DK170339B1 - Azelastine Embonate, Method of Preparation, Preparations Containing, and Stable, Aqueous Suspensions of this Compound, and Use of Azelastine Embonate in the Preparation of Medicines - Google Patents

Abstract

Azelastine embonate and pharmaceutical compositions which contain azelastine embonate as the active ingredient.

Description

t DK 170339 B1

The invention relates to a novel acid addition salt of azelastine, a process for its preparation, compositions containing, and stable aqueous suspensions of this compound, and to the use of azelastine embonate for the manufacture of drugs.

Azelastine is an active agent with antiallergic and asthma prophylactic effects. The chemical designation is: 4- (p-Chlorobenzyl) -2-hexahydro-1-methyllazepin-4-yl-1- (2H) -phthalazinone (see German Patent No. 21 64 058).

An important method of use of azelastine as an allergic agent is oral administration, especially as tablets, capsules, solutions or suspensions, in addition also administration as aerosols.

However, the use of azelastine as solutions or suspensions has not been possible until now, as azelastine has such a bitter taste that any attempt at oral administration of such azelastine solutions or azelastine suspensions will be rejected by the patients. This bitter taste has not been able to be removed even by transferring to the most diverse salts.

It has now surprisingly been found that by salt formation between azelastine and embonic acid, a product which no longer has the above-mentioned pervasive bitter taste is obtained and is therefore suitable for use e.g. in preparations for oral intake. This azelastine embonate is a salt between azelastine and embonic acid, this salt consisting of 2 moles of azelastine and 1 mole of embonic acid (see Example 1).

Accordingly, the azelastine acid addition salt of the invention is peculiar in that it is azelastine embonate.

Azelastine embonate of the invention is particularly suitable for the preparation of pharmaceutical compositions for oral administration with azelastine in the form of stable suspensions, e.g. like a juice. Of course, the composition of the invention may also be used for the preparation of other pharmaceutical preparations with azelastine such as e.g. tablets, capsules or sprays. The compositions of the invention are characterized in that they contain as active agent azelastine embonate, optionally together with usual physiologically useful excipients, carriers and / or diluents. .

If the azelastine embonate of the invention is used to prepare stable aqueous suspensions, such a property is characterized in that it contains, as active agent 10, 3-3000 mg of azelastine embonate per day. 100 ml of suspension, the suspension having a pH of 3-9.

The suspensions of the invention preferably contain 15-240 mg and especially 60-120 mg azelastine embonate per day. 100 ml suspension. Preferably, 15 azelastine embonate having a particle size below 100 microns is used. The pH of such a suspension is preferably in the range 5-8, especially 6-7.

Particularly useful is an azelastine emulsion suspension which forms a thixotropic system which has a high viscosity at rest, whose structure, however, breaks down by a weak mechanical influence (e.g., by pouring), whereby the suspension, e.g. the juice can be brought to flow.

For preparing such a thixotropic suspension in water, e.g. apply swelling agents.

Examples of such swelling agents are: natural macromolecules (e.g., alginates, peptines, tragacanth, hydrocolloid polysaccharides such as xanthan gum), semi-synthetic macromolecules (e.g., cellulose ethers), synthetic macromolecules (e.g., polyacrylates or polyvinylpyrrolides). ) as well as inorganic agents for the formation of hydrogels (e.g., colloidal silicic acid or ben- tonite). These swelling agents can be used alone or as mixtures thereof. Xanthan gum compositions have proved particularly suitable for the preparation of stable liquid-liquid suspensions due to their pronounced thixotropic properties.

3 GB 170339 B1 Such swelling agents can be used alone or in mixtures. The total amount of swelling agents per 100 ml suspension is e.g. When using xanthan gum, the amount of 5 xanthan gum is e.g. 0.1-3, preferably 0.3-1.5, especially 0.5-1 g, the amount of polyacrylates is 0.1-1 g, the amount of alginates and tragacanth is 0.1-0.2 g, the amount of pectins or cellulose ethers is 0.5-5 g and the amount of polyvinylpyrrolidone or inorganic agents for the formation of hydrogels is 1-10 g (overall per 100 ml suspension).

In addition, the azelastine carbonate suspensions of the invention optionally contain the usual pharmaceutically useful preservatives, sweeteners, flavorings and dyes.

Examples of preservatives: organic acids (eg sorbic acid or benzoic acid), phenols (eg lower alkyl esters of p-hydroxybenzoic acid), organic mercury compounds (eg thiomersal), quaternary ammonium compounds (e.g. benzethonium chloride), aromatic and aliphatic alcohols (eg 1,2-propylene glycol or benzyl alcohol) and chlorhexidine. The preservatives can also be used as their salts (e.g., alkali salts such as sodium benzoate) and, of course, also as mixtures thereof.

The amount of preservative in 100 ml of suspension can for sorbic acid e.g. be 0.05-1.0 g, for benzoic acid 0.1-0.2 g, for thiomersal 0.001-0.01 g, for benzethonium chloride 0.005-0.02 g, for 1,2-propylene glycol 10- 30 g, for benzyl alcohol 1.0-2.0 g and for chlorhexidine 0.001-0.01 g.

Preferably, a mixture of lower alkyl esters of p-hydroxybenzoic acid is used. The sum of the lower alkyl esters of p-hydroxybenzoic acid is 100 ml suspension for example. 0.1-0.3 g, preferably 0.15-0.25 g, especially 0.15-0.20 g.

4 DK 170339 B1

Examples of sweeteners are: saccharin, cyclamate, aspartame, fructose, sucrose, sorbitol, mannitol and preferably xylitol. The amount of sweetener, of course, depends on the sweetness. In general, the amount per

100 ml suspension for saccharin 0.005-0.1 g, for cyclone 0.5-2.0 g, for aspartame 0.005-0.3 g, for fructose, sucrose, sorbitol and mannitol 1.0-60 g. xylitol is this amount, for example, 1-60, preferably 15-60, and especially 30-40 g.

10 Examples of flavors are: essential oils (eg peppermint oil, lemon balm oil or lemon oil), fruit extracts (eg from lemons, grapefruit or pineapple), aromatic plant extracts (from licorice root, anise or fennel) as well as natural identical and synthetic flavors . An example of a particularly suitable flavoring is raspberry flavor.

The amount of flavorings is e.g. per. 100 ml suspension between 0.001-5 or optionally 10, preferably 0.01-1, in particular 0.01-0.1 g. using 0.01-0.1, preferably 0.01-0.05, especially 0.02-0.04 g per 100 ml suspension.

Examples of dyes are: the usual ones. soluble dyes for food, dyes from natural foods (eg curcumin, riboflavin, chlorophyll or xanthophylls), synthetic organic dyes (azo dyes or azo dyes), inorganic synthetic dyes (eg titanium dioxide or iron oxides). Particularly suitable are synthetic azo dyes such as e.g. amaranth.

The amount of dyes can e.g. range from 0.001 to 1.0, preferably 0.001 to 0.1, especially 0.001 to 0.01 g per minute.

100 ml suspension. For amaranth, for example. using 1-10, preferably 1-5, especially 2-4 mg per day. 100 ml suspension * 35 sion.

The adjustment to the required pH value can conveniently be carried out by means of inorganic acids (hydrochloric acid, sulfuric acid or phosphoric acid), organic acids (eg citric or maleic acid), inorganic bases (eg sodium hydroxide or potassium hydroxide). or by salts usually used for such purpose (e.g., ammonium chloride, sodium citrate, or sodium dihydrogen phosphate).

In the preparation of suspensions of azelastine embonate according to the invention, in addition to water, other physiologically acceptable liquids can be used. Examples of 10 such liquids are: monovalent and polyhydric lower alcohols, e.g. ethanol, propylene glycol, glycerol and polyglycols with molecular weights of 200-600. Mixtures of these liquids can also be used with each other or with water. Other examples of liquid carriers are: 15 natural oils (e.g., olive oil), synthetic and semi-synthetic oily liquid pharmaceutical carriers, such as 8-12 C saturated saturated plant acids and mixtures thereof.

However, a purely aqueous suspension is preferably used.

If mixtures of water and other liquids are used, it may e.g. be mixtures in which the proportion of non-water is 1-60, preferably 10-40, and especially 20-30% by weight, calculated on 100 g of suspension.

Optionally, network forming agents may also be added to the suspensions of the invention. Examples of such network forming agents are: anionic surfactants, e.g. soaps, fatty alcohol sulfates, non-ionic surfactants, e.g. polyethylene glycol fatty acid esters (MyrjR), polyethylene glycol fatty alcohol ethers (Brij), sorbitan fatty acid esters (SpanR), polyethylene glycol sorbitan fatty acid esters (TweenR), polyethylene glycol polypropylene glycol derivatives (Pluronics). It is preferred to use sorbitan fatty acid esters (with saturated or unsaturated aliphatic carboxylic acids of 10-20 carbon atoms), polyoxyethylene fatty alcohol ethers (alcohols with 10-20 carbon atoms) and polyethylene glycol sorbitan carboxylic acid esters (saturated 20 carbon atoms.) The amount of network forming agents per 100 ml of suspension may e.g. constitute: 1-10-5, preferably 0.5-0.001, in particular 0.1-0.01 g. The network forming agents should cause an optimum dispersion of the undissolved active agent. Optionally, tests should be performed to find the optimal amount for the network-forming agent used.

For example, the azelastine embonate suspension of the invention may have viscosities of 0.05-0.22, preferably 0.09-0.18, and most preferably 0.12-0.15 Pa * s at a shear rate of 110 second in a rotational viscometer.

In addition, embonic acid can further be added to the azelastine embonate suspensions of the invention. Pr.

For example, 100 ml of suspension may be used. add 1-2000 mg, preferably 20-1000 mg, and especially 50-150 mg of embonic acid in addition to the already present azelastine embonate.

Surprisingly, the excess of embonic acid improves the taste.

In order to make suspensions with propellants (aerosols), conventional propellants 25 (propane, butane or fluorochlorohydrocarbons) may be used in addition to the auxiliary substances respectively. For example, for use in such suspensions, azelastine embonate must have a particle size with a diameter of 5-10 microns.

One can, for example. prepare such aerosols, dispersing at a temperature of -55-55 ° C, 3-3000 mg azelastine embonate in 100 ml of a mixture of chlorinated fluorinated hydrocarbons and / or hydrocarbons with the addition of 0.25-3 g of sorbitan trioleate and, optionally, additional auxiliaries and filling the provided suspension on cans closed with metering valves, e.g. such as per operation releases 0.025-0.1 ml of the suspension.

7 DK 170339 B1

Preparation of azelastine embonate of this particle size is accomplished by grinding in a conventional micronizer.

The usual pharmaceutical auxiliaries and carriers are used for the preparation of other oral preparations with azelastine embonate. For example, for tablets, the following adjuvants or carriers are used (amount by weight% per tablet).

Fillers (5-95%): e.g. starch, cellulose, milk sugar, sucrose, fructose, sorbitol, mannitol or calcium phosphate.

Binders (1-80%): gelatin, cellulose ethers, pectins, alginates, polyvinylpyrrolidone, lactose or microcrystalline cellulose.

Explosives (1-10%): alginates, starch, pectins, carboxymethyl cellulose, polyvinylpyrrolidone, ultramylopectin or bentonites. 1 2 3 4 5 6 7 8 9 10 11

Lubricants (0.2-10%): stearic acid, stearates, polygly-.

2 cols, talc or high dispersion 3 silica.

In addition, the tablets may contain: adhesives, resorbents, hydrophilizers, water-binding agents, and the like, 7 agents. Coated tablets 8 are often prepared which may optionally also contain suitable film 9 forming agents and coating materials as well as dyes 10, softening agents and polishing agents.

11

Said fillers, binders and lubricants can also be used with other oral preparations (capsules, granules and the like).

8 DK 170339 B1

Tablets as well as other oral preparations (capsules or granules) may e.g. contain 0.5-30 mg, preferably 1-20 mg, and most preferably 1.5-12 mg azelastine embonate.

The method according to the invention is characterized by the characterizing part of claim 4.

Examples of suitable solvents for this are: lower aliphatic C ^-Cg alcohols (methanol, ethanol, propanol, isopropanol or butanol), lower aliphatic ketones C3-C8 (acetone, methylethyl ketone), glycol ether, cyclic ethers (dioxane, tetrahydrofuran) , esters of lower aliphatic carboxylic acids with lower aliphatic alcohols, amides and N-alkyl substituted amides of aliphatic C 1 -C 2 carboxylic acids (dimethylformamide, dimethylacetamide), C 1 -C 6 dialkylsulfones (dimethylsulfone, tetramethylene sulfone), dimethylsulfoxide) and additional aprotic agents such as N-methylpyrrolidone, tetramethylurea, hexamethylphosphoric triamide or acetonitrile, mixtures of these agents with one another, and mixtures with water. For 20 aqueous mixtures, the water content is usually not higher than 30% by volume. Further, the reaction can be carried out in alcohol-ether mixtures, whereby e.g. uses aliphatic C 2 -C 8 ethers and cyclic ethers. Furthermore, the reaction is possible in mixtures of 25 lower aliphatic alcohols with halogenated aliphatic or aromatic hydrocarbons.

Azelastine and embonic acid are introduced in a 2: 1 ratio.

It is preferred to use an excess of azelastine of 1-20, in particular 1-5%, based on the amount of 30 embonic acid needed to achieve the above-mentioned ratio.

If you use azelastine as a salt thereof ,? one can hereby, e.g. use salts with the following acids: strong and medium inorganic acids (halohydric acids such as HCl, HBr, nitric acid, phosphoric acid, sulfuric acid), strong and weak organic acids.

9 DK 170339 B1 such as aliphatic and aromatic sulfonic acids (methanesulfonic acid, toluenesulfonic acid), aliphatic saturated and unsaturated mono- and polyhydric carboxylic acids, aromatic carboxylic acids (benzoic acid, toluene carboxylic acid). The embryonic acid can also be used as a salt thereof. As salts of embonic acid, one can mention: aliphatic metal salts (Na, K,

Li), alkaline earth metal salts, magnesium salts, ammonium salts and alkylammonium salts.

The pharmaceutical azelastine embonate preparations are prepared by admixing, respectively, homogenizing, the azelastine embonate and the usual adjuvants and carriers at temperatures between 15-80, preferably 18-40 and more preferably 20-30 ° C. Optionally, to reduce the seed count (sterilization), 15-60 minutes can be heated to 80-140, preferably 110-125 ° C.

In preparing suspensions, for example, Proceed as follows: The swelling agent (0.1-10, preferably 0.3-1.5 g per 100 ml suspension and optionally part of the other excipients) is dissolved in water, respectively in one of the others mentioned. liquids or mixtures of liquids at 20-30 ° C using so much water or liquid, respectively, that the final suspension contains 0.03-30, preferably 0.4-6, and most preferably 0.8-1.2 liters water, respectively liquid per 1 g of azelastine embonate.

The aqueous solution thus obtained can then be heated 10-120, preferably 15-60 minutes to 80-134 ° C, preferably for 20-30 minutes to 110-121 ° C. After cooling to 25-35 ° C, one may optionally add to this solution a networking agent and then add a mixture of azelastine embonate prepared at a temperature of 20-30 ° C and optionally preservatives, sweeteners, dyes and optionally flavorings and further auxiliaries. and / or carriers, and homogenize the mixture at a temperature of 15-35 ° C, preferably at 20-30 ° G.

Then you can optionally add flavorings and adjust the pH to 3-9.

10 DK 170339 B1

In preparing the aforementioned azela-stoninate suspension, for example, for each 1 g of aze cargo embonate use:

A

0.005-600 g, preferably 300-400 g sweetener; 0.01 to 10 g, preferably 0.2 to 0.4 g of flavor.

Optionally, a portion of the amount of flavoring r listed here may also be added to the suspension later.

Example 1 10

Azelastine Embryo Afrya Tjooh · 15 in C— <2OQ- <h> - «3 + igoo ) azelastine hydrochloride in 4500 ml of 80% ethanol with stirring. After the addition of 90.6 g (0.21 mol) of embonic acid, disodium salt, stir for an additional ca. 4 minutes until dissolved.

Filter immediately through a folding filter and allow the filtrate to stand overnight. The embonate precipitates rapidly. It is filtered off with suction, washed with 80% ethanol and then with pure ethanol and dried for 20 hours under vacuum at 60 ° C. Yield.

195 g (80% of theory).

For further purification, the product thus obtained is stirred for 5 hours in ice-water, filtered off 35 under suction, washed first with ice-water and then with ethanol, and dried under vacuum for 20 hours at 60 ° C.

11 DK 170339 B1

Yield 195 g (80% of theory). The azelastine package is available as a crystalline, slightly yellowish powder.

Mp: 197-201 ° C.

5 The IR spectrum is shown in FIG. First

An NMR spectrum is seen in FIG. 2nd

Example 2 Azelastine Embonate Suspension 3000 ml suspension, corresponding to 3300 g, contains:

Azelastine embonate 3,600 g Xanthan gum 21,000 g

Xylitol 1200,000 g

Sodium propyl 4-hydroxybenzoate (Na salt of 4-hydroxybenzoic acid propyl ester 1,200 g

Sodium methyl 4-hydroxybenzoate (Na salt of 4-hydroxybenzoic acid methyl ester 4,200 g

Hydrochloric acid, 1 N 21,000 g (a)

Raspberry flavor 0.900 g

Amaranth (allowed red dye) 0.150 g

Purified water 2047,950 g 25 3300,000 g a) The hydrochloric acid is used to adjust the pH to 6.5. If a different amount of hydrochloric acid is used, the amount of purified water is adjusted accordingly.

35 12 DK 170339 B1

Preparation:

800.0 g of xylitol and 21.0 g of xanthan gum are dissolved in 2000 g of water in a 3000 ml beaker with stirring. The solution is then autoclaved for 30 minutes at 115 ° C. After cooling to approx. 40 ° C is sucked into the solution under vacuum and recirculated in the working container of a homogenizer.

400.0 g of xylitol, 1.2 g of sodium propyl-4-hydroxybenzoate, 4.2 g of sodium methyl-4-hydroxybenzoate, 0.15 g of amaranth and 3.6 g of azelastine embonate in a porcelain dish are suctioned in the solution prepared above in the working vessel of the homogenizer.

Now 0.9 g of raspberry aroma and 21.0 g of hydrochloric acid are sucked under vacuum and recirculated into the working vessel of the homogenizer, after which the suspension is homogenized for 15 minutes. The pH of this suspension is adjusted by adding hydrochloric acid 20 to 6.5. The consumption of hydrochloric acid is balanced by a smaller consumption of purified water. The formula for calculating the required amount of water is: 47.95 g - hydrochloric acid used in g = amount of water in g.

The suspension provided is a viscous, red-colored juice (pH 6.3-6.7).

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

Fragrance: like raspberry Taste: raspberry flavor 30 Viscosity: 0.1-0.15 Pa * s.

The juice (stock item) can e.g. Filled on small * bottles of brown glass with screw cap. The filling must be done so slowly that no air is entrained.

The juice can, for example. stored at room temperature. ** 35 DK 170339 B1 13

Example 3

Azelastine Bonding Suspension 5 5000 ml suspension, corresponding to 5500 g, contains:

Azelastine Embonate 6,000 g (1)

Xanthan gum 32,500 g

Xylitol 1500,000 g Sodium propyl 4-hydroxybenzoate 2,000 g

Sodium methyl 4-hydroxybenzoate 7,000 g

Embryonic acid 5,000 g

Raspberry flavor 1,500 g

Amaranth (red dye) 0.250 g Citric acid 64,000 g

Sodium hydroxide 32,500 g

Purified Water 3849,250 g (2) 5500,000 g 1) Prior to preparation, azelastine embonate 20 is sieved through a mesh of 100 µm mesh.

2) Optionally adjust the pH of the suspension with 1 N sodium hydroxide to 6.5. Consumption of sodium hydroxide is matched with less water consumption.

25

Preparation: I. 400 g of xylitol and 32.5 g of xanthan gum are triturated with each other and this mixture is dissolved in 3000 g of water with stirring, after which the solution is autoclaved for 30 minutes at 115 ° C. The water evaporated by autoclaving is replaced. After cooling to approx. At 30 ° C, the solution is sucked under vacuum and recirculated into the working vessel on a homogenizer.

3 14 DK 170339 B1 II. In the order indicated, 64 g of citric acid, 5 g of embonic acid, 2 g of sodium propyl 4-hydroxybenzoate, 7 g of sodium methyl 4-hydroxybenzoate, 0.25 g of amaranth, 6 g of azelastine embonate, 5 g of raspberry aroma and 1100 g of xylitol under vacuum and recycling in the working container of the * homogenizer. Optionally, adjust the pH by means of 1 N sodium hydroxide solution to 6.5.

10 Rinse with water and make up to a final volume of 5000 ml. Now, the suspension is homogenized for 15 minutes under vacuum and recycling.

The suspension thus obtained is a certain juice of red juice.

Viscosity = 0.1-0.15 Pa * s. pH = 6.3 - 6.7

Density = 1.09 - 1.11 g / ml

Odor: like raspberry 20 Taste: raspberry flavor

Claims (5)

DK 170339 B1 1. Acid addition salt of azelastine, characterized in that it is azelastine embonate. 2. Compositions characterized in that they contain, as active agent, azelastine embonate, optionally together with conventional physiologically useful excipients, carriers and / or diluents. 3. Stable aqueous suspension, characterized in that it contains as an active agent 3-3000 mg azelastine embonate per day. 100 ml of suspension, the suspension having a pH of 3-9. Process for the preparation of azelastine embonate, characterized by reacting 1 mole of embonic acid (optionally in the form of a salt) with 2-2.4 moles of azelastine or with 2-2.4 moles of an acid addition salt of azelastine, in a hydrophilic solvent or mixture of solvents, especially alcohol-ether mixtures or alcohol-halohydrocarbon mixtures, at a temperature of 18-150 ° C. 5. Use of azelastine embonate for the preparation. drug delivery.