WO2023014361A1

WO2023014361A1 - Novel pharmaceutical compositions and methods for treatment of psychiatric disorders

Info

Publication number: WO2023014361A1
Application number: PCT/US2021/044654
Authority: WO
Inventors: Jianmin Wang; Geping Cui
Original assignee: La Pharma Tech Inc.
Priority date: 2021-08-05
Filing date: 2021-08-05
Publication date: 2023-02-09

Abstract

Pharmaceutical compositions comprising azelastine or a pharmaceutically acceptable salt of azelastine and folic acid or folate, and/or salts, metabolites, or derivatives thereof are disclosed. Methods of using the pharmaceutical compositions for treating patients suffering from one or more psychiatric disorders or symptoms, such as major depressive disorder, generalized anxiety disorder, panic disorder, agitation, social anxiety disorder, mild chronic depression, obsessive-compulsive disorder, premenstrual dysphoric disorder, seasonal affective disorder, dysthymia, bipolar disorder, posttraumatic stress disorder, sleep disorder related to anxiety, are also disclosed.

Description

NOVEL PHARMACEUTICAL COMPOSITIONS AND METHODS FOR TREATMENT OF PSYCHIATRIC DISORDERS

FIELD OF THE INVENTION

[001] The invention relates to the field of practical medicine, namely, to the use of pharmaceutical compositions for treating, preventing and/or alleviating manifestations of one or more psychiatric disorders or symptoms thereof, including anxiety or depression disorders, such as major depressive disorder, generalized anxiety disorder, panic disorder, agitation, social anxiety disorder, mild chronic depression, obsessive-compulsive disorder, premenstrual dysphoric disorder, seasonal affective disorder, childhood enuresis, dysthymia, bipolar disorder, posttraumatic stress disorder and sleep disorder related to anxiety.

BACKGROUND OF THE INVENTION

[002] Anxiety, depression, panic disorder, and agitation, affect more than one in ten people globally (10.7%) as reported by the Institute for Health Metrics and Evaluation in their flagship Global Burden of Disease study in 2017. Two examples of psychiatric disorders, major depressive disorders (MDDs) and generalized anxiety disorder (GAD), are common, severe, chronic and often life-threatening illnesses. More than 20% of the adult population suffers from these conditions at some time during their life. Suicide is estimated to be a cause of death in up to approximately 15% of individuals with MDDs. In addition, MDDs represent a major risk factor for the development of cardiovascular disease and death after myocardial infarction.

[003] Treatments for anxiety, depression and the like include selective serotonin reuptake inhibitors (SSRIs), such as citalopram (Celexa), escital opram oxalate (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine HRI (Paxil), and sertraline (Zoloft); selective serotonin & norepinephrine inhibitors (SNRIs), such as desvenlafaxine (Khedezla), desvenlafaxine succinate (Pristiq), duloxetine (Cymbalta), levomilnacipran (Fetzima), and venlafaxine (Effexor); tetracyclic antidepressants of noradrenergic and specific serotonergic antidepressants (NaSSAs), such as Remeron; tricyclic antidepressants, such as Elavil, imipramine (Tofranil), nortriptyline (Pamelor), and Sinequan; monoamine oxidase inhibitors (MAOIs), such as isocarboxazid (Marplan), phenelzine (Nardil), selegiline (EMSAM), and tranylcypromine (Parnate); and benzodiazepines, such as alprazolam (Xanax), diazepam (Valium), buspirone (Buspar), and lorazepam (Ativan). These drugs do carry a risk of addiction, tolerance, loss of effectiveness, inciting violent or self-destructive actions, fatigue, and drowsiness along with nausea, increased appetite and weight gain, loss of sexual desire and other sexual problems, insomnia, dry mouth, blurred vision, and so on.

[004] Clinically, new treatments are highly and urgently needed that have tremendous improvement and significant impact to the management of patients with psychiatric disorders, such as treatments being highly effective and with much less adverse effects.

[005] Treatments of psychiatric disorders based on pharmacological mechanisms of action of SSRI, SNRI, NaSSA and MAOI have shown their limitations. Increasing evidence indicates that inflammatory processes can cause and contribute to the development of psychiatric disorders.

[006] Inflammation can be defined as one of the immune responses for protecting living organisms from damage. The immune system can be triggered by various factors such as pathogens, damage to cells and stress that may induce acute or chronic inflammatory responses in organs including the brain, potentially leading to tissue damage or disease. The latest advancements in neurobiological research provide increasing evidence that inflammatory and neurodegenerative pathways play a relevant role in depression and anxiety. Preclinical and clinical studies on depression and anxiety highlighted an increased production of inflammatory markers, such as interleukin (IL)-l, IL-6, tumor necrosis factor (TNF)-a and interferon (INF)- a and y, and overactivated inflammatory signaling pathways including nuclear factor kappa B (NF-KB). Other studies show that acute and chronic administration of cytokines or cytokine inducers were found to trigger depressive and/or anxiety symptoms. According to the cytokine hypothesis, depression and anxiety would be due to a stress-related increased production of pro-inflammatory cytokines that, in turn, would lead to increased oxidative and nitrosative brain damage and consequent reduced availability of tryptophan and serotonin (5-HT). Cytokines would also play a role in the onset of the glucocorticoid resistance, underlying the overdrive of the hypothalamic-pituitaryadrenal axis. Therefore, activation of the inflammatory and neurodegenerative pathways would lead to the brain damage observed in depression and/or anxiety through both reduced neurogenesis and increased neurodegeneration.

[007] Azelastine is classified pharmacologically as a second-generation antihistamine and is a relatively selective, non-sedative, competitive antagonist at Hi receptors for treatment of allergic rhinitis and asthma. But, more uniquely, its inhibition of inflammatory mediators and its mast cell stabilizing effects, in addition to its antihistaminic activity, place it among the new generation of dual-acting anti-inflammatory drugs. Its ability to modify several other mediators of inflammation, such as IL-1, IL-6, TNF-a and INF-a, and to reduce overactivation of NF-KB inflammatory signaling pathway might contribute to its mechanism of action of potential treatment of psychiatric disorders, such as anxiety, depression, panic disorder, agitation, bipolar disorder (BD), and premenstrual dysphoric disorder (PDD). In vitro and in vivo studies, as well as clinical trials, support the dual effects of direct inhibition and stabilization of inflammatory cells. In vitro data indicate that azelastine’s affinity for inhibition of mast cell degranulation may also decrease the release of other inflammatory mediators, including leukotrienes and interleukin- ip, among others. Preclinical studies show that azelastine also directly antagonizes other mediators of inflammation, such as tumor necrosis factor-a, leukotrienes, endothelin-1, and platelet-activating factor.

[008] Folic acid, a form of vitamin B9, is important for the synthesis and repair of DNA and other genetic material, and it is necessary for cells to divide and for functioning of the nervous system at all ages. It facilitates the methionine-synthase mediated conversion of homocysteine to methionine and that is important for nucleotide synthesis and genomic and non-genomic methylation. It has been known that the methylation processes are central to the biochemical basis of the neuropsychiatry of folic acid deficiency. There is also considerable evidence that impaired methylation has some etiologic significance in depression, dementia and folic acid deficiency may specifically affect central monoamine neurotransmitter metabolism and lead to an increase in depressive disorders.

[009] The deficiency of folate, the nature form of folic acid, is shown to reduce proliferation in multiple cell types by causing nucleotide imbalances and subsequent accumulation of cells in the S phase and changes in folate levels may also manipulate the proliferation of T cells which is often associated with various chronic inflammatory disorders. Studies have demonstrated that folic acid significantly attenuated the release of proinflammatory mediators in LPS-activated microglia, blocking NF-KB, and overregulating IL- 10 dependent suppressors of cytokine signaling proteins expression through p38 pathways, and effects production of inflammatory markers, such as interleukin (IL)-l, IL-6, tumor necrosis factor (TNF)-a.

[0010] Therefore, a unique combination of azelastine (antihistamine agent with anti-inflammatory activities) with folic acid or folate, and/or salts, metabolites, or derivatives thereof would potentially be, in terms of working through multi-mechanisms of actions, an effective treatment for behavioral and psychiatric disorders.

SUMMARY OF THE INVENTION

[0011] The present invention includes a pharmaceutical composition that comprises two active pharmaceutical ingredients. This pharmaceutical composition comprises the first active ingredient that is azelastine or a pharmaceutically acceptable salt of azelastine and the second active ingredient that is folic acid or folate, and/or salts, metabolites, or derivatives thereof.

[0012] In some embodiments of this invention, the pharmaceutically acceptable salt of azelastine in the pharmaceutical composition is azelastine hydrochloride.

[0013] In some embodiments of this invention, azelastine hydrochloride (and/or other salt thereof) in the pharmaceutical composition is provided in an amount of about 1 mg to about 8 mg and folic acid or folate, and/or salts, metabolites, or derivatives thereof in an amount of about 0.1 mg to about 2 mg.

[0014] The present invention also includes an oral pharmaceutical dosage form of the pharmaceutical composition that is a solid, liquid, gel, or solution form.

[0015] The present invention further includes use of the composition, such as by oral dosage, through administration to patients with psychiatric disorders, such as one or more of major depressive disorder (MDD), generalized anxiety disorder (GAD), panic disorder, agitation, social anxiety disorder (SAD), mild chronic depression (MCD), obsessive-compulsive disorder (OCD), premenstrual dysphoric disorder (PDD), seasonal affective disorder (SAD), dysthymia, bipolar disorder, posttraumatic stress disorder (PSD) and sleep disorders related to anxiety (SDRA).

[0016] In some embodiments of this invention, an oral pharmaceutical dosage form of the pharmaceutical composition containing azelastine hydrochloride (and/or other salt thereof) in an amount of about 1 mg to about 8 mg and folic acid or folate, and/or salts, metabolites, or derivatives thereof in an amount of about 0.1 mg to about 2 mg is administered to patients with any one or more psychiatric disorder, such as one or more of major depressive disorder (MDD), generalized anxiety disorder (GAD), panic disorder, agitation, social anxiety disorder (SAD), mild chronic depression (MCD), obsessive-compulsive disorder (OCD), premenstrual dysphoric disorder (PDD), seasonal affective disorder (SAD), dysthymia, childhood enuresis, bipolar disorder, posttraumatic stress disorder (PSD or PTSD) and sleep disorders related to anxiety (SDRA). [0017] Embodiments include Aspect 1, which are pharmaceutical compositions comprising: azelastine or a pharmaceutically acceptable salt of azelastine; folic acid or folate, and/or salts, metabolites, or derivatives thereof; and one or more pharmaceutically acceptable excipients.

[0018] Aspect 2 is the pharmaceutical composition of Aspect 1, wherein the azelastine or the pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount in the range of about 1 mg to about 8 mg, or present at least in some amount and up to about 8 mg, such as in the range of about 2-8 mg, or about 3-7 mg, or about 4-6 mg, or any range in between.

[0019] Aspect 3 is the pharmaceutical composition of Aspect 1 or 2, wherein the folic acid or folate, and/or salt, metabolite, or derivative thereof is present in the pharmaceutical composition in an amount in the range of about 0.1 mg to about 2 mg, or present at least in some amount and up to about 2 mg, such as in the range of about 0.2 mg to about 0.9 mg, or about 0.3 mg to about 0.8 mg, or about 0.4 mg to about 0.7 mg, or about 0.5 mg to about 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, or 1.9 mg, or any range in between.

[0020] Aspect 4 is the pharmaceutical composition of any of Aspects 1-3, wherein the folic acid or folate, and/or salt, metabolite, or derivative thereof is present in the pharmaceutical composition in an amount in the range of about 0.1 mg to about 0.4 mg.

[0021] Aspect 5 is the pharmaceutical composition of any of Aspects 1-4, wherein: the azelastine or the pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount in the range of about 1 mg to about 6 mg, such as in the range of about 1-4 mg and the folic acid or folate, and/or salt, metabolite, or derivative thereof is present in the pharmaceutical composition in an amount in the range of about 0.1 mg to about 2 mg, such as in the range of about 0.1-0.4 mg; or the azelastine or the pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount in the range of about 1 mg to about 8 mg, and the folic acid is present in the pharmaceutical composition in an amount in the range of about 0.1-1.0 mg or about 0.1-0.4 mg.

[0022] Aspect 6 is the pharmaceutical composition of any of Aspects 1-5, wherein the pharmaceutically acceptable salt of azelastine is azelastine hydrochloride. [0023] Aspect 7 is the pharmaceutical composition of any of Aspects 1-6, wherein the pharmaceutically acceptable salt of azelastine is azelastine hydrochloride and is present in an amount in the range of up to about 8 mg.

[0024] Aspect 8 is the pharmaceutical composition of any of Aspects 1-7, wherein the azelastine hydrochloride is present in an amount in the range of about 1 mg to about 4 mg.

[0025] Aspect 9 is the pharmaceutical composition of any of Aspects 1-8, wherein the pharmaceutical composition is formulated as an oral pharmaceutical dosage form.

[0026] Aspect 10 is the pharmaceutical composition of any of Aspects 1-9, wherein the oral pharmaceutical dosage form is a solid form or a liquid form.

[0027] Aspect 11 is a method comprising: administering a pharmaceutical composition to a patient; wherein the pharmaceutical composition comprises effective amounts of azelastine or a pharmaceutically acceptable salt of azelastine and folic acid or folate, and/or salts, metabolites, or derivatives thereof; and wherein the effective amounts together are sufficient to treat one or more symptoms of one or more psychiatric disorder of the patient.

[0028] Aspect 12 is the method of Aspect 11, wherein one or more of the psychiatric disorders or symptoms of psychiatric disorders are selected from major depressive disorders, generalized anxiety disorder, panic disorder, agitation, social anxiety disorder, mild chronic depression, premenstrual dysphoric disorder, obsessive-compulsive disorder, dysthymia, childhood enuresis, bipolar disorder, posttraumatic stress disorder, seasonal affective disorder, and anxiety -related sleep disorder.

[0029] Aspect 13 is the method of Aspect 11 or 12, wherein the pharmaceutical composition is administered once or twice a day, or once every 2 or 3 or 4 days to the patient, such as in an oral solid or liquid form.

[0030] Aspect 14 is the method of any of Aspects 11-13, wherein the azelastine or the pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount in the range of about 1 mg to about 8 mg, or present at least in some amount and up to about 8 mg, such as in the range of about 2-8 mg, or about 3-7 mg, or about 4-6 mg, or any range in between.

[0031] Aspect 15 is the method of any of Aspects 11-14, wherein the folic acid or folate, and/or salt, metabolite, or derivative thereof is present in the pharmaceutical composition in an amount in the range of about 0.1 mg to about 2 mg, or present at least in some amount and up to about 2 mg, such as in the range of about 0.2 mg to about 0.9 mg, or about 0.3 mg to about 0.8 mg, or about 0.4 mg to about 0.7 mg, or about 0.5 mg to about 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, or 1.9 mg, or any range in between. [0032] Aspect 16 is the method of any of Aspects 11-15, wherein the folic acid or folate, and/or salt, metabolite, or derivative thereof is present in the pharmaceutical composition in an amount in the range of about 0.1 mg to about 0.4 mg.

[0033] Aspect 17 is the method of any of Aspects 11-16, wherein the azelastine or the pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount in the range of about 1 mg to about 4 mg.

[0034] Aspect 18 is the method of any of Aspects 11-17, wherein: the azelastine or the pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount in the range of about 1 mg to about 8 mg; and the folic acid or folate, and/or salt, metabolite, or derivative thereof is present in the pharmaceutical composition in an amount in the range of about 0.1 mg to about 2 mg, such as from about 0.1 mg to about 1 mg.

[0035] Aspect 19 is a pharmaceutical composition comprising at least some amount of azelastine, or a pharmaceutically acceptable salt of azelastine, in an amount up to about 8 mg (such as in the range of about 2-8 mg, or about 3-7 mg, or about 4-6 mg, or any range in between), and comprising folic acid, and one or more pharmaceutically acceptable excipients.

[0036] Aspect 20 is the pharmaceutical composition of Aspect 19, wherein the folic acid or folate, and/or salt, metabolite, or derivative thereof is present in the pharmaceutical composition at least in some amount and in the range of up to about 2 mg, such as in the range of about 0.2 mg to about 0.9 mg, or about 0.3 mg to about 0.8 mg, or about 0.4 mg to about 0.7 mg, or about 0.5 mg to about 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, or 1.9 mg, or any range in between.

[0037] Aspect 21 is the pharmaceutical composition of Aspect 19 or 20, wherein the azelastine or the pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount that is 1, 2, 3, 4 or 5 times the amount of the folic acid present in the pharmaceutical composition.

[0038] Aspect 22 is the pharmaceutical composition of any of Aspects 19-21, wherein the azelastine or the pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount in the range of about 2 mg, and the folic acid or folate, and/or salt, metabolite, or derivative thereof is present in the pharmaceutical composition at least in some amount, which is an amount of up to about 0.5 mg.

[0039] Aspect 23 is the pharmaceutical composition of any of Aspects 19-22, wherein the pharmaceutically acceptable salt of azelastine is azelastine hydrochloride.

[0040] Aspect 24 is the pharmaceutical composition of any of Aspects 19-23, wherein the pharmaceutical composition is formulated as an oral pharmaceutical dosage form.

[0041] Aspect 25 is a method comprising administering a pharmaceutical composition to a patient, wherein the pharmaceutical composition comprises azelastine, or a pharmaceutically acceptable salt of azelastine, and folic acid or folate, and/or salt, metabolite, or derivative thereof. [0042] Aspect 26 is the method of Aspect 25, wherein the pharmaceutical composition is administered once or twice a day, or once every 2 or 3 or 4 days to the patient, optionally in an oral solid or liquid form.

[0043] Aspect 27 is the method of Aspect 25 or 26, wherein the pharmaceutical composition is administered for a period of at least 2 weeks.

[0044] Aspect 28 is the method of any of Aspects 25-27, wherein the azelastine or the pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount in the range of about 1 mg to about 8 mg.

[0045] Aspect 29 is the method of any of Aspects 25-28, wherein the azelastine or the pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount that is 1, 2, 3, 4 or 5 times the amount of folic acid or folate, and/or salt, metabolite, or derivative thereof present in the pharmaceutical composition.

[0046] Aspect 30 is the method of any of Aspects 25-29, wherein the folic acid or folate, and/or salt, metabolite, or derivative thereof is present in the pharmaceutical composition in an amount in the range of about 0.1 mg to about 2 mg.

[0047] Aspect 31 is the method of any of Aspects 25-30, wherein the azelastine or the pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount in the range of about 1 mg to about 6 mg.

[0048] Aspect 32 is the method of any of Aspects 25-31, wherein the azelastine or the pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition and is present in an amount in the range of up to about 8 mg, and the folic acid or folate, and/or salt, metabolite, or derivative thereof is present in the pharmaceutical composition and is present in an amount in the range of up to about 2 mg.

[0049] Aspect 33 is a pharmaceutical composition, comprising a first active agent, which is azelastine or a pharmaceutically acceptable salt of azelastine; and a second active agent, which is folic acid, folate, and/or salts, metabolites, or derivatives thereof; and one or more pharmaceutically acceptable excipients; wherein the second active agent is present in the pharmaceutical composition in a synergistically effective amount relative to the amount of the first active agent (i.e., the azelastine or pharmaceutically acceptable salt of azelastine and the folic acid, folate, and/or salts, metabolites, or derivatives thereof, are present in synergistically effective amounts).

[0050] Aspect 34 is the use of a pharmaceutical composition in the preparation of a medicament for treating a patient having one or more psychiatric disorder or symptom thereof, wherein the pharmaceutical composition comprises any composition of any of the above Aspects and/or the use involves any of the methods or any one or more method steps of the above Aspects. [0051] Aspect 35 is a pharmaceutical composition for use in treating one or more psychiatric disorder or symptom, wherein the pharmaceutical comprises any composition of any of the above Aspects and/or the use involves any of the methods or any one or more method steps of the above Aspects.

DETAILED DESCRIPTION OF THE INVENTION

[0052] Through clinical practice, the inventors of the present invention found that a pharmaceutical composition with oral dosage forms comprising the active agents, a salt form of azelastine and folic acid, is suitable for treating patients suffering from psychiatric disorders or symptoms of psychiatric disorders such as one or more of major depressive disorder (MDD), generalized anxiety disorder (GAD), panic disorder, agitation, social anxiety disorder (SAD), mild chronic depression (MCD), obsessive-compulsive disorder (OCD), premenstrual dysphoric disorder (PDD), seasonal affective disorder (SAD), dysthymia, childhood enuresis, bipolar disorder, posttraumatic stress disorder (PSD or PTSD) and sleep disorders related to anxiety (SDRA).

[0053] The present application is related by subject matter to International Patent Application Nos. PCT/US 19/27293, PCT/US 19/29885, PCT/US19/33359, PCT/US20/34735, PCT/US20/39916, and PCT/US20/59846, each of which are hereby incorporated by reference herein in their entireties.

[0054] The detailed description provided below is intended as a description of the present examples and is not intended to represent the only forms in which the present example may be constructed or utilized. The description sets forth the functions of the example and the sequence of steps for constructing and operating the example. However, the same or equivalent functions and sequences may be accomplished by different examples.

[0055] Definitions

[0056] As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0057] Psychiatric disorders and symptoms of psychiatric disorders can include but are not limited to major depressive disorder (MDD), generalized anxiety disorder (GAD), panic disorder, agitation, social anxiety disorder (SAD), mild chronic depression (MCD), obsessive-compulsive disorder (OCD), premenstrual dysphoric disorder (PDD), seasonal affective disorder (SAD), dysthymia, childhood enuresis, bipolar disorder, posttraumatic stress disorder (PSD or PTSD) and sleep disorders related to anxiety (SDRA).

[0058] As used herein, the term “folic acid” refers to folic acid, the synthetic form of folate, also called vitamin B9. In certain embodiments, folic acid also includes any pharmaceutically acceptable salt, such as calcium, sodium, potassium, magnesium, and various amines. In embodiments, folic acid includes pharmaceutically acceptable derivatives, such as esters, including mono- or di-esters. In other embodiments, folic acid can be replaced with folate or derivatives/metabolites of folate. Reference to the amounts and dosage ranges of folic acid, for example in the solid oral dosage forms, are to the amounts and dosage ranges of folate, folate derivatives and/or metabolites, or any pharmaceutically acceptable salt(s) thereof.

[0059] In embodiments, the one or more derivatives or biological metabolites of folate include dihydrofolate, tetrahydrofolate, levomefolic acid (levomefolate, 5-methyltetrahydrofolate (5-MTHF), L-methylfolate, L-5-methyltetrahydrofolate, or (6S)-5-methyltetrahydrofolate), 5, 10-methylenetetrahydrofolate, 5, 10-methenyltetrahydrofolate, 5, 10-formiminotetrahydrofolate, 5-formyltetrahydrofolate, and/or 10-formyltetrahydrofolate. In embodiments, the levomefolic acid is provided as a pharmaceutically acceptable salt, such as a calcium or magnesium salt. [0060] As used herein, the term “azelastine” refers to azelastine free base, or 4-(p-Chlorobenzyl)-2-(hexahydro-l -methyl- lH-azepin-4-yl)-l-(2H)-phthalazinone. In certain embodiments, azelastine also includes any pharmaceutically acceptable salt, such as the hydrochloride or HC1 salt. Preferably, in any embodiments of the invention as described herein, azelastine is in the form of its hydrochloride salt, as azelastine hydrochloride or azelastine HC1. More preferably, in any embodiment of the invention as described herein, reference to the amounts and dosage ranges of azelastine in the solid oral dosage forms are to the amounts and dosage ranges of azelastine hydrochloride, and reference to the amounts and dosage ranges of azelastine hydrochloride, for example in the solid oral dosage forms, are to the amounts and dosage ranges of azelastine or any pharmaceutically acceptable salt(s) thereof.

[0061] As used herein, “treating” or “treatment” means complete cure or incomplete cure, or it means that the symptoms of the underlying disease or associated conditions are at least affected, prevented, reduced, eliminated and/or delayed, and/or that one or more of the underlying cellular, physiological, or biochemical causes or mechanisms causing the symptoms are affected, prevented, reduced, delayed and/or eliminated. It is understood that reduced or delayed, as used in this context, means relative to the state of the untreated disease, including the molecular state of the untreated disease, not just the physiological state of the untreated disease.

[0062] The term “effective amount” refers to an amount that is sufficient to affect treatment, as defined below, when administered to an animal or mammal in need of such treatment. The therapeutically effective amount will vary depending upon the patient being treated, the weight and age of the patient, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The pharmaceutical compositions may be administered in either single or multiple doses by oral administration. Administration may be by way of any one or more of capsule, tablet, gel, spray, drops, solution, suspensions, syrups, or the like.

[0063] The term “about” used herein in the context of quantitative measurements means the indicated amount ±10%. For example, with a ±10% range, “about 2 mg” can mean 1.8-2.2 mg. [0064] The pharmaceutical compositions may be formulated for pharmaceutical use using methods known in the art, for example, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems Tenth (Loyd Allen, 2013) and Handbook of Pharmaceutical Manufacturing Formulations (Volumes 1-6, Sarfaraz K. Niazi). Accordingly, incorporation of the active compounds and a controlled, or slow release matrix may be implemented.

[0065] Either fluid or solid unit dosage forms can be readily prepared for oral administration, for example, admixed with any one or more of conventional ingredients such as dicalcium phosphate, magnesium aluminum silicate, magnesium stearate, calcium sulfate, starch, talc, lactose, acacia, methyl cellulose and/or functionally similar materials as pharmaceutical excipients or carriers. A sustained release formulation may optionally be used. In older or incoherent subjects, sustained release formulations may even be preferred. Capsules may be formulated by mixing the pharmaceutical composition with a pharmaceutical diluent which is inert and inserting this mixture into a hard gelatin capsule having the appropriate size. If soft capsules are desired, a slurry of the pharmaceutical composition with an acceptable vegetable, light petroleum or other inert oil can be encapsulated by forming into a gelatin capsule.

[0066] Suspensions, syrups and elixirs may be used for oral administration or fluid unit dosage forms. A fluid preparation including oil may be used for oil soluble forms. A vegetable oil such as corn oil, peanut oil or a flower oil, for example, together with flavoring agents, sweeteners and any preservatives produces an acceptable fluid preparation. A surfactant may be added to water to form a syrup for fluid unit dosages. Hydro-alcoholic pharmaceutical preparations may be used having an acceptable sweetener, such as sugar, saccharin or other non-nutritive sweetener, and/or a biological sweetener and/or a flavoring agent, such as in the form of an elixir.

[0067] The solid oral dosage formulation of this disclosure means a form of tablets, caplets, bi-layer tablets, film-coated tablets, pills, capsules, or the like. Tablets in accordance with this disclosure can be prepared by any mixing and tableting techniques that are well known in the pharmaceutical formulation industry. In some examples, the dosage formulation is fabricated by direct compressing the respectively prepared sustained-release portion and the immediate-release portion by punches and dies fitted to a rotary tableting press, ejection or compression molding or granulation followed by compression.

[0068] The pharmaceutical compositions provided in accordance with the present disclosure can be typically administered orally. This disclosure therefore provides pharmaceutical compositions that comprise a solid dispersion comprising azelastine and folic acid as described herein and one or more pharmaceutically acceptable excipients or carriers including but not limited to, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers, disintegrants, lubricants, binders, glidants, adjuvants, and combinations thereof. Such compositions are prepared in a manner well known in the pharmaceutical arts (see, e.g., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, Tenth (Loyd Allen, 2013) and Handbook of Pharmaceutical Manufacturing Formulations (Volumes 1-6, Sarfaraz K. Niazi)).

[0069] The pharmaceutical compositions may further comprise pharmaceutical excipients such as diluents, binders, fillers, glidants, disintegrants, lubricants, solubilizers, and combinations thereof. Some examples of suitable excipients are described herein. When the pharmaceutical compositions are formulated into tablets, tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed. In embodiments, the pharmaceutical compositions are formulated as tablets, caplets, pills, or capsules capable of delaying disintegration until the pharmaceutical composition is in the gastrointestinal tract of a patient. In embodiments, delaying disintegration is achieved using a coating.

[0070] In embodiments, the pharmaceutical compositions can comprise a) about 1 mg - 8 mg of azelastine HC1 (or other salt thereof) and b) about 0.1 mg to 2 mg of folic acid or a) about 2 mg - 6 mg of azelastine HC1 (or other salt thereof) and b) about 0.1 mg to 0.8 mg of folic acid or folate, and/or salts, metabolites, or derivatives thereof or a) about 2 mg - 4 mg of azelastine HC1 (or other salt thereof) and b) about 0.2 mg to 0.4 mg of folic acid or folate, and/or salts, metabolites, or derivatives thereof, or any amount of azelastine or folic acid within these ranges. Additional embodiments include pharmaceutical compositions comprising a) above zero and about up to and including any of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg or 8 mg azelastine, such as azelastine HC1 or any salt of azelastine, or any amount within any of these ranges and b) above zero and about up to and including any of 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, or 2 mg folic acid or folate, and/or salts, metabolites, or derivatives thereof, or any amount within any of these ranges. For example, the compositions can comprise a) about 2 mg of azelastine HC1 and b) about 0.4 mg of folic acid or folate, and/or salts, metabolites, or derivatives thereof. Further, for example, compositions of the invention can comprise azelastine or a pharmaceutically acceptable salt of azelastine present in an amount in the range of about Img to about 8 mg and folic acid or folate, and/or salts, metabolites, or derivatives thereof in an amount in the range of about 0.1 mg to about 2 mg. In embodiments, the amount of azelastine HC1 (or other salt thereof) present in the composition can be equal to, more than, or less than the amount of folic acid or folate, and/or salts, metabolites, or derivatives thereof present in the composition. In embodiments, azelastine is present in the pharmaceutical composition in an amount of at least 1 mg and folic acid or folate, and/or salts, metabolites, or derivatives thereof is present in an amount of at least 0.1 mg. In embodiments, the amount of azelastine HC1 (and/or other salt thereof) present in the composition can be the same as, or 2 times as much, or 3 times as much, or 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 10, 15, or 50 times as much as the amount of folic acid or folate, and/or salts, metabolites, or derivatives thereof present in the composition, or vice versa. Any one or more of the compositions of the invention can be used with any one or more the methods of the invention disclosed herein, or other methods of using the compositions.

[0071] In embodiments, the folic acid or folate, and/or salts, metabolites, or derivatives thereof, is present in the pharmaceutical composition in a synergistically effective amount relative to the amount of azelastine or the pharmaceutically acceptable salt of azelastine.

[0072] In embodiments, a pharmaceutical composition (e.g., comprising azelastine and folic acid) is used in the preparation of a medicament for treating a patient having one or more psychiatric disorder or symptom thereof. Such compositions can comprise a) about 1 mg - 8 mg of azelastine (or salt thereof) and b) about 0.1 mg to 2 mg, such as about 0.1 mg to 1 mg, of folic acid or folate, and/or salts, metabolites, or derivatives thereof, or any of the amounts disclosed herein, or in synergistic amounts. Further, in embodiments, the pharmaceutical compositions can be for use in treating one or more psychiatric disorder or symptom, wherein the pharmaceutical comprises a) about 1 mg - 8 mg of azelastine (or salt thereof) and b) about 0.1 mg to 2 mg, such as about 0.1 mg to 1 mg, of folic acid or folate, and/or salts, metabolites, or derivatives thereof, or any of the amounts disclosed herein, or in synergistic amounts.

[0073] It will be understood, that the amount of the pharmaceutical composition containing azelastine HC1 and folic acid or folate, and/or salt, metabolite, or derivative thereof actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

[0074] The pharmaceutical compositions, pharmaceutical dosage forms, and tablets containing azelastine, such as azelastine HC1, and folic acid or folate, and/or salts, metabolites, or derivatives thereof as described herein are administered to a patient suffering from one or more psychiatric disorders or symptoms such as major depressive disorder (MDD), generalized anxiety disorder (GAD), panic disorder, agitation, social anxiety disorder (SAD), mild chronic depression (MCD), obsessive-compulsive disorder (OCD), premenstrual dysphoric disorder (PDD), seasonal affective disorder (SAD), dysthymia, childhood enuresis, bipolar disorder, posttraumatic stress disorder (PSD or PTSD) and sleep disorders related to anxiety (SDRA), by administration (such as oral administration) once daily, twice daily, up to four times a day, once every other day, once a week, two times a week, three times a week, four times a week, or five times a week, or combinations thereof.

[0075] In embodiments, patients are administered the pharmaceutical composition(s) with a therapeutic effective daily dosage of azelastine (such as azelastine HC1) in the range of about 1 mg to about 8 mg and folic acid or folate, and/or salts, metabolites, or derivatives thereof in an amount in the range of about 0.1 mg to about 2 mg.

[0076] In embodiments, the pharmaceutical dosage forms and tablets of pharmaceutical compositions containing azelastine, such as azelastine HC1, and folic acid or folate, and/or salts, metabolites, or derivatives thereof as described herein are effective in reversing, reducing, alleviating, and/or treating one or more symptoms in patients with one or more psychiatric disorders or symptoms thereof, such as major depressive disorder (MDD), generalized anxiety disorder (GAD), panic disorder, agitation, social anxiety disorder (SAD), mild chronic depression (MCD), obsessive-compulsive disorder (OCD), premenstrual dysphoric disorder (PDD), seasonal affective disorder (SAD), dysthymia, childhood enuresis, bipolar disorder, posttraumatic stress disorder (PSD or PTSD) and sleep disorders related to anxiety (SDRA)in about 1-8 weeks, such as within 1, 2, 3, 4, 5, 6, 7, or 8 weeks, or any range in between. [0077] In embodiments, the pharmaceutical composition is effective in reversing, reducing alleviating, and/or treating any one or more symptoms including, but not limited to, depression, anxiety, feelings of panic, agitation, delusions, hallucinations, irritability, insomnia, sleep disorder, aggression, etc. [0078] The following Examples are illustrative and should not be interpreted to limit the scope of the claimed subject matter.

[0079] Example 1

[0080] A 45-year-old female patient had MDD and panic disorder. She was treated with sertraline for 2 months and buspirone for 2 months but had no significant clinical improvement. When all of her symptoms worsened, she was given a composition of folic acid (0.19 mg) and azelastine (2 mg) once daily for 1 week, her symptoms started having a dramatic improvement. By 4 weeks of the treatment, she showed no panic disorder and her MDD was reduced by more than 80%. Because azelastine is approved for the treatment of allergic rhinitis and asthma, and the combination composition of azelastine and folic acid had never been expected to be used to treat patients with depression or anxiety, this dramatic clinical outcome which included a fast reduction of symptoms was unexpected. Although the inventors do not intend to be bound by this theory, it is believed that folic acid, through multiple signaling pathways, modulates the inflammatory response in microglia cells, shifting proinflammatory to anti-inflammatory responses, and those responses enhance and are synergistic with azelastine’ s anti-inflammatory action by its own function of suppressing release of cytokines, such as IL-1, IL-6, TNF-a and INF-a, in the CNS system. This composition with two mechanisms of action of anti-inflammation would provide a new solution for treating psychiatric diseases which are incurable by other options, such traditional SSRIs, NSRIs, benzodiazepines, and the like alone.

[0081] Example 2

[0082] A 55-year-old female patient was diagnosed with mild chronic depression and anxiety induced sleep disorder and was treated with citalopram and lorazepam for 3 months. Her symptoms were never improved to the level of her satisfaction. Then she was treated with a composition of folic acid (0.19 mg) and azelastine (2 mg) once daily. After 2 weeks, she exhibited dramatic clinical improvement and showed improvement of her depression by 80% and was satisfied with her sleeping quality. The inventors believe the hypothesis as explained in Example 1 above is applicable here as well. In this case, the composition of two mechanisms of action provided a new solution for treating her chronic depression and insomnia which could not be treated with other options, such traditional SSRIs, NSRIs, benzodiazepines, and the like alone.

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[00114] Aiko Hatakeyama, 2008, Azelastine hydrochloride on behavioral and psychological symptoms and activities of daily living in dementia patients. Geriatr Gerontol Int 2008; 8: 59-61.

[00115] Duraisamy Kempuraj, et al. 2003, Azelastine Inhibits Secretion of IL-6, TNF-alpha and IL-8 as Well as NF-kappaB Activation and Intracellular Calcium Ion Levels in Normal Human Mast Cells. Int Arch Allergy Immunol. 132 (3), 231-9 Nov 2003.

[00116] Kazunori Yoneda, et al. 1997, Suppression by Azelastine Hydrochloride of NF-KB Activation Involved in Generation of Cytokines and Nitric Oxide. Japanese Journal of Pharmacology, 73: 145-53.

[00117] Loyd Allen, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, Tenth (2013)

[00118] Sarfaraz K. Niazi, Handbook of Pharmaceutical Manufacturing Formulations Volumes 1-6.

[00119] The present invention has been described with reference to particular embodiments having various features. In light of the disclosure provided above, it will be apparent to those skilled in the art that various modifications and variations can be made in the practice of the present invention without departing from the scope or spirit of the invention. One skilled in the art will recognize that the disclosed features may be used singularly, in any combination, or omitted based on the requirements and specifications of a given application or design. When an embodiment refers to “comprising” certain features, it is to be understood that the embodiments can alternatively “consist of’ or “consist essentially of’ any one or more of the features. Any of the methods disclosed herein can be used with any of the compositions disclosed herein or with any other compositions. Likewise, any of the disclosed compositions can be used with any of the methods disclosed herein or with any other methods. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention.

[00120] It is noted in particular that where a range of values is provided in this specification, each value between the upper and lower limits of that range is also specifically disclosed. The upper and lower limits of these smaller ranges may independently be included or excluded in the range as well. The singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. It is intended that the specification and examples be considered as exemplary in nature and that variations that do not depart from the essence of the invention fall within the scope of the invention. Further, all of the references cited in this disclosure are each individually incorporated by reference herein in their entireties and as such are intended to provide an efficient way of supplementing the enabling disclosure of this invention as well as provide background detailing the level of ordinary skill in the art.

Claims

1. A pharmaceutical composition, comprising: azelastine or a pharmaceutically acceptable salt of azelastine; folic acid or folate, and/or salts, metabolites, or derivatives thereof; and one or more pharmaceutically acceptable excipients.

2. The pharmaceutical composition of claim 1, wherein the azelastine or the pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount in the range of about 1 mg to about 8 mg.

3. The pharmaceutical composition of claim 1, wherein the folic acid or folate, and/or salt, metabolite, or derivative thereof is present in the pharmaceutical composition in an amount in the range of about 0.1 mg to about 2 mg.

4. The pharmaceutical composition of claim 2, wherein the folic acid or folate, and/or salt, metabolite, or derivative thereof is present in the pharmaceutical composition in an amount in the range of about 0.1 mg to about 2 mg.

5. The pharmaceutical composition of claim 1, wherein: the azelastine or the pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount in the range of about 1 mg to about 4 mg; and the folic acid or folate, and/or salt, metabolite, or derivative thereof is present in the pharmaceutical composition in an amount in the range of about 0.1 mg to about 0.4 mg.

6. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt of azelastine is azelastine hydrochloride.

7. The pharmaceutical composition of claim 2, wherein the pharmaceutically acceptable salt of azelastine is azelastine hydrochloride.

8. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt of azelastine is azelastine hydrochloride and is present at least in some amount and in an amount in the range of up to about 8 mg.

9. The pharmaceutical composition of claim 6, wherein the azelastine hydrochloride is present in an amount in the range of about 1 mg to about 4 mg.

10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated as an oral pharmaceutical dosage form.

11. The pharmaceutical composition of claim 10, wherein the oral pharmaceutical dosage form is a solid form or a liquid form.

12. A method of treating psychiatric disorders or symptoms thereof comprising: administering a pharmaceutical composition to a patient having a psychiatric disorder or having symptoms thereof; wherein the pharmaceutical composition comprises azelastine, or a pharmaceutically acceptable salt of azelastine, and folic acid or folate, and/or salts, metabolites, or derivatives thereof.

13. The method of claim 12, wherein one or more of the psychiatric disorders or symptoms are selected from major depressive disorders, generalized anxiety disorder, panic disorder, agitation, social anxiety disorder, mild chronic depression, premenstrual dysphoric disorder, obsessive- compulsive disorder, dysthymia, childhood enuresis, bipolar disorder, posttraumatic stress disorder, seasonal affective disorder, and anxiety-related sleep disorder.

14. The method of claim 12, wherein the pharmaceutical composition is administered once or twice a day, or once every 2 or 3 or 4 days to the patient in an oral solid or liquid form.

15. The method of claim 12, wherein the azelastine or the pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount in the range of about 1 mg to about 8 mg.

16. The method of claim 15, wherein the folic acid or folate, and/or salt, metabolite, or derivative thereof is present in the pharmaceutical composition in an amount in the range of about 0.1 mg to about 2 mg.

17. The method of claim 12, wherein the folic acid or folate, and/or salt, metabolite, or derivative thereof is present in the pharmaceutical composition in an amount in the range of about 0.1 mg to about 2 mg.

18. The method of claim 17, wherein the azelastine or the pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount in the range of about 1 mg to about 4 mg.

19. The method of claim 12, wherein: the azelastine or the pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount in the range of about 1 mg to about 4 mg; and the folic acid or folate, and/or salt, metabolite, or derivative thereof is present in the pharmaceutical composition in an amount in the range of about 0.1 mg to about 0.4 mg.

20. A pharmaceutical composition comprising: a first active agent, which is azelastine hydrochloride, wherein the first active agent is present in an amount in the range of about 1 mg to about 4 mg; a second active agent, which is folic acid or folate, and/or salts, metabolites, or derivatives thereof, wherein the second active agent is present in an amount in the range of about 0.1 mg to about 0.4 mg; and one or more pharmaceutically acceptable excipients; wherein the first active agent, the second active agent and the one or more pharmaceutically acceptable excipients are present together in an oral pharmaceutical dosage form.

21. A pharmaceutical composition, comprising: a first active agent, which is azelastine or a pharmaceutically acceptable salt of azelastine; a second active agent, which is folic acid, folate, and/or salts, metabolites, or derivatives thereof; and one or more pharmaceutically acceptable excipients; wherein the first and second active agents are present in synergistically effective amounts.

22. Use of a pharmaceutical composition in the preparation of a medicament for treating a patient having one or more psychiatric disorder or symptom thereof, wherein the pharmaceutical composition comprises the composition of any of claims 1-11, 20 or 21 and/or the use involves any of the methods o method steps of claims 12-19.

23. A pharmaceutical composition for use in treating one or more psychiatric disorder or symptom, wherein the pharmaceutical comprises the composition of any of claims 1-11, 20 or 21 and/or the use involves any of the methods or method steps of claims 12-19.