METERING SPRAY DESIGNED FOR PERNASAL APPLICATION

AEROSOL DOSEUR CONCU POUR ADMINISTRATION D'UN PRODUIT PAR VOIE NASALE

English Abstract

Described is a metering spray designed for
pernasal application, the spray containing at least one sex
hormone or at least one metabolic precursor of a sex hormone
or at least one derivative of a sex hormone or combinations
of these, excepting the precursors of testosterone, or at
least one biogenic amine, with the exception of
catecholamines.

Claims

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THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Use of at least one sex hormone or at least one
precursor of a sex hormone in a metabolic process or at least
one derivative of a sex hormone or of a combination thereof,
apart from the precursors of testosterone or of dopamine, a
dopamine derivative, NADH, NADPH or a combination thereof for
producing a medicament in the form of a dispensing spray for
pernasal application for controlled dosage reduction or for
facilitating the passage through the blood-brain barrier.
2. Use according to claim 1, wherein the dispensing
spray is applied at a dosage of from 2 to 20 mg active
substance per spray stroke.

Description

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METERING SPRAY DESIGNED FOR PERNASAL APPLICATION
The invention relates to the use of novel dosing or metering
sprays for pernasal application.
Numerous pharmaceutical substances have their pharmacodynamic
action in the central nervous system. Thus, the latest
research has revealed that sex hormones and their derivatives
in part reveal unexpected, positive side-effects in the
central nervous system, particularly in that the general
psychophysiological stressability of the patient perceptibly
rises. Other substances, such as certain biogenic amines
have a therapeutic activity which is directly dependent on a
facilitated access to the central nervous system. This is a
decisive action prerequisite for example, for medicaments for
treating Parkinson's disease, such as, for example, dopamine,
dopamine derivatives, NADH or NADPH.
If, as a result of their chemical properties, active
substances undergo modifications in the gastrointestinal
tract due to the varying pH-conditions and enzymatic
processes (such as e.g. most biogenic amines) or if they are
only water-soluble to a limited extent (such as sex hormones)
hitherto complicated galenic administration forms have been
necessary, or it has been necessary to use the parenteral
administration form, which stresses the patient and requires
the calling in of the doctor.
EP-A-272 097 points out that progesterone from the nasal
cavity is absorbed in such a way that the resulting blood
levels are virtually equivalent to intravenous
administration.
EP-A-160 501 discloses an intranasal formulation for
catecholamine, which is suspended fatty acid or ester and
emulsified with polyoxyethylene.
The object of the present invention is to provide an
administration form, which favours the access of certain

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active substances to the central nervous system and therefore
permits a reduction in the single dose and/or supply of
active substances, which cannot be perorally supplied for the
indicated reasons.
According to the invention this object is achieved by a
dosing spray having a content of at least one sex hormone or
at least one metabolic precursor of a sex hormone or a
combination thereof, excepting the precursors of
testosterone, or at least one biogenic amine, excepting
catecholamines.
Particular preference is given to a dosing spray having a
content of dopamine, dopamine derivative, NADH, NADPH or a
combination thereof.
Thus, according to the invention, there is provided a use of
at least one sex hormone or at least one precursor of a sex
hormone in the metabolic process or at least one derivative
of a sex hormone or of a combination thereof, apart from the
precursors of testosterone or of dopamine, a dopamine
derivative, NADH, NADPH or a combination thereof for
producing a medicament in the form of a dispensing spray for
pernasal application for controlled dosage reduction or for
facilitating the passage through the blood-brain barrier.
The preferred dosage is from 2 to 20 mg of active substance
per spray stroke.
Further features and advantages of the invention can be
gathered from the following description of a preferred
embodiment.
Ap~lication of testosterone by means of a dosinq sPraY
The advantages of administration by means of a dosing spray
were tested in comparison with the oral administration of
testosterone.
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The peroral supply of 100 mg of testosterone by means of a
capsule increased the blood level from a starting
concentration between 32.5 and 37.5 nmole/l to values
between 45 and 50 nmole/l. The concentration maximum was
reached 30 minutes after administration, but was subject to
marked individual fluctuations.
The profile of the steroids eliminated in the urine reacted
very strongly and there were increases in the
testosterone/epitestosterone quotient starting from the
normal range between 0.9 and 2.8 to values of up to 60.
The blood level kinetics individually varied widely and in
part 60 to 90 minutes following administration the initial
values were again reached.
When testosterone was administered by means of a nasal spray,
only a dose of 7 or 14 mg per application was needed in order
to achieve the same rise in the blood level.
Application was much better to control. The blood
concentrations which increased in individual test persons in
a stable manner were 1.5 to 2 times the individual starting
concentrations. The time during which the maximum blood
concentration was reached was clearly reduced to from 15 to
a maximum of 90 minutes.
The disturbances in the urine steroid profile were clearly
reduced and the testosterone/epitestosterone quotient only
rose to values between 15 and 20 and was normalized within 24
3 0 hours .
Following pernasal application all the test persons mentionedan improved psychophysiological stressability. This effect
was not observed with peroral administration. It is
attributed to the preferred influencing of the central
nervous steroid receptors, probably caused by easier passage
through the blood-brain barrier in pernasal application.

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A~plication of anti-Parkinson's disease aqents
For therapeutics used in the treatment of Parkinson's
disease, an essential action prerequisite is the passage
through the blood-brain barrier.
Building up on the aforementioned results NADH was pernasally
applied in a pilot study. In pilot studies with parenteral
administration of 5 to 10 mg of NADH (infusion over 30
minutes it was found that the tremor frequency significantly
decreased and both the mobility and target accuracy or aim of
the movements improved. For the same dosage intranasal NADH
application revealed the same action. Thus, it is possible
to avoid the risky, stressing intravenous infusion and
instead to obtain by means of the dosing spray an application
which is more appropriate for the disease and age.
In the case of pernasal application the active substance can
also be available in powder form. As a result of the spray
stroke there is a very fine distribution in the vicinity of
the nose and nasal sinuses, which favours absorption over a
large surface. The galenic formulation as a dry substance
eliminates the problems associated with the keeping quality
and stability of the active substance. The preferred
administration as a nasal spray is consequently particularly
suitable for out-patient therapy of Parkinson's disease.
The features of the invention disclosed in the description
and claims can be essential to the implementation of the
invention in its various embodiments either singly or in
random combination.