UTILISATION D'AU MOINS UNE SUBSTANCE A BASE DE NICOTINE ET/OU D'UNE SUBSTANCE PRODUITE A PARTIR DE LA SUBSTANCE PRECITEE ET DESTINEE A LA PREPARATION D'UN MEDICAMENT ET METHODE DETRAITEMENT DE MALADIES PULMONAIRES OBSTRUCTIVES

USE OF AT LEAST ONE SUBSTANCE BASED ON NICOTINE AND/OR A SUBSTANCE PRODUCED FROM SAID ONE SUBSTANCE FOR THE MANUFACTURE OF A MEDICAMENT, AND A METHOD FOR TREATMENT OF OBSTRUCTIVE LUNG DISEASE

Abrégé français

L'invention concerne l'utilisation d'au moins une substance à base de nicotine et/ou d'une substance produite à partir de la substance précitée et destinée à la préparation d'un médicament à administrer à une personne ou à un animal afin de neutraliser, de manière prophylactique ou thérapeutique, des maladies pulmonaires obstructives, en particulier l'emphysème pulmonaire. Le médicament est conçu pour être libéré dans le sang et administré par le tube digestif, par voie transdermique, intravasculaire, intranasale ou intravaginale. L'invention concerne également une méthode de traitement prophylactique ou thérapeutique de maladies pulmonaires obstructives chez une personne ou un animal, selon laquelle on administre à cette personne une substance à base de nicotine.

Abrégé anglais

The invention refers to a use of at least one substance based on nicotine
and/or a substance produced from said one substance for the manufacture of a
medicament to be supplied to an individual of a human being or an animal for
the purpose of counteracting, in a prophylactic or therapeutic manner,
obstructive lung diseases, in particular pulmonary emphysema. The medicament
is intended to be supplied via the blood path and to be administered via the
gastrointestinal tract, transdermally, intravascularly, intranasally or
intravaginally. The invention also refers to a method for prophylactic or
therapeutic treatment of obstructive lung diseases of an individual of a human
being or an animal, wherein said individual is supplied with a nicotine-based
substance.

Revendications

8
Claims
1. Use of at least one substance based on nicotine and/or a
substance produced from said one substance for the manufacture
of a medicament to be supplied to an individual of a human being or
an animal for the purpose of counteracting obstructive lung
diseases in a prophylactic or therapeutic manner.
2. Use according to claim 1, wherein the medicament is supplied
via the blood path.
3. Use according to claim 2, wherein the medicament is intended
to be administered via the gastrointestinal tract.
4. Use according to claim 2, wherein the medicament is intended
to be administered transdermally.
5. Use according to claim 2, wherein the medicament is intended
to be administered intravascularly.
6. Use according to claim 2, wherein the medicament is intended
to be administered intranasally.
7. Use according to claim 2, wherein the medicament is intended
to be administered intravaginally.
8. Use according to any one of the preceding claims, wherein
said purpose is to counteract pulmonary emphysema.
9. Use according to any one of the preceding claims, wherein
said nicotine-based substance includes substantially pure nicotine.
10. Use according to any one of the preceding claims, wherein
said nicotine-based substance includes nicotine derivative,
intermediate metabolites of nicotine or degradation products of
nicotine.

9
11. Use according to any one of the preceding claims, wherein
said one substance based on nicotine and/or substances produced
from said one substance are absorbed by a binding agent.
12. Use according to any one of the preceding claims, wherein
said individual has a congenital bilateral bronchial anomaly.
13. A method for prophylactic or therapeutic treatment of
obstructive lung diseases of in individual of a human being or an
animal, wherein said individual is supplied with a nicotine-based
substance.
14. A method according to claim 13, wherein the medicament is
supplied via the blood path.
15. A method according to claim 14, wherein the medicament is
intended to be administered via the gastrointestinal tract.
16. A method according to claim 14, wherein the medicament is
intended to be administered transdermally.
17. A method according to claim 14, wherein the medicament is
intended to be administered intravascularly.
18. A method according to claim 14, wherein the medicament is
intended to be administered intranasally.
19. A method according to claim 14, wherein the medicament is
intended to be administered intravaginally.
20. A method according to any one of claims 13 to 19, wherein
said individual has a congenital bilateral bronchial anomaly.

Description

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Use of at least one substance based on nicotine andlor a
substance produced from said one substance for the
manufacture of a medicament, and a method for treatment of
obstructive lung diseases
THE BACKGROUND OF THE INVENTION AND PRIOR ART
The present invention refers to a use of at least one substance
based on nicotine andlor a substance produced from said one
substance for the manufacture of a medicament to be supplied to
an individual of a human being or an animal. The invention also
refers to a method for prophylactic or therapeutic treatment of
obstructive lung diseases of in individual of a human being or an
animal.
Pulmonary emphysema is a common disease, which in particular
affects smokers. The disease is characterised by a permanent
expansion and destruction of the finest bronchi and the walls of the
alveoli. Pulmonary emphysema is a very serious disease and the
destruction process is irreversible so that the disease leads to
increasing respiratory difficulties.
Pulmonary emphysema belongs to a group of diseases usually
called obstructive lung diseases due to the fact that the disease
obstructs the flow in the respiratory tracts. The obstruction is the
underlying cause also to pulmonary barotrauma, including
spontaneous pneumothorax. These diseases have symptoms and
localised effects to the lung tissue similar to pulmonary
emphysema.
During normal inhalation the bronchi are expanded, which
counteracts the obstruction to a certain extent. During the following
exhalation the lung tissue is compressed, including the bronchi, and

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a somewhat smaller gas volume may therefore flow through the
respiratory tract. This leads to a valve effect when a certain balance
arises. By a certain overpressure in the respiratory tracts and the
lung, the obstruction may be overcome and the inhaled gas volume
be emptied. The pressure in the lung is however not sufficient for
completely emptying the lung. There is always a certain amount of
air (residual volume; normally about 500 ml of an adult) in the lung
after the first breath. This balance depends inter alia on and is
influenced by the ambient air pressure; the more the weaker the
respiratory tracts, especially for early born, immature children.
During smoking the mucous membrane in the respiratory tracts and
bronchi is irritated, which leads to a swelling of the mucous
membrane. This swelling decreases the lumen of the respiratory
tracts, i.e. the obstruction arises and thus the air flow in the
respiratory tracts is restrained. This leads to an increase of the so-
called valve effect, to a higher pressure in the respiratory tracts and
the lung, and to a larger residual volume in the lung. The increase
also leads to a destruction of tissue, which further reduces the gas
exchange, i.e. the breathing capacity. If nicotine or nicotine-like
substances are supplied, not via the respiration, a vessel
contracting, decongestant effect, which reduces the obstruction, is
obtained.
Pulmonary barotrauma appears due to such a tissue destruction by
the inner pressure. Pulmonary barotrauma may principally refer to
one single alveolus or a smallest respiratory tract, or several small
alveoli within the lung. If this tissue destruction process is expanded
to the whole lung it is called pulmonary emphysema. In the cases
when air is collected diffusely in the lung tissue proper, we have an
interstitial emphysema or in a delimited way, a bulls (blister). If the
air is collected adjacent to the pleura in a delimited manner we
have a subpleural bleb. The air may also come to the
intrapulmonary space and we have a so-called pneumomediastinum
or into the heart sack; pneumopericardium. If the tissue destruction
is expanded so that the pleura is destroyed, we have a
spontaneous pneumothorax (SP). With regard to the fact that

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pathophysiological changes in the lung are documented in case of
SP, it is not any longer relevant to call SP a disease of the pleura.
The obstruction leads to an expansion in a lung part and thus to a
compression of the surrounding lung part. Such an expansion and
compression is irreversible for a smoker even if he would stop
smoking. If the surrounding compressed lung part is very large,
surgery could be considered for removing a large significant blister
and thus create space for the respiratory work. However, it is very
rare that a patient is suitable for such an operation, whereby an
expected effect is far from being optimal.
The destruction of tissue may be localised to the upper part of the
lung, due to bronchial anomaly at spontaneous pneumothorax or to
the lower part of the lung at alfa-1-antitrypsin AAT-deficiency. AAT
is an enzyme protecting the elastic fibres of the lung. The fibres are
subjected to the largest load in the lower part, where the largest
expansion of the lung takes place when we breathe. if the
protecting effect ceases, the elasticity is lost and this can be easily
seen on the most stressed tissue part.
The destruction may also be general without anomaly or AAT-
deficiency due to smoking.
Bilateral bronchial anomaly is an anatomical congenital obstruction
with a characteristically changed branching structure of the
respiratory tracts and this obstruction may be increased by
smoking. Bilateral bronchial anomaly may today be shown by
diagnostic methods known per se, for instance by means of X-ray
pictures disclosing the bronchial structure of a patient. The
respiratory tracts consist of bronchi, which from the main bronchus
are divided to smaller and smaller bronchi. The first bronchus forms
the bronchus of the first generation, the bronchi after the first
division are called the bronchi of the second generation, after the
second division the bronchi of the third generation, etc. Bilateral
bronchial anomaly means that the bronchi of the third generation
are missing in an individual and are replaced by very characteristic,

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irregular narrowing connections. The air exchange to and especially
from the alveoli will thus be hampered by this defect bronchial
structure, which is identifiable.
SUMMARY OF THE INVENTION
The object of the present invention is to provide a means, which
counteracts such obstructive lung diseases in a prophylactic or
therapeutic manner.
This object is obtained by the use of at least one substance based
on nicotine and/or a substance produced from said one substance
for the manufacture of a medicament to be supplied to an individual
of a human being or an animal for the purpose of counteracting
obstructive lung diseases in a prophylactic or therapeutic manner.
The applicant has realised that nicotine, if it is not supplied via the
respiration, has an inhibitory effect on the development of
respiratory tract obstruction followed by the irreversible substance
loss, elasticity loss and expansion of the lung tissue, i.e. the
negative effects arising from pulmonary emphysema, pulmonary
barotrauma and spontaneous pneumothorax. By supplying nicotine
to the body of the persons suffering by pulmonary emphysema, it is
thus possible to prevent or delimit the development of the disease.
Nicotine also ought to have a prophylactic effect, i.e. the origin of
pulmonary emphysema of persons having a risk to be effected by
this disease, for instance smokers, which have stopped smoking,
may be prevented by the supply of nicotine, however not via the
bronchi, respiratory organs.
The definition at least one substance based on nicotine andlor a
substance produced from said one substance is to be given a broad
interpretation and in this definitian are included substantially pure
nicotine, nicotine compounds, nicotine related compounds, nicotine
derivatives, intermediate metabalites of nicotine and/or nicotine
compounds, degradation products from nicotine or nicotine
compounds with completely or partly identical, similar effects.

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Nicotine acts via nicotine receptors partly in the vegetative system
and partly in the muscles. The nicotine has firstly an irritating
(vasoconstrictive) effect on the blood vessels. The vasoconstriction
5 leads to a decongestion of the mucous membrane in the respiratory
tracts, which counteracts the obstruction. If nicotine is supplied in
significantly higher doses than intended by the present invention, a
paralysis (vessel relaxion) arises via the vegetative ganglions and
the central nervous system.
According to an embodiment of the invention, the nicotine is to be
supplied via the blood. It is essential that the nicotine reaches the
lungs via the blood and not via the respiration. The positive effect of
nicotine to the disease pulmonary emphysema can thus not be
obtained if nicotine is supplied via tobacco smoke. However, it is
not excluded that nicotine has a positive effect if it is supplied to the
blood immediately at the same time as the patient is smoking even
if the positive effect in this case will be reduced.
According to a further embodiment of the invention, the nicotine
may be administered via the gastrointestinal tract, transdermally,
intravascularly, intranasally or intravaginally. The nicotine may thus
be supplied in various manners except via the respiratory tracts and
the lungs. For instance, the nicotine may be supplied by means of
plasters, spray, suppository, pills to be swallowed or in the form of
chewable tablets or oral tablets, which are known in connection with
smoking cessation. According to a further example, the nicotine
may be administered by means of inhalation in such a way that
most of the nicotine is taken up by the mucous membranes in the
mouth (gastrointestinal tract).
According to a further embodiment of the invention, said substance
based on nicotine and/or substances produced by said one
substance are absorbed in a binding agent. Such a binding agent
may permit a slow administration of the active nicotine substance,
so-called "slow release".

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According to a further embodiment of the invention, the use is
intended for said individual, which has a congenital bilateral
bronchial anomaly. As mentioned initially, the destruction of the
lung tissue, due to smoking, may be general without anomaly or
due to AAT-deficiency. The applicant has however realised that the
risk of serious obstructions in the lungs, which leads to pulmonary
barotrauma, such as spontaneous pneumothorax and pulmonary
emphysema, is substantially higher for smokers having a congenital
bilateral bronchial anomaly than for smokers not having such an
anomaly. This risk ought to be in the order of 2000-3000 % higher
for smokers with, than smokers without bilateral bronchial anomaly.
The formed structure of a bilateral bronchial anomaly is associated
with a different function, such as ventilation, perfusion, and a high
sensibility for external factors, such as smoking.
The object is also obtained by a method for prophylactic or
therapeutic treatment of obstructive lung diseases of an individual
of a human being or an animal, wherein said individual is supplied
with a nicotine-based substance.
DESCRIPTION OF EMBODIMENTS OF THE INVENTION
Investigations have been made showing an inverted correlation
between smoking habits of pregnant women and the risk of
pulmonary barotrauma of the new-born children of the women.
Thus, new-born children of smoking women have a lower
predisposition to get pulmonary barotrauma than new-born children
of women which are not smoking. Investigations also show that
foetuses of women which smoke have nicotine in the blood. This
inverted relation thus indicates that nicotine may counteract
obstructive lung diseases.
It is known to use nicotine, i.e. 3-(1-metyl-2-pyrrolidyl) pyridine for
smoking cessation, i.e. for reducing the abstinence complaints. The
use now proposed according to the present invention may thus be
regarded as a second medical indication. The medical effect
mentioned above may be obtained for smokers which are smoking,

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smokers which are giving up their smoking, smokers which have
giving up their smoking until this disease risk is reduced, individuals
with a lung obstruction and when one wishes to reduce the
obstruction in remaining parts of the lungs andlor no other
treatment is available.
It is of course important that the quantity of nicotine supplied is
adapted to the individual to receive the medicament. A suitable
dosing for obtaining the desired effect may be 1-100 mgl24h,
preferably 5-50 mgl24h, for instance 7mg/24h, 14mg/24h or
21 mg/24h. These doses refer to a medicament with nicotine in
substantially pure form.
Such a dose may for instance be obtained by means of tablets of
the type called "slow release". Such tablets may contain a binding
agent permitting a slow release of the active nicotine substance.
The tablets are suitably designed in such a way that the patient may
take one or two tablets per 24h. The dose may also be obtained by
the plasters mentioned above or chewable tablets which also may
contain flavouring substances, consistency agents and/or any
binding agent having an ability to bind nicotine and permit the
release thereof at a suitable speed. The nicotine may be present in
a substantially free form in such a binding agent, be chemically
bounded to any substance or any nicotine compound or as a
nicotine derivative.
In contrast to the medicament for smoking cessation, there is no
desire of the present invention to obtain any quick addition when
the patient suffers from abstinence but rather a slow and over the
time uniform dosing speed in order to obtain an equal plasma
concentration and bioavailability.
The invention is not limited to the examples given but may be varied
and modified within the scope of the following claims.