NO332524B1 - Inhalable solution formulation containing a tiotropium salt, such preparations for use as a medicament and the use thereof for the manufacture of medicaments for the treatment of disease - Google Patents

Abstract

The present invention relates to a propellant-free inhalable formulation of tiotropium bromide or tiotropium bromide monohydrate dissolved in water or in a mixture of water and ethanol and the propellant-inhalable aerosol resulting therefrom.

Description

The present invention relates to a propellant-free inhalable preparation of

a pharmaceutically acceptable salt of tiotropium dissolved in water or a mixture of water and ethanol, together with at least one other active substance, preferably administered by inhalation and propellant-free inhalable aerosol preparations resulting therefrom. The preparation according to the invention is particularly suitable for administration of the active substance by inhalation, especially for the production of medicines for the treatment of asthma and COPD.

Tiotropium, chemical (1a,2p,4p,5a,7p)-)-7-[(hydroxy-di-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0< 2,4>]nonane, is known as tiotropium bromide from European patent application EP 418 716 A1. The bromide salt of tiotropium has the following chemical structure:

The compound has valuable pharmacological properties and is known by

the name tiotropium bromide. Tiotropium and its salts are highly effective anticholinergic agents and may provide therapeutic benefit in the treatment of asthma or COPD (chronic obstructive pulmonary disease). The monohydrate of

tiotropium bromide is also pharmacologically valuable.

Both compounds are a preferred target of the present invention.

The present invention relates to liquid active substance preparations of

those compounds which can be administered by inhalation; the liquid preparations according to the invention must meet high quality standards.

To achieve an optimal distribution of active substances in the lung it is

sensible to use a liquid preparation without propellant gases administered using suitable inhalers. The inhalers that can atomize a small

quantity of a liquid preparation in the dose necessary for therapeutic purposes within a few seconds in an aerosol suitable for therapeutic inhalation is particularly suitable. Preferred nebulizers are those in which an amount of less than 100 microliters, preferably less than 50 microliters, most preferably less than 20 microliters of active substance solution can be nebulized preferably in one puff to form an aerosol having an average particle size of less than 20 microns, preferably less than 10 microns, so that the inhalable portion of the aerosol corresponds to the therapeutically effective amount.

An apparatus for this type of propellant-free administration of a measured amount of a liquid pharmaceutical preparation for inhalation is described in detail in, for example, international patent application WO 91/14468 "Atomizing Device and Methods" and also in WO 97/12687, cf. Figures 6a and 6b and the accompanying description. In a nebulizer of this type, a pharmaceutical solution is converted by means of a high pressure of up to 500 bar into an aerosol intended for the lungs, which is sprayed.

In inhalers for this type of preparation, solutions are stored in a reservoir. It is essential that the preparations with the active substance used are sufficiently stable when stored and at the same time are such that they can be administered directly, if possible without further handling, according to their medicinal purpose. Furthermore, they must not contain any ingredients that may interact with the inhaler in such a way as to damage the inhaler or the pharmaceutical quality of the solution or of the aerosol produced.

To atomize the solution, a special nozzle is used as described for example in WO 94/07607 or WO 99/16530.

WO 98/27959 describes preparations of solutions for the inhaler described above which contain as an additive the disodium salt of editic acid (sodium edetate). For aqueous preparations of solutions to be converted into inhalable aerosol preparations using the inhaler described above, the specification favors a minimum sodium edetate concentration of 50 mg/100 ml, to reduce the occurrence of spray irregularities. Among the examples described is a preparation containing tiotropium bromide. In this preparation, the active substance is dissolved in water. The ratio of sodium edetate is again 50 mg/100 ml.

Surprisingly, it has now been found that preparations of solutions of tiotropium salts in water or a water-ethanol mixture where the ratio of additive sodium edetate is significantly less than 50 mg/100 ml show a reduction in the spread of the preparation delivered, compared to the preparation containing tiotropium bromide known from prior art. In addition, the spray quality is very good. The resulting aerosol has very good properties for administration by inhalation.

Another advantage of the preparation is that, due to the reduction of the additive sodium edetate in the preparation with the active substance, the pH of the solution preparation can be lowered. Low pH levels are necessary for long-term stability of tiotropium salts in the preparation.

It is therefore an aim of the present invention to provide an aqueous active substance preparation containing a pharmaceutically acceptable tiotropium salt that meets the high standards necessary to be able to achieve optimal atomization of a solution when using the inhalers mentioned above. The active substance preparations according to the invention must have a sufficiently high pharmaceutical quality, i.e. they must be pharmaceutical stable over a storage period of a few years, preferably at least one year, more preferably two years.

Another aim is to provide propellant-free preparations of solutions containing tiotropium salts that are atomized under pressure using an inhaler, where the preparation delivered by the aerosol produced falls reproducibly within a specified range.

Another aim is to provide preparations of solutions with tiotropium and another active substance which can be administered by inhalation.

According to the invention, any pharmaceutically acceptable salts of tiotropium can be used for the preparation. When the term tiotropium salt is used within the scope of the present invention, this shall be taken as a reference to tiotropium. In the invention, a reference to tiotropium, which is the free ammonium cation, corresponds to a reference to tiotropium in the form of a salt (tiotropium salt) which contains an anion as a counterion. Tiotropium salts which can be used within the scope of the present invention are preferably compounds which contain, in addition to tiotropium as counterion (anion), chloride, bromide, iodide, methanesulfonate, para-toluenesulfonate and/or methylsulfate.

Within the scope of the present invention, tiotropium bromide is preferred as the salt. References to tiotropium bromide within the scope of the present invention must always be taken as a reference to all possible amorphous and crystalline modifications of tiotropium bromide. These can, for example, contain molecules of solvent in their crystalline structure. Of all the crystalline modifications of tiotropium bromide, those which also contain water (hydrates) are preferred by the invention. It is particularly preferred within the scope of the present invention to use tiotropium bromide monohydrate.

In the preparations according to the invention, combinations with a tiotropium salt and only one other active substance are preferred.

In the preparations according to the invention, the tiotropium salts are dissolved in a solvent. The solvent can be exclusively water or it can be a mixture of water and ethanol. Ethanol can be added to the preparation to increase the solubility of additives or other active substances apart from the tiotropium salt, preferably tiotropium bromide or tiotropium bromide monohydrate. The relative ratio of ethanol to water is not limited; it can be, for example, 90% by volume. Preferably, the maximum limit for ethanol is 70% by volume, especially 60% by volume and most preferably 30% by volume. The remaining % by volume consists of water. The preferred solvent is water without the addition of ethanol.

The concentration of the tiotropium salt based on the ratio of tiotropium in the final pharmaceutical preparation depends on the desired therapeutic effect. The concentration of tiotropium is between 0.0005 and 5% by weight, preferably between 0.001 and 3% by weight.

The pH of the preparation according to the invention is between 2.0 and 3.1, preferably between 2.5 and 3.0.

The pH is adjusted by adding pharmacologically acceptable acids.

Examples of inorganic acids which are preferred for this purpose include: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and/or phosphoric acid.

Examples of particularly suitable organic acids are: ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid. Preferred inorganic acids are hydrochloric acid and sulfuric acid. It is also possible to use acids which form an acid addition salt with the active substance or, in the case of combined preparations, with one of the active substances.

Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred, especially citric acid. If desired, mixtures of the above-mentioned acids can also be used, especially in the case of acids which have other properties in addition to their acidifying properties, e.g. those that act as flavorings or antioxidants, such as, for example, citric acid or ascorbic acid.

Hydrochloric acid can be particularly mentioned as an inorganic acid.

If desired, pharmacologically acceptable bases can be used to titrate the pH accurately. Suitable bases include, for example, alkali metal hydroxides and alkali metal carbonates. The preferred alkali ion is sodium. If bases of this type are used, care must be taken to ensure that the resulting salts, which are then included in the final pharmaceutical preparation, are pharmacologically compatible with the above-mentioned acid.

The preparation contains ethidinic acid salt in an amount of more than 0 and up to 25 mg/100 ml. The remarks regarding ethidinic acid salt also apply analogously to other comparable additives that have complexing properties and can be used in addition, such as, for example, nitrilotriacetic acid and its salts.

By complexing agents is preferably meant within the scope of the present invention, molecules which can participate in complex bonds. Preferably, these compounds should have the effect of complexing cations, most preferably metal cations.

The other active substances apart from the tiotropium salt in the combined preparation are specially selected from among antihistamines, antiallergic agents, leukotriene antagonists and/or steroids.

These active substances include:

As steroids:

Alclomethasone, 35 Aminoglutethimide, Alclomethasone dipropionate, Aristocort diacetate,

Alisactide, Beclomethasone,

Amcinonide Beclomethasone, Douglas,

Beclomethasone-17,21-35Fluticasone,

dipropionate, Fluticasone propionate, Betamethasone valerate, Formebolon, Betamethasone adamantoate, Formocortal,

Budesonide, Halcinonide,

Butixocort,40 Halogenmethasone, Canesten-HC, Halogenpredone acetate, Ciclometasone, Hydrocortisone,

Clobetasol, Hydrocortisone-17-butyrate, Clobetason, Hydrocortisone-aceponate, Cloprednol,45Hydrocortisone-butyrate-propionate, Cloprednol Icomethasone-enbutate Fluocortin-butyl, Ciclometasone,

Cortivazole, Lotrisone,

Deflazacort, Mazipredone,

Deflazacort,50Medryson,

Demetex, Meprednisone,

Deprodone, Methylprednisolone aceponate, Deprodone propionate, Mometasone,

Dexamethasone, Mometasone furoate, Dexamethasone-21-isonicotinate, 55 Mycophenolate mofetil Dexamethasone isonicotinate, Pranlukast,

Diflorazone, Paramethasone acetate, Difluprednate, Prednicarbate,

Endrison, Promedrol,

Fluazacort, 60Seratrodast, Fluclorolon acetonide, Tipredan,

Flunisolide, Tixocortol pivalate, Fluocinolone acetonide, Triamcinolone,

Fluocinonide, Triamcinolone hexaacetonide, Fluocortin, 65Trilostan,

Fluocortolone capronate, Trimacinolone benetonide, Fluodexan, Ulobetasol propionate, Fluormetholone, Zileuton methyl-9-alpha-chloro-6-alpha-fluoro-11-beta-17-alpha-dihydroxy-16-alpha-methyl-3-oxo -1,4-androstadien-1 7-beta-carboxylate-17-propionate,

Particularly preferred are the combinations of tiotropium bromide or tiotropium bromide monohydrate and budesonide, flunisolide, beclomethasone dipropionate or fluticasone, as well as the pharmacologically acceptable (possibly other) salts thereof.

The preferred combination comprises tiotropium bromide or tiotropium bromide monohydrate and budesonide.

The concentration of the steroid, e.g. budesonide, flunisolide, beclomethasone dipropionate or fluticasone, in the preparations according to the invention is preferably 0.05 to 10% by weight, preferably up to 5% by weight, more preferably 0.1 to 2.5% by weight, especially preferably 0.2 to 2, 5% by weight. When the preparation is used with the inhaler mentioned above, the concentration of steroid is preferably regulated so that 12.5 to 250 micrograms of steroid are delivered per spray. Particularly preferred are concentrations where the pharmacologically active dose is administered in one or two sprays.

If the combined preparation contains a leukotriene antagonist, this is preferably chosen from montelukast, pranlukast, zafirlukast, 1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl) -3-(2-(2-hydroxy-2-propyl)phenyl)thio)-methylcyclopropane-acetic acid, 1-(((R)-3-(3-(2-(2,3-dichlorothieno[3,2 -b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)-cyclopropane-acetic acid or [2-[ [2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic acid. Montelukast, pranlukast and/or zafirlukast are preferred.

The concentration of the leukotriene antagonist is from 0.05 to 10% by weight, preferably up to 5% by weight, more preferably 0.1 to 3.5% by weight.

The following are mentioned as examples of antihistamines and antiallergic agents:

azelastine,

astemizole,

Bamipin,

Carbinoxamine hydrogen maleate,

cetirizine,

Cexchlorpheniramine,

Chlorphenoxamine,

Clemastine,

Clemastine Hydrogen Fumarate,

Desloratidine,

Dimene hydrinate,

Dimetinden,

disodium cromoglycate,

Diphenhydramine,

doxylamine,

Ebastine,

emedastine,

epinastine,

fexofenadine,

ketotifen,

Levocabastine,

Loratadine,

meclozine,

Mequitazine,

Mizolastine,

Nedocromil,

Pheniramine and/or

Promethazine.

Epinastin, nedocromil, disodium cromoglycate, astemizole, mequitazine, carbinoxamine and/or clemastine and/or the corresponding pharmaceutically acceptable salts are preferred.

In the overall preparation, the concentration of the antiallergic agents and/or antihistamines is preferably 0.05 to 15% by weight, preferably up to 10% by weight, more preferably 0.1 to 10% by weight, most preferably 0.1 to 7% by weight.

All of the above-mentioned active substances can optionally also be used in the form of their pharmacologically acceptable salts thereof.

The combined preparations are preferably preparations where tiotropium is present in solution. The second active substance can be dissolved or suspended; this is generally determined by the other active substance and the particular solvent used.

If the additional active substance is one that is vulnerable at low pH values,

it is preferably formulated as a suspension. The advantage of a suspended form is that the pH can be made more acidic, which is an advantage for the stability of the dissolved tiotropium. The preferred pH range for tiotropium bromide is between 2.0 and 3.1, preferably 2.5 and 3.0.

In the case of steroids, these are preferably used in suspended form, especially fluticasone. This applies in particular if the solvent used is only water without ethanol. If ethanol is added, the steroid can also be formulated as a solution. However, it has been found that budesonide, for example, is also sufficiently stable at a pH of 3.5 if it is dissolved in a mixture of water and ethanol.

With regard to the use of the preparations according to the invention in the inhaler described within the scope of the present invention, it may be advantageous that all the components of the preparation are present in solution.

As well as ethanol, other co-solvents and/or other additives can be added to the preparation according to the invention.

Other preferred co-solvents are those containing hydroxyl groups or other polar groups, for example alcohols - especially isopropyl alcohol, glycols - especially propylene glycol, polyethylene glycol, polypropylene glycol, glycol ethers, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters.

By adjuvants and additives is meant, in this context, any pharmacologically acceptable and therapeutically applicable substance that is not an active substance, but can be formulated together with the active substance(s) in a pharmacologically suitable solvent, in order to improve the quality of the preparation with the active substance. Preferably, these substances have no pharmacological effects or no noticeable or at least no undesirable pharmacological effects in connection with the desired therapy. The adjuvants and additives include, for example, surfactants such as e.g. soy lecithin, oleic acid, sorbitan esters such as sorbitan trioleate, polyvinylpyrrolidone, other stabilizers, complexing agents, antioxidants and/or preservatives that extend the shelf life of the final pharmaceutical preparation, flavorings, vitamins and/or other additives known in the field. The additives also include pharmacologically acceptable salts such as, for example, sodium chloride.

Suitable surfactants or suspension stabilizers include all the pharmacologically acceptable substances which have a lipophilic hydrocarbon group and one or more functional hydrophilic groups, in particular C5-2o fatty alcohols, C5-20 fatty acids, C5-2o fatty acid esters, lecithin, glycerides, propylene glycol esters , polyoxyethylenes, polysorbates, sorbitan esters and/or carbohydrates. C5-20 fatty acids, propylene glycol diesters and/or triglycerides and/or sorbitans of C5-20 fatty acids are preferred, while oleic acid and sorbitan mono-, di- or tri-oleates are particularly preferred. Alternatively, toxicologically and pharmaceutically acceptable polymers and/or block polymers can be used as suspension stabilizers.

The amount of surfactant can be up to 1:1 based on the ratio by weight of the suspended active substances; with amounts of 0.0001:1 to 0.5:1 being preferred while amounts of from 0.0001:1 to 0.25:1 being particularly preferred.

The preferred additives include antioxidants such as for example ascorbic acid, provided it is not already used to regulate pH, vitamin A, vitamin E, tocopherols and similar vitamins or provitamins that occur in the human body.

Preservatives can be added to protect the preparation against contamination by pathogenic bacteria. Suitable preservatives are those known from the prior art, in particular benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in a concentration known from the prior art.

Preferred preparations contain only benzalkonium chloride, an acid for adjusting pH and sodium edetate, in addition to the solvent water and/or water/ethanol and the tiotropium salt.

As already mentioned several times, tiotropium bromide is described in EP 418 716 A1 and crystalline tiotropium bromide monohydrate can be obtained using a method which is described in more detail below.

To prepare the crystalline monohydrate according to the present invention, the tiotropium bromide obtained by the method described in, for example, EP

418 716 A1, first be taken up in water, heated, purified with activated charcoal and, after removal of the activated charcoal, tiotropium bromide monohydrate is slowly crystallized by slow cooling.

The following procedure is preferably followed:

In a reaction vessel with suitable dimensions, the solvent is mixed with tiotropium bromide, which is for example obtained by the method described in EP 418716 A1.

For each mole of tiotropium bromide used, 0.4 to 1.5 kg, preferably 0.6 to 1 kg, most preferably approx. 0.8 kg of water used as solvent.

The resulting mixture is heated with stirring, preferably to above 50°C, most preferably to above 60°C. The maximum temperature that can be selected is determined by the boiling point of the solvent used. Preferably, the mixture is heated to a range of 80-90°C.

Activated charcoal, either dry or moistened with water, is added to this solution. Preferably 10 to 50 g, more preferably 15 to 35 g, most preferably approx. 25 g of activated charcoal used per moles of tiotropium bromide used. If desired, the activated charcoal is suspended in water before it is added to the solution containing tiotropium bromide. 70 to 200 g, preferably 100 to 160 g, more preferably approx. 135 g of water is used per moles of tiotropium bromide used, to suspend the activated charcoal. If the activated charcoal is suspended in water beforehand, before it is added to the solution containing tiotropium bromide, it is advisable to rinse again with the same amount of water.

After the activated charcoal is added, stirring is continued at constant temperature for between 5 and 60 minutes, preferably between 10 and 30 minutes, more preferably for approx. 15 minutes and the mixture obtained is filtered to remove the activated charcoal. The filter is then rinsed with water. 140 to 400 g, preferably 200 to 320 g, most preferably approx. 270 g of water is used for this, per moles of tiotropium bromide used.

The filtrate is then slowly cooled, preferably to a temperature of 20-25X. Cooling preferably takes place at a cooling rate of 1 to 10°C every 10 to 30 minutes, preferably 2 to 8°C every 10 to 30 minutes, more preferably 3 to 5°C every 10 to 20 minutes, most preferably 3 to 5°C approximately every 20 minutes. If desired, cooling to 20 to 25°C can be followed by further cooling to below 20°C, more preferably to 10 to 15°C.

After cooling is complete, stirring is continued for between 20 minutes and 3 hours, preferably between 40 minutes and 2 hours, more preferably for approx. one hour to complete crystallization.

The crystals obtained are then isolated by filtration or suction filtration to remove the solvent. If it should prove necessary to subject the obtained crystals to a further washing step, it is advisable to use water or acetone as washing solvent. 0.1 to 1.0 I, preferably 0.2 to 0.5 I, more preferably approx. 0.3 I solvent can be used per moles of tiotropium bromide used to wash the obtained tiotropium bromide monohydrate crystals. If necessary, the washing step can be repeated. The product obtained is dried under vacuum or using circulating heated air until a water content of 2.5-4.0% is obtained.

According to one aspect, the present invention therefore also relates to preparations of solutions of the type described above using crystalline tiotropium bromide monohydrate which can be obtained by the method described above.

The pharmaceutical preparations containing tiotropium salts are preferably used in an inhaler of the type described above to produce the propellant-free aerosol preparations according to the invention.

As indicated at the outset, a further developed embodiment of the preferred inhaler is described in WO 97/12687 and Figure 6 thereof. This nebulizer (Respimat<®>) can advantageously be used to prepare the inhalable aerosol preparations containing a tiotropium salt as active substance. Due to its cylindrical shape and practical size of less than 9 to 15 cm long and 2 to 4 cm wide, the device can be carried anywhere by the patient. The nebulizer sprays a defined volume of the pharmaceutical preparation through small nozzles at high pressure, to produce inhalable aerosol preparations.

The nebulizer essentially consists of an upper chamber, a pump chamber, a nozzle, a locking clip, a spring chamber, a spring and a storage container, characterized by - a pump chamber fixed in the upper chamber part and which at one end has a nozzle body with the nozzle or nozzle arrangement,

- a hollow piston with a valve,

- a force-releasing flange where the hollow chamber is attached and which is located in the upper chamber part,

- a locking clamp mechanism located in the upper chamber part,

- a spring chamber with the spring located therein, which is rotatably mounted on the upper chamber part by means of a pivot bearing, - a lower chamber part which is mounted on the spring chamber in the axial direction.

The hollow piston with valve corresponds to a device described in WO 97/12687. It partially enters the cylinder in the pump chamber and is axially movable in the cylinder. Reference is especially made to Figures 1-4 - especially Figure 3 - and the associated parts of the description. Upon release of the spring, the hollow piston with the valve body exerts, at its high pressure end, a pressure of 5 to 60 Mpa (approx. 50 to 600 bar), preferably 10 to 60 Mpa (approx. 100 to 600 bar) on the liquid , and gives the measured amount of active substance solution. Volumes of 10 to 50 microliters are preferred, volumes of 10 to 20 microliters are more preferred, while a volume of 15 microliters per commissioning is particularly preferred.

The valve body is preferably mounted at the end of the hollow piston facing the nozzle body.

The nozzle in the nozzle body is preferably microstructured, i.e. produced by micro-construction. Microstructured nozzle bodies are described in, for example, WO-94/07607 and in WO 99/16530, particularly Figure 1 of WO-94/07607 and the associated specification.

The nozzle body consists, for example, of two plates of glass and/or silicon securely fastened together, at least one of which has one or more microstructured channels connecting the nozzle inlet end to the nozzle outlet end. At the nozzle outlet end there is at least one round or non-round opening which is 2 to 10 microns deep and 5 to 15 microns wide, the depth preferably being 4.5 to 6.5 microns and the length being 7 to 9 microns.

If there are several nozzle openings, preferably two, the directions of the spray from the nozzles in the nozzle body may run parallel to each other or may be deflected relative to each other in the direction of the nozzle opening. In the case of a nozzle body having at least two nozzle openings at the outlet end, the directions of the spray may be deflected relative to each other by an angle of 20 degrees to 160 degrees, preferably by an angle of 60 to 150 degrees, most preferably 80 to 100 °.

The nozzle openings are preferably arranged with a spacing of 10 to 200 microns, more preferably with a spacing of 10 to 100 microns, even more preferably 30 to 70 microns. A gap of 50 microns is most preferred.

The directions of the spray are therefore met in the region of the nozzle openings.

As already mentioned, the liquid pharmaceutical preparation hits the nozzle body with an inlet pressure of up to 600 bar, preferably 200 to 300 bar and is atomized through the nozzle openings into an inhalable aerosol. The preferred particle sizes of the aerosol are up to 20 microns, preferably 3 to 10 microns.

The locking clip mechanism contains a spring, preferably a cylindrical helical compression spring, which stores the mechanical energy. The spring acts on the force release flange as a spring element whose movement is determined by the position of a locking mechanism. The distance of the force release flange is precisely limited by an upper stop and a lower stop. The spring is preferably tensioned via a force-escalating gear, e.g. a helical sliding gear, with an external torque that is generated when the upper chamber part is rotated relative to the spring chamber in the lower chamber part. In this case, the upper chamber part and power release flange contain a single or multi-speed wedge gear.

The locking mechanism with associated locking surfaces is arranged in an annular configuration around the force release flange. It consists, for example, of a plastic or metal ring which is naturally radially elastically deformable. The ring is arranged in a plane perpendicular to the axis of the atomizer. After locking the spring, the locking surfaces of the locking mechanism slide into the path of the force release flange and prevent the spring from being released. The locking mechanism is operated using a button. The drive button is connected or connected to the locking mechanism. To drive the locking clip mechanism, the driving button is moved parallel to the annular plane, preferably into the atomizer and the deformable ring is thereby deformed in the annular plane. Details of the construction of the locking clip mechanism are described in WO 97/20590.

The lower chamber part is pressed axially over the spring chamber and covers the bearing, the driving force for the spindle and the storage container for the liquid.

When the atomizer is operated, the upper part of the chamber is rotated relative to the lower part, the lower part taking the spring chamber with it. In the meantime, the spring is compressed and tensioned by the helical thrust gear and the clamping mechanism is activated automatically. The rotation angle is preferably an integer fraction of 360 degrees, e.g. 180 degrees. At the same time as the spring is tensioned, the force-release component in the upper chamber part is moved by a given amount, the hollow piston is drawn back into the cylinder in the pump chamber, where as a result some of the liquid from the storage container is sucked into the high-pressure chamber in front of the nozzle.

If desired, a number of replaceable storage containers containing the liquid to be atomized can be inserted into the atomizer one by one and then used. The storage container contains the aqueous aerosol preparation according to the invention.

The atomization process is initiated by carefully pressing the drive button. The clamp mechanism then opens the power start component. The actuated spring pushes the piston into the cylinder in the pump housing. The liquid comes out of the nozzle in the atomizer in the form of a spray.

Further details of the construction are described in PCT applications WO 97/12683 and WO 97/20590.

The components of the spray bottle (nebulizer) are made of a material suitable for their function. The housing of the atomizer and - if the function allows it - also other parts are preferably made of plastic, e.g. by injection molding. For medical applications, physiologically acceptable materials are used. Figures 1a/b, which are identical to Figures 6 a/b in WO 97/12687, show the Respimat® nebulizer with which the aqueous aerosol preparations according to the invention can advantageously be inhaled. Figure 1 a shows a longitudinal section through the atomizer with the spring under tension, Figure 1 b shows a longitudinal section through the atomizer with the spring released.

The upper container part (51) contains the pump housing (52), at the end of which is mounted the holder (53) for the atomizer nozzle. In the holder is the nozzle body (54) and a filter (55). The hollow piston (57) secured in the power start flange (56) of the locking clamp mechanism partially protrudes into the cylinder of the pump housing. At its end, the hollow piston carries the valve body (58). The hollow piston is sealed by the gasket (59). Inside the upper container part is the stopper (60) on which the power start flange rests when the spring is relaxed. Located on the power start flange is the stopper (61) on which the power start flange rests when the spring is under tension. After tensioning the spring, the locking device (62) slides between the stopper (61) and a carrier (63) in the upper container part. The release button (64) is connected to the locking device. The upper container part ends in the nozzle (65) and is closed by the removable protective cover (66).

The spring housing (67) with the pressure spring (68) is rotatably mounted on the upper container part by means of pressure lock pins (69) and rotating supports. The lower container part (70) is pushed over the spring housing. Inside the spring housing is the replaceable storage container (71) for the liquid (72) to be atomized. The storage container is closed by the stopper (73), through which the hollow piston sticks into the storage container and dips its end into the liquid (the reservoir of active substance solution).

The spindle (74) for the mechanical counter is mounted outside the spring housing. The pinion drive (75) is located at the end of the spindle facing the upper container part. On the spindle is the slider (76).

The atomizer described above is suitable for atomizing the aerosol preparations according to the invention to form an aerosol suitable for inhalation.

If the preparation according to the invention is nebulized using the method described above (Respimat<®>), the mass expelled must, in at least 97%, preferably at least 98% of all releases of the inhaler (puff), correspond to a defined quantity with a tolerance range of no more than 25%, preferably 20% of this amount. Preferably between 5 and 30 mg, more preferably between 5 and 20 mg preparation is delivered as a defined mass per poof.

The ratio of the mass delivered which is outside the tolerance limit of not more than 25% in relation to the desired mass should be less than 1.5%, preferably less than 1.2%.

However, the preparation according to the invention can also be nebulized using inhalers other than those described above, for example jet-stream inhalers.

Examples

I. Example of synthesis of tiotropium bromide monohydrate

15.0 kg of tiotropium bromide is added to 25.7 kg of water in a suitable reaction vessel. The mixture is heated to 80-90X and stirred at constant temperature until a clear solution is formed. Activated charcoal (0.8 kg), moistened with water, is suspended in 4.4 kg of water, this mixture is added to the solution containing tiotropium bromide and rinsed with 4.3 kg of water. The mixture thus obtained is stirred for at least 15 min. at 80-90X and then filtered through a heated filter into an apparatus preheated to an external temperature of 70°C. The filter is rinsed with 8.6 kg of water. The contents of the apparatus are cooled to a temperature of 20-25X at a rate of 3-5X every 20 minutes. Using cold water, the apparatus is further cooled to 10-15X and crystallization is completed by stirring for at least an additional hour. The crystals are isolated using a suction filter drier, the isolated crystal slurry is washed with 9 L of cold water (10-15<X>) and cold acetone (10-15X). The crystals obtained are dried at 25X for 2 hours in a stream of nitrogen.

Yield: 13.4 kg of tiotropium bromide monohydrate (86% of theoretical).

II. Examples of preparations

100 g of pharmaceutical preparation contains:

The rest is water or water/ethanol and one of the above-mentioned active substances in an amount known from prior art.

Examples 9 to 12: Budesonide

Each of Examples 1 to 8 may additionally contain:

Example 9a: budesonide: 0.3 g, pH, adjusted with HCl: 3.0, solvent only water, no ethanol;

Example 9b: budesonide: 0.3 g, pH, adjusted with HCl: 3.5;

Example 9c: budesonide: 0.3 g, pH, adjusted with HCl: 4.0;

Example 10: analogous to Examples 9a to 9c with budesonide: 0.6 g, Example 11: analogous to Examples 9a to 9c with budesonide: 1.3 g, Example 12: analogous to Examples 9a to 9c with budesonide: 2.0 g .

In Examples 9 to 12, the steroid is present in the preparation in suspension. Sorbitan trioleate can be used as a surfactant.

Examples 13 to 15

Analogous to Examples 9 to 12. Benzalkonium chloride is replaced by sodium benzoate.

Examples 16 to 19

Analogous to Examples 9 to 12. Instead of hydrochloric acid, exclusively citric acid is used to regulate the pH.

Examples 20 to 30

The ingredients and quantities are analogous to Examples 9 to 19.

Instead of water, a mixture of water (10 vol.%) and ethanol (90 vol.%) is used. Budesonide is present in solution.

Other Examples

Analogous to Examples 9 to 30 described above, the same amount of flunisolide, beclometasone dipropionate or fluticasone is used instead of budesonide. In the case of fluticasone, lecithin is preferably added instead of sorbitan trioleate in the case of the suspension preparation. The steroids are formulated as a suspension if the solvent used is only water. In the case of a mixture of water and ethanol, the steroid may be in solution.

Example 31

Epinastine: 0.2 g

EDTA: 25 mg

Tiotropium bromide monohydrate: 29 mg,

0.1 N hydrochloric acid to adjust the pH to 3.0,

water to 100 ml.

Claims (24)

1. Liquid, propellant-free pharmaceutical preparation comprising at least two combinable active substances containing • a tiotropium salt as one of the active substances, in a concentration based on tiotropium of between 0.0005 and 5% by weight, • a further active substance which is either a steroid, an antiallergic or an antihistamine or a leukotriene antagonist, • water as a solvent, in which at least the tiotropium salt is dissolved, • acid to achieve a pH of between 2.0 and 3.1, • a pharmacologically acceptable preservative, • a ethidine acid salt in an amount of more than 0 and up to 25 mg/100 ml • possibly a stabilizer and/or a pharmacologically acceptable co-solvent and/or other pharmacologically acceptable adjuvants and additives in addition to the preservative. 2. Pharmaceutical preparation according to claim 1, characterized in that the tiotropium salt is a salt selected from bromide, chloride, iodide, methanesulfonate and p-toluenesulfonate. 3. Pharmaceutical preparation according to claim 1 or 2, characterized in that the active substance is tiotropium bromide. 4. Pharmaceutical preparation according to claim 1 or 2, characterized in that the active substance is tiotropium bromide monohydrate. 5. Pharmaceutical preparation according to claim 1 or 2, characterized in that it does not contain a stabilizer. 6. Pharmaceutical preparation according to claim 1 or 2, characterized in that the editic acid salt is present in an amount of from 5 to less than 10 mg/100 ml. 7. Pharmaceutical preparation according to claim 1 or 2, characterized in that the editic acid salt is sodium edetate. 8. Pharmaceutical preparation according to claim 1 or 2, characterized in that the pH is between 2.5 and 3.0. 9. Pharmaceutical preparation according to claim 1 or 2, characterized in that the preparation contains benzalkonium chloride as a preservative. 10. Pharmaceutical preparation according to claim 1 or 2, characterized in that pharmacologically acceptable adjuvants and additives are used in addition to the preservative. 11. Pharmaceutical preparation according to claim 1 or 2, characterized in that the preparation contains an antioxidant selected from ascorbic acid, viramine A, vitamin E or a tocopherol as adjuvant. 12. Pharmaceutical preparation according to claim 1 or 2, characterized in that no co-solvents and/or pharmacologically acceptable adjuvants and additives are used apart from the preservative. 13. Pharmaceutical preparation according to claim 1 or 2, characterized in that the concentration of tiotropium is between 0.001 and 3% by weight. 14. Pharmaceutical preparation according to claim 1 or 2, characterized in that all the components are dissolved in the solvent. 15. Pharmaceutical preparation according to claim 1 or 2, characterized in that the further active substance is in suspension in the solvent. 16. Pharmaceutical preparation according to claim 1 or 2, characterized in that the further active substance is one of the steroids in a concentration of between 0.05 to 5% by weight. 17. Pharmaceutical preparation according to claim 16, characterized in that the steroid is budesonide, beclomethasone dipropionate, fluticasone or flunisolide. 18. Pharmaceutical preparation according to claim 1 or 2, characterized in that the further active substance is an antiallergic or an antihistamine in a concentration of 0.05 to 15% by weight. 19. Pharmaceutical preparation according to claim 18, characterized in that the antiallergic agent or antihistamine is epinastin, nedocromil, disodium cromoglycate, astemizole, mekitazine, carbinoxamine and/or clemastine and/or a corresponding pharmaceutically acceptable salt thereof. 20. Pharmaceutical preparation according to claim 1 or 2, characterized in that the further active substance is a leukotriene antagonist in a concentration of between 0.05 to 10% by weight. 21. Pharmaceutical preparation according to claim 20, characterized in that the leukotriene antagonist is montelukast, pranlukast, zafirlukast, 1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)- 3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropane-acetic acid, 1-(((R)-3-(3-(2-(2,3dichlorothieno[3,2-b]pyri methylethyl)phenyl)propyl)thio)methyl)cyclopropane-acetic acid or [2-[[2-(4-tertbutyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic acid. 22. Pharmaceutical preparation according to claim 1 or 2, containing water, a surfactant, 0.1% by weight tiotropium bromide, a further active substance in a concentration of between 0.05 to 5% by weight which is a steroid selected from budesonide, beclomethasone- dipropionate, fluticasone or flunisolide, 0.01% by weight benzalkonium chloride, 0.05% by weight sodium edetate, which preparation is adjusted to pH 3.0 with hydrochloric or citric acid. 23. Pharmaceutical preparation according to one of claims 1 to 22 for use as a pharmaceutical preparation for administration by inhalation. 24. Use of a pharmaceutical preparation according to one of claims 1 to 23 for the production of a drug for the treatment of asthma and/or COPD.