Compositions and methods for treating alzheimer's disease and parkinson's disease

Abstract

Disclosed are pharmaceutical compositions comprising azelastine or a pharmaceutically acceptable salt of azelastine and methylcobalamin. Also disclosed are methods of using the pharmaceutical compositions to treat patients suffering from Alzheimer's disease or Parkinson's disease.

Description

[0001] Cross-reference to related applications

[0002] This application is a continuation-in-part of U.S. Patent Application No. 16 / 382,885, filed April 12, 2019, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] This invention relates to the field of practical medicine, specifically to the use of pharmaceutical compositions for the treatment of Alzheimer's disease and Parkinson's disease. More specifically, this invention relates to novel combinations of compounds that can effectively treat Alzheimer's disease (AD) and Parkinson's disease (PD). Background Technology

[0004] Alzheimer's disease (AD) is a progressive, chronic neurodegenerative disease that typically begins slowly and worsens over time. AD is the most common cause of dementia in older adults. Dementia is the loss of cognitive function (thinking, memory, and reasoning) and behavioral abilities to the point of interfering with a person's daily life and activities. In its early stages, memory loss is mild, but in late-stage AD, individuals lose the ability to engage in conversation and respond to their environment. Without treatment, AD eventually leads to death. While the rate of progression may vary, the typical life expectancy after diagnosis is 3 to 9 years.

[0005] Neuropathologically, Alzheimer's disease (AD) is characterized by the accumulation of neuroinflammatory plaques of β-amyloid (Aβ) and neurofibrillary tangles of hyperphosphorylated tau protein (p-tau). Most current evidence suggests that Aβ accumulation is a key major precipitating factor in sporadic AD. To date, all promising approaches to reducing Aβ or p-tau levels (including mechanisms such as inhibiting Aβ or p-tau production, reducing soluble Aβ levels, and enhancing the clearance of Aβ or p-tau from the CNS) have failed to deliver the expected results from their clinical trials. While the development of Aβ-based therapies logically follows known Aβ mechanisms, many factors may limit the effectiveness of such treatments if applied alone. More importantly, many other potential mechanisms may constitute significant precipitating factors for AD. These non-Aβ mechanisms may even play a greater role or potentially have a synergistic effect as the disease progresses. Therefore, the concurrent application of neuroprotective strategies is likely to play a crucial role in delaying AD onset and slowing AD progression.

[0006] Homocysteine ​​is a sulfur-containing amino acid involved in essential metabolic pathways, including methylation. Elevated blood homocysteine ​​levels are a hallmark of genetic disorders and vitamin B12 deficiency. Elevated homocysteine ​​is associated with vascular disease, neuropsychiatric disorders, and neurovascular ischemic diseases (including stroke, asymptomatic infarction, and white matter disease). Studies have linked homocysteine ​​to amyloid and glutamate neurotoxicity, as well as cognitive impairment and Alzheimer's disease (AD). For example, in transgenic mice with brain amyloid deposition, elevated homocysteine ​​levels led to hippocampal neuronal loss. Studies have also demonstrated a relationship between plasma homocysteine ​​levels and AD and cognitive function in non-dementia individuals. This relationship persists across the normal range of homocysteine ​​levels. Lowering homocysteine ​​levels can be readily achieved using high doses of vitamin B12 and may represent a disease-modifying intervention for AD.

[0007] Compared to other analogues, methylcobalamin (one of the two active forms of the four vitamin B12 analogues) is most effectively taken up by the subcellular organelles of neurons. Therefore, the combination of methylcobalamin and azelastine may provide a better treatment option for neurological conditions such as Alzheimer's disease (AD).

[0008] On the other hand, genetic, cellular, and molecular changes associated with AD provide evidence that activated immune and inflammatory processes are part of the disease. Furthermore, epidemiological studies have shown significant benefits with long-term NSAID use. Therefore, AD is generally considered to be partly an inflammatory disease, and suppressing inflammation is a treatment option for AD.

[0009] Inflammation occurs prominently in pathologically vulnerable areas of the AD brain, and it is accompanied by the full complexity of localized peripheral inflammatory responses. Peripherally, degenerated tissue and the deposition of highly insoluble foreign bodies are typical stimuli of inflammation. Similarly, in the AD brain, damaged neurons and neurites, as well as highly insoluble amyloid-β-peptide deposits and neurofibrillary tangles, provide significant stimuli for inflammation. Because these stimuli are discrete, micro-localized, and present from the early preclinical stage to the late stage of AD, the local upregulation of complement, cytokines, acute-phase reactants, and other inflammatory mediators is also discrete, micro-localized, and long-term. Over many years, direct and indirect damage from the AD inflammatory mechanisms is likely to significantly exacerbate the pathogenesis of AD. Therefore, animal models and clinical studies to date strongly suggest that AD inflammation significantly promotes the pathogenesis of AD. By better understanding the inflammatory and immune regulatory processes in AD, it should be possible to develop anti-inflammatory approaches that can reverse, delay, or prevent the development of this devastating disease.

[0010] Azelastine is pharmacologically classified as a second-generation antihistamine and is 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 of dual-action anti-inflammatory drugs. Besides its high affinity for the H1 receptor, azelastine's ability to modify several other inflammatory and allergic mediators also contributes to its mechanism of action. In vitro and in vivo studies, as well as clinical trials, support its dual action of directly inhibiting and stabilizing inflammatory cells. In vitro data suggest that azelastine's affinity for the H1 receptor is estimated to be several times higher than that of chlorpheniramine (a first-generation H1 antagonist). Azelastine has only a weak affinity for the H2 receptor. Histamine release from mast cells may also be inhibited by reversible inhibition of voltage-dependent L-type calcium channels. Furthermore, inhibition of mast cell degranulation can reduce the release of other inflammatory mediators, including leukotrienes and interleukin-1β. Azelastine also directly antagonizes other inflammatory mediators, such as tumor necrosis factor-α, leukotrienes, endothelin-1, and platelet-activating factor.

[0011] Therefore, in terms of their multiple mechanisms of action, the unique combination of azelastine (an antihistamine with anti-inflammatory activity) and mecobalamin (used to maintain myelin synthesis, neuronal metabolism, and neuronal regeneration in the nervous system) may be an effective treatment for AD patients. Summary of the Invention

[0012] This invention includes a pharmaceutical composition comprising two active pharmaceutical ingredients. The pharmaceutical composition comprises a first active ingredient as azelastine or a pharmaceutically acceptable salt of azelastine and a second active ingredient as methylcobalamin.

[0013] In some embodiments of the present invention, the pharmaceutically acceptable salt of azelastine in the pharmaceutical composition is azelastine hydrochloride.

[0014] In some embodiments of the invention, azelastine hydrochloride (and / or other salts) in the pharmaceutical composition is provided in an amount of about 8 mg to about 24 mg and mecobalamin is provided in an amount of about 0.5 mg to about 50 mg.

[0015] The present invention also includes oral pharmaceutical dosage forms of pharmaceutical compositions in solid, liquid, gel or solution form.

[0016] The present invention further includes the medical use of an oral dosage form of a pharmaceutical composition administered to a patient suffering from Alzheimer's disease or Parkinson's disease.

[0017] The scope of this invention includes the use of compositions comprising azelastine or a pharmaceutically acceptable salt of azelastine, methylcobalamin, and one or more pharmaceutically acceptable excipients for the treatment of Alzheimer's disease or Parkinson's disease.

[0018] The implementation scheme further includes the use of a composition comprising azelastine or a pharmaceutically acceptable salt of azelastine, mecobalamin, and one or more pharmaceutically acceptable excipients for the manufacture of a medicament for the treatment of Alzheimer's disease or Parkinson's disease.

[0019] In some embodiments of the invention, an oral pharmaceutical dosage form comprising a pharmaceutical composition containing azelastine hydrochloride (and / or other salts) in an amount of about 8 mg to about 24 mg and containing mecobalamin in an amount of about 0.5 mg to about 50 mg is given to a patient with Alzheimer's disease or Parkinson's disease.

[0020] Embodiments of the present invention include aspect 1, which includes a pharmaceutical composition comprising azelastine or a pharmaceutically acceptable salt of azelastine, methylcobalamin, and one or more pharmaceutically acceptable excipients.

[0021] Aspect 2 is a pharmaceutical composition of aspect 1, wherein azelastine or a pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount ranging from about 8 mg to about 24 mg, for example, from about 8 mg to about 18 mg, or from about 12 mg to about 16 mg, or about 12 mg, or from about 8 mg to about 24 mg, or about 8 mg, or from about 8 mg to about 22 mg, or about 10 mg to about 20 mg, or about 10 mg to about 16 mg, or about 10 mg to about 12 mg, or about 12 mg to about 20 mg, or about 8 mg to about 12 mg, or in an amount ranging from any of these endpoints.

[0022] Aspect 3 is a pharmaceutical composition of aspect 1 or 2, wherein methylcobalamin is present in the pharmaceutical composition in an amount ranging from about 0.5 mg to about 50 mg, for example, from about 0.5 mg to about 45 mg, or from about 0.5 mg to about 35 mg, or from about 1 mg to about 10 mg, or from about 0.5 mg to about 5 mg, or from about 0.5 mg to about 20 mg, or at most about 25 mg, or at most about 15 mg, or at most about 8 mg, or at most about 5 mg, or from about 5 mg to about 12 mg, or from about 2 mg to about 8 mg, or in an amount of about 1 mg, or in any range between any of these endpoints.

[0023] Aspect 4 is a pharmaceutical composition of any one of Aspects 1-3, wherein methylcobalamin is present in the pharmaceutical composition in an amount ranging from about 0.5 mg to about 10 mg.

[0024] Aspect 5 is a pharmaceutical composition of any one of Aspects 1-4, wherein, in the pharmaceutical composition, azelastine or a pharmaceutically acceptable salt of azelastine is present in an amount ranging from about 8 mg to about 24 mg and mecobalamin is present in an amount ranging from about 0.5 mg to about 50 mg.

[0025] Aspect 6 is a pharmaceutical composition of any one of Aspects 1-5, wherein a pharmaceutically acceptable salt of azelastine is azelastine hydrochloride.

[0026] Aspect 7 is a pharmaceutical composition of any one of Aspects 1-6, wherein methylcobalamin is present in the pharmaceutical composition in an amount ranging from about 0.5 mg to about 50 mg.

[0027] Aspect 8 is a pharmaceutical composition of any one of aspects 1-7, wherein azelastine hydrochloride is present in an amount ranging from about 8 mg to about 18 mg.

[0028] Aspect 9 is a pharmaceutical composition of any one of Aspects 1-8, wherein the pharmaceutical composition is formulated as an oral pharmaceutical dosage form.

[0029] Aspect 10 is a pharmaceutical composition of any of Aspects 1-9, wherein the oral pharmaceutical dosage form is in solid or liquid form.

[0030] Aspect 11 is a pharmaceutical composition of any of Aspects 1-10, wherein azelastine hydrochloride is present in the pharmaceutical composition in an amount ranging from about 8 mg to about 12 mg and mecobalamin is present in the pharmaceutical composition in an amount ranging from about 1 mg to about 5 mg.

[0031] Aspect 12 is a method of treating a patient with Alzheimer's disease or Parkinson's disease, comprising administering to the patient an effective amount of a pharmaceutical composition for a period of time sufficient to alleviate, reduce, prevent and / or eliminate one or more symptoms of Alzheimer's disease and / or Parkinson's disease, said pharmaceutical composition comprising azelastine or a pharmaceutically acceptable salt of azelastine, methylcobalamin and one or more pharmaceutically acceptable excipients.

[0032] Aspect 13 is a method of any of Aspects 1-12, wherein the pharmaceutical composition is administered to the patient orally in solid or liquid form once or twice daily, or three times daily, or once every 2, 3, or 4 days.

[0033] Aspect 14 is a method of any of Aspects 1-13, wherein azelastine or a pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount ranging from about 8 mg to about 24 mg.

[0034] Aspect 15 is a method of any of Aspects 1-14, wherein methylcobalamin is present in the composition in an amount ranging from about 0.5 mg to about 50 mg.

[0035] Aspect 16 is a method of any one of aspects 1-15, wherein the pharmaceutical composition is administered to the patient for at least 6 weeks.

[0036] Aspect 17 is a method of any of Aspects 1-16, wherein methylcobalamin is present in the pharmaceutical composition in an amount ranging from about 0.5 mg to 10 mg.

[0037] Aspect 18 is a method of any of Aspects 1-17, wherein methylcobalamin is present in the pharmaceutical composition in an amount ranging from about 1 mg to about 10 mg.

[0038] Aspect 19 is a method of any of aspects 1-18, wherein, in the pharmaceutical composition, a pharmaceutically acceptable salt of azelastine is azelastine hydrochloride and is present in an amount ranging from about 8 mg to about 24 mg, and mecobalamin is present in an amount ranging from about 0.5 mg to about 50 mg.

[0039] Aspect 20 is a method of any of Aspects 1-19, wherein methylcobalamin is present in the composition in an amount ranging from about 0.5 mg to about 10 mg.

[0040] Aspect 21 is the use of a composition comprising azelastine or a pharmaceutically acceptable salt of azelastine, mecobalamin and one or more pharmaceutically acceptable excipients disclosed in any of aspects 1-20 for the treatment of Alzheimer's disease or Parkinson's disease.

[0041] Aspect 22 is the use of a composition comprising azelastine or a pharmaceutically acceptable salt of azelastine, mecobalamin and one or more pharmaceutically acceptable excipients disclosed in any of aspects 1-20 for the manufacture of a medicament for the treatment of Alzheimer's disease or Parkinson's disease. Detailed Implementation

[0042] Through clinical practice, the inventors of this invention have discovered that pharmaceutical compositions containing active agents (a salt form of azelastine and methylcobalamin) in oral dosage forms can be a therapy that can slow down or even stop the progression of Alzheimer's disease or Parkinson's disease.

[0043] The detailed description provided below is intended to describe this example and is not intended to represent the only form in which this example can be built or utilized. This description explains the functionality of the example and the order of steps for building and operating it. However, the same or equivalent functionality and order can be implemented through different examples.

[0044] definition

[0045] As used in this specification, the following words and phrases are generally intended to have the meanings described below, unless the context in which they are used indicates otherwise.

[0046] As used in this article, the term "methylcobalamin" refers to cobalamin (a form of vitamin B12), co-methylcobalamin, and also means MeCbl, mecobalamin, mecobalamina, mecobalaminum, or methyl vitamin B12.

[0047] As used herein, the term "azelastine" refers to the free base of azelastine or 4-(p-chlorobenzyl)-2-(hexahydro-1-methyl-1H-aza) -4-yl)-1-(2H)-phthalazinone. In some embodiments, azelastine also includes any pharmaceutically acceptable salt, such as hydrochloride or HCl salt. Preferably, in any embodiment of the invention as described herein, azelastine is in the form of its hydrochloride salt, such as azelastine hydrochloride or azelastine HCl. More preferably, in any embodiment of the invention as described herein, references to the amount and dose range of azelastine included in a solid oral dosage form refer to the amount and dose range of azelastine hydrochloride.

[0048] As used herein, the term "salt" refers to the salt formed by azelastine and an acid selected from the following group of acids: 1-hydroxy-2-naphthylcarboxylic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetaminobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+), capric acid, caproic acid, caproic acid, octanoic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid. ), gentian acid, glucoheponic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutamate, glycerophosphate, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid (DL), methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, palmitic acid, phosphoric acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanate, p-toluenesulfonic acid, undecenoic acid.

[0049] As used herein, “treating” or “treatment” means complete or incomplete cure, or it means at least a reduction and / or delay in the symptoms of an underlying disease or related condition, and / or a reduction, delay, and / or elimination of one or more underlying cellular, physiological, or biochemical causes or mechanisms that cause the symptoms. It should be understood that, as used in this context, reduction or delay refers to the state of the untreated disease, including the molecular state of the untreated disease, and not just the physiological state of the untreated disease.

[0050] The term "effective amount" refers to the amount that, when administered to a mammal requiring such treatment, is sufficient to affect the treatment, as defined below. The therapeutically effective amount will vary depending on the patient receiving treatment, the patient's weight and age, the severity of the disease condition, and the route of administration, and can be readily determined by a person skilled in the art. The pharmaceutical composition can be administered orally in single or multiple doses. It can be administered via capsules, tablets, gels, sprays, drops, solutions, suspensions, or syrups, etc.

[0051] In this article, the term “about” as used in the context of quantitative measurement means a specified amount ±10%. For example, in the case of a ±10% range, “about 2 mg” could mean 1.8–2.2 mg.

[0052] Pharmaceutical compositions for pharmaceutical use can be formulated using methods known in the art, such as 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). Therefore, the introduction of the active compound and the controlled-release or sustained-release matrix can be implemented.

[0053] Fluid or solid unit dosage forms for oral administration can be readily prepared, for example, by mixing with conventional components as pharmaceutical excipients or carriers, such as dicalcium phosphate, magnesium aluminum silicate, magnesium stearate, calcium sulfate, starch, talc, lactose, gum arabic, methylcellulose, and materials with similar functions. Sustained-release formulations may be optionally used. Sustained-release formulations may even be preferred in older or incoherent subjects. Capsules can be formulated by mixing the pharmaceutical composition with an inert pharmaceutical diluent and filling the mixture into hard gelatin capsules of appropriate size. If soft capsules are desired, the pharmaceutical composition can be encapsulated with a slurry of acceptable vegetable oil, light petroleum, or other inert oil by forming gelatin capsules.

[0054] Suspensions, syrups, and elixirs can be used for oral administration or in fluid unit dosage forms. Oil-containing fluid formulations can be used in oil-soluble forms. For example, vegetable oils such as corn oil, peanut oil, or flower oil can be used with flavoring agents, sweeteners, and any preservatives to produce acceptable fluid formulations. Surfactants can be added to water to form syrups for fluid unit dosages. Water-alcohol pharmaceutical formulations in elliptical form with acceptable sweeteners such as sugar, saccharin, or biological sweeteners, as well as flavoring agents, can be used.

[0055] Solid oral dosage forms disclosed herein refer to the forms of tablets, capsules, bilayer tablets, film-coated tablets, pills, or capsules. Tablets according to this disclosure can be prepared using any mixing and tableting techniques known in the pharmaceutical formulation industry. In some instances, the formulation is manufactured by directly pressing separately prepared sustained-release and immediate-release portions using a punch and die mounted to a rotary tablet press, ejecting or compressing, or granulating after pressing.

[0056] Pharmaceutical compositions provided according to this disclosure are typically administered orally. Therefore, this disclosure provides pharmaceutical compositions comprising solid dispersions containing azelastine and methylcobalamin 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, solubilizers, disintegrants, lubricants, binders, flow aids, adjuvants, and combinations thereof. Such compositions are prepared in a manner known in the pharmaceutical field (see, for example, 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)).

[0057] This article describes some examples of suitable excipients. When a pharmaceutical composition is formulated into tablets, the tablets may be uncoated or may be coated using known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract and thereby provide a longer duration of action. For example, delaying materials such as glyceryl monostearate or glyceryl distearate may be used alone or in combination with waxes.

[0058] In the embodiments, the pharmaceutical composition may comprise a) about 8 mg to 24 mg of azelastine or azelastine HCl (or other salts) and b) about 0.5 mg to 50 mg of mecobalamin, or a) about 8 mg to 18 mg of azelastine or azelastine HCl (or other salts) and b) about 0.5 mg to 10 mg of mecobalamin, or a) about 12 mg to 16 mg of azelastine or azelastine HCl (or other salts) and b) about 0.5 mg to 5 mg of mecobalamin. For example, the composition may comprise a) about 12 mg of azelastine or azelastine HCl (or other salts) and b) about 1 mg of mecobalamin HCl, or a) about 8 mg to 24 mg of azelastine or azelastine HCl (or other salts) and b) any amount of mecobalamin.

[0059] In the embodiments, the pharmaceutical composition may contain a) azelastine or azelastine HCl (or other salts), or contain any amount of azelastine, azelastine HCl (or other salts), in an amount ranging from about 8 mg to about 22 mg, for example, from about 10 mg to about 20 mg, or from about 10 mg to about 16 mg, or from about 8 mg to about 18 mg, or from about 10 mg to about 12 mg, or from about 12 mg to about 20 mg, or in any amount between any of these endpoints. And contains b) methylcobalamin in an amount ranging from about 0.5 mg to about 50 mg, for example, from about 0.5 mg to about 45 mg, or from about 0.5 mg to about 35 mg, or from about 1 mg to about 10 mg, or from about 0.5 mg to about 5 mg, or from about 0.5 mg to about 20 mg, or up to about 25 mg, or up to about 15 mg, or up to about 8 mg, or up to about 5 mg, or from about 5 mg to about 12 mg, or from about 2 mg to about 8 mg, or in an amount of about 1 mg, or in an amount ranging from any of these endpoints.

[0060] In embodiments, the amount of azelastine or azelastine HCl (or other salts) present in the composition may be equal to, greater than, or less than the amount of methylcobalamin present in the composition. In embodiments, the amount of azelastine or azelastine HCl (and / or other salts) present in the composition may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, or 100 times the amount of methylcobalamin present in the composition, or vice versa, using any of the amounts disclosed or claimed above. Any one or more compositions of the present invention may be used in conjunction with any one or more methods of the present invention disclosed herein or other methods of using the composition.

[0061] It will be understood that the amount of the drug composition containing azelastine HCl and mecobalamin actually administered will generally be determined by the physician based on relevant circumstances, including the condition to be treated, the route of administration chosen, the compounds actually administered and their relative activity, the individual patient's age, weight and response, and the severity of the patient's symptoms.

[0062] Pharmaceutical compositions, dosage forms, and tablets comprising azelastine HCl and mecobalamin, as described herein, may be administered orally once daily, twice daily, three times daily, four times daily, every other day, once weekly, twice weekly, three times weekly, four times weekly, or five times weekly, or combinations thereof, to patients with Alzheimer's disease or Parkinson's disease. Those skilled in the art will understand that the amounts of azelastine and mecobalamin in the compositions disclosed or claimed above may optionally be as a daily dose and therefore may be formulated as a single dose.

[0063] In the implementation plan, the patient is given a pharmaceutical composition of azelastine HCl in the range of 8 mg to about 24 mg and methylcobalamin in the range of about 0.5 mg to about 50 mg, having a therapeutically effective daily dose.

[0064] In the implementation plan, pharmaceutical dosage forms and tablets comprising azelastine or azelastine HCl (or other salts) and methylcobalamin, as described herein, are effective in delaying the progression of Alzheimer's disease or Parkinson's disease or reversing the symptoms of Alzheimer's disease or Parkinson's disease within approximately 2–16 weeks, for example, within 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks, or within any range therebetween. When patients with AD or PD are assessed on the Mini-Mental State Examination (MMSE) and Activities of Daily Living (ADL), MMSE and ADL scores can improve by more than 50%.

[0065] The following examples are illustrative and should not be construed as limiting the scope of the claimed subject matter.

[0066] Example

[0067] A 70-year-old patient with intermediate-stage Alzheimer's disease (AD) for 2 years and a baseline MMSE score of 12 and a Barthel Index (BI) score of 30 for activities of daily living before treatment may be treated up to twice daily with a combination of mecobalamin and azelastine, for example, a combination containing mecobalamin in a dose of 1.0 mg and azelastine in a dose of 8 mg, azelastine HCl, or other salts (or any of the above or claimed combinations, or any of the above or claimed treatment regimens or durations). After 2, 3, 4, 5, 6, 7, 8 weeks, or longer, one or more of his / her AD symptoms are expected to improve by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more. For example, his / her MMSE score is expected to improve from 12 to at least 22, which is an 83% improvement, and his / her BI score is expected to improve from 30 to at least 80, which is a 167% improvement. This significant clinical outcome of the combination is unexpected for patients with Alzheimer's disease (AD) and should be better than azelastine alone. Azelastine reduces the inflammatory process in AD by decreasing microglial activation, inhibiting cytokine expression, neutralizing reactive oxygen species, and inhibiting the role of nuclear factor κB in the inflammatory process, thereby delaying and even halting neurodegeneration in AD. However, when combined with azelastine, mecobalamin, which promotes neuronal cell growth by promoting myelin synthesis, neurometabolism, and neuronal regeneration, maintains the effects of azelastine and increases the reversal of symptoms in AD patients. Therefore, this combination provides a more effective and durable treatment for AD patients.

[0068] A 70-year-old patient with Parkinson's disease (PD) for 3 years and a baseline Unified Parkinson's Disease Rating Scale (UPDRS) total score of 90 prior to treatment may be treated up to twice daily with a combination of mecobalamin and azelastine, for example, a combination containing 1.0 mg of mecobalamin and 8 mg of azelastine, azelastine HCl, or other salts (or any of the above or claimed combinations, or any of the above or claimed treatment regimens or durations). After 2, 3, 4, 5, 6, 7, 8 weeks, or longer, one or more of his / her PD symptoms are expected to improve by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more. For example, his / her UPDRS total score is expected to improve from 90 to at least 40, which is a 56% improvement. Furthermore, if the patient's MMSE score is evaluated, an improvement of more than 50% is expected.

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[0092] The invention has been described with reference to specific embodiments having various features. Based on the disclosure provided above, it will be apparent to those skilled in the art that various modifications and variations can be made in practice without departing from the scope or spirit of the invention. Those skilled in the art will recognize that the disclosed features may be used alone, in any combination, or omitted, depending on the requirements and specifications of a given application or design. When an embodiment refers to "comprising" certain features, it should be understood that the embodiment may optionally consist of any one or more of the stated features or substantially consist of any one or more of the stated features. Any method disclosed herein may be used with any composition disclosed herein or with any other composition. Similarly, any disclosed composition may be used with any method disclosed herein or with any other method. Other embodiments of the invention will be apparent to those skilled in the art in consideration of the specification and practice of the invention.

[0093] It is particularly noteworthy that, where numerical ranges are 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 also be independently included in or excluded from the range. Unless the context clearly specifies otherwise, the singular forms “a,” “an,” and “the” include plural indicators. It is intended that the specification and embodiments be illustrative in nature and that variations that do not depart from the essence of the invention fall within the scope of the invention. Furthermore, all references cited in this disclosure are independently incorporated herein by reference in their entirety and are also intended to provide an effective means of supplementing the disclosure of the invention and to provide background knowledge detailing the ordinary level of skill in the art.

Claims

1. A pharmaceutical composition for oral administration, comprising: Azelastine or a pharmaceutically acceptable salt of azelastine; Methylcobalamin; and One or more pharmaceutically acceptable excipients; The azelastine or a pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount ranging from 8 mg to 12 mg. The methylcobalamin is present in the pharmaceutical composition in an amount ranging from 0.5 mg to 1 mg; The pharmaceutical composition is formulated into capsules, tablets, or pills for oral administration and absorption in the gastrointestinal tract; and The pharmaceutical composition contains azelastine or a pharmaceutically acceptable salt of azelastine and mecobalamin in a therapeutically effective daily dose for treating human patients with Alzheimer's disease or Parkinson's disease.

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

3. Use of the oral pharmaceutical composition of claim 1 in the preparation of a medicament for treating Alzheimer's disease or Parkinson's disease in human patients.

4. Use of the oral pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is administered in a single daily dose for at least 6 weeks to treat Alzheimer's disease or Parkinson's disease in human patients.

5. Use of the oral pharmaceutical composition according to claim 3, wherein: The pharmaceutically acceptable salt of azelastine is azelastine hydrochloride and is present in the pharmaceutical composition in an amount ranging from 8 mg to 12 mg; and The mecobalamin is present in the pharmaceutical composition in an amount ranging from 0.5 mg to 1 mg.