CH668188A5

CH668188A5 - Corticosteroid ointment compsns. - comprise e.g. dexamethasone in poly:alkylene glycol base, and are used esp. for treating rhinitis

Info

Publication number: CH668188A5
Application number: CH231686A
Authority: CH
Inventors: Franz Rappai
Original assignee: Franz Rappai
Priority date: 1986-06-09
Filing date: 1986-06-09
Publication date: 1988-12-15

Abstract

Ointment compsns., esp. for treating allergic and vasomotor rhinitis, contain (a) at least one steroid (I) of the 16-methyl-1,4-pregnadiene-3,20-dione series and (b) an ointment base comprising mainly a physiologically acceptable component (II) which is liq. or semi-liq. at body temp. and is capable of reducing surface tension. (I) is pref. dexamethasone (Ia) or its derivs., e.g. the t-butyl acetate, or beclomethasone (Ib) or its derivs., e.g. the 21-acetate or dipropionate. (II) is a polyalkylene glycol, esp. a polyethylene glycol (PEG) mixt., opt. mixed with a higher fatty alcohol. The compsns. may also contain preservatives and/or NaCl. ADVANTAGE - Unlike conventional nasal sprays, the ointments do not cause drying of the nasal mucosa.

Description

       

  
 

**WARNUNG** Anfang DESC Feld konnte Ende CLMS uberlappen **.

 



      PATENTANSPRÜCHE   
1. Mittel in Salbenform, insbesondere zur Behandlung von allergischen und vasomotorischen Rhinitiden, dadurch gekennzeichnet, dass es mindestens eine Steroidverbindung der 16-Methylpregna-1,4-dien-3,20-dion-Reihe und eine Salbengrundlage, welche zur Hauptsache aus einer bei Körpertemperatur flüssigen oder halbflüssigen, die Oberflächenspannung herabsetzenden, physiologisch annehmbaren Komponente besteht, enthält.



   2. Mittel nach Patentanspruch 1, dadurch gekennzeichnet, dass die Salbengrundlage zur Hauptsache aus Polyalkylenglykolen besteht.



   3. Mittel nach Patentanspruch 1 oder 2, dadurch gekennzeichnet, dass die Polyalkylenglykole aus einem Gemisch von Polyäthylenglykolen von verschiedenem Molekulargewicht bestehen.



   4. Mittel nach einem der Patentansprüche 1 bis 3, dadurch gekennzeichnet, dass die Salbengrundlage ausserdem mindestens einen höheren Fettalkohol wie z.B. Cetylalkohol und/oder Stearylalkohol enthält.



   5. Mittel nach einem der Patentansprüche 1 bis 4, dadurch gekennzeichnet, dass es ausserdem ein Konservierungsmittel enthält, z.B. ein Salz- oder einen Ester der Benzoesäure.



   6. Mittel nach einem der Patentansprüche 1 bis 5, dadurch gekennzeichnet, dass es ausserdem Natriumchlorid, vorzugsweise in Form von Meersalz, enthält.



   7. Mittel nach einem der Patentansprüche 1 bis 6, dadurch gekennzeichnet, dass es als Wirkstoff 9-Fluor   1113, 17,21-trihydroxy-16z-methylpregna- 1 ,4-dien-3,20-dion    oder einen Ester davon, z.B. das tert.-Butylacetat, enthält.



   8. Mittel nach einem der Patentansprüche 1 bis 6, dadurch gekennzeichnet, dass es als Wirkstoff 9-Chlor   -11      1      7,21-trihydroxy- 1 613-methylpregna-l    ,4-dien-3,20-dion oder dessen Ester, z.B. das 21-Acetat oder das Dipropionat, enthält.



   BESCHREIBUNG



   Die Erfindung betrifft ein Mittel in Salbenform, insbesondere zur Behandlung von allergischen und vasomotorischen Rhinitiden, dessen wesentliche Bestandteile ein oder mehrere Wirkstoffe der 16-Methylpregna-1,4-dien-3,20dion-Reihe sowie eine Salbengrundlage auf der Basis von bei Körpertemperatur flüssigen oder   halbflüssigen,    die Oberflächenspannung herabsetzenden Verbindungen sind.



   Die als Wirkstoffe verwendeten Corticosteroide üben eine ausgezeichnete antiallergische Wirkung auf die Nasenschleimhäute aus. Bisher wurden sie zu diesem Zweck als Nasensprays eingesetzt, wobei sie aber eine sehr unangenehme und unerwünschte Austrocknung der Schleimhäute hervorriefen.



   Aufgabe der Erfindung war es daher, ein Mittel zu entwickeln, welches die positiven Wirkungen der Corticosteroide ohne das Austrocknen der Nasenschleimhäute erzielt.



   Das erfindungsgemässe Mittel ist in Patentanspruch 1 definiert.



   Das erfindungsgemässe Mittel bekämpft mit Hilfe der Corticosteroide insbesondere die unten genannten Krankheitssymptome. Durch die spezielle Salbengrundlage bleibt die Wirkung der Corticosteroide voll erhalten und gleichzeitig bleiben überraschenderweise die Schleimhäute während der Entfaltung der Wirkung feucht. Die austrocknende Nebenwirkung der Corticosteroide wird durch die   befeuchtende    Wirkung der Salbengrundlage aufgehoben. Dadurch bleiben die physiologischen Zustände der Schleimhäute erhalten, was mit wässerigen Präparaten nicht immer der Fall ist.



   Als Hauptbestandteil der Salbengrundlage dient eine bei Körpertemperatur flüssige oder halbflüssige die Oberflächenspannung herabsetzende Komponenente, die selbstverständlich physiologisch annehmbar sein muss. Verbindungen dieser Art, die allein oder im Gemisch verwendet werden können, sind z. B. Polyalkylenglykole, insbesondere Poly äthylenglykole. Eine besonders bevorzugte Komponente besteht aus einem Gemisch von Polyäthylenglykolen von verschiedenem Molekulargewicht, z.B. Polyäthylenglykol 600, Polyäthylenglykol 1000, Polyäthylenglykol 2000, Polyäthylenglykol 3000 und Polyäthylenglykol 5000, die in verschiedenen Gemischen von zwei oder mehr Komponenten und in verschiedenen Mengenverhältnissen miteinander vermischt werden können.



   Es hat sich ferner als vorteilhaft erwiesen, der Salbe weitere, für Nasensalben bekannte Zusätze beizufügen, z.B.



  Verbindungen mit einer gewissen Schmierwirkung, wie höhere Fettalkohole; Kochsalz, insbesondere in Form von Meersalz, sowie Konservierungsmittel, z. B. Benzoesäuresalze oder -ester.



   Als Wirkstoffe eignen sich bekannte Verbindungen der   16-Methyl-pregna-1,4-dien-3,20-dion-Reihe    wie Dexamethason und Beclomethason und deren Derivate, insbesondere deren Ester.



   Geeignete Wirkstoffkonzentrationen liegen im allgemeinen bei etwa   0,1 - 2    Gew.%.



   Patienten, welche auf Pollen oder andere Substanzen allergisch reagieren, leiden jährlich und in ständig steigendem Masse an den Folgen dieser Allergien mit Nasentropfen, tränenden und geschwollenen Augen, etc. In extremen Fällen sind diese Patienten so stark behindert, dass Arbeitsunfähigkeit auftritt. Viele dieser Patienten werden mit Medikamenten behandelt, die als unerwünschte Nebenwirkung die Schleimhäute austrocknen lassen. Dies wird durch das erfindungsgemässe Mittel verhindert. Eine weitere Patientengruppe leidet an vasomotorischen Rhinitiden, deren Symptome den allergischen Rhinitiden ähnelt.



   Es besteht daher auch hier die Notwendigkeit, diese unangenehmen Symptome mit einem geeigneten Mittel zu behandeln, dessen Nebenwirkungen auf ein Minimum reduziert sind, was mit dem erfindungsgemässen Mittel auf einfache Weise ermöglicht wird. Durch die spezielle Salbengrundlage,   z.B.    auf Polyalkylenglykol-Basis, werden die Nebenwirkungen der Wirkstoffe aufgehoben und eine optimale Behandlung ist gewährleistet.



   Mit Hilfe dieses erfindungsgemässen Mittels wird die Austrocknung der Nasenschleimhäute erfolgreich verhindert und Erkrankungen, wie z. B. Rhinitis allergica und vasomotorica, können innert kurzer Zeit erfolgreich behandelt werden, so dass nach wenigen Minuten schon subjektiv und objektiv eine wesentliche Besserung des Zustandes des Patienten festgestellt werden kann.



   Nachstehend wird die Erfindung durch zwei Beispiele näher erläutert.



   Beispiel 1
Aus den folgenden Bestandteilen wurde auf übliche Weise eine Nasensalbe hergestellt: Polyäthylenglykol 600 40 g Polyäthylenglykol 2000 20 g Cetylalkohol 10 g Sorbitol   5g      Meersalz (NaCl    + Spurenelemente) 1,3 g Methylparabenzoat 0,1 g   Wasser 22,6 g Dexamethason (9-Fluoro-   1113,17,21 -tri-    hydroxy- 1 6a-methylpregna- 1   ,4-dien-    3,20-dion) oder dessen Derivate, wie z. B.

  Dexamethason-tert.-butylacetat, etc. 1 g
100 g
Beispiel 2
Die folgenden Bestandteile wurden zu einer Nasensalbe verarbeitet: Wasser 25,2 g Polyäthylenglykol 600 30 g Polyäthylenglykol 1000 10 g Polyäthylenglykol 3000 10 g Polyäthylenglykol 5000   10    g Stearylalkohol 10 g Meersalz (NaCl   +    Spurenelemente) 0,6 g Sorbitol   4g      Beclomethason (9-Chlor-l Iss,17,21-tri- hydroxy- 1 6ss-methylpregna- 1 ,4-dien-      3;20-dion)    oder dessen Derivate, wie z.B. Beclomethason-21-acetat und Beclomethason-dipropionat 0,2 g
100 g
Zur Anwendung des erfindungsgemässen Mittels wird es in geeigneten Zeitabständen auf die Nasenschleimhäute aufgetragen. 

  Zur Erzielung des gewünschten Effektes werden im allgemeinen Salbenmengen aufgetragen, die 10 bis 1000 mg Reinwirkstoff pro Applikation entsprechen.



   Zur Applikation der Salbe geeignete Vorrichtungen, die auf dem Markt erhältlich sind, sind verlängerte Tubenkanülen oder Tubenöffnungen, die in die Nasenöffnungen eingeführt werden. Das Mittel kann gegebenenfalls auch mit dem Finger oder einem Wattestäbchen auf die Nasenschleimhäute appliziert werden. Die Anwendung kann bei Bedarf mehrmals und über längere Zeit wiederholt werden, ohne dass unerwünschte Nebenwirkungen auftreten, wie klinische Versuche an Menschen gezeigt haben. 



  
 

** WARNING ** beginning of DESC field could overlap end of CLMS **.

 



      PATENT CLAIMS
1. Agent in ointment form, in particular for the treatment of allergic and vasomotor rhinitis, characterized in that there is at least one steroid compound of the 16-methylpregna-1,4-diene-3,20-dione series and an ointment base, which mainly consists of a contains at body temperature liquid or semi-liquid, the surface tension-reducing, physiologically acceptable component.



   2. Composition according to claim 1, characterized in that the ointment base consists mainly of polyalkylene glycols.



   3. Composition according to claim 1 or 2, characterized in that the polyalkylene glycols consist of a mixture of polyethylene glycols of different molecular weights.



   4. Agent according to one of claims 1 to 3, characterized in that the ointment base is also at least one higher fatty alcohol such as Contains cetyl alcohol and / or stearyl alcohol.



   5. Agent according to one of claims 1 to 4, characterized in that it also contains a preservative, e.g. a salt or an ester of benzoic acid.



   6. Composition according to one of claims 1 to 5, characterized in that it also contains sodium chloride, preferably in the form of sea salt.



   7. Composition according to one of the claims 1 to 6, characterized in that it contains 9-fluorine 1113, 17,21-trihydroxy-16z-methylpregna-1,4-diene-3,20-dione or an ester thereof, e.g. contains the tert-butyl acetate.



   8. Composition according to one of the claims 1 to 6, characterized in that it contains 9-chloro -11 1 7,21-trihydroxy-1,613-methylpregna-l, 4-diene-3,20-dione or its ester as active ingredient, e.g. 21-acetate or dipropionate.



   DESCRIPTION



   The invention relates to an agent in ointment form, in particular for the treatment of allergic and vasomotor rhinitis, the essential components of which are one or more active ingredients of the 16-methylpregna-1,4-diene-3,20dione series and an ointment base on the basis of those which are liquid at body temperature or semi-fluid compounds that reduce surface tension.



   The corticosteroids used as active substances have an excellent anti-allergic effect on the nasal mucosa. So far, they have been used for this purpose as nasal sprays, but they have caused a very unpleasant and undesirable drying of the mucous membranes.



   The object of the invention was therefore to develop an agent which achieves the positive effects of corticosteroids without drying out the nasal mucous membranes.



   The agent according to the invention is defined in claim 1.



   With the help of corticosteroids, the agent according to the invention in particular combats the disease symptoms mentioned below. Due to the special ointment base, the effect of the corticosteroids is fully preserved and, at the same time, surprisingly the mucous membranes remain moist during the development of the effect. The drying side effect of the corticosteroids is eliminated by the moisturizing effect of the ointment base. As a result, the physiological conditions of the mucous membranes are preserved, which is not always the case with aqueous preparations.



   The main component of the ointment base is a component which is liquid or semi-liquid at body temperature and which reduces the surface tension, which of course must be physiologically acceptable. Compounds of this type, which can be used alone or in a mixture, are e.g. B. polyalkylene glycols, especially poly ethylene glycols. A particularly preferred component consists of a mixture of polyethylene glycols of different molecular weights, e.g. Polyethylene glycol 600, polyethylene glycol 1000, polyethylene glycol 2000, polyethylene glycol 3000 and polyethylene glycol 5000, which can be mixed in different mixtures of two or more components and in different proportions.



   It has also proven advantageous to add further additives known to nasal ointments to the ointment, e.g.



  Compounds with a certain lubricating effect, such as higher fatty alcohols; Cooking salt, especially in the form of sea salt, and preservatives, e.g. B. benzoic acid salts or esters.



   Known compounds of the 16-methyl-pregna-1,4-diene-3,20-dione series, such as dexamethasone and beclomethasone and their derivatives, in particular their esters, are suitable as active ingredients.



   Suitable drug concentrations are generally around 0.1-2% by weight.



   Patients who are allergic to pollen or other substances suffer annually and to an ever increasing extent from the consequences of these allergies with nose drops, watery and swollen eyes, etc. In extreme cases, these patients are so severely handicapped that they are unable to work. Many of these patients are treated with medications that cause the mucous membranes to dry out as an undesirable side effect. This is prevented by the agent according to the invention. Another group of patients suffers from vasomotor rhinitis, the symptoms of which are similar to allergic rhinitis.



   There is therefore also a need to treat these unpleasant symptoms with a suitable agent, the side effects of which are reduced to a minimum, which is made possible in a simple manner with the agent according to the invention. Due to the special ointment base, e.g. based on polyalkylene glycol, the side effects of the active ingredients are eliminated and optimal treatment is guaranteed.



   With the help of this agent the drying of the nasal mucous membranes is successfully prevented and diseases such as. B. Rhinitis allergica and vasomotorica, can be treated successfully within a short time, so that after a few minutes, a substantial improvement in the patient's condition can be determined subjectively and objectively.



   The invention is explained in more detail below by means of two examples.



   example 1
A nasal ointment was prepared in the usual way from the following constituents: polyethylene glycol 600 40 g polyethylene glycol 2000 20 g cetyl alcohol 10 g sorbitol 5 g sea salt (NaCl + trace elements) 1.3 g methyl parabenzoate 0.1 g water 22.6 g dexamethasone (9-fluoro - 1113,17,21 -tri- hydroxy- 1 6a-methylpregna- 1, 4-diene-3.20-dione) or its derivatives, such as. B.

  Dexamethasone tert-butyl acetate, etc. 1 g
100 g
Example 2
The following ingredients were processed into a nasal ointment: water 25.2 g polyethylene glycol 600 30 g polyethylene glycol 1000 10 g polyethylene glycol 3000 10 g polyethylene glycol 5000 10 g stearyl alcohol 10 g sea salt (NaCl + trace elements) 0.6 g sorbitol 4 g beclomethasone (9-chlorine -l Iss, 17,21-tri-hydroxy-1 6ss-methylpregna-1, 4-diene-3; 20-dione) or its derivatives, such as Beclomethasone 21-acetate and beclomethasone dipropionate 0.2 g
100 g
To use the agent according to the invention, it is applied to the nasal mucosa at suitable intervals.

  To achieve the desired effect, amounts of ointment are generally applied which correspond to 10 to 1000 mg of pure active ingredient per application.



   Devices suitable for applying the ointment that are available on the market are elongated tube cannulas or tube openings that are inserted into the nostrils. If necessary, the agent can also be applied to the nasal mucosa using a finger or a cotton swab. If necessary, the application can be repeated several times and over a longer period of time without undesirable side effects, as clinical trials in humans have shown.

Claims

PATENT CLAIMS 1. Agent in ointment form, in particular for the treatment of allergic and vasomotor rhinitis, characterized in that there is at least one steroid compound of the 16-methylpregna-1,4-diene-3,20-dione series and an ointment base, which mainly consists of a contains at body temperature liquid or semi-liquid, the surface tension-reducing, physiologically acceptable component.

2. Composition according to claim 1, characterized in that the ointment base consists mainly of polyalkylene glycols.

3. Composition according to claim 1 or 2, characterized in that the polyalkylene glycols consist of a mixture of polyethylene glycols of different molecular weights.

4. Agent according to one of claims 1 to 3, characterized in that the ointment base is also at least one higher fatty alcohol such as Contains cetyl alcohol and / or stearyl alcohol.

5. Agent according to one of claims 1 to 4, characterized in that it also contains a preservative, e.g. a salt or an ester of benzoic acid.

6. Composition according to one of claims 1 to 5, characterized in that it also contains sodium chloride, preferably in the form of sea salt.

7. Composition according to one of the claims 1 to 6, characterized in that it contains 9-fluorine 1113, 17,21-trihydroxy-16z-methylpregna-1,4-diene-3,20-dione or an ester thereof, e.g. contains the tert-butyl acetate.

8. Composition according to one of the claims 1 to 6, characterized in that it contains 9-chloro -11 1 7,21-trihydroxy-1,613-methylpregna-l, 4-diene-3,20-dione or its ester as active ingredient, e.g. 21-acetate or dipropionate.

DESCRIPTION

The invention relates to an agent in ointment form, in particular for the treatment of allergic and vasomotor rhinitis, the essential components of which are one or more active ingredients of the 16-methylpregna-1,4-diene-3,20dione series and an ointment base on the basis of those which are liquid at body temperature or semi-fluid compounds that reduce surface tension.

The corticosteroids used as active substances have an excellent anti-allergic effect on the nasal mucosa. So far, they have been used for this purpose as nasal sprays, but they have caused a very unpleasant and undesirable drying of the mucous membranes.

The object of the invention was therefore to develop an agent which achieves the positive effects of corticosteroids without drying out the nasal mucous membranes.

The agent according to the invention is defined in claim 1.

With the help of corticosteroids, the agent according to the invention in particular combats the disease symptoms mentioned below. Due to the special ointment base, the effect of the corticosteroids is fully preserved and, at the same time, surprisingly the mucous membranes remain moist during the development of the effect. The drying side effect of the corticosteroids is eliminated by the moisturizing effect of the ointment base. As a result, the physiological conditions of the mucous membranes are preserved, which is not always the case with aqueous preparations.

The main component of the ointment base is a component which is liquid or semi-liquid at body temperature and which reduces the surface tension, which of course must be physiologically acceptable. Compounds of this type, which can be used alone or in a mixture, are e.g. B. polyalkylene glycols, especially poly ethylene glycols. A particularly preferred component consists of a mixture of polyethylene glycols of different molecular weights, e.g. Polyethylene glycol 600, polyethylene glycol 1000, polyethylene glycol 2000, polyethylene glycol 3000 and polyethylene glycol 5000, which can be mixed in different mixtures of two or more components and in different proportions.

It has also proven advantageous to add further additives known to nasal ointments to the ointment, e.g.

Compounds with a certain lubricating effect, such as higher fatty alcohols; Cooking salt, especially in the form of sea salt, and preservatives, e.g. B. benzoic acid salts or esters.

Known compounds of the 16-methyl-pregna-1,4-diene-3,20-dione series, such as dexamethasone and beclomethasone and their derivatives, in particular their esters, are suitable as active ingredients.

Suitable drug concentrations are generally around 0.1-2% by weight.

Patients who are allergic to pollen or other substances suffer annually and to an ever increasing extent from the consequences of these allergies with nose drops, watery and swollen eyes, etc. In extreme cases, these patients are so severely handicapped that they are unable to work. Many of these patients are treated with medications that cause the mucous membranes to dry out as an undesirable side effect. This is prevented by the agent according to the invention. Another group of patients suffers from vasomotor rhinitis, the symptoms of which are similar to allergic rhinitis.

There is therefore also a need to treat these unpleasant symptoms with a suitable agent, the side effects of which are reduced to a minimum, which is made possible in a simple manner with the agent according to the invention. Due to the special ointment base, e.g. based on polyalkylene glycol, the side effects of the active ingredients are eliminated and optimal treatment is guaranteed.

With the help of this agent the drying of the nasal mucous membranes is successfully prevented and diseases such as. B. Rhinitis allergica and vasomotorica, can be treated successfully within a short time, so that after a few minutes a substantial improvement in the patient's condition can be determined subjectively and objectively.

The invention is explained in more detail below by means of two examples.

example 1 A nasal ointment was prepared in the usual way from the following constituents: polyethylene glycol 600 40 g polyethylene glycol 2000 20 g cetyl alcohol 10 g sorbitol 5 g sea salt (NaCl + trace elements) 1.3 g methyl parabenzoate 0.1 g ** WARNING ** End of CLMS field could overlap beginning of DESC **.