DE3839258A1 - Process for the production of a suspension aerosol - Google Patents

Abstract

To produce a suspension aerosol based on disodium chromoglycate and, where appropriate, other active substances such as reproterol hydrochloride with halogenated hydrocarbons as propellant, initially the active substances are introduced in the form of a suspension in liquid sym-tetrafluorodichloroethane at a temperature of </= -25@C under atmospheric pressure into an aerosol container, after which the latter is closed with a metering valve and then filled under pressure with difluorodichloromethane, the sym-tetrafluorodichloroethane and difluorodichloromethane being used in a ratio of 1:2 to 1:1 by weight.

Description

The invention relates to a method for producing a Suspension aerosols for inhalation, which is used as active disodium cromoglycate (DNCG) and optionally further Active ingredients, e.g. Reproterol hydrochloride or fenoterol hydro contains chloride. Such suspension aerosols have become for the treatment and prevention of respiratory distress in the respiratory crane As asthma or allergic bronchitis proven. By a directed into the mouth opening spray can the patient receives a relatively precisely dosed amount Add active substance (s), the active ingredients depending on the part size in the mouth and throat are held or into the trachea, the bronchi and finally the alveoli reach.

In the preparation of such suspension aerosols under Use of physiologically inert and non-combustible Chlorofluorocarbons as propellants are different some problems. In the previously used Kaltab filling using a mixture of difluorodichloro methane (F12) and sym-tetrafluorodichloroethane (F114) must be the Active ingredient suspension in the propellants to about -55 ° C ge to be cooled to a bottling under normal conditions to allow open doses. Here, however, the weight is rather inaccurate, because the cooled, highly viscous mixture transported from the batch kettle in the filling machine must be, with losses due to heating occur. Further It is not possible with this procedure, the aerosol cans immediately after the filling process after the Closing to check for leaks, as the propellant at the low temperature the necessary internal pressure still do not produce. It is therefore necessary the bottled Intermediate aerosol cans (usually six weeks long at room temperature) and then back again. at this method of production is up to 20%, because both overweight and underweight weight must be eliminated.

The invention has for its object to provide a solution for to find the aforementioned problems.

It has now been found that the pressure conditions in the aerosol can do not change significantly, given the Proportion of F114 increased and accordingly the proportion of F12 lowers. It has also been shown that even among these amended conditions are obtained, wel a constant dosage of the active ingredients in the later Use: The concentration of e.g. DNCG and Reproterol hydrochloride remained useful at 200 sprays constant.

By changing the ratio of F114 to F12 it becomes possible to carry out a combined pressure and cold filling to lead. The invention therefore relates to a method for Preparation of a suspension aerosol for inhalation purposes based on disodium cromoglycate (DNCG) and optionally other active substances with halogenated hydrocarbons as blowing agent, which is characterized in that one first the active substance or the active ingredients in the form of a Suspension together with liquid sym.-Tetrafluordichlorethan at a temperature of -25 ° C without pressure in an aerosol fills container, this closes with a metering valve and then filled under pressure with difluorodichloromethane, wherein sym-tetrafluorodichloroethane and difluorodichloromethane used in a weight ratio of 1: 2 to 1: 1. before Preferably, the ratio is about 1: 1.5. One be particularly preferred drug combination is the one from DNCG and reproterol hydrochloride, especially in one Weight ratio of DNCG to reproterol hydrochloride of 2: 1. Other agents which advantageously with DNCG combined and administered as a suspension aerosol can, are e.g. Fenoterol and Terbutaline.  

The inventive method brings a number of Vor share with:

• - The weighing accuracy can be significantly improved, because the drug suspension in F114 at only -25 ° C a has significantly improved flow behavior.
• - It saves a considerable amount of energy since the one used exclusively for cold filling Blowing agent F114 only cooled to approx. -25 ° C must be while for the time being for cold filling used combination of F114 and F12 temperatures of about -55 ° C were required.
• - At the pressure filling of already closed cans with the propellant F12 to the target weight can Inadmissible weight deviations during production be largely avoided, the committee is sinking below 3%.
• - The cans can be put on immediately after filling Tightness to be tested as the propellant F12 at the higher filling temperature immediately necessary Internal pressure generated, which for the leak test is required; In this way, the uner accounts Wanted interim storage times of up to 6 weeks.

For a more detailed explanation of the invention, the following Example serve.

example

The following ingredients (each expressed in mg / ml) were administered in the stated amount of sym-tetrafluorodichloroethane (Cryo fluoran BP 80) at about -25 ° C suspended:

Disodium salt of cromoglycic acid (DNCG) BP 80 (90% <10 μm, 50% <6 μm) 20.00 Reproterol hydrochloride (100% <5 μm, 80% <4 μm, 10% <3 μm) 10.00 Saccharin sodium × 2 H₂O DAB 8 (95% <5 μm) 1.00 trioleate 8.32 Dentomint PH 799959 8.00 F 114 (Cryofluoran) BP 80 535.87

This suspension was kept at a constant Filling weight filled in cooled aerosol cans, whereupon the valves are used with the associated valve disk and the cans were airtight (crimped). Subsequently, under pressure, liquid F12 (Difluordi Chloromethane BP 80) through the valve until reaching the Refilled target weight.

The suspension aerosol cans thus obtained could subsequently immediately be checked for leaks without intermediate storage. The committee on cans with inadmissible weight deviation up or down was less than 3%.

Claims (4)

1. A process for the preparation of a suspension aerosol for inhalation purposes based on disodium cromoglycate (DNCG) and optionally other active substances with halo genierten hydrocarbons as propellant, characterized in that first the active substance or the active ingredients in the form of a suspension in liquid sym. Tetrafluordichlorethan at a temperature of -25 ° C depressurized into an aerosol container, closes this with a metering valve and then filled under pressure with difluorodichloromethane, using sym-tetrafluoro dichloroethane and difluorodichloromethane in a weight ratio of 1: 2 to 1: 1 , 2. The method according to claim 1, characterized in that sym-tetrafluorodichloroethane and difluorodichloromethane used in a weight ratio of about 1: 1.5. 3. The method according to claim 1 or 2, characterized that as another active substance reproterol hydrochloride starts. 4. The method according to claim 3, characterized in that one behaves DNCG and reproterol hydrochloride in weight of 2: 1.