SK286027B6 - Propellant-free pharmaceutical preparation, method for its preparation and use thereof - Google Patents

Abstract

Propellant-free pharmaceutical preparation for administration by inhalation for the treatment of asthma and/or CODP comprising a tiotropium salt as active substance, water on its own or a water/ethanol mixture as a solvent for the active substance, acid for achieving a pH between 2.0 and 3.1, pharmacologically acceptable preservative, editic acid or salt thereof and pharmacologically acceptable ancillary substances.

Description

Technical field

The invention relates to a pharmaceutical composition for propellant-free inhalation from a pharmaceutically acceptable salt of tiotropium dissolved in water or a mixture of water and ethanol, and the resulting propellant-free inhalable aerosols. The pharmaceutical composition according to the invention is particularly suitable for inhaled administration of the active ingredient, in particular for the indications of asthma and COPD.

BACKGROUND OF THE INVENTION

Tiotropium, chemically (1α, 2β, 4β, 5α, 73) -7 - [(hydroxy-di-2-thienylacetyl) oxy] -9,9-dimethyl-3-oxa-9-azoniatricyclo [3.3.1.0] nonane, is known as tiotropium bromide from European patent application EP 418 716 A1. The tiotropium bromide salt has the following chemical structure:

This compound has valuable pharmacological properties and is known as tiotropium bromide. Tiotropium and its salts are highly potent anticholinergics and may therefore show therapeutic utility in the treatment of asthma or COPD (chronic obstructive pulmonary disease). Also pharmacologically interesting is tiotropium bromide monohydrate. Both compounds are a preferred object of the invention.

The present invention is directed to inhalable liquid pharmaceutical formulations of the active ingredients with these compounds, wherein the liquid pharmaceutical formulations of the invention must meet a high quality standard. In order to achieve an optimal distribution of the active substances in the lungs, application of a propellant-free liquid pharmaceutical formulation is possible by means of inhalers suitable for this purpose. Particularly suitable are those inhalers which can spray a small amount of a liquid pharmaceutical preparation in a therapeutically necessary dose into a therapeutically inhalable suitable aerosol within a few seconds. In the context of the present invention, such nebulisers are preferred in which an amount of the active ingredient solution of less than 100 microlitres, preferably less than 50 microlitres, most preferably less than 20 microlitres, can be sprayed, preferably with one stroke, into an aerosol with an average particle size less than 20 microns, preferably less than 10 microns, in such a way that the inhalable aerosol proportion corresponds to a therapeutically effective amount. Such a device for delivering a metered amount of a liquid medicament for inhalation without propellant is described in detail in International Patent Application WO 91/14468 "Atomizing Device and Methods" as well as in WO 97/12687, there 6a and 6b and the corresponding description. In such a nebulizer, the drug solution is converted to an aerosol which is passable through the lungs by means of a high pressure of up to 50 MPa (500 bar) and sprayed. These references are incorporated by reference herein in their entirety. In such inhalers, the solution preparations are stored in a reservoir. In this connection, it is essential that the active ingredient preparations used have sufficient storage stability and at the same time be adapted to be applied directly for the therapeutic purpose, preferably without further manipulation. Furthermore, they must not have any components that can interact with the inhaler in such a way that the inhaler or the pharmaceutical quality of the solution or aerosol formed is damaged.

A special nozzle is used for spraying the solution as described, for example, in WO 94/07607 or in WO 99/16530. Both are expressly incorporated herein by reference.

WO 98/27959 discloses solution formulations for the described inhaler which contain, as an additive, a disodium salt of ethylenediaminetetraacetic acid (sodium edetate). This document prefers a minimum sodium edetate concentration of 50 mg / 100 ml for aqueous solution formulations to be nebulized to inhalable aerosols using the inhaler described above in order to reduce the incidence of nebulization anomalies. Among those examples is a formulation with tiotropium bromide. In this formulation, the active ingredient is dissolved in water. The proportion of sodium edetate is also 50 mg / 100 ml.

SUMMARY OF THE INVENTION

Surprisingly, it has now been found that solution formulations of tiotropium salts in water or in an aqueous-ethanol mixture in which the proportion of sodium edetate additive is significantly less than 50 mg / 100 ml, have a reduction compared to the prior art formulation. dispersion of the plotted amount of the substance. In addition, the spray quality is very good. Water is preferably used as the solvent. The resulting aerosol has very good inhalation properties.

A further advantage of the formulation is that, as a result of the By reducing the content of the sodium edetate additive in the active ingredient preparation, the pH of the solution preparation can be reduced. Low pH values are required for long-term stability of the formulation.

It is therefore an object of the present invention to provide an aqueous pharmaceutical formulation of the active ingredient with a pharmaceutically acceptable salt of tiotropium that meets the high standards necessary to optimally disperse the solution using the inhalers mentioned above. The active compound preparations according to the invention must also be of sufficient pharmaceutical quality, i.e. j. they should be pharmaceutically stable over a storage period of several years, preferably at least one year, more preferably two years.

A further object is to provide propellant-free solution formulations with tiotropium salts which can be sprayed by means of a pressurized inhaler, wherein the amount of substance carried in the aerosol formed lies reproducible within a certain range.

According to the invention, all pharmaceutically acceptable salts of tiotropium can be used in the formulations. When used in the present invention, the term tiotropium salt is to be understood as referring to tiotropium. Reference to tiotropium, which forms a free ammonium cation, corresponds in accordance with the invention to tiotropium in the form of a salt (tiotropium salt) which contains an anion as a counterion. Tiotropium salts which are useful in the present invention are preferably understood to mean, in addition to tiotropium, chloride, bromide, iodide, methanesulfonate, para-toluenesulfonate and / or methylsulfate as counterion (anion).

Within the present invention, tiotropium bromide is preferred as the tiotropium salt. References to tiotropium bromide in the context of the present invention should always be understood as referring to all possible amorphous and crystalline modifications of tiotropium bromide. These may, for example, also include solvent molecules in the crystal structure. Of all the crystalline modifications of tiotropium bromide, those that include water (hydrates) are preferred according to the invention. Tiotropium bromide monohydrate can be particularly preferably used in the present invention. Preferably, the formulation does not contain any other active agent which is not tiotropium or a pharmaceutically acceptable salt thereof.

In the compositions of the invention, tiotropium salts are dissolved in a solvent. The solvent may be exclusively water or a mixture of water and ethanol. The relative proportion of ethanol with respect to water is not limited, but preferably the maximum level is up to 70 volume percent, in particular up to 60 volume percent and particularly preferably up to 30 volume percent. Make up the remaining volume percentages with water. The preferred solvent is water without the addition of ethanol.

According to the invention, the composition preferably comprises only a single tiotropium salt. However, the composition may also contain a mixture of various tiotropium salts and solvates. Preferably, the formulation does not contain any substance other than tiotropium as defined above.

The concentration of tiotropium salt, based on the proportion of tiotropium in the finished pharmaceutical formulation, depends on the desired therapeutic effect. For most diseases that respond to tiotropium, the concentration of tiotropium is between 0.0005 and 5 wt%, preferably between 0.001 and 3 wt%. In the case of tiotropium bromide, respectively. % of tiotropium bromide monohydrate, preferably 0.0005 to 0.5 wt.%, more preferably 0.0005 to 0.25 wt.%, based on tiotropium. % and particularly preferably 0.001 to 0.1 wt.

The pH of the composition of the invention is between 2.0 and 4.5, preferably between 2.5 and 3.5, more preferably between 2.7 and 3.3, and particularly preferably between 2.7 and 3.2. Most preferred are pHs with an upper limit of 3.1.

The pH is adjusted by the addition of pharmacologically acceptable acids.

Examples of inorganic acids which are preferred in this regard are: 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 and others. Preferred inorganic acids are hydrochloric acid, sulfuric acid. Those acids which form acid addition salts with the active ingredient may also be used. Among the organic acids, ascorbic acid, fumaric acid and citric acid are preferred, citric acid being most preferred. If desired, mixtures of the abovementioned acids may also be used, in particular in the case of acids which, in addition to their acidifying properties, have other properties, for example as flavorings or antioxidants, such as citric acid or ascorbic acid. Inorganic acids will specifically mention hydrochloric acid.

Alternatively, pharmacologically acceptable bases may be used to accurately titrate the pH. Suitable bases are, for example, alkali metal hydroxides and alkali metal carbonates. The preferred alkali metal ion is sodium. If such bases are used, care should be taken that the resulting salts, which are then present in the finished pharmaceutical formulation, are pharmacologically acceptable with said acid.

According to the invention, it is not necessary to add ethylene diamine tetraacetic acid (EDTA) or its known salt, sodium edetate as a stabilizer or complexing agent to the formulation.

Another embodiment comprises ethylenediaminetetraacetic acid and / or said salts thereof.

In one such preferred embodiment, the content based on sodium edetate is below 10 mg / 100 ml. In this case, a preferred range is between 5 mg / 100 ml and less than 10 mg / 100 ml or another between more than 0 and 5 mg / 100 ml.

In another embodiment, the sodium edetate content is 10 to 30 mg / 100 ml, preferably at most 25 mg / 100 ml.

In a preferred embodiment, the additive is completely omitted.

Analogously, as mentioned for sodium edetate, this also applies to other comparable additives which have complex-forming properties and can be used instead, such as nitrilotriacetic acid or salts thereof.

For the purposes of the present invention, complexing agents are preferably understood to mean molecules which are capable of forming complex compounds. Preferably, cations, particularly preferably metal cations, are to be complexed with these compounds.

In addition to ethanol, other co-solvents and / or other excipients may be added to the composition of the invention.

Preferred cosolvents are those containing hydroxyl groups or other polar groups, for example alcohols - especially isopropyl alcohol, glycols - especially propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters, if they are no longer a solvent or a solvent.

An adjuvant or additive in this context will be understood to mean any pharmacologically acceptable and therapeutically useful substance which is not an active substance but can be formulated together with the active substance in a pharmacologically acceptable solvent in order to improve the qualitative properties of the active substance preparation. Preferably, these substances have no or, in the context of the desired therapy, no appreciable or at least no undesirable pharmacological effects. Such excipients and additives include, for example, surfactants such as soya lecithin, oleic acid, sorbitan ester such as sorbitan trioleate, polyvinylpyrrolidone, other stabilizers, complexing agents, antioxidants and / or preservatives, which extend the shelf life of the finished pharmaceutical formulation. flavorings, vitamins and / or other ingredients known in the art. The additives also include pharmacologically acceptable salts such as sodium chloride.

Preferred excipients include antioxidants, such as ascorbic acid, unless it has been used to adjust the pH, vitamin A, vitamin E, tocopherols, and the like vitamins or provitamins found in the human body.

Preservatives may be used to protect the preparation from contamination with pathogenic germs. Suitable preservatives are those known in the art, in particular benzalkonium chloride or benzoic acid, respectively. benzoates, such as sodium benzoate, at a concentration known in the art.

Preferred preparations contain, in addition to water, only benzalkonium chloride and sodium edetate as solvents and tiotropium salts. In another preferred embodiment, sodium edetate is omitted.

As mentioned several times, the tiotropium bromide described in EP418 716A1, crystalline tiotropium bromide monohydrate, can be obtained by a production method which will be described in more detail.

In order to produce the crystalline monohydrate of the present invention, tiotropium bromide, which is obtained, for example, by the process described in EP 418 716 A1, is transferred to water, heated, activated charcoal cleaned and slowly allowed to crystallize tiotropium bromide monohydrate slowly after cooling.

Preferably, the procedure is as described.

In a suitably sized reaction vessel, the solvent is mixed with tiotropium bromide, which is obtained, for example, by the process described in EP 418 716 A1. 0.4 to 1.5 kg, preferably 0.6 to 1 kg, particularly preferably about 0.8 kg of water are used per mole of tiotropium bromide used as solvent. The resulting mixture is heated with stirring, preferably to more than 50 ° C, particularly preferably to more than 60 ° C. The maximum selectable temperature is determined by the boiling point of the solvent used - water. Preferably, the mixture is heated to a temperature in the range of 80 to 90 ° C. Activated charcoal, dry or moist, is introduced into this solution. Preferably 10 to 50 g, particularly preferably 15 to 35 g, most preferably about 25 g of activated carbon are used per mole of tiotropium bromide used. Alternatively, the activated carbon is decanted before being introduced into the solution containing tiotropium bromide in water. For one mole of tiotropium bromide used, 70 to 200 g, preferably 100 to 160 g, particularly preferably about 135 g of water are used to wash the activated carbon. If activated carbon is first leached in water before being introduced into a solution containing tiotropium bromide, it is recommended to flush it with the same amount of water.

At constant temperature, stirring is continued for 5 to 60 minutes, preferably 10 to 30 minutes, particularly preferably about 15 minutes, after the addition of the activated carbon, and the resulting mixture is filtered to remove the activated carbon. The filter is then rinsed with water. To this end, 140 to 400 g, preferably 200 to 320 g, most preferably about 270 g of water are used per mole of tiotropium bromide used.

The filtrate is then slowly cooled, preferably to a temperature of 20-25 ° C. The cooling is preferably carried out with a cooling rate of 1 to 10 ° C in 10 to 30 minutes, preferably 2 to 8 ° C in 10 to 30 minutes, particularly preferably 3 to 5 ° C in 10 to 20 minutes, most preferably 3 to 5 ° C in about 20 minutes. Optionally, the cooling to 20-25 ° C may be followed by further cooling to a temperature below 20 ° C, particularly preferably 10-15 ° C.

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

The resulting crystals are finally isolated by filtration or suction filtration. Should the crystals obtained be subjected to a further washing step, it is recommended to use water or acetone as solvent. For one mole of tiotropium bromide used, 0.1 to 1.0 L, preferably 0.2 to 0.5 L, particularly preferably about 0.3 L of solvent can be used to wash the obtained tiotropium bromide monohydrate crystals. Optionally, the washing step may be repeated. The product obtained is dried under vacuum or with heated air until a water content of 2.5 to 4.0% is reached.

One aspect of the present invention therefore also relates to solution formulations of the kind described, wherein crystalline tiotropium bromide monohydrate is obtainable by the process described.

The pharmaceutical compositions of the present invention with tiotropium salts are preferably used in an inhaler of the kind described to form aerosols of the present invention without propellant. At this point, let us once again refer explicitly to the patent documents described above, which are hereby incorporated herein.

As mentioned at the outset, WO 97/12687 and its Figures 6 describe a further developed embodiment of a preferred inhaler. This nebulizer (Respimat®) can be advantageously used to form the inhalable aerosols of the present invention with tiotropium salt as the active ingredient. Due to its cylindrical shape and convenient size with a length of less than 9-15 cm and a width of 2-4 cm, the patient can always carry the device with him. The nebulizer dispenses a specified volume of the pharmaceutical formulation using high pressures through small nozzles to form inhalable aerosols.

A preferred sprayer consists essentially of the upper housing part, the pump body, the nozzle, the locking tensioner, the spring housing, the spring and the reservoir and is characterized by:

a pump body which is fixed in the upper part of the body and at one end carries the nozzle body with the nozzle, respectively. assembly of nozzles,

- hollow piston with valve body,

- a driven flange, in which the said hollow piston is fixed and which is located in the upper part of the housing,

- a locking tensioning device located in the upper part of the housing,

- a spring cover with a spring therein which is rotatably mounted on the upper part of the cover by means of a rotary bearing,

- a lower part of the cover which is soaked on the spring cover in the axial direction.

The hollow piston with the valve body corresponds to one of the devices described in WO 97/12687. It partially extends into the cylinder of the pump body and is arranged in the cylinder axially displaceably. Referring in particular to FIG. 1 to 4, in particular in FIG. 3, and the corresponding parts of the description. The hollow piston with the valve body exerts a pressure of 5 to 60 MPa (about 50 to 600 bar), preferably 10 to 60 MPa (about 100 to 600 bar) per liquid on its high pressure side at the moment of spring release, for a measured amount of active substance solution. Volumes from 10 to 50 microlitres are preferred, with volumes from 10 to 20 microlitres being particularly preferred, with a volume of 15 microlitres per stroke being most preferred.

The valve body is preferably located at that end of the hollow piston that faces the nozzle body.

The nozzle in the nozzle body is preferably microstructured, i. j. produced by micro-technique. Microstructured nozzle bodies are described, for example, in WO 94/07607, reference being made to the contents of this specification, in particular to FIG. 1 and its description.

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

In the case of a plurality of nozzle orifices, two are preferred, the nozzle jet directions in the nozzle body may run parallel to each other or be inclined in the direction of the nozzle orifice. In a nozzle body with at least two nozzle openings on the outlet side, the flow directions may be inclined to each other at an angle of 20 to 160 degrees, preferably this angle will be from 60 to 150 degrees, most preferably 80 to 100 °. The nozzle openings are preferably spaced 10 to 200 microns apart, more preferably 10 to 100 microns, particularly preferably 30 to 70 microns. Most preferred is 50 microns. Accordingly, the flow directions meet in the vicinity of the nozzle openings.

As already mentioned, the liquid pharmaceutical formulation comes with an inlet pressure of up to 60 MPa (preferably 200 MPa to 30 MPa) (200 to 300 bar) and is sprayed through the nozzle openings into an inhalable aerosol. Preferred aerosol particle sizes are up to 20 microns, preferably 3 to 10 microns.

The locking tensioning mechanism comprises a spring, preferably a cylindrical coil compression spring, as a reservoir of mechanical energy. This spring acts on the driven flange as a spring piece, the movement of which is determined by the position of the locking member. The path of the driven flange is limited by the upper and lower stops. The spring is preferably tensioned via a force transmission mechanism, such as a helical stroke transmission, by the external torque generated when the upper housing part rotates with respect to the spring housing in the lower housing part. In this case, the upper housing part and the driven flange comprise a single or multi-stage wedge mechanism.

The locking member with the engaging locking surfaces is arranged on the driven flange in the form of a ring. It consists, for example, of a radially elastically deformable ring of plastic or metal. This ring is arranged in a plane perpendicular to the axis of the atomiser. When the spring is tensioned, the locking surfaces of the locking member are moved into the path of the driven flange and prevent the spring from loosening. The locking member is released using the button. The trigger button is connected or bound to the locking member. In order to release the locking tensioning mechanism, the trigger button is displaced parallel to the plane of the ring, preferably to the atomiser; the deformable ring is deformed in the plane of the ring. The construction details of the locking tensioning mechanism are described in WO 97/20590.

The lower part of the cover slides in the axial direction over the spring cover and covers the bearing, the spindle drive and the fluid reservoir.

When using a sprayer, the upper housing part is rotated relative to the lower housing part, the lower housing part carrying the spring housing therewith. In this case, the spring is compressed and tensioned by means of the helical stroke transmission and the locking mechanism engages automatically. The rotation angle is preferably an integer fraction of 360 degrees, for example 180 degrees. Simultaneously with the spring tensioning, the driven flange in the upper housing part is moved by a specified path, the hollow piston inside the cylinder in the pump body is retracted, so that some liquid is sucked from the reservoir into the high-pressure space before the nozzle.

Optionally, a plurality of exchangeable containers containing the liquid to be atomized can be inserted one after the other and can be used. The cartridge comprises an aqueous aerosol formulation according to the present invention.

The spraying process is started by lightly pressing the start button. The locking mechanism releases the path for the driven part. The tensioned spring slides the piston into the pump body cylinder. The liquid emerges from the atomizer nozzle in a sprayed form.

Further construction details are described in PCT applications WO 97/12683 and WO 97/20590, the contents of which are hereby incorporated by reference.

The components of the nebulizer (misting device) consist of a material of a suitable function. The sprayer housing and - if the function permits - other parts are preferably made of plastic, for example by an injection molding process. Physiologically harmless materials are used for medical purposes.

In FIG. 1a / b, which are identical to Figures 6a / b of WO 97/12687, a nebulizer (Respimat®) is described by means of which the aqueous aerosol formulations according to the invention can be advantageously inhaled.

Fig. 1a shows a longitudinal section through the atomiser with the spring tensioned; FIG. 1b shows a longitudinal section through the atomiser with the spring released.

The upper housing part 51 comprises a pump body 52, at the end of which the sprayer nozzle holder 53 is disposed. A nozzle body 54 and a filter 55 are located in the holder. The hollow piston 57, attached to the driven flange 56 of the locking tensioning mechanism, extends partially into the cylinder of the pump body. The hollow piston carries a valve body 58 at its end. The hollow piston is sealed by means of a gasket 59. Inside the upper housing part there is a stop 60 on which the driven flange rests with the spring released. On the driven flange there is a stop 61 on which the driven flange rests when the spring is tensioned. After the spring is tensioned, the locking member 62 is moved between the stop 61 and the support 63 in the upper housing part. The trigger button 64 is coupled to the locking member. The upper part of the cover ends in the mouthpiece 65 and is closed by a snap-on protective cap 66.

The spring cover 67 with the compression spring 68 is rotatably mounted on the upper housing part by means of snap fingers 69 and a rotary bearing. The lower housing part 70 is slid over the spring cover. Inside the spring cover there is a replaceable fluid container 71 to be atomized. The reservoir is closed by a plug 73 through which the hollow piston protrudes into the reservoir and is immersed in the liquid (the stock of the active substance solution).

A mechanical counter spindle 74 is disposed on the housing surface of the spring body. At that end of the spindle, which faces the upper housing part, there is a drive pinion 75. A slider 76 is mounted on the spindle.

The described nebulizer is suitable for nebulizing aerosol formulations of the invention to an aerosol suitable for inhalation.

When the formulation of the present invention is sprayed using the described method (Respimat®), the plotted amount of substance should be at least 97%, preferably at least 98% of all actuations of the inhaler (strokes) corresponding to the specified amount with a tolerance range of at most 25%, preferably 20%. Advantageously, 5 to 30 mg of the preparation, particularly preferably 5 to 20 mg, are dispensed as a specified amount in one stroke.

However, the formulation according to the invention can also be nebulized by means of inhalers other than those described, for example by means of Jet-Stream inhalers.

BRIEF DESCRIPTION OF THE DRAWINGS

Figures 1a / b, which are identical to Figures 6a / b in WO 97/12687, disclose a nebulizer (Respimat ®), by means of which it is possible to advantageously inhale the aqueous aerosol formulations according to the invention.

DETAILED DESCRIPTION OF THE INVENTION

I. Example of Synthesis of Tiotropium Bromide Monohydrate

In a suitable reaction vessel, 15.0 kg of tiotropium bromide is added to 25.7 kg of water. The mixture is heated to 80-90 ° C and stirred at a constant temperature until a clear solution is formed. The wet activated carbon (0.8 kg) was dissolved in 4.4 kg of water, this mixture was introduced into a solution containing tiotropium bromide and rinsed with 4.3 kg of water. The mixture thus obtained is stirred for at least 15 minutes at 80 to 90 ° C and then filtered through a heated filter into a device preheated to a jacket temperature of 70 ° C. Rinse the filter with 8.6 kg of water. Cool the contents of the apparatus to 20-25 ° C at a rate of 3-5 ° C in 20 minutes. With cold water cooling, the apparatus is further cooled to 10-15 ° C and crystallization is completed by stirring for at least 1 hour. The crystallizate is isolated with a suction dryer, the isolated crystal slurry is washed with 9 L of cold water (10-15 ° C) and cold acetone (10-15 ° C). The crystals obtained are dried at 25 ° C for more than 2 hours in a stream of nitrogen.

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

II. Examples of pharmaceutical formulations

100 g of the pharmaceutical preparation contains:

Example Amount of tiotropium bromide with the proportion based on tiotropium Amount of tiotropium bromide monohydrate with proportion based on tiotropium Amount of benzalkonium chloride Amount of sodium edetate PH adjusted with HCl (IN) 1 0.099 g - 10 mg 25 mg 3.0 2 0.006 g - 10 mg 25 mg 3.0 3 0.099 g - 10 mg 10 mg 3.0 4 0.006 g - 10 mg 10 mg 3.0 5 - 0.099 g 10 mg 25 mg 3.0 6 - 0.006 g 10 mg 25 mg 3.0 7 - 0.099 g 10 mg 10 mg 3.0 8 - 0.006 g 10 mg 10 mg 3.0

The remaining component is water.

Claims (6)

PATENT CLAIMS A propellant-free pharmaceutical composition for administration by inhalation, comprising: - tiotropium salt as active substance, at a concentration based on tiotropium, of between 0.0005 and 5% by weight, - water per se or a water / ethanol mixture as a solvent for the active substance, - an acid to adjust the pH between 2.0 and 3.1, - a pharmacologically acceptable preservative, - optionally, editic acid or editic acid salt in an amount of greater than 0 to 25 mg / 100 ml, - optionally a pharmacologically acceptable complexing agent and / or stabilizer, and / or a pharmacologically acceptable cosolvent, and / or other pharmacologically acceptable excipients and additives other than a preservative. Pharmaceutical preparation according to claim 1, characterized in that pi 1 is chloride, bromide, iodide, methanesulfonate, para-toluenesulfonate or methylsulfate. is characterized by the fact that the salt of tiotrope The pharmaceutical composition of claim 1, wherein the composition is tiotropium bromide. Pharmaceutical preparation according to claim 1, characterized in that it is tiotropium bromide monohydrate. Pharmaceutical preparation according to any one of claims 1 to 4, characterized in that the solvent is water per se. Pharmaceutical preparation according to any one of claims 1 to 4, characterized in that the solvent is a water-ethanol mixture, preferably with up to 70% by volume, ethanol, particularly preferably up to 60% by volume, ethanol and most preferably up to 30% by volume, ethanol.