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

Abstract

This invention provides a pharmaceutical composition combining azelastine and methylcobalamin. [Solution] An orally administered pharmaceutical composition is provided, comprising azelastine or a pharmaceutically acceptable salt of azelastine, methylcobalamin, and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition is formulated as a capsule, caplet, tablet, or pill configured for oral administration and absorption in the gastrointestinal tract, and the azelastine or a pharmaceutically acceptable salt of azelastine and methylcobalamin are present together in the pharmaceutical composition in a therapeutically effective daily dose for treating Alzheimer's disease or Parkinson's disease in human patients.

Description

Technical Field

[0001] Cross - reference to related applications

[0001] This application is a partial continuation application of U.S. Patent Application No. 16 / 382,88 5, filed on April 12, 2019, and the disclosure of the said patent application is hereby incorporated by reference in its entirety into this specification.

[0002] Technical Field

[0002] The present invention relates to the field of practical medicines, that is, the use of pharmaceutical compositions for treating Alzheimer's disease and Parkinson's disease. More specifically, the present invention relates to a novel combination of compounds that can effectively treat Alzheimer's disease (AD) and Parkinson's disease (PD).

Background Art

[0003]

[0003] Alzheimer's disease (AD) is a progressive chronic neurodegenerative disease that usually starts slowly and gradually worsens over time. AD is the most common cause of dementia in the elderly. Dementia is a decline in cognitive function, that is, thinking, memory, and logical thinking, as well as the ability to act, to the extent that it interferes with a person's daily life and activities. In the early stages of AD, the decline in memory is mild, but in the later stages of AD, the individual loses the ability to continue conversations and respond to their environment. Without treatment, AD will ultimately lead to death. The speed of progression can vary, but the typical life expectancy after diagnosis is 3 - 9 years.

[0004]

[0004] Neuropathologically, AD is characterized by the accumulation of senile plaques of amyloid - beta protein (Aβ) and neurofibrillary changes of hyperphosphorylated tau protein (p - tau). Current shrimp ​The majority of studies cite Aβ accumulation as a key primary causative factor in sporadic AD. To date, all promising approaches to reduce Aβ or p-tau levels, including mechanisms such as inhibiting Aβ or p-tau production, reducing soluble Aβ levels, and enhancing Aβ or p-tau clearance from the CNS, have not shown desirable results in their clinical trials. While the development of Aβ-based treatments is logically derived from known Aβ mechanisms, many factors, when applied individually, may limit the effectiveness of such treatments. More importantly, however, many other potential mechanisms may be significant causative factors in AD. Such non-Aβ mechanisms may play an even larger, or perhaps synergistic, role as the disease progresses. Therefore, the parallel application of neuroprotective strategies is likely to play a crucial role in delaying the onset and slowing the progression of AD.

[0005]

[0005] Homocysteine ​​is a sulfur-containing amino acid involved in essential metabolic pathways, including methylation reactions. Elevated blood homocysteine ​​is a marker of genetic disorders and vitamin B12 deficiency. Elevated homocysteine ​​is associated with vascular disease, neuropsychiatric disorders, stroke, silent infarction, and neurovascular ischemic diseases, including white matter lesions. Studies have linked homocysteine ​​to the neurotoxicity of amyloid and glutamate, and to cognitive impairment and AD. For example, elevated homocysteine ​​induces the loss of hippocampal neurons in transgenic mice with amyloid deposition in the brain. Studies have also demonstrated a relationship between plasma homocysteine ​​levels and AD and cognitive function in individuals without dementia. This relationship spans the normal range of homocysteine ​​levels. Reducing homocysteine ​​levels can be readily achieved with high doses of vitamin B12 and may be the most appropriate disease-modifying intervention in AD.

[0006]

[0006] Methylcoba, one of the two active forms of the four vitamin B12 vitamers. Lamin is most effective in being taken up by neuronal organelles compared to other analogs. Therefore, methylcobalamin combined with azelastine may offer a better treatment option for neurological disorders such as Alzheimer's disease (AD).

[0007]

[0007] On the other hand, the genetic, cellular, and molecular changes associated with AD are linked to activated immunity. This supports the evidence that the process and inflammatory processes are part of this disease. Furthermore, epidemiological studies have demonstrated significant benefits from long-term use of NSAIDs. Therefore, it is generally accepted that AD is partly an inflammatory disease, and that inhibiting inflammation is a treatment option for AD.

[0008]

[0008] Inflammation is clearly occurring in pathologically vulnerable areas of the AD brain, which is local This involves the full complexity of a typical peripheral inflammatory response. In the periphery, degenerated tissue and deposition of highly insoluble abnormal substances are conventional inflammatory stimuli. Similarly, in the AD brain, damaged neurons and neurites, as well as deposition of highly insoluble amyloid-beta peptides and neurofibrillary tangles, provide obvious inflammatory stimuli. These stimuli arise separately, are microlocalized, and are present from the early preclinical to the late stages of AD, and the local upregulation of complement, cytokines, acute-phase reactants, and other inflammatory mediators also arises separately, is microlocalized, and is chronic. With long-term accumulation, direct and bystander damage originating from the inflammatory mechanisms of AD is likely to significantly exacerbate the highly pathogenic processes that gave rise to it. Thus, animal models and clinical studies so far strongly suggest that AD inflammation is significantly involved in the pathogenesis of AD. A better understanding of the inflammatory and immunomodulatory processes of AD will make it possible to develop anti-inflammatory approaches that can reverse, delay, or prevent the onset of this devastating disorder.

[0009]

[0009] Azelastine is pharmacologically classified as a second-generation antihistamine. It is a relatively selective, non-sedating, competitive antagonist at the H1 receptor. More uniquely, azelastine is a new generation anti-inflammatory drug with a dual mechanism of action, due to its inhibition of inflammatory mediators in addition to its antihistamine and mast cell stabilization effects. Its high affinity for the H1 receptor, along with its ability to modify several other inflammatory and allergic mediators, is involved in its mechanism of action. In vitro and in vivo studies, as well as clinical trials, support this dual effect of direct inhibition and stabilization of inflammatory cells. In vitro data suggest that azelastine's affinity for the H1 receptor is several times greater than that of chlorpheniramine, a first-generation H1 antagonist. Azelastine has only weak affinity for the H2 receptor. Histamine release from mast cells is also likely inhibited by reversible inhibition of voltage-dependent L-type calcium channels. Inhibition of mast cell degranulation can also reduce the release of other inflammatory mediators, including leukotrienes and interleukin-1β, among others. Azelastine also directly antagonizes other inflammatory mediators such as tumor necrosis factor α, leukotrienes, endothelin-1, and platelet-activating factor. [Overview of the project] [Problems that the invention aims to solve]

[0010]

[0010] Therefore, the unique combination of azelastine (an antihistamine with anti-inflammatory activity) and methylcobalamin (for maintaining myelin synthesis, neuronal metabolism, and neuronal regeneration in the nervous system) may be an effective treatment for AD patients in that it functions through multiple mechanisms of action. [Means for solving the problem]

[0011]

[0011] The present invention comprises a pharmaceutical composition 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.

[0012]

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

[0013]

[0013] In some embodiments of the present invention, azelastine hydrochloride (and / or other salts thereof) in the pharmaceutical composition is provided in an amount of about 8 mg to about 24 mg, and methylcobalamin is provided in an amount of about 0.5 mg to about 50 mg.

[0014]

[0014] The present invention also includes oral pharmaceutical administration forms of pharmaceutical compositions in the form of solids, liquids, gels, or solutions.

[0015]

[0015] The present invention further includes the medical use of an oral pharmaceutical dosage form of a pharmaceutical composition through administration in an oral pharmaceutical dosage form to patients having Alzheimer's disease or Parkinson's disease.

[0016]

[0016] Within the scope of the present invention is the use of a composition 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.

[0017]

[0017] Embodiments further include the use of 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 treating Alzheimer's disease or Parkinson's disease.

[0018]

[0018] In some embodiments of the present invention, an oral pharmaceutical administration form of a pharmaceutical composition containing about 8 mg to about 24 mg of azelastine hydrochloride (and / or other salts thereof) and about 0.5 mg to about 50 mg of methylcobalamin is administered to a patient having Alzheimer's disease or Parkinson's disease.

[0019]

[0019] Embodiments of the present invention include Embodiment 1, which comprises a pharmaceutical composition comprising azelastine or a pharmaceutically acceptable salt of azelastine, methylcobalamin, and one or more pharmaceutically acceptable excipients.

[0020]

[0020] Embodiment 2 is a pharmaceutical composition of Embodiment 1 in which azelastine or a pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount in the range of about 8 mg to about 24 mg, for example, 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 8 mg to about 12 mg, or any range in between any of these endpoints.

[0021]

[0021] Embodiment 3 is a methylcobalamin in the range of about 0.5 mg to about 50 mg, for example, 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, or about 1 mg, or the endpoints of these. A pharmaceutical composition according to embodiment 1 or 2, wherein the pharmaceutical composition contains the pharmaceutical composition in any amount within a range between either of the above.

[0022]

[0022] Embodiment 4 is one of the pharmaceutical compositions from Embodiments 1 to 3, wherein methylcobalamin is present in the pharmaceutical composition in an amount ranging from about 0.5 mg to about 10 mg.

[0023] Aspect 5 is a pharmaceutical composition according to any one of Aspects 1 to 4, wherein 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.

[0024] Aspect 6 is a pharmaceutical composition according to any one of Aspects 1 to 5, wherein the pharmaceutically acceptable salt of azelastine is azelastine hydrochloride.

[0025] Aspect 7 is a pharmaceutical composition according to any one of Aspects 1 to 6, wherein methylcobalamin is present in the pharmaceutical composition in an amount ranging from about 0.5 mg to about 50 mg.

[0026] Aspect 8 is a pharmaceutical composition according to any one of Aspects 1 to 7, wherein azelastine hydrochloride is present in an amount ranging from about 8 mg to about 18 mg.

[0027] Aspect 9 is a pharmaceutical composition according to any one of Aspects 1 to 8, which is formulated as an oral pharmaceutical dosage form.

[0028] Aspect 10 is a pharmaceutical composition according to any one of Aspects 1 to 9, wherein the oral pharmaceutical dosage form is in a solid form or a liquid form.

[0029] Aspect 11 is a pharmaceutical composition according to any one of Aspects 1 to 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 the pharmaceutical composition in an amount ranging from about 1 mg to about 5 mg.

[0030]

[0030] Embodiment 12 is a method for treating a patient having Alzheimer's disease or Parkinson's disease, comprising administering to the patient an effective amount of a pharmaceutical composition comprising azelastine or a pharmaceutically acceptable salt of azelastine, methylcobalamin, and one or more pharmaceutically acceptable excipients 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 in the patient.

[0031]

[0031] Embodiment 13 is one of the methods from Embodiments 1 to 12, wherein the pharmaceutical composition is administered to a patient once or twice a day, or three times a day, or once every two, three, or four days, in an oral solid or liquid form.

[0032]

[0032] Embodiment 14 is one of embodiments 1 to 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.

[0033]

[0033] Embodiment 15 is one of the methods from Embodiments 1 to 14, wherein methylcobalamin is present in the composition in an amount ranging from about 0.5 mg to about 50 mg.

[0034]

[0034] Embodiment 16 is one of the methods of Embodiments 1 to 15, wherein the pharmaceutical composition is administered to the patient over a period of at least 6 weeks.

[0035]

[0035] Embodiment 17 is one of the methods from Embodiments 1 to 16, wherein methylcobalamin is present in the pharmaceutical composition in an amount ranging from about 0.5 mg to 10 mg.

[0036]

[0036] Embodiment 18 is one of the methods from Embodiments 1 to 17, wherein methylcobalamin is present in the pharmaceutical composition in an amount ranging from about 1 mg to about 10 mg.

[0037]

[0037] Embodiment 19 is one of the methods from Embodiments 1 to 18, wherein the pharmaceutical composition contains azelastine hydrochloride as the pharmaceutically acceptable salt of azelastine in an amount ranging from about 8 mg to about 24 mg, and methylcobalamin in an amount ranging from about 0.5 mg to about 50 mg.

[0038]

[0038] Embodiment 20 is one of the methods from Embodiments 1 to 19, wherein methylcobalamin is present in the composition in an amount ranging from about 0.5 mg to about 10 mg.

[0039]

[0039] Embodiment 21 is the use of a composition comprising azelastine or a pharmaceutically acceptable salt of azelastine, methylcobalamin, and one or more pharmaceutically acceptable excipients, as disclosed in any one of Embodiments 1 to 20, for the treatment of Alzheimer's disease or Parkinson's disease.

[0040]

[0040] Embodiment 22 is the use of a composition comprising azelastine or a pharmaceutically acceptable salt of azelastine, methylcobalamin, and one or more pharmaceutically acceptable excipients, as disclosed in any one of Embodiments 1 to 20, for the manufacture of a drug for treating Alzheimer's disease or Parkinson's disease. [Modes for carrying out the invention]

[0041]

[0041] Through clinical trials, the inventors of the present invention have found that a pharmaceutical composition having an oral administration form containing an active agent in the form of a salt of azelastine and methylcobalamin may be a treatment that can slow or even halt the progression of Alzheimer's disease or Parkinson's disease.

[0042]

[0042] The detailed description provided below is intended to illustrate this embodiment and is not intended to represent only the forms in which this embodiment may be constructed or used. This description describes the function of the embodiment and the sequence of steps for constructing and operating the embodiment. However, the same or equivalent functions and sequence may also be achieved by different embodiments.

[0043]

[0043] Definition

[0044] As used herein, the following words and expressions generally have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0044]

[0045] As used herein, the term "methylcobalamin" refers to cobalamin, comethylcobalamin, a form of vitamin B12, and also to MeCbl, mecobalamin, mecobalamina, mecobalaminum, or methyl It also means vitamin B12.

[0045]

[0046] 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 hydrochloride or HCl salt. Preferably, in any embodiment of the invention described herein, Zelastine is in the form of its hydrochloride salt, such as azelastine hydrochloride or azelastine HCl. More preferably, in any embodiment of the present invention described herein, references to amounts and dosage ranges of azelastine, including solid oral administration forms, refer to amounts and dosage ranges of azelastine hydrochloride.

[0046]

[0047] As used herein, the term “salt” includes 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), benzenesulfonic 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, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D), and gluconic acid. This refers to a salt of azelastine formed with an acid selected from the group of acids consisting of (D), glucuronic acid (D), glutamic acid, glutaric acid, 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, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p), and undecylenic acid.

[0047]

[0048] As used herein, “treatment” means complete or incomplete cure, or treatment means at least reduction and / or delay of the symptoms or associated conditions of the underlying disease, and / or reduction, delay and / or elimination of one or more underlying cellular, physiological or biochemical causes or mechanisms that give rise to the symptoms. Reduction or delay, as used in this context, is understood to mean a comparison with the state of the untreated disease, including not only the physiological state of the untreated disease but also the molecular state of the untreated disease.

[0048]

[0049] The term “effective dose” refers to an amount sufficient to produce such treatment when administered to a mammal in need of treatment, as defined below. The therapeutic effective dose varies depending on the patient being treated, the patient’s weight and age, the severity of the disease, the mode of administration, and similar factors, which can be readily determined by those skilled in the art. The pharmaceutical composition may be administered orally as a single or multiple dose. Administration may be via capsules, tablets, gels, sprays, drops, liquids, suspensions, syrups, or similar preparations.

[0049]

[0050] In the context of quantitative measurement, the term "about" as used herein means within ±10% of the indicated amount. For example, within a ±10% range, "about 2 mg" may mean between 1.8 and 2.2 mg.

[0050]

[0051] Pharmaceutical compositions are prepared for pharmaceutical use using methods known in the art, for example, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems Tenth (by Loyd Allen, 2013) and Handbook of Pharmaceutical Manufacturing Formulations (Volumes 1-6, by Sarfaraz K. Niazi). This allows for the formulation of the active compound and the realization of a controlled-release or delayed-release matrix.

[0051]

[0052] Either a fluid or solid dosage form can be readily prepared for oral administration by mixing it with conventional components such as dicalcium phosphate, magnesium aluminum silicate, magnesium stearate, calcium sulfate, starch, talc, lactose, acacia, methylcellulose, and functionally similar materials as pharmaceutical excipients or carriers. A sustained-release formulation may be optionally used. For older or cognitively impaired subjects, a sustained-release formulation may be even more preferable. Capsules can be formulated by mixing the pharmaceutical composition with an inert pharmaceutical diluent and inserting this mixture into a hard gelatin capsule of appropriate size. If soft capsules are preferred, a slurry of the pharmaceutical composition with an acceptable vegetable oil, petroleum ether, or other inert oil can be formed within a gelatin capsule.

[0052]

[0053] Suspensions, syrups, and elixirs can be used in oral or fluid-unit dosage forms. Fluid preparations containing oils can be used in oil-soluble forms. Acceptable fluid preparations can be obtained from vegetable oils such as corn oil, peanut oil, or floral oils, combined with flavorings, sweeteners, and any preservatives. Surfactants can be added to water to form syrups for fluid-unit dosages. Water-alcoholic pharmaceutical preparations can be used, having acceptable sweeteners such as sugars, saccharin, or biological sweeteners, and flavorings in the form of elixirs.

[0053]

[0054] The solid oral formulations of this disclosure mean in the form of tablets, caplets, bilayer tablets, film-coated tablets, pills, capsules, or similar. Tablets according to this disclosure can be prepared by any mixing and tableting techniques well known in the pharmaceutical industry. In some examples, the formulations are produced by directly compressing the prepared sustained-release portion and immediate-release portion using a rotary tablet press, injection molding or compression molding, or punches and dies adapted for granulation and subsequent compression.

[0054]

[0055] The pharmaceutical compositions provided in accordance with this disclosure are typically administered orally. This disclosure therefore provides pharmaceutical compositions comprising solid dispersions of 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 enhancers, adjuvants, and combinations thereof. Such compositions are prepared in ways well known in the pharmaceutical art (see, for example, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, Tenth (by Loyd Allen, 2013) and Handbook of Pharmaceutical Manufacturing Formulations (Volumes 1-6, by Sarfaraz K. Niazi)).

[0055]

[0056] Some examples of suitable excipients are described herein. When the pharmaceutical composition is formulated into tablets, the tablets may be uncoated or coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract and provide a sustained effect over a long period of time. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate, either alone or in combination with wax, can be utilized.

[0056]

[0057] In embodiments, the pharmaceutical composition may be: a) approximately 8 mg to 24 mg of azelastine or azelastine HCl (or other salts thereof) and b) approximately 0.5 mg to 50 mg of methylcobalamin; or a) approximately 8 mg to 18 mg of azelastine or azelastine HCl (or other salts thereof) and b) approximately 0.5 mg to 10 mg of methylcobalamin; or a) approximately 12 mg to 16 mg of azelastine or azelastine HCl (or other salts thereof). and b) may contain about 0.5 mg to 5 mg of methylcobalamin. For example, a composition may contain a) about 12 mg of azelastine or azelastine HCl (or other salt thereof) and b) about 1 mg of methylcobalamin HCl, or a) about 8 mg to 24 mg of azelastine or azelastine HCl (or other salt thereof) and b) any amount of methylcobalamin.

[0057]

[0058] In embodiments, the pharmaceutical composition comprises a) an amount of azelastine or azelastine HCl (or other salts thereof) in the range of about 8 mg to about 22 mg, for example, about 10 mg to about 20 mg, or about 10 mg to about 16 mg, or about 8 mg to about 18 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 any range between any of these endpoints, or any amount of azelastine, azelastine HCl (or other salts thereof), and b It may contain amounts of methylcobalamin ranging from approximately 0.5 mg to approximately 50 mg, for example, approximately 0.5 mg to approximately 45 mg, or approximately 0.5 mg to approximately 35 mg, or approximately 1 mg to approximately 10 mg, or approximately 0.5 mg to approximately 5 mg, or approximately 0.5 mg to approximately 20 mg, or up to approximately 25 mg, or up to approximately 15 mg, or up to approximately 8 mg, or up to approximately 5 mg, or approximately 5 mg to approximately 12 mg, or approximately 2 mg to approximately 8 mg, or approximately 1 mg, or any range in between any of these endpoints.

[0058]

[0059] In embodiments, the amount of azelastine or azelastine HCl (or other salts thereof) present in the composition may be equal to, greater than, or less than the amount of methylcobalamin present in the composition. In embodiments, using any of the amounts disclosed above or claimed, the amount of azelastine or azelastine HCl (and / or other salts thereof) present in the composition may be twice, three times, or four, five, six, seven, eight, nine, ten, fifteen, twenty, twenty, twenty-five, thirty-five, four-five, four-five, seventy-five, or one-hundred times the amount of methylcobalamin present in the composition, or vice versa. One or more compositions of the present invention may be used in conjunction with one or more methods of the invention disclosed herein or other methods of using the compositions.

[0059]

[0060] The actual amount of the pharmaceutical composition containing azelastine HCl and methylcobalamin administered is usually determined by a physician in light of relevant circumstances, including the condition of the patient being treated, the chosen route of administration, the actual compounds administered and their relative activity, the individual patient's age, weight, and response, the severity of the patient's symptoms, and similar factors.

[0060]

[0061] The pharmaceutical compositions, pharmaceutically active forms, and tablets containing azelastine HCl and methylcobalamin described herein are administered orally to patients with Alzheimer's disease or Parkinson's disease once daily, twice daily, three times daily, four times daily, once every two days, once weekly, twice weekly, three times weekly, four times weekly, or five times weekly, or in combination thereof. Those skilled in the art will understand that the amounts of azelastine and methylcobalamin in the compositions disclosed above or described in the claims may instead constitute a daily dose, or rather, may be formulated into single doses as appropriate.

[0061]

[0062] In the embodiment, the patient is administered a pharmaceutical composition having a therapeutically effective daily dose consisting 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.

[0062]

[0063] In embodiments, the pharmaceutical dosage forms and tablets of the pharmaceutical compositions containing azelastine or azelastine HCl (or other salts thereof) and methylcobalamin as described herein are administered over approximately 2 to 16 weeks, for example, in doses of 2, 3, 4, 5, 6, 7, 8, 9, It is effective in slowing the progression of Alzheimer's disease or Parkinson's disease or reversing symptoms within 10, 11, 12, 13, 14, 15, or 16 weeks, or within any range in between. In patients with AD or PD, when the Mini-Mental State Examination (MMSE) and Activities of Daily Living (ADL) are assessed, MMSE and ADL scores improve by more than 50%. It is possible.

[0063]

[0064] The following examples are illustrative and should not be construed as limiting the scope of the invention as described in the claims.

[0065] [Examples]

[0064]

[0066] A 70-year-old patient who has had intermediate-stage Alzheimer's disease (AD) for two years, has a baseline MMSE score of 12 prior to treatment, and a Barthel Index (BI) of activities of daily living of 30, can be treated up to twice daily with a pharmaceutical composition comprising methylcobalamin and azelastine, for example, a composition containing 1.0 mg of methylcobalamin and 8 mg of azelastine, azelastine HCl, or other salts thereof (or any of the compositions described above or in the claims, or any treatment protocol or time described above or in the claims). After two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, or thereafter, one or more of the AD symptoms in the patient are expected to improve by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more. For example, the patient's MMSE score is expected to improve from 12 to at least 22, representing an 83% improvement, and their BI score is expected to improve from 30 to at least 80, representing a 167% improvement. These dramatic clinical results with this composition are unexpected in AD patients and are superior to those obtained with azelastine alone. Azelastine can reduce the inflammatory process in AD by reducing microglial activation, inhibiting cytokine expression, counteracting reactive oxygen species, and suppressing the role of nuclear factor kappa B in the inflammatory process, thereby slowing and even stopping neurodegeneration in AD. However, methylcobalamin, which promotes nerve cell growth by stimulating myelin synthesis, nerve metabolism, and neuronal regeneration, when combined with azelastine, maintains the effects of azelastine and increases symptom recovery in AD patients, thus this composition provides a more effective and sustained treatment for AD patients.

[0065]

[0067] 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 before treatment was given methyl A pharmaceutical composition comprising cobalamin and azelastine, for example, a composition containing 1.0 mg of methylcobalamin and 8 mg of azelastine, azelastine HCl, or other salts thereof, can be administered up to twice a day (or any of the compositions described above or in the claims, or any treatment protocol or time described above or in the claims). After 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, or thereafter, one or more of the patient's PD symptoms are expected to improve by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more. For example, the patient's UPDRS total 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 assessed, this is expected to improve by more than 50%.

[0066]

[0068] References

[0069] US Patent Nos. 9,919,050 (Mar. 20, 2018, Dang, et al); 9,901,585 (Feb. 27, 2018, Lulla, et al); 8,859,531 (Oct. 14, 2014, Lee, et al); 8,758,816 (June 24, 2014, Fuge, et al); 8,318,709 (Nov. 27, 2012, Lulla, et al); 8,304,405 (Nov. 6, 2012, Lulla, et al); 8,168,620 (May 1, 2012, Lulla, et al); 8,071,073 (Dec. 6, 2011, Dang, et al); 7,022,687 (Apr. 4, 2006, Szelenyl, et al); 6,017,909 (Jan. 25, 2000, Hettche, et al); 5,994,357 (Nov. 30, 1999, Theoharides); 5,086,050 (Feb. 4, 1992, Hettche, et al); and 5,068,233 (Nov. 26, 1991, Achterrath-Tuckerman, et al.); 8,741,319 (June 3, 2014, Crain et al); and U.S. Published Application Nos. 2010 / 0168053 (Kurtz); 2009 / 0012039 (Kurtz); and 2014 / 0127328 (Crain et al).

[0070] Carlos Alberto Calderon-Ospina, Mauricio Orlando Nava, 2020. B Vitamins in the nervous system: Current knowledge of the biochemical modes of action and synergies of thiamine, pyridoxine, and cobalamin. CNS Neurosci Ther. 2020; 26:5-13.

[0071] Katsushi, Koyoma et al. 2002. Efficacy of Methylcobalamin on Lowing Total Homocysteine Plasma Concentrations in Haemodialysis Patients Receiving High-dose Folic Acid Supplementation. Nephrol Dial Transplant, 2002, 16: 911-22.

[0072] Yiting Zhang, et al. 2016. Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia. PLOS ONE, 0146797 January 22, 2016.

[0073] Theresa Kobe, et al. 2016. Vitamin B-12 concentration, memory performance, and hippocampal structure in patients with mild cognitive impairment. American Journal of Clinical. Nutrition, 2016; 103:1045-54.

[0074] Michael Leon, Darrell Sawmiller, R. Douglas Shytle, and Jun Tan, 2018. Therapeutic Cocktail Approach for Treatment of Hyperhomocysteinemia in Alzheimer ’s Disease. Cell Med. 2018; 10: 2155179017722280.

[0075] Paul S. Aisen, et al. 2008. High Dose B Vitamin Supplementation and Cognitive Decline in Alzheimer’s Disease: A Randomized Controlled Trial. JAMA. 2008 October 15; 300(15): 1774-1783.

[0076] A. David Smith, et al, 2010. Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial. PLOS ONE, September 2010, Volume 5, Issue 9, e12244.

[0077] Uwe Grober, Klaus Kisters and Joachim Schmidt, 2013. Neuroenhancement with Vitamin B12-Underestimated Neurological Significance. Nutrients, 2013, 5, 5031-5045.

[0078] Gupta JK and Qureshi Shaiba Sana, 2015. Potential Benefits of Methylcobalamin: Austin J. Pharmacol. Ther. Volume 3, Issue 3, 2015.

[0079] Patricia B Williams, Elizabeth Crandall and John D Sheppard, 2010, Azelastine hydrochloride, a dual-acting anti-inflammatory ophthalmic solution, for treatment of allergic conjunctivitis. Clinical Ophthalmology, 2010:4 993-1001.

[0080] Casale T. The interaction of azelastine with human lung histamine H1, beta, and muscarinic receptor-binding sites. J Allergy Clin Immunol. 1989; 83:771-776.

[0081] Hazama H, Nakajima T, Hisada T, Hamada E, Omata M, Kurachi Y. Effects of azelastine on membrane currents in tracheal smooth muscle cells isolated from the guinea-pig. Eur J Pharmacol. 1994; 259: 143-150.

[0082] Szelenyi I, Achterrath-Tuckermann U, Schmidt J, Minker E, Paegelow I, Werner H. Azelastine: A multifaceted drug for asthma therapy. Agents Actions Suppl. 1991; 34:295-311.

[0083] Galatowicz G, Ajayi Y, Stern ME, Calder VL. Ocular antiallergic compounds selectively inhibit human mast cell cytokines in vitro and conjunctival cell infiltration in vivo. Clin Exp Allergy. 2007; 37:1648-1656.

[0084] Ciprandi G, Pronzato C, Passalacqua G, et al. Topical azelastine reduces eosinophil activation and intercellular adhesion molecule-1 expression on nasal epithelial cells: An antiallergic activity. J Allergy Clin Immunol. 1996; 98(6 Pt 1):1088-1096.

[0085] Simons FE, Simons KJ. Clinical pharmacology of new histamine H1 receptor antagonist. Clin Pharmacokinet. 1999; 36:329-352.

[0086] Aiko Hatakeyama, et al, 2008, Azelastine hydrochloride on behavioral and psychological symptoms and activities of daily living in dementia patients. Geriatr Gerontol Int 2008; 8: 59-61.

[0087] Duraisamy Kempuraj, et al. 2003, Azelastine Inhibits Secretion of IL-6, TNF-alpha and IL-8 as Well as NF-kappaB Activation and Intracellular Calcium Ion Levels in Normal Human Mast Cells. Int Arch Allergy Immunol. 132 (3), 231-9 Nov 2003.

[0088] Kazunori Yoneda, et al. 1997, Suppression by Azelastine Hydrochloride of NF-KB Activation Involved in Generation of Cytokines and Nitric Oxide. Japanese Journal of Pharmacology, 73: 145-53.

[0089] Loyd Allen, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, Tenth (2013).

[0090] Sarfaraz K. Niazi, Handbook of Pharmaceutical Manufacturing Formulations Volumes 1-6.

[0067]

[0091] The present invention has been described with reference to specific embodiments having various features. In light of the disclosures provided above, it will be apparent to those skilled in the art that various modifications and changes can be made in practice of the present invention without departing from the scope or spirit of the invention. Those skilled in the art will recognize that the disclosed features can be used individually, in any combination, or omitted based on the requirements and specifications of a given application or design. Where an embodiment is described as "including" a particular feature, it will be understood that the embodiment may instead "consist of" or "belong to" one or more of the features. Any of the methods disclosed herein can be used with any of the compositions disclosed herein or with any other compositions. Similarly, any of the disclosed compositions can be used with any of the methods disclosed herein or with any other methods. Other embodiments of the present invention will become apparent to those skilled in the art by considering the specification and practice of the present invention.

[0068]

[0092] Where a range of values ​​is indicated herein, it should be noted that each value between the upper and lower limits of that range is also specifically disclosed. These smaller upper and lower limits may be independently included in or excluded from this range. The singular forms "a," "an," and "the" include plural references unless the context makes otherwise clear. The specification and examples are considered to be of a typical nature, and any modifications that do not depart from the essence of the invention are within the scope of the invention. Furthermore, all references cited herein are incorporated herein in whole by individual reference, each intended to efficiently supplement the feasible extent of disclosure of the invention and to provide background art detailing the level of skill of those skilled in the art.

Claims

1. Azelastine or a pharmaceutically acceptable salt of azelastine, Methylcobalamin, and one or more pharmaceutically acceptable excipients A pharmaceutical composition containing the following:

2. The pharmaceutical composition according to claim 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.

3. The pharmaceutical composition according to claim 1, wherein methylcobalamin is present in the pharmaceutical composition in an amount ranging from about 0.5 mg to about 50 mg.

4. The pharmaceutical composition according to claim 1, wherein methylcobalamin is present in the pharmaceutical composition in an amount ranging from about 0.5 mg to about 10 mg.

5. Azelastine or a pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount ranging from approximately 8 mg to approximately 24 mg, and Methylcobalamin is present in the pharmaceutical composition in an amount ranging from approximately 0.5 mg to approximately 50 mg. The pharmaceutical composition according to claim 1.

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

8. The pharmaceutical composition according to claim 6, wherein azelastine hydrochloride is present in an amount ranging from about 8 mg to about 18 mg.

9. The pharmaceutical composition according to claim 1, which is formulated as an oral pharmaceutical administration form.

10. The pharmaceutical composition according to claim 9, wherein the oral pharmacopoeia is in solid or liquid form.

11. The pharmaceutical composition according to claim 6, 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 the pharmaceutical composition in an amount ranging from about 1 mg to about 5 mg.

12. A method for treating a patient with Alzheimer's disease or Parkinson's disease, Azelastine or a pharmaceutically acceptable salt of azelastine, Methylcobalamin, and one or more pharmaceutically acceptable excipients An effective amount of a pharmaceutical composition containing the following: A method comprising the step of administering to a patient for a sufficient period of time to alleviate, reduce, prevent, and / or eliminate one or more symptoms of Alzheimer's disease or Parkinson's disease in the patient.

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

14. The method according to claim 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.

15. The method according to claim 12, wherein methylcobalamin is present in the pharmaceutical composition in an amount ranging from about 0.5 mg to about 50 mg.

16. The method according to claim 12, wherein the pharmaceutical composition is administered to a patient over a period of at least six weeks.

17. The method according to claim 12, wherein methylcobalamin is present in the pharmaceutical composition in an amount ranging from about 0.5 mg to 10 mg.

18. The method according to claim 12, wherein methylcobalamin is present in the pharmaceutical composition in an amount ranging from about 1 mg to about 10 mg.

19. A pharmaceutically acceptable salt of azelastine is azelastine hydrochloride, which is present in the pharmaceutical composition in an amount ranging from approximately 8 mg to approximately 24 mg, and Methylcobalamin is present in the pharmaceutical composition in an amount ranging from approximately 0.5 mg to approximately 50 mg. The method according to claim 12.

20. The method according to claim 19, wherein methylcobalamin is present in the pharmaceutical composition in an amount ranging from about 0.5 mg to about 10 mg.

21. Use of a composition 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.

22. Use of 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 treating Alzheimer's disease or Parkinson's disease.