FIELD OF THE INVENTION

The present invention relates to the field of practical medicine, namely, to the use of pharmaceutical compositions for treatment of Alzheimer's disease and Parkinson's disease. More specifically, the invention relates to novel combinations of compounds which can effectively treat Alzheimer's disease (AD) and Parkinson's disease (PD).

BACKGROUND OF THE INVENTION

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 among older adults. Dementia is the loss of cognitive functioning—thinking, remembering, and reasoning—and behavioral abilities to such an extent that it interferes with a person's daily life and activities. In its early stages, memory loss is mild, but with late-stage AD, individuals lose the ability to carry on a conversation and respond to their environment. If untreated, AD ultimately leads to death. Although the speed of progression can vary, the typical life expectancy following diagnosis is three to nine years.

Neuropathologically, AD is characterized by accumulation of neurotic plaques of amyloid beta protein (Aβ) and neurofibrillary tangles of hyperphosphorylated tau protein (p-tau). The bulk of current evidence points to Aβ accumulation as a critical primary causative factor in sporadic AD. So far, all promising approaches for decreasing Aβ or p-tau levels including mechanisms such as inhibition of Aβ or p-tau generation, reduction of soluble Aβ levels and enhancement of Aβ or p-tau clearance from the CNS have not provided desired outcomes from their clinical trials. While development of Aβ based treatments follows logically from known Aβ mechanisms, a number of factors might limit the effectiveness of such treatments if applied in isolation. But more importantly, a number of other potential mechanisms might constitute important causative factors in AD. Such non-Aβ mechanisms might play even larger roles, or perhaps synergistic roles, as the disease progresses. Thus, it is likely that parallel application of neuroprotective strategies will play a vital role in delaying AD onset and slowing AD progression.

Homocysteine is a sulfur amino acid involved in essential metabolic pathways, including methylation reactions. Elevation of homocysteine in blood is a marker of genetic disorders and deficiencies of vitamins B12. Homocysteine elevation is associated with vascular disease, neuropsychiatric disorders, neurovascular ischemic disease, including stroke, silent infarctions and white matter disease. Studies have linked homocysteine to amyloid and glutamate neurotoxicity, and to cognitive dysfunction and AD. For example, homocysteine elevation induces hippocampal neuron loss in transgenic mice with brain amyloid deposition. Studies also have demonstrated a relationship between plasma homocysteine level and AD and cognitive function in non-demented individuals. This relationship spans the normal range of homocysteine levels. Reduction of homocysteine levels can be readily achieved with high doses of vitamin B12, and could plausibly represent a disease-modifying intervention in AD.

Methylcobalamin, one of two active forms of four vitamin B12 vitamers, compared with other analogs, is the most effective in being up-taken by subcellular organelles of neurons. Therefore, methylcobalamin in combination with azelastine may provide a better treatment option for nervous disorders such as AD.

On the other hand, the genetic, cellular, and molecular changes associated with AD support the evidence that activated immune and inflammatory processes is a part of the disease. Also, a strong benefit of long-term use of NSAIDs was shown in epidemiological studies. So, it is generally accepted that AD is partially an inflammatory disease and that inhibiting inflammation is an option of treating AD.

Inflammation clearly occurs in pathologically vulnerable regions of the AD brain, and it does so with the full complexity of local peripheral inflammatory responses. In the periphery, degenerating tissue and the deposition of highly insoluble abnormal materials are classical stimulants of inflammation. Likewise, in the AD brain, damaged neurons and neurites and highly insoluble amyloid β peptide deposits and neurofibrillary tangles provide obvious stimuli for inflammation. Because these stimuli are discrete, micro-localized, and present from early preclinical to terminal stages of AD, local upregulation of complement, cytokines, acute phase reactants, and other inflammatory mediators is also discrete, micro-localized, and chronic. Cumulated over many years, direct and bystander damage from AD inflammatory mechanisms is likely to significantly exacerbate the very pathogenic processes that gave rise to it. Thus, animal models and clinical studies so far strongly suggest that AD inflammation significantly contributes to AD pathogenesis. By better understanding AD inflammatory and immune-regulatory processes, it should be possible to develop anti-inflammatory approaches that may reverse or delay or prevent developing of this devastating disorder.

Azelastine is classified pharmacologically as a second-generation antihistamine and is a relatively selective, non-sedating, competitive antagonist at H1 receptors. More uniquely, its inhibition of inflammatory mediators, in addition to antihistaminic and mast cell stabilizing effects, places it among the new generation of dual-acting anti-inflammatory drugs. In addition to azelastine's high affinity for H1 receptors, its ability to modify several other mediators of inflammation and allergy contributes to its mechanism of action. In vitro and in vivo studies, as well as clinical trials support the dual effects of direct inhibition and stabilization of inflammatory cells. In vitro data indicate that azelastine's affinity for H1 receptors is estimated to be several times greater than that of chlorpheniramine, a first-generation H1 antagonist. Azelastine has only weak affinity for H2 receptors. Release of histamine from mast cells is also inhibited possibly by reversible inhibition of voltage-dependent L-type calcium channels. Inhibition of mast cell degranulation may also decrease the release of other inflammatory mediators, including leukotrienes and interleukin-1β, among others. Azelastine also directly antagonizes other mediators of inflammation, such as tumor necrosis factor-α, leukotrienes, endothelin-1, and platelet-activating factor.

Therefore, a unique combination of azelastine (antihistamine agent with anti-inflammatory activities) with methylcobalamin (for maintaining myelin synthesis, neuronal metabolism, and neuronal regeneration in the nervon system) would potentially be, in terms of working through multi-mechanisms of actions, an effective treatment for AD patients.

SUMMARY OF THE INVENTION

The present invention includes a pharmaceutical composition that comprises two active pharmaceutical ingredients. This pharmaceutical composition comprises the first active ingredient that is azelastine or a pharmaceutically acceptable salt of azelastine and the second active ingredient that is methylcobalamin.

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

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

The present invention also includes an oral pharmaceutical dosage form of the pharmaceutical composition that is a solid, liquid, gel, or solution form.

The present invention further includes the medical use of the oral pharmaceutical dosage form of the pharmaceutical composition through administration of the dosage form to patients with Alzheimer's disease or Parkinson's disease.

In some embodiments of this invention, an oral pharmaceutical dosage form of the pharmaceutical composition containing azelastine hydrochloride (and/or other salt thereof) in an amount of about 8 mg to about 24 mg and methylcobalamin in an amount of about 0.5 mg to about 50 mg is administered to patients with Alzheimer's disease or Parkinson's disease.

Included in embodiments of the invention is Aspect 1, which encompasses a pharmaceutical composition, comprising azelastine or a pharmaceutically acceptable salt of azelastine, methylcobalamin, and one or more pharmaceutically acceptable excipients.

Aspect 2 is the pharmaceutical composition of Aspect 1, wherein the azelastine or the 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, 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 8 mg to about 12 mg, or any range in between any of these endpoints.

Aspect 3 is the pharmaceutical composition of Aspect 1 or 2, wherein the methylcobalamin is present in the pharmaceutical composition in an amount 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 about 2 mg to about 8 mg, or about 1 mg, or any range in between any of these endpoints.

Aspect 4 is the pharmaceutical composition of any of Aspects 1-3, wherein the methylcobalamin is present in the pharmaceutical composition in an amount in the range of 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 the azelastine or the pharmaceutically acceptable salt of azelastine is present in an amount in the range of about 8 mg to about 24 mg and the methylcobalamin is present in an amount in the range of 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 the methylcobalamin is present in the pharmaceutical composition in an amount in the range of about 0.5 mg to about 50 mg.

Aspect 8 is the pharmaceutical composition of any of Aspects 1-7, wherein the azelastine hydrochloride is present in an amount in the range of 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 the azelastine hydrochloride is present in the pharmaceutical composition in an amount ranging from about 8 mg to about 12 mg and the amount of methylcobalamin is present in the pharmaceutical composition in an amount ranging from about 1 mg to about 5 mg.

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 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 the patient's Alzheimer's disease and/or Parkinson's disease.

Aspect 13 is the method of any of Aspects 1-12, 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 an oral solid or liquid form.

Aspect 14 is the method of any of Aspects 1-13, wherein the azelastine or the 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.

Aspect 15 is the method of any of Aspects 1-14, wherein the methylcobalamin is present in the composition in an amount in the range of 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 the 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 the methylcobalamin is present in the pharmaceutical composition in an amount in the range of 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 in the range of about 8 mg to about 24 mg and the methylcobalamin is present in an amount in the range of about 0.5 mg to about 50 mg.

Aspect 20 is the method of any of Aspects 1-19, wherein the methylcobalamin is present in the composition in an amount in the range of about 0.5 mg to about 10 mg.

