centanafadine may be administered with food and escitalopram may be administered without food. Alternatively, in another embodiment, centanafadine may be administered without food and escitalopram may be administered with food.

[0046] If a patient needs to discontinue treatment with centanafadine and escitalopram, to minimize withdrawal symptoms, the patient can gradually taper off the medication by gradually reducing the dosage until the body adjusts to lower levels of the medication.

[0047] As used herein, the term "comprising" indicates that other agents, elements, steps or features are potentially included in addition to those specified.

[0048] As used herein, the term "treatment" includes one or more of the following: (a) reducing or alleviating at least one symptom of major depressive disorder in a subject; (b) reducing or alleviating the intensity and / or duration of symptoms of major depressive disorder experienced by the subject; and (c) preventing or delaying the onset (i.e., the period before clinical symptoms appear) of major depressive disorder and / or reducing the risk of developing or worsening major depressive disorder;

[0049] In jurisdictions that prohibit patents on methods performed on the human body, "administering" a composition to a human subject shall mean only prescribing a controlled substance for self-administration by any technique (oral, 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 patents on methods performed on the human body, "administering" a composition includes both the method and the aforementioned activity performed on the human body.

[0050] Patients with "treatment-resistant depression" include: (1) those who do not respond to a standard dose of an antidepressant (e.g., an SSRI) given for at least 6 consecutive weeks (i.e., significantly better than placebo in a double-blind study); and (2) those who do not respond to a standard dose of an antidepressant (e.g., an SSRI) given for at least 12 consecutive weeks (monotherapy).

[0051] The term "sustained release dosage form" used herein is synonymous with sustained release.Dosage form is characterized by its overall release profile, for example, the profile resulting from multiple regions present in the formulation.Dosage form that exhibits sustained release properties can be characterized as a sustained release formulation even if it further comprises a fast-release region, such as beads, in addition to a sustained release formulation region.Similarly, dosage form that exhibits sustained release properties can be characterized as a sustained release formulation even if it further comprises a delayed-release region, such as beads, in addition to a sustained release formulation region (for example, beads).

[0052] As used herein, the terms "sustained release," "extended release," "modified release," and "extended or modified release" refer to a formulation that provides a lower peak plasma concentration and a longer T than a fast release formulation. max This refers to the release of the active ingredient over a long period of time.

[0053] As used herein, "XR" stands for extended release.

[0054] As used herein, "QD" means "once daily."

[0055] As used herein, "adjunctive" refers to another treatment used in conjunction with the primary treatment to supplement the primary treatment, or administered in combination with or simultaneously with the primary treatment. For example, the primary treatment with centanafadine or a pharmaceutically acceptable salt thereof can be administered simultaneously with the secondary treatment, or on another schedule during the treatment period.

[0056] As used herein, the term "co-administration" refers to the administration of two or more drugs within 24 hours, for example, as part of a clinical treatment plan. Optionally, "co-administration" refers to the administration of two or more drugs within 2 hours. Optionally, "co-administration" refers to the administration of two or more drugs within 30 minutes. Optionally, "co-administration" refers to the administration of two or more drugs within 15 minutes. Optionally, "co-administration" refers to administration at the same time, either as part of a single formulation or as multiple formulations administered by the same or different routes.

[0057] As used herein, an adverse event (AE) refers to an undesired medical occurrence in a patient that is not necessarily causally related to the disclosed treatment. Adverse events do not include information recorded in the medical history at screening for a pre-planned procedure in which the underlying disease was known and no exacerbation occurred.

[0058] An adverse reaction is an unwanted and unintended reaction to any dose of the investigational medicinal product (IMP) administered. AEs are rated on a 3-point scale, with 1 being mild (e.g., causing discomfort but not interfering with daily activities), 2 being moderate (e.g., discomfort that reduces or impacts normal daily activities), and 3 being severe (e.g., unable to work or carry out normal daily activities).

[0059] A suspected adverse reaction is an AE where there is a high probability that an IMP caused the AE. For the purposes of investigational new drug (IND) safety reporting, "reasonable possibility" means that there is evidence suggesting a causal relationship between the IMP and the AE. A suspected adverse reaction means there is low certainty about the causal relationship.

[0060] As used herein, the term "treatment-emergent adverse event" (TEAE) is defined as any adverse event (AE) that occurs after the start date of double-blind IMP treatment. More specifically, a TEAE is any AE that began after the start of double-blind IMP treatment or that continues from baseline and is worsening, serious, IMP-related, or led to death, discontinuation, interruption, or reduction of IMP.

[0061] As used herein, the term "serious adverse event" (SAE) includes any event that leads to any of the following outcomes: death. Life-threatening events, i.e., events that put the subject at immediate risk of death when the event occurred (does not include events that may have caused death if they had occurred in a more severe form). Persistent or significant incapacity / impairment or significant interruption in ability to perform normal life functions. Requiring hospitalization or prolonged hospitalization. Congenital anomalies / birth defects. Other medically significant events that, based on sound medical judgment, may endanger the subject and require medical or surgical intervention to prevent any of the above consequences, such as allergic bronchospasm requiring intensive care in an emergency room or at home, blood disorders or seizures not resulting in hospitalization, or the development of drug addiction or substance abuse.

[0062] As used herein, "non-serious adverse events" refers to any AE that does not meet the criteria for a "serious" AE. As used herein, "adverse events of particular interest" refers to events of interest related to a particular product / IMP or product class that the sponsor wishes to monitor closely.

[0063] Extended-release centanafadine (CTN XR) formulation The methods disclosed herein can include administering CTN or a pharmaceutically acceptable salt thereof in a sustained-release formulation comprising a plurality of CTN beads, each of which comprises a core granule containing CTN or a pharmaceutically acceptable salt thereof and an excipient, and the plurality of CTN beads includes a mixture of one or more rapid-release (IR) beads, one or more sustained-release (SR) beads, and one or more delayed-release (DR) beads. In the following description, CTN beads are described as an example of such a formulation type. The characteristics of the described formulation, such as the ratio of different bead types, also apply to unit dosage forms, such as a collection of beads arranged in a capsule.

[0064] Suitable sustained-release CTN formulations are described in U.S. Patent Application No. 17 / 677,726, filed February 22, 2022, the disclosure of which is incorporated herein by reference in its entirety.

[0065] The disclosed dosage forms allow the appropriate CTN dose to be measured prior to administration, or the formulations can be packaged in unit dosage form, e.g., capsules, sachets, etc. Alternatively, the formulations can be molded into single dosage forms, e.g., compressed into a single unit form, e.g., a tablet.

[0066] A sustained-release formulation can include multiple CTN-containing regions, and the multiple CTN regions can optionally include one or more release characteristics selected from, for example, delayed release, sustained release, fast release, and delayed-sustained release. These regions can be physically associated or separated. For example, one type of dosage form includes multiple CTN-containing beads (CTN beads), each of which includes a core granule and an excipient. The multiple CTN beads can include one or more types of beads selected from fast-release beads, sustained-release beads, and delayed-release beads, and optionally a combination of one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads.

[0067] The sustained release formulation can be provided in unit dosage form, for example, as a collection of beads disposed within a capsule shell or as a collection of beads disposed within a sachet. In another type of embodiment, a collection of granules is compressed into tablet form, with or without extragranular components such as extragranular disintegrants. Other forms will be apparent to those skilled in the art in light of the disclosure herein.

[0068] Also provided for the methods and uses described herein are formulations comprising CTN and excipients, wherein the pharmaceutical formulation has a bimodal in vivo absorption profile.

[0069] As described above, dosage forms according to the present disclosure can include multiple CTN beads containing 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 can include at least some beads with a delayed-release or delayed-sustained-release coating, at least some beads with a sustained-release coating, and at least some fast-release beads. Such dosage forms have been shown to exhibit favorable pharmacokinetics, are suitable for administration to pediatric subjects, and are suitable for once-daily administration. Without wishing to be bound by theory, it is believed that the pharmacokinetics are influenced by multiple CTN beads with a combination of bead types, such as fast-release, sustained-release, and delayed-release.

[0070] As used herein, the term "wt. %" refers to a weight percentage based on the total weight of what is being described, such as the core granules, coating, or entire beads, as the context or explicitly states. Unless otherwise specified, "wt. %" is intended to represent a weight percentage based on dry weight (such as the core granules after drying). Unless otherwise specified, the terms "wt. %" and "% by weight" are used interchangeably herein.

[0071] While the discussion herein refers to beads, and beads made by extrusion or spheronization have certain advantages, such as being more uniform and sized, particles of any size or shape made by other processes are considered alternatives as well, and monolithic unit forms are also considered alternatives.

[0072] All ranges provided herein include all possible subsets of ranges and all combinations of such subset ranges. By default, ranges include the specified endpoints unless otherwise specified. When a range of values ​​is provided, it is understood that each intermediate value between the upper and lower limits of that range, as well as any other specified or intermediate value within that specified range, is included within the disclosed range. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are included within the disclosed range, subject to any specifically excluded limit in the stated range. When a stated range includes one or both of the limits, it is contemplated that ranges excluding one or both of those included limits are also part of the disclosure.

[0073] Bead molding In some embodiments, 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 weight ratio of the CTN can be in the range of about 1:100 to about 1:1 for a collection of one or more fast-release beads and one or more sustained-release beads. In some embodiments, the weight ratio of the CTN can be in the range of about 1:50 to about 1:1 for a collection of one or more fast-release beads and one or more sustained-release beads, or in the range of about 1:20 to about 1:1, or in the range of about 1:15 to about 1:1, e.g., 1:10.

[0074] In some embodiments, 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 weight ratio of the CTN between the collection of one or more fast-release beads and the collection of one or more delayed-release beads ranges from about 1:100 to about 1:1. In some embodiments, the weight ratio of the CTN between the collection of one or more fast-release beads and the collection of one or more delayed-release beads ranges 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., 1:10.

[0075] In some embodiments, 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 weight ratio of the CTN of one or more delayed-release bead populations to one or more sustained-release bead populations can be 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, or about 1.5:1 to about 1:1.5, e.g., about 1:1.

[0076] In some embodiments, 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 weight ratio of the CTN can be in the range of about 1:100 to about 1:1 for the collection of one or more fast-release beads and the collection of one or more delayed-sustained release beads. In some embodiments, the weight ratio of the CTN can be in the range of about 1:50 to about 1:1 for the collection of one or more fast-release beads and the collection of one or more delayed-sustained release beads, or in the range of about 1:20 to about 1:1, or in the range of about 1:15 to about 1:1, e.g., in the range of 1:10.

[0077] In some embodiments, the plurality of beads includes 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 in the one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads can be in a ratio ranging from about 0.1-1:1-20:1-20 parts by weight based on the weight of CTN. In some embodiments, the ratio of CTN in the one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads can be in a ratio ranging from about 0.5-1:5-20:5-20 parts by weight based on the weight of CTN. In some embodiments, the ratio of CTN or a pharmaceutically acceptable salt thereof in the one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads can be in a ratio ranging from about 0.7-1.3:3-6:3-6 parts by weight based on the weight of CTN. In an embodiment, 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.

[0078] In some embodiments, 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 the one or more fast-release beads, one or more sustained-release beads, and one or more delayed-sustained-release beads can be present in a ratio ranging from about 0.1-1:1-20:1-20 parts by weight based on the weight of CTN. In some embodiments, the ratio of CTN or a pharmaceutically acceptable salt thereof in the one or more fast-release beads, one or more sustained-release beads, and one or more delayed-sustained-release beads can be present in a ratio ranging from about 0.5-1:5-20:5-20 parts by weight based on the weight of CTN. In some embodiments, the ratio of CTN or a pharmaceutically acceptable salt thereof in the one or more fast-release beads, one or more sustained-release beads, and one or more delayed-sustained-release beads can be present in a ratio ranging from about 0.7-1.3:3-6:3-6 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-sustained-release beads can be present 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 in one or more fast-release beads, one or more sustained-release beads, and one or more delayed-sustained-release beads can be present in a ratio of about 1:3.6:3.6 parts by weight based on the weight of CTN.

[0079] In some embodiments, the fast-release beads can 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 are present in the dosage form 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 embodiments, the fast-release beads are present in the dosage form in an amount ranging from about 1% to about 50%, based on the total weight of the plurality of CTN beads. In embodiments, the fast-release beads are present in the dosage form in an amount ranging from about 1% to about 25% based on the total weight of the plurality of CTN beads. In embodiments, the fast-release beads are present in the dosage form 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 can be present in the dosage form 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 load in the beads is about 40% to about 60% by weight, e.g., 50% by weight. In some embodiments, the fast-release beads can be present in the dosage form 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 load 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 dosage form in an amount ranging from about 18% to about 28% based on the total weight of the plurality of CTN beads.

[0080] 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 fast-release beads or bead cores can 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 can include first fast-release beads or bead cores in which 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 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 can include bead cores with one or more coatings on the bead cores, each 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.

[0081] In some embodiments, the sustained release beads can 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 are present in the 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 are present in the 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 are present in the 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.

[0082] In some embodiments, the sustained release beads can 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 can 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 can 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 can contain CTN in an amount ranging from 50% to 70% by weight, based on the total weight of the sustained release beads.

[0083] In some embodiments, the delayed-release beads can 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 are present in the dosage form 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 are present in the 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 delayed-release beads are present in the dosage form 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.

[0084] In some embodiments, the delayed-release beads can 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 can 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 can 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 can contain CTN in an amount ranging from 50% to 70% by weight, based on the total weight of the delayed-release beads.

[0085] In some embodiments, fast-release beads can be present in the formulation or dosage form in an amount ranging from about 1% to about 10% by weight of the formulation or dosage form, sustained-release beads can be present in the formulation or dosage form in an amount ranging from about 45% to about 55% by weight of the formulation or dosage form, and delayed-release beads can be present in the formulation or dosage form in an amount ranging from about 40% to about 50% by weight of the formulation or dosage form. In some embodiments, fast-release beads can be present in the formulation or dosage form in an amount ranging from about 4% to about 28% by weight of the formulation or dosage form, sustained-release beads can be present in the formulation or dosage form in an amount ranging from about 15% to about 40% by weight of the formulation or dosage form, and delayed-release beads can be present in the formulation or dosage form in an amount ranging from about 30% to about 65% by weight of the formulation or dosage form.

[0086] In some embodiments, the fast-release beads can 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 can 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) can 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. Such embodiments are particularly contemplated when the drug loading in each bead type is about 5% to about 10%, about 45% to about 55%, and about 45% to about 55% by weight, respectively, based on the total weight of the beads. In embodiments, the fast-release beads can 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 can 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 can 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. Such embodiments are particularly contemplated when the drug load in each bead type is about 45% to about 55% by weight.

[0087] Nuclear Bead Molding Each of the plurality of CTN beads includes a core granule. The core granule includes CTN and excipients. The CTN bead can consist of the uncoated core granule itself. As further described below, the CTN bead includes a core granule and one or more coatings.

[0088] In some embodiments, the core granules can be characterized by having a particle size distribution. In embodiments, at least some of the core granules of a plurality of CTN beads, or all of the core granules, can have a core granule 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 granules of a plurality of CTN beads have a core granule 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 about 0.85 mm, or about 0.5 mm to about 0.71 mm. In an embodiment, at least a portion of the core granules of the plurality of CTN beads have a core granule size of about 0.5 mm to about 0.71 mm. In an embodiment, the core granules of the plurality of CTN beads have a core granule size of about 0.5 mm to about 0.71 mm. The size of the core granules can be selected, for example, by sieving to eliminate particles having sizes outside the desired range. In an embodiment, the particle size distribution of the core granules can be characterized by at least 60% by weight of the core granules 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 granules may be characterized by at least 60% by weight of the core granules 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 about 0.85 mm, or about 0.5 mm to about 0.71 mm. In embodiments, the particle size distribution of the core granules is characterized by at least 60% by weight of the core granules having a particle size in the range of about 0.5 mm to about 0.71 mm. In some embodiments, the particle size distribution of the core granules is characterized by at least 80% by weight of the core granules 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 granules is characterized in that at least 80% by weight of the core granules 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 embodiments, the particle size distribution of the core granules is characterized in that at least 80% by weight of the core granules have a particle size in the range of about 0.5 mm to about 0.71 mm. In some embodiments, the particle size distribution of the core granules is characterized in that at least 90% by weight of the core granules 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 granules is characterized in that at least 90% by weight of the core granules 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 some embodiments, the particle size distribution of the core granules is characterized in that at least 90% by weight of the core granules have a particle size in the range of about 0.5 mm to about 0.71 mm. In some embodiments, the plurality of CTN beads can have an average particle size (diameter) in the range of about 0.2 mm to about 2.8 mm. For example, the CTN beads can 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 can have an average particle size (diameter) ranging from about 0.5 mm to about 0.71 mm.

[0089] The amount of CTN in the core granule 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 granule 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 granule 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 granule 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 granule containing CTN in an amount of about 50% by weight. For example, the rapid-release beads can include core granules 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 includes core granules 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 includes core granules 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 includes core granules containing CTN in an amount ranging from about 75% to about 85% by weight. In some embodiments, at least some of the plurality of CTN beads include a core granule containing CTN in an amount of about 80% by weight. For example, sustained-release beads can include a core granule containing CTN in an amount in the range of about 80% by weight. For example, delayed-release beads can include a core granule containing CTN in an amount in the range of about 80% by weight.

[0090] The core granules 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 embodiments, the dosage form comprising the pharmaceutical formulation may not include a disintegrant.

[0091] Fillers include, but are not limited to, lactose, saccharose, glucose, starch, microcrystalline cellulose, microfine cellulose, mannitol, sorbitol, calcium hydrogen phosphate, aluminum silicate, amorphous silica, sodium chloride, starch, and dibasic calcium phosphate anhydrous. In some embodiments, the filler can absorb water but is not water-soluble. In some embodiments, the filler is a spheronization aid. Examples of spheronization aids include one or more of crospovidone, carrageenan, chitosan, pectic acid, glycerides, β-CD, cellulose derivatives, microcrystalline cellulose, powdered cellulose, polyplasdone crospovidone, polyethylene oxide, etc. In one embodiment, the filler includes microcrystalline cellulose.

[0092] Binders include, but are not limited to, cellulose ethers, methylcellulose, ethylcellulose, hydroxyethylcellulose, propylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose, e.g., hypromellose 2910, METHOCELTM E-5 [CAS 9004-65-3], Sigma or DuPont TM Examples of binders include hydroxypropyl methylcellulose (same as HPMC available from Co., Ltd.), carboxymethylcellulose, starch, pregelatinized starch, acacia, tragacanth, gelatin, polyvinylpyrrolidone (povidone, PVP), cross-linked polyvinylpyrrolidone, sodium alginate, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose. In some embodiments, the binder is selected from wet binders. In some embodiments, the binder is selected from cellulose ethers, such as hypromellose.

[0093] Surfactants include, but are not limited to, anionic surfactants such as sodium lauryl sulfate, sodium deoxycholate, dioctyl sodium sulfosuccinate, sodium stearyl fumarate, nonionic surfactants such as polyoxyethylene ethers, polysorbate 80, and cationic surfactants such as quaternary ammonium compounds. In some embodiments, the surfactant is selected from anionic surfactants such as, for example, sodium lauryl sulfate.

[0094] Disintegrants include, but are not limited to, starch, cross-linked sodium carboxymethylcellulose, croscarmellose sodium, croscarmellose calcium, cross-linked polyvinylpyrrolidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, and the like.

[0095] Glidants 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, stearol, talc, and the like.

[0096] Lubricants include stearic acid, magnesium stearate, calcium stearate, aluminum stearate, siliconized talc, and the like.

[0097] 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). 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 granules may include an excipient comprising microcrystalline cellulose.

[0098] The amount of filler in the core granule is not particularly limited. In some embodiments, the amount of filler (e.g., crystalline cellulose) can be in the range of 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.

[0099] The amount of binder in the core granules 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% by weight to about 10% by weight, or about 2% by weight to about 8% by weight, or about 4% by weight to about 6% by weight, for example, about 5% by weight.

[0100] The amount of surfactant, for example, as a processing aid, in the core granules 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.

[0101] coating In some embodiments, the sustained release formulations disclosed herein comprise a plurality of beads, at least some of which are coated. In some embodiments, at least some of the beads can be uncoated. In embodiments, the coating can 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 can comprise a delayed-release coating. In some embodiments, at least some of the beads can comprise a sustained-release coating. In embodiments, at least some of the beads can comprise a delayed-sustained-release coating.

[0102] The coating materials, e.g., polymers, disclosed herein may be delayed-release coatings. In embodiments, delayed-release coatings dissolve in intestinal fluids at pH levels higher than those of the stomach, e.g., pH 4.5 or higher, such as in the small intestine, thereby releasing the active agent in or after the small intestine and substantially preventing release in the upper gastrointestinal tract. In some embodiments, the enteric coating begins to dissolve in aqueous solutions having a pH of about 4.5 to about 5.5. In some embodiments, the delayed-release material rapidly dissolves in aqueous solutions having a pH of about 5. In another type of embodiment, the delayed-release material rapidly dissolves in aqueous solutions having a pH of about 5.5. For example, a pH-sensitive material can be selected that does not significantly dissolve until the formulation has left 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 some embodiments, 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 to the distal portion of the small intestine or colon. In some embodiments, the delayed-release material is insoluble in water and gastric fluids, but instead swells to provide a membrane through which the CTN active agent can diffuse. Insoluble polymers can also be selected to swell at a specific pH threshold, for example, a pH of at least 7, or at least 7.2, or at least 7.4, for example, to target release to the distal portion of the small intestine or colon.

[0103] Delayed-release coating materials include, but are not limited to, one or more of the following: cross-linked polyvinylpyrrolidone; non-cross-linked polyvinylpyrrolidone; hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate succinate, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate; starch acetate phthalate; polyvinyl acetate phthalate; carboxymethylcellulose; methylcellulose phthalate; methylcellulose succinate; methylcellulose phthalate succinate; methylcellulose phthalate half ester; ethylcellulose phthalate. sodium alginate; galactomannone; carboxypolymethylene; sodium carboxymethyl starch; copolymers of acrylic acid and / or methacrylic acid with a monomer selected from: 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 of Essen, Nord Rhine-Westphalia, Germany. TM-L and -S series (including L 100-55, L 30 D-55, L 100, S 100, L 12.5, and S 12.5); polyvinyl acetate; fats; oils; waxes; fatty alcohols; shellac; zein; gluten; ethyl acrylate-maleic anhydride copolymer; maleic anhydride-vinyl methyl ether copolymer; styrene-maleic acid copolymer; 2-ethylhexyl acrylate-maleic anhydride; crotonic acid-vinyl acetate copolymer; glutamic acid / glutamic acid ester copolymer; carboxymethylethylcellulose glycerol monooctanoate; polyarginine; polyethylene; polypropylene; polyethylene oxide; polyethylene terephthalate; polyvinyl isobutyl ether; polyvinyl chloride; and polyurethane.

[0104] Combinations of delayed-release coatings may also be used. In one embodiment, the delayed-release coating dissolves at a pH of 7.0 or higher, or 7.2 or higher, or 7.4 or higher, for example, to provide release in the colon. For example, the delayed-release coating can be selected from copolymers of methacrylic acid and methyl methacrylate and copolymers of methacrylic acid and ethyl acrylate. In some embodiments, the delayed-release coating can 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 embodiments, the delayed-release coating may include one or more materials selected from copolymers of methacrylic acid, methyl methacrylate, and methyl acrylate, and methacrylic acid-acrylate copolymers. In embodiments, the delayed-release coating may include a copolymer of methyl arylate, methyl methacrylate, and methacrylic acid, for example, in a molar ratio of about 7:3:1 (e.g., Eudragit TM FS 30D). Eudragit TM FS 30D 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 comprises a cationic copolymer of ethyl acrylate, methyl methacrylate, and methacrylic acid esters with quaternary ammonium groups (e.g., Eudragit TM RL and Eudragit TM RS polymers) are not included. TM RL 30D and EudragitTM RS 30D 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.

[0105] In some embodiments, the delayed-release coating can also provide sustained release of CTN. In some embodiments, the delayed-release coating includes an anionic polymer, optionally containing carboxylate moieties. In some embodiments, the delayed-release coating is a coating based on 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 The beads contain poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) and also have sustained-release capabilities. Without being bound by any particular theory, the poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) polymer is anionic and has negatively charged carboxyl groups (the ratio of carboxyl groups to ester groups is approximately 1:10), and centanafadine is a positively charged secondary amine; therefore, the polymer may affect the release rate of centanafadine from the beads through ionic interactions.

[0106] Examples of delayed-release coatings are disclosed in U.S. Pat. No. 5,225,202, and include coatings such as beeswax and glyceryl monostearate; beeswax, shellac, and cellulose; and cetyl alcohol, mastic, 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); copolymer of methacrylic acid and methacrylic acid methyl ester (Eudragit TMPolymers), or neutral copolymers of polymethacrylates with 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, shellac and shellac derivatives, and cellulose acid phthalates (e.g., those with free carboxyl content). For a description of suitable enteric coating compositions, see also 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).

[0107] The coating materials disclosed herein, such as polymers, may also 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 substance capable of providing sustained release of CTN can be used in accordance with the present invention. In some embodiments, the sustained-release coating may include one or more materials selected from ethyl cellulose, alkyl celluloses such as acrylic and methacrylic acid polymers and copolymers, and cellulose ethers, particularly hydroxyalkyl celluloses (particularly hydroxypropylmethylcellulose) and carboxyalkyl celluloses. Acrylic and methacrylic acid polymers and copolymers may include methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylate, ethyl acrylate, trimethylammonium ethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymers, polyacrylic acid, polymethacrylic acid, methacrylic acid alkylamine copolymers, polymethyl methacrylate, polymethacrylic anhydride, polymethacrylate, polyacrylamide, polymethacrylic anhydride, and glycidyl methacrylate copolymers. In some embodiments, the sustained release coating material is insoluble in water.

[0108] In some embodiments, the sustained-release coating may include one or more materials selected from alkyl celluloses such as ethyl cellulose, acrylic acid polymers, methacrylic acid polymers, acrylic acid copolymers, methacrylic acid copolymers, cellulose ethers, hydroxyalkyl celluloses (particularly hydroxypropylmethylcellulose), and carboxyalkyl celluloses. In embodiments, the sustained-release coating may include one or more materials selected from hydroxyalkyl celluloses, carboxyalkyl celluloses, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylate, ethyl acrylate, trimethylammonium ethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymers, polyacrylic acid, polymethacrylic acid, methacrylic acid alkylamine copolymers, polymethyl methacrylate, polymethacrylic acid (anhydride), polymethacrylate, polyacrylamide, polymethacrylic acid anhydride, and glycidyl methacrylate copolymers. In some embodiments, the sustained release polymer can include 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 can include, for example, poly[ethyl acrylate, methyl methacrylate] (e.g., Eudragit) in a molar ratio of about 2:1. TM In an embodiment, the sustained release coating may include EUDRAGIT RL30D, RS30D, NE30D, NM30D, available from Evonik Industries. TM The formulation may contain one or more materials selected from the -RL, -RS, -NE, and -NM series. A sustained release coating may also be used in combination. TM NM30D [CAS 9010-88-4] and Eudragit TMNE30D [CAS 9010-88-2] is an aqueous dispersion of a neutral copolymer based on ethyl acrylate and methacrylate, with a polymer content of about 30%, sold by Evonik Industries. In an embodiment, the sustained release polymer is ethyl cellulose, e.g., DuPont TM Aquacoat available from TM An ECD30D coating may be included.

[0109] 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 some embodiments, 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 FS30D) may contain, for example, in the range of 5% to 30% by weight, based on the dry polymer weight, of a plasticizer, such as PlasACRYL available from Evonik Industries. TM An anti-adhesion system containing about 8% to about 12% by weight of T20, glycerol monostearate, triethyl citrate, and polysorbate 80, with a solids content of about 20%, is effective.

[0110] As is known in the art, one or more anti-adherents may also be added to the enteric coating mixture to reduce film stickiness and prevent clumping. Examples of anti-adherents include talc, glyceryl monostearate, fumed silica (e.g., AEROSIL® from Evonik Industries), and the like. TM 200), precipitated silica (e.g. SIPERNATTM PQ), magnesium stearate, and the like. The anti-blocking agent can be used in any suitable amount, for example, in the range of about 10% to 100% by 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, based on the dry polymer 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 some embodiments, the amount of talc is in the range of 1% to about 10% by weight, based on the dry polymer weight.

[0111] As is known in the art, one or more surfactants can also be added to the delayed-release and / or sustained-release coatings to improve substrate wetting and / or stabilize the suspension, such as, for example, polysorbate 80, sorbitan monooleate, sodium dodecyl sulfate, and the like.

[0112] The delayed-release coating and / or sustained-release coating can be formed by any suitable process. Coating processes include pan coating, fluidized-bed coating, and dry coating (thermal dry coating, electrostatic dry coating, etc.). 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 formulation in a pan coater or fluidized-bed dryer and dried with hot air. For example, in the Wurster fluidized-bed coating process, the coating liquid is sprayed from the bottom of the fluidized-bed apparatus; alternatively, the coating liquid is applied by top spray, and alternatively, by tangential spray.

[0113] The amount of delayed-release coating applied is an amount sufficient to achieve the desired release profile. For example, in one embodiment, the amount of delayed-release coating is determined to be in accordance with the United States Pharmacopoeia (USP) for delayed-release dosage forms 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 in an amount sufficient to meet the requirements (USP 43-NF 38 2S). In another embodiment, the formulation is in an amount sufficient to meet the requirements (USP 43-NF 38 2S section, for example). <711> The buffer solution is sufficient to release at least 80% of the active substance using the dissolution test method of

[0114] In some embodiments, the median amount of delayed-release coating disposed on the core granules is at least 10% by weight of the total weight of the CTN beads. In some embodiments, the median amount of delayed-release coating disposed on the core granules is 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, or about 12% to about 50% by weight, or about 12% to about 35% by weight, based on the total weight of the CTN beads. In some embodiments, the median amount of delayed-release coating disposed on the core granules is in the range of about 15% to about 45% by weight, based on the total weight of the CTN beads.

[0115] In some embodiments, the median amount of sustained-release coating disposed on the core granules is at least 5% by weight of the total weight of the coated CTN beads. In some embodiments, the median amount of sustained-release coating disposed on the core granules is 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 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 coated CTN beads. In some embodiments, the median amount of sustained-release coating disposed on the core granules is about 20% to about 40% by weight, based on the total weight of the coated CTN beads.

[0116] In some embodiments, the median amount of sustained-release coating disposed on the core granules is at least 5% by weight gain based on the weight of the entire uncoated CTN beads. In some embodiments, the median amount of sustained-release coating disposed on the core granules 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 weight of the entire uncoated CTN beads. In some embodiments, the median amount of sustained-release coating disposed on the core granules is about 20% to about 40% by weight based on the weight of the entire uncoated CTN beads.

[0117] Additional lubricants (glidants, anti-adherents) can be added to the coated beads in powder form. Anti-adherents include, for example, talc, glyceryl monostearate, fumed silica (e.g., AEROSIL TM 200), precipitated silica (e.g. SIPERNAT TM For example, talc powder can be added to the coated beads in an amount of 0.1% to about 3% by weight based on the total weight of the beads.

[0118] Additionally, the coatings disclosed herein can further include a pore-forming agent. The release rate of CTN through a release coating can be reduced or increased by adding a pore-forming agent to the coating. Pore-forming agents are often hydrophilic polymers that dissolve in water and / or gastric fluids to form pores in the coating layer. The amount and type of pore-forming agent can be selected to affect the release profile and achieve a desired release profile. In embodiments, the pore-forming agent can 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.

[0119] In embodiments, the pore-forming agent can comprise one or more materials selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyvinylpyrrolidone. In some embodiments, the pore-forming agent comprises hydroxypropyl methylcellulose. In some embodiments, the pore-forming agent does not comprise polyvinylpyrrolidone. In some embodiments, when the release coating comprises ethylcellulose, the pore-forming agent does not comprise polyvinylpyrrolidone. The pore-forming agent can be present in the release coating in an amount of about 5 wt% or more, or about 10 wt% or more, or about 13 wt% or more, or about 15 wt% or more, or in a range of about 5 wt% to about 20 wt%, based on the total weight of the coating. In some embodiments, the pore-forming agent is present in an amount of about 15 wt%, or less than 50 wt%, or less than 20 wt%, based on the total weight of the coating, or in a range of about 1 wt% to about 16 wt%, or about 1 wt% to about 12 wt% based on the total weight of the coating.

[0120] It is also contemplated herein that at least some or all of the plurality of beads may include a coating, such as a seal coating, that includes only a soluble polymer that does not affect the release of CTN from the formulation. In embodiments, the seal coating may include hydroxypropyl methylcellulose. In embodiments, the core beads may be coated with the seal coating before other coatings. In embodiments, at least some of the core granules are seal coated.

[0121] In some embodiments, the pharmaceutical formulation may include a plurality of CTN beads enclosed in one or more containers selected from, for example, capsules, sachets, and stick packs. In some embodiments, the pharmaceutical formulation includes a plurality of CTN beads enclosed in a capsule. Soft capsules and hard capsules are known. In some embodiments, the capsule is a hard capsule, such as a gelatin capsule or a vegetable-based hard capsule.

[0122] Thus, for example, some embodiments combining various features described above include pharmaceutical formulations comprising a plurality of CTN beads, the beads comprising core granules comprising CTN and a filler (optionally, microcrystalline cellulose and / or mannitol), the core granules 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, the core granules can include an optional coating surrounding the core granules, and the plurality of CTN beads can include fast-release beads, sustained-release beads, and delayed-release beads.

[0123] A unit dosage form comprising a CTN formulation according to the present disclosure can contain any suitable dose of CTN. For example, the amount of CTN in a unit dosage form may be in the range of about 1 mg to about 1800 mg, for example, about 10 mg to about 1800 mg, for example, about 25 mg to about 1800 mg, for example, about 10 mg to about 1600 mg, for example, about 10 mg to about 1200 mg, for example, about 50 mg to about 490 mg, for example, about 50 mg to about 250 mg, for example, about 50 mg to about 1200 mg, for example, about 50 mg to about 1000 mg, for example, about 75 mg to about 1000 mg, for example, about 75 mg to about 800 mg, for example, about 75 mg to about 500 mg, for example, about 100 mg to about 750 mg, for example, about 100 mg to about 500 mg, for example, about 100 mg to about 400 mg, for example, about 100 mg to about 300 mg, for example, about 100 mg to about 200 mg.

[0124] Functional properties As described above, pharmaceutical formulations or dosage forms can be advantageously designed to have one or more pharmacokinetic properties, e.g., in humans. Pharmaceutical formulations herein can be characterized by the amount of CTN released in vitro over a predetermined period of time. In embodiments where the pharmaceutical formulation includes fast-release beads, at least 90% of the CTN or a salt thereof is released from the fast-release beads at a time point ranging from 0 to 2 hours. In embodiments where the pharmaceutical formulation includes sustained-release beads, at least 90% of the CTN or a salt thereof is released from the sustained-release beads at a time point ranging from 2 to 6 hours. In embodiments where the pharmaceutical formulation includes delayed-release beads, at least 90% of the CTN or a salt thereof is released from the delayed-release beads at a time point ranging from 4 to 14 hours. In embodiments where the pharmaceutical formulation includes delayed-sustained-release beads, at least 90% of the CTN or a salt thereof is released from the delayed-sustained-release beads at a time point ranging from 4 to 14 hours.

[0125] In some embodiments, the formulation or dosage form may be characterized by one or more release profiles in vivo and / or in vitro selected from fast release, sustained release, delayed release, and delayed-sustained release. In some embodiments, the formulation, e.g., a formulation suitable for pediatric use, may suitably have a multiphasic 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> According to the method described above, the release profile measured in 1000 mL of 0.1 N hydrochloric acid at 37° C.±0.5° C. and 100 rpm for 2 hours using Apparatus I (basket), followed by 1000 mL of pH 7.4 phosphate buffer at 37° C.±0.5° C. and 100 rpm for 16 hours using Apparatus I (basket), can have a multiphasic release profile, optionally at least a biphasic release profile, and optionally at least a triphasic release profile. Such a profile is optionally characterized by about 22% to about 45% release of CTN at 3 hours, 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 such release rates at all three time points. In another embodiment, such a profile may be characterized by a release of about 24% to 48% of the CTN at 3 hours, and further optionally by at least 66% of the CTN at 6 hours, and further optionally by at least 86% of the CTN at 10 hours, or further optionally by such release rates at all three time points.More optionally, the release profile may be characterized by a release of 49% to 73% at 4 hours.

[0126] The pharmaceutical formulations herein can be characterized as optionally providing a bimodal in vivo absorption profile. In some embodiments, pharmaceutical formulations having a bimodal in vivo absorption profile provide a first centanafadine plasma C α value at a time point within a range of 0 to 4.5 hours, or about 0.5 hours to about 2 hours, or about 3.5 hours to about 4.5 hours. max In some embodiments, the first centanafadine plasma C is provided by a plurality of CTN beads. maxIn some embodiments, the pharmaceutical formulation having a bimodal in vivo absorption profile has a second centanafadine plasma C of about 6 hours to about 10 hours, or about 7 hours to about 9 hours, or about 7.5 hours to about 8.5 hours. max In some embodiments, the second centanafadine plasma C is provided by a plurality of CTN beads. 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 a first centanafadine plasma C max and second centanafadine plasma C max and are separated by a time period ranging from 1.5 to 8.5 hours, or from about 2 hours to about 6 hours, or from about 3 hours to about 5 hours.

[0127] The pharmaceutical formulations and uses thereof described herein may be designed to provide one or more of the following pharmacokinetic profile characteristics:

[0128] The formulation provides a relatively rapid increase in plasma concentration of centanafadine in a subject, allowing the subject to approach or achieve therapeutic concentrations in a relatively short time. Thus, for example, the formulation provides a therapeutically effective dose of centanafadine in an adult subject within 1 hour after administration (C 1h ) can provide centanafadine plasma concentrations 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, and optionally such exposure can be achieved at a dosage in the range of about 145 mg to about 185 mg CTN (e.g., 164.4 mg CTN).

[0129] This formulation was administered to adult subjects to measure the cumulative plasma exposure of CTN (AUC 0-1h ) can be provided such that the CTN is 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 in the range of 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, optionally with a dosage ranging from about 145 mg to about 185 mg of CTN (e.g., 164.4 mg of CTN).

[0130] The formulations exhibit sustained efficacy, maintaining plasma concentrations of CTN within the therapeutic range in adult subjects for extended periods. 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 after administration. These plasma concentrations can be achieved, for example, at a dose of about 145 mg to about 185 mg of CTN (e.g., 164.4 mg of CTN).

[0131] The formulation or its use is intended to assess the cumulative CTN plasma exposure (AUC 0-8h) can be provided in a 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; optionally, such exposure can be achieved at a dosage ranging from about 145 mg to about 185 mg of CTN (e.g., 164.4 mg of CTN).

[0132] The cumulative plasma exposure (AUC 2-8h ) 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 at a dosage ranging from about 145 mg to about 185 mg of CTN (e.g., 164.4 mg of CTN).

[0133] The pharmaceutical preparation or its use is to be administered to adult subjects for 12 hours (C 12h) can provide a plasma concentration of CTN 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 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 at a dosage ranging from about 145 mg to about 185 mg of CTN (e.g., 164.4 mg of CTN).

[0134] 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-administration, and can promote the maintenance of a relatively low plasma concentration of CTN at 16 hours post-administration and until the next administration. Thus, for example, the ratio of the plasma concentration at 16 hours post-administration to the plasma concentration at 12 hours post-administration (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 suitably such ratios can be achieved at dosages ranging from about 145 mg to about 185 mg CTN (e.g., 164.4 mg CTN).

[0135] The pharmaceutical formulations or uses thereof can provide an adult subject with a CTN concentration in the range 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 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, 16 hours after administration. Optionally, such exposure can be achieved with a dose in the range of about 145 mg to about 185 mg CTN (e.g., 164.4 mg CTN). For example, plasma concentrations can be relatively low at such time points to facilitate repeated once-daily administration without CTN accumulation. In another embodiment, for example, if administration is performed in the morning, plasma concentrations can be relatively low at such time points to avoid one or more side effects, such as insomnia, in the subject.

[0136] The pharmaceutical formulation or its use is to evaluate the cumulative plasma exposure of CTN (AUC 0-24h ) 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. The pharmaceutical formulation or its use may be used to provide an adult subject with a cumulative CTN plasma exposure (AUC 0-48h) can be provided 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, optionally, such exposure can be achieved at a dosage ranging from about 145 mg to about 185 mg of CTN (e.g., 164.4 mg of CTN).

[0137] The pharmaceutical formulation or its use is to evaluate the cumulative plasma exposure of CTN (AUC 0-inf ) can be provided in a 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, optionally, such exposure can be achieved at a dosage ranging from about 145 mg to about 185 mg of CTN (e.g., 164.4 mg of CTN).

[0138] The pharmaceutical formulation or its use in an adult subject provides a time to maximum CTN plasma concentration (t) ranging from about 1.5 hours to about 11 hours, or from about 2.25 hours to about 10 hours, or from about 2.7 hours to about 8.8 hours, or from about 3 hours to about 8 hours, or from about 4 hours to about 6 hours. max ) can be provided.

[0139] The pharmaceutical formulations disclosed herein can be characterized 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 provides a diffusive release mechanism. In some embodiments, one or more of the plurality of CTN beads have a pH-induced diffusive release mechanism. In some embodiments, one or more of the plurality of CTN beads have a combination of a pH-induced dissolution release mechanism and a diffusive release mechanism. In some embodiments, as partially disclosed above, delayed-release beads have a combination of a pH-induced dissolution 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 comprise a porous matrix.

[0140] One type of pharmaceutical formulation disclosed herein comprises a plurality of centanafadine beads, each of which comprises a core granule comprising centanafadine or a pharmaceutically acceptable salt thereof and excipients, and the plurality of centanafadine beads comprises a mixture of one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads, the ratios of which are in the range of approximately 0.1-1:1-20:1-20 parts by weight, respectively.

[0141] The plurality of centanafadine beads can include centanafadine or a pharmaceutically acceptable salt thereof in an amount ranging from about 10 mg to about 490 mg.

[0142] The pharmaceutical preparation can comprise at least a portion of core granules containing centanafadine or a pharmaceutically acceptable salt thereof in an amount ranging from about 70% to about 90% by weight.

[0143] The pharmaceutical preparation may contain core granules characterized by a maximum diameter of about 0.2 mm to about 2 mm.

[0144] The pharmaceutical preparation can include core granules in which at least 60% by weight of the core granules are characterized by a maximum diameter in the range of about 0.4 mm to about 1.5 mm.

[0145] The pharmaceutical formulation can include a plurality of centanafadine beads having an average particle size characterized by a particle size ranging from about 0.2 mm to about 2.8 mm.

[0146] The pharmaceutical formulation can contain rapid-release beads in the range of about 1% to about 75% based on the total weight of the plurality of centanafadine beads.

[0147] The pharmaceutical formulation can contain sustained-release beads in the range of about 5% to 80% based on the total weight of the plurality of centanafadine beads.

[0148] The pharmaceutical formulation can contain delayed-release beads in the range of about 5% to 80% based on the total weight of the plurality of centanafadine beads.

[0149] This pharmaceutical formulation was administered to adult subjects to evaluate centanafadine plasma concentration (C 1hr ) can be provided at least 150 ng / mL, or in the range of about 150 ng / mL to about 610 ng / mL.

[0150] The pharmaceutical formulation is effective in achieving centanafadine plasma concentrations (C ) of at least 95 ng / mL, or in the range of about 95 ng / mL to about 450 ng / mL, 12 hours after administration to adult subjects. 12hr ) can be provided.

[0151] This pharmaceutical formulation was developed to measure centanafadine plasma concentrations (C 16hr ) can be less than 300 ng / mL, or in the range of about 95 ng / mL to about 300 ng / mL.

[0152] The pharmaceutical formulations are capable of providing adult subjects with post-administration centanafadine plasma concentrations that are maintained at at least 75 ng / mL, or in the range of about 75 ng / mL to about 1500 ng / mL, for a period of 2 to 8 hours after administration.

[0153] The pharmaceutical formulation was designed to provide a cumulative plasma exposure (AUC) of centanafadine of at least 2400 ng·h / mL within 24 hours after administration, or in the range of 2400 ng·h / mL to 12500 ng·h / mL, in adult subjects. 0-24h ) can be provided.

[0154] This pharmaceutical formulation was administered to adult subjects to evaluate the cumulative plasma exposure of centanafadine (AUC 0-inf ) can be provided at least 2400 ng·h / mL, or in the range of 2400 ng·h / mL to 12500 ng·h / mL.

[0155] The pharmaceutical formulation contains centanafadine hydrochloride and is designed to achieve a centanafadine plasma concentration (C ) of at least 150 ng / mL at 1 hour after administration to adult subjects. 1hr ), a post-dose centanafadine plasma concentration that is maintained at least 250 ng / mL over a period of 2 to 8 hours after administration, and a centanafadine plasma concentration of less than 300 ng / mL at 16 hours after administration (C 16h ) can be provided.

[0156] Pharmaceutical preparations are based on the United States Pharmacopoeia <711> When treated using Apparatus 1 (basket) according to the method described above, first in 1000 ml of 0.1 N HCl solution for 2 hours at 37°C ± 0.5°C, 100 rpm, and then in 1000 ml of pH 7.4 aqueous buffer solution for the remaining time at 37°C ± 0.5°C, 100 rpm, at least 40% of centanafadine or a salt thereof can be released from the bead mixture at a time point within a range of 3 to 5 hours, and at least 90% of centanafadine or a salt thereof can be released from the bead mixture at a time point within a range of 12 to 14 hours.

[0157] This pharmaceutical formulation has been shown to produce centanafadine plasma concentrations (C ) ranging from approximately 150 ng / mL to approximately 610 ng / mL at 1 hour after administration in adult subjects. 1hr ), centanafadine plasma concentrations (C ) ranging from approximately 95 ng / mL to approximately 450 ng / mL 12 hours after administration. 12h ), centanafadine plasma concentrations (C ) ranging from approximately 95 ng / mL to approximately 300 ng / mL 16 hours after administration. 16h ) and the ratio C 16h / C 12h is less than 1.

[0158] The pharmaceutical formulation may include at least some of the sustained release beads that include a coating that is a sustained release coating, and at least some of the delayed release beads that include a delayed release coating and / or a delayed-delayed release coating.

[0159] The pharmaceutical formulation may comprise a delayed-release coating comprising one or more materials selected from amylose acetate phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate trimellitate, carboxymethylethylcellulose, copolymerized methacrylic acid / methacrylic acid methyl ester, copolymerized methacrylic acid / methyl methacrylate, copolymerized methyl acrylate / methyl methacrylate / methacrylic acid, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, styrene maleic acid copolymer, and styrene-vinylpyridine copolymer.

[0160] The pharmaceutical formulation may comprise a sustained-release coating comprising one or more materials selected from alkylcellulose, acrylic acid polymers, methacrylic acid polymers, acrylic acid copolymers, methacrylic acid copolymers, and cellulose ethers. The sustained-release coating may further comprise a pore-forming agent. The pore-forming agent may comprise one or more materials selected from hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyethylene glycol, poloxamer 188, polyvinylpyrrolidone, d-mannitol, methylcellulose, polyvinyl alcohol-polyethylene glycol graft copolymer, and saccharides.

[0161] The pharmaceutical formulation may comprise a plurality of centanafadine beads, each of which comprises a core granule comprising centanafadine or a pharmaceutically acceptable salt thereof and excipients; the plurality of centanafadine beads comprises a mixture of one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads, the weight ratio of which is in the range of about 0.1 to 1:1 to 20:1 to 20 parts by weight; the plurality of centanafadine beads comprises centanafadine or a pharmaceutically acceptable salt thereof in an amount in the range of about 10 mg to about 490 mg; at least some of the sustained-release beads comprise a coating that is a sustained-release coating comprising a copolymer of ethyl acrylate and methyl methacrylate; and at least some of the delayed-release beads comprise a delayed-release coating comprising poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid); and the plurality of centanafadine beads have an average particle size characterized by a particle diameter in the range of about 0.2 mm to about 2.8 mm.

[0162] Major depressive disorder (MDD) Depression is caused by a deficiency or imbalance of monoamine neurotransmitters such as serotonin, dopamine, and norepinephrine.

[0163] A diagnosis of depression requires five or more symptoms (Diagnostic and Statistical Manual of Mental Disorders - DSM-5, Frontiers in Psychiatry, 2018, Vol. 9, Art. 450). One of these must be either depressed mood or anhedonia, which are considered primary criteria. Secondary symptoms are divided into somatic and non-somatic symptom clusters, but DSM-5 categorizes depression as "all" or "none." In contrast, depression severity is a continuous variable. A diagnosis of a major depressive episode (MDE) requires the presence of five or more symptoms within a two-week period. At least one of the symptoms must be either depressed mood (DM) or anhedonia (loss of interest or pleasure - LI). The secondary symptoms of MDE are appetite or weight changes (AW), sleep disturbances (insomnia or hypersomnia), psychomotor agitation or retardation (PAR), fatigue or loss of energy (FE), impaired thinking or concentration (C), feelings of worthlessness or excessive guilt (FW), and suicidality (SU). These symptoms are rated as all or none (0 or 1).

[0164] According to DSM-5 criteria, the presence or absence of a severe depressive episode is determined by summing up the symptoms. The present invention provides a method for treating MDD and / or alleviating, ameliorating, or alleviating the symptoms of MDD in a human patient in need of treatment, comprising administering to the patient a therapeutically effective amount of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof. The CTN is administered in a sustained-release formulation comprising a plurality of CTN beads, each of which comprises a core granule comprising CTN or a pharmaceutically acceptable salt thereof and an excipient, and the plurality of CTN beads comprises a mixture of one or more rapid-release (IR) beads, one or more sustained-release (SR) beads, and one or more delayed-release (DR) beads. The present invention provides a method for treating MDD and / or alleviating, ameliorating or reducing the symptoms of MDD in a human in need thereof, the method comprising administering to said patient a therapeutically effective amount of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof as an adjunct to escitalopram, wherein the CTN is administered in a sustained release formulation.

[0165] Dosage As described herein, the methods disclosed herein include administering a therapeutically effective amount of CTN or a pharmaceutically acceptable salt thereof at about 10 mg or more per day, e.g., 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, or about 400 mg or more of CTN or a pharmaceutically acceptable salt thereof. Additionally, the disclosed methods and uses can include administering about 750 mg or less of CTN or a pharmaceutically acceptable salt thereof per day, e.g., 750, 740, 730, 720, 710, 700, 690, 680, 670, 660, 650, 640, 630, 620, 610, 600, 590, 580, 570, 560, 550, 540, 530, 520, 510, 500, 490, 480, 470, 460, 450, 440, 430, 420, or about 410 mg or less of CTN or a pharmaceutically acceptable salt thereof.Thus, the methods and uses disclosed herein involve administering CTN or a pharmaceutically acceptable salt thereof in an amount limited by any of the aforementioned values, for example, in the range of about 10 mg to about 750 mg per day (e.g., about 10 to 750 mg, about 20 to 740 mg, about 30 to 730 mg, about 40 to 720 mg, about 50 to 710 mg, about 60 to 700 mg, about 70 to 690 mg, about 80 to 680 mg, about 90 to 670 mg, about 100 to 660 mg, about 110 to 650 mg, about 120 to 640 mg, about 130 to 630 mg, about 140 to 620 mg, about 150 to 610 mg, about 160 to 600 mg, about 170 to 590 mg per day). mg, about 180 to 580 mg, about 190 to 570 mg, about 200 to 560 mg, about 210 to 550 mg, about 220 to 540 mg, about 230 to 530 mg, about 240 to 520 mg, about 250 to 510 mg, about 260 to 500 mg, about 270 to 490 mg, about 280 to 480 mg, about 290 to 470 mg, about 300 to 460 mg, about 310 to 450 mg, about 320 to 440 mg, about 330 to 430 mg, about 340 to 420 mg, about 350 to 410 mg, about 360 to 400 mg, about 370 to 410 mg, or about 380 to about 400 mg of CTN or a pharmaceutically acceptable salt thereof. In an embodiment, the amount of CTN or a pharmaceutically acceptable salt thereof administered, optionally in combination with other embodiments described above or below, is in the range of about 10 to about 750 mg per day, e.g., about 50 to about 600 mg per day, about 60 to about 450 mg per day, or about 200 to about 400 mg per day.

[0166] The disclosed methods for treating MDD contemplate oral administration at dosages such as those described above, and additionally or alternatively, administration in amounts ranging from about 0.01 to about 2.0 mg / kg body weight. The recommended daily oral dose ranges from about 0.10 mg to about 200 mg, conveniently administered once daily, two to four times daily, or in sustained-release form. For example, a unit dosage form for oral administration can contain about 20 mg to about 75 mg or about 150 mg of CTN, e.g., about 10 mg, about 20 mg, about 50 mg, about 75 mg, or about 100 mg to 200 mg, or about 500 mg, in free or pharmaceutically acceptable salt form, together with a pharmaceutically acceptable diluent or carrier.

[0167] In embodiments, the disclosed methods may include administering about 200 mg of CTN daily. In embodiments, the disclosed methods may include administering about 400 mg of CTN daily. In embodiments, the disclosed methods may include administering about 41.1 mg of CTN daily. In embodiments, the disclosed methods may include administering about 82.2 mg of CTN daily. In embodiments, the disclosed methods may include administering about 123.3 mg of CTN daily. In embodiments, the disclosed methods may include administering about 164.4 mg of CTN daily. In embodiments, the disclosed methods may include administering about 246.6 mg of CTN daily. In embodiments, the disclosed methods may include administering about 328.8 mg of CTN daily. Doses corresponding to any of the foregoing daily dosage amounts can be administered as a single dosage unit per day.

[0168] These and other effective dosages, as described herein, can be administered in a single dose or in multiple doses daily, weekly, or monthly, e.g., in a dosing regimen including 1-5, or 2-3 doses per day, week, or month, to provide the desired TDD of CTN.

[0169] In an embodiment, CTN or a pharmaceutically acceptable salt thereof can be administered 1 to 4 times daily, optionally in combination with other above or below described embodiments.

[0170] In an embodiment, CTN or a pharmaceutically acceptable salt thereof is administered twice daily, optionally in combination with other above or below described embodiments.

[0171] In an embodiment, CTN or a pharmaceutically acceptable salt thereof is administered once daily, optionally in combination with other embodiments described above or below.

[0172] As described herein, in embodiments, CTN dosage can be calculated based on body weight and can be administered in amounts of, for example, about 0.5 mg / kg to about 30 mg / kg per day, 1 mg / kg to about 15 mg / kg per day, 1 mg / kg to about 10 mg / kg per day, 2 mg / kg to about 20 mg / kg per day, 2 mg / kg to about 10 mg / kg per day, or 3 mg / kg to about 15 mg / kg per day.

[0173] As described herein, the disclosed methods include administering a therapeutically effective amount of CTN or a pharmaceutically acceptable salt thereof as an adjunct to escitalopram or a pharmaceutically acceptable salt thereof.

[0174] As described herein, the disclosed methods include administering a therapeutically effective amount of CTN or a pharmaceutically acceptable salt thereof in the range of about 10 to about 750 mg per day, e.g., about 35 to about 400 mg per day, about 50 to about 600 mg per day, about 60 to about 450 mg per day, or about 200 to about 400 mg per day, as a supplement to escitalopram or a pharmaceutically acceptable salt thereof in an amount of about 2.5 to about 20 mg per day, e.g., about 5 to about 20 mg per day, about 5 to about 10 mg per day, or about 10 to about 20 mg per day. The disclosed methods include administering a therapeutically effective amount of CTN or a pharmaceutically acceptable salt thereof in the range of about 10 to about 750 mg per day, as a supplement to escitalopram or a pharmaceutically acceptable salt thereof in an amount of about 2.5 to about 20 mg per day. The disclosed methods involve administering a therapeutically effective amount of CTN or a pharmaceutically acceptable salt thereof in the range of about 35 to about 400 mg per day, supplemented with escitalopram or a pharmaceutically acceptable salt thereof in an amount of about 10 to about 20 mg per day. These dosages can be in a single oral dosage form or in separate dosage forms administered simultaneously or sequentially.

[0175] As described herein, the disclosed method includes administering a therapeutically effective amount of CTN as a hydrochloride salt.As described herein, the disclosed method includes administering a therapeutically effective amount of escitalopram as a hydrobromide salt.As described herein, the disclosed method includes administering a therapeutically effective amount of escitalopram as an oxalate salt.

[0176] As described herein, the disclosed methods involve orally administering a therapeutically effective amount of CTN hydrochloride as an adjunct to a therapeutically effective amount of escitalopram oxalate or escitalopram hydrobromide.

[0177] A therapeutically effective amount of CTN hydrochloride ranges from about 35 to about 400 mg per day, and a therapeutically effective amount of escitalopram as the oxalate or hydrobromide salt ranges from 2.5 to 20 mg per day.

[0178] The amount, timing, and method of delivery of the compositions of the invention, including an effective amount of a compound of the invention, can be routinely adjusted on an individual basis depending on factors such as the individual's weight, age, sex, condition, target medical condition, acuity of the disorder and / or associated symptoms, whether administration is prophylactic or therapeutic, and other factors known to affect drug delivery, absorption, pharmacokinetics including half-life, and efficacy. An effective dose or multi-dose treatment regimen using the compounds described herein is typically selected to approach the minimum dosing regimen necessary and sufficient to substantially treat, prevent, assist, or alleviate one or more symptoms of major depressive disorder.

[0179] Thus, for example, after administration of CTN or a pharmaceutically acceptable salt thereof in a method for treating MDD or alleviating, ameliorating, or reducing the symptoms of MDD, a patient may exhibit a 10%, 20%, 30%, 50% or greater reduction, up to a 75-90%, or 95% or greater reduction in one or more symptoms associated with MDD, compared to subjects receiving a placebo or other suitable control group.

[0180] In methods for treating MDD or alleviating, ameliorating, or reducing the symptoms of MDD, after administering CTN or a pharmaceutically acceptable salt thereof as an adjunct to escitalopram or a pharmaceutically acceptable salt thereof, patients may exhibit a 10%, 20%, 30%, 50% or greater reduction, up to a 75-90%, or 95% or greater reduction in one or more symptoms associated with MDD compared to subjects receiving a placebo or other suitable control group.

[0181] Route of administration The disclosed methods and uses include administering CTN or a pharmaceutically acceptable salt thereof in a form appropriate for the desired route of administration. For example, CTN, in free or pharmaceutically acceptable salt form, can be administered by any suitable route, including oral, buccal, nasal, aerosol, topical, mucosal, injection, parenteral, transdermal, or inhalation (including sustained release), although various other known delivery routes, devices, and methods can be used as well.

[0182] In embodiments, CTN or a pharmaceutically acceptable salt thereof (e.g., CTN) is administered intravenously, transdermally (e.g., via a transdermal patch, optionally including microneedles), or orally, optionally in combination with other embodiments described above or below.

[0183] In embodiments, optionally in combination with other embodiments described above or below, CTN or a pharmaceutically acceptable salt thereof is administered orally. Non-limiting examples of suitable oral dosage forms include capsules or tablets. In some embodiments, the dosage form is a capsule.

[0184] In embodiments, CTN, in free or pharmaceutically acceptable salt form, can be released from the composition and delivered in a sustained release profile to the subject's plasma or other active target site (including, but not limited to, brain regions such as the prefrontal cortex, frontal cortex, thalamus, striatum, ventral tegmental area, other cortical regions, hippocampus, hypothalamus, or nucleus accumbens). One type of sustained release profile is described in in vitro release (USP <711> , providing an in vitro release profile that is multiphasic (optionally at least biphasic) according to USP <711> (Apparatus 1 (basket) is placed in 1000 mL of 0.1 N hydrochloric acid at 37°C ± 0.5°C for 2 hours at 100 rpm, followed by placing Apparatus 1 (basket) in 1000 mL of pH 7.4 phosphate buffer at 37°C ± 0.5°C for 16 hours at 100 rpm. Such a profile is optionally characterized by about 22% to about 45% release of CTN at 3 hours, further optionally about 40% to about 65% release of CTN at 8 hours, further optionally about 65% to about 95% release of CTN at 12 hours, and further optionally such release rates at all three time points. Alternatively, such a profile can be characterized by 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 such release rates at all three time points. Further optionally, the release profile can be characterized by 49% to 73% release at 4 hours.In another embodiment, the release profile can be determined in vivo and is characterized by about 0%-20% of the active compound being released and delivered within 0-2 hours (e.g., as determined by measuring plasma levels), 20%-50% of the active compound being released and delivered within about 2-12 hours, 50%-85% of the active compound being released and delivered within about 3-20 hours, and greater than 75% of the active compound being released and delivered within about 5-18 hours.

[0185] In embodiments, the in vivo absorption profile of the pharmaceutical formulation may be such that 16 hours after administration, the plasma CTN concentration is less than 300 ng / mL, or less than 250 ng / mL, or less than 230 ng / mL, or less than 200 ng / mL. For example, the plasma concentration may be relatively low at such times to facilitate repeated once-daily administration without CTN accumulation. In another embodiment, the plasma concentration may be relatively low at such times to avoid insomnia in the subject, for example, when administration is performed in the morning.

[0186] In an embodiment, the C of CTN in free or pharmaceutically acceptable salt form provided after administration of a sustained release pharmaceutical composition comprising CTN in free or pharmaceutically acceptable salt form. max is the C obtained after administering an equivalent dose of CTN in free or pharmaceutically acceptable salt form in a fast-release pharmaceutical composition. max In an embodiment, the C of CTN in free or pharmaceutically acceptable salt form provided after administration of a sustained release pharmaceutical composition comprising CTN in free or pharmaceutically acceptable salt form may be less than about 80%, e.g., less than about 75%, e.g., less than about 60%, e.g., less than about 50%, e.g., less than about 40%, e.g., less than about 30%. max is the C obtained after administering an equivalent dose of CTN in free or pharmaceutically acceptable salt form in a fast-release pharmaceutical composition. maxIn one embodiment, the C of CTN in the free or pharmaceutically acceptable salt form provided after administration of a sustained-release pharmaceutical composition containing CTN in the free or pharmaceutically acceptable salt form can be about 20 to 80%, optionally about 30 to 80%, optionally about 20 to 70%, optionally about 30 to 70%, optionally about 30 to 60%, optionally about 30 to 50%, or optionally about 30 to 40%. max is the C obtained after administering an equivalent dose of CTN in free or pharmaceutically acceptable salt form in a fast-release pharmaceutical composition. max In an embodiment, the C of CTN in free or pharmaceutically acceptable salt form provided after administration of a sustained release pharmaceutical composition comprising CTN in free or pharmaceutically acceptable salt form may be less than about 50%, optionally less than about 40%, and optionally less than about 30%. max is the C obtained after administering an equivalent dose of CTN in free or pharmaceutically acceptable salt form in a fast-release pharmaceutical composition. max It may be about 20 to 50%, appropriately about 30 to 50%, or appropriately about 30 to 40% of the total.

[0187] The composition of the rapid-release centanafadine core beads, 50 nominal wt% CTN HCl, used in these formulations is shown in Table 1. [Table 1] The compositions of 10 wt% and 50 wt% rapid-release centanafadine HCl core beads in these formulations are shown in Table 2. [Table 2]

[0188] The composition of the centanafadine core beads (drug content 80% by weight) is shown in Table 3. The centanafadine core beads were produced by weighing CTN HCl and microcrystalline cellulose, dry-mixing them in a high-shear granulator, granulating the blended mixture with purified water, extruding and spheronizing them to form wet beads, fluid-bed drying the core beads, and sieving the beads to retain them in the desired size range. [Table 3]

[0189] The composition of the seal-coated beads of centanafadine (80 wt% drug content) is shown in Table 4. For seal coating, the Wurster process was used with a controlled set of process parameters to spray the required amount of aqueous hypromellose solution, after which the coated beads were dried to the required moisture content and hardened. [Table 4] The composition of the sustained release coated beads is shown in Table 5. [Table 5] The composition of the delayed release coated beads is shown in Table 6. [Table 6] The compositions of various centanafadine sustained-release capsules are shown in Tables 7, 8, and 9. [Table 7] [Table 8] [Table 9] [Table 10]

[0190] The plasma pharmacokinetics of a CTN HCl formulation with a dose of 164.4 mg may be as shown in Table 11. [Table 11] The plasma pharmacokinetics of CTN HCl formulations with doses of 164.4 mg or 328.8 mg may be as shown in Table 12. [Table 12]

[0191] When two active agents are administered, the therapeutically effective amount of each agent may be lower than the amount required for monotherapy activity. Thus, a subthreshold amount (i.e., an amount below the level required for monotherapy efficacy) may be considered therapeutically effective. Indeed, in certain situations, the advantage of administering another agent with a different mechanism of action and side effect profile is that the dosage and side effects of one or both agents may be reduced.

[0192] Combination therapy In some embodiments, the present disclosure provides methods of using centanafadine or a pharmaceutically acceptable salt thereof in combination with one or more other antidepressants, antipsychotics, or cognitive enhancers to treat MDD or to alleviate, ameliorate, or reduce the symptoms of MDD. Examples of classes of antidepressants that can be used in combination with centanafadine or a pharmaceutically acceptable salt thereof include norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), NK-1 receptor antagonists, monoamine oxidase inhibitors (MAOs), reversible monoamine oxidase inhibitors (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin-releasing factor (CRF) antagonists, alpha-adrenergic receptor antagonists, benzodiazepines, anxiolytics, and atypical antidepressants.

[0193] Suitable norepinephrine reuptake inhibitors include tertiary amine tricyclic compounds and secondary amine tricyclic compounds.Suitable tertiary amine tricyclic compounds and secondary amine tricyclic compounds include amitriptyline, clomipramine, doxepin, imipramine, trimipramine, dothiepin, butriptyline, iprindole, lofepramine, nortriptyline, protriptyline, amoxapine, desipramine and maprotiline.Suitable selective serotonin reuptake inhibitors include fluoxetine, citropram, escitalopram, fluvoxamine, paroxetine, dapoxetine, vortioxetine and sertraline.

[0194] Examples of monoamine oxidase inhibitors include isocarboxazid, phenelzine, and tranylcypromine. Suitable reversible inhibitors of monoamine oxidase include moclobemide.

[0195] Suitable serotonin and noradrenaline reuptake inhibitors for use in the present invention include venlafaxine, nefazodone, milnacipran, and duloxetine.

[0196] In some embodiments, the present disclosure provides methods of treating MDD or alleviating, ameliorating, or reducing the symptoms of MDD in a patient in need thereof, the methods comprising administering a therapeutically effective amount of centanafadine or a pharmaceutically acceptable salt thereof in combination with one or more natural remedies or supplements promoted by marketers as effective against depression, including, but not limited to, St. John's wort (herbal supplement), S-adenosylmethionine (SAMe), omega-3 fatty acids, saffron, 5-hydroxytryptophan (5-HTP), dehydroepiandrosterone (DHEA), and the like.

[0197] In some embodiments, the present disclosure provides a method for treating MDD or alleviating, ameliorating, or reducing the symptoms of MDD in a patient in need of treatment, the method comprising administering a therapeutically effective amount of centanafadine or a pharmaceutically acceptable salt thereof in combination with one or more other antidepressants, antipsychotics, or cognitive enhancers, either in a single formulation or multiple combinations co-administered within a specific period and for a duration. ... (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof, and b) a selective serotonin reuptake inhibitor (SSRI) and / or a serotonin-norepinephrine reuptake inhibitor (SNRI), optionally selected from and administering one or more antidepressants optionally selected from the group consisting of fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine, vilazodone, venlafaxine, desvenlafaxine, dapoxetine, vortioxetine, venlafaxine, and duloxetine, wherein (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof is administered in a sustained release formulation as described herein.

[0198] In some embodiments, the one or more SSRIs are selected from fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, escitalopram, and vilazodone.

[0199] In some embodiments, the one or more SSRIs are selected from fluoxetine, sertraline, paroxetine, citalopram, and escitalopram.

[0200] In some embodiments, the one or more SSRIs are selected from fluoxetine and fluvoxamine.

[0201] In some embodiments, the SSRI is fluvoxamine.

[0202] In some embodiments, the SSRI is escitalopram.

[0203] In some embodiments, the one or more SNRIs are selected from venlafaxine, desvenlafaxine, duloxetine, levomilnacipran, and reboxetine.

[0204] In some embodiments, the antidepressant comprises escitalopram.

[0205] In some embodiments, the antidepressant comprises citalopram.

[0206] The pharmaceutical combination therapy composition may include a therapeutically effective amount of CTN or a pharmaceutically acceptable salt thereof, as described above, and a therapeutically effective amount of an additional therapeutic agent. In embodiments where the method includes administering CTN or a pharmaceutically acceptable salt thereof in combination with one or more antidepressants (e.g., SSRIs and / or one or more SNRIs), the additional antidepressant is administered in an appropriate amount. For example, therapeutic doses of antidepressants are shown in Table 13. [Table 13] TIFF2025529250000015.tif130160

[0207] In some embodiments, a patient is initially given a low dose of the antidepressant and then titrated up to the recommended therapeutic dose over a period of time.

[0208] In some embodiments, the antidepressant is escitalopram, and the amount of escitalopram or a pharmaceutically acceptable salt thereof (e.g., escitalopram oxalate or escitalopram hydrobromide) administered is in the range of about 2.5, 4, 5, 10, 15, or 20 mg per day. In some embodiments, the amount of escitalopram administered is about 10 mg per day. In some embodiments, the amount of escitalopram administered is about 20 mg per day.

[0209] In embodiments involving combination therapy, CTN or a pharmaceutically acceptable salt thereof can be administered together (e.g., simultaneously) or at separate intervals (e.g., sequentially) with an additional antidepressant (e.g., an SSRI and / or SNRI). When administered together, CTN or a pharmaceutically acceptable salt thereof and the additional therapeutic agent can be incorporated into a single pharmaceutical composition, e.g., a pharmaceutical combination therapy composition. Alternatively, two separate compositions, one containing CTN or a pharmaceutically acceptable salt thereof and the other containing the additional therapeutic agent, can be administered simultaneously.

[0210] Combination therapy, formulations containing CTN or a pharmaceutically acceptable salt thereof and / or escitalopram may be formulated to provide modified release of CTN or a pharmaceutically acceptable salt thereof, and fast or modified release of escitalopram or a pharmaceutically acceptable salt thereof. Modified release profiles of CTN or a pharmaceutically acceptable salt thereof, escitalopram or a pharmaceutically acceptable salt thereof, or both, can be achieved by combining sustained release and pulsatile release formulations.

[0211] A pulsatile release profile can be achieved in a closed dosage form, such as a sealed capsule or tablet, containing two or more drug-containing dosage units. The dosage form can include one, two, three, or more types of dosage units, each with a different drug release profile. Each dosage unit can provide a multiphasic release of CTN or a pharmaceutically acceptable salt thereof and / or escitalopram or a pharmaceutically acceptable salt thereof.

[0212] The combination therapy may include administering a CTN described herein in combination with counseling and / or behavioral therapy. The combination therapy may include administering a CTN described herein in combination with digital therapy and / or a digital app. The combination therapy may include administering a CTN described herein and escitalopram in combination with counseling and / or behavioral therapy. The combination therapy may include administering a CTN described herein and escitalopram in combination with digital therapy and / or a digital app.

[0213] When administered separately, the therapeutically effective dose of a composition containing CTN or a pharmaceutically acceptable salt thereof and the additional therapeutic agent can be administered on different schedules. One may be administered before the other, as long as the time between the two administrations falls within the therapeutically effective interval. The therapeutically effective interval is the period beginning when either (a) CTN or a pharmaceutically acceptable salt thereof or (b) the additional therapeutic agent is administered to a human and ending at the end of the beneficial effect of the combination of (a) and (b) in treating MDD or alleviating, ameliorating, or alleviating MDD symptoms. The administration methods for CTN or a pharmaceutically acceptable salt thereof and the additional therapeutic agent can vary. Thus, either or both agents may be administered rectally, topically, orally, sublingually, or parenterally.

[0214] Aspects Aspect 1. A method for treating major depressive disorder or ameliorating, alleviating, or alleviating the symptoms of major depressive disorder, comprising administering a therapeutically effective amount of centanafadine or a pharmaceutically acceptable salt thereof to a human patient in need of treatment, wherein the centanafadine or a pharmaceutically acceptable salt thereof is administered in a sustained-release formulation comprising a plurality of centanafadine beads.

[0215] Aspect 2. The method of embodiment 1, wherein each bead in each of the plurality of centanafadine beads comprises a core granule containing centanafadine or a pharmaceutically acceptable salt thereof and excipients, and the plurality of centanafadine beads comprises a mixture of one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads.

[0216] Aspect 3. The method of embodiment 2, wherein the one or more sustained release beads contain a sustained release coating comprising one or more materials selected from alkyl celluloses, acrylic acid polymers, methacrylic acid polymers, acrylic acid copolymers, methacrylic acid copolymers, and cellulose ethers.

[0217] Aspect 4. 4. The method of embodiment 2 or 3, wherein the one or more delayed release beads contain a delayed release coating comprising 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.

[0218] Aspect 5. The method of any of embodiments 2-4, wherein the mixture of one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads is in a ratio ranging from about 0.1-1:1-20:1-20 parts by weight.

[0219] Aspect 6. The method of any of Aspects 1-5, wherein the sustained release formulation is a once-daily oral formulation.

[0220] Aspect 7. The method of embodiment 6, wherein the formulation is a capsule.

[0221] Aspect 8. The method of any of aspects 1-7, wherein the pharmaceutically acceptable salt of centanafadine is the hydrochloride salt.

[0222] Aspect 9. The method of any of aspects 1 to 8, wherein the amount of centanafadine or a pharmaceutically acceptable salt thereof administered ranges from about 10 mg to about 750 mg per day.

[0223] Aspect 10. The method of embodiment 9, wherein the amount of centanafadine or a pharmaceutically acceptable salt thereof administered ranges from about 35 mg to about 400 mg per day.

[0224] Aspect 11. A method for treating major depressive disorder or ameliorating, alleviating, or reducing the symptoms of major depressive disorder, comprising administering to a patient in need of treatment a therapeutically effective amount of centanafadine or a pharmaceutically acceptable salt thereof as an adjunct to one or more antidepressants.

[0225] Aspect 12. 12. The method of embodiment 11, wherein the one or more antidepressants are selected from selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, benzodiazepines, anxiolytics, noradrenergic-specific serotonergic antidepressants, tricyclic antidepressants, and monoamine oxidase inhibitors.

[0226] Aspect 13. The method of embodiment 11, wherein the one or more antidepressants is a selective serotonin reuptake inhibitor.

[0227] Aspect 14. The method of embodiment 13, wherein the selective serotonin reuptake inhibitor comprises escitalopram.

[0228] Aspect 15. The method of any of aspects 11-14, wherein centanafadine or a pharmaceutically acceptable salt thereof is administered in a sustained release formulation comprising a plurality of centanafadine beads.

[0229] Aspect 16. A method according to claim 15, wherein each of the plurality of centanafadine beads comprises a core particle comprising centanafadine or a pharmaceutically acceptable salt thereof and excipients, and the plurality of centanafadine beads comprises a mixture of one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads.

[0230] Aspect 17. The method of embodiment 16, wherein the one or more sustained release beads contain a sustained release coating comprising one or more materials selected from alkyl celluloses, acrylic acid polymers, methacrylic acid polymers, acrylic acid copolymers, methacrylic acid copolymers, and cellulose ethers.

[0231] Aspect 18. 18. The method of embodiment 16 or 17, wherein the one or more delayed release beads contain a delayed release coating comprising 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.

[0232] Aspect 19. The method of any of embodiments 16-18, wherein the mixture of one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads is in a ratio ranging from about 0.1-1:1-20:1-20 parts.

[0233] Aspect 20. 20. The method of any of aspects 11-19, wherein the amount of centanafadine or a pharmaceutically acceptable salt thereof is administered in the range of about 10 mg to about 750 mg per day, as an adjunct to escitalopram or a pharmaceutically acceptable salt thereof in an amount of about 2.5 to about 20 mg per day.

[0234] Aspect 21. The method of embodiment 20, wherein the amount of centanafadine or a pharmaceutically acceptable salt thereof administered ranges from about 35 mg to about 400 mg per day, as an adjunct to escitalopram or a pharmaceutically acceptable salt thereof in an amount of about 10 to about 20 mg per day.

[0235] Aspect 22. 1. A method for treating major depressive disorder or ameliorating, alleviating, or reducing the symptoms of major depressive disorder, comprising administering to a human patient in need of treatment a therapeutically effective amount of centanafadine or a pharmaceutically acceptable salt thereof, as an adjunct to a selective serotonin reuptake inhibitor, Centanafadine or a pharmaceutically acceptable salt thereof is administered in a sustained release dosage form comprising a plurality of centanafadine beads; Each bead in each of the plurality of centanafadine beads includes a core granule containing centanafadine or a pharmaceutically acceptable salt thereof and an excipient; the plurality of centanafadine beads comprises a mixture of one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads; a mixture of 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 0.1-1:1-20:1-20 parts; Centanafadine or a pharmaceutically acceptable salt thereof is administered in a range of about 35 mg to about 400 mg per day, the selective serotonin reuptake inhibitor is escitalopram or a pharmaceutically acceptable salt thereof; The method, wherein escitalopram or a pharmaceutically acceptable salt thereof is administered in the range of about 10 to about 20 mg per day. Aspect 23. The method of embodiment 22, wherein the cetanafadine is administered as the hydrochloride salt and the escitalopram is administered as the oxalate salt. Aspect 24. 24. The method of embodiment 22 or 23, wherein the mixture of one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads is in a ratio ranging from about 1:3.6:3.6 parts. Aspect 25. The method of any of embodiments 1-24, wherein centanafadine hydrochloride is administered in an amount of 328.4 mg per day and escitalopram oxalate is administered in an amount of 10 mg per day. Aspect 26. The method of any of embodiments 1-25, wherein centanafadine hydrochloride is administered in an amount of 328.8 mg per day and escitalopram oxalate is administered in an amount of 20 mg per day. [Example]

[0236] The following examples are provided for illustrative purposes and are not intended to limit the scope of the present invention. In the following examples, centanafadine was formulated and administered as centanafadine hydrochloride unless otherwise specified.

[0237] In the example below, escitalopram is TM (escitalopram) will be administered in accordance with the US prescribing information (Allergan USA, Inc.; Madison, NJ, August 2020).

[0238] The phase 2 clinical trial described here is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy, safety, and tolerability of centanafadine extended-release capsules as monotherapy or an adjunct to an SSRI in adult subjects with major depressive disorder. Thus, the clinical trial has several objectives.

[0239] The objective of this study was to evaluate the efficacy of centanafadine QD XR 328.8 mg as monotherapy for MDD in adults.

[0240] Another objective of this study was to evaluate the efficacy of centanafadine QD XR 328.8 mg as an adjunct to SSRI (escitalopram) in adults with MDD.

[0241] A further objective of this study is to evaluate the safety and tolerability of centanafadine QD XR 328.8 mg as monotherapy in adults with MDD.

[0242] Another objective of this study was to evaluate the safety and tolerability of centanafadine QD XR 328.8 mg as an adjunct to an SSRI (escitalopram) in adults with MDD.

[0243] Eligible subjects will be randomly assigned 1:1:1:1 at baseline to one of four treatment groups: Treatment group 1: two centanafadine QD XR 164.4 mg oral capsules plus one placebo escitalopram tablet; Treatment group 2: two centanafadine QD XR 164.4 mg oral capsules + one escitalopram tablet; Treatment group 3: one escitalopram tablet + two centanafadine QD XR capsules placebo; Treatment group 4: two placebo centanafadine QD XR capsules plus one placebo escitalopram tablet.

[0244] Arm 1: Eligible subjects received centanafadine QD XR 328.8 mg plus placebo-equivalent escitalopram for 6 weeks (monotherapy). Arm 2: Eligible subjects received centanafadine QD XR 328.8 mg plus placebo-equivalent escitalopram for 6 weeks (adjunctive therapy).

[0245] Arm 3: Eligible subjects will receive centanafadine QD XR 328.8 mg matching placebo and escitalopram for 6 weeks. Arm 4: Eligible subjects will receive centanafadine QD XR 328.8 mg matching placebo and escitalopram matching placebo for 6 weeks.

[0246] Eligible subjects assigned to the centanafadine QD XR treatment group (i.e., treatment arms 1 or 2) will receive 328.8 mg of centanafadine (i.e., two centanafadine QD XR 164.4 mg oral capsules) starting on Day 1.

[0247] Eligible subjects assigned to the escitalopram treatment groups (i.e., arms 2 or 3) will receive 10 mg once daily on Day 1. During Week 1, the dose will increase to 20 mg once daily and will be maintained for the remainder of study participation.

[0248] Subjects who cannot tolerate the daily dose administered during the 6-week treatment period or who require a change in medication to treat depression will be removed from the study. Dose reductions will not be permitted.

[0249] Example 1 Treatment of MDD patients with centanafadine monotherapy A phase 2, multicenter, randomized, double-blind, placebo-controlled study will be conducted to evaluate the efficacy, safety, and tolerability of centanafadine as monotherapy in adult patients with MDD. Subjects with major depression who meet the inclusion and exclusion criteria will be randomly assigned at baseline in a 1:1 ratio (84 subjects per treatment group) to receive either centanafadine extended-release (XR) capsules (328.8 mg centanafadine hydrochloride, once daily) or placebo for 6 weeks. The study will consist of a screening period of up to 28 days, a baseline visit, a 6-week double-blind treatment period, and a 7-day safety follow-up period. The study will be conducted in outpatient settings.

[0250] Inclusion criteria were individuals aged 18–65 years, currently suffering from a major depressive episode (MDE) with a primary diagnosis of MDD (single or recurrent episode), without psychotic features, not meeting criteria for the mixed-feature subtype, and confirmed by the Mini International Neuropsychiatric Interview (MINI), a widely used structured diagnostic interview tool developed for DSM-5 psychiatric disorders. All subjects had a HAM-D17 score of ≥18 at screening and baseline, and a comprehensive BMI of 18–40 kg / m. 2 , and a CGI-S rating of 4 or greater at screening and baseline. Other inclusion criteria include subjects who reported an inadequate response to at least one and up to three prior depression treatments in their current MDE. Inadequate response was defined as less than a 50% reduction in depressive symptom severity after adequate dose and duration (i.e., at least 6 weeks at the minimum therapeutic dose or greater) according to the MGH-ATRQ administered at screening. Subjects who, in the opinion of the investigator, could safely discontinue their current antidepressant medication.

[0251] Exclusion criteria were: currently pregnant and / or breastfeeding, or planning to become pregnant during the study period; a history of a depressive episode for 2 years or more; meeting DSM-5 criteria for a personality disorder, substance use disorder, or lifetime or current comorbid psychiatric disorder (e.g., experiencing hallucinations, delusions, or psychotic symptoms) that is likely to require treatment with concomitant medications or psychotherapy prohibited in this study or that may confound the evaluation of efficacy or safety, allergic reaction to medication, or history of adverse skin reactions or anaphylaxis due to drug exposure; epilepsy, a history of epilepsy, or a history of seizures; clinically significant current suicidal intent; significant cardiac, medical, or progressive neurological or medical disease; facial pain or trigeminal neuralgia; and the following laboratory and ECG results at screening: 1) platelet count <75,000 / mm 3 2) hemoglobin <9 g / dL, 3) absolute neutrophil count <1000 / mm 3 4) AST >2x upper limit of normal, 5) ALT >2x upper limit of normal, 6) creatinine ≥2mg / dL, 7) HbA1c ≥7%, 8) QTcF ≥450ms for men and ≥470ms for women, and 9) abnormal free T4 unless discussed and approved by a medical monitor. Other exclusion criteria included a lifetime history of treatment with ketamine, alketamine, or esketamine, current MDE and treatment with psychopharmacological augmentation therapy for depression (e.g., lithium, triiodothyronine, or antipsychotics added to ADT, multiple ADTs), initiation of individual or group psychotherapy within the past 3 months prior to screening, or treatment with electroconvulsive therapy or neuromodulation devices (e.g., transcranial magnetic stimulation, vagus nerve stimulation, or transcranial direct current stimulation) for depression, or a history of nonadherence.

[0252] All subjects agree to discontinue all prohibited medications (i.e., various antidepressants, anticonvulsants, mood stabilizers, benzodiazepines, hypnotics, stimulants, opioid analgesics, dietary supplements, and over-the-counter herbal preparations that act on the central nervous system) during screening and throughout the study to meet the protocol-specified washout period. Subjects taking antidepressants at screening will undergo a washout period before baseline. The required washout period varies depending on the type of antidepressant. For example, for SSRIs (e.g., sertraline), monoamine oxidase inhibitors (e.g., selegiline), serotonin-norepinephrine reuptake inhibitors (e.g., venlafaxine, duloxetine), norepinephrine-dopamine reuptake inhibitors (e.g., bupropion), or other antidepressants (e.g., vortioxetine, vilazodone), the required washout period is 7 days. For fluoxetine or fluvoxamine, the required washout period is 28 days. Drug screening will be conducted at screening and baseline (day -1). The screening period will last up to 4 weeks (maximum 28 days).

[0253] All subjects will receive centanafadine XR capsules as monotherapy or placebo for 6 weeks. Subjects assigned to receive centanafadine XR once daily will receive 328.8 mg of centanafadine (i.e., two 164.4 mg centanafadine QD XR oral capsules) starting on Day 1. All doses of centanafadine XR and the corresponding placebo will be taken orally with approximately 240 mL of water upon awakening at approximately the same time each day. Do not take after a high-fat meal. Subjects will be instructed not to take more than one dose per day.

[0254] Subjects who cannot tolerate the administered daily dose at any time during the 6-week treatment period or who require a change in medication for the treatment of depression will be discontinued from the study. Efficacy assessments will be conducted at screening and / or baseline (Day -1), and then at Weeks 1, 2, 4, and 6. After the 6-week double-blind treatment period, subjects will undergo a 7(+2) day safety follow-up period after the Week 6 / Early Termination (ET) visit.

[0255] Primary efficacy evaluation The primary efficacy of centanafadine QD XR as monotherapy in adults will be evaluated by assessing the change from baseline in the MADRS total score at Week 6. For analysis of data from the double-blind treatment phase, baseline is defined as the last available measurement prior to the first dose of double-blind centanafadine QD XR.

[0256] The MADRS is a 10-item scale for assessing depressive symptoms. Each MADRS item is rated on a scale of 0 to 6, with 0 being "highest" and 6 being "lowest." Higher MADRS scores indicate higher levels of depressive symptoms. The MADRS total score is the sum of the ratings on all 10 items; therefore, the total score ranges from 0 to 60. If fewer than 8 of the 10 items are recorded, no MADRS total score is assessed. If 8 or 9 of the 10 items are recorded, the MADRS total score is the average of the recorded items multiplied by 10, rounded to one decimal place.

[0257] Secondary efficacy evaluation Other efficacy measures evaluated in this study included: 1) change from baseline in the MADRS total score at weeks 1, 2, and 4; 2) change from baseline in the Clinical Global Impression Scale-Severity (CGI-S) score; 3) Clinical Global Impression Scale-Change (CGI-C) score; 4) change from baseline in the Patient Global Impression Scale-Severity (PGI-S) score; 5) Patient Global Impression Scale-Change (PGI-C) score; 6) change from baseline in the Major Depressive Disorder Symptom Scale (SMDDS) total score; 7) change from screening in the 36-Item Short-Term Health Survey, Version 2 (SF-36v2); 8) change from screening in the Apathy Scale-Self-Rating (AES-S) score; 9) MADRS response rate (response defined as a 50% reduction in the MADRS total score from baseline at the follow-up visit); and 10) MADRS remission rate (remission defined as a MADRS total score of 10 or less at the follow-up visit). Exploratory efficacy measures assessed in this study included change from baseline in the MADRS anhedonia factor.

[0258] Clinical Global Impression Scale-Severity (CGI-S) The CGI-S is a clinician-administered standardized global rating scale that measures illness severity on a 7-point scale, with higher scores indicating greater illness severity. Response options are: 1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = significantly ill; 6 = severely ill; and 7 = most severely ill. Eligible subjects had a CGI-S score of 4 or greater at screening and baseline.

[0259] Clinical Global Impression Scale-Change (CGI-C) The CGI-C is a single-item, 7-point scale that requires clinicians to rate how much the subject's illness has improved or worsened since the start of treatment, with ratings of 1 = very improved, 2 = quite improved, 3 = slightly improved, 4 = no change, 5 = slightly worse, 6 = quite worse, and 7 = very worse.

[0260] Patient Global Impression Scale-Severity (PGI-S) The PGI-S is a single-item report of the severity of a subject's symptoms. Subjects are asked, "Considering all of your symptoms, how severe would you say your depression is at this time?" Scores range from 1 (no symptoms) to 7 (very severe).

[0261] Patient Global Impression Scale-Change (PGI-C) The PGI-C is a 7-point, single-item self-report scale that assesses the overall change in a patient's condition since starting study medication. Subjects answer the question, "How much have your depression symptoms changed since you started taking the study medication?" Scores range from 1 (much improved) to 7 (much worse).

[0262] 36-item Short-Form Health Questionnaire Version 2 (SF-36v2) The SF-36v2 is a subject-reported questionnaire with a standard recall period of 4 weeks. The questionnaire measures general health-related quality of life in two broad domains, physical and mental composite, across eight health domain scales: physical functioning, pain, role physical, general health, vitality / fatigue, social functioning, role emotional, and mental health. The SF-36v2 uses norm-based scoring to generate scores on a scale of 0 to 100, with lower scores on the physical component summary and mental component summary indicating poorer health-related quality of life, and a score of 50 representing the US population. In addition to the composite score and individual health domain scores, the SF-36v2 provides a depression risk score and an SF-36v2 health utility index on a scale of 0.0 (worst measured health state) to 1.0 (best measured health state).

[0263] Major Depressive Disorder Symptom Scale (SMDDS) The SMDDS is a 16-item patient-reported outcomes (PRO) questionnaire developed in accordance with the U.S. Food and Drug Administration (FDA) PRO Guidance (2009) and the guidelines proposed in the International Society for Pharmacoeconomics and Outcomes Research Good Research Practices Task Force Report for the development and validation of patient-reported outcomes (PROs) for drug evaluation. It is designed to assess subject perception of the severity of MDD symptoms over the past 7 days in adults receiving outpatient treatment for MDD. The SMDDS consists of nine domains of MDD symptoms: negative affect / mood (4 items), anxiety (2 items), low energy (1 item), cognition (2 items), sleep disturbance (1 item), self-harm / suicide (1 item), self-consciousness (1 item), and eating behavior (2 items scored as 1 item). The SMDDS was approved by the FDA in 2017 to assess global MDD symptoms in a clinical trial setting.

[0264] Apathy Scale-S (AES-S) The Apathy Scale was developed to assess apathy as a "psychological dimension defined by simultaneous overt behavioral, cognitive, and emotional deficits associated with goal-directed behavior." The self-assessment version (AES-S) has 18 items and uses a response scale of "not at all," "a little," "somewhat," and "very much." The AES-S asks respondents to respond based on "thoughts, feelings, and activities over the past four weeks." Items are categorized into domains of goal-directed behavior, goal-related situations, or goal-related emotional reactions, and scores range from 18 to 72, with higher scores indicating higher levels of apathy.

[0265] Safety evaluation Safety will be assessed through standard measures, including treatment-emergent adverse events (TEAEs), adverse events of special interest (AESIs [sudden]), laboratory tests (chemistry, hematology, urinalysis), physical examination, vital sign measurements, and 12-lead electrocardiograms. The Study Medication Withdrawal Questionnaire (SMWQ), Generalized Anxiety Disorder Rating Scale (GAD-7), and Columbia-Suicide Severity Rating Scale (C-SSRS) will also be used to assess safety. Abuse potential will be assessed through active monitoring of events eligible for additional monitoring (ESAMs), such as AEs related to abuse potential and AEs related to medication handling abnormalities (MHIs).

[0266] result CTN significantly reduced all primary efficacy measures (i.e., MADRS total score) in patients remaining after the 6-week double-blind treatment period, whereas no significant reductions were observed in the placebo group. Furthermore, significant reductions from baseline in CGI-S, CGI-C, PGI-S, and PGI-C scores were also observed in patients receiving CTN, whereas no significant reductions were observed in the placebo group. Increases in SF-36v2 general scores from baseline and a reduced risk of depression were also observed in patients receiving CTN.

[0267] Centanafadine (CTN) demonstrates clinically significant improvement as monotherapy in patients with MDD.

[0268] Example 2 Centanafadine as an adjunctive therapy for the treatment of MDD This phase 2, multicenter, randomized, double-blind, placebo-controlled study will evaluate the efficacy, safety, and tolerability of centanafadine XR capsules as an adjunct to an SSRI(c) in adult patients with MDD. Subjects with major depression who meet the inclusion and exclusion criteria will be randomly assigned at baseline in a 1:1:1 ratio (84 subjects per treatment group) to receive 6 weeks of treatment with centanafadine XR capsules (centanafadine hydrochloride 328.8 mg once daily) plus escitalopram, escitalopram monotherapy (escitalopram administered once daily (QD)), or placebo. The study will consist of a screening period of up to 28 days, a baseline visit, a 6-week double-blind treatment period, and a 7-day safety follow-up period. The study will be conducted in outpatient settings.

[0269] Inclusion and exclusion criteria are the same as in Example 1. Additionally, subjects taking escitalopram or citalopram at screening, subjects who have been exposed to escitalopram or citalopram in their current MDE, or subjects who have previously reported an inadequate response to escitalopram or citalopram at an appropriate dose / duration will also be excluded.

[0270] All subjects agree to discontinue all prohibited medications during screening and throughout the study to meet the protocol-specified washout period. Subjects taking antidepressants at screening will undergo a washout period before baseline. The required washout period varies depending on the type of antidepressant (see Example 1). Drug screening will be conducted at screening and baseline (day -1). The screening period will last up to 4 weeks (maximum 28 days).

[0271] All subjects will receive either escitalopram monotherapy, centanafadine QD XR capsules plus escitalopram (combination therapy), or matching placebo for 6 weeks.

[0272] Subjects assigned to receive centanafadine XR + escitalopram combination therapy will receive centanafadine 328.8 mg (i.e., two centanafadine QD XR 164.4 mg oral capsules) and one escitalopram tablet starting on Day 1. Escitalopram tablets will be taken at 10 mg QD on Day 1. At Week 1, the dose will increase to 20 mg QD for the remainder of the subject's study participation.

[0273] Subjects assigned to receive escitalopram monotherapy will receive 10 mg QD on Day 1. At Week 1, the dose will increase to 20 mg QD for the remainder of the subject's study participation. Dose reductions will not be permitted. Subjects who cannot tolerate the daily dose administered during the 6-week treatment period or who require a change in medication for the treatment of depression will be removed from the study.

[0274] All doses of centanafadine QD XR, escitalopram, and matching placebo were to be taken orally with approximately 240 mL of water at approximately the same time each day, in the morning upon awakening. No doses were to be taken after a high-fat meal. After the 6-week double-blind treatment period, subjects underwent a 7(+2)-day safety follow-up period following the Week 6 / Early Termination (ET) visit.

[0275] Efficacy evaluation The primary efficacy of centanafadine QD XR as an adjunct to an SSRI (escitalopram) in adult subjects with MDD will be assessed by comparing the efficacy of centanafadine QD XR plus escitalopram with escitalopram monotherapy or by comparing the change from baseline in the MADRS total score at week 6. For analyses of data from the double-blind treatment phase, baseline is defined as the last available measurement before the first dose of double-blind escitalopram or centanafadine QD XR plus centanafadine.

[0276] Other efficacy measures evaluated in this study included: 1) change from baseline in MADRS total score at weeks 1, 2, and 4; 2) change from baseline in Clinical Global Impression Scale-Severity (CGI-S) score; 3) Clinical Global Impression Scale-Change (CGI-C) score; 4) change from baseline in Patient Global Impression Scale-Severity (PGI-S) score; 5) Patient Global Impression Scale-Change (PGI-C) score; 6) change from baseline in Major Depressive Disorder Symptom Scale (SMDDS) total score; 7) change from screening in 36-Item Short-Term Health Survey Version 2 (SF-36v2); 8) change from screening in Apathy Scale-Self-Rating (AES-S) score; 9) MADRS response rate (response defined as a 50% reduction in MADRS total score from baseline at the follow-up visit); and 10) MADRS remission rate (remission defined as a MADRS total score of 10 or less at the follow-up visit). These efficacy endpoints are defined similarly to Example 1. Exploratory efficacy measures assessed in this study included change from baseline in the MADRS anhedonia factor.

[0277] Safety evaluation Safety will be assessed through standard measures, including treatment-emergent adverse events (TEAEs), adverse events of special interest (AESIs [sudden]), laboratory tests (chemistry, hematology, urinalysis), physical examination, vital sign measurements, and 12-lead electrocardiograms. The Study Medication Withdrawal Questionnaire (SMWQ), Generalized Anxiety Disorder Rating Scale (GAD-7), and Columbia-Suicide Severity Rating Scale (C-SSRS) will also be used to assess safety. Abuse potential will be assessed through active monitoring of events eligible for additional monitoring (ESAMs), such as AEs related to abuse potential and AEs related to medication handling abnormalities (MHIs).

[0278] The mean reduction in all primary efficacy measures (i.e., MADRS total score) in patients after 6 weeks of combination therapy was greater than the mean reduction in patients after 6 weeks of escitalopram monotherapy. No significant reductions were observed in the placebo group. Centanafadine (CTN) is effective as adjunctive therapy to SSRIs (escitalopram) in patients with MDD.

[0279] Statistical analysis methods The study sample size calculation was based on evaluating the efficacy of centanafadine QD XR as adjunctive therapy to escitalopram in adult subjects with MDD. The primary comparison was centanafadine QD XR plus escitalopram versus escitalopram monotherapy for the primary efficacy endpoint, change from baseline in the MADRS total score at week 6.

[0280] Primary Efficacy-Endpoint Analysis The objective of the primary efficacy analysis was to compare the efficacy of centanafadine QD XR plus escitalopram with escitalopram monotherapy on the change from baseline in MADRS total score at week 6.

[0281] The primary estimand, which defines the treatment effect of interest in the protocol, uses the hypothesis strategy specified in the International Conference on Harmonization (ICH) E9 Addendum. The estimand, or target, according to the hypothesis strategy is the treatment effect that would have been observed if discontinuation had not occurred. For subjects who discontinued IMP treatment, the treatment effect may have been lost if they had not received other treatment after discontinuation, or the treatment effect may have been masked if they had received other treatment after discontinuation. This means that observations made after subjects discontinued IMP are unlikely to contribute relevant information about the drug's treatment effect. This strategy ensures that the last efficacy assessment collected after early discontinuation from the study is performed only once, at the ET visit. Every effort is made to complete all ET assessments before administering additional medications for the treatment of MDD. In the event of terminal illness or loss to follow-up, no ET assessments are performed; only assessments scheduled before such illnesses occurred are performed.

[0282] The primary endpoint of this study is defined by the following components: target population: efficacy sample, endpoint: change from baseline to week 6 in MADRS total score, concurrent event: early discontinuation of treatment, intervention effect measure: difference in mean endpoint between centanafadine QD XR + escitalopram and escitalopram monotherapy at 6 weeks.

[0283] The primary efficacy analysis was performed by fitting an MMRM analysis using an unstructured (UN) variance-covariance structure with the change from baseline in the MADRS total score (Weeks 1, 2, 4, and 6) as the dependent variable based on the observed case (OC) dataset from the efficacy sample. The model included fixed class effects for treatment, study center, and visit week, as well as an interaction term for treatment by visit week. The model also included an interaction term for the baseline value of the MADRS total score by visit week as a covariate. The primary comparison between centanafadine QD XR + escitalopram combination therapy and escitalopram monotherapy at Week 6 of the double-blind treatment period was estimated as the difference between least-squares means using the SAS procedure PROC MIXED.

[0284] Other efficacy endpoint analyses Comparisons will be made for the following other efficacy endpoints, all of which will be tested nominally at the 0.05 level: 1) Change from baseline in MADRS total score at weeks 1, 2, and 4; 2) change from baseline in CGI-S scores at weeks 1, 2, 4, and 6; 3) CGI-C scores at weeks 1, 2, 4, and 6; 4) Change from baseline in PGI-S scores at weeks 1, 2, 4, and 6; 5) PGI-C scores at weeks 1, 2, 4, and 6; 6) Change from baseline in SMDDS total score at day 4, week 1, week 2, week 4, and week 6; 7) change from screening in SF-36v2 physical component summary score, mental component summary score, and SF-36v2 subscales; 8) change from screening in AES-S score; 9) MADRS response rate (response defined as a 50% reduction in MADRS total score from baseline at weeks 1, 2, 4, and 6); and 10) MADRS remission rate (remission is defined as a MADRS total score ≤ 10 at weeks 1, 2, 4, and 6).

[0285] Endpoints (1), (2), (4), and (6) will be assessed using the same MMRM model described in the primary analysis. Endpoints (3) and (5) will be assessed by the CMH row mean score difference test, controlling for study center, using the LOCF dataset. Endpoints (7) and (8) will be assessed using analysis of covariance with baseline values ​​as covariates and study center as the main effect in the treatment and LOCF analyses. Endpoints (9) and (10) will be assessed by the CMH general association test, controlling for study center, using the LOCF dataset. OC analyses will also be performed for endpoints (3), (5), (7)–(10), but without controlling for study center.

[0286] Exploratory efficacy endpoint analysis Change from baseline and descriptive statistics will be used for the MADRS anhedonia factor score (total score of MADRS items 1, 2, 6, 7, and 8).

[0287] Pharmacokinetic evaluation Pharmacokinetic samples will be collected at weeks 2, 4, and 6 (±2 days).

[0288] Pharmacokinetic Blood Samples Single, small PK samples will be collected at weeks 2, 4, and 6. PK samples will be collected after efficacy and other safety assessments (AE monitoring, vital sign measurements, electrocardiograms, drug withdrawal scales, and suicidality assessments). At week 2, one sample will be collected either before the morning dose (trough value) or 4 hours after the dose, followed by another sample at week 4. At week 6, subjects will be instructed to take their medication before the morning visit and have the PK sample collected at the same time as the serum chemistry sample. Visit times will be scheduled as needed to achieve different sample times.

[0289] Blood samples will be collected by venipuncture (2 mL whole blood, dipotassium ethylenediaminetetraacetic acid [K2EDTA]) and processed to plasma to measure centanafadine and metabolite concentrations.

[0290] If vital signs or an electrocardiogram (ECG) are scheduled for the same nominal time as PK sample collection, measure vital signs and perform an ECG before collecting the PK sample.

[0291] The actual date and time of PK sample collection and the date and time of IMP administration prior to PK sample collection will be recorded on the eCRF.

[0292] Clinical laboratory evaluation Clinical laboratory samples will be collected at screening and at baseline (Day -1), Weeks 1, 4, and 6, to perform the clinical laboratory assessments described herein, and, if possible, after efficacy assessments have been completed.

[0293] Subjects are not required to fast for the screening test. Subsequent tests will be performed in the fasting state. If possible, subjects will be instructed to fast for at least 8 hours prior to blood collection.

[0294] All screening test results will be available and comprehensive before randomization. These test results will be reviewed by personnel before initiating IMP administration. If necessary, additional urine and blood samples may be collected for further safety assessment.

[0295] Urine or serum pregnancy tests will be performed on CBP subjects throughout the study. If pregnancy is suspected, an unscheduled urine or serum pregnancy test may be performed. A positive urine pregnancy test will be verified by a serum pregnancy test. Pregnancy test results must be obtained before administration of IMP. Subjects will be counseled about the risk of pregnancy while participating in the clinical trial.

[0296] Drug screens will be conducted at screening and baseline (day -1). Additional assessments may be conducted at any time at the investigator's discretion. Subjects with a positive drug test for prohibited substance use at screening will be required to undergo a washout period. Subjects with a positive drug screen for prohibited substance use at baseline will be considered screen failures and will not be permitted to rescreen.

[0297] Subjects will be monitored for laboratory values ​​of potential clinical importance.

[0298] Other safety data Drug withdrawal symptoms, assessed by SMWQ total score at scheduled visits, will be summarized by treatment group using descriptive statistics.

[0299] Anxiety assessed with the GAD-7 at scheduled visits will be summarized by treatment group using descriptive statistics.

[0300] Suicidality monitored during the study using the C-SSRS will be summarized by treatment group using descriptive statistics.

[0301] Other analyses Pharmacokinetic analysis To confirm dosing compliance, small PK samples are evaluated and concentrations can also be used in a population PK analysis reported separately.

[0302] The foregoing description has been given for clarity of understanding only, and no unnecessary limitations should be understood therefrom, since modifications within the scope of the invention will be apparent to those skilled in the art.

[0303] Throughout this specification and the claims that follow, unless the context clearly indicates otherwise, the word "comprise" and variations such as "comprises" and "comprising" will be understood to mean the inclusion of a specified integer or step or group of integers or steps, but not the exclusion of other integers or steps or groups of integers or steps.

[0304] Throughout, ranges are used as a shorthand for describing all values ​​within a range. Any value within a range can be selected as an endpoint of the range. Additionally, all references cited herein are incorporated by reference in their entirety. In the event of a conflict between a definition in this disclosure and a definition in a reference, the present disclosure controls.

[0305] Throughout this specification, when a composition is described as comprising components or materials, it is also understood that the composition consists essentially of, or consists of, any combination of the described components or materials, unless otherwise specified. Similarly, when methods and uses are described as including particular steps, it is also understood that the methods and uses consist essentially of, or consist of, any combination of the described steps, unless otherwise specified. The invention illustratively disclosed herein may suitably be practiced in the absence of any element or step not specifically disclosed herein.

[0306] The implementation of the methods disclosed herein and their individual steps can be performed manually and / or with the assistance of or automation provided by electronic devices. While processes have been described with reference to specific embodiments, one skilled in the art will readily recognize that other ways of performing the operations associated with the methods may also be used. For example, unless otherwise indicated, the order of various steps may be changed without departing from the scope or spirit of the methods. Furthermore, some of the individual steps may be combined, omitted, or further subdivided into additional steps.

[0307] All patents, publications, and references cited herein are incorporated by reference in their entirety. In the event of a conflict between the present disclosure and the incorporated patents, publications, and references, the present disclosure shall control.

[0308] The foregoing description has been given for clarity of understanding only, and no unnecessary limitations should be understood therefrom, since modifications within the scope of the invention will be apparent to those skilled in the art.

[0309] Throughout this specification and the claims that follow, unless the context clearly indicates otherwise, the word "comprise" and variations such as "comprises" and "comprising" will be understood to mean the inclusion of a specified integer or step or group of integers or steps, but not the exclusion of other integers or steps or groups of integers or steps.

[0310] Throughout, ranges are used as a shorthand for describing all values ​​within a range. Any value within a range can be selected as an endpoint of the range. Additionally, all references cited herein are incorporated by reference in their entirety. In the event of a conflict between a definition in this disclosure and a definition in a reference, the present disclosure controls.

[0311] Throughout this specification, when a composition is described as comprising components or materials, it is also understood that the composition consists essentially of, or consists of, any combination of the described components or materials, unless otherwise specified. Similarly, when methods and uses are described as including particular steps, it is also understood that the methods and uses consist essentially of, or consist of, any combination of the described steps, unless otherwise specified. The invention illustratively disclosed herein may suitably be practiced in the absence of any element or step not specifically disclosed herein.

[0312] The implementation of the methods disclosed herein and their individual steps can be performed manually and / or with the assistance of or automation provided by electronic devices. While processes have been described with reference to specific embodiments, one skilled in the art will readily recognize that other ways of performing the operations associated with the methods may also be used. For example, unless otherwise indicated, the order of various steps may be changed without departing from the scope or spirit of the methods. Furthermore, some of the individual steps may be combined, omitted, or further subdivided into additional steps.

[0313] All patents, publications, and references cited herein are incorporated by reference in their entirety. In the event of a conflict between the present disclosure and the incorporated patents, publications, and references, the present disclosure shall control.

Claims

1. A method for treating major depressive disorder, comprising administering a therapeutically effective amount of centanafadine or a pharmaceutically acceptable salt thereof to a human patient in need of treatment, wherein the centanafadine or a pharmaceutically acceptable salt thereof is administered in a sustained-release formulation comprising a plurality of centanafadine beads.

2. The method of claim 1, wherein each bead in each of the plurality of centanafadine beads comprises a core granule containing centanafadine or a pharmaceutically acceptable salt thereof and excipients, and the plurality of centanafadine beads comprises a mixture of one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads.

3. 3. The method of claim 2, wherein the one or more sustained release beads contain a sustained release coating comprising one or more materials selected from alkyl celluloses, acrylic acid polymers, methacrylic acid polymers, acrylic acid copolymers, methacrylic acid copolymers, and cellulose ethers.

4. 4. The method of claim 2 or 3, wherein the one or more delayed release beads contain a delayed release coating comprising 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.

5. 5. The method of any one of claims 2 to 4, wherein the mixture of one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads comprises centanafadine or a salt thereof in a ratio ranging from about 0.1 to 1:1 to 20:1 to 20 parts by weight, based on the weight of centanafadine or a salt thereof.

6. The method according to any one of claims 1 to 5, wherein the administration is a sustained release formulation administered once a day.

7. The method of claim 6, wherein the sustained release formulation is a capsule.

8. 8. The method of any one of claims 1 to 7, wherein the pharmaceutically acceptable salt of centanafadine is the hydrochloride salt.

9. 9. The method of any of claims 1 to 8, wherein the amount of centanafadine or a pharmaceutically acceptable salt thereof administered ranges from about 10 mg to about 750 mg per day.

10. 10. The method of claim 9, wherein the amount of centanafadine or a pharmaceutically acceptable salt thereof administered ranges from about 35 mg to about 400 mg per day.

11. A method for treating major depressive disorder, comprising administering to a patient in need of treatment a therapeutically effective amount of centanafadine or a pharmaceutically acceptable salt thereof as an adjunct to one or more antidepressants.

12. 12. The method of claim 11, wherein the one or more antidepressants are selected from selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, benzodiazepines, anxiolytics, noradrenergic-specific serotonergic antidepressants, tricyclic antidepressants, and monoamine oxidase inhibitors.

13. 12. The method of claim 11, wherein the one or more antidepressants is a selective serotonin reuptake inhibitor.

14. 14. The method of claim 13, wherein the selective serotonin reuptake inhibitor comprises escitalopram.

15. 15. The method of any of claims 11 to 14, wherein centanafadine or a pharmaceutically acceptable salt thereof is administered in a sustained release formulation containing a plurality of centanafadine beads.

16. The method of any of claims 11 to 15, wherein each bead in each of the plurality of centanafadine beads comprises a core granule containing centanafadine or a pharmaceutically acceptable salt thereof and excipients, and the plurality of centanafadine beads comprises a mixture of one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads.

17. 17. The method of any of claims 11-16, wherein the one or more sustained release beads contain a sustained release coating comprising one or more materials selected from alkyl celluloses, acrylic acid polymers, methacrylic acid polymers, acrylic acid copolymers, methacrylic acid copolymers, and cellulose ethers.

18. 18. The method of any of claims 11 to 17, wherein the one or more delayed release beads contain a delayed release coating comprising 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.

19. 19. The method of any one of claims 16 to 18, wherein the mixture of one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads comprises centanafadine or a salt thereof in a ratio ranging from about 0.1 to 1:1 to 20:1 to 20 parts by weight, based on the weight of centanafadine or a salt thereof.

20. 20. The method of any of claims 11-19, wherein the amount of centanafadine or a pharmaceutically acceptable salt thereof is administered in the range of about 10 mg to about 750 mg per day as an adjunct to escitalopram or a pharmaceutically acceptable salt thereof in an amount of about 2.5 to about 20 mg per day.

21. 21. The method of claim 20, wherein the amount of centanafadine or a pharmaceutically acceptable salt thereof administered is in the range of about 35 mg to about 400 mg per day, as an adjunct to escitalopram or a pharmaceutically acceptable salt thereof in an amount of about 10 to about 20 mg per day.

22. 1. A method for treating major depressive disorder, comprising administering to a human patient in need of treatment a therapeutically effective amount of centanafadine or a pharmaceutically acceptable salt thereof as an adjunct to a selective serotonin reuptake inhibitor, Centanafadine or a pharmaceutically acceptable salt thereof is administered in a sustained release formulation comprising a plurality of centanafadine beads; Each bead in each of the plurality of centanafadine beads includes a core granule containing centanafadine or a pharmaceutically acceptable salt thereof and an excipient; the plurality of centanafadine beads comprises a mixture of one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads; the mixture of one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads comprises centanafadine or a salt thereof in a ratio ranging from about 0.1 to 1:1 to 20:1 to 20 parts by weight based on the weight of centanafadine or a salt thereof; centanafadine or a pharmaceutically acceptable salt thereof is administered in a range of about 35 mg to about 400 mg per day; the selective serotonin reuptake inhibitor is escitalopram or a pharmaceutically acceptable salt thereof; The method wherein escitalopram or a pharmaceutically acceptable salt thereof is administered in the range of about 10 to about 20 mg per day.

23. 23. The method of claim 22, wherein centanafadine is administered as the hydrochloride salt and escitalopram is administered as the oxalate salt.

24. The method of claim 22 or 23, wherein the mixture of one or more fast-release beads, one or more sustained-release beads, and one or more delayed-release beads contains centanafadine or a salt thereof in a ratio ranging from about 1:3.6:3.6 parts by weight, based on the weight of centanafadine or a salt thereof.

25. 25. The method of any of claims 22 to 24, wherein centanafadine hydrochloride is administered in an amount of 328.4 mg per day and escitalopram oxalate is administered in an amount of 10 mg per day.

26. 25. The method of any of claims 22 to 24, wherein centanafadine hydrochloride is administered in an amount of 328.8 mg per day and escitalopram oxalate is administered in an amount of 20 mg per day.

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