PT88984B - METHOD FOR THE PREPARATION OF AZELASTINE EMBONATE AND EARMACEUTICAL COMPOSITIONS CONTAINING AS ACTIVE INGREDIENT - Google Patents

Description

DESCRIPTION

GIVES

INVENTION PATENT

No. 88 984

APPLICANT: ASTA Medica Aktiengesellschaft, based in Weismíillerstr. 45, D-6000 Frankfurt am Main 1, German Federal Republic

EPIGRAPH: PROCESS FOR THE PREPARATION OF EMBONATE OF

AZELASTIN AND EARMACÂUTX COMPOSITIONS THAT CONTAIN AS AN ACTIVE INGREDIENT

INVENTORS: Dr. Gerhard Scheffler Dieter Sauerbier and Dr.

Jurgen Engel, residing in West Germany as

Claim of the right of priority under Article 4 of the Paris Convention of 20 March 1883.

Germany on November 13, 1987, under ο N2. P 37 38 641. Ç

INPI. MOD. 113 R F 16732

Description concerning the ASTÀ Medica Âktiengesellschaft, German, industrial and commercial patent, based in Weismullerstr. 45, D-6000 Frank furt am Main 1, German Federal Republic, (inventors; Lr. Ger-hard Scheffler Dieter Sauerbier and Dr. Jurgen Engel, residing in West Germany), for PROCESS FOR. A. PREPARATION OF

AZELASTINE AND COMBORATE

PHARMACEUTICAL POSITIONS THAT THE COLOR HAS AS AN ACTIVE INGREDIENT

DESCRIPTION

Azelastine is an active substance with prophylactic action of asthma. Your chemical name is

4- (p iorooenzil _c) -2-hemahidro-methyl-azepin-4-yl-l- (2H) -ftala zinana (Patent _, Lema 2,164,058).

An important use of azelastine as an allergic is oral application, especially in the form of tablets, capsules, solutions or suspensions, and in addition to these also in the form of aerosols.

However, the use of azelastine in the form of solutions or suspensions has not been possible until now, since azelastine has a bitter penetrating taste in such a way that all oral applications of these solutions or suspend

azelastine sections are refused by patients. This bitter taste cannot yet be eliminated by transformation into the most diverse salts.

It has now been discovered that azelastine, by conversion into the salt with carbonic acid, can be converted into a product that no longer has the said penetrating bitter taste and is therefore suitable for use in compositions intended for oral administration. As far as azelastine embonate is concerned, it is a salt of azelastine with embonic acid, this salt consisting of 2 moles of azelastine and 1 mole of embonic acid (see example 1), azelastine embonate according to the invention is particularly suitable for. preparation of azelastine galenic compositions, to be taken orally in the form of stable suspensions, for example in the form of a juice. Of course, the embonate according to the invention can also be used for the preparation of other galenic compositions of azelastine, such as for example tablets, capsules or sprays ”.

In the case where the azelastine embonate according to the invention is used for the preparation of aqueous suspensions, in this case these are suspensions containing as active ingredient 3 to 30C0 mg but preferably 15 to 2C0 mg and especially 6 to 120 mg, as parts by weight of azelastine embonate, referred to 100 ml of the suspension. Preferably an azelastine embonate is used in this case. with a granulometry less than 100 / um. The pH of these suspensions is in the range 3 to 9, preferably 5 to 8 and in particular 6 to 7.

Particularly favorable is a suspension of azelastine embonate which consists of a thixotropic system, which at rest has a high viscosity, but whose structure changes to a weak mechanical stress (for example by leakage) so that the suspension (for example a juice) become fluid. For the preparation of a thixotropic suspension in water of this nature, for example thickeners are used. As thickeners, for example, natural macromolecules (for example alginates, pectin, tragacanth, hydrocolloid polysaccharides, such as gum, xaatan) semisynthetic macromolecules (eg cellulosic ether) syntetic macromolecules (eg polyacrylates, polyvinylpyrrolidone and so on) (eg colloidal silica, ben tonite). These thickeners can be applied individually or in a mixture. Due to their pronounced thixotropic properties, xanthan gum compositions have proved to be especially suitable for repairing and stable fluid suspensions.

These thickeners can be applied individually, individually or as a mixture. The total amount of thickener referred to 100 ml of the suspension is, for example, 0.1 to 10 g and preferably 0.5 to 5 g. xanthan the amount of this gum is for example 0.1 to 3 g, preferably 0.3 to 1.5 S θ particularly 0.5 to 1 g, in the case of polyacrylate it is 0.1 to 1 g , for alginates and tragacanth it is 0.1 to 0.2 g, for pectins and cellulose ethers it is 0.5 to 5 g, and in the case of polyvinylpyrrolidone and inorganic gelling agents it is 1 to 10 g (referred to in each case 100 ml of the suspension).

In addition, the azelastine embonate suspensions according to the invention may optionally contain additives common in the pharmacy or in the galenic technique, such as, for example, preservatives, sweeteners, flavors and dyes.

As preservatives, for example, organic acids (eg, sorbic acid, benzoic acid) phenols (eg lower alkyl p-hydroxybenzoate) organic mercury compounds (eg · thiomersal) quaternary ammonium compounds (eg benzothenium chloride) aromatic alcohols and aliphatics (e.g. 1,2-propylene glycol, venyl alcohol) and chlorhexidine. Preservatives can also be used in the form of their salts (for example alkaline salts such as sodium benzoate) and natura.lraente also as mixtures.

The amount of preservative per 100 ml of suspension can be comprised, for example, for sorbic acid between 0.05 g to 1.0 g, for benzoic acid between 0.1 g

up to 0.2 g, for thiomersal ”between 0.001 g to 0.01 g, for benzethonium chloride between 0.005 g to 0.02 g, for 1,2-propylene glycol between 10 g and 30 g, for benzyl alcohol between 1 , 0 g and 2.0 g, and for chloroliexidine between 0.0001 to 0.01 g.

Preferably, a mixture of lower alkyl p-hydroxybenzoates is used. The sum of the lower alkyl p-hydroxybenzoates referred to 100 ml of suspension is between, for example, between 0.1 and 0.3 g, preferably between 0.15 g θ 0.25 g, especially between 0.15 g ® 0.20 g.

Sweeteners include, for example, saccharin, cyclamate, aspartame, fructose, sucrose, sorbite, manite, and preferably xylite. The amount of sweetener naturally depends on its sweetening power. In general, the amount referred to 100 ml of the suspension is for saccharin from 0.005 to 0.1 g, for cyclamate it is 0.5 to 2.0 g, for aspartame it is 0.005 to 0.3 g, for , fructose, sucrose, sorbite and menite is from 1.0 g to ÓO g. For xylite this amount is, for example, 1 to 60 g, preferably 15 to 60 g and especially 30 to 4θ g.

Volatile oils (for example peppermint oil, melisse oil, lemon oil), fruit extracts (for example lemon, grapefruit, pineapple), aromatic extracts (liquorice root, anise, fennel) and other flavorings are mentioned as flavorings. natural and synthetic. Especially suitable for example raspberry aroma. The amount of tinting ring is comprised, for example, of 100 ml of the suspension, between 0.001 to 5 g ^or also 10 g, preferably from 0.01 to 1 g, especially from 0.01 to 0.1 g. For the raspberry aroma, for example, amounts of Q10 to 0.1 g, preferably from 0.01 to 0.05 g, especially from 0.02 to 0.04 g per 100 ml of the suspension are of interest.

As dyes stand out, for example, current admissible dyes for food products, dyes for natural food products (eg curcumin, riboflavin, chlorophyll, xanthophyll) synthetic organic dyes (azo dyes, azo varnishes) inorganic synthetic dyes (eg titanium dioxide or iron oxide). Azo synthetic dyes such as amaranth,

The amount of the dye can be, for example, between 0.01 g to 1.0 g, preferably from 0.001 to 0.1 g and especially from 0.001 to 0.01 g, based on 100 ml of the suspension. For the amarante, for example, quantities of 1 to 10 mg, preferably 1 to 3 mg and especially 2 to U mg, referred to 100 ml of the suspension are indicated.

Adjustment of the most convenient pH is preferably carried out by means of inorganic acids (eg hydrochloric acid, sulfuric acid, or phosphoric acids) or with organic acids (for example citric acid or maleic acid) by means of inorganic bases (for example caustic soda or caustic potash) using common salts for this purpose (eg ammonium chloride, sodium citrate, sodium dihydrogen phosphate).

For the preparation of suspensions of the azelastine embonate according to the invention, in addition to water, other physiologically acceptable liquids can also be used. This type of liquids includes, for example, monofunctional or polyfunctional lower alcohols, such as ethanol, propylene glycol, glycerin and polyglycols with molecular weights between 200 and 600. Mixtures of these liquids between themselves and also with water can also be used. As liquid carrier substances, for example, natural oils (for example olive oil), oily, synthetic and semi-synthetic liquid carrier substances, such as triglycerides of saturated fatty acids of vegetable origin with 8 to 12 carbon atoms , and their mixtures.

Pure aqueous suspensions are preferred.

If mixtures of water and other liquids are used, for example, mixtures in which the content of the non-aqueous component is from 1 to 60% by weight, preferably 10 to -C, and especially 20 to 30%. by weight, referred to 100 g of the suspension.

If necessary, humectants can be added to the suspensions according to the invention. This category includes, for example, anionic surfactants, for example soaps, fatty alcohol sulphates, non-ionogenic surfactants, for example fatty acid esters of polyethylene glycol (l-iyrj) fatty alcohol and polyethylene glycol (Brij) ethers, esters of sorbinate fatty acids (Span), polyethylene glycol-sorbitan fatty acid esters (Tween), (Tween), polyethylene glycol-polypropylene glycol derivatives (pluronics). Preferred are the fatty acid esters of the sorbitan (with saturated and unsaturated aliphatic carboxylic acids having 10 to 20 carbon atoms), fatty alcohol and polyoxyethylene ethers (alcohols with 10 to 20 carbon atoms) and carboxylic acid esters with polyethylene glycol-sorbitan (saturated or unsaturated aliphatic carboxylic acids having 10 to 20 carbon atoms,

The amount of humectant referred to 100 ml of the suspension can be, for example, 1 to 10 ^J g, preferably 0.5 to 0.001 g and especially 0.1 to 0.01 g. The humectant has the function of ensuring an optimal dispersion of the undissolved active substance. Eventually, the required amount of each humectant is determined by previous tests.

Azelastine embonate suspensions, according to the invention, have, for example, viscosities ranging from 0.05 nt to 0.22 and preferably 0.09 to 0.18 Pascal-seconds, especially 0.12 to 0.5 Pascal-second (pa. S) for a transverse speed of 110 per second on the rotation viscometer.

In addition, the olive oil embonate suspensions according to the invention may also contain additional carbonic acid. For every 100 ml of the suspension, for example, 1 to 2000 mg and preferably 20 to 100 mg, especially 50 to 150 mg of additional embenic acid, can be added to the azelastine embonate already present.

excess embenic acid, surprisingly, acts as a taste-enhancing agent.

For the preparation of suspensions with propellant substances (aerosols) in addition to or instead of the auxiliary substances mentioned, conventional propellant gases are used

(propane, butane, fluorinated chlorocarbons). For these suspensions the azelastine embonate must have, for example, a particle size with diameters between 5 and 10 µm.

The preparation of these aerosols is carried out, for example, by dispersing at a temperature between -55 ° C and + 55 ° C, 3 to 3000 mg of azelastine embonate in 100 ml of a mixture formed by chloro-fluorinated hydrocarbons and / or hydrocarbons with the addition of 0.25 to 3 g of sorbitan trioleate, as well as possibly other auxiliary substances, and packing the suspension obtained in containers that are closed with metering valves, which for each pulse release 0.025 to 0.1 ml of the suspension.

The preparation of the azelastine embonate with this grartulometry is carried out by grinding in a common micronization device.

For the preparation of other oral compositions of the azelastine embonate, the current carrier and auxiliary substances that can be used pharmaceutically and in galenic technique are used. For example, for tablets, the following auxiliary or carrier substances are used (amounts by weight percentage per tablet).

loads (5 to 95%)! for example starches, cellulose, lactose, sucrose, fructose, sorbite, mannite and calcium phosphate.

binders (1 to 80%): gelatin, ether, cellulose, pectin, alginate, polyvinylpyrrolidone, lactose, microcrystalline cellulose.

Disintegrants (1 to 10%): alginate, starches, pectin, carboxymethylcellulose, polyvinylpyrrolidone, ultramylopectin and bentonite.

Lubricants (0.2 to 10%); stearic acid, stearates, polyglycels. talc, finely dispersed silica.

In addition to these components, tablets can also contain; anti-caking agents, resorption accelerators, hydrophilic agents, moisture retainers and equivalent agents.

Coated tablets are often prepared which then contain, for example, the corresponding film-forming means and coating products, such as dyes, softeners and polishing waxes.

The fillers, binders and lubricants mentioned above can also be used in other oral forms of compositions (capsules, granules and the like).

The tablets, hem as well as other oral compositions (capsules and granules) contain for example between 0.5 and 300 mg and preferably 1 to 20 mg but especially 1.5 to 12 mg of the azelastine embonate.

The preparation of the eaifoonate according to the invention is carried out by reacting azelastine or an azelastine acid addition salt with embenic acid, or with an embonic acid salt in an appropriate solvent, where appropriate heating. The reaction is carried out at temperatures between 18 and 150 ° C, especially 20 to 100 ° C and preferably between 20 and 50 ° C.

Examples of solvents are aliphatic lower alcohols with 1 to 6 carbon atoms (methanol, ethanol, propanol, isopropanol or butanol) lower aliphatic ketones with 3 ώ θ carbon atoms (acetone., Methyl ethyl ketone) glycols, cyclic ethers (dioxane, tetrahydrofuran) esters of lower aliphatic carboxylic acids with lower aliphatic alcohols, N-alkyl substituted amides and amides derived from aliphatic carboxylic acids with 1 to 4 carbon atoms (dimethylformamide or diniethylacetamide), dialkylsulfones with 1 to 6 carbon atoms in each group alkyl (dimethyl sulfone, tetramethylsulfone) dialkyl sulfoxides with 1 to 6 carbon atoms each, and alkyl group (dimethyl sulfoxide) as well as other aprotic agents such as N-methylpyrrolidone, tetramethylurea, hexamethylphosphonic acid triamide, acetonitrile mixtures of these media and mix them with water. In the case of aqueous mixtures, the proportion of water in general does not exceed 30 parts by volume ($>). In addition, the reaction can also be carried out and mixtures of alcohol

-ether, then aliphatic ethers with 2 to 6 carbon atoms and cyclic ethers can be used for example. The reaction is also possible in mixtures of lower aliphatic alcohols with halogenated aliphatic or aromatic hydrocarbons.

Azelastine and carbonic acid enter the reaction in a 2: 1 ratio. Preferably in this case, an excess of azelastine of 1 to 20% and especially 1 to 5%, referring to the amount of embonic acid that is necessary for the proportion mentioned above.

If azelastine is used in the form of its salt, for example, salts with the following acids are of interest: strong and moderately strong inorganic acids (halogen hydrides, such as hydrochloric acid and hydrobromic acid, azotic acid, phosphoric acids or sulfuric acid) strong or weak organics, such as aliphatic and aromatic sulfonic acids (methanesulfonic acid, toluenesulfonic acid), saturated and unsaturated monobasic carboxylic acids, with aliphatic chain, aromatic carboxylic acids (benzoic acid, toluene-carboxylic acid).

embotic acid can also be used as a salt. As salts of embonic acid, for example, alkaline salts (sodium, potassium, lithium), alkaline earth salts, magnesium salts, ammonium salts and alkyl ammonium salts are of interest.

The preparation of the azelastine embonate pharmaceutical compositions is carried out by mixing or homogenizing the azelastine embonate with the other carrier and auxiliary substances, at temperatures between 15 and 80 ° C. but preferably 18 to 4 ° C and in particular 20 to 30 ° C 'For the reduction of the germs present (sterilization) it can possibly be heated for 15 to 6 min, up to temperatures between 80 to 140 ° C and preferably 110 at 120 ° C.

For the preparation of suspensions, for example, the following can be done: the thickener (0.1 to 10 g and preferably 0.3 to 1.5 g per 100 ml of the suspension and possibly a part of the other auxiliary substances) are dissolved in water or other liquids or mixtures of liquids already mentioned = 9 = at 20 to 30 ° C, the amount of water or the amount of liquid being chosen so that the ready suspension contains 0.03 to 30 and preferably 0 , 4 to 6 1, especially 0.8 to 1.2 1 of water or liquids, referred to 1 g of azelastine embonate. The aqueous solution thus obtained can then be heated for example for 10 to 120 min. but preferably 15 to 60 min., at temperatures between 80 to 134 ° C, but are preferably heated for 20 to 30 min. at temperatures between 110 and 121 ° C.

After cooling to 25 to 35 ° C, a humectant is eventually added to this solution and then the ready mixture, cooled to temperatures of 20 to 30 ° C, is added with the azelastine embonate and possibly with preservatives, sweeteners, dyes and possibly flavorings and other auxiliary / vehicular substances, and the whole is homogenized (temperature between 15 to 35 ° θ preferably 20 to 30 ° C)

Then the possible addition of flavorings is carried out, as well as the adjustment of the pH to a value between 3 and

9.

In the preparation of the aforementioned suspension of azelastine embonate, for example, for 1 g of azelastine bonate:

0.005 to 600 g but preferably 300 to 400 g of the sweetener, 0.01 to g but preferably 0.2 to 0.4 g of flavoring.

A portion of the amounts of flavoring indicated here may eventually be added to the suspension.

Example 1

Azelastine Embonate

Azelastine ¹¹ (2 Mol)

Embonic acid (l Mol)

In a dissd glass container. 177.5 g (1.01 x 2 x 0.21 moles) of azelastine hydrochloride are added in 4500 ml of 80% ethanol by stirring. After adding 90.6 g (θ, 21 moles) of the disodium acid of embonic acid, continue until it has completely dissolved, that is, about 4 min.

Then it is immediately filtered through a pleated filter and the filtrate is left to stand overnight.

embonate precipitates quickly, separating in this way. This precipitate is removed by filtration, washed with 80% ethanol and then with pure ethanol and dried in vacuo for 20 h at 6 ° C. Yield 195 g (80 $ of theoretical value).

The product thus obtained is triturated in ice water for 5 hours for further purification, removed by filtration, washed first with ice water and then with ethanol and dried in vacuo at 60 ° C for 20 h. Yield 195 g (80 $ of theoretical value). The azelastine embonate is obtained in the form of a slightly yellowish crystalline powder. M.p .: 197 to 201 ° C.

= IR spectrum is shown in fig. 1.

nuclear magnetic resonance spectrum is shown in fig. 2.

Example 2

Azelastine embonate suspension

3000 ml of suspension corresponding to 3300 g contains:

azelastine embonate xanthan gum xylite propyl-4-hydroxybenzoate sodium (sodium salt of propyl 4-hydroxy-benzoate) sodium methyl-4-hydroxybenzoate (sodium salt of methyl 4-hydroxy-benzoate) hydrochloric acid IN aroma of raspberry amarante (persistent red dye) pure water

3,600 g

21.00 g 1 200.00 g

1,200 g

4,200 g

21.00 g (a) 0.900 g 0.150 g

2047,950 g

3300,000 g

a) Hydrochloric acid is necessary to adjust the pH value to 6.5. A different use of hydrochloric acid, compared to the value indicated above, is compensated by a corresponding reduction in the amount of pure water.

Preparation

800.0 g of xylite and 21.0 g of xanthan gum are dissolved in 2000 g of water in a 3000 ml glass beaker, with stirring. The solution is then heated in an autoclave for 30 min. at 115 ° C. After cooling to about 40 ° C the solution is aspirated by vacuum and recirculated to the chamber of a homogenisation device.

=

400.0 g of xylite, 1.2 g of sodium propyl-4-hydroxybenzoate, 4.2 g of sodium methyl-4-hydroxybenzoate, 0.3-5 g of amaranth and 3.6 g of azelastine embonate are mixed in a porcelain capsule and added to the solution previously prepared in the working chamber of the homogenization apparatus ·

0.9 g of raspberry flavor and 21.0 g of hydrochloric acid are aspirated by means of vacuum and recirculation to the homogenization apparatus chamber. The suspension is homogenized for 15 min.

The pH of the suspension thus obtained is adjusted to 6.5 by the addition of hydrochloric acid. The consumption of hydrochloric acid is compensated for by minimal additions of pure water. Formula for calculating the amount of water needed:

^ 7.95 g - hydrochloric acid added in grams = amount of water in grams.

The suspension obtained is a reddish-colored viscous juice (pH between 6.3 θ 6.7).

Active constituent per 100 ml: 0.1200 g of azelastine embonate.

Aroma: raspberry.

Palate: raspberry.

Viscosity: 0.1-0.15 pascal-second (Pa.s).

juice (batch) is packaged, for example, in brown glass bottles with a screw cap. The filling from the initial quantity must be carried out in such a way that air is not trapped by the rapid leak,

The juice is stored for example at room temperature.

= 13 =

5000 ml of suspension corresponding to 5000 g

Example 3

Azelastine embonate suspension contains;

azelastine embonate xanthan gum xylite sodium propyl-4-hydroxybenzoate sodium methyl-4-hydroxybenzoate embonic acid raspberry aroma amaranth (red dye) citric acid sodium hydroxide pure water

6,000 g (i) 32,500 g

500,000 g

2,000 g 7,000 g 5,000 g 1,500 g 0,250 g

64,000 g 32,500 g 3 849,250 g (2)

500,000 g

1) The azelestine embonate prior to incorporation was passed through a 100 µm mesh crest with openings.

2) The pH of the suspension is adjusted with caustic soda IN to 6.5 · The need for caustic soda is deducted from water. Preparation steps

I. 400 g of xylite and 32.5 g of xanthan gum are ground together and this mixture is dissolved in 3000 g of water, with stirring. The solution is heated in an autoclave for 30 min. at 115 ° C. The water lost by vaporization in the autoclave is replenished. After cooling to about 30 ° C, the solution is transferred, under vacuum and recirculation, to the working container of a homogenization apparatus.

II. In the order shown below, 64 g of citric acid, 5 g of embonic acid, 2 g of sodium propyl-4-hydroxybenzoate, 7 g of methyl-4-hydroxybenzoate are aspirated by vacuum and recirculation into the container of the homogenization apparatus. of sodium, 0.25 g of amaranth, 6 g of olive oil embonate, 1.5 g of raspberry aroma and 1100 g of xylite. Eventually, adjust the pH of the suspension to 6.5 with IN caustic soda.

Rinse the container with water and make up to 5000 ml with the final desired volume of water. The suspension is homogenized for 15 min, under vacuum and recirculation.

The suspension thus obtained is a viscous red juice.

Viscosity = 0.1-0.15 pascal according to (Pa, s).

_P H = 6.3-6.7

Density = 1.09-1.11 g / ml

Aroma: raspberry.

Palate: the aroma of raspberry.

Claims (1)

- 15 Process for the preparation of azelaxin embonate characterized by the fact that one mole of embonic acid (which may be in the form of a salt) is reacted with 2 to 2.4 moles of azelastine or with 2 to 2.4 moles moles of an azelastine acid addition salt, in a hydrophilic solvent or in a mixture of solvents, in alcohol-ether mixtures or in halogenated alcohol-hydrocarbon mixtures, at a temperature between 18 and 150 ° C. - 25 Process for the preparation of compositions containing azelastine embonate as an active ingredient, characterized by the fact that azelastine embonate is mixed as a therapeutically usable composition at a temperature between 15 and 80 ° C, together with substances carrier or pharmaceutical diluents, or with other auxiliary substances, thus obtaining solid compositions containing per dosage unit 0.5 to 30 mg of azelastine embonate and suspensions with 3 to 3000 mg of azelastine embonate in 100 ml of the suspension. - 3 ^a Process for the preparation of a suspension containing azelastine embonate as an active ingredient, characterized by the fact that it is homogenized at a temperature between 15 and 80 ° C and up to 3000 mg of azelastine embonate with possibly humectant thickeners, preservatives, sweetness. flavors and flavorings, as well as dyes, in water or in mixtures of water and other physiologically acceptable liquids miscible with water, the suspension thus obtained containing the aforementioned quantity of azelastine embonate in 100 ml of the suspension, and possibly adjusting to suspension to a pH between 3 ® 9 · - 4 & Process for the preparation of an aqueous suspension containing azelastine embonate as an active ingredient, characterized in that it is prepared, at a purchased temperature; between 15 and 80 ° C, a homogeneous mixture containing 3 to 3000 mg of azelastine embonate (per 100 ml of the suspension) hem as preservatives, sweeteners, dyes and flavorings, using each 100 ml of the suspension 0.001 to 30 g of preservatives (total amount), 0.005 to 6θ g of sweeteners, 0.001 to 1.0 g of dyes and 0.001 to 10 g of flavorings, and mix this mixture at a temperature between 15 and 80 ° C with a solution from 0.1 to 10 g of a thickener in water (referring to 100 ml of final suspension) and up to 60% by weight of water can be replaced by other physiologically acceptable liquids miscible with water, of possibly adjusting the pH of the suspension as well obtained at a value between 3 θ 9 by adding acids, bases or acid salts, and possibly adding the rest of the flavorings and / or sweeteners not yet fully incorporated. = l6 = Process for preparing a suspension containing azelastine embonate as an active ingredient according to claim 4, characterized in that during the preparation of the suspension 1 to 10% of humectants (referred to 100 ml of the final suspension) are added. - 6 & Process for the preparation of a suspension containing azelastine embonate as an active ingredient, characterized by the fact that at a temperature between -55 ° C to + 55 ° ^c , 3 to 3000 mg of azelaxine embonate in 100 ml of a mixture of fluorinated and chlorinated hydrocarbons and / or hydrocarbons, with the addition of 0.25 to 3 g of sorbitan trioleate, as well as possibly other auxiliary substances, and the suspension obtained is packed in closed containers with dosing valves that release , each time they are activated, 0.025 to 0.1 ml of the suspension. - 7 * Process for the preparation of a solid composition containing as active ingredient 0.5 to 30 mg of azelastine embonate in the dosage unit, characterized in that the azelastine embonate is mixed with at least one of the auxiliary substances starch, cellulose, cellulosic ether, sugars, hexite, calcium hydrogen phosphate, calcium phosphate, modified starches, alginate, pectin, carboxymethyl cellulose, ultraamylopectin, bentonite, polyvinylpyrrolidone, granulate the mixture with an aqueous solution of gelatin or starch solution or with a copolymer aqueous vinylpyrrolidone-vihilacetate, and to mold tablets or fill capsules with the granulate thus obtained, possibly with the use of stearates, stearic acid, talc, polyglycols and / or silica, as well as possibly also starches and / or cellulose, or put in suspension or homogenize, possibly after the addition of soy lecithin, at temperatures between 33 and 3 7 ° O in fused solid fats, and then the mixture is poured into hollow molds, which may be added to the solid composition during the preparation process, possibly also anti-binders, resorption accelerators, hydrophilic agents and / or moisture absorbers . ft The applicant declares that the first application for this patent was filed in the German Federal Republic on 13