Note: Descriptions are shown in the official language in which they were submitted.
CA 02426492 2003-05-08
A combination of an NlI~IDA-antagonist and acetylcholine esterase inhibitors
for
the treatment of Alzheimer's disease.
The present invention provides a treatment for mild cognitive impairment
(1VICI~ and
for dementia of different types such as dementia of Alzheimer's type, vascular
dementia, Lewy body dementia, AIDS dementia and frontotemporal dementia
by administration of medicaments having dual mechanisrne of action.
1o Dementia of different origin are a growing problem in the world. Among the
elderly,
Alzheimer's disease is the most common type of dementia. The prevalence of the
disease raises from 2% of the people aged 65-70 to as high as 20% of the
people aged
80 and older. Though perhaps not the only contributing factor, the increased
life
expectancy and the increased elderly population explains the raise in the
frequency of
15 the disease.
Alzheimer's disease is a slowly progressing neurodegenerative disease
characterised
by significant loss of function in more than one cognitive domain. Associated
diseases
such as psychiatric illness and change in behaviour or personality are common.
Presently, the disease cannot be cured. Current treatment gives for some
patients a
delay in the symptoms, for others a modest cognitive improvement and a
dramatic
improvement in only a small number of patients. A slower progression of the
disease
is also desirable for improving the life quality for the patient and the
patient's
relatives. However, experience with the current treatment with Alzheimer's
therapy,
still 30% of the patients do not respond to the treatment. Consequently, a
great need
for improvement in the treatment of Alzheimer's disease exists.
The mechanisms behind the different types of dementia, including Alzheimer's
3o disease, are not fully understood. Of medicaments available for treatment,
which
presently is only slowing the progression of the disease, they represent
different
mechanism of action in the central nervous system.
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One group of medicaments are represented by the acetylcholinesterase
inhibitors, of
which medicaments like Donepezil, Rivastigmine, Galantamine and Tacrine are
pharmaceuticals having this particular activity. The acetylcholinesterase
inhibitors are
presently approved in many countries for treatment of mild to rraoderate
Alzheimer's
disease.
Another group of medicaments are the NMDA antagonist of which Memantine is a
representative. Memantine was recently approved in the EU for treatment of
moderate
severe to severe Alzheimer's disease.
Though of very different mechanisms of action, both types of medicaments are
useful
in the treatment of Alzheimer's disease, though in different stages of the
disease
progression.
The invention thus provides the combined treatment of a patient suffering from
a
dementia syndrome with a first component which is an acetylcholinesterase
inhibitors) and a second component which is an NMDA antagonist.
The invention also provides a pharmaceutical composition which comprises a
first
2o component which is an acetylcholinesterase inhibitors) a:nd a second
component
which is an NMDA antagonist.
The acetylcholinesterase inhibitors include, but are not limited to:
Donepezil, a known compound described in EP 296560 and US 4895841.
Galantamines use in the treatment of Alzheimer's disease is described in
EP236684
and US 4663318.
3o Rivastigmine as described in national applications corresponding to US
5602176 and
GB 2203040.
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3
Tacrine as used in the treatment of cholinergic deficit state, such as
Alzheimer's
disease, is described in EP 328535 and US 416456.
Similarly, when the invention is regarded in its broadest sense, the second
component
is a compound which functions as an NMDA antagonist or partial antagonist of
which
s assays like Ebert et. al European Journal of Pharmacology 1997, 333 , 99-104
exists
for determining this activity. Other compounds than the compounds mentioned
here
have the desired effect. It is intended to include compounds which show
antagonisme
in the assay described above.
1o In the present invention, the combination of one compound of the group of
acetylcholinesterase inhibitors with one compound of the group of NMDA
antagonist
is included. Likewise, the combination of two compounds of the first group
with one
or two or the compounds selected from the second group is also within the
present
invention and vice versa.
1s
While all combinations of first and second group compounds are useful the
following
combinations are considered as the preferred combinations:
Memantine/Donepezil, Memantine/Galantamine, Memantine/Rivastigmine and
20 Memantine/Tacrine.
Where the compounds exists as different polymorphs, isomers, enantiomers or
tautomers the present invention also embraces these variations as well as
different
salts or solvates etc.
Active metabolites of the compounds described are also embraced by the
invention.
Alzheimer's Disease
Characteristics of Alzheimer's Disease are some of the following symptoms
occuring:
~ Dementia
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4
~ Deficits in cognition (such as language, memory, motor skills and perception
ie.
aphasia, apraxia, agnosia)
Progressive worsening of memory and cognitive functions
Some of the following associated symptoms often occur:
Depression, insomnia, incontinence, delusions, illusion, hallucinations,
emotional or
physical outbursts, shouting, wandering , aggression, agitation, apathy,
abnormal
eating, sexual disorders and weight loss.
to
Increased motor tone, myoclonus or gait disorder in the late stages of the
disease
progression.
Since Alzheimer's disease is not curable at present, the complexity of the
disease
15 progression and the associated symptoms often gives rise to a multiplicity
of diseases,
which all need medical treatment. Such treatment regimens and side-effects are
difficult to administerable for the patient as well as for the health carer.
Consequently, a positive outcome of an Alzheimer's treatrnent is an improved
2o cognitive function. A slower progression of the disease, or a delay in the
normal
disease progression is a positive outcame of a treatment.
Improvements could also be measured in the secondary or associated symptoms of
more psychiatric character. Diminished intake or complete stop in the intake
of for
25 example antipsychotic, antidepressive, tran.quilising or sedative
medication will also
be signs of a positive response to the treatment of the underlying cause of
the
dementia, ie. the Alzheimer's Disease.
When combination treatment is evaluated a synergistic effect of the combined
30 administration could be evaluated and the total. dose of the combination
treatment of
individual compounds relative to the doses used for single compound
administration
could be lowered.
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The present invention covers treatment of mild cognitive impairment and
dementia
regardless of the underlying cause. For example the dementia can be
Alzheimer's
disease, vascular dementia, Lewy body dementia, AIDS dementia or
frontotemporal
dementia.
5
In the context of this invention, Alzheimer's disease includes all stages of
the disease,
ie. mild, moderate and severe Alzheimer's disease.
In the context of this invention, mild cognitive impairment are characterised
by
symptoms defined by Petersen et. al.
Pharmaceutical compositions:
To prepare the pharmaceutical compositions of this invention, an effective
amount of
the active ingredients, in acid or base addition salt form or base form, is
combined in
intimate admixture with a pharmaceutically acceptable carrier, which can take
a wide
variety of forms depending on the form of preparation desired for
administration.
These pharmaceutical compositions are desirably in unitary dosage form
suitable, for
administration orally, nasal, rectally, percutaneously or by parenteral
injection. For
example, in preparing the compositions in oral dosage form, any of the usual '
pharmaceutical media may be employed, such as, for example, water, glycols,
oils,
alcohols and the like in the case of oral liquid preparations such as
suspensions,
syrups, elixirs and solutions; or solid carriers such as starches, sugars,
kaolin,
lubricants, hinders, disintegrating agents and the like in the case of
powders, pills,
capsules and tablets. Because of their ease in administration, tablets and
capsules
represent the most advantageous oral dosage unit form, in which case solid
pharmaceutical carriers are obviously employed. For parenteral compositions,
the
carrier will usually comprise sterile water, at least in large part, though
other
ingredients, for example, to aid solubility, may be included.
It is especially advantageous to formulate the aforementioned pharmaceutical
compositions in dosage unit form for ease of administration and uniformity of
dosage.
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Dosage unit form as used in the specification and claims herein refer to
physically
discrete units suitable as unitary dosages; each unit containing a
predetermined
quantity of active ingredient calculated to produce the desired therapeutic
effect, in
association with the required pharmaceutical carrier. Examples of such dosage
unit
forms are tablets (including scored or coated tablets), capsules, pills,
powder packets,
wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and
the like,
and segregated multiples thereof.
The NMDA antagonist may be administered before, during or after the
administration
1o of the acetylcholinesterase inhibitor provided that the time between the
administration
of the acetylcholinesterase inhibitor and the administration of the
acetylcholinesterase
inhibitor is such that ingredients are allowed to act synergistically on the
CNS.
When simultaneous administration of NMDA antagonist and an
acetylcholinesterase
inhibitor is envisaged, a composition containing both an acetylcholinesterase
inhibitor
and an NMDA antagonist may be particularly convenient. The compositions may be
prepared as described herein above.
Simultaneous administration may also be accomplished by administration of the
2o active ingredients in two separate unit dosage forms.
When sequential administration of the NMDA antagonist is envisaged, the
pharmaceutical composition may comprise, for example, a kit including discrete
unit
dosage forms containing the NMDA antagonist and discrete unit dosage forms
containing an acetylcholinesterase inhibitor, all contained in the same
container or
pack, e.g. a blister pack.
Dose Ranges
The selection of dosage of the first and second component is that which gives
the
patient relief of the symptoms of the disease. The dosage depends on several
factors
such as the potency of the selected compounds, the mode of administration, the
age
CA 02426492 2003-05-08
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and weight of the patient, the severity of the condition to be treated and the
like. This
is considered to be the skill of the artisan and suitable literature can be
consulted for
the dosages recommended for each compound.
The dosage ranges for the NMDA antagonist; Memantine are O.lmg -SOOmg of
active
ingredient pr. dosage. More preferred are 1- 50 mg and most preferred are 2 -
25 mg.
Presently the preferred dosage administered is 20mg.
The dosage of the second component, the acetylcholinesterase inhibitor, will
depend
on the dosage of the NMDA antagonist administered or vice versa. The average
daily
dosage of the acetylcholinesterase inhibitor are from 0. lmg -500mg of active
ingredient pr. dosage. More preferred are 1- 50 mg and most preferred are 2 -
25 mg.
Presently, the dosage regime for the available acetylcholinesterase inhibitor
are the
following:
Tacrine 10-40 mg four times a day
Donepezil 5-10 mg per day
Rivastigmine 3-12 mg per day
Galantamine 4-24 mg per day
