THERAPY FOR IMPROVING COGNITION

THERAPIE VISANT A AMELIORER LA COGNITION

English Abstract

The present invention is concerned with pharmaceutical compositions comprising
a carrier and as first active ingredient an atypical antipsychotic agent (I)
and as second active ingredient an acetylcholinesterase inhibitor (II), each
in an amount producing a therapeutically beneficial effect in patients
suffering from psychosis, or Alzheimer's disease or related dementias. Said
therapeutically beneficial effect can be a synergistic effect on the cognitive
functioning of patients suffering from Alzheimer's disease or related
dementias or the prevention of the further deterioration of cognition in said
patients, or the reduction of adverse effects associated with the one of the
active ingredients by the other of the active ingredients.

French Abstract

Cette invention a trait à des compositions pharmaceutiques renfermant un excipient et, comme premier ingrédient actif, un agent antipsychotique atypique (I), ainsi que, comme second ingrédient actif, un inhibiteur de l'acétylcholinestérase (II), chacun sous des quantités produisant un effet thérapeutique bénéfique chez des patients atteints de psychose, de la maladie d'Alzheimer ou de démences connexes. Cet effet thérapeutique bénéfique peut être un effet de synergie sur le fonctionnement cognitif de patients atteints de la maladie d'Alzheimer ou de démences connexes, être prophylactique, évitant une dégradation ultérieure de la cognition chez ces patients, ou encore atténuant les réactions indésirables dues à l'action sur l'un des ingrédients actifs des autres ingrédients actifs.

Claims

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Claims

1. A pharmaceutical composition comprising a carrier and as first active
ingredient an
atypical antipsychotic agent (I) and as second active ingredient an
acetylcholinesterase inhibitor (II), each in an amount producing a
therapeutically
beneficial effect in patients suffering from psychosis, Alzheimer's disease or
related dementias.

2. A composition according to claim 1 wherein said therapeutically beneficial
effect is
a synergistic effect on the cognitive functioning of patients suffering from
Alzheimer's disease or related dementias, or the prevention of the further
deterioration of cognition in said patients, or the reduction of adverse
effects
associated with the one of the active ingredients by the other of the active
ingredients.

3. A composition according to claim 1 wherein the atypical antipsychotic (I)
is
selected from risperidone, 9-hydroxyrisperidone or a C10-20 alkanoic acid
ester
thereof, olanzapine, quetiapine, iloperidone or ziprasidone, and the
acetylcholinesterase inhibitor (II) is selected from galantamine, rivastigmine
or
donepezil.

4. A composition according to claim 3 wherein the amount of each of the active
ingredients is equal to or less than that which is approved in monotherapy
with said
active ingredient.

5. A composition according to claim 3 wherein the atypical antipsychotic (I)
is
risperidone and the acetylcholinesterase inhibitor (II) is galantamine.

6. A composition according to claim 5 wherein the amount of risperidone is
0.5, 1, 2,
4, or 6 mg and that of galantamine (as base) is 8, 16, 24 or 32 mg per dosage
form.

7. A product containing as first active ingredient an atypical antipsychotic
agent (I)
and as second active ingredient an acetylcholinesterase inhibitor (II), as a
combined
preparation for simultaneous, separate or sequential use in the treatment of
patients
suffering from psychosis, Alzheimer's disease or related dementias.


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8. The use of an acetylcholinesterase inhibitor (II) for the preparation of a
medicament for enhancing the effect of an atypical antipsychotic agent (I) on
cognition in patients suffering from psychosis.

9. The use of an atypical antipsychotic agent (I) for the preparation of a
medicament
for enhancing the effect of an acetylcholinesterase inhibitor (II) on
cognition in
patients suffering from Alzheimer's disease or related dementias.

10. The use of an atypical antipsychotic agent (I) for the preparation of a
medicament
for reducing adverse effects associated with acetylcholinesterase inhibitors
(II) in
patients suffering from Alzheimer's disease or related dementias.

11. Use according to claim 10 wherein the adverse effect is nausea, vomiting,
sweating, restlessness or insomnia.

12. The use of an acetylcholinesterase inhibitor (II) for the preparation of a
medicament for reducing adverse effects associated with atypical antipsychotic
agents (I) in patients suffering from psychoses.

13. Use according to claim 12 wherein the adverse effect is extrapyramidal
syndrome
or tardive dyskinesia.

14. Use according to any one of claims 8 to 13 wherein the atypical
antipsychotic (I) is
risperidone and the acetylcholinesterase inhibitor (II) is galantamine.

Description

CA 02345767 2001-03-30
WO 00123057 PCTIEP99/07804
THERAPY FOR IIVVtPROVING COGNITION
The present invention is concerned with pharmaceutical compositions comprising
a
earner and as first active ingredient an atypical antipsychotic agent (I) and
as second
active ingredient an acetylcholinesterase inhibitor (II}, each in an amount
producing a
therapeutically beneficial effect in patients suffering from psychosis, or
Alzheimer's
disease or related dementias. Said therapeutically beneficial effect can be a
synergistic
effect on the cognitive functioning of patients suffering from Alzheimer's
disease or
related dementias, or the prevernion of the further deterioration of cognition
in said
patients, or the reduction of adverse effects associated with the one of the
active
ingredients by the other of the active ingredients.
Of particular interest is the use of an atypical antipsychotic agent (1] for
the preparation
of a medicament for reducing adverse effects associated with
acetylcholinesterase
inhibitors {II) in patients suffering from Alzheimer's disease or related
dementias, such
as nausea, vomiting, sweating, restlessness and insomnia. Especially
interesting is the
use of an, atypical antipsychotic agent {n for the preparation of a medicament
for
improving sleep in patients suffering from Alzheimer's disease or related
dementias
while being treated with acetylcholinesterase inhibitors {II).
The present invention is concerned with a pharmaceutical composition
comprising a
carrier and as f rst active ingredient an atypical antipsychotic agent (l~ and
as second
active ingredient an acetylcholinesterase inhibitor (11), each in an amount
producing a
therapeutically beneficial effect in patients suffering from psychosis, or
Alzheimer's
disease or related dementias. Said therapeutically beneficial effect can be a
synergistic
effect on the cognitive functioning of patients suffering from Alzheimer's
disease or
related demential, or the prevention of the further deterioration of cognition
in said
patients, or the reducti~n of adverse effects associated with the one of the
active
ingredients by the other of the active ingredients.
The atypical antipsychotic (I) is selected from risperidone, 9-
hydroxyrisperidone or a
Cio-zo alkanoic acid ester thereof, olanzapine, quetiapine, iloperidone or
ziprasidone,
and the acetylcholinesterase inhibitor (ll) is selected from galantamine,
rivastigmine or
donepezil, or therapeutically active acid addition salt form of any of the
foregoing. Said
salts comprise salt forms which the active ingredients (I) and (TI) are able
to form with
appropriate acids, such as, for example, inorganic acids such as hydrohalic
acids, e.g.
hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like
acids; or


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organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic,
pyruvic,
oxalic, mulonic, succinic, malefic, fumaric, malic, tartaric, citric,
methanesulfonic,
ethanesulfonic, benzenesuifonic, p-toluenesulfonic, cyclamic, salicylic, p-
amino-
salicylic, pamoic and the like acids. For example, galantamine may
conveniently be
used as the (1:1) hydrobromide salt.
C10-20uIkanoic acids are selected from the group consisting of decanoic
(cupric),
undecanoic, dodecanoic (Iauric), tridecanoic, tetradecanoic (myristic),
pentadecanoic,
hexadecanoic (palmitic), heptadecanoic, octadecanoic {stearic), nonadecanoic
and
eicosanoic acid. Due to their limited aqueous solubility, it was generally
believed that
the esters had to be suspended into oils. The ester having a C15 (pentadecyl)
chain and
the active ingredient corresponding thereto being the 9-hydroxyrisperidone
palmitate
ester was found to be the superior ester from a pharmacokinetic, as well as
from a
tolerance point of view.
Preferably, the amount of each of the active ingredients is equal to or less
than that
which is approved in monotherapy with said active ingredient.
Most preferred are compositions wherein the atypical antipsychotic (>7 is
risperidone
and the acetylcholinesterase inhibitor {II) is galantamine, in particular as
galantamine
hydrobromide. Tn said compositions, the amount of risperidone is 0.5, 1, 2, 4,
or 6 mg
and that of galantamine (as base) is 8, 16, 24 or 32 mg per dosage form.
The present invention also relates to products containing as first active
ingredient an
atypical antipsychotic agent (I) and as second active ingredient an
acetylcholinesterase
inhibitor (II), as combined preparations for simultaneous, separate or
sequential use in
the treatment of patients suffering from psychosis, Alzheimer's disease or
related
dementias.
The present invention also concerns the use of an acetylcholinesterase
inhibitor (II) for
the preparation of a medicament for enhancing the effect of an atypical
antipsychotic
agent (I) on cognition in patients suffering from psychosis.
Conversely, the present invention also concerns the use of an atypical
antipsychotic
agent (>7 for the preparation of a medicament for enhancing the effect of an
acetylcholinesterase inhibitor (>I) on cognition in patients suffering from
Alzheimer's
disease or related dementias.


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Additionally, the present invention concerns the use of an atypical
antipsychotic agent
(I) for the preparation of a medicament for reducing adverse effects
associated with
acetylcholinesterase inhibitors (II) in patients suffering from Alzheimer's
disease or
related dementias. Said adverse effect can be nausea, vomiting, sweating,
restlessness
or insomnia. Especially interesting is the use of an atypical antipsychotic
agent (I} for
the preparation of a medicament for improving sleep in patients suffering from
Alzheimer's disease or related dementias while being treated with
acetylcholinesterase
inhibitors (II).
Finally, the present invention also concerns the use of an
acetylcholinesterase inhibitor
(II) for the preparation of a medicament for reducing adverse effects
associated with
atypical antipsychotic agents (n in patients suffering from psychoses. Said
the adverse
effect can be extrapyramidal syndrome or tardive dyskinesia.
In all the preceding uses the atypical antipsychotic (T} is preferably
risperidone and the
acetylcholinesterase inhibitor (lI) is preferably galantamine, in particular
the (1:1)
hydrobromide.