CN115776885A - Compositions and methods for treating alzheimer's disease and parkinson's disease - Google Patents

Abstract

Pharmaceutical compositions comprising azelastine or a pharmaceutically acceptable salt of azelastine and mecobalamin are disclosed. Also disclosed are methods of using the pharmaceutical compositions to treat patients with alzheimer's disease or parkinson's disease.

Description

Compositions and methods for treating Alzheimer's disease and Parkinson's disease

Cross References to Related Applications

This application is a continuation-in-part of US Patent Application No. 16/382,885 filed April 12, 2019, the disclosure of which is hereby incorporated by reference in its entirety.

technical field

The present invention relates to the field of applied medicine, ie to the use of a pharmaceutical composition for the treatment of Alzheimer's disease and Parkinson's disease. More specifically, the present invention relates to novel combinations of compounds that are effective in the treatment of Alzheimer's disease (AD) and Parkinson's disease (PD).

Background technique

Alzheimer's disease (AD) is a progressive, chronic neurodegenerative disease that usually begins slowly and progressively worsens over time. Among older adults, AD is the most common cause of dementia. Dementia is the loss of cognitive function (thinking, memory, and reasoning) and behavioral abilities to the extent that it interferes with a person's daily life and activities. In its early stages, memory loss is mild, but in advanced AD, individuals lose the ability to carry on conversations and respond to their environment. If left untreated, AD eventually leads to death. Typical life expectancy after diagnosis is 3 to 9 years, although the rate of progression may vary.

Neuropathologically, AD is characterized by the accumulation of neuroinflammatory plaques of amyloid beta (Aβ) and neurofibrillary tangles of hyperphosphorylated tau protein (p-tau). Most of the current evidence indicates that A[beta] accumulation is a key primary predisposing factor in sporadic AD. To date, none of the promising approaches for reducing Aβ or p-tau levels (including mechanisms such as inhibition of Aβ or p-tau production, reduction of soluble Aβ levels, and enhanced Aβ or p-tau clearance from the CNS) have been reported. Their clinical trials provide the desired results. Although the development of Aβ-based therapies logically follows the known Aβ mechanisms, a number of factors may limit the effectiveness of such treatments if applied in isolation. But more importantly, many other potential mechanisms may constitute important predisposing factors for AD. As the disease progresses, such non-Aβ mechanisms may even play a greater or possibly synergistic role. Therefore, the parallel application of neuroprotective strategies is likely to play an important role in delaying the onset of AD and delaying the progression of AD.

Homocysteine is a sulfur amino acid involved in essential metabolic pathways including methylation reactions. Elevated homocysteine in the blood is a sign of genetic disorders and vitamin B12 deficiency. Elevated homocysteine is associated with vascular disease, neuropsychiatric disease, and neurovascular ischemic disease including stroke, silent infarction, and white matter disease. Studies have linked homocysteine to amyloid and glutamate neurotoxicity as well as cognitive impairment and AD. For example, in transgenic mice with brain amyloid deposits, elevated homocysteine led to loss of hippocampal neurons. Studies have also demonstrated a relationship between plasma homocysteine levels and AD and cognitive function in non-demented individuals. This relationship runs through the normal range of homocysteine levels. Reduction of homocysteine levels can be readily achieved using high doses of vitamin B12 and may represent a disease-modifying intervention in AD.

Methylcobalamin (one of the two active forms of the four vitamin B12 potent vitamins) is most efficiently taken up by the subcellular organelles of neurons compared to other analogues. Therefore, the combination of methylcobalamin and azelastine may provide a better treatment option for neurological disorders such as AD.

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 have shown that long-term use of NSAIDs has great benefits. Thus, AD is generally considered to be partly an inflammatory disease and inhibiting inflammation is an option for the treatment of AD.

Inflammation clearly occurs in pathologically vulnerable areas of the AD brain, and it occurs with the full complexity of local peripheral inflammatory responses. In the periphery, degenerated tissue and deposition of highly insoluble foreign bodies are typical stimuli of inflammation. Likewise, in AD brains, damaged neurons and neurites as well as highly insoluble amyloid-β peptide deposits and neurofibrillary tangles provide distinct stimuli for inflammation. Local upregulation of complement, cytokines, acute-phase reactants, and other inflammatory mediators as these stimuli are discrete, micro-localized, and present from the early preclinical stage to the end stages of AD Also discrete, micro-local and long-term. Cumulatively over the years, direct and indirect insults from AD inflammatory mechanisms are likely to significantly exacerbate the pathogenic processes leading to AD. Thus, animal models and clinical studies to date strongly suggest that AD inflammation contributes significantly to AD pathogenesis. With a better understanding of AD inflammatory and immunomodulatory processes, it should be possible to develop anti-inflammatory approaches that can reverse or delay or prevent the development of this devastating condition.

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 antihistamine and mast cell stabilizing effects, its inhibition of inflammatory mediators makes it a new generation of dual-effect anti-inflammatory drugs. In addition to azelastine's high affinity for the H1 receptor, its 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 the dual role of direct suppression and stabilization of inflammatory cells. In vitro data indicate that the affinity of azelastine for the H1 receptor is estimated to be several times higher than that of chlorpheniramine (the first generation H1 antagonist). Azelastine has only weak affinity for H2 receptors. Histamine release from mast cells may also be inhibited by reversible inhibition of voltage-dependent L-type calcium channels. Among them, inhibiting mast cell degranulation can also reduce the release of other inflammatory mediators including leukotrienes and interleukin-1β. Azelastine also directly antagonizes other inflammatory mediators such as tumor necrosis factor-alpha, leukotrienes, endothelin-1, and platelet-activating factor.

Thus, azelastine (an antihistamine with anti-inflammatory activity) and methylcobalamin (for the maintenance of myelin synthesis, neuronal metabolism and neuronal regeneration) may be an effective treatment for AD patients.

Contents of the invention

The present invention includes pharmaceutical compositions comprising two active pharmaceutical ingredients. 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 methylcobalamin.

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

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

The present invention also includes oral pharmaceutical dosage forms as pharmaceutical compositions in solid form, liquid form, gel form or solution form.

The invention further includes the medical use of the oral pharmaceutical dosage form of the pharmaceutical composition by administering the oral pharmaceutical dosage form to a patient suffering from Alzheimer's disease or Parkinson's disease.

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 are included within the scope of the present invention use in patients with Meridian disease or Parkinson's disease.

Embodiments further include compositions comprising azelastine or a pharmaceutically acceptable salt of azelastine, methylcobalamin and one or more pharmaceutically acceptable excipients for the manufacture of Use of medicines for Haimer's disease or Parkinson's disease.

In some embodiments of the present invention, the pharmaceutical composition comprising azelastine hydrochloride (and/or other salts) in an amount from about 8 mg to about 24 mg and methylcobalamin in an amount from about 0.5 mg to about 50 mg The oral dosage form is administered to a patient suffering from Alzheimer's disease or Parkinson's disease.

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

Aspect 2 is the pharmaceutical composition of aspect 1, wherein azelastine or a pharmaceutically acceptable salt of azelastine is present in an amount of about 8 mg to about 24 mg, such as about 8 mg to about 18 mg, or about 12 mg to about 16 mg, or about 12 mg, or about 8 mg to about 24 mg, or about 8 mg, or 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 The pharmaceutical composition is present in an amount ranging from 8 mg to about 12 mg, or in any range between any of these endpoints.

Aspect 3 is the pharmaceutical composition of aspect 1 or 2, wherein methylcobalamin is present in an amount of about 0.5 mg to about 50 mg, such as about 0.5 mg to about 45 mg, or about 0.5 mg to about 35 mg, or about 1 mg to about 10 mg, or about 0.5 mg to about 5 mg, or 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 about 5 mg to about 12 mg, or about 2 mg to about 8 mg amount, or in an amount of about 1 mg, or in an amount within any range between any of these endpoints.

Aspect 4 is the pharmaceutical composition of any 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.

Aspect 5 is the pharmaceutical composition of any 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 methylcobalamin is present in an amount ranging from about 0.5 mg to about 50 mg.

Aspect 6 is the pharmaceutical composition of any of aspects 1-5, wherein the pharmaceutically acceptable salt of azelastine is azelastine hydrochloride.

Aspect 7 is the pharmaceutical composition of any 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.

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

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

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

Aspect 11 is the 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 methylcobalamin is present in an amount ranging from about 1 mg to about An amount of 5 mg is present in the pharmaceutical composition.

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

Aspect 13 is the method of any of aspects 1-12, wherein the pharmaceutical composition is administered to the patient in oral solid or liquid form once or twice a day, or three times a day, or once every 2 or 3 or 4 days.

Aspect 14 is the 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.

Aspect 15 is the 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.

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

Aspect 17 is the method of any of aspects 1-16, wherein methylcobalamin is present in the pharmaceutical composition in an amount in the range of about 0.5 mg to 10 mg.

Aspect 18 is the 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.

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

Aspect 20 is the 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.

Aspect 21 is a combination comprising azelastine or a pharmaceutically acceptable salt of azelastine, methylcobalamin and one or more pharmaceutically acceptable excipients as disclosed in any of aspects 1-20 Use of a drug for the treatment of Alzheimer's disease or Parkinson's disease.

Aspect 22 is a combination comprising azelastine or a pharmaceutically acceptable salt of azelastine, methylcobalamin and one or more pharmaceutically acceptable excipients as disclosed in any of aspects 1-20 Use of a substance for the manufacture of a medicament for the treatment of Alzheimer's disease or Parkinson's disease.

Detailed ways

Through clinical practice, the inventors of the present invention have found that a pharmaceutical composition in an oral dosage form comprising the active agents (azelastine in salt form and methylcobalamin) would be able to slow down or even terminate Alzheimer's disease or Parkinson's disease progress of therapy.

The detailed description provided below is intended as a description of the present example and is not intended to represent the only forms in which the present example may be constructed or utilized. The description sets forth the functionality of the instance and the sequence of steps to build and operate the instance. However, the same or equivalent functions and sequences may be implemented by different examples.

definition

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.

As used herein, the term "methylcobalamin" refers to cobalamin (a form of vitamin B12), methylcobalamin (co-methylcobalamin), and also means MeCbl, Mecobalamin ( mecobalamin), mecobalamina, mecobalamine, or methyl vitamin B12.

-4-基)-1-(2H)-酞嗪酮。在某些实施方案中，氮卓斯汀还包括任何药学上可接受的盐，例如盐酸盐或HCl盐。优选地，在如本文中所述的本发明的任何实施方案中，氮卓斯汀为其盐酸盐的形式，如盐酸氮卓斯汀或氮卓斯汀HCl。更优选地，在如本文中所述的本发明的任何实施方案中，提及固体口服剂型中包括的氮卓斯汀的量和剂量范围是指盐酸氮卓斯汀的量和剂量范围。As used herein, the term "azelastine" refers to azelastine free base or 4-(p-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepine

-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 of the embodiments of the invention as described herein, azelastine is in the form of its hydrochloride, such as azelastine hydrochloride or azelastine HCl. More preferably, in any of the embodiments of the invention as described herein, references to amounts and dosage ranges of azelastine included in the solid oral dosage form refer to amounts and dosage ranges of azelastine hydrochloride.

As used herein, the term "salt" refers to a salt of azelastine with an acid selected from the group consisting of 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-Hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonate Acid, benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid) , caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, lauryl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid , formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerin Phosphoric acid, 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, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid, p-toluenesulfonic acid, undecylenic acid.

As used herein, "treating" or "treatment" means complete cure or incomplete cure, or it means at least alleviation and/or delay of symptoms of the underlying disease or associated condition, and/or Alleviation, delay and/or elimination of one or more of the underlying cellular, physiological or biochemical causes or mechanisms causing symptoms. It should be understood that alleviation or delay as used in this context means relative to the state of the untreated disease, including the molecular state of the untreated disease and not only the physiological state of the untreated disease.

The term "effective amount" means an amount, as defined below, sufficient to effect treatment when administered to a mammal in need of such treatment. A therapeutically effective amount will vary depending on the patient being treated, the patient's weight and age, the severity of the condition, the mode of administration, etc., and can be readily determined by one of ordinary skill in the art. The pharmaceutical composition can be administered in single or multiple doses by oral administration. It can be administered via capsules, tablets, gels, sprays, drops, solutions, suspensions or syrups and the like.

The term "about" as used herein in the context of a quantitative measurement means ± 10% of the specified amount. For example, "about 2 mg" may mean 1.8-2.2 mg in the context of a range of ±10%.

Pharmaceutical compositions can be formulated using methods known in the art, for example, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, 10th Edition (Loyd Allen, 2013) and Handbook of Pharmaceutical Manufacturing Formulations (Volumes 1-6, Sarfaraz K. Niazi) For pharmaceutical use. Thus, the introduction of the active compound and a controlled or sustained release matrix can be carried out.

Fluid or solid unit dosage forms can be readily prepared for oral administration, for example, with conventional ingredients such as dicalcium phosphate, magnesium aluminum silicate, magnesium stearate, calcium sulfate, starch, talc, Blend of lactose, acacia, methylcellulose and functionally similar materials. Sustained release formulations may optionally be used. In older or incoherent subjects, extended release formulations may even be preferred. Capsules can be formulated by mixing the pharmaceutical composition with an inert pharmaceutically acceptable diluent and filling the mixture into hard gelatin capsules of suitable size. If soft capsules are desired, a slurry of the pharmaceutical composition and acceptable vegetable oil, light petroleum, or other inert oil can be encapsulated by forming a gelatin capsule.

Suspensions, syrups, and elixirs can be used for oral administration or in fluid unit dosage form. Fluid formulations containing oil may be used in oil soluble forms. Vegetable oils such as corn oil, peanut oil or flower oil, for example, are combined with flavoring, sweetening and any preservatives to produce acceptable fluid formulations. A surfactant can be added to water to form a syrup for the fluid unit dosage. Hydro-alcoholic pharmaceutical preparations may be used in the form of elixirs with acceptable sweetening agents, such as sugar, saccharine, or biological sweeteners, and flavorings.

The solid oral preparations of the present disclosure mean the forms of tablets, caplets, bilayer tablets, film-coated tablets, pills or capsules, and the like. Tablets according to the present disclosure may be prepared by any of the mixing and tabletting techniques well known in the pharmaceutical formulation industry. In some examples, the formulation is manufactured by directly compressing the respectively prepared sustained-release part and immediate-release part by means of punches and dies attached to a rotary tablet press, ejection or compression molding, or granulation after compression.

Pharmaceutical compositions provided according to the present disclosure are typically administered orally. Accordingly, the present disclosure provides a pharmaceutical composition comprising a solid dispersion comprising azelastine and methylcobalamin as described herein and one or more pharmaceutically acceptable excipients or carriers , the pharmaceutically acceptable excipients or carriers include but are not limited to inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, disintegrants, lubricating agents Agents, 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 (LoydAllen, 2013) and Handbook of Pharmaceutical Manufacturing Formulations (Volumes 1-6, Sarfaraz K. Niazi)).

Some examples of suitable excipients are described herein. When the pharmaceutical composition is formulated as tablets, the tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide longer duration of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

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

In embodiments, the pharmaceutical composition may be present in an amount ranging from about 8 mg to about 22 mg, such as 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 about 12 mg to about 20 mg, or about 8 mg to about 12 mg, or in an amount within any range between any of these endpoints comprising a) azelastine or azelastine HCl ( or other salts), or contain any amount of azelastine, azelastine HCl (or other salts), and in the range of about 0.5 mg to about 50 mg, such as about 0.5 mg to about 45 mg, or about 0.5 mg to about 35 mg , or about 1 mg to about 10 mg, or about 0.5 mg to about 5 mg, or 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 about 5 mg to about 12 mg , or in an amount ranging from about 2 mg to about 8 mg, or in an amount of about 1 mg, or comprising b) methylcobalamin in an amount in any range between any of these endpoints.

In embodiments, the amount of azelastine or azelastine HCl (or other salt) 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 times, or 3 times, the amount of methylcobalamin present in the composition, or 4x, 5x, 6x, 7x, 8x, 9x, 10x, 15x, 20x, 25x, 30x, 35x, 40x, 45x, 50x, 75x or 100x , or vice versa, using any amount disclosed or claimed above. Any one or more compositions of the invention can be used in conjunction with any one or more of the methods of the invention disclosed herein or other methods using the compositions.

It will be understood that the amount of the pharmaceutical composition comprising azelastine HCl and methylcobalamin actually administered will generally be determined by the physician according to the relevant circumstances, including the condition to be treated, the route of administration chosen, the compound actually administered and its relative activity, the age, weight and response of the individual patient, and the severity of the patient's symptoms, etc.).

Pharmaceutical compositions, pharmaceutical dosage forms and tablets comprising azelastine HCl and methylcobalamin as described herein are administered orally once a day, twice a day, three times a day, four times a day, once 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, is administered to a patient with Alzheimer's disease or Parkinson's disease. Those skilled in the art will appreciate that the amounts of azelastine and methylcobalamin in compositions as disclosed or claimed above may optionally be taken as a daily dose and thus may be formulated as a single dose.

In an embodiment, a patient is administered a pharmaceutical composition having a therapeutically effective daily dose of azelastine HCl in an amount ranging from 8 mg to about 24 mg and methylcobalamin in an amount ranging from about 0.5 mg to about 50 mg.

In an embodiment, pharmaceutical dosage forms and tablets of a pharmaceutical composition as described herein comprising azelastine or azelastine HCl (or other salts) and methylcobalamin are within about 2-16 weeks, e.g. Within 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, or 16 weeks, or any period in between It is 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 the range. If the Mini-Mental State Examination (MMSE) and Activities of Daily Living (ADL) are assessed in patients with AD or PD, the scores of MMSE and ADL can be improved by more than 50%.

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

Example

A 70-year-old patient with intermediate-stage Alzheimer's disease (AD) for 2 years and a baseline MMSE score of 12 before treatment and a Barthel Index (BI) of 30 for Activities of Daily Living scores can be treated with methylcobalamin and nitrogen up to twice daily A pharmaceutical composition of justlastine, for example, a composition therapy comprising methylcobalamin in an amount of 1.0 mg and azelastine, azelastine HCl or other salts in an amount of 8 mg (or any of the above or claimed composition, or any treatment regimen or time period described above or claimed). One or more of his AD symptoms is expected to improve by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or higher. For example, his MMSE score is expected to improve from 12 to at least 22, which is an 83% improvement, and his BI score is expected to improve from 30 to at least 80, which is a 167% improvement. Such remarkable clinical results of the combination are unexpected for patients with AD and should be better than azelastine alone. Azelastine reduces the inflammatory process in AD by reducing 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 terminating Neurodegeneration in AD. However, in combination with azelastine, methylcobalamin, which promotes the growth of neuronal cells by promoting myelin synthesis, nerve metabolism and neuronal regeneration, maintains the effect of azelastine and increases the reversal of symptoms in AD patients, therefore, the combination Drugs would lead to more effective and durable treatments for AD patients.

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 receive a drug combination of methylcobalamin and azelastine up to twice daily For example, a composition treatment (or any composition described above or claimed, or any of the above or claimed any treatment regimen or time period claimed). One or more of his PD symptoms is expected to improve by at least 10%, 20%, 30%, 40% after 2, 3, 4, 5, 6, 7, 8 weeks or more %, 50%, 60%, 70%, 80%, 90%, 100% or higher. For example, his UPDRS overall score is expected to improve from 90 to at least 40, which is a 56% improvement. In addition, if the patient's MMSE score is evaluated, an improvement of more than 50% is expected.

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The invention has been described with reference to specific embodiments having various features. From the disclosure provided above it will be apparent to those skilled in the art that various modifications and changes can be made in the practice of the invention 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 based on the requirements and specifications of a given application or design. Where an embodiment refers to "comprising" certain features, it is to be understood that an embodiment may alternatively consist of or consist essentially of any one or more of said features. Any method disclosed herein can be used with any composition disclosed herein or with any other composition. Likewise, 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 from consideration of the specification and practice of the invention.

It is particularly noted that where a range of values is provided in this specification, each value between the upper and lower limits of that range is also specifically disclosed. The upper and lower limits of these smaller ranges may also independently be included in or excluded from that range. The singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. It is intended that the specification and examples be considered exemplary in nature and that variations which do not depart from the essence of the invention are within the scope of the invention. Furthermore, all references cited in this disclosure are each independently incorporated by reference in their entirety and are likewise intended to provide an effective means of supplementing the disclosure of the present invention as well as provide a background detailing the level of ordinary skill in the art.

Claims (22)

1. A pharmaceutical composition comprising: Azelastine or a pharmaceutically acceptable salt of azelastine; Methylcobalamin; and One or more pharmaceutically acceptable excipients. 2. The pharmaceutical composition according to claim 1, wherein said azelastine or a pharmaceutically acceptable salt of azelastine is present in said pharmaceutical combination in an amount ranging from about 8 mg to about 24 mg in things. 3. The pharmaceutical composition according to claim 1, wherein said methylcobalamin is present in said pharmaceutical composition in an amount ranging from about 0.5 mg to about 50 mg. 4. The pharmaceutical composition of claim 1, wherein the methylcobalamin is present in the pharmaceutical composition in an amount ranging from about 0.5 mg to about 10 mg. 5. The pharmaceutical composition according to claim 1, wherein: said azelastine or a pharmaceutically acceptable salt of azelastine is present in said pharmaceutical composition in an amount ranging from about 8 mg to about 24 mg; and The methylcobalamin is present in the pharmaceutical composition in an amount ranging from about 0.5 mg to about 50 mg. 6. The pharmaceutical composition according to claim 2, wherein the pharmaceutically acceptable salt of azelastine is azelastine hydrochloride. 7. The pharmaceutical composition according to claim 6, wherein said methylcobalamin is present in said pharmaceutical composition in an amount ranging from about 0.5 mg to about 50 mg. 8. The pharmaceutical composition of claim 6, wherein the azelastine hydrochloride is present in an amount ranging from about 8 mg to about 18 mg. 9. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is formulated as an oral pharmaceutical dosage form. 10. The pharmaceutical composition according to claim 9, wherein the oral pharmaceutical dosage form is a solid form or a liquid form. 11. The pharmaceutical composition according to claim 6, wherein said azelastine hydrochloride is present in said pharmaceutical composition in an amount ranging from about 8 mg to about 12 mg and said methylcobalamin is present in an amount ranging from The pharmaceutical composition is present in an amount from about 1 mg to about 5 mg. 12. A method of treating a patient suffering from Alzheimer's disease or Parkinson's disease, said method comprising: Administering an effective amount of the pharmaceutical composition to the patient for a period of time sufficient to alleviate, reduce, prevent and/or eliminate one or more symptoms of Alzheimer's disease or Parkinson's disease in the patient, the drug The composition contains: Azelastine or a pharmaceutically acceptable salt of azelastine; Methylcobalamin; and One or more pharmaceutically acceptable excipients. 13. The method of claim 12, wherein the pharmaceutical composition is administered to the patient once or twice a day, or three times a day, or once every 2 or 3 or 4 days in oral solid or liquid form. 14. The method of claim 13, wherein the 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 . 15. The method of claim 12, wherein the methylcobalamin is present in the pharmaceutical composition in an amount ranging from about 0.5 mg to about 50 mg. 16. The method of claim 12, wherein the pharmaceutical composition is administered to the patient for a period of at least 6 weeks. 17. The method of claim 12, wherein the methylcobalamin is present in the pharmaceutical composition in an amount ranging from about 0.5 mg to 10 mg. 18. The method of claim 12, wherein the methylcobalamin is present in the pharmaceutical composition in an amount ranging from about 1 mg to about 10 mg. 19. The method of claim 12, wherein: The pharmaceutically acceptable salt of azelastine is azelastine hydrochloride and is present in the pharmaceutical composition in an amount ranging from about 8 mg to about 24 mg; and The methylcobalamin is present in the pharmaceutical composition in an amount ranging from about 0.5 mg to about 50 mg. 20. The method of claim 19, wherein the methylcobalamin is present in the pharmaceutical composition in an amount ranging from about 0.5 mg to about 10 mg. 21. The composition comprising azelastine or a pharmaceutically acceptable salt of azelastine, methylcobalamin and one or more pharmaceutically acceptable excipients is used for the treatment of Alzheimer's disease or Alzheimer's disease Uses for Kimson's disease. 22. A composition comprising azelastine or a pharmaceutically acceptable salt of azelastine, methylcobalamin and one or more pharmaceutically acceptable excipients for the manufacture of a drug for the treatment of Alzheimer's use of drugs for Parkinson's disease or Parkinson's disease.