Combination therapy for depression and other disorders

Abstract

The present invention provides dosage forms containing both monoamine oxidase inhibitors (MAOIs) and beta-blockers (e.g., propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebiborol, sotalol, bucindolol, nadalol, cerilpolol, nebiborol, betaxolol, esmolol, bisoprolol, oxprenolol, penbutrol, labetalol, acebutrol, and pindolol), as well as methods for preparing and using them for the treatment of mental disorders (e.g., depression, major depressive disorder, major depressive disorder with anxiety distress, treatment-resistant depression, anxious depression, and combinations of anxiety and depression). This abstract is intended as a scan tool for searching in a specific art and is not intended to limit the present invention.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the interests of U.S. Application No. 63 / 521,578 filed on 16 June 2023, U.S. Application No. 63 / 528,285 filed on 21 July 2023, and U.S. Application No. 63 / 638,117 filed on 24 April 2024, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Depression is a leading cause of disorder worldwide (Friedrich, MJ (2017) JAMA 317(15):1517), yet few new antidepressants have been approved, and the lack of effectiveness in antidepressant treatment contributes to the enormous public health burden of depression (Hyman, Steven E. (2012) Science translational medicine 4(155):155cm11). Major depressive disorder (MDD) is the most common and distressing form of depression, with a lifetime prevalence of 20.6% in the United States (US) (Hasin et al. (2018) JAMA Psychiatry 75(4):336-346). MDD frequently occurs with other comorbidities in patients, including the presence of anxiety disorders. In fact, the prevalence of anxiety or anxiety symptoms in MDD is estimated to be 40-78% (These et al. (2017) J Clin Psychiatry 78(9):1351-1362, Gaspersz et al. (2017) J Clin Psychiatry 78(2):207-213, Zimmerman et al. (2019) Depress Anxiety 36(1):31-38, Fava et al. (2006) Journal of Psychiatric Research 40(4):328-336, Yang et al. (2014) Psychiatry Clin Neurosci 68(9):712-720). In some patients, the coexistence of depression and anxiety symptoms reflects an ongoing anxiety disorder, while in others, a marked increase in anxiety occurs with depressive episodes, complicating the clinical picture and treatment (These et al. al. (2017) J Clin Psychiatry 78(9):1351-1362).Patients with both MDD and distressing anxiety (MDD-AD) tend to have more severe depression, severe functional impairment, increased panic and stress, and a reduced response to treatment (Trivedi et al. (2006) The American journal of psychiatry 163(1):28-40, Rosellini et al. (2018) Journal of Psychiatric Research 103:54-60, Hasin et al. (2018) JAMA Psychiatry 75(4):336-346).

[0003] There is no standardized care for patients with MDD-AD. Research and clinical practice have shown that monoamine oxidase inhibitors (MAOIs) are effective in treating MDD when other therapies fail (see Bender and Walker, 2012, Fiedorowicz and Swartz, 2004, and Thate, et al., 1995 for reviews). As demonstrated by McGrath et al. 1993, one MAOI, phenelzine (PHZ), has been shown to be very effective in treating treatment-refractory depression, with 55% of patients who previously did not respond to imipramine, a tricyclic antidepressant (TCA) traditionally used as a benchmark for antidepressant efficacy, responding positively to PHZ (McGrath et al. (1993) The American journal of psychiatry 150(1):118-123). Furthermore, a recent meta-analysis comparing 14 antidepressants (and placebo) demonstrated that PHZ has superior efficacy compared to all other treatments (Suchting et al. (2021) Journal of affective disorders 282:1153-1160). Phenelzine sulfate has been proposed to increase brain levels of gamma-aminobutyric acid (GABA) by inhibiting GABA transaminase (GABA-T), an inhibitory neurotransmitter widely accepted for its role in anxiety disorders (Nemeroff, Charles B. (2003) Psychopharmacol Bull 37(4):133-146). The enhancement of GABA, serotonin, norepinephrine, and dopamine by PHZ has all been proposed to play a role in mediating depression and anxiety disorders, which may explain the reported efficacy of PHZ and its potential for treating MDD-AD.

[0004] Despite their success in treating difficult-to-treat patients, PHZ and other MAOIs are rarely used to treat MDD, mixed anxiety and depression, or MDD-AD, even after several treatment options have failed, primarily due to safety concerns associated with tyramine accumulation ("cheese effect"). In patients receiving MAOIs in the 1960s, tyramine was shown to be the cause of many medically significant cardiovascular events (e.g., dangerous hypertension) and 21 deaths (Gillman, P. Ken (2011) Journal of psychopharmacology (Oxford, England) 25(3):429-436). After being temporarily withdrawn from the market in 1964, MAOIs were reintroduced with dietary restrictions imposed by regulators to limit their efficacy, including restrictions on the consumption of cheese, beer, wine, and preserved meats, in order to prevent the "cheese effect." Since 1967, it has been reported that identifying deaths associated with the cheese effect has been difficult (Gillman, P. Ken (2011) Journal of psychopharmacology (Oxford, England) 25(3):429-436). However, the potential tyramine effect continues to be reported as a significant deterrent to the use of MAOIs today (Rabkin et al. (1985) J. Clin. Psychopharmacol. 5(1):2-9), and prescribers are concerned about the risks of patient non-compliance, misunderstandings of the risks of dietary non-adherence, and the potential medical risks resulting from dangerous hypertensive reactions in patients who deviate from dietary restrictions.

[0005] Therefore, there remains a need for dosage forms, compositions, and methods for treating depression and other mental disorders using MAOIs that reduce or eliminate tyramine-induced pressor responses. These and other needs are met by the present invention. [Overview of the Initiative]

[0006] In accordance with the object(s) of the present invention, as embodied and broadly described herein, in one aspect the present invention relates to dosage forms containing both MAOIs and beta-blockers (e.g., propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebiborol, sotalol, bucindolol, nadalol, cerilpolol, nebiborol, betaxolol, esmolol, bisoprolol, oxprenolol, penbutrol, labetalol, acebutrol, and pindolol), as well as methods for preparing and using them in the treatment of mental disorders such as depression, major depressive disorder, major depressive disorder with anxiety distress, treatment-resistant depression, anxious depression, and mixed anxiety and depression.

[0007] Accordingly, a dosage form is disclosed comprising (a) a therapeutically effective amount of a monoamine oxidase inhibitor (MAOI), and (b) a therapeutically effective amount of a beta-blocker selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebibolol, sotalol, bucindolol, nadalol, cerilpolol, nebibolol, betaxolol, esmolol, bisoprolol, oxprenolol, penbutolol, labetalol, acebutolol, and pindolol, or pharmaceutically acceptable salts or free bases thereof, and a pharmaceutically acceptable carrier.

[0008] Also disclosed is a dosage form comprising (a) a therapeutically effective amount of phenelzine or a pharmaceutically acceptable salt or free base thereof, and (b) a therapeutically effective amount of a beta-blocker selected from pindolol and bisoprolol, or a pharmaceutically acceptable salt or free base thereof, and a pharmaceutically acceptable carrier, wherein the MAOI is formulated as a controlled-release dosage form, and the beta-blocker is formulated as a controlled-release dosage form.

[0009] Also disclosed is a dosage form comprising a therapeutically effective amount of a MAOI, the improvement including further comprising, in the dosage form, a therapeutically effective amount of a beta blocker selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebivolol, sotalol, bucindolol, nadolol, celiprolol, nebivolol, betaxolol, esmolol, bisoprolol, oxprenolol, penbutolol, labetalol, acebutolol, and pindolol, or a pharmaceutically acceptable salt or free base thereof.

[0010] Also disclosed is a dosage form comprising a therapeutically effective amount of a beta blocker, the improvement including further comprising, in the dosage form, a therapeutically effective amount of a MAOI.

[0011] Also disclosed is a method for treating a mental disorder in a subject who needs treatment for the mental disorder, the method comprising administering to the subject an effective amount of the disclosed dosage form.

[0012] Also disclosed is a method for treating a mental disorder in a subject who needs treatment for the mental disorder, the method comprising administering to the subject (a) a therapeutically effective amount of a monoamine oxidase inhibitor (MAOI) and (b) a therapeutically effective amount of a beta blocker selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebivolol, sotalol, bucindolol, nadolol, celiprolol, nebivolol, betaxolol, esmolol, bisoprolol, oxprenolol, penbutolol, labetalol, acebutolol, and pindolol, or a pharmaceutically acceptable salt or free base thereof, wherein the subject has not been previously diagnosed with migraine and the subject is not currently experiencing migraine.

[0013] Furthermore, a method for treating mental disorders in subjects requiring treatment of mental disorders by administering MAOIs is disclosed, the improvement comprising co-administering to the patient a beta-blocker selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebiborol, sotalol, bucindolol, nadalol, cerilpolol, nebiborol, betaxolol, esmolol, bisoprolol, oxprenolol, penbutrol, labetalol, acebutrol, and pindolol, or pharmaceutically acceptable salts or free bases thereof, together with the MAOI in a dose effective in reducing migraine recurrence and / or producing a longer-lasting effect compared to administration of the MAOI in the absence of the beta-blocker, wherein the MAOI and beta-blocker exist together in a single dosage form.

[0014] Furthermore, a method for treating mental disorders in subjects requiring treatment of mental disorders by administering MAOIs is disclosed, the improvement comprising co-administering to the patient a beta-blocker selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebiborol, sotalol, bucindolol, nadalol, cerilpolol, nebiborol, betaxolol, esmolol, bisoprolol, oxprenolol, penbutrol, labetalol, acebutrol, and pindolol, or pharmaceutically acceptable salts or free bases thereof, together with the MAOI in a dose effective in reducing migraine recurrence and / or producing a longer-lasting effect compared to administration of the MAOI in the absence of the beta-blocker, the subject has not been previously diagnosed with migraine, and the subject is not currently experiencing migraines.

[0015] Furthermore, a method for treating mental disorders in subjects requiring treatment of mental disorders by administering beta-blockers is disclosed, the improvement comprising co-administering an MAOI to the patient in a dose effective in reducing migraine recurrence and / or producing a longer-lasting effect compared to administration of the beta-blocker in the absence of the MAOI, wherein the MAOI and beta-blocker exist together in a single dosage form.

[0016] Furthermore, a method for treating mental disorders in subjects requiring treatment of mental disorders by administering beta-blockers is disclosed, the improvement comprising administering to the patient a beta-blocker selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebiborol, sotalol, bucindolol, nadalol, cerilpolol, nebiborol, betaxolol, esmolol, bisoprolol, oxprenolol, penbutrol, labetalol, acebutrol, and pindolol, or pharmaceutically acceptable salts or free bases thereof, together with an MAOI in a dose effective in reducing migraine recurrence and / or producing a longer-lasting effect compared to the administration of the MAOI in the absence of the beta-blocker, the subject has not been previously diagnosed with migraines and is not currently experiencing migraines.

[0017] Also disclosed is a method for treating mental disorders in subjects requiring treatment for mental disorders, the method comprising administering to the subject an effective dose of a dosage form comprising (a) a therapeutically effective dose of a monoamine oxidase inhibitor (MAOI) selected from phenelzine and tranylcypromine (TCP), (b) a therapeutically effective dose of a beta-blocker selected from pindolol and carvedilol, or pharmaceutically acceptable salts or free bases thereof, and (c) a pharmaceutically acceptable carrier, wherein the subject has not been previously diagnosed with migraine.

[0018] Aspects of the present invention may be described and claimed in a specific legal class, such as a system legal class; however, this is for convenience only, and those skilled in the art will understand that each aspect of the present invention may be described and claimed in any legal class. Unless otherwise expressly stated, no method or aspect described herein is ever intended to be construed as requiring its steps to be performed in a particular order. Accordingly, no order is ever intended to be inferred in any respect unless the claims or specification specifically state that the steps should be limited to a particular order. This is reserved for any possible implicit grounds for interpretation, including the arrangement of steps or operational flows, the obvious meaning arising from grammatical structure or punctuation, or logical matters relating to the number or type of aspects described in the specification.

[0019] The accompanying figures incorporated herein and constituting part of this specification illustrate several embodiments and are useful in illustrating the principles of the present invention together with this specification. [Brief explanation of the drawing]

[0020] [Figure 1] A typical schematic diagram of the predictive Phase 1 trial described herein is shown. [Figure 2] Representative data showing the IC50 of MAO-A using phenelzine is presented. [Figure 3] Representative data showing the IC50 of MAO-B using phenelzine is shown. [Figure 4A] Representative data showing the maximum change in systolic blood pressure after tyramine administration are presented for either phenylidine (Figure 4A) or tranylcypromine (Figure 4B) alone, and in combination with pindolol. [Figure 4B] Representative data showing the maximum change in systolic blood pressure after tyramine administration are presented for either phenylidine (Figure 4A) or tranylcypromine (Figure 4B) alone, and in combination with pindolol. [Figure 5] This shows a typical time course of systolic blood pressure in rats treated with phenelzine alone or in combination with pindolol after tyramine administration. [Figure 6] This shows typical time courses for pindolol and tranylcypromine after tyramine administration. [Figure 7] Representative data showing the maximum change from baseline for phenelzine alone or in combination with pindolol are presented. [Figure 8] Representative data showing the maximum change from baseline for tranilcypromine alone or in combination with either pindolol or bisoprolol are presented. [Figure 9] Representative data showing the area under the curve (AUC) for tranilcypromine alone or in combination with either pindolol or bisoprolol are shown. [Figure 10] Representative data showing the time course from baseline for tranilcypromine alone or in combination with pindolol are presented. [Figure 11] Representative data showing the time course from baseline for tranilcypromine alone or in combination with bisoprolol are presented. [Figure 12] Representative data showing the maximum change from baseline for tranilcypromine alone or in combination with carvedilol are presented. [Figure 13] Representative data showing the AUC for tranilcypromine alone or in combination with carvedilol are presented. [Figure 14] Representative data showing the time course from baseline for tranilcypromine alone or in combination with carvedilol are presented. [Figure 15] Representative data showing a comparison of transient changes from baseline in systolic blood pressure after tranylcypromine dose administration compared to tranylcypromine with pindolol or bisoprolol are presented.

[0021] Further advantages of the present invention are partially described in the following description, partially evident from the description, or can be learned through the practice of the invention. The advantages of the present invention will be realized and achieved by the elements and combinations specifically pointed out in the appended claims. It should be understood that both the above general description and the following detailed description are illustrative and descriptive only and do not limit the invention as described in the claims. [Modes for carrying out the invention]

[0022] The present invention can be more easily understood by referring to the following detailed description of the invention and the examples contained herein.

[0023] Before the compounds, compositions, articles, systems, devices, and / or methods described herein are disclosed and described, it should be understood that, unless otherwise specified, they are not limited to specific synthesis methods or specific reagents, as they may naturally differ. It should also be understood that the terms used herein are for illustrative purposes only and are not intended to limit any particular aspect. Any methods and materials similar or equivalent to those described herein may be used in carrying out or testing the present invention, but only illustrative methods and materials are described here.

[0024] Aspects of the present invention may be described and claimed in a specific legal class, such as a system legal class; however, this is for convenience only, and those skilled in the art will understand that each aspect of the present invention may be described and claimed in any legal class. Unless otherwise expressly stated, no method or aspect described herein is ever intended to be construed as requiring its steps to be performed in a particular order. Accordingly, no order is ever intended to be inferred in any respect unless the claims or specification specifically state that the steps should be limited to a particular order. This is reserved for any possible implicit grounds for interpretation, including the arrangement of steps or operational flows, the obvious meaning arising from grammatical structure or punctuation, or logical matters relating to the number or type of aspects described in the specification.

[0025] Throughout this application, various publications are referenced. The disclosures of these publications are incorporated herein by reference in their entirety to more completely describe the cutting edge of the technology relating to this application. The disclosed references are also incorporated herein by reference individually and specifically to the content contained within the references considered in the sentences in which they are cited. Nothing herein should be construed as admitting that the present invention does not have prior rights to such publications by prior invention. Furthermore, the dates of publications provided herein may differ from the actual publication dates and can be independently verified.

[0026] A.Definition As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include multiple referents unless otherwise clearly indicated by the context. Thus, for example, a reference to “an antidepressant,” “a psychological disorder,” or “a subject” includes two or more such antidepressants, psychological disorders, or subjects, as well as a mixture thereof.

[0027] As used herein and in the claims, the term “comprising” may include the forms “consisting of” and “consisting essentially of.”

[0028] In this specification, a range can be expressed as "approximately" from one particular value and / or "approximately" to another particular value. When such a range is expressed, another aspect includes "approximately" from one particular value and / or to another particular value. Similarly, when a value is expressed as an approximation using the antecedent "approximately", it will be understood that the particular value forms another aspect. It will be further understood that each endpoint of a range is significant, whether related to other endpoints or independent of other endpoints. Also, it will be understood that several values ​​are disclosed in this specification, and each value is disclosed in this specification not only as the value itself but also "approximately" that particular value. For example, if the value "10" is disclosed, then "approximately 10" is also disclosed. It will also be understood that each unit between two particular units is disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0029] Where used herein, the terms “about” and “at or about” mean that the quantity or value in question may be a value that is approximately or roughly the same as several other values. Where used herein, unless otherwise indicated or inferred, it is generally understood that it is a nominal value with a variation of ±10%. The terms are intended to convey that similar values ​​facilitate equivalent results or effects described in the claims. That is, quantities, sizes, formulations, parameters, and other quantities and characteristics are understood to be approximate and / or greater or less, not exact and not necessarily, but to reflect tolerances, conversion factors, rounding, measurement errors, and other factors known to those skilled in the art, as desired. In general, quantities, sizes, formulations, parameters, or other quantities or characteristics are “about” or “approximate,” whether or not they are explicitly stated to be so. When “about” is used before a quantitative value, it is understood that the parameter also includes the specific quantitative value itself, unless otherwise specifically indicated.

[0030] References in the specification and the final claims to parts by weight of a particular element or component in a composition indicate the weight relationship between the element or component in the composition or article for which the parts by weight are represented and any other element or component. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight of component Y, X and Y exist in a weight ratio of 2:5, and such a ratio exists whether or not additional components are present in the compound.

[0031] The weight percentage (W%) of a component is based on the total weight of the formulation or composition containing that component, unless otherwise specified.

[0032] As used herein, the terms “optional” or “optional” mean that the events or circumstances described thereafter may or may not occur, and that examples of such events or circumstances occurring and examples of them not occurring are included in the description.

[0033] As used herein, the term “subject” can be a vertebrate, such as a mammal, fish, bird, reptile, or amphibian. Thus, the subjects of the methods disclosed herein may be humans, non-human primates, horses, pigs, rabbits, dogs, sheep, goats, cattle, cattle, guinea pigs, or rodents. The term does not indicate a specific age or sex. Therefore, it is intended to encompass adult and neonatal subjects, as well as fetuses, regardless of whether they are male or female. In one embodiment, the subject is a mammal. Patient refers to a subject suffering from a disease or disorder. The term “patient” includes human and veterinary subjects.

[0034] As used herein, the term “treatment” refers to the medical management of a patient intended to cure, improve, stabilize, or prevent a disease, condition, or disorder. This term includes active treatment, i.e., treatment aimed specifically at improving the disease, condition, or disorder, and causal treatment, i.e., treatment aimed at eliminating the cause of the associated disease, condition, or disorder. In addition, this term includes palliative treatment, i.e., treatment designed to alleviate symptoms rather than cure the disease, condition, or disorder; preventive treatment, i.e., treatment aimed at minimizing, or partially or completely suppressing, the onset of the associated disease, condition, or disorder; and supportive treatment, i.e., treatment used to complement another specific therapy aimed at improving the associated disease, condition, or disorder. In various aspects, this term encompasses any treatment of subjects, including mammals (e.g., humans), including (i) preventing the development of disease in subjects who may be predisposed to the disease but have not yet been diagnosed with it, (ii) suppressing the disease, i.e., preventing its onset, or (iii) mitigating the disease, i.e., causing disease regression. In one aspect, the subject is a mammal such as a primate, and in further aspects, the subject is a human. The term “subject” also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mice, rabbits, rats, guinea pigs, fruit flies, etc.).

[0035] As used herein, the terms “prevent” or “preventing” mean, in particular, preventing, avoiding, eliminating, deterring, or hindering something from happening through prior action. Where “reduce,” “hinder,” or “prevent” are used herein, it is understood that the use of the other two terms is also expressly disclosed unless otherwise specifically indicated.

[0036] As used herein, the term “diagnosed” means that a person skilled in the art, for example, has undergone a physical examination by a physician and has been found to have a condition that can be diagnosed or treated by any of the compounds, compositions, or methods disclosed herein.

[0037] As used herein, the terms “administering” and “dosing” refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral, transdermal, inhalation, nasal, topical, vaginal, ophthalmic, intraotoral, intracerebral, rectal, sublingual, oral, and injectable methods such as intravenous, intra-arterial, intramuscular, and subcutaneous administration, as well as parenteral administration. Dosing may be continuous or intermittent. In various embodiments, preparations may be administered therapeutically, i.e., to treat an existing disease or condition. In further various embodiments, preparations may be administered prophylactically, i.e., to prevent a disease or condition.

[0038] As used herein, the terms “effective dose” and “effective amount” refer to an amount sufficient to achieve a desired outcome or to cause an undesirable condition. For example, “therapeutic effective dose” refers to an amount sufficient to achieve a desired therapeutic outcome or to have an effect against an undesirable symptom, but insufficient to cause generally harmful side effects. The specific therapeutic effective dose level for any particular patient will depend on a variety of factors, including the disorder being treated and its severity; the specific composition used; the patient’s age, weight, overall health, sex, and diet; the timing of administration; the route of administration; the rate of excretion of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors well known in the medical field. For example, starting with a dose of a compound at a level lower than necessary to achieve the desired therapeutic effect and gradually increasing the dose until the desired effect is achieved is well within the scope of the art. If desired, an effective daily dose can be divided into multiple doses for administration. Consequently, a single-dose composition may contain such an amount or a fraction thereof to constitute a daily dose. In any contraindicated event, the dosage may be adjusted by the individual physician. Dosage may vary and may be administered once or twice daily for one day or several days. Guidance can be found in the literature on appropriate dosages for a given class of medicinal products. In various further embodiments, the preparation may be administered in a “preventive effective dose,” i.e., a dose effective in preventing the disease or condition.

[0039] As used herein, the term “dosage form” means one or more pharmacologically active agents in a culture medium, carrier, excipient, binder, vehicle, or packing material suitable for administration to a subject. As used herein, “dosage form” may refer to a liquid or solid dosage form. “Dosage form” refers to one or more disclosed compounds, combinations of disclosed compounds, fixed-dose drug combinations (FDCs), products of disclosed manufacturing methods, or their salts, solvates, free bases, or polymorphs, combined with pharmaceutically acceptable excipients such as preservatives, buffers, saline, or phosphate-buffered saline, or with pharmaceutically acceptable binders such as pre-gelatinized maize starch or hydroxypropyl methylcellulose of various degrees, packing materials (e.g., lactose, microcrystalline cellulose, calcium carbonate, or calcium phosphate), disintegrants (potato starch, croscarmellose, etc.). It may also be blended with inert components of tablets, pellets, or spheres for matrix release, including melose sodium or sodium starch glycolate, humectants (e.g., sodium lauryl sulfate or nonionic surfactants), other agents suitable for tableting, or nonionic homopolymers of ethylene oxide, water-swellable but insoluble polysaccharides (water-soluble natural gums), high molecular weight homopolymers and copolymers of acrylic acid chemically crosslinked with polyalkenyl alcohols, polyvinyl acetate and povidone, crosslinked amylose starch, and ionic methacrylate copolymers. In addition, fatty acids, fatty acid esters, and mono, di, and triglycerides with different melting points, as well as hydrophobic polymers, naturally occurring waxes, and ammoniace methacrylate copolymers, are used in non-swellable matrices. Lipid or hydrophobic matrices can delay drug release and are also used in delayed-release techniques.Coating materials for regulated drug release from formulation matrices (tablets, pellets, or spheres), including enteric-coated and other release targets, include naturally derived shellac and zein, cellulose derivatives (cellulose phthalate acetate, hydroxypropyl methylcellulose phthalate), and methacrylic (acid and ester copolymers containing carboxylic acid functional groups), which resist solubility at low pH and protect delivery to other pH levels above 5.5. Plasticizers (such as triacetin, triethanol citrate, glycerin, and polyethylene glycol) may or may not be necessary to enhance the release profile and flexibility of the coating.

[0040] Dosage forms can be prepared using conventional pharmaceutical manufacturing and formulation techniques. Dosage forms may include inorganic or organic buffers (e.g., sodium or potassium salts of phosphates, carbonates, acetates, or citrates), pH adjusters (e.g., hydrochloric acid, sodium or potassium hydroxide, salts of citrates or acetates, amino acids and their salts), antioxidants (e.g., ascorbic acid, alpha-tocopherol), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxyethylene 9-10 nonylphenol, sodium deoxycholate), solutions, and / or cold / freeze stabilizers. The compounds may include (e.g., sucrose, lactose, mannitol, trehalose), osmotic regulators (e.g., salts or sugars), antimicrobial agents (e.g., benzoic acid, phenol, gentamicin), antifoaming agents (e.g., polydimethylsilozone), preservatives (e.g., thimerosal, 2-phenoxyethanol, EDTA), polymer stabilizers and viscosity modifiers (e.g., polyvinylpyrrolidone, polyoxame 488, carboxymethylcellulose), and cosolvents (e.g., glycerol, polyethylene glycol, ethanol). Dosage forms formulated for injectable use may have the disclosed compounds, products of the disclosed methods of preparation, or salts, solvates, free bases, or polymorphs thereof, suspended in sterile saline for injection together with preservatives.

[0041] As used herein, “kit” means a collection of at least two components that make up a kit. Together, the components constitute a functional unit for a given purpose. Individual member components may be packaged together or separately. For example, a kit that includes instructions for using the kit may or may not physically include instructions for other individual member components. Alternatively, instructions may be supplied as a separate member component, either in paper form, on a computer-readable memory device, or in electronic form, such as a recorded presentation, or as a computer-readable memory device.

[0042] As used herein, “Instructions” means a document describing related materials or methodologies relating to the kit. These materials may include: background information, a list of components and their availability information (such as purchase information), a simple or detailed protocol for using the kit, troubleshooting, references, technical support, and any other related documents in any combination. Instructions may be supplied with the kit or as a separate member component, either in paper form, on a computer-readable memory device, or downloaded from an internet website, or as a recorded presentation. Instructions may include one or more documents and include future updates.

[0043] As used herein, the term “therapeutic agent” includes any synthetic or naturally occurring biologically active compound or substance composition that, when administered to a living organism (human or non-human animal), induces a desired pharmacological, immunogenic, and / or physiological effect by local and / or systemic action. Thus, the term encompasses compounds or chemical substances conventionally considered drugs, vaccines, and biopharmaceuticals, including molecules such as proteins, peptides, hormones, nucleic acids, and gene constructs. Examples of therapeutic agents are listed in well-known references such as the Merck Index (14th edition), Physicians' Desk Reference (64th edition), and The Pharmacological Basis of Therapeutics (12th edition), which include, without limitation, pharmaceuticals, vitamins, mineral supplements, substances used to treat, prevent, diagnose, cure, or alleviate diseases or illnesses, substances that affect the structure or function of the body, or prodrugs that become biologically active or more active after being placed in a physiological environment.For example, the term "therapeutic agent" includes adjuvants; anti-infective agents such as antibiotics and antivirals; analgesics and combinations of analgesics, appetite suppressants, anti-inflammatory agents, anticonvulsants, topical and general anesthetics, hypnotics, sedatives, antipsychotics, nerve relaxants, antidepressants, anxiolytics, antagonists, neuroleptics, anticholinergics and cholinergics, anti-muscarinic agents and muscarinergics, anti-adrenergics, antiarrhythmics, antihypertensives, hormones, and nutrients; anti-arthritis agents, anti-asthmatics agents, anticonvulsants, antihistamines, antiemetics, antineoplastic agents, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, beta-agonists, and antiarrhythmics), antihypertensives, diuretics, vasodilators; central nervous system stimulants; cough suppressants and cold medicines. Drugs; decongestants; diagnostic agents; hormones; bone growth stimulants and bone resorption inhibitors; immunosuppressants; muscle relaxants; psychostimulants; sedatives; tranquilizers; proteins, peptides, and their fragments (whether naturally occurring, chemically synthesized, or recombinantly produced); as well as nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) including both double-stranded and single-stranded molecules, gene constructs, expression vectors, antisense molecules, etc.), small molecules (e.g., doxorubicin), and other bioactive macromolecules such as proteins and enzymes, including but not limited to these, compounds or compositions for use in all major therapeutic areas. Drugs may be bioactive drugs used in medical applications, including veterinary medicine, and agriculture such as plants, as well as in other areas. The term “therapeutic agent” also includes, but is not limited to, drugs; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or alleviation of disease or illness; or substances that affect the structure or function of the body; or prodrugs that become biologically active or more active after being placed in a given physiological environment.

[0044] The term "pharmaceutically acceptable" describes a material that is not biologically or otherwise undesirable, i.e., does not cause undesirable levels of biological effects or interact in a harmful manner.

[0045] As used herein, the term “pharmaceutically acceptable carrier” generally refers to non-sterile and sterile carriers or excipients that are considered safe (non-toxic), non-biologically non-activating, and may be part of aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions immediately before use, or non-sterile powders for oral administration. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, and polyethylene glycol), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Adequate fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants. Prevention of microbial action can be ensured by the inclusion of various antimicrobial and antifungal agents such as parabens, chlorobutanol, phenol, and sorbic acid. The inclusion of isotonic agents such as sugars and sodium chloride may also be desirable. Long-term absorption of injectable drug forms can be achieved by the inclusion of drugs such as aluminum monostearate and gelatin, which delay absorption. Injectable depot formulations are prepared by forming a microcapsule matrix of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoester), and poly(anhydride). The drug release rate can be controlled depending on the drug-to-polymer ratio and the properties of the specific polymer used. Depot injectable formulations are also prepared by encapsulating the drug in liposomes or microemulsions compatible with body tissues. Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media immediately before use.Suitable inert carriers include sugars such as lactose. Preferably, at least 95% by weight of the active ingredient particles have an effective particle size in the range of 0.01 to 10 micrometers.

[0046] As used herein, the terms “monoamine oxidase inhibitors” or “MAOIs” mean compounds that inhibit the activity of one or more monoamine oxidase enzymes (e.g., MAO-A, MAO-B). MAOIs can inhibit MAO non-selectively (e.g., inhibiting both MAO-A and MAO-B) or selectively (e.g., inhibiting either MAO-A or MAO-B), and can also act in a reversible manner (inactivating MAO-A and / or MAO-B via non-covalent, reversible interactions, e.g., competitive inhibitors, non-competitive inhibitors) or irreversible manner (inactivating MAO-A and / or MAO-B via covalent, irreversible interactions). Examples of MAOIs include, but are not limited to, tranylcypromine (TCP) (e.g., tranylcypromine sulfate, tranylcypromine hydrochloride), phenelzine (e.g., phenelzine sulfate), isocarboxazide, selegiline (e.g., selegiline hydrochloride), rasagiline (e.g., rasagiline mesylate), and moclobemide (e.g., moclobemide hydrochloride). Free base form, pharmaceutically acceptable salt form, and unsalted form are intended.

[0047] The term “beta-blocker” means a compound used to block beta-adrenergic signaling and treat cardiovascular conditions, including hypertension. As used herein, “beta-blocker” includes non-selective beta-blockers (e.g., propranolol, nadolol, pindolol, labetalol, penbutolol, sotalol, carvedilol, timolol), beta-1 selective blockers (e.g., metoprolol, atenolol, acebutolol, betaxolol, esmolol, bisoprolol, nevivolol), beta-blockers with intrinsic sympathomimetic activity (ISA) or partial agonism (e.g., acebutolol, pindolol, carteolol, penbutolol), and / or bialpha-beta-blockers (e.g., carvedilol, labetalol, dilevalol). Examples of beta-blockers include, but are not limited to, propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebibolol, sotalol, bucindolol, nadalol, cerilpolol, nebibolol, betaxolol, esmolol, bisoprolol, oxprenolol, penbutolol, labetalol, acebutolol, and pindolol. Free base form, pharmaceutically acceptable salt form, and unsalted form are intended.

[0048] The term "beta-blocker having intrinsic sympathetic nerve stimulation (ISA)" as used herein refers to a beta-blocker that can stimulate beta-adrenergic receptors (agonist effect) and can competitively counteract the stimulating effect (antagonist effect) of catecholamines. Examples of beta-blockers having ISA include, but are not limited to, pindolol, carteolol, pembutolol, and acebutolol.

[0049] As used herein, the term “modified release” refers to a dosage form in which the timing and / or rate of release of a drug substance is altered compared to that of a conventional immediate-release dosage form. Modified release dosage forms may include long-release, extended-release, sustained-release, controlled-release, and delayed-release dosage forms. As described herein, modified release dosage forms may be designed to achieve an extended therapeutic effect over a long period after a single dose. Therefore, for example, in various embodiments, a controlled-release dosage form can release the drug substance (e.g., MAOI) during a dissolution period lasting approximately 6 to 24 hours, 6 to 20 hours, 6 to 16 hours, 6 to 12 hours, 6 to 8 hours, 7 to 24 hours, 8 to 24 hours, 10 to 24 hours, 12 to 24 hours, 14 to 24 hours, 16 to 24 hours, 18 to 24 hours, 20 to 24 hours, 22 to 24 hours, 8 to 22 hours, 10 to 20 hours, 12 to 18 hours, or 14 to 16 hours after administration of the dosage form to the patient. In various embodiments, a controlled-release dosage form can release a drug substance (e.g., a beta-blocker) for a dissolution period lasting approximately 6 to 16 hours, 6 to 14 hours, 6 to 12 hours, 6 to 10 hours, 6 to 8 hours, 8 to 16 hours, 10 to 16 hours, 12 to 16 hours, 14 to 16 hours, 8 to 14 hours, or 10 to 12 hours after administration of the dosage form to the patient. In some embodiments, a controlled-release dosage form may contain two or more drug substances such that each drug substance is released over a different dissolution period. In some embodiments, a controlled-release dosage form may contain two or more drug substances such that each drug substance is released over approximately the same dissolution period.

[0050] In various further embodiments, the controlled-release dosage form can release the drug substance (e.g., MAOI) during an absorption period lasting approximately 6 to 24 hours, 6 to 20 hours, 6 to 16 hours, 6 to 12 hours, 6 to 8 hours, 7 to 24 hours, 8 to 24 hours, 10 to 24 hours, 12 to 24 hours, 14 to 24 hours, 16 to 24 hours, 18 to 24 hours, 20 to 24 hours, 22 to 24 hours, 8 to 22 hours, 10 to 20 hours, 12 to 18 hours, or 14 to 16 hours after administration of the dosage form to the patient. In various embodiments, a controlled-release dosage form can release a drug substance (e.g., a beta-blocker) for an absorption period lasting approximately 6 to 16 hours, 6 to 14 hours, 6 to 12 hours, 6 to 10 hours, 6 to 8 hours, 8 to 16 hours, 10 to 16 hours, 12 to 16 hours, 14 to 16 hours, 8 to 14 hours, or 10 to 12 hours after administration of the dosage form to the patient. In some embodiments, a controlled-release dosage form may contain two or more drug substances such that each drug substance is released over a different absorption period. In some embodiments, a controlled-release dosage form may contain two or more drug substances such that each drug substance is released over approximately the same absorption period.

[0051] As used herein, the term “long-release” refers to a dosage in which the timing and / or rate of release of a drug substance is prolonged or extended at a constant rate compared to that of a conventional immediate-release dosage form. For example, the timing and / or rate of release of a drug substance may be extended to occur over several hours (e.g., 6 to 16 hours) or even over a day (e.g., 6 to 24 hours).

[0052] As used herein, the terms “sustained-release” and “extended-release” are interchangeable and refer to dosage forms in which the timing and / or rate of release of a drug substance(s) is extended or prolonged compared to conventional immediate-release dosage forms. Sustained or extended-release is characterized by a slow rise in drug concentration in the blood, followed by a slow decline, which provides a therapeutic dose that is long enough to reduce the frequency of administration compared to immediate-release dosage forms.

[0053] As used herein, the term “controlled release” or “CR” refers to a dosage form in which the timing and / or rate of release of a drug substance(s) is modified to allow the release of the drug substance(s) at a specific rate such that the drug level remains constant for a particular period of time.

[0054] As used herein, the term “delayed release” or “DR” refers to a dosage form in which the timing and / or rate of release of the drug substance(s) is modified so that the drug substance(s) are not rapidly released after administration.

[0055] As used herein, the term “prodrug” generally refers to a modified variation of a parent drug that is biologically inactive at its site of action but can be broken down, modified, rearranged, dissociated, or cleaved by one or more enzymatic, non-enzymatic, or other in vivo or ex vivo processes into its parent bioactive form or a derivative thereof, the derivative generally retaining the bioactive components of the parent drug or a derivative thereof. Generally, prodrugs have a different pharmacokinetic profile from their parent drug, for example, having improved salt formation or solubility and / or better systemic stability (e.g., increased plasma half-life). For a discussion of prodrugs, see (a) Stella, VJ; Borchardt, RT; Hageman, MJ; Oliyai, R.; Maag, H. et al. Prodrugs: Challenges and Rewards Part 1 and Part 2; Springer, p. 726: New York, NY, USA, 2007, (b) Rautio, J.; Kumpulainen, H.; Heimbach, T.; Oliyai, R.; Oh, D. et al. Prodrugs: design and clinical applications. Nat. Rev. Drug Discov. 2008, 7, 255, (c) T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the ACSSymposium Series, and (d) Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon. It is available in Press.

[0056] As used herein, the term “fixed-dose combination” refers to a dosage form in which two or more active drugs (e.g., MAOIs and beta-blockers) are combined in a single dosage form.

[0057] As used herein, the term “dissolution period” refers to the time required for 80% of the drug to be released from the dosage form to form a solution or to reach an asymptote in vitro. The in vitro dissolution profile of the dosage form in water is specified in the USP <711> It is determined according to the following.

[0058] As used herein, the term “absorption period” refers to the time required for a drug to move from the injection site into the bloodstream. Therefore, for example, the absorption period may be the time required for 80% of the drug to be released from the dosage form or to reach an asymptote in vivo.

[0059] As used herein, the terms “norepinephrine reuptake inhibitor” and “NRI” refer to compounds that inhibit the neurotransmitters norepinephrine (i.e., noradrenaline) and epinephrine (i.e., adrenaline) by blocking the action of the norepinephrine transporter. Examples of norepinephrine reuptake inhibitors include, but are not limited to, reboxetine, atomoxetine, biloxazine, bupropion, desipramine, maprotiline, nortriptyline, protriptyline, tapentadol, and teniroxazine.

[0060] As used herein, the term “subthermal dose” means a dose of a drug that does not achieve a particular therapeutic effect. While this is generally undesirable, a drug intended for one purpose may be administered in subthermal doses to achieve a different effect. For example, a subthermal dose of an NRI may refer to a dose of an NRI that is too low to treat a disease (e.g., depression, ADHD, narcolepsy) but sufficient for another purpose (e.g., reducing the pressure effect).

[0061] As used herein, the term “half-life” refers to the time it takes for the concentration of a drug in plasma to decrease by 50%. For example, among MAOIs, the half-life of TCP is approximately 2.5 hours, the half-life of phenelzine is approximately 11.6 hours, and the half-life of selegiline is approximately 10 hours. Among beta-blockers, the half-life of esmolol is approximately 9 minutes, the half-life of bisoprolol ranges from 9 to 12 hours, and the half-life of pindolol is approximately 3 to 4 hours.

[0062] As used herein, the term “derivative” means a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein), whose structure is sufficiently similar to that disclosed herein, and which, based on that similarity, is expected to exhibit the same or similar activity and utility as the claimed compound, or to induce the same or similar activity and utility as the claimed compound as a precursor. Examples of derivatives include salts, esters, and amides of the parent compound, salts of esters or amides, and N-oxides.

[0063] The compounds according to this disclosure may form prodrugs at hydroxyl or amino functional groups using alkoxy, amino acids, etc., as the prodrug-forming moiety. For example, the hydroxymethyl position may form monophosphate, diphosphate, or triphosphate, and similarly these phosphates can form prodrugs. Preparations of such prodrug derivatives have been discussed in various literature (e.g., Alexander et al., J.Med.Chem. 1988, 31, 318; Aligas-Martin et al., PCT WO 2000 / 041531, p.30). The nitrogen function converted in preparing these derivatives is one (or more) nitrogen atoms of the compounds according to this disclosure.

[0064] The compounds described herein can contain atoms in both their natural abundance and their non-natural abundance. The disclosed compounds can be isotopically labeled or isotopically substituted compounds identical to those described, but due to the fact that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include, respectively, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, and 36 Cl and other isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine. The compounds further include their prodrugs, and pharmaceutically acceptable salts of the compounds or of such prodrugs containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, for example, those incorporating radioactive isotopes such as 3 H and 14 C are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C isotopes are particularly preferred because of the ease of their preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H can provide certain therapeutic advantages resulting in increased metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and thus may be preferred in some situations. The isotopically labeled compounds and their prodrugs of the present invention can generally be prepared by carrying out the following procedures by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents.

[0065] Certain materials, compounds, compositions, and components disclosed herein are commercially available or can be readily synthesized using techniques generally known to those skilled in the art. For example, the starting materials and reagents used in the preparation of the disclosed compounds and compositions are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wis.), Acros Organics (Morris Plains, NJ), Strem Chemicals (Newburyport, MA), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.), or from Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and supplemental volumes (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and Larock's Comprehensive Organic Transformations (VCH Publishers). It is either prepared by a method known to those skilled in the art, following the procedures described in references such as Inc., 1989.

[0066] Unless otherwise expressly stated, no method described herein is ever intended to be construed as requiring its steps to be performed in a particular order. Therefore, unless the method claim actually lists the order in which its steps are performed, or unless the claims or specification specifically state that the steps should be limited to a particular order, no order is ever intended to be inferred in any respect. This is reserved for any possible implicit grounds for interpretation, including the arrangement of steps or operational flows, the obvious meanings arising from grammatical structure or punctuation, and logical matters relating to the number or type of embodiments described in the specification.

[0067] Disclosed are the components used to prepare the compositions of the present invention, as well as the compositions themselves used in the methods disclosed herein. These and other materials are disclosed herein, and where combinations, subsets, interactions, groups, etc., of these materials are disclosed, specific references to each of the various individual and collective combinations and permutations of these compounds cannot be expressly disclosed, but each is understood to be specifically intended and described herein. For example, where a particular compound is disclosed and considered, and a number of modifications that can be made into several molecules containing the compound are considered, every possible combination and permutation of the compound and possible modifications is specifically intended unless otherwise indicated. Thus, if class molecules A, B, and C, and classes D, E, and F are disclosed, and AD, an example of a combined molecule, is disclosed, even if each is not individually listed, each is intended to mean a combination individually and collectively, and AE, AF, BD, BE, BF, CD, CE, and CF are considered to be disclosed. Similarly, any subset or combination of these is also disclosed. Therefore, for example, the subgroups AE, BF, and CE are considered to be disclosed. This concept applies to all aspects of this application, including, but not limited to, steps in a method for preparing and using the compositions of the present invention. Therefore, where various additional steps that can be carried out exist, it is understood that each of these additional steps can be carried out in any specific embodiment or combination of embodiments of the method of the present invention.

[0068] It is understood that the compositions disclosed herein have a particular function. Disclosed herein are certain structural requirements for performing the disclosed function, and it is understood that there are various structures that can perform the same function related to the disclosed structure, and these structures typically achieve the same result.

[0069] Dosage forms containing B.MAOIs and beta-blockers In one embodiment, a dosage form is disclosed comprising (a) a therapeutically effective amount of a monoamine oxidase inhibitor (MAOI), and (b) a therapeutically effective amount of a beta-blocker selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebibolol, sotalol, bucindolol, nadalol, cerilpolol, nebibolol, betaxolol, esmolol, bisoprolol, oxprenolol, penbutolol, labetalol, acebutolol, and pindolol, or pharmaceutically acceptable salts or free bases thereof, and a pharmaceutically acceptable carrier.

[0070] In one embodiment, a dosage form is also disclosed, comprising (a) a therapeutically effective amount of phenelzine or a pharmaceutically acceptable salt or free base thereof, and (b) a therapeutically effective amount of a beta-blocker selected from pindolol and bisoprolol, or a pharmaceutically acceptable salt or free base thereof, and a pharmaceutically acceptable carrier, wherein the MAOI is formulated as a controlled-release dosage form, and the beta-blocker is formulated as a controlled-release dosage form.

[0071] In one embodiment, a dosage form containing a therapeutically effective amount of MAOI is disclosed, the improvement comprising further comprising in the dosage form a therapeutically effective amount of a beta-blocker selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebiborol, sotalol, bucindolol, nadalol, cerilpolol, nebiborol, betaxolol, esmolol, bisoprolol, oxprenolol, penbutolol, labetalol, acebutolol, and pindolol, or pharmaceutically acceptable salts or free bases thereof.

[0072] In one embodiment, a dosage form containing a therapeutically effective amount of a beta-blocker is disclosed, and the improvement includes further including a therapeutically effective amount of an MAOI in the dosage form.

[0073] Pharmacologically acceptable salts of compounds are conventional acid-addition salts or base-addition salts formed from suitable non-toxic organic or inorganic acids, or organic or inorganic bases, that retain the biological efficacy and properties of the compound. Exemplary acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, as well as those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, and fumaric acid. Exemplary base-addition salts include those derived from ammonium, potassium, sodium, and quaternary ammonium hydroxides, such as tetramethylammonium hydroxide. Chemical modification of salts of pharmaceutical compounds is a known technique for obtaining improved physical and chemical stability, hygroscopicity, fluidity, and solubility of the compound. For example, see H. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995), pp. 196 and 1456-1457.

[0074] In some embodiments, it may be desirable to delay the absorption of a compound (e.g., through the preparation of a controlled-release formulation) in order to extend the effect of the compound used herein (e.g., an MAOI or a beta-blocker). This can be achieved, for example, through a liquid suspension of a crystalline or amorphous substance with low water solubility. The absorption rate of the compound then depends on its dissolution rate, which in turn may depend on the size and form of the crystals. Alternatively, delayed absorption of the compound can be achieved by dissolving or suspending the compound in an oily vehicle. Controlled-release formulations may consist of tablets, capsules, suppositories, or coated or uncoated microparticles, pellets, or granules in a suspension. Controlled-release formulations can also be prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. The rate of compound release can be controlled depending on the ratio of the compound to the polymer and the properties of the particular polymer used. Other examples of biodegradable polymers include poly(orthoesters) and poly(anhydrous). Alternatively, controlled-release formulations can be prepared by capturing the compound in liposomes or microemulsions that are compatible with body tissues.

[0075] Inactive components for matrix-release tablets, pellets, or spheres include binders for solid oral dosage forms (tablets and capsules), pregelatinized maize starch or hydroxypropyl methylcellulose of various degrees of substitution, fillers (e.g., lactose, microcrystalline cellulose, calcium carbonate, or calcium phosphate), disintegrants (potato starch, croscarmellose sodium, or sodium starch glycolate), wetting agents (e.g., sodium lauryl sulfate or nonionic surfactants), or other agents suitable for tableting. In addition, components may include nonionic homopolymers of ethylene oxide, water-soluble natural gums of polysaccharides, water-swellable but insoluble, high molecular weight homopolymers and copolymers of polyalkenyl alcohols and chemically crosslinked acrylic acids, polyvinyl acetate and povidone, crosslinked amylose starch and ionic methacrylate copolymers. In addition, fatty acids, fatty acid esters, and mono, di, and triglycerides with different melting points, as well as hydrophobic polymers, naturally occurring waxes, and ammonia methacrylate copolymers, can be used as non-swelling matrices. Lipid or hydrophobic matrices can delay drug release and can also be used in delayed-release technologies.

[0076] Tablets can be compressed as single-layer, double-layer, or multi-layer tablets, and may or may not be coated. Tablet coatings can function in terms of the release profile. Drug release can be achieved by other methods, such as reservoir polymer systems or osmotic pump systems using laser-perforated tablets or capsules. There are many options for tableting methods, including compressing a core tablet within an outer tablet or a multi-layer tablet. Compression of granulated or powdered drug matrices is achieved by controlled pressure and appropriate dyes for tablet formation. Pellet, granulated, or prepared spheres can be delivered into capsule shells designed for immediate or regulated release.

[0077] Coating materials for regulated drug release from formulation matrices (tablets, pellets, or spheres), including enteric-coated and other release targets, include naturally derived shellac and zein, cellulose derivatives (cellulose phthalate acetate, hydroxypropyl methylcellulose phthalate), and methacrylic (acid and ester copolymers containing carboxylic acid functional groups), which resist solubility at low pH and protect delivery to other pH levels above 5.5. Plasticizers (such as triacetin, triethanol citrate, glycerin, and polyethylene glycol) may or may not be necessary to enhance the release profile and flexibility of the coating.

[0078] The material for the reservoir system uses components for a drug-release coating that surrounds the drug core matrix (most commonly a tablet) to form a controlled barrier, which may be a water-insoluble coating such as cellulose acetate. The tablet core contains a penetrant such as sodium chloride and other hydrophilic polymers, allowing the drug to be pushed out through a laser-cut orifice as designed.

[0079] Methods for producing dosage forms include: a drug matrix preparation being a close mixture of the drug and excipients that affect the drug behavior in production and drug delivery in the dosage form; including granulation, compression, hot-melt and cold-melt pelletizing and spheroidization. The resulting matrix (granules, blends, pellets or spheres) may be a ready dosage form, which may involve tableting or encapsulation, or may be further manipulated for a desired release profile.

[0080] The drug matrix can be granulated and compressed / tableted as a single-layer or multi-layer tablet. This tablet can be coated with a coating to further control drug release from the tablet core. The coating can function to regulate core release or contain additional drugs for release in a multimodal profile. The granulated or drug matrix can be further manipulated to form small pellets or spheres using methodologies such as extrusion spheroidization and rotational processing. Extruded and pelletized drug matrices are methodologies used for lipid nanoparticles and pellets.

[0081] In addition, the drug substance is sprayed onto inert or drug matrix spheres, and then coated with a device designed to handle small beads / pellets / spheres. These drug-loaded spheres can then be further coated to deliver controlled / regulated release.

[0082] In some embodiments, the disclosed controlled-release dosage forms are formulated to satisfy one or more of the solubility, release, delivery, and / or pharmacokinetic properties disclosed herein. Therefore, for example, Cmax (i.e., peak drug concentration in blood or plasma after administration) may be influenced by the drug dose (e.g., higher doses typically produce higher Cmax values), the route of administration (e.g., higher Cmax values ​​may occur after IV bolus administration compared to oral administration), and the type of formulation (e.g., higher Cmax may occur after administration with an immediate-release oral formulation compared to a controlled-release formulation). Other drug properties such as solubility, permeability, how it is absorbed into the body, metabolism, and metabolites may also affect Cmax, meaning that while certain predictions may be made based on the factors above, the actual observed behavior may be difficult to predict without meaningful human experimentation and may be unexpected. In some embodiments, the disclosed release-modulated dosage forms, after administration of a single dose, are approximately 1 ng / mL to 500 mg / mL, 1 ng / mL to 400 ng / mL, 1 ng / mL to 300 ng / mL, 1 ng / mL to 100 ng / mL, 1 ng / mL to 50 ng / mL, 1 ng / mL to 25 ng / mL, 1 ng / mL to 10 ng / mL, 1 ng / mL to 5 ng / mL, 5 ng / mL to 500 ng / mL, 10 ng / mL to 500 ng / mL, 25 ng / mL to 500 ng / mL, 50 ng / mL to 500 ng / mL, and 100 ng / mL to 500 ng / mL. The Cmax is approximately 200 ng / mL to 500 ng / mL, approximately 300 ng / mL to 500 ng / mL, approximately 400 ng / mL to 500 ng / mL, or approximately 5 ng / mL to 100 ng / mL. As will be understood by those skilled in the art, the Cmax may depend on the MAOI or beta-blocker used. Thus, in various embodiments, the MAOI is phenelzine, and the controlled-release dosage form has a Cmax of approximately 5 ng / mL to 250 ng / mL. In various further embodiments, the beta-blocker is pindolol, and the controlled-release dosage form has a Cmax of approximately 5 ng / mL to 100 ng / mL.

[0083] In some embodiments, the disclosed release-modulated dosage forms are available every 12 hours or after five doses at steady state, with concentrations ranging from approximately 1 ng / mL to approximately 500 mg / mL, 1 ng / mL to approximately 400 ng / mL, approximately 1 ng / mL to approximately 300 ng / mL, approximately 1 ng / mL to approximately 100 ng / mL, approximately 1 ng / mL to approximately 50 ng / mL, approximately 1 ng / mL to approximately 25 ng / mL, approximately 1 ng / mL to approximately 10 ng / mL, approximately 1 ng / mL to approximately 5 ng / mL, approximately 5 ng / mL to approximately 500 ng / mL, approximately 10 ng / mL to approximately 500 ng / mL, approximately 25 ng / mL to approximately 500 ng / mL, approximately 50 ng / mL to approximately 500 ng / mL, and approximately 100 ng / mL to approximately 500 ng / mL. It has a Cmax of approximately 200 ng / mL to 500 ng / mL, approximately 300 ng / mL to 500 ng / mL, approximately 400 ng / mL to 500 ng / mL, or approximately 5 ng / mL to 100 ng / mL.

[0084] Tmax refers to the time (Tmax) at which the peak drug concentration is reached. In some embodiments, the disclosed controlled-release formulations have an activator Tmax of at least about 0.5 hours, at least about 1 hour, at least about 1.5 hours, at least about 2 hours, at least about 2.5 hours, at least about 3 hours, at least about 3.5 hours, at least about 4 hours, at least about 4.5 hours, at least about 6 hours, at least about 8 hours, at least about 10 hours, at least about 11 hours, or at least about 12 hours. In some embodiments, the disclosed controlled-release formulations have an average activator Tmax of about 1 hour to about 8 hours, about 2 hours to about 6 hours, about 3 hours to about 5 hours, or about 1.5 hours to about 3.5 hours. As will be understood by those skilled in the art, Tmax may depend on the MAOI or beta-blocker used. Thus, in various embodiments, the MAOI is phenelzine, and the controlled-release formulation has an average phenelzine Tmax of about 2 hours to about 6 hours. In various further embodiments, the beta-blocker is pindolol, and the controlled-release formulation has an average Tmax of pindolol of approximately 2 to 6 hours.

[0085] The term AUC refers to the area under the drug concentration-time curve in blood or plasma. While we do not wish to be bound by theory, AUC reflects systemic exposure to a drug after administration. Again, the size of AUC is influenced by several factors: the dose administered, the ease and rate of drug absorption, how widely the drug is distributed in the body, and the rate of drug elimination from the body. All of these variables make it difficult to accurately predict AUC without meaningful experiments in humans. In some embodiments, the disclosed release-controlled dosage forms have an AUC0-∞ of approximately 10 ng·hours / mL to approximately 2,000 ng·hours / mL, approximately 93 ng·hours / mL to approximately 460 ng·hours / mL, approximately 292 ng·hours / mL to approximately 521 ng·hours / mL, approximately 549 ng·hours / mL to approximately 1543 ng·hours / mL, approximately 1353 ng·hours / mL to approximately 3260 ng·hours / mL, or approximately 3205 ng·hours / mL to approximately 5216 ng·hours / mL after administration of a single dose. In some embodiments, the disclosed controlled-release dosage forms have an average AUC0-∞ of approximately 3205 ng·hours / mL to approximately 5216 ng·hours / mL, approximately 35 ng·hours / mL to approximately 156 ng·hours / mL, approximately 58 ng·hours / mL to approximately 287 ng·hours / mL, approximately 145 ng·hours / mL to approximately 328 ng·hours / mL, approximately 608 ng·hours / mL to approximately 1583 ng·hours / mL, approximately 1124 ng·hours / mL to approximately 2557 ng·hours / mL, or approximately 2381 ng·hours / mL to approximately 3666 ng·hours / mL after five doses administered every 12 hours. As will be understood by those skilled in the art, the AUC may depend on the MAOI or beta-blocker used. Therefore, in various embodiments, the MAOI is phenelzine, and the controlled-release dosage form has an AUC0-∞ of about 500 ng·time / mL to about 2,000 ng·time / mL. In various further embodiments, the beta-blocker is pindolol, and the controlled-release dosage form has an AUC0-∞ of about 50 ng·time / mL to about 800 ng·time / mL.

[0086] In some embodiments, the disclosed controlled-release dosage forms are formulated according to routine procedures as compositions suitable for oral administration to human subjects. Compositions for oral delivery may take various forms, including but not limited to tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs. Compositions for oral administration may also contain one or more sweeteners, such as fructose, aspartame, or saccharin; flavoring agents, such as peppermint, wintergreen oil, or cherry; colorants; and / or preservatives, to provide a pharmaceutically acceptable preparation. Furthermore, in tablet or pill form, the composition may be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period. Selectively permeable membranes surrounding osmotically active compounds are also suitable for oral administration. In these latter forms, fluids from the environment surrounding the capsule are absorbed by the driving compound, which swells to move the drug or drug composition. For example, time-delaying materials such as glycerol monostearate or glycerol stearate may also be useful. The oral composition may contain standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In some embodiments, the excipients are of pharmaceutical grade.

[0087] In some embodiments, controlled-release formulations can be administered by controlled-release means or by delivery devices well known to those skilled in the art. Examples include, but are not limited to, those described in U.S. Patents No. 3,845,770, 3,916,899, 3,536,809, 3,598,123, 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,556. Such dosage forms, for example, using hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, permeation systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof, may be useful in providing controlled or sustained release of the compositions disclosed herein to provide desired release profiles at various proportions. Accordingly, in some embodiments, disclosed herein are single-unit dosage forms suitable for oral administration, such as tablets, capsules, gel caps, and caplets, adapted for controlled or sustained release.

[0088] In various embodiments, the dosage form consists essentially of an MAOI and a beta-blocker. In further embodiments, the dosage form consists of an MAOI and a beta-blocker.

[0089] In various embodiments, the dosage form consists essentially of phenelzine and a beta-blocker. In further embodiments, the dosage form consists of phenelzine and a beta-blocker.

[0090] In various embodiments, the dosage form does not contain an alpha-blocker selected from doxazosin, silodosin, prazosin, tamsulosin, alfuzosin, terazosin, trimazosin, phenoxybenzamine, and phentolamine. In further embodiments, the dosage form does not contain an alpha-blocker.

[0091] In various embodiments, the dosage form does not contain carvedilol or labetalol.

[0092] In various embodiments, the dosage form does not contain a 5HT1A agonist.

[0093] In various embodiments, the MAOI is phenelzine (e.g., phenelzine sulfate), and the beta-blocker is selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebibolol, sotalol, bucindolol, nadalol, cerylpolol, nebibolol, betaxolol, esmolol, bisoprolol, oxprenolol, penbutolol, labetalol, acebutolol, and pindolol, or their pharmaceutically acceptable salts or free bases. In further embodiments, the MAOI is phenelzine sulfate, and the beta-blocker is selected from pindolol and bisoprolol (e.g., bisoprolol fumarate). In even further embodiments, the MAOI is phenelzine sulfate, and the beta-blocker is pindolol. In even further embodiments, the MAOI is phenelzine sulfate, and the beta-blocker is bisoprolol fumarate.

[0094] In various embodiments, the ratio of MAOIs to beta-blockers can be approximately 1:1 to 400:1, 2:1 to 400:1, 4:1 to 400:1, 8:1 to 400:1, 10:1 to 400:1, 20:1 to 400:1, 50:1 to 400:1, 100:1 to 400:1, 200:1 to 400:1, 1:1 to 200:1, 1:1 to 100:1, 1:1 to 50:1, 1:1 to 20:1, 1:1 to 10:1, 1:1 to 5:1, or 1:1 to 2:1.

[0095] As will be understood by those skilled in the art, the ratio of MAOI to beta-blocker may depend on the MAOI and beta-blocker used. Thus, in various embodiments, the MAOI may be phenelzine and the beta-blocker may be pindolol, and the MAOI to beta-blocker ratio may be about 1:1 to about 100:1, about 2:1 to about 100:1, about 4:1 to about 100:1, about 8:1 to about 100:1, about 10:1 to about 100:1, about 24:1 to about 100:1, about 50:1 to about 100:1, about 1:1 to about 50:1, about 1:1 to about 24:1, about 1:1 to about 10:1, about 1:1 to about 8:1, about 1:1 to about 4:1, and about 1:1 to about 2:1. In various further embodiments, the MAOI is phenelzine, the beta-blocker is pindolol, and the MAOI-to-beta-blocker ratio is approximately 2:1 to approximately 24:1.

[0096] In various embodiments, MAOIs and beta-blockers are co-formulated. In further embodiments, MAOIs and beta-blockers are not co-formulated.

[0097] 1. Monoamine oxidase inhibitors (MAOIs) In one embodiment, the disclosed dosage form comprises a therapeutically effective amount of a monoamine oxidase inhibitor (MAOI). Examples of MAOIs include, but are not limited to, tranylcypromine (TCP) (e.g., tranylcypromine sulfate, tranylcypromine hydrochloride), phenelzine (e.g., phenelzine sulfate), isocarboxazide, selegiline (e.g., selegiline hydrochloride), rasagiline (e.g., rasagiline mesylate), and moclobemide (e.g., moclobemide hydrochloride).

[0098] In various embodiments, MAOIs are formulated as controlled-release formulations. In further embodiments, MAOIs are formulated as long-release, sustained-release, extended-release, controlled-release, or delayed-release formulations. In even further embodiments, MAOIs are formulated as long-release formulations. In even further embodiments, MAOIs are formulated as sustained-release formulations. In even further embodiments, MAOIs are formulated as extended-release formulations. In even further embodiments, MAOIs are formulated as controlled-release formulations. In even further embodiments, MAOIs are formulated as delayed-release formulations.

[0099] In various embodiments, the controlled-release dosage form releases the MAOI during a dissolution period lasting approximately 6 to 16 hours. In further embodiments, the controlled-release dosage form releases the MAOI during dissolution periods lasting approximately 6 to 16 hours, 8 to 16 hours, 10 to 16 hours, 12 to 16 hours, 14 to 16 hours, 6 to 14 hours, 6 to 12 hours, 6 to 10 hours, 6 to 10 hours, or 6 to 8 hours.

[0100] In various embodiments, the controlled-release dosage form releases the MAOI during an absorption period lasting approximately 6 to 16 hours after administration to the patient. In further embodiments, the controlled-release dosage form releases the MAOI during an absorption period lasting approximately 6 to 16 hours, 8 to 16 hours, 10 to 16 hours, 12 to 16 hours, 14 to 16 hours, 6 to 14 hours, 6 to 12 hours, 6 to 10 hours, 6 to 10 hours, or 6 to 8 hours after administration to the patient.

[0101] In various aspects, substantially all MAOIs are released approximately 6 to 16 hours, 8 to 16 hours, 10 to 16 hours, 12 to 16 hours, 14 to 16 hours, 8 to 14 hours, 8 to 12 hours, 8 to 10 hours, 10 to 16 hours, or 12 to 16 hours after administration to the patient.

[0102] In various embodiments, MAOIs are present in amounts of approximately 20 mg to 1000 mg, 50 mg to 1000 mg, 100 mg to 1000 mg, 250 mg to 1000 mg, 500 mg to 1000 mg, 750 mg to 1000 mg, 20 mg to 750 mg, 20 mg to 500 mg, 20 mg to 250 mg, 20 mg to 100 mg, 20 mg to 50 mg, 30 mg to 90 mg, or 30 mg to 120 mg. As will be understood by those skilled in the art, the amount of MAOI present may depend on the MAOI used. For example, in various embodiments, the MAOI is phenelzine (e.g., phenelzine sulfate), and the MAOI is present in amounts of approximately 30 mg to 120 mg.

[0103] In various embodiments, the MAOI is phenelzine sulfate, which is present in amounts of approximately 20 mg to 1000 mg, 50 mg to 1000 mg, 100 mg to 1000 mg, 250 mg to 1000 mg, 500 mg to 1000 mg, 750 mg to 1000 mg, 20 mg to 750 mg, 20 mg to 500 mg, 20 mg to 250 mg, 20 mg to 100 mg, 20 mg to 50 mg, 30 mg to 90 mg, or 30 mg to 120 mg. In some embodiments, phenelzine sulfate is present in amounts of approximately 30 mg to 120 mg.

[0104] In various embodiments, the MAOI is selected from isocarboxazide, phenelzine, selegiline, TCP, and moclobemide. In further embodiments, the MAOI is selected from isocarboxazide, phenelzine, selegiline, and TCP. In yet further embodiments, the MAOI is selected from phenelzine and TCP. In yet another embodiment, the MAOI is TCP. In yet another embodiment, the MAOI is isocarboxazide. In yet another embodiment, the MAOI is selegiline. In yet another embodiment, the MAOI is phenelzine. In yet another embodiment, the phenelzine is phenelzine sulfate.

[0105] 2. Beta-blockers In one embodiment, the disclosed dosage form contains a therapeutically effective amount of a beta-blocker. Examples of beta-blockers include, but are not limited to, propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebiborol, sotalol, bucindolol, nadalol, cerilpolol, nebiborol, betaxolol, esmolol, bisoprolol, oxprenolol, penbutolol, labetalol, acebutolol, bopindolol, and pindolol or any pharmaceutically acceptable salt or free base thereof.

[0106] In various embodiments, a beta-blocker is a prodrug such that the prodrug can be converted to the corresponding beta-blocker intracellularly (in vivo or in vitro). This conversion can occur by one or more mechanisms, such as enzyme-catalyzed chemical reactions, metabochemical reactions, and / or spontaneous chemical reactions (e.g., solvation), including, for example, hydrolysis in the blood. Examples of modifications of the parent drug to obtain a prodrug include, but are not limited to, (1) ester or amide derivatives that are easily cleaved by esterases or lipases, (2) peptide derivatives that can be recognized by specific or nonspecific proteases, and (3) derivatives that allow the prodrug to accumulate at the site of action by membrane selection, as well as combinations of the above techniques. Beta-blocker prodrugs are commercially available or prepared by methods known to those skilled in the art (Buur, A., et al., (1988) Intl. J. Pharmaceutics, 42 1-3, 51-60; Ghosh B., et al., (2010) Drug Delivery, 17:7, 532-540).

[0107] In various embodiments, the beta-blocker is pindolol or its prodrugs. Exemplary pindolol prodrugs include, but are not limited to, pindolol O-acetyl, pindolol O-propionyl, pindolol O-butryl, pindolol O-pivaloyl, pindolol O-benzoyl, and pindolol O-cyclopropanyl. In various further embodiments, the pindolol prodrug is a pendant chain polymer prodrug. See, for example, Chau et al. (1991) Drug Development and Industrial Pharmacy 17(10):1279-1292.

[0108] In various embodiments, the beta-blocker is propranolol or its prodrugs. Exemplary propranolol prodrugs include, but are not limited to, propranolol O-acetyl ester, propranolol O-propionyl ester, propranolol O-butryl ester, propranolol O-pivaloyl ester, propranolol O-benzoyl ester, propranolol O-cyclopropanyl ester, and propranolol 2-oxazolidone derivatives. In further embodiments, the propranolol prodrug is the O-acetyl ester, propionyl ester, butyryl ester, or pivaloyl ester of propranolol. See, for example, Buur et al. (1988) International Journal of Pharmaceutics 42(1-3):51-60. See, for example, D'Emanuele et al. (2004) J Control Release 95(3):447-53. In a further embodiment, propranolol prodrugs are ester prodrugs of propranolol. See, for example, Shameem et al. (1993) Journal of Pharmacy and Pharmacology 45(4):246-252.

[0109] In various embodiments, the beta-blocker is metoprolol or its prodrugs. Examples of metoprolol prodrugs include, but are not limited to, metoprolol O-acetyl ester, metoprolol O-propionyl ester, metoprolol O-butryl ester, metoprolol O-pivaloyl ester, metoprolol O-benzoyl ester, and metoprolol O-cyclopropanyl ester. In further embodiments, the metoprolol prodrug is an acetyl ester, acetamide, or benzamide prodrug. See, for example, Patel et al. (2016) International Journal for Pharmaceutical Research Scholars 5(3):12-20. In yet another embodiment, the metoprolol prodrug is metoprolol acetate or metoprolol propionate. See, for example, Nair et al. (2006) Acta Pharmaceutica Sciencia 48:179-193.

[0110] In various embodiments, the beta-blocker is labetalol or its prodrugs. Examples of labetalol prodrugs include, but are not limited to, labetalol O-acetyl, labetalol O-propionyl, labetalol O-butryl, labetalol O-pivaloyl, labetalol O-benzoyl, and labetalol O-cyclopropanyl.

[0111] In various embodiments, the beta-blocker is esmolol or its prodrugs. Exemplary esmolol prodrugs include, but are not limited to, esmolol O-acetyl, esmolol O-propionyl, esmolol O-butryl, esmolol O-pivaloyl, esmolol O-benzoyl, and esmolol O-cyclopropanyl. In further embodiments, the esmolol prodrug is selected from esmolol acetate, esmolol propionate, esmolol butyrate, and esmolol valerate. See also Bijaya et al. (2010) Drug Deliv. 17(7):532-540.

[0112] In various embodiments, the beta-blocker is acebutrol or its prodrugs. Exemplary acebutrol prodrugs include, but are not limited to, acebutrol O-acetyl, acebutrol O-propionyl, acebutrol O-butryl, acebutrol O-pivaloyl, acebutrol O-benzoyl, and acebutrol O-cyclopropanyl. In further embodiments, the acebutrol prodrug is O-cycloproprancarboxylic acid. See, for example, Hovgaard et al. (1995) Pharm. Res. 12(3):387-92.

[0113] In various embodiments, the beta-blocker is timolol or its prodrug. Exemplary timolol prodrugs include, but are not limited to, timolol O-acetyl, timolol O-propionyl, timolol O-butryl, timolol O-pivaloyl, timolol O-benzoyl, and timolol O-cyclopropanyl. See, for example, Chang et al. (1987) Invest Ophthalmol Vis Sci. Mar 28(3):487-91. In various further embodiments, the timolol prodrug is an amphiphilic timolol prodrug. In yet another embodiment, the timolol prodrug is selected from octanoyltimolol, decanoyltimolol, dodecanoyltimolol, myristoyltimolol, and palmitoyltimolol. See, for example, Pech et al. (1993) J Ocul Pharmacol. Summer 9(2):141-50.

[0114] In various embodiments, the beta-blocker is carvedilol or its prodrugs. Exemplary carvedilol prodrugs include, but are not limited to, carvedilol O-acetyl, carvedilol O-propionyl, carvedilol O-butryl, carvedilol O-pivaloyl, carvedilol O-benzoyl, and carvedilol O-cyclopropanyl.

[0115] In various embodiments, the beta-blocker is atenolol or its prodrug. Exemplary atenolol prodrugs include, but are not limited to, atenolol O-acetyl, atenolol O-propionyl, atenolol O-butryl, atenolol O-pivaloyl, atenolol O-benzoyl, and atenolol O-cyclopropanyl. In further embodiments, the atenolol prodrug is atenolol N-maleamide or atenolol N-(methyl)maleamide. See, for example, Karaman et al. (2014) Scientific World Journal Jan 12:248651.

[0116] In various embodiments, the beta-blocker is nadolol or its prodrug. Exemplary nadolol prodrugs include, but are not limited to, nadolol O-acetyl ester, nadolol O-propionyl ester, nadolol O-butryl ester, nadolol O-pivaloyl ester, nadolol O-benzoyl ester, and nadolol O-cyclopropanyl ester. In further embodiments, the nadolol prodrug is selected from diacetylnadolol, nadolol dilaurate, dibenzoylnadolol, and di(phenylacetyl)nadolol. See, for example, U.S. Patent No. 4,029,676 and Chiang et al. (1987) J Pharm Sci. Dec 76(12):914-7.

[0117] In various embodiments, beta-blockers are oxprenol or its prodrugs. Exemplary oxprenol prodrugs include, but are not limited to, oxprenol O-acetyl, oxprenol O-propionyl, oxprenol O-butryl, oxprenol O-pivaloyl, oxprenol O-benzoyl, and oxprenol O-cyclopropanyl. See, for example, Jordan (1997) J Pharm Sci. Oct 86(10):1085-91 and Kour et al. (2021) Asian J Pharm Sci, Mar 16(2):175-191.

[0118] In various embodiments, the beta-blocker is bisoprolol or its prodrugs. Examples of bisoprolol prodrugs include, but are not limited to, bisoprolol O-acetyl, bisoprolol O-propionyl, bisoprolol O-butryl, bisoprolol O-pivaloyl, bisoprolol O-benzoyl, and bisoprolol O-cyclopropanyl.

[0119] In various embodiments, the beta-blocker is carteolol or its prodrugs. Examples of carteolol prodrugs include, but are not limited to, carteolol O-acetyl, carteolol O-propionyl, carteolol O-butryl, carteolol O-pivaloyl, carteolol O-benzoyl, and carteolol O-cyclopropanyl.

[0120] In various embodiments, the beta-blocker is nebiborol or its prodrugs. Examples of nebiborol prodrugs include, but are not limited to, nebiborol mono-O-acetyl, nebiborol bis-O-acetyl, nebiborol mono-O-propionyl, nebiborol bis-O-propionyl, nebiborol mono-O-butryl, nebiborol bis-O-butryl, nebiborol mono-O-pivaloyl, nebiborol bis-O-pivaloyl, nebiborol mono-O-benzoyl, nebiborol bis-O-benzoyl, nebiborol mono-O-cyclopropanyl, and nebiborol bis-O-cyclopropanyl.

[0121] In various embodiments, the beta-blocker is sotalol or its prodrugs. Examples of sotalol prodrugs include, but are not limited to, sotalol O-acetyl ester, sotalol O-propionyl ester, sotalol O-butryl ester, sotalol O-pivaloyl ester, sotalol O-benzoyl ester, and sotalol O-cyclopropanyl ester.

[0122] In various embodiments, the beta-blocker is busindrol or its prodrugs. Examples of busindrol prodrugs include, but are not limited to, busindrol O-acetyl ester, busindrol O-propionyl ester, busindrol O-butryl ester, busindrol O-pivaloyl ester, busindrol O-benzoyl ester, and busindrol O-cyclopropanyl ester.

[0123] In various embodiments, the beta-blocker is betaxol or its prodrug. Examples of betaxol prodrugs include, but are not limited to, betaxol O-acetyl, betaxol O-propionyl, betaxol O-butryl, betaxol O-pivaloyl, betaxol O-benzoyl, and betaxol O-cyclopropanyl.

[0124] In various embodiments, beta-blockers are penbutarol or its prodrugs. Examples of penbutarol prodrugs include, but are not limited to, penbutarol O-acetyl, penbutarol O-propionyl, penbutarol O-butryl, penbutarol O-pivaloyl, penbutarol O-benzoyl, and penbutarol O-cyclopropanyl.

[0125] In various embodiments, beta-blockers are formulated as controlled-release formulations. In further embodiments, beta-blockers are formulated as long-release, sustained-release, extended-release, controlled-release, or delayed-release formulations. In yet another embodiment, beta-blockers are formulated as long-release formulations. In yet another embodiment, beta-blockers are formulated as sustained-release formulations. In yet another embodiment, beta-blockers are formulated as extended-release formulations. In yet another embodiment, beta-blockers are formulated as controlled-release formulations. In yet another embodiment, beta-blockers are formulated as delayed-release formulations.

[0126] In various embodiments, the controlled-release dosage form releases the beta-blocker during a dissolution period lasting approximately 6 to 24 hours. In further embodiments, the controlled-release dosage form releases the beta-blocker during a dissolution period lasting approximately 7 to 24 hours, 8 to 24 hours, 10 to 24 hours, 12 to 24 hours, 14 to 24 hours, 16 to 24 hours, 18 to 24 hours, 20 to 24 hours, 22 to 24 hours, 6 to 22 hours, 6 to 20 hours, 6 to 18 hours, 6 to 16 hours, 6 to 14 hours, 6 to 12 hours, 6 to 10 hours, 6 to 10 hours, 6 to 8 hours, or 6 to 7 hours. In a further embodiment, the controlled-release dosage form releases the beta-blocker during a dissolution period lasting approximately 7 to 24 hours.

[0127] In various embodiments, the controlled-release dosage form releases the beta-blocker during an absorption period lasting approximately 6 to 24 hours after administration to the patient. In further embodiments, the controlled-release dosage form releases the beta-blocker during an absorption period lasting approximately 7 to 24 hours, 8 to 24 hours, 10 to 24 hours, 12 to 24 hours, 14 to 24 hours, 16 to 24 hours, 18 to 24 hours, 20 to 24 hours, 22 to 24 hours, 6 to 22 hours, 6 to 20 hours, 6 to 18 hours, 6 to 16 hours, 6 to 14 hours, 6 to 12 hours, 6 to 10 hours, 6 to 10 hours, 6 to 8 hours, or 6 to 7 hours after administration to the patient. In a further embodiment, the controlled-release dosage form releases the beta-blocker during an absorption period lasting approximately 7 to 24 hours after administration to the patient.

[0128] In various aspects, substantially all beta-blockers are released approximately 6 to 24 hours, 8 to 24 hours, 10 to 24 hours, 12 to 24 hours, 14 to 24 hours, 16 to 24 hours, 4 to 24 hours, 8 to 24 hours, 8 to 10 hours, 10 to 16 hours, or 12 to 16 hours after administration to the patient.

[0129] In various embodiments, beta-blockers are formulated as controlled-release formulations, MAOIs are formulated as controlled-release formulations, and MAOIs and beta-blockers are released over different periods.

[0130] In various embodiments, beta-blockers are formulated as controlled-release dosage forms, MAOIs are formulated as controlled-release dosage forms, and MAOIs and beta-blockers are released over approximately the same period.

[0131] In various embodiments, beta-blockers can have low half-lives, such as approximately 1 to 6 hours, 2 to 6 hours, 3 to 6 hours, 4 to 6 hours, 1 to 5 hours, 1 to 4 hours, 1 to 3 hours, 1 to 2 hours, 2 to 5 hours, 2 to 4 hours, 2 to 3 hours, 3 to 5 hours, or 3 to 4 hours. In further embodiments, the half-life is approximately 3 to 4 hours.

[0132] In various aspects, when beta-blockers are determined using the Hoffman method, for example, approximately 1 nM to 500 nM, approximately 5 nM to 500 nM, approximately 10 nM to 500 nM, approximately 20 nM to 500 nM, approximately 30 nM to 500 nM, approximately 40 nM to 500 nM, approximately 50 nM to 500 nM, approximately 100 nM to 500 nM, approximately 200 nM to 500 nM, approximately 300 nM to 500 nM, approximately 400 nM to 500 nM, approximately 1 nM to 400 nM, approximately 1 nM to 300 nM, About 1nM to about 200nM, about 1nM to about 100nM, about 1nM to about 50nM, about 1nM to about 40nM, about 1nM to about 30nM, about 1nM to about 20nM, about 1nM to about 10nM, about 1nM to about 5nM, about 5nM to about 10nM, about 10 K of nM to about 20nM, about 20nM to about 30nM, about 30nM to about 40nM, about 40mM to about 50nM, about 50nM to about 100nM, about 100nM to about 200nM, about 200nM to about 300nM, or about 300nM to about 400nM i Low K at beta receptors, etc. iIt may have. See Hoffman et al. (2004) Naunyn-Schmiedeberg's Arch Pharmacol 369:151-159. In various further embodiments, beta-blockers, when determined using the Hoffman method, have K at beta receptors less than 1 nM. i It can have. As will be understood by those skilled in the art, the K of existing beta-blockers i This may depend on the beta-blocker used.

[0133] In various embodiments, when the beta-blocker is determined using the Hoffman method, for example, a K content of at least about 5,000, at least 6,000 nM, at least about 7,000 nM, at least about 8,000 nM, or at least about 9,000 nM. i High K at alpha receptors, etc. i It may have. See Hoffman et al. (2004) Naunyn-Schmiedeberg's Arch Pharmacol 369:151-159. As will be understood by those skilled in the art, the K of existing beta-blockers i This may depend on the beta-blocker used.

[0134] In various embodiments, beta-blockers exhibit beta:alpha blocking ratios of at least about 10:1, at least about 100:1, at least about 500:1, at least about 1,000:1, at least about 2,000:1, or at least about 3,000:1.

[0135] In various embodiments, beta-blockers can have large therapeutic windows, such as approximately 12 to 24 hours, approximately 12 to 20 hours, approximately 12 to 16 hours, approximately 16 to 24 hours, approximately 20 to 24 hours, or approximately 16 to 20 hours. As will be understood by those skilled in the art, for example, a low half-life (e.g., 3 to 4 hours) and a low K i By selecting a beta-blocker with the properties of [specific characteristic], a large therapeutic window can be achieved.

[0136] In various forms, beta-blockers exist in amounts ranging from approximately 2.5 mg to approximately 1000 mg. In a further embodiment, beta-blockers exist in amounts of approximately 2.5 mg to 800 mg, approximately 2.5 mg to 600 mg, approximately 2.5 mg to 400 mg, approximately 2.5 mg to 200 mg, approximately 2.5 mg to 100 mg, approximately 2.5 mg to 80 mg, approximately 2.5 mg to 60 mg, approximately 2.5 mg to 40 mg, approximately 2.5 mg to 30 mg, approximately 5 mg to 1000 mg, approximately 10 mg to 1000 mg, approximately 20 mg to 1000 mg, approximately 200 mg to 1000 mg, approximately 400 mg to 1000 mg, approximately 600 mg to 1000 mg, approximately 800 mg to 1000 mg, approximately 5 mg to 30 mg, approximately 10 mg to 40 mg, approximately 20 mg to 50 mg, or approximately 30 mg to 90 mg.

[0137] As will be understood by those skilled in the art, the amount of beta-blocker present may depend on the beta-blocker used. Thus, in various embodiments, the beta-blocker is pindolol, and the amount present ranges from approximately 2.5 mg to approximately 60 mg. In even further embodiments, the beta-blocker is bisoprolol (e.g., bisoprolol fumarate), and the amount present ranges from approximately 2.5 mg to approximately 30 mg.

[0138] In various forms, pindolol exists in amounts ranging from approximately 2.5 mg to approximately 1000 mg. In some embodiments, pindolol is present in amounts of approximately 2.5 mg to 800 mg, approximately 2.5 mg to 600 mg, approximately 2.5 mg to 400 mg, approximately 2.5 mg to 200 mg, approximately 2.5 mg to 100 mg, approximately 2.5 mg to 80 mg, approximately 2.5 mg to 60 mg, approximately 2.5 mg to 40 mg, approximately 2.5 mg to 30 mg, approximately 5 mg to 1000 mg, approximately 10 mg to 1000 mg, approximately 20 mg to 1000 mg, approximately 400 mg to 1000 mg, approximately 600 mg to 1000 mg, approximately 800 mg to 1000 mg, approximately 5 mg to 30 mg, approximately 10 mg to 40 mg, approximately 20 mg to 50 mg, or approximately 30 mg to 90 mg. In a further embodiment, pindolol is present in amounts ranging from approximately 2.5 mg to approximately 60 mg. In yet another embodiment, pindolol is present in amounts ranging from approximately 2.5 mg to approximately 30 mg.

[0139] In various forms, bisoprolol fumarate is present in amounts ranging from approximately 2.5 mg to approximately 1000 mg. In some embodiments, bisoprolol fumarate is present in amounts of approximately 2.5 mg to 800 mg, approximately 2.5 mg to 600 mg, approximately 2.5 mg to 400 mg, approximately 2.5 mg to 200 mg, approximately 2.5 mg to 100 mg, approximately 2.5 mg to 80 mg, approximately 2.5 mg to 60 mg, approximately 2.5 mg to 40 mg, approximately 2.5 mg to 30 mg, approximately 5 mg to 1000 mg, approximately 10 mg to 1000 mg, approximately 20 mg to 1000 mg, approximately 400 mg to 1000 mg, approximately 600 mg to 1000 mg, approximately 800 mg to 1000 mg, approximately 5 mg to 30 mg, approximately 10 mg to 40 mg, approximately 20 mg to 50 mg, or approximately 30 mg to 90 mg. In a further embodiment, bisoprolol fumarate is present in an amount of approximately 2.5 mg to approximately 60 mg. In yet another embodiment, bisoprolol fumarate is present in an amount of approximately 2.5 mg to approximately 30 mg.

[0140] In various embodiments, the beta-blocker is selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebiborol, sotalol, bucindolol, nadalol, cerilpolol, nebiborol, betaxolol, esmolol, bisoprolol, oxprenolol, penbutolol, labetalol, acebutolol, and pindolol, or their pharmaceutically acceptable salts or free bases. In further embodiments, the beta-blocker is selected from pindolol and bisoprolol, or their pharmaceutically acceptable salts or free bases.

[0141] In various embodiments, the beta-blocker is selected from oxprenolol, penbutrol, labetalol, acebutrol, and pindolol, or pharmaceutically acceptable salts or free bases thereof. In further embodiments, the beta-blocker is selected from pindolol, carteolol, penbutrol, and acebutrol, or pharmaceutically acceptable salts or free bases thereof. In yet another embodiment, the beta-blocker is pindolol. In yet another embodiment, the beta-blocker is bisoprolol, or a pharmaceutically acceptable salt or free base thereof. In yet another embodiment, the beta-blocker is bisoprolol fumarate.

[0142] In various embodiments, the beta-blocker is a non-selective beta-blocker. In further embodiments, the beta-blocker is a selective beta-blocker (e.g., a beta-1 selective beta-blocker). In even further embodiments, the beta-blocker is a beta-blocker having an ISA. In even further embodiments, the beta-blocker is an alpha-beta biblocker.

[0143] In various embodiments, the beta-blocker is an alpha-beta bireceptor blocker. In further embodiments, the alpha-beta bireceptor blocker is selected from labetalol and carvedilol, or their pharmaceutically acceptable salts or free bases. In even further embodiments, the bialpha-beta blocker is labetalol, or its pharmaceutically acceptable salt or free base. In even further embodiments, the bialpha-beta blocker is carvedilol, or its pharmaceutically acceptable salt or free base.

[0144] In various embodiments, beta-blockers may have intrinsic sympathomimetic activity (ISA). In further embodiments, the beta-blocker having ISA is selected from pindolol, carteolol, penbutolol, and acebutolol, or their pharmaceutically acceptable salts or free bases. In further embodiments, the beta-blocker having ISA is selected from acebutolol and pindolol, or their pharmaceutically acceptable salts or free bases. In further embodiments, the beta-blocker having ISA is pindolol, or its pharmaceutically acceptable salt or free base. In further embodiments, the beta-blocker having ISA is acebutolol, or its pharmaceutically acceptable salt or free base.

[0145] In various embodiments, the beta-blocker is a beta-1 selective beta-blocker. In further embodiments, the beta-1 selective beta-blocker is selected from atenolol, betaxolol, bisoprolol, esmolol, acebutolol, metoprolol, and nevivolol, or their pharmaceutically acceptable salts or free bases.

[0146] 3. Norepinephrine reuptake inhibitors (NRIs) In various embodiments, the dosage form further comprises an effective amount of a norepinephrine reuptake inhibitor (NRI). Exemplary NRIs include, but are not limited to, reboxetine, atomoxetine, biloxazine, bupropion, desipramine, maprotiline, nortriptyline, protriptyline, tapentadol, and teniroxazine. In further embodiments, the NRI is selected from bupropion, desipramine, maprotiline, nortriptyline, protriptyline, tapentadol, and teniroxazine. In even further embodiments, the NRI is selected from nortriptyline and protriptyline. In yet another embodiment, the NRI is protriptyline.

[0147] In various embodiments, the effective dose of an NRI is a therapeutic dose. In further embodiments, the effective dose of an NRI is less than a therapeutic dose.

[0148] In various embodiments, NRIs are formulated as controlled-release dosage forms. Therefore, in some embodiments, NRIs are formulated as long-release, sustained-release, extended-release, controlled-release, or delayed-release dosage forms. In further embodiments, NRIs are formulated as long-release dosage forms. In even further embodiments, NRIs are formulated as sustained-release dosage forms. In even further embodiments, NRIs are formulated as extended-release dosage forms. In even further embodiments, NRIs are formulated as controlled-release dosage forms. In even further embodiments, NRIs are formulated as delayed-release dosage forms.

[0149] In various forms, NRIs exist in amounts ranging from approximately 1 mg to approximately 1000 mg. In further embodiments, the NRI may be present in amounts of approximately 1 mg to 800 mg, approximately 1 mg to 600 mg, approximately 1 mg to 400 mg, approximately 1 mg to 200 mg, approximately 1 mg to 100 mg, approximately 1 mg to 80 mg, approximately 1 mg to 60 mg, approximately 1 mg to 40 mg, approximately 1 mg to 30 mg, approximately 5 mg to 1000 mg, approximately 10 mg to 1000 mg, approximately 20 mg to 1000 mg, approximately 200 mg to 1000 mg, approximately 400 mg to 1000 mg, approximately 600 mg to 1000 mg, approximately 800 mg to 1000 mg, approximately 5 mg to 30 mg, approximately 10 mg to 40 mg, approximately 20 mg to 50 mg, or approximately 30 mg to 90 mg. As will be understood by those skilled in the art, the amount of NRI present may depend on the NRI used. Therefore, in various embodiments, the NRI is protriptyline, and the NRI is present in amounts ranging from approximately 1 mg to approximately 150 mg. In further embodiments, the NRI is present in amounts ranging from approximately 5 mg to approximately 50 mg.

[0150] In various forms, protriptyline exists in amounts ranging from approximately 1 mg to approximately 1000 mg. In further embodiments, protriptyline is present in amounts of approximately 1 mg to 800 mg, approximately 1 mg to 600 mg, approximately 1 mg to 400 mg, approximately 1 mg to 200 mg, approximately 1 mg to 100 mg, approximately 1 mg to 80 mg, approximately 1 mg to 60 mg, approximately 1 mg to 40 mg, approximately 1 mg to 30 mg, approximately 5 mg to 1000 mg, approximately 10 mg to 1000 mg, approximately 20 mg to 1000 mg, approximately 200 mg to 1000 mg, approximately 400 mg to 1000 mg, approximately 600 mg to 1000 mg, approximately 800 mg to 1000 mg, approximately 5 mg to 30 mg, approximately 10 mg to 40 mg, approximately 20 mg to 50 mg, or approximately 30 mg to 90 mg. In further embodiments, protriptyline is present in amounts ranging from approximately 1 mg to approximately 150 mg. In yet another embodiment, protriptyline is present in amounts ranging from approximately 5 mg to approximately 50 mg.

[0151] In various embodiments, the MAOI to NRI ratio is approximately 100:1 to approximately 1:1. In further embodiments, the MAOI to NRI ratio is approximately 100:1 to approximately 2:1, approximately 100:1 to approximately 5:1, approximately 100:1 to approximately 10:1, approximately 100:1 to approximately 20:1, approximately 100:1 to approximately 50:1, approximately 50:1 to approximately 1:1, approximately 20:1 to approximately 1:1, approximately 10:1 to approximately 1:1, approximately 5:1 to approximately 1:1, and approximately 2:1 to approximately 1:1. As will be understood by those skilled in the art, the MAOI to NRI ratio may depend on the MAOI and NRI used. Therefore, in various embodiments, the MAOI is phenelzine (e.g., 60-90 mg / day) and the NRI is protriptyline (e.g., 15-40 mg / day), with an MAOI-to-NRI ratio of approximately 10:1 to approximately 1:2.

[0152] In various embodiments, the beta-blocker to NRI ratio is approximately 1:1 to approximately 100:1. In further embodiments, the beta-blocker to NRI ratio is approximately 2:1 to approximately 100:1, approximately 5:1 to approximately 100:1, approximately 10:1 to approximately 100:1, approximately 20:1 to approximately 100:1, approximately 50:1 to approximately 100:1, approximately 1:1 to approximately 50:1, approximately 1:1 to approximately 20:1, approximately 1:1 to approximately 10:1, approximately 1:1 to approximately 5:1, and approximately 1:1 to approximately 2:1. As will be understood by those skilled in the art, the beta-blocker to NRI ratio may depend on the beta-blocker and NRI used. Therefore, in various embodiments, the beta-blocker is pindolol (e.g., 5-60 mg / day), the NRI is protriptyline (e.g., 15-40 mg / day), and the beta-blocker to NRI ratio is approximately 3:2 to approximately 1:3.

[0153] C. Methods for treating mental disorders The present invention also provides a method for treating mental disorders in a subject by administering a dosage form comprising a monoamine oxidase inhibitor (MAOI) and a beta-blocker selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebibolol, sotalol, bucindolol, nadalol, cerilpolol, nebibolol, betaxolol, esmolol, bisoprolol, oxprenolol, penbutolol, labetalol, acebutolol, and pindolol, or pharmaceutically acceptable salts or free bases thereof. In various embodiments, one or both of the MAOI and the beta-blocker may be formulated as a controlled-release dosage form, and the MAOI and the beta-blocker may be released over approximately the same or different absorption periods.

[0154] Accordingly, in one embodiment, a method for treating a mental disorder in a subject is disclosed, the method comprising administering an effective amount of a disclosed dosage form to the subject.

[0155] In one embodiment, a method for treating a mental disorder in a subject requiring treatment for a mental disorder is disclosed, the method comprising administering to the subject (a) a therapeutically effective amount of a monoamine oxidase inhibitor (MAOI) and (b) a therapeutically effective amount of a beta-blocker selected from propranolol, metoprolol, carvedilol, sotalol, bucindolol, nadalol, cerilpolol, nebivolol, betaxolol, esmolol, bisoprolol, oxprenolol, penbutrol, labetalol, acebutrol, and pindolol, or pharmaceutically acceptable salts or free bases thereof, wherein the subject has not been previously diagnosed with migraine and is not currently experiencing migraines.

[0156] In one embodiment, a method is disclosed for treating a mental disorder in a subject requiring treatment of a mental disorder by administering an MAOI, the improvement comprising co-administering to the patient a beta-blocker selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebiborol, sotalol, bucindolol, nadalol, cerilpolol, nebiborol, betaxolol, esmolol, bisoprolol, oxprenolol, penbutrol, labetalol, acebutrol, and pindolol, or pharmaceutically acceptable salts or free bases thereof, together with the MAOI in an amount effective in reducing migraine recurrence and / or producing a longer-lasting effect compared to administration of the MAOI in the absence of the beta-blocker, wherein the MAOI and the beta-blocker exist together in a single dosage form.

[0157] In one embodiment, a method is disclosed for treating a mental disorder in a subject requiring treatment of a mental disorder by administering an MAOI, the improvement comprising co-administering to the patient a beta-blocker selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebiborol, sotalol, bucindolol, nadalol, cerilpolol, nebiborol, betaxolol, esmolol, bisoprolol, oxprenolol, penbutrol, labetalol, acebutrol, and pindolol, or pharmaceutically acceptable salts or free bases thereof, together with the MAOI in an amount effective in reducing migraine recurrence and / or producing a longer-lasting effect compared to administration of the MAOI in the absence of the beta-blocker, the subject has not been previously diagnosed with migraine, and the subject is not currently experiencing migraines.

[0158] In one embodiment, a method is disclosed for treating a mental disorder in a subject requiring treatment of a mental disorder by administering a beta-blocker, the improvement comprising co-administering an MAOI to the patient in a dose effective in reducing migraine recurrence and / or producing a longer-lasting effect compared to administration of the beta-blocker in the absence of the MAOI, wherein the MAOI and the beta-blocker exist together in a single dosage form.

[0159] In one embodiment, a method is disclosed for treating a mental disorder in a subject requiring treatment of a mental disorder by administering a beta-blocker, the improvement comprising administering to the patient a beta-blocker selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebiborol, sotalol, bucindolol, nadalol, cerilpolol, nebiborol, betaxolol, esmolol, bisoprolol, oxprenolol, penbutrol, labetalol, acebutrol, and pindolol, or a pharmaceutically acceptable salt or free base thereof, together with an MAOI in a dose effective in reducing migraine recurrence and / or producing a longer-lasting effect compared to the administration of the MAOI in the absence of the beta-blocker, the subject has not been previously diagnosed with migraine, and the subject is not currently experiencing migraines.

[0160] In one embodiment, a method for treating a mental disorder in a subject requiring treatment for a mental disorder is also disclosed, the method comprising administering to the subject an effective dose of a dosage form comprising (a) a therapeutically effective dose of a monoamine oxidase inhibitor (MAOI) selected from phenelzine and tranylcypromine (TCP), (b) a therapeutically effective dose of a beta-blocker selected from pindolol and carvedilol, or pharmaceutically acceptable salts or free bases thereof, and (c) a pharmaceutically acceptable carrier, wherein the subject has not been previously diagnosed with migraine.

[0161] To treat or control disorders, the compound and pharmaceutical compositions containing the compound are administered to subjects in need, such as vertebrates, including mammals, fish, birds, reptiles, or amphibians. Subjects may be humans, non-human primates, horses, pigs, rabbits, dogs, sheep, goats, cattle, cattle, guinea pigs, or rodents. This term does not indicate a specific age or sex. Therefore, it is intended to include adult and neonatal subjects, as well as fetuses, regardless of whether they are male or female. Subjects are preferably mammals, such as humans. Before administering the compound or composition, subjects may be diagnosed as needing treatment for mental disorders such as depression.

[0162] The controlled-release dosage form can be administered to the subject by any method. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, inhalation administration, nasal administration, topical administration, vaginal administration, ophthalmic administration, intraotoral administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration including injections such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration may be continuous or intermittent. The preparation may be administered therapeutically, that is, to treat an existing disease or condition. The preparation may also be administered prophylactically, that is, to prevent conditions such as infection or mental disorders.

[0163] The therapeutically effective dose or dosage of a compound can vary within a wide range. Such dosages are adjusted for the individual requirements of each specific case, including the specific compound(s) administered, the route of administration, the condition being treated, and the patient being treated. Generally, for oral or parenteral administration to adult humans weighing approximately 70 kg or more, a daily dosage of approximately 10 mg to approximately 10,000 mg, preferably approximately 200 mg to approximately 1,000 mg, should be appropriate, although it may exceed the upper limit. The daily dosage can be administered as a single dose, in divided doses, or as a continuous infusion for parenteral administration. Consequently, a single-dose composition may contain such an amount or fraction of the compound or composition to constitute a daily dose. In any contraindicated event, the dosage may be adjusted by the individual physician. Dosages may vary and may be administered in doses once or more times daily for one day or several days.

[0164] In various aspects, the mental disorder is depression. Examples of depression include, but are not limited to, major depressive disorder, major depressive disorder with distressing anxiety, treatment-resistant depression, anxious depression, and a combination of anxiety and depression. In further aspects, depression is selected from major depressive disorder, major depressive disorder with distressing anxiety, and treatment-resistant depression. In yet further aspects, depression is major depressive disorder. In yet further aspects, depression is major depressive disorder with distressing anxiety. In yet further aspects, depression is treatment-resistant depression,

[0165] In various embodiments, the subjects are not currently on a tyramine-restricted diet. In further embodiments, the subjects are not on a tyramine-restricted diet after the administration step. In even further embodiments, the tyramine-restricted diet eliminates the consumption of meals containing 100 mg or more of tyramine. For example, the tyramine-restricted diet can eliminate the consumption of meals containing at least 100 mg, at least 150 mg, at least 200 mg, at least 250 mg, at least 300 mg, at least 350 mg, at least 400 mg, at least 450 mg, or at least 500 mg of tyramine.

[0166] In various embodiments, the dosage form is administered in doses ranging from approximately 100 mg to approximately 1000 mg. In further embodiments, the dosage form is administered in doses ranging from approximately 200 mg to approximately 1000 mg, approximately 300 mg to approximately 1000 mg, approximately 400 mg to approximately 1000 mg, approximately 500 mg to approximately 1000 mg, approximately 600 mg to approximately 1000 mg, approximately 700 mg to approximately 1000 mg, approximately 800 mg to approximately 1000 mg, approximately 900 mg to approximately 1000 mg, approximately 100 mg to approximately 900 mg, approximately 100 mg to approximately 800 mg, approximately 100 mg to approximately 700 mg, and approximately 10 The drug is administered in doses of 0 mg to approximately 600 mg, approximately 100 mg to approximately 500 mg, approximately 100 mg to approximately 400 mg, approximately 100 mg to approximately 300 mg, approximately 100 mg to approximately 200 mg, approximately 200 mg to approximately 300 mg, approximately 300 mg to approximately 400 mg, approximately 400 mg to approximately 500 mg, approximately 500 mg to approximately 600 mg, approximately 600 mg to approximately 700 mg, approximately 700 mg to approximately 800 mg, or approximately 800 mg to approximately 900 mg. In a further embodiment, the dosage form is administered in doses of approximately 150 mg to approximately 500 mg.

[0167] In various embodiments, the dosage form is administered once daily. In further embodiments, the dosage form is administered twice daily.

[0168] In various embodiments, MAOIs and beta-blockers are administered simultaneously. In further embodiments, MAOIs and beta-blockers are administered sequentially.

[0169] In various embodiments, MAOIs and beta-blockers are administered as a fixed-dose combination.

[0170] In various embodiments, MAOIs and beta-blockers are co-formulated. In further embodiments, MAOIs and beta-blockers are not co-formulated.

[0171] In various forms, MAOIs are not phenelzine.

[0172] In various embodiments, the method involves administering exactly two activators to a subject, wherein the two activators are an MAOI and a beta-blocker. In various further embodiments, the method involves administering exactly two activators to a subject, wherein the two activators are phenelzine and a beta-blocker.

[0173] In various embodiments, an alpha-blocker selected from doxazosin, silodosin, prazosin, tamsulosin, alfuzosin, terazosin, trimazosin, phenoxybenzamine, and phentolamine is not administered to the subject within a period of approximately one week or less before or after the administration step. In further embodiments, an alpha-blocker selected from doxazosin, silodosin, prazosin, tamsulosin, alfuzosin, terazosin, trimazosin, phenoxybenzamine, and phentolamine is not administered to the subject within a period of approximately 24 hours or less before or after the administration step. In even further embodiments, an alpha-blocker selected from doxazosin, silodosin, prazosin, tamsulosin, alfuzosin, terazosin, trimazosin, phenoxybenzamine, and phentolamine is not administered to the subject simultaneously.

[0174] In various embodiments, the alpha-blocker is not administered to the subject within a period of approximately one week or less before or after the administration step. In further embodiments, the alpha-blocker is not administered to the subject within a period of approximately 24 hours or less before or after the administration step. In even further embodiments, the alpha-blocker is not administered to the subject simultaneously.

[0175] In various embodiments, neither carvedilol nor labetalol is administered to the subject within a period of approximately one week or less before or after the administration step. In further embodiments, neither carvedilol nor labetalol is administered to the subject within a period of approximately 24 hours or less before or after the administration step. In even further embodiments, neither carvedilol nor labetalol is administered to the subject simultaneously.

[0176] In various embodiments, the 5HT1A agonist is not administered to the subject within a period of approximately one week or less before or after the administration step. In further embodiments, the 5HT1A agonist is not administered to the subject within a period of approximately 24 hours or less before or after the administration step. In even further embodiments, the 5HT1A agonist is not administered to the subject simultaneously.

[0177] In various aspects, when beta-blockers are determined using the Hoffman method, for example, approximately 1 nM to 500 nM, approximately 5 nM to 500 nM, approximately 10 nM to 500 nM, approximately 20 nM to 500 nM, approximately 30 nM to 500 nM, approximately 40 nM to 500 nM, approximately 50 nM to 500 nM, approximately 100 nM to 500 nM, approximately 200 nM to 500 nM, approximately 300 nM to 500 nM, approximately 400 nM to 500 nM, approximately 1 nM to 400 nM, approximately 1 nM to 300 nM, About 1nM to about 200nM, about 1nM to about 100nM, about 1nM to about 50nM, about 1nM to about 40nM, about 1nM to about 30nM, about 1nM to about 20nM, about 1nM to about 10nM, about 1nM to about 5nM, about 5nM to about 10nM, about 10 K of nM to about 20nM, about 20nM to about 30nM, about 30nM to about 40nM, about 40mM to about 50nM, about 50nM to about 100nM, about 100nM to about 200nM, about 200nM to about 300nM, or about 300nM to about 400nM i Low K at beta receptors, etc. i It may have. See Hoffman et al. (2004) Naunyn-Schmiedeberg's Arch Pharmacol 369:151-159. In various further embodiments, beta-blockers, when determined using the Hoffman method, have K at beta receptors less than 1 nM. i It can have. As will be understood by those skilled in the art, the K of existing beta-blockers i This may depend on the beta-blocker used.

[0178] In various embodiments, when the beta-blocker is determined using the Hoffman method, for example, a K content of at least about 5,000, at least 6,000 nM, at least about 7,000 nM, at least about 8,000 nM, or at least about 9,000 nM. i High K at alpha receptors, etc. i It may have. See Hoffman et al. (2004) Naunyn-Schmiedeberg's Arch Pharmacol 369:151-159. As will be understood by those skilled in the art, the K of existing beta-blockers i This may depend on the beta-blocker used.

[0179] In various embodiments, beta-blockers exhibit beta:alpha blocking ratios of at least about 10:1, at least about 100:1, at least about 500:1, at least about 1,000:1, at least about 2,000:1, or at least about 3,000:1.

[0180] In various embodiments, the method further includes using a software application to monitor one or more characteristics of the patient. In some embodiments, the characteristics are one or more vital signs selected from the group consisting of body temperature, blood pressure, heart rate, respiratory rate, or any combination thereof. In some embodiments, the characteristics are detected blood levels of beta-blockers, which are used to determine whether the dosage of MAOIs, beta-blockers, or both MAOIs and beta-blockers should be adjusted during the treatment regimen. In some embodiments, the characteristics are indicators of patient compliance.

[0181] In various embodiments, the dosage form consists of an MAOI and a beta-blocker.

[0182] In various embodiments, the dosage form does not contain an alpha-blocker. In further embodiments, the dosage form does not contain a 5HT1A agonist.

[0183] In various embodiments, one or both of the MAOI and / or beta-blockers are formulated as controlled-release dosage forms. In further embodiments, the MAOI is formulated as a controlled-release dosage form. In even further embodiments, the beta-blocker is formulated as a controlled-release dosage form.

[0184] In various embodiments, MAOI is phenelzine. In further embodiments, MAOI is TCP.

[0185] In various embodiments, the beta-blocker is pindolol. In further embodiments, the beta-blocker is carvedilol.

[0186] In various scenarios, the subjects did not follow a tyramine-restricted diet after the administration step.

[0187] D. Examples The present invention is further defined in the following embodiments. These embodiments illustrate preferred aspects of the invention, but should be understood to be provided for illustrative purposes only. From the above discussion and these embodiments, those skilled in the art can identify the essential features of the present invention and make various changes and modifications to the invention to adapt it to various uses and conditions without departing from its spirit and scope.

[0188] 1. Proposed mechanism of action This specification describes MAOI-based compositions designed to enable safer use in the treatment of patients with mental disorders such as depression. While we do not wish to be bound by theory, the approach detailed herein uses a mechanism-based strategy to reduce the effects of tyramine pressers. Specifically, this approach reduces the tyramine-induced presser response by directly blocking norepinephrine stimulation of beta-1 adrenergic receptors, thereby preventing an increase in cardiac output and minimizing changes in heart rate and blood pressure.

[0189] Phenelzine (PHZ) is a potent, non-selective MAOI used to treat depression in adults (Sidhu, G., & Marwaha, R. (2023). Phenelzine. In StatPearls. StatPearls Publishing). Phenelzine irreversibly binds to both MAO-A and MAO-B. Phenelzine inhibits the oxidation of monoamines by MAO enzymes, which is thought to lead to the accumulation of endogenous catecholamines serotonin, norepinephrine, and dopamine, resulting in an extension of their effects on their target receptors. However, it is unclear whether MAO inhibition itself or other pharmacological effects (or both) are involved in the observed antidepressant effect (Parke Davis 2007).

[0190] Tyramine is a naturally occurring monoamine compound that is endogenously present in trace amounts in humans and lower animal species, and can often be found in certain foods, such as cheese or other fermented foods and beverages, as a result of fermentation or tyrosine breakdown-induced decarboxylation (Philips, SR, et al., (1978) Biological Psychiatry, 13(1), 51-57). Tyramine functions as an indirect sympathetic mimetic agent that enters neurons via reuptake transporters, mainly norepinephrine transporters, resulting in the movement of catecholamines such as norepinephrine from the catecholamine storage sites of neurons (Da Prada et al. (1988) Pharmacol Res Commun. 20 Suppl 4, pp. 21-33 and Meck et al. (2003) J Cardiovasc Pharmacol 41(1), pp. 126-131). Excessive release of norepinephrine can lead to cardiovascular effects, primarily a dose-dependent increase in systolic blood pressure, and in severe cases, a dangerous risk of hypertension.

[0191] Tyramine is metabolized by several enzymes, including MAO, catechol-O-methyltransferase, aldehyde dehydrogenase, and cytochrome P450, but MAO-A has been proposed to be the main metabolic enzyme for tyramine. In typical circumstances, it is estimated that less than 1% of dietary tyramine enters systemic circulation (Schwenk (1989) Strat. Mgmt. J. 10(3), pp. 303-306). However, when MAO is substantially inhibited by drugs such as MAOIs, significantly more tyramine becomes systemically available, mainly due to the reduction in metabolism by MAO. The significant increase in systemic tyramine due to metabolism blocked by MAOIs means that low oral doses of tyramine are needed to raise blood pressure and increase the risk of hypertensive events.

[0192] While we do not wish to be bound by theory, it is conceivable that the downstream effects of PHZ (and other MAOIs) on tyramine accumulation and the resulting cardiovascular effects may be attenuated by the addition of beta-blockers such as pindolol (PIN).

[0193] Beta-blockers are a class of drugs that block beta-adrenergic signaling and are used to treat cardiovascular diseases, including hypertension (Farzam and Jan 2021). There are three types of beta receptors: beta-1 (B1), beta-2 (B2), and beta-3 (B3). B1 receptors are mainly located in the heart and mediate cardiac activity. Beta-2 receptors are located across many organ systems (particularly the lungs) and mediate smooth muscle relaxation. Activation of B3 receptors has been noted for inducing the breakdown of adipocytes. Beta-blockers have different specificities for different receptors, and the effects produced depend on the type of receptor blocked and the organ system(s) involved (Farzam and Jan 2021).

[0194] Pindolol is a non-selective beta-blocker, and its activity against cardiac B1 receptors is expected to reduce heart rate and contractility, leading to a decrease in blood pressure (Blumenfeld et al. 1999). In addition, pindolol may also suppress the renin-angiotensin-aldosterone system, thereby further reducing blood pressure (Blumenfeld et al. 1999). Importantly, pindolol is a notable partial agonist of beta receptors and therefore possesses an intrinsic sympathomimetic effect (ISA) that manifests as a lesser reduction in resting heart rate and cardiac output compared to beta-blockers lacking ISA (Novartis 2007). The ISA of pindolol may help minimize fatigue or "weakness" in patients receiving beta-blockers, which may be important for patients with major depressive disorder or major depressive disorder with anxiety distress.

[0195] 2. In vitro interference testing MAO inhibitory enzyme assays were performed to evaluate whether the inhibition of MAO-A and MAO-B by phenelzine is affected by the presence of beta-blockers. The method was adapted from previously described methods. See, for example, Urban et al. (1991) FEBS Lett. 286(1-2):142-146 and Youdim and Finberg (1991) Biochem. Pharmacol. 41(2):155-162. Note that the test concentrations correspond to the concentrations of phenelzine sulfate and biosprolol fumarate, which are salt forms of phenelzine and bisoprolol, respectively. The free base concentration of phenelzine is equivalent to that of the salt form, while the free base concentration of bisoprolol is twice that of its salt form.

[0196] The assay was carried out as detailed below. [Table 1]

[0197] To ensure the validity of the results, reference standards were performed as an integral part of each assay. See Table 2. [Table 2]

[0198] First, the IC of phenelzine against MAO-A and MAO-B 50 The following was determined. Please refer to Table 3, Figure 2, and Figure 3. IC of phenelzine against MAO-A and MAO-B. 50 These values ​​were determined to be 15 nM and 18.9 nM, respectively, from the fitted curves. [Table 3]

[0199] Next, the binding of the beta-blockers pindolol, bisoprolol, and carvedilol to MAO-A and MAO-B was evaluated at concentrations associated with typical drug dosing of these drugs. As shown in Table 4 below, no significant inhibitory activity of MAO-A and MAO-B was observed. A significant response in the biochemical assay was defined as inhibition of 50% or more. [Table 4]

[0200] Next, interference of MAO-A and MAO-B inhibition by phenelzine in the presence of pindolol, bisoprolol, or carvedilol was investigated at a low dose (IC). 50 The optimal doses were determined to be 15 nM for MAO-A and 18.9 nM for MAO-B (Tables 5 and 6), and evaluated using both high doses (150 nM, Table 7). As shown, no interference was observed with the inhibition of MAO-A and MAO-B by phenelzine in the presence of individual beta-blockers. In other words, phenelzine inhibits MAO-A and MAO-B to a similar degree in the presence and absence of beta-blockers. [Table 5] [Table 6] [Table 7]

[0201] 3. Inhibition of MAO-A and MAO-B by isocarboxade To evaluate the inhibition of MAO-A and MAO-B by 10 μM isocarboxazide, MAO inhibitory enzyme assays were performed as described above and in Table 1.

[0202] To ensure the validity of the results obtained, reference standards were performed as an integral part of each assay. See Table 8. [Table 8]

[0203] The inhibition of MAO-A and MAO-B by isocarboxide at 10 μM was determined. See Table 9. [Table 9]

[0204] 4. In vivo rat telemetry study #1 To evaluate the effect of MAOI and beta-blocker combinations on blood pressure changes after tyramine dose, an in vivo study was completed in rats implanted with telemetry transmitters, and the rats were allowed to recover for 7 days. Briefly, phenelzine (first dose 50 mg / kg, then 8 mg / kg daily) was administered orally alone (N=3) or in combination with pindolol (100 mg / kg) (N=4). Pindolol is a non-selective beta-blocker with ISA. The maximum change in systolic blood pressure after oral tyramine dose (7 mg / kg) 10–60 minutes after MAOI and beta-blocker administration is shown in Figure 4A. A similar combination study was also completed with tranylcypromine (first dose 8 mg / kg, then 5 mg / kg daily) as the MAOI administered in combination with pindolol (1 mg / kg [N=3] or 100 mg / kg [N=3]) (Figure 4B). In the case of phenelzine, sequential administration of pindolol with an MAOI reduces the maximum change in systolic blood pressure after oral tyramine by 48%. In the case of tranylcypromine, the maximum change in systolic blood pressure after oral tyramine administration is reduced in a dose-dependent manner when various pindolol dose levels are administered. Figure 5 shows the time course of systolic blood pressure in rats after administration of tyramine (7 mg / kg) with phenelzine (8 mg / kg) alone or in combination with pindolol (100 mg / kg). Figure 6 shows a similar time course with tranylcypromine (5 mg / kg) with two doses (1 mg / kg and 100 mg / kg) of pindolol after administration of tyramine (7 mg / kg). The area under the curve (AUC) of systolic blood pressure is reduced by 61% for phenelzine with pindolol compared to phenelzine alone (Figure 7). The reduction in the maximum changes in systolic blood pressure and AUC, as well as the time course, demonstrate that the change in systolic blood pressure from tyramine administration during MAOI treatment is reduced when pindolol is administered sequentially.

[0205] 5. In vivo rat telemetry study #2 To evaluate the effect of MAOI and beta-blocker combinations on blood pressure changes after tyramine dose, an in vivo study was completed in rats implanted with telemetry transmitters, and the rats were allowed to recover for 7 days. Briefly, rats received tranylcypromine (first dose 8 mg / kg, then 5 mg / kg daily) alone (N=5), or in combination with pindolol (60 mg / kg, N=5) or bisoprolol (20 mg / kg, N=5). Pindolol is a non-selective beta-blocker with ISA. Bisoprolol is a selective beta-blocker without ISA. On day 8, in addition to the described daily doses, tyramine (3 mg / kg) was administered 30 minutes after tranylcypromine and pindolol or bisoprolol administration, and blood pressure was monitored. The maximum change in systolic blood pressure was 46% and 7% lower with tranylcypromine in combination with pindolol or bisoprolol compared to tranylcypromine alone (Figure 8). The AUC of systolic blood pressure was also reduced by 49% and 23% with tranylcypromine in combination with pindolol or bisoprolol compared to tranylcypromine alone (Figure 9). Figures 10 and 11 show the time course after subtracting baseline systolic blood pressure for tranylcypromine (5 mg / kg) compared to tranylcypromine in combination with pindolol (60 mg / kg) or bisoprolol (20 mg / kg) after administration of tyramine (3 mg / kg), respectively. The reduction in maximum change in systolic blood pressure and AUC, as well as the differences in time courses between the groups, demonstrate that the change in systolic blood pressure due to tyramine administration during MAOI treatment is reduced when pindolol is administered sequentially. In addition, continuous administration of bisoprolol reduces the change in systolic blood pressure caused by tyramine administration during MAOI treatment, although the reduction is smaller than that of pindolol.

[0206] 6. In vivo rat telemetry study #3 In another study to evaluate the effect of MAOI and beta-blocker combinations on blood pressure changes after tyramine dose, an in vivo study was completed in rats implanted with telemetry transmitters, allowing the rats to recover for 7 days. After recovery, the rats were administered phenelzine (8 mg / kg / day) alone (N=5) for 3 days and carvedilol (50 mg / kg, N=5) together for 4 days. Carvedilol is a non-selective beta-blocker without ISA. On day 8, in addition to the described daily doses of phenelzine and carvedilol, tyramine (3 mg / kg) was administered 30 minutes after the administration of phenelzine and carvedilol, and blood pressure was monitored. The maximum change in systolic blood pressure with phenelzine and carvedilol was 63% lower compared to phenelzine alone (Figure 12). The AUC of systolic blood pressure was also reduced by 82% for phenelzine with carvedilol compared to phenelzine alone (Figure 13). Figure 14 shows the time course of phenelzine (8 mg / kg) administration, compared to phenelzine with carvedilol (50 mg / kg) after tyramine (3 mg / kg) administration, with the difference calculated by subtracting phenelzine (8 mg / kg) from baseline systolic blood pressure. The maximum change in systolic blood pressure, the reduction in AUC, and the elapsed time demonstrate that the change in systolic blood pressure due to tyramine administration during MAOI treatment is reduced when carvedilol is administered consecutively.

[0207] 7. Evaluation of the effects of MAOI and beta-blocker combinations on transient changes in systolic blood pressure. Significant transient blood pressure elevation (≥20 mmHg in either systolic or diastolic blood pressure) may occur in approximately 50% of patients immediately after taking either the MAOI phenelzine or tranilcypromine, and this returns to normal after 1–2 hours (Keck et al. (1989) J. Clin. Psychopharmacol. 9(3):203-6, Lott R. AAPP Pharmacist Toolkit: Monoamine Oxidase Inhibitors [Internet]. Lincoln, NE: American Association of Psychiatric Pharmacists, 2022). To evaluate the effect of MAOI and beta-blocker combinations on transient changes in systolic blood pressure, an in vivo study was completed in rats implanted with telemetry transmitters, and the rats were allowed to recover for 7 days. In short, rats received tranylcypromine (first dose 8 mg / kg, then 5 mg / kg daily) for 5 days, either alone (N=4), with pindolol (60 mg / kg, N=5), or with bisoprolol (20 mg / kg, N=5). Pindolol is a non-selective beta-blocker with an ISA. Bisoprolol is a selective beta-blocker without an ISA. On day 5, the change in systolic blood pressure from baseline was evaluated for each group: MAOI alone or MAOI with a beta-blocker +10 to +60 minutes after administration. Compared to tranylcypromine alone, the tranylcypromine and pindolol groups showed a 46% reduction in the post-administration increase in systolic blood pressure from baseline, while the tranylcypromine and bisoprolol groups showed a 24% reduction (Figure 15). While we do not wish to be bound by theory, these results demonstrate that the combination of tranylcypromine and pindolol or bisoprolol reduces transient post-administration blood pressure elevation compared to tranylcypromine alone.

[0208] 8. Predictive manufacturing protocols for dosage forms The combination of phenelzine sulfate and pindolol [1-(indole-4-yloxy)-3-(isopropylamino)-2-propanol] is manufactured as a single dosage form in the form of tablets, capsules, suppositories, injections, or other delivery doses. The dosage form(s) delivers the two compounds at a targeted pharmacological level in co-delivery to maintain the effective level of phenelzine and the protective level of pindolol for the safety of this fixed-dose drug / drug combination.

[0209] Each active pharmaceutical ingredient (API) can be formulated together or separately. Each matrix (API with corresponding excipients) is developed considering the drug solubility and pharmacology inherent to its chemical properties. API matrices can be combined into a single dosage form and presented to the patient as a single dosage form, or administered simultaneously as two APIs. Pharmaceutical-grade excipients can be incorporated into the formulation(s) to individually achieve desired release profiles. Modified release profiles can consist of coated or uncoated microparticles, pellets, or granules in tablets, capsules, suppositories, or suspensions. As detailed elsewhere herein, a modified release dosage form refers to any dosage form in which the solubility or availability of the drug substance in the dosage form is modified or altered. This includes terms such as sustained-release, long-acting, delayed-release, enteric-coated, colonic, pulsating, and biphasic. Tablets can be compressed as monolayer, bilayer, or multilayer and can be coated or uncoated. Tablet coatings can function in terms of release profile. Drug release can be achieved by other methods, such as a reservoir polymer system or an osmotic pump system using laser-perforated tablets or capsules.

[0210] Typical binders for solid oral dosage forms (tablets and capsules) include: pregelatinized maize starch or hydroxypropyl methylcellulose of various degrees of substitution; fillers (e.g., lactose, microcrystalline cellulose, calcium carbonate, or calcium phosphate); disintegrants (potato starch, croscarmellose sodium, or sodium starch glycolate); wetting agents (e.g., sodium lauryl sulfate or nonionic surfactants); or other agents suitable for tableting.

[0211] Inactive components for tablets, pellets, or spheres for matrix release include the previously identified typical components and nonionic homopolymers of ethylene oxide, water-swellable but insoluble polysaccharides, water-soluble natural gums, high molecular weight homopolymers and copolymers of polyalkenyl alcohols and chemically crosslinked acrylic acids, polyvinyl acetate and povidone, crosslinked amylose starch and ionic methacrylate copolymers. In addition, fatty acids, fatty acid esters, and mono, di, and triglycerides with different melting points, as well as hydrophobic polymers, naturally occurring waxes and ammoniace methacrylate copolymers, can be used as non-swellable matrices. Lipid or hydrophobic matrices can delay drug release and can also be used in delayed-release techniques.

[0212] Coating materials for the regulated release of drug(s) from formulation matrices (tablets, pellets, or spheres), including enteric-coated and other release targets, include naturally derived shellac and zein, cellulose derivatives (cellulose phthalate acetate, hydroxypropyl methylcellulose phthalate), and methacrylics (acid and ester copolymers containing carboxylic acid functional groups), which resist solubility at low pH and protect delivery to other pH levels above 5.5. Plasticizers (such as triacetin, triethanol citrate, glycerin, and polyethylene glycol) may or may not be necessary to enhance the release profile and flexibility of the coating.

[0213] The material for the reservoir system uses the aforementioned components for the drug-release coating that surrounds the drug core matrix (most commonly a tablet) to form a controlled barrier, which can be a water-insoluble coating such as cellulose acetate. The tablet core contains a penetrant such as sodium chloride or other hydrophilic polymers, which can push the drug out through a laser-cut orifice as designed.

[0214] Further exemplary methods of manufacture include: a drug matrix preparation being a close mixture of a drug and excipients that affects the drug behavior in manufacture and drug delivery in the dosage form; including granulation, compression, hot-melt and cold-melt pelletizing and spheroidization. The resulting matrix (granules, blends, pellets or spheres) may be a ready dosage form, involving tableting or encapsulation, or further manipulated for a desired release profile.

[0215] The drug matrix granules can be compressed / tabletized as single-layer or multi-layer tablets. These tablets can be coated with a coating to further control drug release from the tablet core. The coating can function to modulate core release or contain additional drugs for release in a multimodal profile.

[0216] Granulation or further manipulation of the drug matrix can be used to form small pellets or spheres using methodologies such as extrusion spheroidization and rotational processing. Extrusion and pelletization of drug matrices are known methodologies used for lipid nanoparticles and pellets.

[0217] The drug is sprayed onto an inert or drug matrix sphere, and then coated with a device designed to handle small beads / pellets / spheres. These drug-loaded spheres can then be further coated to deliver controlled / regulated release.

[0218] There are many options for tableting methods, including compressing a core tablet within an outer tablet or a multi-layer tablet. Compression of granulated or powdered drug matrices can be achieved by controlled pressure and appropriate dyes for tablet formation. Pellets, granules, or prepared spheres can be delivered into capsule shells designed for immediate or controlled release.

[0219] 9. Predictive pharmacokinetic studies a.Dissolution The controlled-release formulation is first tested by dissolution in vitro and compared to the dissolution results from the immediate-release formulation. Dissolution methods are well known to those skilled in the art. While we do not wish to be bound by theory, it is expected that the release of both phenelzine and pindolol from the controlled-release formulation will be significantly slower than the release of the same drugs from the immediate-release formulation.

[0220] b. In vivo rat studies Single-dose PK studies in rats include doses of phenelzine ranging from approximately 2 to 20 mg / kg and pindolol ranging from approximately 2 to 8 mg / kg. Doses are selected based on converting typical human doses of phenelzine and pindolol to rats, taking into account known potential differences in interspecies metabolism, based on body surface area (60 kg human; 0.3 kg rat, 6.2 scaling factor). Doses are administered by oral enteral nutrition of phenelzine and pindolol controlled-release formulations. Blood samples are collected approximately pre-dose, 0.25, 0.5, 1, 2, 4, 8, 16, and 24 hours. Plasma is isolated from blood and frozen until analysis by LC / MS / MS to measure plasma phenelzine and pindolol concentrations compared to immediate-release formulations. Using phenelzine and pindolol plasma concentration data, C max , T max AUC 0-24 AUC 0-inf , V / F, Cl / F, k a , and k e Calculate pharmacokinetic parameters including those included.

[0221] c. Invivoy dog ​​research Single-dose PK studies in dogs include doses of phenelzine ranging from approximately 1 to 4 mg / kg and doses of pindolol ranging from approximately 0.5 to 4 mg / kg. Doses are selected based on converting typical human doses of phenelzine and pindolol to rats, taking into account potential differences in metabolism between known species, based on body surface area (60 kg human; 8 kg dog, 1.8 scaling factor). Doses are administered orally by capsules or tablets containing regulated-release formulations of phenelzine and pindolol. Blood samples are collected approximately pre-dose, 0.25, 0.5, 1, 2, 4, 8, 16, and 24 hours. Plasma is isolated from blood and frozen until analysis by LC / MS / MS to measure plasma phenelzine and pindolol concentrations compared to immediate-release formulations. Using the phenelzine and pindolol plasma concentration data, C max , T max AUC 0-24 AUC 0-inf , V / F, Cl / F, k a , and k e Calculate pharmacokinetic parameters including those included.

[0222] d. Predicted pharmacokinetics of controlled-release formulations While we do not wish to be bound by theory, the pharmacokinetics of the controlled-release formulation are expected to change as follows for phenelzine: (1) C compared to the immediate-release formulation. max A significant decrease, for example, up to 60%, (2) compared to the immediate-release formulation. max Significant delays, for example, up to 10 hours (similarly, this is k a (This is reflected in the decrease in AUC), (3) the decrease or similarity in AUC when comparing the controlled-release formulation with the immediate-release formulation, and (4) the pharmacokinetics of phenelzine support the once-daily dosing regimen of the controlled-release formulation compared to administration of immediate-release tablets.

[0223] While we do not wish to be bound by theory, the pharmacokinetics of the controlled-release formulation are expected to change as follows for pindolol: (1) C compared to the immediate-release formulation.max A significant decrease, for example, up to 80%, (2) compared to immediate-release formulations. max Significant delays, for example, up to 10 hours (similarly, this is k a (This is reflected in the decrease in AUC), (3) the decrease or similarity in AUC between the controlled-release formulation and the immediate-release formulation, (4) the plasma concentration-time curve showing the minimum plasma concentration of pindolol at 6 ng / mL over a 24-hour period (this is reflected in the decrease in pindolol K i (and correlates with a prediction of 85% beta-blockade based on plasma levels, which may be important for blocking the tyramine effect), and (5) the pharmacokinetics of pindolol support a once-daily dosing regimen of the controlled-release formulation compared to administration of immediate-release tablets.

[0224] 10. Predictive nonclinical safety studies in Beagle dogs The non-clinical safety studies provided herein are conducted using beagle dogs. In these studies, subjects are compared to a control group receiving only the vehicle, a high-dose or low-dose phenelzine and pindolol-releasing dosage form, or an oral dosage form containing high-dose phenelzine or high-dose pindolol once daily.

[0225] Endpoints include mortality / cage-side observation, detailed clinical observation, body weight, food consumption, ophthalmology, electrocardiogram, respiratory assessment, clinicopathology (hematology, clinical chemistry, coagulation, urinalysis), organ weight, histopathology (full set of tissues), and toxicological analysis of pindolol and phenelzine and their major metabolites (after initial dose and before end of study).

[0226] 11. Predictive Phase 1 trials: Combined dose-detection PK and tyramine challenge trials A placebo-controlled, parallel-group design will be developed to evaluate the potential of NW-352 (PHZ+PIN) to minimize blood pressure elevation after oral administration of tyramine (TYR) in a fasted state (Figure 1). Once six participants in each group have completed the treatment, analyses will be conducted to compare the treatment effects between the NW-352 and phenelzine + placebo (PHZ+PBO) treatment groups, including the determination of TYR30 and the calculation of TSF values.

[0227] Eligibility is assessed during the screening period. Participants who meet the inclusion criteria will begin the baseline period and be selected for enrollment in the Clinical Research Unit (CRU) pre-enrollment TYR Challenge Series. A TYR Challenge will be conducted once daily until TYR30 is achieved. Patients who are confirmed eligible (TYR30 ≥ 200 mg and ≤ 700 mg) will enter Period 1 (open-label PHZ and blinded PIN / PBO).

[0228] A TYR dosage escalation procedure (also known as the TYR algorithm), based on an approximate linear relationship between TYR and SBP changes, is applied to determine whether any single dose of TYR in the sequence can be skipped during pre-treatment and intra-treatment TYR challenges.

[0229] a. Pre-treatment baseline TYR challenge The pre-treatment (pre-registration) fasting TYR challenge is used as the final screening procedure to determine registration. The TYR dose sequence is provided in the section below the description of the TYR challenge algorithm. The TYR challenge continues until TYR30 is achieved or until the end of the TYR dosing sequence is reached.

[0230] After the baseline TYR challenge is completed and the baseline TYR30 is determined, PHZ is titrated to a maintenance dose of 30 mg BID with either 5 mg BID PIN or PBO. Day 1 of Period 1 begins in the afternoon of the CRU following the last TYR challenge of the baseline period. Participants are randomized (1:1) to one of two study drug treatments administered approximately 12 hours apart, as follows: (a) PHZ 30 mg BID + PBO BID, and (b) NW-352 (PHZ 30 mg BID + PIN 5 mg BID). PHZ is open-label, while the PIN and PBO capsules are blinded.

[0231] After approximately 27 days of administration of the study drug in Period 1, participants will be admitted to the CRU on day 27 of Period 1. Period 2 will begin the day after admission, following morning administration of the study drug, with 12 hours of PK sample collection. The TYR Challenge Series will be administered during treatment to allow for treatment comparisons in response to TYR when treated with either NW-352 or PHZ+PBO.

[0232] b. TYR administration during treatment For Period 2, if participants are taking NW-352 and PHZ+PBO, TYR dosing will be determined using the sequence described below in the TYR Challenge Algorithm Description. Compared to the pre-treatment TYR challenge, participants taking PHZ+PBO are expected to require lower doses of TYR to reach TYR30. The TYR challenge will continue until TYR30 is achieved or until the end of the TYR dosing sequence is reached.

[0233] Participants will remain bound to the CRU throughout all challenges.

[0234] In Period 3, participants are discharged to complete tapering of the study drug over approximately 6 days, have a safety follow-up visit around day 7 of Period 3, and receive a safety phone call around day 18.

[0235] a. TYR Challenge - Algorithm Description Generally, only one TYR challenge is performed per day. With the exception of noted exceptions, all TYR challenges begin two hours after the AM dose of the study drug is administered.

[0236] The objective of the TYR dosing sequence or algorithm is to gradually advance the TYR dose until TYR30 is achieved. For each participant, the TYR challenge begins with the lowest TYR dose in the sequence associated with the participant's treatment group. The provided dosing procedure is designed to proceed safely through the TYR dose to TYR30 while minimizing risk and burden to the participant. This procedure is based on published literature demonstrating an approximately linear relationship between TYR and SBP changes (Cantarini et al. 2004, Schafers et al. 1999, Freychuss et al. 1970). This procedure may also be applied to determine whether any single dose of TYR in the sequence can be skipped.

[0237] Open-label pharmacists and / or physicians(s) will use safety and SBP data from each TYR challenge available to each participant to manage the TYR medication advancement procedure and blinded TYR medication.

[0238] Dosage sequence: For pre-randomization fasting TYR challenges: TYR doses are 100, 200, 300, 400, 500, 600, and 700 mg. For algorithm-selected PHZ+PBO treatment-in-treatment fasting TYR challenges: TYR doses are 5, 10, 25, 35, 50, 75, 100, 125, 150, and 200 mg. For algorithm-selected PHZ+PIN treatment-in-treatment fasting TYR challenges: TYR doses are 10, 25, 50, 100, 150, 200, 300, 400, 500, 600, and 700 mg.

[0239] The oral TYR challenge is designed to induce an increase in subject SBP in response to a TYR dose. TYR30 is the dose of TYR required to raise SBP by 30 mmHg or more compared to the baseline mean taken prior to the dose of the study drug (measured as three consecutive measurements taken at 5-minute intervals within 2 hours of fasting TYR administration). Pre-dose baseline SBP is defined as the average of five SBP measurements taken at 5-minute intervals during the 30 minutes immediately preceding the start of each TYR challenge. All measurements are taken in a semi-supine position, and subjects remain in this position throughout the pre-dose period and the TYR challenge monitoring period.

[0240] TYR30 is observed by monitoring BP at the following frequencies: Q5 minutes over a 2-hour period; Q15 minutes (for an additional 2 hours for the fasting challenge). A more frequent VS schedule may be implemented if the subject is deemed not stable by PI at any point.

[0241] The TYR dose for PHZ+PBO and PHZ+PIN mono-challenges is determined using an algorithm. Changes in TYR dose for the study drugs PHZ+PBO and PHZ+PIN are explained by tyramine sensitivity factor (TSF) (before TYR30 treatment / after TYR30 treatment). After the algorithm, TYR30 is expected to be induced within approximately 3–5 days.

[0242] Blood samples for TYR, PIN, and PHZ PK will be collected throughout the study to evaluate the respective concentrations of these at various time points.

[0243] 12. Predictive Phase II Trial: Pivotal Tyramine Challenge Trial and Evaluation of Tyramine Presser Response in Patients Receiving Combination Therapy with MAOIs and Beta-Blockers a. Tyramine-Sensitivity Factor (TSF) TYR30 is a metric defined as the minimum dose of tyramine that increases systolic blood pressure (SBP) by at least 30 mmHg at three consecutive measurement points within two hours of tyramine administration. TYR30 is determined by clinical trials in which subjects are administered gradually increasing doses of oral tyramine under fasting conditions, and blood pressure is measured regularly, typically every 5 minutes for two hours after tyramine administration. SBP baseline is established before tyramine administration. As the tyramine dose is absorbed, SBP will typically increase by an amount that is dose-dependent and varies from subject to subject. The SBP peak is typically 30–60 minutes after tyramine dose administration, up to a maximum of two hours. Experiments begin with low doses of tyramine to ensure the safety of subjects and are repeatedly increased according to a predetermined dose sequence. TYR30 is determined as the minimum TYR dose that produces three consecutive measurement points in which the increase in SBP relative to baseline is 30 mmHg or greater.

[0244] The TSF is designed to determine the enhancement of tyramine by a test drug, such as an MAOI. This requires the determination of two TYR30 measurements: (1) pre-treatment TYR30, which is the TYR30 that would be achieved by tyramine without the test drug; and (2) post-treatment TYR30, which is the TYR30 that would be achieved by tyramine after the test drug has been administered at a therapeutic dose, for a sufficient period of time for the test drug to reach a steady state.

[0245] TSF is calculated as the ratio of pre-treatment TYR30 to post-treatment TYR30. When the ratio exceeds 1, it indicates that a low dose of tyramine can increase SBP by 30 mmHg when taking the drug compared to not taking it. It can also be interpreted as the level of enhanced tyramine pressor response. Most drugs that interact with tyramine and are approved without the need for dietary restrictions have a TSF in the range of 1.5 - 3.5. In contrast, the TSF of 45 mg / day of phenelzine is 13.3 and that of 20 mg / day of tranylcypromine is 55 (Bieck and Antonin (1989) J Neural Transm.Suppl 28, pp.21 - 31). Considerable tyramine attenuation (5 - 15 times) is required to fall within the TSF range of drugs approved without dietary restrictions. Achieving these types of levels depends on the selected beta blocker and its dosage. Attention should be paid to the adverse effects associated with high dosages. Consideration should also be given to tyramine attenuation at the trough of the beta blocker concentration where beta blockade is lowest and tyramine attenuation is weakest.

[0246] A model was developed to link the dosage of a given beta blocker to the estimated TSF of several major MAOIs and beta blockers. This includes the following steps: (1) Establish an estimated free plasma concentration profile for each beta blocker between 1 hour and 24 hours after a single dose. (2) Estimate the beta blockade associated with the beta blocker dosage at two time points, 2 and 6 hours after administration of the beta blocker dosage. (3) Use a competitive binding model to estimate the proportion of beta receptors bound by norepinephrine for a tyramine dosage that increases SBP by approximately 60 mmHg when administered with a placebo pill. Integrate steps 1 through 3 using the model to estimate the increase in SBP for a given dosage of a beta blocker. (4) Calculate the estimated TSF of the MAOI when given with the beta blocker dosage in step 3.

[0247] Table 10 shows the estimated attenuation of the tyramine SBP pressor response when the dose of tyramine producing a 60 mmHg SBP pressor response was administered with placebo compared to when the same dose of tyramine was administered with a beta blocker. The attenuation is shown as the ratio of the SBP pressor response with a beta blocker compared to the SBP pressor response without a beta blocker.

Table 10

[0248] Table 11 shows the range of estimated TSF based on the previously reported MAOI range without beta blockers, and the sensitivity analysis of the above model. It shows the calculated reduction of MAOI TSF 6 hours after the morning beta blocker dose. The range represents the TSF values reported in the literature for each of the MAOIs.

Table 11

[0249] b. Tyramine challenge test The studies herein include a small group of volunteers with major depressive disorder with the distress of anxiety. The subjects are administered placebo, the disclosed extended release dosage forms of phenelzine and pindolol, or phenelzine.

[0250] The TSF for each group is estimated individually for each subject as a first step by dividing the Tyr30 dose at baseline (before treatment) by the Tyr30 during treatment (after treatment). The TSF values are summarized by treatment.

[0251] As a comparison of the study validity, the TSF of phenelzine alone is compared to the TSF of the placebo treatment group. A parallel comparison is made using an ANOVA / ANCOVA model of the log-transformed TSF to estimate the GMR and 90% confidence interval (CI). To demonstrate sufficient sensitivity of the study, i.e., the lower limit of the 90% CI of the TSF, GMR must exceed 125% to demonstrate a higher range of the TSF of phenelzine versus placebo (superiority).

[0252] The primary comparison using the same approach is for controlled-release formulations compared to placebo. The evaluation includes a comparison of the upper limit of the 90% CI of the GMR of TSF for approved drugs from a fasting tyramine challenge to controlled-release formulations without labeling restrictions, which is considered clinically significant.

[0253] During the week following the tyramine challenge for TSF measurement, subjects will be tested for their response to tyramine-rich meals under three different standard dietary types: (1) a light meal primarily consisting of carbohydrates, (2) a normal fat-rich meal, and (3) a normal protein-rich meal. Evaluation of this data will focus on systolic blood pressure during the tyramine challenge with a diet (under treatment) of ≤30 mmHg.

[0254] It will be apparent to those skilled in the art that various modifications and variations can be made without departing from the scope or spirit of this disclosure. Other embodiments will also be apparent to those skilled in the art from the considerations of this specification and the practices disclosed herein. The specification and examples are for illustrative purposes only, and the true scope and spirit are intended to be shown by the following claims.

Claims

1. A method for treating a mental disorder in a person requiring treatment for a mental disorder, wherein the method applies to the person, (a) A therapeutically effective dose of a monoamine oxidase inhibitor (MAOI) selected from phenelzine and tranylcypromine (TCP), (b) A therapeutically effective amount of a beta-blocker selected from pindolol and carvedilol, or their pharmaceutically acceptable salts or free bases, (c) administering an effective dose of a dosage form comprising a pharmaceutically acceptable carrier, The method wherein the subject has not been previously diagnosed with migraines.

2. The method according to claim 1, wherein the dosage form comprises the MAOI and the beta-blocker.

3. The method according to claim 1 or 2, wherein the dosage form does not contain an alpha-blocker.

4. The method according to any one of claims 1 to 3, wherein the dosage form does not contain a 5HT1A agonist.

5. The method according to any one of claims 1 to 4, wherein one or both of the MAOI and the beta-blocker are formulated as a controlled-release dosage form.

6. The method according to any one of claims 1 to 5, wherein the MAOI is phenelzine.

7. The method according to any one of claims 1 to 5, wherein the MAOI is TCP.

8. The method according to any one of claims 1 to 7, wherein the beta-blocker is pindolol.

9. The method according to any one of claims 1 to 7, wherein the beta-blocker is carvedilol.

10. The method according to any one of claims 1 to 9, wherein the subject does not undergo a tyramine-restricted diet after the administration step.

11. It is a dosage form, (a) A therapeutically effective dose of a monoamine oxidase inhibitor (MAOI), (b) A therapeutically effective amount of a beta-blocker selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebiborol, sotalol, bucindolol, nadalol, cerilpolol, nebiborol, betaxolol, esmolol, bisoprolol, oxprenolol, penbutolol, labetalol, acebutolol, and pindolol, or pharmaceutically acceptable salts or free bases thereof, A dosage form comprising a pharmaceutically acceptable carrier.

12. The dosage form according to claim 11, wherein the dosage form essentially consists of the MAOI and the beta-blocker.

13. The dosage form according to claim 11, wherein the dosage form comprises the MAOI and the beta-blocker.

14. The dosage form according to claim 11, wherein the dosage form does not contain an alpha-blocker selected from doxazosin, silodosin, prazosin, tamsulosin, alfuzosin, terazosin, trimazosin, phenoxybenzamine, and phentolamine.

15. The dosage form according to claim 11, wherein the dosage form does not contain an alpha-blocker.

16. The dosage form according to any one of claims 11 to 15, wherein the dosage form does not contain carvedilol or labetalol.

17. The dosage form according to any one of claims 11 to 16, wherein the dosage form does not contain a 5HT1A agonist.

18. The dosage form according to any one of claims 11 to 17, wherein the MAOI is formulated as a controlled-release dosage form.

19. The dosage form according to claim 18, wherein the release-controlled dosage form releases the MAOI during a dissolution period lasting approximately 6 to 16 hours.

20. The dosage form according to claim 18, wherein the release-controlled dosage form releases the MAOI during an absorption period lasting approximately 6 to 16 hours after administration to a patient.

21. The dosage form according to any one of claims 11 to 20, wherein the beta-blocker is formulated as a controlled-release dosage form.

22. The dosage form according to claim 21, wherein the release-controlled dosage form releases the beta-blocker during a dissolution period lasting approximately 6 to 24 hours.

23. The dosage form according to claim 21, wherein the controlled-release dosage form releases the beta-blocker during an absorption period lasting approximately 6 to 24 hours after administration to a patient.

24. The dosage form according to claim 21, wherein the controlled-release dosage form releases the beta-blocker during an absorption period lasting approximately 7 to 24 hours after administration to a patient.

25. The dosage form according to claim 21, wherein the MAOI is formulated as a controlled-release dosage form, and the MAOI and the beta-blocker are released over different periods of time.

26. The dosage form according to claim 21, wherein the MAOI is formulated as a controlled-release dosage form, and the MAOI and the beta-blocker are released over approximately the same period of time.

27. The dosage form according to any one of claims 11 to 26, wherein the MAOI is present in an amount of about 20 mg to about 1000 mg.

28. The dosage form according to any one of claims 11 to 26, wherein the MAOI is present in an amount of about 30 mg to about 120 mg.

29. The dosage form according to any one of claims 11 to 28, wherein the MAOI is selected from isocarboxazide, phenelzine, selegiline, tranylcypromine (TCP), and moclobemide.

30. The dosage form according to claim 29, wherein phenelzine is phenelzine sulfate.

31. The dosage form according to any one of claims 11 to 20, wherein the beta-blocker is present in an amount of about 2.5 mg to about 1000 mg.

32. The dosage form according to any one of claims 11 to 30, wherein the beta-blocker is present in an amount of about 2.5 mg to about 60 mg.

33. The dosage form according to any one of claims 11 to 30, wherein the beta-blocker is present in an amount of about 2.5 mg to about 30 mg.

34. The dosage form according to any one of claims 11 to 33, wherein the beta-blocker is selected from oxprenolol, pembutrol, labetalol, acebutolol, and pindolol, or pharmaceutically acceptable salts or free bases thereof.

35. The dosage form according to any one of claims 11 to 33, wherein the beta-blocker is selected from pindolol, carteolol, penbutrol, and acebutrol.

36. The dosage form according to any one of claims 11 to 33, wherein the beta-blocker is pindolol, or a pharmaceutically acceptable salt thereof or a free base.

37. The dosage form according to any one of claims 11 to 33, wherein the beta-blocker is bisoprolol fumarate.

38. The dosage form according to any one of claims 11 to 37, wherein the beta-blocker exhibits a beta:alpha blocking ratio of at least about 1,000:

1.

39. The dosage form according to any one of claims 11 to 38, wherein the ratio of the MAOI to the beta-blocker is about 1:1 to about 400:

1.

40. The dosage form according to any one of claims 11 to 38, wherein the ratio of the MAOI to the beta-blocker is about 2:1 to about 24:

1.

41. The dosage form according to any one of claims 11 to 40, wherein the MAOI and the beta-blocker are co-formulated.

42. The dosage form according to any one of claims 11 to 41, further comprising an effective amount of norepinephrine reuptake inhibitor (NRI).

43. The dosage form according to claim 42, wherein the effective amount of the NRI is less than a therapeutic amount.

44. The dosage form according to claim 42 or 43, wherein the NRI is formulated as a controlled-release dosage form.

45. The dosage form according to claim 44, wherein the release-controlled dosage form releases the NRI during a dissolution period lasting approximately 6 to 24 hours.

46. The dosage form according to claim 44, wherein the release-controlled dosage form releases the NRI during an absorption period lasting approximately 6 to 24 hours after administration to a patient.

47. The dosage form according to any one of claims 42 to 44, wherein the NRI is present in an amount of about 1 mg to about 1000 mg.

48. The dosage form according to any one of claims 42 to 44, wherein the NRI is present in an amount of about 1 mg to about 150 mg.

49. The dosage form according to any one of claims 42 to 44, wherein the NRI is present in an amount of about 5 mg to about 50 mg.

50. The dosage form according to any one of claims 42 to 49, wherein the ratio of the beta-blocker to the NRI is about 3:2 to about 1:

3.

51. A method for treating a mental disorder in a subject requiring treatment for a mental disorder, the method comprising administering to the subject an effective amount of the dosage form described in any one of claims 11 to 50.

52. The method according to claim 51, wherein the mental disorder is depression.

53. The method according to claim 52, wherein the depression is selected from major depressive disorder, major depressive disorder with anxiety distress, treatment-resistant depression, anxious depression, and a combination of anxiety and depression.

54. The method according to any one of claims 51 to 53, wherein the subject is not currently on a tyramine-restricted diet.

55. The method according to any one of claims 51 to 54, wherein the subject does not undergo a tyramine-restricted diet after the administration step.

56. The method according to claim 54 or 55, wherein the tyramine-restricted diet eliminates the consumption of meals containing 100 mg or more of tyramine.

57. The method according to any one of claims 51 to 56, wherein the dosage form is administered in a dose of approximately 100 mg to approximately 1000 mg.

58. The method according to claim 57, wherein the dosage form is administered once a day.

59. The method according to any one of claims 51 to 58, wherein the dosage form is administered in a dose of approximately 150 mg to approximately 500 mg.

60. The method according to claim 59, wherein the dosage form is administered once a day.

61. It is a dosage form, (a) A therapeutically effective amount of phenelzine or a pharmaceutically acceptable salt or free base thereof, (b) A therapeutically effective amount of a beta-blocker selected from pindolol and bisoprolol, or their pharmaceutically acceptable salts or free bases, A pharmaceutically acceptable carrier, MAOIs are formulated as controlled-release dosage forms. A dosage form in which the beta-blocker is formulated as a controlled-release dosage form.

62. The dosage form according to claim 561, wherein the dosage form essentially consists of phenelzine and the beta-blocker.

63. The dosage form according to claim 61, wherein the dosage form comprises phenelzine and the beta-blocker.

64. The dosage form according to any one of claims 61 to 63, wherein the dosage form does not contain an alpha-blocker selected from doxazosin, silodosin, prazosin, tamsulosin, alfuzosin, terazosin, trimazosin, phenoxybenzamine, and phentolamine.

65. The dosage form according to any one of claims 61 to 64, wherein the dosage form does not contain an alpha-blocker.

66. The dosage form according to any one of claims 61 to 66, wherein the dosage form does not contain carvedilol or labetalol.

67. The dosage form according to any one of claims 61 to 66, wherein the dosage form does not contain a 5HT1A agonist.

68. The dosage form according to any one of claims 61 to 67, wherein phenelzine is phenelzine sulfate.

69. The dosage form according to any one of claims 61 to 68, wherein bisoprolol is bisoprolol fumarate.

70. The dosage form according to any one of claims 61 to 69, further comprising an effective amount of norepinephrine reuptake inhibitor (NRI).

71. The dosage form according to claim 70, wherein the NRI is formulated as a controlled-release dosage form.

72. A method for treating a mental disorder in a subject requiring treatment for a mental disorder, the method comprising administering to the subject an effective amount of the dosage form described in any one of claims 61 to 71.

73. A method for treating a mental disorder in a person requiring treatment for a mental disorder, wherein the method applies to the person, (a) A therapeutically effective dose of MAOI and (b) administering a therapeutically effective amount of a beta-blocker selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebibolol, sotalol, bucindolol, nadalol, cerilpolol, nebibolol, betaxolol, esmolol, bisoprolol, oxprenolol, penbutolol, labetalol, acebutolol, and pindolol, or pharmaceutically acceptable salts or free bases thereof, The aforementioned subjects have not been previously diagnosed with migraines. The aforementioned subjects do not currently experience migraines.

74. The method according to claim 73, wherein the method comprises administering exactly two activators to the subject, the two activators being the MAOI and the beta-blocker.

75. The method according to claim 73 or 74, wherein an alpha-blocker selected from doxazosin, silodosin, prazosin, tamsulosin, alfuzosin, terazosin, trimazosin, phenoxybenzamine, and phentolamine has not been administered to the subject within a period of about one week or less before or after the administration step.

76. The method according to any one of claims 73 to 75, wherein an alpha-blocker selected from doxazosin, silodosin, prazosin, tamsulosin, alfuzosin, terazosin, trimazosin, phenoxybenzamine, and phentolamine has not been administered to the subject within a period of approximately 24 hours or less before or after the administration step.

77. The method according to any one of claims 73 to 76, wherein an alpha-blocker selected from doxazosin, silodosin, prazosin, tamsulosin, alfuzosin, terazosin, trimazosin, phenoxybenzamine, and phentolamine is not administered simultaneously to the subject.

78. The method according to any one of claims 73 to 77, wherein the alpha-blocker is not administered to the subject within a period of approximately one week or less before or after the administration step.

79. The method according to any one of claims 73 to 78, wherein the alpha-blocker is not administered to the subject within a period of approximately 24 hours or less before or after the administration step.

80. The method according to any one of claims 73 to 79, wherein the alpha-blocker is not administered to the subject at the same time.

81. The method according to any one of claims 73 to 80, wherein neither carvedilol nor labetalol is administered to the subject within a period of approximately one week or less before or after the administration step.

82. The method according to any one of claims 73 to 81, wherein neither carvedilol nor labetalol is administered to the subject within a period of approximately 24 hours or less before or after the administration step.

83. The method according to any one of claims 73 to 82, wherein neither carvedilol nor labetalol is administered simultaneously to the subject.

84. The method according to any one of claims 73 to 83, wherein the 5HT1A agonist is not administered to the subject within a period of approximately one week or less before or after the administration step.

85. The method according to any one of claims 73 to 84, wherein the 5HT1A agonist is not administered to the subject within a period of approximately 24 hours or less before or after the administration step.

86. The method according to any one of claims 73 to 85, wherein the 5HT1A agonist is not administered simultaneously to the subject.

87. The method according to any one of claims 73 to 86, wherein the MAOI and the beta-blocker are administered simultaneously.

88. The method according to claim 87, wherein the MAOI and the beta-blocker are administered as a fixed dose combination.

89. The method according to claim 87, wherein the MAOI and the beta-blocker are co-formulated.

90. The method according to any one of claims 73 to 89, wherein the MAOI is not phenelzine.

91. The method according to any one of claims 73 to 90, wherein the beta-blocker exhibits a beta:alpha blocking ratio of at least about 1,000:

1.

92. An improvement comprising further comprising in a dosage form containing a therapeutically effective amount of MAOI, a therapeutically effective amount of a beta-blocker selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebiborol, sotalol, bucindolol, nadalol, cerilpolol, nebiborol, betaxolol, esmolol, bisoprolol, oxprenolol, penbutrol, labetalol, acebutrol, and pindolol, or pharmaceutically acceptable salts or free bases thereof.

93. An improvement comprising further comprising a therapeutically effective amount of MAOI in a dosage form containing a therapeutically effective amount of a beta-blocker.

94. An improvement to a method for treating a mental disorder in a subject requiring treatment of a mental disorder by administering a MAOI, comprising co-administering to the patient a beta-blocker selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebiborol, sotalol, bucindolol, nadalol, cerilpolol, nebiborol, betaxolol, esmolol, bisoprolol, oxprenolol, penbutrol, labetalol, acebutrol, and pindolol, or pharmaceutically acceptable salts or free bases thereof, together with the MAOI in an amount effective in reducing migraine recurrence and / or producing a longer-lasting effect compared to administration of the MAOI in the absence of the beta-blocker, wherein the MAOI and the beta-blocker are present together in a single dosage form.

95. An improvement in a method for treating a mental disorder in a subject requiring treatment of a mental disorder by administering a MAOI, comprising administering to the patient a beta-blocker selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebiborol, sotalol, bucindolol, nadalol, cerilpolol, nebiborol, betaxolol, esmolol, bisoprolol, oxprenolol, penbutrol, labetalol, acebutrol, and pindolol, or pharmaceutically acceptable salts or free bases thereof, together with the MAOI in an amount effective in reducing migraine recurrence and / or producing a longer-lasting effect compared to administration of the MAOI in the absence of the beta-blocker, wherein the subject has not been previously diagnosed with migraines and is not currently experiencing migraines.

96. An improvement to a method for treating a mental disorder in a subject requiring treatment of a mental disorder by administering a beta-blocker, comprising administering to the patient a MAOI together with the beta-blocker in an amount effective in reducing migraine recurrence and / or producing a longer-lasting effect compared to administration of the beta-blocker in the absence of the MAOI, wherein the MAOI and the beta-blocker are present together in a single dosage form.

97. An improvement in a method for treating a mental disorder in a subject requiring treatment of a mental disorder by administering a beta-blocker, comprising administering to the patient a beta-blocker selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebiborol, sotalol, bucindolol, nadalol, cerilpolol, nebiborol, betaxolol, esmolol, bisoprolol, oxprenolol, penbutrol, labetalol, acebutrol, and pindolol, or pharmaceutically acceptable salts or free bases thereof, together with an MAOI in an amount effective in reducing migraine recurrence and / or producing a longer-lasting effect compared to administration of the MAOI in the absence of the beta-blocker, wherein the subject has not been previously diagnosed with migraines and is not currently experiencing migraines.

Images