COMPOSITION PHARMACEUTIQUE PERMETTANT DE TRAITER LA DEPENDANCE A LA NICOTINE

PHARMACEUTICAL COMPOSITION FOR TREATING NICOTINE DEPENDENCE

Abrégé anglais

Galanthamine, as well as its pharmaceutically acceptable acid addition salts,
is used to treat
nicotine dependence. The active substances are released orally, transdermally
or in any other
parenteral manner from pharmaceutical compositions in a continuous and
controlled way.

Revendications

10
CLAIMS
1. The use of galanthamine or a pharmaceutically acceptable acid addition salt
thereof in the
production of a pharmaceutical formulation for the treatment of nicotine
dependence.
2. The use according to claim 1 characterized in that the galanthamine or the
pharmaceutically acceptable salt thereof is present in an orally applicable
form.
3. The use according to claim 1 characterized in that the galanthamine or the
pharmaceutically acceptable salt thereof is present in a parenterally
applicable form.
4. The use according to claim 3 characterized in that the galanthamine or the
pharmaceutically acceptable salt thereof is present in a transdermally
applicable form.
5. The use according to any one of claims 1 to 4 characterized in that the
galanthamine or
the pharmaceutically acceptable salt thereof is comprised in proportions of
0.1-50%-wt.
calculated as free galanthamine in the pharmaceutical formulation.
6. The use according to any one of claims 1 to 5 characterized in that the
galanthamine or
the pharmaceutically acceptable salt thereof is combined with suitable
adjuvants.
7. The use according to claim 5 wherein said galanthamine or the
pharmaceutically
acceptable salt thereof is comprised in proportions of 2-15%-wt. as calculated
as free
galanthamine in the pharmaceutical formulation.

Description

CA 02153570 2006-08-18
Pharmaceutical Composition for Treating Nicotine Dependence
DESCRIPTION
The present invention relates to pharmaceutical formulations for the treatment
of
nicotine dependence.
The present invention is particularly directed to pharmaceutical formulations
and
devices by which galanthamine or one of its pharmaceutically acceptable acid
addition
salts is released in a controlled, for instance continuous manner to treat
nicotine
dependence.
The dependence on nicotine complies with ali criteria of drug addiction
defined by the
WHO:
- compulsive use
- psycho-active effects
-influence on the behavior
- stereotyped consumption habits
- abstinence symptoms on withdrawal or tolerance development
Accordingly, smoking is not a "bad habit and cannot be suppressed by will
alone in all
cases. Pharmacologists discovered nicotine receptors in the brain which are
the
biological explanation for the fact that so many smokers, despite their high
motivation
and good psychological support, backslide again and again.
In 1975, this finding resulted in a completely new therapeutic approach, the
nicotine
supply via chewing gum. Although welcomed enthusiastically at first, the
system soon
showed drawbacks. The bitter taste and the poor social acceptance of the
chewing
gums

21~3~70
2
were some of the objections. In addition, abuse by overdosage
also occured with these systems.
All these drawbacks led to the development of transdermal thera-
peutic systems which comprise nicotine, e.g., described in Ger-
man patent DE 36 29 304 and U.S. patent 4,597,961.
When nicotine is administered transdermally, taste is of no impor-
tance, the application is invisible, the substance is delivered
without oral substitutive gratification, and plasma peaks are
avoided.
Observed side effects are skin irritations at the site of application;
i.e. reddenings, slight swellings and itching, which in some cases
caused the stop of the therapy.
In addition, another disadvantage of this nicotine therapy is the
fact that this form of treatment does not take into account the ex-
treme toxicity of nicotine.
Accordingly, there is a demand for drugs which reliably suppress
the symptoms of nicotine dependence; however, the therapeutic
doses of the active substance may not have a toxicity comparable
to that of nicotine.
Until today, substances from the following groups have been used
to treat nicotine dependence:
- natural substances without nitrogen, e.g. ~-pyrones, citric acid,
acetic acid, camphor, glucose, vitamins, terpenes, and others
alkaloids, e.g. lobeline, caffeine and apocynaceae alkaloids

_ 3 21~3~7p
- tricyclic antidepressants, e.g. fluoxetin
- clonidine
- pyrrolopyrimidine
The diversity of therapy principles alone reveals that an efficacious
drug for the treatment of nicotine dependence which is not as tox-
ic as nicotine has not yet been found.
Accordingly, it is the object of the present invention to provide a
drug in an oral, transdermal, or otherwise parenteral formulation
which allows a controlled release of the drug to the greatest pos-
sible extent and ensures a reduction in the desire for nicotine. The
term parenteral is used to include all forms of application, except
for the oral form, such as the rectal, intravenous, intramuscular,
intraperitoneal and nasal form of administration.
According to the present invention this object is surprisingly
achieved by a formulation for the treatment of nicotine depen-
dence, which is characterized in that it comprises an effective
amount of the active substance galanthamine (4a,5,9,1 1,12-hexa-
hydro-3-methoxy-1 1-methyl-6H-benzofuro [3a, 3, 2-ef] (2] benza-
zepine-6-ol) or one of the pharmaceutically acceptable acid addi-
tion salts thereof.
OH
O I
CH~O
\ Y NJ
CHI
This solution is surprising all the more since, although galanth-
amine has been examined in great detail and the pharmacological

zm~~7o
4
effects thereof have been studied thoroughly, the application of a
galanthamine-containing formulation to treat nicotine dependence
according to the present invention has not been described until
today.
Owing to its pharmacological properties galanthamine belongs to
the group of reversibly acting cholinesterase inhibitors, its effects
are similar to those of physostigmine and neostigmine, however, it
stands out for particular specific properties. The therapeutic range
of galanthamine is three to six times broader since it is not as tox-
ic as physostigmine or neostigmine.
This advantage compensates for its slightly lower cholinesterase
inhibiting-action, relative to the unit of weight.
In medicine, galanthamine is used for various indications, e.g. in
anaesthesia to compensate muscle relaxation after administration
of non-depolarizing muscle relaxants. The extensive duration of
action makes galanthamine,which combines the properties of
physostigmine and neostigmine,a valuable drug in anaesthesio-
logy, since many patients suffer from a central anticholinergic
syndrome after a general anaesthesia. In addition, it is a useful an-
tidote for neuroleptanalgesia.
In contrast to neostigmine, galanthamine passes the blood-brain-
barrier and antagonizes the cerebral effects of cholinergic poisons.
Galanthamine promotes awakening from the twilight sleep caused
by scopolamine.
In neurology, galanthamine is used to treat facial nerve pareses
and other mono and polyneurophaties, residual paraplegia after
polymyelitis or brain and spinal cord injuries, and in myasthenia

~1~3~'~0
gravis. In ophthalmology, galanthamine is used for the symptomat-
ic treatment of the narrow-angle glaucoma.
The use of galanthamine in the treatment of the Alzheimer's dis-
ease is in an experimental stage.
In addition, it was proposed to use galanthamine in clinical studies
on alcohol withdrawal (Opitz, K., DE-PS 40 10 079). '
Galanthamine is obtained, for example, by isolation from the Caucasian
snowdrops Galanthus woronowi Vel., Amaryllidaceae, or by
synthesis.
Drug forms releasing active substances in a controlled manner are
known in the state of the art. The administration of pharmaceuti-
cally effective compounds by means of such formulations may be
effected via the oral, transdermal or otherwise parenteral route. In
such drugs galanthamine may be present as such or in the form of
pharmaceutically acceptable acid addition salts, e.g. as hydro hal-
ide, in particular hydrochloride or hydrobromide, or as a salt of
another pharmaceutically acceptable acid. Usually, these means
additionally comprise adjuvants, such as carriers, free-flow agents,
solvents and oils, the kind and amount of which may vary with the
respective form of administration. In general, the content of active
substance in the drug ranges between 0.1 and 50%-wt., prefer-
ably between 2 and 15%-wt., calculated as free galanthamine.
Some suitable oral formulations for oral administration that are
within the scope of the present invention will be described in
the following.
For example, in such a formulation the pharmaceutical active sub-
stance is encapsulated in a semipermeable membrane, e.g. in cel-
lulose acetate. A tiny hole is bored into the capsular material by
means of a piercer or laser. Within the body of the treated patient

6
water is absorbed through the capsular material. The pharmaceuti-
cal active substance is forced through the tiny aperture in the
desired gradual, constant and controlled manner by osmotic pres-
sure. Such systems are described, e.g., in U.S.-Patent Nos.
3,760,805 and 3,987,790. The pharmaceutical active substances
may be present in the systems in solid form or absorbed to ion-
exchange resins.
Another system for oral administration is described by Sheth and
Leeson in U.S.-Patent No. 4 137 300. This patent describes a
formulation comprising a wax matrix.
The active substances of the present invention are administered
by means of adequate formulations in a convenient and suitable
manner. The solid active substances may be administered in solu-
tion or as suspension. The solution or suspension medium may be
an aqueous or organic one. Suitable solution or suspension media
for galanthamine include, for example, water, silicone fluid or
mineral oil.
In order to facilitate the administration of a compound by means
of a formulation as described above, a free-flow agent may be ad-
ded to the system. Some suitable free-flow agents for oral formu-
lations, for example, include polyethylene glycol, hydroxypropyl
methyl cellulose and sugar.
In a formulation for the transdermal administration of compounds
according to the present invention, the pharmaceutical active sub-
stance may be comprised in a matrix from which it is released in
the desired gradual, constant and controlled manner. The permea-
bility of the matrix during the release of the compound is based on
diffusion. Such a system is described in German patent 33 15 272
(U.S. 4 769 028). This system consists of an impermeable cover

__ 2153~'~~
layer, an oversaturated active substance reservoir of a polymeric
matrix, which is attached to the cover layer and has a particular
construction, a pressure sensitive adhesive layer bonded to the
reservoir and permeable to the active substance, and a removable
protective layer which covers the pressure sensitive adhesive layer
and is removed prior to use. Systems having a reservoir layer
whose self-tackiness is strong enough to form the pressure sensi-
five adhesive layer are also suitable.
German patent DE 38 43 239 (U.S. 5 089 267) describes such a
system.
When the active substance is absorbed through the skin the per-
son to be treated thus receives a controlled and predetermined ac-
tive substance flow.
Other suitable transdermal formulations are described in U.S.-pat-
ent Nos. 3,742,951; 3,797,494; 3,996,934, and 4,031,894. In
principle these formulations consist of a backing layer representing
one surface, an adhesive layer permeable to the active substance
and representing the other surface, and, finally, a reservoir com-
prising the active substance between the two layers forming the
surfaces. Alternatively, the active substance may be comprised
within a variety of microcapsules which are distributed in the per-
meable adhesive layer. In any case, the active substance is contin-
uously released from the reservoir or the microcapsules through a
membrane into the adhesive layer which is permeable to the active
substance and in contact with the skin or mucosa of the treated
person. In the case of microcapsules the capsular material may act
as membrane too.
Suitable formulations to apply galanthamine and the salts thereof
in another parenteral manner are those allowing a depot effect of

~1535'1~
8
the active substance. In this case, the formulation is applied as
injectable solution on a non-aqueous base. Suitable solvents are
known to those skilled in the art. Vegetable oils specified by some
pharmacopoeias are mentioned as example, they include peanut
oil, olive oil, almond oil, sunflower oil, soybean oil, and sesame oil.
Caster oil often has a particularly favorable solubility for drugs; in
addition, oils of animal origin are also suitable.
The oils are physiologically indifferent and well tolerated. A pre-
condition for this is that they are specially purified and have low
acid and peroxide values. Since an intravenous application is not
possible due to the nonexistent miscibility within the blood serum
and because it may result in pulmonary embolism, they may only
be used for intramuscular and subcutaneous injection prepara-
tions. Oily solutions and suspensions remain at the site of applica-
tion for a rather long period (frequently up to one month) and re-
lease the active substances in a protracted manner.
The dosage of galanthamine or its pharmaceutically acceptable
acid addition salts must be large enough and must be effected
over a long period to achieve a lasting effect, and it requires indi-
vidual stabilization/control.
The present invention will be illustrated by the following example.
Example:
The influence of galanthamine on the smoking of healthy test per-
sons
During a test series for a transdermal therapeutic system, which in
vivo releases about 10 mg galanthamine base per day, two smok-
ers were also among the test persons since "smoking" was no

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9
criterion to exclude them from the test. Most surprisingly, both
smokers showed a noticeable suppression in the desire for ciga-
rettes. The duration of application amounted to 24 hours. The
data is listed in the following table:
Cigarette consumptionCigarette consump-
without galanthamine tion after trarisdermal
administration
of 10
mg/day galanthamine
Male test 15-20 cigarettes/day none
person
Female test an average of 60 7 cigarettes/day
person cigarettes/day
Table 1
Table 1 shows that the single administration of 10 mg galanth-
amine/day resulted in a considerable reduction in the cigarette
consumption.