Preparations and methods for treating neuropsychiatric disorders

Abstract

This disclosure includes formulations and methods for treating cerebrovascular and / or behavioral health disorders and their associated symptoms. In particular, this disclosure includes formulations designed to optimize the release of the compositions disclosed herein under a wide range of post-administration biological conditions.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 472,213, filed on June 9, 2023, which is hereby incorporated by reference in its entirety.

Background Art

[0002] Background of the Invention Brain and behavioral health disorders are the leading cause of physical disabilities worldwide. Brain and behavioral health disorders include all of the major disorders belonging to the specialties of neurology, psychiatry, and psychology. Anxiety, emotional blunting, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, pain (e.g., physical pain), and psychosis are the ten main symptoms caused by brain and behavioral health disorders. Each of these symptoms is a physical disability characteristic of these disorders and causes functional deficits.

[0003] Most, if not all, of the ten main symptoms of brain and behavioral health disorders are affected by more than one cause in people with brain and behavioral disorders, making treatment difficult. In actual clinical practice, the causes of symptoms may be due to neurological, psychiatric, and / or psychological factors. However, patients seek separate treatments for their symptoms. Anxiety, depression, and psychosis are typically treated by psychiatrists. Headache, pain, and cognitive difficulties are often treated by neurologists. Irritability, emotional blunting, insomnia, and fatigue are often treated by psychologists or primary care physicians. Anxiety is an example of a disabling, difficult - to - treat, and multifactorial symptom. Physical anxiety (hypersensitivity to stimuli) is an example of a neurological cause of anxiety and is often associated with migraine. Extreme shyness is an example of a psychological cause of anxiety and is often associated with social phobia. Extreme worry is an example of a psychiatric cause of anxiety and is often associated with generalized anxiety disorder.

[0004] Despite the fact that the ten primary physical symptoms of brain and behavioral health disorders (i.e., anxiety, emotional blunting, cognitive difficulties, depression, fatigue, headaches, insomnia, irritability, pain (e.g., physical pain), and psychiatric disorders) are multifactorial in actual clinical practice, current FDA-approved treatments typically target only one component of the disorder at a time. For example, selective serotonin reuptake inhibitors ("SSRIs"), the first-line treatment for anxiety disorders, are specifically designed to target the serotonergic mechanisms of anxiety. The effectiveness of these drug therapies themselves has been proven to be limited. Cognitive behavioral therapy is specifically designed to address the psychological components of anxiety. Patients receiving both drug therapy and cognitive behavioral therapy are expected to have better outcomes than those receiving only one of the targeted treatments. Even with the use of cognitive behavioral therapy and drug therapy, treatment success remains limited, suggesting that the neurological basis of anxiety remains untreated in the majority of patients seeking anxiety reduction.

[0005] Currently, there are no treatments designed to address the multifactorial characteristics associated with most of the physical symptoms of brain and behavioral health disorders. Therefore, there is an urgent need for new treatments to address brain and behavioral health disorders and their symptoms. [Overview of the Initiative]

[0006] As described below, the present invention features formulations comprising calcium channel blockers (e.g., anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil) and angiotensin II receptor blockers (e.g., candesartan or telmisartan), as well as methods of using such formulations in the treatment of brain and behavioral health disorders.

[0007] In one aspect, the present disclosure provides a formulation comprising a therapeutic combination comprising a first composition comprising an effective amount of a first agent having calcium channel blocking activity and a second composition comprising an effective amount of a second agent having angiotensin II receptor blocking activity. The first composition is formulated to release the first agent sustainably upon administration to a subject, and the second composition is formulated to release the second agent immediately upon administration to a subject.

[0008] In another aspect, the disclosure provides a formulation comprising a therapeutic combination comprising a first composition comprising an effective amount of a first agent having calcium channel blocking activity and a second composition comprising an effective amount of a second agent having angiotensin II receptor blocking activity. The second composition is formulated such that, when administered to a subject, the second agent has a faster release rate compared to the release rate of the first agent of the first composition.

[0009] In another aspect, the disclosure provides a formulation comprising a therapeutic combination comprising a first composition comprising an effective amount of a first agent having calcium channel blocking activity and a second composition comprising an effective amount of a second agent having angiotensin II receptor blocking activity. The second composition is formulated to immediately release and dissolve the second agent when in contact with a solution having a pH between 1 and 5.

[0010] In another aspect, the Disclosure provides a formulation comprising a therapeutic combination comprising a first composition comprising an effective amount of a first agent having calcium channel blocking activity and a second composition comprising an effective amount of a second agent having angiotensin II receptor blocking activity. The second composition is formulated to immediately release and dissolve the second agent in a subject under gastric or intestinal conditions upon administration to the subject.

[0011] In another aspect, the disclosure provides a tablet comprising a therapeutic combination comprising a first composition comprising an effective amount of a first agent having calcium channel blocking activity and a second composition comprising an effective amount of a second agent having angiotensin II receptor blocking activity. The second composition is formulated such that when the tablet is administered to a subject, the second agent is released before the first composition releases the first agent.

[0012] In another aspect, the present disclosure provides a compressed tablet comprising a formulation in any of the above aspects or embodiments thereof.

[0013] In another aspect, the present disclosure provides a nucleated tablet comprising a formulation in any of the above aspects or embodiments thereof.

[0014] In another aspect, the present disclosure provides a capsule formulation comprising any of the above aspects or embodiments thereof.

[0015] In another aspect, the present disclosure provides pharmaceutical compositions comprising formulations and pharmaceutically acceptable excipients in any of the above aspects or embodiments thereof.

[0016] In another aspect, the present disclosure provides a push-pull osmotic pump tablet comprising a formulation in any of the above aspects or embodiments thereof. The osmotic pump tablet further comprises a first layer comprising a first composition, a second layer comprising a second composition, and a semipermeable coating. The first layer further comprises a polymeric osmogene. The osmotic pump tablet is configured such that, upon contact with an aqueous solution, the second agent is released by burst release and the first agent is released by leaching through the semipermeable coating.

[0017] In another aspect, the present disclosure provides a method for treating a subject having a brain or behavioral health disorder. The method includes administering to a subject a formulation of any of the above aspects, a tablet of any of the above aspects, a compressed tablet of any of the above aspects, a core tablet of any of the above aspects, a capsule of any of the above aspects, a pharmaceutical composition of any of the above aspects, or a push-pull osmotic pump tablet of any of the above aspects, thereby treating the brain or behavioral health disorder.

[0018] In another aspect, the present disclosure provides a method for treating anxiety disorders. The method includes administering a formulation of any of the above aspects or embodiments thereof, a tablet of any of the above aspects or embodiments thereof, a compressed tablet of any of the above aspects or embodiments thereof, a core tablet of any of the above aspects or embodiments thereof, a capsule of any of the above aspects or embodiments thereof, a pharmaceutical composition of any of the above aspects or embodiments thereof, or a push-pull osmotic pump tablet of any of the above aspects or embodiments thereof to a subject, thereby treating an anxiety disorder.

[0019] In another aspect, the present disclosure provides a method for increasing progress in an object in accordance with Maslow's hierarchy of needs. The method comprises administering to an object a formulation, a tablet, a compressed tablet, a core tablet, a capsule, a pharmaceutical composition, or a push-pull osmotic pump tablet of any of the above aspects or embodiments, thereby increasing progress in an object in accordance with Maslow's hierarchy of needs. The first agent modifies metabolism and / or blood flow associated with the adrenergic system, and the second agent modifies metabolism and / or blood flow associated with the cerebral renin-angiotensin-aldosterone system. The increase in progress is relative to the reference.

[0020] In another aspect, the Disclosure provides formulations in any of the above aspects or embodiments thereof, tablets in any of the above aspects or embodiments thereof, compressed tablets in any of the above aspects or embodiments thereof, core tablets in any of the above aspects or embodiments thereof, capsules in any of the above aspects or embodiments thereof, pharmaceutical compositions in any of the above aspects or embodiments thereof, or push-pull osmotic pump tablets in any of the above aspects or embodiments thereof, as well as a kit including instructions for using the formulations, tablets, compressed tablets, core tablets, capsules, pharmaceutical compositions, or push-pull osmotic pump tablets to treat brain and / or behavioral health disorders or symptoms thereof.

[0021] In the above situations or any of their embodiments, the first agent is anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, or verapamil.

[0022] In any of the above situations or embodiments thereof, the second agent is telmisartan or candesartan.

[0023] In any of the above situations or aspects thereof, the combination is labeled for the treatment of brain and / or behavioral health disorders.

[0024] In any of the above situations or aspects thereof, the combination is labeled for the treatment of symptoms of brain and / or behavioral health disorders. The symptoms of brain and / or behavioral health disorders are anxiety, emotional blunting, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, pain or mental abnormalities.

[0025] In any of the above situations or aspects thereof, the first agent is verapamil.

[0026] In any of the above situations or aspects thereof, the second agent is telmisartan.

[0027] In any of the above situations or aspects thereof, the second composition is formulated such that more than 80% of the second agent is released within 1 hour from administration to the subject.

[0028] In any of the above situations or aspects thereof, the second composition is formulated such that more than 95% of the second agent is released within 2 hours from administration to the subject.

[0029] In any of the above situations or aspects thereof, the second composition is formulated such that more than 85% of the second agent is released within 1.5 hours from administration to the subject.

[0030] In any of the above situations or aspects thereof, the first composition is formulated to release the first agent over a 24-hour period.

[0031] In any of the above situations or aspects thereof, the effective amount of the first agent is from about 10 mg to about 720 mg, and the effective amount of the second agent is from about 2 mg to about 240 mg.

[0032] In the situations described above or any of those aspects, the effective dose of the first agent is approximately 60 mg to 360 mg, and the effective dose of the second agent is approximately 20 mg to 180 mg.

[0033] In the situations described above or any of those aspects, the effective dose of the first agent is approximately 10 mg to 120 mg, and the effective dose of the second agent is approximately 1 mg to 40 mg.

[0034] In the situations described above or in any of those embodiments, the effective dose of the first agent is approximately 15 mg and the effective dose of the second agent is approximately 2.5 mg, or the effective dose of the first agent is approximately 30 mg and the effective dose of the second agent is approximately 5 mg.

[0035] In the situations described above or any of those aspects, the effective dose of the first agent is approximately 288 mg, and the effective dose of the second agent is approximately 96 mg.

[0036] In the above situations or any of their embodiments, the mass ratio of the first agent to the second agent is approximately 2:1 to approximately 5:1.

[0037] In the above-described situations or any of their embodiments, the mass ratio of the first agent to the second agent is approximately 2:1.

[0038] In the situations described above or any of their manifestations, the amount of the first agent is approximately 1 to 4 times the amount of the second agent.

[0039] In any of the above situations or embodiments thereof, the amount of the first agent is approximately twice the amount of the second agent.

[0040] In any of the above aspects or embodiments thereof, the formulation or tablet further comprises magnesium oxide.

[0041] In any of the above situations or embodiments thereof, the formulation or tablet further comprises at least about 150 mg of magnesium oxide.

[0042] In the above aspects or any of the embodiments thereof, the second composition further comprises sodium hydroxide.

[0043] In the situations described above or any of their embodiments, sodium hydroxide is present in an amount necessary to dissolve the second agent when administered to the subject.

[0044] In any of the above aspects or embodiments thereof, the first composition further comprises a hydrophilic matrix.

[0045] In the above aspects or any of their embodiments, the hydrophilic matrix comprises hydroxypropyl methylcellulose.

[0046] In the above aspects or any of the embodiments thereof, the second composition is formulated to form a coating around the first composition.

[0047] In the above aspects or any of their embodiments, the first composition and the second composition are each formulated as separate layers.

[0048] In the above aspects or any of those embodiments, the first composition is formulated in tablet form, and the second composition is formulated in particle form. The first and second compositions are compressed together to form a compressed tablet.

[0049] In the above aspects or any of the embodiments thereof, the first composition and the second composition are each formulated as pellets, particles, or granules.

[0050] In the above aspects or any of those embodiments, the core tablet comprises a first composition surrounded by a compressed layer of a second composition. The first composition is formulated as a tablet, and the second composition is formulated as a powder.

[0051] In the above-described situations or any of the embodiments thereof, the first composition is formulated as a tablet, and the second composition is formulated as a pellet, particle, granule, or powder.

[0052] In the above-described situations or any of their embodiments, the first composition and the second composition are each formulated as tablets.

[0053] In the above aspects or any of the embodiments thereof, the pharmaceutical composition further comprises magnesium oxide.

[0054] In the above-described aspects or any of those embodiments, the formulation, tablet, compressed tablet, core tablet, capsule, pharmaceutical composition, or push-pull osmotic pump tablet is formulated to enhance the bioavailability of the second agent under feeding conditions when administered to a subject.

[0055] In the situations described above or any of these embodiments, the formulation, tablet, compressed tablet, core tablet, capsule, pharmaceutical composition, or push-pull osmotic pump tablet is administered once daily.

[0056] In the situations described above or any of these embodiments, the formulation, tablet, compressed tablet, core tablet, capsule, pharmaceutical composition, or push-pull osmotic pump tablet is administered twice daily.

[0057] In any of the above situations or embodiments thereof, administration is associated with alteration of cerebral metabolism or cerebral blood flow.

[0058] In the situations described above or any of their manifestations, cerebral blood flow is altered in one or more of the telencephalon, diencephalon, and midbrain.

[0059] In the situations described above or any of their manifestations, alterations in local cerebral blood flow are associated with the establishment of hemodynamic equilibrium in a particular region of the brain.

[0060] In any of the above situations or aspects thereof, the method enhances the primary outcome, which is cognitive function, life satisfaction, sense of purpose and significance, sense of purpose and emotional or instrumental support, social relationships, or life satisfaction.

[0061] In any of the above aspects or embodiments thereof, the method further includes the step of administering magnesium oxide to the subject.

[0062] In any of the above situations or embodiments thereof, at least about 150 mg of magnesium oxide is administered to the subject daily.

[0063] The present invention provides formulations comprising calcium channel blockers (e.g., verapamil) and angiotensin II receptor blockers (e.g., candesartan or telmisartan), as well as methods for using such formulations in the treatment of cerebrovascular and behavioral health disorders. The compositions and articles defined by the present invention were isolated or otherwise manufactured in connection with the examples provided below. Other features and advantages of the present invention will be apparent from the detailed description and claims.

[0064] definition Unless otherwise defined, all technical and scientific terms used herein have the meanings generally understood by those skilled in the art to which this invention pertains. The following references provide general definitions of many of the terms used herein: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, unless otherwise specified, the following terms have the meanings given therein.

[0065] "Agent" means any small molecule chemical compound. Examples of agents include, but are not limited to, anipamil, candesartan, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, telmisartan, thiapamil, and verapamil.

[0066] "Modification" means a positive or negative change. As used herein, modification includes changes of 5%, 10%, 15%, 20%, 25%, 30%, 35%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. The change may be an increase or decrease in the analyte or clinical indicator. For example, the amount measured may be the amount of focal cerebral blood flow. The clinical indicator measured may be a quantitative assessment of the magnitude of symptoms of a disease (e.g., anxiety, emotional blunting, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, pain (e.g., physical pain), or mental disorder). In some embodiments, modification is a reduction in symptoms associated with a cerebral and / or behavioral health disorder. In some embodiments, modification is an increase in function associated with the treatment of a cerebral and / or behavioral health disorder.

[0067] "To induce remission" means to reduce, inhibit, weaken, decrease, block, or stabilize the onset or progression of a disease or disorder. In various aspects, a disease or disorder is a disorder of the brain or a behavioral health disorder (e.g., affective disorders, anxiety disorders, neurodegenerative disorders, neurodevelopmental disorders, psychotic disorders, personality disorders, migraine disorders, somatoform disorders, substance use disorders, paroxysmal disorders, neuroimmunological disorders, and cerebrovascular disorders. Examples of affective disorders include bipolar disorder, cyclothymic disorder, depression, dysthymia, major depressive disorder, postpartum depression, and seasonal affective disorder. Examples of anxiety disorders include generalized anxiety disorder, panic disorder, social anxiety disorder, post-traumatic stress disorder, obsessive-compulsive disorder, and specific phobias).

[0068] An "analog" means a molecule that is not identical to the molecule of interest but possesses similar functional and / or structural characteristics. In some embodiments, the analog is an agent that targets the adrenergic system. In some embodiments, the analog is an agent that targets the renin-angiotensin-aldosterone system.

[0069] "Anipamil" has the following structure: This refers to a compound having TIFF2026522575000001.tif47128, or a pharmaceutically acceptable salt thereof. In some embodiments, anipamil has calcium channel blocking activity.

[0070] Candesartan has the following structure: This refers to compounds containing TIFF2026522575000002.tif33128, or pharmaceutically acceptable salts thereof. In some embodiments, candesartan has angiotensin II receptor blocking activity.

[0071] "Cerebral metabolism" refers to the metabolic rate in the brain or in any region thereof. Cerebral metabolism is measured using a variety of methods available to practitioners, for example, not limited to, X-ray computed tomography (CT), positron emission tomography (PET), near-infrared spectroscopy (NIRS), magnetic resonance imaging (MRI), and any of such methods provided herein. In some embodiments, an increase in metabolism in a region of the brain is associated with an increase in blood flow to that region. Cerebral blood flow is measured using a variety of methods available to practitioners, for example, not limited to, single-photon emission computed tomography (SPECT), positron emission tomography (PET), functional MRI (fMRI), arterial spin labeling (ASL) MRI, transcranial Doppler ultrasound imaging (i.e., ultrasound), phase-contrast MRI, and near-infrared spectroscopy (NIRS).

[0072] In this disclosure, “comprises,” “comprising,” “containing,” and “having,” etc., may have the meanings given to them in U.S. patent law, and may mean “includes,” “including,” etc.; “essentially from” or “essentially from” also has the meanings given to them in U.S. patent law, and the term is open-ended, allowing for more than what is described, as long as the basic or novel features of what is described are not altered by more than what is described, but excluding aspects of the prior art. Any aspect that expresses “comprising” a particular component or element may, in some aspects, also be intended to “consist of” or “essentially from” that particular component or element.

[0073] "Essentially" means that the components consist only of the listed components, along with any other additives present in levels that do not affect the implementation of this disclosure, such as less than 5% by weight, 1% or even less than 0.5% by weight, and are not ordinary impurities present in commercially available materials.

[0074] "Decrease" means a negative change.

[0075] "Devapamil" has the following structure: This refers to a compound having TIFF2026522575000003.tif36128, or a pharmaceutically acceptable salt thereof. In one embodiment, devapamil has calcium channel blocking activity.

[0076] "Diltiazem" has the following structure: This refers to a compound having TIFF2026522575000004.tif51128, or a pharmaceutically acceptable salt thereof. In some embodiments, diltiazem has calcium channel blocking activity.

[0077] "Disease" means any condition or disorder that impairs or interferes with the normal functioning of a cell, tissue, or organ. In aspects, a disease or disorder is a neuropsychiatric disorder, examples of which include disorders of brain and / or behavior and their symptoms. Non-exclusive examples of disorders of brain and behavior include affective disorders, anxiety disorders, neurodegenerative disorders, neurodevelopmental disorders, psychotic disorders, personality disorders, migraine disorders, somatoform disorders, substance use disorders, paroxysmal disorders, neuroimmunological disorders, and cerebrovascular disorders. Examples of affective disorders include bipolar disorder, cyclothymic temperament, dysthymia, major depressive disorder, postpartum depression, and seasonal affective disorder. Examples of anxiety disorders include generalized anxiety disorder, panic disorder, social anxiety disorder, post-traumatic stress disorder, obsessive-compulsive disorder, and specific phobias. Examples of neurodegenerative disorders include Alzheimer's disease, Parkinson's disease, and Lewy body dementia. Examples of neurodevelopmental disorders include autism spectrum disorder, attention deficit hyperactivity disorder (ADHD), and learning disabilities. Examples of psychotic disorders include schizophrenia, schizoaffective disorder, and major depressive disorder with psychiatric abnormalities. Examples of personality disorders include paranoid personality disorder, schizotypal personality disorder, schizotypal personality disorder, antisocial personality disorder, borderline personality disorder, histrionic personality disorder, narcissistic personality disorder, avoidant personality disorder, dependent personality disorder, and obsessive-compulsive personality disorder. Examples of migraine-related disorders include migraine with aura, migraine without aura, painless migraine, and vestibular migraine. Examples of somatoform disorders include somatization disorder, hypochondriasis, conversion disorder, body dysmorphic disorder, and chronic pain. Examples of substance use disorders include alcohol use disorder and opioid use disorder. Examples of seizure disorders include epileptic disorders and psychogenic non-epileptic seizure disorders. An example of neuroimmunological disorders is multiple sclerosis. Examples of cerebrovascular disorders include cerebrovascular disease, vascular dementia, and cerebrovascular accidents.Symptoms associated with the disorder are selected from one or more of the “ten major symptoms” associated with brain and behavioral disorders, including but not limited to anxiety, emotional blunting, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, pain (e.g., physical pain), and mental abnormalities. In some embodiments, the disorder is associated with altered focal cerebral blood flow compared to a reference (e.g., blood flow present in the brain of a healthy control). The disorder may be a brain or behavioral disorder as defined above.

[0078] “Effective dose” means the amount of agent sufficient to treat a disease or disorder. In one embodiment, the effective dose of a combination therapy described herein is sufficient to treat a disorder of the brain and / or behavior or its symptoms, or to result in an improvement in a primary outcome (e.g., an increase in cognitive function, life satisfaction, sense of purpose and significance, sense of purpose in emotional or instrumental support, social relationships, and life satisfaction).

[0079] "Faripamir" has the following structure: This refers to a compound having TIFF2026522575000005.tif39128, or a pharmaceutically acceptable salt thereof. In some embodiments, falipamil has calcium channel blocking activity.

[0080] "Ferodipine" has the following structure: This refers to a compound having TIFF2026522575000006.tif51128, or a pharmaceutically acceptable salt thereof. In some embodiments, felodipine has calcium channel blocking activity.

[0081] "Galopamyl" has the following structure: This refers to a compound having TIFF2026522575000007.tif44128, or a pharmaceutically acceptable salt thereof. In some embodiments, gallopamil has calcium channel blocking activity.

[0082] "Hemodynamic equilibrium" refers to a state of balance regarding relative blood flow velocity between corresponding regions of the brain. In some embodiments, hemodynamic equilibrium is associated with approximately equal relative blood flow velocity and / or metabolic activity between regions.

[0083] "Increase" means a positive change.

[0084] "Isradipin" has the following structure: This refers to compounds containing TIFF2026522575000008.tif47128, or pharmaceutically acceptable salts thereof. In some embodiments, isradipine has calcium channel blocking activity.

[0085] Nicardipine has the following structure: This refers to compounds containing TIFF2026522575000009.tif44128, or pharmaceutically acceptable salts thereof. In some embodiments, nicardipine has calcium channel blocking activity.

[0086] Nifedipine has the following structure: This refers to compounds containing TIFF2026522575000010.tif54128, or pharmaceutically acceptable salts thereof. In some embodiments, nifedipine has calcium channel blocking activity.

[0087] "Nimodipine" has the following structure: This refers to compounds containing TIFF2026522575000011.tif49128, or pharmaceutically acceptable salts thereof. In some embodiments, nimodipine has calcium channel blocking activity.

[0088] Nisoldipine has the following structure: This refers to compounds containing TIFF2026522575000012.tif50128, or pharmaceutically acceptable salts thereof. In some embodiments, nisoldipine has calcium channel blocking activity.

[0089] As used herein, “obtaining the agent” includes synthesizing, purchasing, or otherwise acquiring the agent.

[0090] As used herein, the terms “prevent,” “prevention,” “prevention,” and “preventive measures” refer to reducing the probability of an impairment or condition occurring in an object that does not currently have an impairment or condition but is at risk of developing one or is prone to developing one.

[0091] "To reduce" implies a negative modification.

[0092] "Subject" refers to mammals. Non-limiting examples of mammals include humans and other mammals, such as animals of the genus Bos, animals of the family Equidae, animals of the family Canidae, sheep, animals of the family Felidae, or rodents.

[0093] "Reference" refers to a standard or control condition. In one embodiment, the effect of an agent on cells is compared to the effect of an agent on control cells. In another embodiment, the reference is a healthy subject. In yet another embodiment, the clinical features of a subject with a brain or behavioral disorder are compared to reference clinical features present in a healthy subject. A healthy subject is one that does not have the disorder or condition of the subject of interest. In some embodiments, the reference is an untreated patient or a subject prior to treatment or modification of treatment.

[0094] "Region of the brain" means a part of the brain. In some embodiments, a region of the brain includes one or more of the telencephalon, diencephalon, and midbrain. The region may include all three of the telencephalon, diencephalon, and midbrain.

[0095] "Simultaneous administration" means administering the drugs at the same time.

[0096] "Continuous administration" means that drugs are administered at separate points in time. For example, one or more drugs are administered consecutively if the administrations are spaced a few minutes, hours, or days apart. For example, in continuous administration, the first drug is administered 15, 30, 45, or 60 minutes before the administration of one or more further drugs. In another example of continuous administration, the first drug is administered 1, 2, 3, 4, 5, 6, 12, or 24 hours before the administration of the second drug. In yet another example of continuous administration, the first drug is administered 1, 2, 3, 4, 5, 6, or 7 days before the administration of the second drug.

[0097] "Telmisartan" has the following structure: This refers to compounds having TIFF2026522575000013.tif27128 or pharmaceutically acceptable salts thereof. In some embodiments, telmisartan has angiotensin II receptor blocking activity.

[0098] "Therapeutic agent" means a substance that has the potential to affect the function of an organism. Such compounds are, for example, natural, semi-synthetic, or synthetic agents. For example, an agent is a drug that targets a specific function of an organism. Therapeutic agents can reduce, inhibit, attenuate, reduce, block, or stabilize the onset or progression of a disease, disorder, or condition. Therapeutic agents are associated with altering local cerebral blood flow in the subject. Non-limiting examples of therapeutic agents described herein include anipamil, candesartan, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, telmisartan, thiapamil, and verapamil, as well as derivatives, analogues, and functional equivalents of such agents. In one embodiment, the therapeutic combination features a first agent selected from one or more of anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan.

[0099] The “effective dose” refers to the amount of agent required to reduce or alleviate the symptoms of the disease compared to a reference dose. The effective dose of the active compounds used for the purpose of carrying out the present invention for the therapeutic treatment of the disease (e.g., anipamil, candesartan, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, telmisartan, thiapamil, and verapamil) will vary depending on the mode of administration, the age, weight, and overall health status of the subject. Ultimately, it is expected that the attending physician or veterinarian will determine the appropriate dose and dosing regimen. Such a dose is referred to as the “effective” dose. The symptoms are selected from one or more of the “ten main symptoms” associated with cerebrovascular and behavioral disorders: anxiety, emotional blunting, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, pain (e.g., bodily pain), and mental disorders. In some embodiments, the therapeutic effective dose is the amount of the required agent or combination of agents.

[0100] The ranges provided herein are understood to be abbreviated notations for all values ​​within a range. For example, the range 1–50 is understood to include any number, combination of numbers, or subrange from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.

[0101] "Chiapamir" has the following structure: This refers to compounds containing TIFF2026522575000014.tif40128 or pharmaceutically acceptable salts thereof. In some embodiments, chiapamil has calcium channel blocking activity.

[0102] As used herein, the terms “to treat,” “to treat,” and “treatment” refer to reducing or relieving a disease and / or its associated symptoms. It will be recognized, though not excluded, that treating a disorder or condition does not require the complete elimination of the disorder, condition, or its associated symptoms.

[0103] "Verapamil" has the following structure: This refers to an agent having TIFF2026522575000015.tif20128 or a pharmaceutically acceptable salt thereof. In some embodiments, verapamil has calcium channel blocking activity.

[0104] Unless otherwise stated or the context makes clear, the term “or” is understood to be inclusive when used herein. Unless otherwise stated or the context makes clear, the terms “a,” “an,” and “the” are understood to be singular or plural when used herein.

[0105] Unless otherwise stated or evident from the context, the term “about” as used herein is understood to mean within the normal tolerance of error in the art, for example, within two standard deviations of the mean. “About” may be understood to mean within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise evident from the context, all numerical values ​​provided herein are qualified with the term “about.”

[0106] Any list of chemical groups in any definition of a variable in this specification includes the definition of that variable as any single group or combination of the enumerated groups. Any enumeration of embodiments of a variable or aspect in this specification includes that embodiment as any single embodiment or in combination with any other embodiments or parts thereof.

[0107] Any composition or method provided herein may be combined with one or more other compositions and methods provided herein. Where various mechanisms of action, hypotheses, or theories are discussed throughout this application, these are not intended to be limiting. [Brief explanation of the drawing]

[0108] [Figure 1] This provides illustrations of 24-hour releasing formulations of telmisartan and verapamil. [Figure 2] This graph shows the results of dissolution tests for verapamil in 24-hour releasing formulations of telmisartan and verapamil at i) 0.1N HCl; ii) pH 4.5; and iii) pH 6.8. [Figure 3] This graph shows the results of dissolution tests for telmisartan and verapamil in 24-hour release formulations at i) 0.1N HCl; ii) pH 4.5; and iii) pH 6.8. [Figure 4] This document provides an illustration of a biphasic formulation example of telmisartan and verapamil. [Figure 5] Figure 4 is a graph showing the results of dissolution tests for verapamil in the biphasic formulation at i) 0.1N HCl; ii) pH 4.5; and iii) pH 6.8. [Figure 6] Figure 4 is a graph showing the results of a dissolution test for telmisartan in 0.1N HCl for the biphasic formulation. [Figure 7] This document provides illustrations of alternative formulations for telmisartan and verapamil. [Figure 8] This document provides illustrations of alternative formulations for telmisartan and verapamil. [Figure 9] This document provides illustrations of alternative formulations for telmisartan and verapamil. [Figure 10] This document provides illustrations of alternative formulations for telmisartan and verapamil. [Figure 11] This document provides illustrations of alternative formulations for telmisartan and verapamil. [Figure 12] This document provides illustrations of alternative formulations for telmisartan and verapamil. [Modes for carrying out the invention]

[0109] Detailed description of the invention The present invention features formulations useful for treating brain and / or behavioral health disorders and their associated symptoms.

[0110] This invention is at least partially based on the discovery of a combination therapeutic formulation of telmisartan and verapamil, which provides immediate release of telmisartan under conditions simulating gastric pH, while verapamil is released over a 24-hour timeframe under all pH conditions. This formulation was achieved by adding an immediate-release coating of telmisartan to the outside of a verapamil controlled-release matrix tablet.

[0111] Accordingly, this disclosure provides formulations comprising telmisartan or candesartan that can be combined with other adrenergic targeting agents (e.g., anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil) to treat cerebrovascular and / or behavioral health disorders and their associated symptoms. In some embodiments, the combination therapy formulations disclosed herein can enhance the bioavailability of adrenergic and cerebral renin-angiotensin-aldosterone system (RAAS) targeting agents, such as telmisartan, compared to standard combination therapy formulations, such as 24-hour release formulations.

[0112] Brain and behavioral disorders Collectively, brain and behavioral disorders are the leading cause of physical disability worldwide. Achieving comprehensive relief across a wide range of distinct symptoms is challenging for most patients, physicians, and families because, in actual clinical practice, patients often have multiple comorbidities. Caring for patients with multiple comorbidities requires separate, individual treatment for each disorder, which increases complexity, costs, and reduces the safety of care.

[0113] Brain and behavioral health disorders, at least in part, result in significant psychosocial problems that negatively impact patients' quality of life, due to their multifaceted nature. However, current treatments are designed to address only a single component (e.g., psychiatric).

[0114] Because brain and behavioral health disorders are clinically diverse groups of disorders, abnormal functional connectivity represents a shared common pathological framework. Regardless of the disorder, two independent systems, namely the adrenergic system and the cerebral renin-angiotensin-aldosterone system, directly affect functional connectivity. Abnormalities within similar functional networks among these different disorders contribute to overall symptoms. For example, anxiety disorders and chronic pain can be classified together as reactive disorders, each characterized by atypical connectivity between the sensorimotor network and the salience network, respectively. Indeed, successful symptomatic treatment for many brain and behavioral disorders has been shown to be associated with the normalization of atypical patterns of regional cerebral blood flow.

[0115] Non-specific examples of brain and behavioral health disorders include affective disorders, anxiety disorders, neurodegenerative disorders, neurodevelopmental disorders, psychotic disorders, personality disorders, migraine disorders, somatosensory somatoform disorders, substance use disorders, paroxysmal disorders, neuroimmunological disorders, and cerebrovascular disorders. Examples of affective disorders include bipolar disorder, cyclothymic temperament, dysthymia, major depressive disorder, postpartum depression, and seasonal affective disorder. Examples of anxiety disorders include generalized anxiety disorder, panic disorder, social anxiety disorder, post-traumatic stress disorder, obsessive-compulsive disorder, and specific phobias. Examples of neurodegenerative disorders include Alzheimer's disease, Parkinson's disease, and Lewy body dementia. Examples of neurodevelopmental disorders include autism spectrum disorder, attention deficit hyperactivity disorder (ADHD), and learning disabilities. Examples of psychotic disorders include schizophrenia, schizoaffective disorder, and major depressive disorder with mental abnormality. Examples of personality disorders include paranoid personality disorder, schizotypal personality disorder, schizotypal personality disorder, antisocial personality disorder, borderline personality disorder, histrionic personality disorder, narcissistic personality disorder, avoidant personality disorder, dependent personality disorder, and obsessive-compulsive personality disorder. Examples of migraine disorders include migraine with aura, migraine without aura, painless migraine, and vestibular migraine. Examples of somatoform disorders include somatization disorder, hypochondriasis, conversion disorder, body dysmorphic disorder, and chronic pain. Examples of substance use disorders include alcohol use disorder and opioid use disorder. Examples of paroxysmal disorders include epileptic disorders and psychogenic non-epileptic seizure disorder. Examples of neuroimmunological disorders include multiple sclerosis. Examples of cerebrovascular disorders include cerebrovascular disease, vascular dementia, and cerebrovascular accidents. Symptoms associated with the disorder are not limited to, but include one or more of the "10 primary symptoms" associated with brain and behavioral health disorders, including anxiety, emotional blunting, cognitive difficulties, depression, fatigue, headaches, insomnia, irritability, physical pain, and mental disturbances.Such symptoms are measured using one of the various methods available to the practitioner, non-limiting examples of such methods are shown in Brenes, “Anxiety, Depression, and Quality of Life in Primary Care Patients”, Prim Care Companion J Clin Psychiatry, 9:437-443 (2007) and Julian, “Measures of Anxiety”, Arthritis Care Res, 63:1-11 (2011).

[0116] Current treatments for the disorders listed above are not designed to address the functional connectivity abnormalities closely associated with the disorders. Selective serotonin reuptake inhibitors ("SSRIs") have limited efficacy for anxiety. Treatment success remains limited even with cognitive behavioral therapy and pharmacotherapy. Because SSRIs do not address symptoms caused by common anxiety comorbidities such as ADHD, comorbid physical impairments remain untreated for the majority of patients seeking anxiety relief. In patients with ADHD, stimulants are ineffective for comorbid mood disorders and may even worsen them. These represent a significant treatment gap, as symptoms caused by psychiatric comorbidities are often the most physically disabling. Furthermore, currently regulated treatment options, particularly benzodiazepines, stimulants, and opiates, are dangerous due to their potential to exacerbate comorbid mood disorders, lead to addiction, and result in fatal overdoses.

[0117] Combination therapy Certain existing drugs that affect the adrenergic and cerebral renin-angiotensin-aldosterone systems and have never been used in combination before can be combined to create novel synergistic changes in cerebral blood flow that lead to desirable clinical outcomes. The combination treatments of the present invention include, for example, the step of administering a combination of two or more agents selected from previously FDA-approved cardiovascular drug therapies. The present invention features combinations of verapamil and telmisartan, verapamil and candesartan, and candesartan or telmisartan, in combination with one or more of anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isuradipine, nicardipine, nifedipine, nimodipine, nisoldipine, and thiapamil, verapamil, and verapamil.

[0118] The agents are selected to target the renin-angiotensin-aldosterone system and the adrenergic system, respectively. Telmisartan and candesartan block angiotensin II receptors, and can be used individually or in combination to balance the intensity of the angiotensin response. While we do not wish to be bound by theory, anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil affect the output of norepinephrine from the midbrain, and can be used individually or in combination to balance the intensity of the adrenergic response. Since both the adrenergic system and the cerebral RAAS interact and modulate functional connectivity, combining agents that independently target each system can create synergistic effects, resulting in novel therapeutic effects.

[0119] Regardless of the underlying diagnosis, novel treatments for relieving the psychiatric, psychological, and neurological components of disorders that manifest as one or more of the 10 major neuropsychiatric symptoms (i.e., anxiety, emotional blunting, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, pain (e.g., physical pain), and mental disorders) are described herein. Not intended to be theoretically bound, compositions and / or dosage forms of the present invention, including therapeutic combinations (e.g., verapamil and telmisartan, verapamil and candesartan, and candesartan and / or telmisartan, in combination with one or more of anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isuradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil), simultaneously target stress-inducing hormones in different areas of the brain. The combination of agents described herein that simultaneously targets both adrenergic activity and the cerebral RAAS with positive multi-way network effects has never been attempted or studied to date.

[0120] Administration to subjects of the compositions and dosage forms of the present invention, comprising a first agent selected from one or more of anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan, delivered simultaneously or sequentially as a combination treatment, is useful for treating brain and / or behavioral disorders and their associated symptoms (i.e., anxiety, emotional blunting, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, physical pain, and mental disorders). The combination treatment leads to positive psychosocial outcomes, which, over time, correlate with significant improvements in an overall measure of quality of life. For example, the compositions are associated with the achievement of patient progress in line with Maslow's hierarchy of needs, which is a comprehensive outcome in health management that reflects not only overall symptoms but also an impact across a wide range of social determinants of health. In some embodiments, the therapeutic combinations described herein have a positive effect on the healthy state of the person being treated (e.g., increased cognitive function, increased life satisfaction, increased meaning and purpose, increased emotional support, increased instrumental support, increased social relationships, increased life satisfaction).

[0121] Pharmacological effects While not intended to be theoretically bound, the pharmacological effects of a composition comprising one or more agents selected from anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil, and one or more agents selected from candesartan and telmisartan, are related to the physiological functions of adrenaline and the cerebral renin-angiotensin-aldosterone system (RAAS). When a person senses danger, two independent bodily systems alter the endogenous functional connectivity of the brain.

[0122] The adrenergic system, also known as the sympathetic / parasympathetic nervous system, influences functional connectivity through signaling by the neurotransmitter norepinephrine (also known as "adrenaline"). When norepinephrine is produced in the adrenal glands, it crosses into the brain, where it binds to beta receptors. When beta receptors bind to norepinephrine, changes occur, such as pupil dilation, reduced pain sensation, and increased alertness.

[0123] The cerebral renin-angiotensin-aldosterone system, also known as the cerebral RAAS system, influences functional connectivity via the neurotransmitter known as angiotensin. When angiotensin precursors are produced in the kidneys, they travel through the lungs to the brain, where they bind to angiotensin receptors. When angiotensin receptors in the brain bind to angiotensin, it alters the connectivity between arterioles and astrocytes, a process known as neurovascular connectivity, which in turn causes localized changes in cerebral blood flow.

[0124] While not intended to be constrained to any particular mode of action, activation of the adrenaline and cerebral RAAS systems alters the brain's functional connectivity. This alteration of connectivity is an evolutionarily conserved stress response system that facilitates the brain's adaptation to metabolic demands. When chronically maintained, this can create a state of functional connectivity deequilibrium, which can be detrimental. Several factors, including the built environment, social determinants of health, and individual differences, can contribute to chronic deequilibrium. These factors can be particularly challenging for patients with brain and / or behavioral health disorders. Without being bound by theory, compositions comprising a first agent selected from one or more of anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan, can re-equilibrium alterations of functional connectivity associated with impaired brain and / or behavioral health.

[0125] While not intended to be constrained by theory, the combination therapy involves administering a composition comprising one or more agents selected from anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil, and one or more agents selected from candesartan and telmisartan. Such combinations act on a central functional network common to one or more neuropsychiatric disorders. While not intended to be constrained by theory, the unique combination of angiotensin II receptor blockade and concomitant adrenergic blockade results in a reequilibrium of cerebral blood flow distribution, particularly in the diencephalon, a brain region important for social and emotional consciousness. In other words, by influencing the functional network associated with emotion (midbrain) and the functional network associated with cognition (telncephalon), the functional network associated with social cognition (diencephalon) is balanced. This hypothesis is based on the finding of significant social changes in patients who received combination therapy. For example, bidirectional changes were observed in social behavior and dressing behavior in patients receiving combination therapy. In particular, introverted patients showed more extroversion during combination therapy, and extroverted patients showed more introversion during combination therapy. The results of the studies described in the examples provided herein showed improvements in social satisfaction in patients receiving combination therapy. The hypothesis that combination therapy brings about a balancing effect in functional brain networks is further supported by an analysis of the results of the Weber test, which is performed as part of regular visits to measure sensorineural function affected by lateralization of the brain's auditory functional network. At the clinic, patients who initiated combination therapy or switched from monotherapy to combination therapy showed a shift in Weber test lateralization from one visit to the next. The lateral shift in the Weber trial does not occur with standard drug therapy. The lateral shift in the Weber trial does not occur when the patient takes individual components of a combination treatment.Notably, these shifts, like the changes in social outcomes, were bidirectional, with some patients shifting to the right and others to the left.

[0126] While we do not wish to be bound by theory, novel bidirectional outcomes associated with compositions comprising a first agent selected from one or more of anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan, suggest that combination treatments may play a modal role in brain regions associated with auditory and / or other functional brain networks. Since changes in auditory function correlate with clinical improvements in social function, the therapeutic combinations described herein may affect not only auditory function but also interoceptive / exteroceptive awareness and social communication skills that rely on auditory function. In fact, the auditory cortex is directly involved in networks related to emotion processing and communication (Disability and poor quality of life associated with comorbid anxiety disorders and physical conditions. Sareen J, Jacobi F, Cox BJ, Belik SL, Clara I, Stein MB. Arch Intern Med. 2006 Oct 23;166(19):2109-16. doi: 10.1001 / archinte.166.19.2109).

[0127] The composition of the present invention modulates adrenergic function and angiotensin function. A composition comprising a first agent selected from one or more of anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan, contains one component for adrenergic modulation and one component for cerebral RAAS. No pharmaceutical agent is designed to target both systems simultaneously. This represents a significant treatment gap, as both systems interact when patients with cerebral and / or behavioral disorders experience distressing, often untreated, symptoms.

[0128] The adrenaline and angiotensin systems influence different functional brain networks. While not intended to be bound by theory, the effects of a composition comprising one or more agents selected from anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil, and one or more agents selected from candesartan and telmisartan, depend in part on the relative density of adrenergic and angiotensin receptors at each of the three phylogenetic levels of the brain. The midbrain is the oldest level of the brain, located at the base of the brain, directly above the spinal cord. The telencephalon is the newest level of the evolved brain, located at the top of the brain. The diencephalon lies between these levels. While not bound by theory, each level of the brain contains receptor-rich brain regions involved in several networks that support different neurological processes.

[0129] Beta receptors (which bind to norepinephrine) are located more densely in the midbrain than in the telencephalon, so the effects of norepinephrine are strongest in brain networks that rely on midbrain regions such as the brainstem. Angiotensin receptors (which bind to angiotensin) are located more densely in the telencephalon than in the midbrain, so the effects of angiotensin are strongest in brain networks that rely on telencephalon regions such as the prefrontal cortex. Clinically, modulating the adrenergic system affects neuropsychiatric symptoms (e.g., insomnia, fatigue, emotional blunting, pain, anxiety) because the midbrain network has extensive connections with somatic organs. Modulating the angiotensin system affects various neuropsychiatric symptoms (e.g., cognitive impairment, headache, aura) because the telencephalon network has extensive connections with brain regions involved in sensory processing.

[0130] Each functional brain network extends to different regions of the older and newer brain. Among the many important functional brain networks involved in brain and / or behavioral health disorders are the default mode network, salience network, somatosensory network, visual network, auditory network, and limbic network. Some of these brain networks rely heavily on newer brain regions. For example, the default mode network works harmoniously between regions located primarily within the telencephalon (the highest phylogenetic level), while the salience network harmonizes regions within the midbrain (the lowest phylogenetic level).

[0131] (Table 1) Functional brain network regions organized at the phylogenetic level TIFF2026522575000016.tif160158

[0132] The therapeutic combination of this invention normalizes the functional connectivity of the entire brain. In some embodiments, a composition comprising a first agent selected from one or more of anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan, achieves a multi-component network effect because the equilibration of lower-order brain networks affects the equilibration of higher-order networks, and vice versa. The composition comprises at least two components to block two different stress-related systems (adrenergic system and cerebral RAAS). Each of these systems can play a crucial role in shifting the functional connectivity of the brain as needed. While not bound by theory, anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil, and combinations thereof, interact with beta receptors in the midbrain. While not bound by theory, telmisartan and candesartan interact with angiotensin receptors in the telencephalon.

[0133] A composition comprising a first agent selected from one or more of anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan, yielded clinical effects suggesting the modulation of functional connectivity throughout the brain, as detailed in the following examples. The clinical effects of this composition include the normalization of not only emotional symptoms but also social and cognitive symptoms, due to the unique multifaceted network effect achieved through this synergistic action. Although not bound by theory, since these functions arise from three separate layers (diencephalon, midbrain, and telencephalon), a composition comprising a first agent selected from one or more of anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan, modifies connectivity at all three levels. The multi-component network effect of this composition enables patients to make rapid psychosocial progress, thereby further improving overall brain connectivity (Safety Needs Mediate Stressful Events Induced Mental Disorders. Zheng Z, Gu S, Lei Y, Lu S, Wang W, Li Y, Wang F. Neural Plast. 2016;2016:8058093. doi: 10.1155 / 2016 / 8058093. Epub 2016 Sep 21). While not bound by theory, improvement in overall symptoms that can be attributed to all three phylogenetic levels does not occur when any of the agents are administered alone. Improvement in overall symptoms that can be attributed to all three phylogenetic levels does not occur with any known standard treatment.

[0134] Prevention of brain and / or behavioral health disorders and medical disorders. The multi-component network effect of compositions comprising a first agent selected from one or more of anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil discussed herein, and a second agent selected from one or more of candesartan and telmisartan, suggests that treatment with these compositions can treat disorders affecting different parts of the brain at different times throughout life (e.g., panic disorder). Many neuropsychiatric disorders suitable for preventive treatment are characterized by imbalances in one or more functional brain networks, suggesting that these disorders are promising candidates for preventive treatment with combination therapies described herein. For example, chronic pain disorders, which become more refractory to treatment throughout life if left untreated, are characterized by abnormalities in the visual, salience, and default mode networks, which may be detectable before the onset of significant physical impairment. Neurodevelopmental disorders such as ADHD, autism spectrum disorder, and learning disabilities, which become more refractory to treatment throughout life if left untreated, are characterized by alterations in multiple networks. Psychotic disorders such as schizophrenia, which become more refractory to treatment throughout life if left untreated, are characterized by dysfunction of multiple brain networks. Anxiety disorders, which become more refractory to treatment throughout life if left untreated, exhibit multiple network effects with some specific differences depending on the disorder. Compositions comprising one or more agents selected from anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isuradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil as a first agent and one or more agents selected from candesartan and telmisartan as a second agent are promising preventive treatments for these conditions because they improve overall functional connectivity of the brain despite individual differences in network equilibrium abnormalities between disorders. There are currently no available treatments to prevent neuropsychiatric disorders that worsen if left untreated throughout a person's life.No research has been conducted to date on the use of such compositions for the prevention of neuropsychiatric disorders or physical disabilities.

[0135] A composition comprising one or more agents selected from anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil, and a second agent selected from one or more agents selected from candesartan and telmisartan, can be used to prevent the risk of neurodegenerative disease beginning in middle age. This composition can cumulatively normalize cerebral metabolism that may be dysregulated in preclinical neurodegenerative disease states. Different neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and frontotemporal lobar degeneration, are characterized by imbalances in different brain networks resulting from abnormal cerebral metabolism. Currently, there are no available treatments that can normalize cerebral metabolism in patients at risk of neurodegenerative disease. The use of such compositions has not been studied from the perspective of preventing or treating neurodegenerative disease.

[0136] A composition comprising one or more agents selected from anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil, and one or more agents selected from candesartan and telmisartan, can normalize cerebral connectivity throughout the brain and can therefore be used for certain indications outside the boundaries of neuropsychiatry (i.e., cancer, autoimmune diseases, and autonomic nervous system disorders). Dysregulated functional connectivity affects the health of the brain's connective immune system and can therefore increase the risk of medical disorders. Medical disorders that are particularly pronounced around the developmental window (e.g., around age 25, when the brain completes myelin formation) are candidates for novel brain-based preventive treatments, including treatment with this composition.

[0137] Pharmaceutical composition This disclosure provides a pharmaceutical composition comprising an effective amount of a first agent selected from one or more of anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil, and an effective amount of a second agent selected from one or more of candesartan and telmisartan. Such combinations can be co-formulated or formulated separately, but can be administered simultaneously or sequentially. When the first and second agents are administered in combination, they are useful for treating cerebral and / or behavioral health disorders (e.g., panic disorder). In some embodiments, combination therapy is administered to treat one or more of ten major neuropsychiatric symptoms (i.e., anxiety, emotional blunting, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, physical pain, and mental disorders).

[0138] In some embodiments, the compositions of the present invention include, for use in combination therapy, a first agent selected from one or more of anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan. In some embodiments, the first agent is verapamil, and the second agent is telmisartan and / or candesartan. In some cases, the first agent is selected to affect beta receptors in the midbrain, and the second agent is selected to interact with angiotensin receptors in the telencephalon. The agents may be selected such that the first agent affects the adrenergic system and the second agent affects the cerebral renin-angiotensin-aldosterone system. In some embodiments, the compositions are associated with modulation of both adrenergic and angiotensinic function.

[0139] In certain embodiments, the compositions of the present invention can prevent, inhibit, interfere with, or reduce by at least 10%, 25%, 50%, 75%, or even 100% one or more of the anxiety, migraines, depression, cognitive difficulties, anger, emotional blunting, fatigue, physical pain, mental disturbances, and insomnia that manifest in individuals suffering from a disorder having one or more psychiatric, psychological, and / or neurological components.

[0140] For the treatment of one or more of the ten major neuropsychiatric symptoms (i.e., anxiety, emotional blunting, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, physical pain, and mental disorders), pharmaceutically acceptable salts of anipamil, candesartan, devapamil, diltiazem, falipamil, felodipine, garopamil, isulazipine, nicardipine, nifedipine, nimodipine, nisoldipine, telmisartan, thiapamil, and verapamil, or combinations thereof, are intended herein. The term "pharmaceutically acceptable salt" also refers to salts prepared by contacting an agent (e.g., anipamil, candesartan, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, telmisartan, thiapamil, or verapamil) with a pharmaceutically acceptable inorganic or organic base, if the agent has an acidic functional group (e.g., a carboxylic acid functional group). Suitable bases include, but are not limited to, alkali metal hydroxides such as sodium, potassium, and lithium; alkaline earth metal hydroxides such as calcium and magnesium; hydroxides of other metals such as aluminum and zinc; ammonia and organic amines, such as unsubstituted or hydroxysubstituted mono, di, or trialkylamines; dicyclohexylamine; tributylamine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono, bis, or tris-(2-hydroxy-lower alkylamines), such as mono-, bis-, or tris-(2-hydroxyethyl)-amine, 2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine; N,N,-di-lower alkyl-N-(hydroxy-lower alkyl)-amine, such as N,N-dimethyl-N-(2-hydroxyethyl)-amine, or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids, such as arginine and lysine.The term "pharmaceutically acceptable salt" also refers to a salt prepared by contacting an agent (e.g., anipamil, candesartan, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, telmisartan, thiapamil, or verapamil) with a pharmaceutically acceptable inorganic or organic acid, if the agent has a basic functional group (e.g., an amino functional group). Suitable acids include, but are not limited to, hydrogen sulfate, citric acid, acetic acid, oxalic acid, hydrochloric acid, hydrogen bromide, hydrogen iodide, nitric acid, phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, succinic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0141] The compositions of the present invention may contain magnesium salts, and optionally magnesium oxide (MgO).

[0142] Pharmaceutical therapeutic agents For therapeutic use, a composition comprising a first agent selected from one or more of anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan, can be administered systemically. Preferred routes of administration include, for example, oral administration, or subcutaneous, intravenous, intraperitoneal, intramuscular, or intradermal injection, which provide a continuous sustained level of the drug in the patient. Treatment of human patients or other animals is expected to be carried out using a therapeutically effective amount of the therapeutic agent specified herein in a physiologically acceptable carrier (e.g., for the treatment of panic disorder). Anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and / or verapamil, in combination with candesartan and / or telmisartan, can be formulated in pharmaceutically acceptable buffers such as saline. Suitable carriers and their formulations are described, for example, in Remington's Pharmaceutical Sciences by EW Martin. The amount of therapeutic agent administered varies depending on the mode of administration, the patient's age and weight, and the clinical symptoms of the cerebrovascular and / or behavioral health disorder. In some embodiments, the clinical symptoms are ten major neuropsychiatric symptoms (i.e., anxiety, emotional blunting, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, pain (e.g., physical pain), and mental disorders). Generally, the amount is considered to be within the range used for other agents used in the treatment of cerebrovascular and / or behavioral health disorders.In some embodiments, verapamil and telmisartan, verapamil and candesartan, or candesartan and / or telmisartan, in combination with one or more of anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil, are administered in a dose effective in reducing one or more of the ten major neuropsychiatric symptoms (i.e., anxiety, emotional blunting, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, physical pain, and mental disturbances). The effectiveness of the administration can be determined by methods known to those skilled in the art, or by using any assay (e.g., behavioral assessment, neuropsychological test, etc.) that measures one or more of the ten neuropsychiatric symptoms. For example, in some embodiments disclosed herein, the effectiveness of the treatment can be measured by patient self-reports of symptoms and / or via NIH toolbox tests. Effectiveness may be measured based on disease-specific gold-standard outcome scales, including scales that assess not only symptoms and function, but also overall life satisfaction or quality of life.

[0143] Pharmaceutical composition preparations Administration of a composition comprising one or more agents selected from anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil, and one or more agents selected from candesartan and telmisartan, can be administered to a subject for the treatment of a brain and / or behavioral health disorder (e.g., panic disorder) by any suitable means, in combination with other components, to result in a concentration of the therapeutic agent effective for the remission, reduction, or stabilization of one or more of the ten major neuropsychiatric symptoms. In some embodiments, this combination treats one or more of the ten major neuropsychiatric symptoms (i.e., anxiety, emotional blunting, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, body aches, and psychosis). The composition may optionally contain magnesium salts, magnesium oxide (MgO). The composition may be contained in any appropriate amount of any appropriate carrier material, which is generally present in an amount of 1 to 95% by weight of the total weight of the composition. The composition can be provided in a dosage form suitable for oral administration. In some embodiments, the composition can be provided in a dosage form suitable for parenteral (e.g., subcutaneous, intravenous, intramuscular, or intraperitoneal) administration routes. The pharmaceutical composition can be formulated according to conventional pharmaceutical practices (see, for example, Remington: The Science and Practice of Pharmacy (20th ed.), ed. AR Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988–1999, Marcel Dekker, New York).

[0144] Human dosages can be initially determined by extrapolating from the amounts used in mice for anipamil, candesartan, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, telmisartan, thiapamil, or verapamil, or combinations thereof. Dosage can also be determined based on the dosages used in humans for the effective treatment of the disorder for which each individual agent is indicated. The dosage (optional, daily dose) of one or more of the following drugs, individually or combined, may be approximately 1 mg to approximately 720 mg, 120 mg to approximately 480 mg, approximately 250 mg to approximately 360 mg, approximately 200 mg to approximately 500 mg, approximately 250 mg to approximately 350 mg, and approximately 120 mg to approximately 720 mg. The dosage of the first agent may be approximately 20 mg to 720 mg, approximately 30 mg to 120 mg, approximately 50 mg to 200 mg, approximately 60 mg to 360 mg, approximately 200 mg to 500 mg, or approximately 288 mg, 15 mg, or 30 mg. The dosage of the second agent may be approximately 1 mg to 240 mg, approximately 2.5 mg to 40 mg, approximately 20 mg to 180 mg, approximately 80 mg to 400 mg, approximately 45 mg to 180 mg, approximately 80 mg to 320 mg, approximately 45 mg to 150 mg, approximately 90 mg to 200 mg, or approximately 96 mg, 2.5 mg, or 5 mg. In some embodiments, the dosage of the second agent exceeds 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, or 150 mg. The dosages of the first agent or its components and the second agent or its components may be contained in one or more dosage forms. The dosages of the first agent and the second agent may vary between adult and pediatric formulations.

[0145] In some embodiments, the daily dose of either the first or second agent is administered more than once per day. For example, in some embodiments, the daily dose (e.g., 80 mg) is delivered twice per day in doses of 40 mg each.

[0146] The first and second agents may be administered to the subject (optionally, in dosage form) in a dosage ratio (mass:mass) of approximately or at least approximately 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, or 8:1 between the first agent (e.g., anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil) and the second agent (e.g., candesartan, telmisartan, or a combination thereof). In some embodiments, the dosage ratio of the first agent (e.g., anipamil, devapamil, diltiazem, faripamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil, or a combination thereof) to the second agent (e.g., candesartan, telmisartan, or a combination thereof) is approximately 3:1, 4:1, 5:1, 6:1, 7:1, or less than 8:1. The first agent (e.g., anipamil, devapamil, diltiazem, faripamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil, or a combination thereof) can be administered to the subject at a daily dose that is approximately two or three times the daily dose of the second agent (e.g., candesartan, telmisartan, or a combination thereof) administered to the subject.In some embodiments, a first agent (e.g., anipamil, devapamil, diltiazem, faripamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil, or a combination thereof), a second agent (e.g., candesartan, telmisartan, or a combination thereof), or their components (e.g., anipamil, candesartan, devapamil, diltiazem, faripamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine) The dosage of telmisartan, thiapamil, and verapamil, or any combination thereof, may vary individually or in combination between approximately 0.1 mg compound / kg body weight and approximately 2 mg compound / kg body weight; or approximately 0.5 mg / kg body weight and approximately 2 mg / kg body weight; or approximately 1.0 mg / kg body weight and approximately 2 mg / kg body weight; or approximately 1.5 mg / kg body weight and approximately 2 mg / kg body weight; or approximately 0.1 mg / kg body weight and approximately 1.5 mg / kg body weight; or approximately 0.10 mg / kg body weight and approximately 1.0 mg / kg body weight; or approximately 0.10 mg / kg body weight and approximately 0.5 mg / kg body weight. In other embodiments, this dose may be approximately 0.1, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, or 3.0 mg / kg body weight. In other embodiments, the dose may be in the range of approximately 0.2 mg compound / kg to approximately 2 mg compound / kg. Naturally, the dosage may be adjusted upward or downward depending on the results of the initial clinical trial and the needs of the specific patient, as is routinely done in such treatment protocols.

[0147] The dosage (optional, daily dose) of magnesium salt (e.g., MgO) in the embodiment is approximately 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, or 500 mg, or at least approximately 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, or 500 mg. The dosage (optional, daily dose) of magnesium salt (e.g., MgO) in the embodiment is approximately 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg or less.

[0148] Pharmaceutical compositions in the manner disclosed herein can be formulated to release an active compound (e.g., anipamil, candesartan, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, telmisartan, thiapamil, and verapamil, or combinations thereof) substantially immediately upon administration or at any predetermined time or period thereafter. The latter type of composition is generally known as controlled-release formulations, which include: (i) formulations that produce substantially constant drug concentrations in the body over a long period of time; (ii) formulations that produce substantially constant drug concentrations in the body over a long period of time after a predetermined lag time; (iii) formulations that sustain action for a predetermined period of time by maintaining a relatively constant effective level in the body while minimizing undesirable side effects associated with fluctuations in plasma levels of the active substance (a sawtooth kinetic pattern); (iv) formulations that localize action, for example, by spatially positioning the controlled-release composition near target cells of interest (e.g., brain cells); (v) formulations that enable convenient dosing, such as when the dose is administered orally once or twice per day; and (vi) formulations that target calcium channels and angiotensin receptors by using carriers or chemical derivatives to deliver the therapeutic agent to specific cell types (e.g., brain cells). For some applications, controlled-release formulations eliminate the need for frequent dosing throughout the day to maintain plasma levels at therapeutic levels.

[0149] Immediate-release formulations of the compositions of this disclosure can be formulated to release the active compound (e.g., anipamil, candesartan, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, telmisartan, thiapamil, and verapamil, or combinations thereof) substantially immediately under one or more of the following conditions: i) fasting gastric conditions; ii) feeding gastric conditions; or iii) intestinal conditions. Such administration conditions can include a wide range of relevant pH conditions, e.g., pH ≤1, pH 4-6, pH 5-8, or pH ≥8. Substantially immediate release can include, but is not limited to, release of 80% or more within 1 hour of administration, release of 90% or more within 1 hour of administration, release of 90% or more within 2 hours of administration, release of 90% or more within 1.5 hours of administration, release of 95% or more within 2 hours of administration, or release of 95% or more within 1.5 hours of administration.

[0150] To obtain controlled release, where the release rate exceeds the metabolic rate of the compound under discussion, one of several strategies can be employed. For example, controlled release can be achieved by appropriately selecting various formulation parameters and components, including, for instance, various types of controlled release compositions and coatings. Thus, therapeutic agents are formulated into pharmaceutical compositions that release the therapeutic agent in a controlled manner upon administration, along with appropriate excipients. Examples include single or multiple unit tablets or capsule compositions, oils, suspensions, emulsions, microcapsules, microspheres, molecular complexes, nanoparticles, patches, and liposomes.

[0151] Solid dosage form for oral use Formulations for oral use include tablets containing one or more of the active ingredients (e.g., anipamil, candesartan, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, telmisartan, thiapamil, and verapamil) in a mixture with non-toxic, pharmaceutically acceptable excipients. Such formulations are known to those skilled in the art. Excipients may include, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugars, mannitol, microcrystalline cellulose, starch, e.g., potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives, e.g., microcrystalline cellulose, starch, e.g., potato starch, croscarmellose sodium, alginate, or alginic acid); binders (e.g., sucrose, glucose, sorbitol, gum arabic, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); as well as lubricants, flow promoters, and anti-sticking agents (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients may include colorants, flavorings, plasticizers, water-retaining agents, and buffering agents.

[0152] Tablets are coated in some embodiments and uncoated in others. Optionally, tablets may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period. The coating can be adapted to release one or more active drugs in a predetermined pattern (e.g., to achieve a controlled-release formulation), or to prevent the release of the active drug until it has passed the stomach (enteric coating). In some embodiments, the coating is a sugar coating, a film coating (e.g., based on hydroxypropyl methylcellulose, methylcellulose, methylhydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylic acid copolymer, polyethylene glycol, and / or polyvinylpyrrolidone), or an enteric coating (e.g., based on methacrylate copolymer, cellulose phthalate acetate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose succinate acetate, polyvinyl acetate phthalate, shellac, and / or ethylcellulose). Furthermore, time-delaying materials such as glyceryl monostearate or glyceryl distearate may be used.

[0153] In some embodiments, the solid tablet composition includes a coating adapted to protect the composition from undesirable chemical changes (e.g., chemical decomposition prior to the release of the first and / or second agent). In some embodiments, the coating is applied to the solid dosage form in a manner similar to that described in the Encyclopedia of Pharmaceutical Technology above.

[0154] One or more of anipamil, candesartan, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, telmisartan, thiapamil, and verapamil are mixed together or divided within a tablet. For example, as shown in Figure 4, the first agent (e.g., one or more of anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil) is contained inside the tablet, and the second agent (e.g., one or more of candesartan and telmisartan) is on the outside, such that a significant portion of the second agent is released before the first agent is released. In some embodiments, the second agent (e.g., one or more of candesartan and telmisartan) is contained inside the tablet, and the first agent (e.g., one or more of anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil) is contained on the outside. In another example, as shown in Figure 7, the tablet may be divided so that the first agent is contained in a different layer from the second agent. In some embodiments, as shown in Figure 4, the outer layer of a tablet containing either the first or second agent is coated onto the inner layer of the tablet containing the other agent, but as shown in Figure 10, the outer layer may be press-coated onto the inner layer from powder, pellet, particle, or granular form. In some embodiments, the agent contained on the outside of the tablet or coated is formulated in an immediate-release form, and the agent contained inside the tablet is formulated in a controlled-release form.

[0155] Formulations for oral use also include compressed tablets in which the active ingredients (i.e., anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil, or combinations thereof) are compressed together, as shown in Figures 8 and 9. For example, the first agent (e.g., one or more of anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil) is provided in tablet or minitablet form, and the second agent (e.g., one or more of candesartan and telmisartan) is provided in powder, pellet, particle, or granule form, and the first and second agents are then compressed together to form a compressed tablet. In other embodiments, both agents may instead be provided in powder, pellet, particle, or granular form prior to compression, or both agents may be provided in tablet or minitablet form. In preferred embodiments of these compressed tablets, the second agent may be provided in an immediate-release form.

[0156] Formulations for oral use also include push-pull osmotic pump tablets in which the active ingredient (i.e., anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil, or combinations thereof) is contained either on the outer layer of the tablet or within the osmotic core of the tablet, surrounded by a semipermeable membrane having one or more pores for the release of the active ingredient from the osmotic core. For example, a first agent (e.g., one or more of anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil) is layered in an osmotic core together with a polymer osmogen layer, both of which are surrounded by a semipermeable membrane having one or more pores, and a second agent (e.g., one or more of candesartan and telmisartan) is coated on the outside of the semipermeable membrane. In this example, upon administration, the second agent is released immediately, while the first agent is subjected to controlled release because the semipermeable membrane allows water to move into the osmotic core, for example, through osmosis, causing the first agent to leach out through the pores in the membrane, and / or as the polymer osmogen swells by absorbing water, the first agent is pushed out through the pores in the membrane. In preferred embodiments of these compressed tablets, the second agent is provided in an immediate-release form.

[0157] Formulations for oral use also include chewable tablets or capsules (e.g., hard gelatin capsules), as shown in Figures 11 and 12, in which the active ingredient (i.e., anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil, or combinations thereof) is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate, or kaolin), or, as soft gelatin capsules, the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil. For example, a first agent (e.g., one or more of anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil) is provided in tablet or minitablet form, and a second agent (e.g., one or more of candesartan and telmisartan) is provided in powder pellet, particle, or granule form, and then the first and second agents are encapsulated to form a capsule. In other embodiments, instead, both agents may be provided in powder, pellet, particle, or granule form before encapsulation, or both agents may be provided in tablet or minitablet form. In preferred embodiments of these capsules, the second agent is provided in an immediate-release form.

[0158] In some embodiments, powders, pellets, particles, and granules are prepared using the components described above under Tablets and Capsules, for example, in a conventional manner using a mixer, fluidized bed apparatus, or spray drying equipment.

[0159] Controlled and immediate-release oral dosage forms Controlled-release compositions (e.g., for oral use) of a first agent selected from one or more of anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan, can be constructed to release the agent by controlling the dissolution and / or diffusion of the active substance. For example, immediate-release formulations are commercially available for verapamil and telmisartan, as are sustained-release versions of verapamil. Sustained-release (ER) formulations of verapamil release the drug over 12 or 24 hours. Dissolution or diffusion-controlled release can be achieved by appropriate coating of tablets, capsules, pellets, or granular formulations of the compound, or by incorporating compositions containing the first and / or second agents into one or more appropriate matrices or matrices. In some embodiments, the controlled-release coating comprises the above-mentioned coating materials and / or one or more of the following: shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resin, dipolylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-hydroxymethacrylate, methacrylate hydrogel, 1,3-butylene glycol, ethylene glycol methacrylate, and / or polyethylene glycol. In controlled-release matrix formulations, the matrix material may also include, for example, hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and / or halogenated fluorocarbons.

[0160] In some embodiments, a composition comprising two of the agents described herein (e.g., one or more of anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil, as well as one or more of telmisartan and candesartan) is in the form of a buoyant tablet or capsule (i.e., a tablet or capsule that floats on top of the stomach contents for a certain period of time after oral administration). A buoyant tablet formulation of the composition can be prepared by granulating one or more of the agents or their components with an excipient and 20-75% w / w of hydrocolloid, such as hydroxyethylcellulose, hydroxypropylcellulose, or hydroxypropylmethylcellulose. The resulting granules can then be compressed into a tablet. Upon contact with gastric juice, the tablet forms a substantially water-impermeable gel barrier around its surface. This gel barrier helps maintain a density of less than 1, thereby allowing the tablet to remain buoyant in gastric juices.

[0161] Further combination therapy Optionally, the therapeutic combinations of the present disclosure may be administered in conjunction with any other standard anxiolytic, anti-migraine therapy, anti-depressant therapy, anti-cognitive difficulty therapy, anti-anger therapy, anti-emotional blunting therapy, anti-fatigue therapy, anti-pain therapy, anti-psychotic therapy, or anti-insomnia therapy, such as cognitive behavioral therapy, sedatives, etc.; such methods are known to those skilled in the art and are described in Remington's Pharmaceutical Sciences by EW Martin. If desired, the therapeutic combinations may be administered in conjunction with any conventional anxiolytic therapy, including, but not limited to, anxiolytics and / or sedatives, antipsychotics, mood stabilizers, anticonvulsants, antihistamines, and antidepressants.

[0162] The therapeutic combinations or compositions of the present invention can be administered to subjects to treat neuropsychological conditions. Neuropsychological conditions may be disorders of the brain and / or behavior. Non-limited examples of brain and behavioral health disorders include affective disorders, anxiety disorders, neurodegenerative disorders, neurodevelopmental disorders, psychotic disorders, personality disorders, migraine-related disorders, stress-related disorders, somatoform disorders, substance use disorders, paroxysmal disorders, neuroimmunological disorders, and cerebrovascular disorders. Examples of affective disorders include bipolar disorder, cyclothymic temperament, dysthymia, major depressive disorder, postpartum depression, and seasonal affective disorder. Examples of anxiety disorders include generalized anxiety disorder, panic disorder, social anxiety disorder, post-traumatic stress disorder, obsessive-compulsive disorder, and specific phobias. Examples of neurodegenerative disorders include Alzheimer's disease, Parkinson's disease, and Lewy body dementia. Examples of neurodevelopmental disorders include autism spectrum disorder, attention deficit hyperactivity disorder (ADHD), and learning disabilities. Examples of psychotic disorders include schizophrenia, schizoaffective disorder, and major depressive disorder with psychiatric abnormalities. Examples of personality disorders include paranoid personality disorder, schizotypal personality disorder, schizotypal personality disorder, antisocial personality disorder, borderline personality disorder, histrionic personality disorder, narcissistic personality disorder, avoidant personality disorder, dependent personality disorder, and obsessive-compulsive personality disorder. Examples of migraine-related disorders include migraine with aura, migraine without aura, painless migraine, and vestibular migraine. Examples of stress-related disorders include acute stress reaction, reactive attachment disorder, adjustment disorder, and hyperhidrosis. Examples of somatoform disorders include somatization disorder, hypochondriasis, conversion disorder, body dysmorphic disorder, and chronic pain. Examples of substance use disorders include alcohol use disorder and opioid use disorder. Examples of seizure disorders include epileptic disorders and psychogenic non-epileptic seizure disorders. Examples of neuroimmunological disorders include multiple sclerosis. Examples of cerebrovascular disorders include cerebrovascular disease, vascular dementia, and cerebrovascular accidents.The symptoms associated with the disease may be selected from one or more of the "10 main symptoms" associated with brain and behavioral disorders: anxiety, emotional blunting, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, physical pain, and mental disorders. Administration of the therapeutic combination, composition, or dosage form of the present invention to a subject may reduce or alleviate one or more of the symptoms associated with brain and / or behavioral disorders.

[0163] The compositions or therapeutic combinations of the present invention can be administered to a subject in an amount sufficient to alter local cerebral blood flow in the subject. The cerebral regions may include one or more of the telencephalon, diencephalon, and midbrain. The compositions or therapeutic combinations of the present invention can be administered to a subject in an amount sufficient to bring hemodynamic equilibrium in a functional brain network that works harmoniously among regions within the telencephalon, diencephalon, and midbrain of the subject.

[0164] Patient selection for treatment This disclosure provides a selection of patients who are likely to benefit from treatment by the therapeutic combinations described herein. Such patients are selected as having cerebrovascular or behavioral disorders or their symptoms (e.g., anxiety, emotional blunting, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, physical pain, and mental disorders). Patients with cerebrovascular or behavioral disorders or their symptoms are selected for therapy with a combination therapy comprising a first agent selected from one or more of anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isuradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil, and a second agent selected from one or more of telmisartan and candesartan.

[0165] While not bound by theory, patients with the greatest energy supply / demand mismatch are likely to benefit most from the compositions of this disclosure. Patients with energy supply / demand mismatch are likely to show the greatest change in functional connectivity before and after combination treatment. Considering energy as a binary (high vs. low), four energy demand / supply phenotypes emerge: high demand / high supply (low risk of total neuropsychiatric symptoms), high demand / low supply (high risk of total neuropsychiatric symptoms), low demand / high supply (low risk of total neuropsychiatric symptoms), and low demand / low supply (low risk of total neuropsychiatric symptoms).

[0166] Kit or pharmaceutical system The composition can be assembled into a kit or pharmaceutical system for treating cerebrovascular or behavioral health disorders or their symptoms (e.g., anxiety, migraines, depression, cognitive difficulties, anger, emotional blunting, fatigue, pain, mental disorders, or insomnia). The kit or pharmaceutical system includes a means of transport, e.g., a box, carton, tube, etc., containing one or more sealed containers, e.g., vials, tubes, ampoules, bottles, etc. The kit or pharmaceutical system may also include relevant instructions for using the agents in the embodiments disclosed herein. In some embodiments, the kit includes a composition comprising one of a first agent (e.g., anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, or verapamil) together with one of a second agent (e.g., candesartan or telmisartan).

[0167] Unless otherwise indicated, the embodiments disclosed herein utilize conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry, and immunology, which are well within the understanding of those skilled in the art. Such techniques are well described in the literature, for example, “Molecular Cloning: A Laboratory Manual”, second edition (Sambrook, 1989); “Oligonucleotide Synthesis” (Gait, 1984); “Animal Cell Culture” (Freshney, 1987); “Methods in Enzymology” “Handbook of Experimental Immunology” (Weir, 1996); “Gene Transfer Vectors for Mammalian Cells” (Miller and Calos, 1987); “Current Protocols in Molecular Biology” (Ausubel, 1987); “PCR: The Polymerase Chain Reaction”, (Mullis, 1994); and “Current Protocols in Immunology” (Coligan, 1991). These techniques are applicable to the production of polynucleotides and polypeptides of the present invention and can therefore be considered in the manufacture and implementation of the present invention. Techniques particularly useful for specific embodiments are discussed in the following sections.

[0168] The following examples are provided to give a complete disclosure and explanation of the methods for manufacturing and using the assays, screenings, and therapeutic methods of the present invention to those skilled in the art, and are not intended to limit the scope of what the inventors consider to be their invention. [Examples]

[0169] Example 1: Formulation Composition The initial product design involved the continuous 24-hour release of both telmisartan and verapamil. Therefore, the initial product design included the steps of granulating telmisartan and verapamil, followed by blending with a controlled-release polymer and diluent, and then compressing into tablets. Figure 1 illustrates this. The formulation composition of batch 341-86 is shown in Table 1 below.

[0170] (Table 1) Formulation composition of 341-86 Core Matrix Tablets TIFF2026522575000017.tif78161

[0171] Multimedia dissolution was performed. The test conditions were as follows: • Strictly simulates the stomach conditions during fasting, using 0.1N HCl. • Strictly simulates stomach conditions during feeding, pH 4.5 • Strictly simulates intestinal conditions, pH 6.8 The data are shown in Figures 2 and 3. Dissolution tests for batch 341-86 yielded unexpected results. Verapamil was steadily released over 24 hours under all medium conditions (Figure 2), while telmisartan was hardly released at all in media at pH 4.5 and 6.8, which are pH levels associated with normal gastric conditions (Figure 3). This malabsorption highlights a challenge for the proper formulation of the combination therapy.

[0172] Example 2: Telmisartan / verapamil preparation The potential for poor absorption in the later gastrointestinal tract due to the lack of telmisartan dissolution was surprising. To overcome this challenge, the design criteria were modified. The redesigned product was intended to release telmisartan immediately under gastric pH conditions, while verapamil was released over a 24-hour timeframe under all pH conditions. This was achieved by removing telmisartan from the core tablet and adding an immediate-release coating of telmisartan to the outside of a verapamil controlled-release matrix tablet. A diagrammatic representation of this formulation is shown in Figure 4. Batch 341-109AO was thus formulated. Details of the formulation composition for the biphasic drug delivery system are shown in Table 2 below.

[0173] (Table 2) Formulation composition of 341-109AO TIFF2026522575000018.tif137161

[0174] Multimedia dissolution was performed on 341-109AO, and the release of verapamil was tested. The test conditions were as follows: • Strictly simulates the stomach conditions during fasting, using 0.1N HCl. • Strictly simulates stomach conditions during feeding, pH 4.5 • pH 6.8 strictly simulates intestinal conditions. Dissolution is shown in Figure 5. Telmisartan was tested only under gastric pH conditions. Data is shown in Figure 6.

[0175] Other embodiments From the above description, it will be clear that modifications and alterations can be made to the present invention as described herein to suit various uses and conditions. Such embodiments are also within the scope of the following claims.

[0176] Any listing of elements in any definition of a variable in this specification includes the definition of that variable as any single element or combination (or subcombination) of the enumerated elements. Any description of an aspect in this specification includes that aspect as any single aspect, or in combination with any other aspect or parts thereof.

[0177] All patents and publications referenced herein are incorporated herein by reference to the same extent as each separate patent and publication is specifically and individually indicated as being incorporated by reference. The present invention may be related to PCT International Application PCT / US2021 / 027641, or U.S. Applications 17 / 477,415, 17 / 477,444, or 17 / 996,413, each of which in whole is incorporated herein by reference for all purposes.

Claims

1. A first composition comprising an effective amount of a first agent having calcium channel blocking activity and A second composition comprising an effective amount of a second agent having angiotensin II receptor blocking activity. A formulation comprising a therapeutic combination including a first composition, wherein the first composition is formulated to release the first agent sustainably when administered to a subject, and the second composition is formulated to release the second agent immediately when administered to the subject.

2. A first composition comprising an effective amount of a first agent having calcium channel blocking activity and A second composition comprising an effective amount of a second agent having angiotensin II receptor blocking activity. A formulation comprising a therapeutic combination including the following, wherein the second composition is formulated such that, when administered to a subject, the second agent has a faster release rate compared to the release rate of the first agent of the first composition.

3. A first composition comprising an effective amount of a first agent having calcium channel blocking activity and A second composition comprising an effective amount of a second agent having angiotensin II receptor blocking activity. A formulation comprising a therapeutic combination including a second composition, wherein the second composition is formulated to immediately release and dissolve the second agent when in contact with a solution having a pH between 1 and 5.

4. A first composition comprising an effective amount of a first agent having calcium channel blocking activity and A second composition comprising an effective amount of a second agent having angiotensin II receptor blocking activity. A formulation comprising a therapeutic combination including a second composition, wherein the second composition is formulated such that, upon administration to a subject, it immediately releases and dissolves the second agent in the subject under gastric or intestinal conditions during ingestion.

5. A first composition comprising an effective amount of a first agent having calcium channel blocking activity and A second composition comprising an effective amount of a second agent having angiotensin II receptor blocking activity. A tablet comprising a therapeutic combination including the second composition, wherein the second composition is formulated such that, when the tablet is administered to a subject, the second composition releases the second agent before the first composition releases the first agent.

6. The formulation according to any one of claims 1 to 4 or the tablet according to claim 5, wherein the first agent is selected from the group consisting of anipamil, devapamil, diltiazem, falipamil, felodipine, garopamil, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, thiapamil, and verapamil.

7. The formulation according to any one of claims 1 to 4 or 6, or the tablet according to claim 5 or 6, wherein the second agent is telmisartan or candesartan.

8. The combination is labeled for the treatment of brain and / or behavioral health disorders, and is a formulation according to any one of claims 1 to 4, 6, or 7, or a tablet according to any one of claims 5 to 7.

9. A formulation or tablet according to any one of claims 1 to 4 or 6 to 8, wherein the combination is labeled for the treatment of symptoms of a brain and / or behavioral health disorder selected from the group consisting of anxiety, emotional blunting, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, pain, and mental disorders.

10. A formulation according to any one of claims 1 to 4 or 6 to 9, or a tablet according to any one of claims 5 to 9, wherein the first agent is verapamil.

11. The formulation according to any one of claims 1 to 4 or 6 to 10, or the tablet according to any one of claims 5 to 10, wherein the second agent is telmisartan.

12. The formulation according to any one of claims 1 to 4 or 6 to 11, or the tablet according to any one of claims 5 to 11, wherein the second composition is formulated such that more than 80% of the second agent is released within one hour of administration to a subject.

13. The formulation according to any one of claims 1 to 4 or 6 to 12, or the tablet according to any one of claims 5 to 12, wherein the second composition is formulated such that more than 95% of the second agent is released within two hours of administration to a subject.

14. The formulation according to any one of claims 1 to 4 or 6 to 13, or the tablet according to any one of claims 5 to 13, wherein the second composition is formulated such that more than 85% of the second agent is released within 1.5 hours of administration to a subject.

15. A formulation according to any one of claims 1 to 4 or 6 to 14, or a tablet according to any one of claims 5 to 14, wherein the first composition is formulated to release the first agent over a period of 24 hours.

16. A formulation according to any one of claims 1 to 4 or 6 to 15, wherein the effective amount of the first agent is about 10 mg to about 720 mg, and the effective amount of the second agent is about 2 mg to about 240 mg, or a tablet according to any one of claims 5 to 15.

17. A formulation according to any one of claims 1 to 4 or 6 to 16, wherein the effective amount of the first agent is about 60 mg to about 360 mg, and the effective amount of the second agent is about 20 mg to about 180 mg, or a tablet according to any one of claims 5 to 16.

18. A formulation according to any one of claims 1 to 4 or 6 to 16, wherein the effective amount of the first agent is about 10 mg to about 120 mg, and the effective amount of the second agent is about 1 mg to about 40 mg, or a tablet according to any one of claims 5 to 16.

19. The formulation or tablet according to claim 18, wherein the effective amount of the first agent is about 15 mg and the effective amount of the second agent is about 2.5 mg, or the effective amount of the first agent is about 30 mg and the effective amount of the second agent is about 5 mg.

20. A formulation according to any one of claims 1 to 4 or 6 to 17, wherein the effective amount of the first agent is about 288 mg, and the effective amount of the second agent is about 96 mg, or a tablet according to any one of claims 5 to 17.

21. A formulation according to any one of claims 1 to 4 or 6 to 20, or a tablet according to any one of claims 5 to 19, wherein the mass ratio of the first agent to the second agent is about 2:1 to about 5:

1.

22. A formulation according to any one of claims 1 to 4 or 6 to 21, or a tablet according to any one of claims 5 to 21, wherein the mass ratio of the first agent to the second agent is approximately 2:

1.

23. A formulation according to any one of claims 1 to 4 or 6 to 22, or a tablet according to any one of claims 5 to 22, wherein the amount of the first agent is about 1 to about 4 times the amount of the second agent.

24. A formulation according to any one of claims 1 to 4 or 6 to 23, or a tablet according to any one of claims 5 to 23, wherein the amount of the first agent is approximately twice the amount of the second agent.

25. The formulation or tablet according to any one of claims 1 to 4 or 6 to 24, wherein the formulation or tablet further comprises magnesium oxide.

26. The formulation or tablet according to any one of claims 1 to 4 or 6 to 25, wherein the formulation or tablet further comprises at least about 150 mg of magnesium oxide.

27. The formulation according to any one of claims 1 to 4 or 6 to 26, or the tablet according to any one of claims 5 to 26, wherein the second composition further comprises sodium hydroxide.

28. The formulation or tablet according to claim 27, wherein the sodium hydroxide is present in an amount necessary to dissolve the second agent when administered to a subject.

29. A formulation according to any one of claims 1 to 4 or 6 to 28, or a tablet according to any one of claims 5 to 28, wherein the first composition further comprises a hydrophilic matrix.

30. The formulation or tablet according to claim 29, wherein the hydrophilic matrix comprises hydroxypropyl methylcellulose.

31. A formulation according to any one of claims 1 to 4 or 6 to 30, or a tablet according to any one of claims 5 to 30, wherein the second composition is formulated to form a coating around the first composition.

32. A formulation according to any one of claims 1 to 4 or 6 to 30, or a tablet according to any one of claims 5 to 30, wherein the first composition and the second composition are each formulated as separate layers.

33. A compressed tablet comprising the formulation according to any one of claims 1 to 4 or 6 to 30.

34. The first composition is formulated in tablet form, and the second composition is formulated in particle form, and here, The first composition and the second composition are compressed together to form a compressed tablet. The compressed tablet according to claim 33.

35. The compressed tablet according to claim 33 or the tablet according to any one of claims 5 to 30, wherein each of the first composition and the second composition is formulated as a pellet, particle, or granule.

36. A nuclear tablet comprising the formulation described in any one of claims 1 to 4 or 6 to 30.

37. The core tablet comprises the first composition surrounded by a compression layer of the second composition, wherein, The first composition is formulated as a tablet, and the second composition is formulated as a powder. The core tablet according to claim 36.

38. A capsule comprising the preparation described in any one of claims 1 to 4 or 6 to 30.

39. The capsule according to claim 38, wherein the first composition is formulated as a tablet, and the second composition is formulated as a pellet, particle, granule, or powder.

40. The capsule preparation according to claim 38, wherein each of the first composition and the second composition is formulated as a tablet.

41. A pharmaceutical composition comprising a formulation according to any one of claims 1 to 4 or 6 to 30 and a pharmaceutically acceptable excipient.

42. The pharmaceutical composition according to claim 41, further comprising magnesium oxide.

43. A push-pull type osmotic pump tablet comprising a formulation according to any one of claims 1 to 4 or 6 to 30, The osmotic pump tablet further comprises a first layer containing the first composition, a second layer containing the second composition, and a semipermeable coating. The first layer further comprises polymer osmogen, and here, The osmotic pump tablet is configured such that, upon contact with an aqueous solution, the second agent is released by burst release and the first agent is released by leaching through the semipermeable coating. Push-pull type osmotic pump tablets.

44. A formulation according to any one of claims 1 to 4 or 6 to 32, a tablet according to any one of claims 5 to 32, a compressed tablet according to any one of claims 33 to 35, a nucleated tablet according to claim 36 or 37, a capsule according to any one of claims 38 to 40, a pharmaceutical composition according to claim 41 or 42, or a push-pull type osmotic pump tablet according to claim 43, which is formulated to enhance the bioavailability of the second agent under feeding conditions when administered to a subject.

45. Methods for treating subjects with brain or behavioral health disorders, including the following: A step of administering to a subject a formulation according to any one of claims 1 to 4, 6 to 32, or 44, a tablet according to any one of claims 5 to 32 or 44, a compressed tablet according to any one of claims 31 to 35 or 44, a core tablet according to any one of claims 36, 37, or 44, a capsule according to any one of claims 38 to 40 or 44, a pharmaceutical composition according to any one of claims 41, 42, or 44, or a push-pull osmotic pump tablet according to claim 43 or 44, thereby treating a brain or behavioral disorder.

46. Methods for treating anxiety disorders, including the following: A step of administering to a person a preparation according to any one of claims 1 to 4, 6 to 32, or 44, a tablet according to any one of claims 5 to 32 or 44, a compressed tablet according to any one of claims 33 to 35 or 44, a core tablet according to any one of claims 36, 37, or 44, a capsule according to any one of claims 38 to 40 or 44, a pharmaceutical composition according to any one of claims 41, 42, or 44, or a push-pull osmotic pump tablet according to claim 43 or 44, thereby treating the anxiety disorder.

47. The method according to claim 45 or 46, wherein the formulation, tablet, compressed tablet, core tablet, capsule, pharmaceutical composition, or push-pull osmotic pump tablet is administered once daily.

48. The method according to claim 45 or 46, wherein the formulation, tablet, compressed tablet, core tablet, capsule, pharmaceutical composition, or push-pull osmotic pump tablet is administered twice daily.

49. The method according to any one of claims 45 to 48, wherein the administration is associated with modification of cerebral metabolism or cerebral blood flow.

50. The method according to claim 49, wherein cerebral blood flow is modified in one or more of the telencephalon, diencephalon, and midbrain.

51. The method according to claim 49 or 50, wherein the modification of local cerebral blood flow is associated with establishing hemodynamic equilibrium in a region of the brain.

52. A method according to any one of claims 45 to 51, which increases a primary outcome selected from the group consisting of cognitive function, life satisfaction, sense of meaning and purpose of the subject, sense of emotional or instrumental support of the subject, social relationships, and life satisfaction.

53. A method of increasing the progress of an object in accordance with Maslow's hierarchy of needs, The process includes administering to a subject a formulation according to any one of claims 1 to 4, 6 to 32, or 44, a tablet according to any one of claims 5 to 32 or 44, a compressed tablet according to any one of claims 33 to 35 or 44, a nucleated tablet according to any one of claims 36, 37, or 44, a capsule according to any one of claims 38 to 40 or 44, a pharmaceutical composition according to any one of claims 41, 42, or 44, or a push-pull type osmotic pump tablet according to claim 43 or 44. The first agent modifies the metabolism and / or blood flow associated with the adrenergic system, and the second agent modifies the metabolism and / or blood flow associated with the cerebral renin-angiotensin-aldosterone system, thereby increasing the progress of the object in accordance with Maslow's hierarchy of needs, where the increase in progress is relative to the reference. The aforementioned method.

54. The method according to any one of claims 45 to 53, further comprising the step of administering magnesium oxide to the subject.

55. The method according to claim 54, wherein at least about 150 mg of magnesium oxide is administered to the subject daily.

56. A formulation according to any one of claims 1 to 4, 6 to 32, or 44; a tablet according to any one of claims 5 to 32 or 44; a compressed tablet according to any one of claims 33 to 35 or 44; a nucleated tablet according to any one of claims 36, 37, or 44; a capsule according to any one of claims 38 to 40 or 44; a pharmaceutical composition according to any one of claims 41, 42, or 44; or a push-pull type osmotic pump tablet according to claim 43 or 44; and Instructions for using the formulation, tablets, compressed tablets, core tablets, capsules, pharmaceutical compositions, or push-pull osmotic pump tablets to treat brain and / or behavioral health disorders or their symptoms. A kit that includes this.

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