Note: Descriptions are shown in the official language in which they were submitted.
CA 02341855 2001-02-27
WO 00/23077 PCT/EP99/07320
Method for treating schizophrenia, and means for use in
this method
The invention is directed at a method and a device for
treating schizophrenia.
Schizophrenia is a psychological disorder which was
first described as a disease by E. Kraepelin by
summarizing individual features, for example of
paranoid and catatonic states. The main deficit on
which this illness is based is a splitting of
psychological functions. However, the appearance of
schizophrenia varies, and the diverse symptoms vary in
the intensity and combination in which they occur.
Typical forms are paranoid hallucinatory schizophrenia,
catatonic schizophrenia, schizophrenia simplex and
hebephrenia. Symptoms of schizophrenia are, inter alia,
disturbances of the thought process, disturbances of
thought contents, hallucinations, so-called "ego
disturbances", emotional disturbances (disturbances of
affect) and disturbances of movement and drive.
Schizoaffective psychoses occupy a middle position
between schizophrenias and cyclothymias.
In cases of schizophrenia a distinction is made between
basic symptoms and accessory symptoms. The basic
symptoms include disturbances of thought (incoherence
of thought, interruption of thought, alterations in the
chain of thought), affective disturbances (apathy,
hypersensitivity, irritability, loss of contact,
ambivalence of feelings) and disturbances of the
perception of self (depersonalization, experiences of
alienation and of being influenced, splitting of
personality). The accessory symptoms (positive
symptoms) include hallucinations (auditory, visual,
- olfactory and gustatory hallucinations), mania
(persecution mania, toxicomania, sex mania inter alia),
disturbances of motor responses and of drive
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(immobility, mutism, athymia) and speech changes
(mannerisms, bizarre modes of expression, neologisms,
continual repetition).
A more detailed description of the pathological states
is to be found in B. Bondy: "Was ist Schizophrenie".
Verlag C.H. Beck, Munich (-1994), the complete contents
of~which are incorporated herein by reference.
For the distinction from other diseases, reference is
made to the diagnostic criteria listed in the
International Classification of Diseases and in the
Diagnostic and Statistical Manual of Mental Disorders.
Schizophrenia is regarded as incurable, i.e. a
causative treatment is regarded as impossible - as is
the case, moreover, for many organic disorders such as,
for example, diabetes. However, palliative treatment is
possible, so that the symptoms in most of the patients
can be suppressed at least to such- an extent that
hospitalization is unnecessary and the patient is made
capable of a controlled everyday life.
Before the second world war, medical treatment mainly
consisted of administration of hypnotics and other
substances for sedation. In addition, physical measures
had the aim of calming the patient through physical
exhaustion. The patients were for this purpose mainly
confined in psychiatric establishments.
Medical treatment was extended by use of
chlorpromazine, and this substance became a starting
point for the development of substances with
antipsychotic activity, called neuroleptics. However,
these substances have a number o~f unwanted side
effects.
Recently, methods for treating schizophrenia by use of
nicotine-containing chewing-gum (L. E. Adler et al.,
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Biol. Psychiatry, 32 (1992) 607-616) and by intestinal
absorption (Rhodes et al., WO 98/02188) have been
disclosed.
The invention is thus based on the object of providing
a method and a medicinal product which makes symptom-
minimizing treatment possible for patients with
schizophrenia and is suitable for use in addition to or
within the framework of psychotherapy and/or
sociotherapy, by which means it is possible to reduce
or avoid the disadvantages of treatment with
neuroleptics or other substances with psychological
activity. It is also intended to avoid the weaknesses
of intermittent nicotine uptake by use of nicotine
chewing-gum and the disadvantages the irritant effect
of nicotine on the mucous membranes on oral
administration.
The object is achieved by a method and a medicinal
product which is suitable for continuous administration
of nicotine, preferably onto and through the skin over
a prolonged, for example over a 16- or 24-hour, and
preferably over a more than 1 day, for example 3-day,
period.
Medicinal products of this type are known, for example
from European patents EP 261 402, EP 289 342,
EP 387 694, EP 400 078, EP 427 741 and EP 708 627.
These are transdermal therapeutic systems (TTS), which
deliver the active ingredient nicotine over a 16-hour
(EP 400 078) or a 24-hour period. According to the
teaching of these patents, the full contents of which
are incorporated herein by reference, it is possible to
produce TTSs which are also able to deliver the active
ingredient nicotine over a longer period, for example
3 days. For this purpose it is merely necessary to suit
.the active ingredient content and the thickness of the
active ingredient-containing matrix, and the skin
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_-
contact area of the TTS type used, to the required time
of use .
The release characteristics of various commercially
available nicotine TTSs are described in H. Ho et al.,
Drug Development and Industrial Pharmacy, 19 (3),
295-313 (1993).
The active ingredient nicotine means the naturally
occurring (-)-nicotine. Nicotine has two nitrogen
atoms. The pharmaceutically acceptable salts of
nicotine include the monosalts of salicylic acid, of
phenylpropionic acid or of dodecanoic acid. Also
preferred as active ingredient are nicotine
monoacetate, nicotine sulfate, nicotine hydrochloride,
nicotine valerate, nicotine pivalate, nicotine lactate
etc. This list cannot, of course, be complete.
It is also suitable to mix nicotine (as free base) with
a nicotine salt as active ingredient. This may be the
case if the planned duration of use is relatively long.
This is because free nicotine base permeates more
quickly through the skin than do many nicotine salts.
After a certain time, this leads to exhaustion of the
nicotine in the active ingredient reservoir of the TTS.
The nicotine salt content in the active ingredient
reservoir is exhausted more slowly than is the free
base in the active ingredient reservoir. The salt then
plays a greater part in the delivery of nicotine and
the maintenance of the nicotine level in the blood
plasma at a later time in the use of the TTS.
The constructional elements of the TTS are a backing
layer, an active ingredient-containing layer and a
layer which brings about adhesion to the skin. It is
moreover possible for the TTS to have a structure such
.that the functions of "active ingredient-containing
layer" and "layer bringing about adhesion to the skin"
are achieved in a single layer.
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A further possibility is for the TTS to have a control
membrane located between the active ingredient
reservoir and the layer bringing about the adhesion to
the skin. The control membrane has. the function of
controlling the rate of release of the active
ingredient from the TTS.
The active ingredient may also be present in micro-
encapsulated form in the active ingredient-containing
layer. In this case, the capsule material enveloping
the active ingredient would then take over this
release-controlling function.
The backing layer is impermeable to the active
ingredient and is preferably impermeable to light and
oxygen, in order to prevent chemical decomposition of
the active ingredient by substances penetrating in from
the outside.
The TTS may also have separate active ingredient
reservoirs in a surrounding matrix.
The TTS is able to reach a nicotine level in the blood
plasma above 2 ng/ml within a period of 4 hours after
application.
A TTS is also suitable for reaching an essentially
constant nicotine level in the blood plasma of between
2 and 20 ng/ml after completion of a period of 4 hours
after application. A preferred TTS is one suitable for
reaching an essentially constant nicotine level in the
blood plasma of between 2 and 10 ng/ml after completion
of a period of 4 hours after application.
The method for treating schizophrenia consists of
. sticking a TTS according to the invention onto the
patient's skin and removing it again after the intended
duration of use. This duration of use of a single TTS
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may be 16 hours or 24 hours. TTS for more than one day,
for example for three days of use, are also suitable.
Long-term therapy is worthwhile, i.e. use of such
nicotine TTS according to the invention designed to
last months or years where appropriate.
This type of medical long-term therapy by use of
transdermally supplied nicotine can be applied at the
same time as psychotherapy and/or sociotherapy and/or
medical therapy, in particular with medicines which
specifically block dopamine receptors (olanzapine,
risperidone etc.).
