Classifications

• • 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
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • 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
• • 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
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P70/00—Climate change mitigation technologies in the production process for final industrial or consumer products
  • Y02P70/50—Manufacturing or production processes characterised by the final manufactured product

Definitions

• the invention relates to the field of practical medicine, namely, to the combined use of pharmaceutical compositions exhibiting a neurotropic action, alleviating manifestations of mental, behavioral, 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.
• AD is a polygenic/multifactorial complex disorder characterized by the premature death of neurons.
• amyloid hypothesis is recognized as the Primum Movens of AD pathogenesis, mutational genetics associated with amyloid precursor protein (APP) and presenilin (PS) genes lone does not explain in full the neuropathologic findings present in AD, represented by amyloid deposition in senile plaques and vessels (amyloid angiopathy), neurofibrillary tangle (NFT) formation due to hyperphosphorylation of tau protein, synaptic and dendritic desarborization and neuronal loss.
• APP amyloid precursor protein
• PS presenilin
• AD-related memory dysfunction was in part due to a cholinergic deficit in the brain of affected people due to a loss of neurons in the basal forebrain, this giving rise to the cholinergic hypothesis of AD.
• AChEIs were proposed as an option to inhibit acetylcholine degradation in the synaptic cleft and to increase choline reuptake at the presynaptic level with the aim of enhancing acetylcholine synthesis in presynaptic terminals, this facilitating cholinergic neurotransmission.
• tacrine tetrahydroaminoacridine
• donepezil was approved by the FDA for the treatment of mild-to- moderate cases of AD.
• AChEIs, rivastigmine and galantamine were introduced several years later.
• acetylcholinesterase inhibitors such as donepezil, rivastigmine and galantamine 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 Alzheimer's disease
• Inflammation clearly occurs in pathologically vulnerable regions of the AD brain, and it does so with the full complexity of local peripheral inflammatory responses.
• degenerating tissue and the deposition of highly insoluble abnormal materials are classical stimulants of inflammation.
• damaged neurons and neurites and highly insoluble amyloid b 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.
• Azelastine is classified pharmacologically as a second generation antihistamine and is a relatively selective, nonsedating, 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. 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 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. Therefore, a unique combination of azelastine and donepezil and/or rivastigmine and/or galantamine is expected to be, in terms of creating synergistic effects, innovative potential treatments for AD.
• the present invention includes a pharmaceutical composition that comprises two active ingredients and one or more pharmaceutically acceptable excipients.
• 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 donepezil and/or rivastigmine and/or galantamine and/or any pharmaceutically acceptable salt thereof.
• composition comprising
• azelastine or a pharmaceutically acceptable salt of azelastine (i) donepezil or rivastigmine or galantamine, or pharmaceutically acceptable salts thereof, or any combination thereof, and (iii) one or more pharmaceutically acceptable excipients for the treatment of one or more mental, behavioral, or cognitive disorder, such as Alzheimer’s disease, vascular dementia, Parkinson’s disease, Huntington’s disease, or any combination thereof.
• composition comprising
• azelastine or a pharmaceutically acceptable salt of azelastine (i) donepezil or rivastigmine or galantamine, or pharmaceutically acceptable salts thereof, or any combination thereof, and (iii) one or more pharmaceutically acceptable excipients for the manufacture of a medicament for treating one or more mental, behavioral, or cognitive disorder, such as Alzheimer’s disease, vascular dementia, Parkinson’s disease, Huntington’s disease, or any combination thereof.
• compositions comprising (i) azelastine or a pharmaceutically acceptable salt of azelastine, (ii) donepezil or rivastigmine or galantamine, or pharmaceutically acceptable salts thereof, or any combination thereof, and (iii) one or more pharmaceutically acceptable excipients for the manufacture of a medicament for treating one or more mental, behavioral, or cognitive disorder, such as Alzheimer’s disease, vascular dementia, Parkinson’s disease, Huntington’s disease, or any combination thereof.
• the pharmaceutically acceptable salt of azelastine in the pharmaceutical composition is azelastine hydrochloride and the pharmaceutically acceptable salt of donepezil or rivastigmine or galantamine in this pharmaceutical composition is donepezil hydrochloride or rivastigmine tartrate or galantamine hydrobromide.
• azelastine hydrochloride (and/or other salt thereof) in the pharmaceutical composition is provided in an amount of about 4 mg to about 20 mg, and donepezil hydrochloride (and/or other salt thereof) in an amount of about 1 mg to about 4 mg, and/or rivastigmine tartrate (and/or other salt thereof) in an amount of about 1 mg to about 2 mg, and/or galantamine hydrobromide (and/or other salt thereof) in an amount of about 1 mg to about 3 mg.
• compositions formulated to deliver azelastine or a salt thereof in an amount of up to about 20 mg per day such as from about 1-20 mg, or 2-19 mg, or 3-18 mg, or 4- 17 mg, or 5-15 mg, or 6-12 mg, or 8-10 mg, or 3-11 mg, or 2-13 mg, or 7-16 mg, and so on
• donepezil or a salt thereof in an amount of up to about 23 mg per day such as from about 1-23 mg, or 2-22 mg, or 3-20 mg, or 4-18 mg, or 5-16 mg, or 6-15 mg, or 7-12 mg, or 1.5-3 mg, or 1-2 mg, or 2.5-5 mg, and so on
• an amount of rivastigmine or a salt thereof in an amount of up to about 9.5 mg per day such as from about 1-9.5 mg, or 2-9 mg, or 3-8 mg, or 4-7 mg, or 5-6 mg, or 3.5-8.5 mg, or 2.5-7.5 mg, and so on
• the present invention also includes an oral pharmaceutical dosage form of the pharmaceutical composition that is a solid form or a liquid 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 a neurodegenerative disorder such as Alzheimer's disease, vascular dementia, or Parkinson's disease.
• a neurodegenerative disorder such as Alzheimer's disease, vascular dementia, or Parkinson's disease.
• 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 12 mg and donepezil hydrochloride in an amount of about 1 mg to about 4 mg or rivastigmine tartrate in an amount of about 1 mg to about 2 mg or galantamine hydrobromide in an amount of about 1 mg to about 3 mg is administered to patients with middle to late stage Alzheimer's disease.
• any of the ranges disclosed herein relating to any of the components of the composition can be formulated as an oral dosage, such as a solid, liquid, gel, or solution.
• a pharmaceutical composition with an oral dosage form comprising the active agents, a salt form of azelastine and a salt form of donepezil or rivastigmine or galantamine, is suitable for treating patients suffering from mental, behavioral, cognitive disorders.
• Alzheimer's disease dementia, Parkinson's disease, Huntington's disease and combinations of any thereof and other neurodegenerative disorders.
• donepezil refers to donepezil free base, 2,3-dihydro-5,6- dimethoxy-2-[[l-(phenylmethyl)-4-piperidinyl]methyl]-lH-inden-l-one.
• donepezil also includes any pharmaceutically acceptable salt, such as the hydrochloride or HC1 salt.
• the donepezil is in the form of its hydrochloride salt, as donepezil hydrochloride or donepezil HC1. More preferably, in any embodiment of the invention as described herein, reference to the amounts and dosage ranges of donepezil in oral dosage forms are to the amounts and dosage ranges of donepezil hydrochloride.
• rivastigmine refers to rivastigmine free base, (S)-3-(l-
• rivastigmine also includes any pharmaceutically acceptable salt, such as the tartrate salt.
• the rivastigmine is in the form of its tartrate salt, as rivastigmine tartrate. More preferably, in any embodiment of the invention as described herein, reference to the amounts and dosage ranges of rivastigmine in oral dosage forms are to the amounts and dosage ranges of rivastigmine tartrate.
• galantamine refers to galantamine free base
• galantamine also includes any pharmaceutically acceptable salt, such as the hydrobromide salt.
• the galantamine is in the form of its hydrobromide salt, as galantamine hydrobromide or galantamine HBr. More preferably, in any embodiment of the invention as described herein, reference to the amounts and dosage ranges of galantamine in oral dosage forms are to the amounts and dosage ranges of galantamine hydrobromide.
• azelastine refers to azelastine free base, or 4-(p-
• 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 solid oral dosage forms are to the amounts and dosage ranges of azelastine hydrochloride.
• treating 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 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 pharmaceutical compositions may be administered in either single or multiple doses by oral administration. Administration may be via capsule, tablet, or the like.
• the pharmaceutical composition 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. If soft capsules are desired, a slurry of the compound 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 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.
• compositions provided in accordance with the present disclosure are usually administered orally.
• This disclosure therefore provides pharmaceutical compositions that comprise a solid dispersion comprising azelastine and donepezil or rivastigmine or galantamine 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 arts (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 pharmaceutical composition 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 tablet When the pharmaceutical composition 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 pharmaceutical composition can comprise a) about 4mg -
• azelastine HC1 (or other salt thereof) and b) about lmg to 4mg of donepezil HC1 or about lmg to 2mg rivastigmine tartrate or about lmg to 3mg galantamine HBr or a) about 8mg - 16mg of azelastine HC1 (or other salt thereof) and b) about lmg to 4mg of donepezil HC1 or about lmg to 2mg rivastigmine tartrate or about lmg to 3mg galantamine HBr or a) about lOmg - 14mg of azelastine HC1 (or other salt thereof) and b) about lmg to 4mg of donepezil HC1 or about lmg to 2mg rivastigmine tartrate or about lmg to 3mg galantamine HBr.
• compositions of the invention can comprise a) about 12mg of azelastine HC1 and b) about 4mg of donepezil HC1 or about 2mg of rivastigmine tartrate or about 3mg of galantamine HBr.
• compositions of the invention can comprise azelastine or a pharmaceutically acceptable salt of azelastine present in an amount in the range of about 4mg to about 50 mg and donepezil HC1 in an amount in the range of about 1 mg to about 4mg or rivastigmine tartrate in an amount in the range of about lmg to about 2mg or galantamine HBr in an amount in the range of about lmg to about 3mg.
• the amount of azelastine HC1 (or other salt thereof) present in the composition can be equal to, more than, or less than the amount of donepezil HC1 or rivastigmine tartrate or galantamine HBr (or other salt thereof) present in the composition.
• the amount of azelastine HC1 (and/or other salt thereof) present in the composition can be 2 times as much, or 3 times as much, or 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, or 50 times as much as the amount of donepezil HC1 or rivastigmine tartrate or galantamine HBr (and/or other salt thereof) present in the composition, or vice versa. Any one or more of the compositions of the invention can be used with any one or more the methods of the invention disclosed herein, or other methods of using the compositions.
• the amount of the pharmaceutical composition containing azelastine HC1 and donepezil HC1 or rivastigmine tartrate or galantamine HBr 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 actual compound administered and its relative activity, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.
• compositions, pharmaceutical dosage forms, and tablets containing azelastine HC1 and donepezil HC1 or rivastigmine tartrate or galantamine HBr as described herein are administered to a patient suffering from a neurodegenerative disorder, such as Alzheimer’s disease, by oral administration once daily, twice daily, once every other day, two times a week, three times a week, four times a week, or five times a week.
• a neurodegenerative disorder such as Alzheimer’s disease
• patients are administered with the pharmaceutical composition with a therapeutic effective daily dosage of azelastine HC1 in the range of 8 mg to about 16 mg and donepezil HC1 in an amount in the range of about lmg to about 4mg or rivastigmine tartrate in an amount in the range of about lmg to about 2mg or galantamine HBr in an amount in the range of about lmg to about 3 mg.
• azelastine HC1 in the range of 8 mg to about 16 mg and donepezil HC1 in an amount in the range of about lmg to about 4mg or rivastigmine tartrate in an amount in the range of about lmg to about 2mg or galantamine HBr in an amount in the range of about lmg to about 3 mg.
• the pharmaceutical dosage forms and tablets of pharmaceutical compositions containing azelastine HC1 and donepezil HC1 or rivastigmine tartrate or galantamine HBr as described herein are effective in reversing symptoms in patients with Alzheimer's disease in about 6-24 weeks.
• the pharmaceutical composition s therapeutic effectiveness on patients with AD is evaluated by improvements on scores of Mini-Mental State Examination (MMSE) and 12 Neuropsychiatric Inventory-Questionnaires (NPI-Q) having severity scores of 0-3 and distress scores of 0-5.
• MMSE Mini-Mental State Examination
• NPI-Q Neuropsychiatric Inventory-Questionnaires
• Giacobini E 2006. Cholinesterases in human brain: the effect of cholinesterase inhibitors on Alzheimer’s disease and related disorders.
• Giacobini E Pepeu G (eds). The Brain Cholinergic System in Health and Disease. Oxon: Informa Healthcare p 235-264.
• Goedert M Spillantini MG. 2006. A century of Alzheimer’s disease. Science,
• Alzheimer’s Disease Internationl “World Alzheimer Report 2010: the global economic impact of dementia.”
• Impairment Battery domains in patients with moderate-to-severe Alzheimer's disease evaluating the impact of baseline severity,” Alzheimer's Research & Therapy, vol. 5, no. 1, article 12, 2013.
• Alzheimer's disease in a Japanese population results from a 24-week, double-blind, placebo- controlled, randomized trial,” Dementia and Geriatric Cognitive Disorders, vol. 25, no. 5, pp. 399- 407, 2008.
• 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.
• Alzheimer's disease results of a global, multinational, clinical experience study. Drugs Aging. 2004;21(l):43-53.

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• 2019
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