Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole

Definitions

• the invention relates to the field of practical medicine, namely, to the use of pharmaceutical compositions exhibiting a neurotropic action, alleviating manifestations of mental, behavioral, or cognitive disorders in cases of organic damage of various origin to the central nervous system.
• AD Alzheimer’s disease
• 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.
• 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.
• the speed of progression can vary, the typical life expectancy following diagnosis is three to nine years.
• LTP long-term potentiation
• LTP is mediated by the neurotransmitter glutamate via the N-Methyl-D-aspartic acid (NMDA) receptor.
• NMDA receptors can be found diffusely throughout the brain. However, they densely populate the dendrites of pyramidal cells in the hippocampus and cortex (areas known to be involved in cognition, learning, and memory). In addition to the relationship between LTP and learning, elevated glutamate levels are associated with excito toxicity. Chronic low-dose administration of NMDA receptor agonists has been shown to induce apoptosis, while high doses induce necrosis. The activation of glutamate receptors has also been found to induce the release of glutamate.
• AB plaques increase a neuron’s vulnerability to excitotoxicity.
• AB plaques a pathological feature of AD, were found to induce depolarization of astrocytes, extracellular accumulation of glutamate, and intracellular deposition of Ca2+. Therefore, the glutamate-induced excitotoxicity pathway made an excellent target for the therapy of AD.
• the glutamate released by neurons is metabolized or taken up by neighboring cells.
• NMDA receptors act as a calcium [II] ion (Ca2+) channel that activates when bound by glycine, glutamate, and/or NMDA.
• Ca2+ calcium [II] ion
• Mg2+ magnesium [II] ion
• NMDA receptor antagonists are looked to as possible neuroprotective agents and potential therapies for neurodegenerative disease.
• NMDA antagonists are competitive antagonists and are not well tolerated by patients due to side effects, which can include hallucinations and schizophrenia-type symptoms.
• the side effects likely result from the competitive antagonists blocking physiological functions of the NMDA receptor.
• Memantine acts on activated NMDA receptors by binding to a site located in the channel of the receptor.
• memantine will not cure AD or prevent the loss of these abilities at some time in the future. So AD has no current cure, and our effort is to find better ways to reverse the disease, delay and prevent it from developing.
• 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 NS A TPs 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. [007] 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 b peptide deposits and neurofibrillary tangles provide obvious stimuli for inflammation.
• Azelastine is classified pharmacologically as a second generation antihistamine and is a relatively selective, non- sedating, competitive antagonist at HI 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 HI 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.
• azelastine s affinity for HI receptors is estimated to be several times greater than that of chlorpheniramine, a first- generation HI 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- 1b, among others.
• Azelastine also directly antagonizes other mediators of inflammation, such as tumor necrosis factor-a, leukotrienes, endothelin-1, and platelet- activating factor.
• the present invention includes the discovery of a method of administering azelastine or a pharmaceutically acceptable salt of azelastine to patients for treating mental, behavioral, cognitive disorders.
• the pharmaceutically acceptable salt of azelastine is azelastine hydrochloride.
• azelastine hydrochloride is provided in a daily effective amount of about 4 mg to about 40 mg.
• the present invention also includes an oral pharmaceutical dosage form of the pharmaceutically acceptable salt form of azelastine that is a solid form or a liquid form.
• the present invention further includes the medical use of the oral pharmaceutical dosage form of azelastine or a pharmaceutically acceptable salt of azelastine which includes administering the dosage form to patients with mental, behavioral, cognitive disorders, such as Alzheimer’s disease, vascular dementia, Huntington’s disease, frontal temporal dementia, traumatic brain injury, corticobasal degeneration, and/or Parkinson’s disease.
• mental, behavioral, cognitive disorders such as Alzheimer’s disease, vascular dementia, Huntington’s disease, frontal temporal dementia, traumatic brain injury, corticobasal degeneration, and/or Parkinson’s disease.
• an oral pharmaceutical dosage form of azelastine hydrochloride in a daily effective amount of about 8 mg to about 16 mg is administered to patients with Alzheimer's disease once daily or twice daily.
• azelastine or a pharmaceutically acceptable salt of azelastine are suitable for treating patients suffering from mental, behavioral, cognitive disorders.
• azelastine refers to azelastine free base
• azelastine also includes any pharmaceutically acceptable salt, such as the hydrochloride or HC1 salt.
• azelastine is in the form of its hydrochloride salt, as azelastine hydrochloride or azelastine HC1. More preferably, in any embodiment of the invention as described herein, reference to the amounts and dosage ranges of azelastine in the oral dosage forms are to the amounts and dosage ranges of azelastine hydrochloride.
• the term“pharmaceutically acceptable salt” refers to a salt of azelastine formed with an acid selected from a group of acids consisting of 1 -hydroxyl- 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, dodecylsulfuric acid, ethane- 1,2- disulfonic acid, ethanesulfonic acid
• “treating” or“treatment” means complete cure or incomplete cure, or it means that the symptoms of the underlying disease or associated conditions are at least reduced and/or delayed, and/or that one or more of the underlying cellular, physiological, or biochemical causes or mechanisms causing the symptoms are reduced, delayed and/or eliminated. It is understood that reduced or delayed, as used in this context, means relative to the state of the untreated disease, including the molecular state of the untreated disease, not just the physiological state of the untreated disease.
• the term“effective amount” refers to an amount that is therapeutically sufficient to effect treatment, as defined below, when administered to a mammal in need of such treatment.
• the therapeutically effective amount will vary depending upon the patient being treated, the weight and age of the patient, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
• the pharmaceutically acceptable salt of azelastine may be administered in either single or multiple doses by oral administration. Administration may be via capsule, tablet, or the like.
• the term“about” used in the context of quantitative measurements means the indicated amount ⁇ 10%. For example, with a ⁇ 10% range,“about 5 mg” can mean 4.5-5.5.
• the oral dosage forms of azelastine or a pharmaceutically acceptable salt of azelastine in the amount of from about 4 mg to about 40 mg may be formulated 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). Accordingly, incorporation of the active compounds and a controlled, or slow release matrix may be implemented.
• Either fluid or solid unit dosage forms can be readily prepared for oral administration.
• conventional ingredients such as dicalcium phosphate, magnesium aluminum silicate, magnesium stearate, calcium sulfate, starch, talc, lactose, acacia, methyl cellulose and functionally similar materials as pharmaceutical excipients or carriers.
• a sustained release formulation may optionally be used. In older or incoherent subjects, sustained release formulations may even be preferred.
• Capsules may be formulated by mixing the compound with a pharmaceutical diluent which is inert and inserting this mixture into a hard gelatin capsule having the appropriate size.
• a slurry of the pharmaceutically acceptable salt of azelastine with an acceptable vegetable, light petroleum or other inert oil can be encapsulated by forming into a gelatin capsule.
• Suspensions, syrups and elixirs may be used for oral administration or fluid unit dosage forms.
• a fluid preparation including oil may be used for oil soluble forms.
• a vegetable oil such as com oil, peanut oil or a flower oil, for example, together with flavoring agents, sweeteners and any preservatives produces an acceptable fluid preparation.
• a surfactant may be added to water to form a syrup for fluid unit dosages.
• Hydro-alcoholic pharmaceutical preparations may be used having an acceptable sweetener, such as sugar, saccharin or a biological sweetener and a flavoring agent in the form of an elixir.
• the solid oral dosage formulation of the pharmaceutically acceptable salt of azelastine in this disclosure means a form of tablets, caplets, bi-layer tablets, film-coated tablets, pills, capsules, or the like. Tablets in accordance with this disclosure can be prepared by any mixing and tableting techniques that are well known in the pharmaceutical formulation industry. In some examples, the dosage formulation is fabricated by direct compressing the respectively prepared sustained-release portion and the immediate-release portion by punches and dies fitted to a rotary tableting press, ejection or compression molding or granulation followed by compression.
• the pharmaceutically acceptable salt of azelastine provided in accordance with the present disclosure are usually administered orally.
• This disclosure therefore provides a pharmaceutically acceptable salt of azelastine that comprise a solid dispersion comprising a pharmaceutically acceptable salt of azelastine in the amount of from about 4 mg to about 40 mg as described herein and one or more pharmaceutically acceptable excipients or carriers including but not limited to, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers, disintegrants, lubricants, binders, glidants, adjuvants, and combinations thereof.
• compositions are prepared in a manner well known in the pharmaceutical art (see, e.g., 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)).
• the pharmaceutically acceptable salt of azelastine in the amount of from about 4 mg to about 40 mg may further comprise pharmaceutical excipients such as diluents, binders, fillers, glidants, disintegrants, lubricants, solubilizers, and combinations thereof. Some examples of suitable excipients are described herein.
• the pharmaceutically acceptable salt of azelastine in the amount of from about 4 mg to about 40 mg is formulated into a tablet, the tablet may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
• a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
• the pharmaceutically acceptable salts of azelastine are administered as daily effective amounts of from about 4 mg to about 40 mg of azelastine HC1 or from about 4 mg to about 20 mg of azelastine HC1 or from about 8 mg to about 16 mg of azelastine HC1
• azelastine HC1 actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.
• the pharmaceutically acceptable salts of azelastine as described herein are administered to a patient suffering from mental, behavioral, cognitive disorders and other neurodegenerative disorders, such as Alzheimer’s disease, with a daily effective amount of from about 4 mg to about 40 mg by oral administration once daily, twice daily, once every other day, once a week, two times a week, three times a week, four times a week, or five times a week.
• the pharmaceutical dosage forms, and tablets of the pharmaceutically acceptable salts of azelastine in a daily effective amount of from about 4 mg to about 40 mg as described in this specification are effective for reversing symptoms in patients suffering from early, middle or late stage Alzheimer's disease in about 6-24 weeks.
• her MMSE scores would similarly have been expected to have improved.
• Beta-amyloid protein increases the vulnerability of cultured cortical neurons to excitotoxic damage. Brain Res. 1990;533(2):315-320.
• Alzheimer’s Disease Internationl “World Alzheimer Report 2010: the global economic impact of dementia.”
• Alzheimer's disease Clinical interventions in aging, vol. 1, no. 2, pp. 143-154, 2006.
• Epstein AB van Hoven PT, Kaufman A, Carr WW. Management of allergic conjunctivitis: An evaluation of the perceived comfort and therapeutic efficacy of olopatadine 0.2% and azelastine 0.05% from two prospective studies. Clin Ophthalmol. 2009;3:329-336.
• Pflugfelder SC Prevalence, burden, and pharmacoeconomics of dry eye disease.
• Baudouin C Detrimental effect of preservative in eye drops: Implications for the treatment of glaucoma. Acta Ophthalmologica. 2008;86:716-726.
• 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.
• any of the methods disclosed herein can be used with any of the compositions disclosed herein or with any other compositions.
• any of the disclosed compositions can be used with any of the methods disclosed herein or with any other methods.
• Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention.

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• 2019
  • 2019-04-30 CN CN201980095741.3A patent/CN113924098A/zh active Pending
  • 2019-04-30 JP JP2021558496A patent/JP2022536017A/ja active Pending
  • 2019-04-30 AU AU2019443520A patent/AU2019443520A1/en not_active Abandoned
  • 2019-04-30 CA CA3137393A patent/CA3137393A1/en active Pending
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