Combination therapy for depression and other conditions

Abstract

The present invention provides compositions comprising a monoamine oxidase inhibitor (MAOI) and a beta receptor blocker (e.g., a beta receptor inhibitor). The invention relates to a dosage form of two of propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebivolol, sotalol, bunenolol, naldalol, seribolol, nebivolol, betalol, esmolol, bisoprolol, oxyprenolol, pentobutolol, labeolol, acebutolol and indolol. And methods of making the dosage forms and using the dosage forms for, for example, the treatment of psychiatric disorders (e.g., depression, major depressive disorder, major depressive disorder associated with anxiety pain, refractory depression, anxiety depression, and mixed anxiety and depression). This abstract is intended as a scanning tool for search purposes in the particular art and is not intended as a limitation on the present invention.

Description

[0001] Cross Reference to Related Applications This application claims priority to U.S. Application No. 63 / 521,578, filed June 16, 2023; U.S. Application No. 63 / 528,285, filed July 21, 2023; and U.S. Application No. 63 / 638,117, filed April 24, 2024, the contents of which are incorporated herein by reference in their entirety. Background Technology

[0002] Depression is a leading cause of disability worldwide (Friedrich, MJ (2017)). JAMA 317(15): 1517), however, few new antidepressants have been approved, and the deficiencies in the effectiveness of antidepressant treatment exacerbate the enormous burden of depression on public health (Hyman, Steven E. (2012)). Science translational medicine 4(155): 155cm11). Major depressive disorder (MDD) is the most common and most disabling form of depression, with a lifetime prevalence of 20.6% in the United States (Hasin et al. (2018)). JAMA Psychiatry 75(4): 336–346). MDD is frequently accompanied by 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 between 40% and 78% (Thase 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 a persistent anxiety disorder, while in others, a significant increase in anxiety occurs alongside depressive episodes, complicating clinical presentation and treatment (Thase et al. (2017)). J Clin Psychiatry 78(9): 1351–1362). Patients with both MDD and anxiety distress (MDD-AD) tend to have more severe depression, severe functional impairment, increased panic and stress, and 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. Studies and clinical practice have shown that monoamine oxidase inhibitors (MAOIs) are effective in treating MDD when other treatments fail (see reviews by Bender and Walker, 2012; Fiedorowicz and Swartz, 2004; and Thase et al., 1995). As shown by McGrath et al. (1993), one MAOI, phenelzine (PHZ), has proven highly effective in treating treatment-resistant depression, with 55% of patients who previously did not respond to the tricyclic antidepressant (TCA) imipramine (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) showed that PHZ was superior to all other treatments (Suchting et al. (2021)). Journal of affective disorders 282: 1153–1160). Phenylezid sulfate is thought to increase γ-aminobutyric acid (GABA) brain levels by inhibiting GABA transaminase (GABA-T), an inhibitory neurotransmitter widely believed to play a role in anxiety disorders (Nemeroff, Charles B. (2003)). Psychopharmacol Bull 37(4): 133–146). The enhancing effects of PHZ on GABA, serotonin, norepinephrine, and dopamine (all of which are thought to play a role in mediating depression and anxiety disorders) may explain the reported efficacy of PHZ and its potential for treating MDD-AD.

[0004] Despite the success of PHZ and other MAOIs in treating treatment-resistant patients, they are rarely used to treat MDD, mixed anxiety and depression, or MDD-AD (even after failure of several treatment regimens), primarily due to safety concerns associated with tyramine accumulation (“cheese effect”). Tyramine has been shown to contribute to many medically significant cardiovascular events in patients treated with MAOIs in the 1960s. For example (Dangerous hypertension) and the cause of 21 deaths (Gillman, P. Ken (2011)) Journal of psychopharmacology (Oxford, England)25(3): 429–436). After a temporary withdrawal from the market in 1964, MAOI was reinstated, and regulators imposed dietary restrictions on its use (including restrictions on the consumption of cheese, beer, wine, and cured meats) to prevent the “cheese effect.” It has been reported that after 1967, it has been difficult to identify any deaths reported as being related to the cheese effect (Gillman, P. Ken (2011)). Journal of psychopharmacology (Oxford, England) 25(3): 429–436). However, the potential impact of the tyramine effect is still reported as a significant obstacle to the current use of MAOIs (Rabkin et al. (1985)). J. Clin. Psychopharmacol. 5(1): 2–9), Prescribing physicians expressed concern about the dangers of patient adherence disruption, misunderstandings about the risks of dietary non-adherence, and the potential medical risks of dangerous hypertensive reactions in patients who deviate from dietary restrictions.

[0005] Therefore, there remains a need for dosage forms, compositions, and methods of using MAOIs to treat depression and other mental disorders in order to reduce or even eliminate tyramine-induced pressor responses. This invention addresses these and other needs. Summary of the Invention

[0006] According to the purposes of this invention, as embodied and broadly described herein, this invention relates in one aspect to a combination of MAOI and a β-receptor blocker ( For example Propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebivolol, sotalol, bucindolol, nadalol, celirpolol, betaxolol, and more. The dosage forms of esmolol, bisoprolol, oxprenolol, penbutolol, labetalol, acebutolol, and pindolol, and methods for preparing the dosage forms and for using the dosage forms to treat mental disorders such as, for example, depression, major depressive disorder, major depressive disorder with anxiety distress, treatment-resistant depression, anxiety depression, and mixed anxiety and depression.

[0007] Therefore, a dosage form comprising: (a) a therapeutically effective amount of a monoamine oxidase inhibitor (MAOI); and (b) a therapeutically effective amount of a β-receptor blocker selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebivolol, sotalol, buxinolol, nadavolol, celiprolol, nebivolol, betalolol, esmolol, bisoprolol, oxenolol, penbuprofenolol, labetalol, acebutolol, and indololol, or a pharmaceutically acceptable salt or free base thereof, and a pharmaceutically acceptable carrier.

[0008] The formulation also discloses: (a) a therapeutically effective amount of phenelzine or a pharmaceutically acceptable salt or free base thereof; and (b) a therapeutically effective amount of a β-receptor blocker selected from indolol and bisoprolol, or a pharmaceutically acceptable salt or free base thereof, and a pharmaceutically acceptable carrier, wherein the MAOI is formulated into a modulated-release formulation, and wherein the β-receptor blocker is formulated into a modulated-release formulation.

[0009] The formulation also discloses a dosage form containing a therapeutically effective amount of MAOI, with modifications including: further containing a therapeutically effective amount of a β-receptor blocker selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebivolol, sotalol, buxinolol, nadavolol, celiprolol, nebivolol, betalolol, esmolol, bisoprolol, oxenolol, penbuprofenolol, labetalol, acebutolol, and indololol, or a pharmaceutically acceptable salt or free base thereof.

[0010] A dosage form containing a therapeutically effective amount of a beta-blocker was also disclosed, with improvements including further including a therapeutically effective amount of MAOI in the dosage form.

[0011] A method for treating mental disorders in subjects in need is also disclosed, which involves administering an effective amount of the disclosed dosage form to the subject.

[0012] A method for treating mental disorders in subjects in need is also disclosed, 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, buxinolol, nadaolol, celiprolol, nebiolol, betalolol, esmololol, bisoprolol, oxenolol, penbuprofenolol, labetalol, acebutolol, and indololol, or a pharmaceutically acceptable salt or free base thereof, wherein the subject has not previously been diagnosed with migraine and wherein the subject is not currently experiencing migraine.

[0013] The method for treating mental disorders in subjects in need by administering an MAOI is also disclosed, with improvements including: simultaneously administering a β-blocker to the patient in a measured amount together with the MAOI, the β-blocker being selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebivolol, sotalol, buxinolol, nadavolol, celiprolol, nebivolol, betalol, esmolol, bisoprolol, oxenolol, penbuprofenolol, labetalol, acebutolol, and indololol, or a pharmaceutically acceptable salt or free base thereof, the measured amount effectively reducing migraine recurrence and / or producing a more durable therapeutic effect compared to administering the MAOI in the absence of the β-blocker, wherein the MAOI and the β-blocker are present together in a single dosage form.

[0014] The method for treating mental disorders in subjects in need by administering an MAOI is also disclosed, with improvements including: administering a β-blocker to the patient simultaneously with the MAOI in a controlled amount, the β-blocker being selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebivolol, sotalol, buxinolol, nadavolol, celiprolol, nebivolol, betalol, esmolol, bisoprolol, oxenolol, penbuprofenolol, labetalol, acebutolol, and indololol, or a pharmaceutically acceptable salt or free base thereof, the controlled amount effectively reducing migraine recurrence and / or producing a more durable therapeutic effect compared to administering the MAOI in the absence of the β-blocker, wherein the subject has not previously been diagnosed with migraine and wherein the subject is not currently experiencing migraine.

[0015] The method for treating mental disorders in subjects in need by administering a beta-blocker is also disclosed, with improvements including: administering an MAOI to the patient simultaneously with the beta-blocker in a measured amount, which effectively reduces migraine recurrence and / or produces a more durable effect compared to administering the beta-blocker in the absence of the MAOI, wherein the MAOI and the beta-blocker are present together in a single dosage form.

[0016] Also disclosed is a method for treating mental disorders in subjects in need by administering a beta-blocker, with improvements including: simultaneously administering a beta-blocker to the patient in an amount selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebivolol, sotalol, buxinolol, nadavolol, celiprolol, nebivolol, betalol, esmolol, bisoprolol, oxenolol, penbuprofenolol, labetalol, acebutolol, and indololol, or a pharmaceutically acceptable salt or free base thereof, in an amount that effectively reduces migraine recurrence and / or produces a more durable therapeutic effect compared to administering the MAOI in the absence of the beta-blocker, wherein the subject has not previously been diagnosed with migraine and wherein the subject is not currently experiencing migraine.

[0017] Methods for treating mental disorders in subjects in need are also disclosed, comprising administering to the subject an effective amount of a dosage form comprising: (a) a therapeutically effective amount of a monoamine oxidase inhibitor (MAOI) selected from phenelzine and transphenylcyclopropane (TCP); (b) a therapeutically effective amount of a beta-blocker selected from indolol and carvedilol, or a pharmaceutically acceptable salt or free base thereof; and (c) a pharmaceutically acceptable carrier wherein the subject has not previously been diagnosed with migraine.

[0018] While aspects of the invention may be described and claimed in specific legal categories (such as the systems category), this is merely for convenience, and those skilled in the art will understand that aspects of the invention may be described and claimed in any legal category. Unless expressly stated otherwise, it is never intended that any method or aspect set forth herein require its steps to be performed in a particular order. Therefore, where a method claim does not specifically state in the claims or description that the steps are limited to a particular order, no inference is ever made in any respect of the order. This applies to any possible non-expressive basis for interpretation, including matters of logic concerning the arrangement of steps or the flow of operations, the general meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the description. Attached Figure Description

[0019] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several aspects and, together with the specification, serve to explain the principles of the invention.

[0020] Figure 1 A representative schematic diagram of the predictive Phase 1 study described in this paper is shown.

[0021] Figure 2 The IC diagram illustrating MAO-A and phenylethylhydrazine is shown. 50 Representative data.

[0022] Figure 3 The IC diagram illustrating MAO-B and phenethylhydrazine is shown. 50 Representative data.

[0023] Figure 4A and Figure 4B The illustration shows that only phenethylhydrazine ( Figure 4A ) or anti-phenylcyclopropylamine ( Figure 4B Representative data on the maximum systolic blood pressure change following tyramine dosage in combination with indorol and indrolol.

[0024] Figure 5 The representative time course of systolic blood pressure in rats after administration of tyramine, either phenelzine alone or in combination with indolol, is shown.

[0025] Figure 6 The representative time course of transphenylcyclopropylamine and indolol after administration of tyramine is shown.

[0026] Figure 7 Representative data illustrating the maximum change relative to baseline for phenethylhydrazine alone or in combination with indolol are shown.

[0027] Figure 8 Representative data illustrating the maximum change relative to baseline for either cyclopropane alone or in combination with indolol or bisoprolol are shown.

[0028] Figure 9 Representative data are shown illustrating the area under the curve (AUC) for either phenylcyclopropane alone or in combination with indolol or bisoprolol.

[0029] Figure 10 Representative data illustrating the time-varying process of transphenylcyclopropane alone or in combination with indolol relative to baseline are shown.

[0030] Figure 11 Representative data illustrating the time-varying process of transphenylcyclopropane alone or in combination with bisoprolol relative to baseline are shown.

[0031] Figure 12 Representative data illustrating the maximum change relative to baseline for either cyclopropane alone or in combination with carvedilol are shown.

[0032] Figure 13 Representative data illustrating the AUC of either cyclopropane alone or in combination with carvedilol are shown.

[0033] Figure 14 Representative data illustrating the time-varying process of transphenylcyclopropane alone or in combination with carvedilol relative to baseline are shown.

[0034] Figure 15Representative data are shown illustrating the instantaneous change in systolic blood pressure relative to baseline after administration of tranylcypromine compared to indolol or bisoprolol.

[0035] Further advantages of the invention will be set forth in part in the description which follows, and in part will be apparent from the description, or may be learned by practice of the invention. The advantages of the invention will be realized and obtained by means of the elements and combinations particularly pointed out in the appended claims. It should be understood that the foregoing general description and the following detailed description are merely exemplary and explanatory, and do not limit the claimed invention. Detailed Implementation

[0036] The invention can be more readily understood by referring to the following specific embodiments and examples included therein.

[0037] Before disclosing and describing the compounds, compositions, articles, systems, devices, and / or methods of the present invention, it should be understood that, unless otherwise stated, they are not limited to specific synthetic methods, or, unless otherwise stated, they are not limited to specific reagents, as these can certainly vary. It should also be understood that the terminology used herein is for descriptive purposes only and is not intended to be limiting. Although any methods and materials similar to or equivalent to those described herein may be used in the practice or testing of the invention, exemplary methods and materials are described hereafter.

[0038] While aspects of the invention may be described and claimed in specific legal categories (such as the systems category), this is merely for convenience, and those skilled in the art will understand that aspects of the invention may be described and claimed in any legal category. Unless expressly stated otherwise, it is never intended that any method or aspect set forth herein require its steps to be performed in a particular order. Therefore, where a method claim does not specifically state in the claims or description that the steps are limited to a particular order, no inference is ever made in any respect of the order. This applies to any possible non-expressive basis for interpretation, including matters of logic concerning the arrangement of steps or the flow of operations, the general meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the description.

[0039] Throughout this application, various disclosures have been cited. The disclosures of these disclosures are hereby incorporated, in their entirety, by reference to provide a more comprehensive description of the current state of the art to which this invention pertains. For material discussed in sentences upon which the references are relied, the disclosed references are also individually and specifically incorporated herein by reference. Nothing herein should be construed as an admission that the invention is not entitled to precedence by prior art. Furthermore, the publication dates provided herein may differ from the actual publication dates, which may require independent verification.

[0040] A. Definition The singular forms “a / an” and “described” used in the specification and appended claims include plural indicators unless the context clearly indicates otherwise. Thus, for example, references to “antidepressant,” “mental disorder,” or “subject” include mixtures of two or more such antidepressants, mental disorders, or subjects.

[0041] As used in the specification and claims, the term "comprising" may include aspects "consisting of" and "consisting essentially of".

[0042] In this document, a range may be expressed as from “about” one specific value and / or to “about” another specific value. When expressing such a range, the other side includes from one specific value and / or to another specific value. Similarly, when a value is expressed as an approximation using the antecedent “about”, it should be understood that the specific value forms the other side. It should be further understood that the endpoints of each in the range are significant relative to and independent of the other endpoint. It should also be understood that many values ​​are disclosed herein, and each value is disclosed herein as “about” the specific value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It should also be understood that each unit between two specific units is also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0043] As used herein, the terms “about” and “for or approximately” mean that the quantity or value in question may be approximately or identical to some other specified value. It should generally be understood that, as used herein, nominal values ​​indicate a variation of ±10%, unless otherwise indicated or inferred. These terms are intended to convey that similar values ​​promote equivalent results or effects as described in the claims. That is, it should be understood that quantities, sizes, formulations, parameters, and other quantities and characteristics are not and need not be precise, but may be approximate and / or larger or smaller as required, reflecting tolerances, conversion factors, rounding, measurement errors, and other factors known to those skilled in the art. Generally, quantities, sizes, formulations, parameters, or other quantities or characteristics are “about” or “approximate,” whether explicitly stated or not. It should be understood that where “about” is used before a quantitative value, unless otherwise specifically stated, the parameter also includes the specific quantitative value itself.

[0044] References to the weight parts of a specific element or component in the composition in the specification and concluding claims indicate the weight relationship between the element or component in the composition or article and any other element or component, expressed as parts by weight. Therefore, in a compound containing 2 parts by weight of component X and 5 parts by weight of component Y, X and Y are present in a weight ratio of 2:5, and this ratio applies regardless of whether the compound contains other components.

[0045] Unless otherwise specified, the weight percentage (wt.%) of a component is based on the total weight of the formulation or composition containing said component.

[0046] As used herein, the terms “optional” or “optionally” mean that the event or situation described below may or may not occur, and the description includes both the occurrence and non-occurrence of the event or situation.

[0047] As used herein, the term "subject" can refer to a vertebrate, such as a mammal, fish, bird, reptile, or amphibian. Therefore, the subject of the methods disclosed herein can be a human, a non-human primate, a horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent. The term does not indicate a specific age or sex. Therefore, adult and neonatal subjects, as well as fetuses, whether male or female, will be included. In one respect, the subject is a mammal. A patient refers to a subject suffering from a disease or ailment. The term "patient" includes both human and veterinary subjects.

[0048] As used herein, the term "treatment" refers to the medical management of a patient with the aim of curing, improving, stabilizing, or preventing a disease, pathological condition, or symptom. This term includes active treatment, meaning treatment specifically aimed at improving a disease, pathological condition, or symptom, and also includes etiological treatment, meaning treatment aimed at removing the cause of the related disease, pathological condition, or symptom. Furthermore, the term includes palliative care, which aims to relieve symptoms rather than cure a disease, pathological condition, or symptom; preventative care, which aims to minimize or partially or completely suppress the development of a related disease, pathological condition, or symptom; and supportive care, which is used to supplement another specific therapy aimed at improving a related disease, pathological condition, or symptom. In all respects, the term covers the treatment of subjects (including mammals). For example Any treatment for (i) a person, including: (i) preventing the disease from occurring in a subject who may be susceptible to the disease but has not yet been diagnosed with the disease; (ii) suppressing the disease. That is (iii) To prevent its development; or (iii) to alleviate the disease. That is To cause the disease to subside. In one respect, the subject is a mammal, such as a primate, and in another respect, the subject is a human. The term "subject" also includes domesticated animals (…). For example Cats, dogs, etc.), livestock ( For example (cattle, horses, pigs, sheep, goats, etc.) and laboratory animals ( For example (Mice, rabbits, rats, guinea pigs, fruit flies, etc.)

[0049] As used herein, the term "prevent" or "preventing" means to hinder, prevent, avoid, preemptively stop, halt, or impede something from happening, especially by taking proactive action. It should be understood that in the context of the use of "reduce," "inhibit," or "prevent" herein, the use of the other two terms is also explicitly disclosed unless otherwise expressly indicated.

[0050] As used herein, the term “diagnosed” means that a person has undergone a physical examination by a technician, such as a physician, and has been found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein.

[0051] As used herein, the terms "administering" and "administration" refer to any method of delivering 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 administration, transdermal administration, inhalation administration, nasal administration, topical administration, vaginal administration, ocular administration, intraocular administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injection, such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration may be continuous or intermittent. In various aspects, the preparation may be administered therapeutically; that is, the preparation is administered to treat an existing disease or symptom. In other aspects, the preparation may be administered prophylactically; that is, the preparation is administered to prevent a disease or symptom.

[0052] As used herein, the terms "effective amount" and "amount effective" refer to an amount sufficient to achieve the desired outcome or to act on an undesirable symptom. For example, a "therapeutic effective amount" is an amount sufficient to achieve the desired therapeutic outcome or to act on an undesirable symptom but generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend on a variety of factors, including the condition being treated and its severity; the specific composition used; the patient's age, weight, general health, sex, and diet; the time of administration; the route of administration; the excretion rate of the specific compound used; the duration of treatment; the drugs used in combination with or concurrently with the specific compound used; and similar factors well known in the medical field. For example, starting the compound at a dose level lower than required to achieve the desired therapeutic effect and gradually increasing the dose until the desired effect is achieved is entirely within the scope of the art. If desired, the effective daily dose can be divided into multiple doses for the purpose of administration. Therefore, a single-dose composition may contain such amounts or approximations thereof to constitute a daily dose. In the event of any contraindications, the dose may be adjusted by an individual physician. The dose may vary and may be administered once or multiple times daily for one or several days. Guidance on appropriate dosages for a given class of pharmaceutical products can be found in the literature. In other respects, formulations can be administered at a “preventatively effective dose”; that is, a dose effective in preventing disease or symptoms.

[0053] As used herein, the term "dosage form" means one or more pharmacologically active agents in a medium, carrier, excipient, binder, mediator, or filler suitable for administration to a subject. As used herein, a dosage form can refer to a liquid or solid dosage form. A dosage form may comprise one or more disclosed compounds, combinations of disclosed compounds, fixed-dose drug combinations (FDCs), products of disclosed methods of preparation or their salts, solvates, free bases, or polymorphs, combined with pharmaceutically acceptable excipients (such as preservatives, buffers, saline, or phosphate-buffered saline), or mixed with pharmaceutically acceptable binders, such as pregelatinized corn starch or hydroxypropyl methylcellulose with varying degrees of substitution; fillers ( For example Lactose, microcrystalline cellulose, calcium carbonate or calcium phosphate; disintegrants (potato starch, croscarmellose sodium cellulose or carboxymethyl starch sodium); wetting agents ( For example Sodium dodecyl sulfate or nonionic surfactants) or other reagents suitable for tableting or for matrix release of inactive ingredients in tablets, microcapsules, or spheres (including nonionic homopolymers of ethylene oxide, water-soluble natural gums of polysaccharides, water-swellable but insoluble homopolymers and copolymers of high molecular weight acrylic acid chemically crosslinked with polyenols, polyvinyl acetate and povidone, crosslinked amyl starch and ionic methacrylate copolymers). In addition, fatty acids, fatty acid esters and monoglycerides, diglycerides, triglycerides, and hydrophobic polymers, naturally occurring waxes, and quaternary ammonium methacrylate copolymers with different melting points are used in non-swelling matrices. Lipids or hydrophobic matrices can delay drug release and are also used in delayed-release technologies. Coating materials used for modulating drug release from a formulated matrix (tablets, pellets, or spheres), including enteric coatings and other release targets (including naturally derived shellac and corn gluten, cellulose derivatives (cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate), and methacrylic acid (acid and ester copolymers containing carboxyl functional groups)), maintain solubility at low pH and protect delivery to other pH values ​​greater than 5.5. Plasticizers (such as glyceryl triacetate, triethanolyl citrate, glycerol, and polyethylene glycol) may or may not be required to enhance the release properties and flexibility of the coating.

[0054] Dosage forms can be prepared using conventional drug manufacturing and compounding techniques. Dosage forms may include inorganic or organic buffer solutions (…). For example Sodium or potassium phosphates, carbonates, acetates, or citrates) and pH adjusters ( For example Hydrochloric acid, sodium hydroxide or potassium hydroxide, citrate or acetate, amino acids and their salts), antioxidants ( For example Ascorbic acid, α-tocopherol), surfactants ( For example Polysorbate 20, polysorbate 80, polyoxyethylene 9-10 nonylphenol, sodium deoxycholate), solution and / or freeze / dissolve stabilizers (For example Sucrose, lactose, mannitol, trehalose), osmotic regulators ( For example Salt or sugar), antibacterial agents ( For example Benzoic acid, phenol, gentamicin), defoamer ( For example Polydimethylsiloxane), preservatives ( For example Thimerosal, 2-phenoxyethanol, EDTA), polymer stabilizers and viscosity modifiers ( For example Polyvinylpyrrolidone, poloxamer 488, carboxymethyl cellulose) and cosolvents ( For example (Glycerin, polyethylene glycol, ethanol). Dosage forms formulated for injectable use may suspend the disclosed compound, the product of the disclosed preparation method, or its salts, solvates, free bases, or polymorphs together with a preservative in a sterile aqueous saline solution for injection.

[0055] As used herein, “kit” means a collection of at least two components that constitute a kit. These components together form a functional unit for a given purpose. Individual component members may be physically packaged together or separately. For example, a kit that includes instructions for use may or may not physically include instructions, even with other individual component members. Conversely, instructions may be provided as a separate component, in print or electronic form, available on a computer-readable storage device or downloadable from an Internet website, or provided as a record.

[0056] As used herein, “instructions for use” means a document describing the relevant materials or methods associated with the kit. These materials may include any combination of the following: background information, a list of components and their availability (purchasing information, etc.), a brief or detailed protocol for using the kit, troubleshooting, references, technical support, and any other relevant documentation. Instructions for use may be supplied with the kit or as a separate component in print or electronic form, available on a computer-readable storage device or downloadable from an internet website, or as a recorded presentation. Instructions for use may include one or more documents and are intended to include future updates.

[0057] As used herein, the term "therapeutic agent" includes any synthetic or naturally occurring biologically active compound or substance composition that, when administered to an organism (human or non-human animal), induces desired pharmacological, immunogenic, and / or physiological effects through local and / or systemic action. The term therefore encompasses those compounds or chemicals traditionally considered to include molecules such as proteins, peptides, hormones, nucleic acids, gene constructs, etc., pharmaceuticals, vaccines, and biological drugs. Examples of therapeutic agents are described in well-known literature references such as the Merck Index (14th edition), the Physicians' Desk Reference (64th edition), and The Pharmacological Basis of Therapeutics (12th edition), and they include, but are not limited to: drugs; vitamins; mineral supplements; substances intended to treat, prevent, diagnose, cure, or alleviate diseases or ailments; substances affecting body structure or function, or prodrugs, which become biologically active or more potent upon placement in a physiological environment. For example, the term "therapeutic agent" includes compounds or compositions used in all major therapeutic areas, including but not limited to: adjuvants; anti-infective agents, such as antibiotics and antiviral agents; analgesics and analgesic compositions, anorexia nervosa, anti-inflammatory agents, antiepileptic agents, local and general anesthetics, hypnotics, sedatives, antipsychotics, neuroleptics, antidepressants, anxiolytics, antagonists, neuronal blocking agents, anticholinergics and cholinergics, antimuscarinic and muscarinic drugs, antiadrenergics, antiarrhythmics, antihypertensives, hormones and nutrients, antiarthritis agents, antiasthmatics, anticonvulsants, antihistamines, antiemetics, antitumor agents, antipruritics, antipyretics; antispasmodics, cardiovascular preparations. (Including calcium channel blockers, beta-blockers, beta-agonists, and antiarrhythmic drugs); antihypertensive drugs, diuretics, vasodilators; central nervous system stimulants; cough and cold preparations; 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 recombinant); and nucleic acid molecules (polymers of two or more nucleotides, ribonucleotides (RNA) or deoxyribonucleotides (DNA), including double-stranded and single-stranded molecules, gene constructs, expression vectors, antisense molecules, etc.), small molecules ( For exampleDoxorubicin and other biologically active macromolecules, such as proteins and enzymes, for example. The agent can be a bioactive agent used in medical (including veterinary) applications and in agriculture (such as plants) and other fields. The term "therapeutic agent" also includes, but is not limited to: pharmaceuticals; vitamins; mineral supplements; substances used to treat, prevent, diagnose, cure, or alleviate diseases or ailments; or substances that affect the structure or function of the body; or prodrugs that become biologically active or more potent upon being placed in a predetermined physiological environment.

[0058] The term "pharmaceutically acceptable" describes material that is not biologically or otherwise undesirable. For example It does not cause undesirable biological effects at unacceptable levels or interact in a harmful manner.

[0059] As used herein, the term "pharmaceutically acceptable carrier" refers to non-sterile and sterile carriers or excipients that are generally safe (non-toxic) and not considered biologically active in themselves, and can be part of an aqueous or non-aqueous solution, dispersion, suspension, or emulsion, as well as a sterile powder reconstituted into a sterile injectable solution or dispersion prior to use, or a non-sterile powder for oral administration. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or mediators include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethyl cellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters, such as ethyl oleate. Suitable flowability can be maintained, for example, by using coating materials such as lecithin, by maintaining the desired 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 including various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, etc. It may also be necessary to include isotonic agents, such as sugars, sodium chloride, etc. Absorption of injectable drug forms can be prolonged by including agents that delay absorption, such as aluminum monostearate and gelatin. Injectable reservoir forms are prepared by forming a microcapsule matrix of the drug within a biodegradable polymer, such as poly(lactide-polyglycolic acid), 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. Reservoir injectable formulations can also be prepared by encapsulating the drug in tissue-compatible liposomes or microemulsions. Injectable formulations can be sterilized, for example, by filtration via a bacterial trap 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 before use. Suitable inert carriers may include sugars, such as lactose. Ideally, at least 95% by weight of the active ingredient particles have an effective particle size in the range of 0.01 to 10 micrometers.

[0060] As used herein, the term "monoamine oxidase inhibitor" or "MAOI" refers to an inhibitor of one or more monoamine oxidases (MAOIs). That is Compounds with active MAO-A and MAO-B. MAOI can be produced in a non-selective manner ( For example Inhibit both MAO-A and MAO-B) or selectively ( For example MAO can be inhibited by inhibiting MAO-A or MAO-B, and it can also be deactivated in a reversible manner (through non-covalent, reversible interactions). For example MAOIs exert their effects through competitive inhibitors, non-competitive inhibitors, or irreversible mechanisms (such as covalent, irreversible interactions that inactivate MAO-A and / or MAO-B). Exemplary MAOIs include, but are not limited to, tranylcyclopropane (TCP). For example (transphenylcyclopropamine sulfate, transphenylcyclopropamine hydrochloride), phenethylhydrazine () For example Phenethylhydrazine sulfate), isocarboxazid, selegiline ( For example Selegiline hydrochloride, rasagiline ( For example Rasagiline mesylate and moclobemide ( For example (Moclobemide hydrochloride). Free base form, pharmaceutically acceptable salt form, and non-salt form were considered.

[0061] The term "β-blocker" refers to compounds that block β-adrenergic signaling and are used to treat cardiovascular conditions, including hypertension. As used herein, "β-blocker" includes non-selective β-blockers (…). For example Propranolol, naldolol, indololol, labetalol, pentbuprofen, sotalol, carvedilol, timolol), β-1 selective blockers ( For example Metoprolol, atenolol, acebutolol, betalolol, esmolol, bisoprolol, nebivolol), and β-receptor blockers with intrinsic sympathomimetic activity (ISA) or partial agonist activity ( For example Acetylbutolol, indololol, carteolol, pentbuprofen) and / or dual α and β receptor blockers ( For example Examples of beta-blockers include, but are not limited to, propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebivolol, sotalol, buspirolol, nadanolol, celiprolol, nebivolol, betalolol, esmololol, bisoprolol, oxenolol, penbuprofenolol, labetalol, acebutolol, and indrolol. Free base forms, pharmaceutically acceptable salt forms, and non-salt forms are considered.

[0062] As used herein, the phrase "β-receptor blocker with intrinsic sympathomimetic activity (ISA)" refers to a β-receptor blocker that can stimulate β-adrenergic receptors (agonist effect) and can competitively antagonize the stimulatory effect of catecholamines (antagonist effect). Exemplary β-receptor blockers with ISA include, but are not limited to, indolol, carteolol, pentbuprofen, and acebutolol.

[0063] As used herein, the term "adjusted release" refers to a dosage form in which the time and / or rate of release of a drug substance is altered compared to a conventional immediate-release dosage form. Adjusted-release dosage forms can include sustained-release, extended-release, continuous-release, controlled-release, and delayed-release dosage forms. As described herein, adjusted-release dosage forms can be designed to achieve a prolonged therapeutic effect over a longer period of time following a single dose. Thus, for example, in various aspects, adjusted-release dosage forms can release a drug substance (…) after administration of the dosage form to the patient. For example The dissolution period for MAOI lasts approximately 6 to 24 hours, approximately 6 to 20 hours, approximately 6 to 16 hours, approximately 6 to 12 hours, approximately 6 to 8 hours, approximately 7 to 24 hours, approximately 8 to 24 hours, approximately 10 to 24 hours, approximately 12 to 24 hours, approximately 14 to 24 hours, approximately 16 to 24 hours, approximately 18 to 24 hours, approximately 20 to 24 hours, approximately 22 to 24 hours, approximately 8 to 22 hours, approximately 10 to 20 hours, approximately 12 to 18 hours, or approximately 14 to 16 hours. In each respect, the modulated-release formulation can release the drug substance (MAOI) after administration to the patient. For example (For beta-blockers) the dissolution period lasts approximately 6 to 16 hours, approximately 6 to 14 hours, approximately 6 to 12 hours, approximately 6 to 10 hours, approximately 6 to 8 hours, approximately 8 to 16 hours, approximately 10 to 16 hours, approximately 12 to 16 hours, approximately 14 to 16 hours, approximately 8 to 14 hours, or approximately 10 to 12 hours. In some aspects, the modulated-release formulation may contain more than one drug substance, such that each drug substance is released within a different dissolution period. In some aspects, the modulated-release formulation may contain more than one drug substance, such that each drug substance is released within approximately the same dissolution period.

[0064] In several other respects, modulated-release formulations can release drug substances after the dosage form is administered to the patient. For exampleThe absorption period for MAOI lasts approximately 6 to 24 hours, approximately 6 to 20 hours, approximately 6 to 16 hours, approximately 6 to 12 hours, approximately 6 to 8 hours, approximately 7 to 24 hours, approximately 8 to 24 hours, approximately 10 to 24 hours, approximately 12 to 24 hours, approximately 14 to 24 hours, approximately 16 to 24 hours, approximately 18 to 24 hours, approximately 20 to 24 hours, approximately 22 to 24 hours, approximately 8 to 22 hours, approximately 10 to 20 hours, approximately 12 to 18 hours, or approximately 14 to 16 hours. In each respect, modulated-release formulations can release the drug substance ( ) after administration to the patient. For example (For beta-blockers) absorption periods of approximately 6 to 16 hours, approximately 6 to 14 hours, approximately 6 to 12 hours, approximately 6 to 10 hours, approximately 6 to 8 hours, approximately 8 to 16 hours, approximately 10 to 16 hours, approximately 12 to 16 hours, approximately 14 to 16 hours, approximately 8 to 14 hours, or approximately 10 to 12 hours. In some aspects, modulated-release formulations may contain more than one drug substance, such that each drug substance is released during a different absorption period. In some aspects, modulated-release formulations may contain more than one drug substance, such that each drug substance is released during approximately the same absorption period.

[0065] As used herein, the term "sustained release" refers to a dosage in which the time and / or rate of release of a drug substance is prolonged or extended at a constant rate compared to a conventional immediate-release dosage form. For example, the time and / or rate of release of a drug substance can be extended to several hours ( For example 6 to 16 hours) or even a day For example It occurs within 6 to 24 hours.

[0066] As used herein, the terms “sustained release” and “extended release” are used interchangeably and refer to a formulation in which the time and / or rate of release of a drug substance is prolonged or extended compared to a conventional immediate-release formulation. Sustained or extended release is characterized by a slow rise in blood drug concentration followed by a slow decline, providing a sufficiently long therapeutic dose to reduce the frequency of administration compared to immediate-release formulations.

[0067] 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 is modified to allow the drug substance to be released at a specific rate, thereby maintaining a constant drug level over a specific time period.

[0068] As used herein, the term "delayed release" or "DR" refers to a dosage form in which the release time and / or rate of the drug is modified such that the drug substance is not released immediately after administration.

[0069] As used herein, the term "prodrug" refers to a modified variant of the parent drug that is typically biologically inactive at its site of action, but can be activated by one or more enzymatic, non-enzymatic, or other methods. For example or For example The process involves degradation, modification, rearrangement, dissociation, or cleavage to its parent bioactive form or a derivative thereof, wherein the derivative typically retains the bioactive components of the parent drug or its derivative. Generally, prodrugs possess pharmacokinetic properties different from their parent drugs, resulting in, for example, improved salt formation or solubility, and / or better system stability. For example (Increased plasma half-life). Discussion of prodrugs is provided in (a) Stella, VJ; Borchardt, RT; Hageman, MJ; Oliyai, R.; Maag, H. et al., Prodrugs: Challenges and Rewards, Parts 1 and 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, Prodrugs as Novel Delivery Systems (1987) 14 of the ACSSymposium Series; and (d) Bioreversible Carriers in Drug Design, (1987) ed., Edward B. Roche, American Pharmaceutical Association and Pergamon Press.

[0070] As used herein, the phrase "fixed-dose combination" refers to two or more active pharmaceutical ingredients (APIs). For example Dosage forms in which MAOIs and β-blockers are combined in a single dosage form.

[0071] As used herein, the term "dissolution period" refers to the time during which 80% of the drug is released from the dosage form to form a solution or For example The time required to reach the asymptote. (According to USP) <711> The dosage form in water was determined. For exampleDissolution curve.

[0072] As used herein, the term "absorption period" refers to the time required for a drug to be transferred from the site of application into the bloodstream. Therefore, for example, the absorption period could be when 80% of the drug has been released from the dosage form or... For example The time required to reach the asymptote.

[0073] As used herein, the terms "norepinephrine reuptake inhibitor" and "NRI" refer to the inhibition of the neurotransmitter norepinephrine by blocking the action of the norepinephrine transporter. For example Norepinephrine and epinephrine For example Norepinephrine (ARA) compounds. Examples of norepinephrine reuptake inhibitors include, but are not limited to, reboxetine, atomoxetine, viloxazine, buproprion, desipramine, maprotiline, nortriptyline, protriptyline, tapentadol, and teniloxazine.

[0074] As used herein, the term "subtherapeutic dose" refers to a dose of medication that does not achieve a specific therapeutic effect. While this is generally undesirable, medications intended for a specific purpose may be administered at subtherapeutic doses to achieve different effects. For example, a subtherapeutic dose of an NRI could refer to a dose of an NRI that is too low to treat the disease (…). For example Depression, ADHD, narcolepsy), but sufficient for another purpose ( For example (Reduce the pressure boosting effect).

[0075] As used herein, the term "half-life" refers to the time period during which the concentration of a drug in plasma decreases by 50%. For example, among MAOIs, TCP has a half-life of approximately 2.5 hours, phenelzine has a half-life of approximately 11.6 hours, and selegiline has a half-life of approximately 10 hours. Among β-blockers, esmolol has a half-life of approximately 9 minutes, bisoprolol has a half-life of 9 to 12 hours, and indolol has a half-life of approximately 3 to 4 hours.

[0076] As used herein, the term "derivative" refers to a compound that is derived from the parent compound ( For exampleCompounds having a structure (such as those disclosed herein) and whose structure is sufficiently similar to those disclosed herein, and based on such similarity, those skilled in the art would expect to exhibit the same or similar activities and utilities as the claimed compounds, or to induce the same or similar activities and utilities as the claimed compounds as precursors. Exemplary derivatives comprise salts, esters, and amides, salts of esters or amides, and N-oxides of the parent compound.

[0077] The compounds according to this disclosure can be used as prodrug-forming moieties, such as alkoxy or amino groups, to form prodrugs at hydroxyl or amino functional groups. For example, monophosphate, diphosphate, or triphosphate can be formed at the hydroxymethyl position, and these phosphates can then be used to form prodrugs again. The preparation of such prodrug derivatives is discussed in various literature resources (examples: Alexander et al., J. Med. Chem. 1988, 31, 318; Aligas-Martin et al., PCT WO 2000 / 041531, page 30). The nitrogen functional group transformed during the preparation of these derivatives is one (or more) nitrogen atoms of the compounds of this disclosure.

[0078] The compounds described herein contain atoms of both natural and non-natural abundance. The disclosed compounds may be isotopically labeled or isotopically substituted compounds, but in fact, one or more atoms are replaced by atoms having atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as... 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 35 S, 18 F and 36 Cl. The compound further comprises its prodrug, and other isotopes of the compound or the prodrug containing the aforementioned isotopes and / or other atoms, or pharmaceutically acceptable salts thereof, are also within the scope of this invention. Certain isotope-labeled compounds of this invention, such as those incorporating radioactive isotopes (such as... 3 H and 14 Those in group C) can be used for drug and / or substrate tissue distribution determination. Tritium-modified ( For example , 3 H) and carbon-14 ( For example , 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, heavier isotopes (such as deuterium) are also preferred. For example ,2 H) Substitution can provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dose requirements, and is therefore preferred in some cases. Isotope-labeled compounds of the present invention and their prodrugs can generally be prepared by performing the following steps, i.e., replacing non-isotope-labeled reagents with readily available isotope-labeled reagents.

[0079] Some of the 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, starting materials and reagents used to prepare the disclosed compounds and compositions may be obtained 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 by methods known to those skilled in the art, in accordance with references such as 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 Supplements (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 (VCHPublishers Inc., Prepared according to the procedure listed in (1989).

[0080] Unless otherwise expressly stated, it is not intended that any method set forth herein require its steps to be performed in a particular order. Therefore, no order is intended to be inferred in any way where the method claims do not actually describe the order in which the steps are followed, or where the claims or description do not otherwise specifically state that the steps are limited to a particular order. This applies to any possible non-expressive basis for interpretation, including matters concerning the logic of the arrangement of steps or the flow of operations; the general meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the description.

[0081] The components used to prepare the compositions of the present invention and the compositions themselves used in the methods disclosed herein are disclosed. These and other materials are disclosed herein, and it should be understood that while specific references to every individual and collective combination and arrangement of these materials cannot be explicitly disclosed, each is specifically considered and described herein. For example, if a particular compound is disclosed and discussed, and numerous modifications that can be made to the plurality of molecules comprising said compound are discussed, then every combination and arrangement of said compound and possible modifications are specifically considered unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C and a class of molecules D, E, and F are disclosed, and an example of the combination molecule AD is disclosed, then each combination is contemplated individually and collectively, even if not described individually; this means that combinations AE, AF, BD, BE, BF, CD, CE, and CF are considered disclosed. Similarly, any subsets or combinations of these combinations are also disclosed. Thus, for example, subgroups AE, BF, and CE would be considered disclosed. This concept applies to all aspects of this application, including but not limited to the steps in methods of making and using the compositions of the present invention. Therefore, if various additional steps are available, it should be understood that each of these additional steps may be performed in conjunction with any specific embodiment or combination of embodiments of the method of the present invention.

[0082] It should be understood that the compositions disclosed herein have certain functions. This document discloses certain structural requirements for performing the disclosed functions, and it should be understood that multiple structures exist that can perform the same function associated with the disclosed structures, and these structures will generally achieve the same result.

[0083] B. Dosage forms containing MAOIs and β-blockers In one aspect, 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 β-receptor blocker selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebivolol, sotalol, buxinolol, nadavolol, celiprolol, nebivolol, betalolol, esmolol, bisoprolol, oxenolol, penbuprofenolol, labetalol, acebutolol, and indololol, or a pharmaceutically acceptable salt or free base thereof, and a pharmaceutically acceptable carrier.

[0084] In one aspect, a dosage form is 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 β-receptor blocker selected from indolol and bisoprolol, or a pharmaceutically acceptable salt or free base thereof, and a pharmaceutically acceptable carrier, wherein the MAOI is formulated into a modulated-release dosage form, and wherein the β-receptor blocker is formulated into a modulated-release dosage form.

[0085] On one hand, a dosage form containing a therapeutically effective amount of MAOI is disclosed, with modifications including: further containing a therapeutically effective amount of a β-receptor blocker selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebivolol, sotalol, buxinolol, nadavolol, celiprolol, nebivolol, betalol, esmolol, bisoprolol, oxenolol, penbuprofenolol, labetalol, acebutolol, and indololol, or a pharmaceutically acceptable salt or free base thereof.

[0086] On one hand, a dosage form containing a therapeutically effective amount of a β-receptor blocker is disclosed, with improvements including further containing a therapeutically effective amount of MAOI in the dosage form.

[0087] Pharmaceutically acceptable salts of compounds are conventional acid or base addition salts that retain the compound's bioavailability and properties and are formed from suitable non-toxic organic or inorganic acids or bases. Exemplary acid addition salts include salts derived from inorganic acids (such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfonic acid, phosphoric acid, and nitric acid) and salts derived from organic acids (such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, etc.). Exemplary base addition salts include salts derived from ammonium, potassium, sodium, and quaternary ammonium hydroxides (such as tetramethylammonium hydroxide). Chemically modifying pharmaceutical compounds into salts is a known technique for obtaining improved physical and chemical stability, hygroscopicity, flowability, and solubility of compounds. See also For exampleH. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th ed., 1995), pp. 196 and 1456–1457.

[0088] In some respects, in order to extend the lifespan of the compounds used in this paper ( For example The effects of MAOIs or β-blockers may require slowing down the absorption of the compound ( For example This can be achieved, for example, via the preparation of a modulated-release formulation. This can be achieved via a liquid suspension of a crystalline or amorphous material with poor water solubility. The absorption rate of the compound then depends on its dissolution rate, which in turn can depend on the crystal size and crystal form. Alternatively, delayed absorption of the compound can be achieved by dissolving or suspending the compound in an oil medium. Modulated-release formulations can consist of microparticles, pellets, or granules, whether coated or uncoated in tablets, capsules, suppositories, or suspensions. Modulated-release formulations can also be prepared by forming a microcapsule matrix of the compound in a biodegradable polymer, such as polylactide-polyglycolic acid. The release rate of the compound can be controlled depending on the ratio of the compound to the polymer and the properties of the specific polymer used. Examples of other biodegradable polymers include poly(orthoester) and poly(anhydride). Alternatively, modified-release formulations can be prepared by encapsulating the compound in liposomes or microemulsions that are compatible with body tissues.

[0089] Inactive ingredients in tablets, pellets, or spheres used for matrix release include binders for solid oral dosage forms (tablets and capsules) and include pregelatinized corn starch or hydroxypropyl methylcellulose with varying degrees of substitution; fillers (e.g., lactose, microcrystalline cellulose, calcium carbonate, or calcium phosphate); disintegrants (potato starch, croscarmellose sodium, or carboxymethyl starch sodium); wetting agents (e.g., sodium dodecyl sulfate or nonionic surfactants) or other agents suitable for tableting. Additionally, ingredients may include nonionic homopolymers of ethylene oxide, water-soluble natural gums of polysaccharides, water-swellable but insoluble homopolymers and copolymers of high molecular weight acrylic acid chemically crosslinked with polyenols, polyvinyl acetate and povidone, crosslinked amyl starch and ionic methacrylate copolymers. Furthermore, fatty acids with different melting points, fatty acid esters and monoglycerides, diglycerides, triglycerides, and hydrophobic polymers, naturally occurring waxes, and quaternary ammonium methacrylate copolymers can be used in non-swelling matrices. Lipid or hydrophobic matrices can delay drug release and can be used in delayed-release technologies.

[0090] Tablets can be compressed into single-layer, double-layer, or multi-layer forms and can be coated or uncoated. Tablet coating can be used to enhance release properties. Drug release can be achieved through other methods, such as reservoir polymer systems or osmotic pump systems for tablets or capsules with laser-drilled holes. Tableting methods offer various options for compressing a core tablet within an outer tablet or a multi-layer tablet. Compression of granular or powdered drug matrices is achieved through controlled pressure and appropriate dyes for tablet formation. Microspheres, granules, or prepared spheres can be delivered into capsule shells designed for immediate or modulated release.

[0091] Coating materials used for modulating drug release from a formulated matrix (tablets, pellets, or spheres), including enteric coatings and other release targets (including naturally derived shellac and corn gluten, cellulose derivatives (cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate), and methacrylic acid (acid and ester copolymers containing carboxyl functional groups)), maintain solubility at low pH and protect delivery to other pH values ​​greater than 5.5. Plasticizers (such as glyceryl triacetate, triethanolyl citrate, glycerol, and polyethylene glycol) may or may not be required to enhance the release properties and flexibility of the coating.

[0092] Materials used in storage systems employ drug-release coatings to surround a drug core matrix (most commonly tablets) to form a controlled barrier. This barrier can be a water-insoluble coating, such as cellulose acetate. The tablet core may contain a permeabilizer, such as sodium chloride, and other hydrophilic polymers, designed to eject the drug from laser-drilled holes.

[0093] Methods for manufacturing dosage forms include the following: drug matrix preparation, which involves the close mixing of the drug and excipients to influence drug behavior during manufacturing and drug delivery in the dosage form; granulation, tableting, hot-melt and cold-melt granulation, and spheroidization. The resulting matrix (particles, mixtures, pellets, or spheres) can be an off-the-shelf dosage form with tableting or encapsulation, or further processed to achieve the desired release characteristics.

[0094] The drug matrix particles can be compressed / tableted into single-layer or multi-layer tablets. The tablet can be coated to further control drug release from the tablet core. Coating can be used for core modulation or to contain additional drug products for release in a multimodal manner. The particles or drug matrix can be further manipulated by methods such as extrusion spheroidization and spin processing to form pellets or spheres. Extrusion and granulation of drug matrices are methods used for lipid nanoparticles and microspheres.

[0095] In addition, the drug substance is sprayed onto inert or drug matrix spheres, which are then coated in a device designed for handling beads / microspheres / spheres. These drug-loaded spheres can be further coated to deliver controlled / modulated release.

[0096] In some respects, the formulation of the disclosed modulated-release dosage form enables one or more of the dissolution, release, delivery, and / or pharmacokinetic properties disclosed herein to be satisfied. Thus, for example, Cmax ( For example Peak drug concentration in blood or plasma after administration can be affected by drug dose ( For example Higher doses typically produce higher Cmax values, and the route of administration ( For example Compared to oral administration, IV bolus administration may result in a higher Cmax value, and the type of formulation ( For example Compared to controlled-release formulations, immediate-release oral formulations may result in higher Cmax. Other drug properties (such as solubility, permeability, the way the drug is absorbed into the body, metabolism, and metabolites) can also affect Cmax. This means that although some predictions can be made based on the above factors, it is difficult to predict the observed actual behavior without extensive human trials, and it may be unexpected. In some respects, the Cmax of the disclosed modulated-release formulations after a single dose is about 1 ng / mL to about 500 mg / mL, 1 ng / mL to about 400 ng / mL, about 1 ng / mL to about 300 ng / mL, about 1 ng / mL to about 100 ng / mL, about 1 ng / mL to about 50 ng / mL, about 1 ng / mL to about 25 ng / mL, about 1 ng / mL to about 10 ng / mL, about 1 ng / mL to about 5 ng / mL, about 5 ng / mL to 500 ng / mL, about 10 ng / mL to about 500 ng / mL, about 25 ng / mL to about 500 ng / mL, about 50 ng / mL to about 500 ng / mL, about 100 ng / mL to about 500 ng / mL, about 200 ng / mL to about 500 ng / mL, about 300 ng / mL to about 500 ng / mL. The concentrations are approximately 400 ng / mL to approximately 500 ng / mL, or approximately 5 ng / mL to approximately 100 ng / mL. As will be understood by those skilled in the art, Cmax can depend on the MAOI or β-blocker used. Thus, in each instance, the MAOI is phenelzine, and the Cmax of the modulated-release formulation is approximately 5 ng / mL to approximately 250 ng / mL. In each other instance, the β-blocker is indolol, and the Cmax of the modulated-release formulation is approximately 5 ng / mL to approximately 100 ng / mL.

[0097] In some respects, after administering 5 doses every 12 hours or at steady state, the disclosed modified-release formulations have Cmax values ​​of about 1 ng / mL to about 500 mg / mL, 1 ng / mL to about 400 ng / mL, about 1 ng / mL to about 300 ng / mL, about 1 ng / mL to about 100 ng / mL, about 1 ng / mL to about 50 ng / mL, about 1 ng / mL to about 25 ng / mL, about 1 ng / mL to about 10 ng / mL, about 1 ng / mL to about 5 ng / mL, about 5 ng / mL to about 500 ng / mL, about 10 ng / mL to about 500 ng / mL, about 25 ng / mL to about 500 ng / mL, about 50 ng / mL to about 500 ng / mL, about 100 ng / mL to about 500 ng / mL, about 200 ng / mL to about 500 ng / mL, and about 300 mg / mL. From about 500 ng / mL to about 400 ng / mL to about 500 ng / mL, or from about 5 ng / mL to about 100 ng / mL.

[0098] Tmax refers to the time it takes for the peak concentration of the drug to occur. In some aspects, the Tmax of the active agent in the disclosed modulated-release formulation is 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 aspects, the average Tmax of the active agent in the disclosed modulated-release formulation is 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 can depend on the MAOI or β-blocker used. Thus, in various aspects, the MAOI is phenelzine, and the average Tmax of the phenelzine in the modulated-release formulation is about 2 hours to about 6 hours. In other respects, the β-receptor blocker is indolol, and the mean Tmax of the modulated-release formulation of indolol is about 2 hours to about 6 hours.

[0099] The term AUC refers to the area under the concentration-time curve of a drug in blood or plasma. Not to be bound by theory, AUC reflects the systemic exposure of a drug after administration. Again, the magnitude of AUC is influenced by several factors—the dose administered, the ease and rate of drug absorption, the distribution of the drug in the body, and the rate of elimination of the drug from the body. All these variables make it difficult to accurately predict AUC without extensive human trials. In some respects, the AUC 0–∞ of disclosed modulated-release formulations after a single dose is approximately 10 ng·h / mL to approximately 2000 ng·h / mL, approximately 93 ng·h / mL to approximately 460 ng·h / mL, approximately 292 ng·h / mL to approximately 521 ng·h / mL, approximately 549 ng·h / mL to approximately 1543 ng·h / mL, approximately 1353 ng·h / mL to approximately 3260 ng·h / mL, or approximately 3205 ng·h / mL to approximately 5216 ng·h / mL. In some respects, after administering 5 doses every 12 hours, the average AUC 0-∞ of the disclosed modulated-release formulations is about 3205 ng·h / mL to about 5216 ng·h / mL, about 35 ng·h / mL to about 156 ng·h / mL, about 58 ng·h / mL to about 287 ng·h / mL, about 145 ng·h / mL to about 328 ng·h / mL, about 608 ng·h / mL to about 1583 ng·h / mL, about 1124 ng·h / mL to about 2557 ng·h / mL, or about 2381 ng·h / mL to about 3666 ng·h / mL. As will be understood by those skilled in the art, the AUC can depend on the MAOI or β-blocker used. Therefore, in each respect, the MAOI is phenelzine, and the AUC 0-∞ of the modulated-release formulation is from about 500 ng·h / mL to about 2,000 ng·h / mL. In each of the other respects, the β-receptor blocker is indolol, and the AUC 0-∞ of the modulated-release formulation is from about 50 ng·h / mL to about 800 ng·h / mL.

[0100] In some aspects, the disclosed modified-release dosage forms are formulated according to conventional procedures into compositions suitable for oral administration to human subjects. Compositions for oral delivery can be in various forms, including but not limited to tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs. Orally administered compositions may also contain one or more sweeteners, such as fructose, aspartame, or saccharin; flavoring agents, such as peppermint, wintergreen oil, or cherry; coloring agents; and / or preservatives to provide a pharmaceutically palatable formulation. Furthermore, when in tablet or pill form, the composition may be coated to delay breakdown and absorption in the gastrointestinal tract, thereby providing sustained action over an extended period. Selective permeable membranes surrounding the permeable active compound are also suitable for oral administration. In these late-release forms, liquid from the environment surrounding the capsule is absorbed by driving the compound to swell and displace the reagent or reagent formulation. Delaying materials, such as glyceryl monostearate or glyceryl stearate, may also be useful. Oral compositions may include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In some respects, the excipients are pharmaceutical grade.

[0101] In some respects, the modulated formulation can be administered via a modulated delivery method or a delivery device well known to those skilled in the art. Examples include, but are not limited to, those described in U.S. Patent Nos. 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 can be used to provide controlled or sustained release of the compositions disclosed herein, for example, using hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, permeation systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof, to provide the desired release characteristics in varying proportions. Therefore, in some respects, this article discloses single-unit dosage forms suitable for oral administration, such as, but not limited to, tablets, capsules, gel caps and capsules suitable for controlled or sustained release.

[0102] In one respect, this dosage form is essentially composed of an MAOI and a β-receptor blocker. In another respect, this dosage form is composed of an MAOI and a β-receptor blocker.

[0103] In one respect, this dosage form is essentially composed of phenelzine and a beta-blocker. In another respect, this dosage form is composed of phenelzine and a beta-blocker.

[0104] In all aspects, this formulation does not contain any alpha-receptor blockers selected from the following: doxazosin, silodosin, prazosin, tamsulosin, alfuzosin, terazosin, trimazosin, phenoxybenzamine, and phentolamine. In another aspect, this formulation does not contain any alpha-receptor blockers.

[0105] In all respects, this formulation does not contain carvedilol or labetalol.

[0106] In all respects, this formulation does not contain the 5HT1A agonist.

[0107] In all respects, MAOI is phenethylhydrazine ( For example Phenethylhydrazine sulfate), and the β-receptor blocker is selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebivolol, sotalol, buspirolol, nadavolol, celiprolol, nebivolol, betalolol, esmolol, bisoprolol, oxenolol, penbuprofenolol, labetalol, acebutolol, and indrolol, or pharmaceutically acceptable salts or free bases thereof. On the other hand, MAOI is phenethylhydrazine sulfate, and the β-receptor blocker is selected from indrolol and bisoprolol (… For example (Bisoprolol fumarate). In another instance, the MAOI is phenethylhydrazine sulfate, and the β-blocker is indolol. In yet another instance, the MAOI is phenethylhydrazine sulfate, and the β-blocker is bisoprolol fumarate.

[0108] In all respects, the ratio of MAOI to β-blocker can be about 1:1 to about 400:1, about 2:1 to about 400:1, about 4:1 to about 400:1, about 8:1 to about 400:1, about 10:1 to about 400:1, about 20:1 to about 400:1, about 50:1 to about 400:1, about 100:1 to about 400:1, about 200:1 to about 400:1, about 1:1 to about 200:1, about 1:1 to about 100:1, about 1:1 to about 50:1, about 1:1 to about 20:1, about 1:1 to about 10:1, about 1:1 to about 5:1, or about 1:1 to about 2:1.

[0109] As those skilled in the art will understand, the ratio of MAOI to β-blocker can depend on the MAOI and β-blocker used. Thus, in each respect, the MAOI is phenelzine and the β-blocker is indolol, and the ratio of MAOI to β-blocker can 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, about 1:1 to about 2:1. In other respects, the MAOI is phenelzine, and the β-blocker is indolol, and the ratio of MAOI to β-blocker is about 2:1 to about 24:1.

[0110] In some aspects, the MAOI and the β-receptor blocker are co-formulated. In others, the MAOI and the β-receptor blocker are not co-formulated.

[0111] 1. Monoamine oxidase inhibitors (MAOIs) In one aspect, the disclosed dosage forms comprise a therapeutically effective amount of a monoamine oxidase inhibitor (MAOI). Exemplary MAOIs include, but are not limited to, tranylcypromine (TCP). For example (transphenylcyclopropamine sulfate, transphenylcyclopropamine hydrochloride), phenethylhydrazine () For example For example Phenylacetyl sulfate), isocarboxazid, selegiline ( For example Selegiline hydrochloride, rasagiline ( For example Rasagiline mesylate and moclobemide ( For example (Moclobemide hydrochloride).

[0112] In some cases, MAOIs are formulated into modulated-release formulations. In others, MAOIs are formulated into sustained-release, extended-release, controlled-release, or delayed-release formulations. In yet another case, MAOIs are formulated into sustained-release formulations. Still another case, MAOIs are formulated into sustained-release formulations. Even further, MAOIs are formulated into extended-release formulations. In yet another case, MAOIs are formulated into controlled-release formulations. And still another case, MAOIs are formulated into delayed-release formulations.

[0113] In each aspect, the dissolution period of the modulated-release formulation for releasing MAOI is approximately 6 hours to approximately 16 hours. In other words, the dissolution period of the modulated-release formulation for releasing MAOI is approximately 6 hours to approximately 16 hours, approximately 8 hours to approximately 16 hours, approximately 10 hours to approximately 16 hours, approximately 12 hours to approximately 16 hours, approximately 14 hours to approximately 16 hours, approximately 6 hours to approximately 14 hours, approximately 6 hours to approximately 12 hours, approximately 6 hours to approximately 10 hours, approximately 6 hours to approximately 10 hours, or approximately 6 hours to approximately 8 hours.

[0114] In each aspect, the modulated-release formulation releases MAOI for an absorption period of approximately 6 hours to approximately 16 hours after administration to the patient. In another aspect, the modulated-release formulation releases MAOI for an absorption period of approximately 6 hours to approximately 16 hours, approximately 8 hours to approximately 16 hours, approximately 10 hours to approximately 16 hours, approximately 12 hours to approximately 16 hours, approximately 14 hours to approximately 16 hours, approximately 6 hours to approximately 14 hours, approximately 6 hours to approximately 12 hours, approximately 6 hours to approximately 10 hours, approximately 6 hours to approximately 10 hours, or approximately 6 hours to approximately 8 hours after administration to the patient.

[0115] In all respects, virtually all MAOIs are released approximately 6 to 16 hours, approximately 8 to 16 hours, approximately 10 to 16 hours, approximately 12 to 16 hours, approximately 14 to 16 hours, approximately 8 to 14 hours, approximately 8 to 12 hours, approximately 8 to 10 hours, approximately 10 to 16 hours, or approximately 12 to 16 hours after administration to the patient.

[0116] In various aspects, MAOI is present in amounts of about 20 mg to about 1000 mg, about 50 mg to about 1000 mg, about 100 mg to about 1000 mg, about 250 mg to about 1000 mg, about 500 mg to about 1000 mg, about 750 mg to about 1000 mg, about 20 mg to about 750 mg, about 20 mg to about 500 mg, about 20 mg to about 250 mg, about 20 mg to about 100 mg, about 20 mg to about 50 mg, about 30 mg to about 90 mg, or about 30 mg to about 120 mg. As will be understood by those skilled in the art, the amount of MAOI present can depend on the MAOI used. Thus, for example, in various aspects, MAOI is phenelzine (… For example (phenylethylhydrazine sulfate), and MAOI is present in amounts of about 30 mg to about 120 mg.

[0117] In all respects, MAOI is phenethylhydrazine sulfate, and phenethylhydrazine sulfate is present in amounts of about 20 mg to about 1000 mg, about 50 mg to about 1000 mg, about 100 mg to about 1000 mg, about 250 mg to about 1000 mg, about 500 mg to about 1000 mg, about 750 mg to about 1000 mg, about 20 mg to about 750 mg, about 20 mg to about 500 mg, about 20 mg to about 250 mg, about 20 mg to about 100 mg, about 20 mg to about 50 mg, about 30 mg to about 90 mg, or about 30 mg to about 120 mg. In some respects, phenethylhydrazine sulfate is present in amounts of about 30 mg to 120 mg.

[0118] In one aspect, MAOI is selected from isocarboxazid, phenelzine, selegiline, TCP, and moclobemide. In another aspect, MAOI is selected from isocarboxazid, phenelzine, selegiline, and TCP. In yet another aspect, MAOI is selected from phenelzine and TCP. In yet another aspect, MAOI is TCP. In yet another aspect, MAOI is isocarboxazid. In yet another aspect, MAOI is selegiline. In yet another aspect, MAOI is phenelzine. In yet another aspect, phenelzine is phenelzine sulfate.

[0119] 2. β-blockers In one respect, the disclosed dosage forms comprise a therapeutically effective amount of a beta-blocker. Exemplary beta-blockers include, but are not limited to, propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebivolol, sotalol, buxinolol, nadavolol, celiprolol, nebivolol, betalolol, esmolol, bisoprolol, oxenolol, penbuprofenolol, labetalol, acebutolol, bopindolol, and indololol, or pharmaceutically acceptable salts or free bases thereof.

[0120] In every respect, β-receptor blockers are prodrugs, allowing the prodrug to be administered intracellularly ( For example or For example The substance is converted into its corresponding β-receptor blocker. This conversion can occur through one or more mechanisms. For example Enzyme-catalyzed chemical reactions, metabolic chemical reactions, and / or spontaneous chemical reactions ( For exampleSolvent decomposition), such as hydrolysis in the blood, for example. Examples of modifying the parent drug to produce a prodrug include, but are not limited to: (1) ester or amide derivatives that are readily cleaved by esterases or lipases; (2) peptide derivatives that can be recognized by specific or non-specific proteases; and (3) derivatives that cause the prodrug to accumulate at the site of action through membrane selection; and combinations of the above techniques. Prodrugs of β-blockers 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).

[0121] In all respects, beta-blockers are indolol or its prodrugs. Exemplary indolol prodrugs include, but are not limited to, indolol. O - Acetyl ester, Indrolol O - Propionyl ester, Indrolol O -Butyryl ester, Indrolol O - Neopentyl ester, Indolol O - Benzoyl ester and indolol O - Cyclopropyl ester. In various other respects, indolol prodrugs are side-chain polymer prodrugs. See also, For example Chau et al. (1991) For example 17(10): 1279-1292.

[0122] In all respects, beta-blockers are propranolol or its prodrugs. Exemplary propranolol prodrugs include, but are not limited to, propranolol. O - Acetyl ester, propranolol O - Propionyl ester, propranolol O -Butyryl ester, propranolol O - Neopentyl ester, propranolol O - Benzoyl ester, propranolol O - Cyclopropyl ester and propranolol 2-oxazolidinone derivative. On the other hand, propranolol prodrugs are propranolol... O - Acetyl ester, propionyl ester, butyryl ester, or neopentanoyl ester. See also, For example Buur et al. (1988) For example 42(1-3): 51-60. See also D'Emanuele et al. (2004) For example 95(3): 447-53. On the other hand, propranolol prodrugs are ester prodrugs of propranolol. See also, For example Shameem et al. (1993) For example 45(4): 246-252.

[0123] In all respects, beta-blockers are metoprolol or its prodrugs. Exemplary metoprolol prodrugs include, but are not limited to, metoprolol. O - Acetyl ester, metoprolol O - Propionyl ester, metoprolol O -Butyryl ester, metoprolol O - Neopentyl ester, metoprolol O - Benzoyl ester and metoprolol O - Cyclopropyl ester. On the other hand, metoprolol prodrugs are acetyl esters, acetamides, or benzamide prodrugs. See also, For example Patel et al. (2016) For example For example 5(3): 12-20. In another respect, the prodrug of metoprolol is metoprolol acetate or metoprolol propionate. See also, For example Nair et al. (2006) For example 48: 179-193.

[0124] In all respects, the β-receptor blocker is labetalol or a prodrug thereof. Exemplary labetalol prodrugs include, but are not limited to, labetalol. O - Acetyl ester, Labetalol O - Propionyl ester, Labetalol O -Butyryl ester, Labetalol O - Neopentyl ester, Labetalol O - Benzoyl ester and Labetalol O -Cyclopropyl ester.

[0125] In all respects, β-receptor blockers are esmolol or its prodrugs. Exemplary esmolol prodrugs include, but are not limited to, esmolol. O - Acetyl ester, esmolol O - Propionyl ester, esmolol O -Butyryl ester, esmolol O - Neopentyl ester, esmolol O - Benzoyl ester and esmolol O -Cyclopropyl ester. On the other hand, esmolol prodrugs are selected from esmolol acetate, esmolol propionate, esmolol butyrate, and esmolol valerate. See also Bijaya et al. (2010). For example 17(7): 532-540.

[0126] In all respects, β-receptor blockers are acebutolol or its prodrugs. Exemplary acebutolol prodrugs include, but are not limited to, acebutolol. O - Acetyl ester, acebutol O - Propionyl ester, Acetyl olol O -Butyryl ester, Acetylolol O- Neopentyl ester, Acetylolol O - Benzoyl ester and Acetyl ester O - Cyclopropyl ester. On the other hand, the prodrug of acebutol is an O-cyclopropane carboxylic acid ester. See also, For example Hovgaard et al. (1995) For example 12(3): 387-92.

[0127] In all respects, beta-blockers are timolol or its prodrugs. Exemplary timolol prodrugs include, but are not limited to, timolol. O - Acetyl ester, timolol O - Propionyl ester, timolol O -Butyryl ester, timolol O - Neopentyl ester, timolol O - Benzoyl ester and timolol O -Cyclopropyl ester. See also, For example Chang et al. (1987) For example For example 28 (3): 487-91. In other respects, the timolol prodrug is an amphiphilic timolol prodrug. In still other respects, the timolol prodrug is selected from octanoyl timolol, decanoyl timolol, dodecanoyl timolol, myristoyl timolol, and palmitoyl timolol. See also, For example Pech et al. (1993) For example 9(2): 141-50.

[0128] In all respects, the beta-blocker is carvedilol or a prodrug thereof. Exemplary carvedilol prodrugs include, but are not limited to, carvedilol. O - Acetyl ester, carvedilol O - Propionyl ester, carvedilol O -Butyryl ester, carvedilol O - Neopentyl ester, carvedilol O - Benzoyl ester and carvedilol O -Cyclopropyl ester.

[0129] In all respects, beta-blockers are atenolol or its prodrug. Exemplary atenolol prodrugs include, but are not limited to, atenolol. O - Acetyl ester, atenolol O - Propionyl ester, atenolol O -Butyryl ester, atenolol O - Neopentyl ester, atenolol O - Benzoyl ester and atenolol O -Cyclopropyl ester. On the other hand, the atenolol prodrug is atenolol N-maleamide or atenolol N-(methyl)maleamide. See also, For exampleKaraman et al. (2014) For example For example January 12: 248651.

[0130] In all respects, β-receptor blockers are nadolol or its prodrugs. Exemplary nadolol prodrugs include, but are not limited to, nadolol. O - Acetyl ester, Nadolol O - Propionyl ester, Nadolol O -Butyryl ester, Nadolol O - Neopentyl ester, Nadolol O - Benzoyl ester and Nadolol O -Cyclopropyl ester. On the other hand, the naldolol prodrug is selected from diacetylnaldolol, naldolol dilaurate, benzoylnaldolol, and di(phenylacetyl)naldolol. See also For example U.S. Patent No. 4,029,676 and Chiang et al. (1987) For example 76th (12): 914-7.

[0131] In all respects, β-receptor blockers are oxenolol or its prodrugs. Exemplary oxenolol prodrugs include, but are not limited to, oxenolol. O - Acetyl ester, oxenolol O - Propionyl ester, oxenolol O -Butyryl ester, Oxylolol O - Neopentyl ester, Oxylolol O -benzoyl ester and oxenolol O -Cyclopropyl ester. See also, For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example Jordan (1997) J Pharm Sci. Oct 86 (10): 1085-91 and Kour et al. (2021) Asian J Pharm Sci, Mar 16th(2): 175-191.

[0132] In all respects, the beta-blocker is bisoprolol or a prodrug thereof. Exemplary bisoprolol prodrugs include, but are not limited to, bisoprolol. O - Acetyl ester, bisoprolol O - Propionyl ester, bisoprolol O -Butyryl ester, bisoprolol O - Neopentyl ester, bisoprolol O - Benzoyl ester and bisoprolol O -Cyclopropyl ester.

[0133] In all respects, the β-receptor blocker is carteolol or a prodrug thereof. Exemplary carteol prodrugs include, but are not limited to, carteolol. O - Acetyl ester, Carterol O - Propionyl ester, Carterol O-Butyryl ester, Carterol O - Neopentyl ester, Carterol O - Benzoyl ester and cartelanol O -Cyclopropyl ester.

[0134] In all respects, the β-receptor blocker is nebivolol or a prodrug thereof. Exemplary nebivolol prodrugs include, but are not limited to, nebivolol monotherapy. O - Acetyl ester, Nebirolide O - Acetyl ester, Nebirolidine O - Propionyl ester, Nebirolide O - Propionyl ester, Nebirolone O -Butyryl ester, Nebirolide O -Butyryl ester, Nebirolidine O - Neopentyl ester, Nebirolide O - Neopentyl ester, Nebirolone O - Benzoyl ester, Nebirolide O - Benzoyl ester, Nebirol mononitrate O -Cyclopropyl ester and Nebirolol O -Cyclopropyl ester.

[0135] In all respects, the beta-blocker is sotalol or a prodrug thereof. Exemplary sotalol prodrugs include, but are not limited to, sotalol. O - Acetyl ester, sotalol O - Propionyl ester, Sotalol O -Butyryl ester, Sotalol O - Neopentyl ester, Sotalol O - Benzoyl ester and sotalol O -Cyclopropyl ester.

[0136] In all respects, beta-blockers are bucinolol or its prodrugs. Exemplary bucinolol prodrugs include, but are not limited to, bucinolol. O - Acetyl ester, Buxinolol O - Propionyl ester, Buxinol O -Butyryl ester, Buxinolol O - Neopentyl ester, Buxinol O - Benzoyl ester and Biusinol O -Cyclopropyl ester.

[0137] In all respects, beta-blockers are betalol or its prodrugs. Exemplary betalol prodrugs include, but are not limited to, betalol. O - Acetyl ester, betalol O - Propionyl ester, betalol O -Butyryl ester, betalol O - Neopentyl ester, betalol O - Benzoyl ester and betalolO -Cyclopropyl ester.

[0138] In all respects, β-receptor blockers are pentbuprofen or its prodrugs. Exemplary pentbuprofen prodrugs include, but are not limited to, pentbuprofen. O - Acetyl ester, pentoxygenate O - Propionyl ester, pentoxygenate O -Butyryl ester, pentoxyl O - Neopentyl ester, pentoxygenate O - Benzoyl ester and pentoxygenate O -Cyclopropyl ester.

[0139] In some cases, beta-blockers are formulated into modulated-release formulations. In others, beta-blockers are formulated into sustained-release, extended-release, controlled-release, or delayed-release formulations. In yet another case, beta-blockers are formulated into sustained-release formulations. Still another case, beta-blockers are formulated into sustained-release formulations. In yet another case, beta-blockers are formulated into extended-release formulations. In yet another case, beta-blockers are formulated into controlled-release formulations. Still another case, beta-blockers are formulated into delayed-release formulations.

[0140] In each aspect, the dissolution period of the modulated-release formulation of the β-receptor blocker is approximately 6 hours to approximately 24 hours. In another aspect, the dissolution period of the modulated-release formulation of the β-receptor blocker is approximately 7 hours to approximately 24 hours, approximately 8 hours to approximately 24 hours, approximately 10 hours to approximately 24 hours, approximately 12 hours to approximately 24 hours, approximately 14 hours to approximately 24 hours, approximately 16 hours to approximately 24 hours, approximately 18 hours to approximately 24 hours, approximately 20 hours to approximately 24 hours, approximately 22 hours to approximately 24 hours, approximately 6 hours to approximately 22 hours, approximately 6 hours to approximately 20 hours, approximately 6 hours to approximately 18 hours, approximately 6 hours to approximately 16 hours, approximately 6 hours to approximately 14 hours, approximately 6 hours to approximately 12 hours, approximately 6 hours to approximately 10 hours, approximately 6 hours to approximately 10 hours, approximately 6 hours to approximately 8 hours, or approximately 6 hours to approximately 7 hours. In yet another aspect, the dissolution period of the modulated-release formulation of the β-receptor blocker is approximately 7 hours to approximately 24 hours.

[0141] In each aspect, the modulated-release formulation releases a beta-blocker for an absorption period of approximately 6 hours to approximately 24 hours after administration to a patient. In another aspect, the modulated-release formulation releases a beta-blocker for an absorption period of approximately 7 hours to approximately 24 hours, approximately 8 hours to approximately 24 hours, approximately 10 hours to approximately 24 hours, approximately 12 hours to approximately 24 hours, approximately 14 hours to approximately 24 hours, approximately 16 hours to approximately 24 hours, approximately 18 hours to approximately 24 hours, approximately 20 hours to approximately 24 hours, approximately 22 hours to approximately 24 hours, approximately 6 hours to approximately 22 hours, approximately 6 hours to approximately 20 hours, approximately 6 hours to approximately 18 hours, approximately 6 hours to approximately 16 hours, approximately 6 hours to approximately 14 hours, approximately 6 hours to approximately 12 hours, approximately 6 hours to approximately 10 hours, approximately 6 hours to approximately 10 hours, approximately 6 hours to approximately 8 hours, or approximately 6 hours to approximately 7 hours after administration to a patient.

[0142] In all respects, virtually all beta-blockers are released approximately 6 to 24 hours, approximately 8 to 24 hours, approximately 10 to 24 hours, approximately 12 to 24 hours, approximately 14 to 24 hours, approximately 16 to 24 hours, approximately 4 to 24 hours, approximately 8 to 24 hours, approximately 8 to 10 hours, approximately 10 to 16 hours, or approximately 12 to 16 hours after administration to the patient.

[0143] In each respect, the β-blocker is formulated as a modulated-release formulation, and the MAOI is formulated as a modulated-release formulation, and the MAOI and the β-blocker are released at different time intervals.

[0144] In each respect, the β-receptor blocker is formulated into a modulated-release formulation, and the MAOI is formulated into a modulated-release formulation, wherein the MAOI and the β-receptor blocker are released within approximately the same time period.

[0145] In various aspects, β-receptor blockers can have low half-lives, such as, for example, about 1 hour to about 6 hours, about 2 hours to about 6 hours, about 3 hours to about 6 hours, about 4 hours to about 6 hours, about 1 hour to about 5 hours, about 1 hour to about 4 hours, about 1 hour to 3 hours, 1 hour to 2 hours, about 2 hours to about 5 hours, about 2 hours to about 4 hours, about 2 hours to about 3 hours, about 3 hours to about 5 hours, or about 3 hours to about 4 hours. On the other hand, the half-life is about 3 hours to about 4 hours.

[0146] In various aspects, β-receptor blockers can have low K+ at the β-receptor. iFor example, about 1 nM to about 500 nM, about 5 nM to about 500 nM, about 10 nM to about 500 nM, about 20 nM to about 500 nM, about 30 nM to about 500 nM, about 40 nM to about 500 nM, about 50 nM to about 500 nM, about 100 nM to about 500 nM, about 200 nM to about 500 nM, about 300 nM to about 500 nM, about 400 nM to about 500 nM, about 1 nM to about 400 nM, about 1 nM to about 300 nM, about 1 nM to about 200 nM, about 1 nM to about 100 nM, about 1 nM to about 50 nM, about 1 nM to about 40 nM, about 1 nM to about 30 nM, about 1 nM to about 20 nM, about 1 nM to about 10 nM, about 1 nM to about 5 nM, about 5 nM K from approximately 10 nM, approximately 10 nM to approximately 20 nM, approximately 20 nM to approximately 30 nM, approximately 30 nM to approximately 40 nM, approximately 40 nM to approximately 50 nM, approximately 50 nM to approximately 100 nM, approximately 100 nM to approximately 200 nM, approximately 200 nM to approximately 300 nM, or approximately 300 nM to approximately 400 nM i As determined using the Hoffmann method. See Hoffman et al. (2004). Naunyn-Schmiedeberg's Arch Pharmacol 369:151-159. In various other respects, β-receptor blockers at the β-receptor K... i It can be less than 1 nM, as determined using the Hoffmann method. As understood by those skilled in the art, the Kc of existing β-receptor blockers... i It can depend on the β-receptor blocker used.

[0147] In various aspects, β-receptor blockers can have high K+ at α-receptors. i For example, K with a value of at least about 5,000, at least about 6,000 nM, at least about 7,000 nM, at least about 8,000 nM, or at least about 9,000 nM. i As determined using the Hoffman method. See Hoffman et al. (2004). Naunyn-Schmiedeberg's Arch Pharmacol 369: 151-159. As understood by those skilled in the art, the K-type of existing β-receptor blockers... i It can depend on the β-receptor blocker used.

[0148] In all respects, β-blockers exhibit β:α 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.

[0149] In various aspects, β-receptor blockers can have a large therapeutic window, such as, for example, about 12 hours to about 24 hours, about 12 hours to about 20 hours, about 12 hours to about 16 hours, about 16 hours to about 24 hours, about 20 hours to about 24 hours, or about 16 hours to about 20 hours. As those skilled in the art will understand, a large therapeutic window can be achieved, for example, by selecting a blocker with a low half-life ( For example 3 to 4 hours) and low K i This is achieved through β-receptor blockers.

[0150] In each of the embodiments, the beta-blocker is present in amounts from about 2.5 mg to about 1000 mg. In another embodiment, the beta-blocker is present in amounts from about 2.5 mg to about 800 mg, from about 2.5 mg to about 600 mg, from about 2.5 mg to about 400 mg, from about 2.5 mg to about 200 mg, from about 2.5 mg to about 100 mg, from about 2.5 mg to about 80 mg, from about 2.5 mg to about 60 mg, from about 2.5 mg to about 40 mg, from about 2.5 mg to about 30 mg, from about 5 mg to about 1000 mg, from about 10 mg to about 1000 mg, from about 20 mg to about 100 mg, from about 200 mg to about 1000 mg, from about 400 mg to about 1000 mg, from about 600 mg to about 1000 mg, from about 800 mg to about 1000 mg, from about 5 mg to about 30 mg, from about 10 mg to about 40 mg, from about 20 mg to about 50 mg, or from about 30 mg to about 90 mg.

[0151] As understood by those skilled in the art, the amount of beta-blocker present can depend on the beta-blocker used. Therefore, in one respect, the beta-blocker is indolol, and the beta-blocker is present in amounts from about 2.5 mg to about 60 mg. In yet another respect, the beta-blocker is bisoprolol (…). For example Bisoprolol fumarate), and the β-receptor blocker is present in amounts of approximately 2.5 mg to approximately 30 mg.

[0152] In all aspects, indolol is present in amounts from about 2.5 mg to about 1000 mg. In some aspects, indolol is present in amounts from about 2.5 mg to about 800 mg, from about 2.5 mg to about 600 mg, from about 2.5 mg to about 400 mg, from about 2.5 mg to about 200 mg, from about 2.5 mg to about 100 mg, from about 2.5 mg to about 80 mg, from about 2.5 mg to about 60 mg, from about 2.5 mg to about 40 mg, from about 2.5 mg to about 30 mg, from about 5 mg to about 1000 mg, from about 10 mg to about 1000 mg, from about 20 mg to about 100 mg, from about 200 mg to about 1000 mg, from about 400 mg to about 1000 mg, from about 600 mg to about 1000 mg, from about 800 mg to about 1000 mg, from about 5 mg to about 30 mg, from about 10 mg to about 40 mg, from about 20 mg to about 50 mg, or from about 30 mg to about 90 mg. In another aspect, indolol exists in amounts from about 2.5 mg to about 60 mg. Still in another aspect, indolol exists in amounts from about 2.5 mg to about 30 mg.

[0153] In all respects, bisoprolol fumarate exists in amounts ranging from about 2.5 mg to about 1000 mg. In some respects, bisoprolol fumarate is present in amounts of about 2.5 mg to about 800 mg, about 2.5 mg to about 600 mg, about 2.5 mg to about 400 mg, about 2.5 mg to about 200 mg, about 2.5 mg to about 100 mg, about 2.5 mg to about 80 mg, about 2.5 mg to about 60 mg, about 2.5 mg to about 40 mg, about 2.5 mg to about 30 mg, about 5 mg to about 1000 mg, about 10 mg to about 1000 mg, about 20 mg to about 100 mg, about 200 mg to about 1000 mg, about 400 mg to about 1000 mg, about 600 mg to about 1000 mg, about 800 mg to about 1000 mg, about 5 mg to about 30 mg, about 10 mg to about 40 mg, about 20 mg to about 50 mg, or about 30 mg to about 90 mg. In another aspect, bisoprolol fumarate is present in amounts from about 2.5 mg to about 60 mg. In yet another aspect, bisoprolol fumarate is present in amounts from about 2.5 mg to about 30 mg.

[0154] In each respect, β-blockers are selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebivolol, sotalol, buspirolol, nadavolol, celiprolol, nebivolol, betalolol, esmolol, bisoprolol, oxenolol, penbuprofenolol, labetalol, acebutolol, and indrolol, or pharmaceutically acceptable salts or free bases thereof. In another respect, β-blockers are selected from indrolol and bisoprolol, or pharmaceutically acceptable salts or free bases thereof.

[0155] In one aspect, the β-receptor blocker is selected from oxenolol, penbuprofen, labetalol, acebutolol, and indrolol, or a pharmaceutically acceptable salt or free base thereof. In another aspect, the β-receptor blocker is selected from indrolol, carteolol, penbuprofen, and acebutolol, or a pharmaceutically acceptable salt or free base thereof. In yet another aspect, the β-receptor blocker is indrolol. In yet another aspect, the β-receptor blocker is bisoprolol or a pharmaceutically acceptable salt or free base thereof. In yet another aspect, the β-receptor blocker is bisoprolol fumarate.

[0156] In every respect, β-receptor blockers are non-selective β-receptor blockers. On the other hand, β-receptor blockers are selective β-receptor blockers. For example (β-1 selective β-receptor blockers). In another aspect, β-receptor blockers are β-receptor blockers with an ISA. In yet another aspect, β-receptor blockers are dual α- and β-blockers.

[0157] In one respect, a β-receptor blocker is a dual α- and β-receptor blocker. In another respect, a dual α- and β-receptor blocker is selected from labetalol and carvedilol, or their pharmaceutically acceptable salts or free bases. In yet another respect, a dual α- and β-receptor blocker is labetalol or its pharmaceutically acceptable salts or free bases. In yet another respect, a dual α- and β-receptor blocker is carvedilol or its pharmaceutically acceptable salts or free bases.

[0158] In various aspects, β-receptor blockers can possess intrinsic sympathomimetic activity (ISA). In another aspect, β-receptor blockers with ISA are selected from indolol, carteolol, pentbuprofen, and acebutolol, or pharmaceutically acceptable salts or free bases thereof. In another aspect, β-receptor blockers with ISA are selected from acebutolol and indololol, or pharmaceutically acceptable salts or free bases thereof. In another aspect, β-receptor blockers with ISA are indololol or pharmaceutically acceptable salts or free bases thereof. In another aspect, β-receptor blockers with ISA are acebutolol or pharmaceutically acceptable salts or free bases thereof.

[0159] In every respect, β-receptor blockers are β-1 selective β-receptor blockers. In another respect, β-1 selective β-receptor blockers are selected from atenolol, betalol, bisoprolol, esmolol, acebutolol, metoprolol, and nebivolol, or pharmaceutically acceptable salts or free bases thereof.

[0160] 3. Norepinephrine reuptake inhibitors (NRIs) In each respect, the dosage form further comprises an effective amount of a norepinephrine reuptake inhibitor (NRI). Exemplary NRIs include, but are not limited to, reboxetine, atomoxetine, veloxacin, bupropion, desipramine, maprotiline, nortriptyline, protriptyline, tapentadol, and tenixazine. In another respect, the NRI is selected from bupropion, desipramine, maprotiline, nortriptyline, protriptyline, tapentadol, and tenixazine. In yet another respect, the NRI is selected from nortriptyline and protriptyline. In still another respect, the NRI is protriptyline.

[0161] In all respects, the effective dose of NRI is the therapeutic dose. In other words, the effective dose of NRI is the subtherapeutic dose.

[0162] In various aspects, NRIs are formulated into modulated-release dosage forms. Therefore, in some aspects, NRIs are formulated into sustained-release, extended-release, controlled-release, or delayed-release dosage forms. In other aspects, NRIs are formulated into sustained-release dosage forms. In yet another aspect, NRIs are formulated into sustained-release dosage forms. In yet another aspect, NRIs are formulated into extended-release dosage forms. In still another aspect, NRIs are formulated into controlled-release dosage forms. In yet another aspect, NRIs are formulated into delayed-release dosage forms.

[0163] In each aspect, the NRI is present in amounts from about 1 mg to about 1000 mg. In another aspect, the NRI is present in amounts from about 1 mg to about 800 mg, from about 1 mg to about 600 mg, from about 1 mg to about 400 mg, from about 1 mg to about 200 mg, from about 1 mg to about 100 mg, from about 1 mg to about 80 mg, from about 1 mg to about 60 mg, from about 1 mg to about 40 mg, from about 1 mg to about 30 mg, from about 5 mg to about 1000 mg, from about 10 mg to about 1000 mg, from about 20 mg to about 100 mg, from about 200 mg to about 1000 mg, from about 400 mg to about 1000 mg, from about 600 mg to about 1000 mg, from about 800 mg to about 1000 mg, from about 5 mg to about 30 mg, from about 10 mg to about 40 mg, from about 20 mg to about 50 mg, or from about 30 mg to about 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 all respects, the NRI is protriptyline, and the NRI exists in amounts from about 1 mg to about 150 mg. In the other respect, the NRI exists in amounts from about 5 mg to about 50 mg.

[0164] In each of the various aspects, protriptyline is present in amounts from about 1 mg to about 1000 mg. In another aspect, protriptyline is present in amounts from about 1 mg to about 800 mg, from about 1 mg to about 600 mg, from about 1 mg to about 400 mg, from about 1 mg to about 200 mg, from about 1 mg to about 100 mg, from about 1 mg to about 80 mg, from about 1 mg to about 60 mg, from about 1 mg to about 40 mg, from about 1 mg to about 30 mg, from about 5 mg to about 1000 mg, from about 10 mg to about 1000 mg, from about 20 mg to about 100 mg, from about 200 mg to about 1000 mg, from about 400 mg to about 1000 mg, from about 600 mg to about 1000 mg, from about 800 mg to about 1000 mg, from about 5 mg to about 30 mg, from about 10 mg to about 40 mg, from about 20 mg to about 50 mg, or from about 30 mg to about 90 mg. In yet another aspect, protriptyline is present in amounts from about 1 mg to about 150 mg. On the other hand, protriptyline is present in amounts of approximately 5 mg to approximately 50 mg.

[0165] In all aspects, the ratio of MAOI to NRI is approximately 100:1 to approximately 1:1. On the other hand, the ratio of MAOI to NRI 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 those skilled in the art will understand, the ratio of MAOI to NRI can depend on the MAOI and NRI used. Therefore, in all aspects, MAOI is phenethylhydrazine (… For example 60 mg / day to 90 mg / day), and the NRI is protriptyline ( For example (15 mg / day to 40 mg / day), and the ratio of MAOI to NRI is approximately 10:1 to approximately 1:2.

[0166] In various aspects, the ratio of β-blocker to NRI is from about 1:1 to about 100:1. On the other hand, the ratio of β-blocker to NRI is from about 2:1 to about 100:1, about 5:1 to about 100:1, about 10:1 to about 100:1, about 20:1 to about 100:1, about 50:1 to about 100:1, about 1:1 to about 50:1, about 1:1 to about 20:1, about 1:1 to about 10:1, about 1:1 to about 5:1, and about 1:1 to about 2:1. As will be understood by those skilled in the art, the ratio of β-blocker to NRI can depend on both the β-blocker and the NRI used. Therefore, in various aspects, the β-blocker is indolol (… For example 5 mg / day to 60 mg / day), and the NRI is protriptyline ( For example (15 mg / day to 40 mg / day), and the ratio of β-blocker to NRI is about 3:2 to about 1:3.

[0167] C. Methods used to treat mental disorders This invention also provides a method for treating a subject's mental disorders by means of an administration dosage form comprising a monoamine oxidase inhibitor (MAOI) and a beta-blocker selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebivolol, sotalol, buspirolol, nadavolol, celiprolol, nebivolol, betalol, esmolol, bisoprolol, oxenolol, penbuprofenolol, labetalol, acebutolol, and indrolol, or a pharmaceutically acceptable salt or free base thereof. In each respect, one or both of the MAOI and the beta-blocker are formulated into a modulated-release dosage form such that the MAOI and the beta-blocker can be released within approximately the same or different absorption periods.

[0168] Therefore, in one respect, a method for treating mental disorders in subjects is disclosed, the method comprising administering an effective amount of the disclosed dosage form to the subject.

[0169] In one aspect, a method for treating mental disorders in subjects in need is disclosed, 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, buxinolol, nadaolol, celiprolol, nebiolol, betalolol, esmololol, bisoprolol, oxenolol, penbuprofenolol, labetalol, acebutolol, and indololol, or a pharmaceutically acceptable salt or free base thereof, wherein the subject has not previously been diagnosed with migraine and wherein the subject is not currently experiencing migraine.

[0170] In one aspect, a method for treating mental disorders in subjects in need by administering an MAOI is disclosed, with improvements including: simultaneously administering a β-blocker to the patient in a measured amount together with the MAOI, the β-blocker being selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebivolol, sotalol, buxinolol, nadavolol, celiprolol, nebivolol, betalol, esmolol, bisoprolol, oxenolol, penbuprofenolol, labetalol, acebutolol, and indololol, or a pharmaceutically acceptable salt or free base thereof, the measured amount effectively reducing migraine recurrence and / or producing a more durable therapeutic effect compared to administering the MAOI in the absence of the β-blocker, wherein the MAOI and the β-blocker are present together in a single dosage form.

[0171] In one aspect, a method for treating mental disorders in subjects in need by administering an MAOI is disclosed, with improvements including: simultaneously administering a β-blocker to the patient in a measured amount along with the MAOI, the β-blocker being selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebivolol, sotalol, buxinolol, nadavolol, celiprolol, nebivolol, betalol, esmolol, bisoprolol, oxenolol, penbuprofenolol, labetalol, acebutolol, and indololol, or a pharmaceutically acceptable salt or free base thereof, the measured amount effectively reducing migraine recurrence and / or producing a more durable therapeutic effect compared to administering the MAOI in the absence of the β-blocker, wherein the subject has not previously been diagnosed with migraine and wherein the subject is not currently experiencing migraine.

[0172] In one aspect, a method for treating mental disorders in subjects in need by administering a beta-blocker is disclosed, with improvements including: administering an MAOI to the patient simultaneously with the beta-blocker in a measured amount, which effectively reduces migraine recurrence and / or produces a more durable therapeutic effect compared to administering the beta-blocker in the absence of the MAOI, wherein the MAOI and the beta-blocker are present together in a single dosage form.

[0173] In one aspect, a method for treating mental disorders in subjects in need by administering a beta-blocker is disclosed, the improvement comprising: simultaneously administering a beta-blocker to the patient in a measured amount with an MAOI, the beta-blocker being selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebivolol, sotalol, buxinolol, nadavolol, celiprolol, nebivolol, betalol, esmolol, bisoprolol, oxenolol, penbuprofenolol, labetalol, acebutolol, and indololol, or a pharmaceutically acceptable salt or free base thereof, the measured amount effectively reducing migraine recurrence and / or producing a more durable therapeutic effect compared to administering the MAOI in the absence of the beta-blocker, wherein the subject has not previously been diagnosed with migraine and wherein the subject is not currently experiencing migraine.

[0174] In one aspect, a method for treating mental disorders in subjects in need is disclosed, the method comprising administering to the subject an effective amount of a dosage form comprising: (a) a therapeutically effective amount of a monoamine oxidase inhibitor (MAOI) selected from phenelzine and transphenylcyclopropane (TCP); (b) a therapeutically effective amount of a beta-blocker selected from indolol and carvedilol, or a pharmaceutically acceptable salt or free base thereof; and (c) a pharmaceutically acceptable carrier wherein the subject has not previously been diagnosed with migraine.

[0175] To treat or control a condition, compounds and pharmaceutical compositions containing those compounds are administered to subjects in need, such as vertebrates. For example Mammals, fish, birds, reptiles, or amphibians. Subjects may be humans, non-human primates, horses, pigs, rabbits, dogs, sheep, goats, cattle, cats, guinea pigs, or rodents. The terms do not indicate a specific age or sex. Therefore, adult and neonatal subjects, as well as fetuses, whether male or female, will be included. Subjects are preferably mammals, such as humans. Subjects may be diagnosed with a mental disorder, such as depression, requiring treatment prior to administration of the compound or composition.

[0176] The modulated-release formulation can be administered to a 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, ocular administration, intraocular administration, intracerebral administration, rectal administration, sublingual administration, oral administration, and parenteral administration, including injectable methods such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. The formulation can be administered therapeutically; that is, to treat an existing disease or condition. The formulation can also be administered prophylactically; that is, to prevent infection or conditions such as mental disorders.

[0177] The therapeutically effective amount or dose of a compound can vary within a wide range of limits. Such doses are adjusted to suit the individual needs of each specific situation, including the specific compound administered, the route of administration, the condition being treated, and the patient being treated. Generally, in the case of oral or parenteral administration to an adult weighing approximately 70 kg or more, a daily dose of about 10 mg to about 10,000 mg, preferably about 200 mg to about 1,000 mg, is appropriate, but may exceed the upper limit. The daily dose can be administered as a single dose or in fractions, or as a continuous infusion for parenteral administration. A single-dose composition may contain such amounts or approximate amounts of the compound or composition to form the daily dose. In the event of any contraindications, the dose may be adjusted by an individual physician. The dose can be varied and can be administered once or multiple times daily for one or several days.

[0178] In every respect, mental disorder is depression. Examples of depression include, but are not limited to, major depressive disorder, major depressive disorder with anxiety distress, treatment-resistant depression, anxiety-related depression, and mixed anxiety and depression. In another respect, depression is selected from major depressive disorder, major depressive disorder with anxiety distress, and treatment-resistant depression. In yet another respect, depression is major depressive disorder. In yet another respect, depression is major depressive disorder with anxiety distress. In yet another respect, depression is treatment-resistant depression.

[0179] In one respect, the subject is not currently on a tyramine-restricted diet. In another respect, the subject is not on a tyramine-restricted diet after the administration step. In yet another respect, a tyramine-restricted diet excludes the consumption of meals containing 100 mg or more of tyramine. For example, a tyramine-restricted diet may exclude 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.

[0180] In all respects, this dosage form is administered at doses of approximately 100 mg to approximately 1000 mg. On the other hand, this dosage form includes 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, approximately 100 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, and approximately 600 mg to approximately 700 mg. The dosage form is administered at doses of approximately 150 mg to approximately 500 mg. Alternatively, it can be administered at doses of approximately 150 mg to approximately 500 mg.

[0181] In one respect, this dosage form is administered once daily. In the other respect, this dosage form is administered twice daily.

[0182] In one instance, MAOIs and beta-blockers are administered simultaneously. In another instance, MAOIs and beta-blockers are administered sequentially.

[0183] In all aspects, MAOIs and beta-blockers are administered in a fixed-dose combination.

[0184] In some aspects, the MAOI and the β-receptor blocker are co-formulated. In others, the MAOI and the β-receptor blocker are not co-formulated.

[0185] In every respect, MAOI is not phenethylhydrazine.

[0186] In various aspects, the method includes administering exactly two active agents to a subject, wherein the two active agents are an MAOI and a β-receptor blocker. In various other aspects, the method includes administering exactly two active agents to a subject, wherein the two active agents are phenelzine and a β-receptor blocker.

[0187] In each aspect, no alpha-receptor blocker selected from doxazosin, silodosin, prazosin, tamsulosin, alfuzosin, terazosin, tramazosin, phenoxybenzamine, and phentolamine was administered to the subject within approximately one week or less before or after the administration step. In another aspect, no alpha-receptor blocker selected from doxazosin, silodosin, prazosin, tamsulosin, alfuzosin, terazosin, tramazosin, phenoxybenzamine, and phentolamine was administered to the subject within approximately twenty-four hours or less before or after the administration step. In yet another aspect, no alpha-receptor blocker selected from doxazosin, silodosin, prazosin, tamsulosin, alfuzosin, terazosin, tramazosin, phenoxybenzamine, and phentolamine was administered to the subject concurrently.

[0188] In each instance, no alpha-receptor blocker was administered to the subject within a period of approximately one week or less before or after the administration step. In another instance, no alpha-receptor blocker was administered to the subject within a period of approximately twenty-four hours or less before or after the administration step. In yet another instance, no alpha-receptor blocker was administered to the subject concurrently.

[0189] In each respect, carvedilol and labetalol were not administered to the subjects within a period of approximately one week or less before or after the administration step. In another respect, carvedilol and labetalol were not administered to the subjects within a period of approximately twenty-four hours or less before or after the administration step. In yet another respect, carvedilol and labetalol were not administered to the subjects simultaneously.

[0190] In each respect, no 5HT1A agonist was administered to the subject within a period of approximately one week or less before or after the administration step. In another respect, no 5HT1A agonist was administered to the subject within a period of approximately twenty-four hours or less before or after the administration step. In yet another respect, no 5HT1A agonist was administered to the subject concurrently.

[0191] In various aspects, β-receptor blockers can have low K+ at the β-receptor. iFor example, about 1 nM to about 500 nM, about 5 nM to about 500 nM, about 10 nM to about 500 nM, about 20 nM to about 500 nM, about 30 nM to about 500 nM, about 40 nM to about 500 nM, about 50 nM to about 500 nM, about 100 nM to about 500 nM, about 200 nM to about 500 nM, about 300 nM to about 500 nM, about 400 nM to about 500 nM, about 1 nM to about 400 nM, about 1 nM to about 300 nM, about 1 nM to about 200 nM, about 1 nM to about 100 nM, about 1 nM to about 50 nM, about 1 nM to about 40 nM, about 1 nM to about 30 nM, about 1 nM to about 20 nM, about 1 nM to about 10 nM, about 1 nM to about 5 nM, about 5 nM K from approximately 10 nM, approximately 10 nM to approximately 20 nM, approximately 20 nM to approximately 30 nM, approximately 30 nM to approximately 40 nM, approximately 40 nM to approximately 50 nM, approximately 50 nM to approximately 100 nM, approximately 100 nM to approximately 200 nM, approximately 200 nM to approximately 300 nM, or approximately 300 nM to approximately 400 nM i As determined using the Hoffmann method. See Hoffman et al. (2004). Naunyn-Schmiedeberg's Arch Pharmacol 369:151-159. In various other respects, β-receptor blockers at the β-receptor K... i It can be less than 1 nM, as determined using the Hoffmann method. As understood by those skilled in the art, the Kc of existing β-receptor blockers... i It can depend on the β-receptor blocker used.

[0192] In various aspects, β-receptor blockers can have high K+ at α-receptors. i For example, K with a value of at least about 5,000, at least about 6,000 nM, at least about 7,000 nM, at least about 8,000 nM, or at least about 9,000 nM. i As determined using the Hoffman method. See Hoffman et al. (2004). Naunyn-Schmiedeberg's Arch Pharmacol 369: 151-159. As understood by those skilled in the art, the K-type of existing β-receptor blockers... i It can depend on the β-receptor blocker used.

[0193] In all respects, β-blockers exhibit β:α 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.

[0194] In various aspects, the method further includes using a software application to monitor one or more patient characteristics. In some aspects, the characteristic is one or more vital signs selected from a group consisting of body temperature, blood pressure, heart rate, respiratory rate, or any combination thereof. In some aspects, the characteristic is the detected blood level of a beta-blocker, and this level is used to determine whether the dosage of the MAOI, the beta-blocker, or both the MAOI and the beta-blocker should be adjusted during the treatment regimen. In some aspects, the characteristic is an indicator of patient adherence.

[0195] In all respects, this formulation consists of an MAOI and a β-receptor blocker.

[0196] In all aspects, this formulation does not contain an alpha receptor blocker. On the other hand, this formulation does not contain a 5HT1A agonist.

[0197] In one aspect, one or both of MAOIs and β-blockers are formulated into modulated-release formulations. In another aspect, MAOIs are formulated into modulated-release formulations. In yet another aspect, β-blockers are formulated into modulated-release formulations.

[0198] In one respect, MAOI is phenethylhydrazine. In another respect, MAOI is TCP.

[0199] In one respect, the beta-blocker is indolol. In another respect, the beta-blocker is carvedilol.

[0200] In all respects, subjects did not follow a tyramine-restricted diet after administration.

[0201] D. Example The invention is further defined by the following examples. It should be understood that while these examples illustrate preferred aspects of the invention, they are given by way of illustration only. From the foregoing discussion and these examples, those skilled in the art can determine the essential characteristics of the invention, and various changes and modifications can be made to adapt it to various uses and conditions without departing from its spirit and scope.

[0202] 1. Proposed Mechanism of Action This article describes MAOI-based compositions designed to make them safer for the treatment of patients with mental disorders such as depression. Not wishing to be bound by theory, the method detailed here employs a mechanism-based strategy to reduce the pressor effects of tyramine. Specifically, this method reduces the tyramine-induced pressor response by directly blocking the stimulation of β-1 adrenergic receptors by norepinephrine, thereby preventing an increase in cardiac output and minimizing changes in heart rate and blood pressure.

[0203] Phenelzine (PHZ) is a potent, non-selective MAOI used to treat adult depression (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 via MAO enzymes, which is thought to lead to the accumulation of endogenous catecholamines serotonin, norepinephrine, and dopamine, thereby prolonging their effects on their target receptors. However, it is unclear whether MAO inhibition itself or other pharmacological effects (or both) are the cause of the observed antidepressant effect (Parke Davis 2007).

[0204] Tyramine is a naturally occurring monoamine compound found in trace amounts in humans and lower animals. It is endogenous and may be found in certain foods, such as cheese or other fermented foods and beverages, usually as a result of decarboxylation caused by tyrosine fermentation or decay (Philips, SR et al., (1978) Biological psychiatry, 13(1), 51–57). Tyramine acts as an indirect sympathomimetic agent, entering neurons via reuptake transporters, primarily norepinephrine transporters, thereby displacing catecholamines (such as norepinephrine) from neuronal catecholamine storage sites (DaPrada et al. (1988) Pharmacol Res Commun. 20 Supplement 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, can result in a dangerous hypertensive crisis.

[0205] Tyramine is metabolized by several enzymes, including MAO, catechol-O-methyltransferase, aldehyde dehydrogenase, and cytochrome P450; however, MAO-A is considered the primary metabolic enzyme for tyramine. Under normal circumstances, it is estimated that less than 1% of dietary tyramine eventually enters systemic circulation (Schwenk (1989) Strat. Mgmt. J. 10 (3), pp. 303–306). However, when MAO is significantly inhibited by drugs such as MAOIs, significantly more tyramine becomes available systemically, primarily due to reduced MAO metabolism. The significant increase in systemic tyramine due to the metabolic blockade by MAOIs necessitates lower oral doses of tyramine to raise blood pressure, thereby increasing the risk of hypertensive events.

[0206] Without being bound by theory, it is believed that by adding β-receptor blockers (such as indolol (PIN)), the downstream effects of PHZ (and other MAOIs) on tyramine accumulation and the resulting cardiovascular effects can be reduced.

[0207] Beta-blockers are a class of drugs that block beta-adrenergic signaling and are used to treat cardiovascular conditions, 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 in many organ systems (especially the lungs) and mediate smooth muscle relaxation. Activation of B3 receptors is thought to induce adipocyte breakdown. Beta-blockers have varying specificities for different receptors, and the effects produced depend on the type of receptor blocked and the organ system involved (Farzam and Jan 2021).

[0208] Indolol is a non-selective beta-blocker, and its activity on B1 receptors in the heart is expected to reduce heart rate and contractility, leading to a decrease in blood pressure (Blumenfeld et al., 1999). Furthermore, indolol can inhibit the renin-angiotensin-aldosterone system, further reducing blood pressure (Blumenfeld et al., 1999). Importantly, indolol is a notable partial agonist of beta receptors and therefore possesses intrinsic sympathomimetic activity (ISA), exhibiting a smaller reduction in resting heart rate and cardiac output compared to beta-blockers lacking ISA (Novartis, 2007). The ISA of indolol may help minimize fatigue or “slowness” in patients receiving beta-blockers, which could be important for patients with major depressive disorder or major depressive disorder with anxiety distress.

[0209] 2. In vitro Interference test To assess whether the inhibition of MAO-A and MAO-B by phenelzine was affected by β-receptor blockers, an MAO inhibitory enzyme assay was performed. The method was adapted from a previously described method. See [link to previous description]. For example Urban et al. (1991) FEBS Lett. 286(1-2): 142-146 and Youdim and Finberg (1991) Biochem. Pharmacol. 41(2):155-162. It should be noted that the test concentrations correspond to the concentrations of phenethylhydrazine sulfate and bisoprolol fumarate (the salt forms of phenethylhydrazine and bisoprolol, respectively). The free base concentration of phenethylhydrazine is comparable to that of its salt form, while the free base concentration of bisoprolol is twice that of its salt form.

[0210] The measurements were conducted in detail below.

[0211] Table 1. Reference standards are run as part of each measurement to ensure the validity of the results obtained. See Table 2.

[0212] Table 2. First, the IC50 values ​​of phenylethylhydrazine with MAO-A and MAO-B were determined. 50 See Table 3. Figure 2 and Figure 3 The IC50 values ​​of phenethylhydrazine with MAO-A and MAO-B were determined from the fitted curves. 50 The values ​​were 15 nM and 18.9 nM, respectively.

[0213] Table 3. Next, the binding of the β-blockers indolol, bisoprolol, and carvedilol to MAO-A and MAO-B was evaluated at concentrations relevant to typical doses of these drugs. As shown in Table 4 below, no significant inhibitory activity was observed for MAO-A and MAO-B. A significant response in biochemical assays was defined as inhibition ≥50%.

[0214] Table 4. Then, the interference of phenelzine on the inhibition of MAO-A and MAO-B in the presence of indolol, bisoprolol, or carvedilol was evaluated using a low dose (IC50). 50 The concentrations were measured at 15 nM (with MAO-A) and 18.9 nM (with MAO-B); Tables 5 and 6, and at a high dose (150 nM; Table 7). As shown, the inhibition of MAO-A and MAO-B by phenelzine was not interfered with in the presence of a single β-blocker. In other words, the degree of inhibition of MAO-A and MAO-B by phenelzine was the same in the presence and absence of a β-blocker.

[0215] Table 5. Table 6. Table 7. 3. Inhibition of MAO-A and MAO-B by isocarboxazid To evaluate the inhibition of MAO-A and MAO-B by 10 μM isocarboxazid, MAO inhibitory enzyme assays were performed as described above and in Table 1.

[0216] Reference standards are run as part of each measurement to ensure the validity of the results obtained. See Table 8.

[0217] Table 8. The inhibition of MAO-A and MAO-B by 10 μM isocarboxazid was determined. See Table 9.

[0218] Table 9. 4. In vivo Rat Remote Sensing Study #1 To evaluate the effect of the combination of MAOI and a β-blocker on blood pressure changes after tyramine administration, a study was conducted in rats implanted with telemetry transmitters. In vivo The study involved rats that were allowed to recover for 7 days. In summary, oral administration of phenelzine alone (initial dose 50 mg / kg, then 8 mg / kg daily) (N=3) or in combination with indrolol (100 mg / kg) (N=4) was administered. Indrolol is a non-selective β-receptor blocker with ISA. The maximum systolic blood pressure change following an oral dose of tyramine (7 mg / kg) was shown between 10 and 60 minutes after MAOI and β-receptor blocker administration. Figure 4A Similar combination studies have also been completed, in which tranylcypromine (initial dose 8 mg / kg, and then 5 mg / kg daily) was administered as an MAOI in combination with indololol (1 mg / kg [N=3] or 100 mg / kg [N=3]). Figure 4B For phenelzine, if indolol and MAOI were administered sequentially, the maximum systolic blood pressure change following oral tyramine was reduced by 48%. For tranylcypromine, the maximum systolic blood pressure change following oral tyramine administration decreased in a dose-dependent manner when different indolol dose levels were administered. The time course of systolic blood pressure in rats after administration of tyramine (7 mg / kg) alone (8 mg / kg) or in combination with indolol (100 mg / kg) is shown in... Figure 5 In the study, a similar time course was observed with tranylcypromine (5 mg / kg) and two doses (1 mg / kg and 100 mg / kg) of indrolol following administration of tyramine (7 mg / kg). Figure 6 In the middle. Compared with phenelzine alone, the area under the curve (AUC) of systolic blood pressure of phenelzine and indolol was also reduced by 61%. Figure 7The maximum systolic blood pressure change and the reduction in AUC, as well as the time course, indicate that during MAOI treatment, when indorol is administered sequentially, the systolic blood pressure change induced by tyramine administration is reduced.

[0219] 5. In vivo Rat Remote Sensing Study #2 To evaluate the effect of the combination of MAOI and a β-blocker on blood pressure changes after tyramine administration, a study was conducted in rats implanted with telemetry transmitters. In vivo The study involved rats undergoing a 7-day recovery period. In brief, rats were administered tranexamic acid alone (initial dose 8 mg / kg, then 5 mg / kg daily) (N=5), tranexamic acid with indolol (60 mg / kg, N=5), or tranexamic acid with bisoprolol (20 mg / kg, N=5). Indolol is a non-selective β-receptor blocker with an ISA. Bisoprolol is a selective β-receptor blocker without an ISA. On day 8, in addition to the daily administrations described above, tyramine (3 mg / kg) was administered 30 minutes after administration of tranexamic acid and either indolol or bisoprolol, and blood pressure was monitored. Compared to tranexamic acid alone, the maximum systolic blood pressure change was reduced by 46% and 7% with tranexamic acid with indolol or bisoprolol, respectively. Figure 8 Compared to tranylcyclopropane alone, the AUC of systolic pressure for tranylcyclopropane with indolol or bisoprolol was also reduced by 49% and 23%, respectively. Figure 9 The time course of baseline systolic blood pressure after administration of tyramine (3 mg / kg) compared to that after administration of tranylcypromine and indololol (60 mg / kg) or bisoprolol (20 mg / kg) is shown in the figures. Figure 10 and Figure 11 The differences in maximum systolic blood pressure changes, AUC reductions, and time courses across groups indicate that, during MAOI treatment, sequential administration of indorol reduces the systolic blood pressure changes induced by tyramine administration. Furthermore, during MAOI treatment, sequential administration of bisoprolol reduces the systolic blood pressure changes induced by tyramine administration, but the reduction is less significant than with indorol.

[0220] 6. In vivo Rat Remote Sensing Study #3 In another study evaluating the effect of a combination of MAOI and a β-blocker on changes in blood pressure after tyramine administration, the study was conducted in rats implanted with telemetry transmitters. In vivoThe study involved rats that were allowed to recover for 7 days. After recovery, rats received phenelzine alone (8 mg / kg daily) (N=5) for 3 days, followed by phenelzine with carvedilol (50 mg / kg, N=5) for 4 days. Carvedilol is a non-selective β-receptor blocker without ISA. On day 8, in addition to the daily administration of phenelzine and carvedilol, tyramine (3 mg / kg) was administered 30 minutes after administration of phenelzine and carvedilol, and blood pressure was monitored. Compared with phenelzine alone, the maximum systolic blood pressure change was reduced by 63% with phenelzine with carvedilol. Figure 12 Compared to phenelzine alone, the AUC of systolic blood pressure was also reduced by 82% with the combination of phenelzine and carvedilol. Figure 13 The time course of baseline systolic blood pressure after administration of tyramine (3 mg / kg) compared to phenelzine and carvedilol (50 mg / kg) is shown in the figure. Figure 14 The maximum change in systolic blood pressure and the reduction in AUC, as well as the time course, indicate that during MAOI treatment, when carvedilol is administered sequentially, the change in systolic blood pressure induced by tyramine administration is reduced.

[0221] 7. Evaluate the effect of the combination of MAOI and β-blockers on transient changes in systolic blood pressure. Approximately 50% of patients may experience a significant transient increase in blood pressure (systolic or diastolic blood pressure of 20 mmHg or higher) immediately after taking MAOIs, phenelzine, or tranylcypromine, which returns to normal within 1 to 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 the combination of MAOI and β-blockers on transient changes in systolic blood pressure, this was performed in rats implanted with telemetry transmitters. In vivoThe study involved rats undergoing a 7-day recovery period. In short, rats received either tranylcypromine alone (initial dose 8 mg / kg, then 5 mg / kg daily) (N=4), tranylcypromine with indolol (60 mg / kg, N=5), or tranylcypromine with bisoprolol (20 mg / kg, N=5) for five consecutive days. Indolol is a non-selective β-receptor blocker with an ISA. Bisoprolol is a selective β-receptor blocker without an ISA. On day 5, changes in systolic blood pressure relative to baseline were assessed at +10 to +60 minutes after administration of either MAOI alone or MAOI with a β-receptor blocker. Compared to tranylcypromine alone, the tranylcypromine and indolol groups showed a 46% reduction in systolic blood pressure relative to baseline after administration, and the tranylcypromine and bisoprolol groups showed a 24% reduction. Figure 15 Not wanting to be bound by theory, these results suggest that the combination of tranexamic acid with indolol or bisoprolol reduces the transient increase in blood pressure after administration, compared to tranexamic acid alone.

[0222] 8. Predictive manufacturing solutions for dosage forms The combination of phenelzine sulfate and indolol [1-(indol-4-yloxy)-3-(isopropylamino)-2-propanol] will be formulated into a single dosage form (tablet, capsule, suppository, injection, or other delivery dose). This dosage form will deliver both compounds at the target pharmacological level, while simultaneously delivering them to maintain effective levels of phenelzine sulfate and protective levels of indolol to ensure the safety of this fixed-dose drug / drug combination.

[0223] Each active pharmaceutical ingredient (API) can be formulated together or separately. Each matrix (API and corresponding excipient) will be developed with consideration of its chemically specific drug solubility and pharmacology. API matrices will be combined into a single dosage form and delivered to the patient as a single dosage form or as two APIs administered simultaneously. Pharmaceutical-grade excipients may be incorporated into the formulation to individually achieve the desired release characteristics. Modified-release characteristics can consist of microparticles, pellets, or granules coated or uncoated in tablets, capsules, suppositories, or suspensions. As detailed elsewhere in this document, 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, extended-release, delayed-release, enteric-coated, colonic-release, pulsatile, and bimodal. Tablets can be compressed into a single layer, double layer, or multilayer and can be coated or uncoated. Tablet coating can be used for release characteristics. Drug release can be achieved by other methods, such as reservoir polymer systems or osmotic pump systems for tablets or capsules with laser-drilled perforations.

[0224] Typical binders for solid oral dosage forms (tablets and capsules) include: pregelatinized corn starch or hydroxypropyl methylcellulose with varying degrees of substitution; fillers ( For exampleLactose, microcrystalline cellulose, calcium carbonate or calcium phosphate; disintegrants (potato starch, croscarmellose sodium cellulose or carboxymethyl starch sodium); wetting agents ( For example Sodium dodecyl sulfate (or nonionic surfactant) or other reagents suitable for tableting.

[0225] Inactive ingredients for matrix-release tablets, microcapsules, or spheres include previously identified typical ingredients, as well as nonionic homopolymers of ethylene oxide, water-soluble natural gums of polysaccharides, water-swellable but insoluble homopolymers and copolymers of high molecular weight acrylic acid chemically crosslinked with polyenols, polyvinyl acetate and povidone, crosslinked amyl starch and ionic methacrylate copolymers. Furthermore, fatty acids, fatty acid esters and monoglycerides, diglycerides, triglycerides, and hydrophobic polymers with different melting points, naturally occurring waxes, and quaternary ammonium methacrylate copolymers can be used in non-swelling matrices. Lipid or hydrophobic matrices can delay drug release and are also used in delayed-release technologies.

[0226] Coating materials used for modulating drug release from a formulated matrix (tablets, pellets, or spheres), including enteric coatings and other release targets (including naturally derived shellac and corn gluten, cellulose derivatives (cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate), and methacrylic acid (acid and ester copolymers containing carboxyl functional groups)), maintain solubility at low pH and protect delivery to other pH values ​​greater than 5.5. Plasticizers (such as glyceryl triacetate, triethanolyl citrate, glycerol, and polyethylene glycol) may or may not be required to enhance the release properties and flexibility of the coating.

[0227] Materials used in storage systems surround the drug core matrix (most commonly tablets) with the previously mentioned drug release coating components to form a controlled barrier, which can be a water-insoluble coating such as cellulose acetate. The tablet core may contain a permeabilizer, such as sodium chloride or other hydrophilic polymers, to eject the drug from the laser-drilled hole as designed.

[0228] Additional exemplary manufacturing methods include the following: drug matrix preparation includes close mixing of the drug and excipients to influence drug behavior during manufacturing and drug delivery in the dosage form; granulation, tableting, hot-melt and cold-melt granulation, and spheroidization. The resulting matrix (particles, mixtures, pellets, or spheres) may be an off-the-shelf dosage form with tableting or encapsulation, or may be further processed to achieve the desired release characteristics.

[0229] The drug matrix particles can be compressed / tableted into single-layer or multi-layer tablets. The tablet can be coated to further control drug release from the tablet core. Coating can be used for core-based release modulation or to contain additional drug products for release in a multimodal manner.

[0230] Particles or drug matrices can be further manipulated by methods such as extrusion spheroidization and spin processing to form pellets or spheres. Extrusion and granulation of drug matrices are known methods for lipid nanoparticles and microspheres.

[0231] The drug is sprayed onto inert or drug matrix spheres, which are then coated in a device designed for handling beads / microspheres / spheres. These drug-loaded spheres can be further coated to deliver controlled / modulated release.

[0232] Tableting methods offer a variety of options for compressing a core tablet within an outer tablet or a multilayer tablet. Compression of granular or powdered drug matrices can be achieved through controlled pressure and appropriate dyes for tablet formation. Microspheres, granules, or prepared spheres can be delivered into capsule shells designed for immediate or modulated release.

[0233] 9. Predictive pharmacokinetic studies a. Dissolution First, through dissolution... In vitro The modified-release formulation was tested, and the dissolution results were compared with those of the immediate-release formulation. Dissolution methods are well-known to those skilled in the art. It is not desirable to be bound by theory, but it is believed that the release of phenelzine and indolol from the modified-release formulation will be significantly slower than the release of the same drug from the immediate-release drug product.

[0234] b. In vivo Rat research Single-dose pharmacokinetic studies in rats will include doses of phenelzine ranging from approximately 2 mg / kg to 20 mg / kg and doses of indrolol ranging from approximately 2 mg / kg to 8 mg / kg. Doses will be selected by converting typical human doses of phenelzine and indrolol to rat doses based on body surface area (60 kg human; 0.3 kg rat; scale factor 6.2), and potential differences in metabolism between species will be considered where understood. Doses will be administered orally via tube feeding of the adjusted-release formulations of phenelzine and indrolol. Blood samples will be collected approximately before administration, and at 0.25, 0.5, 1, 2, 4, 8, 16, and 24 hours. Plasma will be separated from the blood and frozen until analysis by LC / MS / MS to measure plasma phenelzine and indrolol concentrations compared to the immediate-release formulations. The plasma concentration data of phenelzine and indrolol will be used to calculate pharmacokinetic parameters, including Cp. max T max AUC 0-24 AUC 0-inf V / F, Cl / F, k a and k e .

[0235] c. In vivo Dog Research Single-dose pharmacokinetic studies in dogs will include doses of phenelzine ranging from approximately 1 mg / kg to 4 mg / kg and doses of indolol ranging from approximately 0.5 mg / kg to 4 mg / kg. Doses will be selected by converting typical human doses of phenelzine and indolol to rat doses based on body surface area (60 kg human; 8 kg dog; scale factor 1.8), and potential differences in metabolism between species will be considered where understood. Doses will be administered orally via capsules or tablets containing modulated-release formulations of phenelzine and indolol. Blood samples will be collected approximately before administration, and at 0.25, 0.5, 1, 2, 4, 8, 16, and 24 hours. Plasma will be separated from the blood and frozen until analysis by LC / MS / MS to measure plasma phenelzine and indolol concentrations compared to the immediate-release formulation. Plasma concentration data for phenelzine and indolol will be used to calculate pharmacokinetic parameters, including Cp. max T max AUC 0-24 AUC 0-inf V / F, Cl / F, k a and k e .

[0236] d. Predicted pharmacokinetics of modulated-release formulations Unwilling to be bound by theory, it is expected that the pharmacokinetics of the modified-release formulation will lead to the following changes in phenelzine: (1) compared with the immediate-release formulation, C max Significant decrease For example (1) reaching 60%; (2) compared with immediate-release formulations, T max Significant delay, For example It reaches 10 hours (similarly, this is also reflected in k). a (3) The AUC of the modified-release formulation is reduced or similar to that of the immediate-release formulation; and (4) the pharmacokinetics of phenelzine will support the once-daily dosing regimen of the modified-release formulation compared to the immediate-release tablet.

[0237] Unwilling to be bound by theory, it is expected that the pharmacokinetics of the modified-release formulation will lead to the following changes in indrolol: (1) compared with the immediate-release formulation, C max Significant decrease For example (1) reaching 80%; (2) compared with immediate-release formulations, T max Significant delay, For example It reaches 10 hours (similarly, this is also reflected in k). a (3) The AUC of the modified-release formulation was reduced or similar to that of the immediate-release formulation; (4) The plasma concentration-time curve showed that the lowest plasma concentration of indrolol within 24 hours was 6 ng / mL (which is consistent with the plasma concentration of indrolol K). i(5) The pharmacokinetics of indolol, compared to immediate-release tablets, would support a once-daily dosing regimen for modulated-release formulations. (6) It is associated with 85% β-receptor blockade predicted by plasma levels and may be important for blocking tyramine effects.

[0238] 10. Predictive nonclinical safety studies in beagles The non-clinical safety studies presented in this article will be conducted using beagle dogs. In these studies, test subjects will be given oral formulations once daily, including a control group receiving only the mediator, a modulated-release formulation of phenelzine and indrolol in high or low doses, or a high dose of either phenelzine or indrolol. Test subjects will be compared.

[0239] Endpoints included: mortality / cage-side observation, detailed clinical observation, body weight, food consumption, ophthalmology, electrocardiogram, respiratory assessment, clinicopathology (hematology, clinical chemistry, coagulation, urinalysis), organ weight, histopathology (complete tissue panel), and toxicokinetics of indolol and phenelzine and their major metabolites (after first administration and before the end of the study).

[0240] 11. Predictive Phase 1 Study: Combination Dosage Exploration of PK and Tyramine Stimulation A placebo-controlled, parallel-group design will be used to evaluate the potential of NW-352 (PHZ+PIN) to minimize the increase in blood pressure following oral administration of fasted tyramine (TYR). Figure 1 Once all six participants in each group have completed their treatment, an analysis will be conducted to compare the treatment efficacy between the NW-352 and phenelzine plus placebo (PHZ+PBO) treatment groups, including the measurement of TYR30 and the calculation of TSF values.

[0241] Eligibility will be assessed during the screening period. Participants who meet the inclusion criteria will begin a baseline period to determine enrollment using a pre-enrollment TYR challenge series in a Clinical Research Unit (CRU). TYR challenge will be performed once daily until TYR30 is achieved. Those who are confirmed to be eligible (TYR30 ≥ 200 mg and ≤ 700 mg) will proceed to Phase 1 (open-label pHZ and blinded PIN / PBO).

[0242] A TYR dosing advance procedure (also known as the TYR algorithm) will be applied, which is based on an approximately linear relationship between TYR and SBP changes to determine whether any single dose of TYR in sequence can be skipped during TYR activation before and during treatment.

[0243] a. Baseline TYR stimulation before treatment Pre-treatment (pre-enrollment) fasting TYR stimulation was used as the final screening procedure to determine enrollment. The order of TYR doses is provided in the “TYR Stimulation - Algorithm Description” section below. TYR stimulation will continue until TYR30 is reached or the end of the TYR dosing sequence is reached.

[0244] After baseline TYR challenge was completed and baseline TYR30 was determined, PHZ was titrated to a maintenance dose of 30 mg BID with 5 mg BID PIN or PBO. Day 1 of Phase 1 began in the afternoon at the CRU following the last TYR challenge at baseline. Participants were randomly assigned (1:1) to one of the 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 was given as an open-label treatment, while PIN and PBO capsules were blinded.

[0245] Participants will enter the CRU on day 27 of Phase 1, approximately 27 days after administration of the study drug. Phase 2 will begin the day after admission, with PK sampling performed 12 hours after morning administration of the study drug. A treatment-comparative TYR stimulation series will be conducted to compare TYR responses to treatment with NW-352 or PHZ + PBO.

[0246] b. TYR administration during treatment For Phase 2, when participants are taking NW-352 and PHZ + PBO, TYR dosing will be determined using the order described in the “TYR Activation - Algorithm Description” section below. Participants taking PHZ + PBO are expected to require a lower dose of TYR to reach TYR30 compared to pre-treatment TYR activation. TYR activation will continue until TYR30 is reached or the end of the TYR dosing sequence is reached.

[0247] During all activation periods, participants will be confined to the CRU.

[0248] In Phase 3, participants will be discharged from the hospital, complete the gradual tapering of the study drug over approximately 6 days, have a safety follow-up visit around day 7 of Phase 3, and a safety telephone call around day 18.

[0249] a. TYR activation - algorithm description Generally, TYR stimulation is administered only once per day. Except in special circumstances, all TYR stimulations begin 2 hours after administration of the study drug AM dose.

[0250] The goal of the TYR dosing sequence or algorithm is to progressively advance the TYR dose until TYR30 is reached. For each participant, TYR activation begins with the lowest TYR dose in the sequence associated with the participant's treatment group. The provided dosing procedure is designed to safely advance the TYR dose to TYR30 while minimizing the risk and burden on the participant. This procedure is based on published literature demonstrating an approximately linear relationship between TYR and changes in SBP (Cantarini et al. 2004, Schafers et al. 1999, Freychuss et al. 1970). This procedure can be used to determine whether any single dose of TYR in the sequence can be skipped.

[0251] Non-blinded pharmacists and physicians will use safety and SBP data available to each participant for each TYR challenge to manage the TYR dosing progression and blinded TYR dosing.

[0252] Dosing sequence: For pre-randomized fasting TYR challenge: TYR doses will be 100, 200, 300, 400, 500, 600, and 700 mg. For fasting TYR challenge during PHZ+PBO treatment, the TYR dose will be selected according to an algorithm: TYR doses will be 5, 10, 25, 35, 50, 75, 100, 125, 150, and 200 mg. For fasting TYR challenge during PHZ+PIN treatment, the TYR dose will be selected according to an algorithm: TYR doses will be 10, 25, 50, 100, 150, 200, 300, 400, 500, 600, and 700 mg.

[0253] Oral TYR challenge aims to induce an increase in SBP relative to the TYR dose in subjects. TYR30 is the dose of TYR required to increase SBP by ≥30 mmHg (measured three times consecutively every 5 minutes within 2 hours after fasting TYR administration) compared to the baseline mean before administration of the study drug. Pre-administration baseline SBP is defined as the average of five SBP measurements taken at 5-minute intervals over a period immediately preceding the start of each TYR challenge. All measurements will be performed in a semi-recumbent position, and subjects will remain in a semi-recumbent position throughout the pre-administration period and during TYR challenge monitoring.

[0254] TYR30 will be monitored for blood pressure (BP) at the following frequencies: Q 5 minutes for 2 hours; Q 15 minutes (for an additional 2 hours of fasting challenge). More frequent VS may be implemented if the PI deems the subject unstable at any time.

[0255] The TYR dose induced by PHZ+PBO and PHZ+PIN alone will be determined using an algorithm. Changes in TYR dose for the study drugs PHZ+PBO and PHZ+PIN are described by tyramine-sensitive factor (TSF) (TYR30 before / after treatment). Based on this algorithm, it is expected that the subject's TYR30 should be induced within approximately 3 to 5 days.

[0256] Throughout the study, blood samples will be taken to measure the pharmacokinetics (PK) levels of TYR, PIN, and PHZ to assess the concentrations of these substances at different time points.

[0257] 12. Predictive Phase II Studies: Assessment of Tyramine Boosting Response in Pivotal Tyramine Provocation Studies and in Patients Receiving Combination Therapy with MAOIs and Beta-Blockers a. Tyramine Sensitivity Factor (TSF) TYR30 is defined as the minimum tyramine dose that produces an increase in systolic blood pressure (SBP) of at least 30 mmHg at three consecutive measurement time points within 2 hours of tyramine administration. TYR30 is determined through clinical trials in which subjects are given gradually increasing doses of oral tyramine while fasting, and blood pressure is measured periodically, typically every 5 minutes for 2 hours after tyramine administration. A baseline SBP is established before tyramine administration. As the tyramine dose is absorbed, SBP typically increases, the amount of which depends on the tyramine dose and varies from individual subject to individual. The SBP peak usually occurs 30 to 60 minutes after tyramine administration, up to a maximum of 2 hours. Experiments begin with a low dose of tyramine to ensure subject safety and are iteratively increased according to a predetermined dose sequence. TYR30 is determined to be the minimum TYR dose that produces an increase in SBP of greater than or equal to 30 mmHg from baseline at three consecutive measurement points.

[0258] The TSF aims to determine the enhancing effect of a test drug (e.g., MAOI) on tyramine. It requires two TYR30 measurements: (1) pre-treatment TYR30, which is the TYR30 that tyramine can achieve without the test drug; and (2) post-treatment TYR, which is the TYR30 that tyramine can achieve after the test drug is administered at a therapeutic dose, and for a sufficient period of time for the test drug to reach steady state.

[0259] TSF is calculated as the ratio of pre-treatment TYR30 to post-treatment TYR30. A ratio greater than 1 indicates that, when taking the drug, a lower dose of tyramine can increase SBP by 30 mmHg compared to not taking the drug. It can also be interpreted as the level of enhancement of the tyramine pressor response. Most drugs that interact with tyramine and are approved without dietary restrictions have TSFs in the range of 1.5 to 3.5. In contrast, phenelzine has a TSF of 13.3 at 45 mg / day, and tranylcypromine has a TSF of 55 at 20 mg / day (Bieck and Antonin (1989) J Neural Transm. Supplement 28, pp. 21–31). To achieve the TSF range of approved drugs without dietary restrictions, tyramine needs to be significantly reduced (5 to 15-fold). Achieving these types of levels depends on the selected β-blocker and its dose. Adverse reactions associated with higher doses must be noted. It is also necessary to consider the tyramine attenuation at the trough of β-blocker concentration, where β-blocker blockade is lowest and tyramine attenuation is weakest.

[0260] A model was developed to correlate a given dose of a β-blocker with estimated TSF for several key MAOIs and β-blockers. It involves the following steps: (1) establishing a table of estimated free plasma concentrations for each β-blocker over 1 to 24 hours following a single dose. (2) estimating β-blocker dose-related β-blocker blockade at two time points: 2 hours and 6 hours after administration of the β-blocker. (3) using a competitive binding model, estimating the percentage of β-receptors binding to norepinephrine when a tyramine dose is administered with placebo, which increases SBP by approximately 60 mmHg. Integrating steps 1 through 3, the model is used to estimate the SBP increase when a given dose of a β-blocker is administered. (4) calculating the estimated TSF of the MAOI when administered with the β-blocker dose from step 3.

[0261] Table 10 shows the estimated reduced SBP boosting response when the dose of tyramine producing a 60 mmHg SBP boosting response was administered with placebo, compared to the same dose of tyramine administered with a beta-blocker. The reduction is expressed as the ratio of the SBP boosting response with a beta-blocker to the SBP boosting response without a beta-blocker.

[0262] Table 10. Table 11 shows the range of TSF estimated for MAOIs without β-blockers based on historical reports, along with a sensitivity analysis of the model above. The decrease in MAOI TSF calculated 6 hours after the morning β-blocker dose is shown. The range represents the TSF value for each MAOI reported in the literature.

[0263] Table 11. b. Tyramine stimulation studies This study included a small group of volunteers with major depressive disorder accompanied by anxiety distress. Participants were given a placebo, a publicly available phenelzine, and either indolol or a modulated-release formulation of phenelzine.

[0264] The TSF for each group will be estimated as a first step by dividing the baseline (pre-treatment) Tyr30 dose by the Tyr30 dose during treatment (post-treatment) for each subject individually. The TSF values ​​will be summed by treatment.

[0265] As a comparison of study efficacy, the TSF of phenelzine alone will be compared with the TSF of the placebo group. Parallel comparisons will be performed on log-transformed TSF using an ANOVA / ANCOVA model to estimate the GMR and 90% confidence interval (CI). To demonstrate sufficient sensitivity of the study, the lower limit of the 90% CI for TSF must be greater than 125% for the GMR to demonstrate a higher range (advantage) in TSF compared to placebo.

[0266] The primary comparison using the same methodology is between modulated-release formulations and placebo. The evaluation will include comparing the upper limit of the GMR 90% CI of the TSF of approved, label-free drugs with the modulated-release formulation in a fasted tyramine challenge to determine its clinical significance.

[0267] Within one week following tyramine stimulation as measured by TSF, subjects will be tested for their responses to tyramine-rich diets under three different standard dietary patterns: (1) a light diet primarily composed of carbohydrates, (2) a normal diet rich in lipids, and (3) a normal diet rich in protein. The evaluation of this data will focus on systolic blood pressure ≤ 30 mmHg during the tyramine stimulation period (during treatment).

[0268] 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 become apparent to those skilled in the art based on the description disclosed herein and practical considerations. This description and examples are intended to be illustrative only, wherein the true scope and spirit are indicated by the appended claims.

Claims

1. A method for treating a mental disorder in a subject in need, the method comprising administering to the subject an effective amount of a dosage form comprising: (a) A therapeutically effective amount of a monoamine oxidase inhibitor (MAOI) selected from phenelzine and transphenylcyclopropane (TCP); (b) A therapeutically effective amount of a β-blocker selected from indolol and carvedilol, or a pharmaceutically acceptable salt or free base thereof; and (c) Pharmaceutically acceptable carriers, The subjects in question had not previously been diagnosed with migraines.

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

3. The method according to claim 1 or claim 2, wherein the dosage form does not contain an α-receptor 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 β-receptor blocker are formulated into a modulated-release dosage form.

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

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 β-receptor blocker is indolol.

9. The method according to any one of claims 1 to 7, wherein the β-receptor 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. A dosage form comprising: (a) A therapeutically effective dose of a monoamine oxidase inhibitor (MAOI); and (b) A therapeutically effective amount of a β-blocker selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebivolol, sotalol, buspirolol, nadavolol, celiprolol, nebivolol, betalolol, esmolol, bisoprolol, oxenolol, penbuprofenolol, labetalolol, acebutolol, and indrolol, or a pharmaceutically acceptable salt or free base thereof, and Pharmaceutically acceptable carrier.

12. The dosage form according to claim 11, wherein the dosage form is substantially composed of the MAOI and the β-receptor blocker.

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

14. The dosage form according to claim 11, wherein the dosage form is free from an α-receptor blocker selected from: doxazosin, silodosin, prazosin, tamsulosin, alfuzosin, terazosin, tramazosin, phenoxybenzamine, and phentolamine.

15. The dosage form according to claim 11, wherein the dosage form does not contain an α-receptor 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 modulated-release dosage form.

19. The dosage form of claim 18, wherein the release formulation releases the MAOI for a dissolution period of about 6 hours to about 16 hours.

20. The dosage form of claim 18, wherein the modulated-release dosage form releases the MAOI for an absorption period of about 6 hours to about 16 hours after administration to the patient.

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

22. The dosage form of claim 21, wherein the release formulation releases the β-receptor blocker over a dissolution period of about 6 hours to about 24 hours.

23. The dosage form of claim 21, wherein the modulated-release dosage form releases the β-receptor blocker for an absorption period of about 6 hours to about 24 hours after administration to the patient.

24. The dosage form of claim 21, wherein the modulated-release dosage form releases the β-receptor blocker for an absorption period of about 7 hours to about 24 hours after administration to the patient.

25. The dosage form of claim 21, wherein the MAOI is formulated as a modulated-release dosage form, and wherein the MAOI and the β-receptor blocker are released at different time intervals.

26. The dosage form of claim 21, wherein the MAOI is formulated as a modulated-release dosage form, and wherein the MAOI and the β-receptor blocker are released within approximately the same time period.

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 isocarboxazid, phenelzine, selegiline, transphenylcyclopropionamide (TCP), and moclobemide.

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

31. The dosage form according to any one of claims 11 to 20, wherein the β-receptor 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 β-receptor 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 β-receptor 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 β-receptor blocker is selected from oxenolol, pentbuprofen, labetalol, acebutolol, and indololol, or a pharmaceutically acceptable salt or free base thereof.

35. The dosage form according to any one of claims 11 to 33, wherein the β-receptor blocker is selected from indolol, carteolol, pentbuprofen, and acebutolol.

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

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

38. The dosage form according to any one of claims 11 to 37, wherein the β-receptor blocker exhibits a β:α 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 β-receptor 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 β-receptor 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 β-receptor 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 a subtherapeutic amount.

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

45. The dosage form of claim 44, wherein the release formulation releases the NRI for a period of about 6 hours to about 24 hours.

46. ​​The dosage form of claim 44, wherein the modulated-release dosage form releases the NRI for an absorption period of about 6 hours to about 24 hours after administration to the 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 β-receptor blocker to the NRI is about 3:2 to about 1:

3.

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

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

53. The method of claim 52, wherein the depression is selected from major depressive disorder, major depressive disorder with anxiety distress, treatment-resistant depression, anxiety depression, and mixed 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 of claim 54 or claim 55, wherein the tyramine-restricted diet excludes the consumption of a diet 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 at a dose of about 100 mg to about 1000 mg.

58. The method of claim 57, wherein the dosage form is administered once daily.

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

60. The method of claim 59, wherein the dosage form is administered once daily.

61. A dosage form comprising: (a) A therapeutically effective amount of phenelzine or its pharmaceutically acceptable salt or free base; and (b) A therapeutically effective amount of a β-blocker selected from indolol and bisoprolol, or their pharmaceutically acceptable salts or free bases, and Pharmaceutically acceptable carriers The MAOI is formulated as a modulated release dosage form, and The β-receptor blocker is formulated as a modulated release formulation.

62. The dosage form according to claim 561, wherein the dosage form is substantially composed of phenelzine and the β-receptor blocker.

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

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

65. The dosage form according to any one of claims 61 to 64, wherein the dosage form does not contain an α-receptor 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 phenethylhydrazine is phenethylhydrazine 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 a norepinephrine reuptake inhibitor (NRI).

71. The dosage form of claim 70, wherein the NRI is formulated as a modulated-release dosage form.

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

73. A method for treating a mental disorder in a subject in need, the method comprising administering to the subject: (a) A therapeutically effective dose of MAOI; and (b) A therapeutically effective amount of a β-receptor blocker selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebivolol, sotalol, buspirolol, nadavolol, celiprolol, nebivolol, betalolol, esmolol, bisoprolol, oxenolol, penbuprofenolol, labetalol, acebutolol, and indrolol, or a pharmaceutically acceptable salt or free base thereof. The subjects in question had not previously been diagnosed with migraines, and The subjects in question are not currently experiencing migraines.

74. The method of claim 73, wherein the method comprises administering exactly two active agents to the subject, wherein the two active agents are the MAOI and the β-receptor blocker.

75. The method of claim 73 or claim 74, wherein, for a period of about one week or less before or after the administration step, the subject was not given an alpha-receptor blocker selected from doxazosin, silodosin, prazosin, tamsulosin, alfuzosin, terazosin, tramazosin, phenoxybenzamine, and phentolamine.

76. The method according to any one of claims 73 to 75, wherein an α-receptor blocker selected from doxazosin, silodosin, prazosin, tamsulosin, alfuzosin, terazosin, tramazosin, phenoxybenzamine, and phentolamine was not administered to the subject for a period of about twenty-four hours or less before or after the administration step.

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

78. The method according to any one of claims 73 to 77, wherein the α-receptor blocker was not administered to the subject for a period of about one week or less before or after the administration step.

79. The method according to any one of claims 73 to 78, wherein the α-receptor blocker was not administered to the subject for a period of about twenty-four hours or less before or after the administration step.

80. The method according to any one of claims 73 to 79, wherein the α-receptor blocker is not administered to the subject simultaneously.

81. The method according to any one of claims 73 to 80, wherein carvedilol and labetalol were not administered to the subject for a period of about one week or less before or after the administration step.

82. The method according to any one of claims 73 to 81, wherein carvedilol and labetalol were not administered to the subject for a period of about twenty-four hours or less before or after the administration step.

83. The method according to any one of claims 73 to 82, wherein carvedilol and labetalol are not administered to the subject simultaneously.

84. The method according to any one of claims 73 to 83, wherein the 5HT1A agonist was not administered to the subject for a period of about 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 was not administered to the subject for a period of about twenty-four 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 to the subject simultaneously.

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

88. The method of claim 87, wherein the MAOI and the β-receptor blocker are administered in a fixed dose combination.

89. The method of claim 87, wherein the MAOI and the β-receptor blocker are co-formulated.

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

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

1.

92. In dosage forms containing a therapeutically effective amount of MAOI, improvements include: The dosage form further comprises a therapeutically effective amount of a β-receptor blocker selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebivolol, sotalol, buxinolol, nadavolol, selipoprolol, nebivolol, betalolol, esmolol, bisoprolol, oxenolol, penbuprofenolol, labetalolol, acebutolol, and indololol, or a pharmaceutically acceptable salt or free base thereof.

93. In dosage forms containing a therapeutically effective amount of a β-blocker, improvements include: The dosage form further comprises a therapeutically effective amount of MAOI.

94. Improvements to methods for treating mental disorders in subjects in need by administering MAOIs include: A certain amount of a beta-blocker, selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebivolol, sotalol, bucenovol, nadavolol, celiprolol, nebivolol, betalol, esmolol, bisoprolol, oxenolol, penbuprofenolol, labetalol, acebutolol, and indrolol, or a pharmaceutically acceptable salt or free base thereof, is administered to the patient concurrently with the MAOI in the absence of the beta-blocker. This dosage effectively reduces migraine recurrence and / or produces a more durable therapeutic effect compared to administering 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. Improvements to the method of treating mental disorders in subjects in need by administering MAOIs include: In a method for treating a mental disorder in a subject in need by administering an MAOI, an improvement includes: simultaneously administering to the patient an amount of a beta-blocker selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebivolol, sotalol, bucenovol, nadavolol, celiprolol, nebivolol, betalol, esmolol, bisoprolol, oxenolol, penbuprofenolol, labetalol, acebutolol, and indrolol, or a pharmaceutically acceptable salt or free base thereof, which, compared to administering the MAOI in the absence of the beta-blocker, effectively reduces migraine recurrence and / or produces a more durable therapeutic effect, wherein the subject has not previously been diagnosed with migraine and wherein the subject is not currently experiencing migraine.

96. In methods for treating mental disorders in subjects in need by administering beta-blockers, improvements include: Administering an MAOI to a patient simultaneously with the β-blocker in a controlled amount, compared to administering the β-blocker in the absence of the MAOI, effectively reduces migraine recurrence and / or produces a more durable therapeutic effect, wherein the MAOI and the β-blocker are present together in a single dosage form.

97. In methods for treating mental disorders in subjects in need by administering beta-blockers, improvements include: A beta-blocker selected from propranolol, metoprolol, carvedilol, timolol, carteolol, atenolol, nebivolol, sotalol, buspirolol, nadavolol, celiprolol, nebivolol, betalolol, esmolol, bisoprolol, oxenolol, penbuprofenolol, labetalol, acebutolol, and indrolol, or a pharmaceutically acceptable salt or free base thereof, was administered to the patient concurrently with an MAOI in the absence of the beta-blocker. This dosage effectively reduced migraine recurrence and / or produced a more durable therapeutic effect compared to administering the MAOI in the absence of the beta-blocker, wherein the subject had not previously been diagnosed with migraine and wherein the subject was not currently experiencing migraine.

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