Note: Descriptions are shown in the official language in which they were submitted.
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A METHOD OF TREATING MENTAL, BEHAVIORAL, COGNITIVE DISORDERS
FIELD OF THE INVENTION
[001] 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.
BACKGROUND OF THE INVENTION
[002] 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.
[003] A central mechanism in learning and memory is long-term potentiation
(LTP).
LTP is mediated by the neurotransmitter glutamate via the N-Methyl-D-aspartic
acid (NMDA)
receptor. The 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 excitotoxicity.
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. Thus, a large build-up of glutamate can occur and induce a
massive accumulation
of Ca2+, leading to apoptosis. It was also noted that amyloid-beta (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.
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[004] Under physiologic conditions, the glutamate released by neurons is
metabolized
or taken up by neighboring cells. When these pathways are disrupted, the
accumulated glutamate
overexcites the NMDA receptor and induces pathology characteristic of
neurodegenerative
diseases. NMDA receptors act as a calcium [II] ion (Ca2+) channel that
activates when bound by
glycine, glutamate, and/or NMDA. However, the channel functions only when the
cell
membrane is depolarized due to the blockade of the channel by the magnesium
[II] ion (Mg2+).
This prevents the influx of Ca2+ when the neuron is at rest. Under
pathological conditions, such
as a chronically depolarized membrane, Mg2+ leaves the channel and neuronal
metabolism is
inhibited, leading to cell death. When this happens, the Ca2+ influx is
unrestricted for a longer
period of time than normal. This influx of Ca2+ contributes to an alteration
of cell function,
leading to cell death either through free radicals or through overload of the
mitochondria,
resulting in free radical formation, caspase activation, and the release of
apoptosis-inducing
factors. Antagonists to the NMDA vary in affinity and in site of action,
resulting in different
alterations to the channel. Regardless of the mechanism of action, antagonists
decrease the
permeability of the channel and prevent an influx of Ca2+. Thus NMDA receptor
antagonists are
looked to as possible neuroprotective agents and potential therapies for
neurodegenerative
disease.
[005] Most 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. Its role in cognition, memory, and learning make it
necessary that any
drug using the NMDA receptor as a target of action must preserve physiologic
function to be
therapeutically useful. Memantine acts on activated NMDA receptors by binding
to a site located
in the channel of the receptor. However, 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.
[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.
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[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 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, 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-10, among others. Azelastine
also directly
antagonizes other mediators of inflammation, such as tumor necrosis factor-a,
leukotrienes,
endothelin-1, and platelet-activating factor.
SUMMARY OF THE INVENTION
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[009] 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.
[0010] In some embodiments of this invention, the pharmaceutically
acceptable salt of
azelastine is azelastine hydrochloride.
[0011] In some embodiments of this invention, azelastine hydrochloride is
provided in a
daily effective amount of about 4 mg to about 40 mg.
[0012] 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.
[0013] 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.
[0014] In some embodiments of this invention, 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.
DETAILED DESCRIPTION OF THE INVENTION
[0015] The inventors of the present invention surprisingly found that
higher oral dosages
of azelastine or a pharmaceutically acceptable salt of azelastine are suitable
for treating patients
suffering from mental, behavioral, cognitive disorders.
[0016] 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
of steps for constructing and operating the example. However, the same or
equivalent functions
and sequences may be accomplished by different examples.
[0017] Definitions
[0018] 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.
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[0019] Mental, behavioral, cognitive disorders include Alzheimer's
disease, vascular
dementia, Huntington's disease, frontal temporal dementia, traumatic brain
injury, corticobasal
degeneration, or Parkinson's disease, and combinations of any thereof and
other
neurodegenerative disorders.
[0020] As used herein, the term "azelastine" refers to azelastine free
base, or
4-(p-Chlorobenz y1)-2-(hexahydro- 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 oral dosage forms are to the
amounts and dosage
ranges of azelastine hydrochloride.
[0021] As used herein, the term "pharmaceutically acceptable salt" refers
to a salt of
azelastine formed with an acid selected from a group of acids consisting of 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, dodecylsulfuric
acid, ethane-1,2-
disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric
acid, gentisic acid,
glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid,
glutaric acid,
glycerophosphoric acid, 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, proprionic acid, pyroglutamic acid (- L),
salicylic acid, sebacic
acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+ L),
thiocyanic acid, toluenesulfonic
acid (p), undecylenic acid.
[0022] 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
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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.
[0023]
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.
[0024]
As used herein, 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.
[0025]
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.
[0026]
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
pharmaceutically acceptable salt of azelastine with an acceptable vegetable,
light petroleum or
other inert oil can be encapsulated by forming into a gelatin capsule.
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[0027]
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.
[0028]
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.
[0029]
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. Such 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)).
[0030]
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. When 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
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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.
[0031] In certain embodiments, 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
[0032] It will be understood, that the amount of 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.
[0033] 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.
[0034] In some embodiments, 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.
[0035] The following Examples are illustrative and should not be
interpreted to limit the
scope of the claimed subject matter. The Examples show that after 6 months of
treatment with 12
mg azelastine HC1, both patients improved significantly on memory, language,
reasoning, and
time arrangement. Mini-Mental State Examination (MMES) was not assessed but it
is
reasonable to predict that MMES would have been significantly improved if
measured.
[0036] Example 1
[0037] An 80 year old female patient with a weight of 51 kilograms and
diagnosed with
late-stage Alzheimer's disease for 6 years required round-the-clock assistance
for her daily
activities such as walking and looking for things, as well as personal care
and her speech was
limited to only a few words. She had very little awareness of her surroundings
before being
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treated with 12 mg azelastine HC1 once daily before bedtime. After 6 weeks of
treatment with
12 mg azelastine HC1 once daily before bedtime, she was able to walk in her
house with light
assistance. After 12 weeks of treatment, she was able to speak for more than 1
minute, know
activities in her house and ask questions about daily activities in her house.
After 6 months of
treatment, she was a completely different person in terms of what she was able
to do in
comparison to what she could do before treatment, and she could actively talk
to people and did
not require assistance for her daily activities and personal care.
Accordingly, her MMSE scores
would similarly have been expected to have improved. Her weight gained by 3
kilograms after
the 6 month treatment.
[0038] Example 2
[0039] An 83 year old female with a weight of 49 kilograms was diagnosed
with mid- to
late-stage Alzheimer's disease. Her daily activities were limited because she
couldn't recall
things which just occurred and could not locate anything that she wanted to
retrieve by herself.
She required assistance for most of her daily activities including personal
care before she started
the treatment of 12 mg azelastine HC1 once daily before bedtime. After 6 weeks
of treatment, she
started to show signs that she was able to find a few things which she
intended to retrieve. After
3 months of treatment, she required assistance for only a few daily activities
or personal care and
could do most of them by herself. Her MMSE scores would similarly have been
expected to have
improved. Her weight gained by 2.5 kilograms after the 6 month treatment.
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[0070] 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.
[0071] 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 is
also specifically
disclosed. The upper and lower limits of these smaller 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.
12
