SI8812092A - PROCEDURE FOR THE MANUFACTURE OF MEDICINAL PRODUCTS CONTAINING AZELASTINE FOR USE IN THE NOSE AND / OR THE EYE - Google Patents

Abstract

A process for the production of medicinal preparations containing azelastine for use in the nose and/or eye, characterized in that 1 to 1000 mg of azelastine, or its physiologically acceptable salt, is dissolved in 50 to 200 ml of water, which may contain up to 15% (weight fraction) of an acceptable solvent, at a temperature of -55 degrees Celsius to +80 degrees Celsius, and simultaneously or later 1 to 400 mg of a preservative and 50 to 4000 mg of a stabilizing agent or solubility enhancer are added, and optionally the solution is brought to a pH of 6.5 to 7.1 using buffers, and optionally an isotonic agent is added, after which the solution thus obtained is converted into a gel by adding 0.5 to 10 g of a thickening agent. According to variants of the process, the above preparation is also produced in the form of an emulsion, suspension or capsules.

Description

PROCEDURE FOR THE PRODUCTION OF MEDICINAL PRODUCTS CONTAINING AZELASTINE FOR USE IN THE NOSE AND / OR THE EYE

TECHNICAL FIELD

The invention is in the field of pharmaceutical chemistry and relates to a new process for the manufacture of medicinal preparations containing azelastine used in the nose and / or eye.

TECHNICAL PROBLEM

A technical problem to be solved by the present invention is how to produce a well-acceptable and relatively effective azelastine-based preparation, or salts thereof, for the treatment of both allergic and vasomotor and rhino-virus effects and their associated phenomena.

BACKGROUND OF THE INVENTION

Various preparations for the treatment of various types of apparitions and their accompanying phenomena are known, but due to their disadvantages, e.g. fatigue, prolonged use, risk of damage to the mucous membranes and the like, there is a need to find more acceptable and more effective remedies.

Azelastine, which is a phthalazinone derivative, i.e. 4- (4-chlorobenzyl) -2- (perhydro-1-methyl-azepin-4-yl) -1- (2H) phthalazinone, has so far been used specifically for the prophylaxis of asthma, it also has anti-allergic and antihistamine properties (see German Patent No. 21 64 058). Until now, azelastine has not been used in the treatment of nasal fever, inter alia because of its strong penetrating bitter taste, which prevented any oral use of the azelastine solution.

-2 DESCRIPTION OF THE TECHNICAL PROBLEM SOLUTION WITH PB1 MEASUREMENTS

This technical problem of the invention is solved by a new process for the production of sterile medicinal preparations containing azelastine for use in the nose and / or eye. Azelastine has the following structural formula ci

The process of the invention is characterized by dissolving from 1 to 1000 mg of azelastine or some physiologically acceptable azelastine salt in 50 to 200 ml of water, possibly containing up to 15% (by weight, at temperatures between - 55 ⁰ and + 80 ° C). ) acceptable water miscible solvent and at the same time or later add 1 to 400 mg of preservative, 50 to 4000 mg of stabilizing agent, or solubility enhancer, and possibly bring the solution by buffer to a pH of 6.5 to 7 , 1, as well as possibly adding an isotonic agent.

The solution thus obtained can be converted to gel by adding 0.5 to 10 g of thickening agent.

Alternative variants of the process of the invention are characterized in that 7.5 mg to 10 g of azelastine, or a physiologically acceptable salt of azelastine, is dissolved in 400 to 900 ml of water with the simultaneous or subsequent addition of 10 - 200 mg of preservative, the solution is emulsified in 100 - 600 g of a solution consisting of a mixture of hydrocarbons and / or silicones and / or other ingredients containing fats (fats, fatty alcohols) and emulsifiers, homogenizing the resulting emulsion and allowing it to cool to room temperature; or

-3to 0.05 to 100 g of azelastine, or a physiologically acceptable salt of azelastine, is dispersed in 5 to 10 kg of a mixture consisting of chlorinated fluorinated hydrocarbons and / or hydrocarbons with the addition of 25 to 150 g of sorbitan trioleate and the suspension thus obtained is filled into doses which are closed or closed by metering valves and which release 0.025 to 0.1 ml of suspension upon activation; or that 5 mg to 10 g of azelastine, or some physiologically acceptable salts of azelastin are mixed with 50 to 1000 g of a physiologically inert carrier of the substance, or that a solution of said amount of azelastin or some physiologically acceptable salts of azelastine is optionally mixed in portions with that amount of an inert carrier of the substance and thereafter the solvent was re-evaporated and the resulting mixture in an amount of 20 to 1000 mg was filled into hard gelatin capsules or bags.

The preparations thus obtained have been found to have a particularly beneficial and surprising effect when used in the nose and / or the corner of the eye.

In this way elimination or significant alleviation of not only allergic conditioned rhinitis (nahoda) is achieved, but also in normal everyday naus (caused, for example, by the action of rhinoviruses), as well as in vasomotor nausea and symptoms resulting from it.

It is surprising that local nasal use also achieves some beneficial effect on the mucous membranes of the eye (eliminating or reducing the redness of the eye and itching of the eye), so that there is often additional use in the form of eye drops.

Further indications for application / use according to the invention are, for example: non-specific conjunctivitis, allergic conditioned conjunctivitis, allergic eyelid edema, catarrhal conditions in the eye or nose, coryza.

It has been surprisingly observed that the use of the composition of the invention does not produce the fatigue that is common in other applications.

Furthermore, azelastine has a very strong penetrating bitter taste that has been prevented so far

-4 any oral administration of azelastin solution because patients refuse such azelastine solutions or suspensions.

The degree of bitterness is so intense that it becomes unpleasant even in solution, that is, in a dilution of 1: 10 ⁶ . As a surprise, the demonstration experiments showed that when spraying the preparations with azelastine according to the invention into the nose, no longer tastes bitter and that solutions or suspensions of azelastine and its salts can be applied nasally without any affects the taste. Even if a dispersed solution or suspension with elastin comes into the pharynx, the bitter taste can hardly appear.

The object of the invention is therefore to provide a well-acceptable and improved azelastine-based preparation, or salts thereof, for the treatment of both allergic and vasomotor-induced and rhino-viros occurrences and their associated phenomena.

A preferred embodiment of the invention is a sterile and persistent aqueous solution of azelastine, or salts thereof, used in the form of droplets, ointments, creams, jellies, blowing powders, or a particular spray form (preferably spray). for the nose) in which the spray is used with the help of a regular spray bottle or small pump. Further, this can be done in the form of a pressurized aerosol device. All of these should release the pressure of your finger, for example, 0.03 to 3 mg azelastine base.

When using nasal drops or some nasal spray used to treat nasal congestion, azelastine dosage is approximately 10% less, thus reducing the possibility of side effects such as, for example, using oral azelastine. form, e.g. in the form of pills or juices that flood the entire body with the active substance. Particularly in the treatment of a common disease such as, for example, It is essential to find a low rate of side effects and therefore this preparation is a very important medical advance.

Preferably, the solvents for the compositions of the invention are: water, saturated aliphatic one and polyvalent alcohols with 2 - 3 C atoms (for example ethanol, isopropanol,

-51,2-propylene glycol, glycerol), liquid polyglycols (molar mass 200 to 600).

Preferably, the solvent is water, or a mixture of water with other physiologically acceptable solvents, for example, with the aforementioned, whereby the amount of solvent in the aqueous mixture should not exceed 15% (by weight).

The solutions or preparations preferably contain preservatives and stabilizers. Examples of such agents include: ethylenediaminetetraacetic acid (edetic acid) and its alkali salts (for example, dialkal salts such as disodium salt, calcium salt, calcium - sodium salt), lower p-hydroxybenzoic acid alkyl ester, chlorhexidine (e.g. in the form of acetate or gluconate), phenyl mercury borate. Furthermore, for example, sodium- (2-ethylmercuritio) -benzoate, commonly known as piomersal, which may be present in the compositions of the invention in an amount of from 0.001 to 0.05, preferably from 0.005 to 0.02, for example 0.01% (weight / volume in liquid preparations, otherwise mass / mass). Further suitable preservatives are: pharmaceutically usable quaternary ammonium compounds, for example cetyl pyridinium chloride, tetradecyl trimethyl-ammonium bromide known as cetrimide, benzyl dimethyl- [2- / 2- / p- (1,1,3,3-tetramethylbutyl) ) / - phenoxy / ethoxy / -ammonium chloride, known as benzentonium chloride and myristyl-γ-picolinium chloride, using each of these compounds at a concentration of 0.002 to 0.05, for example 0.02% (weight / volume at liquid preparations, otherwise mass / mass). Among the quaternary ammonium compounds, however, are the preserving agents which are preferred alkyl benzyl dimethyl ammonium chlorides and mixtures thereof, for example compounds commonly known as benzalkonium chloride. The latter consists of a mixture of compounds of formula

-6 in which R represents an alkyl group of the formula ^ H ^^, where n denotes an integer from 8 to 18. Particular preference is given to the use of a mixture of compounds wherein n is a number of 10 to 14 and the special compounds used therein, are those for which R = C ₁₂ H ₂₅ . Benzalkonium chloride and the compounds of the above formula may be used in concentrations of 0.005 to 0.10, preferably 0.005 to 0.05, for example 0.01% (weight / volume in liquid preparations, otherwise, weight / weight), and may be given for example, in combination with 0.2 to 2.0 for example 0.4% (w / v) of 2-phenyl ethanol.

The compositions of the invention (solutions, suspensions, as well as oily solutions or suspensions, ointments, emulsions, creams, jellies, aerosol dispensers) contain 0.0005 to 2, preferably 0.001 to 1, especially 0.003 to 0.5% (weight / weight) azelastine (relative to free azelastine base). If azelastine is in the form of salts, these quantities should therefore be appropriately calculated. The same concentrations of azelastine as in the nasal form are also applicable to eye drops.

When used in powder form, the concentration of azelastine base is 0.0005 to 2% by weight relative to solids.

In the case of solutions, the dosage per nasal cavity, for example 0.01 to 0.2 ml, in particular 0.05 to 0.15 ml, should be administered once or several times, preferably once to five times daily (possibly every hour).

When used in the eye (as eye drops), the dosage, for example, is 1 drop (about 0.05 ml) of solution or an appropriate amount of semi-solid formulation.

For example, the acid components for azelastine salts are: hydrogen halide / = aqueous hydrogen halide solutions - op. (HCI, HBr), sulfuric (VI) acid, phosphoric acid (H ₃ PO ₄ , metaphosphoric acid, polyphosphoric acids), nitric acid, organic mono-, di- or tricarboxylic acids, namely aliphatic, alicyclic, aromatic or heterocyclic organic acids (embonic acid, citric acid, tartaric acid), aliphatic and aromatic sulfonic acids (for example, caffeic sulfonic acid)

The total amount of preservatives in the preparations (solutions, ointments, etc.) is per 100 ml

-7 solutions / suspensions, respectively 100 g of the preparation, between 0.001 and 0.10 and preferably 0.01 9 ·

For certain substances, the following quantities may be considered as preservatives, for example:

thiomersal 0.002 - 0.02% benzalkonium chloride 0.002 - 0.02% (when combined with thiomersal the amount of thiomersal, for example 0.002 to 0.005%) chlorhexidine acetate or -gluconate 0.01 to 0.02% phenyl mercury nitrate, - borate, -acetate 0.002 - 0.004% p-hydroxybenzoic acid ester (for example a mixture of methyl ester and propyl ester 7: 3) 0.05 0.15 and preferably 0.1%.

Preferably, the combination of ethylenediaminetetraacetic acid (for example as disodium salt) and benzalkonium chloride is used as a preservative, using ethylenediaminetetraacetic acid at a concentration of 0.005 to 0.1% and benzalkonium chloride at a concentration of 0.005 to 0.05% and preferably 0.1 %.

For concentrations in%, the solutions / suspensions are always the weight / volume ratio and the solid or semi-solid preparations are the weight (weight / weight) of the preparation.

Other excipients for the compositions of the invention include, for example: polyvinylpyrrolidone, sorbitan fatty acid esters such as sorbitan trioleate, polyethoxylated sorbitan fatty acid esters (for example polyethoxylated sorbitan trioleate), sorbimacetinetrololate, ethylene oxide ethers of octyl-phenol-formaldehyde condensation products, phosphatides such as lecithin, polyethoxylated fats, polyethoxylated oleotriglycerides, polyethoxylated fatty alcohols. Here, the term polyethoxylated means that it contains an appropriate substance of a polyoxyethylene chain, the polymerization step of which is generally between two and forty (2 - 40) and especially between 10 and 20. These substances are used primarily to improve the solubility of the azelastine component.

In the case of formulations containing water, isotonic agents may also be added. Suitable isotonic agents, for example: sucrose, glucose, glycerol,

-8sorbit, 1,2-propylene glycol, NaCl.

Isotonic agents allow the osmotic pressure of the preparations to be adjusted to that of the nasal secretions.

For this purpose, we always use so much of these substances that, for example, in the case of a solution, the freezing point is reduced by 0.50 to 0.56 ° C compared to pure water. In Example 1, such an amount of iso-osmotic 68 g (0.68%) of sodium chloride should be used.

In Example 1, e.g. instead of NaCl per 100 ml solution use:

glucose 1H ₂ O 3.81 g; sucrose 6.35 g; glycerol 2.2 g; 1,2-propylene glycol 1,617 g; sorbitol 3.84 g (in the case of mixtures of these substances, smaller amounts may be appropriate).

Further, thickening agents are added to the solutions, which prevent the solution from flowing rapidly from the nose and which bring the viscosity of the solution to about 1.5 to 3, preferably to 2 mPa.s. As such thickening agents come into consideration, for example: cellulose derivatives (for example cellulose ether) in which celulozine hydroxy groups partially etherified with lower unsaturated aliphatic alcohols and / or lower unsaturated aliphatic oxyalcohol (such as methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose) , gelatin, polyvinylpyrrolidone, tragacanth, ethoxose (water soluble ethylcellulose-based binders and thickeners), alginic acid, polyvinyl alcohol, polyacrylic acid, pectin and equivalent. In addition, if they contain an acid group, the corresponding physiologically acceptable salts are also considered.

If hydroxypropylcellulose is used for this purpose, it is used, for example, at a concentration of 0.1% (by weight).

In addition, buffering agents can be added to the preparations, such as citric acid / sodium hydrogen phosphate, borate buffer, phosphates (sodium dihydrogen orthophosphate, disodium hydrogen phosphate), trometamol, or equivalent conventional buffers, but with the aim of achieving, in the preparation, for example, a pH value of 6 to 7.5, preferably 6.5 to 7.1.

-9The amount of citric acid, for example, is 0.01 to 0.14 and preferably 0.04 to 0.05 g, the amount of disodium hydrogen phosphate is 0.1 to 0.5 and preferably 0.2 to 0.3 g per 100 ml solutions. The quantities indicated always refer to anhydrous substances.

For solutions and suspensions, the maximum total concentration of the drug and buffer should be less than 5% and especially less than 2% (weight / volume).

The nasal application preferably uses a solution or suspension in the form of an aerosol, which means in the form of its fine distribution in the air or in some other conventional carrier gas, for example by means of a conventional pump for spray application.

The application is also possible in the form of an aerosol dispenser. Dosing aerosol dispensers should be understood to mean pressure vessels containing azelastine or its salts in the form of a solution or suspension in a so-called propellant. As a propellant, it is to be understood here as the pressure of liquid and normal pressure and room temperature of gaseous chlorinated fluorinated hydrocarbons, or mixtures of different chlorinated fluorinated hydrocarbons, as well as propane, butane, isobutane, or their mixtures, or mixtures with chlorinated, fluorinated hydrocarbons. The pressurized container has a metering valve, by which only a certain amount of solution or suspension of the drug preparation is released upon its activation. By rapid evaporation of the propellant, the solution or suspension of azelastine is dispersed into the finest droplets, or particles, which are blown into the nose or dragged into the nose by inhalation of air. There are various plastic applications for activating the valve and for injecting the spray suspension into the nose. The following are included as propellants: CO ₂ , nitrous oxide, compressed air.

For the application, we can also use a conventional adapter as an aerosol device.

When used in suspensions, the maximum particle size of solids (azelastine + excipients) should not exceed 30 pm.

When used as blowing powder, the maximum particle size of the substance should not be present

-10pm 20pm.

In these cases, for example, it is some azelastine dispersed from solid azelastine, or salts thereof. In this case, for example, azelastine or its salt is mixed with an inert carrier, or the inert carrier may carry azelastine. Suitable carriers include: sugars such as glucose, sucrose, lactose, fructose, further starch, or starch derivatives, oligosaccharides, such as dextrins, cyclodextrins and their derivatives, polyvinylpyrrolidone, alginic acid, tylose, silicic acid, cellulose, cellulose, cellulose, cellulose (for example, cellulose ether), sugars such as mannitol or sorbitol, calcium carbonate, calcium phosphate. The concentration of azelastine is 1 part by weight of azelastine per 50 to 200,000 parts by weight of the carrier substance (0.0005 to 2% azelastin).

EXAMPLE 1

Nasal spray, nasal drops, or eye drops with 0.1% azelastine hydrochloride as active substance.

Dissolve 9.00 kg of water in the following order: 10 g azelastine hydrochloride, 5 g ethylenediaminetetraacetic acid disodium salt. 2H ₂ O, 68 g of sodium chloride, 1.25 g of alkyl benzyl dimethyl ammonium chloride (benzalkonium chloride), 4.38 g of citric acid, 64.8 g of sodium monohydrogen phosphate. 12 H ₂ O as well as 10 g of hydroxypropyl methyl cellulose ¹ . The resulting solution was made up to 10.05 kg = 10 liters with water and, after careful stirring, was filtered through a 0.2 pm pore size membrane filter, discarding 500 ml of the flow. The filtrate has a pH value of 6.8 ± 0.3. It is filled with plastic bottles that have the usual spray attachment or plastic bottles or glass with a regular spray pump. In the latter case, the pumps also have a special additive for dispersion into the nasal cavity by spraying about 0.14 ml of solution with one actuation of the pump. In this way, 0.14 mg azelastine hydrochloride is injected into the nose with one actuation as a solution.

for example, a product with the trade name Methocel E4M premium

-11If the filtrate thus obtained is filled with conventional nasal droplets or eye droplets, the solution may then be infused into the nose or eye with the aid of droplets.

EXAMPLE 2

Nasal grease with 0.1% azelastine hydrochloride:

Add 5 kg of polyoxyethylene stearate ² , 8 kg of cetyl stearyl alcohol (Lanette 0), 20 kg of white petroleum jelly, 15 kg of liquid paraffin and 0.5 kg of silicone oil to a warming container and mix everything together. Dissolve 125 g of p-hydroxybenzoic acid methyl ester and 53 g of p-hydroxybenzoic acid propyl ester in solution (melting point or 80 ° C). Finally, a heated solution of 0.1 kg of azelastine hydrochloride, 40 g of p-hydroxybenzoic acid methyl ester and 60 g of p-hydroxybenzoic acid propyl ester were emulsified in 51,021 kg of purified water using a high-speed mixer and stirred at 70 ° C. until cooled and homogenized again at regular intervals.

The fats are filled into tubes that have a tube extension on the thread, which allows the application of fat to the nose in a very easy way.

EXAMPLE 3

Aerosol dispenser by administering 0.5 mg azelastine hydrochloride at one activation.

In a suitable cooling vessel, cool about 8.0 kg of a mixture of 70 parts by weight of difluorodichloromethane and 30 parts by weight of 1,2-dichlorotetrafluoroethane to about - 55 ° C. To this mixture was added at - 55 ° C a mixture of 0.086 kg of pre-cooled sorbitan trioleate and 0.8600 kg of pre-cooled trichlorofluoromethane and while stirring ² polyoxyethylene-40-stearate, solid, white to cream color, D. ²⁵ about 1.1 , tal. 40-44 ° C, solidification point around 41 ° C

-12 dissolve. 0.0688 kg of micronized azelastine hydrochloride and 0.0688 kg of micronized lactose are then added to the solution thus obtained under vigorous stirring, in specific portions. Further adding to the - 55 ° C cooled mixture of 70 parts by weight of difluorodichloromethane and 30 parts by weight of 1,2-dichlorotetrafluoroethane, the total weight of the resulting suspension will be 9,541 kg.

The cooling vessel was then closed and cooled again to about - 55 ° C with vigorous stirring. This is the way to prepare for filling the appropriate containers.

Continue stirring to fill the suspension in suitable conventional aluminum monoblock (one piece) doses. The doses should be closed immediately after filling the suspension with conventional dosing valves which, upon activation, release 0.05 ml of the suspension via one valve. Upon activation of the valve, 0.5 mg azelastine hydrochloride is thus administered. This administration is carried out by means of a conventional application device which allows the administration of the active substance to the patient's nose.

EXAMPLE 4

Eye drops with 0.05% azelastine hydrochloride

Mix 140 g of polyvinyl alcohol (trade name, for example: Mowiol 26-88 Hoechst AG, Frankfurt 80) in 4 liters of cold water for injection, then heat the suspension to 90 ° C and allow to stand at this temperature for 45 minutes. After cooling, mix the resulting solution with the following solutions: 5 g azelastine hydrochloride in one liter of water for injection, 0.2 g phenyl mercury nitrate in 2 liters of water for injection, 70 g sodium chloride in one liter of water for injection.

The mixture was adjusted to pH 6.8 with the addition of 0.1 N sodium hydroxide and mixed with a solution of 15 g of sodium hydrogen phosphate. 2H ₂ O and 21 g of disodium hydrogen phosphate. 2H ₂ O in one liter of water for injection and make up to 10 liters with water for injection.

-13After careful mixing, filter the solution through a 0.2 pm pore size membrane filter and a glass fiber prefilter and, after discarding 500 ml of the flow, fill in aseptic conditions into sterile drip bottles. \

Claims (1)

PATENT APPLICATIONS A process for the manufacture of preparations containing azelastine for use in the nose and / or the eye, characterized in that at temperatures between - 55 and + 80 ° C 1 to 1000 mg of azelastine, or dissolve some physiologically acceptable salts of azelastin in 50 to 200 ml of water, possibly containing up to 15% (by weight) of an acceptable solvent miscible with water and at the same time, or subsequently added 1 to 400 mg of preservative, 50 to 4000 mg of stabilizing agent, or solubility enhancer, and eventually bring the solution by buffer to a pH of 6.5 to 7.1 and possibly add an isotonic agent.