Novel pharmaceutical compositions and methods for treating psychiatric, behavioral, cognitive disorders

Abstract

Disclosed are pharmaceutical compositions comprising azelastine or a pharmaceutically acceptable salt of azelastine and a therapeutically active ingredient of donepezil or rivastigmine or galantamine or a pharmaceutically acceptable salt thereof. Also disclosed are methods of using the pharmaceutical compositions to treat patients with mental disorders, behavioral disorders, cognitive disorders.

Description

TECHNICAL FIELD

[0001] The present invention relates to the field of practical medicine, i.e. to the combined use of a pharmaceutical composition showing neurotropic action in case of organic damage of various origin to the central nervous system, reducing the clinical manifestations of mental disorders, behavioral disorders, cognitive disorders. BACKGROUND

[0002] Alzheimer's disease (AD) is a progressive, chronic neurodegenerative disease that usually begins slowly and worsens over time. In older people, Alzheimer's disease is the most common cause of dementia. Dementia is the loss of cognitive functioning (thinking, memory, and reasoning) and behavioral abilities to such an extent that normal activities of daily living become difficult. In its early stages, memory loss is mild, but as Alzheimer's disease progresses, individuals may experience changes in behavior, mood and personality, growing confusion, and diminishing physical abilities. If untreated, AD eventually leads to death. While the rate of progression can vary, the typical life expectancy following diagnosis is 3 to 9 years.

[0003] AD is a polygenic / polyfactorial complex disorder characterized by premature death of neurons. While the amyloid hypothesis is considered the main driving force in the pathogenesis of AD, the mutation genetics associated with amyloid precursor protein (APP) and presenilin (PS) genes alone do not fully explain the neuropathological findings present in AD, represented by amyloid deposits in senile plaques and blood vessels (amyloid angiopathy), formation of neurofibrillary tangles (NFTs) due to hyperphosphorylation of tau protein, synaptic and dendritic desarborization, and neuronal loss. These findings are accompanied by neuroinflammatory responses, oxidative stress and free radical formation, which are likely to be associated with mitochondrial dysfunction, excitotoxic responses, alterations in cholesterol metabolism and lipid rafts, deficits in neurotransmitter (especially acetylcholine) and neurotrophic factor function, deficits in ubiquitin-proteasome activity, and chaperone system and cerebrovascular dysregulation. All these neurochemical events are potential therapeutic targets; however, a single drug is unlikely to counteract the complex mechanisms involved in neurodegeneration alone.

[0004] In the early 1980s, the memory dysfunction associated with AD was thought to be due, in part, to cholinergic deficits in the affected human brain resulting from loss of neurons in the basal forebrain, which led to the cholinergic hypothesis of AD. Since choline donors (precursors) and acetylcholine itself are substances that are difficult to manage pharmacologically (or are ineffective in enhancing brain cholinergic neurotransmission), and, paradoxically, given that acetylcholinesterase activity progressively decreases in the AD brain in synchrony with cognitive deterioration, AChEIs were proposed as a choice to inhibit acetylcholine degradation in the synaptic cleft and to enhance choline reuptake at the presynaptic level, with the aim of enhancing acetylcholine synthesis in the presynaptic terminal, which promotes cholinergic neurotransmission. The first candidate drug to meet this criterion was tacrine (tetrahydroaminoacridine), which was launched in 1993 and was soon abandoned due to its hepatotoxicity and poor tolerability; 3 years later, in 1996, donepezil was approved by the FDA for the treatment of mild to moderate AD cases. Other AChEIs (rivastigmine and galantamine) were launched a few years later.

[0005] However, acetylcholinesterase inhibitors such as donepezil, rivastigmine and galantamine will not cure AD or prevent the loss of these abilities at some time in the future. Therefore, there is currently no cure for AD and the inventors’ efforts are to find better ways to reverse the disease, delay and prevent its development.

[0006] On the other hand, genetic, cellular and molecular changes associated with AD support evidence that activated immune and inflammatory processes are part of the disease. In addition, epidemiological studies show great benefits from long-term use of NSAIDs. Therefore, it is generally accepted that AD is, in part, an inflammatory disease and that the inhibition of inflammation is an option for treating AD.

[0007] Inflammation is prominently present in the pathologically vulnerable areas of the AD brain and it occurs with the full complexity of a local peripheral inflammatory response. In the periphery, degenerating tissues and deposits of highly insoluble foreign material are the classic stimuli for inflammation. Likewise, in the AD brain, damaged neurons and neurites and deposits of highly insoluble amyloid beta peptide and neurofibrillary tangles provide prominent stimuli for inflammation. Since these stimuli are discrete, micro-localized and present from the early preclinical stage to the terminal stage of AD, the local upregulation of complement, cytokines, acute phase reactants and other inflammatory mediators is also discrete, micro-localized and long-lasting. Over the years, the direct and indirect damage from the inflammatory mechanisms of AD likely significantly exacerbates the pathogenic processes that cause AD. Thus, animal models and clinical studies to date strongly suggest that AD inflammation significantly contributes to the pathogenesis of AD. By better understanding the AD inflammation and immunomodulatory processes, it should be possible to develop anti-inflammatory approaches that can reverse or delay or prevent the development of this devastating disorder.

[0008] The pharmacology of azelastine classifies it as a second-generation antihistamine and a relatively selective, non-sedating, competitive antagonist of the H1 receptor. More uniquely, in addition to its antihistamine and mast cell stabilizing effects, its inhibition of inflammatory mediators makes it a new generation dual-acting anti-inflammatory agent. Its ability to modify several other inflammatory and allergic mediators contributes to its mechanism of action. In vitro and in vivo studies as well as clinical trials support the dual action of direct inhibition and stabilization of inflammatory cells. Among these, in vitro data indicate that azelastine's affinity to inhibit mast cell degranulation also reduces the release of other inflammatory mediators including leukotrienes and interleukin-1 beta. Azelastine also directly antagonizes other inflammatory mediators such as tumor necrosis factor-alpha, leukotrienes, endothelin-1 and platelet-activating factor. Thus, the unique combination of azelastine with donepezil and / or rivastigmine and / or galantamine has the potential to be an innovative potential therapy for AD in terms of producing a synergistic effect. SUMMARY

[0009] The present invention includes a pharmaceutical composition comprising two active ingredients and one or more pharmaceutically acceptable excipients. The pharmaceutical composition comprises a first active ingredient which is azelastine or a pharmaceutically acceptable salt of azelastine and a second active ingredient which is donepezil and / or rivastigmine and / or galantamine and / or any pharmaceutically acceptable salt thereof.

[0010] The use of a composition comprising (i) azelastine or a pharmaceutically acceptable salt of azelastine, (ii) donepezil or rivastigmine or galantamine, or a pharmaceutically acceptable salt thereof, or any combination thereof, and (iii) one or more pharmaceutically acceptable excipients for the treatment of one or more mental, behavioral or cognitive disorders, such as Alzheimer's disease, vascular dementia, Parkinson's disease, Huntington's disease, or any combination thereof, is included in embodiments of the present application.

[0011] The use of a composition comprising (i) azelastine or a pharmaceutically acceptable salt of azelastine, (ii) donepezil or rivastigmine or galantamine, or a pharmaceutically acceptable salt thereof, or any combination thereof, and (iii) one or more pharmaceutically acceptable excipients for the manufacture of a medicament for the treatment of one or more mental, behavioral or cognitive disorders, such as Alzheimer's disease, vascular dementia, Parkinson's disease, Huntington's disease, or any combination thereof, is also included within the scope of the present application.

[0012] In some embodiments of the present application, the pharmaceutically acceptable salt of azelastine in the pharmaceutical composition is azelastine hydrochloride, and the pharmaceutically acceptable salt of donepezil or rivastigmine or galantamine in the pharmaceutical composition is donepezil hydrochloride or rivastigmine tartrate or galantamine hydrobromide.

[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 4 mg to about 20 mg, and donepezil hydrochloride (and / or other salts) is provided in an amount of about 1 mg to about 4 mg, and / or rivastigmine tartrate (and / or other salts) is provided in an amount of about 1 mg to about 2 mg, and / or galanthamine hydrobromide (and / or other salts) is provided in an amount of about 1 mg to about 3 mg. Preferred compositions are formulated to deliver azelastine or a salt thereof in an amount of up to about 20 mg per day (e.g., about 1-20 mg, or 2-19 mg, or 3-18 mg, or 4-17 mg, or 5-15 mg, or 6-12 mg, or 8-10 mg, or 3-11 mg, or 2-13 mg, or 7-16 mg, etc.), and delivered donepazil in an amount of up to about 23 mg per day (e.g., about 1-23 mg, or 2-22 mg, or 3-20 mg, or 4-18 mg, or 5-16 mg, or 6-15 mg, or 7-12 mg, or 1.5-3 mg, or 1-2 mg, or 2.5-5 mg, etc.). In some embodiments, rivastigmine or a salt thereof is delivered in an amount of at most about 9.5 mg (e.g., about 1-9.5 mg, or 2-9 mg, or 3-8 mg, or 4-7 mg, or 5-6 mg, or 3.5-8.5 mg, or 2.5-7.5 mg, etc.) per day, and / or galanthamine or a salt thereof is delivered in an amount of at most about 24 mg (e.g., about 1-24 mg, or 2-22 mg, or 3-20 mg, or 4-18 mg, or 5-16 mg, or 6-15 mg, or 7-12 mg, or 8-10 mg, or 0.5-2 mg, or 0.8-2.8 mg, or 1-1.5 mg, or 1.2-2.5 mg, etc.) per day. Depending on the application, any one or more of these in higher amounts may be used in certain embodiments.

[0014] The present invention also encompasses oral pharmaceutical dosage forms of the pharmaceutical composition as solid form or liquid form.

[0015] The present invention further includes the medical use of an oral pharmaceutical dosage form of the pharmaceutical composition by administering the oral pharmaceutical dosage form to a patient suffering from a neurodegenerative disorder such as Alzheimer's disease, vascular dementia or Parkinson's disease.

[0016] In some embodiments of the application, an oral pharmaceutical dosage form of a pharmaceutical composition comprising azelastine hydrochloride (and / or other salts) in an amount of about 8 mg to about 12 mg and donepezil hydrochloride in an amount of about 1 mg to about 4 mg or rivastigmine tartrate in an amount of about 1 mg to about 2 mg or galantamine hydrobromide in an amount of about 1 mg to about 3 mg will be administered to patients with moderate to late stage Alzheimer's disease. In embodiments, any range disclosed herein in connection with any component of the composition can be formulated as an oral dosage, for example, a solid, liquid, gel or solution. DETAILED DESCRIPTION

[0017] The inventors of the present application have surprisingly found that a pharmaceutical composition having an oral dosage form comprising active agents, a salt form of azelastine and a salt form of donepezil or rivastigmine or galantamine is useful in the treatment of patients with psychiatric disorders, behavioral disorders, cognitive disorders.

[0018] 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 examples can be constructed or utilized. The description sets forth the functions of the examples and the sequence of steps for constructing and operating the examples. However, changes and modifications can be made to the description that will be apparent to those skilled in the art. For example, the sequence of steps can be changed or reordered.

[0019] Definitions

[0020] As used in this specification, the following words and phrases are generally intended to have the meanings set forth below, except to the extent that the context in which they are used indicates otherwise.

[0021] Psychiatric disorders, behavioral disorders, cognitive disorders can include, but are not limited to, Alzheimer's disease, dementia, Parkinson's disease, Huntington's disease, and combinations of any of the foregoing with other neurodegenerative disorders.

[0022] As used herein, the term "donepezil" refers to donepezil free base, 2,3-dihydro-5,6-dimethoxy-2-[[l-(phenylmethyl)-4-piperidinyl]methyl]-lH-inden-l-one. In certain embodiments, donepezil also includes any pharmaceutically acceptable salt, for example, a hydrochloride salt or HC1 salt. Preferably, in any embodiment of the present application as described herein, donepezil is in the form of its hydrochloride salt, for example, donepezil hydrochloride or donepezil HC1. More preferably, in any embodiment of the present application as described herein, reference to the amount and dosage range of donepezil in an oral dosage form refers to the amount and dosage range of donepezil hydrochloride.

[0023] As used herein, the term "rivastigmine" refers to rivastigmine free base, (S)-3-(l- (dimethylamino)ethyl)phenyl ethyl(methyl)carbamate. In certain embodiments, rivastigmine also includes any pharmaceutically acceptable salt, such as a tartrate salt. Preferably, in any embodiment of the application as described herein, rivastigmine is in the form of its tartrate salt, such as rivastigmine tartrate. More preferably, in any embodiment of the application as described herein, reference to the amount and dosage range of rivastigmine in an oral dosage form refers to the amount and dosage range of rivastigmine tartrate.

[0024] As used herein, the term "galantamine" refers to galantamine free base, (4aS,6R,8aS)- 5,6,9,10,11,12-hexahydro-3-methoxy-11-methyl-4aH-[l]benzofuran[3a,3,2-ef][2]benzazepin-6-ol. In certain embodiments, galantamine also includes any pharmaceutically acceptable salt, such as a hydrobromide salt. Preferably, in any embodiment of the application as described herein, galantamine is in the form of its hydrobromide salt, such as galantamine hydrobromide or galantamine HBr. More preferably, in any embodiment of the application as described herein, reference to the amount and dosage range of galantamine in an oral dosage form refers to the amount and dosage range of galantamine hydrobromide.

[0025] 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 a hydrochloride salt or HC1 salt. Preferably, in any embodiment of the application as described herein, azelastine is in the form of its hydrochloride salt, such as azelastine hydrochloride or azelastine HC1. More preferably, in any embodiment of the application as described herein, reference to the amount and dosage range of azelastine in a solid oral dosage form refers to the amount and dosage range of azelastine hydrochloride.

[0026] As used herein, "treating" or "treatment" means complete cure or incomplete cure, or it means at least alleviation and / or delay of the symptoms of the underlying disease or related condition, and / or causing one or more of the underlying cellular, physiological, or biochemical causes or mechanisms of the symptoms to be alleviated, delayed, and / or eliminated. It is to be understood that alleviation or delay, as used in this context, means relative to the state of the disease being untreated, including the molecular state of the disease being untreated, and not only the physiological state of the disease being untreated.

[0027] ​​The term "effective amount" means an amount adequate to affect the treatment as defined below, when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending upon the patient to be treated, the severity of the disease state, the mode of administration and the like, which can readily be determined by the ordinarily skilled worker, The pharmaceutical composition can be administered orally in single or multiple doses. Administration can be via capsules or tablets and the like.

[0028] The term "about" as used herein in the context of quantitative measurements means ±10% of the designated amount. For example, "about 5 mg" can mean 4.5-5.5 mg, in the context of ±10%.

[0029] The pharmaceutical compositions can be formulated for pharmaceutical use using methods known in the art, for example, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, 10thEdition (Loyd Allen, 2013) and Handbook of Pharmaceutical Manufacturing Formulations (Vols. 1-6, Sarfaraz K. Niazi). Thus, the incorporation of active compounds and controlled- or sustained-release matrices can be implemented.

[0030] Fluid or solid unit dosage forms can be readily prepared for oral administration. For example, mixing with conventional ingredients such as dicalcium phosphate, magnesium aluminate silicate, magnesium stearate, calcium sulfate, starch, talc, lactose, acacia, methyl cellulose, and functionally similar materials as pharmaceutical excipients or carriers. Sustained-release preparations can optionally be used. In subjects who are elderly or incoherent, sustained-release preparations can even be preferred. Capsules can be formulated by mixing the compounds with inert pharmaceutical diluents and embedding the mixture in a hard gelatin capsule of appropriate size. If soft gelatin capsules are desired, a slurry of the compounds with acceptable vegetable oils, light petroleum, or other inert oil can be encapsulated by forming into gelatin capsules.

[0031] Suspensions, syrups, and elixirs can be used for oral administration or fluid unit dosage forms. Fluid preparations containing oils can be used in oil-soluble forms. Vegetable oils such as corn oil, peanut oil, or flower oil, for example, produce acceptable fluid preparations, for example, with flavoring, sweetening, and any preservatives. Surfactants can be added to water to form syrups for fluid unit dosages. Water-alcohol pharmaceutical preparations in the form of elixirs can be used with acceptable sweeteners such as sugar, saccharin, or a biosweetener, and flavoring.

[0032] The solid oral formulation of the present disclosure means a form of a tablet, a caplet, a bilayer tablet, a film-coated tablet, a pill, or a capsule, etc. The tablet according to the present disclosure can be prepared by any mixing and tableting techniques well known in the pharmaceutical formulation industry. In some examples, the formulation is manufactured by directly compressing, ejection or compression molding, or granulating and then compressing the separately prepared sustained release portion and immediate release portion by means of punches and dies installed to a rotary tablet machine.

[0033] The pharmaceutical composition provided according to the present disclosure is generally administered orally. Accordingly, the present disclosure provides a pharmaceutical composition comprising a solid dispersion comprising azelastine and donepezil or rivastigmine or galantamine 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 art (see, e.g., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, 10th edition (Loyd Allen, 2013) and Handbook of Pharmaceutical Manufacturing Formulations (vols. 1-6, Sarfaraz K. Niazi)).

[0034] The pharmaceutical composition can 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 composition is formulated as a tablet, the tablet can be uncoated or can be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over an extended period. For example, time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax can be employed.

[0035] In embodiments, the pharmaceutical composition can comprise a) about 4 mg - 20 mg of azelastine HC1 (or other salt) and b) about 1 mg to 4 mg of donepezil HC1 or about 1 mg to 2 mg of rivastigmine tartrate or about 1 mg to 3 mg of galantamine HBr, or a) about 8 mg - 16 mg of azelastine HC1 (or other salt) and b) about 1 mg to 4 mg of donepezil HC1 or about 1 mg to 2 mg of rivastigmine tartrate or about 1 mg to 3 mg of galantamine HBr, or a) about 10 mg - 14 mg of azelastine HC1 (or other salt) and b) about 1 mg to 4 mg of donepezil HC1 or about 1 mg to 2 mg of rivastigmine tartrate or about 1 mg to 3 mg of galantamine HBr. For example, the composition can comprise a) about 12 mg of azelastine HC1 and b) about 4 mg of donepezil HC1 or about 2 mg of rivastigmine tartrate or about 3 mg of galantamine HBr. Further, for example, the compositions of the present application can comprise azelastine or a pharmaceutically acceptable salt of azelastine present in an amount ranging from about 4 mg to about 50 mg and donepezil HC1 present in an amount ranging from about 1 mg to about 4 mg or rivastigmine tartrate present in an amount ranging from about 1 mg to about 2 mg or galantamine HBr present in an amount ranging from about 1 mg to about 3 mg. In embodiments, the amount of azelastine HC1 (or other salt) present in the composition can be equal to, greater than, or less than the amount of donepezil HC1 or rivastigmine tartrate or galantamine HBr (or other salt) present in the composition. In embodiments, the amount of azelastine HC1 (and / or other salt) present in the composition can be 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 donepezil HC1 or rivastigmine tartrate or galantamine HBr (and / or other salt) present in the composition, or vice versa. Any one or more of the compositions of the present application can be used with any one or more of the methods of the present application disclosed herein or other methods using the compositions.

[0036] It will be understood, that the amount of a pharmaceutical composition comprising azelastine HC1 and donepezil HC1 or rivastigmine tartrate or galantamine HBr actually administered will generally be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the relative activity of the compounds actually administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, etc.

[0037] The pharmaceutical compositions, pharmaceutical dosage forms, and tablets comprising azelastine HC1 and donepezil HC1 or rivastigmine tartrate or galantamine HBr as described herein are administered orally once daily, twice daily, every other day, twice a week, three times a week, four times a week, or five times a week to patients suffering from neurodegenerative disorders such as Alzheimer's disease.

[0038] In embodiments, the pharmaceutical compositions are administered to patients in a therapeutically effective daily dose that is azelastine HC1 in the range of 8 mg to about 16 mg and donepezil HC1 in an amount in the range of about 1 mg to about 4 mg or rivastigmine tartrate in an amount in the range of about 1 mg to about 2 mg or galantamine HBr in an amount in the range of about 1 mg to about 3 mg.

[0039] In embodiments, the pharmaceutical dosage forms and tablets of the pharmaceutical compositions comprising azelastine HC1 and donepezil HC1 or rivastigmine tartrate or galantamine HBr as described herein are effective in reversing the symptoms of patients suffering from Alzheimer's disease within about 6-24 weeks.

[0040] The therapeutic effectiveness of the pharmaceutical compositions on patients suffering from AD is evaluated by improvement in scores of the Mini-Mental State Examination (MMSE) and the 12-item Neuropsychiatric Inventory-Questionnaires (NPI-Q) (severity scores of 0-3 and distress scores of 0-5).

[0041] For the treatment of AD, as one of the acetylcholinesterase inhibitors, donepezil alone improved MMES by 9.2%, improved NPI total by 40.9%, and improved NPI distress by 41.5%.

[0042] The following examples are illustrative and should not be construed as limiting the scope of the subject matter of the application.

[0043] Example 1

[0044] Ten patients diagnosed with late-stage Alzheimer's disease with MMSE scores of 10-1 and NPI-Q severity scores of 3 and distress scores of 4 or 5 are treated once daily with a pharmaceutical composition comprising 12 mg azelastine HC1 and 3 mg donepezil HC1 in the form of a tablet. After 12 weeks, the MMSE scores of the ten patients will increase by at least 9 points, reaching the range of 20-10, the MMSE scores will be improved by 1 to 9 times, and their NPI-Q will have a severity score of 1 and a distress score of 1 or 2, improving by 2.5 to 4 times.

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[0100] The application has been described with reference to particular embodiments having various features. It will be apparent to those skilled in the art that various modifications and variations can be made to the method of practicing the present application without departing from the scope or spirit of the application. One skilled in the art will recognize the disclosed features can be used alone or in any combination depending on the requirements and specifications of a given application or design. When embodiments refer to "comprising" certain features, it is understood that the embodiments can alternatively be "consisting of or "consisting essentially of any one or more of the recited features. Any method disclosed herein can be used with any composition disclosed herein or with any other composition. Likewise, any disclosed composition can be used with any method disclosed herein or with any other method. Other embodiments of the application will be apparent to those skilled in the art from consideration of the specification and practice of the application.

[0101] It is especially noted that where a range of values is provided in the specification, each intervening value, to the tenth of the unit of the disclosed value, is also specifically disclosed. Any smaller range or any other smaller range that might be described in terms of the provided ranges is also specifically disclosed. The upper and lower limits of the ranges are independently includable and excludable from the range. Unless otherwise expressly specified, the singular forms "a," "an," and "the" include plural referents. It is contemplated that the description and examples set forth herein are exemplary and that changes in the nature of the invention that are not recited herein will fall within the scope of the application. Furthermore, all references cited in the present disclosure are each incorporated by reference in their entirety to the same extent as if each was incorporated individually and are likewise intended to provide effective access to descriptions of the state of the art at the time of the application for the present application and to provide effective access to background information pertinent to the present application.

Claims

1. Use of a pharmaceutical composition for the preparation of a medicament for treating Alzheimer's disease by improving memory and reasoning, the pharmaceutical composition comprising: Azelastine or a pharmaceutically acceptable salt of azelastine; Donepezil or rivastigmine or galantamine, or a pharmaceutically acceptable salt thereof, or any combination thereof; and one or more pharmaceutically acceptable excipients.

2. The use according to claim 1, wherein the azelastine or a pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount ranging from 4 mg to 50 mg.

3. The use according to claim 1, wherein the donepezil is present in the pharmaceutical composition in an amount ranging from 1 mg to 4 mg.

4. The use according to claim 1, wherein: The azelastine or a pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount ranging from 4 mg to 50 mg; and The rivastigmine or its salt is present in the pharmaceutical composition in an amount ranging from 1 mg to 2 mg.

5. The use according to claim 2, wherein the pharmaceutically acceptable salt of azelastine is azelastine hydrochloride.

6. The method according to claim 1, wherein the pharmaceutically acceptable salt of donepezil, rivastigmine or galanthamine is donepezil hydrochloride, rivastigmine tartrate or galanthamine hydrobromide.

7. The use according to claim 5, wherein the azelastine hydrochloride is present in an amount ranging from 6 mg to 20 mg.

8. The use according to claim 5, wherein the azelastine hydrochloride is present in an amount ranging from 8 mg to 12 mg.

9. The use according to claim 6, wherein the galanthamine hydrobromide is present in an amount ranging from 1 mg to 3 mg.

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

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