Novel pharmaceutical compositions and methods for the treatment of mental disorders

Abstract

A pharmaceutical composition comprising azelastine or a pharmaceutically acceptable salt of azelastine, and folic acid or a folate, and / or a salt, metabolite, or derivative thereof is disclosed. Also disclosed is a method of using the pharmaceutical composition for treating patients suffering from one or more mental 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, mood swings, bipolar disorder, post-traumatic stress disorder, sleep disorders associated with anxiety.

Description

Technical Field

[0001] Field of the Invention

[0001] The present invention relates to the use of a pharmaceutical composition for treating, preventing, and / or alleviating the signs of one or more mental disorders or their symptoms, including, in the field of practical medicine, anxiety disorders or depressive 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, nocturnal enuresis in children, mood swings, bipolar disorder, post-traumatic stress disorder, and anxiety-related sleep disorders.

Background Art

[0002] Background of the Invention

[0002] Anxiety, depression, panic disorder, and agitation affect more than 2 in 10 people (10.7%) worldwide, as reported in the major Global Burden of Disease study published by the Institute for Health Metrics and Evaluation in 2017. Two examples of mental disorders, major depressive disorder (MDD) 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 point in their lives. Suicide is estimated to be the cause of death in approximately 15% of MDD patients. In addition, MDD is a major risk factor for the development of cardiovascular disease and death after myocardial infarction.

[0003]

[0003] For the treatment of anxiety and depression, etc., there are selective serotonin reuptake inhibitors (SSRI), such as citalopram (Celexa), escitalopram oxalate (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine HRI (Paxil), and sertraline (Zoloft); selective serotonin and norepinephrine inhibitors (SNRI), such as desvenlafaxine (Khedezla), desvenlafaxine succinate (Pristiq), duloxetine (Cymbalta), levomilnacipran (Fetzima), and venlafaxine (Effexor); noradrenergic and specific serotonergic antidepressants (NaSSA) tetracyclic antidepressants, such as mirtazapine; tricyclic antidepressants, such as Elavil, imipramine (Tofranil), nortriptyline (Pamelor), and sinequan; monoamine oxidase inhibitors (MAOI), such as isocarboxazid (Marplan), phenelzine (Nardil), selegiline (EMSAM), and tranylcypromine (Parnate); benzodiazepines, such as alprazolam (Xanax), diazepam (Valium), buspirone (Buspar), and lorazepam (Ativan). These drugs have risks such as poisoning, tolerance, loss of effectiveness, induction of violent or self-destructive behavior, fatigue, and drowsiness accompanied by nausea, increased appetite, and weight gain, loss of libido, and other sexual problems, insomnia, dry mouth, and blurred vision.

[0004]

[0004] Clinically, there is a very urgent need for new treatment methods, such as treatments that are very effective and have far fewer side effects, which can bring about great improvements and have a great impact on the management of patients with mental disorders.

[0005]

[0005] The treatment of mental disorders based on the pharmacological mechanisms of action of SSRI, SNRI, NaSSA, and MAOI has shown its limitations. There is increasing evidence indicating that inflammatory processes cause and contribute to the onset of mental disorders.

[0006]

[0006] Inflammation can be defined as one of the immune responses to protect organisms from damage. The immune system can cause acute or chronic inflammatory reactions in organs including the brain, and can be induced by various factors such as pathogens, cell damage, and stress, which may lead to tissue damage or disease. Recent advances in neurobiological research have provided increasing evidence that inflammatory pathways and neurodegenerative pathways play appropriate roles in depression and anxiety. In preclinical and clinical studies on depression and anxiety, increased production of inflammatory markers such as interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α, interferon (INF)-α and γ, and overactivation of inflammatory signaling pathways including nuclear factor kappa B (NF-κB) have been emphasized. Other studies have shown that acute and chronic administration of cytokines or cytokine inducers can cause depressive symptoms and / or anxiety symptoms. According to the cytokine hypothesis, depression and anxiety are due to increased production of stress-related inflammatory cytokines, which consequently leads to increased oxidative and nitrosative brain damage, and as a result, the availability of tryptophan and serotonin (5-HT) is decreased. Cytokines also play a role in the development of glucocorticoid resistance underlying the overactivation of the hypothalamic-pituitary-adrenal system. Therefore, activation of inflammatory pathways and neurodegenerative pathways results in brain damage observed in depression and / or anxiety due to both decreased neurogenesis and increased neurodegeneration.

[0007] [

[0007] ] Azelastine is pharmacologically classified as a second-generation antihistamine and is a relatively selective and non-sedating competitive antagonist for the H1 receptor for the treatment of allergic rhinitis and asthma. However, more uniquely, in addition to its antihistamine activity, azelastine is positioned as one of the new generation of dual-action anti-inflammatory drugs due to its inhibition of inflammatory mediators and mast cell stabilization effects. The ability to modify several other inflammatory mediators, such as IL-1, IL-6, TNF-α, INF-α, and reduce the overactivation of the NF-κB inflammatory signaling pathway may contribute to the potential therapeutic mechanism of action in mental disorders such as anxiety, depression, panic disorder, mania, 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 show that azelastine's affinity for inhibiting mast cell degranulation can also reduce the release of other inflammatory mediators, particularly leukotrienes and interleukin-1β. In preclinical studies, azelastine has been shown to directly antagonize other inflammatory mediators such as tumor necrosis factor-α, leukotrienes, endothelin-1, and platelet-activating factor.

[0008] [

[0008] ] Folic acid, a form of vitamin B9, is important for the synthesis and repair of DNA and other genetic materials and is necessary for cells to divide and for the nervous system to function at all ages. This promotes the conversion of homocysteine to methionine via methionine synthase, and this conversion is important for nucleotide synthesis and genomic and non-genomic methylation. The methylation process is known to be central to the biochemical basis of neuropsychiatry in folate deficiency. There is also important evidence that methylation disorders have some etiological significance in depression, dementia, and folate deficiency, specifically affect central monoamine neurotransmitter metabolism, and can lead to an increase in depressive disorders.

[0009]

[0009] Deficiency of folate, the natural form of folic acid, has been shown to cause nucleotide imbalance and subsequent cell accumulation in the S phase, thereby reducing proliferation in multiple cell types, and it is also possible to manipulate the proliferation of T cells, which are often associated with various chronic inflammatory diseases, by changing folate levels. Studies have demonstrated that folic acid significantly reduces the release of pro-inflammatory mediators in LPS-activated microglia, blocks NF-κB, overregulates the IL-10-dependent suppressor of cytokine signaling protein expression via the p38 pathway, and affects the production of inflammatory markers such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α.

[0010]

[0010] Therefore, a unique combination of azelastine (an antihistamine with anti-inflammatory activity) and folic acid or folate, and / or its salts, metabolites, or derivatives may be an effective treatment for behavioral disorders and mental illnesses in terms of functioning through multiple mechanisms of action.

Summary of the Invention

Means for Solving the Problems

[0011] Summary of the Invention

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

[0012]

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

[0013]

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

[0014]

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

[0015]

[0015] The present invention further includes the use of a composition, for example, by oral administration, to a patient having one or more of a mental disorder 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), mood swings, bipolar disorder, post-traumatic stress disorder (PSD), and sleep disorder related to anxiety (SDRA).

[0016]

[0016] In some embodiments of the present invention, an oral pharmaceutical dosage form of a pharmaceutical composition comprising azelastine hydrochloride (and / or other salts) in an amount of about 1 mg to about 8 mg, and folic acid or folate, and / or its salts, metabolites, or derivatives in an amount of about 0.1 mg to about 2 mg, is administered to a patient having one or more of any one or more mental disorders 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), mood swings, enuresis, bipolar disorder, post-traumatic stress disorder (PSD or PTSD), and sleep disorder related to anxiety (SDRA).

[0017]

[0017] An embodiment includes aspect 1, which is a pharmaceutical composition comprising azelastine or a pharmaceutically acceptable salt of azelastine; folic acid or folate, and / or its salts, metabolites, or derivatives; and one or more pharmaceutically acceptable excipients.

[0018] Aspect 2 is the pharmaceutical composition of Aspect 1, wherein azelastine or a 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 in at least a certain amount, up to about 8 mg, for example, in the range of about 2 - 8 mg, or about 3 - 7 mg, or about 4 - 6 mg, or in an amount in any range therebetween.

[0019]

[0019] Aspect 3 is the pharmaceutical composition according to Aspect 1 or 2, wherein folic acid or a folate, and / or a 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 in at least a certain amount, up to about 2 mg, for example, in the range of about 0.2 mg - about 0.9 mg, or about 0.3 mg - about 0.8 mg, or about 0.4 mg - about 0.7 mg, or about 0.5 mg - 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 in an amount in any range therebetween.

[0020]

[0020] Aspect 4 is the pharmaceutical composition according to any one of Aspects 1 - 3, wherein folic acid or a folate, and / or a 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]

[0021] Aspect 5 is the pharmaceutical composition according to any one of Aspects 1 - 4, wherein azelastine or a 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, for example, in the range of about 1 - about 4 mg, and folic acid or a folate, and / or a 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, for example, in the range of about 0.1 - 0.4 mg; or azelastine or a 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 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 a pharmaceutical composition according to any one of Aspects 1 to 5, wherein the pharmaceutically acceptable salt of azelastine is azelastine hydrochloride.

[0023]

[0023] Aspect 7 is a pharmaceutical composition according to any one of Aspects 1 to 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]

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

[0025]

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

[0026]

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

[0027]

[0027] Aspect 11 is a method comprising administering to a patient a pharmaceutical composition comprising an effective amount of azelastine or a pharmaceutically acceptable salt of azelastine and folic acid or a folate, and / or a salt, metabolite, or derivative thereof; the effective amounts together being sufficient to treat one or more symptoms of one or more mental disorders of the patient.

[0028]

[0028] Aspect 12 is a method according to Aspect 11, wherein one or more of the mental disorders or symptoms of the mental disorder are selected from major depressive disorder, generalized anxiety disorder, panic disorder, mania, social anxiety disorder, mild chronic depression, premenstrual dysphoric disorder, obsessive-compulsive disorder, mood swings, nocturnal enuresis in children, bipolar disorder, post-traumatic stress disorder, seasonal affective disorder, and anxiety-related sleep disorders.

[0029]

[0029] Aspect 13 is a method according to Aspect 11 or 12, wherein the pharmaceutical composition is administered to the patient once or twice a day, or once every two, three, or four days, in an oral solid or liquid form, etc.

[0030] Aspect 14 is any of the methods of Aspects 11 - 13, wherein azelastine or a 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 at least an amount up to about 8 mg, for example, in the range of about 2 - 8 mg, or about 3 - 7 mg, or about 4 - 6 mg, or any range therebetween.

[0031] Aspect 15 is any of the methods of Aspects 11 - 14, wherein folic acid or a folate, and / or a 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 at least an amount up to about 2 mg, for example, in the range of about 0.2 mg - about 0.9 mg, or about 0.3 mg - about 0.8 mg, or about 0.4 mg - about 0.7 mg, or about 0.5 mg - 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 therebetween.

[0032] Aspect 16 is any of the methods of Aspects 11 - 15, wherein folic acid or a folate, and / or a 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 any of the methods of Aspects 11 - 16, wherein azelastine or a 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 any of the methods of Aspects 11 - 17, wherein azelastine or a 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 folic acid or a folate, and / or a 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, for example, in the range of about 0.1 mg to about 1 mg.

[0035] Aspect 19 is a pharmaceutical composition comprising azelastine or a pharmaceutically acceptable salt thereof in an amount of at least a certain degree, up to about 8 mg (for example, about 2 - 8 mg, or about 3 - 7 mg, or about 4 - 6 mg, or any range therebetween), and further comprising folic acid and one or more pharmaceutically acceptable excipients.

[0036]

[0036] Aspect 20 is the pharmaceutical composition of Aspect 19, wherein folic acid or folate, and / or a salt, metabolite, or derivative thereof, is present in the pharmaceutical composition in an amount of at least a certain degree, within a range up to about 2 mg, for example, 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 therebetween.

[0037]

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

[0038]

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

[0039]

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

[0040]

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

[0041] Aspect 25 is a method comprising administering to a patient a pharmaceutical composition comprising azelastine, or a pharmaceutically acceptable salt of azelastine, and folic acid or a folate, and / or a salt, metabolite, or derivative thereof.

[0042]

[0042] Aspect 26 is the method of aspect 25, wherein the pharmaceutical composition is administered to the patient in an oral solid or liquid form, optionally once or twice a day, or once every two, three, or four days.

[0043]

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

[0044]

[0044] Aspect 28 is any of the methods of aspects 25 - 27, wherein azelastine or a 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]

[0045] Aspect 29 is any of the methods of aspects 25 - 28, wherein azelastine or a 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 a folate, and / or a salt, metabolite, or derivative thereof, present in the pharmaceutical composition.

[0046]

[0046] Aspect 30 is any of the methods of aspects 25 - 29, wherein folic acid or a folate, and / or a 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]

[0047] Aspect 31 is any of the methods of aspects 25 - 30, wherein azelastine or a 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 any of the methods of Aspects 25 - 31, wherein azelastine or a pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount in the range up to about 8 mg, and folic acid or a folate, and / or a salt, metabolite, or derivative thereof is present in the pharmaceutical composition in an amount in the range 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, a folate, and / or a salt, metabolite, or derivative 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., azelastine or a pharmaceutically acceptable salt of azelastine and folic acid, a folate, and / or a salt, metabolite, or derivative 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 mental disorders or symptoms thereof, wherein the pharmaceutical composition comprises any composition of any of the above aspects, and / or the use comprises any method or any one or more method steps of the above aspects.

[0051] Aspect 35 is a pharmaceutical composition for use in the treatment of one or more mental disorders or symptoms, wherein the pharmaceutical composition comprises any composition of any of the above aspects, and / or the use comprises any method or any one or more method steps of the above aspects. **Mode for Carrying Out the Invention**

[0052] **Detailed Description of the Invention**

[0052] Through clinical practice, the inventors of the present invention have found that an oral pharmaceutical composition containing an active agent, azelastine, and a salt form of folic acid is suitable for the treatment of patients suffering from one or more of mental disorders or symptoms of mental disorders, 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), mood swings, nocturnal enuresis in children, bipolar disorder, post-traumatic stress disorder (PSD or PTSD), and sleep disorders related to anxiety (SDRA).

[0053]

[0053] This application is related to the subject matter of International Applications PCT / US19 / 27293, PCT / US19 / 29885, PCT / US19 / 33359, PCT / US20 / 34735, PCT / US20 / 39916, and PCT / US20 / 59846, each of which is incorporated herein by reference in its entirety.

[0054]

[0054] The detailed description set forth below is intended to be illustrative of the example and is not intended to represent the only form in which the example can be constructed or utilized. This description will describe the functions of the example as well as a series of steps for constructing and operating the example. However, the same or equivalent functions and sequences can be achieved by different examples.

[0055]

[0055] Definitions

[0056] As used herein, the following words and phrases are intended to have the meanings generally described below, unless the context in which they are used indicates otherwise.

[0056]

[0057] Mental disorders and symptoms of mental disorders include, but are not limited to, major depressive disorder (MDD), generalized anxiety disorder (GAD), panic disorder, mania, social anxiety disorder (SAD), mild chronic depression (MCD), obsessive-compulsive disorder (OCD), premenstrual dysphoric disorder (PDD), seasonal affective disorder (SAD), mood swings, enuresis, bipolar disorder, post-traumatic stress disorder (PSD or PTSD), and sleep disorders related to anxiety (SDRA).

[0057]

[0058] As used herein, the term "folic acid" refers to folic acid, a synthetic form of folate also known as vitamin B9. In certain embodiments, folic acid 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 monoester or diester. In other embodiments, folic acid can be replaced with folate or a derivative / metabolite of folate. For example, references to the amount and dosage range of folic acid in a solid oral dosage form are for the amount and dosage range of folate, folate derivative and / or metabolite, or any pharmaceutically acceptable salt thereof.

[0058]

[0059] In embodiments, 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, levomefolic acid is provided as a pharmaceutically acceptable salt, such as a calcium salt or a magnesium salt.

[0059]

[0060] As used herein, the term "azelastine" refers to azelastine free base or 4-(p-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1-(2H)-phthalazinone. In certain embodiments, azelastine also includes any pharmaceutically acceptable salt, such as the hydrochloride or HCl salt. Preferably, in any embodiment of the invention as described herein, azelastine is in its hydrochloride form as azelastine hydrochloride or azelastine HCl. More preferably, in any embodiment of the invention as described herein, references to the amount and dosage range of azelastine in a solid oral dosage form are to the amount and dosage range of azelastine hydrochloride, e.g., references to the amount and dosage range of azelastine hydrochloride in a solid oral dosage form are to the amount and dosage range of azelastine or any of its pharmaceutically acceptable salts.

[0060]

[0061] As used herein, "treating" or "treatment" means complete or incomplete cure, or that the symptoms of the underlying or related disease are at least affected, prevented, reduced, removed, and / or delayed, and / or that one or more of the underlying cellular, physiological, or biochemical causes or mechanisms that cause the symptoms are affected, prevented, reduced, delayed, and / or removed. It should be understood that when used in this context, "reduced" or "delayed" means a comparison to the untreated disease state, including both the physiological state and the molecular state of the untreated disease.

[0061]

[0062] The term "effective amount" refers to an amount sufficient to affect treatment when administered to an animal or mammal in need of such treatment, as defined below. The therapeutically effective amount varies depending on the patient being treated, the patient's weight and age, the severity of the disease state, the method of administration, etc., and can be readily determined by one of ordinary skill in the art. The pharmaceutical composition can be administered in a single dose or multiple doses by oral administration. The administration can be carried out by any one or more of capsules, tablets, gels, sprays, drops, solutions, suspensions, or syrups.

[0062]

[0063] As used herein in the context of quantitative measurements, the term "about" means the indicated amount ± 10%. For example, in the range of ± 10%, "about 2 mg" can mean 1.8 to 2.2 milligrams.

[0063]

[0064] The pharmaceutical composition can be formulated for pharmaceutical use using methods known in the art, such as 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 compound and a controlled release or sustained release matrix can be carried out.

[0064]

[0065] Either liquid or solid unit dosage forms can be easily prepared for oral administration and can be mixed, for example, with any one or more conventional ingredients such as dibasic calcium phosphate, magnesium aluminum silicate, magnesium stearate, calcium sulfate, starch, talc, lactose, acacia, methylcellulose, and / or materials that function similarly as pharmaceutical excipients or carriers. Sustained release formulations can be optionally used. In elderly or inconsistent subjects, sustained release formulations may even be preferred. Capsules can be formulated by mixing the pharmaceutical composition with an inert pharmaceutical diluent and inserting this mixture into hard gelatin capsules of appropriate size. If soft capsules are desired, the pharmaceutical composition can be encapsulated by forming a slurry of the pharmaceutical composition containing an acceptable vegetable oil, light oil, or other inert oil in gelatin capsules.

[0065]

[0066] Suspensions, syrups, and elixirs can be used for oral administration or in the dosage form of liquid units. Fluid formulations containing oil can be used in oil-soluble forms. Vegetable oils such as corn oil, peanut oil, or essential oils can produce acceptable fluid formulations, for example, together with flavorings, sweeteners, and any preservatives. Surfactants can be added to water to form a syrup of liquid unit dosage. Hydroalcoholic pharmaceutical formulations can use acceptable sweeteners such as sugar, saccharin, or other non-nutritive sweeteners, and / or biological sweeteners, and / or flavoring agents such as those in the form of elixirs.

[0066]

[0067] The solid oral dosage forms of the present disclosure mean forms such as tablets, caplets, bilayer tablets, film-coated tablets, pills, or capsules. Tablets according to the present disclosure can be prepared by any mixing techniques and tableting techniques well-known in the pharmaceutical manufacturing industry. In some examples, the dosage form is manufactured by directly compressing the sustained release portion and the immediate release portion prepared respectively by punches and dies mounted on a rotary tableting press, discharging after compression, or compression molding, or granulating.

[0067]

[0068] The pharmaceutical compositions provided in accordance with the present disclosure can typically be administered orally. Accordingly, the present disclosure provides a pharmaceutical composition comprising 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 solutions and various organic solvents, penetration enhancers, solubilizing agents, disintegrants, lubricants, binders, glidants, adjuvants, and combinations thereof. Such compositions are prepared by methods well known in the pharmaceutical art (see, 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)).

[0068]

[0069] The pharmaceutical composition may further comprise pharmaceutical excipients such as diluents, binders, fillers, glidants, disintegrants, lubricants, solubilizing agents, and combinations thereof. Some examples of suitable excipients are described herein. When the pharmaceutical composition is formulated into tablets, the tablets may or may not be coated, or may be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a long period of time. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate can be used alone or in combination with waxes. In embodiments, the pharmaceutical composition is formulated as a tablet, caplet, pill, or capsule that can delay disintegration until the pharmaceutical composition enters the patient's gastrointestinal tract. In embodiments, the delay in disintegration is achieved using a coating.

[0069]

[0070] In an embodiment, the pharmaceutical composition comprises (a) about 1 mg to 8 mg of azelastine HCl (or other salts) and (b) about 0.1 mg to 2 mg of folic acid, or (a) about 2 mg to 6 mg of azelastine HCl (or other salts) and (b) about 0.1 mg to 0.8 mg of folic acid or folate, and / or its salts, metabolites, or derivatives, or (a) about 2 mg to 4 mg of azelastine HCl (or other salts) and (b) about 0.2 mg to 0.4 mg of folic acid or folate, and / or its salts, metabolites, or derivatives, or may contain any amount of azelastine or folic acid within these ranges. Additional embodiments include pharmaceutical compositions comprising (a) from 0 to up to about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, or 8 mg (including any of these) or any amount within any of these ranges of azelastine, such as azelastine HCl or any salt of azelastine, and (b) from 0 to up to 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 (including any of these) or any amount within any of these ranges of folic acid or folate, and / or its salts, metabolites, or derivatives. For example, the composition may comprise (a) about 2 mg of azelastine HCl and (b) about 0.4 mg of folic acid or folate, and / or its salts, metabolites, or derivatives. Further, for example, the composition of the present invention may comprise azelastine or a pharmaceutically acceptable salt of azelastine present in an amount in the range of about 1 mg to about 8 mg and folic acid or folate, and / or its salts, metabolites, or derivatives in an amount in the range of about 0.1 mg to about 2 mg. In an embodiment, the amount of azelastine HCl (or other salts) present in the composition may be equal to, greater than, or less than the amount of folic acid or folate, and / or its salts, metabolites, or derivatives present in the composition. In an embodiment, azelastine is present in the pharmaceutical composition in an amount of at least 1 mg, and folic acid or folate, and / or its salts, metabolites, or derivatives are present in an amount of at least 0.1 mg.In an embodiment, the amount of azelastine HCl (and / or other salts) present in the composition is the same as, or 2 times, or 3 times, or 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 15 times, 20 times, 25 times, 30 times, 35 times, 40 times, 45 times, or 50 times the amount of folic acid or folate, and / or its salts, metabolites, or derivatives present in the composition, or vice versa. Any one or more of the compositions of the present invention can be used in combination with any one or more of the methods or other methods of using the compositions of the present invention disclosed herein.

[0070]

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

[0071]

[0072] In an embodiment, a pharmaceutical composition (e.g., containing azelastine and folic acid) is used in the preparation of a medicament for treating a patient having one or more mental disorders or symptoms thereof. Such a composition comprises (a) about 1 mg to 8 mg of azelastine (or its salt), 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 its salts, metabolites, or derivatives, or may contain these in any amount or synergistic amount disclosed herein. Further, in an embodiment, the pharmaceutical composition may be for use in the treatment of one or more mental disorders or symptoms, and the pharmaceutical composition comprises (a) about 1 mg to 8 mg of azelastine (or its salt) 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 its salts, metabolites, or derivatives, or may contain these in any amount or synergistic amount disclosed herein.

[0072]

[0073] The amount of the pharmaceutical composition containing azelastine HCl, folic acid or folate, and / or its salts, metabolites, or derivatives actually administered will usually be determined by a physician in light of relevant circumstances including the condition to be treated, the selected route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.

[0073]

[0074] A pharmaceutical composition, pharmaceutical dosage form, and tablet containing azelastine as described herein, such as azelastine HCl, and folic acid or folate, and / or its salts, metabolites, or derivatives, are administered to patients suffering from one or more mental 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), mood swings, enuresis in children, bipolar disorder, post-traumatic stress disorder (PSD or PTSD), and sleep disorder related to anxiety (SDRA), once a day, twice a day, up to four times a day, every other day, once a week, twice a week, three times a week, four times a week, or five times a week, or a combination thereof (e.g., oral administration).

[0074]

[0075] In an embodiment, a pharmaceutical composition containing azelastine (e.g., azelastine HCl) in the range of about 1 mg to about 8 mg of a therapeutically effective daily dose and an amount of folic acid or folate, and / or its salts, metabolites, or derivatives in the range of about 0.1 mg to about 2 mg is administered to a patient.

[0075]

[0076] In an embodiment, the pharmaceutical forms and tablets of a pharmaceutical composition comprising azelastine as described herein, such as azelastine HCl, folic acid or folate, and / or its salts, metabolites, or derivatives, are effective in restoring, reducing, alleviating, and / or treating one or more symptoms of one or more mental disorders or their 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), mood swings, enuresis in children, bipolar disorder, post-traumatic stress disorder (PSD or PTSD), and sleep disorders related to anxiety (SDRA) in patients having one or more such symptoms within about 1 to 8 weeks, such as within 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks, or within any range therebetween.

[0076]

[0077] In an embodiment, the pharmaceutical composition is effective in restoring, reducing, alleviating, and / or treating any one or more symptoms including, but not limited to, depression, anxiety, panic, agitation, delusions, hallucinations, hypersensitivity, insomnia, sleep disorders, aggression, etc.

[0077]

[0078] The following examples are illustrative and should not be construed as limiting the scope of the claimed subject matter.

[0078]

[0079] Example 1

[0080] A 45-year-old female patient suffered from MDD and panic disorder. She was treated with sertraline for 2 months and buspirone for 2 months, but there was no significant clinical improvement. When all her symptoms worsened, a composition of folic acid (0.19 mg) and azelastine (2 mg) was administered once a day for one week, and the symptoms began to improve dramatically. By 4 weeks of treatment, she showed no panic disorder and her MDD decreased by more than 80%. Azelastine is approved as a therapeutic agent for allergic rhinitis and asthma, and the combined composition of azelastine and folic acid was not expected to be used to treat patients with depression or anxiety, so this dramatic clinical outcome, including the rapid reduction of symptoms, was unexpected. Although the inventors do not intend to be bound by this theory, folic acid regulates the inflammatory response in microglial cells through multiple signaling pathways, shifts the pro-inflammatory nature to an anti-inflammatory response, and these reactions enhance the anti-inflammatory effect of azelastine by its own function of suppressing the release of cytokines in the CNS system, such as IL-1, IL-6, TNF-α and INF-α, and is considered to have a synergistic effect. This composition with two mechanisms of anti-inflammatory action will provide a new solution for treating psychoses that cannot be treated by other options, such as conventional SSRIs, NSRIs, and benzodiazepines alone.

[0079]

[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 did not improve to a satisfactory level. Subsequently, she was treated once a day with a composition of folic acid (0.19 mg) and azelastine (2 mg). After 2 weeks, she showed dramatic clinical improvement, showing an 80% improvement in depression and was also satisfied with the quality of her sleep. The inventors believe that the hypothesis as described in Example 1 above is also applicable here. In this case, the two mechanisms of action of the composition provided a new solution for treating her chronic depression and insomnia that could not be treated by other options, such as conventional SSRIs, NSRIs, benzodiazepines, etc.

[0080]

[0083] References

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[0085] A. F. Kolb and L. Petrie, “Folate deficiency enhances the inflammatory response of macrophages,” Molecular Immunology, vol. 54, no. 2, pp. 164-172, 2013 6.

[0086] D. Feng, Y. Zhou, M. Xia, and J. Ma, “Folic acid inhibits lipopolysaccharide-induced inflammatory response in RAW264.7 macrophages by suppressing MAPKs and NF-κB activation,” Inflammation Research, vol. 60, no. 9, pp. 817-822, 2011.

[0087] Patrice B. Jones, et al. 2019. Folate and Inflammation - links between folate and features of inflammatory conditions. British Journal of Clinical Pharmacology, 18 (2019) 100104.

[0088] Reynolds EH., Folic acid, vitamin B12, and the nervous system: historical aspects. In: Botez MI, Reynolds EH, eds. Folic acid in neurology.

[0089] James P. Zacny, Judith A. Paice, and Dennis W. Coalson, 2012. Separate and combined psychopharmacological effects of folic acid and oxycodone in healthy volunteers, 2012 August 1; 121(3): 271-282.

[0090] Bottiglieri T, et al., 2000. Homocysteine, folate, methylation and monoamine metabolism in depression. J Neurol Neurosurg Psychiatry 2000;69:228-32.

[0091] Olga A. Balashova, et al., 2018. Folate action in nervous system development and disease. Dev Neurobiol. 2018 April ; 78(4): 391-402.

[0092] Ruihua Hou et al., 2017, Peripheral inflammatory cytokines and immune balance in Generalized Anxiety Disorder: case-controlled study. Brain Behav Immun. 2017 May; 62:212-218.

[0093] Michelle Guignet et al., 2020, Persistent behavior deficits, neuroinflammation, and oxidative stress in a rat model of acute organophosphate intoxication, Vol 133, January 2020, 101131.

[0094] Chun-Hong Liu et al., 2019, Role of inflammation in depression relapse, Journal of Neuroinflammation (2019) 16:90.

[0095] F. C. Bennett and A. V. Molofsky, 2019, The immune system and psychiatric disease: a basic science perspective, Clinical and Experimental Immunology, 197: 291-307.

[0096] Ruihua Hou and David S. Baldwin, 2012, A neuroimmunological perspective on anxiety disorders, Human Psychopharmacol Clin Exp. Vol 27: 6-11.

[0097] N Kappelmann, G Lewis, R Dantzer, PB Jones and GM Khandaker, 2018, Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions, Molecular Psychiatry. Vol. 23, 335-313.

[0098] Conti, Pio et al., 2018, Impact of Mast Cells in Depression Disorder: Inhibitory Effect of IL-37 (New Frontiers). Immunol Res, vol. 66 (3), 323-331 Jun 2018.

[0099] Sung Ho Maeng and Heeok Hong, 2019, Inflammation as the Potential Basis in Depression. Int Neurourol J 2019; Vol 23(Suppl 2): S63-71.

[0100] Ole Koehler, et al. van Hoven PT, Kaufman A, Carr WW. Inflammation in Depression and the Potential for Anti-Inflammatory Treatment. Current Neuropharmacology, 2016, 11, 732-712.

[0101] Anzela Niraula et al. 2019, Interleukin-6 Induced by Social Stress Promotes a Unique Transcriptional Signature in the Monocytes That Facilitate Anxiety. Biol Psychiatry 85 (8), 679-689 2019 Apr 15.

[0102] M Catena-Dell’Osso, et al, 2011, Inflammatory and Neurodegenerative Pathways in Depression: A New Avenue for Antidepressant Development? Curr Med Chem. 18 (2), 245-55.

[0103] S Georgin-Lavialle et al. 2016, Mast Cells’ Involvement in Inflammation Pathways Linked to Depression: Evidence in Mastocytosis. Mol Psychiatry. 21 (11), 1511-1516 Nov 2016.

[0104] Sang Won Jeon, Yong Ku Kim, 2016, Detrimental effect of preservative in eye drops: Neuroinflammation and cytokine abnormality in major depression: Cause or consequence in that illness? World Journal of Psychiatry, 2016 September 22; 6(3): 283-293.

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[0106] Ja Wook Kooa, et al, 2010, Nuclear factor-κB is a critical mediator of stress impaired neurogenesis and depressive behavior. PNAS, February 9, 2010, Vol. 107 (6) 2669-2674.

[0107] Patricia B Williams, Elizabeth Crandall and John D Sheppard, 2010, Azelastine hydrochloride, a dual-acting anti-inflammatory ophthalmic solution, for treatment of allergic conjunctivitis. Clinical Ophthalmology 2010:4 993-1001

[0108] Casale T. The interaction of azelastine with human lung histamine H1, beta, and muscarinic receptor-binding sites. J Allergy Clin Immunol. 1989;83:771-776.

[0109] Hazama H, Nakajima T, Hisada T, Hamada E, Omata M, Kurachi Y. Effects of azelastine on membrane currents in tracheal smooth muscle cells isolated from the guinea-pig. Eur J Pharmacol. 1994;259: 143-150.

[0110] Szelenyi I, Achterrath-Tuckermann U, Schmidt J, Minker E, Paegelow I, Werner H. Azelastine: A multifaceted drug for asthma therapy. Agents Actions Suppl. 1991;34:295-311.

[0111] Galatowicz G, Ajayi Y, Stern ME, Calder VL. Ocular antiallergic compounds selectively inhibit human mast cell cytokines in vitro and conjunctival cell infiltration in vivo. Clin Exp Allergy. 2007;37:1648-1656.

[0112] Ciprandi G, Pronzato C, Passalacqua G, et al. Topical azelastine reduces eosinophil activation and intercellular adhesion molecule-1 expression on nasal epithelial cells: An antiallergic activity. J Allergy Clin Immunol. 1996;98(6 Pt 1):1088-1096.

[0113] Simons FE, Simons KJ. Clinical pharmacology of new histamine H1 receptor antagonist. Clin Pharmacokinet. 1999;36:329-352.

[0114] 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.

[0115] 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.

[0116] 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.

[0117] Loyd Allen, Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems, Tenth (2013)

[0118] Sarfaraz K. Niazi, Handbook of Pharmaceutical Manufacturing Formulations Volumes 1-6.

[0081]

[0119] The present invention has been described with reference to specific 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 present invention. Those skilled in the art will recognize that the disclosed features may be used alone, in any combination, or omitted, based on the requirements and specifications of a given application or design. When an embodiment refers to a particular feature as “comprising,” it should be understood that the embodiment may alternatively “consist of” or “consist essentially of” any one or more of the features. Any of the methods disclosed herein can be used in conjunction with any of the compositions disclosed herein or any other composition. Similarly, any of the disclosed compositions can be used in conjunction with any of the methods disclosed herein or any other method. Other embodiments of the present invention will be apparent to those skilled in the art from consideration of the specification and practice of the present invention.

[0082]

[0120] In particular, when ranges of values are provided herein, it should be noted that each value between the upper and lower limits of such ranges is also specifically disclosed. The upper and lower limits of these narrower ranges may be included in or excluded from the range independently. The singular forms "a", "an", and "the" include the plural referents unless the context clearly dictates otherwise. It is intended that the specification and examples be considered essentially exemplary and that variations that do not depart from the essence of the invention fall within the scope of the invention. Further, all references cited in this disclosure are hereby individually incorporated by reference in their entirety into this specification, and thus are intended to provide an efficient way to supplement the effective disclosure of the invention and to provide a background that details the level of those skilled in the art.

Claims

1. Azelastine or a pharmaceutically acceptable salt thereof; Folic acid or folate, and / or a salt, metabolite, or derivative thereof; And a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients.

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

3. The pharmaceutical composition according to claim 1, wherein the folic acid or folate, and / or a 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 according to claim 2, wherein the folic acid or folate, and / or a 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 azelastine or the pharmaceutically acceptable salt thereof 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 a 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, the pharmaceutical composition according to claim 1.

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

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

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

9. The pharmaceutical composition according to 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 according to claim 1, formulated as an oral pharmaceutical dosage form.

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

12. A method for treating a mental disorder or its symptoms, comprising: administering a pharmaceutical composition to a patient having the mental disorder or its symptoms; wherein the pharmaceutical composition comprises azelastine or a pharmaceutically acceptable salt of azelastine, and folic acid or a folate, and / or a salt, metabolite, or derivative thereof.

13. One or more of the mental disorders or symptoms are selected from major depressive disorder, generalized anxiety disorder, panic disorder, agitation, social anxiety disorder, mild chronic depression, premenstrual dysphoric disorder, obsessive-compulsive disorder, mood swings, enuresis, bipolar disorder, post-traumatic stress disorder, seasonal affective disorder, and anxiety-related sleep disorder, according to the method of claim 12.

14. The method according to claim 12, wherein the pharmaceutical composition is administered to the patient once or twice a day, or once every two, three, or four days, in an oral solid or liquid form.

15. The method according to 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 according to claim 15, wherein the folic acid or folate, and / or a 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 according to claim 12, wherein the folic acid or folate, and / or a 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 according to claim 17, wherein the azelastine or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount in the range of about 1 mg to about 4 mg. **Claim 19** The azelastine or a pharmaceutically acceptable salt thereof 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 a 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, the method according to claim 12. **Claim 20** A first active agent which is azelastine hydrochloride 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 a salt, metabolite, or derivative thereof present in an amount in the range of about 0.1 mg to about 0.4 mg; and Comprising one or more pharmaceutically acceptable excipients; A pharmaceutical composition, 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. **Claim 21** A first active agent which is azelastine or a pharmaceutically acceptable salt thereof; A second active agent which is folic acid, folate, and / or a salt, metabolite, or derivative thereof; and Comprising one or more pharmaceutically acceptable excipients; A pharmaceutical composition, wherein the first active agent and the second active agent are present in synergistically effective amounts. **Claim 22** Use of a pharmaceutical composition in the preparation of a medicament for treating a patient having one or more mental disorders or symptoms thereof, wherein the pharmaceutical composition comprises the composition according to any one of claims 1 to 11, 20, or 21, and / or the use comprises any method or method step according to any one of claims 12 to 19. **Claim 23** A pharmaceutical composition for use in the treatment of one or more mental disorders or symptoms, comprising the composition according to any one of claims 1 to 11, 20, or 21, and / or wherein said use comprises any method or method step according to any one of claims 12 to 19.

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