Note: Descriptions are shown in the official language in which they were submitted.
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Antlsnoring agent
The invention concerns an anti snoring agent for oral or for
local administration in the nose/pharynx cavities.
Snoring is a phenomenon which is based on rattling breathing,
which may occur with human beings when asleep. Due to the
resultant disturbance to other people, numerous attempts have
been made in the past to remedy this phenomenon.
It was found that the cause of snoring is obstruction or
unevenness in the area of the upper respiratory tracts During
the process of breathing in and oath air is guided via
complex flow paths. Unevenness in the area of these flow
paths necessarily leads turbulence in the air flow. This
results in an obstruction of breathing which is below the
consciousness threshold The obstructions in the flow path
and the turbulence caused thereby have the result that foe-
ally an underpressure(suction) occurs. This unaerpressure
leads to fluttering motions OX soft slack structures in the
area of the airflow python particular there is a reciproc-
cling movement of the soil palate caused by the named turn
balances.
Although numerous investigations have been made to prevent
snoring they have not yet led to the desired success The
basis was provided by agents which were composed on the
foundation of chemotherapeutical or antibiotics,corticoids
or antihistaminics.But these agents have been found not to
Abe active enough to prevent snoring over long periods or
they lowdown taken over the long term, to damage to the
nasal and pharyngal mucous membrane. This applies also to
the tests made earlier using eureka oils such as for ox-
ample menthol, camomile eucalyptus oil etc., in higher
concentration.
, .......
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Only recently has it been possible to show that obstructions
which may be regarded as the cause of the snoring, are formed
especially by the drying out of the mucous membranes or
additional mucous areas with micro fissures due to the deposit
of tough mucous etc.
Canadian patent application ~29,349, filed May 31, l983 from
the same applicant describes an agent for combating snoring
which contains a surfactant substance, a stabilizer and a
substance which softens the mucous membranes in physiological
saline. This agent is to prevent the drying out of the mucous
membranes during the night. To attain this it is necessary to
infuse a certain amount of the agent into the nose-pharynx
cavities before going to sleep.
The object of this invention is to make available an agent
for combating snoring, with which even stubborn cases of
snoring can be prevented, but without the appearance of
damaging side effects due to adverse influences on the nasal
and pharyngal mucous membranes. Especially the noise of
snoring during "common snoring" is to be suppressed.
This object is solved according to the invention by an
anti snoring agent which contains an active content of a
secretolytically and/or secretoproductively active substance
together with the usual mucous membrane-compatible carriers
and/or thinning agents, and which is suitable for oral
administration as well as introduction into the
nose~pharyngal cavities. Preferred is an agent with an active
dose of a secretolytic substance. The oral administration of
the agent according to the invention is especially preferred.
The inventive oral anti snoring agent is distinguished by a
potent content of an active ingredient which excites the
function of the mucous membrane glands of the respiratory
tract with usual carriers or thinning agents.
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Further the invention comprises a process for the use of
the inventive anti snoring agent.
It is especially advantageous when the inventively used
s~cretolytic drug has the hollowing properties:
a) regulation and normalization of the mucus viscosity,
b) reduction of mucus adhesion by the activation of en-
ogenous surfactant properties of the secretion,
c) stimulation of the serious mucus production and
d) activation of the operation of the mucoc~liary lung-
lion.
According to the invention suitable secretolytic drugs
are known in the prior art These known drugs are used
in the treatment of illnesses of the respiratory tract,
which are accompanied by pathologically altered secretion
and applied in the form of tablets etc. or
which axe administered orally as juices.
According to the invention it has now been found surpri-
singly that by the use of suitable secretoly'ic drugs, the
snoring which is not an illness but is US described above,
i.e. a troublesome phenomenon for other people, can be
prevented or reduced. The preferred orally administered
secretolytic drugs lead to a stimulation of the mucous
membrane glands in the respiratory tract whereby a Lowe-
faction of tough mucus in the nasal and pharyngal cavity
and/or a stimulation of the mucus secretion is caused,
which prevents the drying out of the mucous membranes and
the formation of microIissures.sut also by the infusion or
use of a spray device the inventive agent can be applied
to the mucous embrace of the nasal/pharyngal cavities.
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It is partially absorbed by the latter, so that both be-
cause of the absorbed secretolytic substance and due to the
effect of the moistening of the nasal/pharyngal mucous
membrane it bucksaws effective The secretolytic drug Abe
sorbed by the nasal and pharyngal mucous membrane causes
A stimulation ox the mucous membrane glands whereby the
result is a liquefaction of tough mucus which covers the
mucous membrane, and/or it leads to a stimulation of the
mucus secretion, whereby the drying out of the mucous -
membranes and the formation of micro fissures therein are
prevented.
Among the known secretolytic drugs which are suitable
according to the invention are inter aria the compounds brow
Maxine, ambroxol,eprazinon, carbocistin, Nastily
Sistine as well as supineness which are contained e.g. in
radix senegae,radix saponariae and radix liquiritiae,
as well as substances containing carbohydrates made from
radix altae,lichen Islandicus, folio Malvae or carrageen
with special preference for bromohexin and ambroxol.
.
The above agents can be used as such or in the form of
their pharmaceutically compatible salts.
:
The anti snoring agent according to the invention can be
administered in various galenic forms Specially prefer-
red airfare long-term activity, tablets, capsules coated
tablets compressed tablets,granulates,microcapsules etc.
But it is also possible to administer the oral anti-
snoring agent in the form Ox drops or as a juice.
For local application, it is preferably formulated in
drops as a spray or as an inhalation solution.
The total dust be administered to 2 snorer of the
active ingredient depends on the respective efficiency
of the active substance used as well as on the form of
I .
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application and is in general within the range between
5 and 500 mg,the preference being for between 10 and
100 mg.This dose should be contained in an amount of-
from 0.5 to 2 ml of the inventive agent, preferably
from 0.5 to 1.0 ml.
In the case of the administration of a~broxol,the
especially preferred range is a dose of active inured-
tent of from 30-100, with preference for from 50 to 100
my. Tests using 30-60 my ambrcxol-HCl produced excellent long-term
effects in suppressing snoring Using Lyman the preferred range
of the active drug is 8-30 mg.Usina carbocis~i~n in Audis of 200-400
my is preferably chosen.
To achieve a long-term effect lasting through the night
it is advisable to formulate the inventive anti snoring
agent in the retard form For this purpose the active in-
gradient must be formulated with adjutant substances so
that it is only released very slowly, which can be of-
footed e.g. by embedding it in a very slyly dissolving
matrix. Moreover it is possible to form the active in-
gradient with adjutants to make tablets,pellets,granul-
ales or any spheroid particles or compressed tablets,
` which are then coated with a suitable covering which
causes a slow release of the active ingredient in the
stomach and/or intestinal tract. From the galenic view-
point the active ingredient for retard form should be
formulated so that there is no change in the resorption
speed in the resorptive part of the stomach-intestinal
tract. In many cases it has been found that the active
ingredient should be mixed with an emulsifier and optionally
- - coated with an acid-insoluble coatings that the active
ingredient is released in the intestinal juices in sol-
utilized form.
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.
In addition it is possible to administer a two-phase
preparation in which e.g. a coated tablet containing
60 my of ambroxol-HCl has an insulated core of 30 go
ambroxol-HC r which is only freed after 3 to a hours,
while the coating dissolves at once.
To the extent that the above secretolytic drugs are no-
sorbed in the stomach or intestinal tract in inadequate
quantities, it is recommended that the active ingredient
should be used in a mixture with resorption-increasing
substances or those which positively influence the pi .
Such a galenic formulation is selected e.g. when using
brom~hexin.It is advantageous to mix the active ingredient
with an acid or an acidic substance in the form of
granules, tablet cores, micro capsules etiquette do this,
1 mow of active ingredient is mixed with 1 to 60 moles
preferably S to 30 moles of acid or of the acidic sub-
stance. Such formulations are described in detail in
DE-A 31 26 703 to which we expressly Rafferty is prefer-
able to pour the preparations containing the active in-
gradient into hard gelatin capsules whose decomposition
and thus the resorption of the active ingredient take
place in the intestinal tract. Therefore the secretolytic - -
drugs are prepared in a form which is surrounded by an
acid-insoluble but intestinal-juice soluble coatings
specially suitable substances of this type are described
in the DE-A 31 26 703 named above to which we refer here.
Special mention is made of: methacrylic acid methacryl-
acid-ester mixed polymerisate,hydroxypropylmethyl-cell-
ulosephthalate or celluloseacetatesuccinate.
The measure of surrounding the preparation containing the
active ingredient with an acid-insoluble but intestinal-
juice soluble coating or a corresponding hard gelatin
capsule is especially suitable for making retard forms.
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.
In this way the partially very good sealability of the in-
vent ion's secretolytic drugs is taken into accountant
only slowly are they released in this manner This method
can achieve the presence of the secretolytic drug for
some hours in dissolved and resorption-capable form.
The retard forms of the secretolytic bro~ohexin and am-
broccoli on the market, known by the trade names bisolvon
and mucosolvan,are especially suitable as anti snoring
agents according to the invention.
The preparation ofnon-retarding tablets coated tablets,
etc. is done by processes known per especially ad van-
tageous is administration of micro capsules surrounded
by a coating layer, since the breakdown of the active
dose takes place into many hundreds of independent small
retard forms and thereby an even release of the active
agent is ensured.
Preferably mucous membrane-compatible additives which can
increase the effect of the active substance or otherwise
have a favorable effect on the nasal/pharyngal mucous
membrane or which protect the inventive anti snoring agent
from contamination, are added to the galenic formulations
for local use, apart from the active ingredient.
The invention provides that a preservative agent may be
added to the local anti snoring agent By the presence of
a preservative especially after its entry into use and
long storage, the anti snoring agent can be protected
against micro bacterial impurities.
It is especially preferred when the added preservative,
which must be mucous membrane-compatible,can take effect
via a function for the prevention of microbial growth
in the anti snoring agent as a bactericide and/or fungi-
aide on the mucous membranes of the nose/pharynx cavities.
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To the extent that the preservative used as mucous mom-
brine -compatible does not have this effect or only acts to
an inadequate extent, it is advisable to add to the agent
a suitable substance acting as a mucous membrane Dyson-
fectant bactericidal and/or fungicidally on the nasal
end pharyngal mucous membranes.
us the preservative in the local antisnorin~ agents act
cording to the invention all the preservatives generally
used in pharmaceutical preparations can be used which
prevent microbial growth and do not irritate the mucous
membranes of the nasal and pharyngal cavities Suitable
preservatives are e.g. ethanol esters of p-hydroxy bent
zoic acid,2-phenoxyethanol,benzoic acid and its salts,
sorbic acid and its esters etc.
Suitable mucous membrane disinfectants which may act
both as disinfectants as well as antiseptic drugs include
acridine and quinoline derivatives, qua ternary ammonium come
pounds as well as compounds with amidine structures.
. .
Especially good results were obtained according to the
invention by an additive of benzalconium chloride which
is a mild mucous membrane-compatible disinfectant.
This substance impedes any possible rapid new obstruction
in that it wards off irritation due to impurities of the
nasal mucous membrane and thereby reduces it. Fast and
excessive mucus formation would again _ in connection with
drunker possibilities of the mucus - initiate prematurely
the snoring process.
Apart from the named benzalconium chloride other quatrain-
cry amine, to the extent that they are not incompatible
with mucous membrane, are suitable as the disinfectants
in the agents of the invention.
I
The use of benzododecinium has also been found suitable as a
further mucous membrane disinfectant. The addition of
chlorobutanol, a compound which has both bactericide as well
as funglstatic properties, is suitable as the fungi statically
active agent.
The preservatives are added to the agents of the invention
for local use, optionally together with bactericide or
fungicide substances, in a concentration of from 0.1 to I
based on the total weight of the agent. Preferably the amount
of the concentration of bactericide and/or fungi static
compounds is from 1 to 5 my based on 1000 ml of the agent of
the invention.
Moreover the inventive agent for local use contains
substances which exert a smoothing or softening effect on the
nasal and pharyngal mucous membranes.
The object of this softening substance is to prevent or
reduce the micro fissures in the mucous membrane.
For this the polyalcohols are e.g. suitable which prevent the
surface drying of the mucous membrane and moreover reduce the
surface tension of the water phase. Suitable polyalcohols
include ethylene glycol, diethylene glycol, propylene glycol,
dipropylene glycol, glycerol, diglycerine, sorbitol, while
glycerine and sorbitol are especially suitable.
Moreover the use of panthenol has also been found
advantageous for smoothing the mucous membranes. It is mucous
membrane-compatible and has an effect similar to that of
pantothenic acid. Panthenol also has a regenerating surface
effect on the mucous membranes.
These substance(s) for softening or smoothing the mucous
membranes are present in the inventive agents in a
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concentration of from 0.1 to I by weight based on the total
weight of the agent. The preferred concentration range is
from 0.2 to I by weight.
Mucous membrane-compatible substances which prevent the
formation of micro fissures or favor the removal of or
dissolution of disturbing substances can also be added to the
agents of the invention. In this since it is advantageous to
add to the inventive agent a mucous-membrane-compatible
enzyme preparation which promotes the dissolution of the
disturbing substances. In particular hydrolytic enzymes,
lapses, and pro teases are suitable as the enzymes. It is
preferable to use enzyme preparations which have at least
approximately their optimal pi value in the pi range to be
found on the nasal and pharyngal mucous membranes, and which
under these conditions are as stable as possible.
Moreover to the inventive anti snoring agent for local use,
apart from the active ingredient, which is secretolytic in
effect, etheric oils as well as mixtures thereof can be
added. Especially preferred is the use of
ol.thymi,ol.anisi,o].ellcalypti,ol.camomi]le,ol.meenthae, and
ol.terebinthiniae. Further the anti snoring agent for local
use can contain substances which support the secretolytic
effect of the active ingredient or which otherwise have a
favorable effect on the properties of the nasal pharyngal
mucous membrane. Especially vitamin A and vitamin E should be
named. The presence of vitamin A is found successful due to
its regenerative influence on tissue formations, while
vitamin E counters all kinds of degeneration, detoxifies,
raises the resistance and regenerates the mesenchymal area,
which causes a vegetative torus increase. In the case of
addition of vitamin A to the inventive anti snoring agent, the
amount used is from about 15000 to 30000 IE/ml. Vitamin E can
be added e.g. as acetate to the inventive agent in an amount
of cay 20-200 mg/ml.
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Special preparation forms of the inventive anti snoring agent
for oral and local use are listed below. The prescriptions
below represent some preferred examples from the abundance of
possible formulations; they serve to explain the invention,
without limiting its scope.
Formulation 1
.
The following composition is prepared for the production of
capsules:
ambroxol-hydrochloride 10.0 g
maize starch (dry) 24.0 g
aerosol 200 0.4 g
The con-tents are mixed, passed through a 0.75 mm screen, and
poured into about 200 hard gelatin capsules with a capsule
filling weight of 170 my.
Formulation 2
Tablets of the following composition were prepared:
1 tablet contains:
Carbocistin 300 my
lactose 50.0 my
Maize starch 50.0 my
polyvinylpyrrolidon 2.0 my
magnesium Stewart 1.0 my
The active agent is mixed with lactose and maize starch
moistened with an aqueous PUP solution, the mixture is passed
through a screen of 1.5 mm and the granulate is dried. After
admixture of the lubricant the tablets are pressed.
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Formulation 3
.. ..
.
To prepare an oral anti snoring agent in retard form
the following pellets were prepared:
First pellets are prepared using alcoholic polyvinyl
pyrrolidon solution, tartaric acid talc and the active
ingredient bromohexin, with about 0.8 mm diameter which
contain cay 20~ of bromohexin and about 75% of tartar-
to acid.
The above dried pellets are then sprayed in a coating
pan with a solution of methacrylic acid-methacrylic acid
ester-mixed polymerized vowel) and hydroxypropyl-
methylcellulosephthalate in isopropanol/acetate in a
ratio of pellet to coating of 10:1, wherein as the soft-
ever Tristan is used.
Formulation
The following solution for infusion in the nose is pro-
purred to 1 ml per nostril):
ambroxol-HCl 10.0 g
glycerine 1.0 ml
benzalconium chloride 1.0 g
physiological saline up to 100 ml.
Formulation 5
props with the following composition were prepared:
.. _ . .. _ .. _ _ _ . .. _ .. . _ .. _ . .. , _ . .. . . . . . . .. .. . . . .. . .. . .. . . . . _ .
Bryan 1.2 g
glycerol 1.0 ml
chlorobutanol 1.0 g
ol.camomille 0.2 g
physiological saline up to 100 g.
.
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To prevent snoring respectively 0.5 to 1 ml are infused
in each nostril. I
The invention further comprises a process for local
application of the inventive agent for combating snoring
which consists of the fact that the agent is applied
in adequate amount to the nasal and pharyngal mucous
membranes by means of a suitable device. To achieve the
effect desired relatively small quantities of the invent-
ivy agent are enough, amounting to from cay 0.2 to 2 ml.
Preferably the inventive agent is applied in an
amount of from 0.5 to 1.0 in the nose and pharynx area.
For this purpose the agent according to the invention
is introduced by infusion or by spraying into each nosy
trip using a suitable device or a suitable instrument,
so that the liquid is applied to the nasal and pharyngal
mucous membranes. Suitable devices for the performance
of the process are known. For example the agent can be
applied by an aerosol device by an atomizer, a rinsing
pipette or by pipette flasks containing the agent.
The agent is used in the evening before going to sleep,
either when lying or standing, but preferably with head
tilted backwards If this is necessary, the use can be
repeated during the night.
The tests of the agent according to the invention which
have been made on human beings have shown that it does
not cause any incompatibilities, not even when taken
over longer periods, because the components in the cited
concentrations are not toxic and are already Used in
rhino logy as such.
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