CA1223210A

CA1223210A - Antisnoring agent

Info

Publication number: CA1223210A
Application number: CA000453961A
Authority: CA
Inventors: Dietrich Reichert
Original assignee: Individual
Current assignee: Individual
Priority date: 1983-05-13
Filing date: 1984-05-09
Publication date: 1987-06-23
Also published as: CH662734A5; ZA843502B; JPS6034909A; DE3317530A1

Abstract

Abstract Antisnoring agent for oral or local application in the nasal/pharyngal cavities comprising an active content of a secretolytically and/or secretoproductively effect-ive substance, as the active ingredient, together with carrier substances for diluents which are compatible with mucous membranes.

Description

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1- i 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.
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The above agents can be used as such or in the form of their pharmaceutically compatible salts.
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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 .
: 5 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.
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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.

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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 ~23~

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 .. ..
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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:
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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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Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. Antisnoring agent for oral administration or for local administration in the nose/pharynx cavities,c h a r a c t-e r i z e d by an active content of a secrolytically and/or secretoproductively active substance together with the usual pharmaceutically compatible carrier substances or extension and/or thinning agents.

2. Antisnoring agent as in claim 1, characterized by an active content of a secretolyticum as the active ingredient together with the usual pharmaceutically compatible carrier substances and/or extension and/or thinning agents.

3. Oral antisnoring agent as in claim 1,characterized in that it is present in the form of a solid preparation.

4. Oral antisnoring agent as in claim 3, characterized in that it is present in the form of tablets, coated tablets,capsules or microcapsules.

5. Antisnoring agent as in claim 1, characterized by an active content of bromohexin.

6. Antisnoring agent as in claim 1, characterized by an active content of ambroxol.

7. Antisnoring agent as in claim 1, characterized by an active content of eprazinon.

8. Antisnoring agent as in claim 1, characterized by an active content of a saponin.

9. Antisnoring agent as in claim 1, characterized by a content of N-acetyl-L-cystein.

10. Antisnoring agent as in claim 1, characterized by an active content of carbocistin.

11. Antisnoring agent as in the claims 1 to 3, characterized in that the total active dose is between 5 and 500 mg.

12. Oral antisnoring agent as in claim 1, characterized in that it contains as additive apart from the active ingredient an acid or an acidic substance.

13. Oral antisnoring agent as in claim 12, characterized in that per 1 mole of active ingredient it contains 1 to 60 mole of acid or of acidic substance.

14. Oral antisnoring agent as in claims 1 to 3, characterized in that the solid preparation form containing the active ingredient is surrounded by an acid-insoluble coating composition which is soluble in the intestinal juices.

15. Oral antisnoring agent as in claims 1 to 3, characterized in that the solid preparation containing the active ingredient is filled into hard gelatine capsules.

16. Oral antisnoring agent as in claim 1, characterized in that it contains an etheric oil or a mixture of etheric oils.

17. Oral antisnoring agent as in claim 16, characterized in that it contains an etheric oil from the group ol.thymi, ol.anisi, ol.leucalypti, ol.terebinthiniae, ol.camomillae, ol.menthae.

18. Oral antisnoring agent as in claimls 1 to 3, characterized in that it contains apart from the active ingredient one or more of the substances from the group vitamin A and vitamin E.

19. Oral antisnoring agent as in claim 1, characterized in that it is formulated in the retard form.

20. Oral antisnoring agent as in claim 19, characterized by a composition consisting of 20%
bromohexin-hydrochloride, 75% tartaric acid and 5% talc.

21. Oral antisnoring agent as in claim 1 in solid preparation form, characterized by the following composition:
ambroxol-hydrochlorid 50 to 150 mg maize (corn) starch 120 mg aerosil 200 2 mg

22. Antisnoring agent as in claim 1 for local administration characterized in that it is present in the form of drops, spray or as an inhalation solution.

23. Antisnoring agent for local administration as in claims 1 and 22, characterized in that it contains a preservative.

24. Antisnoring agent for local administration as in claim 1, characterized in that it contains a mucous membrane disinfectant.

25. Antisnoring agent for local administration as in claim 1 and 24, characterized in that the mucous membrane disinfectant is chosen from the group benzalconium chloride and chlorobutanol.

26. Antisnoring agent for local administration as in claim 1, characterized in that it contains a substance softening the nasal and pharyngal mucous membrane.

27. Antisnoring agent for local adinistration as in claim 26, characterized in that it contains as a substance softening the mucous membranes glycerine and/or panthenol.

28. Antisnoring agent for local administration as in claim 1, characterized in that it contains an etheric oil or a mixture of etheric oils.

29. Antisnoring agent for local administration as in claim 1 in the form of drops, characterized in that it has the following composition per ml:
ambroxol-hydrochloride 50 to 150 mg glycerine 0.01 ml benzalconium chloride 0.02 mg remainder: physiological saline.