1-(naphthalen-2-yl)-3-azabicyclo [3.1. 0] hexane for treatment of major depression

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., sentanfardine) or a pharmaceutically acceptable salt thereof. More particularly, the present disclosure relates to the treatment of conditions affected by monoamine neurotransmitters.

Description

Technical Field

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS)

[0002] This article claims the benefit of U.S. Provisional Patent Application No. 63 / 403,624, filed on September 2, 2022, under 35 USC § 119(e), the disclosure of which is hereby incorporated by reference.

[0003] (Field of the Disclosure)

[0004] The present disclosure generally relates to methods of treating central nervous system disorders using (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane (ie, centanafadine) or a pharmaceutically acceptable salt thereof. More particularly, the present disclosure relates to treating conditions affected by monoamine neurotransmitters. Background Art

[0005] Major depressive disorder has a severe impact on overall functioning and is the leading cause of disability worldwide in terms of total years lost due to disability. In the United States, depression-related expenditures exceeded $210 billion in 2010, including $102 billion in employer losses due to absence, presenteeism, and disability, and $99 billion in direct medical costs. There is an urgent need to improve treatment outcomes related to major depressive disorder.

[0006] To relieve a major depressive episode (MDE) and return patients to their pre-MDE level of functioning, the American Psychiatric Association recommends that health care providers choose from a variety of treatment modalities during the acute phase. Available options include antidepressant treatment (ADT), depression-focused psychotherapy (e.g., cognitive-behavioral therapy), a combination of ADT and psychotherapy, or other somatic treatments (e.g., electroconvulsive therapy, transcranial magnetic stimulation). Clinical characteristics (e.g., symptom severity, presence of comorbid disorders, or psychosocial stressors) and other factors (e.g., patient preference, prior treatment experience) influence clinicians' choice of initial treatment modality. In most patient populations, when ADT is indicated and psychotherapy is an available and practical option, combining ADT and psychotherapy generally provides the most rapid and durable response. Combination therapy also appears to be significantly more effective in improving depressive symptoms, improving quality of life, and increasing treatment adherence.

[0007] Additional unmet needs exist among patients who are receiving medication. Currently readily available prescription oral treatments take several weeks to work. The need for faster treatments is well recognized and approved. During treatment, patients with conventional depression continue to experience significant disability while waiting for full efficacy.

[0008] In addition, some patients may be refractory or resistant to existing ADT treatments and fail to respond to one or, in some cases, multiple monotherapy and combination antidepressant medications. Thus, new approaches to treat major depressive disorder remain needed. Summary of the invention

[0009] The present disclosure provides a method for treating major depressive disorder in a human patient in need thereof, 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, or a stereoisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof.

[0010] In another embodiment, the present disclosure provides a method of treating major depressive disorder in a human patient in need thereof, 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, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in combination with one or more antidepressants, the antidepressants being optionally selected from a selective serotonin reuptake inhibitor (SSRI) and / or a serotonin-norepinephrine reuptake inhibitor (SNRI).

[0011] In another embodiment, the present disclosure provides a method of treating major depressive disorder in a human patient in need thereof, 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, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in combination with a selective serotonin reuptake inhibitor (SSRI).

[0012] Provided herein are methods for treating major depressive disorder in a human patient in need thereof, comprising administering to the patient a therapeutically effective amount of santanafacil or a pharmaceutically acceptable salt thereof to effectively treat MDD, wherein the santanafacil is optionally administered in an extended release dosage form comprising a plurality of CTN beads; each of the plurality of santanafacil beads comprising a core particle containing santanafacil or a pharmaceutically acceptable salt thereof and an excipient, wherein the plurality of santanafacil beads comprises a mixture of one or more immediate release (IR) beads, one or more sustained release (SR) beads, and one or more delayed release (DR) beads.

[0013] As a molecular entity with inhibitory activity on norepinephrine (NE), dopamine (DA), and serotonin (5-HT) reuptake transporters, sentanafadine has been shown to be generally safe and well tolerated, as indicated by low adverse event (AE) rates.

[0014] Provided herein are methods for treating major depressive disorder in a patient in need thereof, comprising administering to the patient sentanafadine extended-release capsules as monotherapy. Provided herein are methods for treating major depressive disorder in a patient in need thereof, comprising administering to the patient sentanafadine extended-release capsules as an adjunct to a selective serotonin reuptake inhibitor.

[0015] Provided herein are methods for alleviating symptoms of major depressive disorder in a patient in need thereof, comprising administering to the patient a sentanafacil extended-release capsule as monotherapy. Provided herein are methods for alleviating symptoms of major depressive disorder in a patient in need thereof, comprising administering to the patient a sentanafacil extended-release capsule as an adjunct to a selective serotonin reuptake inhibitor.

[0016] Also provided herein is a method for treating major depressive disorder in a patient in need thereof, comprising administering to the patient 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 a selective serotonin reuptake inhibitor (SSRI), wherein the SSRI is selected from fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine, vilazodil (vilazodone), venlafaxine, desvenlafaxine, dopaxetine, vortioxetine, venlafaxine and duloxetine; and wherein the CTN is optionally administered in an extended release dosage form comprising a plurality of CTN beads, each of the plurality of CTN beads comprising a core particle comprising CTN or a pharmaceutically acceptable salt thereof and an excipient, and wherein the plurality of CTN beads comprises a mixture of one or more immediate release (IR) beads, one or more sustained release (SR) beads and one or more delayed release (DR) beads.

[0017] Also provided herein is a method for treating major depressive disorder in a patient in need thereof, comprising administering to the patient 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 optionally administered in an extended release dosage form comprising a plurality of CTN beads, each of the plurality of CTN beads comprising a core particle comprising CTN or a pharmaceutically acceptable salt thereof and an excipient, and wherein the plurality of CTN beads comprises a mixture of one or more immediate release (IR) beads, one or more sustained release (SR) beads, and one or more delayed release (DR) beads.

[0018] A method of treating major depressive disorder (MDD) in a patient in need thereof may include administering to the patient (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane (CTN) or a pharmaceutically acceptable salt thereof in combination with other classes of antidepressants such as, but not limited to, benzodiazepines, anxiolytics, noradrenergic and specific serotonergic antidepressants (NaSSAs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs).

[0019] The present disclosure also provides (1R,5S)-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof for use in the methods disclosed herein.

[0020] For the compositions, methods and uses described herein, it is contemplated that optional features (including but not limited to components, composition ranges thereof, substituents, conditions and steps) are selected from the various aspects, embodiments and examples provided herein.

[0021] Other aspects and advantages will be apparent to those of ordinary skill in the art by reviewing the following detailed description in conjunction with the drawings. Although the compositions, methods and uses described herein are susceptible to different forms of implementation, the following description includes specific embodiments, provided that the disclosure is illustrative and is not intended to limit the invention to the specific embodiments described herein. DETAILED DESCRIPTION

[0022] Methods of treating central nervous system disorders using santanafadine (CTN) or a pharmaceutically acceptable salt thereof are described herein. CTN is classified as a BSC class I molecule and is highly soluble and highly permeable. Unless otherwise expressly stated, as used herein, CTN should be understood to refer to santanafadine, and its pharmaceutically acceptable salts are also contemplated in each of the methods, uses and formulations described herein in addition to or as one or more alternatives to CTN. Santanafadine [CAS924012-43-1], also chemically known as (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane or (+)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, has the following structure:

[0023] [Chemical formula 1]

[0024] ,

[0025] It is an unbalanced triple reuptake inhibitor that is most potent at the norepinephrine reuptake transporter (NET), one-sixth as potent at the dopamine reuptake transporter (DAT), and one-fourteenth as potent at the serotonin reuptake transporter (SERT).

[0026] The present disclosure provides a method for treating major depressive disorder, comprising administering a therapeutically effective amount of santanafacil or a pharmaceutically acceptable salt thereof, wherein, as described herein, the santanafacil is optionally administered in an extended release dosage form comprising a plurality of beads. In some embodiments, the present disclosure provides santanafacil or a pharmaceutically acceptable salt thereof for use in the disclosed methods.

[0027] The terms "sentanafidine", "(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 herein. The term "sentanafidine" as used herein includes "(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane", optionally containing less than 5 wt%, 3 wt%, 2 wt%, 1 wt%, 0.5 wt% or 0.2 wt% of "(1S,5R)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane" based on 100% of the total weight of the compound.

[0028] 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" refer to the enantiomers of the (-)-enantiomer of CTN and are used interchangeably herein.

[0029] In some embodiments described herein that include administering santanafacil or a pharmaceutically acceptable salt thereof, santanafacil may contain varying amounts of other stereoisomers.

[0030] In any of the embodiments comprising 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.

[0031] As used herein, "substantially free of (1S,5R)-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane" or "substantially free of the corresponding (-) enantiomer" means that (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane is at least more than the corresponding (-) enantiomer. Optionally, "substantially free of the corresponding (-) enantiomer" means containing no more than 5% w / w (weight / weight) of the corresponding (-) enantiomer in free or pharmaceutically acceptable salt form, optionally no more than 3% w / w of the corresponding (-) enantiomer in free or pharmaceutically acceptable salt form, optionally no more than 2% w / w of the corresponding (-) enantiomer in free or pharmaceutically acceptable salt form, optionally no more than 1% w / w of the corresponding (-) enantiomer in free or pharmaceutically acceptable salt form, optionally no more than 0.5% w / w of the corresponding (-) enantiomer in free or pharmaceutically acceptable salt form, optionally no more than 0.2% w / w of the corresponding (-) enantiomer in free or pharmaceutically acceptable salt form.

[0032] As used herein, it is contemplated that any aspect or embodiment comprising "(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane" includes or uses the compound in any form, such as a free base or a pharmaceutically acceptable salt form, for example, as a pharmaceutically acceptable acid addition salt.

[0033] The term "pharmaceutically acceptable" generally means biologically or pharmacologically compatible for use in animals or humans, and optionally means approved by a federal or state regulatory agency or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0034] Pharmaceutically acceptable salts are known in the art and include salts that are physiologically acceptable at the dosages and forms administered. CTN is provided as CTN hydrochloride.

[0035] As used herein, it is also contemplated that any aspect or embodiment comprising "(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane" includes or uses a compound in crystalline or amorphous form, including, for example, polymorphs, solvates (including hydrates), unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compound, and mixtures thereof. "Crystalline form" and "polymorph" are used interchangeably herein, and unless a specific crystalline form is mentioned, it is intended to encompass any crystalline form 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), unsolvated polymorphs (including anhydrates), and conformational polymorphs, and mixtures thereof.

[0036] The amount of CTN in the description herein and in any method or use disclosed herein, the weight percentage of CTN or its range in a pharmaceutical formulation (e.g., tablet, capsule, bead, core particle, etc.) applies to CTN free base as well as its pharmaceutically acceptable salt, so unless otherwise specified, any description by weight should be considered to be for CTN free base, and further, in the alternative, be considered to be applicable to the description of the pharmaceutically acceptable salt form. In each such description, CTN in the form of the hydrochloride salt is specifically contemplated.

[0037] The crystalline form and the amorphous form of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane may be used in any combination or in a form substantially free of one or more other crystalline forms or free of the amorphous form.

[0038] As used herein, "substantially free of other polymorphic forms" means that the crystalline material contains no more than 20% of any other crystalline form, optionally no more than 10% w / w of any other crystalline form, optionally no more than 5% w / w of any other crystalline form, or no more than 2% w / w of any other crystalline form, optionally no more than 1% w / w of any other crystalline form.

[0039] (1R,5S)-1-(Naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane can be provided or used in the form of a prodrug. A prodrug is considered to be any covalently bonded carrier that releases the active parent drug in vivo.

[0040] (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 Nos. WO 2007 / 016155, WO 2013 / 019271, and WO 2021 / 075494, or Japanese Patent JP2019147794A, each of which is incorporated herein by reference in its entirety.

[0041] As used herein, the term "escitalopram", chemically known as (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 as Lexapro TM Marketed for the treatment of major depressive disorder and generalized anxiety disorder.

[0042] As used herein, the term "patient" includes human or non-human (i.e., animal) patients. In some embodiments, the patient encompasses both humans and non-humans. In some embodiments, the patient refers to a non-human. In other embodiments, the patient refers to a human.

[0043] As used herein, "therapeutically effective amount" or "therapeutic dose" refers to an amount effective to provide a therapeutic benefit, optionally one or more of preventing symptoms, ameliorating symptoms, and delaying the development of symptoms, when administered to a human or non-human patient. Depressive symptoms include depressed mood, decreased interest in activities, psychomotor slowing or agitation, changes in appetite, difficulty concentrating or indecisiveness, excessive guilt or worthlessness, and suicidal ideation may occur in the setting of depression, bipolar disorder, mood disorders caused by a common medical condition, substance-induced mood disorders, other unspecified mood disorders, and may also be associated with a range of other psychiatric disorders, including but not limited to psychotic disorders, cognitive disorders, eating disorders, anxiety disorders, and personality disorders.

[0044] Of course, the specific dose of the substance administered to achieve a therapeutic benefit will depend on the particular circumstances surrounding the case, including, for example, the specific substance administered, the route of administration, the condition being treated, and the individual being treated.

[0045] As used herein, the term "improvement of depressive symptoms" refers to a gradual reduction in one or more depressive symptoms selected from avoidance, isolation, withdrawal, anxiety, and suicidal tendencies; an increase in participation in previously enjoyed activities; and an increase in activities that have been proven to improve mood.

[0046] As used herein, the term "mitigate" means to reduce severity, alleviate, relieve, soothe, lessen, be more manageable.

[0047] As used herein, the term "relieve" means to reduce severity, alleviate, relieve, lessen, lessen, be more manageable.

[0048] As used herein, the term "concurrently" means that the compounds are administered "simultaneously," at the same time, or in the same composition. In an embodiment, the compounds may be administered simultaneously. In an embodiment, the compounds may be administered in the same composition.

[0049] As used herein, the term "sequentially" means that the compounds are administered in a certain order or consecutively.

[0050] In one type of embodiment, santanafacil and escitalopram can be co-administered or administered in a single oral dosage form containing both active substances. In another related embodiment, santanafacil and escitalopram can be co-administered or administered in two or more oral dosage forms containing one or both active substances. Optionally, the single dosage form or separate dosage forms are once-daily formulations, i.e., once-daily administration of each dosage form is sufficient to treat the desired CNS disorder. In another embodiment, santanafacil and escitalopram can be administered sequentially.

[0051] In another embodiment, santanafacil and escitalopram can be administered at different times of the day, for example, santanafacil can be administered in the morning and escitalopram can be administered in the evening. In another embodiment, santanafacil and escitalopram can be administered with food. In another embodiment, santanafacil and escitalopram can be administered without food. In another embodiment, santanafacil can be administered with food and escitalopram can be administered without food. Alternatively, in another embodiment, santanafacil can be administered without food and escitalopram can be administered with food.

[0052] If a patient needs to stop treatment with sentanafidine and escitalopram, to minimize withdrawal symptoms, the patient can slowly and gradually stop the medication by slowly reducing the dose of the medication until the body adjusts to the lower levels of the medication.

[0053] As used herein, the term "comprising" means that other agents, elements, steps or features may be included in addition to what is specified.

[0054] As used herein, the term "treatment" includes one or more of the following:

[0055] (a) relieve or alleviate at least one symptom of major depressive disorder in a subject,

[0056] (b) relieve or reduce the intensity and / or duration of manifestations of major depressive disorder experienced by the subject, and

[0057] and (c) prevent, delay the onset (i.e., the period of time before clinical manifestation of major depressive disorder), and / or reduce the risk of developing or worsening major depressive disorder.

[0058] In jurisdictions that prohibit patenting of methods practiced on humans, "administering" a composition to a human subject shall be limited to prescribing a controlled substance for self-administration by a human subject by any technique (e.g., oral, inhalation, topical application, injection, insertion, etc.). This is intended to be the broadest reasonable interpretation consistent with the statute or regulation defining patentable subject matter. In jurisdictions that do not prohibit patenting of methods practiced on humans, "administering" a composition includes both methods practiced on humans and the activities described above.

[0059] Patients with “treatment-resistant depression” include those who (1) have not responded to standard doses of multiple antidepressants (e.g., SSRIs) for at least 6 weeks (i.e., significantly better than placebo in double-blind studies) and (2) have not responded to standard doses of a single antidepressant (e.g., SSRI) (monotherapy) for at least 12 weeks.

[0060] As used herein, the term "extended release dosage form" is equivalent to extended release. A dosage form can be characterized by its overall release profile, such as the curve generated by multiple regions when there are multiple regions in the dosage form. A dosage form that exhibits extended release characteristics can be characterized as a sustained release dosage form, even if it contains an immediate release region in addition to a sustained release formulation region such as beads. Likewise, a dosage form that exhibits extended release characteristics can be characterized as a sustained release dosage form, even if it contains a delayed release region in addition to a sustained release formulation region such as beads.

[0061] As used herein, the terms "extended release," "sustained release," "modified release," and "sustained or modified release" refer to the release of the active ingredient over an extended period of time compared to an immediate release formulation, resulting in lower peak plasma concentrations and a prolonged T max.

[0062] As used herein, "XR" means extended release.

[0063] As used herein, "QD" means "once daily."

[0064] As used herein, "as an adjunct" refers to another therapy used with a primary therapy, with the intent to assist the primary therapy, or in combination or co-administered with the primary therapy. For example, a primary therapy with santanafacil or a pharmaceutically acceptable salt thereof may be co-administered with a secondary therapy during the course of treatment, or administered in accordance with other regimens.

[0065] As used herein, the term "co-administration" refers to the administration of two or more agents within a 24-hour period of time from each other, for example, as part of a clinical treatment regimen. Optionally, "co-administration" refers to the administration of two or more agents within 2 hours of each other. Optionally, "co-administration" refers to the administration of two or more agents within 30 minutes of each other. Optionally, "co-administration" refers to the administration of two or more agents within 15 minutes of each other. Optionally, "co-administration" refers to administration at the same time, as part of a single formulation or as multiple formulations administered by the same or different routes.

[0066] As used herein, an adverse event (AE) refers to any untoward medical occurrence in a patient that does not necessarily have a causal relationship to a disclosed treatment. For preplanned procedures where the underlying condition is known and no exacerbation occurs, adverse events do not include information recorded as medical history at screening.

[0067] An adverse reaction is any undesirable unexpected response to an investigational medicinal product (IMP) at any dose administered. AEs are graded on a 3-point scale, where 1 is mild (e.g., discomfort noted but not interfering with daily activities); 2 is moderate (e.g., discomfort sufficient to reduce or interfere with normal daily activities); and 3 is severe (e.g., inability to work or conduct normal daily activities).

[0068] A suspected adverse reaction is any AE for which there is a reasonable possibility that the IMP caused the AE. For the purposes of an Investigational New Drug (IND) safety report, “reasonable possibility” means there is evidence of a causal relationship between the IMP and the AE. A suspected adverse reaction means that there is a low degree of certainty about the causal relationship.

[0069] As used herein, the term "treatment-emergent AE" (TEAE) is defined as an AE with an onset date at or after the start of double-blind treatment. In more detail, TEAEs are all AEs that begin to occur after the start of double-blind IMP treatment; or if the event persists from baseline and worsens, is severe, is related to IMP, or results in death, IMP is discontinued, interrupted, or reduced.

[0070] As used herein, the term "serious adverse event" (SAE) includes any event resulting in any of the following outcomes: death; life-threatening, i.e., the subject was at immediate risk of death at the time of the event, but does not include events that could result in death if they occurred in a more severe form; persistent or severe incapacity / disability or severe disruption of the ability to perform normal life functions; requiring inpatient hospitalization or prolonged hospitalization; congenital anomaly / birth defect; other medically significant event that, based on appropriate medical judgment, could endanger the subject and may require medical or surgical intervention to prevent one of the above outcomes; for example, allergic bronchospasm requiring intensive treatment in the emergency room or at home, blood dyscrasias or seizures not requiring hospitalization, or the development of drug dependence or drug abuse.

[0071] As used herein, "non-serious adverse events" are all AEs that do not meet the criteria for a "serious" AE. As used herein, "adverse events of special concern" refer to noteworthy events for a particular product / IMP or product class that a sponsor may wish to monitor carefully.

[0072] Extended-release sentanafide (CTN XR) dosage form

[0073] The methods disclosed herein may include administering CTN or a pharmaceutically acceptable salt thereof in an extended release dosage form comprising a plurality of CTN beads, each of which comprises a core particle comprising CTN or a pharmaceutically acceptable salt thereof and an excipient, and wherein the plurality of CTN beads comprises a mixture of one or more immediate 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 this type of formulation. The features of the described formulations, such as the ratio of different bead types, also apply to unit dosage forms, such as a collection of beads set in a capsule.

[0074] Suitable extended-release CTN dosage forms are described in U.S. patent application Ser. No. 17 / 677,726, filed on February 22, 2022, the disclosure of which is incorporated herein by reference in its entirety.

[0075] The disclosed dosage forms can be measured before administration to obtain the appropriate CTN dosage strength, or the preparations can be packaged in unit dosage forms, such as in capsules, sachets, etc. In the alternative, the preparations can be compounded in unit dosage forms, for example by compression into a single unit form, such as a tablet.

[0076] The extended release dosage form may include a plurality of CTN-containing regions, optionally, the plurality of CTN regions may include, for example, one or more release characteristics selected from delayed release, sustained release, immediate release, and delayed-sustained release. The regions may be physically connected or separated. For example, a dosage form includes a plurality of CTN-containing beads (CTN beads), each of the plurality of CTN beads including a core particle and an excipient. The plurality of CTN beads may include one or more types of beads selected from immediate release beads, sustained release beads, and delayed release beads, optionally including a combination of one or more immediate release beads, one or more sustained release beads, and one or more delayed release beads.

[0077] The extended release dosage form can be provided in a unit dosage form, for example as a collection of beads disposed in a capsule shell or as a collection of beads disposed in a bag. In another type of embodiment, the collection of particles is compressed into a tablet form, with or without extragranular components, such as extragranular disintegrants. In view of the disclosure herein, other forms will be apparent to the skilled person.

[0078] Also provided for the methods and uses described herein is a dosage form comprising CTN and an excipient, wherein the pharmaceutical dosage form has a bimodal in vivo absorption profile.

[0079] As described above, the dosage form according to the present disclosure may include a plurality of CTN beads, including one or more types selected from immediate release beads, sustained release beads, delayed release beads, and delayed-sustained release beads. The plurality of CTN-containing beads may include at least a portion of the beads comprising a delayed release or delayed-sustained release coating, at least a portion of the beads comprising a sustained release coating, and at least a portion of the beads being immediate release beads. This dosage form has been shown to exhibit favorable pharmacokinetics, is suitable for administration to pediatric subjects, and is suitable for once-daily administration. Without wishing to be bound by any particular theory, it is envisioned that pharmacokinetics are affected by a plurality of CTN beads having a combination of bead types including immediate release, sustained release, and delayed release.

[0080] As used herein, the term "wt%" is the weight percentage based on the total weight of the material being described, e.g., the core particle or coating or total bead as described in context or explicitly. Unless otherwise indicated, "wt%" is intended to describe the weight percentage based on dry weight (e.g., for the core particle after drying). Unless otherwise indicated, the terms "wt%" and "wt%" are used interchangeably herein.

[0081] Although the description herein refers to beads, and beads such as those made by extrusion and spheronization may have certain advantages such as greater uniformity and size, particles of any size and shape and made by other methods are also contemplated as alternatives, as are monolithic tablet dosage forms.

[0082] All ranges set forth herein include all possible subsets of ranges and any combination of such subset ranges. Unless otherwise stated, the default range includes the endpoints. Where a range of values ​​is provided, it is to be understood that each intermediate value between the upper and lower limits of the range and any other described or intermediate values ​​within the described range are encompassed within the present disclosure. The upper and lower limits of these smaller ranges may be independently included within the described smaller ranges and are also encompassed within the present disclosure, subject only to any specifically excluded limits within the described ranges. Where the described range includes one or two limits, it is also contemplated that one or two of the ranges excluding those included limits are included as part of the present disclosure.

[0083] Bead preparation

[0084] In some embodiments, the plurality of beads comprises a mixture of one or more immediate release beads and one or more sustained release beads. In some embodiments, the amount of CTN may be present in a collection of one or more immediate release beads and in a collection of one or more sustained release beads at a ratio in the range of about 1:100 to about 1:1 by weight. In some embodiments, the amount of CTN may be present in a collection of one or more immediate release beads and in a collection of one or more sustained release beads at a ratio in the range of about 1:50 to about 1:1, or in the range of about 1:20 to about 1:1, or in the range of about 1:15 to about 1:1, for example, 1:10 by weight.

[0085] In some embodiments, the plurality of beads comprises a mixture of one or more immediate release beads and one or more delayed release beads. In some embodiments, the amount of CTN may be present in a collection of one or more immediate release beads and in a collection of one or more delayed release beads at a ratio in the range of about 1:100 to about 1:1 by weight. In some embodiments, the amount of CTN may be present in a collection of one or more immediate release beads and in a collection of one or more delayed release beads at a ratio in the range of about 1:50 to about 1:1, or in the range of about 1:20 to about 1:1, or in the range of about 1:15 to about 1:1, for example, 1:10 by weight.

[0086] 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 amount of CTN may be present in a collection of one or more delayed release beads and a collection of one or more sustained release beads in a ratio 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, for example about 1:1 by weight.

[0087] In some embodiments, the plurality of beads comprises a mixture of one or more immediate release beads and one or more delayed-sustained release beads. In some embodiments, the amount of CTN may be present in a collection of one or more immediate release beads and in a collection of one or more delayed-sustained release beads at a ratio in the range of about 1:100 to about 1:1 by weight. In some embodiments, the amount of CTN may be present in a collection of one or more immediate release beads and in a collection of one or more delayed-sustained release beads at a ratio in the range of about 1:50 to about 1:1, or in the range of about 1:20 to about 1:1, or in the range of about 1:15 to about 1:1, for example, 1:10 by weight.

[0088] In some embodiments, the multiple beads include a mixture of one or more immediate release beads, one or more sustained release beads and one or more delayed release beads. In an embodiment, the ratio of CTN can be based on the weight of CTN in the ratio of about 0.1-1: 1-20: 1-20 weight parts range is present in the one or more immediate release beads, one or more sustained release beads and one or more delayed release beads. In some embodiments, the ratio of CTN can be based on the weight of CTN in the ratio of about 0.5-1: 5-20: 5-20 weight parts range is present in the one or more immediate release beads, one or more sustained release beads and one or more delayed release beads. In some embodiments, the ratio of CTN or its pharmaceutically acceptable salt can be based on the weight of CTN in the ratio of about 0.7-1.3: 3-6: 3-6 weight parts range is present in the one or more immediate release beads, one or more sustained release beads and one or more delayed release beads. In an embodiment, the ratio of CTN or a pharmaceutically acceptable salt thereof can be present in the one or more immediate release beads, the one or more sustained release beads, and the one or more delayed release beads in a ratio 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 that can be present in the one or more immediate release beads, the one or more sustained release beads, and the one or more delayed release beads can be 1:3.6:3.6.

[0089] In some embodiments, the multiple beads include a mixture of one or more immediate release beads, one or more sustained release beads and one or more delayed-sustained release beads. In some embodiments, the ratio of CTN can be based on the weight of CTN in the range of about 0.1-1: 1-20: 1-20 weight parts in the ratio of the one or more immediate release beads, one or more sustained release beads and one or more delayed-sustained release beads. In some embodiments, the ratio of CTN or its pharmaceutically acceptable salt can be based on the weight of CTN in the range of about 0.5-1: 5-20: 5-20 weight parts in the ratio of the one or more immediate release beads, one or more sustained release beads and one or more delayed-sustained release beads. In some embodiments, the ratio of CTN or its pharmaceutically acceptable salt can be based on the weight of CTN in the range of about 0.7-1.3: 3-6: 3-6 weight parts in the ratio of the one or more immediate release beads, one or more sustained release beads and one or more delayed-sustained release beads. In some embodiments, the ratio of CTN or a pharmaceutically acceptable salt thereof may be present in the one or more immediate release beads, the one or more sustained release beads, and the one or more delayed-sustained release beads in a ratio ranging from 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 may be present in the one or more immediate release beads, the one or more sustained release beads, and the one or more delayed-sustained release beads in a ratio of about 1:3.6:3.6 parts by weight based on the weight of CTN.

[0090] In some embodiments, the immediate release beads may be present in the formulation or dosage form in an amount ranging from about 1% to about 75% based on the total weight of the plurality of CTN beads in the formulation or dosage form. For example, the immediate release beads are present in the formulation in an amount ranging from about 1% to about 60%, or about 1% to about 50%, or about 5% to about 50%, or about 5% to about 40%, or about 5% to about 30%, or about 5% to about 25%, or about 10% to about 30%, 9% to about 55%, or about 18% to about 28%, or about 5% to about 20%, or about 5% to about 15%, or about 1% to about 25%, or about 1% to about 10%. In an embodiment, the immediate release beads may be 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 an embodiment, the immediate release beads may be 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 immediate release beads may be 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 immediate release beads may 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; such embodiments are particularly contemplated when the drug load in the beads is from about 40% to about 60% by weight, such as 50% by weight. In some embodiments, the immediate release beads may 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; such embodiments are particularly contemplated when the drug load in the beads is from about 5% to about 15% by weight, such as 10% by weight. In some embodiments, the immediate release beads may be 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.

[0091] In some embodiments, the immediate release bead or bead core may include CTN in an amount ranging from about 5 wt % to about 90 wt % based on the total weight of the bead or bead core. For example, the immediate release bead or bead core may include CTN in an amount ranging from about 5 wt % to about 85 wt %, about 5 wt % to about 80 wt %, about 5 wt % to about 60 wt %, about 5 wt % to about 30 wt %, or about 25 wt % to about 60 wt %, or about 40 wt % to about 60 wt %, or about 5 wt % to about 15 wt % based on the total weight of the bead or bead core. In some embodiments, the immediate release bead or bead core may include CTN in an amount ranging from 5 wt % to 15 wt % based on the total weight of the bead or bead core. In some embodiments, the immediate release bead or bead core may include CTN in an amount ranging from 40 wt % to 60 wt % of the immediate release bead based on the total weight of the immediate release bead or bead core. In some embodiments, the immediate release bead or bead core may include CTN in an amount ranging from about 70 wt % to about 90 wt %, or from about 75 wt % to about 80 wt % based on the total weight of the immediate release bead or bead core. In some embodiments, the pharmaceutical dosage form herein may include a first immediate release bead or bead core (wherein CTN is present in an amount ranging from 5 wt % to 15 wt % based on the total weight of the immediate release bead or bead core) and a second immediate release bead (wherein CTN is present in an amount ranging from 40 wt % to 60 wt % based on the total weight of the immediate release bead or bead core). In some embodiments, the pharmaceutical dosage form may include a bead core (which has CTN in an amount ranging from about 70 wt % to about 90 wt %, or from about 75 wt % to about 80 wt % based on the total weight of the bead core) and one or more coatings on the bead core.

[0092] In some embodiments, the sustained release beads may be present in the formulation or dosage form in an amount ranging from about 5% to about 80% based on the total weight of the plurality of CTN beads in the formulation or dosage form. For example, the sustained release beads 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 may be 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.

[0093] In some embodiments, the sustained release beads may include CTN in an amount ranging from 10% to 95% by weight based on the total weight of the sustained release beads. For example, the sustained release beads may include CTN in an amount ranging from about 30% to about 90% by weight, about 40% to about 90% by weight, or about 50% to about 90% by weight, or about 50% to about 80% by weight, or about 50% to about 70% by weight based on the total weight of the sustained release beads. In some embodiments, the sustained release beads may include CTN in an amount ranging from 40% to 90% by weight based on the total weight of the sustained release beads. In an embodiment, the sustained release beads may include CTN in an amount ranging from 50% to 70% by weight based on the total weight of the sustained release beads.

[0094] In some embodiments, the delayed release beads may be present in the formulation or dosage form in an amount ranging from about 5% to about 80% based on the total weight of the plurality of CTN beads in the formulation or dosage form. For example, the delayed release beads 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 may be 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.

[0095] In some embodiments, the delayed-release beads may include CTN in an amount ranging from 10 wt % to 95 wt % based on the total weight of the delayed-release beads. For example, the delayed-release beads may include CTN in an amount ranging from about 30 wt % to about 90 wt %, from about 40 wt % to about 90 wt %, or from about 50 wt % to about 90 wt %, or from about 50 wt % to about 85 wt %, or from about 50 wt % to about 70 wt % based on the total weight of the delayed-release beads. In some embodiments, the delayed-release beads may include CTN in an amount ranging from 40 wt % to 90 wt % based on the total weight of the delayed-release beads. In some embodiments, the delayed-release beads may include CTN in an amount ranging from 50 wt % to 70 wt % based on the total weight of the delayed-release beads.

[0096] In some embodiments, the immediate release beads may 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, the sustained release beads may 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 the delayed release beads are present in an amount ranging from about 40% to about 50% by weight of the formulation or dosage form. In some embodiments, the immediate release beads may be present in an amount ranging from about 4% to about 28% by weight of the formulation or dosage form, the sustained release beads may be present in an amount ranging from about 15% to about 40% by weight of the formulation or dosage form, and the delayed release beads are present in an amount ranging from about 30% to about 65% by weight of the formulation or dosage form.

[0097] In some embodiments, the immediate release beads may be present in the formulation or dosage form in an amount ranging from about 11 wt % to about 17 wt % of the formulation or dosage form, the sustained release beads may be present in the formulation or dosage form in an amount ranging from about 42 wt % to about 48 wt % of the formulation or dosage form, and the delayed release beads (or delayed-sustained release beads) may be present in the formulation or dosage form in an amount ranging from about 38 wt % to about 44 wt % of the formulation or dosage form; such embodiments are particularly contemplated when the drug load in each bead type is about 5 wt % to about 10 wt %, about 45 wt % to about 55 wt %, and about 45 wt % to about 55 wt %, respectively, based on the total weight of the beads. In an embodiment, the immediate release beads may be present in the formulation or dosage form in an amount ranging from about 43% to about 49% by weight of the formulation or dosage form, the sustained release beads may be present in the formulation or dosage form in an amount ranging from about 25% to about 31% by weight of the formulation or dosage form, and the delayed release beads may be present in the formulation or dosage form in an amount ranging from about 38% to about 44% by weight of the formulation or dosage form; such embodiments are particularly contemplated when the drug load in each bead type is from about 45% to about 55% by weight.

[0098] Core bead preparation

[0099] Each of the plurality of CTN beads comprises a core particle. The core particle comprises CTN and an excipient. The CTN beads may consist of the core particle itself without a coating. As further described below, the CTN beads may comprise a core particle and one or more coatings.

[0100] In some embodiments, the core particles can be characterized by having a certain particle size distribution. In an embodiment, at least a portion of the core particles or all of the core particles of the plurality of CTN beads may have a core particle size (maximum diameter) of about 0.2 mm to about 2 mm, or about 0.3 mm to about 1.5 mm, about 0.4 mm to about 1.5 mm. For example, at least a portion of the core particles of the plurality of CTN beads have a core particle size of about 0.2 mm to about 2 mm, or about 0.3 mm to about 1.5 mm, 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 an embodiment, at least a portion of the core particles of the plurality of CTN beads have a core particle size of about 0.5 mm to about 0.71 mm. In an embodiment, the core particles of the plurality of CTN beads have a core particle size of about 0.5 mm to about 0.71 mm. The core particle size can be selected, for example, by sieving to exclude particles having a particle size outside the desired range. In an embodiment, the particle size distribution of the core particles can be characterized by at least 60% by weight of the core particles having a particle size in the range of about 0.4 mm to about 1.5 mm. For example, the particle size distribution of the core particles can be characterized by at least 60% by weight of the core particles having a particle size in the range of about 0.4 mm to about 1.4 mm, or about 0.4 mm to about 1.3 mm, or about 0.4 mm to about 1.2 mm, or about 0.4 mm to about 1.1 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm. In an embodiment, the particle size distribution of the core particles can be characterized by at least 60% by weight of the core particles having a particle size in the range of about 0.5 mm to about 0.71 mm. In some embodiments, the particle size distribution of the core particles is characterized by at least 80% by weight of the core particles having a particle size in the range of about 0.4 mm to about 1.5 mm. For example, the particle size distribution of the core particles can be characterized by at least 80% by weight of the core particles having a particle size in the range of about 0.4 mm to about 1.4 mm, or about 0.4 mm to about 1.3 mm, or about 0.4 mm to about 1.2 mm, or about 0.4 mm to about 1.1 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm. In an embodiment, the particle size distribution of the core particles can be characterized by at least 80% by weight of the core particles having a particle size in the range of about 0.5 mm to about 0.71 mm.In some embodiments, the particle size distribution of the core particles is characterized by at least 90% by weight of the core particles having a particle size in the range of about 0.4 mm to about 1.5 mm. For example, the particle size distribution of the core particles can be characterized by at least 90% by weight of the core particles having a particle size in the range of about 0.4 mm to about 1.4 mm, or about 0.4 mm to about 1.3 mm, or about 0.4 mm to about 1.2 mm, or about 0.4 mm to about 1.1 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm. In embodiments, the particle size distribution of the core particles can be characterized by at least 90% by weight of the core particles having a particle size in the range of about 0.5 mm to about 0.71 mm. In some embodiments, the plurality of CTN beads can have a median particle size (diameter) in the range of about 0.2 mm to about 2.8 mm. For example, the median particle size (diameter) of the plurality of CTN beads can be in the range of about 0.2 mm to about 2.5 mm, or about 0.2 mm to about 2.0 mm, or about 0.7 mm to about 2.5 mm, or about 0.7 mm to about 2.8 mm, or about 0.5 mm to about 2.8 mm, or about 0.8 mm to about 1.7 mm, or about 0.5 mm to about 1.2 mm, or about 0.5 mm to about 1.0 mm, or about 0.5 mm to about 0.71 mm. In some embodiments, the median particle size (diameter) of the plurality of CTN beads can be in the range of about 0.5 mm to about 0.71 mm.

[0101] The amount of CTN in the core particles may be an amount in the range of about 5 wt % to about 95 wt %. In some embodiments, at least a portion of the plurality of CTN beads include core particles having a CTN content in the range of about 5 wt % to about 75 wt %. For example, at least a portion of the plurality of CTN beads include core particles having a CTN content in the range of about 5 wt % to about 70 wt %, or about 10 wt % to about 70 wt %, or about 20 wt % to about 60 wt %, or about 30 wt % to about 60 wt %, or about 40 wt % to about 60 wt %, or about 45 wt % to about 55 wt %. In some embodiments, at least a portion of the plurality of CTN beads include core particles having a CTN content in the range of about 45 wt % to about 55 wt %. In some embodiments, at least a portion of the plurality of CTN beads include core particles having a CTN content of about 50 wt %. For example, immediate release beads may include core particles having a CTN content of about 10 wt % or about 50 wt %. In some embodiments, at least a portion of the plurality of CTN beads include core particles having a CTN content in the range of about 25 wt % to about 95 wt %. For example, at least a portion of the plurality of CTN beads include core particles having a CTN content in the range of about 25 wt % to about 90 wt %, or about 35 wt % to about 90 wt %, or about 45 wt % to about 90 wt %, or about 50 wt % to about 85 wt %, or about 60 wt % to about 85 wt %, or about 75 wt % to about 85 wt %, or about 50 wt %, about 60 wt %, about 70 wt %, or about 80 wt %. In an embodiment, at least a portion of the plurality of CTN beads include core particles having a CTN content in the range of about 75 wt % to about 85 wt %. In some embodiments, at least a portion of the plurality of CTN beads include core particles having a CTN content of about 80 wt %. For example, sustained release beads may include core particles having a CTN content of about 80 wt %. For example, the delayed release beads include core particles having a CTN content in the range of about 80 wt %.

[0102] The core particles disclosed herein include excipients. In some embodiments, the excipients include one or more materials selected from fillers, binders, glidants, surfactants, polymer coatings, lubricants, disintegrants and plasticizers. In some embodiments, the excipients may include one or more materials selected from fillers, binders, glidants, surfactants, polymer coatings and plasticizers. In some embodiments, the excipients may include fillers and binders. In some embodiments, the excipients may include binders and polymer coatings. In some embodiments, the excipients may include fillers, binders and polymer coatings. In some embodiments, the excipients may include fillers, binders, polymer coatings and plasticizers. In some embodiments, the pharmaceutical preparation may not contain a disintegrant. In an embodiment, the dosage form containing the pharmaceutical preparation may not contain a disintegrant.

[0103] Filler can include but not limited to lactose, sucrose, glucose, starch, microcrystalline cellulose, microfine cellulose, mannitol, sorbitol, calcium hydrogen phosphate, aluminum silicate, amorphous silicon dioxide and sodium chloride, starch and dehydrated calcium hydrogen phosphate. In some embodiments, the filler is insoluble in water, but it may absorb water. In some embodiments, the filler is a spheronization aid. Spheronization aids can include one or more of, for example, crospovidone, carrageenan, chitosan, pectin acid, glyceride, β-CD, cellulose derivatives, microcrystalline cellulose, powdered cellulose, Polyplasdone crospovidone and polyethylene oxide. In one type of embodiment, the filler includes microcrystalline cellulose.

[0104] Binders may include, but are not limited to, cellulose ethers, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, propyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose (hydroxypropyl methyl cellulose, such as hydroxypropyl methyl cellulose 2910, METHOCEL TM E-5 [CAS 9004-65-3], the latter of which can be obtained from Sigma or DuPont TM In some embodiments, the binder is selected from wet binders. In some embodiments, the binder is selected from cellulose ethers, such as hypromellose.

[0105] Surfactants may include, but are not limited to, anionic surfactants (including sodium lauryl sulfate, sodium deoxycholate, sodium sulfosuccinate dioctyl ester, and sodium stearyl fumarate), nonionic surfactants (including polyoxyethylene ether and polysorbate 80), and cationic surfactants (including quaternary ammonium compounds). In some embodiments, the surfactant is selected from anionic surfactants, such as sodium lauryl sulfate.

[0106] Disintegrants may include, but are not limited to, starch, cross-linked sodium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, cross-linked calcium carboxymethylcellulose, cross-linked polyvinyl pyrrolidone, and sodium starch glycolate, low-substituted hydroxypropyl cellulose, and hydroxypropyl starch.

[0107] Glidants may include, but are not limited to, polyethylene glycol of various molecular weights, magnesium stearate, calcium stearate, calcium silicate, fumed silica, magnesium carbonate, magnesium lauryl sulfate, aluminum stearate, stearic acid, palmitic acid, cetyl alcohol, stearyl alcohol, and talc.

[0108] Lubricants may include, but are not limited to, stearic acid, magnesium stearate, calcium stearate, aluminum stearate, and siliconized talc.

[0109] In some embodiments, the excipient may include one or more materials selected from the group consisting of lactose, mannitol, corn starch, microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hydroxypropyl methylcellulose), polyvinyl pyrrolidone, talc, polysorbate 80, glyceryl monostearate, triethyl citrate, polyvinyl alcohol-polyethylene glycol graft copolymer (e.g., Kollicoat available from Sigma), TM In some embodiments, the excipients may include microcrystalline cellulose and mannitol. In some embodiments, the excipients may include microcrystalline cellulose, talc, hypromellose and polysorbate 80. In embodiments, the excipients may include microcrystalline cellulose. In some embodiments, the core particles may include an excipient containing microcrystalline cellulose.

[0110] There is no particular limitation on the amount of filler in the core particles. In some embodiments, the amount of filler (e.g., microcrystalline cellulose) may be in the range of about 10% to about 90% by weight, about 10% to about 75% by weight, or about 10% to about 60% by weight, or at least 10% by weight, or at least 15% by weight, such as about 20% by weight, or about 30% by weight, or about 40% by weight, or about 50% by weight.

[0111] There is no particular limitation on the amount of binder in the core particles. In some embodiments, the amount of binder (e.g., hypromellose and / or polyvinyl alcohol-polyethylene glycol graft copolymer) may be in the range of about 1 wt % to about 10 wt %, or about 2 wt % to about 8 wt %, or about 4 wt % to about 6 wt %, for example, about 5 wt %.

[0112] There is no particular limitation on the amount of surfactant, such as a processing aid, in the core particles. In some embodiments, the amount of surfactant (e.g., microcrystalline cellulose) may be in the range of about 0.1 wt % to about 1 wt %, or about 0.2 wt % to about 0.8 wt %, or about 0.4 wt % to about 0.6 wt %, such as about 0.5 wt %.

[0113] Coating

[0114] In some embodiments, the disclosed extended release dosage form disclosed herein comprises a plurality of beads, wherein at least a portion of the plurality of beads are coated. In some embodiments, at least a portion of the plurality of beads may be uncoated. In an embodiment, the coating may be one or more coatings selected from a delayed release coating, a sustained release coating, and a delayed-sustained release coating. In some embodiments, at least a portion of the plurality of beads may include a delayed release coating. In some embodiments, at least a portion of the plurality of beads may include a sustained release coating. In an embodiment, at least a portion of the plurality of beads may include a delayed-sustained release coating.

[0115] Coating materials disclosed herein, such as polymers, can be delayed release coatings. In an embodiment, the delayed release coating can be a coating that will dissolve in the intestinal fluid, for example, in the small intestine, at a pH level higher than gastric fluid, such as a pH of more than 4.5, thereby allowing the release of active substances in the small intestine or in a more posterior region and substantially not in the upper part of the GI tract. In some embodiments, the enteric material begins to dissolve in an aqueous solution at a pH between about 4.5 and about 5.5. In some embodiments, the delayed release material dissolves rapidly in an aqueous solution at a pH of about 5. In another type of embodiment, the delayed release material dissolves rapidly in an aqueous solution at a pH of about 5.5. For example, a pH-sensitive material can be selected so that it does not undergo significant dissolution before the dosage form is emptied from the stomach. The pH of the small intestine gradually increases from about 4.5 to about 6.5 in the duodenal bulb to about 7.2 in the distal part of the small intestine (ileum). In some embodiments, the delayed release material will dissolve at a pH of at least 7 or at least 7.2 or at least 7.4, for example, targeted release in the distal portion of the small intestine or the colon. In some embodiments, the delayed release material is insoluble in water and gastric fluid, but will instead swell to provide a membrane through which the CTN active substance can diffuse. The insoluble polymer may also be selected so that it swells at a specific pH threshold, for example, at a pH of at least 7 or at least 7.2 or at least 7.4, for example, targeted release in the distal portion of the small intestine or the colon.

[0116] The delayed release coating material may include, but is not limited to, one or more of the following: cross-linked polyvinyl pyrrolidone; non-cross-linked polyvinyl pyrrolidone; 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; carboxymethyl cellulose; methylcellulose phthalate; methylcellulose succinate; methylcellulose phthalate succinate; methyl Cellulose phthalate half ester; ethylcellulose succinate; carboxymethylamide; potassium methacrylate divinylbenzene copolymer; polyvinyl alcohol; polyoxyethylene glycol; polyethylene glycol; sodium alginate; galactomannan; carboxypolymethylene; sodium carboxymethyl starch; copolymers of acrylic acid and / or methacrylic acid with monomers selected from the group consisting of 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 (North Rhine-Westphalia, Germany) TM L and S series, including L 100-55, L 30D-55, L 100, S100, 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-ethyl-hexyl acrylate maleic anhydride; crotonic acid-vinyl acetate copolymer; glutamic acid / glutamate copolymer; carboxymethylethylcellulose monocaprylylglyceride; polyarginine; poly(ethylene); poly(propylene); poly(ethylene oxide); poly(ethylene terephthalate); poly(vinyl isobutyl ether); poly(vinyl chloride); and polyurethane.

[0117] Combinations of delayed release coatings may also be used. In one type of embodiment, the delayed release coating dissolves at a pH of more than 7.0, or more than 7.2, or more than 7.4, for example, to provide release in the colon. For example, the delayed release coating may 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 may include one or more materials selected from the following: amylose acetate phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate trimellitate, carboxymethyl ethyl cellulose, copolymerized methacrylic acid / methyl methacrylate, copolymerized methacrylic acid / methyl methacrylate, copolymerized methacrylate / methyl methacrylate / methacrylic acid, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, styrene maleic acid copolymer, styrene vinyl pyridine copolymer. In an embodiment, the delayed release coating may include one or more materials selected from the group consisting of methacrylic acid, copolymers of methyl methacrylate and methyl acrylate, and methacrylic acid-acrylate copolymers. In an embodiment, the delayed release coating may include copolymers of methyl acrylate, methyl methacrylate, and methacrylic acid, for example, in a molar ratio of about 7:3:1 (e.g., Eudragit TM FS 30 D). Eudragit TM FS 30 D is poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) [CAS 26936-24-3] available from Evonik Industries. In other embodiments, the delayed release coating will not include cationic copolymers of ethyl acrylate, methyl methacrylate and methacrylate with quaternary ammonium groups (e.g. Eudragit TM RL and Eudragit TM RS polymers) Eudragit TM RL 30 D and Eudragit TM RS 30 D is an aqueous dispersion of a copolymer of acrylic acid and methacrylic acid esters having a low content of quaternary ammonium groups, available from Evonik Industries.

[0118] In some embodiments, the delayed release coating may also provide sustained release of CTN. In some embodiments, the delayed release coating will include an anionic polymer, optionally including a formate moiety. In some embodiments, the delayed release coating comprises a copolymer based on methyl acrylate, methyl methacrylate, and methacrylic acid (e.g., in a molar ratio of about 7:3:1) (e.g., EudragitTM Without wishing to be bound by any particular theory, it is possible that since the poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) polymer is anionic with negatively charged formate moieties (the ratio of carboxyl groups to ester groups is about 1:10), and santanafacil is a positively charged secondary amine, the polymer may affect the release rate of santanafacil from the beads due to ionic interactions.

[0119] Some examples of delayed release coatings are disclosed in U.S. Pat. No. 5,225,202 and include beeswax and glyceryl monostearate; beeswax, shellac, and cellulose; and cetyl alcohol, mastic, and shellac; and shellac and stearic acid (U.S. Pat. No. 2,809,918); polyvinyl acetate and ethylcellulose (U.S. Pat. No. 3,835,221); and neutral copolymers of polymethacrylates (Eudragit TM L30D) (FW Goodhart et al., Pharm. Tech., pp. 64-71, April 1984); copolymer of methacrylic acid and methyl methacrylate (Eudragit TM Polymers), or neutral copolymers of polymethacrylates containing metal stearates (Mehta et al., U.S. Pat. Nos. 4,728,512 and 4,794,001). Such coatings include mixtures of fats and fatty acids, shellac and shellac derivatives, and cellulose acid phthalates (e.g., those with a certain free carboxyl content). For descriptions of suitable enteric coating compositions, see also Remington's Pharmaceutical Sciences, A. Osol, ed., Mack Publishing Company, Easton, Pa. (16th ed., 1980) pp. 1590-1593, and Zeitova et al. (U.S. Pat. No. 4,432,966).

[0120] The coating materials disclosed herein, such as polymers, can be sustained release coatings. A non-limiting list of suitable sustained release materials includes hydrophilic and / or hydrophobic materials, such as gums, cellulose ethers, acrylic resins, protein-derived materials, waxes, shellacs, and oils, such as hydrogenated castor oil and hydrogenated vegetable oils. However, according to the present invention, any pharmaceutically acceptable hydrophobic or hydrophilic sustained release material capable of providing sustained release of CTN can be used. In some embodiments, the sustained release coating can include one or more materials selected from the following: alkyl celluloses, such as ethyl cellulose; acrylic and methacrylic acid polymers and copolymers; and cellulose ethers, particularly hydroxyalkyl celluloses (particularly hydroxypropyl methylcellulose) and carboxyalkyl celluloses. Acrylic acid and methacrylic acid polymers and copolymers can include methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylate, ethyl acrylate, trimethylammonioethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymers, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), polymethacrylates, polyacrylamide, poly(methacrylic anhydride) and glycidyl methacrylate copolymers. In some embodiments, the sustained release coating material is insoluble in water.

[0121] In some embodiments, the sustained release coating may include one or more materials selected from the following: alkyl cellulose, such as ethyl cellulose, acrylic acid polymers, methacrylic acid polymers, acrylic acid copolymers, methacrylic acid copolymers and cellulose ethers hydroxyalkyl cellulose (particularly hydroxypropyl methylcellulose) and carboxyalkyl cellulose. In an embodiment, the sustained release coating may include one or more materials selected from the following: hydroxyalkyl cellulose, carboxyalkyl cellulose, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylate, ethyl acrylate, trimethylammonioethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymers, poly (acrylic acid), poly (methacrylic acid), methacrylic acid alkylamine copolymers, poly (methyl methacrylate), poly (methacrylic acid) (anhydride), polymethacrylate, polyacrylamide, poly (methacrylic acid anhydride) and glycidyl methacrylate copolymers. In some embodiments, the sustained release polymer may include one or more materials selected from the following: poly [ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride], hydroxypropyl methylcellulose and poly [ethyl acrylate, methyl methacrylate]. In some embodiments, the sustained release polymer may include, for example, poly[ethyl acrylate, methyl methacrylate] (e.g., Eudragit TMNM 30 D). In an embodiment, the sustained release coating may include one or more materials selected from the group consisting of: EUDRAGIT available from Evonik Industries TM RL, RS, NE and NM series, including RL30D, RS30D, NE 30 D, NM 30 D. Combinations of sustained-release coatings are also available. Eudragit TM NM 30D [CAS 9010-88-4] and Eudragit TM NE 30D [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% available from Evonik Industries. In an embodiment, the sustained release polymer may include ethyl cellulose, such as available from DuPont TM Obtained Aquacoat TM ECD 30 D coating.

[0122] As is known in the art, one or more plasticizers may be added to the delayed release coating and / or sustained release coating to increase its 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), acetyl triethyl citrate, and triacetin. In some embodiments, the plasticizer is triethyl citrate. Although some delayed release coatings and / or sustained release coatings are flexible and do not require the addition of plasticizers, more brittle polymers (e.g., Eudragit TM L / S type, Eudragit TM RL / RS and Eudragit TM FS 30 D) will benefit from a plasticizer, such as PlasACRYL available from Evonik Industries in the range of 5 to 30 wt %, such as about 8 to about 12 wt %, based on the dry mass of the polymer. TM T20, an anti-adhesive system containing glyceryl monostearate, triethyl citrate and polysorbate 80, with a solids content of about 20%.

[0123] As is known in the art, one or more anti-adherents (anti-sticking agents) may also be added to the enteric coating mixture to reduce the stickiness of the film and prevent agglomeration. Anti-adherents include, for example, talc and glyceryl monostearate, fumed silica (e.g., AEROSIL available from Evonik Industries, Inc.), TM200), precipitated silica (e.g. SIPERNAT TM PQ) and magnesium stearate. Anti-adhesives can be used in any suitable amount, for example, in the range of about 10 wt % to 100 wt %, or about 1 wt % to about 30 wt %, or about 10 wt % to about 50 wt %, or about 10 wt % to about 30 wt %, or about 15 wt % to about 30 wt % based on the dry mass of the polymer. For example, in one embodiment, the amount of talcum is in the range of 15 wt % to about 30 wt % based on the dry mass of the polymer. In some embodiments, the amount of talcum is in the range of 1 wt % to about 10 wt % based on the dry mass of the polymer.

[0124] As known in the art, one or more surfactants may also be added to the delayed release coating and / or sustained release coating to improve substrate wetting and / or stabilize the suspension. Surfactants include, for example, polysorbate 80, sorbitan monooleate, and sodium lauryl sulfate.

[0125] The delayed release coating and / or sustained release coating can be formed by any suitable method. Coating methods include, for example, pan coating, fluidized bed coating and dry coating (e.g., hot dry coating and electrostatic dry coating). Pan coating and fluidized bed coating using solvents are generally recognized methods. In liquid coating, enteric materials and optional excipients (e.g., pigments, plasticizers and / or anti-adherents) are mixed in an organic solvent or water to form a solution or dispersion. The coating solution or dispersion is sprayed in a solid dosage form in a pan coater or fluidized bed dryer and dried by hot air. For example, in the Wurster fluidized bed coating method, a coating fluid is sprayed from the bottom of a fluidized bed device, and in an alternative, a coating fluid is applied by top spraying, and in another alternative, a tangential spray is applied.

[0126] The amount of delayed release coating applied is sufficient to achieve the desired release characteristics. For example, in one embodiment, the amount of delayed release coating will be sufficient to meet the United States Pharmacopeia (USP) <711> The requirement for a delayed release dosage form (USP 43-NF 382S) is that 10.0 wt% of the drug is not released after 2 hours in 0.1 N HCl. On the other hand, for example, using USP 43-NF 372S <711> The formulation will be sufficient to release at least 80% of the active substance in the buffer phase.

[0127] In some embodiments, the median amount of the delayed release coating disposed on the core particles is at least 10 wt % of the total weight of the CTN beads. In some embodiments, the median amount of the delayed release coating disposed on the core particles is in the range of about 10 wt % to about 50 wt %, or about 10 wt % to about 40 wt %, or about 10 wt % to about 30 wt %, or about 20 wt %, or about 12 wt % to about 50 wt %, or about 12 wt % to about 35 wt %, based on the total weight of the CTN beads. In some embodiments, the median amount of the delayed release coating disposed on the core particles is in the range of about 15 wt % to about 45 wt %, based on the total weight of the CTN beads.

[0128] In some embodiments, the median amount of the sustained release coating disposed on the core particles is at least 5 wt % of the total weight of the coated CTN beads. In some embodiments, the median amount of the sustained release coating disposed on the core particles is in the range of about 5 wt % to about 50 wt %, or about 7.5 wt % to about 45 wt %, or about 10 wt % to about 40 wt %, or about 15 wt %, or about 5 wt % to about 40 wt %, 15 wt % to about 40 wt %, or about 20 wt % to about 40 wt %, based on the total weight of the coated CTN beads. In some embodiments, the median amount of the sustained release coating disposed on the core particles is about 20 wt % to about 40 wt %, based on the total weight of the coated CTN beads.

[0129] In some embodiments, the median amount of sustained-release coating disposed on the core particles is increased by at least 5 wt % based on the total weight of the uncoated CTN beads. In some embodiments, the median amount of sustained-release coating disposed on the core particles is in the range of about 5 wt % to about 60 wt %, or about 15 wt % to about 60 wt %, or about 20 wt % to about 50 wt %, or about 5 wt % to about 40 wt %, 15 wt % to about 40 wt %, or about 20 wt % to about 40 wt %, based on the total weight of the uncoated CTN beads. In some embodiments, the median amount of sustained-release coating disposed on the core particles is about 20 wt % to about 40 wt %, based on the total weight of the uncoated CTN beads.

[0130] Other lubricants (glidants, anti-adherents) may be added to the coated beads in powder form. Anti-adherents include, for example, talc, glyceryl monostearate, fumed silica (e.g., AEROSIL TM 200) and precipitated silica (e.g. SIPERNAT TM PQ). For example, talc may be added to the coated beads, optionally in an amount of 0.1 wt % to about 3 wt % based on the total bead weight.

[0131] In addition, the coating disclosed herein may further include a pore former. The rate at which CTN is released by the release coating material may be low and can be increased by adding a pore former to the coating. Pore formers are typically hydrophilic polymers that dissolve in water and / or gastric juice to form pores in the coating layer. The amount and type of pore former material can be selected to affect the release profile and obtain the desired release profile. In an embodiment, the pore former may include one or more materials selected from the following: hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, poloxamer 188, polyvinyl pyrrolidone, d-mannitol, methylcellulose, polyvinyl alcohol-polyethylene glycol graft copolymers and sugars.

[0132] In an embodiment, the pore-forming agent may include one or more materials selected from the following: hydroxypropyl methylcellulose, hydroxypropyl cellulose and polyvinyl pyrrolidone. In some embodiments, the pore-forming agent includes hydroxypropyl methylcellulose. In some embodiments, the pore-forming agent does not include polyvinyl pyrrolidone. In some embodiments, when the release coating includes ethyl cellulose, the pore-forming agent does not include polyvinyl pyrrolidone. The pore-forming agent may be included in the release coating in an amount in the range of about 5% by weight or more, or about 10% by weight or more, or about 13% by weight or more, or about 15% by weight or more, or about 5% by weight to about 20% by weight based on the total weight of the coating. In some embodiments, the pore-forming agent is present in an amount of about 15% by weight based on the total weight of the coating or less than 50% by weight, or less than 20% by weight, or in an amount in the range of about 1% by weight to about 16% by weight or about 1% by weight to about 12% by weight.

[0133] It is also contemplated herein that at least a portion or all of the plurality of beads include a coating that includes only soluble polymers that do not affect the release of the CTN from the formulation, such as a seal coat. In an embodiment, the seal coat may include hydroxypropyl methylcellulose. In an embodiment, the core beads may be coated with a seal coat prior to other coatings. In an embodiment, at least a portion of the core particles are seal coated.

[0134] In some embodiments, the pharmaceutical preparation may include a plurality of CTN beads encapsulated in one or more containers, such as selected from capsules, sachets, and stick packs. In some embodiments, the pharmaceutical preparation includes a plurality of CTN beads encapsulated 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 plant-based hard capsule.

[0135] Thus, for example, some embodiments combining various of the above features include a pharmaceutical formulation comprising a plurality of CTN beads, the beads comprising a core particle comprising CTN and a filler (optionally microcrystalline cellulose and / or mannitol), wherein the core particles are characterized by a particle size (maximum diameter) distributed in the range of about 0.2 mm to about 1.5 mm, or about 0.3 mm to about 1.2 mm, or about 0.5 mm to about 0.85 mm, and wherein the core particles may include an optional coating surrounding the core particles, wherein the plurality of CTN beads include immediate release beads, sustained release beads, and delayed release beads.

[0136] Unit dosage forms containing CTN formulations according to the disclosure herein can include any suitable CTN strength. For example, the amount of CTN in a unit dosage form can 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.

[0137] Features

[0138] As described above, the pharmaceutical formulation or dosage form can be advantageously designed to have one or more pharmacokinetic characteristics, for example, in humans. The pharmaceutical formulation herein can be characterized by the amount of CTN released in vitro over a given time period. In an embodiment where the pharmaceutical formulation includes immediate release beads, at least 90% of the CTN or its salt is released from the immediate release beads within a time range of 0 to 2 hours. In an embodiment where the pharmaceutical formulation includes sustained release beads, at least 90% of the CTN is released from the sustained release beads within a time range of 2 to 6 hours. In an embodiment where the pharmaceutical formulation includes delayed release beads, at least 90% of the CTN or its salt is released from the delayed release beads within a time range of 4 to 14 hours. In an embodiment where the pharmaceutical formulation includes delayed-sustained release beads, at least 90% of the CTN or its salt is released from the delayed-sustained release beads within a time range of 4 to 14 hours.

[0139] In some embodiments, the formulation or dosage form can be characterized by one or more in vivo and / or in vitro release profiles selected from immediate release, sustained release, delayed release, and delayed-sustained release. In some embodiments, the formulation, such as a formulation suitable for pediatric use, can optionally have a multiphasic release profile when tested in an acidic medium for 2 hours and then in a pH 7.4 buffered medium. For example, when tested according to USP <711> The release profile may have a multiphasic release profile, optionally at least a two-phase release profile, optionally at least a three-phase release profile when measured using Apparatus I (basket) in 1000 mL 0.1 N hydrochloric acid at 37°C + / - 0.5°C and 100 rpm for 2 hours, followed by Apparatus I (basket) in 1000 mL pH 7.4 phosphate buffer solution at 37°C + / - 0.5°C and 100 rpm for 16 hours. Such a profile may optionally be characterized by a release of about 22% to about 45% of the CTN at the 3 hour mark, further optionally by a release of about 40% to about 65% of the CTN at the 8 hour mark, further optionally by a release of about 65% to about 95% of the CTN at the 12 hour mark, further optionally by having such release rates at all three time points. In another type of embodiment, such a profile may be characterized by releasing about 24% to 48% of the CTN at the 3 hour mark, further optionally by releasing at least 66% of the CTN at the 6 hour mark, further optionally by releasing at least 86% of the CTN at the 10 hour mark, further optionally by having such release rates at all three time points. Further optionally, the release profile may be characterized by releasing 49% to 73% at the 4 hour mark.

[0140] The pharmaceutical formulations herein may optionally be characterized by providing a bimodal in vivo absorption profile. In some embodiments, the pharmaceutical formulations having a bimodal in vivo absorption profile provide a first sentanafadine plasma C in the 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 sentanfacil plasma C provided by the plurality of CTN beads max In the range of about 320 ng / mL to about 420 ng / mL or about 325 ng / mL to about 390 ng / mL. In some embodiments, the pharmaceutical formulation having a bimodal in vivo absorption profile provides a second sentanafide plasma C at a time in the range of about 6 hours to 10 hours, or about 7 hours to 9 hours, or about 7.5 to about 8.5 hours. max In some embodiments, the second sentanafide plasma C provided by the plurality of CTN beads maxIn the range of about 450 ng / mL to about 550 ng / mL or about 470 ng / mL to about 530 ng / mL. In some embodiments, the in vivo absorption profile has a first sentanafide plasma C max and second sentanafacil plasma C max wherein the first sentanfacillin plasma C max With the second sentanafacil plasma C max Separated by a time 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.

[0141] Pharmaceutical formulations and uses thereof as described herein may be designed to provide one or more of the following pharmacokinetic profile characteristics.

[0142] The formulation can provide a relatively rapid increase in santanafacil plasma concentration for a subject, thereby reaching or satisfying a therapeutic concentration in a relatively short period of time. Thus, for example, the formulation can provide a santanafacil plasma concentration (C ) of at least 150 ng / mL, or at least 200 ng / mL, or at least 250 ng / mL, or at least 280 ng / mL, or in the range of about 180 ng / mL to about 610 ng / mL, or about 200 ng / mL to about 590 ng / mL, or about 220 ng / mL to about 540 ng / mL, or about 245 ng / mL to about 490 ng / mL, for an adult subject at one hour after administration. 1h ); Optionally, such exposure can be achieved using a dosage strength ranging from about 145 mg to about 185 mg CTN, for example 164.4 mg CTN.

[0143] The formulation can provide an adult subject with a cumulative plasma exposure of CTN (AUC 100) of at least 30 ng·h / mL, or at least 40 ng·h / mL, or at least 100 ng·h / mL, or at least 200 ng·h / mL, or 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, to an adult subject one hour after administration. 0-1h ); Optionally, such exposure can be achieved using a dosage strength ranging from about 145 mg to about 185 mg CTN, for example 164.4 mg CTN.

[0144] The formulation can maintain the plasma concentration of CTN in an adult subject within the therapeutic range over an extended period of time to achieve a continuous therapeutic effect. Thus, for example, the formulation can provide a post-administration CTN plasma concentration that is maintained 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 in the range of about 150 ng / mL to about 4125 ng / mL, or about 160 ng / mL to about 3960 ng / mL, or about 180 ng / mL to about 3630 ng / mL, or about 200 ng / mL to about 3300 ng / mL over a period of 2 to 8 hours after administration; optionally, such plasma concentrations can be achieved using a dosage strength in the range of about 145 mg to about 185 mg CTN, for example 164.4 mgCTN.

[0145] The formulation or use thereof can provide a cumulative CTN plasma exposure (AUC 0.0404 / 0.0005) over a period of 0-8 hours post-administration to an adult subject of at least 1275 ng·h / mL, or at least 1530 ng·h / mL, or at least 1700 ng·h / mL, or at least 2500 ng·h / mL, or about 1275 ng·h / mL to about 6250·ng·h / mL, or about 1275 ng·h / mL to about 6250 ng·h / mL, or about 1360 ng·h / mL to about 6000 ng·h / mL, or about 1530 ng·h / mL to about 5500 ng·h / mL, or about 1700 ng·h / mL to about 5000 ng·h / mL. 0-8h ); Optionally, such exposure can be achieved using a dosage strength ranging from about 145 mg to about 185 mg CTN, for example 164.4 mg CTN.

[0146] The formulation can provide a cumulative plasma exposure (AUC) within a period of 2-8 hours after administration in the range of at least 1050 ng·h / mL, or at least 1120 ng·h / mL, or at least 1330 ng·h / mL, or at least 2000 ng·h / mL, or at least 2500 ng·h / mL, or about 1050 ng·h / mL to about 5250 ng·h / mL, or about 1120 ng·h / mL to about 5040 ng·h / mL, or about 1260 ng·h / mL to about 4620 ng·h / mL, or about 1330 ng·h / mL to about 4410 ng·h / mL, or about 1400 ng·h / mL to about 4200 ng·h / mL. 2-8h); Optionally, such exposure can be achieved using a dosage strength ranging from about 145 mg to about 185 mg CTN, for example 164.4 mg CTN.

[0147] The pharmaceutical formulation or use thereof can provide a plasma CTN concentration (CTN) in an adult subject 12 hours after administration 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 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. 12h ); Optionally, such plasma concentrations can be achieved using a dosage strength ranging from about 145 mg to about 185 mg CTN, for example 164.4 mg CTN.

[0148] The pharmaceutical formulation or its use can provide a relatively rapid decline in CTN plasma concentration in adult subjects 12 hours after administration to promote a relatively low CTN plasma concentration 16 hours after administration until the next administration. Thus, for example, the ratio of the plasma concentration 16 hours after administration to the plasma concentration 12 hours after administration (C 16h / C 12h ) can be less than 1, or less than 0.75, or less than 0.5, or less than 0.3, or in the range of about 0.5 to 0.1; optionally, this ratio can be achieved using a dosage strength in the range of about 145 mg to about 185 mg CTN, for example 164.4 mg CTN.

[0149] The pharmaceutical formulation or its use can provide an adult subject with a plasma CTN concentration 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 using a dose strength in the range of about 145 mg to about 185 mg CTN, for example, 164.4 mg CTN. For example, the plasma concentration can be relatively low at this time to facilitate repeated once-daily dosing without accumulating CTN. On the other hand, the plasma concentration can be relatively low at this time to avoid one or more adverse reactions in the subject, such as insomnia, for example, when administration is performed in the morning.

[0150] The pharmaceutical formulation or use thereof can provide a cumulative CTN plasma exposure (AUC 200, 250, or 3000 ng·h / mL) to an adult subject over a 24-hour period following administration in the range of at least 2400 ng·h / mL, or at least 2880 ng·h / mL, or at least 3200 ng·h / mL, or at least 5000 ng·h / mL, or at least 7100 ng·h / mL, or about 2400 ng·h / mL to about 12500 ng·h / mL, or about 2560 ng·h / mL to about 12000 ng·h / mL, or about 2880 ng·h / mL to about 11000 ng·h / mL, or about 3040 ng·h / mL to about 10500 ng·h / mL, or about 3200 ng·h / mL to about 10000 ng·h / mL, or about 7000 ng·h / mL to about 10000 ng·h / mL. 0-24h The pharmaceutical formulation or its use can provide a cumulative CTN plasma exposure (AUC) in a 48-hour period after administration to an adult subject in the range of at least 2400 ng·h / mL, or 2880 ng·h / mL, or 3200 ng·h / mL, 5000 ng·h / mL, or 7100 ng·h / mL, or about 2400 ng·h / mL to about 12500 ng·h / mL, or about 2560 ng·h / mL to about 12000 ng·h / mL, or about 2880 ng·h / mL to about 11000 ng·h / mL, or about 3040 ng·h / mL to about 10500 ng·h / mL, or about 3200 ng·h / mL to about 10000 ng·h / mL, or about 7000 ng·h / mL to about 10000 ng·h / mL. 0-48h ); Optionally, such exposure can be achieved using a dosage strength ranging from about 145 mg to about 185 mg CTN, for example 164.4 mg CTN.

[0151] The pharmaceutical formulation or use thereof can provide a cumulative CTN plasma exposure (AUC ) in a post-administration period in an adult subject 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 about 2400 ng·h / mL to about 12500 ng·h / mL, or about 2560 ng·h / mL to about 12000 ng·h / mL, or about 2880 ng·h / mL to about 11000 ng·h / mL, or about 3040 ng·h / mL to about 10500 ng·h / mL, or about 3200 ng·h / mL to about 10000 ng·h / mL, or about 7000 ng·h / mL to about 10000 ng·h / mL. 0-∞ ); Optionally, such exposure can be achieved using a dosage strength ranging from about 145 mg to about 185 mg CTN, for example 164.4 mg CTN.

[0152] The pharmaceutical formulation or use thereof can provide a time to maximum CTN plasma concentration (tmax) in an adult subject in the range of about 1.5 hours to about 11 hours, or about 2.25 hours to about 10 hours, or about 2.7 hours to about 8.8 hours, or about 3 hours to about 8 hours, or about 4 hours to about 6 hours. max ).

[0153] The pharmaceutical formulations disclosed herein can be characterized by the release mechanism of the active pharmaceutical ingredient (API), such as sentanafadine 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, penetration, distribution, swelling, and targeting. In some embodiments, one or more of the plurality of CTN beads have a diffusion release mechanism. In some embodiments, one or more of the plurality of CTN beads have a porous matrix that causes a diffusion release mechanism. In some embodiments, one or more of the plurality of CTN beads have a pH-triggered diffusion release mechanism. In some embodiments, one or more of the plurality of CTN beads have a combination of a pH-triggered dissolution release mechanism and a diffusion release mechanism. In some embodiments, as disclosed in the above section, the delayed release beads have a combination of a pH-triggered dissolution release mechanism and a diffusion release mechanism. The term "porous matrix" as used herein refers to an insoluble framework comprising a porous matrix. In some embodiments, at least a portion of the plurality of beads comprises a porous matrix. In some embodiments, the sustained release beads comprise a porous matrix.

[0154] One type of pharmaceutical formulation disclosed herein comprises a plurality of sentanafadine beads, each of the plurality of sentanafadine beads comprising a core particle containing sentanafadine or a pharmaceutically acceptable salt thereof and an excipient, wherein the plurality of sentanafadine beads respectively comprise a mixture of one or more immediate-release beads, one or more sustained-release beads and one or more delayed-release beads in a ratio in the range of about 0.1-1: 1-20: 1-20 parts by weight.

[0155] The plurality of senantanafacil beads may include senantanafacil or a pharmaceutically acceptable salt thereof in an amount ranging from about 10 mg to about 490 mg.

[0156] The pharmaceutical formulation may include at least a portion of core particles comprising santanafadine or a pharmaceutically acceptable salt thereof in an amount ranging from about 70 wt % to about 90 wt %.

[0157] The pharmaceutical formulation may comprise core particles characterized by a maximum diameter of about 0.2 mm to about 2 mm.

[0158] The pharmaceutical formulation may comprise core particles, wherein at least 60% by weight of the core particles are characterized by a maximum diameter in the range of about 0.4 mm to about 1.5 mm.

[0159] The pharmaceutical formulation may include a plurality of senantanafacil beads having a median particle size characterized by a particle size ranging from about 0.2 mm to about 2.8 mm.

[0160] The drug formulation may comprise immediate release beads in a range of about 1% to about 75% based on the total weight of the plurality of senafadine beads.

[0161] The drug formulation may comprise sustained release beads in a range of about 5% to 80% based on the total weight of the plurality of senafadine beads.

[0162] The drug formulation may comprise delayed-release beads in a range of about 5% to 80% based on the total weight of the plurality of senafadine beads.

[0163] The pharmaceutical formulation can provide an adult subject with a plasma concentration (C ) of santanafacillin at one hour after administration of at least 150 ng / mL or in the range of about 150 ng / mL to about 610 ng / mL. 1h ).

[0164] The pharmaceutical formulation can provide an adult subject with a 12-hour post-administration santanafil plasma concentration (C 12h).

[0165] The pharmaceutical formulation can provide an adult subject with a 16-hour post-administration santanafacilitation plasma concentration (C 16h ).

[0166] The pharmaceutical formulation can provide an adult subject with a post-dosing plasma concentration of santanafacillin that is maintained at least 75 ng / mL or within a range of about 75 ng / mL to about 1500 ng / mL over a period of 2 to 8 hours after dosing.

[0167] The pharmaceutical formulation can provide an adult subject with a cumulative plasma exposure of santanafacil (AUC 1000) of at least 2400 ng·h / mL or within a range of 2400 ng·h / mL to 12500 ng·h / mL over a 24-hour period after administration. 0-24h ).

[0168] The pharmaceutical preparation can provide an adult subject with a cumulative plasma exposure (AUC) of at least 2400 ng·h / mL or within the range of 2400 ng·h / mL to 12500 ng·h / mL after administration to santanafacil 0-∞ ).

[0169] The pharmaceutical formulation may comprise santanafacil hydrochloride and provide a santanafacil plasma concentration (C 1h ), maintaining a post-dose santanafil plasma concentration of at least 250 ng / mL in the 2- to 8-hour period following administration and a santanafil plasma concentration of less than 300 ng / mL at 16 hours following administration (C 16h ).

[0170] According to the United States Pharmacopeia <711> , using Apparatus 1 (basket), first in 1000 ml 0.1 N hydrochloric acid at 37°C + / - 0.5°C and 100 rpm for 2 hours, and then in 1000 ml pH 7.4 buffered water at 37°C + / - 0.5°C and 100 rpm for the remaining time, the pharmaceutical formulation may comprise releasing at least 40% of santanafacil or its salt from the bead mixture in a time ranging from 3 hours to 5 hours, and releasing at least 90% of santanafacil or its salt from the bead mixture in a time ranging from 12 hours to 14 hours.

[0171] The pharmaceutical formulation can provide an adult subject with a 1-hour post-administration santanafacilitation plasma concentration (C 1h); 12-hour post-dose sentanafacil plasma concentrations (C 12h ); 16-hour post-dose sentanafacil plasma concentrations (C 16h ); and where C 16h / C 12h The ratio is less than 1.

[0172] The pharmaceutical preparation may comprise at least a portion of sustained-release beads and at least a portion of delayed-release beads, wherein the coating comprised by the sustained-release beads is a sustained-release coating, and the delayed-release beads comprise a delayed-release coating and / or a delayed-sustained-release coating.

[0173] The pharmaceutical formulation may comprise a delayed release coating comprising one or more materials selected from the group consisting of amylose acetate phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate trimellitate, carboxymethyl ethyl cellulose, copolymerized methacrylic acid / methyl methacrylate, copolymerized methacrylic acid / methyl methacrylate, copolymerized methacrylate / methyl methacrylate / methacrylic acid, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, styrene maleic acid copolymer, and styrene vinyl pyridine copolymer.

[0174] The pharmaceutical preparation may include a sustained release coating, the sustained release coating including one or more materials selected from the following: alkyl cellulose, acrylic acid polymer, methacrylic acid polymer, acrylic acid copolymer, methacrylic acid copolymer and cellulose ether. The sustained release coating also includes a pore former. The pore former includes one or more materials selected from the following: hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol, poloxamer 188, polyvinyl pyrrolidone, d-mannitol, methyl cellulose, polyvinyl alcohol-polyethylene glycol graft copolymer and sugar.

[0175] The pharmaceutical formulation may comprise a plurality of santanafacil beads, each of the plurality of santanafacil beads comprising a core particle comprising santanafacil or a pharmaceutically acceptable salt thereof and an excipient, wherein the plurality of santanafacil beads comprise a mixture of one or more immediate release beads, one or more sustained release beads, and one or more delayed release beads in a ratio in the range of about 0.1-1: 1-20: 1-20 parts by weight, wherein the plurality of santanafacil beads comprise santanafacil or a pharmaceutically acceptable salt thereof in an amount in the range of about 10 mg to about 490 mg, wherein at least a portion of the sustained release beads comprise a coating, which is a sustained release coating comprising a copolymer of ethyl acrylate and methyl methacrylate; wherein at least a portion of the delayed release beads comprise a delayed release coating, which comprises poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid); and wherein the plurality of santanafacil beads have a median particle size characterized by a particle size in the range of about 0.2 mm to about 2.8 mm.

[0176] Major depressive disorder (MDD)

[0177] Depression is caused by a deficiency or imbalance of monoamine neurotransmitters such as serotonin, dopamine, and norepinephrine.

[0178] The diagnosis of depression requires five or more symptoms (Diagnostic and Statistical Manual of Mental Disorders - DSM-5). Frontiersin Psychiatry, 2018. Vol. 9, Art. 450. One of these must be depressed mood or anhedonia, called the primary criterion. Although secondary symptoms can be divided into somatic and non-somatic groups, DSM-5 identifies depression in an all-or-none manner. In contrast, the severity of depression is a continuous variable. The diagnosis of a major depressive episode (MDE) requires the presence of five or more symptoms over a 2-week period. At least one of the symptoms should be depressed mood (DM) or anhedonia (loss of interest or pleasure—LI). Secondary symptoms of MDE are changes in appetite or weight (AW), difficulty sleeping (insomnia or hypersomnia), psychomotor agitation or retardation (PAR), fatigue or loss of energy (FE), decreased ability to think or concentrate (C), feelings of worthlessness or excessive guilt (FW), and suicidal tendencies (SU). These symptoms are rated in an all-or-none (0 or 1) manner.

[0179] Symptoms were summarized according to DSM-5 criteria to determine whether a major depressive episode was present.

[0180] The present disclosure provides a method for treating MDD and / or alleviating, improving or alleviating MDD symptoms in a human patient in need thereof, 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, wherein the CTN is administered in an extended release dosage form comprising a plurality of CTN beads; each of the plurality of CTN beads comprises a core particle containing CTN or a pharmaceutically acceptable salt thereof and an excipient, wherein the plurality of CTN beads comprises a mixture of one or more immediate release (IR) beads, one or more sustained release (SR) beads and one or more delayed release (DR) beads.

[0181] The present disclosure provides a method for treating MDD and / or alleviating, ameliorating or alleviating the symptoms of MDD in a person in need thereof, 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 as an adjunct to escitalopram, wherein CTN is administered in an extended release dosage form.

[0182] dose

[0183] As described herein, the methods disclosed herein include administering a therapeutically effective amount of CTN or a pharmaceutically acceptable salt thereof in an amount of about 10 mg or more per day, for example, 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 per day of CTN or a pharmaceutically acceptable salt thereof. In addition, the disclosed methods and uses can include administering CTN or a pharmaceutically acceptable salt thereof in an amount of about 750 mg or less per day, for example, 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 per day of CTN or a pharmaceutically acceptable salt thereof. Thus, the methods and uses disclosed herein may include administering CTN or a pharmaceutically acceptable salt thereof in an amount defined by any of the above values, for example, in the range of about 10 mg to about 750 mg per day (e.g., about 10-750 mg, about 20-740 mg, about 30-730 mg, about 40-720 mg, about 50-710 mg, about 60-700, about 70-690 mg, about 80-680 mg, about 90-670 mg, about 100-660 mg, about 110-650 mg, about 120-640 mg, about 130-630 mg, about 140-620 mg, about 150-610 mg, about 160-600 mg, about 170-590 mg, about 180-580 mg, about 190-570 mg, about 200-560 mg, about 210-550 mg, about 2 or a pharmaceutically acceptable salt thereof).In an embodiment optionally combined with the above or below embodiments, CTN or a pharmaceutically acceptable salt thereof is administered in an amount ranging from about 10 to about 750 mg per day, for example, 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.

[0184] The disclosed methods of treating MDD contemplate oral administration at doses as described above, additionally or alternatively based on body weight, for example, in an amount in the range of about 0.01 to about 2.0 mg / kg. The indicated daily oral administration dose may be in the range of about 0.10 mg to about 200 mg, conveniently administered once a day or in divided doses 2 to 4 times a day, or in extended release form. For example, a unit dosage form for oral administration may contain about 20 mg to about 75 mg or about 150 mg, for example about 10 mg or about 20 mg or about 50 mg or about 75 mg or about 100 mg to 200 mg or about 500 mg of CTN in free or pharmaceutically acceptable salt form, and a pharmaceutically acceptable diluent or carrier thereof.

[0185] In embodiments, the disclosed methods may include administering about 200 mg CTN per day. In embodiments, the disclosed methods may include administering about 400 mg CTN per day. In embodiments, the disclosed methods may include administering about 41.1 mg CTN per day. In embodiments, the disclosed methods may include administering about 82.2 mg CTN per day. In embodiments, the disclosed methods may include administering about 123.3 mg CTN per day. In embodiments, the disclosed methods may include administering about 164.4 mg CTN per day. In embodiments, the disclosed methods may include administering about 246.6 mg CTN per day. In embodiments, the disclosed methods may include administering about 328.8 mg CTN per day. Doses according to any of the above daily doses may be administered in a single unit dose per day.

[0186] These and other effective dosage amounts can be administered in a single dose, or in the form of multiple daily, weekly or monthly doses, for example, according to a dosing regimen comprising 1 to 5 or 2 to 3 doses per day, week or month to provide the desired TDD of CTN as described herein.

[0187] In an embodiment optionally combined with other embodiments described above or below, CTN or a pharmaceutically acceptable salt thereof may be administered one to four times per day.

[0188] In an embodiment that is optionally combined with other embodiments above or below, CTN or a pharmaceutically acceptable salt thereof may be administered twice daily.

[0189] In an embodiment that is optionally combined with other embodiments above or below, CTN or a pharmaceutically acceptable salt thereof may be administered once a day.

[0190] As described herein, in embodiments, CTN dosages can be calculated based on body weight and can be administered, for example, in an amount of 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.

[0191] 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.

[0192] 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 an adjunct to an amount of escitalopram or a pharmaceutically acceptable salt thereof in the range 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 an adjunct to an amount of escitalopram or a pharmaceutically acceptable salt thereof in the range of about 2.5 to about 20 mg per day. The disclosed method comprises 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 as an adjunct to escitalopram or a pharmaceutically acceptable salt thereof in an amount of about 10 to about 20 mg per day. These doses may be in the form of a single oral dosage form or separate dosage forms administered simultaneously or sequentially.

[0193] As described herein, the disclosed methods include administering a therapeutically effective amount of CTN in the form of a hydrochloride salt. As described herein, the disclosed methods include administering a therapeutically effective amount of escitalopram in the form of a hydrobromide salt. As described herein, the disclosed methods include administering a therapeutically effective amount of escitalopram in the form of an oxalate salt.

[0194] As described herein, the disclosed methods include orally administering a therapeutically effective amount of CTN hydrochloride as an adjunct to a therapeutically effective amount of escitalopram oxalate or escitalopram hydrobromide.

[0195] The therapeutically effective amount of CTN hydrochloride is in the range of about 35 to about 400 mg per day, and the therapeutically effective amount of escitalopram in the form of the oxalate or hydrobromide salt is in the range of 2.5 to 20 mg per day.

[0196] The amount, time and mode of delivery of the compositions of the present invention comprising an effective amount of the compounds of the present invention can be routinely adjusted on an individual basis, depending on factors such as the individual's weight, age, sex and condition, the acuteness of the target condition, the disorder and / or associated symptoms, whether the administration is preventive or therapeutic, and other factors known to affect drug delivery, absorption, pharmacokinetics, including half-life and efficacy. An effective dose or multiple dose treatment regimen using the compounds described herein will generally be selected to approximate the minimum dose regimen necessary to substantially treat, prevent, assist or alleviate one or more symptoms of major depressive disorder.

[0197] Thus, for example, in a method for treating MDD or alleviating, improving or alleviating symptoms of MDD, after administration of CTN or a pharmaceutically acceptable salt thereof, the patient may exhibit a 10%, 20%, 30%, 50% or more reduction in one or more MDD-related symptoms, up to a 75% to 90% or more reduction, compared to placebo-treated or other suitable control subjects.

[0198] In the method for treating MDD or reducing, improving or alleviating the symptoms of MDD, after administering CTN or a pharmaceutically acceptable salt thereof as an adjunct to escitalopram or a pharmaceutically acceptable salt thereof, the patient may exhibit a reduction of 10%, 20%, 30%, 50% or more, and a maximum reduction of 75% to 90% or more, in one or more MDD-related symptoms compared to placebo-treated or other suitable control subjects.

[0199] Route of administration

[0200] The disclosed methods and uses include administering CTN or a pharmaceutically acceptable salt thereof in a form suitable for the desired route of administration. For example, CTN in free or pharmaceutically acceptable salt form can be administered by any suitable route, including orally, buccal, nasal, by aerosol, topically, mucosally, by injection, parenterally, transdermally, or by inhalation, including by sustained release, but a variety of other known delivery routes, devices, and methods can also be employed.

[0201] In an embodiment that is optionally combined with other embodiments described above or below, CTN or a pharmaceutically acceptable salt thereof (eg, CTN) can be administered intravenously or transdermally (eg, a transdermal patch and a patch optionally comprising microneedles) or orally.

[0202] In an embodiment optionally combined with other embodiments above or below, CTN or a pharmaceutically acceptable salt thereof is administered orally. Suitable non-limiting examples of oral dosage forms include capsules or tablets. In some embodiments, the dosage form is a capsule.

[0203] In embodiments, in a sustained release profile, free or pharmaceutically acceptable salt form of CTN may be released from the composition and delivered to the plasma or other target activity site of a subject (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 may be characterized by providing an in vitro release profile (according to USP <711> , using Apparatus I (basket) in 1000 mL 0.1 N HCl at 37°C + / - 0.5°C and 100 rpm for 2 hours, followed by using Apparatus I (basket) in 1000 mL pH 7.4 phosphate buffer at 37°C + / - 0.5°C and 100 rpm for 16 hours). Another type of sustained release profile can be characterized by providing an in vitro release profile (according to USP <711> , using Apparatus I (basket) in 1000 mL 0.1 N hydrochloric acid at 37°C + / - 0.5°C and 100 rpm for 2 hours, then using Apparatus I (basket) in 1000 mL pH 7.4 phosphate buffer solution at 37°C + / - 0.5°C and 100 rpm for 16 hours), the in vitro release is multiphasic, optionally at least biphasic. Such a profile may optionally be characterized by a release of about 22% to about 45% of the CTN at the 3 hour mark, further optionally by a release of about 40% to about 65% of the CTN at the 8 hour mark, further optionally by a release of about 65% to about 95% of the CTN at the 12 hour mark, further optionally by having such release rates at all three time points. Alternatively, such a profile can be characterized by releasing about 24% to 48% of the CTN at the 3 hour mark, further optionally by releasing at least 66% of the CTN at the 6 hour mark, further optionally by releasing at least 86% of the CTN at the 10 hour mark, further optionally by having such release rates at all three time points. Further optionally, the release profile can be characterized by releasing 49% to 73% at the 4 hour mark. On the other hand, the release profile can be determined in vivo and characterized by releasing and delivering about 0% to 20% of the active compound (as determined by measuring plasma levels) within 0 to 2 hours, releasing and delivering 20% ​​to 50% of the active compound within about 2 to 12 hours, releasing and delivering 50% to 85% of the active compound within about 3 to 20 hours, and releasing and delivering more than 75% of the active compound within about 5 to 18 hours.

[0204] In an embodiment, the plasma CTN concentration 16 hours after administration of the in vivo absorption profile of the pharmaceutical formulation may be 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 this time to facilitate repeated once-daily dosing without accumulation of CTN. On the other hand, the plasma concentration may be relatively low at this time to avoid insomnia in the subject, for example, when administration is performed in the morning.

[0205] In an embodiment, administration of a sustained release pharmaceutical composition comprising CTN in free or pharmaceutically acceptable salt form provides CTN in free or pharmaceutically acceptable salt form. max It may be the C obtained after administration of an equivalent dose of an immediate release pharmaceutical composition containing CTN in free or pharmaceutically acceptable salt form. max In an embodiment, the 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 is less than about 80%, such as less than about 75%, such as less than about 60%, such as less than about 50%, such as less than about 40%, such as less than about 30%. max It may be the C obtained after administration of an equivalent dose of an immediate release pharmaceutical composition containing CTN in free or pharmaceutically acceptable salt form. max % 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%, optionally about 30% to 40%. In an embodiment, the 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 It may be the C obtained after administration of an equivalent dose of an immediate release pharmaceutical composition containing CTN in free or pharmaceutically acceptable salt form. max In an embodiment, the 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 is less than about 50%, optionally less than about 40%, optionally less than about 30%. max It may be the C obtained after administration of an equivalent dose of an immediate release pharmaceutical composition containing CTN in free or pharmaceutically acceptable salt form. max From about 20% to 50%, optionally from about 30% to 50%, optionally from about 30% to 40%.

[0206] The composition of the immediate release sentanafidine core beads (50 nominal wt % CTN HCl) used in these formulations is summarized in Table 1.

[0207] [Table 1]

[0208]

[0209] The composition of the immediate release sentanafidine hydrochloride core beads (10 wt % and 50 wt %) in these formulations is summarized in Table 2.

[0210] [Table 2]

[0211]

[0212] The composition of the sentanafadine core beads (80 wt% drug load) is provided in Table 3. The sentanafadine core beads were manufactured by weighing out CTN hydrochloride and microcrystalline cellulose and dry mixing in a high shear granulator, granulating the blended mixture with purified water, extruding and spheronizing to form wet beads, fluid bed drying the core beads, and sieving the beads to maintain the desired size range.

[0213] [Table 3]

[0214]

[0215] The composition of the santanafadine seal coated beads (80 wt% drug load) is provided in Table 4. For seal coating, the Wurster process was used to spray the required amount of hypromellose aqueous solution with a set of controlled process parameters, and then the coated beads were dried to the desired moisture content and cured.

[0216] [Table 4]

[0217]

[0218] The composition of the sustained release coated beads is provided in Table 5.

[0219] [Table 5]

[0220]

[0221] The composition of the delayed release coated beads is provided in Table 6. [Table 6]

[0222]

[0223] The compositions of various santanafacil extended-release capsules are provided in Tables 7, 8 and 9.

[0224] [Table 7]

[0225]

[0226] [Table 8]

[0227]

[0228] [Table 9]

[0229]

[0230] [Table 10]

[0231]

[0232] The plasma pharmacokinetics of the CTN hydrochloride formulation at a dose of 164.4 mg can be seen in Table 11.

[0233] [Table 11]

[0234]

[0235] The plasma pharmacokinetics of CTN hydrochloride formulations at doses of 164.4 mg or 328.8 mg can be seen in Table 12.

[0236] [Table 12]

[0237]

[0238] When two active agents are administered, the therapeutically effective amount of each agent may optionally be lower than the amount required for activity as a monotherapy. Thus, a subthreshold amount (i.e., an amount below the level required for efficacy as a monotherapy) may be considered therapeutically effective. Indeed, in some cases, the advantage of administering different agents with different mechanisms of action and different side effect profiles may be to reduce the dose and side effects of one or both agents.

[0239] Combination therapy

[0240] In some embodiments, the present disclosure provides a method for treating MDD or reducing, improving or alleviating MDD symptoms using santanafadine or a pharmaceutically acceptable salt thereof in combination with one or more other antidepressants, antipsychotics or cognitive enhancers. Examples of antidepressant classes that can be used in combination with santanafadine 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 norepinephrine reuptake inhibitors (SNRIs), corticotropin (CRF) antagonists, alpha-adrenergic receptor antagonists, benzodiazepines, anxiolytics and atypical antidepressants.

[0241] Suitable norepinephrine reuptake inhibitors include tertiary and secondary amine tricyclics. Suitable tertiary and secondary amine tricyclics include amitriptyline, clomipramine, doxepin, imipramine, trimipramine, dothiepin, butriptyline, iprindole, lofepramine, nortriptyline, protriptyline, amoxapine, desipramine and maprotiline. Suitable selective serotonin reuptake inhibitors include fluoxetine, citolopram, escitalopram, fluvoxamine, paroxetine, dapoxetine, vortioxetine and sertraline.

[0242] Examples of monoamine oxidase inhibitors include isocarboxazid, phenelzine and tranylcypromine. Suitable reversible monoamine oxidase inhibitors include moclobemide.

[0243] Serotonin and norepinephrine reuptake inhibitors suitable for use in the present invention include venlafaxine, nefazodone, milnacipran and duloxetine.

[0244] In some embodiments, the present disclosure provides a method of treating MDD or reducing, ameliorating or alleviating symptoms of MDD in a patient in need thereof, comprising administering a therapeutically effective amount of santanafacil or a pharmaceutically acceptable salt thereof in combination with one or more natural medicines or supplements that are marketed as helpful in treating depression, such as, but not limited to: St. John's wort (herbal supplement), S-adenosylmethionine (SAMe), omega-3 fatty acids, saffron, 5-hydroxytryptophan (5-HTP), dehydroepiandrosterone (DHEA).

[0245] In some embodiments, the present disclosure provides a method for treating MDD or alleviating, improving or relieving symptoms of MDD in a patient in need thereof, comprising administering a therapeutically effective amount of santanafadine or a pharmaceutically acceptable salt thereof in combination with one or more other antidepressants, antipsychotics or cognitive enhancers, wherein the combination is a single formulation or a multiple combination co-administered within a specific time period and continued for a period of time. In some embodiments, the present disclosure provides a method for treating MDD or alleviating, improving or relieving symptoms of MDD in a patient in need thereof, comprising administering to the patient a) a therapeutically effective amount of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof, and b) one or more antidepressants, the antidepressants being optionally selected from selective serotonin reuptake inhibitors (SSRIs) and / or serotonin-norepinephrine. A SNRI, optionally selected from an SSRI, further optionally selected from the group consisting of fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine, vilazodone, venlafaxine, desvenlafaxine, dopaxetine, 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 an extended release dosage form as described herein.

[0246] In some embodiments, the one or more SSRIs are selected from fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, escitalopram, and vilazodone.

[0247] In some embodiments, the one or more SSRIs are selected from fluoxetine, sertraline, paroxetine, citalopram, and escitalopram.

[0248] In some embodiments, the one or more SSRIs are selected from fluoxetine and fluvoxamine.

[0249] In some embodiments, the SSRI is fluvoxamine.

[0250] In some embodiments, the SSRI is escitalopram.

[0251] In some embodiments, the one or more SNRIs are selected from venlafaxine, desvenlafaxine, duloxetine, levomilnacipran, and reboxetine.

[0252] In some embodiments, the antidepressant comprises escitalopram.

[0253] In some embodiments, the antidepressant comprises citalopram.

[0254] As described above, the pharmaceutical combination therapeutic composition can include a therapeutically effective amount of CTN or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an additional therapeutic agent. In embodiments where the method comprises administering a combination of CTN or a pharmaceutically acceptable salt thereof 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.

[0255] [Table 13]

[0256]

[0257] In some embodiments, a low dose of an antidepressant is initially administered to a patient and then titrated to the recommended therapeutic dose over a period of time.

[0258] In some embodiments, the antidepressant is escitalopram, wherein the amount of escitalopram or a pharmaceutically acceptable salt thereof (such as 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.

[0259] In embodiments involving combination therapy, CTN or a pharmaceutically acceptable salt thereof can be administered simultaneously (e.g., concurrently) or at separate intervals (e.g., sequentially) with an additional antidepressant (e.g., SSRI and / or SNRI). When administered simultaneously, 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, i.e., one containing CTN or a pharmaceutically acceptable salt thereof and the other containing the additional therapeutic agent, can be administered simultaneously.

[0260] Dosage forms comprising the combination therapy CTN or a pharmaceutically acceptable salt thereof and / or escitalopram can be formulated to provide a modified release of CTN or a pharmaceutically acceptable salt thereof and an immediate release or a modified release of escitalopram or a pharmaceutically acceptable salt thereof. The modified release profile of CTN or a pharmaceutically acceptable salt thereof, escitalopram or a pharmaceutically acceptable salt thereof, or both can be achieved by a combination of a sustained formulation and a pulsatile formulation.

[0261] The pulsatile release profile can be achieved with a closed dosage form, such as a sealed capsule or tablet containing two or more drug-containing dosage units. The dosage form may include one, two, three or more types of dosage units, each dosage unit having a different drug release profile. Each dosage unit may provide a multiphasic release of CTN or a pharmaceutically acceptable salt thereof and / or escitalopram or a pharmaceutically acceptable salt thereof.

[0262] The combination therapy may include the administration of CTN as described herein in combination with psychological counseling and / or behavioral therapy. The combination therapy may include the administration of CTN as described herein in combination with digital therapy and / or digital applications. The combination therapy may include the administration of CTN and escitalopram as described herein in combination with psychological counseling and / or behavioral therapy. The combination therapy may include the administration of CTN and escitalopram as described herein in combination with digital therapy and / or digital applications.

[0263] When administered alone, a therapeutically effective amount of a composition containing CTN or a pharmaceutically acceptable salt thereof and an additional therapeutic agent may be administered in different regimens. One may be administered before the other, as long as the time between the two administrations is within the therapeutically effective interval. The therapeutically effective interval is the time period from when one of (a) CTN or a pharmaceutically acceptable salt thereof or (b) an additional therapeutic agent is administered to a person until the beneficial effect of the combination of (a) and (b) in treating MDD or alleviating, improving or relieving symptoms of MDD reaches a limit. The method of administration of CTN or a pharmaceutically acceptable salt thereof and the additional therapeutic agent may vary. Thus, either agent or both agents may be administered rectally, topically, orally, sublingually or parenterally.

[0264] Implementation

[0265] 1. A method of treating major depressive disorder or ameliorating, alleviating or alleviating the symptoms of major depressive disorder in a human patient in need thereof, comprising administering to the patient a therapeutically effective amount of santanafacil or a pharmaceutically acceptable salt thereof, wherein santanafacil or a pharmaceutically acceptable salt thereof is administered in an extended release dosage form comprising a plurality of santanafacil beads.

[0266] 2. The method according to 1, wherein each of the plurality of sentanafadine beads comprises a core particle containing sentanafadine or a pharmaceutically acceptable salt thereof and an excipient, and wherein the plurality of sentanafadine beads comprises a mixture of one or more immediate-release beads, one or more sustained-release beads and one or more delayed-release beads.

[0267] 3. The method according to 2, wherein the one or more sustained-release beads comprise a sustained-release coating comprising one or more materials selected from the group consisting of alkyl cellulose, acrylic acid polymers, methacrylic acid polymers, acrylic acid copolymers, methacrylic acid copolymers and cellulose ethers.

[0268] 4. The method according to 2 or 3, wherein the one or more delayed-release beads comprise a delayed-release coating, which comprises one or more materials selected from the group consisting of amylose acetate phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate trimellitate, carboxymethyl ethyl cellulose, copolymerized methacrylic acid / methyl methacrylate, copolymerized methacrylic acid / methyl methacrylate, copolymerized methacrylate / methyl methacrylate / methacrylic acid, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, styrene maleic acid copolymer and styrene vinyl pyridine copolymer.

[0269] 5. The method according to any one of 2 to 4, wherein the ratio of the mixture of the one or more immediate-release beads, the one or more sustained-release beads and the one or more delayed-release beads is in the range of about 0.1-1: 1-20: 1-20 parts.

[0270] 6. The method according to any one of 1 to 5, wherein the extended release dosage form is a daily oral dosage form.

[0271] 7. The method of claim 6, wherein the dosage form is a capsule.

[0272] 8. The method according to any one of 1 to 7, wherein the pharmaceutically acceptable salt of santanafadine is a hydrochloride salt.

[0273] 9. The method according to any one of 1 to 8, wherein the amount of santanafadine or a pharmaceutically acceptable salt thereof administered is in the range of about 10 mg to about 750 mg per day.

[0274] 10. The method according to 9, wherein the amount of santanafadine or a pharmaceutically acceptable salt thereof administered is in the range of about 35 mg to about 400 mg per day.

[0275] 11. A method for treating major depressive disorder or improving, alleviating or alleviating the symptoms of major depressive disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of sentanafadine or a pharmaceutically acceptable salt thereof as an adjunct to one or more antidepressants.

[0276] 12. The method of claim 11, wherein the one or more antidepressants are selected from the group consisting of selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, benzodiazepines, anxiolytics, noradrenergic and specific serotonergic antidepressants, tricyclic antidepressants, and monoamine oxidase inhibitors.

[0277] 13. The method of claim 11, wherein the one or more antidepressants are selective serotonin reuptake inhibitors.

[0278] 14. The method of 13, wherein the selective serotonin reuptake inhibitor comprises escitalopram.

[0279] 15. The method according to any one of 11 to 14, wherein santanafacil or a pharmaceutically acceptable salt thereof is administered in an extended release dosage form comprising a plurality of santanafacil beads.

[0280] 16. The method of claim 15, wherein each of the plurality of sentanafadine beads comprises a core particle containing sentanafadine or a pharmaceutically acceptable salt thereof and an excipient, and wherein the plurality of sentanafadine beads comprises a mixture of one or more immediate-release beads, one or more sustained-release beads, and one or more delayed-release beads.

[0281] 17. The method according to any one of 16, wherein the one or more sustained release beads comprise a sustained release coating comprising one or more materials selected from the group consisting of alkyl cellulose, acrylic acid polymers, methacrylic acid polymers, acrylic acid copolymers, methacrylic acid copolymers and cellulose ethers.

[0282] 18. The method according to 16 or 17, wherein the one or more delayed-release beads comprise a delayed-release coating, the delayed-release coating comprising one or more materials selected from the group consisting of amylose acetate phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate trimellitate, carboxymethyl ethyl cellulose, copolymerized methacrylic acid / methyl methacrylate, copolymerized methacrylic acid / methyl methacrylate, copolymerized methacrylate / methyl methacrylate / methacrylic acid, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, styrene maleic acid copolymer and styrene vinyl pyridine copolymer.

[0283] 19. The method according to any one of 16 to 18, wherein the ratio of the mixture of the one or more immediate release beads, the one or more sustained release beads and the one or more delayed release beads is in the range of about 0.1-1: 1-20: 1-20 parts.

[0284] 20. The method according to any one of 11 to 19, wherein the administration amount of sentanafidine or a pharmaceutically acceptable salt thereof is in the range of about 10 mg to about 750 mg per day as an adjunct drug to escitalopram or a pharmaceutically acceptable salt thereof in an amount of about 2.5 to about 20 mg per day.

[0285] 21. The method according to 20, wherein the administration amount of sentanafidine or a pharmaceutically acceptable salt thereof is in the range of about 35 mg to about 400 mg per day as an adjunct drug to escitalopram or a pharmaceutically acceptable salt thereof in an amount of about 10 to about 20 mg per day.

[0286] 22. A method for treating major depressive disorder or improving, alleviating or alleviating the symptoms of major depressive disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of santanafacil or a pharmaceutically acceptable salt thereof as an adjunct to a selective serotonin reuptake inhibitor; wherein santanafacil or a pharmaceutically acceptable salt thereof is administered in an extended release dosage form comprising a plurality of santanafacil beads; wherein each of the plurality of santanafacil beads comprises a core particle comprising santanafacil or a pharmaceutically acceptable salt thereof and an excipient;

[0287] wherein the plurality of santanafacil beads comprises a mixture of one or more immediate release beads, one or more sustained release beads and one or more delayed release beads; wherein the ratio of the mixture of the one or more immediate release beads, the one or more sustained release beads and the one or more delayed release beads is in the range of about 0.1-1: 1-20: 1-20 parts; wherein santanafacil or a pharmaceutically acceptable salt thereof is administered in the range of about 35 mg to about 400 mg per day; wherein the selective serotonin reuptake inhibitor is escitalopram or a pharmaceutically acceptable salt thereof; and wherein escitalopram or a pharmaceutically acceptable salt thereof is administered in the range of about 10 mg to about 20 mg per day.

[0288] 23. The method of 22, wherein sentanafidine is administered in the form of a hydrochloride salt and escitalopram is administered in the form of an oxalate salt.

[0289] 24. The method according to 22 or 23, wherein the ratio of the mixture of the one or more immediate release beads, the one or more sustained release beads and the one or more delayed release beads is in the range of about 1:3.6:3.6 parts.

[0290] 25. The method according to any one of 1 to 24, wherein santanafil 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.

[0291] 26. The method according to any one of 1 to 25, wherein santanafil 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.

[0292] Example

[0293] The following examples are provided for illustration purposes and are not intended to limit the scope of the present invention.In the following examples, unless otherwise stated, santanafadine was formulated and administered as santanafadine hydrochloride.

[0294] In the following examples, escitalopram was prepared according to LEXAPRO TM (escitalopram) U.S. Prescribing Information (Allergan Inc.; Madison, NJ; August 2020) Administration.

[0295] The Phase 2 clinical trial described here was a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial designed to evaluate the efficacy, safety, and tolerability of santanafacillin extended-release capsules as monotherapy or as an adjunct to an SSRI in adult subjects with major depressive disorder. Therefore, this clinical trial had several objectives.

[0296] One objective of the trial was to evaluate the efficacy of santanafacil QD XR 328.8 mg monotherapy in adults with MDD.

[0297] A secondary objective of the trial was to evaluate the efficacy of santanafacil QD XR 328.8 mg as an adjunct to an SSRI (escitalopram) in adults with MDD.

[0298] A secondary objective of the trial was to evaluate the safety and tolerability of santanafacil QD XR 328.8 mg monotherapy in adults with MDD.

[0299] A secondary objective of the trial was to evaluate the safety and tolerability of santanafacil QD XR 328.8 mg as an adjunct to an SSRI (escitalopram) in adults with MDD.

[0300] Eligible subjects were randomized 1:1:1:1 at baseline to 1 of 4 treatment groups as follows:

[0301] Treatment Group 1: 2 tablets of Sentanafacil QD XR 164.4 mg oral capsules + 1 tablet of escitalopram tablet as placebo;

[0302] Treatment group 2: 2 tablets of Sentanafacil QD XR 164.4 mg oral capsules + 1 tablet of escitalopram;

[0303] Treatment group 3: 1 escitalopram tablet + 2 santanafacil QD XR capsules of placebo;

[0304] Treatment group 4: 2 placebo capsules of Sentanafacil QD XR capsules + 1 placebo tablet of Escitalopram tablet.

[0305] Treatment Group 1: Eligible subjects received santanafacil QD XR 328.8 mg and escitalopram-matched placebo for 6 weeks (monotherapy). Treatment Group 2: Eligible subjects received santanafacil QD XR 328.8 mg and escitalopram for 6 weeks (adjunctive therapy).

[0306] Treatment Group 3: Eligible subjects received matching placebo of Sentanafacil QD XR 328.8 mg and escitalopram for 6 weeks. Treatment Group 4: Eligible subjects received matching placebo of Sentanafacil QD XR 328.8 mg and matching placebo of escitalopram for 6 weeks.

[0307] Eligible subjects assigned to receive santanafacil QD XR (ie, treatment group 1 or treatment group 2) received 328.8 mg of santanafacil (ie, 2 santanafacil QD XR 164.4 mg oral capsules) beginning on day 1.

[0308] Eligible subjects assigned to receive escitalopram (ie, treatment group 2 or treatment group 3) received a dose of 10 mg QD on day 1. For the remaining subjects in the trial, the dose was increased to 20 mg QD at week 1.

[0309] Subjects who cannot tolerate the administered daily dose or require a change in medication to treat their depression at any time during the 6-week treatment period will be discontinued from the study. Dose reductions will not be permitted.

[0310] Example 1

[0311] Treating patients with MDD with santanafacil monotherapy

[0312] A phase 2, multicenter, randomized, double-blind, placebo-controlled trial was conducted to evaluate the efficacy, safety, and tolerability of santanafacil as monotherapy in adult subjects with MDD. Subjects with major depressive disorder who met the inclusion and exclusion criteria were randomized 1:1 at baseline (84 subjects per treatment group) to receive 6 weeks of santanafacil extended-release (XR) capsules (328.8 mg santanafacil hydrochloride once daily) monotherapy or placebo. The trial consisted of a 28-day screening period, a baseline visit, a 6-week double-blind treatment period, and a 7-day safety follow-up period. The trial was conducted in outpatients.

[0313] Inclusion criteria were: age 18-65 years, current primary diagnosis of MDD, single or recurrent episodes, no psychotic features, not meeting criteria for the mixed feature subtype, current major depressive episode (MDE) as defined by DSM-5 criteria, confirmed by the Mini-International Neuropsychiatric Interview (MINI). The MINI is a widely used structured diagnostic interview tool developed for DSM-5 psychiatric disorders. All subjects had a HAM-D17 score >18 at screening and baseline and a BMI of 18 to 40 kg / m 2 (inclusive) with a CGI-S rating of 4 or higher at screening and baseline. Other inclusion criteria included: subjects who reported an inadequate response to at least 1 but no more than 3 depression treatments on their current MDE. Inadequate response was defined as a < 50% reduction in depressive symptom severity after an appropriate dose and duration (i.e., at least 6 weeks at the lowest therapeutic dose) based on the MGH-ATRQ administered at screening. Subjects were deemed by the investigator to be able to safely wash off their current antidepressant.

[0314] Exclusion criteria were: currently pregnant and / or breastfeeding, or intending to become pregnant during the study; current depressive episode history of more than 2 years; DSM-5 criteria for personality disorder, substance use disorder, or lifetime or current comorbid psychiatric disorder that may require contraindicated concomitant medication or psychotherapy in this trial or confound efficacy or safety evaluation (e.g., hallucinations, delusions, or any psychotic symptoms); allergic reaction to medication, or history of adverse skin reactions or allergic reactions secondary to drug exposure; epilepsy, history of epilepsy, or history of seizures; current clinically significant suicidal intent; serious cardiac, medical, or progressive neurological or medical disease; facial pain or trigeminal neuralgia; the following test and ECG results at screening: 1) platelets < 75,000 / mm 3 ; 2) Hemoglobin <9 g / dL; 3) Absolute neutrophil count <1000 / mm 3 ; 4) AST>2×upper limit of normal value; 5) ALT>2×upper limit of normal value; 6) Creatinine 2 mg / dL; 7) HbA1c 7%; 8) Male QTcF 450 ms, female QTcF 470 ms; 9) abnormal free T4 unless discussed with and approved by the medical supervisor. Other exclusion criteria included a lifetime history of treatment with ketamine, arsketamine, or esketamine; treatment with psychopharmacological augmentation for depression (e.g., lithium, triiodothyronine, or antipsychotics plus ADT, multiple ADT) in the current MDE; initiation of individual or group psychotherapy within the past 3 months prior to screening, or previous treatment with electroconvulsive therapy or neuromodulatory devices (e.g., transcranial magnetic stimulation, vagus nerve stimulation, or transcranial direct current stimulation) for depression, or a history of noncompliance.

[0315] All subjects agreed to discontinue all prohibited medications (i.e., antidepressants, anticonvulsants, mood stabilizers, benzodiazepines, hypnotics, stimulants, opioid analgesics, nutritional supplements, and over-the-counter herbal preparations with effects on the central nervous system) during the screening period (in order to comply with the protocol-specified washout period) and during the trial. Subjects taking antidepressants at screening underwent a washout before baseline. The required washout period depends 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 was performed at screening and baseline (Day -1). The screening period is up to 4 weeks (maximum 28 days).

[0316] All subjects received Sentanafacil XR capsules as monotherapy or matching placebo for 6 weeks. Subjects assigned to receive Sentanafacil QD XR received 328.8 mg (i.e., 2 Sentanafacil QD XR 164.4 mg oral capsules) starting on Day 1. All doses of Sentanafacil XR and matching placebo were taken orally with approximately 240 mL of water at approximately the same time each morning upon awakening. This dose should not be taken after a high-fat meal. Subjects were instructed not to take more than 1 dose in 1 day.

[0317] Subjects who are intolerant to the administered daily dose or require a change in medication to treat their depression at any time during the 6-week treatment period will be discontinued from the study. Efficacy assessments will be conducted at Screening and / or Baseline (Day -1), then at Weeks 1, 2, 4, and 6. Following the 6-week double-blind treatment period, subjects will undergo a 7(+2) day safety follow-up period following the Week 6 / Early Termination (ET) visit.

[0318] Main efficacy evaluation

[0319] The primary efficacy of santanafacil QD XR as monotherapy in adults was assessed by evaluating the change from baseline in the MADRS total score at Week 6. For the analysis of double-blind treatment period data, baseline was defined as the last available measurement before the first dose of double-blind santanafacil QD XR.

[0320] The MADRS is a 10-item scale used to assess depressive symptoms. Each MADRS item is rated on a scale of 0 to 6, with zero being the "best" rating and 6 being the "worst" rating. Higher MADRS scores indicate greater levels of depressive symptoms. The total MADRS score is the sum of the ratings for all 10 items; therefore, the possible total scores range from 0 to 60. If fewer than 8 of the 10 items are recorded, the total MADRS score cannot be assessed. If 8 or 9 of the 10 items are recorded, the total MADRS score will be the average of the recorded items multiplied by 10 and rounded to one decimal place.

[0321] Secondary efficacy assessments

[0322] 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-Severity (CGI-S) score; 3) Clinical Global Impression of Change (CGI-C) score; 4) change from baseline in the Patient Global Impression-Severity (PGI-S) score; 5) Patient Global Impression of Change (PGI-C) score; 6) change from baseline in the Major Depressive Disorder Symptom Scale (SMDDS) total score; 7) screening change in the 36-Item Brief Health Survey, Version 2 (SF-36v2); 8) screening change in the Apathy Evaluation Scale-Self-Assessment (AES-S) score; 9) MADRS response rate (where response was defined as a 50% decrease from baseline in the MADRS total score at a scheduled visit); and 10) MADRS remission rate (where remission was defined as a decrease from baseline in the MADRS total score at a scheduled visit). 10). The exploratory efficacy evaluated in this study also included the change from baseline in the MADRS anhedonia factor.

[0323] Clinical Global Impression-Severity (CGI-S)

[0324] The CGI-S is a standardized Clinical Management Global Rating Scale that measures disease severity on a 7-point scale, where higher scores represent greater disease severity. Response options are 1 = normal, no problems at all; 2 = borderline disease; 3 = mild disease; 4 = moderate disease; 5 = marked disease; 6 = severe disease; and 7 = the sickest patient. Eligible subjects had a CGI-S score of 4 or higher at screening and baseline.

[0325] Clinical Global Impression-Change (CGI-C)

[0326] The CGI-C is a single-item, 7-point scale that requires the clinician to rate how much the subject's disease has improved or worsened relative to the start of treatment, with ratings of 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; or 7 = very much worse.

[0327] Patient Global Impression-Severity (PGI-S)

[0328] The PGI-S is a single-item report of the subject's symptom severity. Subjects are asked, "Taking all your symptoms into account, how severe is your depression right now?" Ratings range from 1 "no symptoms" to 7 "very severe."

[0329] Patient Global Impression of Change (PGI-C)

[0330] The PGI-C is a 7-point, single-item self-report scale that describes the patient's rating of the overall change in their symptoms since starting the study drug. Subjects answer the following question: "How much have your depressive symptoms changed since starting the study drug?" Scores range from 1 "very much improved" to 7 "very much worse."

[0331] 36-Item Short Form Health Survey Version 2 (SF-36v2)

[0332] The SF-36v2 is a participant-reported questionnaire with a standardized recall period of 4 weeks that measures general health-related quality of life in 2 major domains: physical and mental. It covers 8 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 0 to 100 scale, where lower scores for the total physical and mental domains represent lower health-related quality of life and 50 points refer to the normal U.S. population. In addition to the composite score and individual health domain scores, the SF-36v2 also provides a depression risk score and the SF-36v2 Health Utility Index, which ranges from 0.0 (worst measured health state) to 1.0 (best measured health state).

[0333] Symptom scale for major depressive disorder (SMDDS)

[0334] The SMDDS is a 16-item patient-reported outcome (PRO) questionnaire developed in accordance with the guidelines proposed by the U.S. Food and Drug Administration (FDA) PRO Guidance (2009) and the Good Research Practices Task Force Report of the International Society for Pharmacoeconomics and Outcomes Research for the development and validation of PROs for medical product evaluation. It is designed to assess the subject-perceived severity of MDD symptoms in the past 7 days in adults treated for MDD in an ambulatory setting. The SMDDS contains 9 domains of MDD symptoms: negative emotions / mood (4 items), anxiety (2 items), lack of energy (1 item), cognition (2 items), sleep disturbances (1 item), self-harm / suicidal (1 item), self-consciousness (1 item), and eating behaviors (2 items, scored as a single item). The SMDDS was approved by the FDA in 2017 for the assessment of overall symptoms of MDD in a trial setting.

[0335] Apathy Evaluation Scale (AES-S)

[0336] The Apathy Assessment Scale was developed to assess apathy as "a psychological dimension defined by the simultaneous absence of overt behavioral, cognitive, and affective accompaniments of goal-directed behavior." The self-rating (AES-S) version has 18 items and uses a response scale of "not at all," "slightly," "a little," and "a lot." The AES-S asks respondents to answer in terms of "thoughts, feelings, and activities during the past 4 weeks." Items are categorized into the domains of goal-directed behavior, goal-related conditions, or goal-related emotional reactions; scores range from 18 to 72, with higher scores indicating greater apathy.

[0337] Safety evaluation

[0338] Safety was assessed using standard measures, including treatment-emergent adverse events (TEAEs), adverse events of special interest (AESI [rash]), clinical laboratory tests (chemistry, hematology, and urinalysis), physical examination, vital sign measurements, and 12-lead ECG. Safety was also assessed using the Study Medication Discontinuation Questionnaire (SMWQ), the Generalized Anxiety Disorder Assessment (GAD-7), and the Columbia-Suicidality Severity Rating Scale (C-SSRS). Abuse potential was assessed by active surveillance for events requiring additional monitoring (ESAM); for example, AEs related to abuse potential and AEs involving medication mishandling (MHI).

[0339] result

[0340] After the 6-week double-blind treatment period, CTN significantly reduced all primary efficacy measures (i.e., MADRS total score) in the remaining patients, while no significant reduction was observed in the placebo group. In addition, significant reductions from baseline in the patients' CGI-S score, CGI-C score, PGI-S score, and PGI-C score were also observed in patients who received CTN, while no significant reduction was observed in the placebo group. An increase from baseline in the SF-36v2 total score and a reduction in the risk of depression were also observed in patients who received CTN.

[0341] Sentanafadine (CTN) has a clinically significant improvement effect as a monotherapy in patients with MDD.

[0342] Example 2

[0343] Sentanafadine as adjunctive drug therapy for the treatment of MDD

[0344] A phase 2, multicenter, randomized, double-blind, placebo-controlled trial was conducted to evaluate the efficacy, safety, and tolerability of Sentanafacil XR capsules as an adjunct to SSRI(c) in adult subjects with MDD. Subjects with major depressive disorder who met the inclusion and exclusion criteria were randomized 1:1:1 at baseline (84 subjects per treatment group) to receive 6 weeks of Sentanafacil XR capsules (328.8 mg sentanafacil hydrochloride once daily) plus escitalopram, escitalopram monotherapy (i.e., escitalopram once daily (QD) dose), or placebo. The trial consisted of a 28-day screening period, a baseline visit, a 6-week double-blind treatment period, and a 7-day safety follow-up period. The trial was conducted as an outpatient.

[0345] Inclusion and exclusion criteria were the same as in Example 1. In addition, subjects who were taking escitalopram or citalopram at screening, had been exposed to escitalopram or citalopram in the current MDE, or had reported an inadequate response to appropriate doses / durations of escitalopram or citalopram in the past were also excluded.

[0346] All subjects agreed to stop taking all prohibited medications during the screening period (in order to meet the protocol-mandated washout period) and during the trial. Subjects taking antidepressants at screening underwent a washout before baseline. The required washout period depended on the type of antidepressant (see Example 1). Drug screening was performed at screening and baseline (Day -1). The screening period was a maximum of 4 weeks (maximum 28 days).

[0347] All subjects received escitalopram monotherapy, sentanafacil QD XR capsules plus escitalopram (combination therapy), or matching placebo for 6 weeks.

[0348] Subjects assigned to receive the combination of santanafacil XR + escitalopram received 328.8 mg santanafacil (i.e., 2 santanafacil QD XR 164.4 mg oral capsules) and 1 escitalopram tablet starting on Day 1. The escitalopram tablet was a 10 mg QD dose on Day 1. For the remaining subjects in the trial, the dose was increased to 20 mg QD in Week 1.

[0349] Subjects assigned to receive escitalopram monotherapy received a 10 mg QD dose on Day 1. For the remaining subjects participating in the trial, the dose was increased to 20 mg QD on Week 1. Dose reductions were not permitted. Subjects who were intolerant of the administered daily dose or required a change in medication to treat their depression at any time during the 6-week treatment period were discontinued from the study.

[0350] All doses of Sentanafacil QD XR, escitalopram, and corresponding placebo were taken orally with approximately 240 mL of water at approximately the same time each morning upon awakening. This dose should not be taken with a high-fat meal. Following 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.

[0351] Efficacy evaluation

[0352] The primary efficacy of santanafacil QD XR as an adjunct to an SSRI (escitalopram) in adult subjects with MDD was assessed by comparing the efficacy of santanafacil QD XR plus escitalopram to escitalopram alone or the change from baseline in the MADRS total score at Week 6. For analyses of double-blind treatment period data, baseline was defined as the last available measurement before the first dose of double-blind escitalopram or santanafacil QD XR plus santanafacil.

[0353] 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-Severity (CGI-S) score; 3) Clinical Global Impression of Change (CGI-C) score; 4) change from baseline in the Patient Global Impression-Severity (PGI-S) score; 5) Patient Global Impression of Change (PGI-C) score; 6) change from baseline in the Major Depressive Disorder Symptom Scale (SMDDS) total score; 7) screening change in the 36-Item Brief Health Survey, Version 2 (SF-36v2); 8) screening change in the Apathy Evaluation Scale-Self-Assessment (AES-S) score; 9) MADRS response rate (where response was defined as a 50% decrease from baseline in the MADRS total score at a scheduled visit); and 10) MADRS remission rate (where remission was defined as a decrease from baseline in the MADRS total score at a scheduled visit). 10). The definitions of these efficacy endpoints are the same as in Example 1. The exploratory efficacy evaluated in this study also includes the change in the MADRS anhedonia factor relative to baseline.

[0354] Safety evaluation

[0355] Safety was assessed using standard measures, including treatment-emergent adverse events (TEAEs), adverse events of special interest (AESI [rash]), clinical laboratory tests (chemistry, hematology, and urinalysis), physical examination, vital sign measurements, and 12-lead ECG. Safety was also assessed using the Study Medication Discontinuation Questionnaire (SMWQ), the Generalized Anxiety Disorder Assessment (GAD-7), and the Columbia-Suicidality Severity Rating Scale (C-SSRS). Abuse potential was assessed by active surveillance for events requiring additional monitoring (ESAM); for example, AEs related to abuse potential and AEs involving medication mishandling (MHI).

[0356] The mean reduction in all primary efficacy measures (i.e., MADRS total score) after 6 weeks of combination therapy was greater than that after 6 weeks of escitalopram monotherapy. No significant reduction was observed in the placebo group. Sentanafadine (CTN) is effective as an adjunct to the SSRI (escitalopram) in patients with MDD.

[0357] Statistical analysis methods

[0358] The sample size calculation for this trial was based on the evaluation of the efficacy of santanafacil QD XR as an adjunctive treatment to escitalopram in adult subjects with MDD. The primary efficacy endpoint of santanafacil QD XR + escitalopram versus escitalopram monotherapy was the change from baseline in the MADRS total score at Week 6.

[0359] Primary Efficacy-Endpoint Analysis

[0360] The objective of the primary efficacy analysis was to compare the efficacy of santanafacil QD XR plus escitalopram with that of escitalopram alone, as measured by the change from baseline in the MADRS total score at week 6.

[0361] The primary estimand in the protocol to determine the relevant treatment effect uses the hypothetical strategy specified in Annex E9 of the International Council for Harmonization (ICH). The estimand or target of the estimand according to the hypothetical strategy is the treatment effect that would have been seen if discontinuation had not occurred. If a subject who withdraws from IMP treatment does not take any other treatment after discontinuation, the subject may lose the treatment effect, or if the subject takes other treatment after discontinuation, the treatment effect may be masked. This means that any observations obtained after the subject stops the IMP are likely to not provide relevant information about the effect of the drug treatment. Due to this strategy, the last efficacy assessment collected after premature discontinuation of the trial was performed only once, at the ET visit. Every effort was made to complete all ET assessments before any additional medication was administered to treat the MDD. In the event of a terminal or loss to follow-up event, ET assessments are not expected to be performed, and only periodic assessments are performed before such an event occurs.

[0362] The primary estimands of this trial were defined by the following components: Target population: efficacy sample; Endpoint: change from baseline to week 6 in MADRS total score; Intercurrent event: premature discontinuation of treatment; Intervention effect measure: difference in the mean of the endpoint between 6-week santanafacil QD XR + escitalopram and escitalopram monotherapy.

[0363] The primary efficacy analysis was performed by fitting an MMRM analysis with an unstructured (UN) variance-covariance structure, in which the change from baseline in the MADRS total score (at Weeks 1, 2, 4, and 6) was the dependent variable based on the observed case (OC) data set of the efficacy sample. The model included fixed category effect terms for treatment, study center, visit week, and an interaction term for treatment as of visit week. The model also included an interaction term for the baseline value of the MADRS total score as of visit week as a covariate. The primary comparison between the combination of santanafacil QD XR + escitalopram and escitalopram monotherapy at Week 6 of the double-blind treatment period was evaluated as the difference in least squares means using the computational software SAS procedure PROC MIXED.

[0364] Other efficacy endpoint analyses

[0365] The following additional efficacy endpoints were compared. All were tested at the nominal 0.05 level.

[0366] 1) Changes in MADRS total score from baseline at week 1, week 2, and week 4;

[0367] 2) changes in CGI-S scores from baseline at weeks 1, 2, 4, and 6;

[0368] 3) CGI-C scores at weeks 1, 2, 4, and 6;

[0369] 4) changes in PGI-S scores from baseline at weeks 1, 2, 4, and 6;

[0370] 5) PGI-C scores at weeks 1, 2, 4, and 6;

[0371] 6) Changes in SMDDS total score from baseline at day 4, week 1, week 2, week 4, and week 6;

[0372] 7) Changes in the SF-36v2 physical component total score, psychological component total score, and SF-36v2 subscales relative to the screening period;

[0373] 8) change in AES-S score relative to screening;

[0374] 9) MADRS response rate, where response was defined as a 50% reduction in MADRS total score from baseline at Week 1, Week 2, Week 4, and Week 6; and

[0375] 10) MADRS response rate, where response was defined as the total MADRS score at week 1, week 2, week 4, and week 6 10.

[0376] Endpoints (1), (2), (4), and (6) were evaluated using the same MMRM model described in the primary analysis. Endpoints (3) and (5) were evaluated by the CMH Row Mean Score Differ Test with a center-based approach using the LOCF data set. Endpoints (7) and (8) were evaluated by analysis of covariance with baseline values ​​as covariates, treatment as a covariate, and a center-based effect in the LOCF analysis. Endpoints (9) and (10) were evaluated by the CMH General Association Test with a center-based approach using the LOCF data set. OC analyses were also performed for end points (3), (5), and (7) to (10), but not by center.

[0377] Exploratory Efficacy Endpoint Analysis

[0378] Changes from baseline and descriptive statistics were used for the MADRS anhedonia factor scores (total scores of MADRS items 1, 2, 6, 7, and 8).

[0379] Pharmacokinetic evaluation

[0380] Pharmacokinetic samples were collected at weeks 2, 4, and 6 (± 2 days).

[0381] Pharmacokinetic blood samples

[0382] A single sparse PK sample was collected at Weeks 2, 4, and 6. PK samples were collected after efficacy evaluations and other safety evaluations (AE monitoring, vital sign measurements, ECG, drug withdrawal scale, and suicidality evaluation). In Week 2, a sample was obtained in the morning before dosing (trough) or 4 hours after dosing; then alternate time points were taken in Week 4. In Week 6, subjects were informed to take the dose before the morning clinic visit, and the PK sample was collected at the same time as the serum chemistry sample. Visits were scheduled as needed to achieve different sampling times.

[0383] Blood samples (2 mL whole blood, dipotassium ethylenediaminetetraacetate [K2EDTA]) were collected by venipuncture and processed to plasma for determination of sentanafadine and metabolite concentrations.

[0384] When vital signs or electrocardiogram (ECG) were scheduled at the same labeled time as PK sample collection, vital signs were measured and ECG was performed before PK sample collection.

[0385] The actual date and time of PK sample collection and the date and time of IMP administration prior to PK sample collection were recorded in the eCRF.

[0386] Clinical laboratory evaluation

[0387] Clinical laboratory samples were collected at Screening and Baseline (Day -1), Weeks 1, 4, and 6 for the clinical laboratory evaluations described herein and, when possible, after completion of efficacy evaluations.

[0388] For the screening laboratory evaluation, subjects were not required to fast. For the subsequent laboratory evaluations, laboratory evaluations were fasting. Subjects were advised to fast for at least 8 hours before blood draw if possible.

[0389] All screening test results are available and included prior to randomization. The results of these tests are reviewed by staff prior to initiation of IMP administration. Additional urine and blood samples may be collected, if authorized, to further evaluate safety.

[0390] Urine or serum pregnancy tests are performed on CBP subjects during the study. Unscheduled urine or serum pregnancy tests may be performed when pregnancy is suspected. Positive urine pregnancy tests are confirmed with serum pregnancy tests. Pregnancy test results must be provided prior to administration of IMP. Subjects are informed of the risk of pregnancy when participating in clinical trials.

[0391] Drug screens were performed at Screening and Baseline (Day -1); additional assessments were performed at any time at the discretion of the investigator. Subjects who had a confirmed positive drug screen result for prohibited drug use at Screening were required to undergo a washout period. Subjects who had a confirmed positive drug screen result for prohibited drug use at Baseline were considered screen failures and were not allowed to be rescreened.

[0392] Monitor subjects for laboratory values ​​that may be clinically significant.

[0393] Other safety data

[0394] Drug withdrawal symptoms assessed by SMWQ total score at scheduled visits were summarized by treatment group using descriptive statistics.

[0395] Anxiety assessed by GAD-7 at scheduled visits was summarized by treatment group using descriptive statistics.

[0396] Suicide rates during the trial period using the C-SSRS were summarized by treatment group using descriptive statistics.

[0397] Other analysis

[0398] Pharmacokinetic analysis

[0399] Sparse PK samples are evaluated to verify adherence to dosing; concentrations may also be used in population PK analyses reported separately.

[0400] The foregoing description has been given for clearness of understanding only, and no unnecessary limitations are to be understood therefrom, as modifications within the scope of the invention will be apparent to one skilled in the art.

[0401] Throughout the present specification and claims, unless the context requires otherwise, the word "comprise" and variations thereof, will be understood to imply the inclusion of stated integers or steps or groups of integers or steps but not the exclusion of any other integers or steps or groups of integers or steps.

[0402] As used throughout, ranges are used as shorthand for describing each value within the range. Any value within the range can be selected as the endpoint of the range. In addition, all references cited herein are incorporated herein by reference in their entirety. In the event that a definition in the present disclosure conflicts with a definition of a cited reference, the present disclosure shall prevail.

[0403] Throughout this specification, where a composition is described as comprising a component or material, unless otherwise described, it is contemplated that the composition may also consist essentially of or consist of any combination of the recited components or materials. Similarly, where a method is described as comprising specific steps, unless otherwise described, it is contemplated that the method may also consist essentially of or consist of any combination of the recited steps. The present invention exemplarily disclosed herein may be suitably practiced in the absence of any element or step not specifically disclosed herein.

[0404] The practice of the methods disclosed herein and their various steps can be performed manually and / or by means of an electronic device or automation provided by an electronic device. Although the methods have been described with reference to specific embodiments, it will be readily understood by those of ordinary skill in the art that other ways of performing actions associated with these methods can be used. For example, unless otherwise stated, the order of the various steps can be changed without departing from the scope or spirit of the methods. In addition, some individual steps can be combined, omitted, or further subdivided into other steps.

[0405] All patents, publications, and references cited herein are fully incorporated herein by reference. In the event of a conflict between the present disclosure and the incorporated patents, publications, and references, the present disclosure shall control.

[0406] The foregoing description has been given for clearness of understanding only, and no unnecessary limitations are to be understood therefrom, as modifications within the scope of the invention will be apparent to one skilled in the art.

[0407] Throughout the present specification and claims, unless the context requires otherwise, the word "comprise" and variations thereof, will be understood to imply the inclusion of stated integers or steps or groups of integers or steps but not the exclusion of any other integers or steps or groups of integers or steps.

[0408] As used throughout, ranges are used as shorthand for describing each value within the range. Any value within the range can be selected as the endpoint of the range. In addition, all references cited herein are incorporated herein by reference in their entirety. In the event that a definition in the present disclosure conflicts with a definition of a cited reference, the present disclosure shall prevail.

[0409] Throughout this specification, where a composition is described as comprising a component or material, unless otherwise described, it is contemplated that the composition may also consist essentially of or consist of any combination of the recited components or materials. Similarly, where a method is described as comprising specific steps, unless otherwise described, it is contemplated that the method may also consist essentially of or consist of any combination of the recited steps. The present invention exemplarily disclosed herein may be suitably practiced in the absence of any element or step not specifically disclosed herein.

[0410] The practice of the methods disclosed herein and their various steps can be performed manually and / or by means of an electronic device or automation provided by an electronic device. Although the methods have been described with reference to specific embodiments, it will be readily understood by those of ordinary skill in the art that other ways of performing actions associated with these methods can be used. For example, unless otherwise stated, the order of the various steps can be changed without departing from the scope or spirit of the methods. In addition, some individual steps can be combined, omitted, or further subdivided into other steps.

[0411] All patents, publications, and references cited herein are fully incorporated herein by reference. 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 in a human patient in need thereof, comprising administering to the patient a therapeutically effective amount of santanafacil or a pharmaceutically acceptable salt thereof, wherein santanafacil or a pharmaceutically acceptable salt thereof is administered in an extended release dosage form comprising a plurality of santanafacil beads.

2. The method of claim 1, wherein each of the plurality of sentanafadine beads each comprises a core particle containing sentanafadine or a pharmaceutically acceptable salt thereof and an excipient, and wherein the plurality of sentanafadine beads comprises a mixture of one or more immediate-release beads, one or more sustained-release beads, and one or more delayed-release beads.

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

4. The method according to claim 2 or 3, wherein the one or more delayed-release beads comprise a delayed-release coating, the delayed-release coating comprising one or more materials selected from the group consisting of amylose acetate phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate trimellitate, carboxymethyl ethyl cellulose, copolymerized methacrylic acid / methyl methacrylate, copolymerized methacrylic acid / methyl methacrylate, copolymerized methacrylate / methyl methacrylate / methacrylic acid, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, styrene maleic acid copolymer and styrene vinyl pyridine copolymer.

5. The method according to any one of claims 2 to 4, wherein the mixture of the one or more immediate release beads, the one or more sustained release beads and the one or more delayed release beads contains santanafidine or its salt in a ratio in the range of about 0.1-1: 1-20: 1-20 parts by weight based on the weight of santanafidine or its salt.

6. The method of any one of claims 1 to 5, wherein administering comprises administering the extended release dosage form once daily.

7. The method of claim 6, wherein the extended release dosage form is a capsule.

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

9. The method of any one of claims 1 to 8, wherein the amount of santanafadine or a pharmaceutically acceptable salt thereof administered is in the range of about 10 mg to about 750 mg per day.

10. The method of claim 9, wherein the amount of santanafadine or a pharmaceutically acceptable salt thereof administered is in the range of about 35 mg to about 400 mg per day.

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

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

13. The method of claim 11, wherein the one or more antidepressants are selected from selective serotonin reuptake inhibitors.

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

15. The method of any one of claims 11 to 14, wherein santanafacil or a pharmaceutically acceptable salt thereof is administered in an extended release dosage form comprising a plurality of santanafacil beads.

16. The method according to any one of claims 11 to 15, wherein each bead of the plurality of sentanafadine beads comprises a core particle comprising sentanafadine or a pharmaceutically acceptable salt thereof and an excipient, and wherein the plurality of sentanafadine beads comprises a mixture of one or more immediate-release beads, one or more sustained-release beads and one or more delayed-release beads.

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

18. The method according to any one of claims 11 to 17, wherein the one or more delayed-release beads comprise a delayed-release coating comprising one or more materials selected from the group consisting of amylose acetate phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate trimellitate, carboxymethyl ethyl cellulose, copolymerized methacrylic acid / methyl methacrylate, copolymerized methacrylic acid / methyl methacrylate, copolymerized methacrylate / methyl methacrylate / methacrylic acid, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, styrene maleic acid copolymer and styrene vinyl pyridine copolymer.

19. The method according to any one of claims 16 to 18, wherein the mixture of one or more immediate release beads, one or more sustained release beads and one or more delayed release beads contains santanafidine or its salt in a ratio in the range of about 0.1-1: 1-20: 1-20 parts by weight based on the weight of santanafidine or its salt.

20. The method of any one of claims 11 to 19, wherein the amount of santanafil or a pharmaceutically acceptable salt thereof administered is 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 mg to about 20 mg per day.

21. The method of claim 20, wherein the amount of sentanafidine 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 mg to about 20 mg per day.

22. A method of treating major depressive disorder in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of sentanafadine or a pharmaceutically acceptable salt thereof as an adjunct to a selective serotonin reuptake inhibitor; wherein the santanafacil or a pharmaceutically acceptable salt thereof is administered in an extended release dosage form comprising a plurality of santanafacil beads; wherein each bead of the plurality of sentanafadine beads comprises a core particle comprising sentanafadine or a pharmaceutically acceptable salt thereof and an excipient; wherein the plurality of sentanafidine beads comprises a mixture of one or more immediate release beads, one or more sustained release beads, and one or more delayed release beads; wherein the mixture of the one or more immediate release beads, the one or more sustained release beads, and the one or more delayed release beads contains sentanafadine or its salt in a ratio in the range of about 0.1-1: 1-20: 1-20 parts by weight based on the weight of sentanafadine or its salt; wherein sentanafadine or a pharmaceutically acceptable salt thereof is administered in the range of about 35 mg to about 400 mg per day; wherein the selective serotonin reuptake inhibitor is escitalopram or a pharmaceutically acceptable salt thereof; and Wherein the escitalopram or a pharmaceutically acceptable salt thereof is administered in the range of about 10 mg to about 20 mg per day.

23. The method of claim 22, wherein santanafil is administered as a hydrochloride salt and escitalopram is administered as an oxalate salt.

24. The method according to claim 22 or 23, wherein the mixture of one or more immediate release beads, one or more sustained release beads and one or more delayed release beads contains santanafidine or its salt in a ratio in the range of about 1:3.6:3.6 parts by weight based on the weight of santanafidine or its salt.

25. The method according to any one of claims 22 to 24, wherein santanafil 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. The method of any one of claims 22 to 24, wherein santanafil 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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