Note: Descriptions are shown in the official language in which they were submitted.
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NOVEL PHARMACEUTICAL COMPOSITIONS AND METHODS
FOR TREATING MENTAL, BEHAVIORAL, COGNITIVE DISORDERS
FIELD OF THE INVENTION
[001] 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.
BACKGROUND OF THE INVENTION
[002] Alzheimer's disease (AD) is a progressive, chronic neurodegenerative
disease that
usually starts slowly and gradually worsens over time. Alzheimer' s disease 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.
[003] AD is a polygenic/multifactorial complex disorder characterized by
the premature
death of neurons. Although the 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. These findings are companied by
neuroinflammatory reactions,
oxidative stress, and free radical formation probably associated with
mitochondrial dysfunction,
excitotoxic reactions, alterations in cholesterol metabolism and lipid rafts,
deficiencies in
neurotransmitters (especially acetylcholine) and neurotrophic factor function,
defective activity of
the ubiquitin-proteasome, and chaperone systems and cerebrovascular
dysregulation. All these
neurochemical events are potential targets for treatment; however, it is very
unlikely that a single
drug be able alone to neutralize the complex mechanisms involved in
neurodegeneration.
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SUBSTITUTE SHEET (RULE 26)
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[004] In the early 1980s it was believed that 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. Since choline
donors (precursors)
and acetylcholine itself were substances of difficult pharmacological
management (or useless to
increase brain cholinergic neurotransmission), and, paradoxically, considering
that
acetylcholinesterase activity progressively decreased in AD brains in parallel
with cognitive
deterioration, 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.
The first candidate to fulfil this criteria was tacrine
(tetrahydroaminoacridine) which after its
introduction in the market in 1993 soon fell out of favor due to its
hepatotoxicity and poor
tolerability; 3 years later, in 1996, donepezil was approved by the FDA for
the treatment of mild-to-
moderate cases of AD. The other AChEIs, rivastigmine and galantamine, were
introduced several
years later.
[005] However, 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.
[006] 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.
[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 0 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
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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.
[008] Azelastine is classified pharmacologically as a second generation
antihistamine and
is a relatively selective, nonsedating, 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. 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-10, 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.
SUMMARY OF THE INVENTION
[009] 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.
[0010] Included in embodiments of the invention is use of a composition
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 treatment of one or
more mental,
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behavioral, or cognitive disorder, such as Alzheimer's disease, vascular
dementia, Parkinson's
disease, Huntington's disease, or any combination thereof.
[0011] Also included within the scope of the invention is use of a
composition 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.
[0012] Further included within the scope of the invention is use of a
composition
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.
[0013] In some embodiments of this invention, 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.
[0014] In some embodiments of this invention, 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. Preferred are 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), and
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) and/or an amount of rivastigmine or a salt thereof
in an amount of up
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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) and/or an amount of galantamine or a
salt thereof in an
amount of up to about 24 mg per day(such as from about 1-24 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 8-10 mg, or 0.5-2 mg, or 0.8-2.8
mg, or 1-1.5 mg,
or 1.2-2.5 mg, and so on). Depending on the application, higher amounts of any
one or more of
these could be used in certain embodiments.
[0015] The present invention also includes an oral pharmaceutical dosage
form of the
pharmaceutical composition that is a solid form or a liquid form.
[0016] 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.
[0017] 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 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. In embodiments, 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.
DETAILED DESCRIPTION OF THE INVENTION
[0018] The inventors of the present invention surprisingly found that 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.
[0019] The detailed description provided below is intended as a
description of the present
examples and is not intended to represent the only forms in which the present
example may be
constructed or utilized. The description sets forth the functions of the
example and the sequence
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of steps for constructing and operating the example. However, the same or
equivalent functions
and sequences may be accomplished by different examples.
[0020] Definitions
[0021] As used in the present specification, the following words and
phrases are generally
intended to have the meanings as set forth below, except to the extent that
the context in which
they are used indicates otherwise.
[0022] Mental, behavioral, cognitive disorders can include but are not
limited to
Alzheimer's disease, dementia, Parkinson's disease, Huntington's disease and
combinations of any
thereof and other neurodegenerative disorders.
[0023] As used herein, the term "donepezil" refers to donepezil free
base, 2,3-dihydro-5,6-
dimethoxy-2-[[1-(phenylmethyl)-4 -piperidinyl] methyl] -1H-inden- 1-one. In
certain embodiments,
donepezil also includes any pharmaceutically acceptable salt, such as the
hydrochloride or HC1
salt. Preferably, in any embodiments of the invention as described herein, 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.
[0024] As used herein, the term "rivastigmine" refers to rivastigmine
free base, (S)-3-(1-
(dimethylamino)ethyl)phenyl ethyl(methyl)carbamate. In certain embodiments,
rivastigmine also
includes any pharmaceutically acceptable salt, such as the tartrate salt.
Preferably, in any
embodiments of the invention as described herein, 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.
[0025] As used herein, the term "galantamine" refers to galantamine free
base,
(4aS ,6R,8aS )-5,6,9,10,11,12-Hexahydro-3-methoxy-11-methy1-4aH4 1 lbenzofuro
[3 a,3 ,2-
ef] [2]benzazepin-6-ol. In certain embodiments, galantamine also includes any
pharmaceutically
acceptable salt, such as the hydrobromide salt. Preferably, in any embodiments
of the invention as
described herein, 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
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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.
[0026] As used herein, the term "azelastine" refers to azelastine free
base, or
Chlorobenzy1)-2-(hex ahydro- 1-methyl- 1H- azepin-4-y1) -1-(2H)-phthalazinone.
In certain
embodiments, azelastine also includes any pharmaceutically acceptable salt,
such as the
hydrochloride or HC1 salt. Preferably, in any embodiments of the invention as
described herein,
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.
[0027] As used herein, "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.
[0028] 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.
[0029] The term "about" used herein 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 mg.
[0030] 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
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Formulations (Volumes 1-6 by Sarfaraz K. Niazi). Accordingly, incorporation of
the active
compounds and a controlled, or slow release matrix may be implemented.
[0031] Either fluid or solid unit dosage forms can be readily prepared
for oral
administration. For example, admixed with 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.
[0032] 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 corn 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.
[0033] 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.
[0034] The pharmaceutical 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
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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. Such
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)).
[0035] 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. 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. For example, a
time delay material such as glyceryl monostearate or glyceryl distearate alone
or with a wax may
be employed.
[0036] In embodiments, the pharmaceutical composition can comprise a)
about 4mg -
20mg 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 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
10mg - 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. For example,
the composition
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. Further, for
example, 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. In
embodiments, 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. In
embodiments, the amount
of azelastine HC1 (and/or other salt thereof) present in the composition can
be 2 times as much, or
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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.
[0037] It will be understood, that 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.
[0038] The pharmaceutical 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.
[0039] In embodiments, 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 3mg.
[0040] In embodiments, 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.
[0041] 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.
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[0042] For treatment of AD, as one of acetylcholinesterase inhibitors,
donepezil alone
improves MMES by 9.2% and NPI total by 40.9% and NPI distress by 41.5%.
[0043] The following Examples are illustrative and should not be
interpreted to limit the
scope of the claimed subject matter.
[0044] Example 1
[0045] 10 Patients who are diagnosed with late stage Alzheimer's disease
with MMSE
scores ranging from 10-1 and NPI-Q having severity scores of 3 and distress
scores of 4 or 5 are
treated with tablet forms of the pharmaceutical composition containing 12mg of
azelastine HC1
and 3mg of donepezil HC1 once daily. After 12 weeks, the MMSE scores of these
10 patients
would be expected to increase by at least 9 to range of 20-10, which is 1 to 9
times of improvement
in MMSE scores, and their NPI-Q would be expected to have severity scores of 1
and distress
scores of lor 2, which is 2.5 to 4 times of improvement.
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[00101] The present invention has been described with reference to
particular embodiments
having various features. In light of the disclosure provided above, it will be
apparent to those
skilled in the art that various modifications and variations can be made in
the practice of the present
invention without departing from the scope or spirit of the invention. One
skilled in the art will
recognize that the disclosed features may be used singularly, in any
combination, or omitted based
on the requirements and specifications of a given application or design. When
an embodiment
refers to "comprising" certain features, it is to be understood that the
embodiments can
alternatively "consist of' or "consist essentially of' any 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. Likewise, 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.
[00102] It is noted in particular that where a range of values is provided
in this specification,
each value between the upper and lower limits of that range, to the tenth of
the unit disclosed, is
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also specifically disclosed. Any smaller range within the ranges disclosed or
that can be derived
from other endpoints disclosed are also specifically disclosed themselves. The
upper and lower
limits of disclosed ranges may independently be included or excluded in the
range as well. The
singular forms "a," "an," and "the" include plural referents unless the
context clearly dictates
otherwise. It is intended that the specification and examples be considered as
exemplary in nature
and that variations that do not depart from the essence of the invention fall
within the scope of the
invention. Further, all of the references cited in this disclosure are each
individually incorporated
by reference herein in their entireties and as such are intended to provide an
efficient way of
supplementing the enabling disclosure of this invention as well as provide
background detailing
the level of ordinary skill in the art.
17
